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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
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9.
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12.
13.
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15.
16.
17.
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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