DUDDECK AND DIAZ GOMEZ HC-o H,C- COOH 片c-0、 COOH A8=8(adduct)-8(free component).in ppm (4) CF, s depend not only on the structural fea (S-27 1S1-28 The nts 说227 nd之 stantsK.an .They ca c ther vaes adduct side which.however,is not aways the case.I er the wil many cases,ho ssful regime can be reached,far enough noicties inside the is no danger induction'”if both con t.On th contrary. whe nd the two pethn er words,a larger dispe n can b in such cases cid MoNp met -2-(1-naph- idly exchanging adduct.which exists omer"sees aways the same enantiomer of the csA Le ation.The a CSA-r ule exch never al at adduct diaster ss a low lifetime and averag of both ()S and (S.which is only dependen on t K,and K on the r han not split into two ne CSA signals contain chir CSA e optimal for chiral resolu information about the a the substrate and the A89 complexation induced shifts which (+)S+(+)-CSA=I+)S一(+)-CSA(K)(3a) (=)-S+(+)CSA=[(-)S-(+)-CSA](K) (3b) 【(+)S/(-S=xyx,y=mole fractions)(⑤) In most cases.the substrate S and the CSA form kineti prethe averged poton beteed t side of the △8=△8+)+y-△8-]/2 (6) stants for the wo the NMR tim vely. nge rates provided that and As)are kr are obs the ee.of the (+)-S/(-)-S mixtu re.This,howev 11 R eomeric adduct.In terms of are generally on the fast-exchange or high-tem- esreaebil6elogoauopicoaionsmeasure substrate in solution by NMR i rmin of the substrate component only. Chirality DOI 10.1002/chir
of this compound can be produced, X-ray diffraction will easily lead to the correct AC of the original substrate. In many cases, however, such crystallization is not successful so that other well-established methods have to be applied. Among them is NMR spectroscopy which relies on selective anisotropy effects of aromatic moieties inside the S– CDA derivative provided a preferred conformation exists. There is a number of such CDA,22,24,62 for determining AC of alcohols and amines, some of the most prominent and effective ones are Mosher’s methoxytrifluorophenylacetic acid (MTPA; 27) 63–65 and Harada’s 2-methoxy-2-(1-naphthyl)propionic acid (MaNP; 28) 66,67 (Scheme 7). To the best of our knowledge, however, there is no report so far where the AC of an ether has been determined by using a CDA. Chiral salvation. The use of chiral solvating agents (CSA) for AC determination is not as straightforward as using CDA,24,29 because CSA-aggregates (adducts, complexes) often possess a low lifetime and a high conformational flexibility; effects generated in individual conformations may be obscured in the equilibrium. On the other hand, CSA are optimal for chiral resolution, i.e., the determination of the ratio of enantiomers in a mixture via forming diastereomeric adducts.21–23,29 ðþÞ-S þ ðþÞ-CSA ½ðþÞ-S ! ðþÞ-CSA ðKþÞ ð3aÞ ðÞ-S þ ðþÞ-CSA ½ðÞ-S ! ðþÞ-CSA ðKÞ ð3bÞ In most cases, the substrate S and the CSA form kinetically weak adducts (charge transfer interaction, hydrogenbonding, etc.) and exist in fast-exchange equilibria formed by the free components (left side of the equilibrium in eq. 3) and the adduct (right side of the equilibrium in eq. 3); the equilibrium constants for the two diastereomeric adducts are K1 and K2, respectively. Exchange rates are generally high on the NMR time-scale. Therefore, substrate NMR signals are observed as averages of those of the free S and the S component in the adduct. This holds for each diastereomeric adduct. In terms of dynamic NMR, the equilibria are on the fast-exchange or high-temperature side of the coalescence. Generally, addition of a CSA to a substrate in solution gives rise to changes of the NMR signals of all components in the adduct; the nuclei may be shielded or deshielded. This shift is called complexation induced shift Dd (see previous section), which is defined as follows: Dd ¼ dðadductÞ d0ðfree componentÞ; in ppm ð4Þ The Dd-values depend not only on the structural features of the adduct system and the interaction of the molecular components itself but also on the equilibrium constants K1 and K2. They can reach their maximal values, Ddmax, only if the equilibria are predominantly on the adduct side which, however, is not always the case. If needed at all, the Ddmax-parameter and thereby K, can be determined by low-temperature NMR under the condition that the low-exchange regime can be reached, far enough below the coalescence. Fortunately, the success of an enantiodifferentiation experiment is not very sensitive to the K1/K2 ratio. There is no danger of ‘‘thermodynamic induction’’ if both constants are significantly different. On the contrary, when they are different, both equilibria are different, as well, and the same holds of the two complexation induced shifts. In other words, a larger dispersion can be expected in such cases. In contrast to CDA-derivatives, resolution/dispersion effects Dm (or DDd) appear only in that component of a rapidly exchanging adduct, which exists in two enantiomeric forms; generally this is the substrate. Each substrate enantiomer ‘‘sees’’ always the same enantiomer of the CSA, i.e., a CSA-molecule exchange never alters that adduct diastereomer. On the other hand, every CSA-molecule ‘‘sees’’ an average of both (1)-S and (2)-S, which is only dependent on the equilibrium