Facile Synthesis and Characterization of a Bromine-Substituted (Chloromethyl)Pyridine Precursor towards the Immobilization of Biomimetic Metal Ion Chelates on Functionalized Carbons

Abstract

Multidentate ligands involving tethered pyridyl groups coordinated to transition metal ions have been frequently used to mimic the 3-histidine (3H), 2-histidine-1-carboxylate (2H1C) brace motifs or other combinations of histidine and carboxylate endogenous ligating residues found in bioinorganic metalloenzymes. It is of interest to immobilize these ligand chelates onto heterogeneous supports. This, however, requires the use of bromine-substituted (chloromethyl)pyridines, whose current synthetic routes involve the use of extremely pyrophoric chemicals, such as n-butyllithium that require cryogenic reaction conditions, and toxic chemicals, such as thionyl chloride, that are challenging to handle and require extensive hazard controls. Herein, we report alternative methodologies towards the syntheses of 2-bromo-6-hydroxymethylpyridine and 2-bromo-6-chloromethylpyridine from inexpensive commercially available 2,6-dibromopyridine using isopropylmagnesium chloride lithium chloride complex (Turbo Grignard) and cyanuric chloride which are easier to handle and require milder reaction conditions than the conventional reagents. Gas chromatography-mass spectrometry (GC-MS) methods were developed and simple 1H- and 13C- nuclear magnetic resonance (NMR) and Fourier-transform infrared (FT-IR) spectroscopies were also used to monitor the conversion of both reaction steps and showed that products could be obtained and isolated through simple workups without the presence of unreacted starting material or undesired overchlorinated 2-chloro-6-chloromethylpyridine side product.