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Chiroptical molecular switchesde Lange, Ben

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CHAPTER 6

A CEIROPTICAL MOLECULAR SWITCH BASED ON A STEREOSPECIFIC CIS-TRANS ISOMERIZATION

In the previous chapters, the synthesis of several different types of sterically overcrowded alkenes has been described, which allowed a detailed examination of the influence of various structural changes on the isomerization barriers. Further exploration of these molecules as chiroptical molecular switches will require an extensive quantitative analysis of the thermal and photochemical behaviour. Investigations on the thermal and photochemical behaviour of an enantiomerically pure cis-2,2'-dimethyl substituted bithioxanthylidene, a sterically overcrowded bistricyclic ethylene, have revealed the occurrence of cis-trans isomerization and conformational inversion simultaneously (see Section 4.5 and process A and B in Scheme 6.1). In order to study alkenes with a phenanthrene unit in the upper part, which are described in Chapters 2 and 3 of this thesis and which were designed to function as molecular switches, the preparation of unsymmetrically substituted ethylenes in this series is needed, i.e. alkenes with four different substituents around the central double bond (Scheme 6.1, R, + H).

Scheme 61. The f a r diffmnt chird isomers of an unrynrmetrical& substituted ethylene.

This may be achieved by introducing a substituent R, in the lower part of the ethylenes (see Scheme 6.1). Of course, in the case when R, = H no distinction can be

6 A Chiroptial Molecular Switch Based on a Stmmpecifi Cis-Dans Isomerization.

made between M-cis and M-trans (or P-cis and P-trans) and therefore when, for example, the photochemical or thermal isomerization of an enantiomerically pure M isomer (cis or trans) is followed, it cannot be recognized whether process A or process B occurs. To circumvent this restriction, the synthesis of unsymmetrically functionalized alkenes was undertaken.

6.2 Synthesis

The target molecules are shown in Figure 6.1, whereby R, can be an alkyl substituent, an electron-donating methoxy group or an electron-withdrawing nitro group.

R, = %I 0% "'0, Figure 61. Target molecules.

Important reasons to prepare ethylenes with a 7-methyl substituted tetrahydro- phenanthrene unit in the upper part and a %-substituted thioxanthene moiety in the lower part are:'

- For the resolution of the unsubstituted derivative (R, = H, Figure 6.1) using HPLC with (+)-poly(triphenylmethy1)methacrylate as a chiral stationary phase, a relatively large separation factor a and consequently an excellent baseline separation in the HPLC chromatogram was found.? Because in the case of the alkenes shown in Figure 6.1 separation of four different isomers has to be achieved, large separation factors, which can also be expected for these compounds, will facilitate resolution.

- Thioxanthones substituted at position 2 can be prepared relatively easily (see Section 6.2.1) and the corresponding thioketones are anticipated to be stable.

- This type of alkenes (Scheme 6.1, X = CH,, Y = S) exhibit a reasonable thermal stability (A@ = 26 kcal.mo1-I).

- The sulfur atom can be oxidized to a sulfone functionality, a strong electron accepting group, whereby the presence of an additional methyl group might enhance the solubility of the alkene. A very low solubility prohibited the resolution of the sulfone functionalized alkenes described in Section 3.2.3.

Similarly to the approach used in the previous chapters, the synthesis of these alkenes via the diazo-thioketone method, will involve the preparation of the "upper" and "lower" part of the molecules followed by coupling the two halves to form the central sterically demanding double bond.

It should be mentioned that at the start of this investigation, we were unaware of the large increase in thermal isomerization barrier, which can be achieved via the introduction of sulfide groups (X, Y = S, Scheme 6.1) in sterically overcrowded alkenes. See: Jager, W.F. forthcoming Ph.D. Thesis, Groningen, 1993.

4 A Chimptical Molecular Switch Based on a Stereospeciific Cis-l'kans Isomcrization

6.2.1 TIie Synthesis of the "Upper" pad

The synthesis of 7-methyl-1,2,3,4-tetrahydrophenanthrene-done (6) starts from 2- methylnaphthalene (3) and is depicted in Scheme 6.2. Friedel-Crafts acylation of 3 with succinic anhydride in nitrobenzene at 5 "C afforded adduct 4 together with isomeric products, due to acylation at other positions in the naphthalene ring! 'H NMR analysis showed the product to consist of approximately 80% of 4, which was separated from the other isomers via one crystallization from acetic acid according to the procedure of Haworth et aL4 Wolff-Kishner reduction of the keto-acid followed by a ring closure in polyphosphoric acid furnished ketone 6 in 30% overall yield. This ketone was easily converted to hydrazone 7 by refluxing with an excess of hydrazine hydrate in ethanol.

NWYHP, KOH

ay. 100% voH$-- d r n ~ e o l v r m C&

5 ay. 77?6

Scheme 62 JLnthesir of W a z o n e 7.

6.2.2 TIie Synthesis of the "Lower" Part

The key step, which has been used frequently for the preparation of the basic skeleton of (substituted) 9H-thioxanthene-9-ones, involves a coupling reaction between an aromatic thiol group and a halo-aryl compound (see Scheme 6.3) although several approaches to achieve this transformation can be followed.5" The synthesis of 2-methyl-9H-thioxanthene-9-one (12) and 2-methoxy-9H-thioxan- thene-9-one (16) is depicted in Scheme 6.3 and started from thiosalicylic acid (8) and 4-iodotoluene (9) or 4-iodoanisole (13), respectively, and was based on the method

The synthesis of this 7-methyl substituted tetrahydrophenanthrenone was initially performed to obtain an "all carbon" phenanthrene derivative via a shorter synthetic route than required for the tetrahydrophenanthrene described in Chapter 2 (see Section 2.5.2). Haworth, R.D.; Letsky, B.M.; Mavin, C.M. J. Chem. Soc. 1932, 1784. ' See e.g: a) Brindle, I.D.; Doyle, P.P. Can J Chem. 1983, 61, 1869. (b) Protiva, M.; Jilek, J.O.; Pel& K; Vejdelek, ZJ. ColL Czech, Chem. Commun. 1966, 31, 269. (c) Gilman, H.; Diehl. J.W. J. Org. Chem 1959,24, 1914. (d) Turnbull, J.H.; Mann, F.G. J. Chem. Soc. 1951,747. See also Section 3.3.1.2 for the reaction between 2-thionaphthol and 2-iodobenzoic acid.

4 A Chimptical Molecular Switch Based on a Stereqecific Cis-ll'ans I s b e

described by Vasiliu et UL' The di-potassium salt of 8 replaced the iodine atom from the 4-iodo compounds 9 or 13 in the presence of copper powder in boiling DMF to form an aryl-sulfur bond. The resulting benzoic acids 10 and 14 were converted to thioxanthones 11 and 15, respectively, by stirring in concentrated H2S0,. This was performed at 10 "C for the methoxy derivative 14 in order to suppress sulfonation, which can easily occur due to the presence of the electron-donating methoxy group. Transformation of the ketones into thioketones 12 and 16 was accomplished by refluxing with a two-fold excess of P& in toluene. Both thioketones were isolated as dark green solids, which did not show any decomposition even after storage for several months at room temperature.

Scheme 43. *thesis of 2-methyl and 2-methmy substiluted 9H-thioxatUhene-9-thiones I2 and 16. Reagents, conditions and yields: Rl = CH3: a) K2C03, Dm, A, 18h; b) con- centrated H2S04, RT, 45 min, 83% (werall yield for steps a and b); c) P&, toluene, A, lh, 89%. R1 = OCH,: a) K p U Dm, A, 18h b) concentrated H2S04, 10 O C , 45 min, 56% (overall yield for s tep a and b); c) P2SS, toluene, A, lh, 76%.

The preparation of the Znitro substituted 9H-thioxanthene-9-thione 19 cannot be achieved via this method, because the Friedel-Crafts type ring closure of benzoic acid 10 (R, = NOa is strongly deactivated due to the presence of this nitro group. This problem was avoided by the approach depicted in Scheme 6.4, starting from commercially available 2-chloro-5-nitrobenzoic acid (18). Substitution of the chloro atom with the thiol 17 in boiling ethanol in the presence of copper powder yielded the 2-(phenylthi0)-5-nitrobenzoic acid: which was transformed to the dark green thioketone 19, following analogous procedures as have been used for 12 and 16.

