4.

(A) Simplified kinetic barrier diagrams describing the reaction (I removed and intermediates III–V combined). Dotted lines represent the largest kinetic barrier in each case. (i) A kinetic barrier for water removal can be included based on the rate constants determined from fitting experimental data in Figure B. This is the highest kinetic barrier in the reaction. (ii) Consequently, lowering the barrier for water removal (increasing the rate of water removal) will accelerate the reaction. (iii) Lowering the barrier to water removal can also be accompanied by an increase in the extent of water removal, which lowers the energy levels for III–V. If this barrier is sufficiently lowered, then the barrier for V–IV will be lowered to below the barrier for II–III. (B) Two-surface representation of the potential energy landscape of the redox-neutral catalytic Mitsunobu reaction (I ⇋ VI). Energies for all species and transition states are quoted in kcal mol^–1. Once generated (step II → III), water can be physically removed from the reaction from any of states III, IV, V, and VI. Removal of water can be thought of as hopping to a new potential energy surface (blue → green), since states I and II are no longer accessible. Addition of water allows return to the hydrated energy landscape (green → blue). The yellow arrows indicate three potential ways in which the reaction can be accelerated: A, increasing the rate of water removal (blue → green); B, lowering the final nucleophilic coupling barrier (V → VI); and C, lowering the barrier for catalyst dehydration (V → VI).