Through-Space Polar-π Interactions in 2,6-Diarylthiophenols.

Jie Jian,Paul Tinnemans,Jordi Poater,F Matthias Bickelhaupt,Jasmin Mecinović,Christine J Mckenzie,Roel Hammink

doi:10.1002/cphc.202000414

Abstract

The front cover artwork is provided by Marijn Maas from the group of Prof. Jasmin Mecinović (University of Southern Denmark). The image shows the stabilization of thiols by aromatic rings, as a result of energetically favorable SH-π interactions in a designed small molecule and in proteins. Read the full text of the Article at 10.1002/cphc.202000132.

Highlights

Thiols represent an important class of molecules that play essential roles in molecular and biological systems.[1,2] The nucleophilic sulfhydryl group (-SH) typically reacts with various electrophiles, enabling a preparation of well-defined biomolecules and biomaterials with novel structure and function.[3,4] Cysteine, the only thiol in the panel of 22 proteinogenic amino acids, has commonly been used for site-specific chemoselective modification of peptides and proteins.[5]
We observed a strong linear correlation with R2 = 0.95, and the ρ value of +0.42. These results indicate that the acidity constant for 2,6-diarylthiophenols is affected by the presence of substituents at distant para position of the flanking aromatic rings; electron-donating substituents (e.g. OMe) make thiols weaker acids, whereas electron-withdrawing substituents (e.g. CF3) make thiols stronger acids
Hammett analyses, based on measurements of acidity constants and calculations of proton affinity energies, demonstrated that electrondonating groups at the distant para position of the flanking rings in 2,6-diarylthiophenols lead to weaker acidic character, whereas the presence of electron-withdrawing groups at the same position results in stronger acids

Summary

Introduction

Thiols represent an important class of molecules that play essential roles in molecular and biological systems.[1,2] The nucleophilic sulfhydryl group (-SH) typically reacts with various electrophiles, enabling a preparation of well-defined biomolecules and biomaterials with novel structure and function.[3,4] Cysteine, the only thiol in the panel of 22 proteinogenic amino acids, has commonly been used for site-specific chemoselective modification of peptides and proteins.[5] the chemical reactivity of cysteine and other thiols has been extensively studied,[3,4,5] the involvement of thiols in molecular recognition has been less understood.[2,6] The polar SH group, for example, can act both as a hydrogen bond donor and acceptor in the presence of the amide backbone in proteins and small molecules.[7] Structural analyses of proteins demonstrated that cysteine can form three type of interactions with aromatic rings, namely SH−π interactions (i.e. interactions between H and the π face), HS−π interactions (i.e interactions between S and the π face), and HS–HC interactions (i.e. interactions between S and the HC face of the aromatic ring), with the second one being the most common.[2,8] Computational analyses, showed that energetically favorable SH−π interactions with the π system of aromatic rings appear to be preferred.[9] In comparison with other types of polar−π interactions (e.g. OH−π, NH−π, cation−π and π−π interactions), direct SH−π interactions appear to be less studied and established.[2]

Objectives

Results

Conclusion