def. nmr studies

NMR studies of cyclophanesq

L. Ernst*

Department of Chemistry, Technical University of Braunschweig, Hagenring 30, D-38106 Braunschweig, Germany

Received 17 January 2000

Contents

1. Introduction and scope. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482. [n]Phanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

2.1. [n]Metacyclophanes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492.2. [n]Paracyclophanes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 552.3. Other [n]phanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652.4. [1.n]Phanes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

3. [2.2]Phanes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 733.1. [2.2]Metacyclophanes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 733.2. [2.2]Paracyclophanes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 833.3. [2.2]Metaparacyclophanes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 953.4. [2.2]Orthometacyclophanes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 973.5. [2.2]Orthoparacyclophanes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 993.6. [2.2]Naphthalenophanes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 993.7. Other [2.2]phanes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1003.8. [2.2]Heterophanes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1083.9. [2.2]- and [3.3]Phanes capable of through-space19F,19F coupling . . . . . . . . . . . . . . . . . . . . . . . 115

4. [3.3]Phanes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1194.1. [3.3]Phane hydrocarbons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

4.1.1. [3.3]Metacyclophanes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1194.1.2. [3.3]Paracyclophanes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1254.1.3. [3.3]Metaparacyclophanes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1274.1.4. Other [3.3]cyclophanes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127

4.2. Dithia- and diaza[3.3]phanes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1284.2.1. Dithia- and diaza[3.3]metacyclophanes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1284.2.2. Dithia- and diaza[3.3]paracyclophanes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1334.2.3. Other dithia- and diaza[3.3]phanes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133

5. [m.n]Phanes (m. 2, n $ 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1456. Multiply bridged phanes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159

6.1. Phanes with multiple bridges between different aromatic rings. . . . . . . . . . . . . . . . . . . . . . . . . 159

Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47–190

0079-6565/00/$ - see front matterq 2000 Elsevier Science B.V. All rights reserved.PII: S0079-6565(00)00022-4

www.elsevier.nl/locate/pnmrs

q I dedicate this review to my parents on the occasion of my mother’s 86th and my father’s 85th birthday in November 1999.* Tel.: 149-531-3915379; fax:149-531-3915387.

E-mail address:[email protected] (L. Ernst).

6.2. in-Phanes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1707. Multilayered phanes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1738. [mn]Phanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1749. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183

Keywords: Cyclophanes; High-resolution NMR; Review

1. Introduction and scope

Cyclophanes are “bridged aromatic compounds”—the title of the first monograph published on thissubject [1]—in particular, as their name implies,those containing aliphatic bridges, hence themorpheme-ane in cyclophane. While, at first, theterm cyclophanesmeant bridged arenes in general,Vogtle and Neumann [2] suggested reserving thisterm specifically for bridged benzenes. They intro-duced the general termphanesfor what used to becalled cyclophanes. Although the title of the presentarticle is “NMR studies of cyclophanes”, it deals withphanes in the sense of Vo¨gtle’s nomenclature. Laterimportant reference books on cyclophanes are the twovolumes edited by Keehn and Rosenfeld [3] and theworks by Vogtle [4] and Diederich [5], the latter treat-ing the supramolecular chemistry of cyclophanes.Moreover, three volumes on cyclophanes, edited byVogtle [6,7] and Weber [8], have appeared in theseriesTopics in Current Chemistry. In Ref. [3], theNMR properties and conformational behaviour ofcyclophanes were treated in a chapter by Mitchell[9], who covered the literature up to the end of1981. Mitchell excluded the NMR behaviour of multi-layered cyclophanes because this was described byMisumi in his chapter on this particular class ofcompounds [10]. Further, the same book containschapters by Rosenfeld and Choe on [n]cyclophanes[11], by Paudler and Bezoari on heterophanes [12]and by Itoet al. [13] on nonbenzenoid cyclophanes.The authors of these chapters also discussed the NMRaspects of their respective classes of compounds.

Comparing the status of cyclophane NMR in 1964,the time of Smith’s book [1], with that in 1983, Mitch-ell in the introduction to his chapter [9] predicted:“Current easy access to high-field NMR instrumenta-tion suggests that a rapid expansion of our knowledge

of cyclophane properties will again occur.” Notsurprisingly, his prophecy has been fulfilled and thenumber of papers relating to the subject of cyclophaneNMR is so large that complete coverage is very diffi-cult and possibly not even desirable. Therefore, thepresent article is essentially a follow-up to Mitchell’s,yet with a number of restrictions in order to limit thevast amount of material to be treated. Firstly, the focuswill be directed on the NMR properties of the cyclo-phanes themselves, not on their changes that occurwhen the cyclophanes interact with other molecules,neutral, anionic or cationic. So, the influences ofhost–guest or supramolecular interactions uponNMR spectra are not covered, which leaves out thecrown ether derivatives of cyclophanes and their thioanalogues, polyazacyclophanes, calixarenes andanalogous compounds, the cavitands, the carcerandsor the spherands, etc., the main interest in whichconsists in their suitability for such interactions.Secondly, I have refrained from including metalloce-nophane (i.e. mostly ferrocenophane) papersalthough, for example, the effect of phane complexa-tion by Cr(CO)3 and related groups is covered.Thirdly, cyclophanes possessing only bridges span-ning ortho-positions are not considered proper cyclo-phanes because they mostly do not show thecharacteristic NMR spectroscopic properties usuallyassociated with cyclophanes such as shielding ofprotons positioned above/below the planes ofaromatic rings. The orthocyclophanes are thereforeomitted. Otherwise compounds like indane, tetralinor 9,10-dihydroanthracene would also qualify forbeing included. It is important to realize that a numberof important basic references concerning cyclophaneNMR may not be listed in this review because theydate from before 1982.

Several Chemical Abstracts Online searches werecarried out to arrive at the selection of papers included

L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47–19048

in this review, for the last time on 13 December 1999.The “CA File” of Chemical Abstracts was searchedfor literature references later than 1981 with occur-rence of both the term (“NMR” or “nuclear magneticresonance”) and the term (“cyclophan…” or “phan…”or names of important aromatic moieties followed by“phan…”, e.g. pyridinophan… or metacyclophan…)in any of the title, abstract or index term fields. Thisimplied that the author must have considered theNMR-related content of his/her paper importantenough to mention it in the title, abstract or keywords.Thus, generally, a paper did not qualify for inclusionif it simply contained undiscussed NMR data of acyclophane, unless this reviewer learned of it someother way and recognized its contents as of interest.The hits of the search were filtered by eye accordingto the restrictions mentioned in the preceding para-graph. Another search, carried out in the “RegistryFile”, looked for “phan…” as a segment in thenames of chemical compounds. The hits were trans-ferred to the CA File and the number of referenceswere reduced by requiring the simultaneous presenceof NMR-related terms in the Basic Index. The refer-ences remaining were filtered using the above restric-tions as the criterion. Finally, between 50 and 60colleagues known to work in the cyclophane areawere asked for reprints of papers they considered rele-vant in the present context. About half of themresponded. The different approaches furnished atotal of ca. 500 papers. This number decreased furtherwhen the papers were inspected for information inter-esting enough to be included.

The material presented in this article is arrangedaccording to classes of compounds. This makes iteasy for the reader to find information related to parti-cular molecules. Cross-references to other sectionsare given when papers deal with compounds belong-ing to different classes.

2. [n]Phanes

There are two main reasons why phanes are inter-esting to NMR spectroscopists. The first consists inunusual1H chemical shifts which are caused by themagnetic anisotropy of the aromatic system(s) inthese molecules and which can only be observed byvirtue of the simultaneous presence of the bridges that

are affected. The second reason lies in the mobility ofthe bridges which is often restricted because of theirshortness and therefore brings the rate of existingconformational processes into the range observableby NMR spectroscopy. The main interest in the[n]phanes concerns metacyclophanes and paracyclo-phanes with short bridges, by which the aromatic ringis forced out of planarity and the chemical and spec-troscopic behaviour of the molecule is altered relativeto cyclophanes possessing longer bridges.

2.1. [n]Metacyclophanes

The shortest-bridged [n]metacyclophanes that areisolable and stable compounds are those withn� 5:The 1H NMR spectrum of the parent hydrocarbon (1)is unchanged between250 and 1508C [14]. It wasfully analysed and the chemical shifts and couplingconstants indicate that, in solution, [5]metacyclo-phane prefers conformation (1A). The spectra of thehalogenated derivatives (2)–(4) [15] showed thepresence of the same major conformer, e.g. (2A)and of 11–15% of a second conformer, e.g. (2B).The interconversion of the conformers was demon-strated by spin saturation transfer experiments,coalescence measurements and full lineshape analy-sis. The ratioB/A remains constant in the temperaturerange250 to 808C. The activation parameters for theconversion ofA into B for (2)–(4) areDG‡�1238C� �55:2–56:1 kJ mol21

; DH‡ � 48:5–51:5 kJ mol21; and

DS‡ � 215:0 to 223.0 J K21 mol21. Some remark-able chemical shift differences were observedbetween conformersA andB, the largest ones beingthose for Ha, which moves by22.29 ppm (upfield),and for Hc, which moves by11.44 ppm (downfield),whenA changes intoB; the numbers quoted refer to(2), see Table 1. These effects are due to the moving ofthese protons into and out of, respectively, the shield-ing zone of the aromatic ring by the conformationalchange. Smaller shift changes were found for Hb

L. Ernst / Progress in Nuclear Magnetic Resonance Spectroscopy 37 (2000) 47–190 49

Table 1NMR chemical shifts (measured at2478C; solvent: toluene-d8) ofthe bridge hydrogens in the two conformers of (2)

Conformer d(Ha) d(Hb) d(Hc) d (Hd) d (He) d(Hf)

(2A) 0.97 1.82 0.04 1.48 1.85 3.39(2B) 2 1.32 0.65 1.48 2.31 1.56 3.18

(21.17 ppm) and Hd (10.83 ppm) which have contri-butions, in addition to that from the ring current effect,from the release and increase, respectively, of stericcompression by the neighbouring chlorine substituent.This interpretation was supported by the result of anX-ray diffraction study of (2). The vicinal H,Hcoupling constants in the bridges of both conformerscould be well fitted to a Karplus-type equationalthough the C–C–C bond angles deviate consider-ably from normal values. A remarkable feature in the13C NMR spectra of (1)–(4) was the deshielding of C-11 (< 8 ppm), the carbon atom between the bridge-

heads, in comparison with C-2 of identically substi-tutedm-xylenes [16]. This observation was tentativelyascribed to long-range anisotropy effects of the bridgeand to the bending of the aromatic ring. The latterargument is supported by a correlation found betweenthe downfield shifts of C-8 and C-11 in (1) and C-9and C-12 in [6]metacyclophane (6) on the one handand the degree of out-of-plane bending of these atomson the other. Ring bending also produces an increaseof the geminalJ(C-8,H-7) coupling constant in (1) to4.0 Hz from the normal value of ca. 1 Hz.

The strong bending imposed by the short aliphatic


YX

(1)(2)(3)(4) Br Br

ClBrCl Cl

HH

X Y

(5) D D

(CH2)6

H9 12

(6)

(2A) (2B)

Ha

HbHa

HbHc

Hd

Hc

Hd

Hf Hf

HeHe

ClCl Cl Cl(1A)

811

XRO

(7), X = Cl(8), X = H, R = Me

811

(9)

H

H

ClCl

H

H 6.94

6.94

0.36

2.18

NOE

NOE

Cl

Cl

≡

7

11 13

R

R

exo- endo-(10), R = H

(11), R = Me

R

R

bridge on the benzene ring of (1) raises the question ofthe aromaticity of the latter. One possibility ofanswering this question makes use of the determina-tion of the magnetic susceptibility anisotropy fromquadrupolar deuterium couplings of molecules insolution aligned by the magnetic field. This wasdone by van Zijl et al. [17] who measured high-fielddeuterium NMR spectra of some ring-deuterated 1,3-dialkylbenzenes as model compounds and of 8,11-dideuterio[5]metacyclophane (5). The principle ofthe technique consists in determining the quadrupolarsplitting and comparing it with the splitting calculatedfor a nonaromatic reference compound from knownlocalized susceptibilities. The results proved beyonddoubt that [5]metacyclophane is fully aromatic.

In the reaction of (2) with NaOR/DMSO, the chlor-ine substituent at C-11 (between the bridgeheadcarbon atoms) was replaced by an alkoxy group togive (7) [18]. The identity of the products followedfrom a comparison of the chemical shifts of theiraromatic carbon atoms with those predicted by incre-ment calculations. Compound (7) and some analoguesprefer conformationA (at2538C), but conformerB isalso significantly populated in the 11-alkoxy deriva-tives, reaching a mole fraction of 0.42 in (8); A andBcorrespond to formulae (2A) and (2B). The 1H NMRspectra of both conformers were analysed as far aspossible with respect to the chemical shifts andJ(H,H)coupling constants in the five-membered bridge.

Dichloro[3.0]orthometacyclophane (9),1 a highlystrained biphenylophane, may also be regarded as a[5]metacyclophane with benzoannelation at thebridge [19]. In contrast to (2), which lacks the benzoanneland, it exists exclusively in theendo-conforma-tion shown [corresponding to (2B)]. This causesstrong shielding of theendo-proton at C-7 �d �0:36� while its geminal partner has a more normalshift of d � 2:18: The conformation was confirmedby an NOE experiment: saturation of the H-7(endo)resonance caused enhancements of the signals of H-11and H-13 which have very similar but not identical

shifts neard � 6:94: This value indicates that, in spiteof the large molecular distortions predicted by densityfunctional computations, themeta-bridged ring is stillfully aromatic.

[6]Metacyclophan-3-ene (10) contains a cis-configurated double bond and its1H and 13C NMRspectra demonstrate the presence of two conformers,exo-(10) andendo-(10), in equal amounts [20]. Spinsaturation transfer experiments using the aromatic andthe olefinic proton resonances proved the reversibleinterconversion of the conformers. The olefinicprotons of exo-(10) absorb atd � 5:40; those ofendo-(10) are shielded atd � 4:75: By measuringthe coalescence of the olefinic proton signals at908C and 500 MHz observation frequency, the barrierto chemical exchange was estimated to be 69:5^

2:1 kJ mol21: In the dimethyl derivative (11) the equi-

librium ratio of endo-conformer�dMe � 1:1� to exo-conformer�dMe � 1:8� is 3:1.


1 In the present article, decimal numbers in chemical formulaemean NMR chemical shifts, usually1H, sometimes13C NMRchemical shifts. In some cases chemical shift differences relativeto a particular model compound are given. The exact meaning of thenumbers follows from the context and is usually not explicitlystated.

NPh

(CH2)n

(12), n = 9(13), n = 8(14), n = 7(15), n = 6

N

(CH2)n

(16), n = 9(17), n = 8(18), n = 7(19), n = 6

NPh

H

H

H

H

1

6

3

4

NPh

1

6

3

4

H

H

H

H

NPh

NPh

43

(15A) (15B)

(15D)(15C)

NPh

7

(14A)

1

Hb

Ha4

NPh

7

(14B)

1

4Hb

Ha

−1.44

1.95

1.95−1.24

−1.45

−1.45

The chemical equivalence of the geminal protons atthe benzylic positions of the [7]- to [9](2,4)pyridino-phanes (12)–(14) indicates rapid flipping of the oligo-methylene chains at room temperature [21,22]. Onlowering the temperature, the averaged proton signalof H-4a/4b in (14) �d � 20:16� disappeared due todecoalescence into broad components and at2608Cthe signal of H-4a in (14A) or H-4b in (14B) reap-peared atd � 21:45: The geminal counterpart atlower field was hidden under other signals. Also, allfour benzylic protons gave separate signals, whichshowed that the flipping of the bridge is frozen. Theenergy barrier (DG‡), determined from signal coales-cence, is 50–55 kJ mol21 at 1208C. The [6]pyridino-phane (15) displayed four anisochronous benzylicproton signals at room temperature already, thus indi-cating slow flipping of the bridge. Signal coalescencewas reached at11508C andDG‡ at this temperaturewas estimated to be 88–92 kJ mol21, significantlylarger than in [6]metacyclophane (72.8 kJ mol21 at176.58C) [23]. There was no1H signal atd , 0 for(15) at room temperature. This suggests that the struc-ture is not fixed in conformer (15A) or (15B) or theirequivalents (15C) and (15D) but that a rapid equili-brium between them is set up by pseudorotation of thehexamethylene chain. At2908C, pseudorotation isfrozen as indicated by the presence of two sets of1H and 13C signals in the ratio of 2:1�DG�1:1 kJ mol21�: Lineshape analysis of the13C signalsat various temperatures (details not given) furnishedDH‡ � 41:0 kJ mol21 and DS‡ � 24:8 J mol21 K21

for the pseudorotational movement of the bridge.However, DG‡(2308C) was also reported to be41.0 kJ mol21, i.e. eitherDG‡ or DH‡ must be inerror. The H-6 signals were distinguished from theH-1 signals by their larger shifts upon addition ofEu(fod)3. 2D shift correlations allowed the assign-ments of all1H and 13C shifts of the two conformers.The major conformer is (15A/C), the minor one (15B/D). Overall, the results bear much resemblance tothose of [6]metacyclophane [23] but not to those of[6](2,6)pyridinophane [24]. Nitta’s group later alsostudied the azuleno-annelated [n](2,4)pyridinophanes(16)–(19), n� 9; 8;7;6 [25]. These behaved basicallylike their nonannelated analogues but the barrierDG‡

to bridge flipping in the [7]phane (18), 45 kJ mol21

(2308C), and in the [6]phane (19), 76 kJ mol21

(1908C), are somewhat lower than in (14) and (15),

respectively. It was suggested that the flexibility of thepyridine ring is increased by azuleno-annelation.

S S4

3

1 13

(20)

XTsN S

(21a), X = H(21b), X =OMe

Et

R

(22), R = Me(23), R = OMe

R

(24), R = H(25), R = OC(=O)Ph

bridge flipping

bridge

pseudorotation

∆G≠ = 42.7 kJ mol−1

∆G≠ = 36.4 kJ mol−1

(−73 ˚C)

(−48 ˚C)

(24)

Some [7]metacyclophanes (20)–(21) with hetero-atoms in the bridge and with or without intraannularsubstituents were studied by variable-temperature1HNMR [26]. The aliphatic bridges in (20) and (21b)have fixed conformations and display chemical none-quivalence of all methylene protons. At roomtemperature, these two compounds show bothrestricted bridge flipping, indicated by AB spectrafor the benzylic protons, and restricted rotation ofthe C-3/C-4/C-5 part of the bridge, indicated bygeminal nonequivalence of these CH2 protons. Oneof the hydrogens at C-4 is strongly shielded[d�H-4a� � 21:16 in (20) and 20.90 in (21b)],which points to its position above them-phenylene


ring, while its geminal partner has a normal chemicalshift [d�H-4b� � 11:19 in (20) and11.40 in (21b)].No coalescence could be reached up to11808C forthese two compounds, thusDG‡(11808C) . 92kJ mol21. In (21a), lacking an intraannular substitu-ent, the barriers for the bridge flip,DG‡�2368C� �47:3 kJ mol21

; and for polymethylene chain rotation,DG‡�2108C� � 51:9 kJ mol21

; could be measuredseparately. The flipping barrier of thiaaza compound(21a) is very similar to that of [7]metacyclophaneitself, 48.1 kJ mol21 at 2288C [23,27]. At roomtemperature, the averaged shift for the protons at C-4 is d � 20:15:

The [7]metacyclophanes (22) and (23) wereobtained as 1:1-diastereomeric mixtures [27]. The1H NMR spectra of the bridges are complicated anddo not change upon raising the temperature to11508C. Hence, neither pseudorotation nor bridgeflipping takes place in this temperature range. Thelarge activation barriers are caused by the bulkyintraannular substituent and the ethyl group on thebridge. The1H NMR spectra of the bridge protonsof [8]metacyclophane (24) show four signals ofequal intensity at room temperature. The authorsclaimed to have observed two coalescence pointsupon lowering the temperature, viz. at273 and at2488C (270 MHz), but this is difficult to recognizefrom the spectra published. The estimatedDG‡

c values

are 36.4 and 42.7 kJ mol21, respectively. In analogyto the known behaviour of [6]metacyclophane, therespective conformational processes were assumedto be bridge pseudorotation and bridge flipping. Toprove this, 14-benzoyloxy[8]metacyclophane (25)was studied, for which bridge flipping is excludedbecause of the bulky internal substituent. The onlyconformational process left, bridge pseudorotation,has aDG‡ value of 37.2 kJ mol21 at 2658C, thusconfirming the above assumptions.

There are not many examples of [n]cyclophaneswith triple bonds in the bridge. In 2,7-dithia[8]meta-cyclophan-4-yne (26a) the intraannular hydrogen issmall enough (and the C–H bond short enough) toallow flipping of the bridge from one side of thearomatic plane to the other, as shown by the singletnature of the1H NMR signals of CH2-1 and CH2-3[28]. These did not even broaden when the tempera-ture was lowered to2508C. However, bridge inver-sion is severely restricted by the presence of anintraannular substituent (F, Cl or Br) in (26b)–(26d)as this would cause very unfavourable interactionswith the triple bond in the transition state. The methy-lene protons at C-1/C-8 give an AB spectrum at roomtemperature and those at C-3/C-6 give an AA0BB 0

spectrum because of the sizeable5J(H,H) couplingsthrough the triple bond. No signal coalescences wereobserved up to11208C. When (26a) or (26d) were


R

S

S1

3

(26a), R = H(26b), R = F(26c), R = Cl(26d), R = Br

R

S

S1

3

(27a), R = H(27b), R = Br

O2

O2

R•

S

S

(28a), R = H(28b), R = Br

O2

O2

R

S

S

(E,Z)-(29a), R = H

O2

O2

R

S

S

O2

O2

(Z,Z)-(29a), R = H(E,Z)-(29b), R = Br

oxidized to the bis-sulfones (27), these were in equili-brium with the corresponding allenes (28) [29]. Whilethe sulfones behave conformationally like thesulfides, the allenes give three AB spectra for theCH2 groups, even in the case of rapidly inverting(28a), due to the lack of molecular symmetry. Thediastereomeric dienes (E,Z)-(29) and (Z,Z)-(29a)were formed by isomerization of (28). For stericreasons, the former dienes cannot be planar andshow AB spectra for the different benzylic methylenegroups. According to MNDO MO calculations, (Z,Z)-(29a) is predicted to exist in two interconverting enan-tiomeric C1 conformations with aC2 transition state.Only one AB and one AA0BB 0 system were observedin the 1H NMR spectrum as expected.

The room temperature 500 MHz1H NMR spectraof the [8]- to [15]metacyclophanes (30) with an inter-nal methoxy group were assigned as completely aspossible and the13C chemical shifts were reported[30]. The equivalence or nonequivalence of thebenzylic protons indicates rapid or slow flipping ofthe alkylene chain. For the [15]metacyclophane thebenzylic proton signals had just coalesced at roomtemperature but activation barriers were not deter-mined. The most stable conformations, as computedby molecular mechanics, agree with the experimentalfinding that thed -proton on the side of the macrocycleopposite to the methoxy group is the most shielded inthe [8]- to [10]phanes, while the protons of the centralmethylene group(s) absorb most upfield in the higherphanes.

As information on the conformational behaviour of[9]metacyclophanes was scarce, Balaban et al. [31]determined the barriers to flipping of the nonamethy-lene bridges in (31)–(33) from the coalescence para-meters of the H-2/H-8 signals in the low-temperature1H NMR spectra. For these protons the chemical shiftdifferences and coalescence temperatures could bemeasured more accurately than for the other protons,which also showed signal splitting. Ample fluctua-tions (pseudorotation) within the bridges, predictedby molecular mechanics calculations, still persistedat 2908C. The lower barrier to bridge flipping in(33) with respect to the other two phanes wassuggested to be due to the larger bond distances (ofthe C14–C15 and C10–C15 bonds?) of about 2 pm inpyrylium relative to pyridinium cations. This wouldlower the energy of the conformational transition-state.

In all of theN-methyl[n](2,6)pyridinophanium salts(34) with n� 6–10 bridge flipping is restricted until atleast 1468C as shown by the temperature-invariant1HNMR spectra [32]. One of the bridge protons, presum-ably of the central methylene group, in the compoundwith n� 7 is strongly shielded, having a chemicalshift of d � 22:27: In the 13C spectra, decreasedshielding of the pyridinium carbon atoms C-2,6from d � 160:8 to 166.2 was observed as the bridgelength was shortened from 10 to 6. According to theauthors’ interpretation, this could be explained by theincreased importance of canonical structure (340) inthe order mentioned. However, they did not consider


(CH2)n

(30), n = 8−15

OMe

X

2 8

1014

(31)15 (32)

(33)N+MeN

O+

41.040.637.2 −78 ˚C

−63 ˚C−58 ˚C

X Tc[kJ mol−1]∆G≠

N

CH3

(CH2)n

+

FSO3−

(34), n = 6−10

N

CH3

(CH2)n

+

(34’)

..

that differences in the bridge conformation would alsoaffect these chemical shifts.

(35)

R

O

O CF3

OMePh(CH2)n

CO2Me

Vogtle’s method [33] for estimating the effectivesize of an intraannular substituent by determining theenergy barrier that must be overcome to move a meta-cyclophane bridge of given length past the substituentwas applied by Kang and Chan [34] to metacyclo-phanes (35). Because of the unsymmetrical substitu-tion pattern of the benzene ring the metacyclophanesystem has a plane of chirality when passage of thesubstituent R through the methylene loop is slow. Asthese compounds also have a centre of chirality in oneof the ester substituents, diastereomeric conformersarise under these conditions. In (35), n� 11;R�Me, doubling of the aromatic proton signal wasobserved at low temperature. Signal coalescenceoccurred atTc � 2508C at 200 MHz; the barrierDG‡ to bridge flipping is 47.9 kJ mol21. Shorteningthe bridge by three methylene groups increasedTc to11338C andDG‡ to 89.9 kJ mol21 in (35), n� 11;R�Me. However, keeping the ring size at 11 andomitting the internal methyl group lowers the barrierso much that signal doubling is not observed down to2708C in (35), n� 11; R� H.

2.2. [n]Paracyclophanes

[4]Paracyclophane is the smallest [n]paracyclo-phane of which a derivative has ever been observed.Okuyama and Tsuji [35] succeeded in preparingphane (36b) by irradiating the Dewar benzene precur-sor (37b) with 365 nm light in CD2Cl2 solution at2908C. Two new singlets appeared in the1H NMRspectrum atd � 7:97 and 5.85 with an intensity ratioof ca. 2:1. They were attributed to (36b) and corre-spond to 6% of product vis-a-vis 94% of startingmaterial. To corroborate the identity of the product,high-level ab initio MO calculations were performedof the 1H NMR chemical shifts of hydrocarbons (36a)and (37a). The calculated shift differences between(36a) and (37a), Dd � 21:48 for Ha and 11.56 for

Hb agree qualitatively with the experimental differ-ences between (36b) and (37b), which are21.35 forHa and11.04 for Hb. Assuming that the effects of thecyano groups in (36b) and (37b) cancel, the authorstook these results as strong evidence that they hadindeed observed a [4]paracyclophane. The upfieldshift that Ha experienced in the formation of (36b)suggests that relatively strong diatropicity is sustainedin the aromatic ring despite its extreme bending. Inagreement with this, the nucleus-independent chemi-cal shift (NICS), which has been proposed as anaromaticity/antiaromaticity criterion [36], wascomputed to be29.0 at the centre of the C6 ring of(36a) compared with29.7 for planar benzene. Suchlarge negative NICS values correspond to a highdegree of aromaticity.

The next smallest [n]paracyclophane described was[5]paracyclophane (38) [37]. It was prepared in THF-d8 solution in an NMR tube at low temperature and its1H NMR spectrum was recorded at2728C. At thistemperature flipping of the pentamethylene bridge isfrozen causing the left and right hand sides of thebenzene ring to be different so that an AA0XX 0 spec-trum results withdH � 7:44 and 7.38 and4J�AX � �1:1 Hz: The protons within the geminal pairs at thebridge carbon atoms are also different. The highest-fieldchemical shifts were found for one of the homobenzylicprotons �d � 0:22� and one of the central methyl-ene protons�d � 0:01�: Coalescence was observednear 08C; line-shape analysis furnishedDH‡ �57:3 kJ mol21 andDS‡ � 211:3 J K21 mol21 for theflipping of the bridge. Tobe et al. [38] prepared the 7-methoxycarbonyl derivative of [5]paracyclophane. At2608C, it is present as two conformers (39A) and(39B) with the chemical shifts given in the formulae.Kostermans et al. [39] described the tetrasubstituted[5]paracyclophane (40a) which, at 2538C, exists asconformers (40aA) and (40aB) in a ratio of 53:47.1HNMR signals hidden by the resonances of the startingmaterial, the corresponding Dewar benzene, could beassigned by decoupling experiments so that all1Hchemical shifts are available, see the formulae. (Thechemical shifts in the formulae correspond to theassignments given in Ref. [40]. There the shift-to-conformer assignments were reversed with respectto Ref. [39].) The shifts of the methyl groups,d �2:33 and 2.31, were considered good indicators ofthe aromaticity of the [5]paracyclophane system; the


olefinic starting material hasd�CH3� � 1:64: Activa-tion parameters for bridge flipping areDH‡ �46:9 kJ mol21 and DS‡ � 245 J K21 mol21

; DH‡

being somewhat lower than in the parent compound(38), probably because of increased strain in theground state conformations of (40a). Later, in a fullpaper [40], the same authors described the1H NMRspectra of further [5]paracyclophane derivatives,(40b)–(40e). For all of these, conformers analogousto (40aA) and (40aB) were observed at low tempera-ture. An important argument in the assignmentprocess of the bridge proton signals is the relativeconstancy in the series (40a)–(40e) of the chemical

shift (d � 20:45 to 20.60) of that proton of thecentral methylene group which in conformerA points“downwards” on the side of thear-methyl substituentsas opposed to its geminal partner which in conformerB points downwards on the side of the variable substi-tuents. This has a larger shift range, extending fromd � 10:21 to 20.17.

The first benzoannelated [5]paracyclophane and atthe same time the smallest [n](1,4)naphthalenophaneis compound (41) [41]. It was observed only in THFsolution at2638C and in the presence of its syntheticprecursor. Two conformers were present in a ratio of95:5. They differ by the centre of the pentamethylene


(36a)

R

R R

R

(36b) R = CNR = H

Hb

Ha

(37a)(37b)

R

R

R

R

R

R

Ha

Hb

H

H H

H

H HH

HH H

HMeO2C

2.16

2.84

0.12

8.083.84

−0.09 H

H H

H

H H

H

H

HMeO2C8.053.86

−0.25

H H0.35

(39A) (39B)

H

H H

H

H HH

HH H

(38)

2.77

2.11

≈1.6≈1.6

0.220.01

H3C

H3C

CO2CH3

CO2CH3

2.99 2.87

2.333.72 0.33

1.21

1.59

0.06

(40aA)

H3C

H3C

CO2CH3

CO2CH3

3.222.44

2.31 3.730.44

1.32

1.59

−0.55

(40aB)

H3C

H3C

R

R

(CH2)5

(40a)(40b)(40c)(40d)(40e)

CO2MeCF3

CNCO2HCO2C6H4-p-NO2

R

bridge pointing towards the second naphthalene ringand away from it, but the major and minor conformercould not be assigned. Activation parameters of thebridge flipping were determined to beDH‡ � 47:3^

5:4 kJ mol21; very similar to the nonannelated [5]para-

cyclophanes, andDS‡ � 263^ 21 J K21 mol21:

Tochtermann et al. [42] described variable-temperature1H NMR experiments on the [6]paracy-clophane derivative (42a). At 2508C the two aromaticprotons are chemically nonequivalent and there arefour different chemical shifts for the four benzylicprotons. This is caused by slow interconversion ofthe enantiomeric conformations (42aA) and (42aB).Inversion of the hexamethylene bridge leads tocoalescence of the signals of the aromatic protonsHa and Hb at 148C. This allowed the ring inversionbarrier to be determined as 58.3 kJ mol21. Later,Gunther and coworkers [43] presented a very detailed1H and 13C NMR study of the conformation anddynamics of the dimethyl ester (42b). The spectrawere assigned and analysed in the slow-exchangelimit (2208C) for the bridge inversion process using

various 2D NMR techniques including 2D exchangespectroscopy (EXSY). In this way all the chemicalshifts of the individual bridge protons could be deter-mined and also the geminal and most of the vicinalH,H coupling constants. The latter showed a Karplus-type dependence on torsional angles and indicatedthat the solution conformation of (42b) closely resem-bles that found in the crystal. A complete1H NMRanalysis of a longer cyclophane chain had previouslybeen performed only for [8]paracyclophan-4-ol (seelater). The boat-shape of the benzene ring of (42b)does not significantly change its1H NMR shieldingproperties and the13C chemical shifts of the methy-lene carbon atoms could be explained without invok-ing ring current contributions. A line shape analysisfor the chemical exchange of the aromatic protonsyielded the activation parameters for the inversion ofthe methylene bridge:DH‡ � 43:3^ 0:7 kJ mol21

;

DS‡ � 251:3^ 2:7 J K21 mol21; and DG‡�298� �

58:5 kJ mol21: The 3-hydroxy derivative (43) of

(42a) occurs in the form of two diastereomers [44].Their 1H NMR spectra are temperature invariant


H3C

H3C

(CH2)5

CO2Me

CO2Me

(41)

R

R

Ha

Hb

Hb

Ha

R

R

A B(42a), R = CO2Et(42b), R = CO2Me

H

H H

HH

H

H

H

H

H H

(42b)

H

H

H

R R2.88

2.33

1.72

1.18

7.48 7.27

2.12

3.45

1.720.931.31

−0.430.64

−0.72

R

R

R

ROH

H

(43a) (43b)R = CO2Et

HO

H

between250 and1708C indicating that each exists inone preferred conformation.1H chemical shift argu-ments and evaluation of most of the vicinal H,Hcoupling constants allowed their configurations andconformations to be derived. The hydroxy groups preferto point towards the outside of the molecule in bothdiastereomers. Hence their bridge conformationsmust be different. They are shown in (43a) and (43b).

R

R

R

R

A B(44), R = CO2Me

HaHb

HH

Ha

Hb

HH

1

6

RR

A B(45), R = CO2Me

HH

OO

HH

OO

R

(CH2)6

(46), R = H(47), R = CH3

(48), R = CH2OH

CH3

(CH2)8

(49)

Tobe et al. [45] found two conformers, (44A) and(44B), in a 20:1 ratio, in the low-temperature1H NMRspectrum of thepara-diester of [6]paracyclophane.The value ofDG‡ for the inversion of the bridge is54.0 kJ mol21 and was determined from the coales-cence of the two aromatic proton signals (d � 7:94and 8.04, 20:1) at2248C. Below 2508C the most

shielded proton absorbs atd � 20:69: The reasonfor the relative instability of conformer (44B) lies inthe severe nonbonded repulsion between the carbonyloxygens and theirsynbenzylic hydrogens, e.g. Hb atC-1. Assignments in the proton spectra were based onthe careful chemical shift assignments that had beencarried out for (42b) [43]. Tobe’s group also studiedmethyl [6]paracyclophane-8-carboxylate with twovicinal carbonyl groups in the bridge, (45) [46]. At2308C, conformers (45A) and (45B) were observed.The integral ratio of the signals of the isolatedaromatic proton is 4:1. Signal coalescence occurs at2158C, giving DG‡ � 54:0 kJ mol21 for the bridgeflip. The comparison with (42b) shows that the vicinaldione group has little influence on the conformationalproperties of the bridge.

Dynamic NMR experiments on the parent [6]para-cyclophane (46) (13C, coalescence method) and its 8-methyl (47) and 8-hydroxymethyl (48) derivatives(both 1H, lineshape analyses) were carried out bySternhell et al. [47]. They found that the barrier toinversion of the six-membered bridge is rather insen-sitive to the nature of the substituent at C-8�DG‡ �56:9–60:4^ 1:1 kJ mol21; T � 110 to 1308C). In a1H NMR study of possible distorted aromatic systems,Sternhell and collaborators [48] used their previouslyderived relationship betweenortho-benzylic couplingconstants involving a methyl group,4J(H–C–C–Me),and the square of the CC bond order [49], to testelectronic distortions in the aromatic rings. No pertur-bations of electronic structure could be observed withthe possible exception of 8-methyl[6]paracyclophane(47), which exhibits a barely significant deviationfrom unstrained values. The4J(H,H) value for (47)is 20.61 Hz, while four less strained cyclophanes,among them 10-methyl[8]paracyclophane (49), have4J(H,H) values of20.65 to20.66 Hz.

Tobe et al. [50] prepared [6](1,4)naphthalenophane(50) and [6](1,4)anthracenophane (51) and fullyassigned their1H NMR spectra at2508C when flip-ping of the bridges is slow. The preferred conforma-tions are analogous to that of (46), cf. also (44), andthe barriers to bridge flipping are in the order (51)�DG‡�258C� � 56:1 kJ mol21�, (50) �DG‡�08C� �56:9 kJ mol21�, (46) �DG‡�158C� � 58:2 kJmol21�; determined from the coalescences of thesignals of H-2 and H-3 (naphthalene and anthracenenumbering). A comparison of the chemical shifts of


the bridge protons of (50) and (51) with those of (46)shows that, in the former two compounds, the protonslocated above the interior of the aromatic rings andpointing downwards onto the naphthalene and anthra-cene system, respectively, are significantly shielded(d � 21:84 and21.81) with respect to the benzeno-phane�d � 20:62�: This is due to the combined influ-ence of the ring currents of more than one aromaticring. The 13C chemical shifts of (50) and (51) werealso reported but no assignments were given. Theperi-substituted [6](1,4)naphthalenophanes (52a)and (52b) and the [6](1,4)anthracenophane (53)behave very similarly to their parent compounds,but they all have barriers to flipping of the hexamethy-lene bridge that are lower than those of (50) and (51)by some 6 kJ mol21 [51,52]. The free energies of acti-vation are 51.0 kJ mol21 (1108C) for (52a),50.6 kJ mol21 (1258C) for (52b), and 50.2 kJ mol21

(1258C) for (53). Lowering of the barriers wasexplained by increased bending of the bridgedaromatic rings due toperi-substitution. One featureworth noting are the upfield shifts of thesyn-benzylic

protons (Dd � 21:2 to 21.9 ppm) due to theperi-phenyl groups in (52a) and (53) at low temperature.

In an attempt to prepare (9,10)anthracenophanes,Tobe and coworkers first succeeded in obtain-ing 1,4,5,8-tetramethyl[6](9,10)anthracenophane (54)[53] as the nonmethylated compound is ratherunstable. At room temperature, flipping of the hexam-ethylene bridge in (54) is rapid on the NMR timescale. There are only three different1H chemical shiftsfor the bridge,d � 3:31; 0.87, and20.38, at ambienttemperature. At2908C, the bridge signals broadenand the most shielded methylene proton appears atd � 21:89; comparable to what was found in[6](1,4)anthracenophane (51). The bridge flippingbarrier DG‡ (temperature not reported) was deter-mined as 39.7 kJ mol21, while it is 56.1 kJ mol21 in(51). The smaller barrier for (54) was attributed todestabilization of the ground-state conformationbecause of steric repulsion between the methyl groupsand the benzyl methylenes. Later, the parent[6](9,10)anthracenophane (55) was also obtained,admixed with 40% of the 9,10-dihydro product [54].


(CH2)6

(50)

(CH2)6

(51)

1.97

1.97 2.79

2.79

0.51

0.51

1.58

1.581.06

1.06

−0.62−0.62

2.86

2.27 3.49

3.01

0.71

0.34

1.74

1.581.11

0.79

−1.84−0.47

3.00

2.36 3.58

3.08

0.80

0.38

1.77

1.601.14

0.71

−1.81−0.31

(46) (50) (51)

(CH2)6

(52a), R = Ph

(CH2)6

(53)

R

R

Ph

Ph

(52b), R = Me

The1H and13C NMR spectra were recorded at2508Cand signal assignments were made with the aid ofH,H-COSY, C,H-HETCOR, and NOE differenceexperiments. At this temperature, the movement ofthe methylene bridge is frozen so that six kinds ofmethylene signals were discerned, the most upfieldone atd � 21:84; similar to the other [6]anthraceno-phanes discussed above. The barrier to bridge flippingwas determined from a line shape analysis of theH-1 and H-8 signals�Tc � 258C� which appear astwo singlets when H-2,7 and H-3,6 are decoupledsimultaneously. DG‡(1258C) is 57.3 kJ mol21,very similar to that of [6](1,4)anthracenophane(51) but distinctly higher than that of (54). Inthe full paper on this subject [55], the authors addi-tionally reported the1H chemical shifts at2508C ofthe diastereomeric diepoxy[6](9,10)anthracenophanes(56)–(58). These shifts were compared with those of[6]paracyclophane (46) and discussed in terms ofsteric compression of the hydrogens by the oxygen

atoms and of shielding by the oxanorbornadienedouble bonds.

The cis double bond in the bridge of (Z)-[6]para-cyclophan-3-ene (59a) [56] entails reduction of itsflexibility and increase of strain which is expectedto lie between that of [5]paracyclophane and of[6]paracyclophane. In the1H NMR spectra of(59a)–(59c), two kinds of aromatic protons wereobserved irrespective of the temperature (up to11508C), those on the same side (syn protons) andthose on the opposite side of the bridge (anti protons).The synprotons are shielded by 0.13–0.27 ppm rela-tive to theanti protons by the magnetic anisotropy ofthe double bond. Similarly, the olefinic protons appearshielded by ca. 1.0 ppm compared to precursor modelcompounds, due to the effect of the aromatic ring. Inthe 13C NMR spectra the carbon atoms of the sameside of the bridge are significantly deshielded�Dd <4 ppm� relative to theanti carbons by what has beentermed p-orbital compression effect [57] due to the


(54)

CH3 CH3

CH3CH3

3.31 0.87

−0.38

(CH2)6

(55)

1 8

(56), R = H, Me orPh

R R

RR

O O

(57), R = H, Me orPh

R R

RR

O O

(58), R = H or Me

R R

RR

O O

olefinic carbon atoms of the bridge. The analysis ofthe olefinic proton signals gave the large vicinalcoupling constant of 12.2 Hz across the double bondin (59a). This was interpreted as indicating wideningof the CyC–C bond angles according to the empiricalcorrelation derived by Cooper and Manatt [58]. An X-ray diffraction study of (59c) confirmed this; the bondangles were found to be 130(2) and 132(1)8 and thedouble bond is lengthened to 137(2) pm. Because ofthe substitution pattern of (59b), the two bridge-inver-sion conformers are diastereomers. They were sepa-rated and their isomerization was followed by HPLC.The kinetic parameters were determined to beDH‡�anti! syn� � 102:9 kJ mol21 and DS‡�anti!syn� � 0:8 J mol21 K21; the equilibrium ratio (syn/anti) is 0.97(1) at 258C.

Tochtermann’s group also studied the [7]paracyclo-phanes (60) and (61) as well as the [7](1,4)naphtha-lenophanes (62) [59]. Due to the specificconformation adopted by the heptamethylenebridge in these compounds, one proton of thecentral methylene group is pointing towards theopposite benzene ring and experiences strongshielding by the aromatic ring current. Its upfieldshift is larger in the naphthalenophanes (d � 22:6to 23.2) than in the benzenophanes (d � 21:7 to22.3). As other [n]paracyclophanes do not showsuch a strong upfield shift, the authors suggestedthat it might be applied as an indicator of 9,10-disub-stituted [7]paracyclophanes. Variable temperature1H NMR spectra of (60, R� CH2OAc) showed nodoubling of the aromatic proton singlet down to


CO2Me CO2Me

134.77.93137.6

7.19

139.07.13 134.6

7.34133.77.34

136.47.69

(59b)anti syn

132.1 or 132.07.20

136.07.07

(59a)

R

R

(CH2)7

(60)

R = CO2Me, CH2OHor CH2OAc

(CH2)7

(61)

O

O

(CH2)7

(62)

E

E

R

E = CO2Me; R = H or Me

(63)

O

CH3

H3C

(63’)

O

H3C

CH3

(64)

S

S

CH3

H3C

R2

R1

(59a)(59b)(59c)

CO2MeCO2Me

H HHCO2Me

R1 R2

21008C and hence no indication of a secondconformer.

At room temperature, the1H and13C NMR spectraof the 4-oxa[7]paracyclophane (63) [60] indicateapparentC2 symmetry and, hence, fast bridge flipping.This could be stopped at low temperature when thesignal of the aromatic protons doubled. Coalescencewas observed at2558C (400 MHz, Dv� 12:5 Hz),which gave aDG‡ value for the conformationalprocess of 47.9 kJ mol21. This process is a topomer-ization reaction with identical educt (63) and product(630) because these may be interconverted by apply-ing a C2 symmetry operation. A similar case, 9,12-dimethyl-2,6-dithia[7]paracyclophane (64), had beenstudied before and its conformational barrier,48.5 kJ mol21 at ca. 2308C, is almost identical tothat of (63) [61].

