Structure sensitivity is the phenomenon where the activity of each available active site of a catalyst varies depending on its specific structure and coordination environment. Understanding structure sensitivity can assist in the rational design of catalysts, allowing for control over activity and selectivity. Here, we demonstrate that the activity and selectivity of acetone coupling to 2,5-hexanedione (2,5-HDN), an important raw material, via a photocatalytic dehydrogenative route are highly structure sensitive and prove how the size of the supported Pt influences the catalytic performance. Under optimized conditions, the formation rate of 2,5-HDN on subnanometer Pt cluster modified anatase−TiO 2 (Pt CL /TiO 2 ) reaches 45.3 μmol/h, 1.5−9.0 times higher than the Pt NPs and Pt single-atom doped TiO 2 photocatalysts. Mechanism studies reveal that water, which is oxidized by the excited hole of the anatase semiconductor, acts as a co-catalyst in the reaction and generates hydroxyl radicals. The formed hydroxyl radicals subsequently assist the cleavage of the sp 3 C−H bond of acetone. The dimerization of the •CH 2 COCH 3 radicals delivers 2,5-HDN. The remarkable •OH radical formation capability and relatively high H-abstraction activity of the Pt CL /TiO 2 photocatalyst account for its excellent activity and selectivity over other Pt/TiO 2 catalysts.