' Vasiliu, G.; Maior, 0 . ; Rasanu, N. Rev. Chim (Wlchnrcst) 1196, 68, 561; Chem Absn. 1969, 71, 38739. Amstutz, ED.; Neumoyer, CR. J. Am. Chm Soc. 1947.69, 1922.

146

6 A Chiqnical Molecular Switch Based on a Stenospecific Ck-lhns Zsomeriatian

6.2.3 l%e Diazo=T%wRetone Coupling

The diazo-thioketone cycloaddition between hydrazone 7 and thioketones 12, 16 or 19 was performed as described in the previous chapters. The episulfides were obtained as cis/trans mixturesg in 5678% yield (Scheme 6.5, only the trans episulfides and alkenes are drawn). No attempts were undertaken to separate these isomers. The thiiranes were desulfurized with copper in boiling xylene to yield the corresponding alkenes 27 - 32 in yields varying between 78 and 89%, with a cisltrans ratio of 5050 in all cases?' The cis and trans isomers of the methyl and methoxy functionalized alkenes are readily distinguished by their 'H NMR spectra: the absorption for the methyl group in the thioxanthene part in mns-28 at 2.43 pprn is shifted upfield to 1.54 pprn in ch-27, due to the shielding effect of the naphthalene moiety. Similarly, the methoxy singlet found in tmm-30 at 3.89 ppm, the "normal" position for this group, is shifted to 2.97 pprn in ck-29.

S

A@, MgSO, -1 0% ether, KOH, ethand

N Y c% 16 R, - OCl$ 7 20 N- 1 9 R , - N q

Scheme 65. Synthesis of aknes 27 - 32.

The characterization of the cis and trans isomersof the nitro substituted alkenes 31 and 32 was based on the absorption of the proton next to the nitro group at position 1' (or 8'):' The doublet for H-1' (H-8', J = 2.2 Hz) is found at 8.40 pprn for truns-32 and is shifted downfield compared to the major part of the aromatic absorptions of 32 due to the presence of the electron-withdrawing nitro group. In ch-31, this doublet is located at 7.13 ppm, again indicating the large shielding induced by the naphthalene moiety.l2

The obtained cis/trans ratios are given in the Experimental Section. lo Although in some experiments, cis- or trans-enriched fractions of episulfides have been

desulfurized, the high temperatures during this reaction (boiling p-xylene) will cause rapid &/trans isomerization of the alkenes formed.

l1 For numbering scheme, see Section 3.5. l2 This 'H NMR absorption for the proton at position 1' next to R1 is found at 5.95 pprn in cis-

27 and at 6.14 pprn in cis-29.

6 A Chiroptical Molecular Switch Based on a Stereospdj'ic Cis-Trans Isom&ti01~

In order to facilitate resolution by HPLC'~ and to allow a more convenient identification of the different fractions obtained from HPLC, we have attempted to separate the cis and trans isomers of alkenes 27 - 32 via crystallization. After one crystallization from ethanol, the methoxy functionalized alkenes ck-29 and tmm-30 were obtained in a 91:9 ratio, as indicated by 'H NMR analysis (vide supra). A second crystallization of this cis-enriched fraction yielded pure cis-29 (35% yield, starting from a 50:SO cis-trans mixture). Trans isomer 30 could not be obtained pure by this procedure and was always contaminated with some cir-29. Interestingly, the sulfide group in the thioxanthene part of pure cir-29 was oxidized with rn-CPBA to sulfone 33 without any formation of the trans isomer (!), as shown in Scheme 6.6.

Scheme 46. Oridation of su@ie group of 29.

Although one crystallization from ethanol afforded c6-27 and tram-28 in a 7426 ratio, the very low yield in this crystallization step (18%) and the observation that the four different isomers could be separated conveniently by HPLC: were the reasons that no further attempts were undertaken to obtain pure cis or trans isomers in this case. Crystallization of the nitro substituted ethylenes from ethanol afforded cis-31 and trans-32 in a 3654 ratio. Surprisingly, after a second crystallization of this trans- enriched fraction, 31 and 32 were again found as a 5050 mixture. Further attempts to separate these isomers via crystallization from other solvents (p-xylene, CHCl,) failed. Some preliminary experiments to achieve separation via thin-layer chromatography on silica (hexane/E$O mixtures were used as eluent) were unsuccessful so far.14 Because only the methoxy functionalized alkenes could be separated into pure cis-29 and enriched tram30 isomers by crystallization, further investigations towards the thermal and photochemical behaviour have so far been focused on 29 and 30.

l3 If the cis and trans isomer are separated by crystallition or chromatography prior to HPLC resolution, only two isomers have to be separated instead of four different isomers when starting from a &/trans mixture (see also Scheme 6.7).

l4 Unfortunatety, also attempts to separate cis-trans mixtures of 31 and 32 into the four different isomers using HPLC did not suoceed so €a2

6 A Chiroptical Molecular Switch &Iscd on a Stereospecific C i s - ~ m Zsomerization

6.3 Chimptical Molecular c witch'^

The mixture of methoxy functionalized alkenes 29 and 30 was separated into the four different stereoisomers M-cis 29a, P-cis 29b, M-trans 30a and P-trans 30b by HPLC (Scheme 6.7). Upon heating of enantiomerically pure M-cis 29a in p-xylene, racemization into the P-cis isomer 29b was observed (AG* = 26.4 kcal.mol-I), without the occurrence of thermal cis-trans isomerization (29a * 30b).

29a M ds 3Ob P trans

29b P cis 30a M trans

Scheme 6. Z PhotochemicaI and thermal behaviour of 29 and 30.

However, upon irradiation with UV-light of 300 nm or 250 nm in n-hexane, cis-trans isomerization of 29 and 30 occurred readily. Irradiation of M-cis 29a (or P-trans 30b) at 300 nm yielded a mixture of 64% M-cis 2% and 36% P-trans 30b as determined by HPLC, whereas no P-cis 29b and M-trans 30a were formed. Irradiation at 250 nm gave a photostationary state containing 68% M-cis 29a and 32% P-trans 30b. Using the fact that irradiation at 250 and 300 nm yielded different M-cis/P-trans photostationary states, the feasibility of sterically overcrowded alkenes to function as chiroptical molecular switches was demonstrated.16 The difference in photostationary state can be monitored by using circular dichroism. Alternating irradiation at two wavelengths, A. = 250 nm and A. = 300 nm resulted in a modulated CD signal, which was measured at 262 nm. A typical example using a switching time of 3 s is shown in Figure 6.2. The cycle between the two photostationary states was repeated for more than 10 times without discernible racemization or degradation.

l5 The thermal and photochemical behaviour of these alkenes has been investigated by W.F. Jager. The principle of the chiroptical molecular switch will be described here briefly. For an extensive discussion the reader is referred to: Jager, W.E forthcoming Ph,D. Thesis, Groningen, 1993.

l6 Feringa, B.L.; Jager, W.E; de Lange, B.; Meijer, E.W. J. Am. Chem. Soc 1991,113,5468.

6. A Chiraptical Molecular Switch Based on a Smeospccifi Cis-naris Isomerizarion

30 60 h = 250 300 nm

total irradiatimtirne ( 5 )

Figure 6 2 Plot of Ae at R = 262 tun vs irradiution time for 2% * 30b irradiated alternately at R = 250 nm and 1 = 300 nm; switching time 3 s.

These results establish that photoisomerization between two "pseudoenantiomeric" isomers M and P' of helically shaped alkenes can be used as a key principle in molecular switching systems using two different wavelengths of light to interconvert both bistable states (Figure 6.3).

Figure 63. Schematic representation of a chimptical molecular switch based on the photoisorncrization of "pseudoenantiom& isomers M and P!

