THEORETICAL-STUDIES ON THE FREE-RADICAL BROMINATION OF METHYL-PYRIDAZINES IN THE SYNTHESIS OF NOVEL HETEROCYCLIC-ANALOGS OF NEUROTRANSMITTERS

Free-radical bromination by N-bromosuccinimide has been performed on a range of methyl 3-methoxy pyridazine derivatives. Depending on the su bstitution pattern, various products and selectivities have been obser ved, including atypical N-methyl bromination. The hypothesis that sele ctivity is dependent primarily on the stability of the free-radical in termediate formed in the reaction has been examined, and a range of se miempirical and ab initio molecular orbital methods has been used to c alculate these stabilities and evaluated for agreement with experiment . Semiempirical calculations using the PM3 Hamiltonian gave the best q ualitative predictions of the methods trialed, thus providing a rapid method for predicting the selectivity of reactions used in the synthes is of novel heterocyclic analogues of the neurotransmitters GABA and g lutamate.