A computational method for revealing the micro-mechanism and the origin of selectivity of palladium-catalyzed 1,2-diarylation of enamines by density functional theory

Abstract

The application discloses a kind of by density functional theory reveals the calculation method of micro-mechanism and selectivity source of palladium catalysis olefin amine 1,2-diarylation reaction, belong to the intersection technical field of organic synthesis and computational chemistry. Including constructing molecular structure;The configuration optimization and calculation are carried out to molecular structure, obtain thermodynamic data;The geometric configuration of intermediate and transition state in each step is calculated, the change of gibbs free energy is obtained, the connection relationship of transition state and corresponding reactant, product is determined;According to thermodynamic data and connection relationship, reaction path diagram is drawn, and reaction mechanism is determined;According to reaction mechanism, the step of determining the selectivity of reaction region, enantioselectivity and chemical selectivity is determined, and selectivity control strategy is analyzed and output. By simulation, the key intermediate and transition state structure of each element step of reaction is determined, the reaction energy barrier of each element step is quantified, the transition state action mechanism determining the selectivity of reaction region, enantioselectivity and chemical selectivity is analyzed in depth, to provide theoretical guidance for the design of high-efficiency catalyst and the optimization of reaction condition.

Description

Technical Field

[0001] This invention belongs to the interdisciplinary field of organic synthesis and computational chemistry, specifically involving a computational method that reveals the microscopic mechanism and selectivity source of palladium-catalyzed 1,2-diarylization reaction of enamines using density functional theory. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Ortho-chiral center-like complex molecules are key structures for many drugs and functional materials, and their efficient and highly selective synthesis is a core requirement for the development of related fields. Among them, palladium-catalyzed asymmetric 1,2-diarylization of enamines has become one of the mainstream synthetic strategies due to its mild conditions and good selectivity.

[0004] A thorough exploration of the microscopic mechanisms of palladium catalysis and a precise analysis of the root causes of reaction selectivity are not only prerequisites for understanding the nature of this type of reaction, but also crucial foundations for optimizing catalyst structures and improving overall reaction performance. However, current optimization of this reaction relies heavily on extensive experimental trial and error, resulting in long development cycles and high costs, severely hindering the development of highly selective and high-yield catalytic systems. Therefore, developing system simulation methods based on density functional theory (DFT) to predict and optimize reaction conditions from a mechanistic perspective is of significant value for improving research efficiency and driving technological breakthroughs. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide a computational method that reveals the microscopic mechanism and selectivity source of palladium-catalyzed 1,2-diarylization of enamines using density functional theory. Through computational simulation, the present invention clarifies the key intermediate and transition state structures of each elementary step of the reaction, quantifies the reaction energy barriers of each elementary step, and deeply analyzes the transition state mechanism that determines regioselectivity, enantioselectivity, and chemoselectivity, providing theoretical guidance for the design of efficient catalysts and the optimization of reaction conditions.

[0006] To achieve the above objectives, the technical solution of the present invention is as follows: The first aspect of this invention provides a computational method for revealing the microscopic mechanism and selectivity origin of palladium-catalyzed 1,2-diarylization of enamines using density functional theory, comprising: Construct the molecular structure of compounds involved in the palladium-catalyzed 1,2-diarylization reaction of enamines; Geometric configuration optimization and frequency calculation were performed on all molecular structures to obtain thermodynamic data at 298.15 K; Calculate the geometry of intermediates and transition states in each elementary step of the palladium-catalyzed 1,2-diarylization reaction of enamines, and obtain the Gibbs free energy changes of each elementary step; determine the connection relationship between the transition state and the corresponding reactants and products by calculating intrinsic reaction coordinates. Based on the connection relationships between thermodynamic data and geometric structures, a reaction pathway diagram is drawn to clarify the reaction mechanism; Based on the reaction mechanism, the steps that determine the regioselectivity, enantioselectivity, and chemoselectivity of the reaction are identified, and the selectivity control strategies are analyzed and output.

