Theoretical free energy profile and benchmarking of functionals for amino-thiourea organocatalyzed nitro-Michael addition reaction.

Amino-thiourea organocatalysis is an important catalytic process for enantioselective conjugate addition reactions. The interaction of the reactants with the catalyst has a substantial effect of dispersion forces and is a challenge for a reliable description when applying density functional theory. In this report, the classical addition of acetylacetone to β-nitro-styrene catalyzed by Takemoto's catalyst in toluene was studied using the PBE functional for geometry optimization and the DLPNO-CCSD(T) benchmark method for single point energy. The complete free energy profile calculated for the reaction was able to explain all experimental observations, including the fact that the carbon-carbon bond formation step is rate-determining. The overall barrier was calculated to be 22.8 kcal mol (experimental value approximately 20 kcal mol), and the enantiomeric excess was calculated to be 88% (experimental value in the range of 84 to 92%). Some functionals were tested for single point energy. The hybrid B3LYP presented a high mean absolute deviation (MAD) from the DLPNO-CCSD(T) benchmark method by approximately 20 kcal mol. The inclusion of empirical dispersion correction in the B3LYP method decreased the MAD to 6 kcal mol. Even the double-hybrid mPW2-PLYP and B2GP-PLYP methods had MAD values of approximately 5 kcal mol. The inclusion of the dispersion correction decreased the MAD to 3.6 kcal mol. M06-2X and ωB97X-D3 were the most accurate among the tested functionals, with MADs of 2.5 kcal mol and 1.8 kcal mol, respectively. Additivity approximation of the correlation energy was also tested and presented a MAD of only 0.6 kcal mol.