Topological [2+2] cycloaddition is known to provide a convenient synthetic route for cyclobutane derivatives from favourably dispositioned dienes. In this study, new diphenylpenta-2,4-dienenitrile derivatives (abbreviated as HDE, MeDE, ClDE, BrDE, MeODE and MeNDE) were synthesized, and their reactivity and selectivity were investigated in relation to their molecular packing in the respective crystals. HDE and MeDE, with head-to-tail (HT) arrangement, yielded only one type of photodimer with high activities. On the contrary, ClDE and BrDE, with head-to-head (HH) packing, reacted to a mixture of photoproducts with low activities. This observation may be due to the strong non-covalent interactions between the potentially reactive olefin pairs as suggested by energy decomposition analysis. Furthermore, the reaction activation energies for photodimerization of the HT-packed olefin pairs are indeed lower than those of the HH-arranged ones. The HT packing of the diphenyldienes not only enhances the reactivity in the topological [2+2] cycloaddition but also contributes chemospecificity, regiospecifity and stereospecificity, all of which are essential for preparation of specific cyclobutanes derivatives based on photodimerization.