Date of Award

Spring 2019

Document Type

Open Access Dissertation

Department

Chemistry and Biochemistry

First Advisor

Aaron K. Vannucci

Abstract

The “Anion pool” approach introduces a greener approach for derivatization of pharmaceutically important molecules by amalgamating both electrochemistry and organic synthesis. This is a base and metal free procedure carried out in organic solvents recommended for pharmaceutical preparations. The anion pool procedure generates reactive nitrogen nucleophiles in situ via electrochemical reduction of heteroaromatic substrates. The adoption of such a methodology prevents generation of waste from bases used for deprotonation. Hydrogen is the main by-product of generation of anion pool, which, if produced at a large enough scale could be used as a renewable fuel. These attributes comply with the principles of green chemistry, allowing synthetic chemists to carry out reactions in an atom-economic and environmentally friendly manner.

The anion pool method was first used to derivatize of benzimidazoles with alkyl, acyl and benzyl halides. We were able to achieve selective substitution at the 1H position in high yields with a variety of benzimidazoles and electrophiles bearing a variety of functional groups. The second study was aimed at selective acylation of indazoles at the N1 position. Indazoles bear two nitrogen atoms on the pyrazole ring that tend to undergo non-selective reactions with electrophiles. By adopting the anion pool approach, we were able to achieve great selectivity to N1-position while also improving the yields, decreasing chemical additives, and utilizing safe solvents and less moisture sensitive acid anhydrides. This procedure can be carried out in an inexpensive set-up connected to a 9V battery, indicating that this reaction could easily be adapted to being driven by the power of a basic solar cell. The adoptability of such a user-friendly set up makes it easier to incorporate green chemistry experiments to classroom teaching. This procedure is applicable for amidation reactions. Amide formation avoiding poor atom economy reagents has been identified as a priority for the ACS GCI Pharmaceutical roundtable. The anion pool method can be extended with a nucleophilic substitution to produce two pharmaceutically important compounds in a single cell with very good atom economy.

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Chemistry Commons

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