Urea and thiourea are common cores of dual-hydrogen-bond donor organocatalysts, a family of cost and energy efficient alternatives to toxic transition metal catalysts. Although urea and thiourea are ubiquitous in the area of organocatalysis, there are still gaps in the fundamental understanding of these molecules. Specifically, the activation barriers from isotopically labelled NMR studies do not align with computationally derived energies, which tend to be lower than experiment. When analyzing (thio)ureas computationally, Moskal et al. has shown that a more rigorous computational treatment, including the complete basis set limit, zero-point energy, and anharmonic vibrations is required due to conjugation frustration within the bonding framework of the molecules. Leveraging this knowledge, our work examines the activation barriers of (thio)urea and the E to Z isomerization of alkyl and aryl-substituted (thio)ureas. We have found that two transition structures occur for the isomerization of alkyl and aryl-(thio)ureas, while there is only one transition structure for unsubstituted (thio)urea. In the gas phase without rigorous treatment, the activation enthalpies are lower than experimental values, suggesting that solvent-urea interactions impact the activation barriers of E to Z isomerization, indicating that a more sophisticated model is required. To better understand how the (thio)urea molecules interact with solvent and nearby (thio)urea molecules, we employed a discrete-continuum model. Our study underscores the need for explicit solvent in satisfying the hydrogen bond donor and acceptor sites of (thio)ureas to achieve alignment with experiment. Obtaining a greater understanding of the energetics and conformations of these substituted (thio)ureas will aid in the design of more efficient organocatalysts that can be used in a wider scope of reactions.

Solvent-assisted conformations and E to Z activation barriers of alkyl and aryl-(thio)urea

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