Dipolar Cycloaddition Reactions

Diazomethane is a useful reagent for preparing methyl esters from carboxylic acids. However, if a chemist tries to make methyl acrylate from acrylic acid in this way, he or she is in for a surprise. An excess of this reagent, as normally used, not only forms a methyl ester, but also adds to the carbon-carbon double bond. As shown in the diagram on the right, a substituted pyrazoline is the major product. Here we see a typical example of a large body of reactions called dipolar cycloadditions. An earlier example involved the addition of ozone to double bonds, although the initial addition product (a molozonide) rearranged rapidly to other compounds.

Dipolar cycloaddition reactions take place between unsaturated hetero atom compounds, such as diazoalkanes, alkyl and aryl azides, nitrile oxides and nitrones, and alkene or alkyne functions. Although the former reactants are neutral, their Lewis structures have formal charges, and may be written as 1,3-dipoles. The alkene and alkyne functions to which the dipoles add are called dipolarophiles. Examples of some common 1,3-dipole reagents are provided at the top of the following diagram.
The terminology used for these reactions may be confusing unless one pays careful attention to the electronic structures of the dipolar reactants. Resonance structures for three of these are drawn in the shaded box. In general, four resonance canonical structures may be written for each compound. Two have adjacent or 1,2-charge separation, and two have the 1,3-dipolar charge separation noted above. The 1,2-dipolar structures retain valence shell octets for all heavy atoms, suffer less charge separation, and have one more covalent bond than do the 1,3-dipolar structures. Therefore, the most representative Lewis structures for these compounds are 1,2-dipoles, not 1,3-dipoles.
Another factor in identifying the best structure for a given compound is electronegativity. Negative charge is best on the most electronegative atom, and positive charge on the least electronegative atom. In the examples drawn for the nitrile oxides and nitrones, the left hand structure is the best 1,2-dipole that can be written. Similar structures are written following the names in the list at the top of the diagram. Finally, the general equation written at the bottom demonstrates the danger of thinking about these reactions as a simple addition of a 1,3-dipole to an unsaturated function. Movement of electron pairs out of the dipolarophile to one end of the dipole, with a second electron pair going from the dipole back to the dipolarophile accounts for only four electrons. As shown by the curved arrows on the right, the cycloaddition actually proceeds by a six pi-electron transition state, and is suprafacial.

By clicking on the diagram, five examples of dipolar cycloaddition reactions will be displayed. Examples 1 and 2 show participation of nitrile oxide and diazoalkane reactants. The two phenyl azide additions in equations 3 and 4 demonstrate the suprafacial stereospecificity of the addition. Finally, reaction 5 shows an intramolecular cycloaddition reaction.
It is evident from these examples that a high degree of regioselectivity characterizes the cycloaddition of unsymmetrically substituted reactants. Calculated molecular orbital coefficients have proven effective in predicting regioselectivity. Unfortunately, no simple mnemonic seems to work for a majority of the known examples.