Dr AnnMarie C. O'Donoghue

(email at annmarie.odonoghue@durham.ac.uk)

Research Interests

Our research centres on organic and biological reaction mechanisms with a focus on catalysis. Through understanding the strategies underpinning catalysis, we aim to inform the design of improved catalyst systems. Our research aligns with the ‘Centre for Sustainable Chemical Processes and Synthesis and Catalysis Research Grouping’ in Chemistry and also overlaps with key themes associated with the ‘Biophysical Sciences Institute’. We use a physical organic chemistry (POC) approach towards deciphering reaction mechanisms based on organic synthesis, reaction kinetics and structure-activity studies. 

Mechanistic Studies of Organocatalysis

Prior to 2000, developments in catalysis had largely focused on metal-based systems. More recently there has been a huge increase in interest in the design and application of non-metal containing organocatalysts.  Although the potential for organocatalysis had been recognized some time ago, only recently has attention focused on exploiting this form of catalysis. Organocatalysts are often cheaper, less toxic and less moisture sensitive than many metal-containing analogues. Despite the large increase in the application of small molecule organocatalysts there have been few detailed studies of catalytic mechanism. We are currently studying the mechanisms of three key classes of organocatalyst: N-heterocyclic carbene 1, dimethylaminopyridine-derived 2 and Brønsted acid/base 3 organocatalysts. We are studying the catalytic mechanisms in a number of key organic transformations including ketene additions, the Mannich reaction and benzoin/Stetter condensations. An improved mechanistic understanding of organocatalytic reactions is needed for the design of better catalysts.

Enzyme Mechanism

Our interests in enzyme catalysis focus on understanding how enzymes achieve such remarkable product specificities. Significant attention has been devoted to the origin of the extraordinary rate accelerations achieved by enzymes, however, much less focus has been dedicated to the key factor of how enzymes suppress competing side reactions. We are currently probing the origin of the product specificities of two ‘textbook’ enzymes, methylglyoxal synthase (MGS) and triosephosphate isomerase (TIM), which have the same substrate, dihydroxyacetone phosphate, but catalyse the formation of different products. Through kinetic and crystallographic studies of a range of mutant substrates with both wild types and mutants of MGS and TIM, we aim to decipher the origin of the two enzyme product specificities. As the proton transfer processes catalysed by both enzymes are ubiquitous, we hope to provide general insight into enzymatic catalysis. This information could be harnessed in the design of de novo artificial enzymes using directed evolution and similar methods. We are also interested in probing for ‘promiscuous activities’ to identify evolutionary links in the convergent/divergent evolution of protein catalysts. Our studies of ‘mutant’ substrates enable us to probe these promiscuous activities.

There is a strong driving force for enzymes to follow the same mechanism observed for the corresponding non-enzymatic reaction in solution. Thus an understanding of non-enzymatic solution chemistry is a prerequisite to the study of enzyme mechanisms, and is also a key principle of our research. This encompasses the study of classical reaction intermediates such as carbocations, carbanions and carbenes.

Determination of Kinetic Acidity and pKa

We have developed methods in the group for measuring kinetic acidities and pK_a values in a range of solvents and solvent mixtures. We are happy to initiate collaborations in this area and welcome enquiries. 

Vacancies and further information

For PhD and postdoctoral positions or summer scholarships please contact Dr AnnMarie O’Donoghue via email (annmarie.odonoghue@durham.ac.uk)

References

1. R. J. Delley, S. Bandyopadhyay, M. A. Fox, C. Schliehe, D. R. W. Hodgson, Florian Hollfelder, A. J. Kirby and A. C. O’Donoghue, Org. Biomol. Chem., 2012, 10, 590.
2. P. Christ, A. G. Lindsay, S. S. Vormittag, J-M. Neudçrfl, Albrecht Berkessel and A. C. O’ Donoghue, Chem. Eur. J., 2011, 17, 8524.
3. E. M. Higgins, J. A. Sherwood, A. G. Lindsay, J. Armstrong, R. S. Massey, R. W. Alder and A. C. O’Donoghue, Chem. Commun., 2011, 47, 1559.
4. <span >4.<span >           <span >L. F. Olguin, S. E. Askew, A. C. O’Donoghue and F. Hollfelder, J. Am. Chem. Soc., 2008, 130, 16547.
5. A. C. O'Donoghue, T. L. Amyes and J. P. Richard, Org. Biomol. Chem., 2008, 6, 391.
6. A. C. O'Donoghue, S. Y. Pyun, M. Yang, J. R. Morrow and J. P. Richard, J. Am. Chem. Soc., 2006, 128, 1615.