Chemical Education Today
Report
2005 Nobel Prize in Chemistry Development of the Olefin Metathesis Method in Organic Synthesis by Charles P. Casey
The 2005 Nobel Prize in Chemistry was awarded to Yves Chauvin of the Institut Français du Pétrole, Robert H. Grubbs of CalTech, and Richard R. Schrock of MIT “for development of the metathesis method in organic synthesis”. The discoveries of the laureates provided a chemical reaction now used daily in the chemical industry for the efficient and more environmentally friendly production of important pharmaceuticals, fuels, synthetic fibers, and many other products. The story of how olefin metathesis became a truly useful synthetic transformation is a triumph for mechanistic chemistry and illustrates the importance of fundamental research. The word metathesis is derived from the Greek words meta (change) and thesis (position). Metathesis is the exchange of parts of two substances. In the generic reaction, AB + CD → AC + BD, B has changed position with C. An example is olefin metathesis. “Olefin” is an older word for an alkene, a compound with a C⫽C double bond. Olefin metathesis is truly an amazing reaction in which the strongest bond in an alkene, the C⫽C double bond, is broken and remade. Olefins are very stable thermally in the absence of transition metal catalysts. R
H C
H
R
+
C R*
H C
H
R
C
H
R*
*R
+
C
C H
R
H C
H
C R*
Chemists were surprised, baffled, and intrigued when the olefin metathesis reaction was first reported because it was exceedingly difficult to see how such an exchange process might occur.
Organometallic chemists became very interested in the olefin metathesis reaction because of its novelty and its potential in synthetic chemistry if new catalysts could be developed to handle functionalized alkenes. A number of imaginative mechanisms for metathesis were suggested that involved two alkenes coming together at a metal center; these were eventually proved incorrect. Chauvin’s Olefin Metathesis Mechanism—Importance of Metal Carbene Complexes In 1971, Yves Chauvin and his student Jean-Louis Hérisson found that the reaction of a mixture of cyclopentene and 2-pentene led to C-9, C-10, and C-11 dienes in a 1 : 2 : 1 ratio. This result was incompatible with mechanisms involving two alkenes coming together and changing partners in a pair-wise fashion. An alternative mechanism was needed to explain the non-pairwise exchange of alkene fragments to produce statistical mixture of dienes. Chauvin’s creative proposal involved metal–carbene complexes, compounds with M⫽C double bonds. This novel class of compounds had first been isolated in 1964 by E. O. Fischer, who received the Nobel Prize in Chemistry, 1973. Chauvin combined these ideas and proposed a mechanism for olefin metathesis that is beautiful in its simplicity: a metal– carbene complex comes together with an alkene to reversibly form a four-member ring metallacycle. This metallacyclobutane ring can open in a different way to generate a new carbene complex and a new alkene. H
Discovery of Olefin Metathesis
M
Transition metal-catalyzed olefin metathesis was discovered in the 1950s by industrial chemists at DuPont, Standard Oil, and Phillips Petroleum (H. S. Eleuterio, E. F. Peters, B. L. Evering, R. L. Banks, and G. C. Bailey) who reported that propene reacted to form ethylene and 2-butenes when passed over a molybdenum on alumina catalyst at high temperature. The ring-opening metathesis polymerization (ROMP) of norbornene catalyzed by WCl6 and AlEt2Cl was observed in the 1960s. Nissim Calderon at Goodyear recognized that the polymerization of cyclic alkenes to polyalkenemers and the disproportionation of acyclic alkenes are the same type of reaction and named it “olefin metathesis”.
etc
etc
n
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H R
M
+ H
H
R
M
R R
H
R
R
H
+ H
R*
R* H *R
H
When this was first proposed (and to this day), it was not clear how reagents such as WCl6 and AlEt2Cl or Mo(CO)6 on alumina might lead to a metal–carbene complex. Typical Fischer carbene complexes, such as (CO)5W⫽C(OMe)Ph, involved low valent metals and had electron donor groups on the carbene carbon. In addition, the basic reaction of a metal–carbene complex with an alkene had not yet been observed. Nevertheless, this mechanistic suggestion appeared very attractive (it has the look of something so simple that it is probably right) and energized organometallic chemists to test its implications and to devise ways to make new types of metal–carbene complexes as potential catalysts.
