Metal Catalysed Decarboxylative C-C Bond Formation Reactions

Organic synthesis has undeniably made tremendous progress over the past two centuries. Nevertheless, our ability to efficiently synthesise molecules is mostly limited to targets of low structural complexity. Preparing more sophisticated compounds is currently possible; however, their syntheses are highly inefficient: they usually involve a high number of reaction and purification steps, with a consequent increase in waste generation, and a dramatic reduction in overall yields. Consequently, these syntheses are generally not applicable to the sustained production of complex molecules of interest. This observation has led to a general consensus in the scientific community as to the urgent need for new chemical processes supporting the development of a "greener" and more sustainable chemical industry.
Traditional synthetic strategies require the presence of reactive functional groups that are used as handles for further functionalisation. This requirement is one of the factors dramatically enhancing the difficulty of syntheses. In addition, often these 'handles' are not part of the final molecule and are lost as waste by-product that may be toxic and needs to be separated and dealt with. The last two decades have seen the emergence of a more straightforward alternative: the direct functionalisation of C-H bonds. Through this strategy the typically inert C-H bonds, ubiquitous in organic molecules, can be activated by transition metal catalysts and subsequently functionalised. A second approach involves the use of carboxylic acids that can be activated via decarboxylation to direct very accurately the reactivity in a given molecule.
In our research we want to combine both of these new types of reactivity to develop a series of methodologies that can form bonds between carbon atoms of molecules with a very limited amount of waste by-product and in an efficient manner. The development of such new transformations will impact on all applied areas, such as the synthesis of pharmaceuticals, agrochemicals and new materials, by providing cheap and easy access to molecules that are very difficult to make to date (and therefore not used commercially).

In our proposed research we will develop a synthetic methodology known as decarboxylative cross-coupling which represents a great advance towards the EPSRC Grand Challenge 'Dial-a-Molecule: 100% efficient synthesis', since it removes the requirement for pre-functionalisation of one or both of the coupling partners required for normal cross-couplings. This pre-functionalisation usually involves the use of large amounts of metals and halogens. Thus our new methodology will save several synthetic steps and the formation of the corresponding metallic toxic waste, greatly increasing efficiency. The biaryl organic structures produced with this methodology are components of myriads of organic compounds in all areas of life.
We expect that this research will have both short and long term impact on the following areas:
i) General organic synthetic chemistry: the creation of this new tool for the efficient and clean synthesis of a wide variety of biaryl organic structures will be of immediate use for synthetic chemists in all areas, such as natural product synthesis, materials, combinatorial chemistry and drug discovery.
The private sector will benefit from the results of this research:
ii) Pharmaceutical and fine chemicals companies are interested in the development of novel C-H and decarboxylative arylation methodologies, which will significantly reduce waste production and synthesis costs compared to traditional cross-couplings reactions. The use of the readily available benzoic acids instead of expensive and toxic organometallic reagents or iodoarenes will reduce costs even more. For example, 1 mol of 2-nitrobenzoic acid costs £16, whereas 1 mol of 2-iodonitrobenzene or of 2-nitrophenylboronic acid cost £576 and £7,448, respectively, representing several orders of magnitude in savings. These factors will combine to allow the production of new medicines and pesticides that at the moment would have prohibitive costs. Our research will have immediate impact on this sector, but the benefits of improved production of medicines will take several years for them to be noticed by the general public, in terms of reduced cost and greater availability of medicines.
iii) The methodologies developed in this research can also be applied to the synthesis of new materials. Specifically in the area of plastic electronics, such as conducting polymers, organic light emitting diodes (OLED) and thin film transistors (OTFT), which will be used in television and computer screens, and displays for portable devices among others. These are all areas of high industrial interest since they involve technologies at the heart of a new generation of electronic devices. Again, impact will be immediate for researchers in this sector, but years will be required before the benefits are observed outside of the sector.
iv) Society in general will also benefit from this research. During the course of this project, a PhD student will be trained in synthetic organic chemistry. This student will gain skills that will make them invaluable either in an academic or an industry environment, since they will become experts in an area of synthetic organic chemistry with numerous applications. Furthermore, the training of a postdoctoral researcher will deliver a highly competent researcher capable of independent work and of generating completely new exciting research areas with future long term benefits for society.
v) Other benefits for society from this research will have more long term effects: our research will be a stepping stone for further clean, efficient and greener methodologies that together will lead to the Holy Grail of synthetic chemistry: the 'perfectly efficient synthesis'. This development will multiply by many orders of magnitude the growth and development in all other scientific areas that depend on the chemical supply of starting materials, such as medicine and drug discovery, engineering, materials, nanotechnology and communication technologies.