An analytical method for the reaction mechanism between propargyl alcohol and benzimidazole thiol molecules

Abstract

The present invention belongs to the technical field of chemical reaction prediction, and discloses an analytical method for the intermolecular reaction mechanism of propargyl alcohol and benzimidazole mercaptan, comprising: (1) constructing a computational model of the structures of Lewis acid BF3·OEt2 catalyst and substrate propargyl alcohol and benzimidazole mercaptan; (2) searching for catalytic active components and activation sites in DCM and DMF solvents; (3) designing reaction pathways under different solvents, constructing key intermediates and corresponding transition states; (4) analyzing the reaction mechanisms and pathways under different solvents. The present invention uses density functional theory to emphasize the key role of solvents in affecting chemical selectivity, and provides valuable insights for understanding and designing solvent-induced reactions. The results obtained by the analytical method are very consistent with the experimental results, and the calculation results are accurate and reliable.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical reaction prediction, and particularly relates to an analysis method for the reaction mechanism between propargyl alcohol and benzimidazole thiol molecules. Background Art

[0002] Nitrogen heterocycles are a class of cyclic compounds containing nitrogen atoms. Whether they are natural products or synthetic compounds, they have a wide range of biological activities and applications. These compounds play an important role in drug discovery, material science, and organic synthesis. In particular, five-membered and six-membered nitrogen heterocycles have attracted widespread attention due to their structural diversity and related applications.

[0003] However, many current synthetic methods for nitrogen heterocycles rely on transition metal catalysts, which pose several economic and environmental challenges.

[0004] The mechanism between the propargyl alcohol and benzimidazole mercaptan molecules in the prior art is also unclear, especially when the reaction conditions such as catalysts or solvents are different, the rate of reaction, the required energy consumption, the reaction path, and even the product may be different. If the appropriate reaction conditions are selected by experimental verification one by one, a large amount of funds and time will be consumed, and the optimal reaction conditions may not be screened out. Moreover, it is difficult to directly detect the formation of intermediates in the experiment, resulting in a lack of profound understanding of the mechanism of the reaction, which also has obstacles to selecting the optimal reaction conditions.

[0005] Therefore, a new method is urgently needed to obtain better reaction conditions and have a deeper understanding of the reaction mechanism. Summary of the invention

[0006] The present invention aims to provide an analytical method for the intermolecular reaction mechanism of propargyl alcohol and benzimidazole thiol, to deeply understand the intermolecular reaction mechanism of propargyl alcohol and benzimidazole thiol, to screen out excellent reaction conditions without conducting experiments, thus greatly reducing the funds and time required for the experiments, and having important application value.

[0007] In order to achieve the above object, the present invention provides the following technical solutions:

[0008] A method for analyzing the reaction mechanism between propargyl alcohol and benzimidazole thiol molecules. The present invention uses density functional theory (DFT) to emphasize the key role of solvent in affecting chemical selectivity. DFT is applied for the first time to study the role of DMF in cyclization reactions, providing valuable insights for understanding and designing solvent-induced reactions. A new reaction mechanism with a lower transition state energy barrier potential energy surface is proposed, which deepens the understanding of the complex interactions between solvents, catalysts and reactants and provides guidance for the rational design of cyclization reactions.

[0009] A method involving Lewis acid BF3 ·OEt 2 The reaction mechanism of propargyl alcohol and benzimidazole mercaptan to form different nitrogen heterocycles in dichloromethane (DCM) and dimethylformamide (DMF) solvents was studied and analyzed. All calculations in the present invention were completed under the Gaussian 16 program. In the reaction model, the present invention used M06-2X / 6-31G (d, p) level to perform geometric optimization and calculate the frequency of all intermediates and transition states.

[0010] An analytical method for the reaction mechanism between propargyl alcohol and benzimidazole mercaptan molecules comprises the following steps:

[0011] (1) Construction of Lewis acid BF 3 ·OEt 2 Computational modeling of the structures of the catalyst and substrate propargyl alcohol and benzimidazole thiol;

[0012] (2) Searching for catalytically active components and activation sites in DCM and DMF solvents;

[0013] (3) Design reaction pathways in different solvents and construct key intermediates and corresponding transition states;

[0014] (4) Analyze the reaction mechanism and pathway under different solvents.

