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Olefin metathesis reactions State of the art and outlook ABSTRACT THERMODYNAMIC CONSIDERATIONS Olefin metathesis is a metal-catalysed organic reaction, which involves the statistical redistribution of carboncarbon double bonds. Since its discovery in the 1950's, this transformation has gained widespread use in research laboratories and industry for making products ranging from drugs and polymers to enhanced fuels. Its advantages include the ability to build up complex structural scaffolds with remarkable atom economy. Major industrial processes usually rely on inexpensive, ill-defined, multicomponent catalytic systems, while research laboratory applications take advantage of well-defined metal alkylidene complexes of molybdenum and ruthenium that combine high activities and ease of set-up under reproducible conditions, albeit at the price of a higher cost. Olefin metathesis is generally reversible and limited to an equilibrium. In many cases, however, the transformation may be brought to completion based on simple thermodynamic considerations. For instance, ringopening processes are enthalpically driven due to the relief of ring strain, whereas ring-closing metathesis is entropically driven because the reaction cuts one substrate into two pieces. In both cases, high selectivities toward products can usually be achieved. On the other hand, the cross-metathesis of acyclic compounds is essentially a thermoneutral process that eventually results in a statistical distribution of reactants and products. Therefore, it is necessary to shift the equilibrium in one direction in order to make the process suitable for preparative applications. Metathesis of an α-olefin yields ethylene and a symmetrical internal olefin. In such a case, the reaction can usually be driven to completion by removal of volatile ethylene. With alkadienes and polyenes the reaction may follow intra- or intermolecular pathways. The intramolecular metathesis of an α, ω-diene yields ethylene and an unsaturated carbocycle (or heterocycle) via ring-closing metathesis, whereas the intermolecular reaction results in the formation of ethylene and an oligomer or a polymer via acyclic diene metathesis polymerisation. Whether the intra- or intermolecular pathway dominates depends on the relative stabilities of the linear and cyclic products. Usually, strained cycloolefins preferentially undergo ringopening metathesis polymerisation. In a manner analogous to step-growth polycondensation of polyesters, polyenes are formed by step-growth metathesis of the double bonds in a diene. If the reaction is run under sufficient vacuum to remove the ethylene as it is formed, the equilibrium may be shifted toward high molecular weight species. Yet, because the acyclic diene metathesis polymerisation is equilibrium-driven, addition of excess ethylene to a macromolecular chain will shift the reaction in the reverse direction and promote depolymerisation. SCOPE OF THE REACTION Olefin metathesis is a metal-catalysed carbon skeleton redistribution, in which a mutual exchange of unsaturated carbon-carbon double bonds takes place (1). In other words, olefin metathesis constitutes a catalytic method for both cleaving and forming C=C double bonds. The reacting alkenes need not be identical. Indeed, many olefinic substrates can undergo metathesis to afford an extensive range of new unsaturated products. Suitable substrates include substituted alkenes, terminal and internal alkenes, cycloalkenes, dienes, and polyenes. Through skeletal rearrangement, unsaturated products that can be acyclic compounds, small- or medium-size carbo- and heterocycles, macrocycles, or polymer chains are obtained. Depending on the types of substrate and transformation, several categories of metathesis have been defined (Scheme 1). Two or more basic operations can be performed consecutively in the so-called tandem, domino, or cascade metathesis processes. Alternatively, various metathesis reactions can proceed simultaneously and independently if suitable polyolefin substrates are employed. Whether the reactions occur in sequence or in parallel, the accumulation of multiple metathesis events allows to build up complex structural scaffolds very efficiently and rapidly in a single operation. In its most recent embodiment, olefin metathesis has also been employed for the desymmetrization of prochiral polyolefins or for the kinetic resolution of racemates. Although research in this field is still in its infancy, recourse to olefin metathesis for inducing chirality in organic substrates provides yet another valuable addition to the already broad scope of this reaction. Metathesis reactions ALBERT DEMONCEAU LIONEL DELAUDE Scheme 1. Various types of olefin metathesis reactions and their acronyms chimica oggi • Chemistry Today • Vol 25 nr 5 • September/October 2007 65 Metathesis reactions 66 parameters that affect the activity of the catalysts based on early transition metals. The Olefin metathesis is a child of strategy elaborated to obtain industry and was discovered by highly efficient, well-defined, accident. The reaction came to four-coordinate high oxidation Scheme 2. Plausible mechanism for olefin crosslight as a