1,3-Dipolar Cycloaddition - Regioselectivity

Regioselectivity

For asymmetric dipole-dipolarophile pairs, two regioisomeric products are possible. Both electronic/stereoelectronic and steric factors contribute to the regioselectivity of 1,3-dipolar cycloadditions. With respect to the electronic/stereoelectronic consideration, the interaction between two orbitals with the largest orbital coefficients (i.e., the largest HOMO orbital with the largest LUMO orbital) is the most dominant interaction. Depending on the type of the 1,3-dipolar cycloaddition (type I, II or III), one can often computationally determine the largest HOMO and LUMO combinations and predict the regiochemical outcome of the reaction. For example, the scheme below illustrates the cycloaddition of diazomethane to three dipolarophiles: methyl acrylate, styrene or methyl cinnamate. In all three cases, diazomethane acts as a nucleophilic dipole, with the largest HOMO lobe residing on the carbon atom, and the dipolarophiles are electrophilic species. Methyl acrylate and styrene bear the largest LUMO lobe on the terminal olefinic carbon -- this can be easily predicted based on resonance structures. Hence, the regiochemistry of the cycloaddition should be dominated by the interaction between the carbon atom of diazomethane and the terminal olefinic carbon of the dipolarophile, giving the carboxyl or the phenyl substitution at the C-3 position. For the more complex case of methyl cinnamate, the two substituents compete at withdrawing electrons from the alkene. Nonetheless, the carboxyl is more electron-withdrawing, making the beta-carbon the more electrophilic center of this molecule. The cycloaddition should yield the carboxyl group on C-3 and the phenyl group on C-4 in the cyclic product. It is important to note that while this approach works in many cases, it is not always applicable.

The second important factor that influences regiochemistry is steric effect. Steric effects can cooperate or compete with the aforementioned electronic orbital overlap and can sometimes completely override the electronic preference, giving the opposite regioisomer. For example, electronic treatment of the cycloaddition between diazomethane and methyl acrylate yield the 3-carboxyl pyrazoline as the major product, as illustrated by the diagram above. However, the more sterically demanding 2-diazopropane reacts with a series of methyl acrylate derivatives to yield a mixture of 3- and 4-carboxyl pyrazoline, as outlined in the scheme below. The ratio of these two products depends on the size of the substituent on methyl acrylate. Increasing the size from hydrogen to t-butyl shifts the regioselectivity from 100% 3-carboxyl to 100% 4-carboxyl substitution. The steric effect is even more pronounced using propiolate derivatives, as the electronic preference is smaller in propiolates than in acrylates.