A series of substituted thiophene dioxides was tested as diene substrates for the antibody 1E9, which was elicited with a hexachloronorbornene derivative and normally catalyzes the inverse electron‐demand Diels–Alder reaction between 2,3,4,5‐tetrachlorothiophene dioxide (TCTD) and N‐ethylmaleimide (NEM). Previous structural and computational studies had suggested that the catalytic efficiency of this system derives in part from a very snug fit between the apolar active site and the transition state of this reaction. Nevertheless, replacing all the Cl‐atoms in the hapten with Br‐atoms leads to no loss in affinity (K_d=0.1 nM ), indicating substantial conformational flexibility in the residues that line the binding pocket. Consistent with this observation, the 2,3,4,5‐tetrabromothiophene dioxide is a good substrate for the antibody (k_cat=1.8 min^?1, K_NEM=14 μM ), despite being considerably larger than TCTD. In contrast, normal electron‐demand Diels–Alder reactions between NEM and unsubstituted thiophene dioxide or 2,3,4,5‐tetramethylthiophene dioxide, which are much smaller or nearly isosteric with TCTD, respectively, are not detectably accelerated. These results show that the electronic properties of the 1E9 active site are optimized to a remarkable degree for the inverse electron‐demand Diels–Alder reaction for which it was designed. Indeed, they appear to play a more important role in catalysis than simple proximity effects.