Direct Functionalization of Heteroarenes using Phosphorus

Direct functionalization converts chemically inert C-H bonds into chemically malleable C-R bonds (R = B, C, N, O, Cl, Br, I). Controlled functionalization in this manner is highly important in synthetic science, as it creates the building blocks necessary for countless man-made goods, from pharmaceuticals to polymers, electronics and agrochemicals. Catalysts that enable this transformation are largely based on expensive nonrenewable precious metals, including palladium and iridium, sourcing of which has significant environmental and geopolitical issues. Finding sustainable alternatives based on cheap and earthabundant p-block elements, including phosphorus, has become increasingly urgent. We propose exploiting the multiple coordination sites offered by p-block clusters to catalyze the direct functionalization of heteroarenes, including pyridine, in one convenient step. About 60% of FDA approved pharmaceuticals alone feature a nitrogen heterocycle, such as pyridine.
PRELIMINARY RESULTS: We have prepared and characterized the first example of a boron functionalized group 15 Zintl cluster. Compound 1 was found to be a very active catalyst for the addition of H-B bonds, hydroboration, across pyridines in a selective 1,4-fashion. Interestingly, it was also found that upon aqueous work-up of the reaction, the pyridine was reformed and H2 gas eliminated. These findings reveal that clusters can act as catalysts to add H-B bonds across pyridines, and re-aromatization and H2 elimination are strong driving forces. Re-aromatization in this hydroboration transformation is undesirable. Can we turn this negative into a positive?
HYPOTHESIS: In our preliminary results, upon aqueous work-up we lose the hydride installed during the catalytic hydroboration. But if a nucleophile other than hydride is installed, and an H atom lost during rearomatization we would metathesis a C-H bond for a C-R bond. Compared to other catalysts that convert C-H bonds to C-R bonds on heteroarenes, our catalysts are based on the cheap and sustainable p-block element phosphorus. Polyphosphorus clusters are attractive platforms as catalysts because they can be structurally related to the heterogenous material red phosphorus.[6] Red phosphorus is very inexpensive and sustainable, but difficult to study. Catalytic transformations established with [P7] clusters will be extended to larger polyposphides, for example [P16] and [P21] systems, and then with red phosphorus itself. Studies with the molecular clusters allow for in situ studies, reaction optimizations, and mechanistic invesigations. While, red phosphorus-based catalysts open the door to industry translation and high recyclability / stability.
OVERALL AIM: Establish phosphorus-based materials as catalysts for direct functionalization of heteroarenes.
We will achieve our overall aim by meeting three Objectives:
Objective A: Using [P7] catalysts activate B-R bonds with phosphorus/boron-based clusters.
Objective B: Using pyridines as a prototype, close the catalytic cycle and optimize catalytic conditions.
Objective C: Develop catalysis with larger polyphosphorus materials.
TRAINING OFFERED: multi-nuclear NMR, XRD diffraction, computational chemistry, inert-atmosphere synthesis, organometallic chemistry, and mechanistic studies.

iCAT will work with industry partners to create an holistic approach to the training of students in biocatalysis, chemocatalysis, and their process integration. Traditional graduate training typically focuses on one aspect of catalysis and this approach can severely restrict innovation and impact. Advances in technology and fundamental reaction discovery are rendering this silo-approach obsolete, and a new training modality is needed to produce the next generation of chemists and engineers who can operate across a far broader chemical continuum. iCAT will meet this challenge with a state-of-the-art CDT, equipping the next generation of scientists and engineers with the skills needed to develop future catalytic processes and create the functional molecules of tomorrow.

The UK has one of the world's top-performing chemical industries, achieving outstanding levels of growth, exports, productivity and international investment. The UK's chemical industry is a significant provider of jobs and creator of wealth, with a turnover in excess of £50 billion and a contribution of over £15 Billion of value to the UK economy [2015 figures]. iCAT will deliver highly skilled people to lead this industry across its various sectors, achieving impact through the following actions:

1. Equip the next generation of science and engineering leaders with the interdisciplinary skills and knowledge needed to work across the bio and chemo catalytic remit and build the functional molecules we need to structure society.

2. Provide a highly skilled workforce and research base, skilled in the latest methodologies, strategies and techniques of catalysis and engineering that is crucial for the UK's Chemical Industry.

3. Build the critical mass necessary to support effective cohort-based training in a world-class research environment.

4. Develop and disseminate new catalytic technologies and processes that will be taken up by industrial and academic teams around the world.

5. Encourage Industry to promote research challenges within the CDT that are of core relevance to their business.

6. Provide cohesion in the integration of biocatalysis, engineering and chemocatalysis to create a more unified voice for strategic dialogue with industry, funders and policy makers, and more generally outreach and public engagement.

7. Draw-in and bring together Industrial partners to facilitate future Industrial collaborations.

8. Benefit Industrial scientists through interactions with the CDT (e.g. training and supervisory experience, exposure to cutting-edge synthesis and catalysis etc).

9. Link with other activities in the landscape: bringing unique expertise in catalysis to, for example, externally-funded University-led initiatives, EPRSC Grand Challenge Networks, and the National Catalysis Hub.