serendipitous outgrowth state alkylidene complexes metathesis showing the intermediacy of metal alkylidenes in the systematic study of Ziegler involved the selection of bulky and metallacyclobutanes polymerisation catalysts with alkoxide ligands, which increase alternate transition metal-based the electrophilicity of the metal systems (2). The first catalysed metathesis reactions were centre and favour reactions with olefins while blocking observed in the late 1950’s when chemists at DuPont, bimolecular decompositions. The design of tetrahedral Standard Oil, and Phillips Petroleum reported the Mo(VI) and W(VI) complexes that contain an alkylidene metathesis of propene with catalysts based on molybdenum and two alkoxide ligands also required that a sterically and tungsten. It was soon established that olefin metathesis bulky dianionic ligand be the fourth substituent. In this could take place in the presence of various homogeneous respect, the 2,6-dimethyl- or 2,6-diisopropylphenyl imido and heterogeneous catalysts. Cyclic olefin monomers were ligands were found to maximize steric bulk while limiting also tested under similar experimental conditions and found the possibility of side reactions. Prominent among the to produce low yields of amorphous, rubbery polymers initiators developed along these lines, are Schrock's with unexpected structures. It took some more years to molybdenum catalysts depicted in Figure 1. They are recognize that the disproportionation of acyclic olefins and commercially available and display very high levels of the ring-opening polymerisation reactions were two sides selectivity and activity that remain unchallenged so far. of the same coin, and even a longer period of time to Their use is, however, restricted to substrates devoid of establish the true nature of the reaction (3). highly polar functional groups. They are also very sensitive to oxygen and moisture and must be handled under rigorously inert conditions using Schlenk or glove MECHANISM: IT TAKES TWO TO DANCE box techniques. Chiral alkoxides may also serve as ligands for high Although many researchers put oxidation state imido alkylidene complexes of forward proposals to explain how molybdenum and tungsten. For example, molybdenummetathesis could take place (4), based compounds associated with enantiomerically pure the breakthrough came in 1971. biphenolate or binaphtholate derivatives were developed In a landmark publication, Jeanin the groups of Schrock and Hoveyda (Figure 2). They Louis Hérrison and Yves Chauvin have been used in a variety of metathesis reactions to proposed that the catalyst was a induce asymmetry (6). compound in which the metal is Figure 1. Schrock bound to the carbon with a molybdenum catalysts double bond, often referred to as LATE TRANSITION METAL INITIATORS a metal alkylidene (5). In the catalytic cycle for crossAmong the many carbene complexes based on late metathesis, this active species first transition metals that were tested as potential metathesis reacts with the olefin to form a catalysts, ruthenium derivatives stand out for their four-membered ring called a versatility and efficiency. The first well-defined alkylidene metallacyclobutane (Scheme 2). complex based on ruthenium was synthesised by Robert This intermediate then cleaves, H. Grubbs in 1992 using triphenylphosphine as an yielding ethylene and a new ancillary ligand (7). Poorly active, it only polymerised metal alkylidene, which reacts highly strained cycloolefins, such as norbornene. In sharp Figure 2. Hoveyawith a new alkene substrate to contrast with the molybdenum-based systems developed Schrock chiral yield another metallacyclobutane. by Schrock, where the more electron-withdrawing the molybdenum catalysts On decomposition in the forward ancillary ligands the higher the catalytic activity, Ru(II) direction, this second intermediate complexes need to be associated with powerful electronyields the internal alkene product donating ligands in order to display high catalytic and regenerates the initial metal activities. Thus, a second initiator containing two strongly alkylidene who is now ready to basic tricylohexylphosphines (PCy3) proved to be a much enter another catalytic cycle. more efficient metathesis promoter than its predecessor (8). This complex is commercially available and often referred to as the (first generation) Grubbs catalyst EARLY TRANSITION METAL (Figure 3). Because of its relative ease of synthesis, high INITIATORS catalytic activity, and broad functional group tolerance, it has been adopted as the standard metathesis catalyst in An important milestone on the many research laboratories. path to modern metathesis A significant leap forward occurred when one phosphine initiators was reached by Richard ligand in the original Grubbs catalyst was replaced by a R. Schrock with the synthesis of N-heterocyclic carbene (NHC). Compared to phosphines, well-defined, high oxidation state NHCs are better σ-donors and form stronger bonds to imido alkylidene complexes of metal centres (9). As a result, mixed NHC/phosphine tantalum first, soon followed by ruthenium alkylidene complexes display higher metathesis Figure 3. Ruthenium tungsten and molybdenum (6). activity and greater