Insights into thiol-aromatic interactions: a stereoelectronic basis for S-H/π interactions

Abstract

Thiols can engage favorably with aromatic rings in S−H/π interactions, within abiological systems and within proteins. However, the underlying bases for S−H/π interactions are not well understood. The crystal structure of Boc-L-4-thiolphenylalanine tert-butyl ester revealed crystal organization centered on the interaction of the thiol S−H with the aromatic ring of an adjacent molecule, with a throughspace Hthiol···Caromatic distance of 2.71 Å, below the 2.90 Å sum of the van der Waals radii of H and C. The nature of this interaction was further examined by DFT calculations, IR spectroscopy, solid-state NMR spectroscopy, and analysis of the Cambridge Structural Database. The S−H/π interaction was found to be driven significantly by favorable molecular orbital interactions, between an aromatic π donor orbital and the S−H σ* acceptor orbital (a π → σ* interaction). For comparison, a structural analysis of O−H/π interactions and of cation/π interactions of alkali metal cations with aromatic rings was conducted. Na+ and K+ exhibit a significant preference for the centroid of the aromatic ring and distances near the sum of the van der Waals and ionic radii, as expected for predominantly electrostatic interactions. Li+ deviates substantially from Na+ and K+ . The S−H/π interaction differs from classical cation/π interactions by the preferential alignment of the S−H σ* toward the ring carbons and an aromatic π orbital rather than toward the aromatic centroid. These results describe a potentially broadly applicable approach to understanding the interactions of weakly polar bonds with π systems.