To elucidate the origin of enantioselectivity in the catalytic nucleophilic desymmetrization of the prochiral P(V) substrates, a density functional theory (DFT) study was performed (Figure ). As the rate-and enantio-determining step in our previous report was the formation of a pentacoordinate anionic intermediate, the kinetic preference for the nucleophilic attack was examined in this computational study, using the model catalyst B-2, phosphonate ester P1 or P7, and phenol nucleophile. Among the located transition states (TSs), the lowest TS structures for the formation of (R)-and (S)-products from P1 were TS1-(R) and TS2-(S), respectively (Figure , middle). The more favored transition state (TS1-(R)) agrees with the experimentally confirmed absolute stereochemical configuration obtained by single crystal X-ray diffraction analysis and is computed to be 3.3 kcal mol -1 lower in energy than TS1-(S). Both transition structures engage in several stabilizing noncovalent interactions (NCIs) such as hydrogen bonding, CH-π, and π-π interactions between the catalyst and the reactants. The simultaneous activation of the P(V) electrophile and the phenol nucleophile is promoted by multiple hydrogen bonding interactions with the BIMP catalyst. The notable difference which contributes to increasing the energy barrier of TS2-(S) is the repulsive interaction between oxygen lone pairs of the phosphonate and thiazolidinone in the substrate. The favored TS benefits from dipole minimization rather than being affected by the substituent on the phosphorus atom. This is evidenced by the minimal change in energy trend (ΔΔG ‡ = 3.1 kcal mol -1 ) when a phenyl substituent is replaced by a methyl group (Figure , right). A major limitation of our first-generation catalytic method was the requirement for an ortho-substituent on the phenol nucleophiles to achieve high levels of enantioselectivity. Our second-generation method, on the other hand, does not. DFT calculations were thus utilized to pinpoint the reason for why an ortho-substituent was required in the first-generation method but not for our newly established system (Figure ). In the computed TSs for the first-generation catalytic system, a high enantioselectivity is obtained with 2,4-dimethylphenol (ΔΔG ‡ = 2.4 kcal mol -1 ), 146 while a dramatic decrease in the energy difference is observed in the absence of a 2-methyl substituent (ΔΔG ‡ = 0.9 kcal mol -1 ). The superimposed structures for both TSs in Figure strongly imply that there is almost no geometry change with or without an ortho-methyl group in TS5-(R)-Me and TS5-(R)-H (RMSD = 0.15; RMSD = root mean square deviation), but there is an obvious geometrical distinction for the phenol nucleophile in the disfavored transition states TS6-(R)-Me and TS6-(R)-H (RMSD = 0.25). This indicates that the steric repulsion between the catalyst and the ortho-substituent of the phenol nucleophile further destabilizes the disfavored transition state structure (TS6-(S)-Me) leading to high levels of enantioselectivity. In comparison, the second-generation catalytic system has sufficient space to accommodate the phenol nucleophile approaching the phosphorus atom (Figure ). As evidenced by the similar RMSD values in both favored and disfavored TSs with and without the ortho-methyl group (RMSD = 0.39 and 0.32), along with the maintained large energy barrier difference in the presence of an ortho substituent (ΔΔG ‡ = 2.5 kcal mol -1 ), the origin of high enantioselectivity relies soley on positive non-covalent interactions between the BIMP catalyst and the P(V) electrophile in the transition state leading to the major enantiomer, rather than relying on an additional destabilization between the catalyst and the nucleophile in the disfavored transition state. These insights from the DFT calculations shed light on the origins of enantioselectivity for both first-and second-generation catalytic systems in the enantioselective nucleophilic substitution at P(V) and provide insight as to why the second-generation system was found to be far more general. An interesting trend was observed when Grignard reagents were examined as nucleophiles for enantiospecific SN2@P reactions (Schemes 4 & 5). The displacement of the thiazolidinone leaving group took place with retention of stereochemical configuration at the P(V) center, whereas phenol displacement took place with inversion of configuration. Thus, we utilized DFT calculations to elucidate the origin of these unique pathways using n-BuMgCl as a representative nucleophile (Figure ). First, the substrate 2 chelates the Grignard reagent and generates a stable complex Int1, which undergoes a nucleophilic attack at phosphorus center (SN2@P) through the transition state structure TS9 (ΔG ‡ = 19.7 kcal mol -1 , Figure ). Once the P-C bond is formed, the thiazolidinone leaving group is dissociated simultaneously without the formation of a pentacoordinate P(V) intermediate. This pathway is referred to as a double-well potential energy surface (PES), and the process, also known as the frontside bimolecular nucleophilic substitution at phosphorus (SN2@P4-f), is the favored pathway compared to the backside SN2@P4-b. Interestingly, the P-C bond formation preferably occurs opposite to the phenoxy group when comparing TS9 and TS10, and this is due to the stabilization of electron density localized at the apical oxygen atom which can further promote the substitution process. In stark contrast, nucleophilic substitution with the Grignard reagent in the absence of thiazolidinone leaving group occurs by SN2@P4-b through the most preferred transition state structure TS12 (Figure ). Again, the phenoxy group tends to be placed at the apical position at the transition state, and in this case the dissociation of the leaving group through the concerted process leads to the formation of the stereochemically inverted product. Taken together, the indepth analyses into both catalytic enantioselective and stoichiometric enantiospecific nucleophilic substitution reactions at the P(V) center revealed the origin of improved generality and diversifiability of our second-generation protocol.