[0015] Specifically, a method for analyzing the reaction mechanism between propargyl alcohol and benzimidazole mercaptan molecules comprises the following steps:

[0016] 1. Building a computational model

[0017] Based on BF 3 ·OEt 2 To obtain experimental conditions for the reaction of propargyl alcohol and benzimidazole mercaptan catalyzed by the catalyst, a computational model of the catalyst and the reaction substrate was constructed, and the density functional theory method was used to optimize the structure of the computational model to obtain the most stable configuration of the catalyst and the reaction substrate;

[0018] 2. Searching for catalytically active components and activation sites in DCM and DMF solvents

[0019] (1) Searching for catalytically active components in DCM solvent

[0020] (a) Building BF 3 ·OEt 2 Precursors coordinated to the hydroxyl group and carbon-carbon triple bond of propargyl alcohol

[0021] Precursor modeling: BF 3 ·OEt 2 Coordinate with the hydroxyl group of propargyl alcohol 1a under the optimized model, adjust the key bond length, and set the distance between the BO bonds to Keeping other settings unchanged, the structure is optimized to obtain the optimized structure of precursor A'. The distance between the BO bonds of the optimized precursor A' is

[0022] BF 3 ·OEt 2 Coordinate with the carbon-carbon triple bond of propargyl alcohol under the optimized model, adjust the key bond length, and set BC β , B.C. γ The distance between the keys is Keeping other settings unchanged, the structure is optimized to obtain the structure of the optimized precursor A". The BC of the optimized precursor A" β , B.C. γ The distances between the keys are

[0023] (b) Constructing BF 3 Precursors coordinated to the hydroxyl group and carbon-carbon triple bond of propargyl alcohol

[0024] BF 3 ·OEt 2 Easily decomposed into BF 3 and OEt 2 , BF 3 Coordinate with the hydroxyl group of propargyl alcohol in the optimized model, adjust the key bond length, and set the distance between the BO bonds to The other settings remain unchanged, and the structure is optimized to obtain the optimized structure of precursor A1. The distance of the BO bond of the optimized precursor A1 is The propargyl alcohol and BF under the optimized model 3 The energy sum of is taken as the reference zero point, and 7.2 kcal / mol of free energy is released when precursor A1 is generated;

[0025] BF 3 Coordinate with the carbon-carbon triple bond of propargyl alcohol under the optimized model, adjust the key bond length, and set BC β , B.C. γ The distance between the keys is Keeping other settings unchanged, the structure is optimized to obtain the optimized structure of precursor A''. The BC β , B.C. γ The distances between the keys are The propargyl alcohol and BF under the optimized model 3 The energy sum of is taken as the reference zero point, and 5.7 kcal / mol of free energy is absorbed when the precursor A'' is generated;

[0026] From the perspective of thermodynamics and molecular structure, BF 3It is obvious that it prefers to activate the hydroxyl group of propargyl alcohol, so it is determined that BF 3 It is the catalytic active center in DCM solvent;

[0027] (2) Searching for catalytically active components in DMF solvent

[0028] (a) Building BF 3 DMF is a precursor that coordinates with the hydroxyl group and carbon-carbon triple bond of propargyl alcohol respectively.

[0029] Precursor modeling: BF 3 Easy to react with DMF solvent to generate BF 3 DMF, BF 3 DMF was coordinated to the hydroxyl group of propargyl alcohol 1a in the optimized model, and the key bond length was adjusted to set the distance between the BO bonds to Keeping other settings unchanged, the structure was optimized to obtain the optimized structure of precursor B'. The distance between the BO bonds of the optimized precursor B' is

[0030] BF 3 DMF coordinates with the carbon-carbon triple bond of propargyl alcohol in the optimized model, adjusts the critical bond length, and sets BC β , B.C. γ The distance between the keys is Keeping other settings unchanged, the structure is optimized to obtain the structure of the optimized precursor B". The BC of the optimized precursor B" β , B.C. γ The distances between the keys are

[0031] (b) Construct [BF 2 DMF] + Precursors coordinated to the hydroxyl group and carbon-carbon triple bond of propargyl alcohol

[0032] BF 3 DMF will further react to form [BF 2 DMF] + With BF 4 – , and [BF 2 DMF] + Coordinate with the hydroxyl group of propargyl alcohol in the optimized model, adjust the key bond length, and set the distance between the BO bonds to The other settings remain unchanged, and the structure is optimized to obtain the optimized structure of precursor B1. The distance of the BO bond of the optimized precursor B1 is The propargyl alcohol and [BF 2 DMF] +The energy sum of is taken as the reference zero point, and 11.3 kcal / mol of free energy is released when precursor B1 is generated;

[0033] [BF 2 DMF] + Coordinate with the carbon-carbon triple bond of propargyl alcohol under the optimized model, adjust the key bond length, and set BC β , B.C. γ The distance between the keys is Keeping other settings unchanged, the structure is optimized to obtain the structure of the optimized precursor B''. The BC β , B.C. γ The distances between the keys are The propargyl alcohol and BF under the optimized model 3 The energy sum of is taken as the reference zero point, and 4.1 kcal / mol of free energy is absorbed when the precursor B"' is generated;

[0034] From the perspective of thermodynamics and molecular structure, [BF 2 DMF] + It is obvious that it prefers to activate the hydroxyl group of propargyl alcohol, so it is determined that [BF 2 DMF] + It is the catalytic active center in DMF solvent;

