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 selec￾tive 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-naph￾thyl)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 deter￾mined 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, com￾plexes) often possess a low lifetime and a high conforma￾tional flexibility; effects generated in individual conforma￾tions may be obscured in the equilibrium. On the other hand, CSA are optimal for chiral resolu￾tion, 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 ð
Þ-S þ ðþÞ-CSA
½ð
Þ-S ! ðþÞ-CSA ðK
Þ ð3bÞ In most cases, the substrate S and the CSA form kineti￾cally weak adducts (charge transfer interaction, hydrogen￾bonding, 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, sub￾strate 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-tem￾perature side of the coalescence. Generally, addition of a CSA to a substrate in solution gives rise to changes of the NMR signals of all compo￾nents 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 fea￾tures of the adduct system and the interaction of the mo￾lecular components itself but also on the equilibrium con￾stants 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 con￾stants 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 rap￾idly exchanging adduct, which exists in two enantiomeric forms; generally this is the substrate. Each substrate enan￾tiomer ‘‘sees’’ always the same enantiomer of the CSA, i.e., a CSA-molecule exchange never alters that adduct diaster￾eomer. 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 ra￾tio of (1)-S and (2)-S. Therefore, such NMR signals do not split into two. Nevertheless, CSA signals contain chir￾ality 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=½ð
Þ-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 Ddð
Þ=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 sam￾ples are available, analogous optical rotation measure￾ments are easier to perform and more precise. As a conclu￾sion, 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