The preparation of therapeutics relies largely on the ability of chemists to construct a wide range of organic molecules. Since many pharmaceuticals contain a sophisticated carbon skeleton, processes that selectively couple two carbon moieties are of paramount importance. One of the most efficient and selective carbon-carbon bond forming methods is the ruthenium-catalyzed olefin metathesis reaction. Since iron is inexpensive and has a low toxicity, a significant technological advance would be to design iron-based olefin metathesis catalysts. Preparing such catalysts will require the synthesis of hitherto unknown low-coordinate iron alkylidenes. As a starting point, neutral iron(ll) alkylidenes of the formula CI2(L)Fe=C(H)R, where L is a cyclic amino carbene ligand, will be prepared. In contrast to ruthenium alkylidenes that are typically low-spin, iron complexes CI2(L)Fe=C(H)R may exist in a high-spin state. Due to the presence of at least one electron in all of the d-orbitals of the transition metal center, high-spin CI2(L)Fe=C(H)R complexes may resist olefin coordination, consequently retarding metathesis activity. A solution to this potential problem would be to synthesize XCI(L)Fe=C(H)R and X2(L)Fe=C(H)R complexes, where X is a CN- or C6F5- group. Replacement of the CI- groups of CI2(L)Fe=C(H)R by these stronger field ligands will increase the ligand field splitting parameter in the system, which should promote a lower-spin state more favorable for olefin coordination. Another approach to providing accessible coordination sites for substrate binding would be to render CI2(L)Fe=C(H)R complexes cationic by chloride abstraction. The resultant XCI(L)Fe=C(H)R and X2(L)Fe=C(H)R, where X is an extremely non-coordinating counterion such as B(C6F5)4- or HBC11Cl11-, should dissociate in solution to form the formally 12 and 10 electron iron mono and dications CI(L)Fe=C(H)R+ and (L)Fe=C(H)R2+, respectively. A different approach would be to prepare neutral iron(O) alkylidenes. An ideal iron(0) species that may display metathesis activity would be (R3P)LFe=(H)R. Complexes of this class should be capable of dissociating the phosphine ligand in solution, to afford LFe=(H)R fragments with at least two vacant coordination sites, independent of the spin state of the metal. The ultimate goal of this research proposal is to provide the synthetic community with inexpensive, environmentally benign, highly active and selective olefin metathesis catalysts.
The proposed research plan intends to use iron compounds to provide methods that allow pharmaceuticals to be produced in a more environmentally friendly and cost effective manner. Thus, this work may ultimately provide clean methods to produce cheaper medicines. ? ? ?
| Lavallo, Vincent; Grubbs, Robert H (2009) Carbenes as catalysts for transformations of organometallic iron complexes. Science 326:559-62 |
