Chiral Discrimination in Crystalline Tri-o-thymotide Clathrate Inclusion Complexes. Chemical and Crystallographic Studies

Crystallization of tri-o-thymotide (TOT) from solutions of appropriate racemic guest species affords chiral single crystals of clathrate inclusion complexes in which the guest enantiomers are incorporated to different degrees. Channel-type complexes (space group P6₁) or cage-type complexes (P3₁21) are obtained. The extracted guest from single crystals of the former has uniformly low, but significant, enantiomeric excess, while this excess (ee) in the latter varies widely. The highest enantiomeric purities were observed for 2,3-dimethyl-trans-oxirane (47%), 2,4-dimethy-trans-oxetane (38%), and 2-bromobutane (37%). Larger scale resolutions of chiral guests are possible by crystallization following seeding solutions of racemic guest and TOT with powdered single crystals of clathrate. Guests with appreciably enhanced optical purity can be obtained by repeated TOT enclathration using a partially enriched guest (an unexpectedly high chiral amplification was observed in a channel complex). The TOT optical rotation, + or -, and dominant guest chirality, R or S, were determined for each clathrate, and correlations between guest chirality and TOT absolute configuration were found, e.g., all (S)-2-haloalkanes crystallize preferentially with /<-(+)-TOT. TOT clathrates may thus be used for guest configurational assignments. Crystal structure analyses of M-(-)-TOT·(R)-2-bromobutane, M-(-)-TOT·(R,R)-2,3-dimethyl-trans-oxirane, the P-(+)-TOT·(S,5)-2,3-dimethyl-trans-thiirane clathrates, and the p-(+)-TOT·2,3-dimethyl-trans-thiirane clathrate containing a 1:2 ratio of the R,R and S,S enantiomers provided cage dimensions and geometry (an ellipsoidal, 2-fold symmetric cavity). Evidence that chiral discrimination is accounted for by the intermolecular interactions in the crystal has been obtained, and therefore the crystal structures also define the discriminating interactions between TOT host molecules and the more favored and less favored guest enantiomers. It is not possible to predict the preferred guest enantiomer solely by considering the van der Waals contacts between guest enantiomers and closest host atoms, but the crystal structure analyses help clarify some of the factors that govern chiral discrimination in TOT clathrates.