The GAUSSIAN 86 series of programs has been used to carry out ab initio quantum mechanical calculations to model nucleophilic additions to beta-lactam antibiotics. So far we have studied the attack of the beta-lactam by water. There are two transitions states to the formation of product. In the first water attacks the carbonyl with transfer of one hydrogen to the carbonyl oxygen. The second occurs after ring opening and is a direct transfer of a hydrogen atom to the nitrogen. At the moment the mechanistic results appear to be basis set dependent, however this project is still in progress and the prediction of a mechanistic pathway remains unanswered. Further aspects of the electronic nature of nucleophilic addition to the beta-lactam will be studied by substituting an amine (donating) group or a formyl (withdrawing) group as the carbon atom adjacent to the carbonyl. Placing substitutents on the lactam ring will give an indication of the polarization changes that occur as nucleophilic addition proceeds. It will also be of interest to study the binding of beta-lactam using molecular dynamics approach for simulating chemical reactions.
