Mechanism-led development of catalytic C-H functionalisation

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.

Our research aims to develop catalytic C-H functionalisation as a means for the formation of new C-Y bonds (Y = O, N, C). Such a process is both chemically efficient and environmentally sustainable and represents a major advance on current approaches which rely on precursors containing C-X (X = Cl, Br, I) and (often) M-C (M = B, Zn, Sn) bonds. Both these classes of compounds require prior synthesis with the attendant energy usage and waste involved in their production. Moreover, catalysis with C-X/M-C substrates is itself atom inefficient due to the production of a metal salt (M-X) for each equivalent of product formed. This then requires further separation and disposal, increasing the energy costs and environmental impact.

Catalytic C-H functionalisation has the potential to revolutionise chemical synthesis by shortening synthetic routes and reducing waste in terms of raw materials and energy usage. The initial benefits will be realised in the fine chemicals industry and, through this, society at large. The post-doctoral research associates (PDRAs) employed on the project will also be direct beneficiaries.

Chemical Industry: The development of new routes via C-H functionalisation to heterocycle and carbocycle synthesis, particularly with well-defined selectivity, would be of enormous benefit to the fine chemicals industries. Such processes will not only offer new, improved routes to current synthetic targets, but also provide a new means to devise new syntheses of previously inaccessible materials.

The intrinsic efficiency of catalytic C-H functionalisation also promises an alternative, more sustainable approach to synthesis. It will achieve this by (i) reducing the waste inherent in current synthetic methods, both in terms of avoiding the pre-activation of substrates and reducing post-production clean up/separation and (ii) providing shorter synthetic routes with fewer steps, thus saving time and energy. In this way catalytic C-H functionalisation will help industry meet the increasing societal demand for environmentally friendly, low-impact chemical production.

Wider Society: The ability of the fine chemicals industry to target new heterocycles via C-H functionalisation will produce new commodities for use in pharmaceuticals, agrochemicals and technological materials. These will generate long-term enhancements in quality of life for the wider public. Societal demand for such products is therefore likely only to increase, however, it is important that the basis of their chemical synthesis is set on an environmentally sustainable footing. The intrinsic efficiency and broad scope of catalytic C-H functionalisation means it can deliver on both fronts.

PDRAs: Both will benefit from a first-class training in laboratory and analytical techniques (at Leicester) or an excellent training in the modern computational chemistry (at Heriot-Watt). They will also have the opportunity to develop employability skills. The collaborative nature of the project will demand and promote excellent communication skills and team-working. Presentation skills will develop through regular research talks, in their respective departments, at the 6-monthly project team meetings, and through presentations at regional, national and international conferences. Both PDRAs will gain experience in supervising undergraduate students.

Communication and team-working skills will be particularly enhanced by the PDRAs being involved in organising a workshop on C-H functionalisation They will emerge from this project as highly skilled workers with the capacity to contribute strongly to the UK, through employment in the chemical industry or in education.