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The Metathesis Dance
1 H2C CH2 CH2
The press release from the Royal Swedish Academy of Sciences described metathesis as a dance in which couples change partners. The couples are the CHR units of olefins linked by a C⫽C bond. Chauvin’s mechanism allows an extension of this dance analogy. Imagine a ball in which the partners (alkenes) dance around and continually bump into one another but are too shy to exchange partners. Then a new couple (the metal–carbene complex, M⫽CHR) joins the dance and the metal component is far from shy! Now when the new couple bumps into an alkene couple, the couples join into a fourmembered ring. They dance around and then break apart with the aggressive metal dancing off with a new partner and leaving its old partner with one of the alkene couple. The metal and new partner then encounter another alkene to trade partners again. Before long, all the alkene partners have been scrambled due to the hyperactivity of the metal complex. My research group played an early role in providing support for the Chauvin mechanism. We had made the very reactive metal–carbene complex (CO)5W⫽CPh2 to study its possible role in reactions with alkenes to form cyclopropanes. Terry Burkhardt in my group found that this carbene complex reacted with the alkene H2C⫽C(OCH3)Ph to form a new alkene and a new metal–carbene complex just as predicted by the Chauvin mechanism. Ph (CO)5W
OMe
Ph
(CO)5W Ph
+
C
CH2
CD2
1 D2C CD2
With the basic mechanism of olefin metathesis understood, the new challenge was to construct efficient catalysts that would tolerate the oxygen functional groups in typical organic molecules. Progress required the synthesis of new metal–carbene complexes whose structures were known and whose reactions with alkenes could be readily studied. These studies allowed steady improvement of catalysts by a tuning process. Schrock’s Tantalum and Molybdenum Catalysts In the early 1970s, Richard Schrock at DuPont tried to synthesize Ta(CH2CMe3)5 but instead isolated the first high valent stable metal–carbene complex, R 3Ta⫽CHCMe 3. Schrock introduced the metal–alkylidene nomenclature for these new compounds, which were nucleophilic at carbon and appeared to be closely related to active metathesis catalysts. Schrock synthesized many tantalum– and niobium–alkylidene complexes in the 1970s and some reacted with alkenes to produce unstable metallacyclobutane complexes, but none catalyzed olefin metathesis. In 1980, Schrock reported a major breakthrough: the tantalum–alkylidene complex A, with the key added feature of alkoxy ligands, catalyzed the metathesis of cis-2-pentene (Figure 1). This was the first example of a well-defined high oxidation state metal–alkylidene complex to catalyze metathesis. Since many ill-characterized metathesis catalysts contained molybdenum or tungsten, Schrock went on to search for molybdenum– and tungsten–alkylidene catalysts. Systematic studies led to very active molybdenum–alkylidene catalysts such as B, which is among the most active alkene metathesis catalysts known. The amount of ligand tuning was enormous: bulky imido ligands and bulky alkoxides with electron withdrawing groups were optimal. More recently, Schrock, together with Amir Hoveyda of Boston College, have developed chiral catalysts such as C for enantioselective olefin metathesis.
H2 C
Ph
+ 2 H2C CD2
+
Ph
OMe
+
C
CD2
Ph
Other support for Chauvin’s metallacyclobutane mechanism came from the labs of Robert Grubbs, then at Michigan State University, and of Thomas Katz, at Columbia University. They carried out incisive labeling studies that demonstrated that alkenes underwent non-pairwise exchange as required by the Chauvin mechanism. For example, Grubbs found that the mixture of deuterated and undeuterated alkenes shown at the top of the next column led to a statistical mixture of d0-, d2-, and d4-ethylene (and that d0- and d4-ethylene were not scrambled after their formation).
