Stereopopulation Control. 7. Rate Enhancement in the Lactonization of 3-(o-Hydroxyphenyl)propionic Acids: Dependence on the Size of Aromatic Ring Substituents

Article abstract of DOI:10.1021/ja00347a040

A series of 4,4-dimethyl-6-hydroxyhydrocoumarins was synthesized with various combinations of methyl and halogen groups at C-5 and C-7.The 5,7-difluoro compound was obtained by condensation of difluorohydroquinone with dimethylacrylic ester.Controlled chlorination of the parent phenolic lactone provided the 5- and 7-chloro isomers, in addition to the 5,7-dichloro product.On the other hand, bromination gave both the 5,7-dibromo and 7-bromo products, without trace of the 5-bromo isomer; finally, iodination gave only the 7-iodo product.These compounds were converted into 6-mesylates as protection against air oxidation of the hydroquinone system in alkaline media.The lactones were hydrolyzed in aqueous base, and the kinetics of relactonization were measured at 30 deg C over a wide pH range.As previously shown for similar systems, lactonization is subject to both general acid and general base catalysis.After adjustment of the rate constants (k') for the electronic effects of ring substituents, the residual rate constants (k'') were found to increase with the size of the C-5 substituent, the value for bromine being 4800 times that for hydrogen.A plot of log k''_cat vs. the van der Waals radius of the substituent is linear, demonstrating the existence of a free energy continuum in the relationship between k'' for lactonization and the conformational mobility of the three-carbon side chain.