Both bromine- and chlorine-substituted 2(5H)-furanones are produced by the chlorination of ligno-humic waters containing bromide ion. The molar mutagenicities of four bromine- and chlorine-substituted 2(5H)-furanones were determined by the Salmonella typhimurium (TA100) assay to explore Cl-by-Br and H-by-OH replacement effects on mutagenicity. Each of these two replacements was expected to enhance mutagenicity based on earlier work showing that lower LUMO energy levels and greater radical anion stability correlated with elevated TA100 mutagenicity. The four compounds investigated were the following: 2,3-dibromo-5-hydroxy-2(5H)-furanone (mucobromic acid, MBA); 2,3-dibromo-2(5H)-furanone (reduced mucobraomic acid, RMBA); 2,3-dichloro-5-hydroxy-2(5H)-furanone (mucochloric acid, MCA); and 2,3-dichloro-2(5H)-furanone (reduced mucochloric acid, RMCA). Mean molar mutagenicities were found to be 5.54, 1.18, 2.92 and 0.105 revertants/nmol for the four compounds in the order named. Mutagenicity enhancements resulting from Cl-by-Br and H-by-OH replacements were analyzed by simple ratios of mean molar mutagenicity and by multiple regression analysis. The effect of the Cl-by-Br replacement on mutagenicity amounted to a 1.9-fold enhancement in the presence of C-5 OH, but an 11-fold enhancement in the presence of C-5 H. This demonstrated that the two replacement effects were interactive. Higher mutagenicity values corresponded to lower AM1 computed LUMO energy levels and greater radical anion stabilities.
Electrophilicity as a general basis for both the mutagenicity and nucleophile inactivation of halogen-substituted 2(5H)-furanones was tested. Lowest unoccupied molecular orbital (LUMO) energy levels and stabilities of 2(5H)-furanone radical anions and C-2, C-3, and C-4 anionic hydride adducts were computed with MNDO-PM3 for each of 10 compounds. These three computed sets of values were considered electrophilicity indicators. Each individual value from a given indicator set was plotted against the logarithm of the Salmonella typhimurium (TA100) mutagenicities (log Mm) for each of the corresponding compounds. Highest occupied molecular orbital (HOMO) energy levels for the 10 compounds were also computed. Strong negative correlations were obtained from the plots of LUMO and radical anion stability against log Mm of the 10 compounds. Also, a negative correlation was observed for the plot of the stability of the C-4 anionic hydride adduct for a smaller set of six compounds possessing a 4-(chloromethyl)-2(5H)-furanone structure and having the same HOMO characteristics. HOMO energies failed to correlate with mutagenicity. Neither computed atomic charge nor 13C chemical shift values for the larger compound group of 10 correlated well with mutagenicity or with each other. Sodium borohydride and borodeuteride reductions of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone demonstrated experimentally that hydride became attached to C-4.
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