A comparison between the chiroptical molecular switch presented here and the molecular switches based on the cis-trans isomerization of azobenzenes, which have been discussed in Chapter 1, clearly indicate the advantages of our system. The two major problems prohibiting the use of azobenzenes in molecular switching devices, namely: (i) low thermal stability and, (ii) a destructive read-out method, are easily overcome due to the unique properties of the sterically overcrowded akenes:

The thermal stability towards racemization (M-cis * P-cis) can be readily controlled by structural changes at the molecular level, as has been shown in Chapters 3 and 4 of this thesis; for example, the racemization barrier of M-cis 29a, might be increased with approximately 2 kcal.mo1-' by introducing a sulfide group in the upper part of the molecule (X = S, Scheme 6.1). The cis-trans isomerization observed for M-cis 29e is accompanied by a reversal in helicity. This leads to a change in optical rotation, which is measured by circular dichroism, providing a non-destructive read-out method, because wavelengths far out of the A,-switch region can be used. Even the relatively small change in photostationary states (4%) obtained for the M-cis 29a * P-trans 30b conversion can be measured conveniently by circular dichroism due to the large chiroptical effects that arise from the inherently dissymmetric structure.

6 A Chimptical Molecular Switch Based on a Stcnospece Cis-lhms Z s d t t o n

- 6.4 Chiroj&kl Mecular Switch; Impmments and O d h k

Although the principle of a photoswitchable molecular system based on the light- induced interconversion of two "pseudoenantiomeric" forms M and P' has been demonstrated, as shown in the previous section, we have accomplished some recent improvements of the initially used alkenes which will be discussed here briefly. These improvements and future developments, which can be im ortant in further application studies, are mainly concerned with the following aspects: 8

1) Increasing the difference in UV absorption between the cis and the trans bistable forms, leading to larger differences in the photostationary states.

2) The thermal racemization bamer for the M-cis * P-cis interconversion should be increased because, unlike the switch based on the use of circularly polarized light, any racemization will deactivate the cis-trans molecular switch described here permanently.

The difference in UV absorption between the cis and trans form might be strongly enhanced by the introduction of donor-acceptor groups in the upper and lower part of these molecules, providing the possibility to form intramolecular charge-transfer interactions. This phenomenon can be illustrated with the target molecules shown in Scheme 6.8. The presence of a methoxy group in the upper part might induce the formation of an intramolecular charge transfer interaction in cir-34 between the methoxynaphthalene group and the nitrophenyl moiety and lead to a bathochromic shift in the long-wavelength UV absorption of the cis form. This interaction will be absent in tram-35.

Scheme 68. Target molecules cis-34 and tram-35.

The diazo-thioketone reaction between hydrazone 36 and thioketone 3718 yielded cis- and trans-episulfides 38 and 39 (Scheme 6.9). The episulfides were contaminated with approximately 20% azine (due to the decomposition of the diazo compound derived from 36, see Section 2.5.4). This impurity was removed by crystallization from

l7 Of course, many other (physical) aspects have to be considered, for example, the switching behaviour in a polymer matrix and the minimum time required to switch between the two bistable isomers.

l8 The additional methyl group in this thioketone compared with 2-nitro-9H-thioxanthene-9- thione (19) will facilitate the assignment of the corresponding cis or trans episulfides or alkenes. The presence of this additional methyl group will also increase the solubility of the corresponding episulfides and alkenes.

6 A Chiropiical Molecular Switch Based on a Stereospecijic C k - D m LFomerization

ethanol to furnish episulfides cis38 and trans39 in a 63:37 ratio (47% yield). Surprisingly, desulfurization with copper powder in boiling p-xylene failed and the episulfides were recovered unchanged from the reaction mixture. The use of boiling mesitylene, in order to increase the reaction temperature, led to the same disappointing result. Alternative procedures, which were found in a later stage of the research described in this thesis, like the triphenyl h o s p h e method described in Section 3.3.1.4, might be a solution to this pr~blem.'~' l l

Scheme 49. (Attempted) preparation of alkenes 34 and 35.

Although so far we have not succeeded in obtaining alkenes 34 and 35, the preparation of this highly interesting type of alkenes can certainly be realized in the near future, considering the possibility to use other desulfurization methods or the opportunity to synthesize various alkenes with similar structural features (see Figure 6.4).

As indicated in Chapter 3, one way to increase the thermal racemization barrier of the P (or M) isomer of sterically overcrowded alkenes is by the introduction of sulfide groups as bridging moieties in the upper phenanthrene part. In order to investigate the thermal and photochemical behaviour of benzannulated alkenes, with an additional aromatic ring in the upper part of the molecule, and to explore the increased racemization barrier found for this type of alkenes (AG* = 28.4 kcal.mol-

we decided to prepare the benzannulated bisthioxanthylidenes 40 and 41, whereby a methyl group in the lower thioxanthene part is introduced to obtain cis and trans isomers (see Scheme 6.10, only the M-cis and P-trans isomer are drawn). The synthesis was accomplished following the method described in Chapter 3 (Scheme 3.13) using 2-methyl-9H-thioxanthene-9-one hydrazone instead of 9H-thioxanthene-9- one hydrazone. The alkenes were obtained as a mixture of ch40 and tram-41 (ratio 5050, 50.5% overall yield). Pure trans alkene 41 (28% yield) was obtained after two

l9 The LiAIH4 method described in Section 3.3.1.4 cannot be used in this case, due to the presence of the nitro group which is sensitive to reduction. Another procedure to accomplish this desulfurization step might be the use of butyl- or phenyllithium; see e.g. Kellogg, R.M.; Buter, J.; Wassenaar, S. J. m. Chem. 1972, 37, 4045.

21 Thermal racemization below 70-80 O C will be prevented in this case.

152

6 A Chiroptical Mdecular Switch Eased on a Stereospeciific Cis-Tkam Isomcrization

- crystallizations from ethanol. Again, the cis and trans isomers are easily distinguished by their 'H bh4R spectra. The methyl singlet at 2.00 ppm in trans-41, is shifted upfield to 1.58 ppm in c k 4 due to the shielding effect of the naphthalene moiety.

40 M cis 41 Ptrans

Scheme 610. Stereospeciifie photochemical and thermal isomerization of benzannulated bithiaramhyIideencs 40 and 41.

Starting from enantiomerically pure P-trans 41 (obtained by HPLC resolution), both thermal@ as well as photochemically a stereospecific isomerization to the M-cis form 40 was found (Scheme 6.10), whereby no other isomers (P-cis or M-trans) were detected." The intriguing finding that no thermal racemization takes place is in strong contrast with the switch described earlier (Section 6.3). These features make P- trans 41 (and M-cis 40) especially suitable for the construction of chiroptical molecular switches, because: (i) these compounds are thermally stable; no isomerizations can be detected below 70 "C and, (ii) if however thermal isomerizations might occur at elevated temperatures, only the P-trans * M-cis interconversion will take place. The written data will be lost, but unlike the system depicted in Scheme 6.7, no permanent damage will be imposed upon the switch, since M-cis and P-trans are still the only isomers present and no other isomerization processes have taken place. In fact, the ultimate switch should combine both properties described under 1) and 2) and some potential target molecules, which might be relatively easy accessible, are drawn in Figure 6.4. The presence of a powerful electron-donating dimethylamino group in the lower part of 42, might induce the formation of strong charge transfer interactions.

Figure 64. Target molecules functionalized with donor and acceptor groups.

" Tkese remarkable stereospecific isornerization pathways can be easily rationalized using the mechanisms proposed by Agranat and Tapuhi for the isomerization of bistricyclic ethylene5 (see Chapter 4, Section 4.3 and ref 2).

153

6 A Chbptical Molecular Switch Based on a Stereospec@ B-Tkans IsomQitation

6.5 Concluding Remarks

The synthetic value of the diazo-thioketone coupling reaction has been underlined by the preparation of unsymmetrically substituted inherently dissymmetric alkenes. Based upon a cis-trans isomerization accompanied by a reversal of helicity, the feasibility of sterically overcrowded alkenes to function as molecular switches was demonstrated. Two important differences emerge when the envisaged molecular switch based on the use of circular polarized light (cpl, see Chapter 2)" and the chiral cisltrans switch described in this chapter are compared:"

- No thermal racemization of the M-cis into the P-cis (or M-trans into P-trans) must occur for the cisltrans switch because this will deactivate the switch permanently. This was solved by the use of a benzannulated bisthioxanthylidene (vide supra). In contrast, the cpl switch will only be temporarily damaged by thermal racemization and function again upon renewed irradiation, independent of the isomer ratio.

- Separation into the enantiomers is necessary for the cisltrans switch, which has only be achieved so far using HPLC on a very small scale (< 1 mg). Probably, larger amounts of enantiomerically pure ethylenes can be obtained via functionalization of the molecules with acid groups followed by a classical resolution with chiral bases. A possible approach to realize this goal is depicted in Scheme 6.1 1.