(65)

α

β

γδ

HH

β

γδ

α

(66)

(67)

H

H

45

HH-0.28

-0.67

(68)

O

H

H1.65

(69)

X H

45

(70)OHCO2H

X (71)

α

β

γδ

+

1 12

Two papers by Hopf and coworkers [62,63] treatthe 1H and 13C NMR spectra of [8]paracyclophane(65) and some derivatives. Comparison of the chemi-cal shifts of the aromatic protons of (65) with those of1,4-di-n-butylbenzene showed that the deformation ofthe benzene ring by the eight-membered bridge doesnot decrease the magnitude of the ring current effectupon the chemical shifts of the aromatic protons [62].

By double resonance experiments the chemical shiftsof the methylene protons were assigned to bed �2:66; 1.47, 0.91, and 0.19 for the CH2 groupsa, b,g and d, respectively, with respect to the aromaticring, i.e. theg andd protons are shielded relative toCH2 protons in an undisturbed aliphatic chain. No ringcurrent effect upon the13C chemical shifts of themethylene carbon chemical shifts could be derivedby comparing (65) with its saturated counterpart(66). Apparently, other factors such as the conforma-tion of the eight-membered bridge are more importantin determining the chemical shifts of the bridgecarbon atoms. Also, the magnitudes of the1J(C,H)coupling constants both for the aromatic and thealiphatic C–H bonds in (65) show that no influenceof the transannular bridging upon the degree of hybri-dization of these carbon atoms can be deduced. Bick-elhaupt and coworkers [64] reported the1J(C-1,C-2)and 1J(C-1,C-12) couplings constants in (65) to be32.6 and 43.4 Hz, respectively. These values arealso very similar to the corresponding values [65] inthe strain-free model compounds cyclohexane,32.7 Hz, and 2-methylnaphthalene,1J(C-2,C-a)�44.3 Hz. The cyclopropane derivative (67) andepoxide (68) both show characteristic shielding oftheir protons in positions 4 and 5 [63], viz.dH �20:67 and 1.65, respectively. These values are ca.1 ppm smaller than in the model compoundstrans-1,2-dimethylcyclopropane andtrans-2,3-epoxybu-tane. The CH2 protons of the cyclopropane ring in(67) still havedH � 20:28 although they are pointingaway from the arene ring. The spectrum of the 15nonequivalent protons of the eight-membered bridgein [8]paracyclophan-4-ol (69) was fully analysedyielding 24 vicinal H,H coupling constants that werecorrelated with the corresponding torsional angles andyielded a conformation similar to that known for[8]paracyclophane-4-carboxylic acid (70) from anX-ray diffraction study [66]. One of the protons atC-5 is pointing toward the interior of the moleculeand experiences substantial shielding�dH � 20:25�;very similar to the corresponding proton in (70). Also,the carbinyl proton has a chemical shift of onlydH �2:07 in spite of its positiona to oxygen. The assign-ment of its signal was confirmed through the spectrumof the 4-deuterio derivative of (69).

An interesting molecule to compare with [8]para-cyclophane (65) is the analogue [8](1,4)tropyliophane


(71) [67]. Its aromatic protons absorb as a broad“singlet” at d � 8:83 as do those of the 1,4-dimethyl-tropylium ion. The methylene protons of the bridgeare distinctly less shielded than those of (65) (seeabove). For the protons in thea-position to thearomatic ring, which showd � 3:28 (4 H), this wasexplained as an effect of the positive charge. The otherprotons absorb atd � 1:98 (4 H) and 1.05 (8 H). Thismeans that thed-protons are deshielded relative to(65) by at least 0.86 ppm. Possible reasons could bea weaker ring-current effect of the tropylium relativeto the benzene ring and/or differing conformations ofthe octamethylene bridges. The assignments of thebridge carbon chemical shifts in (65) have beensecured by experiment [62] and the relative shiftsare d (C-a) . d(C-b) . d (C-d) . d (C-g). Unsup-ported by experiments, Thummel and Chayangkoon[67] assigned the bridge carbon signals of (71) in theorderd � 42:3 (C-a), 31.6 (C-b), 28.1 (C-g), 25.3 (C-d). They argued that the decrease of the one-bond C,Hcoupling constants which occur in the same order(134, 128, 123, 121 Hz; all 1 Hz) parallels theexpected decrease of ring strain. In the opinion ofthe reviewer this is unsatisfactory and the questionshould be resolved by experiment.

N

O

O

N

NTs

Ts

R

(CH2)n

(72), R = H, n = 5−10(73), R = Me, n = 5−10,12

Two series of (2,5)pyridinophanes with varyingbridge length, (72) and (73), were studied by Iwataand Kuzuhara [68] with respect to restricted rotationof the pyridine ring. At ambient temperature, the1HNMR spectra of (72) with n # 7; i.e. a total bridgelength m # 11; showed geminal proton nonequiva-lence in the three methylene groups connected to thepyridine ring. This indicates slow rotation of the unsub-stituted side of the pyridine ring through the macro-cycle. Compounds (73) where additional stericinterference is present due to the methyl group on

the pyridine ring, have nonequivalent geminal protonsalready whenn # 10 �m # 14�; but from the variable-temperature spectra of (73), n� 12 �m� 16�; it wasestimated that the largest bridge length causing CH2

nonequivalence at room temperature would ben� 11�m� 15�; although the corresponding compound wasnot available.

Elschenbroich et al. [69] compared the1H NMRchemical shifts of [10]paracyclophane (74) withthose of bis(h6-[10]paracyclophane)chromium(0)(75). From the chemical shift difference theyconcluded that the coordination of chromium to thearene ring goes along with a weakening of the ringcurrent but does not abolish it. This approach wascriticized by Jenneskens et al. [70] who reported astrong solvent dependence (CDCl3 vs.C6D6) of the1H NMR coordination shifts of tricarbonyl(h6-[8]paracyclophane)chromium (76a, n� 8). Theseauthors warned that the solvent dependence may actas an obstacle to the use of the coordination shifts as aprobe in assessing the quenching of the aromatic ringcurrent due toh6-complexation. The origin of thesolvent dependence of the coordination shifts prob-ably lies in the different solvent–solute interactionsof the chromium complexes and the parent hydrocar-bons. Ref. [70] also reports that Cr(CO)3-complexa-tion of (65) goes along with an increase of1J(C-a,H-a) from 125.7 to 131.9 Hz. This could be interpretedby an increase in s-character of the carbon orbitalinvolved and would imply a decrease of the C–C(a)–C(b) valence angle. It is in line with the X-ray diffraction results of [2.2]paracyclophane(113.78) and its Cr(CO)3-complex (110.98). Kreindlinet al. [71] determined the complexation shifts in the1H NMR spectra of the [10]paracyclophanecomplexes (77)–(81). The downfield shifts of theb-to e-protons in the bridge observed in (77)–(80)relative to the uncomplexed ligand wereexplained by a weakening of the paracyclophanering current and partly by the effect of the posi-tive charge in (78) and (79). In (80), the twofoldpositive charge was assumed to override the ringcurrent effect. An exceptional effect was observedin the tetranuclear cluster (81), viz. increasedshielding of theb- to e-methylene protons uponcomplexation. This effect was deemed to requirefurther investigation.

The complexation shifts in the13C NMR spectra of


([n]paracyclophane)Cr(CO)3 (76a) and ([n]paracyclo-phane)Fe1(C5H5) (76b) complexes (n� 8; 9, 11, 12,15), i.e. the differencesDd between complex and freephane ligand, were reported by Mori and Takamori[72]. The aromatic carbon atoms have complexationshifts that depend on the bridge lengthn and can becorrelated with the interatomic distances between themetal and the ligand carbons; for details see thediscussion of the [2.2]phane complexes later. The1J(C,H) coupling constants in thep-phenylene ringsof the complexes are independent ofn and amount toca. 171 Hz for (76a) and ca. 177 Hz for (76b). 13Ccomplexation shifts were also determined forMo(CO)3 complexes (76c) of [8]–[15]paracyclo-phanes [73] and the conclusions reached were similarto those for the Cr(CO)3- and (C5H5)Fe1-complexes,except that the aromatic1J(C,H) coupling constantsvary slightly in (76c) and this variation seems tocorrelate with the complexation shifts. In a furtherstudy Mori and coworkers [74] investigated

complexes of the type [(h6–C6H6)Ru(h6–[n]paracy-clophane)]21·2BF4

2 (76d), wheren was 8, 9, 12, and15, and came to similar conclusions as in the cases ofthe Mo, Cr, and Fe complexes mentioned above.

The pressure dependence of the rate of internalrotation of thep-phenylene ring in thecis-1,12-disub-stituted [12]paracyclophane (82) was studied byYamada et al. [75]. It had been expected that anincrease of pressure would slow down the rate of rota-tion because of compression of the macrocyclic ringstructure. In fact, the opposite effect was observed.Simulation of the signals of the aromatic protonsshowed that at11058C the rate of rotation of thep-phenylene ring increases from 33 s21 at 5 MPa to52 s21 at 300 MPa. The corresponding dihydroxycompound behaves similarly. The explanation offeredwas a negative activation volumeDV‡ of the order of26 to 27 cm3 mol21 as the transition state conforma-tion (83) requires less space than the ground stateconformation (82).

In the [14]- to [16]paracyclophanes (84)–(87), thebarriers top-phenylene ring rotation (Table 2) areobviously not only determined by the length of thebridging chain [cf. (84a) with (84b) and (85a) with(85b)] but also by the presence and configuration ofthe substituents at the pyrrolidine ring. The barrierswere determined from the coalescence of the H-20

with the H-60 signals and of the H-30 with the H-50

signals. All of these were individually assigned byNOE measurements [76].

In an important paper on the empirical calculationof 1H NMR shielding in cyclophanes, Schneider et al.[77] tested various published methods for calculatingring current effects, viz. those by Haigh and Mallion


Cr

(75)(74)

7.09

1.54

2.62

1.080.72

0.50

4.132.08

1.50

1.250.90

0.70

(CH2)nM

(76a)(76b)(76c)

Cr(CO)3

Mo(CO)3

(C5H5)Fe+ PF6−

M

n = 8, 9, 11, 12, 15

(76d) (C6H6)Ru2+ 2BF4−

(74)

M

HCr(CO)3

Mn(CO)3+

Ru(C5Me5)+

Rh(C5Me5)2+

Co4(CO)9

M

(77)(78)(79)(80)(81)

Table 2Activation barriersDG‡

c to p-phenylene ring rotation determined atcoalescence temperaturesTc for the [14]- and [16]paracyclophanes(84)–(87)

Compound DG‡c [kJ mol21] Tc [8C]

(84a) 65a 40a

(84b) 51 218(85a) 57 13(85b) , 46 , 245(86) 55 1(87) 51^ 4 210

a The DG‡c and Tc values quoted are averages over the values

obtained from the H-20/H-60 and the H-30/H-50 signals.

[78], by Johnson and Bovey [79,80], and by Ha¨felin-ger et al. [81]. The [n]paracyclophanes withn� 6–10were used as the test compounds. Their geometrieswere determined by molecular mechanics calculations(MM2 and CHARMm). The best agreement betweenthe calculated ring current effects upondH on the onehand and the effects determined experimentally on the

other (i.e. chemical shifts with respect to suitablereference compounds) was found for the Johnson–Bovey model, the double loop model parameterizedwith a radius of 139 pm and a separation of the loopsfrom the aromatic plane of 64 pm. This gave a smallmean deviation of 0.1 ppm. Thus, the model and para-meters were used to calculated ring current effects inin-cyclophanes (Section 6.2), adamantanophanes andother phanes (Section 3.7).

2.3. Other [n]phanes

Increasing strain in the series of (2,7)troponophanes(88)–(90) [82] leads to reduced conjugation of thecarbonyl group with the triene system in the ordermentioned. This is visible from the decreasing chemi-cal shifts of H-b and C-b and the increasing shift ofthe carbonyl carbon atom (Table 3). The lower andhigher homologues of (88), the [3]phane (91) and the


C

(CH2)10

OAcH

C

OAcH

(82)

C

(CH2)10

OAcH

C

OAcH

(83)

O

O

NE

EO

O

(CH2)n

O

O

NE

EO

O

(CH2)n

O

O

NE

EO

O

(CH2)n

O

O

NE

EO

O

(CH2)n

(84a), n = 8(84b), n = 10

(85a), n = 8(85b), n = 10

(86), n = 8 (87), n = 8

R = CH2Ph, E = CO2Me

R R

R R

2’

6’

5’

3’

Table 3Comparison of important chemical shifts in the troponophane series(88)–(90) and in the series (92), (88), (91)

Compound Bridge(s) d(H-b) d(C-b) d(CyO)

(88) [4] 6.21 118.3 203.7(89) [4 1 2] 6.07 116.5 210.1(90) [4 1 1] 6.04 114.3 214.0

(92) [5] 6.48 121.5 202.5(88) [4] 6.21 118.3 203.7(91) [3] 5.96 113.7 210.6

[5]phane (92) [83], behave in an analogous manner.The shorter the bridge, the more severely the troponering is bent and the less effective is the carbonyl/trieneconjugation as shown by the series [5]phane (92),[4]phane (88), [3]phane (91). In this order, the chemi-cal shifts of H-b and C-b decrease and that of CyOincreases (Table 3).

In the [n](3,5)troponophanes (93) and (94),decreasing the bridge length fromn� 9 to 7 producedsmall changes of13C and 1H chemical shifts, whichwere thought to possibly reflect decreased carbonyl–triene conjugation [84]. In view of the minor deshield-ing of C-1 (0.7 ppm), this may be over-interpreted.Changes in the1H shifts are20.11 ppm or less forH-2, H-6, and H-7, but10.24 ppm for H-4, probably aconsequence of altered ring strain and/or bridgeconformation. By a coalescence measurement thebarrierDG‡ to flipping of the seven-membered bridgein (93) was determined to be 34.7 kJ mol21 at 2938C.This is distinctly lower than the barrier of48.1 kJ mol21 found in [7]metacyclophane [23] andreflects the larger CCC bond angles in the troponerelative to the benzene ring. The properties of thetropyliophanes (95) and (96) differ strongly fromthose of the troponophanes: C-3 to C-6 are deshieldedby 12–21 ppm, C-1 is shielded by 7 ppm and theolefinic protons are deshielded by 1.2–1.7 ppm. Thedifferences between the [7]- and the [9]tropyliophane,however, are again very small with the exception ofH-4 which is deshielded by 0.40 ppm in (95) withrespect to (96).

A paper by Paquette et al. [85] describes the reduc-tion of 13-methyl[10](1,5)cyclooctatetraenophane

(97) (called “14-methyl-…” in the paper) to itsdianion (98). The diatropic 10p aromatic systemformed caused characteristic shieldings of somebridge protons (dH � 0:44 and 20.72; number ofprotons not specified) and deshielding of the methylprotons�dH � 2:86�: The corresponding shifts of (97)aredH � 1:37 (8 CH2) and 1.76 (CH3). The dianions(99a) and (99c) of [9](1,3)cyclooctatetraenophane(100a) and of [7](1,3)cyclooctatetraenophane(100c), respectively, were mentioned in a relatedpaper [86]. At2608C in ND3, the triplet nature ofthe allylic proton signal (4 H) of (99a) at d � 3:06indicates rapid flipping of the nonamethylene chainfrom one side of the 10p ring to the other whereasthis process is slow for the heptamethylene chain in(99c) at the same temperature as shown by the broa-dened allylic proton signal atd � 3:17: The[n](1,3)cyclooctatetraenophanes (100a–c) are chiraland can racemize either by ring inversion or by doublebond shifting. These processes could be distinguishedby 2D-NMR exchange spectroscopy (EXSY) becausering inversion in (101) exchanges the geminalprotons, HA with HC and HB with HD, to give (1010),whereas bond shifting exchanges HA with HB or HD

and HC with HB or HD, to give (10100). It was foundthat in (100c) ring inversion is the sole process oper-ating below1378C, with bond shifting setting in onlyabove this temperature. The rate constants of the ringinversion processes in (100a–c) were determinedfrom the cross-peak volumes in the1H 2D EXSYspectra at six to seven different temperatures. Therate constants of bond shifting were extracted from13C 2D EXSY spectra at four temperatures. Table 4


O

β

(88)

O

(89)

O

(90)

O

(CH2)n (CH2)n

HO

+

1

4

(93), n = 7(94), n = 9 (96), n = 9

(95), n = 7

(CH2)n

(91), n = 3(92), n = 5

O

β


CH3

(CH2)10 (CH2)10

CH3

2−

(97) (98)

(CH2)n

(CH2)n

2−

(99c), n = 7(100c), n = 7(100b), n = 8

(99a), n = 9 (100a), n = 9

(CH2)n−2HC

HA

HD

HB

(CH2)n−2 3

1

1

3

HB

HD

HC

HA

(CH2)n−2HC

HA

HD

HB

1

3

(101)

(101’)

(101")

bond shift

ring inversion

Table 4Activation parameters for the enantiomerization of the [n](1,3)cyclooctatetraenophanes (100a–c)

Compound DH‡ [kJ mol21] DS‡ [J K21 mol21] DG‡�258C� [kJ mol21]

Ring inversion(100a) 50.2^ 2.9 258.6^ 10.5 67.86 0.46(100b) 65.7^ 2.1 9.2^ 7.1 68.41 0.21(100c) 78.2^ 1.7 7.9^ 5.9 75.69 0.13

Bond shifting(100a) 66.5^ 3.3 228.0^ 10.0 74.77 0.21(100b) 65.7^ 3.8 239.3^ 12.1 76.99 0.29(100c) 92.0^ 1.7 32.2 5.9 82.68 0.13

shows the activation parameters obtained. In all casesthe rate of ring inversion exceeds the rate of bondshifting.

N

N

N

N

NH

(102)

N

N

N

N

NH

anti-(103)

N

N

N

N

HN

syn-(103)

N

N

N

N

NH

(104)

6

9

6’

In order to explore the diamagnetic anisotropy ofthe adenine system,N60,N9-octamethylenepurine(102) was studied by 1H NMR [87]. Its nine-membered bridge is short enough to permit only mini-mal motion of the methylenes but not so taut as tocause significant bending of the purine ring. At ameasuring frequency of 500 MHz, the chemical shiftsof all 16 nonequivalent methylene protons areresolved. The shifts of the NCH2 protons are betweend � 4:7 and 3.4, those of the CH2 groups not bound tonitrogen are betweend � 1:8 and 20.6. The 13Cchemical shifts were assigned by 2D heteronuclearcorrelation [88]. The next higher homologue (103)[89] occurs as two conformers,anti and syn, thatdiffer by the torsional angle about the C6–N60

bond. Their H-2 and H-8 signals coalesce at ca.2258C (500 MHz), giving DG‡�2258C� � 50:2^2:5 kJ mol21

: Two-dimensional H,H-COSY andC,H-HETCOR experiments at1758C and at2608Callowed the assignment of all13C and1H resonancesapart from thepro-R/pro-S 1H assignments withinmethylene groups possessing diastereotopic protons.The spectra of the decamethylene compound (104)[90] are very broad at room temperature and couldonly be assigned at1908C by the usual 2D correlationtechniques. At2778C, several isomers, again likelydue to anti–syn isomerization about the N60–C6bond, appear in the spectra. Theanti conformer ispreferred by ca. 4:1 over thesyn. Variable temperatureproton NMR measurements revealed aDG‡(2208C)of 59.4^ 5.5 kJ mol21 associated with the inter-change between the two major conformers. Thelarge error in the barrier is caused by a number ofsignals of minor conformers coalescing about thepeaks of interest, which made it difficult to accuratelymatch simulated spectra with the actual peaks. Thechemical shifts of the methylene protons of (102)and (103), apart from the benzylic ones, were calcu-lated by adding to the standard methylene shift ofd �1:3 the effects of ring currents [91] and local atomicmagnetic anisotropies [92]. The relative chemicalshifts were roughly reproduced and the purinophaneswere found useful in the assessment of the chemicalshift calculation procedure.

The enantiomerizations, by the jump rope mechan-ism, of several dioxa[n](1,5)naphthalenophanes (105)with n� 16–18 (i.e. containing 14–16 methylenegroups) were studied by dynamic NMR spectroscopy[93,94]. These enantiomerizations go along withinterconversion of the diastereotopic protons of each


O

O

(CH2)m

(105)m [n]141516

161718

D2

D2

D2

D2

D2

O

O

D2

(106)

methylene group in the chain except the central one inthe odd-numbered bridge. As the protons in the CH2

groups positionedg to the oxygen atoms have thelargest chemical shift differences, their signals wereused to follow the kinetics. Theb-, d-, andh-CH2

groups were deuterated as in (106) to simplify thespectra. A complete lineshape analysis (CLSA) at500 MHz was performed for (105, n� 18) in thetemperature range287 to 2398C. To obtain maxi-mum possible accuracy, complete lineshape analysesat 90 and 500 MHz observation frequencies in therangeT � 235 to 1158C were carried out for (105,n� 17), and both CLSA and saturation transferexperiments were applied to (105, n� 16). For thelatter compound, this allowed a determination of therate constants over a very large temperature interval

from 130 to 11448C. The activation parametersobtained for the jump rope movement of the chainsare given in Table 5. The important finding is thatlarge, negative entropies of activation are observedwhen n� 16 or 17 and thatDS‡ is rather smallwhen n� 18: The results of molecular mechanicscalculations explain this by unrestricted and confor-mationally very flexible polymethylene chains in theground state of all three compounds and by a veryrestricted chain in the enantiomerization transitionstate whenn� 16 or 17 as opposed to a relativelyunrestricted chain whenn� 18:

The bridged porphyrins (107a)–(107f) with vary-ing bridge lengths from 14 to 20 show increasedshielding of their amide protons H-g and methyleneprotons H-d and H-e relative to the open chain modelcompound (108). Shortening of the bridges leads tohigher-field shifts of these protons as they cannotevade the shielding zone of the diamagnetically aniso-tropic porphyrin macrocycle [95] (Table 6).

In an attempt to test the tolerance of pyrene towardsdistortions from planarity Bodwell and coworkerssynthesized 1,8-dioxa[8](2,7)pyrenophane (109) [96]and 1,7-dioxa[7](2,7)pyrenophane (110) [97]. Thestrain imposed on the molecule by the short bridges


N

N N

N

Zn

NH

O

O

HN

(CH2)n

α

β

γ

δ

δγ

β

αZn

NH HN

O O

(CH2)n

Zn

NH HN

O O

α

βγ

δ

ε

ε

α

βγ

δ

ε[m]Cyclophane n

(107a)(107b)(107c)(107d)(107e)(107f)

[14][15][16][17][18][20] 10

87654

(107a-f)

(108)

Table 5Activation parameters for the jump rope enantiomerization of (105,n� 16–18)

Compound DH‡ [kJ mol21] DS‡ [J K21 mol21]

(105, n� 16) 43:47^ 0:42 297:9^ 1:2(105, n� 17) 32:01^ 0:25 280:8^ 0:9(105, n� 18) 36:94^ 0:59 213:8^ 2:7

is distributed evenly over the polycyclic aromaticsystem as shown by X-ray diffraction. Increasingdeformation leads to slight upfield shifts of thearomatic protons relative to model compound (111).The most shielded bridge protons havedH � 21:47and 22.10 in (109) and (110), respectively, whichcompares withdH � 20:6 for [6]paracyclophane.By taking the synthetic precursor (112) as an openchain reference compound, one arrives at upfieldshifts of up to almost 4 ppm for the methylene protons(see formulae) caused by the large ring current effectof the extended pyrene system.

In the dihydropyrenophane (113) the 2,7-positionsof the [14]annulene are bridged by an 18-memberedchain which is long enough for the annulene ring tospin freely [98]. As a consequence both the bridge andthe annulene protons give symmetrical spectra. Freerotation on the NMR time scale is maintained even at600 MHz and 21008C. The bridge protons wereassigned by a DQF-COSY experiment, starting atthe CH2C(yO) group with its characteristic shift.When the chemical shifts were compared with thoseof the reference compound 1,14-tetradecanedioicacid, the resultingDd values gave an idea of the


Table 61H NMR chemical shifts of theg-, d-, ande-hydrogens in the porphyrins (107a)–(107f) and in the model compound (108)

Compound (107a) (107b) (107c) (107d) (107e) (107f) (108)Bridge length [14] [15] [16] [17] [18] [20] –H-g 5.94 6.64 7.27 7.81 8.00 8.20 8.28

H-d 2.0–1.6 3.0–2.3 3.2–2.8 2.90 2.90 3.4–3.2 3.20H-e 21.4 21.0 21.2 to22.6 0.2 0.2 0.70 1.20

22.1 22.5 21.0 20.5 0.1022.7 23.4 21.4 21.0 20.4

21.4

OMeMeO

O O

CH2Br

CH2BrBrCH2

BrCH2

(CH2)n

n = 5, 6

(111)

(112)

OO

(∆δH values)

−3.02−0.40−1.72

OO

−3.77−0.68−1.89

(109)

(110)

−0.25−0.13

−0.25−0.47

CH3

CH3

OO

O O

(113)∆δ values, see text

0.24

0.05−0.39

−0.26

−0.68

−0.48

annulene ring current effect upon the bridge protonshifts. The largest shielding effect was not observedat the central methylene groups 7 and 8 but at theadjacent ones 6 and 9. The order of the induced shifts(H-6 . H-7 . H-4 . H-5) agrees with the order ofobserved signal intensities in a gradient-selectedNOE experiment when the methyl signal was satu-rated. It also agrees with the order of distancesbetween the methylene carbons and the centre of thering current, averaged over the 10 most populatedconformers, as computed by molecular mechanics.The 13C NMR spectrum of (113) was fully assignedby the use of 2D heteronuclear shift correlations.

A large number of compounds are known of thetype of myricanone (114), a natural product fromthe bark ofMyrica ceriferaL. [99]. These compoundsmay be considered as [7](3,30)biphenylophanes or[7.0]metacyclophanes. The parent hydrocarbon(115) has also been described [100]. As suchcompounds do not show the NMR properties that

are usually associated with phanes they are notconsidered in this review.

(115)(114)O

OH

OMeOMeHO

2.4. [1.n]Phanes

Staab and coworkers [101] assigned the1H NMRspectra of thea-phenyl[1.n]paracyclophanes�n�5–8� (116)–(119). These are triphenylmethanes inwhich thepara positions of two of the phenyl ringsare connected by a (CH2)n bridge. From the relative


H

α(H2C)5

Ha

Hb

Hc

Hc

(116A), parallel

H

α(H2C)5

Ha

Hb

(116B), perpendicular

Hc

Hc

H

Phα

(H2C)n

(116) 5678(119)

(118)(117)

n

Ph(H2C)n

(120) 567(122)

(121)

n

α(H2C)n

(123a)

8(123d)(123c)(123b)

n

O

(123e)9

101112

−

chemical shifts of Ha �d � 6:94� and Hb �d � 7:05�and the considerable low-field shift of Hc �d � 7:78�in (116), they inferred the preference of the perpendi-cular conformation (116B) over the parallel confor-mation (116A). Compounds (117)–(119) behavesimilarly to (116). Conversion of (116)–(118) intothe triarylmethyl carbanions (120)–(122) [102] isaccompanied by high-field shifts of theortho, meta,and para protons of the phenyl ring of20.70 to20.85, 20.65 to 20.75, and21.35 to 21.50 ppm,respectively, while the aromatic protons of the para-cyclophane systems are slightly deshielded(10.1 ppm, H-ortho) with respect to the hydrocarbonsor are substantially less shielded [20.27 to20.31 ppm, H-meta] than the meta protons of thephenyl ring. This is in accord with the averaged

perpendicular orientation of the C-a orbital formallycarrying the negative charge and the paracyclophanephenylene rings.

In the a-oxo[1.n]paracyclophanes (123a)–(123e)with 12- to 8-memberedn-bridges [103], the13Cchemical shift of the carbonyl carbon increasesslightly with increasing ring strain:d(CyO)� 199.1(123a), 200.4 (123b), 201.3 (123c), 202.1 (123d),203.5 (123e); solvent CDCl3. In the same order, thecarbonyl band in the infrared spectrum is shifted tohigher frequencies, from 1675 (123a) to 1710 cm21

(123e), similar to the well-known trend in the smallercycloalkanones.

The first two [2.1]paracyclo(1,7)naphthalenophanederivatives, (124) and (125), were described by Buch-holz and de Meijere [104]. In these compounds, H-8


(124) (125)

4.54 4.49

HMeO2C(126)

H

HH

H

HA CO2Me7.60 3.94

HB HC

?

4.446.95

7.14

CO2Me

HA

HC

HB

CO2Me

(127)

hν

(128)

H

HH

H

6.94

3.38

(129)

H

HH

H

7.67

3.67, 3.61

XH

Y Y

HX

Y Y

X = CONMe2, Y = CH 2SiMe3

(naphthalene numbering) is strongly shielded. It is notexactly centred over thep-phenylene ring because, asshown by X-ray diffraction of (124), C-8 is bent out ofthe plane of the atoms C-6/C-7/C-8a/C-4a by 118.Otherwise, even stronger shielding might have beenexpected.

The first [1.1]paracyclophane, (126), was preparedphotochemically from the bis(Dewar benzene)compound (127) [105]. It could not be isolated butonly characterized in the reaction mixture by1HNMR at 2708C. It shows the normal couplingconstants between aromatic protons,J(HA,HB)� 2.5Hz andJ(HB,HC)� 8.8 Hz, while those of the startingmaterial areJ(HA,HB) , 1 Hz andJ(HB,HC)� 2.4 Hz.The chemical shifts of the aromatic ring protons areca. 0.45–0.50 ppm downfield from the values in thecorresponding [2.2]paracyclophane derivative [106].The chemical shift of one of the methylene protonswas not found, probably because the signal is coveredby the much stronger methoxyl absorption. Later, theparent [1.1]paracyclophane (128) was also prepared insolution [107]. Its1H NMR spectrum consists of twosinglets atd � 6:94 and 3.38 (THF-d8, 2808C). Thehexasubstituted derivative (129) is so stable that acrystal structure could be obtained. The bridge andthe aromatic protons have chemical shiftsd �3:67=3:61 and 7.67, respectively [108].

3. [2.2]Phanes

3.1. [2.2]Metacyclophanes

The basic facts on NMR of [2.2]metacyclophanesare found in Ref. [9]. More recent material ispresented here, roughly in the following order: substi-tutedanti- andsyn-[2.2]metacyclophanes, [2.2]meta-cyclophanes with heteroatoms in the bridges, metalcomplexes of [2.2]metacyclophanes, and partiallysaturated [2.2]metacyclophanes.

A paper by Tsuzuki et al. [109] reported1H and13CNMR data of [2.2]metacyclophane (130) with onearomatic ring fully deuterated. The results do notprovide new insights and the quality of the1H spectralanalysis of the nondeuterated ring is questionable as,for example, a value forJ(H-12,H-14) is reportedalthough this coupling should not be detectable, if,as expected, the protons involved are magnetically

equivalent. Later, the same group measured deuteriumisotope effectsD on 13C chemical shifts in 4-D-(131a), 5-D- (131b), and 8-D-[2.2]metacyclophane(131c) [110]. These effects are defined asD �d�R–D�2 d�R–H�; are usually negative (shielding)and are given in ppb (� 0.001 ppm) in the formulae.The deuteratedmeta-xylenes (132a)–(132c) wereused for comparison. The authors pointed out thatthe isotope effects over one and two bonds in thecyclophane isotopomers (131a) and (131b) are verysimilar to the effects in the corresponding xylenes(132a) and (132b), whereas substantial differencesexisted between the effects in (131c) with its intraan-nular deuteron and the effects in xylene (132c). As the1J(C,D) coupling in (131c) is also larger (24.4 Hz)than in its isotopomers or in the xylenes (23.6–24.1 Hz), the authors assumed higher than normal s-character in the C-8 orbital involved in bonding thedeuteron. For such a situation they expected adecrease in the one-bond isotope effect. That thiswas not found in (131c) was attributed to “structuralstrain and/or through-space electronic interaction


D

D

D

12

14

D

(130)

(131a)

D

D

D

(131b) (131c)

(132a)

D

D(132b) (132c)

D

−305

−112

−81−59

−6

−307

−86

−112−7

−289−108

−4

−84

−333

−283

−108

−16

−60

−106

−7

−7

−362

−7

−4

Isotope effects ∆ [ppb]

which originates from the unique metacyclophaneskeleton”.

Lai and Zhou [111] achieved a rather completeassignment of the1H NMR spectra of the 8-fluoro-16-methyl derivatives ofanti-[2.2]metacyclophane(133), -cyclophan-1-ene (134), and -cyclophane-1,9-diene (135) by 500 MHz 1D NMR, including NOEmeasurements, and 2D H,H-COSY. Their assign-ments also include the individual protons of the satu-rated bridges. They noted an increasing downfieldshift of the methyl protons in the above series(d � 0:67; 0.91, 1.67), i.e. with increasing unsatura-tion in the bridges, and explained this by the sliding ofthe benzene rings relative to each other due to thechange in bond angles of the bridges with the effectof moving the methyl group towards the periphery (C-8) of the opposite ring. They further suggested thatdue to the increased steric hindrance in the ordermentioned between the inner substituents and therespective opposite rings, the fluorine bearing ringmay tilt in order to decrease its interaction with the

methyl group. (This movement would, however,increase the interaction of the fluorine with the methy-lated ring.) The trend found for the methyl protonshifts was also observed for the shifts of the fluorinenuclei. However, this is probably not due to thegeometrical changes but only fortuitous, as shownby consideration of other model compounds.

Mitchell et al. [112] synthesizedsyn-8,16-difluor-o[2.2]metacyclophane (136) and its diene (137) andshowed that the compounds previously claimed [113]to have these structures are, in fact, theanti isomers(138) and (139), respectively. The aromatic protons ofbothsynisomers are shielded by ca. 0.7 ppm relativeto those of theanti isomers. Syn-phane (136) isconformationally extremely stable. Five minutes ofheating to 3008C was necessary to convert it to theanti isomer (138). However, whensyn-diene (137)was warmed to 358C, it underwent valence isomeriza-tion to cis-10b,10c-difluoro-10b,10c-dihydropyrene(140). Through-space19F,19F spin–spin coupling in(136) is discussed in Section 3.9.


FCH3

7.13

6.91

H

H

H

H

(133)

FCH3

7.25

H

MeS

H

H

(134)

FCH3

7.16

6.78

6.82

7.01

(135)

6.59

6.16

1.616.80

6.39

7.68 *

**

*: 7.17−6.94*

2.95

2.56

3.79

0.910.67

7.10−7.05

2.80

2.63

2.96

2.72

FF

(136)

FF

(137)

F

F F

F

(138) (139)

F F

(140) (141), anti

tBu

H3.47

0.73

(141a)

tBu

Hi

In a study ofanti- and syn-dithia[3.3]metacyclo-phanes (see Section 4), Mitchell et al. [114] alsoobtained a [2.2]metacyclophane possessing atert-butyl group as the internal substituent (i.e. bound toC-8). The1H chemical shifts of thetert-butyl group�d � 0:73� and of the remaining internal proton�d �3:47� clearly show the compound to have theanticonformation (141) because of the shielding by themagnetic anisotropy of the opposite aromatic ring.The d value of 3.47 corresponds to the strongestshielding of an aromatic proton in a [2.2]metacyclo-phane, at least at the time of the original publication. Itwas explained by a distortion of the molecule into aconformation like (141a), in which unfavourableinteractions with thetert-butyl group are somewhatrelieved but the internal hydrogen Hi is pushed intothe cavity of the opposite benzene ring. Restrictedrotation of thetert-butyl group was observed not tooccur down to2908C.

The synthesis of [2.2]metacyclophane (142) [115]furnished a 6:1-ratio ofanti and syn isomers. Thesecan easily be assigned from the large1H chemicalshift differences between the two methoxy�Dd �0:95� and the two methyl ester signals�Dd � 0:55�in anti-(142) as opposed to the very similar shifts,Dd � 0:02 for both OMe and CO2Me signals, insyn-(142). Also the aromatic protons in thesyn aredistinctly shielded relative to theanti isomer (Table7). Support of the isomer assignment comes from themagnitudes of the vicinal H,H coupling constants inthe cyclophane bridges. Ideally, the vicinal C–H

bonds in the bridges form a staggered (143A) andan eclipsed conformation (143B) in the anti and thesyn isomers, respectively. Hence, in theanti isomerone of the four vicinal coupling constants should belarge (for theanti orientation of C–H bonds) and threeshould be small (for thegauche orientations). Incontrast, thesyn isomer should show two large(eclipsedorientation) and two small (gaucheorienta-tion) vicinal couplings as borne out by experiment(Table 7). The coupling constant criterion was alsoapplied to prove theanti structure of (144) and(145). Confirmatory evidence comes from the


Table 71H NMR chemical shiftsd and H,H coupling constantsJ(H,H) [Hz]in the isomers of (142)

anti-(142) syn-(142)

d(OMe) 3.79, 2.84 3.48, 3.46d(CO2Me) 3.92, 3.37 3.81, 3.79d(H-aryl) 7.85, 6.63 7.08, 5.94d(H-1)a 3.70 4.21d(H-2) 3.05 3.42d(H-3) 2.59 2.80d(H-4) 2.72 2.50J(H-1,H-2) 212.3 213.1J(H-1,H-3) 12.0 9.6J(H-1,H-4) 5.5 3.7J(H-2,H-3) 5.4 5.1J(H-2,H-4) 2.1 9.5J(H-3,H-4) 212.0 212.8

a For the numbering of the bridge protons, cf. formulae (143a)and (143b).

anti-(142) syn-(142)

MeO OMe

CO2MeMeO2C

MeO OMe

Y X

anti-(144)anti-(145)

NO2

CO2Me CO2MeHHH

X Y

H3

H4H1

H2

(143A)H3

H4H2

H1

(143B)

chemical shifts of the intraannular proton(s) in thesetwo compounds:d � 4:39 and 4.14, respectively.

The anion of [2.2](4,6)indenometacyclophane(146) was investigated by1H NMR in order toprobe through-space charge transfer from the indenidemoiety to the benzene ring [116]. A comparison of thechemical shifts of H-13,14,15 in (146) with those ofthe neutral 4-H-indenophane (147) or its 6-H isomershows that the shifts are in the normal range foraromatic protons�d � 7:3–7:0� in both the anionand the reference compounds. Thus, charge transferdoes not take place. However, H-17 experiencesincreased shielding�d � 3:92� in (146) relative to(147) and its isomer (d � 4:26 and 4.22, respectively).This demonstrates the increased diatropicity of theindenide anion with respect to its indene precursors.

Syn-[2.2]metacyclophanes without internal substi-tuents are not stable at room temperature. The parentcompound (148) was described by Mitchell et al. onlyin 1985 [117]. It was prepared at2458C and its1Hchemical shifts were determined at2308C. The exter-nal protons, H-4/6/12/14 and H-5/13, are shielded by0.62–0.65 ppm relative to theanti isomer (149) by theopposite aromatic ring. H-8/16 is only shielded by0.3 ppm relative to H-2 ofm-xylene, probably dueto a superimposed steric deshielding of the internalhydrogens. Thesyn isomer rapidly isomerizes toanti above 08C. Kinetic parameters for thesyn! antiisomerization were disclosed later, in a conference

lecture [118] and a full paper [119]. Due to the scar-city of material, only three runs of kinetic measure-ments (at110, 120, and1308C) could be carriedout. They led to DH‡ � 74:5^ 4:6 kJ mol21

;

DS‡ � 232^ 16 J K21 mol21; and DG‡�298 K� �

84:1 kJ mol21: Cr(CO)3-complexation of one of the

aromatic rings raises the barriers by about17 kJ mol21. The later paper also contains the1Hand 13C NMR chemical shifts of a fair number ofother syn- and anti-[2.2]metacyclophanes, mostlysynthetic intermediates, i.e. mono- or bis-Cr(CO)3

complexed phanes and/or those carrying SCH3 substi-tuents at the bridges. A13C NMR spectrum of theparentsyn-[2.2]metacyclophane (148) could not beobtained, but spectra of derivatives showed that the“internal” C-8/C-16 have similar low-field shifts�dC . 135� as their counterparts in theanti series. Infact, shortly afterwards the 5,13-dimethyl isomer(150) was reported [120] which showsd�C-8=C-16� �136:2: Assuming thepara-SCS of a methyl group tobe about23 ppm, this translates intod�C-8=C-16� <139 for (148). Activation parameters for thesyn!anti isomerization were also reported for (150),DH‡ � 81:2 kJ mol21

; DS‡ � 236:4 J K21 mol21;

and DG‡�298 K� � 94:6 kJ mol21: The differences

between (148) and (150) are probably not significantbecause of the experimental errors involved. Later, Itoˆet al. repeated the determination of the activationparameters of (150) and also determined those of


−13

1517

3.92

(147)

4.26

64

(149)

3

1

5

(148)

H

H6.63

6.41

6.62

(150), X = Y = CH 3

X

Y

HH

2.933.13

(151), X = CH3, Y = CHO

(152), X = Y = CHO

(146)

(151) and (152) by following thesyn! anti intercon-version kinetics in the1H NMR spectra at fourtemperatures (115, 120, 125, and1308C) [121].If transannularp–p interaction contributes signifi-cantly to the stability of thesyn conformers, (151)should have the largest energy of activation for ringflipping. The results show that this is not the case.Instead, the following order was found (DH‡ inkJ mol21, DS‡ in J K21 mol21, andDG‡ in kJ mol21,at 1258C): (150s)! (150a): 85.5, 216.3, 90.4;(151s)! (151a): 89.9, 26.2, 91.8; (152s)! (152a):94.6,25.1, 93.1.

Three isomericsyn-[2.2]metacyclophanes (153)–(155) were obtained in a 50:45:5 ratio by photoche-mical cyclodimerization of 1,3-distyrylbenzene [122].Their structures were derived from the symmetry oftheir 1H and 13C NMR spectra and from the NOEsobserved between aromatic and cyclobutane protons.The important1H shifts are given with the formulae.Thesyn-configuration followed from the upfield shiftsof the outer cyclophane protons and from the missingupfield shift of the internal protons. The internalproton in (155) is particularly deshielded due to stericinteractions from both sides. Analogous compoundsin which the phenyl substituents of (153)–(155) arereplaced by 2-naphthyl and methoxycarbonyl groups,respectively, were reported later [123]. Nishimura’sgroup derived the structures of (156)–(158) [124],the phenyl-free analogues of (153)–(155), by thesame techniques as used in Ref. [122].

The first [2.2]metacyclophanes containing a singleheteroatom in the bridges were prepared by Vo¨gtle’sgroup, viz. 1-oxa- (159) and 1-thia[2.2]metacyclo-

phane (160) [125,126] as well as 1-tosyl-1-aza[2.2]metacyclophane (161) [127]. All of theseare characterized by strongly shielded intraannularprotons and hence possess theanti conformation:dH � 4:46 and 3.86 in (159), dH � 4:85 and 4.32 in(160) anddH � 4:34 (H-16) and 4.13 (H-8) in (161).The value of 3.86 in (159) is attributed by the reviewerto H-16 by comparison with the data of differentisomeric 1-oxa[2.2]metacyclopyridinophanes to bediscussed in Section 3.8. This enormous shieldingwas explained by the authors as being due to thetight bridging of the molecule (probably on accountof the shorter C–O with respect to C–C bond lengths).However, the mesomeric substituent effect of theoxygen upon the chemical shift of itsortho-Hi mustnot be overlooked. Inspection of the1H NMR data of1-oxa-10-thia[2.2]metacyclophane (162) and its“diagonal” 1-oxa-9-thia counterpart (163) shows thatthe sulphur atom of the bridge deshields itsortho-proton, so in (162) the upfield shift by the oxygenis cancelled by the sulphur atom [128]. An evenslightly larger high-field shift than in (159) wasobserved in 1,10-diaza[2.2]metacyclophane (164)[129]. Of the two chemical shifts for the intraannularprotons atd � 4:41 and 3.81, the latter is probably dueto H-16. Here also, the (1)-M effect of the aminogroups should contribute to the shielding, in additionto the tight clamping of them-phenylene ringsinvoked by the authors. Takimiya et al. [130]described the diagonally 1,9-dithiasubstituted[2.2]metacyclophane (165). Its intraannular protonsabsorb atdH � 4:90; hence it isanti. The AB spec-trum of the CH2 protons (d � 3:93 and 3.36,


(153)

PhPh

PhPh

(154)

PhPh

(155)

PhPh

PhPh

6.58 4.56

6.77

6.88

4.42

4.68

4.44

7.05

6.82 6.50

6.79

4.39

4.61Ph

Ph

7.33

4.73

4.42

6.54

6.67

(156) (157) (158)

J � 12:2 Hz) do not change up to11708C, indicatingdifficult ring inversion.

