TheThorpe–Ingold effect,gem-dimethyl effect, orangle compression is an effect observed inchemistry where increasingsteric hindrance favours ring closure and intramolecular reactions. The effect was first reported by Beesley,Thorpe, andIngold in 1915 as part of a study ofcyclization reactions.[1] It has since been generalized to many areas of chemistry.[2]
The comparative rates oflactone formation (lactonization) of various 2-hydroxybenzenepropionic acids illustrate the effect. The placement of an increasing number of methyl groups accelerates the cyclization process.[3]
One application of this effect is addition of aquaternary carbon (e.g., agem-dimethyl group) in analkyl chain to increase thereaction rate and/orequilibrium constant of cyclization reactions. An example of this is anolefin metathesis reaction:[4] In the field ofpeptidefoldamers,amino acidresidues containingquaternary carbons such as2-aminoisobutyric acid are used to promote formation of certain types of helices.[5]
One proposed explanation for this effect is that the increased size of the substituents increases the angle between them. As a result, the angle between the other two substituents decreases. By moving them closer together, reactions between them are accelerated. It is thus a kinetic effect.
The effect also has some thermodynamic contribution as thein silicostrain energy decreases on going fromcyclobutane to 1-methylcyclobutane and 1,1-dimethylcyclobutane by a value between 8 kcal/mole[6] and 1.5 kcal/mole.[7]A noteworthy example of the Thorpe-Ingold effect insupramolecular catalysis is given by diphenylmethane derivatives provided with guanidinium groups.[8] These compounds are active in the cleavage of the RNA model compound HPNP. Substitution of the methylene group of the parent diphenylmethane spacer with cyclohexylidene and adamantylidene moieties enhances catalytic efficiency, with gem dialkyl effect accelerations of 4.5 and 9.1, respectively.
