DiscussionLong term storage of compounds solubilised in DMSO can lead to significant sample degradation to the detriment of subsequent screening assays. Compound degradation corresponding to simple transformations were clustered by incremental mass shifts identified by LC-UV-MS. Compounds susceptible to oxidative dechlorination were analysed by comparing substituent effects (SE); from which rules were compiled to identify the structural features responsible for instability by oxidative degradation on a variety of common N-heterocyclic cores in the sample library. An unusual trend revealed para- substituted methyl groups located on a variety of double ring systems including pyrimidines and 1,3,5- triazines, unexpectedly conferred compound stability. This trend had not been previously modelled and an electronic effect was found to occur up to 10 bonds from the reactive site despite the inability of the methyl groups to pi (p) conjugate to the system. These stability predictions should be considered in the identification and selection of lead chemistry series during drug discovery.