Metathesis is a catalytic rearrangement reaction and has emerged as a greener and more sustainable way of synthesising important organic molecules. Metathesis embodies all the principles of Green Chemistry and has applications in diverse fields such as petrochemicals, polymers, pharmaceuticals, agrochemicals and other specialty chemicals.
The world of organic chemistry is dominated by the C-C bond. It is the one of the most stable and robust chemical bonds and is responsible for some of the most wonderful substances prevalent in nature. They are thus the key building blocks in the synthesis of new chemical compounds. Life as we know would not exist without the C-C bond.
Metathesis Reaction
The metathesis reaction, discovered almost 50 years ago, was a breakthrough in C–C bond formation and has emerged as a powerful tool in the synthesis of chemicals in a sustainable manner. The word metathesis means ‘change-places’. In metathesis reactions, double bonds are broken and reconstructed between carbon atoms in ways that cause atom groups to change places. Essentially: AB + CD → AD + CB. Metathesis can be compared to a dance in which the couples change partners. This happens with the assistance of special catalysts.
Olefin Metathesis
Olefin Metathesis allows the exchange of substituents between different olefins. The most important applications of olefin metathesis in the field of petrochemicals are the olefins conversion technology (OCT) process (originally the Phillips triolefin process) and the Shell Higher Olefins Process (SHOP). The triolefin process, developed by Phillips was the first commercial application for olefin metathesis to convert propylene into ethylene and but-2-ene.
2 CH3CH=CH2 ↔ CH2=CH2 + CH3CH=CHCH3
At Phillips Petroleum Co. this reaction was discovered serendipitously by Banks and Bailey, when they were seeking an effective heterogeneous catalyst to replace the HF acid catalyst for converting olefins into high-octane gasoline via olefin–isoparaffin alkylation. When using a supported molybdenum catalyst, they found that instead of alkylating the paraffin, the olefin molecules were split, and discovered that propylene can be catalytically converted into ethylene and butylene. A large-scale industrial process incorporating olefin metathesis is the Shell Higher Olefins Process (SHOP) for converting ethylene to detergent-range alkenes for the production of lubricants, plasticiser alcohols, detergent alcohols, synthetic fatty acids etc. The catalytic olefin metathesis reaction has led to profound developments in the synthesis of molecules relevant to the petroleum, materials, agricultural and pharmaceutical industries.
Catalysts
Catalysed metathesis was discovered in the industry following observations in the 1950s of the polymerization of ethylene by Ziegler. Catalyst systems for the olefin metathesis generally contain a transition metal compound, but often require the presence of a second compound (co-catalyst), and sometimes a third (promoter). Systems most commonly used were based on the chlorides, oxides, or other easily accessible compounds of Molybdenum, Ruthenium, Tungsten, Titanium, Vanadium etc. In 1971 Yves Chauvin was able to elucidate the mechanism of metathesis reactions and identify what types of metal-compound act as catalysts in the reactions. Richard Schrock was the first to produce an efficient metal-compound catalyst for metathesis in 1990. With this discovery, chemists began to realise that olefin metathesis could be used as a powerful tool in organic synthesis. Metathesis gained increasing attention among researchers active in synthetic chemistry. Yet another breakthrough in the development of metathesis catalysts came in 1992 when Grubbs discovered a catalyst with ruthenium. It was stable in air and demonstrated higher selectivity but lower reactivity than Molybdenum catalysts. The new catalyst also had the ability to initiate metathesis in the presence of alcohols, water and carboxylic acids. Chauvin, Schrock and Grubbs were recognised for their pioneering work with the Nobel Prize in chemistry in 2005.
Pharmaceutical Applications
Many important APIs used in treating major diseases such as hepatitis C, cancer, Alzheimer’s disease, Down’s syndrome, osteoporosis, arthritis, fibrosis, HIV/AIDS, migraine, etc have been manufactured using Metathesis reaction. Metathesis has been used in the synthesis of a 7-membered azepine compound called balanol, which is used as anticancer agent and in controlling inflammation, cardiovascular disorders, central nervous system dysfunction, and HIV infection. Another anticancer drug epothilone and its derivatives were also prepared by using the ring closing metathesis. Similar type of ring closing metathesis was applied to produce Civetone (cyclo-9-heptadecenone) used in the perfume industry from ethyl oleate. Another class of natural compounds, easily obtainable through metathesis are insect pheromones, which are useful as environment friendly pest-control agents.
Other applications
Olefin metathesis excites researchers because of its ease of use and versatility and the reduction in synthetic steps required to achieve complex target molecules. Continuous investigation over the past decades has led to the development of highly active olefin metathesis catalysts for sophisticated synthetic tasks. In the field of materials science, Grubbs catalysts are used to promote ring-opening metathesis polymerisation to manufacture high-performance thermoset resins from abundant petrochemical by-products such as dicyclopentadiene. In the oleochemical industry there are many interesting possibilities for olefin metathesis. The metathesis of unsaturated natural fats and oils and their derivatives offers new synthesis routes from cheap renewable feedstocks to valuable new chemical products from with high chemo-selectivity.
Green Chemistry
Metathesis reactions embody the principles of green chemistry by exhibiting high atom economy, catalytic efficiency, solvent versatility, and compatibility with renewable feedstocks. Metathesis reactions excel in atom economy as they involve the redistribution of atoms within the reactants, resulting in the formation of new products without the need for additional reagents. This high atom efficiency translates into minimal waste production and contributes to sustainable synthesis. This makes metathesis ideal for creating new C-C bonds in an atom-efficient and sustainable manner. Metathesis reactions offer versatility in solvent selection, as they can be performed in environmentally benign solvents like water or bio-based solvents. Catalysts used in metathesis exhibit remarkable efficiency, enabling the reactions to proceed rapidly at mild conditions with low catalyst loadings. Metathesis reactions exhibit a broad substrate scope and compatibility with various functional groups. This versatility allows for the synthesis of diverse chemical structures, often eliminating the need for multiple synthetic steps and auxiliary reagents.
Epilogue
Metathesis has a rich history from its initial discovery to its comprehensive mechanistic understanding and the development of powerful catalysts. It has become an indispensable tool in green chemistry, offering efficient and selective transformations with significant environmental benefits. Success stories in pharmaceuticals and renewable fuels demonstrate its vast potential. However, challenges such as catalyst stability, scalability, and commercial adoption must be addressed to fully unlock the potential of metathesis. Ongoing research and innovation are crucial to overcome these hurdles and pave the way for broader applications in various industries. With continued advancements, metathesis has the potential to play an even more significant role in the quest for sustainable and environmentally friendly chemical processes.
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