[0035] 3. Designing the reaction pathway

[0036] (1) Reaction pathway design in DCM solvent

[0037] (a) Construct C α -O cleavage transition state TS A1

[0038] Transition state modeling: Using the flexible scanning method, the structural changes that may be caused by the change of key chemical bonds are analyzed, and the energy of each step of the structure is further calculated to obtain the potential energy curve of the key chemical bond change process. The corresponding structure of the highest energy point on the potential energy curve is used as the initial transition state structure to complete the preliminary modeling;

[0039] After adjusting the key bond length of the structure of the optimized precursor A1, C α -O key from Adjust to The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency. The vibration direction of the imaginary frequency is analyzed to be consistent with C α The -O bond breaks, proving that the transition state search is correct;

[0040] (b) Constructing BF 3 OH –Intermediate A2 after leaving

[0041] Intermediate modeling: After optimizing the transition state TS A1 Based on the structure, remove the BF that is about to leave 3 OH – part, other settings remain unchanged, and the adjusted structure is geometrically optimized to obtain the structure of the corresponding intermediate A2;

[0042] (c) Construction of SC γ Bond formation transition state TS A2

[0043] Transition state modeling: The tautomer 2a' of benzimidazole thiol was compared with the C of intermediate A2 in the optimized model. γ Coordinate, adjust key bond length, adjust SC γ The distance between the keys is The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency; and the vibration direction of the imaginary frequency is analyzed to be consistent with SC γ The bond is formed, proving that the transition state search is correct;

[0044] (d) Construction of SC γ Bond-forming intermediate A3

[0045] Intermediate modeling: After optimizing the transition state TS A2 Based on the structure, adjust the key bond length and adjust the SC γ The distance between the keys is The other settings remain unchanged, and the adjusted structure is geometrically optimized to obtain the structure of the corresponding intermediate A3. The SC γ The distance between the keys is

[0046] (e) Construction of the transition state TS of 1,5-HAT A3

[0047] Transition state modeling: Adjust the key bond length of the optimized intermediate A3 structure and adjust the distance of the NH bond to C β -The distance of the H bond is The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency. The vibration direction of the imaginary frequency is consistent with NH fracture, C β -H bond formation proves that the transition state search is correct;

[0048] (f) Construction C β -H bond forming intermediate A4

[0049] After the optimization of the transition state TS A3 Based on the structure, adjust the key bond length and adjust the C β -The distance between H bonds is The other settings remain unchanged, and the adjusted structure is geometrically optimized to obtain the structure of the corresponding intermediate A4. After optimization, the C β -The distance of the H bond is

[0050] (g) Construction of NC α TS A4

[0051] Transition state modeling: Adjust the key bond length of the optimized intermediate A4 structure and adjust NC α The distance between the keys is The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency; and the vibration direction of the imaginary frequency is analyzed to be consistent with NC α The bond is formed, proving that the transition state search is correct;

[0052] (h) Construction of NC α Ring-bonded intermediate A5

[0053] After the optimization of the transition state TS A4 Based on the structure, adjust the key bond length and adjust the NC α The distance between the keys is The other settings remain unchanged, and the adjusted structure is geometrically optimized to obtain the structure of the corresponding intermediate A5. The NC α The distance between the keys is

[0054] (i) Constructing the product A6 with hydrogen proton leaving

[0055] Based on the optimized structure of intermediate A5, the hydrogen proton on nitrogen was removed, and other settings remained unchanged. The adjusted structure was geometrically optimized to obtain the structure of the corresponding product A6;

[0056] (2) Reaction pathway design in DMF solvent

[0057] (a) Construct C α -O cleavage transition state TS B1

[0058] Transition state modeling: Using the flexible scanning method, the structural changes that may be caused by the change of key chemical bonds are analyzed, and the energy of each step of the structure is further calculated to obtain the potential energy curve of the key chemical bond change process. The corresponding structure of the highest energy point on the potential energy curve is used as the initial transition state structure to complete the preliminary modeling;

[0059] Adjust the key bond length of the optimized precursor B1 structure and change C α -O key from Adjust to The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency. The vibration direction of the imaginary frequency is analyzed to be consistent with C α The -O bond breaks, proving that the transition state search is correct;

[0060] (b) Construct [BF 2 DMF]OH after leaving the intermediate B2

[0061] Intermediate modeling: After optimizing the transition state TS B1 Based on the structure, remove the [BF 2 DMF]OH part, other settings remain unchanged, and the adjusted structure is geometrically optimized to obtain the structure of the corresponding intermediate B2;

[0062] (c) Construction of SC γ Bond formation transition state TS B2

[0063] Transition state modeling: The tautomer 2a' of benzimidazole thiol was compared with the C of intermediate B2 in the optimized model. γ Coordinate, adjust key bond length, adjust SC γ The distance between the keys is The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency; and the vibration direction of the imaginary frequency is analyzed to be consistent with SC γ The bond is formed, proving that the transition state search is correct;

