The Origin of Chalcogen-Bonding Interactions

Favorable molecular
interactions between group 16 elements have
been implicated in catalysis, biological processes, and materials
and medicinal chemistry. Such interactions have since become known
as chalcogen bonds by analogy to hydrogen and halogen bonds. Although
the prevalence and applications of chalcogen-bonding interactions
continues to develop, debate still surrounds the energetic significance
and physicochemical origins of this class of σ-hole interaction.
Here, synthetic molecular balances were used to perform a quantitative
experimental investigation of chalcogen-bonding interactions. Over
160 experimental conformational free energies were measured in 13
different solvents to examine the energetics of O···S,
O···Se, S···S, O···HC,
and S···HC contacts and the associated substituent
and solvent effects. The strongest chalcogen-bonding interactions
were found to be at least as strong as conventional H-bonds, but unlike
H-bonds, surprisingly independent of the solvent. The independence
of the conformational free energies on solvent polarity, polarizability,
and H-bonding characteristics showed that electrostatic, solvophobic,
and van der Waals dispersion forces did not account for the observed
experimental trends. Instead, a quantitative relationship between
the experimental conformational free energies and computed molecular
orbital energies was consistent with the chalcogen-bonding interactions
being dominated by n → σ* orbital delocalization between
a lone pair (n) of a (thio)­amide donor and the antibonding σ*
orbital of an acceptor thiophene or selenophene. Interestingly, stabilization
was manifested through the same acceptor molecular orbital irrespective
of whether a direct chalcogen···chalcogen or chalcogen···H–C
contact was made. Our results underline the importance of often-overlooked
orbital delocalization effects in conformational control and molecular
recognition phenomena.