Research

  1. Guiding Principles for the Rational Design of Chiral N-Heterocyclic Carbene Ligands

    During the last decade, N-heterocyclic carbenes (NHCs) derived from imidazole, pyrazole and triazole (A - C, respectively; Chart 1) and the C=C saturated (imidazolinylidine) D have emerged as an important class of ligands for the transition metals. Although the first complexes were made as early as 1968, the isolation of imidazolylidenes (A) as free, stable species by Arduengo et al. in 1991 initiated a renewed flurry of research in the area that continues to this day.

    Chart 1

    N-heterocyclic carbenes

    In the early 1990s, striking similarities between NHCs and tertiary phosphines in terms of ligand properties and metal complex syntheses were observed, and a flood of reports detailing the use of NHCs in homogeneous catalysis ensued. Metal-NHC complexes continue to fill an ever-expanding role as catalysts, in part because of their remarkable thermal stability and tolerance of air and moisture.

    However, subsequent calorimetric and structural studies showed that early apparent similarities between NHCs and phosphines, which had been useful in extending the chemistry of this new class of ligands, were somewhat misleading. NHCs are now recognised to be stronger sigma-donors than the best phosphine donors, are generally more sterically demanding, and, unlike phosphines, have almost no pi-acidity.

    Although a range of chiral NHCs is now known, there are very few reported cases in which these give good enantiomeric excesses (ees) in asymmetric catalytic reactions, whereas examples involving chiral phosphines are extremely numerous. This contrast may have arisen because the early analogy ensured that the same strategies that had been used in the syntheses of chiral phosphines were applied in making chiral NHC derivatives. Direct attention has not been paid to the significant electronic differences between the two ligand classes.

    To date, and possibly as a consequence, chiral NHCs have found successful application in only a handful of highly-enantioselective (> 90 % ee) catalytic reactions. These include the asymmetric hydrogenation of aryl alkenes (Ir), alkylation of aryl allyls (Pd), and ring-opening metathesis/cross metathesis (AROM/CM) of cyclic and linear alkenes (Ru), which are catalyzed by the complexes shown in Chart 2 and their derivatives (Ar = 2,6-diisopropylphenyl.)

    Chart 2

    Chiral NHC complexes for asymmetric catalysis

    The lack of highly enantioselective catalytic applications of NHCs may not only be a simple consequence of the relative immaturity of the field, but also of hitherto unappreciated electronic as opposed to steric effects. Using detailed kinetic, thermodynamic and computational methods, we are exploring this and other hypotheses in an attempt to elucidate guiding principles for the synthesis of highly enantioselective catalysts based on NHCs.

  2. Chiral "Pincer" N-Heterocyclic Carbene Ligands for Asymmetric Catalysis

    The chemistry of "pincer" complexes based on cyclometallated phosphine, amine, (thio)ether and mixed donor ligands (Chart 3) continues to attract attention. Since the pioneering investigations of the mid 1970s, the field has experienced prolific growth both in the variety of known complexes and in the range of their stoichiometric and catalytic applications. The chemistry of pincer complexes now incorporates reactions as diverse as alkane dehydrogenation, activation of small, relatively inert molecules like CO2 and N2, C-X bond formation1 and activation (X = C, N, O), polymerization of alkynes and transfer hydrogenation catalysis.

    Chart 3

    General pincer ligands

    The unique pincer manifold allows for the synthesis of a wide variety of useful and interesting derivatives, as shown in Chart 4. The many opportunities for variation have been well exploited, and several interesting applications outside of catalysis have emerged. For example, Pt NCN pincer complexes have been used as sensors for SO2 and bimetallic Ru NCN complexes have been employed as "molecular switches."

    Chart 4

    The advantageous aspects of pincer ligands

    Whereas the chemistry of phosphine-, amine, and thiol-based pincer complexes is now relatively mature, investigations into analogous N-heterocyclic carbene (NHC) derivatives are still in their infancy; the earliest communications appeared in 2001. Since then only a handful of reports. Chart 5 shows a generic representation of the types of imidazolium precursors to bis(NHC) pincer ligands that have so far been described in the literature.

    Chart 5

    NHC pincer ligands

    There are a few reported investigations into the use of these complexes in catalysis. Palladium derivatives have been used in Heck and Sonagashira C-C bond forming reactions, while ruthenium complexes have been used in transfer hydrogenation of ketones and in oxidative cleavage of alkenes.

    We are developing a series of novel chiral pincer NHC ligands for use in other asymmetric catalytic applications.

  3. High-throughput Screening for Enantiomeric Excess

    Enantiomerically pure compounds are becoming increasingly important in today's chemical industry. A recent Chemical and Engineering News article estimates that in the pharmaceutical division alone, this "chiral market" accounted for US$ 159 billion in 2002.

    An attractive way to access enantiomerically pure compounds is by asymmetric catalytic synthesis. Two core technologies are being developed to discover the requisite chiral catalysts. These are combinatorial synthesis and high-throughput ee-screening (ee = enantiomeric excess.)

    Whereas combinatorial synthesis is undergoing rapid development, high-throughput ee-screening remains the stumbling block to rapid discovery of (bio)catalysts for asymmetric transformations. Even as recently as 1997, not a single high-throughput, ee-screening system existed

    We are pursuing methods for quantitative, high-throughput, ee-screening that rely on molecular recognition events which are coupled to massive colour changes.