[0064] (d) Construction of SC γ Bond-forming intermediate B3

[0065] Intermediate modeling: After optimizing the transition state TS B2 Based on the structure, adjust the key bond length and adjust the SC γ The distance between the keys is The other settings remain unchanged, and the adjusted structure is geometrically optimized to obtain the structure of the corresponding intermediate B3. The SC of the optimized intermediate B3 γ The distance between the keys is

[0066] (e) Constructing BF 4 – Attack C β The transition state TS B3

[0067] Transition state modeling: Adjust the key bond length of the optimized intermediate B3 structure and adjust the distance of the BF bond to C β -The distance of the F key is The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency. The vibration direction of the imaginary frequency is consistent with BF fracture, C β -F bond formation proves that the transition state search is correct;

[0068] (f) Construction C β -F bond forming intermediate B4

[0069] After the optimization of the transition state TS B3 Based on the structure, adjust the key bond length and adjust the C β -The distance between F keys is The other settings remain unchanged, and the adjusted structure is geometrically optimized to obtain the structure of the corresponding intermediate B4. After optimization, the C β -The distance of the F key is

[0070] (g) Construction of the transition state TS of 1,6-HAT B4

[0071] Transition state modeling: Adjust the key bond length of the optimized intermediate B4 structure and adjust the distance of the NH bond to C α -The distance of the H bond is The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency. The vibration direction of the imaginary frequency is consistent with NH fracture, C α -H bond formation proves that the transition state search is correct;

[0072] (h) Construction C α -H bond forming intermediate B5

[0073] After the optimization of the transition state TS B4 Based on the structure, adjust the key bond length and adjust the C α -The distance between H bonds is The other settings remain unchanged, and the adjusted structure is geometrically optimized to obtain the structure of the corresponding intermediate B5. After optimization, the C α -The distance of the H bond is

[0074] (i) Construction of the product B6 with hydrogen proton leaving

[0075] Based on the optimized structure of intermediate B5, the hydrogen proton on nitrogen was removed, and other settings remained unchanged. The adjusted structure was geometrically optimized to obtain the structure of the corresponding product B6;

[0076] (j) Construction of NC β TS B6

[0077] Transition state modeling: Adjust the key bond length of the optimized intermediate B6 structure and adjust NC β The distance between the keys is C β -The distance of the F key is The distance of the BF bond is The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency; and the vibration direction of the imaginary frequency is analyzed to be consistent with NC β Bond formation, C β -F bond breaks and BF bond forms, proving that the transition state search is correct;

[0078] (k) Construct NC β The product of the ring bond B7

[0079] After the optimization of the transition state TS B6 Based on the structure, adjust the key bond length and adjust the NC β The distance between the keys is The other settings remain unchanged, and the adjusted structure is geometrically optimized to obtain the structure of the corresponding product B7. The NC β The distance between the keys is

[0080] The input files for the optimization calculation are as follows:

[0081] Intermediate optimization input file: #opt freq M06-2X / 6-31G(d,p)scrf=(smd,solvent=Dichloromethane) in DCM solvent; #opt freq M06-2X / 6-31G(d,p)scrf=(smd,solvent=n,n-DiMethylFormamide) in DMF solvent.

[0082] Transition state optimization input file: in DCM solvent, #opt=(calcfc,ts,noeigentest,maxstep=3)freq M06-2X / 6-31G(d,p)scrf=(smd,solvent=Dichloromethane); in DMF solvent, #opt=(calcfc,ts,noeigentest,maxstep=3)freq M06-2X / 6-31G(d,p)scrf=(smd,solvent=n,n-DiMethylFormamide).

[0083] All intermediates have no imaginary frequency, and the transition state has only one imaginary frequency. The Gibbs thermodynamic correction value is extracted from the output file *.log at the end of the optimization. In order to obtain more accurate energy, the M06-2X / 6-311+G(d,p) level is used on the basis of the optimized structure and the SMD solvation model is used to calculate the large basis set solvation single point energy of the intermediates and transition states.

[0084] The input files for the higher level single point energy calculation are as follows: #M06-2X / 6-311+G(d,p)scrf=(smd,solvent=Dichloromethane) in DCM solvent; #M06-2X / 6-311+G(d,p)scrf=(smd,solvent=n,n-DiMethylFormamide) in DMF solvent; Gaussian16 software is used to calculate the output file *.log of the single point, read the single point energy in the log file; add the single point energy to the Gibbs heat correction value to obtain the Gibbs free energy of each structure. The minimum energy path obtained by the intrinsic reaction coordinate (IRC) theory is used to determine the accuracy of the transition state.

[0085] The present invention adopts a density functional theory method to design reactants, intermediates, transition states and products on each reaction path, adjusts the geometric structure of the intermediate based on the generation and breaking forms of chemical bonds and the coordination conditions of key groups, then optimizes the geometric structure at the M06-2X / 6-31G (d, p) calculation level, calculates the single-point energy at the M06-2X / 6-311+G (d, p) calculation level and obtains the thermal correction of the vibration harmonic frequency and the Gibbs free energy, and all stationary points are identified as minimum values ​​(zero imaginary frequency) or transition states (one imaginary frequency); obtains the activation energy of each elementary reaction, draws the corresponding potential energy surface diagram, determines the best reaction path and its rate-determining step, and determines the best active center structure and reaction mechanism of the catalyst after reliability analysis by comparison with experimental results.