[0007] A second aspect of the present invention provides a computational system for revealing the microscopic mechanism and selectivity origin of palladium-catalyzed 1,2-diarylization of enamines using density functional theory, comprising: A structure building module for constructing the molecular structure of compounds in palladium-catalyzed 1,2-diarylization reactions of enamines; The data calculation module is used to optimize the geometry and calculate the frequency of all molecular structures, and to obtain thermodynamic data at 298.15 K. The connection calculation module is used to calculate the geometric configuration of intermediates and transition states in each elementary step of the palladium-catalyzed 1,2-diarylation reaction of enamines, and to obtain the Gibbs free energy change of each elementary step; the connection relationship between the transition state and the corresponding reactants and products is determined by calculating the intrinsic reaction coordinates. The mechanism determination module is used to draw reaction pathway diagrams based on thermodynamic data and connectivity relationships to determine the reaction mechanism. The analysis output module is used to determine the steps that determine the regioselectivity, enantioselectivity and chemoselectivity of the reaction based on the reaction mechanism, and to analyze and output the selectivity control strategy.

[0008] A third aspect of the present invention provides a computer-readable storage medium having a computer program stored thereon, characterized in that, when executed by a processor, the program implements the steps of the computation method as described in the first aspect.

[0009] A fourth aspect of the present invention provides a computer device including a memory, a processor, and a computer program stored in the memory and executable on the processor, characterized in that the processor executes the program to implement the steps in the calculation method described in the first aspect.

[0010] The beneficial effects of this invention are as follows: This invention, based on density functional theory, systematically reveals the root causes of the regioselectivity, enantioselectivity, and chemoselectivity of palladium-catalyzed 1,2-diarylization of enamines at the microscopic level, filling the theoretical gap in the selective guidance of this reaction and solving the problem of experimental research relying on trial and error. By clarifying the regulatory mechanisms of electronic effects, steric effects, weak interactions, and ligand properties on selectivity, this method can output targeted regulatory strategies, shortening the development cycle of highly selective catalytic systems and reducing experimental costs. The calculation process does not involve the use of chemical reagents, resulting in no chemical pollution and conforming to the concept of green environmental protection. The calculation parameters are reasonably set, balancing computational accuracy and efficiency, and can be implemented on ordinary servers, making it easy to promote and apply.

[0011] This invention is not only applicable to palladium-catalyzed 1,2-diarylization of enamines, but its core concept (mechanism calculation - selectivity analysis - strategy output) can be extended to other transition metal-catalyzed olefin dicarbon functionalization reactions, and has wide applicability. Attached Figure Description

[0012] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0013] Figure 1 This invention provides a technical approach for revealing the microscopic mechanism and selectivity root causes of palladium-catalyzed 1,2-diarylization of enamines using density functional theory.

[0014] Figure 2 This is a Gibbs potential profile of the oxidative addition of aryl diazonium salts to palladium centers. Bond lengths are in Å.

[0015] Figure 3 Gibbs potential profile for the formation of the 1,2-diarylized main product P and the direct cross-coupling of the byproduct P' between R2 and R3.

[0016] Figure 4 Gibbs potential profiles for the formation of the 1,2-diarylized main product P and the Heck reaction byproduct P''. Bond lengths are in Å.

[0017] Figure 5 To determine the relative Gibbs free energy of the regioselective transition state. The charge unit of the natural bond orbital (NBO) is... e The bond length is measured in Å.

[0018] Figure 6The geometry and relative Gibbs free energy of the transfer metallization transition states (TS3, TS3a, TS3b) and the β-H elimination transition states (TS7, TS7a, TS7b) are given. Bond lengths are in Å. The isosurface values ​​for IGMH analysis are 0.005 au. Where a represents the geometry and relative Gibbs free energy of TS3 and TS7; b represents the geometry and relative Gibbs free energy of TS3a and TS7a; and c represents the geometry and relative Gibbs free energy of TS3b and TS7b.

[0019] Figure 7 To determine the enantioselectivity of the olefin insertion transition state TS2 SR and TS2 RS The geometric configuration. Bond length is measured in Å.

