Hybrid Magnesium-Zinc Reagents:Structural Tailoring for Synthetic and Catalytic Applications

Drawn up to break new ground quickly and to establish new frontiers in the area of mixed-metal chemistry, this proposal focuses on the general area of Synthesis, and specifically on the development and exploitation of a fundamental new type of organometallic reagent, namely Mg-Zn hybrids, featuring two environmentally friendly metals.One of the main missions for synthetic chemists is to improve and to add to the catalogue of reagents available, searching for new compounds that can offer enhanced reactivities but also superior selectivities and compatibility with a wide range of different substrates. In organometallic chemistry, organolithium reagents constitute one of the most important reagents in synthesis as reflected by that fact that it is estimated that 95% of the drugs manufactured in the pharmaceutical industry involve the use of these reagents at one or more steps in their synthesis. Organolithium compounds exhibit high reactivities, however their main limitation is their frequent lack of compatibility with many common organic functional groups, which ussually impose the use of sub-ambient temperatures. In this application we propose the development of an alternative type of reagent to conventional organolithium reagents, namely mixed magnesium-zinc reagents (Mg-Zn hybrids), prepared by combining two important but fundamentally distinct families of classical organometallic reagent: polar hard organomagnesium (R2Mg or RMgX) and non-polar soft organozinc (R*2Zn or R*ZnX) compounds. By using this mixed-metal approach we will instil into these compounds a new cooperative set of chemical properties and reactivity profiles, which will extend beyond the confines of traditional monometallic chemistry. A key aspect of the project will be to screen the reactivity of these new hybrids in fundamental organic reactions including metal-halogen exchange, deprotonative metallation or nucleophilic addition, not only stoichiometrically but also catalytically, by importing the high reactivity of organomagnesium reagents into organozinc reagents endowed with high functional group tolerance.

Direct short-term beneficiaries from this project will be the vast community of synthetic chemists both academic or and industrial (working on fine chemicals, agrochemicals, pharmaceutical manufacture, etc). The development of new hybrid synthetic methodologies for the functionalisation of organic molecules with a broad range functional groups that are not compatible with conventional monometallic reagents and also that allow the employment of mild reaction conditions (ambient temperature) may have an economic impact in scale up industrial processes. Furthermore, the extension of this bimetallic approach to catalytic processes using inexpensive and environmentally friendly inorganic salts such as MgCl2 or ZnCl2 as catalysts can have a global impact in the longer term. Advances in the catalytic aspects of the project will lead to potentially new synthetic methodologies that will reduce energy consumption, and waste compared to industrial stoichiometric applications. This project will also unveil new structural motifs in Mg-Zn chemistry which will be extremely valuable not only for organometallic chemists but also in the longer term to other scientists working in fields such as biomimetics and Mg/Zn bioinorganic chemistry, as both metals play essential roles in many biological processes. Eva Hevia as a principal investigator and the PDRA who will undertake this project will also be major beneficiaries. The success of this First Grant Scheme application will enable Eva Hevia to build up her research team by recruiting a PDRA, to strengthen her international profile in organozinc chemistry and also to extend her research portfolio, allowing the tackling of more experimentally challenging areas of research and ensuring that fast progress. The PDRA will have an excellent opportunity to broader her/his knowledge and this project will provide her/him with a string of new molecules/results suitable for publication in high impact chemistry journals in the international arena which will undoubtedly extend her/his career prospects whether in academia or in any other industrial or commercial concern. The results emerging from this project will be disseminated mainly via publication in internationally leading chemistry journals such as Angewandte Chemie or the Journal of the American Chemical Society. Another essential dissemination channel will be participation in international and national conferences (for example: PacificChem 2010, December 2010, Hawaii where a dedicated main group symposium will be held; the Gordon Organometallic Conference, Newport, Rhode Island, 2012;or ACS national meetings) which will provide an excellent forum for discussion and debate and also will help facilitate the establishment of future new collaborations.