The conjugation of glutathione with chlorobenzene and di‐, tri‐, tetra‐, and hexa‐chlorinated benzenes via nucleophilic aromatic substitution was modeled for isolated reacting species by ab initio molecular orbital theory to provide an understanding of the intrinsic reactivity of unactivated chloroaromatic systems. Computations at the HF/6‐31+G(d,p) level were augmented with electron correlation corrections using MP2 theory and density functional theory at the B3LYP level. Features of the reaction hypersurface were elaborated using thiolate (thiomethoxide) as the model for an enzyme‐activated glutathione molecule. Unlike the similar reaction with 1‐chloro‐2, 4‐dinitrobenzene a known substrate with glutathione, no σ‐complex or Meisenheimer complex was isolated as a true intermediate on the hypersurface. Instead, the σ‐complex appears as a transition state, preceded and followed by two ion‐molecule complexes in which the approaching and departing anions reside in the plane of the aromatic ring. Solvent calculations show a very similar hypersurface landscape with only one transition state and no intermediate. Activation energies are somewhat greater than for 1‐chloro‐2, 4‐dinitrobenzene owing to the lack of nitro substituents, which provide stabilization in these systems. Nevertheless, activation energies calculated at correlated levels indicate that these reactions are still feasible and consistent with experiment. Transition states and activation energies for dichlorobenzenes and polychlorobenzenes are lower in energy than for chlorobenzene implying greater stability conferred to the transition state by ortho and para substituents.