Computation was used to design a transcyclooctene derivative that displays enhanced reactivity in the tetrazine-trans-cycloctene ligation. The optimized derivative is an (E)-bicyclo[6.1.0]non-4-ene with a cis-ring fusion, in which the eight-membered ring is forced to adopt a highly strained 'half-chair' conformation. Toward 3,6-dipyridyl-s-tetrazine in MeOH at 25 degrees C, the strained derivative is 19 and 27 times more reactive than the parent transcyclooctene and 4E-cyclooct-4-enol, respectively. Toward 3,6-diphenyl-s-tetrazine in MeOH at 25 degrees C, the strained derivative is 160 times more reactive than the parent transcyclooctene.