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.

Training Undergraduate Sophomore or Junior Students in Air- and Moisture-Sensitive Reaction Techniques through a Multistep Synthesis of the Tripodal Bis[2-(2,3-dihydroxyphenyl)-6-pyridylmethyl](2-pyridylmethyl)amine (BCATTPA) Compound

“…These samples were then characterized by students during a separate class period using 1 H NMR spectroscopy, FT-IR spectroscopy, and GC-MS techniques. The student groups were able to assess their success by calculating isolated percent yields (typically 67%) and comparing their results to the literature . While all three characterization techniques were used, instructors have flexibility to use any combinations of these techniques depending on their instrument resources.…”

“…The student groups were able to assess their success by calculating isolated percent yields (typically 67%) and comparing their results to the literature. 39 While all three characterization techniques were used, instructors have flexibility to use any combinations of these techniques depending on their instrument resources. This first experiment can also be implemented in a more traditional laboratory course setting if the instructor sets up the flasks under nitrogen in the ice-baths prior to the students' arrivals, and if the reagent additions are split up over multiple class periods.…”

“…For the formation of the TPA core of BCATTPA, the 2bromo-6-hydroxymethylpyridine alcohol first needed to be converted into 2-bromo-6-chloromethylpyridine (Scheme 1). 39 Setup of the reaction took a total of 2 h and was performed on the first day. The reaction was allowed to stir until the following class period, where it was quenched and workup was performed.…”

“…The first step to synthesizing BCATTPA involved the synthesis of 2-bromo-6-hydroxymethylpyridine (Scheme 1). 39 This reaction required 1 day to complete the synthesis steps, 1 day to complete the workup, and 1 day to perform the characterization.…”