[0020] Figure 8 To determine the enantioselectivity of the olefin insertion transition state TS2 SR and TS2 RS The results of deformation-interaction analysis. Detailed Implementation

[0021] It should be noted that the following detailed description is illustrative and intended to provide further explanation of the invention. Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0022] Example 1 This embodiment provides a calculation method using density functional theory to reveal the microscopic mechanism and selectivity source of palladium-catalyzed 1,2-diarylization of enamines, such as... Figure 1 As shown, the specific steps include the following: S1: Construct the molecular structure of the compound in the palladium-catalyzed 1,2-diarylization reaction of enamines.

[0023] In step S1, the compound includes a substrate, a palladium catalyst, an additive, a main product, and a byproduct.

[0024] The substrates include enamines, aryl diazonium salts, and arylboronic acids, the additive is silver carbonate, the main product includes 1,2-diarylized products (target chiral molecule P), and the byproducts include direct cross-coupling product P' and Heck reaction product P''.

[0025] In step S1, the palladium catalyst is a zero-valent palladium catalyst containing isopropyl biphenyl oxazoline and dimethyl fumarate ligands, namely Pd(0)L, where L is isopropyl biphenyl oxazoline and dimethyl fumarate.

[0026] S2: Perform geometric optimization and frequency calculations on all molecular structures to obtain thermodynamic data at 298.15 K.

[0027] In step S2, Gaussian 09 software is used to optimize the geometry and calculate the frequencies of all molecular structures.

[0028] In step S2, the geometric configuration optimization and frequency calculation for all structures includes: selecting the B3LYP-D3(BJ) functional and mixed basis set, using the SMD continuous medium solvation model to simulate the tert-amyl alcohol solvent environment, calculating the harmonic vibration frequencies of the stagnation points of all geometric structures, confirming that the intermediate is a local minimum point, and obtaining thermodynamic data at 298.15 K. In the mixed basis set, the metal atoms use the LanL2DZ basis set, and the non-metal atoms use the 6-31g** basis set.

[0029] In step S2, the local minimum has no imaginary frequency, while the transition state has one and only one imaginary frequency.

[0030] In step S2, the thermodynamic data include the Gibbs free energy data of each intermediate and transition state in the reaction.

[0031] S3: Calculate the geometry of intermediates and transition states in each elementary step of the palladium-catalyzed 1,2-diarylization reaction of enamines, and obtain the Gibbs free energy changes of each elementary step; determine the connection relationship between the transition state and the corresponding reactants and products by calculating the intrinsic reaction coordinates.

[0032] In step S2, the connectivity is obtained through intrinsic reaction coordinates, and the reaction mechanism is determined based on the reaction sequence. First, the molecular structure is optimized, and then the reaction pathway is determined based on the order in which the reactants are added.

[0033] S4: Draw a reaction path diagram based on the thermodynamic data and the connection relationship of the geometric structure to determine the reaction mechanism.

[0034] In step S4, a reaction path diagram is drawn based on the thermodynamic data and the connection relationship of the geometric structure, and the optimal reaction mechanism is determined, including: The main product is generated based on elementary processes, and the reaction energy barrier of the main product is lower than that of the side reactions. The elementary processes include oxidative addition, denitrogenation, olefin migration insertion, transfer metallization, and reductive elimination.

[0035] S5: Based on the reaction mechanism, determine the steps that determine the regioselectivity, enantioselectivity and chemoselectivity of the reaction, analyze and output the selectivity control strategy.

[0036] In step S5, based on the reaction mechanism, combined with the energy span model and the Curtin-Hammett principle, the steps that determine the regioselectivity, enantioselectivity, and chemoselectivity of the reaction are determined.

[0037] There are four possible insertion modes in the olefin insertion step, and the process is irreversible. Therefore, this step can be considered the key step in determining the regioselectivity and enantioselectivity of the reaction. On the other hand, the chemoselectivity of the main product and the direct cross-coupling byproduct is determined by the competition between olefin insertion and transfer metallization of aryl palladium. The chemoselectivity of the main product and the Heck byproduct is determined by whether the aryl alkyl palladium intermediate undergoes transfer metallization or β-H elimination. The calculated data show that the formation energy of the main product is lower, so the main product is more likely to form.

