Periodic Reporting for period 1 - NHC2Breslow (Mechanistic Studies of NHC Organocatalysis – Quantifying the Reactivity of the Breslow Intermediate)
Reporting period: 2022-03-01 to 2024-02-29
The main aim of this proposal was to generate a quantitative understanding of the behaviour of the so called Breslow Intermediate that has been implicated in NHC based catalysis. This proposal aimed to deliver quantitative underpinning knowledge of this key intermediate that could (i) be used to develop a fundamental scale to quantify BI reactivity with a range of electrophilic species and (ii) be applied to answer unresolved mechanistic and chemoselectivity questions in contemporary NHC-based catalysis.
Work in this project has achieved - for the first time - a novel kinetic approach othat allows the relative quantification and reactivity of diverse Michael acceptors when they interact with the presumed N-C6F5 Breslow intermediate in the intermolecular Stetter reaction. This encompasses all workpackages WP1-WP6 and goes beyond the current state-of-the-art. The new synthetic methods developed that use catalytic quantities of non-toxic organocatalysts to generate new chiral organic materials address issues relating to sustainability. Futhermore the mechanistic insight generated will be of widespread interest to the synthetic community and industry and so may longer term have significant benefits for society.
Potential users of the project results are other academic groups around the world alongside industry who recognise the mechanistic insight provided.
Work in this project has achieved - for the first time - a novel kinetic approach othat allows the relative quantification and reactivity of diverse Michael acceptors when they interact with the presumed N-C6F5 Breslow intermediate in the intermolecular Stetter reaction. This encompasses all workpackages WP1-WP6 and goes beyond the current state-of-the-art. The new synthetic methods developed that use catalytic quantities of non-toxic organocatalysts to generate new chiral organic materials address issues relating to sustainability. Futhermore the mechanistic insight generated will be of widespread interest to the synthetic community and industry and so may longer term have significant benefits for society.
Potential users of the project results are other academic groups around the world alongside industry who recognise the mechanistic insight provided.
The project was accomplished via the following workpackages (WPs) and their linked deliverables;
WP 1: Synthesis of NHC and BAC catalysts (deliverable 1 – complete)
WP 2: Kinetic analysis of BI formation from aldehyde precursors (deliverable 2 – complete and publication in progress)
WP 3: Steady state kinetic determination of relative reactivities by NMR spectroscopy (deliverable 3 – complete and publication in progress)
WP 4: Kinetic determination of absolute BI reactivities by stopped flow spectroscopy (deliverable 4 – attempted but lifetime did not allow for reactivity determination)
WP 5: Development of relative and absolute BI reactivity scales (deliverable 5 – complete on a model system and publication in progress
WP 6: Kinetic analysis of the NHC-catalysed reactions: (deliverables 6 and 7 complete on a model system of chalcone addition and publication is in progress.
WP 1: Synthesis of NHC and BAC catalysts (deliverable 1 – complete)
WP 2: Kinetic analysis of BI formation from aldehyde precursors (deliverable 2 – complete and publication in progress)
WP 3: Steady state kinetic determination of relative reactivities by NMR spectroscopy (deliverable 3 – complete and publication in progress)
WP 4: Kinetic determination of absolute BI reactivities by stopped flow spectroscopy (deliverable 4 – attempted but lifetime did not allow for reactivity determination)
WP 5: Development of relative and absolute BI reactivity scales (deliverable 5 – complete on a model system and publication in progress
WP 6: Kinetic analysis of the NHC-catalysed reactions: (deliverables 6 and 7 complete on a model system of chalcone addition and publication is in progress.
Scientific publications based upon this work are submitted/planned and all include a reference to EU funding.
1. alpha-phenylthioaldehydes for the effective generation of acyl azolium and azolium enolate intermediates, P. M. D. A. Ewing, P. K. Majhi, C. Prentice,a C.M. Young, K. van Rees, P. L. Arnold, E. Zysman-Colman, A. D. Smith, Chemical Science, in revision.
2. Enantioselective Synthesis of Tetra-substituted 3-Hydroxyphthalide Esters by Isothiourea-Catalysed Acylative Dynamic Kinetic Resolution, S. K. Agrawal, P. K. Majhi, A. S. Goodfellow, R. K. Tak, D. B. Cordes, A. P. McKay, Kevin Kasten, Michael Bühl, Andrew D. Smith, Angew. Chem. Int. Ed, manuscript submitted.
3. Insights into Breslow Intermediate Reactivity in Intermolecular Stetter Reactions, Z. Duan, C. M. Young, J. Zhu, P. K. Majhi, A. C. O’Donoghue, A. D. Smith, Chemical Science, in preparation
4. Rate and Equilibrium constants for the addition of BACS to Aldehydes, P. K. Majhi, Z. Duan, C. M. Young, J. Zhu, A. C. O’Donoghue, A. D. Smith, Chemical Science, in preparation
5. Developing gamma-ammonium enolate reactivity with isothioureas: Catalytic enantioselective synthesis of spirocyclic oxindoles, P. K. Majhi, A. Mondal, M. Westwood, K. Kasten, A. D. Smith, Angew. Chem. Int. Ed., in preparation
1. alpha-phenylthioaldehydes for the effective generation of acyl azolium and azolium enolate intermediates, P. M. D. A. Ewing, P. K. Majhi, C. Prentice,a C.M. Young, K. van Rees, P. L. Arnold, E. Zysman-Colman, A. D. Smith, Chemical Science, in revision.
2. Enantioselective Synthesis of Tetra-substituted 3-Hydroxyphthalide Esters by Isothiourea-Catalysed Acylative Dynamic Kinetic Resolution, S. K. Agrawal, P. K. Majhi, A. S. Goodfellow, R. K. Tak, D. B. Cordes, A. P. McKay, Kevin Kasten, Michael Bühl, Andrew D. Smith, Angew. Chem. Int. Ed, manuscript submitted.
3. Insights into Breslow Intermediate Reactivity in Intermolecular Stetter Reactions, Z. Duan, C. M. Young, J. Zhu, P. K. Majhi, A. C. O’Donoghue, A. D. Smith, Chemical Science, in preparation
4. Rate and Equilibrium constants for the addition of BACS to Aldehydes, P. K. Majhi, Z. Duan, C. M. Young, J. Zhu, A. C. O’Donoghue, A. D. Smith, Chemical Science, in preparation
5. Developing gamma-ammonium enolate reactivity with isothioureas: Catalytic enantioselective synthesis of spirocyclic oxindoles, P. K. Majhi, A. Mondal, M. Westwood, K. Kasten, A. D. Smith, Angew. Chem. Int. Ed., in preparation