SOLVENT EFFECTS ON THE BARRIER TO ISOMERIZATION FOR A TERTIARY AMIDE FROM ABINITIO AND MONTE-CARLO CALCULATIONS

The effects of solvation on the free energies of activation for rotation about the carbonyl C-N bond in N,N-dimethylacetamide (DMA) have been examined through a combination of gas-phase ab initio calculations and solution-phase statistical mechanics simulations. The geometries of the planar ground state and the transition states with the nitrogen lone-pair anti and syn to the oxygen were optimized with the 6-31G(d) basis set. Subsequent calculations of the vibrational frequencies and correlation energies (MP4(fc)SDTQ/6-31G(d)//6-31G(d)) predict DELTA-G double dagger,s of 14.6 and 18.7 kcal/mol for the anti and syn transition states at 298 K. NMR measurements have yielded a gas-phase DELTA-G double dagger of 15-16 kcal/mol. Solute-solvent potential functions were refined by fitting to results of 6-31G(d) calculations for the ground and transition states interacting with a water molecule in 17 low-energy orientations. These potentials were used in Monte Carlo simulations that yielded the changes in free energies in solvation in TIP4P water and the OPLS model of carbon tetrachloride. The observed ca. 2-kcal/mol increase in DELTA-G double dagger for water versus the aprotic solvent was reproduced; however, only a 0.4-kcal/mol barrier increase was computed for CCl4 relative to the gas phase, while the experimental shift is 1-2 kcal/mol. The discrepancy may come from amide aggregation and variations in the transmission coefficient, whereas an explanation involving activation volumes is rejected. It is also predicted that the syn transition state becomes competitive with the anti in water, and hydrogen bonding analyses clarify the origin of the differential hydration.