Enantiotopic discrimination in the NMR spectrum of prochiral solutes in chiral liquid crystals.

The splitting of signals in the NMR spectra originating from enantiotopic sites in prochiral molecules when dissolved in chiral solvents is referred to as spectral enantiotopic discrimination. This phenomenon is particularly noticeable in chiral liquid crystals (CLCs) due to the combined effect of the anisotropic magnetic interactions and the ordering of the solute in the mesophase. The enantiorecognition mechanisms are different for rigid and flexible solutes. For the former, discrimination results from symmetry breaking and is restricted to solutes whose point groups belong to one of the following four ("allowed") symmetries, Cs, C2v, D2d and S4. The nature of the symmetry breaking for each one of these groups is discussed and experimental examples, using mainly (2)H 1D/2D-NMR in chiral polypeptide lyotropic mesophases, are presented and analyzed. When flexible optically active solutes undergo fast racemization (on the NMR timescale) their spectrum corresponds to that of an average prochiral molecule and may exhibit enantiotopic sites. In CLCs, such sites will become discriminated, irrespective of their average (improper) symmetry. This enantiodiscrimination results mainly from the different ordering of the interchanging enantiomers. Several examples of such flexible molecules, including solutes with average axial and planar symmetries, are commented. Dynamic processes in solution that are not accompanied by the modulation of magnetic interactions remain "NMR blind". This is sometimes the case for interconversion of enantiomers (racemization) or exchange of enantiotopic sites in isotropic solvents. The limitation can be lifted by using CLCs. In such solvents, non-equivalence between enantiomers or between enantiotopic sites is induced by the chiral environment, thus providing the necessary interactions to be modulated by the dynamic processes. Illustrative examples involving exchange of both, enantiotopic sites and enantiomers are examined. In this comprehensive review, various important aspects of enantiodiscrimination by NMR are presented. Thus the possibility to reveal enantiotopic recognition using residual dipolar couplings or to determine the absolute configuration of enantiotopic NMR signals is discussed. The various kinds of chiral mesophases able to reveal enantiotopic discrimination in guest prochiral molecules are also described and compared with each other. Finally to illustrate the high analytical potentialities of NMR in CLCs, several and various applications involving the enantiodiscrimination phenomenon are described. A strategy for assigning the NMR signals of meso compound in a meso-threo mixture of cyclic molecules is first discussed. This is followed by a description of advantages of the method for the determination of (D/H) natural isotopic fractionation in biocompounds.

NMR discrimination in nonrigid prochiral solutes dissolved in chiral liquid crystals: symmetry considerations.

Enantiodiscrimination in the NMR spectra of flexible prochiral solutes dissolved in chiral liquid crystals (CLCs) is reviewed and compared with the analog phenomenon in such rigid solutes. In rigid prochiral solutes, the discrimination is brought about by the cancellation of improper symmetry elements upon dissolving in CLC within the frame of solute-solvent ordering mechanisms. If this reduction in symmetry renders the ordering of enantiotopic sites dissimilar, spectral discrimination may be observed. Symmetry considerations indicate that this is only possible for improper nonaxial groups lacking inversion symmetry. Nonrigid prochiral solutes consist of rapidly (on the NMR timescale) interconverting enantiomers, in which the racemization is accompanied by exchange of nonequivalent sites. These sites become, on the average, enantiotopically related, and in CLC, they exhibit spectral discrimination. The mechanism of the effect and the symmetry selection rules are different for the two cases. Specifically, the discrimination in flexible prochiral compounds results from the different ordering of the interchanging enantiomers in CLC. Using Altman's definition of average symmetry (Proc. R. Soc. A, 1967, 298, 184), selection rules for the phenomenon are derived. It follows that chiral discrimination in nonrigid prochiral solutes is much more abundant and can occur in all symmetry types except those possessing inversion. In particular, contrary to earlier thoughts, the effect can occur in compounds with axial symmetry. Illustrative examples of such studies with particular emphasis on compounds with average axial symmetry of the type D(3h), C(3v) and C(3h) are reviewed in this contribution.

Conformation and dynamics of 18-membered hexathiametacyclophanes: a two step racemization as studied by deuterium NMR in chiral lyotropic liquid crystals.