[0038] In step S5, the analysis and output of selective control strategies includes: performing regioselectivity analysis and outputting regioselectivity control strategies, performing enantioselectivity analysis and outputting enantioselectivity control strategies, and performing chemoselectivity analysis and outputting chemoselectivity control strategies.

[0039] The regioselectivity analysis and output of the regioselectivity regulation strategy include: calculating the energy difference between the 2,1-olefin insertion transition state and the 1,2-olefin insertion transition state; obtaining the NBO charge value of the atom through natural bond orbital analysis; and comparing the electrostatic interactions between atoms with the conjugation effect of the amide group and the C=C double bond in the enamine substrate. The substrate carbon atom with stronger electrostatic interactions dominates regioselectivity, thus determining the regulatory mechanism of electronic effects on regioselectivity. Based on the regulatory mechanism of electronic effects on regioselectivity, the amide group in the enamine substrate is replaced or adjusted to enhance the conjugation effect, increase the energy difference between transition states, and improve regioselectivity. The enantioselectivity analysis and enantioselectivity regulation strategy includes: calculating the energy difference of the Si or Re facets of the olefin in the 2,1-olefin insertion participating in the reaction transition state; using deformation-interaction analysis, it was found that in the unfavorable transition state, there is a strong repulsion between the nitrogen heterocyclic group of the catalyst moiety and the aromatic ring of the substrate, leading to increased catalyst structural deformation, thus revealing the mechanism by which steric effects regulate the enantioselectivity of the reaction; based on this mechanism, the ligand substituents of the palladium catalyst are further optimized by enhancing steric hindrance, increasing the energy difference between transition states, increasing the steric repulsion between the enamine and the ligand, promoting greater deformation of the substrate and catalyst moiety in the unfavorable transition state, and ultimately improving enantioselectivity; The chemoselectivity analysis and output of chemoselectivity regulation strategies include: comparing the energy barrier difference between the transition states of the main reaction and the direct cross-coupling side reaction, and calculating the HOMO-LUMO energy level difference using frontier molecular orbitals. The smaller HOMO-LUMO energy level difference in the main reaction compared to the side reaction explains why the aryl palladium intermediate preferentially occurs in the main reaction rather than the direct cross-coupling side reaction; accordingly, optimizing the amount of silver carbonate to stabilize the complex formed by silver carbonate and arylboronic acid, thus suppressing the occurrence of direct cross-coupling; using an independent gradient model to analyze and compare the weak interaction strength between the main reaction transfer metallization transition state and the Heck side reaction transition state; calculating the energy of the transition state by replacing the carbonyl substituent in the enamine substrate to verify the regulatory effect of the carbonyl group on the chemoselectivity unfavorable to the Heck reaction; based on the regulatory effect of the carbonyl group on chemoselectivity, selecting enamine substrates containing strong electron-withdrawing groups to suppress the Heck side reaction; and selecting electron-deficient ligands with low steric hindrance as ligands for the reductive elimination step, thereby increasing the positive charge of the palladium center, reducing the reductive elimination energy barrier, and strengthening the main reaction pathway advantage.

[0040] In some embodiments of the present invention, the main reaction is an olefin insertion reaction, a transfer metallization reaction, or a reductive elimination reaction, and the side reactions are a direct cross-coupling reaction and a Heck reaction.

[0041] By way of example, the method of the present invention will be further described in detail below with reference to specific calculation examples. Figure 1 This is a technology roadmap.

