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

• Published in: Journal of the American Chemical Society 2017-02, Vol.139 (5), p.1842-1855
• Main Authors: Forbes, Christina R, Sinha, Sudipta K, Ganguly, Himal K, Bai, Shi, Yap, Glenn P. A, Patel, Sandeep, Zondlo, Neal J
• Format: Article
• Language: English
• Subjects: Crystallography, X-Ray; Hydrocarbons, Aromatic - chemistry; Models, Molecular; Molecular Structure; Quantum Theory; Stereoisomerism; Sulfhydryl Compounds - chemistry
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.6b08415

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.