The conformation and interconversion dynamics of two derivatives of the 18-membered hexathia metacyclophane 1 and 2 were studied by (1)H NMR spectroscopy in isotropic solvents and by (2)H NMR in chiral liquid crystalline (CLC) solutions, as well as by molecular structure computations. For the analysis of the dynamic effects, we made use of the concepts of "average symmetry" and "isodynamic groups", introduced by Altmann (Altmann, Proc. R. Soc.1967, 184, A298). Compound 1, which is unsubstituted in the inner aromatic site, has, according to the NMR and molecular force field calculations, a boat shaped ground conformation with C(2) symmetry. It is highly flexible and in the NMR spectrum exhibits two successive dynamic processes. There is a low temperature (170-210 K, E(a) = 10.5 kcal/mol) alternate "wing flipping", which corresponds to interchange between pairs of enantiomers and results, in the fast exchange limit, in an average prochiral molecule with C(2v) symmetry. This process is followed, at higher temperatures (290-320 K, E(a) = 28.5 kcal/mol), by an umbrella flipping type inversion with an average structure of D(2h) symmetry. This second process involves averaging of effective enantiotopic into homotopic sites and can only be studied in chiral solvents. The origin of the chiral discrimination and of their stepwise averaging is discussed. Compound 2, which is substituted with methoxy groups at the inner sites of the benzene rings, is much less flexible and exhibits dynamic effects in the NMR spectrum only at temperatures above 370 K. We were able to study the kinetic parameters of this process in isotropic solvents (E(a) = 21.4 kcal/mol). As for 1, the detailed mechanism of this process can in principle be established using dynamic NMR in CLC; however, experimental limitation precluded us from doing so. Possible alternatives and their effect on the 1D and 2D exchange spectra in CLC are discussed in a concluding section.

Enantiotopic discrimination in the deuterium NMR spectrum of solutes with S4 symmetry in chiral liquid crystals.

Enantiotopic discrimination in the NMR spectra of prochiral rigid solutes in chiral liquid crystals (CLC), by the ordering mechanism, is limited to molecules possessing one of the four, so called, "allowed" symmetries, D(2d), C(2v), C(s), and S(4). So far, such spectral discrimination was demonstrated only for solutes possessing one of the first three symmetries. In this work, we present deuterium NMR measurements on a rigid S(4) compound dissolved in a chiral nematic solvent and demonstrate, for the first time, enantiotopic discrimination in such symmetry. The measurements were performed on the isotopically normal icosane derivative (1) and on its isotopomer (1-d(8)), specifically deuterated in its four core methylene groups. As a CLC solvent, a lyotropic mesophase, consisting of a solution of poly-γ-benzyl-L-glutamate (PBLG) in pyridine, was employed. For comparison with a corresponding achiral liquid crystal (ALC) solvent, a solution of a racemic mixture of poly-γ-benzylglutamate (PBG) of similar composition in the same co-solvent was used. The spectra were recorded at 92.1 MHz using the 2D Q-COSY Fz sequence with proton decoupling. In the CLC solvents they exhibited clear discrimination due to different enantiotopic sites, with components displaced symmetrically, at frequencies below and above those in the corresponding ALC, as expected for discrimination by ordering. Two procedures were employed for correlating the enantiotopic sites in the CLC spectra. For 1-d(8) the dipolar cross-peaks in a 2D (2)H-(2)H COSY-90 experiment provided identification of signals belonging to the same methylene (and hence the same enantiotopic) groups. For 1 the correlation was achieved using a least-square-deviation fitting of the experimental quadrupole splittings with respect to those expected from the molecular geometry. These results, with appropriate symmetry considerations were used to determine the symmetric (S(zz)) and antisymmetric (S(xy) and S(xx)-S(yy)) components of the Saupe ordering matrix. Interpretation of the NMR spectra of prochiral solutes in CLC suffers from the ambiguity in identifying the signals with specific enantiotopic groups. For this reason only the relative (but not the absolute) signs of the antisymmetric elements of the ordering matrix can be determined. For the S(4) group this leads to sign ambiguity in the rhombic term in the diagonalized ordering matrix. Similar (but not identical) ambiguities occur for solutes belonging to the other allowed groups. In a concluding section of the paper, the ambiguities in the antisymmetric order parameters for the various allowed groups are compared and their physical meaning are discussed.

Mesomorphic properties of the neat enantiomers of a chiral pyramidic liquid crystal.