[0042] Density functional theory (DFT) calculations for this invention were all performed using the Gaussian 09 software package. The geometry was optimized using the B3LYP-D3(BJ) functional. For palladium and silver atoms, the LanL2DZ effective nuclear potential (ECP) basis set was used, with f-type polarization functions added (palladium: ζf = 1.472, silver: ζf = 1.611). For other atoms, the 6-31G(d,p) basis set was used. In the geometry optimization, the SMD continuum solvation model was used to consider the solvent effect of tert-amyl alcohol, with custom solvent parameters set to "solvent=generic, eps=5.78, epsinf=1.97". Harmonic vibrational frequencies were calculated for all stagnation points at the same theoretical level to confirm whether they were local minima (without imaginary frequencies) or transition states (with only one imaginary frequency), and thermochemical correction values ​​at 298.15 K were obtained. Intrinsic reaction coordinates (IRCs) were also calculated to confirm that each transition state is associated with the corresponding reactant and product.

[0043] To improve computational accuracy, the same B3LYP-D3(BJ) functional and a larger mixed basis set were used for single-point energy calculations: the SDD basis set was used for palladium and silver atoms, while the larger 6-311+G(d,p) basis set was used for other atoms. The SMD continuum solvation model and custom solvent parameters (solvent=generic, eps=5.78, epsinf=1.97) remained unchanged. Natural bond orbital (NBO) analysis was performed using NBO version 3.1, which is embedded in the Gaussian 09 software package. Frontier molecular orbital (FMO) and IMH analyses were performed using the Multiwfn program, and the orbital isosurfaces were visualized using VMD software.

[0044] A computational method for revealing the microscopic mechanism and selectivity source of palladium-catalyzed 1,2-diarylization of enamines using density functional theory includes the following steps: Step 1. Calculation and analysis of the formation process of arylpalladium(II) complex B Basic model construction: The initial complex A of Pd(0)L catalyst (L is isopropyl biphenyl oxazoline) and aryl diazonium salt was constructed, and the Gibbs free energy of A was set as the zero energy reference point.

[0045] Calculation of oxidative addition pathway: The Gaussian 09 software package was used to optimize the geometry and calculate the frequencies of all structures. The B3LYP-D3(BJ) functional and mixed basis sets were selected (the LanL2DZ basis set was used for metal atoms and the 6-31g** basis set was used for non-metal atoms). The SMD continuous medium solvation model was used to simulate the tert-amyl alcohol solvent environment. The harmonic vibration frequencies of all stagnation points were calculated to confirm that the intermediate is a local minimum (without imaginary frequencies). Thermodynamic data at 298.15 K were obtained.

[0046] Specifically, the structure of the traditional three-center oxidative addition transition state TS1 was optimized, and its energy barrier was calculated to be 0.9 kcal / mol; the structure of the four-center σ bond metathesis transition state TS1' was optimized, and its energy barrier was 2.4 kcal / mol. Both pathways are barrier-free processes.

[0047] The structure of the planar tetragonal palladium(II) complex was optimized, and the process of its dissociation from N2 to form the T-shaped aryl palladium(II) complex was calculated. The formation of B is thermodynamically and kinetically favorable. The calculation results are shown in […]. Figure 2 .

[0048] Results: Arylpalladium(II) complex B was determined to be formed via two oxidative addition mechanisms, providing an intermediate model for subsequent selectivity analysis. The subsequent reaction pathway is similar to the calculations in this step and will not be described further here.

[0049] Step 2. Regional Selectivity Analysis and Regulation Transition state calculation: Optimization of 1,2-olefin insertion transition state TS2 SR and 2,1-olefin insertion transition state TS2 2,1-RR TS2 2,1-SS The structure was calculated to yield TS2. 2,1-RR TS2 2,1-SS Energy ratio of TS2 SR The concentration was above 2.5 kcal / mol. Analytical results are shown below. Figure 5 .

[0050] NBO charge analysis: TS2 SR The NBO charge of Pd is 0.365. e The NBO charge of the C2 atom is -0.290. e Strong electrostatic interaction; TS2 2,1-RR TS2 2,1-SS The NBO charge of the C1 atom is -0.046. e The electrostatic interaction is weak; the conjugation effect of the amide group in the enamine substrate causes the C2 atom to accumulate more negative charge, which dominates the regioselectivity.

[0051] Validation of the regulation strategy: Replacing the amide group of the enamine substrate with a formamide group (enhancing the conjugation effect) resulted in a further widening of the energy difference between transition states and improved regioselectivity.

