Reactions of 1,4-naphthoquinones with Nucleophiles

Abstract

Derivatives of 1,4-naphthoquinone play an important role in various biological processes through their extensive reactivity with nucleophiles. The reaction of vitamin K3, 2-methyl-1,4-naphthoquinone with a nucleophilic cysteine residue in the active site of protein tyrosine phosphatase (PTP) is responsible for the anticancer properties in PTP. Here we study the reactivity of several derivatives of 1,4-naphthoquinones with various nucleophiles. The nucleophiles we primarily focus on are amines and thiols, two most important and prevalent nucleophiles in the biological environment. Depending on the strength and types of the nucleophiles, the fate of 1,4-naphthoquinone reactivities was found to be quite different. With stronger nucleophiles such as alkylthiolate anions, the 1,4-naphthoquinones served as electrophiles in a substitution and a subsequent elimination reaction. However, with moderate nucleophiles with a pair of free electrons such as alkylamines, which can also serve as electron donors, the 1,4-naphthoquinone derivatives served as electron acceptors in an oxidation-reduction process. In addition to this phenomenal dual nature of 1,4-naphthoquinones, a third dimension of 1,4-naphthoquinones was found. Using a stronger base led to the discovery of an acidic component of some 1,4-naphthoquinone derivatives. Here, the acidic nature of the α-proton of 3-methyl substituent helps them serve as proton donors in an acid-base type reaction. This acidity was confirmed by an H-D exchange reaction in CH3OD in presence of a base on ¹H-NMR spectroscopy.