Lactonization of cis,cis-3-halomuconates: influence of pH and halo substituent on the regiochemistry

Abstract

The (2E,4Z)-3-fluoro-2,4-hexadienedioate (1a; cis,cis-3-fluoromuconate) and its chloro 1b and bromo 1c analogues, which are important metabolites in the microbial degradation of halogenated aromatic pollutants, lactonize under acidic conditions. Two modes of lactonization can occur involving either carboxylat4e group. The authors show here that the lactonization and stereomutation of 1a-c are dependent not only on the pH but also on the halo substituent. The major product from reaction of 1a-c at pH 1-6, (2,5-dihydro-5-oxofuranylidene)acetic acid (2), arose from attack of the C-6 carboxylate on the halide-bearing carbon and subsequent expulsion of the halide. The rate of formation of 2 was maximal at pH 3-4 and approached zero at pH 0 and 7. At pH 3.2 and below, reaction of 1b and 1c, but not 1a, produced the (2E,4E)-3-halo-2,4-hexadienedioates as additional products. At pH 0 the major product fromr eaction of 1a, 2,5-dihydro-2-fluoro-5-oxofuranacetic acid (4a), was due to lactonization via the C-6 carboxylate. The 3-chloro- and -bromomuconates (1b,c), in contrast, lactonized at pH 0 via attack of the C-1 carboxylate on the unsubstituted C-4 to the 2,5-dihydro-3-halo-5-oxofuranacetic acids. The mechanism of the observed pH and substitutent-dependent changes in regiochemistry of lactonization is discussed.