The intraannular protons of 8-substitutedN-tosyl-1-thia-10-aza[2.2]metacyclophanes (166a–k), of theS-dioxides (167a–b), and of the 5-substituted analogues(168a–b) show chemical shifts in the regiond �3:78–4:77 [131]. This proves that these compoundsare present in theanti conformation. Thet-butyl deri-vative (166i) possesses the most shielded aromatichydrogen of all because the repulsive interactionbetween the bulky substituent and the opposite

benzene ring causes a mutual tilt of the two ringswhich forces H-16 into thep-cloud of the ring carry-ing the t-butyl group. This shifts the resonance of H-16 in (166i) to d � 3:78; cf. the analogous situation int-butyl[2.2]metacyclophane described earlier. Themethyl derivative has onlyd � 4:16: In the lattercompound, the methyl protons are shielded tod �0:64: The t-butyl hydrogens in (166i) might beexpected to be even more shielded, butd (t-Bu) isonly 0.78 because of rotational averaging of thethree t-butyl methyl groups. Cooling the sample to


X

(159), X = O

816

(160), X = S(161), X = NTs

SO

(162)

4.44*4.52*

O

(163)

3.935.08 S

NHHN

(164)

3.814.41

S

S

(165)

4.90

NTsS 16R

(166)

NTsO2S 16R

(167)

NTsS 16

(168)

R

N

NTsS 16

(169)

N

NTsS 16

(170)

O+−

a: Meb: tBu

a: Meb: CN

a: Hb: Mec: OMe

d: SMee: CNf: CO2Me

g: SO2Meh: OCH2CH=CH2

i: tBuk: Ph

R R R

RR

2708C does not slow downt-butyl rotation on theNMR time scale. The1H spectrum of theO-allyl deri-vative (166h) shows decreasing upfield shifts of thesubstituent hydrogens relative to allyl-2,6-bis(bromo-methyl)phenyl ether as one goes outwards from thepoint of attachment of the substituent. Thus, the CH2

protons in (166h) are shielded by 0.8 ppm, thegeminal andcis olefinic protons by 0.6 ppm and thetrans olefinic proton by 0.3 ppm. In the phenylcompound (166k) the anti conformation could notbe deduced from the upfield shift of H-16 becausesuch a shift is also to be expected for thesynconfor-mer where Hi lies above the phenyl ring. Instead, theanti conformation is indicated by the high-field shifts(d � 5:33 and 6.46) of theo,o0-protons of the phenylring which rotates slowly at room temperature.Coalescence of theo- and o0-proton signals gaveDG‡�1478C� � 64 kJ mol21

: The paper also includedthe H-16 chemical shifts in the pyridine analogue(169) �d � 4:94� and itsN-oxide (170) �d � 5:82�:

In the series of [2.2]metacyclophanes (171)–(173)[132] the first and third compounds possess theanticonformation as clearly indicated by strong shieldingof their intraannular protons Hi: dH � 4:66 and 5.36(Hi ortho to S) (171), dH � 4:10 and 4.19 in (173), yetthe azadithia element combination in (172) favoursthe syn arrangement. No high-field intraannularproton signal was found for this compound.

Sakurai et al. [133] prepared octamethyl-1,2,9,10-tetrasila[2.2]metacyclophane (174) and reported its1H, 13C, and29Si NMR chemical shifts. The intraan-nular protons Hi absorb atd � 6:43: As there is onlyone1H and one13C signal for the Si–Me groups, a fastequilibrium between two conformers probably exists.The rather high-field shift of Hi indicates substantialparticipation of theanti conformer, so it is either asynO anti or an antiO anti0 equilibrium. The 1Hchemical shifts of the aromatic protons would seemto speak for the latter. The deshielding of the intraan-nular proton Hi relative toanti-[2.2]metacyclophane(149) can be explained partly by the longer Si–Si andSi–C bond lengths compared to those of C–C bonds.They diminish the effect of the ring current of theopposite aromatic ring ond(Hi). (Preceding interpre-tations by the reviewer.)

Tetrasilaphane (174) was also studied byNishiyama and Sugawara [134] who additionallyinvestigated the trisila compound (175) and the three

isomeric disilaphanes (176)-(178). These authors alsodiscussed the decreasing shielding of the intraannularproton(s) with increasing sila substitution in thebridges. However, when comparisons of chemicalshifts are made, the number of silicon atoms in theortho positions must be taken into account because oftheir electronic effect upon the shift of theorthoproton(s). Inversely, comparing the chemical shiftsof the internal carbon atoms Ci with the same numberof ortho silicon substituents, one finds increasedshielding of these carbon atoms in the compoundswith the higher degree of sila substitution. The largerinterring distance diminishes the so-calledp-orbitalcompression effect that had been made responsible forthe downfield shifts of Ci in [2.2]metacyclophanes[57]. Concerning the conformational mobility of thesila compounds, Nishiyama and Sugawara found fastring inversion at room temperature for (174) and(175)—indicated by one1H and one13C signal pergroup of equivalent SiMe2 units and one1H signal pergroup of equivalent CH2 units—and slow inversionfor the three disila compounds (176)–(178). The freeenergies of activation, determined by the coalescencemethod, are given in Table 8. The lower barriers forthe higher silasubstituted phanes are due to lowerenergies of the transition states of ring inversionbecause of the longer Si-containing bonds. The vary-ing barriers for the isomeric disilaphanes were inter-preted by the different degrees of Hi/Hi interactioncaused by the different arrangements of longer andshorter bonds in the molecules.

Swann and Boekelheide [135] studied the1H NMRchemical shift changes whichanti-[2.2]metacyclo-phanes undergo when one or both aromatic rings areh6-coordinated with (cyclopentadienyl)iron(II). We


Table 8Free energies of activation for the inversion of the 10-memberedring in [2.2]metacyclophanes (174), (175)–(178), and (149) withdiffering degrees of sila substitution in the bridges

Compound Degree of silasubstitution

DG‡ [kJ mol21] Tc [8C]

(174) Tetra , 250(175) Tri 51 217(176) Di 66 69(177) Di 75 103(178) Di . 80 . 131(149) Nil . 113 . 190

report here only the monocomplexation results. Theseare given in formulae (179) and (180) and are to be readas complexation shift Dd � d(cpFe-complex)2d(hydrocarbon). The authors put their emphasis on thecomplexation shifts that occur in the uncoordinated ringand interpret the slight downfield shifts suffered by theprotons at the outer end of the ring as being due to adecrease of electron density in the uncoordinatedaromatic ring when the other ring is coordinated. Thelarger downfield shifts of the internal proton (or thecorresponding methyl protons) of the uncoordinatedring were explained by an additional deshielding effectdue to the reduced ring current in the coordinated ring.

13C complexation shifts were studied by Mori andcoworkers for tricarbonyl(h6-[2.2]cyclophane)chro-mium [136] and (h6-[2.2]cyclophane)(cyclopentadie-nyl)iron(II) hexafluorophosphate [137]. Here[2.2]cyclophane stands for [2.2]meta- and for[2.2]paracyclophane. These authors compared thecomplexation shifts Dd � d (phane complex)2d (phane hydrocarbon) with the complexation shiftsof model compounds such asDd � d (m-xylenecomplex)2 d(m-xylene). Examples for chromiumcomplexation shifts are shown in (181)–(184),where the signs are reversed with respect to the origi-nal literature. The differencesDDd between phane


Y

X

X

X

SS

CH2 CHN

CH

Y

(171)(172)(173)

anti

antisyn

confor-mation

(174)

Me2Si

Me2Si

SiMe2

SiMe2

(175)

Me2Si

Me2Si

SiMe2

(176)

Me2Si

Me2Si

(177)

Me2Si

SiMe2

(178)

Me2Si SiMe2

(149)

6.43 6.145.71

5.34

5.38 5.974.87

4.27

(179) (180)

Me

Me

(C5H5)Fe (C5H5)Fe

-0.68

-0.94

+0.19

+0.17

-1.13

+0.59

-0.25

-0.89

+0.10

+0.47-0.01

+0.17

complexation shifts and model compound complexa-tion shifts, cf. (1810) and (1830), were correlated withphane ring deformations which, in turn, werepresumed to reflect the variations in the metal–ligandcarbon distances. Carbon atoms bent towards theoutside of the phane skeleton thus have negativeDDd values (i.e. stronger, more negative complexa-tion shifts), those bent inwards have positiveDDdvalues. Unfortunately, actual geometrical data wereavailable only for the paracyclophane complexes.The authors’ conclusion was thatDDd is likely tobe related to orbital interaction between chromium(iron) and carbon and that this interaction should bedependent on the Cr(Fe)···C distance and the orienta-tion of the 2pz orbital axis with respect to the Cr(Fe)atom.13C data of the Mo(CO)3-complex of [2.2]meta-cyclophane (185a) are described in Ref. [73], those ofthe ruthenium sandwich complex (185b) in Ref. [74].Schulz et al. [138] interpreted the13C complexationshifts of (186) along the same lines as Mori [136].

1H and 13C NMR data were reported [139] for themethylated [2.2]metacyclophan-1-enes (187) and(188) and for their mono-Fe1(C5H5) complexes(187-Fe) and (188-Fe), their mono-Cr(CO)3complexes (187-Cr) and (188-Cr), and their bis-Cr(CO)3 complexes (187-Cr2) and (188-Cr2). Thechemical shifts of the bridge hydrogens werediscussed in terms of the reduction of the ring currentof the adjacent ring by the complexation, of the ringcurrent of the opposite ring, and of the magnetic aniso-tropy of the Cr(CO)3 group of the adjacent ring. Insome cases these effects cancel each other so that nonet effect is observed upon bis-complexation.

The chemical shifts of the protons bound to thenonmetal-coordinated carbon atoms in bis([2.2]meta-cyclophane)chromium(0) (189) were used to study thespatial dependence of the coordination shiftDd �d(complex)2 d (free ligand) [140]. A positive valueabove the plane of the complexed metacyclophanerings (H-4,10.76 ppm) and negative values at their


(183)

Cr(CO)3

−41.5−36.2

−31.6

−23.4

(183’)

Cr(CO)3

−7.2−5.4

+2.5 +1.5

Cr(CO)3

−32.6

−25.8

(OC)3Cr

−34.3

−24.9−34.1

−30.8

(184)

(182)

(OC)3Cr

(181)

−38.7−16.6

(OC)3Cr

(181’)

−6.1+9.2

∆δ values ∆δ values

∆δ values∆δ values ∆∆δ values

∆∆δ values

(185a)

M

Mo(CO)3

(185b) (C6H6)Ru2+ 2BF4−

M

(186)

Cr(CO)3

Cr(CO)3

CO2Et

EtO2C

side (hydrogens at C-1: equatorial,20.61 ppm; axial,20.26 ppm) are in accord with the notion of ringcurrent reduction by complexation. A comparison ofthe shift differenced (H-7) 2 d(H-4) in the free ligand(2.85 ppm) and in the complex (2.05 ppm) led to thequalitative estimate that the ring current of thecomplexed metacyclophane rings is reduced byabout 25%. The combined effects ofh6-arene coordi-nation and shielding by the ring current of the outermetacyclophane ring resulted in the unusual chemicalshift of d � 1:98 for the arene(!) proton H-12. Further

points on the map that correlatesDd values with thepolar coordinates (r, r ) of protons (with respect to thecentre of the coordinated arene ring) were defined bythe 1H NMR spectrum of bis(h6-[2.2.2]paracyclopha-ne)chromium(0) (190) [141].

In metacyclophane (191), in which one ring is acis-1,4-cyclohexanediyl moiety, the most upfield shiftobserved isd � 0:25 [142]. The authors attributedthis to the bridging protons being “far away fromthe benzene ring current cone”. The same authorsalso reported [2.2]metacyclophanes in which one of


L1

L2

L1

L2

(187) L1 = L2 = nilL1 = Fe+(C5H5); L2 = nil(187-Fe)L1 = Cr(CO)3; L2 = nil(187-Cr)

(187-Cr2) L1 = L2 = Cr(CO)3

(188)(188-Fe)(188-Cr)(188-Cr2)

(189)

Cr1

7

H12

H4

Cr

(190)

H H

(191)

H

(192)

H

(193)

H

H

them-phenylene rings is replaced bycis- (192) or bytrans-1,3-cyclohexanediyl (193) [143]. Thesecompounds show a number of interesting1H NMRchemical shifts at high field, viz. (192) at d �21:62; 20.65, and20.24 (1 H each) and (193) atd �21:68 and 10.24 (1 H each). Unfortunately, noattempts were made to assign the spectra.

3.2. [2.2]Paracyclophanes

This section will first treat [2.2]paracyclophanessubstituted at the aromatic rings, approximately inthe order of increasing number of substituents, thenbridge-modified derivatives, and finally anions,cations, metal complexes and partly saturated[2.2]paracyclophanes.

Inspection of molecular models of [2.2]paracyclo-phane (194) may give the impression that the mole-cule is rather rigid. From the13C-satellites in the1H

NMR spectrum the vicinal H,H coupling constantswere determined [144] to be3J�H;H�cis � 10:6 Hzand 3J�H;H�trans� 4:1 Hz: These values could bedue to a fixed eclipsed conformation ofD2h symmetrywith torsional angles u [C(sp2)–C(sp3)–C(sp3)–C(sp2)] of 08 or to an equilibrium between two confor-mations ofD2 symmetry which are twisted away fromthe eclipsed form by torsional angles of1a8 and2a8;respectively. When a substituent X is introduced at anaromatic position, the3J(H,H)cis values in theortho-bridge remain rather constant, but the3J(H,H)trans

values change, one value increasing (up to 7.2 Hzfor X � NO2) and one value decreasing (down to1.5 Hz for X� NO2) [145]. This behaviour cannotbe explained by a simple change of the torsionalangle of a single conformer because in this case one3J(H, H)cis coupling should increase and the other oneshould decrease. Instead, the behaviour can beexplained by a shift of the equilibrium so as to favour


X1

(194) HCNNOBr(197)

(196)(195)

(198)

(199)(200) NO2

CHO

CH3

XX

3

48

9

12

15

CH2DCHD2

CD3(203)(202)(201)

(204)

CHD2

1s2a2s1a

NO2NO2

2s2a

1a1s

4

2s2a

1s

1a2a 2s

1a

1s

ΘΘRR

(200A) (200B)

A B

one of the skew conformers over the other, yet bothconformers still equilibrating rapidly, as shown for(200A)/(200B). This averages thecis-couplingsJ(1a,2a) and J(1s,2s) (1 and 2 indicate the numberof the carbon atom to which a proton is bound;aands indicate itsanti or synrelationship with respectto the substituent at C-4) over the torsional angles1aand2a , so their averages are more or less indepen-dent of the conformer populations because theKarplus function is symmetrical with respect to 08.The trans-couplings behave differently. They areaveraged over the torsional angles 1208 1 a and1208 2 a: Hence, if one conformer is preferred overthe other, e.g. populationp(200B) . p(200A),J(1a,2s) will decrease relative to its value in [2.2]para-cyclophane because3J(H,H) decreases fromu � 1208towardsu � 908 and J(1s,2a) will increase because3J(H,H) increases fromu � 1208 towards highervalues. This is indeed what is observed: the biggerthe substituent, the largerJ(1s,2a) and the smallerJ(1a,2s) (Table 9), i.e. the more strongly conformerB is preferred over conformerA. Molecularmechanics computations indicate that the main reasonfor the increased preference ofB with increasing sizeof the substituent is the unfavourable interaction inAof the substituent at C-4 with H-2s, which liesapproximately in the plane of the aromatic ring. The13C-NMR spectra of (195)–(200) have also beencompletely assigned [145].

4-Methyl[2.2]paracyclophane, mono- through tri-deuteriated in the methyl group [(201)–(203)], wasthe first example for which a through-space deuteriumisotope effect upon13C chemical shifts could bedemonstrated [146]. The chemical shift of C-15, thecarbon atom pseudo-geminal with respect to theCHnD32n group, is increased by 12 ppb (0.012 ppm)per deuteron in the methyl group. This is particularly

interesting as deuterium isotope effects are usuallyexpected to be shielding and not deshielding. A possi-ble influence of the deuteration upon an existingconformational equilibrium in 4-methyl[2.2]paracy-clophane could be ruled out by studying the CHD2

derivative (204) of the rigid [24](1,2,4,5)cyclophanewhich showed an even slightly larger isotope effect of130 ppb on the chemical shift of the pseudo-geminalcarbon, i.e.115 ppb per deuteron.

As monosubstituted [2.2]paracyclophanes arechiral, molecules containing two [2.2]paracyclopha-nyl moieties bound, for example, to a common atomZ can exist as ameso-diastereomer (R-pc)-Z-(S-pc)with heterochiral paracyclophanyl (pc) groups or asa pair of chiral enantiomers in which the para-cyclophanyl groups are homochiral, (R-pc)-Z-(R-pc)and (S-pc)-Z-(S-pc). Bis([2.2]paracyclophan-4-yl)methane (205), Z� CH2, and the analogues withZ� C�O (206), SiMe2 (207), S (208) and P(O)(OMe)(209) were investigated by Ernst and Wittkowski[147], mainly with the aim of determining the differ-ences in chemical shifts between the diastereomers.Generally rather small shift differences were found�DdH # 0:3 ppm; DdC # 1:0 ppm�; with somewhatlarger ones only for some protons in the ketones(206). These were interpreted as due to the differentpreferred orientations in the diastereomers of theseprotons with respect to the magnetically anisotropiccarbonyl group. When suitable ligands (H or Me) arebound to the central atom, the chiral diastereomerscan easily be distinguished from themeso-isomersbecause the former have a twofold axis of symmetryrendering the ligands chemically equivalent (singleline absorptions for the protons of the central CH2

group in (205), dH � 3:58; and for the methyl protonsand carbons in (207), dH � 0:79; dC � 1:09). In themeso-isomers these ligands lie in a plane of symmetrywhich does not render them equivalent, hencemeso-(205) gives an AX system (dH � 3:85 and 3.27;J � 15:9 Hz) for its central methylene group andmeso-(207) gives two 1H lines (dH � 0:79 and 0.57)and two13C signals (dC � 1:86 and 0.56) for its SiMe2group. Compound (209) is interesting because itpossesses a pseudoasymmetric phosphorus atom.There are twomeso-diastereomers withr- ands-config-urations, respectively, of the phosphorus centre eachgiving a set of 1613C signals for the paracyclophanylgroups which are enantiomorphic. By way of contrast,


Table 9Vicinal H,H coupling constantsJ(H,H) [Hz] in the ortho-bridge ofmonosubstituted [2.2]paracyclophanes [145]

Compound (194) (195) (196) (197) (198) (199) (200)Substituent H CN NO Br CH3 CHO NO2

J(1a,2a) 10.6 10.7 10.5 10.7 10.7 10.3 10.1J(1a,2s) 4.1 2.9 2.6 2.2 2.1 1.8 1.5J(1s,2a) 4.1 4.5 5.4 6.0 6.2 6.8 7.2J(1s,2s) 10.6 10.5 10.6 10.3 10.2 10.3 9.9

the homomorphic paracyclophanyl groups in thechiral diastereomer of (209) are diastereotopic andthus give rise to 32 paracyclophanyl13C signalswith shift differences of up to 1.85 ppm (for C-4)between corresponding carbon nuclei in the twoligands. Rozenberg et al. described diastereomeric(chiral andmeso) b-diketones containing two paracy-clophanyl groups [148]. These are present as theenolic chelates (210). The differences between the1H NMR chemical shifts of the diastereomers arerather small (uDdu � 0:05; 0.03, and 0.02 for OH, H-5, and H-17, respectively) because of the large separa-tion of the chiral subunits.

Reich and Yelm [149] prepared the diastereomericparacyclophanyl tolyl sulfoxides (211) and (212) andestablished their configurations chemically. Thisallowed them to determine the preferred conforma-tions of the sulfoxide groups from the chemical shiftsof their surrounding protons, i.e. theortho (H-5) andpseudo-gem(H-15) protons and thesynproton (H-2s)at theortho bridge. It was assumed that proximity ofthe sulfoxide oxygen caused deshielding. As indicatedby a deshielded H-5 in (211) and a deshielded H-2s in(212), the sulfoxide oxygen is pointing towards thesehydrogens and, consequently, the sulfur lone pair ofelectrons towards the second cyclophane ring. This is


ZS

S

Z

S

R

chiral meso

Z

CH2

C=OSiMe2

S(208)(207)(206)(205)

PS

S

P

S

R

chiral meso-1

S

R

meso-2

O

OMe

OMe

OP

O

OMe

(209)

4

4

4’

O

O

H

517

(210)

reasonable in view of the small steric requirement ofthe lone pair. Assuming analogous conformations forthe related selenium compounds (213) and (214), theirrelative configurations were suggested to be thoseshown in the formulae.

H,H-NOESY was used to determine the configura-tions of the asymmetric centres in diastereomers(215a) and (215b) with known (R)-configuration ofthe [2.2]paracyclophanyl moiety [150]. SignificantNOEs found in the major but not in the minor diaster-eomer are those between Ha and one of thei-Prmethyl groups and between Hb and 2-Hs. By contrast,the minor diastereomer shows NOEs from the hydro-xyl proton to H-15 and H-16, from Ha to the syn-protons 1-Hs and 2-Hs of the adjacent bridge andalso from Ha to H-15. If one supposes that the bulkyethyl group tends to avoid the opposite paracyclo-phane ring (as AM1 computations indicate), then theNOE results lead to the configurations shown in theformulae, i.e. (R,R) for the major (215a) and (R,S) forthe minor diastereomer (215b). Some regularities

were found for the relative1H chemical shifts of thediastereomers of (215) and (216). Protons 15 and 16are deshielded by< 0.4 ppm and 2-Hs by < 0.7 ppmin the (R,S)- relative to the (R,R)-isomers. In the (R,S)-isomers where intramolecular hydrogen bondingis facile, the hydroxyl proton is deshielded(d � 5:0–4:5 in C6D6) and spin-coupled to Ha

(J � 6:2 Hz) whereas it has a broad singlet atd <1:6 in the (R,R)-isomers.

Ernst [151] has detailed a procedure for determin-ing the configurations of the isomeric [2.2]paracyclo-phanes with two identical substituents, one at eachring, taking the dimethyl [2.2]paracyclophane-ar,ar 0-dicarboxylates (217)–(220) as the example.The symmetries of the bridge-proton spin systemsput the isomers into two groups. In the pseudo-gem(217) and pseudo-meta(219) isomers the two bridgesare different, furnishing an AA0XX 0 spectrum for thebridge flanked by two substituents and a YY0ZZ 0

spectrum for the bridge distant from the substituents.So there are two different spin systems with two


OS

Tol

••HH

H

H

6.97

3.50

7.12

(211)

OSe

Me

••HH

(213)O

SeMe

••HH4.08

(214)

< 3.6

2.40

2.69

OS

Tol

••HH

H

H

6.80

3.85

6.58

(212)

OH

H

Et

OR

R

(215), R = iPr

12

Hs

Hα

CH

O

H

Hβ

H3C

Hs45

H

16 15

H

OH

H3C CH3

(215a), major, (R,R)

12

Hs

Hα Hs45

H

16 15

H

OH

H3C CH3

(215b), minor, (R,S)

Et

O

H

(216), R = Me

chemical shifts each. In the pseudo-ortho (218) andpseudo-para (220) isomers the two bridges are inequivalent environments but the four protons of abridge are chemically nonequivalent giving oneAXYZ spectrum. These two possible situations canbe clearly distinguished in an H,H-COSY spectrum.The spacings of the intenseN lines �� uJ�AX �1J�AX 0�u� in the AA0XX 0 coupling patterns of thepseudo-gemand the pseudo-metaisomers are charac-teristically different. In the former, the spacing corre-sponds to the sum of2J (ca. 213 Hz) and3Jtrans (ca.4 Hz) and in the latter to2J (ca.213 Hz)1 3Jcis (ca.10.5 Hz);J values from Ref. [145]. Hence,N values of9 and 2.5 Hz are expected for (217) and (219), respec-

tively, the experimental findings being 8.8 and 3.0 Hz.The distinction between (218) and (220) is somewhatmore elaborate. It can either be achieved by irradiat-ing the resonance of H-5 (d,J < 2 Hz) in (220) andobserving a NOE at the signal of H-16 (d,J < 8 Hz)or the bridge AXYZ spectrum must be analysed first(A and Z being the protons at C-2,syn and anti,respectively, relative to the substituent at C-4) andthe spatial relationship between protons X, Y andthose (or their connected carbon nuclei) of the secondbenzene ring must be determined by a long-rangeH,H-COSY or a C,H-COLOC or -HMBC experiment.The procedure is based on the larger H,H coupling ofan aromatic proton with thesyn-benzylic proton of its


RR

X’ A’

Z’ Y’YZ

X A

1

2

5

8

15

R

Y X

Z AXY

Z A

R

R

A’ X’

Y’ Z’YZ

X A

RR

Y X

A Z YX

Z A

R

(217) (218)

(220)(219)

R = CO2CH3

R

(221)

910

12

R2

(222a)

R1

NO2 CO2MeCO2HCO2HNH2

NO2(222b)(222c)

R2

(223a)

R1

(223b)(223c)

R1 R2pseudo-geminal pseudo-ortho

pseudo-geminal pseudo-ortho

pseudo-meta pseudo-para

516

ortho-bridge than with theanti-proton and on thelarger transoid C,H-coupling of an aromatic carbonatom with theanti-benzylic proton at theortho-bridgethan the cisoid coupling with thesyn-proton; see ref.[151] for details. Much earlier, Reich and Cram [152]have distinguishedar,ar 0-disubstituted isomers of[2.2]paracyclophanes, e.g. the dibromo derivatives,by comparing the experimental chemical shifts andthose predicted by assuming additivity of the substi-tuent effects determined from the monosubstitutedderivative. This procedure requires, however, thatthe monosubstituted derivative is available, that itsNMR spectrum of the aromatic protons can beanalysed and that the transannular substituent effectson the chemical shifts (SCS) are sufficiently different(normally: pseudo-gem-SCSq other SCS). This isthe case in the bromo derivative (197) [152] but notin the methyl ester (221) [151].

Pelter and coworkers [153] also derived substituenteffects (CO2Me, CO2H, NO2, NH2) upon the 1Hchemical shifts of [2.2]paracyclophane. Assumingadditivity of the effects, they used them to elucidatethe stereochemistry of the pseudo-geminal andpseudo-ortho disubstituted derivatives (222) and(223), respectively. Some of the substituent effectswere corrected later [154].

In a paper on the synthesis of mono- anddiaryl[2.2]paracyclophanes [155], the1H NMR dataof 4-mesityl[2.2]paracyclophane (224) and two dime-sityl[2.2]paracyclophanes were reported. Rotation ofthe mesityl rings is restricted at room temperature,leading to a spectrum with three different methylsignals [d � 2:82; 2.36, and 1.80 for (224)] and twosignals for the aromatic protons (d � 7:08 and 6.68).Unfortunately, no attempts were made to specificallyassign these chemical shifts although it is clear thatthe middle methyl shift must belong to thepara-methyl group. At the same time, Kus´ [156] alsodescribed a number of aryl-[2.2]paracyclophanes,among them (225) and (226). Examination of CPKmolecular models suggests that the preferred torsionalangle between the aryl and its connected cyclophanering, defined by the asterisks in formula (225), shouldbe of the order of 40–508. Then theexo-methyl group(a) of (224) and (225) resides in the shielding zone ofthe cyclophane system as shown by the upfield shiftsin (224) and (225) of d � 1:80 and 1.82, respectively.The endo-methyl group (b) resides at the side of the

paracyclophane unit. This area is the deshielding zoneand theendo-methyl protons are shifted tod � 2:82and 2.84 in (224) and (225), respectively. As themethyl group of 2-methylnaphth-1-yl derivative(226) has a shift�d � 1:99� similar to theexo-methylgroups of the xylyl and mesityl compounds, it ispresumably also orientedexo and, hence, thehydrogen in position 8 of the naphthalene moietyshould be deshielded beyond the shift of H-8 in 1-phenylnaphthalene (d � 7:9 [157]). Kusreported theshift of a single aromatic proton of (226) to be d �8:86; while all the others are in the ranged �7:82–6:37; and he attributed the single low-field reso-nance to an unspecified cyclophane proton. However,for the reason given above, this signal should beassigned to H-8 of the naphthyl group and it is notconceivable that one of the cyclophane protons shouldbe deshielded so strongly.

In a study directed toward the synthesis ofortho-dialkylated [2.2]paracyclophanes [158], compound(227) was obtained and its1H and 13C NMR spectrawere fully assigned by the use of 2D H,H-COSY,C,H-HETCOR, and C,H-COLOC techniques. Theconfiguration at C-1 was determined from a phase-sensitive NOESY spectrum in which a strong cross-peak between the chemical shifts of H-1 and H-15 wasobserved.

NMR data of sulfonated [2.2]paracyclophanes werereported by van Lindert et al. [159], viz. the1H chemi-cal shifts of the 4-sulfonic acid (228), of the pseudo-geminal (4,15), pseudo-ortho (4,16), pseudo-meta(4,13), and pseudo-para (4,12) disulfonic acids(229) and disulfonates (230), and the pseudo-geminaldisulfonic anhydride (231). For the latter compound,the pseudo-geminaldisulfonates (230), and the mono-sulfonic acid (228), the 13C chemical shifts andassignments are also given and theJ(H,H) couplingconstants in the bridges are tabulated for the pseudo-geminal isomer of (230) and for (231). 1H and 13Cchemical shifts were also assigned in theN-substi-tuted disulfonimides (232) with alkyl, cycloalkyl,allyl, benzyl and aryl substituents [160]. Rotation ofthe phenyl ring about the C–N bond in theN-phenylderivative is restricted at room temperature whichleads to different chemical shifts of theortho-protons(d � 8:50 and 7.94 at1508C). From signal coales-cence at 1808C, DG‡ was determined to be71 kJ mol21. The N-cyclohexyl derivative shows


slow rotation below 08C when the AA0XX 0 spectrumof the ethano bridge next to the disulfonimide bridgeturns into an ABCD spectrum. The preferred confor-mation of the cyclohexyl system was assumed to havethe cyclohexane “plane” parallel to the planes of thebenzene rings in the paracyclophane moiety.

[2.2](1,4)Phenanthrenoparacyclophane (233) wasthe first unsymmetrical [2.2]paracyclophane deriva-tive for which the spin systems of both CH2CH2

bridges were completely analysed [161]. This wasfacilitated by the wide spread of the chemical shifts�dH � 4:32–2:77� of the bridge protons. The chemicalshifts of the aromatic protons are also distributed overa wide range�dH � 8:51–5:24� which is due to thedifferent orientations of these protons with respect tothe ring currents of the phenanthrene and benzenesystems. A rough correlation was demonstrated

between the1H chemical shift differences of (233)and [2.2]paracyclophane (194) and the ring currenteffects predicted by the Johnson–Bovey model [79]for annelating the outer two phenanthrene rings to(194). Possible reasons for the less-than-perfect corre-lation were discussed. NOE difference and 2D H,H-COSY experiments helped in the complete assign-ment of the1H NMR spectrum of (233) and the13Cspectrum was also fully assigned by the use of 2Done-bond and long-range C,H-correlation spectra.An unexpected feature in the1H spectrum is anH,H-coupling of 0.6 Hz between the bay proton ofthe outer phenanthrene ring and thesyn-proton ofthe bay methylene group at the bridged phenanthrenering. These protons are fixed at a very small nonbond-ing distance, and a through-space mechanism for thiscoupling was assumed.


H3C(a)

H3C(a)

H3C(b)

H

R

(225), R = H(226)

*** *

15

O

H CH3

1

(227)

(228)

SO3H R

(229), R = SO3H(230), R = SO3

−K+

4

12

13

16

15

R

(231)

S

S

O

O2

O2

(232), R = alky, aryl

S

S

NR

O2

O2

(233)

HH

H

HHHH

H

8.51

7.53

7.52

7.86

7.70

7.63

3.833.02

3.19 2.98

6.75

6.93

5.24

5.866.53

6.51

2.91 2.77

3.37 4.32

(224), R = CH3

The structures of the first threear,ar,ar 0-tribro-mo[2.2]paracyclophanes (234)–(236) [162] werederived from theJ(H,H) values in the dibrominatedring and the substituent effects of the bromine atomsupon the chemical shifts of their pseudo-geminalprotons. The assignments were confirmed by theobservation of interring H,H-NOEs.

Filler et al. [163], in a discussion of the1H and 19FNMR spectra of 4,5,7,8-tetrafluoro[2.2]paracyclophane(237), withdrew their earlier suggestion [164] that thequintet splitting with an apparent coupling constant of0.8 Hz, observed for the aromatic proton signal atd �6:84; is caused by transannular through-space19F,1H

spin–spin coupling. Instead, they reported that irradia-tion of the CH2 resonance atd � 3:07 caused thearomatic proton signal to collapse to a singlet. Thissuggests that the observed coupling is a benzylic one,viz. an average of the coupling of one aromatic protonwith two ortho-benzylic and two meta-benzylicprotons, one arrangedsyn, the other anti in eachgroup. In the authors’ opinion, however, the nature ofthe interaction is unclear. On the other hand, theauthors’ original interpretation of the quintet splittingwould have been very reasonable because through-space coupling between fluorine and the pseudo-geminal proton in 4-fluoro[2.2]paracyclophane


Br

BrBr

Br

Br

Br

Br

Br

Br

(235)(234) (236)

(237)

F

F F

F

3.07

6.84

2.98

(238a)

OMe

R

Cl

MeO Cl

OMe

MeO

R

(238b)

OMe

R

Cl

OMeCl

MeO

MeO

R

HHHH H H

HHHH H H

H H

H H

R = (CH2)4C6H4(2-CO2Me)

trans

syn

syn

(E)-(239)

1

2

17 CO2CH3

H

(Z)-(239)

1

2

17 H

H3COCO

amounts to 3.1 Hz [165], so the splitting caused by fourchemically equivalent but magnetically nonequivalentfluorines, of which three have a zero coupling constantwould be expected to be a quintet with a spacing of�3:1 1 0 1 0 1 0�=4 < 0:8 Hz as found experimen-tally. A clarification of this matter seems desirable.Section 3.9 treats compounds in which through-space19F,19F spin–spin coupling has been observed, e.g. anar,ar 0-difluoro[2.2] paracyclophane.

Fischer et al. [166] described the structural elucida-tion of a fully ring-substituted synthetic [2.2]paracy-clophane derivative. The possible isomeric structureswere (238a) and (238b) and only one isomer ispresent. The correct structure was proved by relatingeach methoxy group, through H,H-NOE and C,H-HMBC correlations, with thesynproton of its neigh-bouring bridge CH2 group. These twosyn protonswere shown to have atransorientation. This followedfrom their mutual coupling constant of 6.5 Hz, whichwas extracted from a phase-sensitive H,H-COSY spec-trum. Consequently, the methoxy groups of the differentrings are pseudo-metato one another as in (238b).

Due to the particular geometry of the semicyclicdouble bond in the isomers (239), these compoundsmay be regarded as “perpendicular styrene” deriva-tives [167]. Their configurations follow from the large(6%) NOE observed at H-17 of the (Z)-isomer whenthe resonance of H-2 was saturated. The correspond-ing enhancement in the (E)-isomer is only 1%. Char-acteristic 13C and 1H chemical shift differences arepresent between the isomers (Table 10). The upfieldshift of the ester protons in (Z)-(239) was attributed tothe possibility of its location in the shielding region ofthe upper aromatic ring.

1H and 19F NMR spectra of ring-monosubstituted1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophanes(OFPs) (240) were described by Roche and Dolbier[168]. The parent OFP (240, R� H) hasdH � 7:30

anddF � 2118:0: Substitution of an aromatic protondestroys all symmetry and renders the eight fluorinesand the seven remaining protons chemically nonequi-valent. Derivatives with the following substituents Rwere studied: NO2, NH2, NHOH, NHAc, NHCOCF3,OH, Cl, Br, I, Ph, and CF3. All fluorine nuclei aregenerally shifted downfield by the substitution but ina rather unsystematic manner. The overall shift rangeis approximatelydF � 2100 to2120 but the assign-ments of most of the19F shifts to specific fluorines arestill due. The19F spectra are governed by the large2J(F,F) values of ca. 240 Hz. As the3J(F,F) are rathersmall, a typical19F spectrum of a monosubstitutedOFP contains four AB-type absorptions. The influ-ences of the substituents on the1H chemical shiftsare not equal but similar to the effects known fromthe corresponding derivatives of [2.2]paracyclophane(194) [145,152]. The trifluoromethyl derivative (240,R� CF3) is of interest because the CF3 group causesthrough-space coupling (quartet splittings) at one ofthe bridge fluorines (assigned as F-2syn) with 29.1 Hzand at a second one (assigned as F-1syn) with 12.1 Hz.Further work by the same authors [169] treatsheteroannularly disubstituted OFPs (241) (i.e. onesubstituent per ring), mainly with equal substituents.

(240)

FsynFF

FFFF

F

R12

(241)

FFF

FFFF

F

R

R

(242)

SiMe2

SiMe2

Me2Si

Me2Si

The pseudo-ortho, pseudo-meta, and pseudo-paraisomers were available of (241) with R� NO2, NH2,


Table 10Some NMR spectroscopic parameters of the isomers of (239)

Isomer (E)-(239) (Z)-(239)

d(C-2) 42.29 45.95d(H-2) 4.33 3.89d(H-17) 6.17 6.10d(OCH3) 3.83 3.64NOE (H-2! H-17) 1% 6%

Br, I, and CF3, also thepara isomers with R� Br andCF3. As an NH2 substituent causes the largest spreadin the 1H chemical shifts of OFP, the NH2-SCS valuesderived [168] could be used to confirm the stereo-chemistry of the isomers of (241, R� NH2) fromtheir 1H NMR spectra. In analogy to (240,R� CF3), the fluorines in the bridgesortho to CF3

in the four isomers of (241, R� CF3) mentionedabove were assigned from the through-space couplingof CF3 with the proximate bridge fluorines and fromthe geminal relationship of each of the latter with oneof the remaining fluorine nuclei. The informationobtained from these isomers and from theorthobridgein the monosubstituted compound together with theassumption of SCS additivity allowed the backwardcalculation of the missing SCS values of CF3 upon the19F chemical shifts in OFP.

1’2’ 3’

(243)

4−

(245), ∆δC values

2−

−22.3

−1.6 −6.4 +5.0

−14.8−0.3−45.6

−17.6−21.7

+2.0−11.6

−7.3

(244), ∆δC values

−22.9

−1.4 −7.7+5.6

−15.2−0.3−48.2

−13.8

+0.3 −7.6

−6.4

−22.3

Sakurai and coworkers [170] reported1H, 13C, and29Si chemical shifts for a tetrasila analogue of[2.2]paracyclophane, viz. octamethyl-1,2,9,10-tetrasi-

la[2.2]paracyclophane (242). The aromatic protons ofthis compound�d � 6:75� are not as strongly shieldedas those of [2.2]paracyclophane�d � 6:48�: It wouldseem logical to attribute this effect mainly to thelarger interring distances, which are a consequenceof the longer Si–Si and Si–C relative to C–Cbonds. However, the electronic effects of the siliconcontaining groups upon the chemical shifts of thearomatic protons must not be neglected either.

Tetrastyryl[2.2]paracyclophane (243) was reducedwith Li, Na, and K metals and shown to be convertedinto its tetraanion from the sum of the induced13Cchemical shift changes,SDd < 2560 ppm �Dd �danion 2 dparent�; i.e. ca. 2140 ppm per electron[171]. The 1H and 13C NMR spectra were fullyassigned by 2D methods. Nonequivalence of theorthoand of themetapositions of the terminal phenylrings and a small3J(H,H) value of 12.3 Hz for thedouble bond point to substantial charge delocaliza-tion, causing bond order decrease and increase ofC20–C30 and C10–C20, respectively. TheDdC valuesgiven with formula (244) are averages for the Li1,Na1, and K1 salts and indicate that the charge isdistributed over the entire molecule with the highestcharge densities on C-20 and at thepara and orthopositions of the phenyl groups. Dianion (245), in theform of its Li1 salt, was used as a referencecompound. Its NMR properties are very similar tothose of (244), yet the charge densities on the centralring are slightly higher at the expense of the doublebonds and phenyl rings. This difference was attributedto through-space interaction of the electrons in thecyclophane system of (244) which causes the chargesto shift to the periphery of the molecule.

Treatment of [2.2]paracyclophane (194) withFSO3H/SO2ClF at 2808C gives the monoareniumion (246) [172]. Protonation occurs only at theipsocarbon atom. This releases bond angle strain andcontrasts with methylsubstituted benzenes that areprotonated at unsubstituted positions. The hydrogensin the protonated ring are more highly shielded thanthe hydrogens of analogous methylbenzenium ionsand the hydrogens of the nonprotonated ring aredeshielded relative to the parent hydrocarbon (194).Possible reasons are charge transfer and alterations inthe magnetic anisotropies of the ring systems. When(194) was treated with FSO3H/SbF5 in SO2ClF at21008C, diarenium ion (247) was formed. The


structure was assumed to be the 3,11-diprotonatedcompound because molecular models showed this tobe much less strained than the 3,14-isomer. The latterwas, however, not excluded experimentally. The 4-methyl and 4,5,12,13-tetramethyl derivatives of(246) and (247) were also investigated and shown topossess analogous structures. In the monomethyl deri-vative, protonation of the substituted ring occurs at thebridgehead carbon next to the methyl group. In the13Cspectrum of (246), studied by Laali and Filler [173],ipso-protonation led to large deshielding effects at thecarbon atomsortho (145 ppm) andpara (158 ppm)to the protonation site. Themetacarbon (110 ppm) ofthe protonated and the bridgehead carbon atoms (ca.7–8 ppm) of the nonprotonated ring are also signifi-cantly shifted, see formula (2460). 4,5,7,8-Tetrafluor-o[2.2]paracyclophane (237) could only be convertedto the monoarenium ion (248). It is protonated atthe nonfluorinated phenylene ring. The effects ofprotonation upon the13C shifts of the nonfluorinatedring (o, 152; m, 19; p, 161 ppm) are of the sameorder as in (246), but those upon the1H shifts (o,10.9; m, 10.2 ppm) are much smaller than in (246),where they amount to11.8 ppm (o) and 11.1 ppm(m) [172]. The smaller effects in (248) were tenta-tively ascribed to transannular interaction (electron

donation) from the fluorinated to the cationicnonfluorinated aromatic ring. The19F nuclei (assign-ment uncertain) in (248) are deshielded by only 1 and3 ppm relative to (237).

The site(s) of complexation in various tricarbonyl-chromium complexes of 4-aryl[2.2]paracyclophaneswere determined from the typical upfield shifts by1.5–2.0 ppm of the protons of the coordinated ring[174]. It was found that in substrates (249), whichhave three potential complexation sites, monocom-plexation takes place preferentially at the unsubsti-tuted paracyclophane ring and dicomplexation ateach of the two paracyclophane rings. Othersubstrates for complexation investigated are thepseudo-meta-(250) and the pseudo-para-diaryl[2.2]-paracyclophanes (251).

13C complexation shifts in tricarbonylchromiumand (cyclopentadienyl)iron(ii) complexes of [2.2]paracyclophane as studied by Mori et al. [136,137]are included in the section on [2.2]metacyclophanes,see Section 3.1.13C data of a Mo(CO)3-complex of[2.2]paracyclophane are described in Ref. [73], thoseof [(h6-C6H6)Ru(h6-[2.2]paracyclophane)]21 2 BF2

4

in Ref. [74]. De Meijere and coworkers reported1Hand 13C complexation shifts in tricarbonylchromiumcomplexes of [2.2]paracyclophane-1,9-diene (252) and


H

34+

H

34

11

14

+

H

+

(246) (247)

4.943.22

3.47

8.07

9.32

4.072.88

3.48

7.19

6.86

8.22

7.59

≈3.63

≈3.63

1213

H

+

(248)

3.45

7.777.05

F F

F

F

(237)

6.84

F F

F

F

129.6 139.1

118.8

146.4

−138.1

δH, δC, and δF values

138.9

181.6 58.7

200.0122.1*

118.7*

146.9

−137.1**

−135.2**

H

+

(246’)

132.4**

133.3**

178.3

142.9

197.4

55.5

146.3*

147.1*

δC values

δH values

two of its derivatives [175]. In the complexed rings of(253)–(255), the protons are shieldedbybetween21.76and21.71 ppm and the carbon nuclei by ca.239 ppm(tertiary) and 219 to 217 ppm (quaternary). The

electron withdrawing effect of the Cr(CO)3 group isapparent from the deshielding effects upon the1H and13C chemical shifts of the uncomplexed rings. Thesemeasure10.30…1 0.34 ppm and10.2…1 1.9 ppm,


(OC)3Cr

(253), X = H;Y = H(252)

X

X

YY

(254), X = OMe;Y = H(255), X = H;Y = SiMe 3

(OC)3Cr

(256)

Cr(CO)3

(257)

Ru2+

Ru2+

(258)

Ru+

Ru+

3

14

103.6

17.6

55.445.987.3110.3

28.3* 27.4*

2.95

4.43 2.41

1.87

2.24

(J = 5.4 Hz)2 e−

H

(259)

H

(260)

H

H

H HH H

(261) (262)

HH H

H

Ar ArAr ArAr

Ar

(249) (250) (251)

Ar = 4-MeC6H4,4-MeOC6H4, or2,4,6-Me3C6H2

Ar = 4-MeOC6H4 or2,4,6-Me3C6H2

Ar = 4-MeC6H4or 4-MeOC6H4

respectively. The complexation shift of the aromaticprotons in the dinuclear complex (256), 21.45 ppm,agrees well with the sum of the effects of a near(21.74 ppm) and a distant (10.32 ppm) Cr(CO)3group. An interesting effect was observed for theone-bond C,H coupling constants in (253). While1J(C,H) in the complexed ring show the usual increase(116.4 Hz) relative to the chromium-free parentcompound, the coupling constant in the uncomplexedring decreases by a considerable 3.1 Hz (from 161.2 to158.1 Hz).

