Mechanistic Studies of Nucleophilic Organocatalysis by N-Heterocyclic Carbenes
Lead Research Organisation:
Durham University
Department Name: Chemistry
Abstract
Nature uses complex molecules known as enzymes as highly specific catalysts for a multitude of chemical transformations that are essential for biological processes. Although efficient, enzyme reactions often need another molecule, known as a co-factor, to promote specific transformations. In order to further our understanding of these processes, synthetic chemists are constantly trying to engineer artificial molecules that have the ability to mimic enzymatic transformations. There is much current interest in one specific branch of this area of research, which is commonly known as organocatalysis . This technique uses small organic molecules instead of enzymes in order to carry out selective chemical reactions. This proposal aims to develop a fundamental understanding of how one particular class of a simple organic molecule, known as an N-heterocyclic carbene, is able to catalyse a wide range of selective chemical transformations. Nature uses a carbene equivalent as a co-factor in a range of chemical transformations and this proposal seeks to understand why they can be used in the laboratory. By understanding how each step in a particular process works, and by comprehending how the rate of each step changes with a change in catalyst structure, we hope to be able to prepare highly selective and efficient catalysts for the future.
Publications
AnnMarie O'Donoghue (Interviewee)
(2013)
SYNFORM ISSUE 2013/07
Collett C
(2013)
Mechanistic insights into the triazolylidene-catalysed Stetter and benzoin reactions: role of the N-aryl substituent
in Chemical Science
Collett CJ
(2015)
Rate and equilibrium constants for the addition of N-heterocyclic carbenes into benzaldehydes: a remarkable 2-substituent effect.
in Angewandte Chemie (International ed. in English)
Higgins EM
(2011)
pKas of the conjugate acids of N-heterocyclic carbenes in water.
in Chemical communications (Cambridge, England)
Massey R
(2016)
Proton transfer reactions of a bridged bis -propyl bis -imidazolium salt
in Journal of Physical Organic Chemistry
Massey Richard Stephen
(2013)
Mechanistic studies of azolium ions and their role in organocatalysis
Massey RS
(2012)
Proton transfer reactions of triazol-3-ylidenes: kinetic acidities and carbon acid pKa values for twenty triazolium salts in aqueous solution.
in Journal of the American Chemical Society
Massey RS
(2021)
Kinetic and structure-activity studies of the triazolium ion-catalysed benzoin condensation.
in Organic & biomolecular chemistry
O'Donoghue A
(2013)
Contemporary Carbene Chemistry - Moss/Contemporary Carbene Chemistry
Tucker D
(2014)
Proton transfer reactions of N -aryl triazolium salts: unusual ortho -substituent effects
in Journal of Physical Organic Chemistry
Description | N-Heterocyclic carbenes offer significant potential as organocatalysts. To capitalise upon recent synthetic achievements, it is necessary to have detailed understanding of their modes of action. Prior to this grant application, there was very little understood in relation to organocatalysis by triazolylidene NHCs despite these being the most often utilised and generally most efficient of this class of catalyst. Our study has provided fundamental mechanistic insight on the influence of catalyst structure and has answered a number of unsolved questions in this synthetic chemistry field. In particular, our kinetic and mechanistic study has answered why N-pentafluorophenyl triazolium-derived catalysts are optimal for benzoin, Stetter and related reactions. Furthermore we have provided essential quantitative insight into the origin of unusual 2-substituent effects in organocatalysis by N-aryl triazolium salts. These results have shown accepted synthetic dogma to be incorrect and provide crucial insight into NHC chemoselectivity, which is generally lacking in this synthetically vibrant area. Since the completion of this grant, I have had three PhD students continue work in this area (related publications pending) with a particular focus on understanding the role of triazolium fused ring size in NHC organocatalysis, mechanistic evaluation of related bis-aminocyclopropenylidene organocatalysts and the origin of the 2-substituent effect. In 2019, Andrew Smith and I were awarded an EPSRC grant to further develop our research portfolio in this area with a particular focus on the onward reactions of the key Breslow Intermediate. |
Exploitation Route | Our publications since 2011 have been very well cited showing that our mechanistic insight is used by academics and industrialists in further reaction design and optimisation. This research programme is still ongoing as similar mechanistic insight is also lacking for other classes of carbene organocatalysts. |
Sectors | Chemicals,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
Description | This research programme lies firmly in the area of fundamental, underpinning rather than applied chemistry. We target comprehensive, molecular level understanding of reaction mechanism and publish our work in high impact top international chemistry journals. Using this strategy, our work influences, underpins and informs broader developments in organic chemistry both in industry and academia and particularly in our focus areas of organocatalysis and biomimetic chemistry. Our papers since 2011 have been well cited and, in particular, one key publication (J. Am. Chem. Soc. 2012, 134, 20421)) was highlighted in a J. Am. Chem. Soc. Spotlight issue in 2013. Also we had two key publications in 2015 - an invited submission to the Journal of Physical Organic Chemistry and also an article in Angewandte Chemie International Edition. |
First Year Of Impact | 2011 |
Sector | Chemicals,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
Impact Types | Economic |
Description | Underpinning Mechanistic Studies of NHC-Organocatalysis: A Breslow Intermediate Reactivity Scale |
Amount | £435,966 (GBP) |
Funding ID | EP/S020713/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2019 |
End | 03/2022 |
Description | Joint Research Consortium of the Chemistry Departments in the Universities of Durham and York |
Organisation | University of York |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | The mechanistic studies enabled by the present grant were presented in a seminar in the University of York in December 2011. Stemming from this two further collaborations were developped in York and led to general discussions on shared mechanistic expertise. This resulted in the set-up of a joint Consortium between the two departments in 2016 (http://chem-mechanism.uk/index.html). A variety of scientific meetings have been spawned from the back of this collaborative initiative. There is a large collective expertise of mechanism-focused chemistry between the two departments and the consortium enables the sharing of collective capabilities in addition to new collaborations. |
Collaborator Contribution | My collaborators in the University of York (Victor Chechik, Ian Fairlamb, Peter O'Brien) were involved in establishing the consortium from the outset. |
Impact | This collaboration is multidisciplinary across all sections of mechanistic chemistry from bioactive chemistry through to atmospheric chemistry. Two major grant applications have resulted from the collaboration and we are awaiting pending outcomes. |
Start Year | 2016 |