The crown form of nona-octanoyloxy tribenzocyclononatriene (C8) with C(3) symmetry was prepared and separated into its enantiomers (C8A and C8B) by HPLC. Like the racemate, the neat enantiomers are also mesogenic, exhibiting two mesophases, M and Col(h). Differential scanning calorimetry, X-ray diffraction, carbon-13 NMR and UV circular dichroism are used to study the structural and dynamic properties of these chiral mesophases. The high-temperature mesophase (Col(h)) was identified by X-ray diffraction as columnar hexagonal; this phase is thermally unstable, undergoing racemization on heating before its clearing point is reached. The low-temperature mesophase (M) is most likely also columnar, but its symmetry could not be determined. In comparison with the racemate, the chiral mesophases are less well ordered, more tightly packed and they have a lower tendency to crystallize. On the other hand they are considerably more mobile, as reflected in their NMR spectra. No helical structure has been identified in the X-ray diffraction of the mesophases.

Enantiodiscrimination in deuterium NMR spectra of flexible chiral molecules with average axial symmetry dissolved in chiral liquid crystals: the case of tridioxyethylenetriphenylene.

Flexible chiral molecules undergoing fast interconversion (on the NMR time scale) between different conformational enantiomers may yield "average" axial species with enantiotopically related sites. Contrary to the situation observed for rigid axial molecules, signals from these enantiotopic sites in NMR spectra recorded in chiral liquid-crystalline solvents can be resolved. In the present work, we studied the deuterium NMR spectra of tridioxyethylenetriphenylene (compound 4) statistically deuterated to 10% in the flexible side chains and dissolved in chiral and achiral lyotropic liquid crystals based on poly(gamma-benzylglutamate). The fast chair-chair flipping of the side chains in 4 on average renders the molecule axially symmetric ( D 3 h ) with pairs of enantiotopic ethylene deuterons. These deuterons exhibit unusually large enantiodiscrimination. To explain this observation, we first describe how the average symmetry of flexible molecules can be derived from the symmetry of the "frozen" conformers and the nature of the averaging process. The procedure is then applied to 4 and used to analyze the NMR results. It is shown that the large enantiodiscrimination in the present case reflects a large difference in the orientational ordering of the conformational enantiomers participating in the interconversion processes as well as a large geometrical factor due to the special shape of the dioxyethylene side groups. (1)H and (13)C NMR spectra of 4 in the same lyotropic liquid crystalline solvent are analyzed to determine its ordering characteristics. Several related cases are also discussed.

Isotopic difference spectra as an aide in determining absolute configuration using vibrational optical activity: vibrational circular dichroism of 13C- and 2H-labelled nonamethoxy cyclotriveratrylene.

The use of isotopic difference spectra in vibrational optical activity is demonstrated as a supplemental aide in determining the absolute configuration of chiral molecules. It is shown that IR and VCD difference spectra associated with isotopic substitution observed in experimental spectra can be accurately reproduced by density functional theory calculations when the IR and VCD spectra of the original isotopomer are calculated to reasonable accuracy. Results for isotopically substituted nonamethoxy cyclotriveratrylene are presented to illustrate the degree of agreement between measured and calculated IR and VCD difference spectra for several isotopomers of this molecule. These findings highlight the utility of isotoptic substitution as an aide to verifying the determination of absolute configuration using vibrational optical activity.

Structural and optical isomers of nonamethoxy cyclotriveratrylene: separation and physical characterization.

The paper concerns the structural and optical isomers of nonamethoxy-tribenzocyclononene (compound 1). In the first part of the paper it is shown that 1 exists in two structural isomers: a rigid crown (c-1) with C3 symmetry and a flexible saddle (s-1) with C1 symmetry. The latter, not previously known, can be prepared from the as-synthesized c-1 by quenching a hot solution (or the melt) followed by HPLC separation. The crown/saddle equilibrium, isomerization kinetics, and associated thermodynamic parameters in various organic solvents are reported. Carbon-13 MAS NMR, X-ray diffraction, and differential scanning calorimetry (DSC) of polycrystalline c-1 and s-1 racemates are also reported. The different melting points of the isomers and their rapid isomerization in the melt result in unconventional DSC thermograms involving multiple endothermic and exothermic transitions. The second part of the paper concerns the chiral properties of 1. Both the saddle and crown isomers are structurally chiral, but due to the fast pseudorotation of s-1 in solution, it cannot be separated into its enantiomers. Those of c-1 were separated by HPLC using a chiral column. Their X-ray structure and melting points differ considerably from those of the racemate. This and their fast racemization in the melt lead to complex DSC thermograms with multiple transitions. Solutions of the neat enantiomers exhibit a relatively small specific optical rotation. In the UV they show circular dichroism for the B1u and B2u transitions, with the latter exhibiting a clear couplet structure. Infrared and vibrational circular dichroism spectra of the enantiomers in solution are reported. Comparison of these spectra with quantum mechanical simulations provides unambiguous identification of the enantiomers.

