In this study, the tautomeric equilibrium between the keto and enol forms has been studied for five typical ketones and aldehydes: i-butanal, acetaldehyde, acetone, acetylacetone, and dimedone. The level of theory used in the gas-phase calculation was Becke, three-parameter, Lee–Yang–Parr/6-311G(d,p)//Becke, three-parameter, Lee–Yang–Parr/6-31G(d). The free energies of solvation were included in the calculation by using the free-energy perturbation method based on Monte Carlo simulation, that is, the quantum mechanical/Monte Carlo/free-energy perturbation method. Three different models, incorporating no-water, one-water, and two-waters, were adopted. The results showed that in the gas phase the addition of water molecules to the reaction mechanism caused the activation barriers (ΔG‡gas) to decrease by half relative to the water-free mechanism, but there was no effect on the relative difference in free energy, ΔGgas. The solvation effects (ΔGsol), based on quantum mechanical/Monte Carlo/free-energy perturbation calculations, were added to those of the gas-phase results of the one-water and two-waters models. The two-waters model produced values that were very consistent with the experimental data for all of the tautomers. The differences in the relative Gibbs free energy (ΔGrxn) were less than 1.0 kcal mol–1. In summary, the inclusion of solvent molecules in gas-phase calculations plays a very important role in producing results consistent with experimental data. Copyright © 2012 John Wiley & Sons, Ltd.
Synthesis yields of organic reactions are one of the most important factors in ranking synthesis routes created by synthesis route design systems such as Transform-Oriented Synthesis Planning and Knowledge base-Oriented Synthesis Planning. If it is possible to predict the yields of synthesis reactions before starting experiments, one can easily determine an order of synthesis routes for experimental works. In the present study, the reaction profiles of the Curtius rearrangement with different substituents were calculated to generate an equation predicting experimental yields of this reaction. Reactions followed by the formation of isocyanates were also analyzed to consider the relationship between reaction times and experimental yields. A partial least squares (PLS) regression was used to correlate the experimental yields with the calculated activation energies, Ea(calc), together with experimental conditions such as dielectric constants of solvents, reaction times, and reaction temperatures as explanatory variables. Although the PLS regression using all the data gave very poor results, we succeeded in making a model equation with R2 = 0.887 using a modified data set. However, there is a conflict between the predictability and the interpretability on the reaction time. This discrepancy mainly comes from unnecessarily long reaction times in the experiments for azides with calculated Ea values of less than 33 kcal mol–1. To construct a good model equation for the experimental yields of the Curtius reaction, we have to use data sets obtained from within 90 min of the reaction for the PLS regression. Copyright © 2011 John Wiley & Sons, Ltd.
The hydrolysis of ethyl benzoate in acidic condition was theoretically studied for models with two (2W) or three water (3WA) molecules at the B3LYP/6-311++G(d,p) levels of theory. Activation free energy of solvation in aqueous solution (ΔG‡cal) was calculated using the QM/MC/FEP method. The value of the 2W model in aqueous solution was calculated to be smaller by more than 5.0 kcal mol−1 than the observed value (26.0 kcal mol−1 at 298 K). The position of the third water molecule in the 3WA model plays an essential role in producing the ΔG‡cal value (26.4 kcal mol−1) consistent with the experimental value.
