Chiral Solvating Agents for Cyanohydrins and Carboxylic Acids†

Abstract

We have shown that a structure as simple as an ion pair of (R)- or (S)-mandelate and dimethylamminopyridinium ions possesses structural features that are sufficient for NMR enantiodiscrimination of cyanohydrins. Moreover, 1H NMR data of cyanohydrins of known configuration obtained in the presence of the mandelate−dimethylaminopyridinium ion pair point to the existence of a correlation between chemical shifts and absolute configuration of cyanohydrins. Mandelate−DMAPH+ ion pair and mandelonitrile form a 1:1 complex with an association constant of 338 M−1 (ΔG0, −3.4 kcal/mol) for the (R)-mandelonitrile/(R)-mandelate−DMAPH+ and 139 M−1 (ΔG0, −2.9 kcal/mol) for the (R)-mandelonitrile/(S)-mandelate−DMAPH+ complex. To understand the origin of enantiodiscrimination, the geometry optimization and energy minimization of the models of ternary complexes of (S)-mandelonitrile/(R)-mandelate/DMAPH+ and (S)-mandelonitrile/(S)-mandelate/DMAPH+ complexes was performed using DFT methodology (B3LYP) with the 6-31+G(d) basis set in Gaussian 3.0. Further, analysis of optimized molecular model obtained from theoretical studies suggested that (i) DMAP may be replaced with other amines, (ii) the hydroxyl group of mandelic acid is not necessary for stabilization of ternary complex and may be replaced with other groups such as methyl, (iii) the ion pair should form a stable ternary complex with any hydrogen-bond donor, provided its OH bond is sufficiently polarized, and (iv) α-H of racemic mandelic acid should also get resolved with optically pure mandelonitrile. These inferences were experimentally verified, which not only validated the proposed model but also led to development of a new chiral solvating agent for determination of ee of carboxylic acids and absolute configuration of aryl but not alkyl carboxylic acids.