COMBINED MOLECULAR MECHANICAL AND QUANTUM-MECHANICAL POTENTIAL STUDY OF A NUCLEOPHILIC-ADDITION REACTION IN SOLUTION

The procedure of combined semiempirical quantum mechanical (AM1) and m olecular mechanical potential(7) was used to study the nucleophilic ad dition of hydroxide to formaldehyde in solution. The gas phase AM1 pot ential surface is approximately 26 kcal/mol more exothermic than the c orresponding ab initio 6-31 + G calculation results. The free energy profile for the reaction in solution was determined by means of molecu lar dynamic simulations. The resulting free energy of activation is ap proximately 5 kcal/mol. The difference of the free energy of solvation between the reactant and the product states is about 38 kcal/mol. As the reaction goes on, the number of hydrogen bonds formed by the hydro xide oxygen with the surrounding water molecules decreases, whereas th e number of hydrogen bonds formed by the carbonyl oxygen increases. Th ere is no significant change in the total number of hydrogen bonds bet ween the solute and the solvent molecules, and the average number of t hese hydrogen bonds is between five and six during the entire reaction process. These results are consistent with previous studies using a m odel based on ad initio 6-31 + G calculations in the gas phase. The r eaction path in solution is different from the gas phase minimum energ y reaction path. When the two reactants are at a large distance, the a ttack route of the hydroxide anion in solution is close to perpendicul ar to the formaldehyde plane, whereas in the gas phase the route is co llinear with the carbonyl group. These results suggests that although AM1 does not yield accurate energies in the gas phase, valuable insigh ts into the solvent effects can be obtained through computer simulatio ns with this combined potential. This combined procedure could be appl ied to chemical reactions within macromolecules, in which a quantitati ve estimation of the effects of the environment would not be easily at tainable by another technique. (C) 1994 by John Wiley & Sons, Inc.