Bromination of alkene 44 followed by lithiation of the dibromo intermediate with n- BuLi and quenching with carbon dioxide ought to furnish diadd 45, following a comparable lithiation procedure which has been applied for the preparation of molecular clefts.25 Resolution of this diacid should succeed with the chiral tetrahydrophenanthrene amine 46, which has been recently developed in our (Scheme 6.11).

Scheme 611. Resolution of 44.

The results which have been obtained for the chiroptical molecular switch based upon the use of r- or lcpl will be discussed in the forthcoming thesis of W.E Jager.

24 Another important (physical) difference is the use of two distinct wavelengths for the writing/ erasing procedure in the Cishrans switch instead of a single wavelength consisting of left- or rightcircularly polarized light, for the cpl-switch.

25 Ballester, P.; Ebmeyer, F.; Nowick, J.S.; Rebek, J. Jr. L Am. Chem. Soc. 1990,112,8902. 26 Gjaltema, D. research report, University of Groningen, 1989.

Another approach to obtain larger amounts of enantiomerically pure alkenes might be resolution of the P and M isomer via the formation of diasteromeric charge-transfer complexes with chiral rr electron-accepting (or donating) ~ompounds .~ This method has been applied successfully for the resolution of helicenes using (+)-TAPA (2- [ ( 2 , 4 , 5 , 7 - t e t r a n i t r o - 9 - f l u o r e n y I i d e n e ) v c acid), as the chiral acceptor, whereby the enantiomer which showed poorest complexing ability with TAPA, separated from the solution." Although enantiomerically pure hexahelicene has been obtained using this procedure, the necessary 12 (!) crystallizations are a severe disadvantage of the reported method.B3 Probably, a proper choice of chiral acceptor, which is well suited for strong charge- transfer interactions with the inherently dissymmetric alkenes described in this thesis, can lead to considerable improved results.31 For the resolution of xanthene functionalized alkenes, with a folded unit in the lower part of the molecules (e-g. 48, Scheme 6.12), the use of the xanthene analogue 47 of TAPA could be successful (Figure 6.5). The flexibility of the central six-membered ring in 47 allows this compound to adopt a bent conformation, which might fit perfectly into the folded structure of the xanthene unit in 48. The chiral tetranitro substituted xanthene derivative 47 should be obtained via nitration of 9H-xanthene-9-0ne:~ followed by reaction with enantiomerically pure a- (isopropylideneaminooxy)propionic acid, similarly as has been described for the synthesis of TAPA.~~

Figure 65. 2-[(~4,5,7-Tetra~-9-xanthenylidene)amkomy]-propwniC acid (47).

" For a discussion on optically active diastereomeric charge-transfer complexes see: Wynberg, H.; Lammertsma, K. I. Am C h m Sac. 1973,95,7913.

28 Newman, M.S.; Lsdnicer, D. 1 Org. Chem. 1956, 78, 4766. 29 This method proved to be unsuccessful for the resolution of heterocirculenes: Wynberg, H.;

Dopper, J.H. J. Org. Chem 1975,40,1957. 30 Kawazura et aL reported the total conversion of a racemic [5]thiaheterohellcene into a single

enantiomer by diastereomeric chargetransfer complex formation with TAPA: Kawahara, H.; Nakagawa, H.; Yamada, K. 1 Chem Soc, Chem. Commun. 1989,1378.

31 A reason for the many crystallizations needed to achieve complete resolution of hexahelicene28 and the disappointing results to raolve heterocirculenes" can be the relatively small charge transfer interactions between the planar fluorene moiety in TAPA and the bend helicene or circulene structures. The fluorene p u p cannot adopt a bend structure, as can clearly be seen from the molecular structure of 6 presented in Section 3.2.6.

32 Le F k e , RJ-W, L C h Soc. 1928,3249. Block Jr., P.; Newman, M.S. Organic Syntheses, Coll.Vo1. 5, 1031.

ti A Chiropticnl Molecular Switch b e d on a Sterempcci@ Cir-%ns Isornerization

The crystallization method to obtain enantiomerically pure P-trans 48a is depicted in Scheme 6.12. Starting from a mixture of P- and M-trans isomer 48a,b,34 selective formation of the charge transfer complex between M-trans 48b (or P-trans 4th) and 47 should occur, for example, in toluene as solvent. Addition of another solvent (for example, ethanol) to this solution might induce precipitation of enantiomerically enriched (or even pure) P-trans 48a (or M-trans 48b). Functionalization of the xanthene unit in 48 with a strong electron-donating dimethylamino group (R1 = NMe,) mi t even further increase the charge-transfer interactions and lead to salt formation. f!'

1) 47, toluene; ethand + M-trans+- 47-

R, 48b

Scheme 6.12 Resolution of alkene 48 using the TAPA analogue 47.

6.6 Erpen'mentnl Section

For general remarks, see Section 2.7. 2-Methyl-7-nitro-9H-thioxanthene-9-thione (37)36 was kindly provided by I. de Baas of our research group.

4-0x0-4-[2-(6-methylnaphthyl)]butanoic acid (4) This compound was prepared according to the method described by Haworth et ~ 1 . ~ Starting from succinic anhydride (73.1 g, 0.73 mol) and Zmethylnaphthalene (3, 102.3 g, 0.72 rnol), crystallization from acetic acid (700 mL) afforded pure 4 as a slightly brown solid (70.3 g, 0.29 mol, 40.3%): mp 158.3-161.0 "C (lit:4 mp 162 "C); 'H NMR (60 MHz) G 2.50 (s, 3H), 2.80 (t, J = 7.0 Hz, 2H), 3.42 (t, J = 7.0 Hz, 2H), 7.17 (m, 5H), 8.40 (s, 1H); the acidic proton was not observed due to the presence of small amounts of acetic acid.

4- [2-(6-Methylnaphthyl)] butanoic acid (5) Keto-acid 4 (60.0 g, 0.25 rnol), KOH (42.0 g, 0.75 mol) and NH,NH,.H,O (33.0 g, 32 mL, 0.63 mol) were successively added to magnetically stirred diethylene glycol (300 mL). This dark brown mixture was heated at 120 - 140 OC for 4 h followed by slow

" The trans isomers can be separated from the cis isomers in several cases via crystallization from ethanol, as has been shown in this chapter.

35 Other procedures which might be attempted to resolve inherently dissymmetric alkenes, can be (similarly as have been used for the resolution of (hetero) helicenes): (i) crystallization from optically active solvents: Wynberg, H.; Groen, M.B.; Schadenberg, H. I. Org. Chem. 1971, 36, 27% or, (ii) crystal picking: Martin, R.H.; Flammang-Barbiew, M.; Cosyn, J.P.; Gelbcke, M. Tetrahedron Len. 1968,3507.

36 This compound has been prepared in an identical way as described for 2-nitro-9H- thioxanthene-9-thione (19) using 4-methyl-thiophenol instead of thiophenol (17).

6 A Chiropricnl Molecular Switch Bas& on a Stereospci@ Cir-l)yms Zs&ation

distillation of the excess of NH2NH,.H20 and some formed H 2 0 until the inner temperature of the flask reached 200-210 OC and kept at this temperature for 4 h. After cooling to 20 OC, H 2 0 (150 mL) was added and this mixture was slowly poured into 20% aqueous HCl (800 mL) under stirring. The precipitated acid was isolated by filtration, washed with H20 (500 mL) and dried in vacuo to afford acid 5 as a yellow solid (59.8 g, 0.26 mol, approximately 100%). This compound proved to be > 90% pure by 'H NMR analysis and was used in .the following step without further purification: mp 107.5-109.5 "C (lit:4 111-112 OC); 'H NMR (60 MHz) G 1.80-2.26 (m, 2H), 2.26-2.40 (m, 2H), 2.40 (s, 3H), 2.75 (t, J = 7.0 Hz, 2H), 7.05-7.90 (m), 8.45 (bs, 1H).