[0086] Beneficial effects achieved by the present invention:

[0087] The present invention adopts density functional theory to analyze the Lewis acid BF under M06-2X functional. 3 ·OEt 2 The reaction mechanism of propargyl alcohol and benzimidazole thiol to form different nitrogen heterocycles was studied in dichloromethane (DCM) and dimethylformamide (DMF) solvents, and a new reaction mechanism with a lower transition state energy barrier potential energy surface than the experimental one was proposed. The results show that in DCM solvent, BF 3 As the catalytic active center, it preferentially coordinates with the hydroxyl group of propargyl alcohol to form a key precursor. 3 ·OEt 2 The generated [BF 2 DMF] + As the catalytic active center, the hydroxyl group of propargyl alcohol is activated. The mechanism in both solvents involves a series of steps such as BO bond formation, CO bond cleavage, SC bond formation, hydrogen atom transfer (HAT), deprotonation and cyclization. The key difference lies in the HAT process. In DCM solvent, the reaction proceeds through 1,5-HAT. In contrast, in DMF solvent, the reaction is carried out by DMF and BF 3 ·OEt 2 Generated BF 4 - As a fluorine source, increasing steric hindrance promotes the 1,6-HAT process.

[0088] The present invention is to BF 3 ·OEt 2 The reaction pathways of propargyl alcohol and benzimidazole thiol in different solvents were fully studied, and the BF 3 ·OEt 2 The process of catalyzing propargyl alcohol and benzimidazole mercaptan to form different nitrogen heterocycles in DCM and DMF solvents. By exploring the reaction mechanism, not only can the reaction path be clarified, but also theoretical research can be provided for the design of more efficient catalysts, which greatly reduces the funds and time required for the experiment and has important application value.

[0089] The present invention uses density functional theory method to study the Lewis acid BF in detail. 3 ·OEt 2The reaction mechanism of propargyl alcohol and benzimidazole thiol to form different nitrogen heterocycles was catalyzed in dichloromethane (DCM) and dimethylformamide (DMF) solvents, and the intermediates and transition state structures that may be obtained in the reaction were found. In DCM solvent, 1,6-HAT is the rate-determining step with an activation energy barrier of 24.6 kcal / mol, while in DMF solvent, the 5-exo-dig cyclization step is the rate-determining step with an activation energy barrier of 28.0 kcal / mol. This is consistent with the reaction conditions required in the experiment.

[0090] Due to the current experimental resource limitations, experimental methods alone cannot fully obtain the reaction mechanism and the configuration and energy of each initial substance, intermediate, transition state, and product. The present invention uses quantum chemical technology to obtain the reaction mechanism at the atomic level. This study is the first to apply density functional theory to explore the role of DMF solvent in cyclization reactions, providing valuable insights for understanding and designing solvent-induced cyclization reactions. This method only requires a personal server to complete, so there is no need to purchase expensive large-scale computing equipment or high computing and analysis costs, and it is also more conducive to speeding up the development of synthesis. It is very consistent with the experimental results, and the calculation results are accurate and reliable. BRIEF DESCRIPTION OF THE DRAWINGS

[0091] Figure 1 (a) BF in DCM solvent at the M06-2X theoretical level 3 ·OEt 2 and (b) BF 3 The optimized structure of the coordination with the hydroxyl group and the carbon-carbon triple bond of propargyl alcohol (the red italic numbers in the figure are the bond lengths in units of The black numbers are the relative Gibbs free energy ΔG, in kcal / mol);

[0092] Figure 2 The optimized structures of (a) int1 and (b) int2 coordinated with the hydroxyl group and carbon-carbon triple bond of propargyl alcohol in DMF solvent at the M06-2X theoretical level (the red italic numbers in the figure are bond lengths in units of The black numbers are the relative Gibbs free energy ΔG, in kcal / mol);

[0093] Figure 3 This is the Gibbs free energy curve for the synthesis of benzimidazole thiazine in DCM solvent at the M06-2X theoretical level (the numbers in the figure are relative Gibbs free energy ΔG, in kcal / mol);

[0094] Figure 4 The three-dimensional structure of the intermediate and transition state after optimization in DCM solvent (the numbers in the figure are bond lengths, in units of );

[0095] Figure 5 The figure is the Gibbs free energy curve of the synthesis of benzothiazole imidazole in DMF solvent at the M06-2X theoretical level (the numbers in the figure are relative Gibbs free energy ΔG, in kcal / mol);

[0096] Figure 6 The three-dimensional structure of the intermediate and transition state after optimization in DMF solvent (the numbers in the figure are bond lengths, in units of );

[0097] Figure 7 Schematic diagram of the reaction mechanism in different solvents (the numbers in the figure are relative Gibbs free energy ΔG, in kcal / mol). DETAILED DESCRIPTION

[0098] In order to make the technical scheme of the present invention more clearly understood by those skilled in the art, the following embodiments are listed for illustration. It should be pointed out that the following embodiments do not limit the protection scope of the present invention.

