Journal of C Carbon Research Article Facile Synthesis and Characterization of a Bromine-Substituted (Chloromethyl)Pyridine Precursor towards the Immobilization of Biomimetic Metal Ion Chelates on Functionalized Carbons Troy T. Handlovic , Tyler Moreira, Anoshia Khan, Haroon Saeed, Yousuf Khan, Mohammed R. Elshaer and Justin A. Bogart * Department of Chemistry, Biochemistry and Physics, Becton College of Arts and Sciences, Fairleigh Dickinson University, Madison, NJ 07940, USA; [email protected] (T.T.H.); [email protected] (T.M.); [email protected] (A.K.); [email protected] (H.S.); [email protected] (Y.K.); [email protected] (M.R.E.) * Correspondence: [email protected]; Tel.: +1-973-443-8761 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 chal- Citation: Handlovic, T.T.; Moreira, T.; lenging to handle and require extensive hazard controls. Herein, we report alternative methodologies Khan, A.; Saeed, H.; Khan, Y.; Elshaer, towards the syntheses of 2-bromo-6-hydroxymethylpyridine and 2-bromo-6-chloromethylpyridine M.R.; Bogart, J.A. Facile Synthesis from inexpensive commercially available 2,6-dibromopyridine using isopropylmagnesium chloride and Characterization of a lithium chloride complex (Turbo Grignard) and cyanuric chloride which are easier to handle and Bromine-Substituted require milder reaction conditions than the conventional reagents. Gas chromatography-mass spec- (Chloromethyl)Pyridine Precursor trometry (GC-MS) methods were developed and simple 1H- and 13C- nuclear magnetic resonance towards the Immobilization of (NMR) and Fourier-transform infrared (FT-IR) spectroscopies were also used to monitor the con- Biomimetic Metal Ion Chelates on version of both reaction steps and showed that products could be obtained and isolated through Functionalized Carbons. C 2021, 7, 54. https://doi.org/10.3390/c7030054 simple workups without the presence of unreacted starting material or undesired overchlorinated 2-chloro-6-chloromethylpyridine side product. Academic Editor: Jandro L. Abot Keywords: substituted pyridines; metal halogen exchange; chlorine transfer; alternative synthesis; Received: 23 June 2021 gas chromatography mass spectrometry Accepted: 20 July 2021 Published: 23 July 2021 Publisher’s Note: MDPI stays neutral 1. Introduction with regard to jurisdictional claims in Pyridine based ligands play an important role in supporting transition metal ions published maps and institutional affil- for biomimetic chemistry [1–10]. Ligands containing two bis[2-(2-pyridyl)ethyl]amine iations. (pye) moieties have been used on copper(I) to mimic copper containing oxygenases or hemocyanin by promoting dioxygen oxidation chemistry or reversible dioxygen binding, respectively, depending on the type of central linker [11–13]. Many non-haem iron con- taining metalloenzymes bind iron through moieties known as the 2-His-1-carboxylate, Copyright: © 2021 by the authors. 3-His facial triads or other combinations of histidine and carboxylate endogenous lig- Licensee MDPI, Basel, Switzerland. ating residues [14–17]. These structural motifs have been extensively modeled using This article is an open access article pyridyl based ligands (Figure1) that have been shown to support high valent metal-oxo distributed under the terms and species capable of activating C–H bonds of substrates similarly to their enzymatic coun- conditions of the Creative Commons terparts [18–23]. The appeal of these heterocyclic N-donor groups is that they function as Attribution (CC BY) license (https:// strong σ donors to support high oxidation states and provide flexibility in their functional creativecommons.org/licenses/by/ derivatization for the tuning of primary coordination spheres [24]. 4.0/). C 2021, 7, 54. https://doi.org/10.3390/c7030054 https://www.mdpi.com/journal/carbon C 2021, 7, 54 2 of 17 C 2021, 7, 54 2 of 16 to support high oxidation states and provide flexibility in their functional derivatization for the tuning of primary coordination spheres [24]. FigureFigure 1.1. SelectSelect pyridine-basedpyridine-based ligandsligands thatthat havehave beenbeen usedused toto synthesizesynthesize biomimeticbiomimetic metalmetal com-com- plexes.plexes. ItIt isis ofof interestinterest toto linklink thesethese biomimeticbiomimetic ligandligand scaffoldsscaffolds to to solid solid supports supports towards towards the the developmentdevelopment ofof heterogeneousheterogeneous catalysts.catalysts. TheseThese