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5914

0 PPM11

5 4 3 0 2 0I~ ~~ P P M6 0

Figure 2. Spectra of CC14 solu tion s of 0.9 M 5 a n d 0.6 M 6 n thepresence of 0.5 M 1. Expanded spectra at left are for t h e d o w n -f ield methy l resonances . Unass igned resonances a re due to 1.

the presence of tris dipivalomethanato)europium III)and in the presence of 1. This comparison showsthat similar pseudocontact shifts (As) are observedwith the two reagentsa8 As illustrated by spectrumb, in the presence of 1 pseudocontact-shift differencesfor enantiomers are observed. The enantiotopic a-methyl singlets are separated 0.29 ppm and th e P-methyltriplets are separated 0.22 ppm which correspondsto -2J and gives rise to a quintuplet. A more dramaticexample of nonequivalence is illustrated by the lowerspectrum in Figure 1. This spectrum of partly active1 2-dimethyl-exo-2-norbornanolg in the presence of 1shows large shift differences for corresponding methylgrou ps of the enantiomers. It is interesting to notethat nonequivalence is largest (>0.5 ppm) for the leastshifted methyl group (presumably the 1-methyl).Effects of 1 on the nmr spectra of some other typesof compound s are summarized in Table I. This tableshows pseudocontact-shift differences (AAs) for theTable I. Pseudocontact-Shift Differences forEnan t iomers (AA8) in the Presence of la

C o m p o u n d P r o t o n2-Octano l a -CH3/ l - C H a1,2-Dimethyl-e/zdo-2-norbornanol lZCH31-P he ny le tha no l CY-HI-Phenylethyl acetate -C02CC H31 - M e t h y l - 2 - n o r b o r n a n o n e 1 - C H 33,3-Dimethyl-2-aminobutane a - C H 3cis-/3-Methylstyrene oxide P-CHa

AA6,PPm0 . 1 10 . 3 70 . 3 30 . 3 00.180 . 1 70.280 . 2 7

a Concen t ra t ion o f 1, 0.4 M (200 mg/0.6 ml of CC1,). Mola rr a t i o o f l / s u b s t r a t e , >0.6.(8) For information regarding pseudocontact shifts and nmr shiftreagents see (a) J K. M . Sanders and D. H . Williams, J . A mer . Chem.Soc. , 93, 641 (1971); (b) R . E. Rondeau and R. E. Sievers, ibid., 93,1522 (1971); and (c) J Briggs, G. H. Fros t , F. A. Har t , G. P. Moss,and M. L. Staniforth, Chem. Commun., 749 (1970), and references inthese papers.(9) H. L. Goering, C. Brown, S. Chang, and J. V. Clevenger, J . Org.Chem. , 34 624 (1969).

indicated enantiotopic proto ns. Nonequivalence wasno t observed with ethers. Magnitudes of pseudo-contact shifts (As) and of AAs depend on the ratioof 1 to substrate. Con dition s have been optimizedonly for 4. In this case A s and AAs (for both methylgroups) increase with the 1/4 ratio until the latterreaches -0.7 after which there is no chang e. Thissuggestssb tha t a t ratios >0.7 (optimum conditions)essentially all of the substrate is coordinated . In thisconnection it is significant tha t nonequivalence wasnot observed for protons that are enantiotopic by in-ternal comparison, e .g . , 2-propanol a nd dimethyl sulf-oxide.Nonequivalence of enantiomers is also observed withthe praseodymium analog of 1 and shift differencesare at least as large as with 1; however, resolution isgenerally poorer. In this case induced shifts are inthe upfield d i r e ~ t i o n . ~ ~ * ~ ~Th e use of 1 for direct determination of enantiomericcompositions is illustrated by Figure 2 which showsspectra of optically active methyl 2-methyl-2-phenyl-butanoate (5) and 3-methyl-3-phenyl-2-pentanone6 )in the presence of 1. Both c ompou nds were preparedfrom th e same sample of partially resolved 2-methyl-2-phenylbutanoic acid (excess S isomer)'O and havethe same optical purities. Fo r 5, nonequivalence isobserved for the 0-methyl R , 5.68 ppm; S, 5.56ppm) and 2-methyl protons R , 2.98 ppm; S, 2.93ppm ). Similarly, for 6, nonequivalence is observedfor the acyl-methyl R, 5.62 ppm; S , 5.49 ppm) and3-methyl protons S, 3.72 ppm; R , 3.62 ppm ). Ex-pan de d sweep widths of the downfield methyl resonancesare shown to the left of the corresponding spectrum.'Peak areas of the expanded signals correspond to o pticalpurities of 27 .7 for 5 and 27 . 3x fo r 6 as comparedto 25.8 for 5 and 25.4 for 6 determined from rota -tions.l0 It is note wort hy that in the spectrum ofthe se nse2 of nonequivalence is reversed for th e acyl-methyl and 3-methyl singlets. This indicates that non-equivalence results from intrinsicly different magneticenvironments for coo rdina ted enantiomers. Differencesin stability constants for complexes of enantiomersmay also con tribut e to nonequivalence.