7-Methyl-1,2,3,4-tetrahydrophenanthrene4one (6) To mechanically stirred polyphosphoric acid (700 mL) heated at 60 "C was added acid 5 (60.0 g, 0.26 mol) in 90 min. After the addition was complete, the temperature was raised to 100 "C and the mixture held at this temperature for 4 h. The mixture became homogeneous and the colour changed to brown. After cooling to 50 "C the viscous liquid was poured into icelwater (1.5 L), to afford a dark brown solid, and stirred to decompose the polyphosphoric acid. The precipitated solid was isolated by extraction with Et,O (4 x 250 mL). The combined Et20 layers were washed with 5% aqueous HCl (1 x 200 mL), 10% aqueous NaOH (2 x 200 mL), saturated aqueous NaHCO, (1 x 200 mL) and brine (1 x 200 mL), dried (Na2S04) and after evaporation of the solvent in vacuo, a brown oil, which slowly solidified, was obtained. This compound was purified by bulb to bulb distillation (150-170 "C, 0.1 mmHg) to yield 6 as a slightly yellow solid (42.5 g, 0.20 mol, 76.9%): mp 59.9-61.8 "C (lit:4 62-63 "C); 'H NMR (300 MHz) 6 2.09-2.15 (m, 2H), 2.45 (s, 3H), 2.72 (dd, J = 7.3, 5.9 Hz, 2H), 3.01 (dd, J = 6.5, 5.9 Hz, 2H), 7.20 (dd, J = 8.8, 0.7 Hz, lH), 7.42 (dd, J = 8.8, 1.5 Hz, lH), 7.50 (s, lH), 7.76 (d, J = 8.8 Hz, lH), 9.31 (d, J = 8.8 Hz, 1H); 13C NMR S 21.09 (q), 22.86 (t), 31.25 (t), 40.86 (t), 126.20 (d), 126.69 (d), 126.81 (s), 127.09 (d), 129.22 (s), 130.69 (d), 132.79 (s), 133.37 (d), 135.08 (s), 145.58 (s), 200.19 (s, C=O); HRMS Calcd for C,,Hl,O: 210.102, found 210.104.

7-Methyl-1,2,3,4-tetrahydrophenanthrene-4-one hydrazone (7) This compound was prepared as described for the synthesis of 1,2,3,4-tetrahydro- phenanthrene-4-one hydrazone 26 in Section 2.7. After refluxing ketone 6 (20.0 g, 95.2 mmol) and NH,NH,.H,O (23.0 mL, 23.8 g, 475.0 mmol, 5 equiv.) in absolute ethanol (100 mL) for 2 h, the yellow solution was filtered while hot and upon cooling to room temperature 7 separated from the solution as yellow crystals (19.8 g, 88.3 mmol, 92.7%): mp 143.7-145.4 "C; 'H NMR (300 MHz) 6 1.84-1.90 (m, 2H), 2.46 (s, 3H), 2.56 (dd, J = 6.6, 6.5 Hz, 2H), 2.74 (dd, J = 6.6, 5.9 Hz, ZH), 5.41 (bs, 2H, NH,), 7.18 (d, J = 8.8 Hz, lH), 7.32 (dd, J = 8.8, 1.5 Hz, lH), 7.53 (s, lH), 7.58 (dd, J = 8.8, 0.7 Hz, lH), 8.96 (d, J = 8.8 Hz, 1H); 13C NMR 6 21.12 (q), 21.33 (t), 25.54 (t), 31.01 (t), 126.38 (d), 126.85 (d), 126.87 (d), 127.42 (d), 128.52 (d), 128.61 (s), 133.59 (s), 134.08 (s), 134.10 (s), 137.86 (s), 148.24 (s); HRMS Calcd for Cl,Hl,N2: 224.131, found 224.131; Anal. Calcd for CI5H,,N2: C, 80.36; H, 7.14; N, 12.50. Found: C, 80.66, H, 7.15; N, 12.50.

2-Methyl-9E-thioxanthene-9-one (11) Finely powdered 10 (49.0 g, 0.20 mol, prepared according to the procedure described by Vasiliu et al.') was added in 30 min to mechanically stirred H2S04 (500 mL) at room temperature. The colour of the mixture changed to blue and after stirring for 45

4 A Chinpica1 Molecular Switch h e d on a Sfmospecijic Cu-nuns I s o m ~ r i o n

min the now green brown solution was poured onto ice (= 3 kg). The precipitated yellow solid was isolated by a difficult slow filtration, washed with water (500 mL), saturated aqueous NaHCO, (250 mL) and the wet solid was dissolved in CH2C1, (2.5 L). The CH2C12 layer was washed with saturated aqueous NaHCO, (2 x 250 mL), brine (1 x 250 mL), dried (N+S04) and after evaporation of the solvent a light yellow solid was obtained which proved to be 11 (36.0 g, 0.16 mol, 82.6% based on 4-iod0- toluene): mp 122.4-125.1 "C (lit:37 mp 125-127 "C); 'H NMR (300 MHz) S 2.47 (s, 3H), 7.41-7.62 (m, 5H), 8.42 (s, lH), 8.61 (d, J = 8.8 Hz, 1H); 13c NMR S 21.00 (q), 125.56 (d), 125.68 (d), 125.77 (d), 128.70 (s), 128.95 (s), 129.32 (d), 129.56 (d), 131.79 (d), 133.37 (d), 133.83 (s), 136.06 (s), 137.16 (s), 179.61 (s, C=O).

2-Methyl-9H-thioxanthene-9-thione (12) To a stirred solution of 11 (15.0 g, 66.4 mmol) in dry toluene (200 mL) was added P2S5 (29.5 g, 132.8 mmol). After refluxing for 1 h TLC analysis (Si02, hexane/EtzO 8515, starting material RF = 0.39, product Rf = 0.47), showed no starting material left. The dark green mixture was cooled, filtered and the residue washed with C H 2 Q (300 mL) until the washings were only slightly green. The solvents were removed in vacuo. Crystallization of the residue from hexane/CH2C12 (400 mL, 5050) yielded 12 as dark green small needles (14.7 g, 60.7 mmol, 88.5%, in two fracticns): mp 118.3- 121.2 "C; 'H NMR (300 MHz) S 2.48 (s, 3H), 7.39-7.62 (m, 5H), 8.84 (s, lH), 9.02 (d, J = 8.5 Hz, 1H); 13C NMR S 21.11 (q), 125.50 (d), 125.65 (d), 126.44 (d), 128.70 (s), 131.14 (d), 131.84 (s), 132.79 (d), 132.91 (d), 133.13 (d), 136.70 (s), 136.94 (s), 137.09 (s), 210.07 (s, C=S); HRMS Calcd for C,,H,,S,: 242.022, found 242.022.

2-Methoxy-9H-thioxanthene-9-e (15) This compound was prepared in a similar way as described for 11. Starting from thiosalicylic acid (8, 53.9 g, 0.35 mol) and biodoanisole (13, 70.2 g, 0.35 mol), acid 14 was obtained (= 70 g). This acid was converted to ketone 15 by stirring in concentrated H2S04 cooled to 10 "C for 45 min. Work-up as described for 11, yielded 15 as a light yellow solid (40.3 g, 0.17 mol, 55.9% based on 4-iodoanisole): mp 126.3- 128.4 "C (lit? 129 "C); 'H NMR (300 MHz) S 3.88 (s, 3H), 7.14-7.18 (m, lH), 7.35- 7.53 (m, 4H), 8.00 (d, J = 2.9 Hq lH), 8.55-8.58 (m, 1H); 13C NMR S 55.38 (q), 110.05 (d), 122.31 (d), 125.65 (d), 125.73 (d), 126.93 (d), 128.26 (s), 128.79 (s), 129.53 (d), 129.89 (s), 131.63 (d), 137.19 (s), 158.03 (s), 179.17 (s, C=O).

