Fundamental principles that determine chemical reactivity and reaction mechanisms are the very foundation of chemistry and many related fields of science. Bimolecular nucleophilic substitutions (SN2) are among the most common and therefore most important reaction types. In this report, we examine the trends in the SN2 reactions with respect to increasing electronegativity of the reaction center by comparing the wellstudied backside SN2 Cl- + CH3Cl with similar Cl- substitutions on the isoelectronic series with the second period elements N, O, and F in place of C. Relativistic (ZORA) DFT calculations are used to construct the gas phase reaction potential energy surfaces (PES), and activation strain analysis, which allows decomposition of the PES into the geometrical strain and interaction energy, is employed to analyze the observed trends. We find that SN2N and SN2O have similar PES to the prototypical SN2C, with the well-defined reaction complex (RC) local minima and a central barrier, but all stationary points are, respectively, increasingly stable in energy. The SN2F, by contrast, exhibits only a single-well PES with no barrier. Using the activation strain model, we show that the trends are due to the interaction energy and originate mainly from the decreasing energy of the empty acceptor orbital (σ∗A-Cl) on the reaction center A in the order of C, N, O, and F. The decreasing steric congestion around the central atom is also a likely contributor to this trend. Additional decomposition of the interaction energy using Kohn-Sham molecular orbital (KS-MO) theory provides further support for this explanation, as well as suggesting electrostatic energy as the primary reason for the distinct single-well PES profile for the FCl reaction.