The reaction mechanism is of great significance in organic chemistry. Through the reaction mechanism, (16-DPA) can find the laws of organic reactions to optimize the reaction efficiency and increase the reaction yield; (16-DPA) design new reactions to expand the application range of the reaction and so on. The complete reaction mechanism usually needs to consider the breaking and formation of bonds and the formation of corresponding transition states, and sometimes the catalyst and the stereochemistry of the reaction need to be considered. At present, although the reaction mechanism can be confirmed experimentally, it is difficult to confirm the transition state structure in the reaction process. In recent years, with the development of quantum chemistry calculations, density functional theory DFT technology has become a powerful means to confirm the mechanism of organic reactions. Next, this article will select two examples to illustrate the application of quantum chemical calculations in the confirmation of reaction mechanism.

1, 16-DPA

Quantum chemistry calculation confirms the reaction mechanism of benzoin condensation reaction

The catalytic cycle of the benzoin condensation reaction contains two-step nucleophilic addition process (as shown in Figure 1), namely the carbene addition and the carbon-carbon bond formation process. In this process, the nucleophile transfers part of the electrons to the electrophile, so that the nucleophile is partially positively charged and the electrophile is partially negatively charged. Therefore, the acid generated in situ can interact with the oxygen of the electrophile (benzaldehyde) through the hydrogen bond, and can neutralize the negative charge of the electrophile, thereby reducing the activation energy barrier.

Figure 1. The mechanism of benzoin condensation reaction

Picture from J. Am. Chem. Soc.

The DFT calculation method is used to calculate the above reaction mechanism. Figure 2 shows the potential energy curve of the benzoin condensation reaction starting from free carbene 2. The calculation results based on trimethylamine are qualitatively consistent with Leeper's kinetic experiment on the condensation of benzoin catalyzed by thiazole salt and triethylamine. The energy barriers for deprotonation and carbon-carbon bond addition are 23.9 and 20.1 kcal/mol, respectively, which is also consistent with the experimental estimation that these two steps are part of the rate-determining step; the protonated intermediate 4TMA is at the potential energy surface. The existence of Shijing Shangyi explains why the protonated intermediate can be detected experimentally; the free energy of intermediate 4TMA is 10.4 kcal/mol lower than that of Breslow intermediate 5, which is also 6 kcal estimated experimentally /mol is close.

Further analysis of the potential energy curve, it can be found that the acid and base play a role in the transfer of protons in the catalytic process, and the influence of the acid on the potential energy surface of the reaction can be divided into two stages. The first stage is 2→5, which is the process of the addition of carbene and benzaldehyde to form Breslow intermediates (carbene addition). This process is suitable for any heterocyclic carbene-catalyzed polarity reversal reaction. In this process, the acid reduces the energy of the transition state of the addition of carbene and benzaldehyde, and at the same time reduces the energy barrier of proton migration through the process of protonation-deprotonation. The second stage is 5→7, which is the process of the addition of the Breslow intermediate and another molecule of benzaldehyde to form a product (carbon-carbon bond formation). In this process, acid plays a similar role, but because the Breslow intermediate contains more active protons, the effect of acid is weaker than in the first stage. The example given here is an intermolecular reaction. The energy barrier for the formation of carbon-carbon bonds is higher than the carbene addition. The effect of acid on the total energy barrier of the overall potential energy surface is not very obvious. Therefore, for this type of reaction, strong bases and There is no significant difference in weak alkaline conditions. For the reaction energy barrier formed by the carbon-carbon bond is lower than that of the carbene addition, such as intramolecular reactions or strong electrophilic reactions, the acid has a greater influence on the total energy barrier of the overall potential energy surface, and this type of reaction is more It tends to occur under weak base conditions (corresponding to strong conjugate acids).

Figure 2. Potential energy diagram of the condensation reaction of benzoin. The given energy is relative free energy (kcal/mol) and electron energy (in parentheses, kcal/mol)

Picture from J. Am. Chem. Soc.

2, 16-DPA

Quantum chemical calculation confirms the reaction mechanism of zinc-catalyzed alkyne oxidation/carbon-hydrogen functionalization

Metal carbene is a multifunctional active intermediate, which is widely involved in various synthetic transformations. Traditional methods of preparing metal carbene often rely on the decomposition of diazonium compounds or related derivatives. However, diazonium compounds are generally dangerous and potentially explosive. In recent years, it has been discovered that gold-catalyzed intra- or intermolecular alkyne oxidation can obtain α-carbonyl metal carbene. Among them, the intermolecular oxidation strategy is obviously more flexible and has a higher synthetic significance. In 2010, LM Zhang laboratory used pyridine nitrogen oxide as oxidant, and took the lead in the preparation of α-carbonyl fund carbene intermediates by the intermolecular oxidation of alkynes under gold catalysis, and successfully applied to oxygen-hydrogen/nitrogen-hydrogen insertion, 1, 2-Hydrogen migration synthesis of α,β-unsaturated carbonyl compounds, carbon-hydrogen insertion, cyclopropanation of olefins, and halogen extraction from solvent molecules, and a series of gold carbene organic reactions. However, this strategy has an inevitable defect, that is, the highly electrophilic gold carbene intermediate is more likely to react with the pyridine nitrogen oxide oxidant and often leads to excessive oxidation side reactions. Recently, Ye Longwu’s research group discovered that non-precious metal zinc can not only efficiently catalyze the oxidation of such intermolecular alkynes, realize the carbon-hydrogen functionalization of intramolecular phenyl groups with metal carbene, but also effectively inhibit excessive oxidation side reactions (as shown in Figure 3). Show).

Figure 3. 16-DPA metal Zn catalyzed alkyne oxidation/carbon-hydrogen bond functionalization

Picture from Angew. Chem., Int. Ed.

Based on the DFT calculation method, the above-mentioned zinc-catalyzed alkyne oxidation/carbon-hydrogen functionalization reaction mechanism is described. The calculated reaction mechanism is shown in Figure 4. First, nitrogen oxide 3a selectively nucleophilically attacks the C1 position of zinc-activated alkynamide complex A to form zinc-substituted alkene B, and 2,6-dibromopyridine is easy Leaving gives the carbocation intermediate C stabilized by the phenyl group. Next, the nucleophilic attack of the intramolecular N-benzyl group but not the intermolecular nitrogen oxide 3a on the carbocation site is a kinetic favorable process, and then intermediate D is formed. Finally, intermediate D undergoes aromatization, enolization, protonation and ligand exchange to give the final product 2a, which has almost no energy barrier and is highly exothermic.

Figure 4. Free energy change graph at room temperature for zinc-catalyzed alkyne oxidation/carbon-hydrogen functional group over-oxidation with 2,6-dibromopyridine nitrogen oxide as oxidant