Chiral discrimination in the 13C and 2H NMR of the crown and saddle isomers of nonamethoxy-cyclotriveratrylene in chiral liquid-crystalline solutions.

We report 2H and 13C NMR spectra of the crown and saddle isomers of nonamethoxy-tribenzocyclononene (1), dissolved in lyotropic achiral and chiral liquid-crystalline solutions based on poly-gamma-benzyl-glutamate and poly-gamma-benzyl-L-glutamate (PBG and PBLG). The 2H-[1H] measurements include spectra of compound 1 deuterated in the ring methylene and in the aromatic sites as well as of the methyl groups in natural abundance. Carbon-13 spectra were recorded in natural abundance as well as in two isotopomers enriched in the ring methylene and one of the methoxy groups. The crown isomer (c-1) is rigid with C3 symmetry and can be separated into its enantiomers using a chiral high-performance liquid chromatography column. The NMR spectra of racemic c-1 in PBLG solutions exhibit two sets of lines due to the enantiomers. The peaks were identified by comparing the spectra with those of the neat enantiomers. Analysis of the 2H quadrupolar splittings and the 13C residual chemical shift anisotropies shows that the dominant factor determining the chiral discrimination is the difference in the ordering of the two enantiomers in the chiral liquid crystals. The saddle isomer (s-1) is highly flexible, undergoing fast pseudorotation between six conformers. The "frozen" conformers have C1 symmetry and are therefore chiral. Three of these comprise one enantiomer, and the other three the second one. However, the rapidly interconverting species has, on the average, a C3h symmetry and is therefore achiral. The methylene groups in the latter are, however, prostereogenic, and their hydrogen/deuterium-carbon bonds constitute enantiotopic pairs. The 2H NMR spectra of the s-1 methylene-deuterated in PBLG solutions exhibit, in fact, enantio-discrimination with two quadrupolar doublets. This is in contrast to rigid prochiral molecules with a threefold symmetry axis, which normally do not show such discrimination. A detailed analysis of the effect is presented, and it is argued that the discrimination observed for s-1 reflects the different ordering of its enantiomers during the pseudorotation cycle.

Mesomorphism, isomerization, and dynamics in a new series of pyramidic liquid crystals.

