Ring closing metathesis reaction mechanism

Cleavage of the carbon-carbon double bond is accompanied by the formation of two new carbon-carbon double bonds. This reaction was first observed ininvestigated by Du Pont and other manufacturers in the 's, [2] and finally defined by Calderon in Four general classes of reactions have emerged: RCM is the focus of this article Eq.

Ring closing metathesis reaction mechanism

The ruthenium catalysts are not sensitive to air and moisture, unlike the molybdenum catalysts. Overall, it was shown that metal-catalyzed RCM reactions were very effective in C-C bond forming reactions, and would prove of great importance in organic synthesischemical biologymaterials scienceand various other fields to access a wide variety of unsaturated and highly functionalized cyclic analogues.

Mechanism of Olefin Metathesis

Association and dissociation of a phosphine ligand also occurs in the case of Grubbs catalysts. While the loss of volatile ethylene is a driving force for RCM, [24] it is also generated by competing metathesis reactions and therefore cannot be considered the only driving force of the reaction.

Common rings, 5- through 7-membered cycloalkenes, have a high tendency for formation and are often under greater thermodynamic control due to the enthalpic favorability of the cyclic products, as shown by Illuminati and Mandolini on the formation of lactone rings.

Ring strain arises from abnormal bond angles resulting in a higher heat of combustion relative to the linear counterpart. A kinetic product distribution could lead to mostly RCM products or may lead to oligomers and polymers, which are most often disfavored. The mechanism can be expanded to include the various competing equilibrium reactions as well as indicate where various side-products are formed along the reaction pathway, such as oligomers.

Increased catalyst activity also allows for the olefin products to reenter the catalytic cycle via non-terminal alkene addition onto the catalyst.

This relationship means that the RCM of large rings is often performed under high dilution 0. A few of the catalyts commonly used in ring-closing metathesis are shown below. Oxygen and nitrogen heterocycles dominate due to their abundance in natural products and pharmaceuticals.

Ring closing metathesis reaction mechanism

This type of reaction is more formally known as enyne ring-closing metathesis. Stereoselectivity is dependent on the catalyst, ring strain, and starting diene. In smaller rings, Z-isomers predominate as the more stable product reflecting ring-strain minimization.

As a general trend, ruthenium NHC N-heterocyclic carbene catalysts favor E selectivity to form the trans isomer. This in part due to the steric clash between the substituents, which adopt a trans configuration as the most stable conformation in the metallacyclobutane intermediate, to form the E-isomer.

However, in Grubbs reported the use of a chelating ruthenium catalyst to afford Z macrocycles in high selectivity.

Ring-closing metathesis - Organic Reactions Wiki

The selectivity is attributed to the increased steric clash between the catalyst ligands and the metallacyclobutane intermediate that is formed.

The increased steric interactions in the transition state lead to the Z olefin rather than the E olefin, because the transition state required to form the E- isomer is highly disfavored. Once the oxygen is chelated with the titanium it can no longer bind to the ruthenium metal of the catalyst, which would result in catalyst deactivation.

This also allows the reaction to be run at a higher effective concentration without dimerization of starting material. In one study, the addition of aluminum tris 2,6-diphenylphenoxide ATPH was added to form a 7-membered lactone.

The aluminum metal binds with the carbonyl oxygen forcing the bulky diphenylphenoxide groups in close proximity to the ester compound. As a result, the ester adopts the E-isomer to minimize penalizing steric interactions.

Without the Lewis acidonly the membered dimer ring was observed. Limitations[ edit ] Many metathesis reactions with ruthenium catalysts are hampered by unwanted isomerization of the newly formed double bond, and it is believed that ruthenium hydrides that form as a side reaction are responsible.

In one study [50] it was found that isomerization is suppressed in the RCM reaction of diallyl ether with specific additives capable of removing these hydrides. Without an additive, the reaction product is 2,3-dihydrofuran and not the expected 2,5-dihydrofuran together with the formation of ethylene gas.

Radical scavengers, such as TEMPO or phenoldo not suppress isomerization ; however, additives such as 1,4-benzoquinone or acetic acid successfully prevent unwanted isomerization.

Both additives are able to oxidize the ruthenium hydrides which may explain their behavior. Another common problem associated with RCM is the risk of catalyst degradation due to the high dilution required for some cyclizations. High dilution is also a limiting factor in industrial applications due to the large amount of waste generated from large-scale reactions at a low concentration.

The following examples are only representative of the broad utility of RCM, as there are numerous possibilities. For additional examples see the many review articles. One example is its use in the formation of the membered ring in the synthesis of the naturally occurring cyclophane floresolide.

Floresolide B was isolated from an ascidian of the genus Apidium and showed cytotoxicity against KB tumor cells. Nicolaou and others completed a synthesis of both isomers through late-stage ring-closing metathesis using the 2nd Generation Grubbs catalyst to afford a mixture of E- and Z- isomers 1: Although one prochiral center is present the product is racemic.

Floresolide is an atropisomer as the new ring forms due to steric constraints in the transition state passing through the front of the carbonyl group in and not the back. The carbonyl group then locks the ring permanently in place. The hydrogen bond stabilized the macrocycle precursor placing both dienes in close proximity, primed for metathesis.

Mechanism of Ring Closing Metathesis

Only the S,S,S diastereomer was reactive illustrating the configuration needed for ring-closing to be possible. At the time, no previous membered ring had been formed through RCM, and previous syntheses were often lengthy, involving a macrolactonization to form the decanolide.Overall, ring-closing metathesis is a highly useful reaction to readily obtain cyclic compounds of varying size and chemical makeup; however, it does have some limitations such as high dilution, selectivity, and unwanted isomerization.

Ring-Closing Metathesis (RCM): The reaction can be driven to the right by the loss of ethylene. possible mechanisms for olefin metathesis: The "dissociative" mechanism assumes that upon binding of the olefin a phosphine is displaced from the metal center to form a electron olefin complex, which undergoes.

Ring-closing metathesis is a variant of the olefin metathesis reaction in which alkylidene moieties are exchanged to form a ring. The most common catalysts for this reaction are complexes of molybdenum or ruthenium. The mechanism is based on three main parts: activation and initiation (part A), a cross metathesis reaction with the first double bond of the olefin (part B) and the reaction of the second double bond of the olefin (part C), which results in ring closing.

Metathesis Reactions in Total Synthesis alphabetnyc.comou,*alphabetnyc.com,andDavidSarlah Angewandte Chemie parallels the mechanism of alkene metathesis.

Subsequently, been primarily the alkene ring-closing metathesis reaction and, more recently, the alkene cross-metathesis reaction that. Ring opening metathesis can employ an excess of a second alkene (for example ethene), but can also be conducted as a homo- or co-polymerization reaction.

The driving force in this case is the loss of ring strain.

Ring-closing metathesis - Wikipedia