Ortho-Methoxy Group as a Mild Inhibitor of the Reactions Between Carboxylic Acid and Phenols

Abstract

According to the current database of natural products, over 25,000 compounds contain a vanillyl ring in their structure. The reasoning behind the high occurrence of the vanillyl ring structure seemed to be poorly understood, specifically the preference for a methoxy-substituted phenol structure as opposed to its dihydroxy analogue. To better understand this, we investigated the reaction mechanisms of two methoxyphenol structures, in syn and anti conformations, two hydroxyphenol structures, also in syn and anti conformations, and phenol as a reference structure, with acetic acid. Of the starting structures, the syn hydroxyphenol was found to be kinetically the most reactive, and formed the most stable product, while both hydroxyl-substituted phenols reacted more favorably with acetic acid than the methoxyphenols. A preference for the methoxyphenol molecule may exist as a way to hinder the formation of stable covalent bonds between natural products and cellular components.