[0099] The present invention adopts density functional theory to perform structural modeling on the reactants, intermediates, transition states, and products on the reaction paths in the explored DCM solvent and the reaction paths in the DMF solvent from the perspective of chemical bond generation and breaking forms and coordination conditions, and then performs structural optimization at the M06-2X functional calculation level to obtain the activation energy and reaction free energy change of each elementary reaction, and finally draws the corresponding Gibbs free energy curve.

[0100] The input files for the optimization calculation are as follows:

[0101] Intermediate optimization input file: #opt freq M06-2X / 6-31G(d,p)scrf=(smd,solvent=Dichloromethane) in DCM solvent; #opt freq M06-2X / 6-31G(d,p)scrf=(smd,solvent=n,n-DiMethylFormamide) in DMF solvent.

[0102] Transition state optimization input file: in DCM solvent, #opt=(calcfc,ts,noeigentest,maxstep=3)freq M06-2X / 6-31G(d,p)scrf=(smd,solvent=Dichloromethane); in DMF solvent, #opt=(calcfc,ts,noeigentest,maxstep=3)freq M06-2X / 6-31G(d,p)scrf=(smd,solvent=n,n-DiMethylFormamide).

[0103] All intermediates have no imaginary frequency, and the transition state has only one imaginary frequency. The Gibbs thermodynamic correction value is extracted from the output file *.log at the end of the optimization. In order to obtain more accurate energy, the M06-2X / 6-311+G(d,p) level is used on the basis of the optimized structure and the SMD solvation model is used to calculate the large basis set solvation single point energy of the intermediates and transition states.

[0104] The input files for the higher level single point energy calculation are as follows: #M06-2X / 6-311+G(d,p)scrf=(smd,solvent=Dichloromethane) in DCM solvent; #M06-2X / 6-311+G(d,p)scrf=(smd,solvent=n,n-DiMethylFormamide) in DMF solvent; Gaussian16 software is used to calculate the output file *.log of the single point, read the single point energy in the log file; add the single point energy to the Gibbs heat correction value to obtain the Gibbs free energy of each structure. The minimum energy path obtained by the intrinsic reaction coordinate (IRC) theory is used to determine the accuracy of the transition state.

[0105] The present invention adopts a density functional theory method to design reactants, intermediates, transition states and products on each reaction path, adjusts the geometric structure of the intermediate based on the generation and breaking forms of chemical bonds and the coordination conditions of key groups, then optimizes the geometric structure at the M06-2X / 6-31G (d, p) calculation level, calculates the single-point energy at the M06-2X / 6-311+G (d, p) calculation level and obtains the thermal correction of the vibration harmonic frequency and the Gibbs free energy, and all stationary points are identified as minimum values ​​(zero imaginary frequency) or transition states (one imaginary frequency); obtains the activation energy of each elementary reaction, draws the corresponding potential energy surface diagram, determines the best reaction path and its rate-determining step, and determines the best active center structure and reaction mechanism of the catalyst after reliability analysis by comparison with experimental results.

[0106] Frequency analysis is mainly used in computational chemistry to determine whether free radicals are stable, evaluate the catalytic performance of complexes, determine the location of energy shells, etc. All calculations use the same calculation level as the intermediate optimization to optimize the transition state structure, followed by frequency calculations, and the calculation results must ensure that there is only one imaginary frequency.

[0107] Intrinsic reaction coordinates (IRC) are a theoretical method used to study the kinetic characteristics of molecular reactions and are used to identify transition states. This method can determine the energy barriers and pathways between reactants and products by tracking the changes in each stage of a chemical reaction. In simple terms, IRC is a continuous curve connecting the starting structure and the transition state, which represents all possible conformations during the reaction. The transition state structures are also calculated using the intrinsic reaction coordinate method to ensure that they are connected to the corresponding reactants and products. In order to simulate the real reaction and obtain more accurate energy, single-point energy calculations are performed on the optimized stationary points at the M06-2X / 6-311+G(d,p) level, which is also essential in studying the mechanism of catalytic reactions. For the solvation effect, the SMD solvation model is used for single-point calculations. Corresponding to the experimental conditions, the calculated solvents are DCM and DMF. Therefore, unless otherwise stated, all values ​​reported in this paper are Gibbs free energies at a temperature of 298.15 K, including reactants, intermediates, and transition states calculated at the M06-2X / 6-311+G(d,p) / / M06-2X / 6-31G(d,p) level, solvation correction energy ECPCM after geometry optimization at the M06-2X / 6-31G(d,p) level, van der Waals effect correction EVDW, and thermal correction of Gibbs free energy Gtc. In all energy distribution diagrams, the unit of relative Gibbs free energy is kcal / mol.

