Unveiling Mechanism of a Quinine-Squaramide Catalyzed Enantioselective Aza-Friedel–Crafts Reaction between Cyclic Trifluoromethyl Ketimine and Naphthol: A DFT Study

Abstract

A mechanism study of quinine-squaramide catalyzed enantioselective aza-Friedel-Crafts (aza-F-C) reaction is described using density functional theory (DFT). The most favorable pathway is obtained through the discussions of four possible modes of hydrogen bond interactions, in which the nucleophile is activated by the squaramide N-H groups (N-Ha and N-Hb) and the electrophile binds to the protonated amine by hydrogen bonding. Meanwhile, we have also studied the energy barrier of the stereocontrolling transition states that might play a role of stereoselectivity. In addition, noncovalent interaction (NCI) analyses show a series of favorable cooperative noncovalent interactions, including N-H···O and C-H···F hydrogen-bonding, and π···π interactions. The strong interactions and lower barrier were found for TS3, indicating the preference for the R-configuration adduct, which is in good agreement with the experimental observations.

Asymmetric Construction of Bispiro[oxindole-pyrrolidine-rhodanine]s via Squaramide-Catalyzed Domino Michael/Mannich [3 + 2] Cycloaddition of Rhodanine Derivatives with N-(2,2,2-Trifluoroethyl)isatin Ketimines

“…As shown in Figure , on the basis of our experiments and previously reported dual activation model, we proposed a plausible mechanism for this domino Michae/Mannich [3 + 2] cycloaddition reaction. In the first Michael addition step, catalyst C2 initially promotes the formation of transition state A through deprotonation of the N -(2,2,2-trifluoroethyl)­isatin ketimine 2a .…”

Insights on the Pseudo‐Enantiomeric Properties of Bifunctional Cinchona Alkaloid Squaramide‐Derived Organocatalyst

“…in which the electrophile is activated by the protonated amine group and the deprotonated nucleophile is coordinated to the squaramide [16] . Further proposals have been made and explored involving a „split“ mode of activation wherein either the nucleophile or the electrophile is hydrogen bound to both the protonated amine group and one of the NH‐groups of the squaramide where the other reacting partner is coordinated to the remaining NH‐group of the squaramide (Mode C and D) [17, 18, 19] . When these were explored in the current system, optimizations led to structures assuming either Mode A or B (see Supporting Information).…”

“…[16] Further proposals have been made and exploredi nvolving a "split" mode of activation wherein either the nucleophile or the electrophile is hydrogen bound to both the protonated amine group and one of the NH-groups of the squaramide where the other reacting partner is coordinated to the remaining NH-group of the squaramide (Mode Ca nd D). [17,18,19] When these were explored in the current system, optimizations led to structuresa ssuming either Mode Ao rB(see Supporting Information). Furthermore, mono-activated binding modes were explored and were all found to be disfavoured.…”

The Role of Aromatic Alcohol Additives on Asymmetric Organocatalysis Reactions: Insights from Theory

“…Previous computational investigations by Wang and co-workers have indicated that the direct attack of the naphthol additive on the catalyst (quinine-squaramide, in their case) was not favourable. [44] Nevertheless, we have investigated the possibility of proton transfer from the 2-naphthol additive to the quinuclidine nitrogen for the BzCPD catalyst case. The deprotonation of 2naphthol with the concomitant protonation of the quinuclidine nitrogen was seen to be not possible, as the quinuclidine nitrogen gave back the proton to the oxygen of the 2-naphthol (see Figure S3 in SI).…”