(9a) NOTEADDEDN PROOF. We have also investigated the europiumand praseodymium chelates derived from 3-heptaf luoropropylhydroxy-methylene-d -camphor. These chiral chelates have nmr shift propertiessimilar to the chelates derived from 3. Nonequivalences for enantio-mers are of about the same magnitude and resolution is similar forcorresponding chelates.(10) D. J. Cram and J. Allinger, J . A mer . Chem. SOC . 76, 4516(1954); D. J. Cram, A. Langemann, J. Allinger, and I

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5915of certain enantiomeric Lewis bases. 2 , 3 This observa-tion demonstrates that nmr spectroscopy using chirallanthanide chelates can in principle be employed toestablish absolute enantiomeric purity ; in practice,the utility of 1 is restricted to applications involvingrelatively basic and unhindered substrates e .g . , pri-mary and secondary amines), and fails with less basicsubstances. Here we wish to repo rt the synthesis ofthe chiral shift reagents 2-7 and to outline data dem-onstrating the general applicability of these materialsto the determination of the enantiomeric purity ofrelatively nonbasic substances.The 0-diketone ligands from which these complexesare derived were prepared either by procedures analo-gous to that described previously for l for 2 and 3 ,or by slow addition of the methyl ketone derived fromR to a refluxing solution of the acid chloride derivedf rom R in dimethoxyethane containing ca. 1 equivof suspended sodium hydride and a catalytic amountof tert-butyl alcohol (for 4-7).4 Conversions of these

H t>u/3RH3 \ /O-Eu/3l , R = R 12 , R = R ,3, R 71 R3 + 23 R, 4 R RP;R R25 R 2; R R,6 R=77 R3 + 23 R2; R R47 R R? ; R 77 R3 + 23 RLR 2 = H3c7 n r

0-diketones to the europium complexes 2-7 were ac-complished as described previously; 2 , 5 crude complexeswere purified by sublimation.Th e collectirje utility of compounds 2-7 in separatingthe resonances of enantiomeric amines, alcohols, ke-tones, esters, and sulfoxides appears t o be quite gene ral;one or another of these shift reagents has inducedshifts between enantiomers present in samples of themajority of these substances that we have examined.However, no single one of these reagents appears to beclearly superior to the others for every application.(2) G M. Whitesides and D. W. Lewis, J . Amer. Chem. SOC. 2, 6979(1970).(3) The utility of lanthanide chelates as shift reagents was firstdemonstra ted by C. C. Hinckley, ibid. 91 5160 1969).(4) Fenchoic acid was obtained from fenchone and campholic acidfrom camphor using s tandard procedures: cf. F . W. Semmler, Chem.Ber. , 39,2577 (1906); K . E. Hamlin and A. W. Weston, O r g . React . , 9 1(1957); F. E . L. Humbe r t , Bull. SOC. him. Fr. , 2867 (1966). The d-fenchone used in this study contained 23 of the enantiom er. Ca r -boxylic acids were converted to the correspondin g methyl ketones andacid chlorides by standard procedures, using methyllithium and thionylchloride, respectively.(5) I

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