2-Methoxy-9H-thioxanthene-9-thione (16) This compound was prepared following the procedure described for 12. After 1 h TLC analysis (SiO, hexane/Et20 85:15, starting material RF = 0.25, product R, = 0.42) indicated the total conversion of 15 (15.0 g, 62.0 mmol) to thioketone 16. The dark-green residue obtained after evaporation of the solvents was dissolved in CH2CI, (200 mL) and filtered. Hexane (200 mL) was added, whereupon the thioketone began to separate from the solution. Upon cooling at -18 "C, 16 was obtained as dark green small needles in a first fraction (6.2 g) and as a green-brown powder in a second fraction (5.9 g), which both proved to be pure thioketone (total amount: 12.1 g, 46.9 mmol, 75.6%): mp 142.6-142.9 "C; 'H NMR S 3.96 (s, 3H), 7.27-7.31 (m, lH), 7.44- 7.51 (m, 2H), 7.57-7.63 (m, ZH), 8.59 (d, J = 2.2 Hz, lH), 9.07-9.09 (m, 1H); 13C NMR 6 55.50 (q), 113.86 (d), 122.38 (d), 124.21 (s), 125.86 (d), 126.65 (d), 127.08 (d),

37 Protiva, M.; Pelz, K . ColL Czech., Chem. Commun 1%7,32, 2161. 38 Roberts, KC.; Smiles, S. J. Chem. Soc. 1929, 863.

158

6 A Chiroptical Mofceular Switch Eased on a Stcteospccific Cis-Tknr Iscwncritarion

- 131.14 (d), 132.05 (s), 133.61 (d), 136.66 (s), 138.22 (s), 158.73 (s), 208.81 (s, C=S); HRMS Calcd for C14HloO$: 258.017, found 258.017; Anal. Calcd for C14H,,0S2: C, 65.12; H, 3.87; S, 24.81. Found: C, 64.94; H, 3.95; S, 24.57.

2-Nitro-9H-thioxanthene-9-0ne (19a) This compound was prepared in two steps from thiophenol (17, 25.0 g, 0.24 mol) and 2-chloro-5-nitrobenzoic acid (18, 43.0 g, 0.21 mol) according to the procedures described by Amstutz and ~ e u m 0 ~ e r . s Ketone 196 was obtained as a yellow powder (50.9 g, 0.20 mol, 92.8%, based on 2-chloro-5-nitrobenzoic acid): mp 221.4-223.9 "C (lit:' 226.8-229.0 O C ) ; 'H NMR (300 MHz) 8 7.50 (ddd, J = 8.8, 8.1, 1.5 Hz, lH), 7.56 (d, J = 8.8 Hz, lH), 7.62-7.68 (m, lH), 7.67 (d, J = 8.8 Hz, lH), 8.34 (dd, J = 8.8, 2.2 Hz, lH), 8.56 (dd, J = 8.1, 1.5 Hz, lH), 9.36 (d, J = 2.2 Hz, 1H).

2-Nitm9H-thioxanthene-9-thione (19) This compound was prepared following the procedure described for 12 with small modifications. To a magnetically stirred suspension of 19a (20.0 g, 77.8 mmol) in toluene (600 mL) was added P2S5 (40.0 g, 180.2 mmol). The mixture was refluxed for 1 h and after cooling to 80 OC more P2S5 (20.0 g, 90.1 mmol) was added to the now dark green coloured toluene mixture. After refluxing for 1 h again P2S, (20.0 g, 90.1 mmol) was added. This mixture was refluxed for. 2 h when TLC analysis (SiO, hexane/CH2C12 5050, starting material R, = 0.21, product Rf = 0.32), showed no starting material left. The dark green mixture was cooled to 50 "C, filtered and the smelly residue washed with hot toluene until the washings were only slightly green. The toluene was removed under reduced pressure and the dark-green mass (20 g) crystallized from xylene (300 mL) to afford 19 in two fractions as dark green small needles (14.6 g, 53.4 mmol, 68.7%): mp 218.3-219.6 "C; 'H NMR (300 MHz) S 7.48 (ddd, J = 8.4, 8.1, 1.1 Hz, lH), 7.57 (dd, J = 8.1, 1.1 Hz, lH), 7.64-7.69 (m, lH), 7.70 (d, J = 8.8 Hz., lH), 8.35 (dd, J = 8.8, 2.2 Hz, lH), 8.90 (dd, J = 8.4, 1.1 Hz, lH), 9.75 (d, J = 2.2 Hz, 1H); due to the very low solubility of 19 no 13c NMR data were obtained; HRMS Calcd for Cl,H,N0,S2: 272.992, found 272.991.

Episulfides 21-26 were prepared according to the general procedures described for 35 in Section 2.7

Cis and tmns dispirot7-methyl-l,2,3,4-tetrahydrophenanthne-4, 2'-thiirane-3', 9"-(2"- methyl)-9"H-thioxanthene] (21, 22) Starting from hydrazone 7 (672 mg, 3.00 mmol) and 2-methyl-9H-thioxanthene-9- thione (12, 583 mg, 2.41 mmol), the mixture of episulfides cis-21 and trans-22 separated from the ether layer as a yellow solid in a 5050 ratio. Crystallization from ethanol afforded episulfides ck-21 and trans-22 (725 mg, 1.66 mmol, 68.8%, based on the amount of added thioketone) as a white powder (ratio 21:22, 70:30). No further attempts were made to separate these compounds. Only the ck-21 NMR data were fully resolved and are listed here: 'H NMR (300 MHz) S 1.36-1.56 (m, 2H), 1.62 (s, 3H, ck-CH,, the trans-CH, was found at 2.42 ppm), 1.88-1.99 (m, lH), 2.41 (s, 3H), 2.43-2.66 (m, 2H), 3.45-3.63 (m, lH), 6.47 (dd, J = 7.7, 1.1 Hz, lH), 6.81 (d, J = 8.1 Hz, lH), 6.86-7.20 (m, 8H), 7.97 (dd, J = 7.7, 1.0 Hz, lH), 9.43 (d, J = 8.8 Hz, 1H); 13C NMR 6 19.99 (q), 21.06 (t), 21.12 (q), 29.79 (t), 34.93 (t), 59.67 (s, C-S), 61.51 (s, CS), 124.02 (d), 124.89 (d), 125.73 (d), 126.21 (d), 126.26 (d), 126.32 (d), 126.50 (d), 126.73 (d), 126.87 (d), 127.07 (d), 129.85 (s), 130.93 (d), 131.20 (s), 131.43 (d), 132.01 (s), 132.41 (s), 132.88 (s), 133.02 (s), 133.36 (s), 134.56 (s), 135.92 (s), 139.92 (s);

4 A ChiropticaI Moteculur Switch Based on a Stereaspccifi Cis-Tram Isomerization

HRMS Calcd for C&l,S,: 436.132, found 436.133.

Cis and tmns dispiro[7-methyl-l,2,3,4-tetmhydrophenanth, 2'-thiirane3', 9"-(2"- methoq)-9"H-thioxanthene] (23, 24) Hydrazone 7 (672 mg, 3.00 mmol) was oxidized to the red diazo compound 20, followed by addition of 2-methoq-9H-thioxanthene-9-thione (16, 490 mg, 1.90 mmol). The mixture of episulfides ch-23 and trans-24 precipitated from the EbO solution as a slightly yellow solid (ratio 23:24, 5050). Crystallization from ethanol yielded episulfides cis-23 and trans-24 (481 mg, 1.06 mmol, 55.8%, based on the amount of added thioketone), as a cis and trans mixture (ratio 2324, 17:83). No further attempts were made to separate these compounds. Only the NMR data of trans-24 were fully resolved and are given: 'H NMR (300 MHz) 6 1.25-1.50 (m, 2H), 1.90-1.95 (m, lH), 2.30-2.38 (m, lH), 2.35 (s, 3H), 2.41-2.57 (m, lH), 3.47-3.58 (m, lH), 3.77 (s, 3H, trans-OCH,, the cis-OCH, was found at 2.98 ppm), 6.31 (ddd, J = 8.1, 7.3, 1.5 Hz, lH), 6.59 (ddd,J= 8.8, 7.3 Hz, 1.5 Hz, lH), 6.77 (dd , J= 8.1, 2.9Hz, lH), 6.84(d,J = 8.1 Hz, lH), 6.88 (d, J = 8.1 Hz, lH), 7.14-7.53 (m, 6H), 9.31 (d, J = 8.8 Hz, 1H); 13C NMR 6 20.94 (t), 21.11 (q), 29.76 (t), 34.99 (t), 55.44 (q), 59.93 (s, C-S), 61.48 (s, C-S), 124.64 (d), 125.30 (d), 126.21 (d), 126.26 (d), 126.63 (d), 126.82 (d), 126.87 (d), 127.16 (d), 127.57 (d), 128.99 (d), 129.20 (d), 129.39 (s), 130.33 (d), 131.07 (s), 132.50 (s), 132.58 (s), 133.02 (s), 133.92 (s), 134.42 (s), 135.06 (s), 140.01 (s), 158.20 (s); HRMS Calcd for C,.$,OS,: 452.127, found 452.126.