Boekelheide and coworkers [176] investigated thetwo-electron reduction of the bis(hexamethylbenze-neruthenium)[2.2]paracyclophane tetracation (257)to give the dication (258). The product has sym-metrical 1H and 13C NMR spectra which have thecharacteristics of a cyclohexadienyl anion complex.Such a structure requires the presence of a bondbetween C-3 and C-14, which was indeed provedby X-ray diffraction and has the extraordinarylength of 196(3) pm. In the upper and the lowerhalf of formula (258) are given the1H chemicalshifts and the 13C chemical shifts, respectively.The symmetry of the molecule in solution is main-tained even at temperatures as low as2100 to21208C as shown by its unchanged1H and 13CNMR spectra. The paper also describes a numberof compounds analogous to (258). In these thecentral [2.2]paracyclophane unit carried methylgroups or was replaced by [2.2]metacyclophaneor by [2.2.2](1,3,5)cyclophane. These compoundshave properties similar to (258).

Two [2.2]paracyclophanes with acis- (259) and atrans-1,3-cyclohexanediyl unit (260) instead of one ofthep-phenylene rings have been reported [143]. Thesecompounds show a number of interesting1H NMRchemical shifts at high field, viz. (259) at d � 21:82(1 H), 21.05 (1 H), and10.46 (2 H) and (260) atd �10:05 and10.32 (1 H each). Unfortunately, the spec-tra were not assigned.

Perhydrogenation of [2.2]paracyclophane (194)gives the highly symmetrical compound (261) whichshows only two CH2 signals and one CH line in its13CNMR spectrum and, by definition, is no longer acyclophane because it lacks an aromatic system. Ontreatment with trifluoromethanesulfonic acid (261)was quantitatively converted into a new productwhich has a highly misleading13C NMR spectrum,

showing four CH2 and four CH signals of equal inten-sity at room temperature [177]. Below258C,however, eight additional lines appear which all corre-spond to CH2 groups. A 2D C,C EXSY experiment at2258C and a 2D C,C INADEQUATE spectrum takenat 2358C proved the new product to be the mono-endo-stereoisomer (262). It exists in equilibriumbetween two conformers ofC1 symmetry, which inter-convert rapidly at elevated temperatures to give anaveraged structure ofCs symmetry. At room tempera-ture, various coalescences between13C signals of verydifferent chemical shifts (Dn � 355–804 Hz at100.6 MHz) occur, which cause the mentioned lackof signals. The coalescence temperatures could onlybe determined with a rather high degree of uncer-tainty. They led to a conformational activation barrierDG‡ of 54^ 5 kJ mol21. Molecular mechanicscomputations show that (262) indeed possesses alower strain energy than (261), making the isomeriza-tion very plausible.

3.3. [2.2]Metaparacyclophanes

A careful 1H and13C NMR study of [2.2]metapara-cyclophane (263) was carried out by Renault et al.[178]. Techniques used were iterative analysis of the1H NMR spectrum, in particular of the bridge protons,NOE difference experiments to assign the nonequiva-lent methylene protons, 2D C,H-HETCOR experi-ments to assign the signals of the proton-bearingcarbon atoms, and a 2D INADEQUATE experimentfor assigning the quaternary carbon signals. Also, all1J(C,H) coupling constants were reported.

Surprisingly, the 12,13-dimethyl derivative (264)of [2.2]metaparacyclophane was obtained as a singleconformer with asyn arrangement of H-8 and themethyl groups [179]. This is visible from the“normal” 1H chemical shifts of the methyl groups�d � 2:34� which are not under the influence of thering current of them-phenylene ring. On the otherhand, there is substantial shielding of H-8�d �5:03� by the p-phenylene ring and of H-15,16�d �5:68� by them-phenylene ring. The molecule appearsto be rather rigid as its1H NMR spectrum does notchange up to a temperature of11508C. The parentcompound (263) itself has a barrier to flipping of theinner corner of the m-phenylene ring of 84–91 kJ mol21, determined by different authors. The


transition state of them-ring flip has the two aromaticrings approximately at a right angle, whereas theyform an acute angle in the ground state with C-8pointing towards thepara-bridged ring. When twomethyl groups were introduced into thep-phenylenering, in the 12,15- (265) or the 12,16-positions (266),the barrier of (263) is lowered to 76 kJ mol21 at 120–1278C in (265) and to 81 kJ mol21 at11268C in (266)[180]. As the methyl groups should have little, if any,influence on the stability of the transition state, lower-ing of the barrier was ascribed to an increase in energyof the ground states by destabilizing interactions ofthe methyl groups with them-phenylene ring. Surpris-ingly, the barrier is not lowered further in compound(267) carrying four methyl groups at thep-phenylenering. Instead, DG‡(11278C) was found to be82 kJ mol21, about the same value as in (266). Theexplanation offered consisted in an increase of thebending angle of thep-phenylene ring, which lowersthe energy of the transition state, and simultaneousoutward bending of the methyl groups (to reducetheir mutual interactions), which lowers the energyof the ground state. The combination of both effects

could keep the conformational barrier constant withrespect to (266). The conformational behaviour of[2.2]metaparacyclophanes, their annelated deriva-tives, and of the corresponding dithia[3.3]phaneshave been reviewed [181].

Compound (268), a terphenylophane, may also beregarded as a [2.2]metaparacyclophane (263) withbenzoannelation at one of the ethylene bridges[182]. As (263) is conformationally mobile�DG‡ �84 kJ mol21�; it is of interest to see to which extent thebarrier to flipping of them-phenylene ring is affectedby benzoannelation. The bridge protons of (268) showan ABCD spectrum at room temperature whichcoalesces to an AA0BB 0 pattern at 100 108C. Thebarrier to meta-ring flipping was estimated as75.8^ 2.0 kJ mol21, ca. 9 kJ mol21 lower than inthe parent compound. For the monothia homologueof (268), see Section 5.

Wong et al. [183] prepared (269), the didehydroanalogue of (268) and the dibenzo derivative (270).These compounds haveDG‡(2418C)� 44 kJ mol21

and DG‡(1248C)� 57 kJ mol21. Together withBoekelheide’s [2.2]metacyclophanediene (271)


(263)

8

CH3

CH3

H5.03

2.345.6812

(264)

R1

R2R3

R4

(265), R1=R3=Me, R2=R4=H(266), R1=R4=Me, R2=R3=H(267), R1=R2=R3=R4=Me

(268)

(269) (271)(270), R = H

R

R

(272), R = CH3

1

15

[184] this gives a nice series of [2.2]metaparacyclo-phanes in which the nature of the central C–C bondsof the bridges is varied systematically (Table 11). Thelower barrier in (271) relative to (263) has been inter-preted by Boekelheide by the lower energy of thetransition state of (271) due to the wider CCC anglesin the bridges which supposedly outweigh the effect ofthe shorter CyC bonds. As a result there is believed tobe less penetration of the intraannular hydrogen intothep-electron cloud of thep-phenylene ring in (271)than in (263). The relative barrier in (268), i.e. lowerthan in (263) and higher than in (271), is also in linewith this argumentation. However, it was not clearhow the barriers of (270) and (269) relative to thatof (271) could fit into the scheme. In these three mole-cules the bond angles should be similar (near 1208), sothe longer bond lengths (aromatic. double bond)should go along with lower barriers, yet the oppositeis found. On the other hand, Vo¨gtle suggested a lower-ing of the energy of the transition state by conjugationof the unsaturated bridges with them-phenylene ring,see Ref. [4, p.117]. Such an explanation would agreewith the experimental findings. In their full paper onthe subject, Wong et al. [185] extended the series ofbenzoannelated [2.2]metaparacyclophanes by includ-ing the dimethyl derivative (272). This has aDG‡

value of 89.9 0.4 kJ mol21 �T . 1408C� as deter-mined by a line shape analysis of the1H NMR signalsof thep-phenylene ring. The increased barrier in (272)relative to (270) was explained by unfavourable stericinteraction in the conformational transition statebetween the methyl group at C-1 and the adjacenthydrogen at C-15. The analogous unfavourable H,H-interactions in (270) and (269), which occur twice andonce, respectively, do then account for the observedsequence of barrier heights (270) . (269) . (271).

The two benzoannelated [2.2]metaparacyclo-phanes, [2.2]metacyclo(1,4)naphthalenophane (273)and its derivative (274) with an intraannular methylgroup, both occur as theanti isomers with the intraan-nular proton �dH � 3:95� and methyl group�dH �0:30�; respectively, over the naphthalene system[186]. Variable temperature1H NMR studies up to1508C have shown no indication ofantiO syn inter-conversion. The precursor dithia[3.3]metacyclo(1,4)-naphthalenophanes are mentioned in Section 4.2.3.The tert-butyl derivatives without a second substitu-ent (275a) or with a methyl group in thepara-position(275b) are formed only in theanti-conformation, nomatter whether the precursor dithia[3.3]phanes andtheir sulfoxides weresyn or anti [187]. However,both syn- and anti-[2.2]phanes (275c) are producedfrom the methoxy-substituted precursor. Recording a1H NMR spectrum ofanti-(275a) at11508C providedno evidence that thesyn-conformer was formed.

(273)

6.05 8.09

7.55

3.95

6.747.03

(274)

6.04 8.07

7.48

6.686.90

Me0.30

(275a), R = H; only anti; δH = 3.77(275b), R = Me; only anti; δMe = 0.27

tBu

R

(275c), R = OMe; anti >> syn; δOMe = 2.63 and 3.17

R

tBu

anti syn

3.4. [2.2]Orthometacyclophanes

The synthesis of [2.2]orthometacyclophane lead toa 4:1-mixture of itssyn- (276) andanti-isomers (277)[188] which up to 1508C interconvert slowly on theNMR time scale. From the line broadening at thehighest attainable temperature, the activation barrierwas estimated to lie between 84 and 100 kJ mol21.Because of the magnetic anisotropy of the oppositebenzene rings, all protons apart from H-16 areshielded in (276) relative to (277), but the inclination


Table 11Activation barriersDG‡

c to m-phenylene ring flipping and coales-cence temperaturesTc in [2.2]metaparacyclophane derivatives

Compound Types of centralbridge bonds

DG‡c

[kJ mol21]Tc

[8C]

(263) Single/single 87 146(268) Single/aromatic 75 116(270) Aromatic/aromatic 57 24(269) Aromatic/double 44 241(271) Double/double 35 296

of the rings in (276) places H-16 into the deshieldingzone of theortho-bridged ring. Although the intraan-nular aromatic protons inanti-[2.2]metacyclophanesare usually strongly shielded (dH < 4.2 [189]), this isnot the case for H-16 in (277), whered�H-16� � 7:08;because its benzene rings are not in such close proxi-mity as in the case of doublemeta-bridging. A verystrong NOE of 16% is observed at H-2b when thesignal of H-16 is saturated although H-2a competesstrongly in the dipolar relaxation of H-2b. This is inaccord with the very small distance of 210 pmbetween H-16 and H-2b, which is predicted bymolecular mechanics computations (MMX). Therewas good agreement between the experimental vicinalcoupling constants in the bridges of (276) and thosepredicted by the Haasnoot equation [190] from thegeometry estimated by the MMX computations. Inthe 13C NMR spectrum strong deshielding of C-16 isobserved in (276), dC � 138:3; relative to (277),dC � 129:9: This deshielding effect in thesyn-conformer is similar to that found for the aromaticintraannular carbon atom in [5]metacyclophane (1)and [6]metacyclophane (6), which had been corre-lated with the degree of nonplanarity of the aromaticring [16]. This explanation does not seem to hold in(276) as the MMX computations predict very similargeometries for themeta-bridged rings of (276) and(277).

The 1H and 13C NMR spectra of theN,N0-ditosyl-diaza[2.2]orthometacyclophane (278) [191] werefully assigned by the use of a variety of 2D techniques

at room temperature and at low temperatures. Themolecule exists as two conformers of approximatelyequal energy, the boat (syn) and the chair (anti)conformer. At room temperature averaged1H (and13C) spectra are observed in which some broadenedsignals (of H-16 and H-2,9) indicate restricted intra-molecular mobility. At ca.238C the methylene signaldecoalesces �DG‡ < 52 kJ mol21� into separatesignals for exo and endo protons due to restrictedCH2 movement, and between258 and2738C thedifferent aromatic proton signals split, some of theminto resonances of widely differing chemical shifts(Table 12). This lower energy process�DG‡ � 43:5^

2 kJ mol21� is the boat/chair interconversion andthe large chemical shift differences between theconformers, e.g. 2.6 ppm for H-16, are caused bythe large change of the relative orientation of thearomatic rings. In contrast to (278), no signaldoubling could be observed for the [6]metacyclo-phan-3-ene derivative (279), which has acis-CyCdouble bond instead of theortho-substituted benzenering. From the lowest temperature reached (2938C),


(277), anti

H16

1a 1b

2a2b

H16

(276), syn (1), n = 5

(CH2)n

H

(6), n = 6

N

Hexo

H16

(278), boat (278), chair

N

N

H16

Ts

TsNTs

Hendo24

56

79

12

1314

Ts

45

HendoHexo

9

N

NTs

Ts

(279)

Table 121H NMR chemical shifts of the boat and chair conformers of (278)in CD2Cl2 solution at2838C

H-2endo H-2exo H-4 H-5 H-12 H-13 H-16

Boat 4.92 4.97 7.66 7.07 6.24 6.83 7.18Chair 3.40 4.81 5.99 6.64 6.98 7.32 4.59Dd 1.52 0.16 1.67 0.43 2 0.74 2 0.49 2.59

an upper limit of the barrier to inversion of the nine-membered ring was determined as 30 kJ mol21. Thetrue barrier was estimated to lie between 20 and25 kJ mol21.

3.5. [2.2]Orthoparacyclophanes

[2.2]Orthoparacyclophane (280) is the moststrained of the [2.2]cyclophanes and was the lastone to be synthesized [192]. The vicinal H,Hcoupling constants in the ethano bridges are nearlyidentical to those in (Z)-[6]paracyclophan-3-ene (59a)[56], proving the similar geometries of these twocompounds.

7.326.27

(280)

7.207.07

(59a)

The only major difference between the1H NMR spec-tra of (59a) and (280) is the shielding effect experi-enced by the protons on thesyn side of the p-phenylene ring. These are strongly influenced by thering current of theo-phenylene ring so that theirchemical shift�d � 6:27� is about 1 ppm to the higherfield than that of theanti protons�d � 7:32�: Mutual

syn/anti isomerization, which is facile for methoxy-carbonyl derivatives of (59a) and takes place at roomtemperature withDG‡�1258C� � 103 kJ mol21

; wasnot observed for the corresponding derivatives of(280) within 48 h at 1508C. Thus, benzoannelationof (59a) brings about a substantial barrier to confor-mational isomerization.

3.6. [2.2]Naphthalenophanes

The 1H NMR spectra of the three constitutionallyisomeric [2]naphthaleno[2]paracyclophanes (281)–(283) [193] nicely reflect the different relative orien-tations of the benzene and naphthalene moieties. Thelarge shift difference of 1.00 ppm between the protonson theendoandexosides of the benzene ring in the(1,4)naphthaleno derivative (281) is mainly due to theinfluence of the ring current of the unbridged naphtha-lene ring. The moderate shift difference of 0.51 ppmbetween the two kinds of benzene protons (AA0BB 0

system withC2 symmetry) in the (1,5)naphthalenocompound (282) is caused by the smaller distance ofthe more shielded proton from the centre of the near-est naphthalene ring. In (283), where the centre of thebenzene ring lies over the centre of the naphthalenesystem, the AB shift difference is very small(0.09 ppm) so that it cannot be used to assign the


(282)(281) (283)

6.09

5.09

6.44 7.55

7.24

7.37 6.99

7.03

6.035.52

6.82 7.22

6.08/5.99

7.04

(284)

6.90 7.21

6.08/6.04

7.11

7.23

6.75

(286)(285)

6.43

3.07

6.80

6.536.996.877.12

3.22/2.68

MeO

OMeMeO

OMe

(287) (288)

XA

A’

X’

two kinds of protons. The spectrum of diene (284) isvery similar [194]. The dithia[3.3]phanes correspond-ing to (281)–(283) are dealt with in Section 4.

The chiral [2.2](2,6)naphthalenophane (285) withcrossed naphthalene units has been known for anumber of years [195], and its structure had beenassigned on the basis of its wide spread chemicalshifts of the aromatic (d1 � 6:43; d3 � 6:87; d4 �7:12; naphthalene numbering) and of the bridgeprotons (AA0BB 0, d � 3:22 and 2.68). The achiral,eclipsed isomer (286) could only be prepared muchlater [196]. Its three different aromatic protons�d1 �6:80; d3 � 6:53; d4 � 6:99� show rather similar high-field shifts relative to 2,6-dimethylnaphthalene:Dd �0:73; 0.72, and 0.66, respectively. Moreover, the twokinds of bridge protons reside in similar environmentsand are accidentally isochronous. Their chemical shiftis the same as in [2.2]paracyclophane,d � 3:07:

The isomeric [2.2](1,3)naphthalenophanes (287)and (288) [197] differ in that the outer naphthalenerings are arranged in atransoidand acisoid manner,respectively. Both are present in theanti-conforma-tion as indicated by their highly shielded intraannularprotons which both absorb aroundd � 4:5: The differ-ent symmetries are apparent from the bridge protonpatterns. In (287) both bridges are equivalent bysymmetry and the protons of a bridge form anAKRX spin system. In (288), the bridges are in differ-ent environments and give two different AA0XX 0

spectra. The latter were misinterpreted as two AXsystems with coupling constants of 10.1 Hz for onesystem and 9.0 Hz for the other. This means that theweaker outer lines of the patterns were not seen orwere neglected. The spacing of each “doublet” doesnot correspond to a single coupling constant but corre-sponds touJ�AX �1 J�AX 0�u; which in this case isu2J 1 3Jgaucheu and corresponds to approximately�2121 3� Hz� 9 Hz; in agreement with the abovevalues.

Photocyclodimerization of 1,3-distyrylnaphthalenecould, in principle, give seven bis(cyclobutano)anne-lated syn-[2.2](1,3)naphthalenophanes, of whichthree, (289)–(291), were isolated in sufficientamounts to solve their structures by NMR spectro-scopy [198]. This was achieved mainly by the use ofthe 1H chemical shifts, of the symmetry in the13Cspectra, and of the results of H{H}-NOE measure-ments. A series of othersyn-[2.2]naphthalenophanes

with cyclobutane rings annelated to the bridges wasprepared by intermolecular [21 2] photocycloaddi-tion of divinylnaphthalenes [199]. The structuresand configurations of the products, (292)–(299),were determined by H,H-COSY and by H,H-NOESY, making use, in particular, of the NOEsbetween the cyclobutane and the aromatic protons.

The [3.2](1,4)naphthalenophan-1-enes (300) and(301) [200] prefer theanti-conformation as shownby the upfield shift of the protons in the naphtha-lene positions 2 and 3 in (300) (d � 5:67 and5.93) and of naphthalene proton H-3�d � 5:81�and its neighbouring methyl protons�d � 1:57� in(301). The spin coupling pattern of the protons inthe three-membered bridge indicate that it makesrapid wobble movements at room temperature. For(300) this was confirmed by the doubling of severalsignals at low temperature. The coalescence tempera-ture of 2758C gives DG‡ � 39 kJ mol21 for thisprocess.

3.7. Other [2.2]phanes

This section deals with phanes containing aromaticsubunits other than naphthalene or heterocycles, suchas fluorene, higher condensed aromatics, azulene, andferrocene (three examples). It also contains adaman-tanophanes.

The preparation of the [2.2](2,7)fluorenophanes(302) and (304) furnished both theanti and thesynisomers while only theanti isomer was obtained in thesynthesis of diketone (303) [201]. In thesynfluoreno-phanes the fluorene units are expected to be arrangedeclipsed and parallel to one another. They are char-acterised by moderate shieldings (Dd � 20:50 to20.68) of their aromatic protons compared with themodel compound 2,7-dimethylfluorene (305). The C–C axes of the bridges are presumably perpendicular tothe aromatic planes. This makes the chemical envir-onments of the bridge protons very similar, in agree-ment with their close chemical shifts; only a broadsinglet was observed atd � 3:14: The 9-endoand 9-exoprotons are shielded byDd � 20:43 and20.17,respectively, relative to (305). An X-ray diffractionstudy ofanti-(302) showed that the fluorene units liein parallel planes, but their centres are shifted relativeto one another so that C-1 and C-8 lie approximatelyabove the centres of the opposite aromatic rings (step-


like conformation). Foranti-(302) in solution, thisleads to strong shielding of H-1/8�Dd � 21:24� andonly weak shielding of H-3/6�Dd � 20:22� and H-4/5 �Dd � 20:27�: The protons at the five-memberedring are also much more shielded than in thesynisomer, Dd�H-9endo� � 21:44 and Dd�H-9exo� �20:65: The nonequivalence of these protons allowsthe direct observation of their geminal coupling:22.0 Hz in anti-, 20.5 Hz in syn-(302). The X-rayresults also show that the axis of the bridges are notperpendicular but skewed with respect to the fluorene

moieties. The geminal protons at a bridge carbontherefore reside in different environments, in agree-ment with their distinct shift difference observed inthe AA0BB 0 spectrum�dA � 3:09; dB � 2:67�: Thegeometries ofanti-(303), anti-(304), and syn-(304)were derived using the same chemical shift argumentsas for (302). The fluorenophanes (302) wereconverted to their dianions (306) and their1H chemi-cal shifts compared with the model anion (307). As forthe neutral hydrocarbon, H-1/8 in theanti phaneshows the strongest high-field shift�Dd � 20:84�;


(291)

PhPh

PhPh

(290)

PhPhPh

Ph

(289)

PhPhPh

Ph

(296) (297)

(293) (294)(292)

(295)

(298), R = CO2Et

RR

RR

(299), R = Ph

Me

Me

R

R

(300), R = H(301), R = Me

2

followed by H-9 �Dd � 20:69�: Generally, the shiftdifferences between the charged phanes and theirmodel compound are smaller than in the cases of theneutral hydrocarbons.

Dianionanti-(306) was reacted with methyl iodideto give a dimethylated phane which must have theexo,exostructure (308, X � CH3, Y � H) because ofthe chemical shifts of the 9-H�d � 2:38� and 9-Me�d � 1:03� protons. Renewed metalation of (308,X � CH3, Y � H) followed by treatment with CH3Iyielded the tetramethyl-phane (308, X � Y � CH3),in which, surprisingly, theendo- and exo-methylprotons have very similar shifts�d � 1:01; 1:03�:

This finding was interpreted by a possible twist ofC-9 out of the plane of the five-membered ring tominimize unfavourable steric interactions of theendo-methyl group. This would lead to a high-fieldshift of the exo-methyl group because it would bemoved more into the shielding area above the fluoreneunit on the outside of the molecule. At the same timetheendo-methyl group would be moved more into thedeshielding zone at the side of the aromatic plane.

In a series of [2.2](1,8)fluorenophanes (309)–(311) described by Tsuge et al. [202] flipping ofthe fluorene moiety is restricted as seen from thedifferent chemical shifts of the geminal protons at


4

1

3

9

X

Y

(302), X = Y = CH 2

(303), X = Y = CO(304), X = CH2, Y = CO

anti-(302) syn-(302)

anti-(306) syn-(306)

(305)

−

−

−

−

(307)

−

2 Li+

2 Li+

Li+

7.356.95

6.093.092.67

H

H3.10

2.31

7.627.17

7.333.75

H

H

3.14(both H)

3.58

3.326.83

6.636.94

6.93

7.606.09

5.73

6.09

6.217.43

5.046.75

5.767.11

5.43

C-9. Relative to di-tert-butylfluorene (312) as areference compound, for whichd�CH2� � 3:95;both methylene protons are strongly shielded inthe parabenzenophane (309), the endo-proton �d �0:00� more so than theexo-proton �d � 2:38�: As tobe expected, the effects are more pronounced in the(2,6)naphthalenophane (310) but only very small influorenophane (311) containing the nonaromaticp-benzoquinone ring. Coalescence of the signals of thediastereotopic protons at C-9 was not observed up toa temperature of11508C for any of these fluoreno-phanes.

The structures and configurations of the bis(cyclo-butano)[2.2]phenanthrenophanes (313) and (314)were determined by H,H-COSY and H,H-NOESYand from the deshielding effect of the annelated cyclo-butane rings upon theortho-protons toward whichthey are pointing [203]. Both series of compoundspossess thesyn-conformation as is evident from theupfield shifts of the aromatic protons relative tophenanthrene. Yet, these upfield shifts are moreremarkable in (313) than in (314). X-ray diffraction

analysis and molecular mechanics calculations showthat this is caused by the different arrangements of thephenanthrene units relative to each other. In theisomers (313) the bridges are on opposite sides ofthe molecule, thus forcing the phenanthrene decksinto a parallel arrangement, whereas they are on thesame side in (314), so the phenanthrene planes canform an angle and evade each other. This decreasestheir mutual shielding effect. Hydrogenation of thecyclobutane rings of (314) led to a [4.4]phane whichis described in Section 5.

Like [2.2]metacyclophanes, the related pyreno-phanes (315a)–(315e) [204] adopt theanti-conforma-tion although some of their dithia[3.3]phaneprecursors preferred thesyn-arrangement, cf. Section4.2.3. The anti-conformation is evident from theupfield shifts, caused by the strong ring current ofthe pyrene system, of the intraannular benzene proton�d � 3:54� in (315a), of the methyl group�d �20:29� in (315b), of the ethyl group�d�CH2� �0:11; d�CH3� � 20:10� in (315c), and of the methoxygroup�d � 2:35� in (315d). Further, the intraannular


anti-(308)

Y

X

Y

X

0.00, 2.38

tBu tBu tBu tBu

−0.69, 2.11

(309) (310)

tBu tBu

(312)

3.95

3.41, 3.68

tBu tBu(311)

O

O

pyrene proton is shifted to 4.50–5.16 in the series(315a)–(315e) by the oppositem-phenylene ring.

An interesting compound, (316), which incorpo-rates a [2.2]metaparacyclophane into a 10b,10c-dihy-dropyrene molecule, was apparently synthesized byLai and Yap [205], although it could not be isolatedin a pure form and only a few of its1H NMR signalscould be identified. As the methyl protons of (316)have almost the same shift�d � 24:19� as in themodel compound trans-dimethyldihydropyrene(317a) �d � 24:25�; the authors concluded that themolecule sustains nearly the full ring current (99%)of the model system. The relative deshielding of the

protons of the methylene group bound to C-10b[d � 23:1; compared to24.14 in the but-4-enyl deri-vative (317b)] was explained by a deflection of thisCH2 group from the central axis (dotted line) ofp-delocalization by the strain in the cyclophane system.

The dianion (318) of [2.2](1,4) benzo[g]chryseno-paracyclophane [206] consists of a paratropic 4npdianion interacting with a neutral benzene ring. The1H NMR chemical shifts of the disodium salt rangefrom d � 10:31 to 0.91, the most interesting part ofthe spectrum being the signals of the protons of thebenzene ring. Hc and Hd were observed atd � 8:68and 10.31, respectively, extremely deshielded with


1

6

(313a), exo,exo (313b), exo,endo

3

6

(314a), exo,exo (314b), exo,endo (314c), endo,endo

(315)

R1

H

R2

tBu

abcde F

OMeEtMeH

tButBu

tButBuH

R2R1

CH3

R

(317a), R = CH3

(317b), R = CH2CH2CH=CH2

−4.25

−4.14

CH3

(316)

−4.19

−3.1

respect to the neutral hydrocarbon (319) where theshifts ared � 5:92 (Hc) and 5.08 (Hd). In fact, redu-cing diatropic (319) to paratropic (318) reverses theorder of the chemical shifts of the benzene ringprotons. The remaining proton shifts of (318) werenot assigned, neither were the13C shifts, which extendfrom d � 176 to 100 and fromd � 38 to 33. In afurther paper by the same group [207], a series of[2.2]indenophanes and their anions were studied inorder to separate the effects of charge transfer andmagnetic anisotropy of the negatively charged cyclo-phane layer upon the1H chemical shifts of the oppo-site layer. The authors concluded that the magneticanisotropy of the (4n 1 2)p system formed has thelargest influence, but that charge transfer effectsfrom the negatively charged layer to the opposite

one must not be neglected. The systems studiedwere (320)–(323), their (di)anions, and some furtherneutral model compounds.

In [2.2](5,13)dibenzochryseno[c,l]phane (324)[208], the central parts of the two dibenzochrysenesubunits are subject to one another’s ring currents.This causes shielding effectsDd of the central protonsamounting to20.87 and20.90 ppm relative to thecorresponding shifts in the reference compounddimethyldibenzochrysene (325) and indicates theobliquely stacking structure of phane (324) asopposed to a structure in which the two halves areeclipsed.

Compared to the free ligand dihydro-s-indaceno-paracyclophane (326) the 1H NMR chemical shiftsin the benzene ring of the rhodium complex (327)


(318) (319)

2−

2 Na+

10.31

8.68

7.96

6.46(a)

(b)

(c)

(d) 6.57(b)

6.70(a)

5.08(d)

5.92(c)

R

R

R

R

(320) (321)

(322), R = H(323), R = Me

R

R

R

R

(321)2− (322)1−, (323)1−

− −

− − −

(320)2−

show deshielding of protons a and b by (1)0.18 ppm(averaged) and shielding of protons c and d by(2)0.13 ppm [209]. This was interpreted by theauthors to indicate a decrease of electron density inthe benzene ring by complexation of the dihydroinda-

cene moiety with (Me5C5)Rh1 and an overcompensa-tion of the expected downfield shift of H-c,d by theshielding of the magnetically anisotropic rhodiocenesubstructure.

The1H NMR signals of the aromatic and the bridgeprotons in anti-[2.2](1,6)azulenophane (328) [210]are well spread out on thed -scale and show doubletand ddd multiplicities, respectively, due to spin–spincoupling. Neglecting enantiomers, there are fourpossible isomers that could have been formed fromthe precursor 1,6-azulylene:synandanti conformersof the syn (1,10;6,60-bridged) and theanti (1,60;6,10-bridged) configuration. Thesyn configurations wereexcluded because they would both give rise to twoAA 0XX 0 bridge spin systems whereas one AKMXsystem was observed. Theanti conformation followedfrom the large upfield shifts of H-7 and H-8 of ca.22.5and22.1 ppm, respectively (relative to 1,6-dimethyla-zulene), which indicates a step-like structure. Assign-ments of the individual bridge proton resonances andtheir coupling constants were reported later [211].

Hafner and coworkers were the first to preparesyn-[2.2](1,6)azulenophane (329). Its configuration issuch that the five-membered rings and the seven-membered rings are over each other [212], but thequestion of the preferred conformation needed to be


(325)(324)

9.127.93

8.227.06

Rh+(Me5C5)

SbF6−

cd

a

b6.48−6.39

6.13

(327)

6.26

(326)

7 8MX

AK

(328)

1

6

1’

6’

6

1

H12

H11

H9H10

4

8

H

H

HH

(329)

6 4

(330)

3.09

2.48

6.77 8.03 7.21

7.71

3.40

2.95

5.17 6.37(−1.90) (−1.84)

H12

H11

3.35

2.34

7.068.31 7.36

7.77

H

H

H H

H9H10

4.252.535.64(−1.46)

7.53

NN

(331) (332)∆δH values

−2.37 −2.04

answered. Comparison of the1H chemical shifts withthose of the reference compound 1,6-dimethylazuleneshows large upfield shifts of H-7 and H-8 (21.90 and21.84 ppm, respectively), while the other aromaticprotons are affected by less than 0.3 ppm. Conse-quently, the molecule assumes the stepped conforma-tion (anti-type) as shown in the formula, with H-7 andH-8 over the centre of the opposite seven-memberedring. The proton chemical shifts of the[2.2](4,6)azulenophane (330) were compared withthose of 4,6-dimethylazulene. Here, H-5 exhibitsstrong shielding (21.46 ppm) relative to the referencecompound, and the remaining aromatic protons aredeshielded by 0.04–0.19 ppm. Hence, this azuleno-phane also assumes ananti-type conformation withH-5 over the centre of the opposite seven-memberedring. For both (329) and (330), the proton shifts werefully assigned, the bridge protons from the NOESYcross peaks with their adjacent azulene protons.Increasing the temperature to11308C hardly affectsthe spectrum of (329) and demonstrates the conforma-tional rigidity of the molecule. The spectrum of (330)shows broadened aliphatic proton signals up to11308C, while the aromatic proton signals, especiallythose of the deshielded protons, remain sharp. Thiswas interpreted as indicating flipping of the azulenerings.

The large upfield shifts of the inner protons in[2.2](1,3)azuleno(2,6)pyridinophane (331) and in[2.2](5,7)azuleno(2,6)pyridinophane (332) [213] rela-tive to the corresponding dimethylazulenes are verysimilar to the shielding observed earlier for the analo-gous azulenometacyclophanes [214,215]. Also, the13C chemical shifts of the azulene carbon atoms aremuch the same in the two classes of compounds.These findings established the conformations of(331) and (332) asanti (step-like). The1H NMR spec-trum of (331) remains unchanged up to11308C, butthe CH2 signals of (332) start to broaden at11208C

before the compound decomposes. Since the aromaticproton signals of (332) do not change, the dynamicprocess observed is anantiO planarO anti and notanantiO synconformational change.

In order to probe the sign and magnitude of themagnetic anisotropy in the region close to the ironatom in ferrocene, [2.2]metacyclo(1,10)ferroceno-phane (333) was studied by1H NMR [216]. Them-phenylene ring in this molecule is situated to the sideof the ferrocene unit and H-9 is close to the iron atom:301 pm apart according to an X-ray diffractionmeasurement. This arrangement causes strongdeshielding of H-9, which absorbs atd � 8:80; ca.1.7 ppm to low field of H-11,12-13. The same groupof authors also studied [2.2]metacyclo(1,3)ferroceno-phane (334) and thepara isomer (335) [217]. Themeta compound possesses theanti conformation asis evident from the upfield shifts of the internalprotons. Withd � 1:18; H-2 of the ferrocene moietyis extremely shielded. This represents an upfield shiftDd of 22.82 ppm relative to the shift of H-2 in 1,3-diethylferrocence as a model compound. In contrast,the internal proton at them-phenylene ring�d � 5:34�is only shielded byDd � 21:58 ppm relative to 1,3-diethylbenzene. Hence, the magnetic anisotropy offerrocene causes considerably less shielding in thearea above the centre of the cyclopentadienide ringthan does the magnetic anisotropy of benzene at acomparable position. Thepara compound (335) hasa step-like structure similar to [2.2]metaparacyclo-phane (263) and one side of thep-phenylene ring isshielded relative to the other, as is the case for the H-2of the ferrocene moiety relative to H-4,5. The [3.3]-and dithia[3.3]-analogues of (334) are mentioned inSections 4.1 and 4.2, respectively.

Vogtle et al. [218] prepared [2.2](1,3)adamantano-metacyclophane (336), the construction principle ofwhich has some resemblance to [2.2]metacyclophane(149), but whose stereochemistry is different because


Fe H 9

11

13

(333)

Fe

(334)

5.341.18

3.75

3.97

7.15−6.80

Fe

(335)

2.37

3.37

3.87

6.23

6.93

three intraannular protons are located within thecentre of the 10-membered ring. Protons Hi and Ho

(d � 20:10 and 10.06, respectively) are stronglyshielded while Hb absorbs atd � 7:75: The 1H NMRspectrum of (336) remains unchanged at hightemperature (11268C) apart from some chemicalshift alterations. This indicates conformational rigid-ity, in contrast to the flexible [7]metacyclophanewhich has aDG‡ of only 48 kJ mol21 for the flippingof the bridge [23]. An X-ray diffraction analysisproved the anti conformation of (336). In theircalculations of the ring current effects upon1Hchemical shifts, using a model and parameterstested on [n]paracyclophanes, Schneider et al.[77] also treated compound (336) and found thatthe calculated shift effect upon Hi is off by1.6 ppm (shielding calculated too high), althoughgood predictions were made in all other casesincluding (337a). The reason lay in the strongsteric compression effect exerted on Hi, which coun-teracted the ring current shielding. Other effects, inparticular a miscalculation of the molecular geometry,were excluded. The dithia-[3.3]phane precursor of(336) is discussed in Section 4.2.3.

[2.2](1,3)Adamantanoparacyclophane (337a) [219]is even more strained than themeta-analogue (336).At room temperature, the intraannular methyleneprotons absorb as a singlet withd � 22:35: Theirabsorption decoalesces at2508C (400 MHz) andgives rise to an AX spectrum at2658C with d �24:08 (Hi) and21.01 (Ho). The axial proton Hi appar-ently intrudes deeply into thep-cloud of the benzenering and experiences an upfield shift of 5.9 ppm (!)relative to the corresponding hydrogen in adamantaneitself. The barrier to the chemical exchange of Hi andHo is surprisingly low,DG‡ � 40^ 10 kJ mol21 at2508C, probably due to the high strain present inthe conformational ground state. This barrier is

much higher in the carboxylic acid (337b) [220].Here the chemical shifts of the intraannular CH2

protons ared � 23:63 and21.12 already at roomtemperature and their signals do not coalesce up to1608C. Another adamantanophane, (338), is the(2,6)pyridino analogue of metaphane (336). It haschemical shiftsd of 20.25 and10.35, for Hi andHo, respectively. Their signals coalesce at1488C(250 MHz), indicating a barrierDG‡ of 62^10 kJ mol21 at this temperature, distinctly lowerthan in (336), a consequence of replacing the intraan-nular hydrogen of them-phenylene ring by the nitro-gen lone pair of electrons.

3.8. [2.2]Heterophanes

The phanes treated in this section possess at leastone heterocyclic (mostly aromatic) ring. Some phanescontaining ag-pyrone moiety are also included. Six-membered heterocycles are followed by five-membered ones.

The results of a number of NMR studies of pyridi-nophanes, mainly [2.2]pyridinophanes, are containedin a review article by Majestic and Newkome [221].According to an X-ray diffraction study [222],[2.2](2,6)pyridinophane (339a) prefers the anticonformation. The ring inversion barrierDG‡ hasbeen determined to be 61.9 kJ mol21 at 1808C[223]. Its 7,15-dimethoxy derivative (339b) [224]has the same conformational preference and a signifi-cantly higher basicity than that of the parent. It was ofinterest to see whether this affects the height of theconformational barrier.DG‡ was determined by acoalescence measurement (AA0BB 0 ! A4) as64.2 kJ mol21 at 1438C. The barrier for (339a) wasdetermined again and this time found to be58.3 kJ mol21 at 1168C. The evaluation of the rateconstants was carried out by using the equation for


Hi

Ho

Hb7.75

+0.06

−0.10

(336)

Hi

Ho

(337a), R = H

Hi

Ho

N

(338)

−1.01

−4.08 −0.25

0.35

R

(337b), R = CO2H[δH values for (337a)]

the coalescence AB! A2. It is not clear how large anerror is introduced by this. Also, the apparently higherbarrier in (339b) relative to (339a) cannot be judgedproperly without knowing the activation entropybecause of the different temperatures of the measure-ments. [2.2](2,6)Pyrazinophane (340) behaves simi-larly to (339a), showing an AA0BB 0 spectrum for its

bridge protons at2108C which coalesces at1548C(500 MHz). Evaluation by means of the AB approx-imation gaveDG‡�1548C� � 61:5 kJ mol21 for theanti/anti0 interconversion [225].

Among [2](1,5)naphthaleno[2](2,6)pyridinophane(341), [2](1,4)naphthaleno[2](2,6)pyridinophane (342)and their dienes (343) and (344), only the firstcompound shows temperature dependent1H NMRspectra in the range between2100 and 1808C[226]. These are caused by chemical exchangebetween two equivalent conformations (3410) and(34100). At 2608C, the naphthalene system gives riseto two ABC spectra, the pyridine system to one ABCspectrum, and the ethano bridges to two ABCD spec-tra. All 1H chemical shifts and H,H coupling constantswere assigned at this temperature, including the para-meters of the bridges (Table 13). At1838C, the spec-trum shows one ABC-type naphthalene, one AB2-typepyridine, and one ABCD-type bridge spectrum. Thesignal of the pyridine H-40 proton remains sharp overthe whole temperature range because its chemicalshift and coupling constants are identical in the twoexchanging conformers. At high temperature, thecoupling constants in the bridges are the averages of


NR N R

(339a), R = H(339b), R = OMe

NN NN

(340)

(341)

N

3’

5’

1516

1718

13

11 12

14

8 7

6

4’

4

2

(341’)

N

N

(341’’)

(343)

N

7.126.46

6.13

7.386.80

7.257.60

(344)

N

7.28

6.79

6.42

7.86

7.20

7.807.01

(342)

N

2.392.76

3.932.82

7.548.15

6.14

6.79

7.38

Table 131H NMR chemical shiftsd and H,H coupling constantsJ(H,H) [Hz]in (341) under slow chemical exchange conditions (measured inCD2Cl2 at 2608C)

Chemical shiftsd(H-2) 6.45 d (H-30) 6.61 d(H-14) 2.49d(H-3) 6.69 d (H-40) 6.98 d(H-15) 3.14d(H-4) 7.14 d (H-50) 6.34 d(H-16) 3.40d(H-6) 7.42 d (H-11) 2.77 d(H-17) 2.06d(H-7) 7.42 d (H-12) 3.91 d(H-18) 2.86d(H-8) 7.83 d (H-13) 2.90

Coupling constantsa

J(11,12) 213.1 J(12,14) 9.0 J(15,18) 2.2J(11,13) 8.2 J(13,14) 212.1 J(16,17) 12.2J(11,14) 9.9 J(15,16) 212.5 J(16,18) 4.5J(12,13) 0.0 J(15,17) 5.9 J(17,18) 212.3

a Only coupling constants of the bridge protons listed.

the low-temperature spectrum according to theexchange pattern. Coalescence measurements of thesignals of the naphthalene protons H-4/8�Tc � 238C�and of the pyridine protons H-30/50 �Tc � 2138C�gave a ring inversion barrierDG‡ of 51.5 kJ mol21,very similar to earlier results for [2](2,6)pyridino[2]-paracyclophane [227]. An analysis of the full lineshapeof the aromatic protons yieldedDH‡ � 49:5^

0:6 kJ mol21 and DS‡ � 27:1^ 2:4 J K21 mol21:

Very likely, the dienes (343) and (344) prefer confor-mations in which the pyridine and naphthalenerings are orthogonal and the nitrogen lone pairs are

pointing towards the naphthalene moiety, while thereexists probably a one-sided equilibrium in (342) withparallel pyridine and naphthalene rings favouringthe conformer with the pyridine ring orientedexo.The [2]naphthaleno[2]pyrazinophanes (345)–(348)give results that resemble those of their pyridinoanalogues, in particular the ring inversion barrierDG‡ of 52.4 kJ mol21 for (345) [228]. The 1H NMRspectroscopic properties of [2](1,4)anthraceno[2](2,6]pyridinophane (349) and its diene (350) arealso very similar to those of the naphthaleno-pyridinophanes (341)–(344) [229]. A number of


(345)

N

N

(347)

N

N

(348)

N

N

(346)

N

N

(350)

N

(349)

N

X

N

(351a)

X

N

(352a)(351b)(352b)X = N

X = CH

HMeS

MeS H

(353a)(354a)

(353b)(354b)X = N

X = CH(354c)

X

NMeS

H

HMeS HMeS

H SMe

N

N

SMeH

MeS H

N

X

SMeH

H SMe

bridge-bis(methylthio)substituted [2](1,4)- and [2](1,5)naphthaleno-[2](2,6)pyridino- and [2]pyrazino(2,6)phanes, (351)–(354), were investigated by1HNMR and their configuration determined from thechemical shifts and, in particular, measurements ofnuclear Overhauser enhancements [230]. The spectraof (353b), (354b), and (354c) are temperature depen-dent, which indicates slow ring inversion as observedin (341) and (345).