thermal stability than their catalysts for olefin His fundamental work helped diphosphine analogues (10). Of particular interest is the metathesis gain a better understanding of the complex bearing a 1,3-dimesitylimidazolidin-2-ylidene HISTORICAL BACKGROUND chimica oggi • Chemistry Today • Vol 25 nr 5 • September/October 2007 Metathesis reactions Figure 4. Chiral Grubbs and Hoveyda-Grubbs catalysts ligand (abbreviated SIMes or H2IMes). This compound is commercially available and is nicknamed the “Super Grubbs” or second generation Grubbs catalyst (Figure 3). Extensive ligand customization led to the introduction of Grubbs-type catalysts containing monodentate and/or chelating N-, O-, P- and Cl-donor ligands. Among them, styrenyl ether complexes stand out for their high stability toward air and moisture (11). Hence, they are conveniently purified and recycled by column chromatography without particular precautions. Compounds bearing a PCy3 or a SIMes ligand are both commercially available, although expensive. They are known, respectively, as the first and second generation Hoveyda-Grubbs catalysts (Figure 3). The internal chelation of the ether influences the initiation and propagation rates defined for the corresponding nonchelated initiators. The Hoveyda-Grubbs complex initiates approximately 30 times slower but propagates nearly 4 times faster than the original Grubbs catalyst, while the second generation Hoveyda-Grubbs complex is a fast initiating catalyst, which proved particularly efficient in cross metathesis of electron-deficient olefins. Chiral NHC ligands were also designed to further expand the scope of ruthenium-promoted olefin metathesis (Figure 4) (12). APPLICATIONS OF ALKENE METATHESIS Olefin metathesis has opened up new routes to important petrochemicals, oleochemicals, polymers, and specialty chemicals (13). The transformation often gives access with remarkable atom economy to structures that are not available by any other means, or only via painstaking multi-step procedures. Cross-metathesis and ring-closing metathesis are particularly suited for the construction of small open-chain molecules and macrocycles, respectively. These reactions serve, inter alia, as key steps in the synthesis of various agrochemicals and pharmaceuticals such as macrocyclic peptides, cyclic sulfonamides, novel macrolides, or insect pheromones (14). Ring-opening metathesis polymerisation has also become an invaluable tool for the preparation of advanced materials when a precise control over the polymer architecture and a good functional group tolerance are needed. Applications in this field range from biosensors to nonlinear optics and electronics to name just a few (15). Currently, there is still a marked dichotomy between major industrial processes, which rely on inexpensive, ill-defined, multicomponent catalytic systems, and laboratory research, where the use of well-defined metal-alkylidene complexes is often preferred to guarantee high activities under reproducible conditions, albeit at the price of a much higher cost (16). Large-scale applications of Grubbs-type catalysts are still scarce but the situation is rapidly evolving. For instance, Boehringer Ingelheim recently disclosed the synthesis of a macrocyclic hepatitis C protease inhibitor labelled BILN 2061 via Scheme 3. Drug manufacture via rutheniumring-closing catalysed ring-closing metathesis metathesis 68 (Scheme 3). The process was successfully scaled-up to produce more than 400 kg of the 15-membered cycle using Hoveyda-Grubbs type catalysts (17). NOBEL PRIZE AND BEYOND By awarding the 2005 Nobel Prize in Chemistry to Chauvin, Schrock, and Grubbs “for the development of the metathesis method in organic synthesis” (18), the Royal Swedish Academy of Sciences has not consecrated a fully grown-up discipline. Instead, it has spotlighted a very active research field that reached an impressive level of maturity in less than 50 years but is still enjoying exciting new developments every day. Olefin metathesis is now a common tool in research laboratories for organic synthesis and drug design. Industrial applications are lining up at the door. REFERENCES AND NOTES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. K. J. Ivin, J. C. Mol, “Olefin Metathesis and Metathesis Polymerization”, Academic Press, London (1997); A. M. Rouhi, Chem. Eng. News December 23, pp. 29-33 (2002); R. H. Grubbs Ed., Handbook of Metathesis, Wiley-VCH, Weinheim (2003); D. Astruc, New J. Chem. 29, pp. 42-56 (2005); D. Astruc, New J. 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Brenner et al., Org. Process Res. Dev. 9, pp. 513–515 (2005); Y. S. Tsantrizos, J.-M. M. Ferland et al., J. Organomet. Chem. 691, pp. 5163-5171 (2006); N. K. Yee, V. Farina et al., J. Org. Chem. 71, pp. 7133-7145 (2006). Y. Chauvin, Angew. Chem. Int. Ed. 45, pp. 3741-3747 (2006); R. R. Schrock, Angew. Chem. Int. Ed. 45, pp. 3748-3759 (2006); R. H. Grubbs, Angew. Chem. Int. Ed. 45, pp. 3760-3765 (2006). ALBERT DEMONCEAU, LIONEL DELAUDE* *Corresponding author University of Liège Center for Education and Research on Macromolecules (CERM) Institut de chimie (B6a) Sart-Tilman par, 4000 Liège, Belgium chimica oggi • Chemistry Today • Vol 25 nr 5 • September/October 2007