Mechanistic understanding of the degradation pathways of high-value organic molecules

Washington, Jack

Thesis

Mechanistic understanding of the degradation pathways of high-value organic molecules

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Creator

Washington, Jack

Rights statement

Strathclyde Thesis Copyright

Awarding institution

University of Strathclyde

Date of award

2020

Thesis identifier

T17401

Person Identifier (Local)

201672318

Qualification Level

Doctoral (Postgraduate)

Qualification Name

Doctor of Philosophy (PhD)

Department, School or Faculty

Department of Pure and Applied Chemistry

Abstract

The chemistry of two classes of high value organic molecules has been explored through monitoring their degradation behaviours. Specifically, the degradation of N,N,N-trimethylanilinium salts and clavulanic acid has been examined systematically using a wide range of reaction monitoring techniques. Through understanding their respective degradation pathways, implications for N,N,N-trimethylanilinium salt use in synthetic organic chemistry, and the optimal manufacturing process of clavulanic acid have each been revealed. Anilinium Salts in Synthesis N,N,N-trimethylanilinium salts have been widely used as cross-coupling substrates, their application as methylating reagents is known but remains underexplored. A thorough mechanistic analysis herein delineates the factors that affect N,N,N-trimethylanilinium salt reactivity and describes resulting implications for both core synthetic use cases (methylation and cross-coupling). N,N,N-trimethylanilinium salts bearing nucleophilic halide counterions were shown to be less stable than those partnered with weakly coordinating anions. Regarding substituent effects, electron-deficient anilinium salts proved less stable than their electron-rich counterparts. Spectroscopic and thermal analyses provided evidence of N,N,N-trimethylanilinium iodide degradation to methyl iodide and the respective N,N-dimethylaniline. The methylating ability of a N,N,N-trimethylanilinium salt library was screened against a phenolic substrate and the scope of nucleophiles amenable to methylation was explored. Mechanistic experiments showed N,N,N-trimethylanilinium salts can act as a methyl iodide surrogate, react directly with nucleophiles, or partake in a solvent-assisted pathway. Clavulanic Acid Production on the Manufacturing Scale The degradation of the industrially and clinically important β-lactamase inhibitor clavulanic acid was explored in the context of its process-scale manufacture. A reliable method of monitoring clavulanic acid degradation with Reversed Phase HPLC in buffered aqueous solutions over the manufacturing-relevant pH range of 3-9 was developed. The most stable pH region for clavulanic acid was found to be between 5-6. A pH profile was constructed which suggested different degradation mechanisms occur in high-pH and low-pH regimes. The effect of pH and temperature on the rate of clavulanic acid degradation was explored in samples from various points in the manufacturing process. The most stable pH for clavulanic acid was shown to vary at different stages of the process. A variety of spectroscopic techniques have been employed in the attempt to gain an insight into the degradation mechanism(s) of clavulanic acid.

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