Cis and tram dispiro[7-methyl-l,2,3,4-tetrabydrophenanthe-4, 2'-thiiraned', 9"-(2"- nitro)-Y'H-thioxanthene] (25, 26) Starting from hydrazone 7 (672 mg, 3.00 mmol) and 2-nitro-9H-thioxanthene-9-thione (19, 573 mg, 2.10 mmol), episulfides cis-25 and trans-26 precipitated from the Et,O solution and proved to > 90% pure according to 'H NMR analysis (766 mg, 1.64 mmol, 78.1%, cisltrans ratio, 6436). These thiiranes were used in the next desulfurization step without further purification: 'H NMR (300 MHz) 8 1.34-1.60 (m, 2H), 1.79-1.92 (m, lH), 2.35 (s, 1.92H, cir-CH,), 2.45 (s, 1.08H, trans-CH,), 2.46-2.73 (m, 2H), 3.28-3.51 (m, lH), 6.44 (ddd, J = 8.8, 7.8, 1.5 Hz, 0.36H), 6.75 (ddd, J = 8.8, 7.3, 1.5 Hz, 0.36H), 6.86-6.98 (m, 2.36H), 7.17-7.51 (m, 6.92H), 7.90 (dd, J = 7.8, 1.5 Hz, 0.64H), 8.18 (d, 3 = 2.0 Hz, 0.36 H), 9.24 (d, J = 9.3 Hz, 0.64H), 9.26 (d, J = 8.8 Hz, 0.36H); 13C NMR (only the data for cis-25 are given, the absorptions of the minor trans isomer were not fully resolved) 8 20.80 (q), 21.25 (t), 29.77 (t), 35.01 (t), 59.58 (s, C-S), 60.17 (s, C-S), 120.93 (d), 123.44 (d), 125.82 (d), 126.11 (d), 126.33 (d), 126.65 (d), 126.78 (d), 126.94 (d), 127.02 (d), 127.18 (d), 127.74 (d), 130.62 (s), 130.81 (d), 130.95 (s), 132.52 (s), 132.60 (s), 133.35 (s), 133.81 (s), 133.94 (s), 139.71 (s), 139.76 (s), 142.51 (s); HRMS Calcd for C&H,,NO,S,: 467.101, found 467.100.

Alkenes 27-32 were prepared from the corresponding episulfides using the general procedure described for 38 in Section 2.7

Cis and tmns 2-methyl-9-(7'-methyl-l',2',3',4'-tetrahydmphenanth~ne4'-ylidene)-9H- thioxanthene (27,28) Starting from a mixture of episulfides cis-21 and nuns-22 (436 mg, 1.00 mmol, ratio 21:22, 70:30), crystallization from ethanol (150 mL) afforded alkenes cis-27 and trans- 28 in a 5050 ratio'' as slightly yellow solids (315 mg, 0.78 mmol, 78.0 %). After a second crystallization from ethanol the ratio of cis-27 and tram-28 was found to be 7426. No further attempts were made to separate these compounds: 'H NMR (300 MHz, the data for the cis-27 and trans-28 in a 5050 ratio are given) S 1.54 (s, 1.5H,

6 A Chwopticaf Molecular Switch Bared on a Stereospecifi Cis-Tram Isomerization

cis-CH,), 1.95-2.19 (m, 2H), 2.32 (s, 3H), 2.32-2.41 (my lH), 2.43 (s, 1.5H, trans-CH,), 3.01-3.18 (m, 2H), 3.32-3.39 (m, lH), 6.14 (d, J = 2.2 Hz, 0.5H, cis), 6.39-6.45 (my lH, trans), 6.58 (dd, J = 7.8, 1.1 Hz, OSH, cis), 6.74-6.77 (m, 0.5H, trans), 6.81-6.86 (m, lH, cis), 7.09 (dd, J = 7.8, 1.5 Hz, 0.5H, trans), 7.18-7.59 (m, 8H); 13c NMR (only the data for cis-27 are given, the absorptions for trans-28 were not fully resolved) S 20.32 (q), 21.24 (q), 22.37 (t), 28.08 (t), 28.63 (t), 125.71 (d), 126.05 (d), 126.17 (d), 126.32 (d), 126.45 (d), 126,54 (d), 127.15 (d), 127.30 (d), 127.36 (d), 127.91 (d), 128.52 (d), 129.38 (d), 132.09 (s), 132.15 (s), 133.50 (s), 134.56 (s), 134.66 (s), 134.87 (s), 135.57 (s), 135.75 (s), 136.58 (s), 136.73 (s), 136.85 (s), 138.59 (s); HRMS Calcd for C&,H,S: 404.160, found 404.160.

Cis and burns 2-metho~-9-(7'-methyl-1',2'~,4'-tetrahydmphenanthrene-4'-yIidene)-9H- thioxanthene (29,30) Starting from a mixture of episulfides cis-23 and tram-24 (226 mg, 0.50 mmol, ratio 2324, 17:83), alkenes cis-29 and trans30 were obtained in a 5050 ratio (187 mg, 0.45 mmol, 89.2 %). Two crystallizations from ethanol yielded pure cis alkene 29 (74.3 mg, 0.18 mmol, 35.4%); cis-29: mp 179.0-179.4 "C; 'H NMR (300 MHz) S 2.01-2.23 (m, 2H), 2.34 (s, 3H), 2.34-2.41 (m, lH), 2.97 (s, 3H), 3.06-3.13 (m, ZH), 3.32-3.40 (m, lH), 5.95 d, J = 2.6 Hz, lH), 6.38 (m, lH), 6.87 (dd, J = 8.8, 1.5 Hz, lH), 7.21-7.60 6 (m, 9H); ' C NMR S 21.24 (q), 22.43 (t), 28.08 (t), 28.63 (t), 54.78 (q), 113.17 (d), 113.99 (d), 124.74 (d), 125.38 (s), 125.71 (d), 125.99 (d), 126.17 (s), 126.32 (d), 126.33 (d), 126.60 (d), 127.21 (d), 127.33 (d), 127.54 (d), 127.94 (d), 131.97 (s), 132.25 (s), 133.71 (s), 134.93 (s), 136.12 (s), 136.33 (s), 136.55 (s), 136.73 (s), 139.66 (s), 157.64 (s); HRMS Calcd for C&HMOS, 420.155, found 420.154; Anal. Calcd for C&HuOS: C, 82.86, H, 5.71; S, 7.62. Found: C, 82.88; H, 5.83; S, 7.63; trans-30: mp not obtained (the trans alkene was always contaminated by cis alkene); 'H NMR (300 MHz) 6 2.10-2.19 (my lH), 2.32 (s, 3H), 2.32-2.36 (my lH), 3.05-3.16 (m, 2H), 3.30-3.37 (m, lH), 3.89 (s, 3H), 6.30-6.37 (m, 2H), 6.81 (ddd, J = 8.8, 7.8, 1.5 Hz, lH), 6.93 (dd, J = 8.8, 1.5 Hz, lH), 7.19 (d, J = 2.6 Hz, lH), 7.23-7.60 (m, 8H); 13c NMR 6 21.25 (q), 22.25 (t), 28.29 (t), 28.50 (t), 55.38 q), 112.94 (d), 113.91 (d), 124.69 (d), 125.10 (d), 125.22 (s), 125.72 (d), 125.98 (d), 126.43 (d), 126.58 (d), 126.65 (s), 127.22 (d), 127.34 (d), 127.51 (d), 128.12 (d), 131.81 (s), 132.01 (s), 133.51 (s), 134.86 (s), 135.96 (s), 136.39 (s), 136.47 (s), 137.95 (s), 138.36 (s), 157.46 (s).

