to encounter each other is inversely proportional to the ring size, the necessary intramolecular cycloaddition becomes increasingly difficult as ring size increases. This relationship means that the RCM of large rings is often performed under high dilution (0.05 - 100 mM) (A) to reduce intermolecular reactions; while the RCM of common rings can be performed at greater concentrations, even neat in rare cases. The equilibrium reaction can be driven to the desired thermodynamic products by increasing temperature (B), to decrease viscosity of the reaction mixture and therefore increase thermal motion, as well as increasing or decreasing reaction time (C). Catalyst choice (D) has also been shown to be critical in controlling product formation. A few of the catalysts commonly used in ring-closing metathesis are shown below. Reaction scope Alkene substrate Ring-closing Metathesis has shown utility in the synthesis of 5-30 membered rings, polycycles, and heterocycles containing atoms such as N, O, S, P, and even Si. Due to the functional group tolerance of modern RCM reactions, the synthesis of structurally complex compounds containing a range of functional groups such as epoxides, ketones, alcohols, ethers, amines, amides, and many others can be achieved more easily than previous methods. Oxygen and nitrogen heterocycles dominate due to their abundance in natural products and pharmaceuticals. Some examples are shown below (the red alkene indicates C-C bond formed through RCM). In addition to terminal alkenes, tri- and tetrasubstituted alkenes have been used in RCM reactions to afford substituted cyclic olefin products. Ring-closing metathesis has also been used to cyclize rings containing an alkyne to produce a new terminal alkene, or even undergo a second cyclization to form bicycles. This type of reaction is more formally known as enyne ring-closing metathesis. E/Z selectivity In RCM reactions, two possible geometric isomers, either E- or Z-isomer, may be formed. 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. In macrocycles, the E-isomer is often obtained as a result of the thermodynamic bias in RCM reactions as E-isomers are more stable compared to Z-isomers. 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. The synthesis of stereopure