[0052] Step 3. Chemical selectivity regulation (suppressing Heck side reactions) Key transition state energy comparison: The calculated energy barrier of the transfer metallization transition state TS3 is 10.4 kcal / mol, while the energy barrier of the β-H elimination transition state TS7 is 15.3 kcal / mol. TS3 has a lower energy by 4.9 kcal / mol.

[0053] IGMH analysis revealed a weak CH…π interaction between the enamine carbonyl group and the benzene ring in TS3 (clearly visible in the green region of IGMH), while the hydrogen bonding between the carbonyl group and the ligand methyl group in TS7 was weak (small green region). Strong CH…π interactions stabilized TS3. The analytical results are shown below. Figure 6 .

[0054] Verification of carbonyl modification: When the carbonyl oxygen atom of the enamine is replaced with two hydrogen atoms, calculations show that β-H elimination is the dominant pathway; after restoring the carbonyl structure, transfer metallization is still the dominant transition state, proving that the carbonyl group can effectively suppress the Heck side reaction.

[0055] Step 4. Enantioselective modulation Transition state energy and structure analysis: TS2 SR Compared to TS2 RSLow energy content: 2.2 kcal / mol Figure 7 Deformation-interaction analysis shows that TS2 SR The deformation energy of the aryl palladium intermediate is 16.2 kcal / mol, TS2 RS The concentration was 18.3 kcal / mol, and the substrate deformation energy was similar. Analytical results are shown below. Figure 8 .

[0056] Ligand optimization: i Pr-BiO x Replacing the isopropyl group with a tert-butyl group (increasing steric hindrance) showed that the energy difference of the corresponding transition state could be expanded, verifying the regulatory role of the steric effect.

[0057] As can be seen from the above embodiments, the method of the present invention can accurately reveal the selective source of palladium-catalyzed 1,2-diarylization reaction of enamines and output effective control strategies, providing theoretical guidance for further optimization of such reactions in experimental systems.

[0058] Example 2 This embodiment discloses a computational system that reveals the microscopic mechanism and selectivity source of palladium-catalyzed 1,2-diarylization of enamines using density functional theory, including: A structure building module for constructing the molecular structure of compounds in palladium-catalyzed 1,2-diarylization reactions of enamines; The data calculation module is used to optimize the geometry and calculate the frequency of all molecular structures, and to obtain thermodynamic data at 298.15 K. The connection calculation module is used to calculate the geometric configuration of intermediates and transition states in each elementary step of the palladium-catalyzed 1,2-diarylation reaction of enamines, and to obtain the Gibbs free energy change of each elementary step; the connection relationship between the transition state and the corresponding reactants and products is determined by calculating the intrinsic reaction coordinates. The mechanism determination module is used to draw reaction pathway diagrams based on thermodynamic data and connectivity relationships to determine the reaction mechanism. The analysis output module is used to determine the steps that determine the regioselectivity, enantioselectivity and chemoselectivity of the reaction based on the reaction mechanism, and to analyze and output the selectivity control strategy.

[0059] Example 3 This embodiment provides a computer-readable storage medium storing a computer program that, when executed by a processor, implements the steps in the computational system described in Embodiment 1, which reveals the microscopic mechanism and selectivity source of palladium-catalyzed enamine 1,2-diarylization reaction using density functional theory. These steps include: S1. Construct the molecular structure of the compound in the palladium-catalyzed 1,2-diarylization reaction of enamines; S2. Perform geometric configuration optimization and frequency calculation on all molecular structures to obtain thermodynamic data at 298.15 K; S3. Calculate the geometry of intermediates and transition states in each elementary step of the palladium-catalyzed 1,2-diarylization reaction of enamines, and obtain the Gibbs free energy changes of each elementary step; determine the connection relationship between the transition state and the corresponding reactants and products by calculating the intrinsic reaction coordinates. S4. Draw a reaction pathway diagram based on thermodynamic data and connectivity relationships to determine the reaction mechanism; S5. Based on the reaction mechanism, determine the steps that determine the regioselectivity, enantioselectivity, and chemoselectivity of the reaction, analyze and output the selectivity control strategy.

