Mechanistic Insights into Organocatalytic Processes
Lead Research Organisation:
Imperial College London
Department Name: Chemistry
Abstract
The use of small organic molecules as catalysts (known as organocatalysis ) is currently attracting intense interest. These systems have the advantage that they avoid the use of potentially toxic metal catalysts and that useful chemical reactions can often be performed under mild conditions without the need for rigorous exclusion of air or water. They also often allow us to control which mirror image form (or enantiomer ) of a molecule is synthesized, which is a crucial requirement for pharmaceutical synthesis. Overall, therefore, they offer the possibility of easier, cleaner, more efficient ( greener ) syntheses of many very important types of compound. Despite the multitude of reactions that have been studied in the laboratory, we do not understand exactly how many of these catalysts work. In particular, many papers have been published claiming beneficial effects of changes of reaction conditions or the inclusion of additives in reactions (for example, water, acids or bases). In this project, we will try to greatly improve our understanding of how these reactions are catalyzed. We will measure the rates of chemical reactions ( chemical kinetics ) using an in situ technique pioneered by one of the applicants, and combine these results with information from spectroscopic and computational methods. We will focus on a reactions which involve additions to carbon-oxygen and carbon-carbon double bonds ( conjugate addition processes ), including the synthesis of aziridines, strained three-membered rings containing nitrogen which are highly valuable building blocks for pharmaceutical synthesis. These studies will lead us into the study of more complex reaction systems aimed at understanding reactions involving more than one catalyst or reaction step, and particularly autocatalytic reactions , ones where the reaction product catalyses its own formation. These reactions have important implications for understanding how life might have originated, as well as in suggesting new and more efficient chemical catalysts.
Organisations
Publications
Armstrong A
(2011)
Enantioselective synthesis of a-alkyl,a-vinyl amino acids via [2,3]-sigmatropic rearrangement of selenimides.
in Organic letters
Armstrong A
(2014)
The Houk-List transition states for organocatalytic mechanisms revisited
in Chem. Sci.
Blackmond DG
(2010)
Unusual reversal of enantioselectivity in the proline-mediated alpha-amination of aldehydes induced by tertiary amine additives.
in Journal of the American Chemical Society
Burés J
(2011)
Mechanistic rationalization of organocatalyzed conjugate addition of linear aldehydes to nitro-olefins.
in Journal of the American Chemical Society
Burés J
(2016)
Explaining Anomalies in Enamine Catalysis: "Downstream Species" as a New Paradigm for Stereocontrol.
in Accounts of chemical research
Burés J
(2014)
Rationalization of an unusual solvent-induced inversion of enantiomeric excess in organocatalytic selenylation of aldehydes.
in Angewandte Chemie (International ed. in English)
Burés J
(2012)
Curtin-Hammett paradigm for stereocontrol in organocatalysis by diarylprolinol ether catalysts.
in Journal of the American Chemical Society
Hein JE
(2011)
Enamine carboxylates as stereodetermining intermediates in prolinate catalysis.
in Organic letters
Hein JE
(2011)
Kinetic profiling of prolinate-catalyzed a-amination of aldehydes.
in Organic letters
| Description | Catalysts are essential to speed up chemical reactions so that new molecules with important properties - such as agrochemicals and pharmaceuticals - can be prepared quickly, cleanly and with mimimal energy consumption. Catalysts that can control the 3D-shape of new molecules are particularly important. Traditionally, catalysts based on transition metals have been used, but these can be toxic, expensive and require carefully-controlled reaction conditions. A relatively recent development, known as organocatalysis, can potentially get round all of these problems by using small organic molecules as catalysts. However, relatively little is known about how these catalysts work, which makes optimising and designing new catalysts difficult. In this project, we looked closely at some important organocatalytic reactions using advanced techniques such as reaction calorimetry, infrared and NMR spectroscopy which allowed us to monitor the chemical species present during the course of these reactions. This allowed us to understand the reactions much more fully and to make them more efficient. We discovered several new phenomena that have big implications for better catalyst design in the future. For example, we found that addition of small amounts of co-catalysts (bases) can make some reactions give the opposite "mirror-image" 3D-form of the reaction product, an important finding for pharmaceuticals synthesis in particular. Also, by identifying some key reaction intermediates which can "protect" the catalyst and key reactants until they are needed, we developed an understanding of how to design so-called "tandem" processes, which can potentially allow several chemical reactions to be carried out at once in the same reaction vessel, thus making enormous savings in time and energy as well as drastically reducing chemical waste. |
| Exploitation Route | Catalysis is extremely important in the fine chemicals, agrochemicals and pharmaceutical industries where efficient preparation of new molecules with minimum energy input and waster is paramount. The improved understanding of organocatalytic processes developed in this project can contribute towards these goals. The discovery in this project that amine co-catalysts can alter the stereochemical outcome of amino acid-catalysed alpha-functionalisations of carbonyl compounds offers enormous potential for the development of new catalysts as well as for tuning the reactivity of existing ones. This effect is of importance to researchers in both academia and industry. The project also revealed another important and potentially general concept: the role of stable catalytic reaction intermediates in determining reactivity and stereochemistry. This can also be put to use in the development of new, improved, more selective catalyst systems with potential application for the synthesis of many important molecules. |
| Sectors | Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology |