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Angewandte Chemie Hot Paper

New research selected as a hot paper and research highlight
Molecular balances

Hydrogen bonds are everywhere. They determine the structure and properties of water and materials. In life, hydrogen bonds govern the structure of proteins, DNA, RNA, and their associated molecular recognition processes. Clearly, biology has mastered the use of hydrogen bonds, yet such interactions occur in the presence of one of the most competitive hydrogen bonding solvents known; water. However, water is such a good hydrogen bond donor and acceptor that the energy of a single hydrogen bond is effectively nullified by the competing interactions with the solvent. Hence, the experimental measurement of hydrogen bonds in competitive polar solvents is challenging. To date, this has only been achieved by examining either exceptionally strong H-bonds, or by measuring changes in the total stability of a complex containing multiple weaker hydrogen bonds.

The Cockroft group, working in collaboration with Syngenta, have tackled this challenge by measuring H-bond energies through changes in the shape of compounds known as molecular balances (see Figure). The molecular balances were designed to form an internal H-bond when in a folded shape, but to break the H-bond when unfolded. The ratio of folded to unfolded molecules was then determined using NMR spectroscopy to measure the strength of the internal H-bonds and the associated solvent effects; crucially, even in competitive polar solvents. Finally, the researchers found that they were able to mathematically dissect away the energetic influence of the solvent by applying a simple solvent model developed by Prof. Christopher Hunter.

Computational modelling of solvent effects is notoriously difficult, which hinders its utility in understanding molecular recognition processes occurring in solution. We showed that by using molecular balances to measure H-bond energies and then ‘peeling away’ the solvent effects, we could instead compare gas-phase calculated energies with those determined experimentally in solution. In doing so, the challenge of computing solvent effects is side-stepped, and the leverage of easily computed gas-phase energies for rationalising molecular recognition is greatly bolstered.

Professor Scott Cockroft

The work was selected as a ‘hot paper’ in Angewandte Chemie, and featured in a research highlight in Nature Reviews Chemistry, ‘Weighing up solvent effects’ .

Thursday, June 16, 2022