Figure 1. Tantalum and molybdenum metathesis catalysts. N N
F3C
Me3P
O Me3C
F3C
Cl
F3C
Ta O
CMe3
F3C F3C
CMe3
Ph O
Mo
•
Me
O
Me
O
Ph Mo
O
Me H
Me H
CMe3
CF3 B
A
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CMe3
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Report Grubbs’s Titanium and Ruthenium Catalysts Robert Grubbs’s early interest in olefin metathesis continued into the 1980s, when his group showed that titanacyclobutanes slowly catalyze olefin metathesis. They demonstrated that the titanacyclobutane D was in equilibrium with a titanium–carbene complexes and an alkene and succeeded in isolating a derivative of the titanium–carbene complexes. But these titanium compounds were very airand water-sensitive and were not compatible with alkenes containing oxygen functional groups.
Ti
+
Ti CH2
Applications of Olefin Metathesis in Fine Organic Synthesis
metathesis catalyst
D
Grubbs, having noticed a 1965 report from Giulio Natta (Nobel Prize in Chemistry, 1963) on RuCl3-catalyzed ringopening metathesis polymerization (ROMP) of cyclobutene, began investigating ruthenium catalysts. In 1988, he discovered the ring-opening polymerization of 7-oxanorbornene into a high molecular weight polymer catalyzed by RuCl3 in water! The compatibility of Ru olefin metathesis catalysts with water and with an oxygenated substrate encouraged Grubbs to synthesize a number of Ru–carbene complexes. In 1992, he reported the first molecularly well-defined ruthenium–carbene complex E that promoted the ROMP of low-strain olefins as well as the catalytic ring closing metathesis (RCM) of functionalized dienes (Figure 2). In 1995, Grubbs reported ruthenium carbene complex F, which is now known as the first generation Grubbs catalyst. While Grubbs’s ruthenium catalysts and Schrock’s molybdenum catalysts promote many of the same reactions, the ruthenium catalysts have been more widely used by organic chemists because of their air stability, greater functional group tolerance, and commercial availability. Grubbs’s detailed mechanistic studies provided evidence that phosphine dissociation to give a reactive 14-electron ru-
Cl
PPh3 Ru
Cl
Ph
H
PPh3
Ph
Figure 2. Ruthenium metathesis catalysts. Cy = cyclohexyl.
H Ru
Cl
Ph
PCy3
F Grubbs 1st generation
E
N
– PCy3 k 1 ≈ 100 × slower than for F
N
Cl Ru Cl
The power of olefin metathesis in fine organic synthesis is highlighted by examples of ring-closing metathesis (RCM) reactions (Figure 3). For example, Hoveyda employed the Schrock molybdenum catalyst B in his total synthesis of fluvirucin B1 for closure of a 14-member lactam ring in 92% yield. The many functional groups in the molecule were tolerated and the only by-product was ethylene. Tandem sequences of ring-opening and ring-closing metathesis have been used in clever approaches to natural products. A beautiful example is Blechert’s use of the second generation Grubbs catalyst, G, in an efficient step in the synthesis of the piperidine alkaloid (᎑)-holosalin. Enantioselective catalysts have been developed for asymmetric ring closing metathesis. Steve Burke at the University of Wisconsin–Madison used the molybdenum catalyst C developed by Schrock and Hoveyda to break the symmetry of a triene as one step in his group’s synthesis of brevicomin. The advent of efficient olefin metathesis catalysts capable of handling complex organic molecules with a multitude of functional groups has transformed the way organic chemists approach synthesizing complex molecules. Olefin metathesis
PCy3
Cl
H
thenium intermediate was required for reaction with alkenes. In an effort to accelerate this dissociative step, Grubbs introduced a strong -donating N-heterocyclic carbene (NHC) ligand in place of one phosphine and in fact obtained catalysts such as G with 100 times higher activity. G is often referred to as Grubbs’s second generation catalyst; it is commercially available and is widely used for efficient cross-metathesis reactions. Similar highly active NHC catalysts were synthesized by the groups of Herrmann, Nolan, and Fürstner. Detailed mechanistic studies by Grubbs and his student Melanie Sanford demonstrated that the rate of formation of the 14e species was actually 100 times slower for the NHC systems and that the catalytic rate increase was due to the greater reactivity of acidic olefins relative to -donor phosphines towards the more electron-rich ruthenium center in the NHC 14e intermediate.