Ck and trans 2-nitm-9-(7'-methyl-1',2y~,4'-tetrahydmphenanthmne4'-ylidene)-9H- thioxanthene (31,32) Desulfurization of a mixture of episulfides cis-25 and trans-26 (467 mg, 1.00 mmol, ratio 2526, 64:36), followed by crystallization from ethanol yielded ck-31 and trans32 in a 3664 ratio (365 mg, 0.84 mmol, 84.3 %; the product obtained after the evaporation of p-xylene in the desulfurization step indicated the presence of cis31 and trans32 in a 5050 ratio). A second crystallization from ethanol afforded the alkenes cis31 and trans32 in a 5050 ratio. Further attempts to separate these isomers via crystallization or chromatography were unsuccessful. 'H NMR (300 MHz, the data for the cis31 and tram32 in a 3664 ratio are given) S 1.97-2.51 (m, 3H), 2.28 (s, 1.08H, ck-CH,), 2.30 (s, 1.92H, tram-CH,), 3.04-3.41 (m, 3H), 6.40 (d, J = 8.8, 1.1 Hz, 0.64H), 6.48 (ddd, J = 8.8, 7.3 Hz, l.lH, 0.64Hz), 6.77 (m, 1.92H), 7.13 (d, J = 2.2 Hz, 0.36H), 7.23-7.62 (m, 6.52H), 7.68 d, J = 8.4 Hz, 0.64H), 8.11 (dd, J = 8.4, 2.2 Hz, 0.64H), 8.40 (d, J = 2.2 Hz, OMH); 13C NMR (no distinction could be made between the absorptions of the cis and trans isomer; however, all 13C NMR data for cis31 and trans32 were fully resolved (!) and are listed here) S 21.17 (q), 21.24 (q),

6 A Chiropticat Molecular Switch Based on a SIcnospcc+ Cis-kns Isomcriratioul.

2l.w (t), 22.36 (t), 28.20 (t), 28.45 (t), 28.50 (t), 28.58 (t), 120.48 (d), 121.20 (d), 122.79 (d), 123.58 (d), 123.77 (d), 123.77 (d), 124.30 (d), 125.37 (s), 125.50 (s), 126.18 (d), 126.24 (d), 126.40 (d), 126.51 (d), 126.60 (d), 126.81 (d), 126.85 (d), 126.93 (d), 127.05 (d), 127.20 (d), 127.35 (d), 127.48 (d), 127.60 (d), 127.63 (d), 127.65 (d), 128.20 (d), 128.82 (d), 129.62 (s), 129.87 (s), 129.98 (s), 132.14 (s), 132.22 (s), 132.26 (s), 133.69 (s), 133.77 (s), 133.86 (s), 134.65 (s), 135.16 (s), 135.57 (s), 137.09 (s), 137.19 (s), 137.47 (s), 137.54 (s), 137.93 (s), 139.19 (s), 142.92 (s), 144.53 (s), 145.35 (s), 146.05 (s); HRMS Calcd for C,H2,N02S: 435.129, found 435.128.

Cis 10,10-dioxo-2-methoxy-9-(7'-metbyl-1'~~,4~-b~hydmphemn~~nd9-y1idene)- 9H-thioxanthene (33) This compound was prepared as described for 9-(2',3'-dihydro-1'H-naphtho[2,l- blpyran-1'-y1idene)-10,lO-dioxo-9H-thioxanthene (29) in Section 3.5. Starting from &- 29 (80 mg, 0.19 mmol) oxidation with m-CPBA yielded 33 as a slightly yellow solid (69 mg, 0.15 mmol, 80.2%): mp 195.3-197.6; 'H NMR (300 MHz) S 2.06-2.38 (m, 3H), 2.28 (s, 3H), 3.01-3.10 (m, 2H), 3.32-3.38 (m, lH), 5.88 (d, J = 2.4 Hz, lH), 6.41 (dd, J = 7.8, 1.5 Hz, lH), 6.95 (dd, J = 8.8, 1.5 Hz, lH), 7.25 d, J = 8.8 Hz, lH), 7.38 (s, $ lH), 7.41-7.78 (m, 6H), 8.10 (dd, J = 7.8, 1.1 Hz, 1H); ' C NMR S 21.27 (q), 21.91 (t), 28.38 (t), 29.17 (t), 54.75 (q), 112.77 (d), 113.75 (d), 123.76 (d), 125.07 (d), 125.13 (d), 125.14 (d), 125.84 (d), 126.14 (d), 126.51 (s), 127.24 (d), 127.54 (d), 128.43 (d), 128.61 (s), 130.99 (d), 132.18 (s), 134.38 (s), 135.66 (s), 136.49 (s), 136.61 (s), 138.47 (s), 138.68 (s), 141.25 (s), 141.98 (s), 160.66 (s); HRMS Calcd for C&IU03S: 452.145, found 452.144.

7-Methoxy-l~J,Qtetrahydmphenanth~ne-4-one hydrazone (36) This compound was prepared following the procedure described for the synthesis of hydrazone 26 in Section 2.7. Starting from 7-methoxy-1,2,3,4-tetrahydrophenanthrene- 4-one3' (2.00 g, 8.84 mmol), 36 was obtained as a slightly yellow solid (1.42 g, 5.92 mmol, 66.9%): mp 145.6-147.4 "C; 'H NMR (300 MHz) S 1.82-1.93 (m, 2H), 2.59 (dd, J = 6.7, 6.4 Hz, 2H), 2.78 (dd, J = 6.7, 5.9 Hz, 2H), 3.78 (s, 3H), 5.42 (bs, 2H, NH2), 7.08 (d, J = 1.1 Hz, lH), 7.18-7.24 (m, 2H), 7.60 (d, J = 8.4 Hz, lH), 9.05 (d, J = 8.8 Hz, 1H); 13C NMR S 21.35 (t), 25.52 (t), 30.86 (t), 54.97 (q), 106.12 (d), 118.39 (d), 125.74 (s), 126.87 (d), 126.92 (d), 128.81 (d), 134.65 (s), 136.56 (s), 136.57 (s), 148.10 (s), 156.40 (s); HRMS Calcd for C1,Hl6N2O: 240.127, found 240.126.

Cis and h n s dispiro[7-rnethoxy-l,2J,4tetrahydrophenanthne, 2'-thiirane-3', 9"- (2"-methyl-7"-nitro)-9"H-thioxanthene] (38, 39) Starting from hydrazone 36 (480 mg, 2.00 mmol) and 2-methyl-7-nitro-9H-thioxan- thene-9-thione (37, 321 mg, 1.12 mmol), the mixture of episulfides cis38 and lram-39 separated from the ether layer as an orange solid (430 mg). NMR analysis indicated the presence of cis38 and mns-39 in a 5050 ratio together with approximately 20% azine). Crystallization from ethanol yielded the pure episulfides cis38 and trans39 as yellow solids in a 63:37 ratio (261 mg, 0.53 mmol, 46.9%): 'H NMR (300 MHz) S 1.38-1.62 (m, 2H), 1.67 (s, 1.11H, lrans-CH,), 1.80-1.97 (m, lH), 2.45 (s, 1.89, ck- CH,), 2.48-2.73 (rn, 2H), 3.31-3.41 (m, lH), 3.83 (s, 1.89H, ch-0CH3), 3.89 (s, 1.11H, trans-OCH,), 6.57 (dd, J = 8.1, 1.5 Hz, 0.37H), 6.76 (d, 3 = 2.2 Hz, 0.63 H), 6.85 (d, 3 = 8.1 Hz, 0.37H), 6.89-6.94 (m, 1.37H), 7.01 (d, J = 8.8 Hz, 0.63H), 7.12-7.32 (m,

39 This compound was prepared starting from 2-methoxy-naphthalene, following the same synthetic route as described for 7-methyl-12,3,4-tetrahydrophenanthrene-4-0 (6).

162

6 A ChiropticaI Molecular Switch Based on a Stereospec@ Cis-Trans Isovncrizalion

the trans isomer, therefore no melting point can be given): 'H NMR (300 MHz) S 1.58 (s, 3H, cis-CH,), 6.09 (s, lH), 6.57 (dd, J = 8.8, 1.5 HZ, lH), 6.72 (dd, J = 8.4, 1.5 Hz, lH), 6.85 (ddd, J = 8.8, 7.8, 1.5 Hz, lH), 6.94-7.02 (m, 3H), 7.06-7.19 (m, 4H), 7.52 (dd, J = 8.1, 1.0 Hz, lH), 7.58-7.68 (m, 5H); 13c NMR S 20.22 (q, cis-CH,), only the methyl absorption was fully resolved.