Our group has recently developed a keen interest in harnessing phase-transfer catalysis (PTC) and tailored non-covalent interactions to tame troublesome nucleophiles. Current research is concerned with two classes of nucleophile – ambident heterocycles and the fluoride anion – in addition to the development of cutting-edge instrumentation for in situ monitoring of heterogeneous reactions.
Controlling the regioselectivity of ambident nucleophiles towards simple electrophiles is a perennial problem in heterocyclic chemistry,1-3 and one that plagues the synthetic laboratories of the pharmaceutical and agrochemical industries. To demonstrate how chemists might tackle this pervasive problem, we have recently devised a strategy for the regioselective N-alkylation of triazole anions – an archetypal class of ambident nucleophile – that exploits the concept of protective phase-transfer catalysis.4 In this approach an amidinium or guanidinium cation is deployed as a bifunctional organocatalyst, to serve both as a phase-transfer agent and a regioselective, non-covalent protecting group for triazole anions. Regioselective hydrogen-bonding with such catalysts perturbs the relative reactivities of the competing nucleophilic sites of the anion, affording access to enhanced (1,2,3‑triazole) or inverted (1,2,4-triazole) selectivities towards N-alkylating agents. Further mechanistic work to establish this approach more generally is ongoing.
Recent research has shown that tailored hydrogen-bonding and phase-transfer catalysis can also be deployed to achieve enantioselective nucleophilic fluorination, using inexpensive alkali metal salts as the fluoride source and chiral bis-ureas as catalysts.5,6 Such transformations are highly desirable for those industries in pursuit of enantiomerically enriched organofluorine compounds.7-9 It has been proposed that the solubility and chemoselectivity of the fluoride anion are tamed by virtue of its participation in a tridentate, hydrogen-bonded complex with the bis-urea catalyst. Our group is interested in interrogating the mechanisms of these transformations, and in devising new instrumentation for their in-situ monitoring.
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