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.

硫醇可以与芳香环在S-H/π相互作用中产生有利结合，这种结合既存在于非生物系统中，也存在于蛋白质内部。然而，S-H/π相互作用的内在基础尚未得到充分理解。Boc-l-4-硫基苯丙氨酸叔丁酯的晶体结构揭示了以硫醇S-H与相邻分子芳香环的相互作用为中心的晶体组织结构，其通过空间H硫醇···芳香环的距离为2.71 Å，低于H和C的范德华半径之和2.90 Å。通过DFT计算、红外光谱、固态核磁共振光谱和剑桥结构数据库的分析进一步探讨了这种相互作用的本质。研究发现，S-H/π相互作用主要是由有利于分子轨道的相互作用驱动的，即芳香π供体轨道与S-H σ*受体轨道之间的π → σ*相互作用。为进行比较，对O-H/π相互作用以及碱金属阳离子与芳香环之间的阳离子/π相互作用进行了结构分析。Na+和K+显示出对芳香环中心及其附近距离的显著偏好，这与以静电相互作用为主的情况相符。Li+与Na+和K+存在显著差异。S-H/π相互作用与经典的阳离子/π相互作用不同，其特点是S-H σ*倾向于与环碳和芳香π轨道而非芳香环中心对齐。这些结果描述了一种可能具有广泛适用性的方法，用于理解弱极性键与π系统的相互作用。