[0060] Example 4 This embodiment provides a computer device, including a memory, a processor, and a computer program stored in the memory and executable on the processor. When the processor executes the program, it implements the steps described in Embodiment 1 of the computational system for revealing the microscopic mechanism and selectivity source of palladium-catalyzed enamine 1,2-diarylization reaction using density functional theory. These steps include: S1. Construct the molecular structure of the compound in the palladium-catalyzed 1,2-diarylization reaction of enamines; S2. Perform geometric configuration optimization and frequency calculation on all molecular structures to obtain thermodynamic data at 298.15 K; S3. Calculate the geometry of intermediates and transition states in each elementary step of the palladium-catalyzed 1,2-diarylization reaction of enamines, and obtain the Gibbs free energy changes of each elementary step; determine the connection relationship between the transition state and the corresponding reactants and products by calculating the intrinsic reaction coordinates. S4. Draw a reaction pathway diagram based on thermodynamic data and connectivity relationships to determine the reaction mechanism; S5. Based on the reaction mechanism, determine the steps that determine the regioselectivity, enantioselectivity, and chemoselectivity of the reaction, analyze and output the selectivity control strategy.

[0061] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A computational method for revealing the microscopic mechanism and selectivity source of palladium-catalyzed 1,2-diarylization reaction of enamines using density functional theory, characterized in that, include: Construct the molecular structure of compounds involved in the palladium-catalyzed 1,2-diarylization reaction of enamines; Geometric configuration optimization and frequency calculation were performed on all molecular structures to obtain thermodynamic data at 298.15 K; Calculate the geometry of intermediates and transition states in each elementary step of the palladium-catalyzed 1,2-diarylization reaction of enamines, and obtain the Gibbs free energy changes of each elementary step; determine the connection relationship between the transition state and the corresponding reactants and products by calculating intrinsic reaction coordinates. Based on the thermodynamic data and the connection relationships of geometric structures, a reaction pathway diagram is drawn to determine the reaction mechanism; Based on the reaction mechanism, the steps that determine the regioselectivity, enantioselectivity, and chemoselectivity of the reaction are identified, and the selectivity control strategies are analyzed and output.

2. The calculation method as described in claim 1, characterized in that, The compound includes a substrate, a palladium catalyst, an additive, a main product, and a byproduct; The substrates include enamines, aryl diazonium salts and arylboronic acids, the additives are silver carbonate, the main products include 1,2-diarylized products, and the by-products include direct cross-coupling products and Heck reaction products. The palladium catalyst is a zero-valent palladium catalyst containing isopropyl biphenyloxazoline and dimethyl fumarate ligands.

3. The calculation method as described in claim 1, characterized in that, The geometric configuration optimization and frequency calculation for all structures include: selecting the B3LYP-D3(BJ) functional and mixed basis set, using the SMD continuous medium solvation model to simulate the tert-amyl alcohol solvent environment, calculating the harmonic vibration frequencies of the stagnation points of all geometric structures, confirming them as local minima, and obtaining thermodynamic data at 298.15 K. In the mixed basis set, the metal atoms use the LanL2DZ basis set, and the non-metal atoms use the 6-31g** basis set; Preferably, the local minima of the intermediate have no imaginary frequency, while the transition state has one and only one imaginary frequency; Preferably, the thermodynamic data includes: Gibbs free energy data of each intermediate and transition state in the reaction.

4. The calculation method as described in claim 1, characterized in that, The process of drawing reaction pathway diagrams based on thermodynamic data and the connection relationships of geometric structures to determine the optimal reaction mechanism includes: The main product is generated based on elementary processes, and the reaction energy barrier of the main product is lower than that of the side reactions. The elementary processes include oxidative addition, denitrogenation, olefin migration insertion, transfer metallization, and reductive elimination.

