It has been widely reported that enzymes make use of hydrogen bonds present in their active sites to speed up reactions by stabilizing the transition state. A better understanding of transition state stabilization could help in designing better and more efficient catalysts. This study gives an insight into the catalytic mechanism of enzymatic systems, thus, providing the groundwork for future innovations in the development of novel hydrogen bonding catalysts. Other applications of molecular rotors include supramolecular assembly, drug-protein interaction, electronics, sensing, and nanotechnology. However, quantifying the effect of hydrogen bonding in the transition state is quite challenging owing to the instability and fleeting nature of transition state structures. To circumvent this problem, a unimolecular rotor, which can interconvert from a syn-conformer to an anti-conformer via a simple bond rotation was synthesized. Carbonyl and RN-H groups are incorporated into the molecular rotor (Scheme 1). In the transition state, the RN-H group is coplanar with the carbonyl group and this geometry places the hydrogen bonding proton in between the imide carbonyl oxygen and the amine nitrogen, thus forming a stabilizing intramolecular hydrogen bond. Consequently, the transition state is lowered, which causes a rapid rotation about the Caryl-Nimide single bond. A control rotor that cannot form a hydrogen bond in the transition state was also synthesized, and rotational barriers of the control rotor and the hydrogen bonding rotor were measured experimentally using dynamic exchange 1H-NMR methods. The difference in energy barriers of both rotors gives the stabilizing effect of a hydrogen bonding proton in the transition state. We observed a significant stabilizing effect of 6.4 kcal/mol by the hydrogen bonding proton in the transition state, which is significantly larger than a previously reported thermodynamically measured hydrogen bond strength (1.5 kcal/mol) in a similar system. In conclusion, a hydrogen bonding rotor, which forms a hydrogen bond in the transition state was successfully designed and used to measure the stabilizing effect of a hydrogen bonding proton in the transition state.

Transition state stabilization of a single hydrogen bond

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