Nona-alkanoyloxy tribenzocyclononene (CTV-n, where n is the number of carbons in the side chains) were prepared for n = 2 to 14. The homologues of this series appear in two stable isomeric forms, rigid crown and flexible saddle. We report on their isomerization equilibria and dynamics in solution and on their mesomorphic properties in the neat state. The crown-saddle equilibrium and interconversion kinetics of the CTV-8 isomers were studied in dimethyl formamide solutions using high-resolution (1)H NMR in the temperature range from 50 to 130 degrees C. At lower temperatures, the isomerization is too slow to measure. In this range the equilibrium saddle fraction increases from approximately 0.40 to approximately 0.65, whereas the isomerization rate increases from approximately 10(-)(4) to approximately 1 s(-)(1). The saddle isomer undergoes fast pseudorotation at room temperature, but below about -50 degrees C, it becomes slow enough to affect the NMR line width. The rate parameters for this process were estimated from the carbon-13 spectra in methylene chloride solutions to be, k(p)(-100 degrees C) approximately 1.7 x 10(3) s(-)(1) and E(a) approximately 9.6 kJ/mol. The slow crown-saddle isomerization at room temperature (half-life of about one year) allows quantitative separation (by chromatography) of the two isomers and their separate investigation. When the alkanoyloxy side chains are sufficiently long both isomers are mesogenic (n >or= 4 for the saddle and n >or= 5 for the crown), exhibiting hexagonal columnar mesophases. The structure, dynamics, and mesomorphic properties of these mesophase were investigated by X-ray diffraction, optical polarizing microscopy, differential scanning calorimetry, and NMR. The lattice parameters of the crown and saddle mesophases of corresponding homologues are almost identical and increase monotonically with increasing length of the side chains. The clearing temperatures of the saddle isomers are consistently lower than those of the corresponding crowns. Within each series, the clearing temperatures are almost independent of the length of the side chains (156 to 170 degrees C for the crown and 115 to 148 degrees C for the saddle). The thermal and kinetic properties of the neat compounds lead to peculiar phase sequences, as observed in the polarizing microscope and in the DSC thermogram, involving repeated, back and forth, interconversion between the two isomers. Carbon-13 MAS NMR measurements of the crown and saddle mesophases of several homologues were carried out. The spectra of the crown mesophase exhibit dynamic features consistent with planar 3-fold molecular jumps about the column axes. A quantitative analysis for the CTV-8 crown homologue yielded the following Arrhenius parameters, A = 3.1 x 10(22)s(-)(1) and E(a) = 130.1kJ/mol. These unusually high values suggest that the barrier to the jump process is temperature dependent, decreasing with increasing temperature. The rate of this 3-fold jump process is slower for the lower homologues and faster for the higher ones. In contrast, the saddle isomers in the mesophase do not show dynamic effects in their carbon-13 MAS spectra. They do not undergo pseudorotation, and it appears that the molecules remain locked within the columns in a saddle conformation, up to the clearing temperature. However, on (super-)cooling to room temperature and below, selective line broadening is observed in their carbon-13 MAS spectra. This suggests that the saddle conformation is twisted in the mesophase and undergoes fast high-amplitude jumps between the twisted forms. On cooling, these high-amplitude librations freeze out to give an orientationally disordered state. On a very long time scale (of the order of days at 100 degrees C), the saddle mesophase transforms into that of the crown, apparently by sublimation.

Enantiomeric and enantiotopic analysis of cone-shaped compounds with C(3) and C(3)(v) symmetry using NMR spectroscopy in chiral anisotropic solvents.

We describe the enantiomeric and enantiotopic analysis of the NMR spectra of compounds derived from the functionalized cone-shaped core, cyclotriveratrylenes (CTV), dissolved in weakly oriented lyotropic chiral liquid crystals (CLCs) based on organic solutions of poly-gamma-benzyl-L-glutamate. The CTV core lacks prostereogenic as well as stereogenic tetrahedral centers. However, depending on the pattern of substitution, chiral and achiral compounds with different symmetries can be obtained. Thus, symmetrically nonasubstituted CTVs (C(3) symmetry) are optically active and exhibit enantiomeric isomers, while symmetrically hexasubstituted (C(3v) symmetry) derivatives are prochiral and possess enantiotopic elements. In the first part we use (2)H and (13)C NMR to study two nonasubstituted (-OH or -OCH(3)) CTVs, where the ring methylenes are fully deuterated, and show for the first time that the observation of enantiomeric discrimination of chiral molecules with a 3-fold symmetry axis is possible in a CLC. It is argued that this discrimination reflects different orientational ordering of the M and P isomers, rather than specific chiral short-range solvent-solute interactions that may affect differently the magnetic parameters of the enantiomers or even their geometry. In the second part we present similar measurements on hexasubstituted CTV with flexible side groups (-OC(O)CH(3) and the, partially deuterated bidentate, -OCH(2)CH(2)O-), having on the average C(3v) symmetry. No spectral discrimination of enantiotopic sites was detected for the -OC(O)CH(3) derivative. This is consistent with a recent theoretical work (J. Chem. Phys. 1999, 111, 6890) that indicates that in C(3v) molecules no chiral discrimination between enantiotopic elements, based on ordering, is possible. In contrast, a clear splitting was observed in the (2)H spectra of the enantiotopic deuterons of the side groups in the tri(dioxyethylene)-CTV. It is argued that this discrimination reflects different ordering characteristics of the various, rapidly (on the NMR time scale) interconverting conformers of this compound. Assuming two twisted structures for each of the dioxyethylene side groups, four different conformers are expected, comprising two sets of enantiomeric pairs with, respectively, C(3) and C(1) symmetries. Differential ordering and/or fractional population imbalance of these enantiomeric pairs leads to the observed spectral discrimination of sites in the side chains that on average form enantiotopic pairs.