Linear Regression Model for Predicting Allyl Alcohol C–O Bond Activity under Palladium Catalysis

Abstract

C−O bond activation assisted by activators such as Brønsted acids greatly improves the value of allyl alcohol in allylation; thus, understanding and predicting the activation energy barrier is of paramount importance. Herein, we reveal that multiple linear regression (MLR) analysis is a suitable tool for unifying and correlating different activators and ligands of Pd-catalyzed C−O bond activation of allyl alcohols. We obtain a simple model predicting activation energy barriers with different activators and ligands of 393 calculated data points. Statistical tools and extensive molecular featurization have guided the development of an inclusive linear regression model, providing a predictive platform and readily interpretable descriptors. It was found that easily available descriptors, such as the acidity (pK a ) of the activators, and the E HOMO , vertical ionization potential (VIP), and bond angle (φ P-Pd-P ) of the ligands, can well describe the combined influences of steric and electronic effects, including hydrogen-bonding interactions. Overall, this strategy highlights the utility of MLR analysis in exploring mechanistically driven correlations across a diverse chemical space in organometallic chemistry and presents an applicable workflow for C−O bond activation.

Efficient and environmentally-friendly access to 4,5-unsaturated sulfonamides through ligand-free copper-BF3-catalyzed three-component alkene carbo-sulfonamidation

“…A plausible mechanism is proposed (Scheme 6) on the basis of the results of the control experiments and the literature. 53–55 The Lewis acid (BF 3 ·ether) first reacts with the basic sulfonamide (NH 2 SO 2 Me) to generate a Lewis acid-sulfonamide pair that further reacts with Cu( i ) to give the copper-Lewis acid-sulfonamide complex ( A ). This key intermediate A coordinates with the cinnamyl cation generated from the dehydration of cinnamyl alcohol, forming the π-allyl-copper intermediate B .…”

“…A plausible mechanism is proposed (Scheme 6) on the basis of the results of the control experiments and the literature. [53][54][55] The Lewis acid (BF 3 •ether) first reacts with the basic sulfonamide (NH 2 SO 2 Me) to generate a Lewis acid-sulfonamide pair that further reacts with Cu(I) to give the copper-Scheme 4 Gram-scale synthesis of 4ad. Lewis acid-sulfonamide complex (A).…”

Organopalladium Catalysis as a Proving Ground for Data-Rich Approaches to Reaction Development and Quantitative Predictions

“…A recent example by Yu, Fu, and co-workers showcases this approach to study the activating effect of Brønsted acids on the Pd-catalyzed C−O bond cleavage of allyl alcohols. 54 They created a computationally derived reaction database containing 393 DFT calculated activation barriers, followed by multivariate linear regression (MLR) model training using calculated molecular descriptors. The prediction accuracy was confirmed by a small experimental test set (taken from the literature 55 ), with good agreement between predicted ΔG ‡ and the experimental product yield.…”

Recent DFT Calculations on the Mechanism of Transition‐Metal‐Catalyzed C−O Activation of Alcohols

“…In a related study, Fu and Yu systematically investigated the elementary step of Pd‐catalysed C−OH bond activation of allyl alcohols, using Brønsted acids and phosphines as activators and ligands. Potential activation modes were examined and are shown in Figure 27 [84] . The relevant calculation level is PBE0‐D3/ma‐TZVP/SMD(THF)//PBE0‐D3/def2‐SVP.…”

“…Potential activation modes were examined and are shown in Figure 27. [84] The relevant calculation level is PBE0-D3/ ma-TZVP/SMD(THF)//PBE0-D3/def2-SVP. Different from the findings in Figure 26, Fu et al found that S N 2 -type oxidative addition is more favorable during CÀ O bond cleavage (TS27 vs TS25 and TS28 vs TS26), and the CÀ O activation in the presence of two molecules of activators is more feasible than the one activator mode (TS27 vs TS28).…”