Phase-Transfer Catalysis

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.

References

  1. H. Mayr, M. Breugst and A. R. Ofial, Angew. Chem. Int. Ed., 2011, 50, 6470–6505.
  2. M. Breugst, H. Zipse, P. Guthrie and H. Mayr, Angew. Chem. Int. Ed., 2010, 49, 5165–5169.
  3. M. Breugst and H. Mayr, J. Am. Chem. Soc., 2010, 132, 15380–15389.
  4. H. J. A. Dale, G. R. Hodges and G. C. Lloyd-Jones, J. Am. Chem. Soc., 2019, 141, 7181–7193.
  5. G. Pupo, F. Ibba, D. M. H. Ascough, A. C. Vicini, P. Ricci, K. E. Christensen, L. Pfeifer, J. R. Morphy, J. M. Brown, R. S. Paton and V. Gouverneur, Science, 2018, 360, 638–642.
  6. G. Pupo, A. C. Vicini, D. M. H. Ascough, F. Ibba, K. E. Christensen, A. L. Thompson, J. M. Brown, R. S. Paton and V. Gouverneur, J. Am. Chem. Soc., 2019, 141, 2878–2883.
  7. Y. Zhou, J. Wang, Z. Gu, S. Wang, W. Zhu, J. L. Acenã, V. A. Soloshonok, K. Izawa and H. Liu, Chem. Rev., 2016, 116, 422–518.
  8. T. Fujiwara and D. O’Hagan, J. Fluor. Chem., 2014, 167, 16–29.
  9. R. Berger, G. Resnati, P. Metrangolo, E. Weber and J. Hulliger, Chem. Soc. Rev., 2011, 40, 3496–3508.