N Cl
H
PCy 3
Ph
k ⴚ1
PCy3
alkene k3 / k −1 ≈ 10,000 greater than for F
N
Ru Cl
H
metathesis
Ph
G Grubbs 2nd generation
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OAc
CH2
OAc H2 C
O
H2 C
H2 C
N(H)COCF3 O
Schrock Mo CHR B
Et
22 °C
O Et
OAc OAc
+
O N(H)COCF3 O
fluvirucin B1
O
HN
Et
Et HN
92% yield Si O
Si
Grubbs 2nd generation CH2 G TsN
CH2
O
CH2
+
CH2Cl2, rt TsN
H2 C
O Me
CH2
Schrock Hoveyda Mo CHR C
O
Me
H H
O
brevicomin
O C6D6, rt
Figure 3. Examples of use of modern metathesis catalysts in synthetic organic chemistry.
CH2
+ CH2
(−)-halosin B1
H2 C
78% yield 59% ee
is now the method of choice for linking organic structures and for closing large rings. It’s hard to randomly open an organic chemistry journal and not find an exciting new example of the use of metathesis. Metathesis catalysts have rapidly become common tools in academic research for the synthesis of natural products and in drug discovery research. Applications to biologically active compounds such as insect pheromones, herbicides, and drug candidates are being pursued aggressively. Because catalytic metathesis opens the door to shorter synthetic routes and produces fewer by-products, it has provided a great step forward for cleaner, more environmentally friendly, and “greener” chemistry.
3.
4. 5.
6.
Societal Benefits from Basic Research In an interview immediately after learning of the Nobel Prize, Richard Schrock highlighted the importance of support for basic research: “…what we accomplished…came through basic research without really knowing exactly how we were proceeding; we ultimately came to realize, step by step, that our basic research was leading to something really useful. And that is very, very pleasing to me; and I think that’s what the Nobel Prize is all about: to do work that turns out to be useful to society in some way and certainly other fields in science.” Links and Further Reading 1. More information on the 2005 Nobel Prize in Chemistry, including the Prize Announcement, Supplementary Information, and
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2.
•
interviews with the laureates can be found at the Web site of the Nobel Prizes, http://www.nobelprize.org (accessed Nov 2005). Advanced information on the Nobel Prize in Chemistry 2005. The Royal Swedish Academy of Sciences: http://nobelprize.org/ chemistry/laureates/2005/chemadv05.pdf (accessed Nov 2005). Rouhi. A. M. Olefin Metathesis: Big-Deal Reaction. Chem. Eng. News 2002, 80 (51), 29–33; Rouhi. A. M. Olefin Metathesis: The Early Days. Chem. Eng. News 2002, 80 (51), 34–38. Grubbs, R. H. Olefin Metathesis. Tetrahedron 2004, 60, 7117– 7140. Astruc, D. The Metathesis Reactions: From a Historical Perspective to Recent Developments. New J. Chem. 2005, 29, 42–56. Schrock, R. R.; Hoveyda, A. H. Molybdenum and Tungsten Imido Alkylidene Complexes as Efficient Olefin-Metathesis Catalysts. Angew. Chem. Int. Ed. 2003, 42, 4592–4633.
Editor’s Note An undergraduate laboratory experiment related to Grubbs’s work (Grubbs’s Cross Metathesis of Eugenol with cis2-Butene-1,4-diol To Make a Natural Product. An Organometallic Experiment for the Undergraduate Lab) appears on pp 283–284 of this issue. The catalysts discussed in this article are the JCE Featured Molecules for February (see page 236). Charles P. Casey is in the Department of Chemistry, University of Wisconsin–Madison, Madison, WI 53706;
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