[0108] The present invention relates to Lewis acid BF 3 ·OEt 2 The reaction mechanism of propargyl alcohol and benzimidazole mercaptan to form different nitrogen heterocycles in dichloromethane (DCM) and dimethylformamide (DMF) solvents is studied and analyzed, and the specific steps are as follows:

[0109] 1. Building a computational model

[0110] Based on BF 3 ·OEt 2 To obtain experimental conditions for the reaction of propargyl alcohol and benzimidazole mercaptan catalyzed by the catalyst, a computational model of the catalyst and the reaction substrate was constructed, and the density functional theory method was used to optimize the structure of the computational model to obtain the most stable configuration of the catalyst and the reaction substrate;

[0111] 2. Searching for catalytically active components and activation sites in DCM and DMF solvents

[0112] (1) Searching for catalytically active components in DCM solvent

[0113] (a) Building BF 3 ·OEt 2 Precursors coordinated to the hydroxyl group and carbon-carbon triple bond of propargyl alcohol

[0114] Precursor modeling: BF 3 ·OEt 2 Coordinate with the hydroxyl group of propargyl alcohol 1a under the optimized model, adjust the key bond length, and set the distance between the BO bonds to Keeping other settings unchanged, the structure is optimized to obtain the optimized structure of precursor A'. The distance between the BO bonds of the optimized precursor A' is ( Figure 1 (a));

[0115] BF 3 ·OEt 2 Coordinate with the carbon-carbon triple bond of propargyl alcohol under the optimized model, adjust the key bond length, and set BC β , B.C. γ The distance between the keys is Keeping other settings unchanged, the structure is optimized to obtain the structure of the optimized precursor A". The BC of the optimized precursor A" β , B.C. γ The distances between the keys are ( Figure 1 (a));

[0116] (b) Constructing BF 3 Precursors coordinated to the hydroxyl group and carbon-carbon triple bond of propargyl alcohol

[0117] BF 3 ·OEt 2 Easily decomposed into BF 3 and OEt 2 , BF 3 Coordinate with the hydroxyl group of propargyl alcohol in the optimized model, adjust the key bond length, and set the distance between the BO bonds to The other settings remain unchanged, and the structure is optimized to obtain the optimized structure of precursor A1. The distance of the BO bond of the optimized precursor A1 is The propargyl alcohol and BF under the optimized model 3 The energy sum is taken as the reference zero point, and the free energy of 7.2 kcal / mol is released when precursor A1 is generated ( Figure 1 (b));

[0118] BF 3 Coordinate with the carbon-carbon triple bond of propargyl alcohol under the optimized model, adjust the key bond length, and set BC β , B.C. γ The distance between the keys is Keeping other settings unchanged, the structure is optimized to obtain the optimized structure of precursor A''. The BC β , B.C.γ The distances between the keys are The propargyl alcohol and BF under the optimized model 3 The energy and is taken as the reference zero point, and the free energy of 5.7 kcal / mol is absorbed when the precursor A"' is generated ( Figure 1 (b));

[0119] From the perspective of thermodynamics and molecular structure, BF 3 It is obvious that it prefers to activate the hydroxyl group of propargyl alcohol. Therefore, we determined that BF 3 It is the catalytic active center in DCM solvent;

[0120] (2) Searching for catalytically active components in DMF solvent

[0121] (a) Building BF 3 DMF is a precursor that coordinates with the hydroxyl group and carbon-carbon triple bond of propargyl alcohol respectively.

[0122] Precursor modeling: BF 3 Easy to react with DMF solvent to generate BF 3 DMF, BF 3 DMF was coordinated to the hydroxyl group of propargyl alcohol 1a in the optimized model, and the key bond length was adjusted to set the distance between the BO bonds to Keeping other settings unchanged, the structure was optimized to obtain the optimized structure of precursor B'. The distance between the BO bonds of the optimized precursor B' is ( Figure 2 a);

[0123] BF 3 DMF coordinates with the carbon-carbon triple bond of propargyl alcohol in the optimized model, adjusts the critical bond length, and sets BC β , B.C. γ The distance between the keys is Keeping other settings unchanged, the structure is optimized to obtain the structure of the optimized precursor B". The BC of the optimized precursor B" β , B.C. γ The distances between the keys are ( Figure 2 (a));

[0124] (b) Construct [BF 2 DMF] + Precursors coordinated to the hydroxyl group and carbon-carbon triple bond of propargyl alcohol

[0125] BF 3 DMF will further react to form [BF 2 DMF] + With BF 4 – , and [BF2 DMF] + Coordinate with the hydroxyl group of propargyl alcohol in the optimized model, adjust the key bond length, and set the distance between the BO bonds to The other settings remain unchanged, and the structure is optimized to obtain the optimized structure of precursor B1. The distance of the BO bond of the optimized precursor B1 is The propargyl alcohol and [BF 2 DMF] + The energy sum is taken as the reference zero point, and the free energy of 11.3 kcal / mol is released when precursor B1 is generated ( Figure 2 b);

