CO2 as a traceless directing group for C-H functionalization

Organic synthesis plays an essential role at the core of other disciplines, both in applied ones - such as drug discovery, or the development of new organic materials and sensors - and in more fundamental areas, such as chemical biology and the understanding of biological interactions at the molecular level. However, despite the many advances in our synthetic arsenal over the last century, this science is still limited in its ability to produce complex structures in an efficient way, hindering progress in all dependent disciplines. In 2009, these limitations were identified in the consultation conducted by the EPSRC, and 'Dial-a-Molecule - 100% efficient synthesis', as it was branded, has become one of the four Grand Challenges in chemical sciences and engineering. This Grand Challenge asks the question: how can we make molecules of interest in days instead of the currently needed years?

Traditional synthetic strategies require the presence of reactive functional groups that are used as handles for further functionalization. This requirement is one of the factors dramatically enhancing the difficulty of syntheses. The last two decades have seen the emergence of a more straightforward alternative: the catalytic direct functionalization 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. This approach has allowed us to dream of a future where any organic molecule could be synthesised in a direct manner by simply replacing the C-H bonds of a substrate with the required functionalities, as if building a ball-and-stick molecular model with our hands. The development of a full set of C-H functionalisation methodologies will impact on all applied areas, such as the synthesis of pharmaceuticals, agrochemicals, and new materials. Furthermore, their atom efficiency and low waste generation ensures a privileged position among the green chemistry methods.

For this strategy to succeed, numerous challenges are still to be overcome. In this research proposal we aim at addressing one of them, called the 'regioselectivity of C-H activation problem': aromatic compounds generally contain many different C-H bonds, so how can chemists select (activate) just one of these bonds in the desired position? In our research we will develop a methodology capable of doing just that: 'selecting' one particular C-H bond in a series of aromatic compounds and transforming it into a different -desired- functionality.

We will develop a catalytic synthetic methodology for the direct meta-functionalization of arenes which represents a great advance towards the EPSRC Grand Challenge 'Dial-a-Molecule: 100% efficient synthesis', since it allows direct access to functionalized molecules from simple and readily available starting material that would take many steps to prepare with current synthetic tools. Our new methodology will involve significant savings in terms of synthesis time (chemist and reactor time), energy cost, and a significant reduction in waste product formation from chemicals, solvents and purification materials that would be required in longer synthesis. Thus, our methodology will achieve significant improvements in terms of efficiency and sustainability. The functionalized organic molecules that will be available from 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 functionalized aromatic compounds will be of immediate use for synthetic chemists in all areas, such as natural product synthesis, materials, combinatorial chemistry and drug discovery.

ii) Pharmaceutical and fine chemicals companies are interested in the development of novel C-H functionalization methodologies, which will significantly reduce waste production and synthesis costs compared to traditional approaches. The use of the readily available starting materials instead of expensive pre-functionalized compounds will involve important economic savings. For example, 1 mol of phenol costs £3 (Aldrich), whereas the traditional starting materials to prepare meta-functionalized phenol, 3-bromophenol or of 3-hydroxyphenylboronic acid cost £576 and £3,160 for 1 mol, 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 that involve functionalized arenes. Specifically there would be applications 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 PDRA will be trained in the development of top-of-the-art catalytic methodologies. These skills will make them invaluable either in an academic or an industry environment, as experts in an expanding area with numerous applications.

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.