Vogtle [126] studied the four isomeric 1-oxa[2.2]metacyclo(x,y)pyridinophanes (355)–(358),for which (x,y) is (2,6), (2,4), (3,5), and (4,2), respec-tively. These compounds are characterized by strongshielding of the intraannular proton next to the oxygenand somewhat smaller but still rather strong shieldingof the intraannular pyridine proton. Comparison of thechemical shifts within this series and with (159)helped the reviewer to specifically assign the intraan-nular protons that had not been done by the authors.The same paper also described [2.2]metacyclo(2,4)-pyridinophane (359) and the isomeric [2.2](2,4)pyri-dino(x,y)pyridinophanes (360)–(363), �x; y� � �2;6�;(2,4), (3,5), (4,2). Unfortunately, complete assign-

ments of the proton spectra of these interestingcompounds have not been reported. The1H NMRspectra of (361) and (363) have also been reportedby Kawashima et al. [231], who addressed the differ-ent symmetries of these compounds,C2 for (361) andCi for (363). The symmetries are reflected in thebridge proton spin systems. While the bridge protonsof (363) absorb in the form of one common ABCDpattern, each bridge of (361) gives a separate AA0BB 0

spectrum, incorrectly described as a “pair of doub-lets”. Kawashima et al. [232] had also reported thearomatic1H and 13C NMR chemical shifts of (359),(362), of the isomeric [2.2]pyridinophanes (364) and(365), and of the isomeric [2.2]metacyclopyridino-phanes (366) and (367). The chemical shifts of theintraannular aromatic carbon atoms and theirconnected hydrogens were discussed in terms of elec-tron densities and steric compression. A paper byVogtle et al. [131], treated in Section 3.1, includesthe H-16 chemical shifts of the [2.2]metacyclo(2,6)-pyridinophane (169) �d � 4:94� and itsN-oxide (170)�d � 5:82�:

The isomeric [2.2](2,5)pyridiniophane diiodides


N

O

(355)

4.03

5.214.33

N

O

(356)

3.90

5.324.38 4.56

N

O

(357)

4.01

5.334.33 4.45

N

O

(358)

3.86

5.194.20 4.52

N

(359)

4.32*4.20*

N

N

(360)

4.60

N

N

(361)

4.344.34

N

N

(362)

4.48*4.33*

N

N

(363)

4.314.31

N

N(364)

N

N

(365)

N

(366)

N

(367)

4.55 4.60 4.364.41 4.39

(368)–(371) show only small upfield shifts(Dd � 20:15 to20.20) of their ring protons comparedto model compound (372) [233]. In contrast, theuncharged pyridine rings in the analogous pyridino-phanes cause mutual shieldingDd of 20.65 to20.70 ppm. Thus, the positive charge neutralizesabout 75% of the usual ring current effect on the1Hchemical shifts in [2.2]paracyclophanes. Partial reduc-tion of (368) forms the 1,4-dihydropyridine (DHP)substructure in (373). This compound is interestingbecause its two rings constitute a redox pair likeNAD1/NADH, yet within the same molecule. In fact,

hydride transfer from the DHP to the pyridinio moietycould be monitored by saturation transfer experiments.Irradiation of theN-methyl signal atd � 4:20 (CH3N

1

group of the oxidized ring) causes the signal atd � 3:12(CH3N of DHP ring) to lose intensity and vice versa. Nosuch saturation transfer could be observed in (374), sothese experiments indicate the orientation dependenceof the rate of the redox reaction.

Like [2.2](2,6)pyridinophane (339a), the (2,6)g-pyronophane (375) lacks intraannular hydrogens andtherefore undergoes unhindered inversion of itsmacrocyclic ring, as evidenced by the sharp singlet


N

N

(368)

+

CH3

E

+

CH3

E N

(369)

+

CH3

E

NH3C

+

EN

(370)

+

CH3

E

N

CH3

+

N

(371)

+

CH3

E

NH3C

+N

CH3

CH3

E

+

H3C

(372)

E

E

N

N

(373)

+

CH3

E

CH3

E N

(374)

+

CH3

E

NH3C

E = CO2Me

E

H

H H

H

O

O

PhPh

O

O

PhPh

(375)

O

O

PhPh

(376a), R = H

R

(376b), R = OMe

O

O

PhPh

(377)

exo

endo

O

O

CO2EtEtO2C

N

(378)

O

O

CO2EtEtO2C

N

(379)

absorption of the methylene protons [234]. X-raydiffraction showed that the compound, like [2.2]meta-cyclophane, prefers theanti conformation in the crys-tal. The [2]metacyclo[2]pyronophane (376a) with itsinternal proton does show hindered inversion at roomtemperature. This results in an ABCD spectrum forthe CH2CH2 bridges. The intraannular proton is some-what shielded by the magnetic anisotropy of the hetero-cycle�d � 6:62�: The methoxy derivative (376b) is, ofcourse, also hindered conformationally. Its bridgeproton spectrum was analysed and the resulting vicinalH,H-coupling constants prove the exclusive presence ofthe anti conformer. At room temperature, the1HNMR spectrum of the [2]paracyclo[2]pyronophane(377) shows coalescence phenomena for the CH2

and –C6H4– protons in the form of very broad lines.At 2558C, the spectra are sharp and the chemicalshifts for thep-phenylene protons ared � 6:94 (exo)and 7.38 (endo). This indicates a much smaller shield-ing effect of the pyrone relative to a phenylene ring asthe former lacks aromaticity, cf. the correspondingshifts in [2.2]metaparacyclophane (263) which ared � 5:79 and 7.13 [178]. At1608C, a singlet wasobserved for H-exo and H-endo, and broad signalsfor both types of methylene groups. The conforma-tional process observed corresponds to a flipping ofthe meta-bridge but no decision could be madewhether rotation of thepara-ring is also involved.The precursor dithia[3.3]pyronophanes and theirsulfones are mentioned in Section 4.2.3.

The [2](2,6)pyridino[2](2,6)g-pyronophane (378)and its unsaturated analogue (379) were studied byvariable temperature1H NMR [235]. The bridgeproton signals of (378) that are broad at roomtemperature show coalescence above1558C andgive an AA0XX 0 spectrum at 11808C (solvent:C6D5NO2). The DG‡ value for the conformationalinterconversion was determined from the linewidthas 59.6 kJ mol21 at 1808C. As in the case of the[2.2](2,6)pyridinophanes, introduction of a doublebond into one of the bridges lowers the barrier. Itamounts to 50.3 kJ mol21 in (379).

A report on pyrylium analogues ofanti-[2.2]meta-cyclophane describes the [2.2](3,5)pyryliophanedication derivative (380) and the [2.2]meta-cyclo(3,5)pyryliophane cation derivative (381)[236]. Both are present as theanti-conformers. Themethyl protons in (380) haved � 2:04; which is an

upfield shift of 0.69 ppm relative to model compound(382) and represents a rather small shielding effect bythe diatropicity of the pyrylium ring. In (381), theprotons of the methyl group at the pyrylium ring arestrongly shielded�d � 1:08� by the ring current of them-phenylene ring. The intraannular proton of thelatter is shielded�d � 4:95� by the pyrylium systembut not as highly as the corresponding protons of[2.2]metacyclophane�d < 4:2�:

Compound (383) [237], claimed to be the firstbenzo-fused heterophane, was reported to be con-formationally rigid as the multiplet for its bridgemethylene groups show no change up to11508C(DMSO-d6, 200 MHz). The multiplet was said to beof the AA0BB 0 type. However, the given structure(383) is correct, the compound hasCi symmetry andthe two bridges should give rise to a common ABCDspectrum.

The synthesis of [2.2](2,5)oxazolophanes (384)can, in principle, give four stereoisomers, in whichboth the five-membered rings (first designation) andthe nitrogen atoms (second designation) can beoriented syn or anti with respect to one another.Two isomers, (384a) and (384b), were in fact isolated[238]. By comparison of the chemical shifts of thearomatic protons with the shift of H-4 in the referencecompound 2,5-dimethyloxazole (385), the syn forms(with respect to the rings) are ruled out because thearomatic protons in both cyclophanes are slightlydeshielded relative to (385). Anisotropic shieldingeffects would, however, be expected for asynorienta-tion. The anti–anti (384a) and anti–syn (384b)isomers formed were assigned from the symmetry ofthe bridge proton spectra at room temperature and at1508C, where rapid oxazole ring rotation takes place.Compound (384a) displays an eight-proton multipletat ambient temperature and one singlet at 1508Cwhereas (384b) exhibits a four-proton singlet and afour-proton multiplet at ambient temperature and twosinglets at 1508C. The elegance of the study sufferssomewhat from a number of accidental shift coinci-dences at the observation frequency of 90 MHz. Coales-cence measurements yield oxazole ring rotationbarriers �DG‡� of 74.5 kJ mol21 at 808C for bothcompounds. This compares with a barrier of70.3 kJ mol21 in [2.2](2,5)furanophane [223]. Thestructures of the isomeric [2.2](2,5)thiazolophanes(386a) and (386b) were derived in a similar manner


as those of the oxazolophanes and accidental shiftcoincidences also occur. Confirmation was achievedby investigation of the tetradeuteriated derivatives(387a) and (387b). These give a common ABspectrum for the two protons in each bridge of(387a) and a singlet (degenerate AA0BB 0 spec-trum) for the nondeuterated bridge of (387b). Nosignal coalescence was achieved by heating thethiazolophanes to 1508C, in accord with the beha-viour of the corresponding thiophenophanes [223].The same authors also found [239] that isoxazolo-cyclophane (388) is conformationally rigid on theNMR time scale, DG‡ being larger than88 kJ mol21 [cf. DG‡ � 84 kJ mol21 for [2.2]meta-paracyclophane (263)].

Sternhell et al. [47] analysed dynamic1H NMRspectra of 4-methyl[2.2](2,5)furanoparacyclophane(389) by the lineshape method and determined activa-tion parametersDG‡�2318C� � 49:7^ 1:0 kJ mol21

;

DH‡ � 46:9^ 1:3 kJ mol21; and DS‡ � 213:8^

5:2 J K21 mol21: The observed process is believed

to be the flipping of the furan ring as had beenpostulated by Otsubo et al. in their earlier study ofthe methyl-free compound [240].

Variable temperature1H NMR spectra wereobtained of the [2]metacyclo[2](3,4)thiophenophane(390) [241], a thiophene analogue of [2.2]orthometa-cyclophane (276/277) [188]. At 1278C the ratio ofsynto anti conformer is 2:1 (in C6D5NO2). Lineshapeanalysis of the methyl signals yields free energies


(380)

O

O

Me

Me

2.04+

Ph

Ph

(381)

O Me

H

1.08+

Ph

Ph

+

Ph

Ph

4.95

(382)

O

Me

+

PhPh

2.73

N

S

N

S

(383) (384a)

NON

O

(384b)

NON

O

NSN

SN

SNS

XX

X X X X X X

(386a), X = H (386b), X = H(387a), X = D (387b), X = D

O

N

(388)

N

O CH3H3C

(385)

of activation at 1278C of DG‡�syn! anti� �85:4^ 0:4 kJ mol21 andDG‡�anti! syn� � 83:7^

0:8 kJ mol21: The barrier in (276/277) has been

estimated as 84–100 kJ mol21.The conformation of [2.2]metacyclo(2,4)pyrrolo-

phane (391) [242] was recognized asanti from theupfield shift of the intraannularm-phenylene proton�d � 4:92� and of the ester methyl group�d � 3:35�that extends over them-phenylene ring. The “normal”ester group hasd � 3:91: When the signal of theshielded ester methyl group was saturated, NOEswere observed for the resonances of the outer protonsof the m-phenylene ring.

3.9. [2.2]- and [3.3]Phanes capable of through-space19F,19F coupling

The present section is used to describe work onthrough-space 19F,19F spin–spin coupling indifluoro[n.n]cyclophanes�n� 2;3� with one fluorinesubstituent per aromatic ring. In order to avoid frag-menting related material, the section covers bothdifluoro[2.2]cyclophanes and difluorodithia[3.3]cy-clophanes even though the latter do not belong hereas far as the general classification by the Table ofContents is concerned. A comprehensive descriptionof the NMR properties of these compounds is givenhere, in addition to a description of their through-space spin–spin couplings.

The relative rigidity of the smaller meta- and para-cyclophanes entails relatively well defined geometrieswhich, in turn, offer themselves for studies of

geometry-dependent NMR phenomena. In an NMRstudy [243] of thesyn-difluoro[3.3]metacyclophanes(392) and (393) and thesyn-difluoro[2.2]metacyclo-phanes (136) and (394), a correlation was foundbetween the nonbonded F,F-distances,dFF, (278–248 pm, as estimated by molecular mechanics compu-tations) and the fluorine–fluorine coupling constants,J(F,F) (42.1–99.2 Hz), which were considered to bedue to through-space spin–spin coupling because ofthe large number of bonds—seven and eight, respec-tively—and the unfavourable geometry and electro-nic pathway between the interacting nuclei. As thefluorines in (392)–(394) are chemically equivalent,the J(F,F) values had to be extracted from the13Csatellites in the19F NMR spectra. Due to the chemicalequivalence of the fluorine nuclei (or their near-equivalence if the isotope effect of13C is taken intoaccount) and their magnetic nonequivalence, theirmutual spin–spin coupling also manifests itself insecond-order effects in the1H and 13C NMR spectraof these compounds. Insyn-(393), for example, theprotonsmetato the fluorines do not absorb as a simpledoublet by coupling with19F but as an apparent tripletwhich represents the X part of an [AX2]2 spin system.Also, the absorption of C-9 in (392) is not a doublet ofdoublets due to1J(F,C) and7J(F,C) but rather the six-line part of an ABX system�A;B � 19F; X � 13C�with the inner two lines having very small intensities.Previously, the distances of 251.5 and 7.8 Hz betweenthe four intense lines had been mistaken for the F,Ccoupling constants [244], while a proper analysisyielded2244.7 and10.3 Hz. In solution, there exists


O

H3C

(389) (390), syn (390), anti

SMe

Me S

Me

Me

(391)

CO2Me

H4.92

3.35

NOEMeN

CO2Me3.91

3.97

a conformational equilibrium betweensyn-(393) andits anti counterpart with asyn/anti ratio of ca. 8:1 atroom temperature, where the conformers interconvertslowly on the 1H NMR time scale (400 MHz). Theanti-conformer gives a first-order1H NMR signalfor the aromatic proton as the F,F-distance is largeand theJ(F,F) value too small to be resolved. Thebarrier to syn/anti interconversion was determinedby observing the coalescence of thet-Bu signals,DG‡�11058C� � 81:3 kJ mol21

: The sign of thethrough-space F,F coupling constant in (392) wasproven to be positive (142.1 Hz) by triple resonanceexperiments of the type13C{ 1Hbb,

19Fcw} (bb �broadband decoupling; cw� continuous wave selec-tive irradiation) [245].

In a later paper [246], the series of compounds wasextended to include both larger and smallerdFF values.

The larger values occur in the pseudo-geminalisomers of the difluoro-dithia[3.3]paracyclophane(395) and of the difluoro[2.2]paracyclophane (396)with computeddFF values of 318 and 300 pm, respec-tively, and observedJ(F,F) coupling constants of 7.2and 13.7 Hz, respectively. Smaller nonbonded F,Fdistances were achieved by introducing bulkytert-butyl groups into the positionspara to the fluorinesubstituents of (136) to give compound (397). Thecalculations gave 242 pm fordFF and a recordJ(F,F)value of 110.1 Hz was observed. The data for thecompounds mentioned so far plus those of themono-tert-butyl derivatives of (392) and (136)allowed the authors to derive a smooth function, Eq.(1), describing the dependence of the through-spaceF,F-coupling constant on the nonbonded F,F-distanceexpressed in picometres. The ranges ofJ(F,F) anddFF


R

R

S

F

F

S

R

R

S

SF

F

syn anti(392), R = H

(393), R = tBu

FF

RR

(136), R = H(394), R = SMe

9

F

F

(397)

242 pm

F F

S

S

10

15

18

X

HsynHanti

14

17X

X

15-F16-F13-F12-F

H(401)(400)(399)(398)(396) (395)

(402)(403)(404)(405) H

14-F15-F18-F17-F

X

12

3

48

9

12

13 15

16

1

3

4

5

7

9

13

values covered are 7.2–110.1 Hz and 318–242 pm,respectively.

J�F;F� � 275 000 exp�20:03211dFF� �1�The curve illustrating Eq. (1) and the data points fromwhich it was derived are shown in Fig. 1 together withthe curve for an equation postulated earlier by otherauthors [247]. Evidently, for the smaller distances, theearlier equation predicts coupling constants that aretoo small by a factor of two. This is caused by under-estimating the F,F-distances in the compounds fromwhich the equation was derived.

The four possible isomeric difluoro[2.2]paracyclo-phanes with one fluorine substituent per aromatic ringare the pseudo-geminal(396), the pseudo-ortho (398),the pseudo-meta (399) and the pseudo-para isomer(400). The pseudo-geminal isomer has already beenmentioned above with respect to its through-spaceF,F-coupling. Surprisingly, spin coupling betweenthe fluorine nuclei is also observed in (398) and(400), and theJ(F,F) values obtained from the13Csatellites in the19F NMR spectrum amount to 0.6and 2.8 Hz, respectively [165]. Only in (399) is theJ(F,F) coupling not resolved, see below, however. AsJ(F,F) in the nonpseudo-geminalisomers is largest in(400) in spite of the largest F,F-distance, this couplingwas assumed to be transmitted through thep-electronsystem of the [2.2]paracyclophane deck. The fourisomers were obtained as a mixture and their1H,13C and19F chemical shifts were assigned from one-

and two-dimensional spectra of the mixture, includingH,H-COSY, C,H- and F,H-HETCOR and C,H-COLOC [165]. The appearance of the H-5 (protonortho to the fluorine) signal for (399), (400) and(396) is instructive because of its dependence on themagnitude ofJ(F,F). The near-zeroJ(F,F) value in(399) leads to a first-order doublet of doublets forH-5 due to3J(F,H) and 4J(H,H), while a broadeneddd is observed for H-5 in (400) with its medium-sizedJ(F,F) and a second-order multiplet in (396) which hasthe largestJ(F,F) (Ref. [165, Fig. 2b]). The mono-fluoro compound (401) was also studied for compar-ison. Interesting features here are the through-spacecouplings between fluorine and its pseudo-geminalproton, J�F;H� � 3:1 Hz; and carbon, J�F;C� �1:6 Hz: The shape of the H-15/C-15 cross peak inthe 2D C,H-HETCOR spectrum shows thesecouplings to have like signs. The through-space F,C-coupling had not been observed previously [248,249].Also interesting is the observation that all13C nucleiof the nonfluorinated ring, apart from C-13, showsmall but observable couplings (0.15–1.57 Hz) tothe fluorine, the largest apart from the pseudo-geminalcarbon being the one with the most distant, thepseudo-para carbon (0.39 Hz). Here again, spincoupling is probably transmitted through the[2.2]paracyclophanep-electron system. The difluoro-dithia[3.3]cyclophanes (395) and (402)–(404), andthe monofluoro compound (405), synthetic precursorsof the [2.2]phanes (396), (398)–(400) and (401), were


240 250 260 270 280 290 300 310 320dFF [pm]

0

20

40

60

80

100

120

J(19

F,19

F)

[Hz]

J(F,F)=6800*exp( −0.0199*dFF)

J(F,F)=275000*exp( −0.03211*dFF)

Fig. 1. ExperimentalJ(19F,19F) values [Hz] vs. intramolecular F,F distancesdFF [pm] in some difluorocyclophanes. The data points are indicatedby the triangles. The curves represent the equationsJ�F;F� � 275 000 exp�20:03211dFF� derived in Ref. [246] andJ�F;F� �6800 exp�20:0199dFF� from Ref. [247].

also studied by the same techniques, the difluorocompounds again as a mixture. Interring F,C couplingconstants of 0.3–0.7 Hz were detectable betweenfluorine and its pseudo-geminal carbon nucleus in(402)–(405). In (405) also two smallJ(F,C) couplingsinvolving the carbon nuclei pseudo-ortho to the fluor-ine substituent were found, having values of 0.19 and0.09 Hz. The only interringJ(F,H) coupling constantobserved was the pseudo-geminal one in (405) of1.3 Hz. The decreased magnitudes of the interringcoupling constants in the dithia[3.3]paracyclophanesare in line with the larger interring distances in thesecompounds relative to the [2.2]paracyclophanes.

The 1H, 13C and 19F NMR spectra of thear,ar 0-difluoro[2.2]paracyclophanes (396) and (398)–(400)were studied again by Huang et al. [250], this time,however, of the separated stereoisomers. Basically,their results agree with those of Ref. [165] and, addi-tionally, they report a long-rangeJ(F,F) value of0.36 Hz in the pseudo-meta isomer (399). Refs.[165,250] differ, however, in the assignment of thechemical shifts of the diastereotopic protons in thebridge CH2 group ortho to a fluorine substituent. In(401), the shifts of the protonssyn and anti withrespect to the fluorine differ by 0.72 ppm, one proton

being shielded �Dd � 20:41�; and the otherdeshielded�Dd � 10:31� relative to the hydrocarbon,[2.2]paracyclophane. The question was settled infavour of Ref. [165] by reinvestigating (401) bymeans of 2D H,H-NOESY and further techniques[251] which clearly show that the deshielded protonis the onesynto fluorine.

Another series of compounds studied [252] withregard to possible long-range F,F spin–spin couplingconsists of difluoro[2.2]metaparacyclophane (406)and difluorodithia[3.3]metaparacyclophane (407). Insolution, both compounds occur as slowly intercon-verting syn and anti conformers in a 1:1 ratio. Theinterconversion barrier in (407) was determinedfrom the coalescence of the two pairs of19F NMRsignals to beDG‡�11258C� � 77:0^ 0:6 kJ mol21

:

This number is very similar to the value of76.2 kJ mol21 found earlier by Boekelheide et al.[184] for the monofluoro derivative (408). Hence,the additional fluorine substituent at thepara-bridgedring in (407) does not significantly increase the barrierto internal rotation. This appears reasonable as mole-cular models show that the C-14–F-14 moiety ishardly involved when the tip of themeta-bridgedring rotates through the interior of the molecule. The


F

X

F

X

1

23

69

11

1215

8

12

X = Fsyn-(406) anti-(406)(409) X = H

S

S

F

X

S

S

F

X

1

5

9

10

14

17

149

X = Fsyn-(407) anti-(407)(408) X = H

15

4

F

(410)

shorter bridges in (406) increase the rotational barriersuch that no coalescence occurs until11508C, so thelower limit of DG‡�11508C� is 89 kJ mol21. Vogtlehas shown long ago [253] that the barrier in 8-fluor-o[2.2]metaparacyclophane (409) is higher than95 kJ mol21 at 11908C. J(F,F) coupling constantscan be resolved in both conformers of both (406)and (407). They are 1.87 Hz in syn-(406),0.42 Hz in anti-(406), 0.49 Hz in syn-(407), and0.66 Hz in anti-(407). The ‘wrong order’ in (407),i.e. smallerJ(F,F) for the compound with the shorternonbonding F,F distance, speaks against a purethrough-space coupling mechanism. Also, the largercoupling constant of 1.87 Hz insyn-(406) is still muchsmaller than the value of 16.9 Hz predicted by Eq. (1)for the computed F,F distance of 302 pm. Thecomputed F,F distance insyn-(407) is 330 pm, forwhich Eq. (1) predictsJ(F,F) to be 6.9 Hz. The inap-plicability of Eq. (1) to these coupling constants maybe due to the different geometrical arrangement of theC–F bonds in the difluorometaparacyclophanescompared to the difluorometa- and -paracyclophanesfrom which the equation was derived. Formally, thearomatic rings in (406) and (407) are twisted relativeto each other by 308 about an axis joining theirmidpoints, whereas no such large twist is present inthe meta- and paracyclophanes. This could indicatethat factors other than the nonbonding distance maycontribute to determining the magnitude of through-space coupling constants. Further investigations alongthese lines are clearly indicated. All1H, 13C and 19FNMR signals in both conformers of (406) and (407)and also of the monofluoro analogues (408) and (409)were carefully assigned by appropriate 1D and 2DNMR techniques. A feature worth mentioning withregard to the difluorometaparacyclophanes is theobservability of relatively large (2.2–4.3 Hz)through-spaceJ(F,C) couplings from the fluorine atthe meta-bridged ring to thesyn-oriented carbonatoms of thepara-bridged ring but not from the fluor-ine at the para-bridged ring to analogous carbonnuclei at themeta-bridged ring. This is due to theparticular geometry of the metaparacyclophanes: thefluorine-bearing carbon atom of themeta-bridged ringlies over the centre of thepara-bridged ring. Thus, itsfluorine substituent is very close to thesyn-orientedcarbon atoms of thepara-bridged ring. The reverse isnot true for the fluorine at thepara-bridged ring and

its syn-carbons in themeta-bridged ring. The chemicalshifts of the aromatic protons and of the13C nuclei ofthe fluorine-bearing ring of 4-fluoro[2.2]metaparacy-clophane (410) have been assigned [249].

4. [3.3]Phanes

4.1. [3.3]Phane hydrocarbons

4.1.1. [3.3]MetacyclophanesAccording to molecular mechanics computations

the lowest conformational energy minimum of[3.3]metacyclophane (411) corresponds to thesyn(chair/chair) form (4110), which was also foundin the crystal by X-ray diffraction [254]. The symme-try of the 1H NMR spectrum at low temperature, thechemical shifts and the H,H coupling constants in thebridges prove that this conformation is also the majorone in solution. The signal for the intraannulararomatic proton of a second, minor conformer,presumably thesyn(chair/boat) one (41100), can alsobe observed at2508C. The benzylic protons of (411)are diastereotopic at low temperature and their signalscoalesce at ca.2298C (200 MHz). The barrierDG‡ tobridge inversion was determined to be 48 kJ mol21 atthis temperature. As the equilibrium constantK ofmajor to minor conformer could not be measureddirectly because of signal overlap in the1H spectrumand crystallization from the solution of the minorisomer, the temperature dependence of the chemicalshift of the internal carbon atom C-9 was used toestimateK. The results do not seem very precise.The signal of C-9 was also used in a lineshape analysisover a temperature range of only 18.58C. TheEa andlog A values reported convey the impression oflimited accuracy. This study implies that the onlyimportant dynamic process in [3.3]metacyclophaneis bridge wobbling (chair-to-boat interconversion),but Shinmyozu and coworkers [255] had concludedthat it is benzene ring inversion. Therefore, the lattergroup of authors designed (412), a [3.3]metacyclo-phane with an ethylenedioxy tether that preventedbenzene ring inversion [256]. In their low-tempera-ture1H NMR study of (412) they confirmed the bridgeinversion process postulated by Semmelhack et al.[254] and could observe all three possible conformers,chair–chair (412cc), chair–boat (412cb), and boat–


boat (412bb) which gave a total of four AB spectra forthe benzylic protons. At2708C the conformers arepresent in the ratio of 47:44:9. Signal coalescencewas observed at2118C and the barrier to bridgeinversion estimated to be 50.6–51.5 kJ mol21. Asthe high-temperature spectrum of the benzylic protonsof (412) consists of an AB pattern but that of (411) ofonly a singlet, the Japanese authors concluded that in(411) benzene ring inversion must occur in addition tobridge wobbling. A further study of the conforma-tional behaviour of a [3.3]metacyclophane derivativewas undertaken by Fukazawa et al. [257]. Theyanalysed variable temperature1H and 13C NMRspectra of 1,1,10,10-tetramethyl[3.3]metacyclophane(413) and, at2968C, observed the presence of thethree possible bridge conformers (cc, cb, and bb)with a syn arrangement of the benzene rings. Theseconformers interconvert by wobble motions of thebridges and aromatic ring flips to give their respectivemirror images. The barrier for the benzene ring flip-

ping process was found to be smaller (39 kJ mol21 at2838C) than the barriers of the wobble motions of thebridges (56 kJ mol21 at 238C). Benzene ring flippingoccurs most easily from thesyn-chair–boat confor-mer. A study of the conformational behaviour of[3.3]metacyclophane, rather similar to that ofSemmelhack et al. [254], was reported later by Sakoet al. [258]. They studied the low-temperature1HNMR spectra of 2,2,11,11-tetradeuterio[3.3]metacy-clophane (414) and its dimethoxy derivative (415)and came to the same conclusions. They also observedthe signals of a minor conformer, probably thesyn(boat/chair) one, but could not obtain furtherdetails because of signal broadening and overlap atlow temperature. Compound (415) behaves like itsparent. Irradiation of its intraannular proton signalcauses a 17% NOE at the axial bridge proton (in thechair conformation), thus proving that the shieldedmethylene protons are axial�d � 2:50�; while thedeshielded ones are equatorial�d � 2:97�:


(411) (411’) (411")

(412cc)

D2 D2

H

H

2.46

2.95

J = 13.8 Hz

6.32

6.61

OO

(412cb)

D2

D2

H

H

2.47

2.95

J = 13.8 Hz

6.29

6.71

OO

6.20

H

H2.35

3.02

J=

14.7

Hz

(412bb)

D2 D2

6.83

OO

6.16

H

H2.32

3.03

J=

14.6

Hz

(413)(414), R = H(415), R = OMe

RR

D2D2

Hax

Heq2.97

2.50

A number of 1-methyl-3-(a-R-b-trans-styryl)[3.3]-metacyclophanes plus a [4.3]- and a [5.3]metacyclo-phane were elucidated with respect to their preferredsyn/anti conformation and thecis/trans substitutionpattern of the three-membered bridges [259]. Themethods applied were Lehner’sd (Hi) 2 d(He) rule[260] (cf. Section 5), variable temperature1H NMRand NOE difference spectra. The compounds studiedwere (416a)–(416c) with 1,3-cis-disubstitution andpreference of thesyn conformation, (417a)–(417c),with 1,3-trans-disubstitution and preference of the

anti conformation, (418) and (419) (cis–anti) andthe model compoundscis- and trans-(420). The low-temperature1H spectra ofcis-(420) shows doubledsignals for the internal proton and the methyl group�DdMe � 0:035�; which the authors attributed to slowinterconversion of the chair–chair and chair–boatconformers.DG‡

c was determined by a coalescencemeasurement to be 48:5^ 0:4 kJ mol21 at 2428C.The separation of the methyl signals for thetransdiastereomer of (420) is much larger�DdMe � 0:38�andDG‡

c is 47:7^ 1:3 kJ mol21 (Tc not reported).


(416)

CH3R

H

H

H Me Ph

cba

R

cis-(420)

(417)

Me H

R

H

(418), n = 4(419), n = 5

(CH2)n

CH3

H3C

H3C H3C

H3C

chair-chair chair-boat

O O5.94

6.7−7.2(4 H)

(422), R = CO2Et (anti)

R

R R

ROMe

tBu

(423), R = H (syn)(421)

[3.3]Metacyclophane-6,9-quinone (421) [261]possesses thesyn conformation as evidenced by thesignificant shielding of its olefinic protons�d � 5:94�relative to the model compound 2,6-dimethyl-p-benzoquinone�d � 6:60�: Its 1H NMR spectrumdoes not change with temperature in the range270to 12008C. Thepara- andmetapara-isomers of (421)are treated in the following sections. In the same refer-ence, the preferred conformations of the [3.3]metacy-clophanes (422) and (423) were determined to beantiand syn, respectively, mainly from the1H chemicalshifts of the internal aromatic and methoxy protons.These ared � 6:13 and 3.50 (422) andd � 7:23 and3.68 (423).

Breitenbach et al. [262] proved the preference oftheanti conformation for [3.3]metacyclophanes (424)and (425) by X-ray diffraction and1H NMR spectro-scopy. The chemical shifts of the intraannular protonsHi in these compounds ared � 5:53 and 6.52, respec-tively, caused by the ring current of the opposite ringin theanti conformation. The authors claimed theanticonformation of (424) and (425) to be unprecedented.This needs to be corrected, cf. the work by Krois andLehner [260]. When diketone (424) is reduced to thediol, product (426) assumes the usualsynconforma-tion with d�Hi� � 7:8:

A paper by Osada et al. [263] reported the1H and13C NMR data of the 9-halo[3.3]metacyclophanes(427a)–(427d), which like the parent compound(411) prefer thesyn conformation, and of the corre-sponding 2,11-diones (428a)–(428d), which favourtheanti arrangement. The main subject of the discus-sion is the influence of the halogens upon the chemicalshifts of the intraannular hydrogens and of the carbonatoms (C-18) to which these are bound. Halogenationof C-9 causes upfield shifts of C-18 by 4.0–5.7 ppm(F , I , Br , Cl) in the [3.3]metacyclophanes andby 1.7–2.6 ppm (I, Cl , Br , F) in the [3.3]meta-cyclophanediones, so there are no obvious trendswithin the halogen series. The chemical shift of H-18 in the diones (428) decreases steadily with increas-ing size of the halogen, beingd � 5:78 for the parentcompound (429) and 5.65, 5.27, 5.20, and 5.12 for theF-, Cl-, Br-, and I-derivatives, respectively. This wasattributed to increased tilting of the halogen-bearingring away from the opposite ring in theanti conforma-tion. At the same time, this movement forces H-18further into the p-cloud of the halogen-bearing

benzene ring, thereby increasing the shielding of H-18. In thesyn-metacyclophanes (427), H-18 is directlyinfluenced by the halogen and its chemical shiftdecreases in the orderd � 7:21; 7.15, 7.12, 6.98,6.87 for the 9-substituents F, Cl, Br, I, and H. In(427a), H-18 shows a through-spaceJ(F,H) couplingof 4.4 Hz. In another study of transannular inter-actions in fluoro[3.3]metacyclophanes, Osada et al.[264] described the difluorophane (430), in whichthe two fluorine substituents approach each otherclosely. The authors give values of 253 and 10 Hzfor J(F-9,C-9) andJ(F-18,C-9), respectively, the latterbeing due to through-space spin–spin coupling.Probably, however, these numbers are the result ofthe neglect of strong F,F spin–spin coupling whichis expected for this molecule and has been shown toexist in the corresponding difluorodithia[3.3]metacy-clophane [243]. A large value ofJ(F,F) in (430) makesC-9 the X part of an ABX spin system (A� F-9,B� F-18). The parameters involved cause the Xpart to have six lines of which two are of rathersmall intensity and are easily lost in the baselinenoise. The line spacings in the remaining apparentdoublet of doublets do not correspond by any meansto the trueJ(F,C) values, cf. the analogous situation in(392) (Section 3.9).

Fukazawa et al. undertook the conformationalanalysis of 1,1,10,10-tetramethyl[3.3]metayclo-phane-2,11-dione (431) [265]. To this end they gener-ated plausible conformers by molecular mechanicscalculations, estimated the chemical shifts of protonsa–d in these conformers [relative to model compound(432)] from contributions expected by the secondaromatic ring and the two carbonyl groups (seebelow) and adjusted the populations of the conformersso as to achieve the best fit between calculated andobserved shifts, cf. Section 5 for details. Optimumagreement was found when three equilibrating confor-mers were assumed, viz. a majoranti (94%), approxi-mated by (431a), and two minor (3% each)synconformers. In this way, the differences between fittedand experimental incremental shifts for protons a–dcould be minimized to 0.03–0.07 ppm. Experimen-tally, flipping of the benzene rings becomes slow at2658C when the methyl signal starts to split into two�DG‡ � 41 kJ mol21�; but no minor signal could bedetected even at21108C. The substituent-inducedchemical shifts exerted by the carbonyl groups (see


above) were calculated by the use of new shieldingparameters [266]. These were obtained by least-squares multiple regression analysis of Zu¨rcher’sexperimental values of keto-steroids [267] andgeometrical factors newly calculated with the MM3molecular mechanics program.

Compound (433) may be considered a [3.3]meta-cyclophane with two oxazole rings annelated to itstrimethylene bridges [268]. The upfield shifts of theouter protons of ring A�Dd < 0:22� relative to m-xylene were taken as indicators of a preferredsyn

conformation. The shifts of the inner protons ofrings A and B were not taken into account becauseof potential disturbing shift effects of the oxazolerings. Coalescence of the methylene AB spectrum at1388C gaveDG‡ � 64:5 kJ mol21

: This is a substan-tially higher barrier to conformational inversion thanin the case of [3.3]metacyclophane (411) whereDG‡

is 48.1 kJ mol21 at 2298C. Hence, (433) is conforma-tionally more rigid than (411) due to annelation of thetwo oxazole rings to the methylene bridges.Compound (434) [269] is the formal product of


(424), anti

O O SS

tBu

tBu

(426), syn

tBu

tBu

H

OH

H

HO

N

N CO2Et

CO2Et

EtO2C

EtO2C

(425), anti

X9

18

(427a), X = F(427b), X = Cl(427c), X = Br(427d), X = I

X

OO

18

9

(428a), X = F(428b), X = Cl(428c), X = Br(428d), X = I

(429)

O O

F9

18

(430)

F

O

Oa

b

c

d

(431) (432)

O

O

(431a)

annelating two imidazole rings to the bridges of[3.3]metacyclophane and additionally carries two 4-bromophenyl groups. The1H NMR spectrum at258Cshows the presence of thesynand theanti conformerin a ratio of ca. 3:5. All proton signals of both confor-mers were assigned by means of an H,H-COSYexperiment. The signals of the nonequivalent methy-lene protons coalesce at1808C, which furnished aninterconversion barrierDG‡ of 69.3 kJ mol21, some-what larger than in both (411) and (433). This wasattributed in part to the bulky substituents on theimidazole rings. Further studies along the same linesdealt with furanometacyclophane (435) [270], whichhas a 2,5-furandiyl moiety instead of them-phenylene

unit B of (433), and the analogous thiophenophane(436) [271]. At room temperature, the furan protonsof (435) are shielded by 0.26 ppm relative to those ofthe acyclic model (437) which was taken as evidenceof the preferredsyn conformation. At low tempera-ture, the CH2 protons become diastereotopic while thearomatic1H signals do not change much. Coalescenceof the CH2 signals at Tc � 1128C gave DG‡ �58:0 kJ mol21 at this temperature. This barrier islower than that of (433) in line with the less congestedtransition state due to the furan oxygen compared toan aromatic C-H unit. By contrast,DG‡ for (436) is69.4 kJ mol21 at1698C, higher than in both (435) and(433). At low temperature, thiophenophane (436)


(433)

N

O

N

O

A

B

(434)

N N

N N

Br Br

(435), X = O

N

O

N

OX

(436), X = S

NO

ON

O

(437)

Hi

X

NR

RR

R R

RR

R

X

(438), X = CH; R,R: =O(439), X = N; R,R: =O(440), X = CH; R = H(441), X = N; R = H

(442), X = O; R,R: =O(443), X = S; R,R: =O(444), X = O; R = H(445), X = S; R = H

Fe

(446)

3.27

3.85

3.83

6.90−6.50 (4 H)

gives two sets of1H signals which, from their chemi-cal shifts, were attributed to thesynandanti-confor-mers. At2318C, thesyn/anti ratio is 2:5. The signalsin the low-temperature spectrum were assigned byH,H-COSY. Important chemical shifts are: thio-phene-H,d � 7:21 (anti) and 6.46 (syn); m-pheny-lene-Hi, d � 6:18 (anti) and 6.89 (syn).

The hetero analogues (438)–(445) of [3.3]metacy-clophane were reported by Shinmyozu et al. [272].Comparison of their aromatic1H NMR chemicalshifts with those ofm-xylene or 2,6-dimethylpyridineindicates preference of thesyn conformation of allcompounds containing unsubstituted trimethylenebridges, viz. (440), (441), (444), (445), and of theanti conformation for the diketones (438), (439),(442), (443). Theanti preference of [3.3] metacyclo-phane-2,11-dione (429) had been demonstrated beforeby Krois and Lehner [260], cf. Section 5. The confor-mation of the bridges in [3.3](2,6)pyridinophane(441) was studied by low-temperature1H NMR ofthe deuterated derivative (441-d4) [273]. Below21108C the benzylic protons and the aromaticprotons each give two major and two minor signalsthat were assigned to the boat–boat conformer(441bb) and the boat–chair conformer (441bc) asshown in the formulae (1H chemical shifts at21358C in CD2Cl2/CBr2F2, 3:2, are given). Themain argument was the deshielding observed for theortho-protons of the bridge in the chair conformation.A rough estimate of the conformer populations at21358C is (441bb):(441bc) < 3:2. The barrier tochair–boat interconversion was estimated asDG‡�21108C� � 36:4^ 1:7 kJ mol21

: This is lowerthan the barriers in [3.3]metacyclo(2,6)pyridinophane(440), 45.6 kJ mol21, and in [3.3]metacyclophane(411), 48.1 kJ mol21.

In the 1H NMR spectrum of [3.3]metacyclo(1,3)-

ferrocenophane (446), the shielding of the ferroceneprotons H-4,5 relative to H-2 and to H-10,20,30,40,50

indicates the preferredsynconformation of the mole-cule [217].

4.1.2. [3.3]ParacyclophanesFollowing earlier work by Anet et al. [274] and by

Benn et al. [275], the conformational behaviour of[3.3]paracyclophane was reinvestigated by Sako etal. [276]. These authors studied variable-temperature1H and 13C NMR spectra of 2,2,11,11-tetradeuter-io[3.3]paracyclophane (447). At low temperature,separate signals were observed for the boat andchair conformers, the former being slightly favouredat 2708C in CD2Cl2 solution (boat/chair� 1.3/1.0;DG�20.4 kJ mol21). The bridge proton signalsturned into AB spectra below2158C and the aromaticproton signals into AA0BB 0 spectra below2308C.Boat and chair conformers could be distinguishedfrom their J(A,B) coupling constants, 7.8 Hz (chair)and,1.5 Hz (boat). Assignment of the proton signalsrelied on NOE measurements (axial benzylic H!aromatic ortho-H), those of the13C signals on thedifferent signal intensities for the conformers. Thebarrier to bridge inversion was determined asDG‡�2158C� � 50:2 kJ mol21

: The assignment ofthe aromatic proton shifts was reversed with respectto Ref. [275]. The trimethylene bridge causesdeshielding of theortho proton in thesynorientation(ca. 10.14 ppm) and shielding of the correspondingortho carbon atom (ca.22.8 ppm), both with respectto the counterpart in theanti orientation.

In the 1-methyl-3-R-[3.3]paracyclophanes (448)–(451) [277] thecis or transconfiguration of the avail-able diastereomers was inferred from the1H chemicalshifts of the 1-methyl groups. In thecis diastereomersthe methyl group always occupies a quasi-equatorial


N

ND

DD

D

(441-d4)

N

(441bc)

NN

(441bb)

N

D2D2D2

D2

Ha

Hb

Heq

Hax Hax’

Heq’

Ha’

Hb’

Ha"

Hax"

Heq"

3.14

2.55

7.01

6.42

2.86

3.25

6.63

7.14 6.42

2.55

3.14

position on the trimethylene bridge while it is fully orpartly quasi-axial in thetrans diastereomers. As thequasi-equatorial position is outside the plane of thearomatic ring, a methyl group in this position willbe shielded relative to one in thetrans diastereomer.For example,dH(CH3) is 1.12 incis-(448) and 1.27 intrans-(448). A safer criterion for the configurationalassignment is the low-temperature behaviour of theisomers. A cis isomer is not expected to show aconformational inversion of the disubstituted chain,because both substituents take quasi-equatorial posi-tions, whereas thetrans isomer is expected to invert

the chain conformation. Variable-temperature1HNMR measurements corroborated these expectations.In these experiments, methyl signal coalescencetemperatures between243 and2288C were found.Line shape analyses over limited temperature rangesyielded DH‡ values for bridge inversion of ca.29 kJ mol21 andDS‡ values of ca.267 J K21 mol21

for the trans isomers of (448)–(450). This corre-sponds toDG‡ values of ca. 48 kJ mol21 at 08C. Therather smallDH‡ value of 19.7 kJ mol21 and the verylargeDS‡ of 2111 J K21 mol21 for (451), which givea similar DG‡(08C) as the other compounds, viz.


D

D

D

D

D

D

D

D

chair boat

(447)

H3C R H3C R

cis- trans-R

CH3

styrylα-methylstyryl

inden-2-yl(450)(451)

(449)(448)

H3C R H3C R

(452) (453)

49.8 kJ mol21, do not appear convincing. The equili-brium populations at low temperature are different forthe different R groups and reflect the relative size ofthe substituents in the order methyl, styryl , a-methylstyrylp indenyl. Later, the same groupstudied 1,3-substituted [3.3]paracyclo(1,4) naphthale-nophanes (452) and [3.3](1,4)naphthalenophanes(453) carrying a methyl group and the same R groupsas above [278]. The structures of the compounds werederived from variable-temperature1H NMR spectraand NOE determinations. The barriers to bridge inver-sion are very similar to those of the [3.3]paracyclo-phanes (448)–(451). In the series (452) there existsthe additional problem of constitutional isomerismbecause one substituent can be adjacent to the pheny-lene and the other adjacent to the naphthylene ring orvice versa.

The olefinic protons�d � 6:05� and, to a lesserdegree, also the aromatic protons�d � 6:90� of[3.3]paracyclophane-5,8-quinone (454) [261] aredeshielded relative to the [2.2]analogue (d � 5:78and 6.84/6.73, resp.) which was described muchearlier by Cram et al. [279]. This shift differencereflects the larger interdeck distance in (454).

4.1.3. [3.3]MetaparacyclophanesPhanes (455) and (456) [268] are isomeric

[3.3]metaparacyclophanes that differ in the positions

of oxazole annelation. While freezing of conforma-tional exchange could not be observed down to2808C for (455) which has its oxazole ringscondensed to the CH2CH2 unit next to them-pheny-lene ring, a barrierDG‡ of 47.7 kJ mol21 was deter-mined for (456), where the oxazole rings are next tothe p-phenylene rings.

Apart from the [3.3]meta-(421) and the [3.3]para-cyclophanequinone (454) discussed in the precedingsections, the paper by Shinmyozu et al. [261]describes the two isomeric [3.3]metaparacyclophane-quinones (457) and (458). In the first one of these,rotation of thep-phenylene ring and flipping of them-bridged quinone ring are both restricted at roomtemperature as two1H chemical shifts are discernedfor the p-phenylene ring, see the formula. The singleolefinic 1H shift in (458) was interpreted as (probably)indicating rapid flipping of them-phenylene ring. Thelatter process is also fast in (459) whereas both rota-tion and flipping are slow in (460) due to the presenceof the internal methoxy substituent.

