Abstract
Nerve agents include a class of organophosphorus compounds (OPs) which have been used as chemical warfare agents (CWAs). They act on the nervous system through inhibition of acetylcholine esterase (AChE) which breaks down the neurotransmitter acetylcholine leading to incapacitation and, potentially death. Accurate detection methods for OPs are therefore desirable. The project aimed (1) to design, synthesise and test compounds that change colour in response to OPs, and (2) to incorporate these compounds into test kits suitable for field use. CWAs of interest have an OP structure with a phosphate ester, and a labile P-F bond, which undergoes hydrolysis to release fluoride. Molecules were designed that incorporated urea and thiourea moieties as binding sites for fluoride, appended to signalling chromogenic units.Three classes of molecules were considered. The first were minimal receptors incorporating a urea or thiourea binding site and a 4-nitrophenyl or 4-trifluoromethyl phenyl signalling unit. These simple receptors were designed to study the binding of the (thio)urea groups with anions, specifically fluoride, by 19F and 1H NMR, UV-vis, and fluorescence spectrophotometry. Crystals of the minimal receptors, together with acetate and hydrogen carbonate complexed were collected and structurally characterised. PM6 and DFT calculations were used to model receptor-anion binding. Hydroxide was found to be a major interferent in the detection of fluoride, but fluorescence spectrophotometry enabled discrimination between the receptor response to fluoride and hydroxide.
The second class incorporated the previously studied (thio)urea binding groups and 4-nitrophenyl urea signalling unit linked to a 2-, 3-, or 4- pyridinium oxime moiety, incorporated to catalyse OP hydrolysis and release fluoride for detection. Oximes are used to treat OP poisoning as reactivators to restore OP-damaged AChE. Interactions of these receptors with anions were investigated by UV-vis and fluorescence spectrophotometry. Potential interactions with CWAs were studied computationally.
The third class of molecules were α- and β-cyclodextrins (CDs) functionalised with the binding and signalling units previously studied. Two different sizes of CDs were used to achieve size-based discrimination between OPs. The CD-based receptors were tested with GD, and the CWA hydrolysis products PMP and IMPA at Dstl, Porton Down by 1H NMR and UV-vis spectrophotometry. Some positive results were seen for the thiourea-based receptors with GD and PMP by 1H NMR, and a lack of response was observed for the urea-based receptors by UV-vis spectrophotometry.
Two of the minimal receptors were incorporated onto wax-printed microfluidic analytical devices to fabricate a visual detector for use by non-specialists. Microfluidics is an emerging low-cost technology for medical diagnostics in developing countries. The simple preparation method allows the devices to be made by a non-specialist in situ without the need for special storage conditions.
| Date of Award | 2024 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Peter Cragg (Supervisor), Bhavik Patel (Supervisor) & Graham Pattison (Supervisor) |