constants K1 and K2 and the molar ratio of (1)-S and (2)-S. Therefore, such NMR signals do not split into two. Nevertheless, CSA signals contain chirality information about the enantiopurity of the substrate, but in another way, the CDA signal (Dd) lies between Dd(1) and Dd(2) , the complexation induced shifts which would result from CSA experiments with enantiopure (1)- S and (2)-S, respectively. If the mixture of enantiomers is ½ðþÞ-S=½ðÞ-S ¼ x=y ðx;y ¼ mole fractionsÞ ð5Þ Dd represents the averaged position between Dd(1) and Dd(2) : Dd ¼ ½x DdðþÞ þ y DdðÞ=2 ð6Þ provided that K1 5 K2. Therefore, if Dd(1) and Dd(2) are known, Dd may reveal the e.e. of the (1)-S/(2)-S mixture. This, however, is not a practical experiment because the two pure enantiomers are generally not available. Anyway, if enantiopure samples are available, analogous optical rotation measurements are easier to perform and more precise. As a conclusion, straightforward determination of enantiomeric ratios by NMR is possible by integrating dispersed NMR signals of the substrate component only. Scheme 7. Structures of Mosher’s acid (MTPA; 27) and Harada’s 2- methoxy-2-(1-naphthyl)propionic acid (MaNP; 28). 56 DUDDECK AND DI´AZ GO´ MEZ Chirality DOI 10.1002/chir
CHIRAL RECOGNITION OF ETHERS BY NMR SPECTROSCOPY 一OH ◇e NH2 CH 0- (S)-29 (R-30 OCH, me-sca acts rather as aCDA than a classical CSA to the introduction of CDAs by Mosher's MR se 3.6 3.4 Ppm 3.634 2meoeEhs0ehaol FPE: e 5 06 naphthyl or anthryl gen bond formatior ring attr not suficient for an efe iral allene eme 11 een des ribed in a y of review uns hav been developed in the early 1970s and ruled out the CSA en designed to bi do not fu H,C AcO CH Pirkle's rful enanti .222t CH与 s capab C=C ycol ether Ph(Me SOCH O-CH CH(Ph DCH 34 H、 0 (R)-29 R CH X=HgCl or H aa9am1r阿m Chirality DOI 10.1002/chir
Occasionally, adducts of substrates and a CSA are kinetically stable. Then, the exchange is slow on the NMR time-scale and NMR spectra map the signals of all coexisting species (free components and adducts). In such cases, the CSA acts rather as a CDA than a classical CSA. Alcohols and amines as chiral solvating agents. Parallel to the introduction of CDAs by Mosher’s and other groups, Pirkle developed an alternative kind of NMR auxiliaries, chiral alcohols and amines as solvating agents; see for example, 2,2,2-trifluoro-1-phenylethanol (TFPE; 29) and 1-phenylethylamine (PEA; 30) in Scheme 8; other CSAs have naphthyl or anthryl groups instead of phenyl.25,26 Further chiral CSAs have been reported later.24 In all cases, the differentiation of enantiomers is not produced by conversion into diastereomers but by the creation of relatively weak solvation complexes, mostly via hydrogen bond formation and aromatic ring attraction. It is a crucial point in this method that a single hydrogen-bond alone is generally not sufficient for an effective chiral discrimination. Secondary binding by further hydrogen-bond formation or by charge-transfer between aromatic moieties in both partners (‘‘dibasic solute model’’ and ‘‘three-point interaction’’)24–26 are most desirable. An early example is shown in Scheme 9 with (R)-(1-(1-naphthyl)ethylamine (31) as CSA and both enantiomers of TFPE (29) as solute.68 Theory and application of the CSA method have been described in a variety of reviews,21–26 so a detailed discussion is not required here. Generally, Pirkle’s CSAs and those of other groups have been designed to bind hard Lewis acids and bases which are good donors, and ethers do not fulfill this condition (see earlier). So, only few reports of CSA experiments have documented that chiral ethers can be differentiated. So, Pirkle’s powerful enantiopure 1-(9-anthryl)-2,2,2-tri- fluoroethanol (32) is capable of differentiating the racemic glycol ether derivative, Ph(Me2Si)CH2-O-CH2CH(Ph)- OCH3 (33) (see Scheme 10)69 (Gassmann S, Bienz S, pers comm, 2007); note that a large surplus of CSA was required: 40 mg of 32 to react with 5 mg 33. As an exception, oxiranes (epoxides) have been studied intensively, probably because of their comparatively favorable donor ability (see earlier).21,70,71 Another interesting example is the application of Pirkle’s alcohol 29 to discriminate the enantiomers of the mercurated allyl ether 35 prepared from a chiral allene 34; allenes are unable to react with CSAs.72 This reaction and the dibasic solute model are depicted in Scheme 11. Chiral lanthanide shift reagents. The method of using lanthanide shifts reagents for chiral discrimination has been developed in the early 1970s and ruled out the CSA Scheme 8. Pirkle alcohol 29 and amine 30. Scheme 9. Solute-CSA adduct with secondary binding. Scheme 10. Pirkle’s alcohol 32 (top left), the glycol ether derivative 33 (top central) and a tentative three-point interaction model (top right); section of the 1 H NMR spectrum of 5 mg 33 in 0.6 ml CDCl3 (bottom left); after addition of 40 mg 32 (bottom right) (reproduced with permission from S. Bienz, Organometallics 2001;20:1849–1859). Scheme 11. Pirkle’s alcohol 29 and a mercurated allyl ether (35) prepared from a chiral allene (34); bottom: solvation model. CHIRAL RECOGNITION OF ETHERS BY NMR SPECTROSCOPY 57 Chirality DOI 10.1002/chir