4.1.4. Other [3.3]cyclophanesStaab and coworkers [280] described [3.3]orthopara-

cyclophane (461). Molecular models show that theplanes of the two aromatic rings are likely to be paral-lel to each other but shifted sideways. As the1H NMRspectrum at1108C has sharp lines for both aliphatic


O

O

6.05

(454)

6.90

(455)

N

O

N

O

(456)

O

N

O

N

O

O

6.90/7.00

6.72

(457)

6.20

(458)

OO

6.55

6.94

6.06 OMe3.28

6.80

tBu 1.30

(460)

7.3−6.5

(459)

OMe

OMe5.73

6.22 3.54

and aromatic protons, there must be a fast transitionbetween the two possible equivalent conformations.One pair of the benzylic protons is shielded by ca.0.9 ppm relative to the other. Presumably these arethe CH2 protons at theortho-substituted ring whichreside in the shielding zone of thepara-ring. At lowertemperature (not specified), the1H NMR signals startto broaden, indicating the slowing down of the confor-mational interconversion. The [4.4]orthopara analo-gue (462) shows less signal broadening. This couldmean a lower conformational barrier or a differentground state conformation. The1H NMR spectrumof [3.3]orthometacyclophane (463) shows that themolecule is frozen in ananti conformation at2608C. This is suggested by the chemical shift ofthe internal proton�d � 6:03� on themeta-substitutedring.

The two sides of thep-phenylene rings in [3.3]para-cyclo(2,5)thiophenophane (464) and its tetracyanoderivative (465) are nonequivalent in the roomtemperature1H NMR spectrum [281]. Signal coales-cence was observed at150 and1988C, respectively,giving free energies of activation for the flipping ofthe thiophene ring of 66.5 and 76.6 kJ mol21.

H-2 of the indole moiety of [3.3](1,3)indoloparacy-clophane (466) [282] has a chemical shiftd � 5:59:This is 1.36 ppm upfield from the value in theimmediate synthetic precursor, a 3-(3-arylpropyl)in-dole, and shows that the indole hydrogen must lie overthep-phenylene ring. The three-membered bridges of

(466) can assume chair or boat conformations. AM1calculations predict the Cchair,Nchair-conformer to bethe most stable. The resonances of thep-phenylenering give a slightly broadened “AB” spectrum(d � 6:65 and 6.57) at room temperature indicatingrapid conformational averaging. The NCH2 protonshave a common shift ofd � 4:00 and their signalshave triplet multiplicity�J � 6:6 Hz�: At 2908C, thep-phenylene ring shows four different1H shifts and apattern termed “two AB systems” by the authors(correct: one ABXY system),d � 7:04=6:94 and6.21/6.00. The NCH2 protons are diastereotopic atlow temperature withd � 4:25 and 3.63. The coales-cence of their signals at237^ 38C yielded a confor-mational barrierDG‡ of 45:6^ 0:8 kJ mol21

: As noneof the bridge wobble motions that interconvert thevarious bridge conformers results in a site exchangeof the diastereotopic NCH2 protons, the processobserved must be a ring flip. This is followed by atwo-fold bridge wobble to furnish the enantiomer ofthe starting conformer. One of several possibleconformational pathways is shown in the formulae.

4.2. Dithia- and diaza[3.3]phanes

4.2.1. Dithia- and diaza[3.3]metacyclophanesMitchell and coworkers [114] have investigated the

influence of large internal substituents upon therelative stability of thesyn and anti conformers of2,11-dithia[3.3]metacyclophanes. When a single


6.92

2.701.91

1.81

6.90−6.69

(461) (462) (463)

6.03

6.93

7.21

−7.15

7.27−7.15

S

X

X

X

X

(464), X = H(465), X = CN

6.17 6.966.41

[shifts given for (464)]

tert-butyl group is present as an internal substituent(i.e. connected to C-9), only thesyn isomer (467) isformed. A methyl group as the second internal substi-tuent leads to asyn/anti mixture (6:4 at 808C and 7:3at 508C) of (468a)/(468b) and the presence of twointernal tert-butyl groups allows the formation ofonly the anti conformer (469). The anti isomerswere identified by the upfield1H shifts of the substi-tuents by the second aromatic ring, cf. thetert-butylshifts ofd < 1:05 in (468b) and (469) and the methylshift of d � 1:68 in (468b). The syn isomers showchemical shifts which are closer to ‘normal’ values.However, the authors point to the exceptional shield-ing of the hydrogenspara to the tert-butyl group in

(467) and (468a) which may arise by a sliding of theopposite ring in order to avoid thet-Bu/Me or t-Bu/Hinteractions. Such sliding should also shield the Me orH in question, which was indeed found:dMe � 2:29anddH � 6:26 compared to the dimethyl compound�dMe � 2:52� and the parent compound�dH � 6:76�:None of the compounds investigated showed signsof hindered tert-butyl rotation in the 1H NMRspectrum down to2908C. For theanti conformer ofmono-tert-butyl[2.2]metacyclophane which was alsostudied by these authors, see Section 3.

The conformation of 2,11-dithia[3.3]metacyclo-phane (470) is syn[283], butsynandanti conformersare known for the derivative which carries two


N

(466)

N NN

ent-Cboat,Nboat ent-Cchair,NchairCchair,Nchair

HA

HB

HA

HB

HB

HA

S

S

H

tBu

S

S

Me

tBu

SMe

tBuS

StBu

tBuS

(468b), anti

(468a), syn(467), syn

(469), anti

6.60

7.02

7.02

6.89 6.26

1.52 1.45

2.296.91

6.83

7.01

6.50

1.047.04

7.15

7.06

7.36

1.68

1.066.95

7.06

internal methyl substituents, i.e. at C-9 and C-18. Laiand Zhou [111] fully assigned the1H NMR spectrum,including the signals of the bridge protons, of amixture of thesynandanti-isomers of the 9-fluoro-18-methyl derivative (471). The most significantdifference between the isomers concerned, of course,the chemical shifts of the methyl groups:d � 2:45(syn) and 1.51 (anti). For C-9 monosubstituted deri-vatives of 2,11-dithia[3.3]metacyclophanes, theconformation is difficult to predict. Mitchell andcolleagues [284] investigated the 9-phenyl derivative(472) and found that it issynboth in the crystal and in

solution. Rotation of the phenyl ring is hindered attemperatures below1608C as seen from the differentchemical shifts of H-20 and H-60. Thesynconforma-tion of the cyclophane rings follows from the goodagreement between the observed relative chemicalshifts of H-18, H-20 and H-60 and the shielding effectsof the three aromatic rings upon these nuclei aspredicted by Johnson–Bovey-type ring current calcu-lations [79]. The indenometacyclophane (473), adithia[3.3]metacyclophane with an annelated cyclo-pentane ring, is interesting because it shows chemicalequivalence of the geminal protons within the three


(470)

SS

F

CH3

SS

H

HH

H

2.454.32

3.63

3.37

4.18

syn

F CH3

S

S

H

H

anti(471)

H

H

3.80

3.763.75

3.32

1.51

7.19

7.34

7.23

7.026.67

6.91

6.707.00

−121.8 −123.2

(472)

SS

H18

H6’H2’

(473)

SS

H

H

HH H

H

(474), cis(e,e)

S SSS

(474), cis(a,a)

S SSS

R

H H

R H

R R

H

(474), trans(e,a)

S SSS

R

H R

H

Fe

(475)

3.65

3.93

3.97

7.0−6.9

S S6.79

methylene groups of the five-membered ring [116].This can only be explained by a fastsyn/syn0

equilibrium on the NMR time scale at room tempera-ture, which interchanges theexoandendohydrogens.It is in accord with the low activation barrier to ringflipping that has been observed in [3.3]metacyclo-phane [258] and computed for 2,11-dithia[3.3]meta-cyclophane [285].

The 2,11-disubstituted 1,3,10,12-tetrathia[3.3]meta-cyclophanes (474) could, in principle, exist as threeconfigurational isomers. In the preferredsyn-conforma-tionof the two arene rings, these diastereomerswould betrans(ea),cis(ee), andcis(aa). Due to fast ring flipping atall readily accessible temperatures, the twocis-isomersinterconvert rapidly, so only two configurationalisomers can be isolated. Beer et al. [286] prepared(474), R�CH3, isolated one diastereomer, which iscis according to X-ray diffraction analysis, and couldthus assign the1H and 13C NMR spectra of thecisandtransisomers. As the chemical shifts do not differmuch, the results do not allow the configurationalassignment of the ferrocenyl-substituted phanes(474), R� �C5H5�Fe�C5H4�: The 1H NMR spectrumof the diastereomeric mixture of (474), R� CH3,shows sharp resonances at room temperature andsignal broadening but no decoalescence of signals at2628C.

In the 1H NMR spectrum of dithia[3.3]metacy-clo(1,3)ferrocenophane (475), the shielding of theferrocene protons H-4,5 relative to H-2 and to H-10,20,30,40,50 indicates the preferredsynconformationof the molecule as has already been mentioned for theanalogous [3.3]phane hydrocarbon (446) [217].

While the effects of Cr(CO)3 complexation uponNMR chemical shifts have been well studied for [n]-and [2.2]cyclophanes (cf. Sections 2 and 3), this is notthe case for dithia[3.3]cyclophanes. Since the spacingbetween the arene rings in these compounds is differ-ent from the [2.2]phanes and sincesyn and antiisomers of dithia[3.3]metacyclophanes are known,this class of complexes promised additional informa-tion. Mitchell et al. [287] conducted a thorough studyof the1H and13C NMR spectra of Cr(CO)3 complexesof substitutedsyn-dithia[3.3]metacyclophanes (476),of anti-9,18-dimethyl-dithia[3.3] metacyclophane(477), of dithia[3.3]paracyclophane (478), and of thebis-Cr(CO)3 complexes ofsyn-dithia[3.3]metacyclo-phanes (479). The chemical shifts of these compounds

were compared with those of the complexes of analo-gous simple benzene derivatives. The conclusionsderived from these data are: (i) the tricarbonyl“umbrella” in the complexed dithiametacyclophanesfavours the conformation in which the carbonylgroups eclipse the cyclophane bridges; (ii) the reduc-tion in ring current in the arene rings is estimated at40% on Cr(CO)3 complexation (cf. Ref. [140]); (iii)the complexation shifts are 1.6–2.0 ppm for protons,32–39 ppm for tertiary, and 26–29 ppm for quatern-ary carbon atoms.

From the1H chemical shifts of the methyl groups�d � 1:31�; 9,18-dimethyl-2,11-diselena[3.3]metacy-clophane (480) was shown to occur mainly as theanti conformer [288]. Thesyn conformer, found inthe mother liquor but not obtained pure, hasd�CH3� �2:43: These chemical shift values compare well withthose of the thia-analogues, which ared � 1:30 and2.54, respectively [9]. Previously, structure (480) haderroneously been assigned to a compound with differ-ent properties [289]. The authentic structure was nowalso proved by X-ray diffraction. Its77Se and13Cshifts are available. The methyl-free diselenacompound (481) was studied by low-temperature1H, 13C and 77Se NMR spectroscopy and found toprefer thesyn over theanti conformation by a ratioof 3:2 at ca.21008C [285]. The barrierDG‡ to syn!anti conversion was determined to be 34.4 kJ mol21

(at 2708C) from the 77Se spectra and 34.8 kJ mol21

(at 2868C) from the 1H spectra. Bridge wobblingbetween chair and boat conformations was notobserved and, hence, must have an even lower barrier.

Very recently, the conformational analysis of (482),the 2,11-diaza analogue of (392) was reported [290].The synand anti isomers could be isolated, theantiisomer slowly converting tosyn in solution. Kineticmeasurements by1H NMR gave Ea � 104^4 kJ mol21 for this process in CD3CN solution. Deter-mination of isomer ratios by1H NMR between1110and11708C gaveDH � 5:94^ 0:46 kJ mol21

; DS�28:0^ 0:8 J K21 mol21 and DG8�1258C� � 8:3^0:8 kJ mol21

: Below 2108C the 1H spectrum of theCH2 groups in thesyn-isomer changes from one ABsystem to four AB systems, one each for the boat–boat (bb) and chair–chair (cc) conformers and two forthe boat–chair (bc) conformer of the diaza bridges. Inagreement with this, the19F NMR spectrum showsthree signals below1108C. At low temperatures the


stability of the conformers is bb. bc. cc, but withincreasing temperature the proportion of bb decreasesand the proportions of both bc and cc increase. Theoverall activation energy of boat–chair interconver-sion was estimated as 50–54 kJ mol21 at 2108C fromthe coalescence of the CH2

1H NMR signals.Formally, cyclophane (483) is also a 2,11-

diaza[3.3]metacyclophane, but with imidazole ringsannelated to the bridges [291]. The intraannularhydrogens have chemical shiftsd � 5:94 and 5.65.This clearly proves theanti conformation. No otherconformation was detected when the sample wascooled to2888C. The benzylic protons have a shiftdifference of 0.49 ppm at room temperature and their

signals coalesce at11028C (300 MHz), soDG‡ is75.3 kJ mol21.

The 2,11-diaza[3.3]metacyclophanes (484) [292]with three methyl groups per aromatic ring preferthe anti conformation as indicated by the highlyshielded protons of the intraannular methyl groups,d � 1:04–1:05: Compound (485) with only onemethyl-substituted ring favours thesynarrangement,dMe � 2:03: No change of its spectrum was observedup to11808C. An indication of thesynconformationof diaza[3.3](2,6)pyridinophanes (486) was obtainedfrom the upfield shifts, by 0.22–0.25 ppm, of theiraromatic protons with respect to the corresponding‘trimeric’ compounds (487).


R S

SS

S

Cr(CO)3

5

6

9

(476)

18

(CO)3Cr

CH3

H3C

(477)

RH6-Me5,7-Me2

9-F18-F9,18-F2

9,18-Me2

R S

S

Cr(CO)3

9

(479)

18

RH9,18-F2

Cr(CO)3

(CO)3Cr

(478)

S S

SeSe

(480) syn-(481)

SeSe SeSe

anti-(481)

379.3 321.9

26.329.57.15.8

(1H) (13C)

(77Se)

NH

F

F

NHHN

NHF

F

syn anti

(482)

4.2.2. Dithia- and diaza[3.3]paracyclophanesDissolution of tetrafluoro-2,11-dithia[3.3]paracy-

clophane and -[3.3]metaparacyclophane in superaci-dic media gave the corresponding acidicbis(sulfonium cations) (488) and (489), respectively[293]. These could not be further (ring-)protonated togive monoarenium-bis(sulfonium) trications.1H, 13C,and 19F NMR chemical shifts were reported for thedications and compared with those of the nonfluori-nated analogues and of the nonprotonated precursors.

The 2,11-diaza[3.3]paracyclophanes (490) [292]are chiral due to their ring substitution pattern. Thiswas proved by addition of the chiral shift reagentEu(dcm)3 to the N-unsubstituted cyclophane, whichcaused doubling of the methyl and aromatic protonsignals. The CH2 groups give an AB pattern in the

1H spectrum. This pattern is unchanged up to11808C which indicates that rotation of thep-pheny-lene rings is not possible even at the high-temperaturelimit.

4.2.3. Other dithia- and diaza[3.3]phanesThe “other [3.3]phanes” covered in this section are

mainly dithiaphanes with only very few examples ofdiaza- and diselenaphanes. Important types containedare metaparacyclophanes, naphthalenophanes, phanescontaining higher aromatic systems, azulenophanes,heterophanes, and adamantanophanes.

The dimethyldithia[3.3]metaparacyclophane (491)was isolated as a single conformer which has the methylgroupsanti to H-9 [179]. This conformation followedfrom the considerable upfield shift of the methyl protons


N

(483)

N

Br

NN

NR

(484)

RN NTs

(485)

TsN

R = H, Me or Ts

NRN

N

(486), R = H or Me

RN

N

NN

RN

N

NR

R

(487), R = H or Me

F

F F

F

S

S

H+

H

+

(488)

F

F F

F

S

S

H+

H

+

(489)

N

NR

R

(490), R = H, Me or Ts

�d � 1:86� and of H-9�d � 5:81�: They both are underthe influence of the ring current of the opposite aromaticring and this is not the case for H-17,18�d � 6:92�: It isof note that the preferred conformation of (491) is oppo-site to that of its [2.2]analogue, (264), cf. Section 3.3.The protons in both types of methylene groups of(491) are nonequivalent at room temperature and,surprisingly, remained so up to11508C. Thus, thereexists a high barrier to conformational inversion inthis [3.3]metaparacyclophane.

A paper by Bodwell et al. treats the conformationalbehaviour of dithia[3.3]orthometa- and -orthoparacy-clophanes [294]. The internal proton of 2,11-dithia[3.3]orthometacyclophane (492) resonates atd � 5:92; strongly indicating that theanti-chair,chairconformation is heavily populated. Out of six limitingconformations (plus their mirror images) suggested byexamination of molecular models, this is the only onein which the internal proton extends into the shieldingzone of the opposite deck. The1H NMR signals of thetwo types of methylene groups are singlets at roomtemperature and decoalesce into two well-resolvedAB spectra below 227 K�Dn � 51:3 Hz� and 219 K�Dn � 21:3 Hz�; respectively. The barrierDG‡ to theexchange of the geminal protons was determined to be45:7^ 0:8 kJ mol21

: A very similar result,DG‡ �46:5^ 0:8 kJ mol21

; was obtained for the indano-phane (493). Compound (494), the diselena analogueof (492), is also known [295]. The chemical shift of itsinternal proton atdH � 6:00 suggests that it behavessimilarly to (492) in solution. The methylene signals

of 2,11-dithia[3.3]orthoparacyclophane (495) are alsosinglets at room temperature, but upon cooling to thelower temperature limit of the spectrometer (170 K),only a broadening of these signals was observed andan upper limit of the energy barrier of ca. 37 kJ mol21

was estimated. According to models, the sole confor-mational process available to (495) is the flipping ofthe ortho ring from one side to the other of thepararing. Two 9-substituted 2,11-dithia[3.3]orthometacy-clophanes, (496) and (497), were reported by Yamatoet al. [296]. The methyl group in (496) has a 1Hchemical shift ofd � 1:38 which supports a strongpreference for theanti conformer. This was alsofound for the solid state by X-ray diffraction. Incontrast, the methoxy group in (497) has a normalchemical shift ofd � 3:64; but the aromatic protonsare more shielded than those of (496). Hence, (497)strongly prefers thesynconformation. At11508C insolution (DMSO-d6) and at 4008C in the solid state,neither compound shows signs of conversion into theother isomer.

Lai et al. [186] studied some dithia[3.3]metacy-clo(1,4)naphthalenophanes in order to see whetherthere is the same change of conformational preferencebetween these compounds (syn) and the correspond-ing [2.2]phanes (anti), cf. Section 3.6, as there isbetween dithia[3.3]metacyclophanes and [2.2]meta-cyclophanes. This is indeed the case. While[2.2]metacyclo(1,4)naphthalenophane (273) assumesthe anti conformation, dithia[3.3]phane (498) existsexclusively in thesyn form which is evident from


S

S

H3C

H3C

1.86

6.92

5.81

(491)

X

X

S

S

(494), X = Se(492), X = S (493)

S

S

(495)

S

S

(496), R = CH3 (anti)(497), R = OCH3 (syn)

R

the absence of an upfield shift of the naphthalene H-2,3 protons. As in dithia[3.3]metacyclophane, intro-duction of an intraannular substituent can alter theconformational preference. Both thesynand theanticonformer of the methyl derivative (499) wereobtained in the preparation. The main differences intheir 1H NMR chemical shifts concern the methylgroup [d � 0:86 (anti) and 1.90 (syn)], its paraproton[d � 6:98 (anti) and 5.94 (syn)], and the naphthaleneH-2,3 protons [d � 6:31 (anti) and 7.20 (syn)]. Thesubstantial difference between the chemical shift ofthe protonpara to methyl in syn-(499), d � 5:94;and the corresponding proton in the methyl-freecompound (498), d � 6:45^ 0:15; was interpretedas being due to a larger tilt of them-bridged ring inthe methyl derivative which forces the proton in ques-tion into the naphthalenep-electron cloud thus caus-ing enhanced shielding. Neither (498) nor (499) showany indication ofantiO syn interconversion in their1H NMR spectra up to 1508C. As their parent (498),the halogenated derivatives (500) and (501) exist inthe synconformation exclusively [297]. This followsfrom the chemical shifts of the protons of them-bridged ring, which are distinctly upfield from theircounterparts in the halogenated 2,11-dithia[3.3]meta-paracyclophanes [184,298] and from the fact that thefluorine nucleus in (500) is not much more shielded�dF � 2118� than in 9-fluoro-2,11-dithia[3.3]meta-paracyclophane (408) which hasdF � 2117 [184].MMP2 molecular mechanics computations were inagreement with these interpretations. Thesyn- andanti-conformers of dithia[3.3]metacyclotriphenyleno-

phane (502) behave much like their naphthalenoanalogues (499). They were assigned from theshielded methyl protons in theanti- and the shieldedprotons of the benzene ring in thesyn-isomer [299].The latter protons are more highly shielded insyn-(502) than in syn-(499) because they are influencedby a more extended diatropic system. A paper hasbeen published describing in detail the conformationalbehaviour of dithia[3.3]metaparacyclophanes, inparticular of methylated and benzoannelated deriva-tives [181].

Like (498), thetert-butyl derivative (503a) assumesonly the syn-form but the methyl and methoxycompounds, (503b) and (503c), respectively, occuras bothsyn - and anti-conformers [187]. While forthe methyl compoundantiq syn, the methoxyderivative showssynq anti, presumably due tounfavourable interactions between the methoxyoxygen and the naphthalenep-electrons in thesyn-conformer. Theanti-conformers are characterized bylarge upfield shifts ($1 ppm) of their substituentprotons relative to the shifts of the same substituentsin 2-R-5-t-Bu-1,3-dimethylbenzenes. Nosyn–antiinterconversion processes were observed up to11308C in dynamic 1H NMR studies (solvent:DMSO-d6).

The aromatic regions of the1H NMR spectra of the2,13-dithia[3]naphthaleno[3]paracyclophanes (504)–(506), precursors to the corresponding [2.2]phanes(281)–(283) treated in Section 3, can be interpretedin the same way as those of the [2.2]phanes [193].Only the interannular shift effects are somewhat


syn-(498)

S

S

7.92 7.32

7.19

5.516.6−6.3

syn-(499)

S

S

7.86 7.33

7.20

1.90

6.62Me

5.94

anti-(499)

S

S

8.11 7.52

6.31

0.86Me

7.216.98

(500), X = F

S

S

(501), X = Br

X

syn-(502)

S

S

7.96

2.09

5.87Me

5.71

anti-(502)

S

S

6.75

0.85Me

7.247.11

smaller than in the [2.2]phanes because of the largerseparations between the benzene and naphthalenemoieties. The AB systems of the bridges in (505)and (506) are unchanged down to a temperature of21108C. Hence, either the barriers between the differ-ent possible bridge conformations are substantiallylower than 49 kJ mol21 or the molecules possessonly a single minimum energy conformation.

The 1H NMR data of a number of dithia[3.3]meta-cyclo(x,y)naphthalenophanes (507)–(510) and of thedithia[3.3](1,3)(2,3)naphthalenophane (511) werereported by Kus´ [300]. Only crude data were given

but the highly shielded intraannular protons of them-phenylene rings of (507) and (509) and of the(1,3)naphthylene ring of (511) sufficed to prove thatthese compounds prefer theanti conformation whilethe remaining two aresyn. The following paper by thesame author [301] treated, among other compounds,the (1,4)benzenophanes (512) and (513) and also theanalogous phanes with a (1,4)naphthaleno instead ofthe (1,4)benzeno moiety. Here as well, the phanescontaining a (1,6)naphthaleno unit areanti, thosewith a (1,7)naphthaleno unit aresyn. Two isomersof dithia[3.3](1,6)naphthalenophane, (514) and


S

(503a), R = H; only syn; δH = 5.31(503b), R = Me; anti >> syn; δMe = 0.78, 1.92

S

tBu

R

(503c), R = OMe; syn >> anti; δOMe = 3.33, 2.69

S

S

R

tBu

anti syn

(505)(504) (506)

6.74

SS S

SS

S

6.42/6.27

7.06 7.22 7.27

6.495.82

7.94 7.19

7.28

6.61

6.24

3.74

4.31/3.93 7.93 7.46

S

S

(507), anti

5.55

S

S

(511), anti

5.98

S

S

(508), syn

(510), syn(509), anti

S

S

5.13

SS

(515), and of dithia[3.3](1,7)naphthalenophane, (516)and (517), were reported later [302]. Their1H NMRchemical shifts were interpreted to indicate therespective preferred conformations (514A), (515A),(516A), and (517A).

Georghiou and coworkers [197] reported thepreparation of four isomeric dimethoxydithia-[3.3](1,3)naphthalenophanes. They occur as a trans-oid isomer (518) and a cisoid isomer (519), both ofwhich exist as stablesyn- andanti-conformers. Their1H NMR spectra were assigned by 2D correlationmethods and ample use was made of NOE differencespectroscopy to derive the stereochemistry of the

isomers. Furthermore, comparisons were made withMitchell’s data of the analogous dimethyl compounds[303].

The favoured conformation of the dithia[3.3]meta-cyclo(1,3)pyrenophanes (520) [204] depend on thenature of the substituents R1 and R2. Thesyn-confor-mation of the parent (520a) was recognized from thechemical shifts of the two intraannular protons, whichare bothd � 6:85; whereasd < 5 would be expectedfor the anti-conformer. The syn-conformation of(520d) and (520e) was inferred from the upfieldshift of one of theirtert-butyl groups (d � 0:10 and0.12, respectively). Further, in (520e) a through-space


(513), syn(512), anti

S

S

SS

5.684.99

S

S

(514)

S S

(515)

S

S

(516)

S S

(517)

SS(514A)

S S

(515A)

S S

(516A)

S S

(517A)

J(F,H) coupling of 2.0 Hz was found for the intraan-nular pyrene proton; this can only arise in asyn-conformation. On the other hand, the intraannularproton of (520b) and (520c) shows d � 5:85 and6.08, respectively, and the methyl and methylenegroups showd � 1:60 and 2.49, respectively. Thisproves the anti-conformation of these twocompounds, which may be preferred because repul-sive interactions between the oxygen or fluorine lonepairs and the aromaticp-electrons will destabilize thesyn-conformers. When the sulfoxides of thesyn-conformers were pyrolyzed, onlyanti-[2.2]phaneswere formed, cf. Section 3.7.

Di-tert-butyldithia[3.3](4,9)pyrenometacyclophane(521) and the corresponding paracyclophane (522)have been described by Yamato et al. [304]. The1Hchemical shifts of the pyrene part of (521) differ verylittle from those of model compound (523), but theintraannular hydrogen of them-phenylene ring has themost upfield shift of any dithia[3.3]phane studied sofar. Obviously this is due to the large ring current ofthe pyrene moiety. The methylene protons adjacent tothe m-phenylene ring are also highly shielded by thepyrene system, so that their shift is upfield by 1.8 ppmrelative to the CH2 protons next to the pyrene group.The absorptions of the methylene protons show no


OMe

OMe

S

S

OMe

OMe

S

S

(518), transoid (519), cisoid

(520)

R1R2

tBu

bc Et

MetButBu

R2R1

ade F

OMeH

tButBu

H

R2R1

S

SR1

R2

tBuS

S

syn anti

tBu tBu

S

S

3.97

6.44

6.15

2.72, 2.84J = 16.5 Hz

4.23, 4.92J = 11.7 Hz

8.33

7.927.70

(522)

tBu tBu

S

S

3.13, 3.39J = 16.1 Hz

4.22, 4.66J = 13.0 Hz

8.30

8.017.70

5.51*

5.38*

tBu tBu

8.24

8.12

7.87

(523)

(521)

change between2100 and11508C. Much the same istrue for the para-isomer (522). The p-phenyleneprotons are of particular interest. Their chemical shiftsare very similar and cannot be specifically assignedwith certainty, but the protons are highly shielded(d � 5:51 and 5.38) and absorb ca. 0.9 ppm upfieldfrom Haenel’s dithia[3.3]metacyclo(2,6)naphthaleno-phane (506) [193].

Some dithia[3.3]phanes based on fluorene substi-tuted in the 1,8-positions were first described by

Tsuge et al. [202]. The hydrogens at C-9 of the fluor-ene moiety in (524)–(526) are substantially shielded�d � 2:8–1:6� by the ring current of the oppositearomatic rings, especially so in the naphthalene deri-vative. This is evident by comparison of their shiftswith that of reference compound (312), which hasd �3:95: The internal diameters of the macrocyclic rings(524)–(526) are wide enough to permit rapid flippingof the fluorene units, as is obvious from the fact that inall three compounds the methylene protons at C-9 are


tBu tBu

S S2.76

tBu tBu

S S2.37

tBu tBu

SS

1.57

(524) (525)

(526)

tBu tBu(312)

3.95

SS R

(527), R = H(528), R = F

SS

(529)

SS

(530)

S

SCH3

1

3

16

18

(531A) (531B)

S

SH3C

chemically equivalent at room temperature. Decoales-cence of the C-9 proton signals was observed at230,250, and2508C for (524), (525), and (526), respec-tively, and the corresponding free energies of activa-tion DG‡ for the fluorene flipping process at thesetemperatures were determined to be 40.9, 38.5, and39.1 kJ mol21.

Lai et al. [305] studied a series of dithia[3.3](2,20)biphenylo(1,x)benzenophanes, x� 2–4;(527)–(530), with a m-, an o-, and ap-phenyleneunit as the benzeno part of the molecules. In (527)–(529), internal rotation about the C-1/C-10 bond of thebiphenyl system is restricted on the NMR time scale atroom temperature (AB spectra for the CH2 protons)and remains so at the highest temperatures attained.Barriers to atropisomerization were estimated to be.90, .80, and.75 kJ mol21 for (527), (528), and(529), respectively. At room temperature there is,however, rapid flipping of them-phenylene ring in(527) and (528) as well as rapidp-phenylene ringrotation in (529). The ortho-bridged compound(530) proves to be the most conformationally mobileone, its AB spectrum coalescing at1438C. Thus,DG‡

is 61.9 kJ mol21 for biphenyl rotation. As inversion ofthem-phenylene ring in (527) and (528) could not bestopped even at2908C, a methyl substituent wasintroduced to give (531) [306]. This compoundassumes a rigid conformation (531A) and the equiva-lent conformation (531B). Lack of symmetry causeseach of the four pairs of methylene protons to bediastereotopic. When them-phenylene ring invertsrapidly, the two pairs of methylene protons at C-1and C-18 are exchanged but each pair remains diaster-eotopic. Hence, two AB spectra should coalesce intoone. The same holds true for the C-3 and C-16 methy-lenes, so overall the four slow-exchange AB systemsshould turn into two fast-exchange ones. This was,however, not observed up to a temperature of11308C and the lower limit of them-phenylene ringinversion barrier was estimated as 84 kJ mol21. Underthe prevailing slow-exchange conditions, the eightbiphenyl protons are also all nonequivalent. Boththeir signals and those of the methylene protonswere individually assigned by the use of H,H-COSYand NOE difference experiments at 500 MHz. Themethyl protons are shielded tod � 1:62 as the methylgroup resides over one of the biphenyl rings.

In dithia[3.3]corannulenoparacyclophane (532)

[307] the endo-hydrogens of thep-phenylene ringare highly shielded by the magnetic anisotropy ofthe corannulene bowl and show a shift ofd � 1:89;very remarkable indeed for aromatic protons. Twodifferent dynamic processes are conceivable for thismolecule: (1) rotation about the bond betweencarbons 3 and 4 which would exchange theendo-and exo-phenylene protons; (2) rotation about thebond between carbons 1 and 2 which would forcethe entire bridge to the outside of the bowl withconcomitant bowl inversion. The latter processwould exchange the environment of the diastereotopicprotons within both types of methylene groups.However, at 300 MHz no coalescence or line broad-ening was observed up to11488C. Hence, the lowerlimit for the barrier of both processes is 754 kJ mol21

: In simple corannulene derivatives bowlinversion is very rapid at room temperature, havinga barrier of the order of 43 kJ mol21 [307,308].

The 1H NMR spectra of thesynandanti-isomersof dimethyldithia[3.3](5,7)azulenometacyclophane(533) were assigned by Mitchell and Zhang [309].In the syn-isomer, H-5 �d � 5:51� and H-4,6 �d �6:29� of the m-phenylene ring are strongly shieldedby the opposite azulene unit, whereas the methylprotons are shifted upfield in theanti-isomer. Theshift difference Dd � dsyn 2 danti is larger for themethyl group at the benzene ring�Dd � 1:48� thanfor the one at C-6 of the azulene moiety�Dd �1:15�; which could be attributed to a larger diamag-netic anisotropy of the azulene with respect to thebenzene system.

The pyridine protons in dithia[3.3](1,3)azule-no(2,6)pyridinophane (534a) and in dithia[3.3](5,7)a-zuleno(2,6)pyridinophane (535) [213] show upfieldshifts between 0.26 and 0.83 ppm relative to 2,6-dimethylpyridine. Hence, both phanes possess thesynconformation. Ring flipping at room temperatureis fast as indicated by the singlet nature of all CH2

proton signals. On cooling to21028C, ring flippingin (534a) slows down to give one broad and oneAB-type CH2 signal. No signal for ananti conformerwas detected. Signal coalescence measurementsyielded the barrier to ring flippingDG‡ as42.7 kJ mol21 (corrected value, cf. Ref. [310]). Thebarrier in (535) is lower than 37.6 kJ mol21 as onlysignal broadening and no decoalescence occurreddown to 21028C. The bis(N,N-dimethylcarbamoyl)-


(534b) and bis(methoxymethyl) derivatives (534c)and the derivatives (536a) and (536b) of the corre-sponding azuleno(3,5)pyridinophane were investi-gated [310] to probe the suggestion [311] that thesyn/anti equilibrium of [3.3]metacyclophanesdepends, among other things, on thep–p interactionbetween the two benzene rings and, hence, on thepresence of electron-withdrawing and -donatingsubstituents. Electron-donating groups are expectedto shift the equilibrium towards theanti form. It wasfound, however, that all of the compounds mentionedpreferred thesyn conformation. No traces ofanticonformers were found at21008C although the AB

patterns of the1H NMR absorptions of the bridge CH2groups indicate that conformational interconversionsare slow. Moreover, the exchange barriersDG‡ of(534b) and (534c) are identical (42.7 kJ mol21) andequal to the value for the parent compound (534a).With 48.5 and 49.0 kJ mol21, the DG‡ values of(536a) and (536b) are also nearly identical but higherthan those of the (2,6)pyridinophanes because of thereplacement of the internal nitrogen atom by the C–Hgroup. The expected substituent influence upon theconformational equilibrium was thus not confirmed.

The conformational properties of the pairs of isomersdithia[3.3](1,3)- and -(5,7)azuleno(2,5) furanophane


S S

(532)

7.73

7.91

7.91

7.62

1.89

6.753.312.64

4.684.45

12

3 4

SS

(533)

7.38

7.19

1.051.52

8.48

7.19

7.73

SS 6.29

5.51

2.53

2.67

7.96

7.09

7.69

anti syn

N N

S

S

S

S

(534a) (535)

R

R

(534b)(534c)

HCONMe2

CH2OMe

R

N

S

S

R

R

(536a)(536b)

CONMe2

CH2OMe

R

(537)/(538) and dithia[3.3](1,3)- and -(5,7)azuleno(2,5)thiophenophane (539)/(540) were studied byFukazawa et al. [312]. Large upfield shifts of thefuran protons in (537) and (538) relative to 2,5-dimethylfuran showed that both compounds preferthe syn conformation. At room temperature there isfast flipping of both rings in both compounds (singletsfor all CH2 groups) and at ca.21008C the two CH2

signals of (537) become two AB patterns, but those of(538) remain singlets. Thus, the barrierDG‡ for the(undefined) conformational process in (537) is

39.3 kJ mol21 (Tc not reported), and that in (538) is,33 kJ mol21. No trace of theanti conformer couldbe found in the low-temperature spectrum of (537).Both thiophenophanes prefer theanti conformation(539) also in the solid state as proved by X-ray diffrac-tion. BarriersDG‡ to thiophene ring flipping weredetermined to be 75.7 kJ mol21 (at 1708C) for (539)and 74.9 kJ mol21 (Tc not reported) for (540). Thebarrier to azulene ring flipping is ca. 38 kJ mol21 (at2828C) for (539) and could not be measured for (540)because of poor solubility.


S

S

S

S

S

S

(539) (540)

O

S

S

O

S

S

(537) (538)

N

(541)

N

SSN

(542)

NS S

SS

N

(543)

NN

N

NMe

NMe

NMe

NMe Mo

(CO)3Mo

(CO)3

SS

H

H

5.15

3.20

6.94

MeN

H

H

4.54

4.01

NOE3.37

CO2Me

OMeO

3 8 9

(544)

Like the parent hydrocarbon, the heterahetero-analogues of [3.3]metacyclophane (411), the dithia-(541) and the tetrathia[3.3](2,6)pyridinophane (542)were shown to possess asynconformation in solution[313]. For (541) this was inferred from the pyridineproton chemical shifts which are shielded by 0.24–0.36 ppm relative to the trimeric trithia[3.3.3]- and thetetrameric tetrathia[3.3.3.3](2,6)pyridinophanes. Asyn/anti-equilibrium had previously been assumedfor (542) [314], but the invariant pyridine region inthe variable-temperature1H NMR spectrum was nowassumed to be more compatible with a mobilesynconformation [313].

N,N0-Dimethyl-2,11-diaza[3.3](2,6)pyridinophaneforms the tridentate Mo(CO)3 complex (543), not atetradentate complex as might have been expected[315]. This complex is fluxional and switches its coor-dination from one aza-bridge to the other slowly onthe NMR time scale below room temperature. A line-shape analysis of the CH2 proton signals as a functionof temperature yieldedDH‡ � 58:1 kJ mol21 andDS‡ � 23:14 J K21 mol21

: DG‡ was given as59.0 kJ mol21 for “room temperature”.

The dithia[3.3]metacyclo(2,4)pyrrolophane (544)[242] prefers thesyn conformation as shown by the

chemical shift of the intraannularm-phenylene proton�d � 6:94� which is similar to that ofsyn-dithia[3.3]-metacyclophane (470) �d � 6:82�: The four CH2

groups all give AB spectra, of which three havechemical shifts in the normal range whereas the fourthhas an unusual downfield shift�d � 5:15� of the axialproton and an unusual upfield shift�d � 3:20� of theequatorial proton. The latter was assigned from theNOE it experienced when theN-methyl signal wassaturated. These unusual shifts, 0.6 ppm downfieldand 0.8 ppm upfield with respect to the correspondingshifts of the CH2-9 group, were attributed to a hydro-gen bridge between the axial hydrogen at C-3 and thecarbonyl oxygen of the ester group at C-8.

Variable-temperature NMR measurements ofdiselena[3.3](2,6)pyridinophane (545) [316] showunchanged13C and 77Se spectra down to21038C.The 1H spectrum at room temperature is very similarto that of the dithia analogue which is known to preferthe syn conformation [313], so the same conclusionwas drawn for the diselena compound. At2908C, theCH2 signal decoalesces andDG‡ was calculated to be37.4 kJ mol21 at this temperature. The dynamicprocesses taking place in (545) were assumed to bebridge wobbling between boat and chair conformations


X Y

Se

Se

(545)(546)(547)

NN

CH CHCHN

X Y

Se

Se

(548)

cyclecycle

(see text)

O

O

PhPh

O

O

PhPh

S S

(549)

O

O

PhPh

S S

(550a), R = H

R

(550b), R = OMe

O

O

PhPh

S S

(551)

alternating with pyridine ring flips. The former arethe processes actually measured while the latterhave too low a barrier to be accessible by NMR inthe usual temperature range. The metacyclopyridino-phane (546) has a lower barrier,DG‡ � 33:9 kJ mol21

at 21058C. From the data of (545) and (546) theauthors extrapolated the barrier and coalescencetemperature in the diselenametacyclophane (547) tobe 30.4 kJ mol21 and21238C, respectively. Inspectionof space-filling molecular models reveal that, in thetransition state of bridge wobbling, the pyridine ringsare “horizontal” (parallel?) to each other, whichincreases the electrostatic interaction between thenitrogen lone pairs. This interaction was assumed toaccount for the difference inDG‡ of 7 kJ mol21

between (545) and (546). If this is the case, however,it is not logical to assume the same change in thebarrier height on going from (546) to (547). In afurther study [317], a large number of diselena[3.3]-phanes of the general structure (548) were character-ized by 1H and 13C NMR and also by77Se whensolubility permitted. The cyclic substructures in(548) areo-, m-, andp-phenylene, pyridine-2,6-diyl,furan-2,5-diyl, thiophene-2,5-diyl, and biphenyl-2,20-diyl. The 77Se chemical shifts appear to correlate withthe size of the cavity of the phanes as estimated fromspace-filling models. Steric crowding in the cavitycorresponds with increased77Se shielding.

The dithia[3.3](2,6)g-pyronophanes (549), (550a),and (551) are conformationally mobile at roomtemperature; their methylene protons give singletabsorptions [234]. The intraannular methoxy groupin (550b) makes this compound less flexible; thereare two AB spectra for the methylene groups andone methoxy signal at room temperature, indicatingslow inversion of the macrocyclic ring but thepresence of only one conformer. It was not possibleto decide whether this has thesynor theanti geome-try. The sulfones behave similarly. The [2.2]phanesproduced from the sulfones have already been treatedin Section 3.8.

Vogtle’s group has studied dithia[3.3](1,3)adaman-tanometacyclophane (552) and its sulfone (553) [318].Both compounds show one extremely shielded protonof the intraannular methylene group atd � 22:18 and21.72, respectively. This corresponds to an upfieldshift Dd of ca. 4.0 ppm relative to the CH2 protons�d � 1:78� in adamantane itself. The second proton of

the methylene group in the sulfide and the sulfone hasd � 11:41 and11.95, respectively. The signals ofthe intraannular methylene protons of (552) coalescedat 50^ 108C (90 MHz), their averaged absorptionbecoming a sharp singlet withd � 20:13 at11548C. The resulting conformational barrier ofDG‡�508C� � 62^ 4 kJ mol21 demonstrates theincreased rigidity of the bridge relative to dithia[3.3]-metacyclophane (470) which has aDG‡�, 2 908C� ofless than 38.9 kJ mol21 [319]. In the crystal, theconformation of (552) is in-betweensynandanti sothat one of the intraannular methylene protons resides

Hi

Ho

Hb

(552)

S

S

−2.18

+1.41 Hi

Ho

Hb

(553)

O2S

SO2

−1.72

+1.95

H

H

N

(554)

S

S

H

H

N

(555)

O2S

SO2

O

SSH H

−0.25

A B

A’B’

(556a)

a b

SSH H

−0.40, −0.25

(556b)

CO2Me

above the plane of the benzene ring while the otherone is pointing toward the periphery of the molecule.This is in line with the large chemical shift differencebetween these hydrogens. The (2,6)pyridino analogue(554) [220] corresponding to (552) has a lower barrier�55^ 10 kJ mol21� to the flipping of the aromaticring because the smaller size of the nitrogen lone


pair compared to a hydrogen reduces the energy of thetransition state. No highly shielded proton wasobserved for (554) at room temperature. When (554)was oxidized to the bis-sulfone, theN,S,S,S0S0-pent-oxide (555) was formed. The nitrogen-bound oxygenprevents ring flipping up to at least11608C: nocoalescence was observed for the intraannular CH2

protons (d � 0:03 and 2.08).In (556a), the para isomer of (552), the internal

methylene protons give rise to a sharp singlet atd �20:25: Broadening of many resonances at roomtemperature indicates conformational mobility. AnAA 0BB 0 spectrum is observed for the aromaticprotons, the chemically equivalent ones beingparato one another. This implies aC2 axis through andperpendicular to the centre of the benzene ring. X-ray diffraction showed that the different chemicalshifts of the aromatic protons are caused by thebenzylic bridges pointing in opposite directions withrespect to a plane through Ca and Cb and perpendicularto the benzene ring. The signals of the benzylicprotons coalesce at135 or 1458C (both 358C and318 K were mentioned [220]) andDG‡ is 64^10 kJ mol21

: In the methoxycarbonyl derivative(556b), the intraannular methylene protons havedvalues of20.40 and20.25 [220]. It was stated that“on warming to1558C the 1H NMR spectra showedno sign of a conformational process”. However, aconformational process like the one assumed for(556a), will not make the intraannular protons of(556b) equivalent because the front and the backside of the molecule are different due to the presenceof the substituent.

5. [m.n]Phanes (m . 2, n $ 2)

The present section deals with [m.n]phanes inwhich the length of one bridge is greater than 2 andthat of the second one is at least 2. It is difficult tomaintain a strictly logical order in the presentationbecause many papers treat whole series of compoundswith increasing length of one or both bridges. Gener-ally, however, smaller phanes are presented first,followed by increasingly larger phanes, and thelargest phanes, [8.8] and [10.10], are mentioned atthe end of the section.

