Tetrazole-Ene Reaction

Upon photoirradiation, 2,5-diaryl tetrazoles undergo an extremely fast cycloreversion to release N2 and produce the corresponding nitrile-imine, which is then available to undergo a cycloaddition with a suitable dipolarophile such as an alkene. Using a hand-held UV lamp operating at a wavelength of 302 nm, Lin and colleagues successfully modified tetrazole-functionalized proteins with acrylamide within a few minutes at ambient temperature 

In a further example, a genetically encoded alkene-containing protein in Escherichia coli was modified with a library of 2,5-diaryl tetrazoles under similar conditions (Song et al., 2008). Although the photoinduced formation of the nitrile-imine was very fast (2 min), the subsequent cycloaddition with the aUyl phenyl ether functional protein was considerably slower (the reaction was allowed to proceed overnight at 4 °C). By comparison, the second-order rate constant of the cycloaddition with allyl phenyl ether was determined to be 0.00202 0.00007 M s, whereas that for acrylamide (as was used in the previous example) was determined to be 0.15s. A reasonable explanation for this observation is the lower LUMO energy of acrylamide than that of allyl phenyl ether, which offers better orbital overlap with the HOMO of the nitrile imine. 

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