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

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.