The benzoannelated monothia[3.2]metaparacyclo-

phane (557) was studied by variable temperature1HNMR [182]. Below2858C, one of the CH2 signals issplit indicating a very low ring inversion barrierDG‡ of 37.3 kJ mol21. Thus, the molecule is muchmore flexible than the analogous [2.2]phanehydrocarbon (268), cf. Section 3. The thia[3.2]me-tacyclophan-10-ene (558), in which a phenan-threne unit is condensed onto the C-10,C-23-double bond, unexpectedly prefers thesyn confor-mation according to its1H NMR spectrum [320].There is no upfield resonance for the ‘internalprotons’ (Hi) but the six outer cyclophane protonsappear relatively shielded atd � 7:1–6:6: This isin contrast with the preferredanti conformation ofthe lower benzoannelated homologue (559),d�Hi� � 6:08; studied earlier by Hammerschmidtand Vogtle [321]. The reason lies in the highsteric strain that would occur inanti-(558) dueto the close proximity of the proton pairs H-7/H-12 and H-21/H-25. The deshielding observed forthe Hi relative to theirpara protons in syn-(558)was attributed to the magnetic anisotropy of thenearby “double” bond, (C-10)y(C-23). Variabletemperature spectra of (558) down to 2708C and ofits sulfoxide up to11508C showed no change over thetemperature range and indicate the absence of cyclo-phane ring flipping, in contrast to (559) whereDG‡ is54.8 kJ mol21 (at 278C).

Krois and Lehner [260] presented a systematicstudy of the preferred conformations (syn vs. anti)of [2.2]- (149), [3.2]- (560), [3.3]- (411), [4.2]-(561), and [4.3]metacyclophanes (562) and of meth-ods to determine them. (i) A symmetry criterion isapplicable to the metacyclophanes containing athree-membered bridge. At temperatures low enoughto stop conformational inversion on the NMR timescale, the protons of the C3 bridges in (560), (411)or (562) form an AA0BB 0CD spin system in thesynconformation, whereas an AA0BB 0CC0 spin system ispresent in theanti conformation because the protonsof the central methylene group are chemically equiva-lent. This criterion showed [3.2]metacyclophane(560) to prefer the anti and [3.3]metacyclophane(411) to prefer thesynconformation. Conformationalinversion in [4.3]metacyclophane (562) could not beslowed down sufficiently to apply the method. (ii) Thesecond way to determine the conformation uses theR-value (ratio of vicinal H,H coupling constants)


method [322] which furnishes the torsional angle(s)fabout the appropriate C–C bond(s). In the C2-bridgesof (149), (560), and (561) f is expected near 08 for asynand near 608 for ananti conformation. Experimen-tally, f was found to be 57, 57, and 638 for [2.2]-,[3.2]-, and [4.2]metacyclophane, respectively. Henceall these compounds prefer theanti conformation. Inthe C3-bridges of [3.3]metacyclophane (411), fshould be 608 (syn) or 308 (anti). The value calculatedfrom the experimentalJ(H,H) coupling constants is708, so the conformation of this compound is againconfirmed to besyn. (iii) The third, most widelyapplicable method is the evaluation of the chemical

shift of an intraannular proton Hi with no ortho-benzylic substituents in comparison with itspara-proton He. A value of Dd � d�Hi�2 d�He� close tozero indicates preference of thesyn conformationwhile a distinctly negative value points to a preferredanti conformation. TheDd values found for [2.2]-,[3.2], [3.3]-, [4.2]-, and [4.3]-metacyclophane are23.0,22.1,10.1,21.5, and21.1 ppm, respectively,which translates into a preferredsynconformation for[3.3]metacyclophane and preferredanti conforma-tions for the other phanes, in agreement with resultsobtained independently by X-ray diffraction andthe NMR methods (i) or (ii) mentioned above.


(557)

S

SHiHi6.08

SHiHi7.36

712

21 25

1023

(558)

(559)

syn-(558)

S

7

25

12

21

Hi

Hi

(561)(560)

(562)

(564)

(563)

(565)

OO

O OO

O

(429)

O O

Substituents at the bridges may cause deviations fromthese regularities. By the use of methods (i)–(iii), suchdeviations were found for diketones (429) and (563)–(565). The first of these isanti and the others aresyn.Krois and Lehner also give a comparison of thebarriers DG‡ to conformational interconversion ofthe basic [m.n]metacyclophanes, determined byNMR or other techniques. These are 133 kJ mol21

(at 442 K), 73 kJ mol21 (at 363 K), 50 kJ mol21 (at253 K), 60 kJ mol21 (at 308 K), and,38 kJ mol21

(at ,193 K) for [2.2]-, [3.2]-, [3.3]-, [4.2], and[4.3]-metacyclophane, respectively.

Transannular interaction in a series of 6-R-9,17-dimethyl[3.2]metacyclophanes (566) was evaluatedby plotting the chemical shifts of H-14 againstHammett’ssp substituent constants [323]. Substitu-ents R were H, NO2, NH2, F, OMe, CHO, and Me. Therange of chemical shifts is relatively small, but anapproximately linear correlation withsp was found.The slope is distinctly smaller than for the correspond-

ing correlation of [2.2]metacyclophanes which wasalso shown. The authors concluded that transannularinteraction is less efficient in [3.2]- than in [2.2]meta-cyclophanes and that this is due, in part, to the differ-ent geometries of the two systems.

The two [3.2]metacyclophan-10-enes (567) and(568) prefer different conformations [324]. While(567) is present as the typicalanti conformer, thebridge-methylated derivative (568) favours thesynarrangement in order to relieve destabilizing interac-tions between the methyl groups at the ethano bridgeand at the aromatic rings. The preferredanti confor-mer of (567) was recognized by the upfield shift�d �6:05� of its intraannular proton. The triplet and quintetmultiplicities of the benzylic methylene signals and ofthe signal of the middle methylene group, respec-tively, indicate fast interconversion of the two possi-bleanti forms by ring flipping. This process is still faston the NMR time scale at2808C, so (567) is a veryflexible molecule. Thesynconformation of (568) was


H

R6

14 CH3

H3C

(566)

(568), syn(567), anti

H3C

H3C

CH3

CH3

H

H

H3C

CH32.78 (t)

1.81 (qi)

6.05

6.98

2.87, 2.51

2.12, 1.35

Hi He

HH

(CH2)nHi

HeH

H

(CH2)n

(569)

n 2 3 4 5 6

a b c d e (570)

n 3 4

b c

inferred from the chemical shift of its intraannularhydrogen �d � 6:98�: The trimethylene bridgeproduced a complicated1H NMR signal pattern withdifferent chemical shifts of the geminal methyleneprotons which were maintained over the temperatureinterval from 2808C to 11008C. This proved theconformational stability (nosyn/syn interconversion)of (568).

Severalcis- (569) and trans-1,2-diphenylcyclobu-tanes (570) with (CH2)n bridges between the 3-posi-tions of the phenyl rings were obtained by Nishimuraet al. [325] through intramolecular [21 2] photocy-cloaddition of a,v-bis(m-vinylphenyl)alkanes. Theproducts can be regarded as [n.2]metacyclophaneswith cyclobutano annelation to the two-memberedbridge. The structural questions to be answeredconcern thecis/trans configurations of the cyclobu-tane rings and thesyn/anti conformations of the meta-cyclophane units. The configurations follow from thechemical shifts of the cyclobutane methine protons.These ared < 4 in thecis series, butd � 2:1–1:3 inthe trans series because the geometry of the lattercauses shielding of H-1 by the phenyl ring at C-2and of H-2 by the phenyl ring at C-1. The metacyclo-phane conformations were determined by applyingLehner’s method discussed above [260]. Allcompounds apart from (569d) have distinctly negativechemical shift differencesDd between the internalproton Hi and itspara counterpart He, indicating theanti conformation whileDd is 10.08 ppm for (569d),suggesting preference of thesynconformation. Inter-estingly, due to the cyclobutano annelation,[2.2]metacyclophane (569a) can only have thecisconfiguration for steric reasons. This renders the twointraannular protons chemically nonequivalent andthe anti conformation does the same to the cyclo-

butane methine protons. The important1H NMRdata for (569) and (570) are gathered in Table 14.

The 10-oxa-2-thia[3.2]metacyclopyridinophanes(571)–(574), their metacyclophane analogue (575)and the 2-thia[3.2]pyridinophanes (576/577, mixture)and (578) were studied by variable temperature1HNMR [126]. The coalescence temperatureTc of theOCH2 signals of (571) is lower than2558C and theconformational barrier was not determined. The lowbarrier is due to the absence of an intraannular hydro-gen at the pyridine ring. For (572) (89 kJ mol21 at388C), (574) (87 kJ mol21 at 308C) and (575)(89 kJ mol21 at 358C) theDG‡ values are equal withinexperimental error but the barrier for (573)(95 kJ mol21 at 638C) is higher by ca. 7 kJ mol21.While a barrier of 55 kJ mol21 (at 288C) has beendetermined for 2-thia[3.2]metacyclophane (579)[319], the barriers in the analogous 2-thia[3.2]pyridi-nophanes (576)/(577) (mixture) and (578) are higherby 23 kJ mol21 (at 0 and 38C, respectively). Theauthors attributed this to the geometrical differencesbetween the benzene and pyridine rings.

At room temperature in CDCl3 solution, 2-thia-10,11-diaza[3.2]metacyclophan-10-ene (580) existsas a 2:1 mixture of thesyn and anti conformers[326]. Coalescence measurements of the SCH2 protonsignals ofanti-(580) give aDG‡ value for the inter-conversion of theanti conformer into its enantiomeranti0 of 56:7^ 1:0 kJ mol21 and the coalescence ofthe intraannular aromatic proton signals of thesynandanti conformers yieldedDG‡ � 56:3^ 1:0 kJ mol21

for the syn into anti conversion. The similar magni-tudes of these barriers make it very likely that thetransition of one conformer into its enantiomerproceeds via the other conformer. In acetone or aceto-nitrile as the solvent, only theanti conformer of (580)


Table 141H NMR data for the cyclobutano[n.2]metacyclophanes (569) and (570)

Compound d(Hi) d (methine) Dd Configuration Conformation

(569a) 4.54, 4.40 3.98, 3.61 22.86 cis anti(569b) 6.55 4.06 20.28 cis anti(569c) 6.46 3.94 20.68 cis anti(569d) 6.87 4.04 10.08 cis syn(569e) 6.72 4.00 20.29 cis anti(570b) 5.49 2.08 21.83 trans anti(570c) 6.01 1.29 21.28 trans anti

is present.1H NMR spectra taken in CDCl3/[D6]acet-one or CDCl3/[D3]acetonitrile mixtures of variouscomposition led to the conclusion that specific solva-tion of thesynconformer takes place by inclusion ofone molecule of acetone or acetonitrile into the spacebetween the NyN and CH2SCH2 bridges. The analo-gue (581) only exists as theanti conformer. The sing-let CH2 signal indicates rapid anti-to-anti0

interconversion. Broadening of the CH2 signal startsonly below2738C; DG‡ is less than 38 kJ mol21.

The benzylic protons and the protonsortho to thethree-membered bridge in [3.2]paracyclophan-10-ene(582a) and its dimethyl (582b) and diethyl derivatives(582c) [327] become diastereotopic at low tempera-tures. Signal coalescences between230 and2258Cgave barriers to bridge wobbling of 48.7–50.7 kJ mol21 which are equal within experimentalerror for the three compounds and also very similar

to the barriers for the same processes in [3.3]paracy-clophane (447) [276] and in [3.3]metacyclophane(411) [254].

Fukazawa and coworkers [328] investigated a[4.4]paracyclophanedione derivative (583). Molecu-lar mechanics computations predicted three confor-mers of approximately equal energy (I –III ) ofwhich the most stable one (I ) corresponds to theconformation found in the crystal. When the solidwas dissolved in precooled solvent, a1H NMR spec-trum of the single conformerI was obtained. Dissol-ving the compound at room temperature and coolingthe solution down gave two additional spectra ofconformersII and III which are broadened at roomtemperature. Interconversion ofII and III occurs bybridge flipping and requires little energy (ca.50 kJ mol21). I and II are interconverted by rotationof ring A (DG‡ � 76:6 kJ mol21 at 1808C), I andIII


SN

O

(571)

S

N

O

(572)

S

N

O

(573)

S

N

O

(574)

SO

(575)

S

N

N

(576)

S

N

N

(577)

S

N

N

(578)

S

(579)

N

N

(580) (581)

S S

RR

(582a), R = H(582b), R = Me(582c), R = Et

by rotation of ring B (DG‡ � 95:0 kJ mol21 at11608C). The conceivable conformerIV into whichI could be transformed by a low-energy bridge flip-ping process is not populated. Hence the signals ofIstay sharp at room temperature and below. The fullpaper treating this subject [329] also includes variabletemperature 1H NMR and molecular mechanicsstudies of compounds (584) and (585). Thesepreferred conformers are closely similar toI –III of(583) and their rotational barriers are also similar tothose in (583).

In the series of 10-substituted 3,12-dithia[4.4]meta-

paracyclophanes (586a–d) [330], those with X� Hand F show no evidence of restricted conformationalmotion down to2518C at 100 MHz1H observationfrequency. When X� Cl, the free energy barrierto rotation of the para-bridged ring, DG‡�para�;is 75 kJ mol21 and the barrier to flipping of themeta-bridged ring, DG‡�meta�; is 88 kJ mol21.Replacing X� Cl by X�OMe lowersDG‡�para� to67 kJ mol21 but increasesDG‡�meta� to.92 kJ mol21.This was explained by the anisotropy of the steric sizeof the methoxy group. Increasing the bridge lengthsby one methylene group each expectedly lowers the


O

O

O

OO

OBA

(583)

O

OA

O

O

O

A

O

O

O

O

O

O

I II

O

OA

O

O

III

O

O

rotation ofring A

rotation ofring B

bridge flip

∆G≠=76.6 kJ mol−1

∆G≠=95.0 kJ mol−1

∆G≠≈50

A

O

O

IV

O

OO

kJ mol−1

activation barriers.DG‡�para� was found to be verysmall in (586e) �Tc , 2518C� andDG‡�meta� is only59 kJ mol21.

A conformational analysis of 2,2,12,12-tetra-methyl[4.4]metacyclophane (587) using the “ringcurrent method” was performed by Fukazawa et al.[331]. Ring-current induced chemical shiftsDd of thearomatic protons (i.e. the effect of one benzene ringupon the shifts of the other) were defined as the shiftdifference between (587) and model compound (588).Trial conformations of (587) were then adjusted untilthe minimum discrepancy factorR was reachedbetween the observedDd values and those calculatedaccording to Mallion [332]. The minimumR value of5.8% was obtained for the anticlinal [333] conforma-

tion (587A) in which the planes of the benzene ringsform an angle of ca. 1008. This conformation is veryclose to the one observed in the crystalline state by X-ray diffraction. At 21008C, the 1H methyl signalresolved into two and the signals of the aromaticprotons remained unchanged. No signals due tominor conformers could be detected. The spectra areconsistent with the hypothesis that only one anticlinalconformer is present and that it interconverts to itsmirror image by a flipping of the two benzene rings.This interpretation was supported by molecularmechanics computations. The “ring current method”was also applied to the conformational analysisof 2,2,13,13-tetramethyl[4.4]metacyclophane (589)[334]. Here it proved necessary to assume an


O

O

O

O

(584)

O

O

O

O

(585)

(CH2)n(CH2)n

S SX

(586a)(586b)(586c)(586d)(586e)

HFClOMeOMe 3

2222

X n

(587A) (588)(587)

(589)

20

10

equilibrium between three conformers whose geome-tries were calculated by molecular mechanics (MM3).Their relative populations were adjusted at eachmeasuring temperature to obtain the best fit betweenthe calculated and the experimental spectrum. Onlyconformationally averaged spectra were observeddown to 21008C. Very interestingly, one of theintraannular protons, H-10, has a chemical shiftd <7:0; which remains rather constant from1278C to21008C, while the shift of the other one, H-20, variesfrom d � 5:4 (1278C) to d � 4:1 (21008C). Theresults indicate that, from21008C to 1278C, thepopulation of the main conformer changes from 56to 18% and that of the next important conformerfrom 39 to 68%.

The conformational mobility of [4.3]- (590a) and[4.4](1,4)naphthalenophane (590b) and of [4.3]-(591a) and [4.4](2,6)naphthalenophane (591b) wasstudied by Nishimura et al. [335]. The three-membered bridge in (590a) and in (591a) is tooshort to allow isomerization ofanti-(590a) to its syn

isomer or of chiral (591a) to the achiral (meso)isomer. The1H NMR spectra were unchanged whenthe samples were heated to 2008C. Hence, the inter-conversion barriers are higher than 105 kJ mol21. Thelonger bridge in [4.4]phane (590b) permits easyisomerization. Coalescence of the intraannular protonNMR signals for thesyn and anti conformer occursalready at 10 58C; giving DG‡ � 54 kJ mol21

: In[4.4](2,6)naphthalenophane (591b) isomerizationcould also be observed, yet at a much higher tempera-ture. The aromatic and the aliphatic proton signals ofthe meso and the chiral conformer coalesced at 175^

58C; which indicates a barrier to rotation of the 2,6-disubstituted naphthalene ring of 92 kJ mol21. Thiswas claimed to be the first observation of naphthalenering rotation in a (2,6)naphthalenophane.

Hydrogenation of the cyclobutane rings of bis(cy-clobutano)[2.2](3,6)phenanthrenophane (314) led to[4.4](3,6)phenantrenophane (592) [203]. Thiscompound prefers theanti-conformation as wasdeduced from the high-field shifts of H-4,5 and the


(CH2)n

(590a), n = 3(590b), n = 4 chiral (591a)

chiral (591b)meso-(591b)

(592), anti

4

5

low-field shifts of the other aromatic protons withrespect to the starting material.

In a study aimed at detecting edge-to-face arrange-ments of two aromatic rings in flexible cyclophanes,Schladetzky et al. [336] compared the chemical shiftsof the intraannular hydrogen Hi in compounds (593)–(596) of the dithia[4.4]metaparacyclophane type and(597)–(598) of the dithia[4.4]metacyclophane typewith reference compounds (599) or (600). The shiftdifferencesDdi � di�phane�2 di�ref: cpd:� at 1228Care 21.5 to 21.0 ppm for the metaparaphanes and20.5 to20.4 ppm for the metaphanes. They increaseto 21.6 to21.3 ppm and to20.8 ppm, respectively,for three compounds whose spectra were alsomeasured at2788C. The authors regarded the upfieldshifts as indicators of the participation of edge-to-facearrangements in the conformational equilibria, but inthe opinion of this reviewer the data do not provide abasis solid enough for such a conclusion.

Funke and Gru¨tzmacher [337] prepared a series ofdiazadithia[n.2]cyclophan-enes,n� 6–16; (601a)–(601h). These are azobenzenes that have theirp,p0-positions joined by –CH2S(CH2)mSCH2– bridges(m� 2; 4–9, 12). The short bridged compounds

(601a)–(601c) exist only in thecis-azo configuration,while (601d) and (601e) were obtained ascis/transmixtures and (601f)–(601h) were formed as puretrans isomers. The latter could be converted photo-chemically into thecis isomers, socis and transdiastereomers were available for (601d)–(601h).The 1H NMR spectra of the isomers differed charac-teristically in that the aromatic protons are shielded inthe cis relative to those in thetrans isomers as inazobenzene itself. In thetrans series, decreasing thebridge length hardly affects the shifts of the aromaticprotons but increasingly shields the CH2 protons asthe centres of the bridges are forced over the azoben-zene moiety. The highest field shift was observed forfour protons in (601e) at d � 20:07: Decreasing thebridge length in thecis series causes high-field shiftsof the aromatic protons but only for the short-bridgedcompounds (601a) and (601b). These studies wereextended to include the dithiadiaza[n.2]metacyclo-phan-enes (602a)–(602f) [338]. Thecis/trans isomer-ism of the azo group andsyn/anti conformation of thebenzene rings were determined from the1H chemicalshifts of the aromatic protons, in particular of Hi.

From the thia[n.3]metacyclophane precursors (603)


SSHi

SSHi

SSHi

SSHi

SSHi

SSHi

(598)(597)

(596)

(594) (595)

(593)

SSHi

(599)

SSHi

(600)

with n� 5; 6;8; and carrying intraannular methylgroups, the [n.2]metacyclophanes (604) were synthe-sized by Yamato et al. [339]. The precursors all occurin theanti conformation as evidenced by their highly

shielded methyl protons and by X-ray diffraction ofcompound (603b). Products (604b) and (604c), n� 6and 8, are alsoanti, but the [5.2]metacyclophane(604a) was formed as asyn and ananti conformer,


N

N

S

CH2

S

CH2

(CH2)m−2

7.88 7.46

3.74

2.36

1.5−0.6

(7.88) (7.38)

(3.78)

(0.2−0.0)

(1.87)

trans-(601)

N

N

cis-(601)

S CH2

S CH2

(CH2)m−2

7.19

6.82 3.652.32(7.00)

(6.44) (3.54) (2.00)

1.6−1.2

a b c d e f g h

2 4 5 6 7 8 9 12m

δH values for m = 12 (m = 6) δH values for m = 12 (m = 2)

N

N

(602)

(CH2)m

a b c d e f2 3 4 6 8 12m

S

S

[n] 6 7 8 10 12 16

Hi

SMe

Me tBu

tBu

(CH2)n

anti-(603a)bc 8

65 1.47

1.491.70

δ(CH3)n

Me

Me tBu

tBu

(CH2)n

anti-(604a)bc 8

65 1.19

1.251.47

δ(CH3)n

Me

Me

syn-(604a)

tBu

tBu(CH2)5

2.25

which can be separated by chromatography. Thesynisomer of (604a) has a normal chemical shift for themethyl group �dH � 2:25� as opposed to itsanticounterpart, which showsdH � 1:19: According tovariable temperature 1H NMR measurements,(603a), anti-(604a), and (604b) are conformationallyrigid and do not lose the nonequivalence of theirmethylene protons up to11508C. Compound(603c), on the other hand, is very flexible and showsCH2 singlets down to2608C. Only for (603b) and(604c) could signal coalescence be observed withinthe accessible temperature range. Theanti Y anti0

interconversion barriers were determined to be69.5 kJ mol21 at 1908C and, respectively,85.8 kJ mol21 at 11408C. Compounds (605) and(606) carrying intraannular methoxy instead of methylgroups behave very similarly [340]. The thia[n.3]me-tacyclophanes (605) with n� 2–6 are exclusivelyanti: dH of the OMe groups ranges from 3.05 forn�2 to 3.28 forn� 5: The same is true for (606) withn� 2 (dH for OMe� 2.90). Of the [n.2]phanes withn� 3–6 both theanti and thesynconformers couldagain be isolated. The longer then-bridge, the higherthe proportion ofsyn conformer in the product. Thesyn conformers have less shielded methoxy groups�dH � 3:51–3:59� but more highly shielded aromaticprotons �dH � 6:29–6:72� than theanti conformers�dH � 6:77–7:12�: All the dimethoxyphanes are

conformationally very stable. None of them showany CH2 signal coalescence below11508C, hencethe barriers to ring inversion exceed 105 kJ mol21.The methoxy compounds were hydrolysed and theanti conformers of the hydroxyphanes (607) with n�2–6 and their syn conformers withn� 3–4 wereobtained. These conformers can be differentiated bytheir OH chemical shifts (anti: d � 2:14 for n� 2 upto 3.32 for n� 6; syn: d � 5:42 for n� 4) and bythose of the aromatic protons (anti: d � 6:92–7:10;syn: d � 6:35–6:64). Anti-(607), n� 5; shows nochange of its 1H NMR spectrum up to11308Cwhile for the [6.2]phane the benzylic signals coalesceat this temperature (solvent CDBr3), henceDG‡�11308C� � 86:2 kJ mol21

: The latter compoundexhibits a strong solvent dependence of itsanti/synratio at1208C. It decreases with increasing dielectricconstant of the solvent from 100:0 (CDCl3) to 65:35(DMSO-d6). At room temperature, characteristicproton shifts of the conformers in DMSO-d6 are:d�t-Bu� � 1:24 (anti), 1.05 (syn) and d�OH� � 5:60(anti), 7.75 (syn). The spectrum of the next lowerhomologue (607), n� 5; shows nosynconformer atroom temperature in CDCl3 or DMSO-d6 but does soat 1608C, and the anti/syn ratio decreases withincreasing temperature. Coalescence ofanti and synsignals is not achieved up to11408C �DG‡ .105 kJ mol21�: The studies described above were


SOMe

MeO tBu

tBu

(CH2)n

anti-(605), n = 2−6

OMe

MeO tBu

tBu

(CH2)n

anti-(606), n = 2−6

OMe

OMe

syn-(606), n = 3−6

tBu

tBu(CH2)n

OH

HO tBu

tBu

(CH2)n

anti-(607), n = 2−6

OH

OH

syn-(607), n = 3−4

tBu

tBu(CH2)n O

O

O

O (CH2)n

(608), n = 4, 5

later extended to compounds (605), (606), and (607)with longer (CH2)n bridges�n� 7;8; 10� [341]. In astudy of [n.2]metacyclophanediquinones (608) [342]it was found that it is much easier to effect ring inver-sion in these quinones�n� 4;5� that haveDG‡ �82:8 kJ mol21 (11308C) and 50.2 kJ mol21 (2308C)than in the dihydroxy[n.2]metacyclophanes (607) forwhich the barriers are higher than 115 kJ mol21 atT . 1408C [340]. The higher barriers in the hydroxy-phanes were attributed to the longer C–O bond whichmakes it more difficult to rotate the oxygen throughthe annulus, but the role of the hydroxy proton shouldalso be taken into account.

The 1H NMR spectra of the dimethoxy[n.n]meta-cyclophanes (609) with n� 2 and 5–10 were fullyassigned and their13C shifts reported [30]. Forn�5; the benzylic protons are still nonequivalent at roomtemperature, indicating slow ring inversion. Forn $6; equivalent benzylic protons show rapid movementon the NMR time scale at room temperature. Activa-tion parameters for this conformational interconver-sion were not determined.

Nishimura’s group prepared a large number ofdifferent metacyclophanes and determined their struc-tures by1H NMR [343]. The compounds studied werethe cyclobutano-annelated [n.2]metacyclophanes,n� 2–6; (610), and the [n.4]metacyclophanes,n�2–6; (611). NOESY spectra served to determine theorientation of the cyclobutane rings in (610). Thesyn/anti conformations of the metacyclophane systemswere derived using theDd technique by Krois andLehner [260] (discussed earlier). TheDd values had,however, to be corrected in order to account for theeffect of the OMe or OH groups. All compoundsprefer the conformer indicated in the formulae except

dimethoxy[2.2]phane (610), which has asyn/antimixture (4:3) that equilibrates slowly enough to seeseparate signals in the NMR spectrum, but too fast toallow isolation of the isomers.

Intramolecular photocycloaddition of (612), n� 4or 5, gavesyn-[4.2]phane (613), n� 4; and anti-[4.2]phane (614), n� 4; while in the case ofn� 5only the anti-conformer (614), n� 5; could beisolated [344].Syn-[4.2]phane (613), n� 4; showsonly one set of seven proton NMR signals in thearomatic region and only one cyclobutane CH absorp-tion, whereasanti-[4.2]phane (614), n� 4; has twosets of aromatic and cyclobutane CH signals becausethe cyclobutano ring destroys theC2 symmetry whichotherwise would be present. Due to the eclipsedarrangement of the two carbazole subunits insyn-[4.2]phane (613), n� 4; there are general upfieldshifts of all aromatic protons compared to referencecompound (612). In anti-[4.2]phane (614), n� 4;only H-1 (Dd � 21:12 and 21.06), H-2(Dd � 21:45 and 21.07), and, to a lesser degree,H-4 (Dd � 20:54 and 20.22) are substantiallyshifted with respect to (612), while the shifts of H-5to H-8 are hardly affected. This proves theanti-struc-ture for this conformer, in which there is only partialoverlap of the carbazole subunits and the outero-phenylene rings are directed away from one another.The properties ofanti-[5.2]phane (614), n� 5; weresimilar to those of its four-membered homologue.

[5.5]Dibenzocyclooctatetraenophane (615) shouldhave been obtained as a mixture of meso and chiraldiastereomers according to the NMR spectra of itsprecursors [345]. However, it shows only a singleset of 1H NMR signals. This was ascribed to adynamic process in which one dibenzo-COT subunit


(CH2)n

(609), n = 2, 5−10

OMe

(CH2)n

OMe

HHXX

(CH2)n

(610)

X = OMe: n = 2, syn/antin = 3−6, syn

X = OH: n = 4−6, syn

XX

(CH2)n

(611)

X = OMe or OH:n = 2−4, antin = 5−6, syn

flattens and rotates about the phenolic C–O bonds by1808, thereby interconverting the diastereomers.Reduction of (615) with potassium to its tetraanion(61542) planarizes the COT rings and two sets ofsignals reappear because internal rotation in the tetra-anion is slow due to the increased steric hindrance bythe solvation shell of the ion pairs. In the tetralithiumsalt of (61542), internal rotation is faster, so broadaveraged signals are observed at ambient temperature.Hence, steric hindrance in the lithium salt is smallerthan in the potassium salt because of the favourableformation of solvent separated ion pairs. Molecularmodels suggest that the reduction of and ring planar-ization in (615) decrease the distance between thecentral CyC bonds of one COT subunit from that ofthe other from 1200 to 500–600 pm. Experimental

evidence for this was obtained from the increased1H shieldings in (61542) of up to 0.4 ppm comparedto the reference dianion (61622). The reason lies in themutual shielding of the flattened parallel-orientedCOT22 subunits.

Staab and coworkers, in a low-temperature1HNMR study of various porphyrin–quinone cyclo-phanes and analogues, observed three differentdynamic processes that occur in these molecules,viz. N–H/N-tautomerism, ring rotation in the cyclo-phane bridges, and a “swinging bridge” process [346].Tautomerism causes doubling of theb-proton signals,has barriersDG‡ of the order of 50 kJ mol21 at235 to2178C, and was confirmed byN-deuteration whichincreases the barriers by ca. 8 kJ mol21 and thecoalescence temperatures by ca. 408C. The barrier in


N

N

(CH2)n

(612), n = 4 or 5

NN

NN

(H2C)n

syn-(613), n = 4

(CH2)n

4

1

2

anti-(614), n = 4 or 5

O O

OO

(CH2)3(CH2)3

OMe

MeO

−−

−−

−−

(CH2)3(CH2)3

O

O O

O −−

(CH2)3(CH2)3

O

OO

O

−−

meso-(6154−) chiral (6154−)

(615)

(6162−)

(617) is 49 kJ mol21 at 2238C. The rate of tautomer-ism is hardly influenced by the incorporation of theporphyrin moiety into the cyclophane framework, as asimilar barrier to N–H/N-tautomerism is observed inthe model compound tetraphenylporphyrin,DG‡ �47 kJ mol21 at 2358C. Expectedly, the barrier toring rotation in the cyclophane bridge dependsstrongly on the size of the substituents present.While free rotation�Tc , 21238C� of the quinonering is observed for (618, X � H, Me, Cl or Br),methoxy and cyano groups efficiently raise the coales-cence temperatures of the porphyrin methyl signals

leading to DG‡�2818C� � 39 kJ mol21 for (618,X �OMe) andDG‡�144–668C� � 70 kJ mol21 for(619, X � CN). The third process was interpreted asa swinging back and forth of the cyclophane bridgebetween two equivalent unsymmetrical conforma-tions, in which the planes of the porphyrin and thering in the bridge are tilted against each other.This process has low activation barriers, e.g.DG‡�21208C� � 31 kJ mol21 for (619, X �OMe)and leads to doubling of the methine and NH protonsignals. The activation barrier of the swinging bridgeprocess is also barely dependent on the substitutionpattern.

Adams and Whitlock [347] studied the1H NMRspectra of the tetraoxa[8.8](1,4)naphthalenophaneswith two triple bonds in each bridge (620) and oftheir analogues with saturated bridges (621). A cycli-zation shift,Dcyc, of a proton was defined as the chemi-cal shift difference between its signal in thecyclophane and the corresponding proton in an uncy-clized model compound,Dcyc � duncyc 2 dphane; posi-tive values corresponding to upfield shifts oncyclization.

O)2

O)2

OX

OX

(620)

O

O

OX

OX

(621)

X

C(=O)CH3

C(=O)C2H5

C(=O)CH2Phcba

)2

)2

In the compounds (620) the rigid diyne bridges keepthe aromatic rings apart so that they do not interact.This results in very smallDcyc values for the aromaticprotons. Those of the acyloxymethyl groups,however, increase with distance from the aromaticring to which they are bound, indicating that thesegroups are under the influence of the opposing trans-annular ring. The flexibly bridged phanes (621) havemoderateDcyc values (0.2–0.4 ppm) for the aromaticprotons resulting from collapse of the rings upon eachother as the rigid constraint of the diyne bridges is


N

NH N

HN

O

O X

X

Me

MeMe

MeMe Me

Me Me

(618)

N

NH N

HN

(617)

MeO

OMe

Ph

Phβ

N

NH N

HN

X

X

Me

MeMe

MeMe Me

Me Me

(619)

OMe

MeO

removed. The strong shieldings of the functionalgroup protons in (620) suggest that this compoundprefers ananti conformation of the two naphthalenesystems. Variable temperature spectra combined withfull band-shape analyses of the CH2 and CH3 signalsin (620a) gave a barrierDG‡

298 for anti–anti0 intercon-version of 51:5^ 1:3 kJ mol21

: The spectra also indi-cate that a further conformer of low concentrationparticipates in the conformational equilibrium, mostprobably thesynconformer, the percentage of whichwas calculated to be 6.5% at2138C �DG0

298�6:6 kJ mol21�: As the same inversion barrier as for(620a) is also found for compounds (620b) and(620c), which possess larger acyloxymethyl substitu-ents, one may reasonably assume that in theanti–syninterconversion it is the fused benzo ring that rotatesthrough the molecular interior, not the acyloxymethylgroups. The hydrogenated naphthalenophanes (621)show no sign of diastereotopic methylene protonsdown to2608C, but at2978C the H-6,7 peak splitsinto two, presumably because of a frozenanti/synequilibrium. At293^ 18C, the equilibrium constantsK(anti/syn) for (621a), (621b), and (621c) are 1.3, 2.1,and 2.6, respectively, in line with the increase of thesubstituent size in this order. The upper limit of theconformational barrier was estimated to be42 kJ mol21. The more compact conformation andthe lower barrier of the hydrogenated phanescompared to the acetylenic analogues imply that theformer undergoes an accordion-like breathing in thesyn/anti interconversion. Complexation studies with(620) and (621) are also described in Ref. [347] butare not discussed here.

The combination of two 10b,10c-dimethyl-dihy-dropyrene units (317a) to form [10.10](2,7)dihydro-pyrenophane (622) was reported by Mitchell and Jin[348]. The compound has a highly symmetrical1HNMR spectrum without unusual shifts�d�CH3� �24:31�: The fact that thetrans-methyl groups of thedihydropyrene (dhp) system absorb as one commonsinglet in the 360 MHz spectrum, suggests that thedhp units can rotate on the axis along the 2,7-bonds.This process is not stopped on cooling to21008C. ANOESY spectrum showed an interaction between the4,5,9,10-dhp and the methyl protons. Since such aninteraction is not observed in the parent (317a), itmust occur between protons of one dhp unit and ofthe other, suggesting that during rotation the methyl

protons pass close to the edge ring protons of theopposite ring.

CH3

CH3

O

O

O

O

CH3

CH3O

O

O

O

(CH2)4(CH2)4

2 7

(622)

6. Multiply bridged phanes

6.1. Phanes with multiple bridges between differentaromatic rings

As in the previous section, it is not possible toarrange the material in a strictly logical order, so theapproach adopted is to proceed from phanes with fewand short bridges to those with more and/or longerbridges.

In an article on multibridged [2n]cyclophanes,the 1H and 13C NMR spectra of all cyclophaneswith two to six two-membered bridges and thesame substitution pattern in both benzene rings,(148), (149), (194), and (623)–(630), and of theskew [2.2.2](1,2,4) (1,2,5)cyclophane (631) areassigned by NOE difference and 2D correlationspectroscopy [144]. The1H NMR spectra of thebridge protons including the13C satellites of thesymmetrical compounds (194), (625) and (630)were analysed by iterative methods, cf. the earlierdiscussion of (194). Chemical shifts and couplingconstants were discussed with regard to moleculargeometries. A through-space isotope effect ofdeuterium upon 13C NMR chemical shifts inCHD2-[24](1,2,4,5)cyclophane (204) was discussedin Section 3.2.

At room temperature, the1H and13C NMR spectraof the doubly positive bis[(hexamethylbenzene)ruthe-nium] complex of [2.2.2.2](1,2,4,5)paracyclophane,(632) [349] shows the molecule to be symmetrical


and to adopt a Ru1…Ru1 structure on the NMR timescale. At low temperature, however, two sets of NMRsignals are present, showing the upper and lowerhalves of the molecule to be different and suggestinga localized Ru21…Ru0 system withh6- andh4-coor-dination, respectively. This implies a net two-electrontransfer between the ruthenium atoms in the equili-brium (632a) Y (632b). The line shapes of the1Hmethyl signals were analysed at eight temperaturesbetween280 and 08C �Tc � 2438C�; and the kineticparameters obtained areDH‡ � 53:1^ 3:4 kJ mol21

;

DS‡ � 33^ 13 J K21 mol21; and DG‡ � 43:1^

5:0 kJ mol21:

(623)

1

3

(148)

1

3

(624)

1

2

4

(625)

1

3

5

(627)

1

3

5

(194)

14

2

(626)

13

2

4

(628)

1

5

2

4

(149)

1

3

2

(629)

13

2

45

(630) (631)

1

12

2

4

5

The 13C chemical shifts and the1H shift ranges ofthe fully bridged [2.2.2.2](2,3,4,5)-thiophenophane(633) (“superthiophenophane”) and its precursor2,10-dithia[3.2.2.3](2,3,4,5)thiophenophane (634)have been reported [350]. Unfortunately, no specific

shift assignments were made, nor were analyses of theAA 0BB 0 spin systems in the1H spectra carried out.

Conformational analysis of hexadeuterio-[3.3.3](1,3,5)cyclophane (635) was undertaken byShinmyozu and collaborators [351]. There are twodiscernible conformers: (635A) and (635B), whichinterconvert slowly at2708C, their aromatic protonsgiving rise to three signals atd � 6:71 (Hii), 6.52(Hio), and 6.36 (Hoo) with relative intensities of ca.1:2:1. This assignment is straightforward if onetakes into account the deshielding effect by almost0.2 ppm of a bridge upon itsortho-syn aromaticproton. Integration gave a 27:73 ratio of conformerpopulations at2708C which corresponds to (635B)being more stable than (635A) by 1.7 kJ mol21.There are two possible bridge inversion processes:those between different conformers�A O B� andthose between like conformers�B O B�: Theseprocesses have different activation energies but thenature of the spectra (four overlapping AB systemsfor the benzylic protons) allowed only the determina-tion of one coalescence temperature (278C at270 MHz) and a common barrier,DG‡�278C� �51:9 kJ mol21

: It was concluded that the inversionsof the three bridges are not correlated but that thebridges move independently. The trione (636) gavesharp spectral lines down to2908C. Hence it ismuch more flexible than the hydrocarbon (635).

The triply bridged trithiacyclophanes (637) and(638) [352], the cyclophane (639) and the cyclopha-netriene (640) [353], each with one fluoro substituentper aromatic ring, were investigated by Lai et al.Compounds (638)–(640) are of interest because ofthrough-space spin–spin coupling between protonand fluorine nuclei of opposite rings which are forcedinto close contact by the molecular geometry. Thearomatic interdeck distances were estimated to be319, 279, and 281 pm in (638), (639), and (640),respectively, from X-ray diffraction studies of thefluorine-free parent compounds. In agreement withthis, the interringJ(F,H) is small, 2.4 Hz, in (638)and distinctly larger, 6.9 Hz, in (639). However, it isunexpectedly small in (640), viz. only 5.0 Hz. It isworth noting that the assignments of the1H chemicalshifts within the methylene groupsortho to fluor-ine in (639) most certainly need to be reversed.The proper assignment is deshielded/shielded forthe proton syn/anti to the fluoro substituent as


already discussed in Section 3.9. Similarly, theassignments within the SCH2 groupsortho to fluorinein (637) and (638) need reversing, cf. the data for(405) in Ref. [165].

In the low-temperature1H NMR spectrum (2808C)of the triply bridged dioxadithia[3.4.3]phane (641)[354], the geminal protons in the three indicatedkinds of methylene groups are anisochronous. At anobservation frequency of 90 MHz their signalscoalesce at ca.2508C (OCH2) and ca. 2558C(SCH2), which give the same barrier of45.3 kJ mol21 for the different exchange processes.The conformational process taking place was believed

to be a concerted wobbling of the three bridges in themanner shown in (641) O (6410).

Cyclophanes (642) and (643) contain four three-membered bridges [355]. The sharp singlet�d �6:90� of the aromatic protons of the 1,2,4,5-isomer(642) at room temperature suggests the mobile natureof this compound. NOE experiments show the moststable conformation to be boat–boat. In the 1,2,3,5-isomer (643), a sharp singlet of the aromatic protons�d � 6:62� as well as averaged benzylic proton signals(Heq, Hax) of the isolated trimethylene bridge indicaterapid inversion of the latter.

The ruthenium(II), osmium(II), and iron(II)


(632)

Ru

Ru

2+

(632a)

Ru2+

Ru0

(632b)

Ru0

Ru2+

S

S

(633)

S

S

(634)

S

S

D2

D2

D2

D2

D2

D2

(A) (B)(635)

Hii Hoo

HioHio

O

O

O

(636)

complexes of [3n]cyclophanes�n� 2–4�; (644a)–(644d), (645a)–(645d), and (646a)–(646d), respec-tively, were studied by1H and 13C NMR [356]. Thecomplexation shifts Dd� d (complex)2 d(free

ligand) of the protons at the metal-bound aromaticrings are ca. 20.5 to 20.7 and 20.1 to20.4 ppm for the Fe(II) and Ru(II) complexes,respectively, whereas those of the Os(II)complexes are ca.10.1 to 10.2 ppm. TheDdvalues of the tertiary carbon atoms in the metal-bound aromatic rings are ca.239 to 242 and245to 250 ppm in the Ru(II) and Os(II) complexes,respectively. The numbers for the quaternary carbonnuclei are216 to224 and221 to228 ppm, respec-tively. The observed complexation shifts are almostindependent of the number of bridges in the cyclo-phane ligands. It was concluded that the1H and 13CNMR chemical shifts of the metal-bound aromaticrings are strongly influenced by the anisotropy effectof the metal.

Cyclophane (647) with five three-memberedbridges [357] also shows conformationally averaged1H and 13C NMR spectra at room temperature,d�Har� � 6:71 (CD2Cl2). The aromatic proton signaldecoalesces at2708C and two singlets (d � 6:58


Ru2+

L

(644a), L = [32](1,4)cyclophane(644b), L = [33](1,3,5)cyclophane(644c), L = [34](1,2,3,5)cyclophane(644d), L = [34](1,2,4,5)cyclophane

2 BF4−

Os2+

L


2 PF6−

Fe+

Fe+

L 2 PF6−


(639)

F

F

(640)

F

F

(637), R1 = F, R 2 = H

F

R2

S

S

S

R1

(638), R1 = H, R2 = F

(641)

S

S

(641’)

S

S

OO

Hb

Ha

He

Hf

Hc

Hd

O

O

H

H

H

H

(643)(642)

and 6.82) were observed at2908C with respectiveintensities of 1.0:1.2. The activation barrier to inter-conversion was determined to beDG‡ �40:2 kJ mol21

: MM3 molecular mechanics computa-tions predict (647b) as the most stable conformationfollowed by (647a). This agrees with the relativechemical shifts of the aromatic protons because ofthe deshielding effect of the three-membered bridgein the syn-conformation, cf. (635). According to theMM3 results, the observed barrier probably corre-sponds to the flipping of the bridges at C-1/C-5. Flip-ping of the other bridges is estimated to have lowerbarriers by about 17 kJ mol21. In line with the above,the correlated inversion of all six trimethylenebridges, which converts conformation (648a) of[3.3.3.3.3.3]cyclophane into (648b), is expected tobe easy and does occur rapidly at room temperature[358]. This is obvious from the presence of only twoaveraged1H NMR signals (benzylic CH2, d � 3:19;and central CH2, d � 2:46) and three13C signals�d �135:4;28:2;20:5�: Variable temperature1H NMRexperiments on (648) [359] showed four differentchemical shifts for the bridge protons below2408C.These were assigned by spin decoupling:da, db, d c,dd � 3:21; 2.78, 2.55, and 1.70, respectively. Simul-taneous decoupling of Hc and Hd at low temperaturesallowed the observation of an AB spectrum for Ha andHb, and its coalescence to a singlet. The inversionbarrierDG‡(2408C) is 45.6 kJ mol21.

H

(647b)

6.82H

(647a)

6.58

(648b)(648a)

Hb

Ha

Hc

Hd

The 1H NMR data of the triply bridged[n.2.2](1,3,4)cyclophanes,n� 4–5; (649), [n.4.4]

(1,3,4)cyclophanes,n� 4–5; (650), and [n.2.2](1,3,5)cyclophanes,n� 2–4; (651) were reported[343]. For geometrical reasons, these compoundsmust assumesynconformations. This was also clearfrom the moderate upfield shifts of the aromaticprotons relative to benzene model compounds andfrom the narrow ranges of these shifts in (649) and(650).