heterogeneousheterogeneous reactionsreactions wouldwould theoreti-theoreti- callycally increaseincrease the the easeease ofof productproduct isolationisolation andand catalystcatalyst recovery.recovery. Zhdankin Zhdankin and and coworkers coworkers showedshowed attachingattaching NN-(2-iodyl-phenyl)-acylamide,-(2-iodyl-phenyl)-acylamide, aa derivativederivative ofof 2-iodoxybenzoic2-iodoxybenzoic acidacid (IBX),(IBX), onto onto a a polymer polymer support support afforded afforded an an efficient efficient oxidizing oxidizing system system that that could could be recycled be recy- withcled onlywith aonly moderate a moderate decline decline in activity in activity over multipleover multiple recovery recovery steps steps [25]. [ Polystyrene-25]. Polysty- basedrene-based supports supports for palladium for palladium catalysts catalysts for Suzuki for Suzuki cross-couplings, cross-couplings, rhodium rhodium catalysts catalysts for ketonefor ketone synthesis, synthesis, and and ruthenium ruthenium catalysts catalysts for olefin for olefin metathesis metathesis have have also beenalso been developed devel- andoped used and to used form to heterogeneous form heterogeneous catalysts catalysts that have that shownhave shown comparable comparable activities activities to their to homogenoustheir homogenous analogues analogues and could and becould reused, be reused, some up some to five up to tenfive times, to ten with times, no with loss inno activityloss in activity [26]. This [26] recyclability. This recyclability of catalyst of catalyst increases increases the efficiency the efficiency and atom and economy atom econ- of theseomy of catalytic these catalytic transformations. transformations. OtherOther solid solid supports supports such such as as silica silica and and activated activated carbons carbons exist exist due todue the to ability the ability to func- to tionalizefunctionalize the surfaces the surfaces of these of materialsthese materials with amine with amine or oxygen or oxygen containing containing groups groups such as such lac- tonesas lactones or carboxylic or carboxylic acids. Indeed, acids. Indeed, Radi and Radi coworkers and coworkers linked a bis(2-pyridylmethyl)amine linked a bis(2-pyridylme- chelatethyl)amine to functionalized chelate to functionalized silica for applications silica for applications in heavy metal in heavy extractions metal extractions [27]. Further- [27]. more,Furthermore, one of us one recently of us recently reported reported the grafting the grafting of polyethyleneimine of polyethyleneimine (PEI) onto (PEI) activated onto ac- carbonstivated carbons for the removal for the removal of Cr(VI) ofions Cr(VI) from ions water from at water pH values at pH rangingvalues ranging from 2 from to 5 [ 282 t].o Extension5 [28]. Extension of this activatedof this activated carbon workcarbon includes work includes linking thelinking biomimetic the biomimetic pyridine pyridine ligand scaffoldsligand scaffolds onto activated onto activated carbon surfaces carbon surfaces to study to catalytic study catalytic activity andactivity recyclability and recyclability of these activatedof these activated carbon supported carbon supported heterogeneous heterogeneous systems. However,systems. However, linking of lin theseking pyridine- of these basedpyridine ligands-based first ligands requires first the requires addition the of addition chloromethyl of chloromethyl groups onto groups the heteroaromatic onto the het- ring to give electrophilic compounds capable of participating in substitution reactions with eroaromatic ring to give electrophilic compounds capable of participating in substitution amine functionalized activated carbon nucleophiles. In addition, bromo substituents on the reactions with amine functionalized activated carbon nucleophiles. In addition, bromo heteroaromatic ring are also highly desirable as they allow for subsequent functionalization substituents on the heteroaromatic ring are also highly desirable as they allow for subse- post tethering to the solid support. This led us to search the literature for ways to synthesize quent functionalization post tethering to the solid support. This led us to search the liter- the previously reported 2-bromo-6-chloromethylpyridine precursor compound [29–31] ature for ways to synthesize the previously reported 2-bromo-6-chloromethylpyridine and we found some concern with the conventional routes and characterization of