5. The calculation method as described in claim 1, characterized in that, Based on the reaction mechanism, combined with the energy span model and the Curtin-Hammett principle, the steps that determine the regioselectivity, enantioselectivity, and chemoselectivity of the reaction are identified.

6. The calculation method as described in claim 1, characterized in that, The analysis and output of selective control strategies include: performing regional selectivity analysis and outputting regional selectivity control strategies, performing enantioselectivity analysis and outputting enantioselectivity control strategies, and performing chemoselectivity analysis and outputting chemoselectivity control strategies. The regioselectivity analysis and output of the regioselectivity regulation strategy include: calculating the energy difference between the 2,1-olefin insertion transition state and the 1,2-olefin insertion transition state; obtaining the NBO charge value of the atom through natural bond orbital analysis; comparing the electrostatic interactions between atoms in conjunction with the conjugation effect of the amide group and the C=C double bond in the enamine substrate; determining the electronic effect regulation mechanism of regioselectivity by identifying the substrate carbon atom with stronger electrostatic interactions that dominates regioselectivity; and, based on the electronic effect regulation mechanism of regioselectivity, replacing and adjusting the amide group in the enamine substrate to enhance the conjugation effect. The process of performing enantioselectivity analysis and outputting enantioselectivity regulation strategies includes: calculating the energy difference between the Si or Re facets of the olefin in the 2,1-olefin insertion and the transition state of the reaction; using deformation-interaction analysis to determine the mechanism by which steric effects regulate the enantioselectivity of the reaction; and optimizing the ligand substituents of the palladium catalyst based on the regulation mechanism. The process of performing chemoselectivity analysis and outputting chemoselectivity regulation strategies includes: comparing the energy barrier difference between the transition states of the main reaction and the direct cross-coupling side reaction, and calculating the HOMO-LUMO energy level difference using frontier molecular orbitals, optimizing the amount of silver carbonate to ensure the HOMO-LUMO energy level difference of the main reaction is smaller than that of the side reaction; using an independent gradient model to analyze and compare the weak interaction strength between the transition state of the main reaction transfer metallization and the transition state of the Heck side reaction; calculating the energy of the transition state by replacing the carbonyl substituent in the enamine substrate to verify the regulatory effect of the carbonyl group on chemoselectivity; and selecting enamine substrates containing strong electron-withdrawing groups based on the regulatory effect of the carbonyl group on chemoselectivity, and choosing electron-deficient ligands with low steric hindrance as ligands for the reductive elimination step.

7. The calculation method as described in claim 6, characterized in that, The main reactions are olefin insertion reaction, transfer metallization reaction, and reductive elimination reaction, while the side reactions are direct cross-coupling reaction and Heck reaction.

8. A computational system for revealing the microscopic mechanism and selectivity origin of palladium-catalyzed 1,2-diarylization of enamines using density functional theory, characterized in that, include: A structure building module for constructing the molecular structure of compounds in palladium-catalyzed 1,2-diarylization reactions of enamines; The data calculation module is used to optimize the geometry and calculate the frequency of all molecular structures, and to obtain thermodynamic data at 298.15 K. The connection calculation module is used to calculate the geometric configuration of intermediates and transition states in each elementary step of the palladium-catalyzed 1,2-diarylation reaction of enamines, and to obtain the Gibbs free energy change of each elementary step; the connection relationship between the transition state and the corresponding reactants and products is determined by calculating the intrinsic reaction coordinates. The mechanism determination module is used to draw reaction pathway diagrams based on thermodynamic data and connectivity relationships to determine the reaction mechanism. The analysis output module is used to determine the steps that determine the regioselectivity, enantioselectivity and chemoselectivity of the reaction based on the reaction mechanism, and to analyze and output the selectivity control strategy.

9. A computer-readable storage medium having a computer program stored thereon, characterized in that, When the program is executed by the processor, it implements the steps in the calculation method as described in any one of claims 1-7.

10. A computer device, comprising a memory, a processor, and a computer program stored in the memory and executable on the processor, characterized in that, When the processor executes the program, it implements the steps in the calculation method as described in any one of claims 1-7.

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