The reaction of 1,2,4,5-tetrakis(bromomethyl)ben-zene with the analogous tetrathiol furnished the twopossible isomers (652) and (653) [360]. Their struc-tures were derived from the1H chemical shifts(considering the distance of the aromatic rings andtheir relative orientation) and confirmed by an X-raydiffraction study of (652). This work disproved theearlier reverse structural assignment by Klieser andVogtle [361]. A similar kind of isomerism arosewhen the two tetrabridged biphenylophanes (654)and (655) were prepared from their two tetrafunc-tional precursors [362]. A comparison of the1Hchemical shifts of (654) and (655) with those of themodel compounds 3,30,5,50-tetramethylbiphenyl and4,40-dimethoxy-3,30,5,50-tetramethylbiphenyl showsthat the aromatic protons in the “parallel” phane(654) are shielded by 0.23–0.43 ppm relative tothose in the model compounds. This is the normalvalue for eclipsed aromatic rings insyn-cyclophanes.In the “crossed” phane (655), the 2,20,6,60-protons inboth biphenyl subunits are shielded by ca 1.0 ppmwith respect to the model compounds. The molecularformula shows that each of these protons is above (orbelow) one aromatic ring, though not exactly centred,of the opposite phane deck.

When certain di-tert-butyl[n.2]metacyclophane-diols are oxidized with K3[Fe(CN)6], their intramole-cular O–C coupling products (656) containing a spiroskeleton are formed [363]. Whenn� 3; the 1H NMRspectrum in DMSO at room temperature shows twodoublets�J � 1:5 Hz� for the diene protons�d � 5:86and 6.40) and a broad singlet�d � 6:93� for thearomatic protons. On raising the temperature, thediene and aromatic proton signals fuse and coalesceat1808C: the compound undergoes rapid [3.3] sigma-tropic rearrangement between degenerate isomers.The barrier increases with increasing numbern ofmethylene groups in the bridge. Forn $ 8 signalcoalescence cannot be achieved at11508C. Thefull paper on this subject [364] also reported [1.5]



MeOOMe

(CH2)n

(651), n = 2−4

(CH2)n

(649), n = 4−5

(CH2)n

(650), n = 4−5

S S

SS

S S

SS

(652) (653)

4.02/3.78

7.74

7.30 4.53/3.68

OMeMeO6.84

6.96

(654)

MeO OMe

(655)

6.54

6.62

6.166.17

(656)

OtBu

O tBu

(CH2)n

OtBu

O tBu

(CH2)n

3

71.180

∆G≠ [kJ mol−1]Tc [˚C]

n 4 5 6 8 10

71.5 77.8 87.9 >105 >105>150>15014011080

OR1

O R2

OR1

O R2

(657a), R1 = H, R2 = Me(657b), R1 = H, R2 = tBu(657c), R1 = Br, R2 = tBu

sigmatropic rearrangements of the type (657) O (6570),in which the spiro centre remains on the same ringwhen this is favoured by the nature of the substituents.For this process, coalescence temperatures of thearomatic and of the olefinic proton signals are nearroom temperature and free energies of activation areof the order of 58 kJ mol21.

The triply bridged [n.2.1](1,2,3)cyclophanes (658),n� 3–12; and (659), n� 3–10; may also be consid-ered dibenzocycloheptenes with an additional bridge.For small values ofn, the protons of the ArCH2Armethylene group are nonequivalent at room tempera-ture because the short bridge restricts the conforma-tional movement of the dibenzocycloheptene system[365]. This is the case for (658), n # 5; and for (659),n # 8: Large values ofn lead to singlet absorptionsfor the ArCH2Ar methylene protons at room tempera-ture, viz. in (658), n $ 7; and in (659), n $ 10:Barriers to conformational flipping of the aromaticrings (� inversion of the benzocycloheptene moiety),determined by the coalescence method, are given inTable 15.

Formally, compounds of type (660) [366] are triplybridged phanes, viz. [n.2.2] (1,3,5)cyclophanes, butthey are better visualized as “tethered [2.2]metacyclo-phanes”. Their conformational preference is deter-

mined by the length of the tether. A very long tethershould have no influence and thus allow the[2.2]metacyclophane to assume its preferredanticonformation (660a) with parallel rings. As the lengthof the tether decreases, the aromatic rings should betilted with respect to one another as in (660b) andfinally the anti conformation will be less stable thanthesyn(660c). At some intermediate tether length thetwo conformers may coexist. Indeed, the synthesis ofphane (661a) with a 12-atom tether yields only thesynconformer which has a normal chemical shift,d �6:19; for the “internal” aromatic proton (para to theether function) [366]. In contrast, phane (661c) with a14-atom tether was isolated exclusively in theantiform. Signals of the internal protons are observed atd � 4:83 and 3.30. These large shieldings prove theanti conformation and the large difference betweenthem is due to the relative tilt of the rings as depictedin (660b). This tilt moves the internal proton of theinner ring further into the shielding region of the outerring and the proton of the outer ring away from theshielding region of the inner ring. The chemical shiftsof the two internal protons of (661c) were onlyassigned by this reasoning, not experimentally, yet itis difficult to devise a suitable experiment to achievesuch assignment. Logically, the properties of


(CH2)n−2

SS

(658), n = 3−8, 12

(CH2)n

(659), n = 3−10

Table 15Activation parameters of benzocycloheptene ring inversion in (658) and (659) as a function of the length of the third bridge

Compound (658) (659)

n 5 6 7 8 8 9 10Total bridge length 7 8 9 10 8 9 10Tc [8C] . 150 50 230 2100 . 120 20 250DG‡ [kJ mol21] . 85.4 65.3 47.7 33.9 . 77 57.3 43.5

compound (661b) with its 13-atom tether are in-between those of the molecules with the longer andthe shorter tether. It occurs as a mixture ofsyn andanti conformers that can be separated by chromato-graphy. In solution at room temperature the confor-mers equilibrate slowly to aanti/synratio of 5.9:1, sotheir difference in free energy is ca. 4.4 kJ mol21. Thechemical shifts ofanti-(661b) are more extreme thanthose of the compound with the longer tether (Table16). anti-Metacyclophane (662) is a good modelcompound for a molecule with untilted rings and thedifferencesDdH between the shifts of the internalprotons in the tilted compound and the internal protonin (662) reveal that the proton of the inner ring isessentially shielded by the same amount by whichthe proton of the outer ring is deshielded. The chemi-cal shift difference between the internal proton of theinner and outer ring may serve as an indication of theextent of the tilt.

A series of triply clamped triphenylmethane deri-vatives has been studied by Karbach and Vo¨gtle [367].

While, at a1H measuring frequency of 90 MHz, thetrithia[3.3.3]phanes (663) and (664) are conforma-tionally flexible (DG‡� 54.9 and 56.0 kJ mol21,respectively; temperature not given), the correspond-ing [2.2.2]phanes are rigid until at least 1408C. Thesymmetrically substituted compounds (665) and (666)show one ABXY spectrum (wrongly described as twoAA 0BB 0 spectra) for theirpara-phenylene rings,which indicates that these are fixed in a propeller-


H

H

syn-(661a), n = 10

O

O

(CH2)n

(CH2)n

O

O

syn-(661b), n = 11anti-(661b), n = 11anti-(661c), n = 12

(662)

H

H OMe

MeO

H

H

(660b)

Hi

Hi

(660a) (660c)

outerring

ringinner

Table 16NMR chemical shifts of the hydrogenspara to the ether functions inthe tethered [2.2]metacyclophanes (661a)–(661c) and in the modelcompound (662)

Compound (661a) (661b) (661b) (661c) (662)Conformation syn syn anti anti –

dH (outer ring) 6.19 6.17 5.07 4.83 4.08dH (inner ring) 3.03 3.30DdH (outer ring)a 0.99 0.75DdH (inner ring)a 2 1.05 2 0.78

a Relative to the chemical shift of (662).

like arrangement. Unsymmetrically substitutedcompounds like (667) show two overlapping ABXYspectra (not four AA 0BB 0 spectra). Upon dissolutionin CDCl3/trifluoroacetic acid-d (7:3), diol (666) isconverted into dication (668) and mono-ol (667)into monocation (669). The ensuing chemical shiftchanges are discussed in terms of the propeller anglesof the para-phenylene rings and the degree of non-planarity of the trityl cation moieties.

For the macrocylic phane (670) [368] a “closed”and two “open” conformations are potentially impor-tant. In the closed conformation, the capping benzenering and the pentacyclic base are nearer to one anotherthan in the open conformations because of a synclinalCa–Cb–Cg–Cd torsional angle. In the open conforma-tions this angle is antiperiplanar, resulting in a largerdistance between benzene ring and base. The analysis

of the 1H spin system of the tetramethylene bridgesand the application of the Haasnoot–Altona variant ofthe Karplus equation [190] to theJ(H,H) valuesobtained, led to the conclusion that the torsionalangle in question is antiperiplanar. Consideration ofthe combined ring current effects of the aromatic ringsof the base (estimated with the Johnson–Bovey model[79]) upon the tetramethylene proton shifts and uponthose of the capping benzene ring also favours anopen conformation.

Hogberg and Wennerstro¨m [369] studied the1HNMR spectra of the “bicyclophanes” (671), (672)and (673), which have unsaturated bridges, and theirsaturated counterparts (674), (675) and (676). Ratherdetailed chemical shift considerations and compari-sons with the shifts of suitable model compoundsled the authors to conclude that the unsaturated


(663)(664) CH3

HR

R1

R2

(665)(666) OH

HR1 R2

HOH

(667) OH(668)(669)

CH3

CH3

⊕⊕

⊕

R

S

S

S

H

O O

O

Me

NH

HN

HN

(670)

α

βγ

δ

Ar

Ar

Ar

Ar

Ar

Ar

(673)

(672)

(671)

(675)

(674)

(676)

Ha

S

Ar

compounds prefer a compressed chiral conformation,in which the distance of the trisubstituted benzenerings from one another and the volume of the centralcavity are minimal and the twist angles (i.e. theprojected angles between the start and end of a bridgeas seen from a point on the threefold axis of symme-

try) are at a maximum. The other extreme conforma-tion, not taken up by the molecules, is that ofC3h

symmetry which has the bridges eclipsed and a maxi-mum distance between the 1,3,5-trisubstituted rings.The saturated compounds also prefer the compressedconformations. Remarkable chemical shifts occur forHa in (671), dH � 8:86; and in the saturated analogue(674), dH � 6:05: In the latter compound, Ha is sand-wiched between the two trisubstituted benzene ringsand exposed to the shielding effects of both of them.

The linear constitution of the belt-shaped phane(677) was determined by X-ray diffraction andconfirmed by an NOE observed between the protonsat positions a and b [370]. This excluded the crossedarrangement (6770) which, in principle, could alsohave been formed in the preparation. At roomtemperature the compound adopts an unsymmetricalconformation as indicated by four AB systems for theCH2N and two methyl signals for the tosyl groups.The CH2N absorptions and the methyl signals areaveraged to one singlet each above11388C. In thesame paper, the geminal protons of the CH2N groupsof the fourfold bridged diaza[3.3.3.3](1,2,4,5)cyclo-


NTs

NTsTsN

NTsa

b NTs

NTsTsN

NTs

a

b

(677) (677’)

H

H

(678)

TsN NTs

7.05

6.48

5.033.53

2J = 22.4 Hz (?)S

N

S

S

S

N

Ts

Ts

a

b

b

(679)

7.35

7.04

7.39

phane (678) were reported as having a very large shiftdifference (d � 5:03 and 3.53), most likely due to theadjacent tosyl group. The geminal coupling constantwas reported as 22.4 Hz. This is an improbable valueas such large magnitudes are found only rarely, viz.for CH2 groups situated between twop-systems in theproper conformation. The most stable conformationof the propylene bridges in (678) were shown to beboat–boat by NOE experiments at1208C. The tube-shaped biphenylophane (679) has two biphenyl unitsparallel to the axis of the tube and one biphenyl atright angles to it. This was shown both by X-raydiffraction and by the NOE between the 2,20-protons

(b) of the parallel biphenyls and the 4-proton (a) of theperpendicular biphenyl unit.

Compounds (680a)–(680h) and (681a)–(681i) aretetraoxa[8.8]paracyclophanes and -phanetetraynes,respectively, in which a third bridge, the diesterbridge, connects the C-2 positions of thep-phenylenerings [371]. Two ring-inversion topologies are possi-ble for these molecules: the diester bridge can passeither through the paracyclophane cavity (donut-holepathway) or around the outside (jump-rope pathway).Variable temperature1H NMR experiments werecarried out and the rate constants of ring inversionwere determined by magnetization transfer for


O

O

(680a)

O

O

O

O

O

OX

O

O

O

O

O

O

O

OX

(CH2)3

(CH2)6

(CH2)7

(CH2)8

(CH2)9

(CH2)10

(CH2)11

(CH2)5CMe2(CH2)5

CH2CHCH2

OSiMe2tBu

(680b)(680c)(680d)(680e)(680f)(680g)(680h)

(681i)

X(681a) (CH2)3

(CH2)6

(CH2)7

(CH2)8

(CH2)9

(CH2)10

(CH2)11

(CH2)5CMe2(CH2)5

(681b)(681c)(681d)(681e)(681f)(681g)(681h)

X

O

O

H3C

OO

OO

a

b

c

(682)

(680a) and (681a) and by lineshape analysis of theremaining molecules apart from (681i). The lattermolecule exists as two diastereomers that are trans-formed into one another by ring inversion, so thekinetics could be followed directly by evaluating thetime dependence of the integrals. Earlier studies hadshown [347] that the framework of diyne bridges isrigid and has a larger hole than the framework offlexible saturated bridges that favours a morecollapsed conformation. Hence, if for a given lengthof the diester bridge the ring-inversion barrier is smal-ler in the (681) than in the (680) series, the donut-holepathway is preferred, while for a smaller barrier in the(680) series, the jump-rope mechanism prevails. Athighn values of the (CH2)n chain, jump-rope inversionis expected to be favoured. Suppression of donut-holeinversion bygem-dimethylation in the middle of anester chain is another topological probe;gem-dimethylation should have little effect on jump-ropeinversion. Applying these criteria, Brown and Whit-lock [371] concluded that forn # 7 the donut-holepathway is followed, while the jump-rope pathwayis followed forn $ 9: The (CH2)8 pair of compoundspresent borderline cases. The ranges of barriersobserved areDG‡�258C� . 100 kJ mol21 (681i) and90 (681a) to 44 kJ mol21 (681g) in the phanetetraynesand.109 (680a) to ,10 kJ mol21 (680g) in the satu-rated-bridge phanes.

The bowl-shaped cyclophane (682) shows equiva-lence of the geminal protons of the three differentkinds of methylene groups at room temperature[372] At low temperatures, however, the methyleneprotons a�d � 3:87� and b �d � 4:90� turn into ABsystems with coalescence temperatures of210 and2118C, respectively. Methylene group c, on theother hand, absorbs as a sharp singlet down to2538C. These results indicate that the side bridgeshave some conformational constraints, while the C–CH2–O–C bonds of the central bridge make a crank-like rotation with a low barrier.

Two isomeric “cappedophanes” (685) and (686)were isolated from the reaction of (683) with (684)[373]. When the “cap” (683) reacts from the bottomside of terphenyl (684), the product is (685); when itreacts from the top side, (686) is formed. The isomerscould be distinguished from the chemical shifts of them-terphenyl H-20 signals [d � 6:24 in (685) and 5.70in (686)] and H-50 signals [d � 4:31 in (685) and 7.35

in (686)]. The strong upfield shift of H-50 in (685) isdue to this proton being sandwiched between the two1,3,5-trisubstituted benzene rings. Furthermore, whenthe signal of the same proton was saturated, a 10.4%NOE was observed at the proton signal�d � 7:62� ofthe para-phenylene ring. The two reaction productswere the first examples of two noninterconvertibleconformers of a single host molecule, one (686)with a substantial cavity, the other, (685), with aself-filled cavity. Compound (685) was thereforecalled anautophagous(“self-devouring”) molecule.For other papers on “cappedophanes” and “cuppedo-phanes” the reader is referred to Ref. [374] and to thereview of Vinod and Hart [375].

6.2. in-Phanes

A class of compounds that is very interesting bothfrom the structural and an NMR point of view are theso-calledin-cyclophanes. In these, a central atom isconnected by several (usually three) bridges to thesame aromatic unit. The geometric situation is suchthat the most stable isomer has the proton or otherconnected atom or group on the central atom pointingtowards the aromatic unit, i.e. into the inside of themolecule. Apparently, the firstin-cyclophanes wereprepared, but not recognized as such, by Ricci et al.[376]. One of their compounds, 2,8,17-trithia[45,12][9]-metacyclophane (687) was later resynthesized by Pascaland Grossman [377]. They showed that the characteris-tic in-proton, whose1H NMR resonance had previouslybeen missed, has a septet absorption�J � 6 Hz� atd �21:68:This is a higher-field shift than the most shieldedmethylene proton of [5]- to [9]paracyclophane andclearly proved thein-stereochemistry. According tothe results of MM2 molecular mechanics computations,thein-isomer ismore stable, byca. 29 kJ mol21, than theout-isomer and the distance of thein-methine hydrogenfrom the mean aromatic plane is 221 pm. Subsequently,the authors succeeded in shortening all three bridges of(687) by oxidation and sulfone pyrolysis and obtainedhydrocarbon (688) [378]. The distance between themean aromatic plane and thein-hydrogen was estimatedto be 178 pm with MM2, consistent with the extremeupfield shift ofd � 24:03 for this proton. The confor-mational ground state of the molecule isC3 as evidentfrom the chemical nonequivalence of the benzylichydrogens and the broadening of the other CH2 signals


at room temperature. The signals of the benzylic protonscoalesce at1478C andDG‡ for the bridge flip from oneside of the symmetrical arrangement to the other is61.9 kJ mol21. The shorter-bridge analogues of (687),compounds (689)–(691) with n CH2SCH2 and 3-nCH2SCH2CH2 bridges�n� 1–3� between the benzenering and the central methine unit, show increased shield-ing of the in-proton with increasing number of theshorter bridges:d � 21:94; 22.43, and22.84 [379].However, the chemical shift of thein-proton of (691)with its three CH2SCH2 linkages does not reach theextreme value of its counterpart in (688), d � 24:03;in agreement with the longer C–S relative to the C–Cbonds. The shift of thein-proton of (691) is 4.90 ppmupfield from the methine resonance in the acyclic modelcompound (CH3SCH2)3CH �d � 2:06�: Compound(691) shows the same dynamic phenomenon as itstricarba analogue (688). At room temperature, the1HNMR spectrum contains several broadened methylene

resonances which indicates slow enantiomerization oftheC3 conformers, (6910) and (69100), on the NMR timescale. At2688C the broadened lines are resolved intotwo pairs of diastereotopic methylene resonances. Theprotons of the CH2 group adjacent to the apical methinehave a chemical shift difference of 1.70 ppm in toluene-d8. Coalescence at1478C (250 MHz) gives aDG‡ valueof 60.3 kJ mol21, just slightly lower than the barrier for(688).Schneider et al. [77]were verysuccessful in semi-empirically calculating the ring current effects upon thein-protons in (688) and (691).

The nextin-cyclophane (692) from Pascal’s group[380] has a central phosphorus atom linked to the1,3,5-positions of a benzene ring by three four-membered bridges. The13C NMR spectrum showsspin–spin coupling between the phosphorus andallof the aromatic carbon atoms. Of particular interestare the couplings to the quarternary and the tertiarycarbon atoms of the basal ring; they amount to 7.5 and


O O

SHHSSHHSBr Br

2’

5’

Br Br

+

SS

SS

O

O

H2’

5’

(686)(685)

(683) (684)

S

O

S

SS

O

H

H2’

5’

H

3.5 Hz, respectively. These are obviously through-space couplings as the nature and arrangement ofthe intervening bonds is not favourable for five- andsix-bond interactions. The31P chemical shift of (692)is d � 5; a substantial shift to high frequencies fromthe starting tris(2-mercaptophenyl)phosphine whichhasd � 226:7: Hence, a shielding effect by the ringcurrent of the basal benzene ring upon the phosphoruswas not observed, in spite of the short distance(290 pm by X-ray diffraction) of the phosphorusatom from the centre of the base plane. The authorssuggested a more phosphonium-like character for the

phosphorus as an explanation for the high-frequencyshift. Typical methyltriarylphosphonium31P shiftsfall into the range ofd � 18–26: Compound (693),the sila-analogue [381], has a chemical shift of theSi–H hydrogen ofd � 1:04: This represents a shield-ing effect of 5.09 ppm relative to model compound(694) and agrees with the high-field shift observedfor the in-methine compound (691). Both the sila-and the phosphaphane have diastereotopic benzylprotons due to the propeller-like conformationsfound also for (688) and (691). In contrast to these,heating to 11808C does not result in signal


H

6.86

2.23/2.91

1.45

0.72

−4.03

(688)

S

S

S

H

7.193.66

2.36

1.07

−1.68

(687)

S

S

H

(689)

S

S

H

(690)

SS S

H

7.18

3.77

(2.90 & 1.20 at −68 ˚C)

−2.84

(691)

SS

−1.94

−2.43

3.1&1.7

S

X

S

S

(692), X = P(693), X = SiH

S

CH2Ph

SCH2Ph

SPhCH2

SiH

(694)

S

P

S

S

(695), X = NH2, Y = H

X

Y

(696), X = NO2, Y = H(697), X = Y = NO 2

(698a), Z = lone pair

PZ

(698b), Z = O(698c), Z = CH3

+ I−

S

S

S

S

S

S

(691’) (691")

coalescence at 500 MHz observation frequency. Thelower limit of the free energy of activation for theenantiomerization of cyclophanes (692) and (693) isthus 92 kJ mol21. Derivatives of (692) substituted atthe basal ring with one amino group (695), one nitrogroup (696) and two nitro groups (697), respectively[382], have irregular chemical shifts of the phos-phorus�dP � 9:3; 6:9;5:8� that could not be correlatedwith the electron donating and withdrawing power ofthe substituents, bearing in mind that (692) itself hasdP � 5:0: The magnitudes of the through-space P,C-coupling constants are only slightly affected by thesubstituents. In this context it is of interest to note theexistence of theout-phosphaphane (698a) with threefive-membered bridges [383]. Its chemical shift�dP �214:2� is much closer to the normal range of triarylpho-sphine shifts than that of (692). The phosphine oxide(698b), dP � 133:1; and the methylphosphonium salt(698c), dP � 121:3; were also reported.

SS

(699)

SF

Si

Si

CH3

S

S

S

(700)

The in-fluorosilaphane (699) [384] with five-membered bridges between the silicon and the basalring has the largestin-functional group in this class ofcompounds so far. Originally, its19F nucleus wasreported [384] to be shielded by 155 ppm relative tothe model compound tris(o-tolyl)fluorosilane, whichhasdF � 2160:6: This would have been an extraordin-ary finding, but the spectra were incorrectly referencedand the chemical shift of (699) was soon corrected todF � 2155:3 [385], so the fluorine nucleus is actuallydeshielded by 5.3 ppm. An attempt to prepare anin-phane with an internal methyl group connected to sili-con and six-membered bridges led toout-isomer (700)[386], which displays a normal Si–CH3 shift of dH �0:73: It shows more than three methylene1H chemical

shifts at room temperature. This indicates that thebridges are rigid under these conditions.

HHH

H

(702)(701)

≈1.65

−2.36

The 1H NMR spectrum oftrans-hexahydro[2.2]-paracyclophane (701) [387] displays a high-field reso-nance atd � 22:36: This is due to the proton in theinterior of the molecule. The rigidity of the moleculeforces the in-proton to face the benzene ring. Itschemical shift is 4.0 ppm upfield from the methineresonance�d < 1:65� in the cis-isomer (702) [388].

7. Multilayered phanes

An extensive review of the NMR aspects of multi-layered phanes has been written by Misumi [10], theprotagonist in this field of chemistry. Following hisretirement the number of papers in this area hasstrongly declined. We mention only two papers, thefirst one on the triple-layered [2.2][2.2]naphthaleno-phane (703) [389]. The subunit comprising the upperand the central naphthalene deck of this compoundrepresents the chiral [2.2]naphthalenophane (285) asdoes the subunit consisting of the central and thelower deck. The protons of the outer decks areshielded by 0.18–0.26 ppm relative to those of (285)while the protons on the central (sandwiched) deckexperience an upfield shift which equals almosttwice that of the naphthalenea-protons of (285)with respect to 2,6-dimethylnaphthalene. The struc-ture of (703), at first derived only from the1H chemi-cal shifts and from MS data, was later confirmed byX-ray diffraction [390]. Other possible stereoisomersof (703) were not formed in the synthesis.

The other paper concerns the two isomeric triple-layered phanes (704) and (705) with outer(3,6)phenanthrene decks and an inner naphthalenedeck [391]. The difference between the isomersconsists in the mode of connection of the phenan-threne rings to the naphthalene ring. It is “parallel”


(2,7)(3,6) in the first case and “crossed” (2,6)(3,7) inthe second. The mode of connection imposes an obli-que structure upon (705) with the concave side of thephenanthrene and the naphthalene over one another.This leads to strong shielding of the phenanthrene H-4�Dd � 21:89� and the naphthalene H-1�Dd �21:58� protons compared to the phenanthrene andnaphthalene reference compounds (706) and (707),respectively. In (704) only phenanthrene H-4 isslightly shielded�Dd � 20:52� with respect to (706).

8. [mn]Phanes

Following Vogtle [4], by [mn]phanes, written with anitalicized subscriptn, we understand a cyclic arrange-ment of alternating aromatic rings and aliphatic bridges,for example [–Ar–(CH2)m–]n. The most common repre-sentatives of this class are the calixarenes. These andtheir close analogues are, however, not treated in thisreview. Instead, arrangements less regular than strict

[mn] are considered, i.e. cyclic sequences with morethan two aromatic rings and intermittent aliphatic parts.

Two conformers of trimethoxy[2.2.1]metacyclo-phane (708) were isolated by Tsuge et al. [392]. Inthe first of these (later called “folded inwards” [393]),there is a parallel arrangement of the two benzenerings (A, B) connected by the single methylenegroup such that the molecule possesses a plane ofsymmetry, cf. (708A). The plane of the third benzenering (C) is perpendicular to the plane of symmetry andthe methoxy group bound to it points into the cavitybetween rings A and B, so it is shielded by the ringcurrents of both and attains the extraordinary1Hchemical shift ofd � 1:21 while the other two meth-oxy groups have almost normal shifts atd � 3:44: Inthe second conformer (708B) rings A and C are heldparallel to one another (proved by X-ray) so that anasymmetric structure results. The fit of the B-methoxygroup into the cavity between rings A and C is not asperfect as that of the C-methoxy group between ringsA and B in (708A). Thus, the shift of the B-methoxy


5.55

6.176.916.69

(703)

(704) (705)

7.57

7.76

7.44

7.93

7.35

7.45

7.58

7.20

6.56

5.86

7.62

7.75

7.39

8.45

(706)

7.44

(707)

group in (708B) is only d � 2:64: Conformer (708B)is chiral and shows doubling of signals in the1H NMRspectrum when Pirkle’s reagent (optically active 1-(9-anthryl)-2,2,2-trifluoroethanol) was added to the solu-tion [394]. The internal methoxy groups of the twoconformers show different reactivities towards BBr3.While that of (708B) is hydrolysed, that of (708A),well shielded by the A and B rings, is not attacked. Aseries of other [2.2.1]- and [2.2.2]metacyclophanes(709) and of dithia[3.3.1]- and [3.3.2]metacyclo-phanes (710) was later studied by the same group ofauthors [393]. It was found that some of the moleculesprefer a “folded inwards” conformation like (708)and others an “alternate” conformation (711). The

preference strongly depends on the nature of thesubstituent R1. Thus, while (710), n� 2; R2�Me,R1� Et, assumes the “folded inwards” conformation(shift of terminal ethyl protons:d � 0:06 as opposedto ethylbenzene,d � 1:20), the analogous compoundwith R1� n-propyl has a chemical shift of the term-inal propyl protons ofd � 0:91; which is practicallyidentical to propylbenzene,d � 0:92: In the lattermolecule the propyl group is too large to fit in-between the two other aromatic rings, so the moleculeadopts the “alternate” conformation.

The trimethoxy[3.2.2]metacyclophanes (712) and(713) proved to be much more flexible than the[2.2.2]- and [2.2.1]phanes [395]. Both exist in an


tBu

(708A)

tBu MeO

OMeOMe

3.44

1.21tBu

(708B)

tBu MeO

OMeOMe

3.24, 3.17

2.64

CB

ring A

A

ring C

B

S S

(CH2)n

R1

R2 R2

(710), n = 1 or 2

(CH2)n

R1

R2 R2

(709), n = 1 or 2

R2 = Me, OMe; R1 = n-alkyl, O(n-alkyl)

R2

R1

R2

(711)

equilibrium between a ‘2,3-alternate’ and a ‘cone’conformation, the former being preferred at roomtemperature. The former was recognized by a highlyshielded and the latter by a deshielded methoxy groupin the1H NMR spectrum. Variable temperature studiesgave the following equilibrium parameters for(712): DH0 � 0:82 kJ mol21

; DS0 � 27:98 J21 K21;

DG0 � 3:20 kJ mol21 at 1258C; for (713): DH0 �6:73 kJ mol21

; DS0 � 11:37 J mol21 K21; DG0 �

6:32 kJ mol21 at 1258C. Lineshape analysis of thespectra of (713) gave an activation barrierDG‡ of 79^4 kJ mol21 for conversion of the ‘2,3-alternate’ into the‘cone’ conformation.

OMe

OMe

OMeR

R

ROMe

OMe

R

RR

OMe

3.56

4.22

5.72

2.72

3.28, 3.31

(712), R = tBu2,3-alternate cone(713), R = H[δ values for (712)]

The coordination shifts in the1H NMR spectrum ofbis(h6-[2.2.2]paracyclophane)chromium(0) (190)have already been referred to in Section 3.1 [141].

The configuration of (714) with cis oriented hydro-gens at the annelated cyclohexadiene ring could bedetermined from low-temperature1H NMR spectra[396]. Upon cooling the sample, the signals due toprotons of type He and Hf broaden first, indicatingslowed rotation of the phenylene rings next to thecyclohexadiene moiety. Further cooling resharpensthe peaks and results in an ABCD-type signal pattern.The Ha, Hb, Hc, Hd proton signals (a sharp singlet atelevated temperatures) broaden more slowly as thetemperature is lowered and resharpen to appear astwo slightly broadened apparent singlets at21108C.This behaviour is consistent only with thecis isomer,in which Ha and Hb are chemically equivalent (as areHc and Hd), the slight residual broadening of thesignals being caused mainly bymetaH,H coupling.If the trans isomer ofC2 symmetry had been present,Ha and Hd would have been equivalent (as would havebeen Hb and Hc) and anortho-like coupling wouldhave been observed between the two signals. Thebarrier to rotation of the unique phenylene ring was


HH

(714) (715)

Ha Hb

HdHc

He,Hf

(716)

2−

H3C CH3

(717) (718)

6.91

7.236.39

6.39

TsN NTsR

(719)(R = H, Me, OMe, Br, CN, NO 2)

estimated to be ca. 50 kJ mol21. It is not possible todetermine this barrier in the parent compound (715)because its solution-phase symmetry is too high.

When [2.2.2]paracyclophene (715) is convertedinto its dianion (716), neither diatropic nor paratropicring current effects on1H or 13C chemical shifts areobserved [397]. The small upfield shifts that do occurcould be interpreted as charge effects. The simpleNMR spectra, two lines in the1H and three lines inthe 13C spectrum, were explained by assuming rapidinterconversion between less symmetrical conformersin which two aromatic rings lie in the plane of theolefinic double bonds and the third one is perpendi-cular to this plane.

By comparing the1H chemical shifts of (717) withthose of the model compound (718), Kasahara et al.[398] demonstrated the mutual shielding effects in(717) of the para-phenylene rings,Dd � d�717�2d�718� � 20:84 and 20.52 ppm. This is forcedupon the molecule by clamping thepara positionswith the vinylene group, which prevents the splayingout of the two phenylethynyl groups that takes placein the ‘opened’ compound.

When [2.2.2]phane (719), containing a triple bondin one of its bridges, has no internal substituent(R� Hi), its benzylic protons absorb as one AB spec-trum �d � 5:06 and 4.23,J � 15:0 Hz�: The intra-annular proton Hi is deshielded tod � 8:18 by themagnetic anisotropy of the neighbouring alkynediylgroup. Internally substituted derivatives of (719) givetwo AB spectra for the CH2 groups. To explain this,the authors suggested a helically twisted conformationof the molecules [399].

Grutzmacher et al. [400] extended their studies ofazocyclophanes by investigating the trinuclear dithia-diazacyclophan-19-enes (720)–(723) and -17-enes(724). The 1H NMR chemical shifts were discussedwith respect to the structures of the molecules. Theazo groups in (720) and (721) are exclusivelycis,whereas for (722)–(724) both cis- and trans-isomersare observed.

Rapid conformational interconversions take placein trimethoxy[5.5.5]metacyclophane (725), as can beinferred from the equivalence of the benzylic protonsthat was observed in the1H NMR spectrum at roomtemperature [30].

Compound (726), [14]paracyclo-bis(1,2)pyrazo-lium-phane, in solution (D2O or DMSO) at room

temperature exists as a mixture of chair and boatconformers, (726c) and (726b), in the ratio of 54:46[401]. The conformers have rather similar1H and13CNMR spectra which were fully assigned and analysed,also with respect to13C,1H coupling constants. Theconformers were distinguished by the differentsymmetries of the1H spin systems of theirp-pheny-lene rings. Both are of the AA0BB 0 type, butJ(A,B) isan ortho-H,H coupling constant in the chair and ameta-H,H coupling in the boat conformer. The differ-ent 1H signals of the conformers coalesce at differenttemperatures from which the free energy of activationfor the chair-to-boat interconversion was determinedas DG‡�1258C� � 72 kJ mol21

: The DH‡ and DS‡

values (the latter negative) were also derived butdeemed not very accurate.

In pyridinophane (727) the proton signals of thepyridinium rings are broad at room temperature[402]. This indicates relatively slow rotations ofthese rings about their N–C4 axes. At lower tempera-tures decoalescence was observed for thea- and theb-proton signals of both rings A and B. Interestingly,determination of the rotational barriersDG‡ from thedifferent coalescence temperatures shows that ringsA and B require different activation energies forinternal rotation. The values determined for ring AareDG‡ � 41:3^ 0:6 kJ mol21 (2638C) and 42:0^

1:0 kJ mol21 (2608C) from the a- and b-protonsignals, respectively. The corresponding values forring B are 46:1^ 0:4 kJ mol21 (2308C) and 45:8^

1:0 kJ mol21 (2408C).The conformational properties of some tetrameric

metacyclophanes incorporating mesitylene units werestudied by Pappalardo et al. [403]. They compared the1H NMR chemical shifts of the methyl groups incompounds (728)–(730) with those in analogousopen-chain bridged di- and tetramesityls and withother cyclophanes of known conformation. Theyconcluded that the 16-membered [1.1.1.1]metacyclo-phane (728) prefers a saddle conformation while the18-membered [2.1.2.1]metacyclophanes (729) and(730) adopt a fixed crown conformation, resultingfrom the peculiar geometry of the disulfide bridges.The same authors also investigated the 13- to 17-membered metacyclophanes (731)–(733) containingsulfide and/or disulfide bridges [404]. Correlationsof their 1H chemical shifts with those of modelcompounds led to the assumption that (731) and


(732) prefer conformations with a propeller-likearrangement of the aromatic rings while (733) prefersa saddle-type conformation. Low-temperature1HNMR spectra of (734) [405], a methoxy analogue of(730) with a differing substitution pattern, showthat a saddle structure withC2 symmetry is present.At room temperature, (734) undergoes fast dynamicinterconversion between two symmetry relatedstructures resulting in overall four-fold symmetry.The activation parameters, obtained by lineshapeanalysis between2101 and 2608C, are DH‡ �41:4 kJ mol21 and DS‡ � 129:7 J K21 mol21

: The

high flexibility of (734) seems to contradict thepresumed fixed conformation of (730). But as thelatter compound could only be studied at11508C innitrobenzene solution because of limited solubility, noexperimental evidence of its low-temperature beha-viour is available.

Pappalardo et al. [406] also reported the1H NMRspectra of the mono- to tetrahydroxy derivatives ofmesitylene-based [1.1.1.1]metacyclophane (735). Allfive compounds occur as 1,3-alternate conformers, i.e.having their benzene rings up-down–up-down. This isapparent from the ca. 1 ppm upfield shift of the


N

N

S

SB

A

C

N

N

S

S

substitution patterns

ring B rings A & CN=N

configuration

ciscis

cis & transcis & trans

cis & trans

1,31,41,31,4

1,31,31,41,4

N=N

configuration

(720)(721)(722)(723)

(724)

OMe MeO

OMe

(CH2)5

(CH2)5(H2C)5

(725)

N

N

N

N

⊕

⊕

(726)

N

N

N

N

⊕

⊕

A B

B’ A’

(726c)

N

N

N

N

⊕

⊕

A

B B’

A’

(726b)

NN

N

N N⊕

⊕ ⊕

⊕

A B

(727)

α αββ

intraannular methyl groups�d < 1:1� relative to anopen chain model compound. The1H NMR spectrado not change between125 and1808C. The 1,3-alternate conformers of the mono- to tetraols havecharacteristic CH2 absorptions, viz. tetraol: 1 s, trioland mono-ol: 1 AB and 1 s (1:1), distal diol: 1 AB;proximal diol: 1 AB1 2 s. The extraannular hydroxygroups appear as sharp singlets atd < 4:5; indicatingweak (if any) intermolecular hydrogen bonding.

The 1H NMR spectra of dithia[3.1.3.1]metacyclo-phane (736) and of tetrathia[4.1.4.1]metacyclophane(737) do not show any signal doubling down totemperatures of2100 and2808C, respectively, indi-cating that these systems are conformationally verymobile [407]. In contrast, the tetramethylateddithia[3.1.3.1]metacyclophanes (738) and their[2.1.2.1]metacyclophane (739) and [2.1.2.1]metacy-clophanediene (740) analogues do show temperaturedependent1H NMR spectra, from which Mitchell andLai derived their conformational behaviour [408].They concluded that all of these compounds undergo

a conformational process of type (741). Depending onthe nature of the bridges X, Y, and Z, the barriers forthis process were estimated to be in the range 39 toover 85 kJ mol21, the low value applying to the dithiacompounds (738). Both of the other series havebarriers centred around 70 kJ mol21, but the dienes(740) are quite sensitive to the nature of the one-membered bridges X and Y (range 57 to.85 kJ mol21), whereas this plays a minor role(range 66–72 kJ mol21) for compounds (739) whichhave saturated bridges. Minor isomers, (742), of (740)were also found and shown to possess twotransdouble bonds. The aryl-CH3 groups of (742) havedH values between 1.30 and 1.14, the spectra beingtemperature independent between2100 and11508C.

The room temperature1H NMR spectrum of octa-methyl[2.2.2.2]paracyclophanetetraene (743) [409]shows only three singlets for aromatic, olefinic andmethyl protons. Around2708C, a dynamic processwith DG‡ < 42 kJ mol21 was observed (doubling ofthe aromatic and the methyl proton signals,


Y

Y

XX

X YCH2

CH2

S

CH2

S—SS—S(730)

(729)(728)

S

S

SS

MeO

MeO OMe

OMe

OMe

OMeMeO

MeO

MeO

MeO OMe

OMe

S

S

(734)

MeO

MeO

S SOMe

OMeXX

OMeMeO

(731), X = S(732), X = S−S

S S

MeO

MeO

S

OMe

OMe

S

S

OMe

OMeMeO

MeO

(733)

appearance of an AB-pattern for the olefinic protons)which was interpreted as a correlated flipping of thefour benzene rings within the favoured conformershown in the formula as opposed to rotation of thebenzene rings. Here, flipping means that the aromaticring passes a plane perpendicular to that of the fourolefinic bridges whereas rotation means that it passesthe plane of the bridges themselves. Support for theflipping mechanism came from the tetraethyltetra-methyl derivative (744), for which ring flipping andring rotation could be observed separately. Ring rota-tions ultimately interconvert one conformer into itsenantiomer and this process exchanges the methyleneprotons that are nonequivalent when ring rotation isslow. The coalescence of their AB signals (CH3

decoupled) gave an approximateDG‡ of 63 kJ mol21

at 1328C. Ring flips interchange the inner and outersites of the aromatic rings and the signals involved withthe aromatic rings and the methyl groups are doubledwhen this process is slow. This was observed between220 and2808C. The free energy of activation for thisprocess is ca. 42 kJ mol21, in agreement with the valuefor (743). The latter barrier was believed to be essen-tially due to loss ofp-electron delocalization ratherthan due to steric crowding in the transition state.

In its NMR spectra, tetraester (745) of[2.2.2.2]cyclophanetetraene shows only one set ofpeaks although, in principle, two rotational isomersare possible [410]. As fast rotation of the ester-bearingarene rings is improbable for steric reasons, thepresence of only one rotamer seems likely. Prepara-tion of the diester (746) resulted in two constitutional


R1

R2

R3

R4

(735a)(735b)(735c)(735d)(735e)

OH OH OH OHHHHH

OH OH OHOHOH

OH OHOH

H

HHH

R3 R4R2R1

XX

(736), X = S(737), X = S−S

X

SS

Y

X

Y

(738)

(739)

X

Y

(740)

a CH2 CH2

bc

C=OC=O C=O

CH2

YX

isomers, one withC2 and the other withCs symmetry.Fast rotation of the unsubstitutedp-phenylene ringsoccurs because different chemical shifts for insideand outside protons are not observed. Given this, theisomers differ in that thep-phenylene hydrogens ofthe C2 isomer should form a common AA0BB 0 spinsystem, whereas they must give rise to an A4 singletfor one ring and a B4 singlet for the other in theCs

isomer. In fact, one isomer shows two singlets of fourprotons each�d � 7:12 and 7.07) at room temperatureand thus has to beCs isomer (746b). The otherisomer shows one singlet of eight protons which, on

improving the resolution by warming to1478C,resolves into a pattern caused by two different chemi-cal shifts with mutual coupling, termed “AB” by theauthors. Hence, this is theC2 isomer (746a). Furthersupport for this assignment was obtained by the obser-vation that on cooling to2538C only one of the sing-lets in the spectrum of (746b) starts to broaden. Thiscan only happen in theCs isomer, in which the twop-phenylene rings are nonequivalent.

Mullen and collaborators [411] examined the1HNMR spectra of the dianions of nine macrocycliccyclophanes and of two tetraanions. Unexpectedly,


X

Y

Z

Z YX

Z

Z

(741)X, Y = CH 2 or C=O

Z = CH2SCH2 or CH2CH2 or CH=CH

X Y

(742a) CH2 CH2

C=OC=O C=O

CH2

YX

(742b)(742c)

R

R

R

RR

R

R

R

(743), R = H

(744), R = CH3

strong diatropic ring currents were observed in all ofthe dianions resulting in deshielding�dH � 8–14� andstrong shielding�dH � –3 to 212) of the protons onthe outside and inside, respectively, of the macro-cycle. The 1H chemical shifts of (747), (749), and(750) are shown as examples. Obviously, the dianionsbehave as annulene-like true diatropic [4n 1 2]p-perimeter systems while the neutral cyclophanesbehave normally and display unspectacular chemicalshifts. The presence of the local aromatic units in theunsaturated cyclophanes does not quench peripheralring current effects in the dianions. Also, incontrast to the neutral hydrocarbons, internal rota-tion of the para-phenylene units is slow in thedianions so that inner and outer hydrogens canbe distinguished. Extensive consideration ofchemical shifts and model calculations of ringcurrent effects led to the conclusion that the globalring current of the dianions may follow an outer,an inner, or where possible (naphthalene units) amiddle route through a local aromatic unit.According to the authors the observed ring currenteffects can be understood in terms of a macro-

cyclic diamagnetic ring current modified by thelocal diamagnetic ring currents. The tetraanionsinvestigated, for example (748), show paratropicshift effects that shield/deshield the outer/innerprotons.

9. Conclusion

This review has tried to point out the importance ofNMR spectroscopy to the field of phane chemistry asevidenced by the literature of the past 18 years. Theprogress of NMR spectroscopy that has occurred sincethe end of the previous review period (1981; cf.Mitchell’s work, Ref. [9]) has allowed much moredetailed investigations of the structure and dynamicsof this class of fascinating molecules than were possi-ble before. In particular, the increasing availability ofhigh-field NMR spectrometers has facilitated theanalysis of often rather intricate1H NMR spectra,allowing the extraction of chemical shifts and spin–spin coupling constants and their application in deriv-ing fine details of the molecular structures. It is hoped


(745)

(746a), C2

(746b), Cs

MeO2C MeO2C

CO2Me CO2Me

6.77

6.54

7.00

7.88

3.80

MeO2C

CO2Me3.85

7.857.41

7.36

6.93

6.49

≈7.11≈7.11

≈6.52

≈6.52

CO2MeMeO2C

7.12

6.50

6.57

7.837.44

7.39

6.92

6.50

7.07

3.84

NOE

NOE

that phane chemists will find the present articlebeneficial to their work.

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2−

9.26-7.07

9.56

4−

4.4812.76

2.09

2−

12.1b-9.1a

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(747) (748)

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