Control of ambident nucleophiles

Lead Research Organisation: University of Edinburgh
Department Name: Sch of Chemistry

Abstract

The addition of nucleophiles to electrophiles is a common step in the synthesis of agrochemical and pharmaceuticals. However, the use of ambident nucleophiles, as for example in cyproconazole (a fungal growth inhibitor) and thiamethoxam (a neonicotinoid insecticide), always presents a challenge, irrespective of whether the nucleophile is simple or complex. Selectivity less than 100%, by necessity, makes a process less economic; the unwanted isomer must be separated or eliminated - e.g., by isomerisation - all of which costs time and materials. This project will apply physical organic techniques to elucidate the fundamental mechanistic aspects that control the regioselectivity of such processes, with the goal of engendering binary control by mechanistic switch, using catalysis.

Publications

10 25 50

Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/P510488/1 01/10/2016 30/09/2021
1941143 Studentship EP/P510488/1 01/10/2017 31/03/2022 Harvey Dale
 
Description A great deal of research efforts in the field of organic chemistry are dedicated towards the development of new synthetic transformations, with significant advances into new regions of chemical space being reported on a daily basis. However, such an unrelenting focus on the discovery of new chemical reactions - accompanied by a somewhat more modest focus on their likely utility - has led to the neglect of perennial problems in more well-established arenas of organic chemistry.

One such neglected area is the control of a class of troublesome molecules termed ambident nucleophiles. Whilst many of these molecules have been known for decades, and their reactivity studied intensely, they continue to pose a substantial problems for synthetic chemists. Even in trivial chemical reactions, ambident nucleophiles will often exhibit promiscuous reactivity, leading to the generation of multiple different isomeric products; controlling the selectivity of such processes is often impossible, and as such it is common to isolate the desired product and discard or otherwise eliminate the undesired side products. A far superior approach would be to target the poor intrinsic selectivity at its source, thereby precluding the formation of the undesired products altogether.

In our project we have developed a new, catalytic strategy for switching or otherwise enhancing the reactivity of triazole anions; these archetypal ambident nucleophiles are pervasive in the agrochemical industry, and until now have proved to be particularly stubborn in the face of all attempts to tame their reactivity. In essence, our approach hinges upon the use of a simple catalyst that modulates the basic reactivity of triazole anions by virtue of carefully designed intermolecular interactions: the catalyst binds to triazole anions in a highly selective manner, and in doing so forces the anions to react with atypical selectivities. With an appropriately structured catalyst, these atypical selectivities can be honed to synthetically useful levels.

This work has been published by us (J. Am. Chem. Soc., 2019, 141, 7181), and independently highlighted in Organic Process Research & Development (OPR&D) as an item of significant interest to industrial chemists (Org. Process Res. Dev., 2019, 23, 1107).
Exploitation Route We expect that our general strategy will lead to the development of similar approaches for controlling all manner of anionic ambident nucleophiles (with molecules including pyridones, pyrazoles etc.), and hope that such strategies will be incorporated into the synthetic routes of key industrial targets.
Sectors Agriculture, Food and Drink,Chemicals,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology