Mechanism-led development of catalytic C-H functionalisation

Lead Research Organisation: Heriot-Watt University
Department Name: Sch of Engineering and Physical Science

Abstract

Methods for the formation of C-C and C-Y (Y = O, N) bonds are crucial for the synthesis of new molecules. In the last 30 years there have been huge advances in Pd-catalysed cross-coupling reactions and this was recognized in the award of the 2011 Nobel Prize. These reactions involve joining together two organic molecules, one of which features a bond between carbon and a halogen (a C-X bond) while the other coupling partner may feature a non-carbon centre such as tin, boron or zinc (a C-M bond). The coupling of these two partners to give a new C-C bond usually involves a palladium catalyst. More recent versions have coupled C-N or C-O bonds. These coupling reactions generally work well, however the efficiency of this individual step masks significant waste of time and energy, as well as problems with environmental sustainability. These problems arise because both C-X and C-M coupling partners ultimately derive from precursors that only contain C-H bonds and therefore require prior synthesis. This preactivation usually involves several steps, each with costly energy and purification implications. Moreover, the final coupling process itself eliminates salts (M-X) that must first of all be separated from the reaction products before disposal. This is a further costly and expensive process that often has a significant environmental impact.

A far more desirable approach would be to use the unactivated C-H containing precursors directly as the coupling partners. Such compounds are readily available and cheap. This approach would circumvent the need for the costly and wasteful preactivation that is required to make C-X and M-C species, as well as the post processing clean up of M-X by-products. Until very recently this approach has not been adopted as C-H based precursors are usually rather chemically inert. However, catalysis based on such C-H species (catalytic C-H functionalisation) is now within reach, mainly due to recent advances where the means to activate the C-H bond with a transition metal catalyst have been understood. A key point in C-H functionalisation is to have a directing group elsewhere on the feedstock molecule so that it can interact with the metal catalyst and so bring the C-H bond close enough to react. The M-C bond that is thus formed can then undergo reactions with other substrates to produce the desired C-C, C-N or C-O bond. Moreover, if instead this new bond is formed with another atom in the same molecule then a ring is formed. Such cyclic compounds containing an N or O atom are called heterocyclic compounds and play a key role as major constituents of pharmaceuticals and agrochemicals. In addition, they often have interesting optical and electrical properties in their own right that are important in a range of technological applications. It is therefore crucial that the synthesis of heterocyclic compounds is as efficient as possible; moreover the need for a wide range of heterocycles with different properties depends upon the development of new, efficient methods for their synthesis.

Although there is precedent for this type of catalytic C-H functionalisation in the scientific literature, to date there is little understanding of what controls this reactivity. Thus the range of species that can be made is limited, the catalysis is not yet efficient and the selectivity of the reaction is poorly understood. To improve this situation requires a deeper understanding of how these systems work. We aim to provide this here through a combination of experimental studies and computational modeling. By understanding the factors that control reactivity and selectivity we will be able to design new, more efficient catalysts and also to widen the scope of the catalytic C-H functionalisation methodology. The ultimate aim is to provide a flexible set of efficient synthetic tools that chemists will be able to use to make a wide range of important heterocycles in an environmentally sustainable manner.

Publications

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Johnson HC (2013) Dehydrogenative boron homocoupling of an amine-borane. in Angewandte Chemie (International ed. in English)

 
Description Understanding mechanism of C-H activation at transition metal catalysts
Exploitation Route In designing better metal catalysts
Sectors Chemicals