American Chemical Society
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Insights into Thiol–Aromatic Interactions: A Stereoelectronic Basis for S–H/π Interactions

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posted on 2017-01-12, 00:00 authored by Christina R. Forbes, Sudipta K. Sinha, Himal K. Ganguly, Shi Bai, Glenn P. A. Yap, Sandeep Patel, Neal J. Zondlo
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 through-space 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.