London Dispersion Favors Sterically Hindered Diarylthiourea Conformers in Solution

We present an experimental and computational study on the conformers of N,N′‐diphenylthiourea substituted with different dispersion energy donor (DED) groups. While the unfolded anti–anti conformer is the most relevant for thiourea catalysis, intramolecular noncovalent interactions counterintuitively favor the folded syn–syn conformer, as evident from a combination of low‐temperature nuclear magnetic resonance measurements and computations. In order to quantify the noncovalent interactions, we utilized local energy decomposition analysis and symmetry‐adapted perturbation theory at the DLPNO‐CCSD(T)/def2‐TZVPP and sSAPT0/6‐311G(d,p) levels of theory. Additionally, we applied a double‐mutant cycle to experimentally study the effects of bulky substituents on the equilibria. We determined London dispersion as the key interaction that shifts the equilibria towards the syn–syn conformers. This preference is likely a factor why such thiourea derivatives can be poor catalysts. Steric crowding counterintuitively favors the folded and apparently more sterically hindered syn–syn conformer of N,N′‐diphenylthiourea derivatives. Combined experimental and computational analyses identified London dispersion interactions to be the decisive factor favoring the conformer equipped with bulky dispersion energy donor groups.