Thorpe–Ingold effect

Thorpe–Ingold effect (also known as the geminal effect or the ligand proximity effect) is a phenomenon observed in organic chemistry where the rate of a chemical reaction or the stability of molecules is affected by the presence of substituents in the vicinity of the reactive site or the bond being formed or broken. This effect is particularly significant in reactions involving the formation or cleavage of carbon-carbon bonds adjacent to a quaternary carbon center. The Thorpe–Ingold effect is named after the British chemists Jocelyn Field Thorpe and Christopher Kelk Ingold, who first described this phenomenon in the early 20th century.

Overview

The Thorpe–Ingold effect can be attributed to several factors, including steric hindrance, electronic effects, and the preorganization of reactants. Steric hindrance occurs when the bulky substituents near the reactive site prevent the approach of reactants or the proper alignment of molecules for the reaction to proceed. Electronic effects involve the donation or withdrawal of electron density by substituents, which can stabilize or destabilize transition states and intermediates. Preorganization refers to the spatial arrangement of atoms or groups within a molecule that predisposes it towards a certain reaction pathway, thereby lowering the activation energy required for the reaction to occur.

Applications

The Thorpe–Ingold effect has wide-ranging applications in synthetic chemistry, including the design of more efficient and selective synthetic routes. One of the most notable applications is in the field of cycloaddition reactions, where the effect is utilized to promote the formation of cyclic compounds with desired configurations. It also plays a crucial role in the synthesis of lactones, lactams, and other cyclic structures by facilitating ring-closure reactions. Additionally, the Thorpe–Ingold effect is instrumental in the development of polymer chemistry, influencing the properties of polymers by affecting the reactivity of monomers and the stereochemistry of polymerization reactions.

Mechanism

The mechanism by which the Thorpe–Ingold effect influences chemical reactions involves a combination of steric and electronic factors. In reactions where steric hindrance is predominant, the presence of bulky groups near the reactive site can significantly slow down or even prevent certain reactions from occurring. On the other hand, electronic effects can either stabilize or destabilize the transition state of a reaction, depending on the nature of the substituents. For example, electron-donating groups can stabilize carbocation intermediates, while electron-withdrawing groups can stabilize carbanion intermediates. The preorganization of reactants, facilitated by the spatial arrangement of substituents, can also lower the activation energy of a reaction, making it more favorable.

Examples

One classic example of the Thorpe–Ingold effect is observed in the Diels-Alder reaction, where the presence of alkyl groups adjacent to the dienophile can enhance the reaction rate by facilitating the proper orientation of the diene and dienophile for cycloaddition. Another example is the accelerated cyclization of gamma,delta-unsaturated carbonyl compounds to form five- or six-membered rings, where the proximity of substituents plays a crucial role in determining the efficiency and selectivity of the ring closure.

Conclusion

The Thorpe–Ingold effect is a fundamental concept in organic chemistry that has profound implications for the design and synthesis of organic molecules. By understanding and exploiting this effect, chemists can develop more efficient and selective synthetic strategies, leading to the creation of novel compounds with a wide range of applications in medicine, materials science, and beyond.