[0126] [BF 2 DMF] + Coordinate with the carbon-carbon triple bond of propargyl alcohol under the optimized model, adjust the key bond length, and set BC β , B.C. γ The distance between the keys is Keeping other settings unchanged, the structure is optimized to obtain the structure of the optimized precursor B''. The BC β , B.C. γ The distances between the keys are The propargyl alcohol and BF under the optimized model 3 The energy and energy of are taken as the reference zero point, and the free energy of 4.1 kcal / mol is absorbed when the precursor B"' is generated ( Figure 2 (b));

[0127] From the perspective of thermodynamics and molecular structure, [BF 2 DMF] + It is obvious that it prefers to activate the hydroxyl group of propargyl alcohol. Therefore, we determined that [BF 2 DMF] + It is the catalytic active center in DMF solvent;

[0128] 3. Designing the reaction pathway

[0129] (1) Reaction pathway design in DCM solvent, such as Figure 3 shown.

[0130] (a) Construct C α -O cleavage transition state TS A1

[0131] Transition state modeling: By using the flexible scanning method, the structural changes that may be caused by the change of key chemical bonds are analyzed, the energy of each step of the structure is further calculated, and the potential energy curve of the key chemical bond change process is obtained. The corresponding structure of the highest energy point on the potential energy curve is used as the initial transition state structure to complete the preliminary modeling;

[0132] After adjusting the key bond length of the structure of the optimized precursor A1, C α -O key from Adjust to The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency. The vibration direction of the imaginary frequency is analyzed to be consistent with C α The -O bond breaks, proving that the transition state search is correct;

[0133] (b) Constructing BF 3 OH – Intermediate A2 after leaving

[0134] Intermediate modeling: After optimizing the transition state TS A1 Based on the structure, remove the BF that is about to leave 3 OH – part, other settings remain unchanged, and the adjusted structure is geometrically optimized to obtain the structure of the corresponding intermediate A2;

[0135] (c) Construction of SC γ Bond formation transition state TS A2

[0136] Transition state modeling: The tautomer 2a' of benzimidazole thiol was compared with the C of intermediate A2 in the optimized model. γ Coordinate, adjust key bond length, adjust SC γ The distance between the keys is The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency; and the vibration direction of the imaginary frequency is analyzed to be consistent with SC γ The bond is formed, proving that the transition state search is correct;

[0137] (d) Construction of SC γ Bond-forming intermediate A3

[0138] Intermediate modeling: After optimizing the transition state TS A2 Based on the structure, adjust the key bond length and adjust the SC γ The distance between the keys is The other settings remain unchanged, and the adjusted structure is geometrically optimized to obtain the structure of the corresponding intermediate A3. The SC γ The distance between the keys is

[0139] (e) Construction of the transition state TS of 1,5-HAT A3

[0140] Transition state modeling: Adjust the key bond length of the optimized intermediate A3 structure and adjust the distance of the NH bond to C β -The distance of the H bond is The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency. The vibration direction of the imaginary frequency is consistent with NH fracture, C β -H bond formation proves that the transition state search is correct;

[0141] (f) Construction C β -H bond forming intermediate A4

[0142] After the optimization of the transition state TS A3 Based on the structure, adjust the key bond length and adjust the C β -The distance between H bonds is The other settings remain unchanged, and the adjusted structure is geometrically optimized to obtain the structure of the corresponding intermediate A4. After optimization, the C β -The distance of the H bond is

[0143] (g) Construction of NC α TS A4

[0144] Transition state modeling: Adjust the key bond length of the optimized intermediate A4 structure and adjust NC α The distance between the keys is The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency; and the vibration direction of the imaginary frequency is analyzed to be consistent with NC α The bond is formed, proving that the transition state search is correct;

[0145] (h) Construction of NC α Ring-bonded intermediate A5

[0146] After the optimization of the transition state TS A4 Based on the structure, adjust the key bond length and adjust the NC α The distance between the keys is The other settings remain unchanged, and the adjusted structure is geometrically optimized to obtain the structure of the corresponding intermediate A5. The NC α The distance between the keys is

[0147] (i) Constructing the product A6 with hydrogen proton leaving

[0148] Based on the optimized structure of intermediate A5, the hydrogen proton on nitrogen was removed, and other settings remained unchanged. The adjusted structure was geometrically optimized to obtain the structure of the corresponding product A6;

[0149] (2) Reaction pathway design in DMF solvent, such as Figure 5 shown.

[0150] (a) Construct C α -O cleavage transition state TS B1

[0151] Transition state modeling: Using the flexible scanning method, the structural changes that may be caused by the change of key chemical bonds are analyzed, and the energy of each step of the structure is further calculated to obtain the potential energy curve of the key chemical bond change process. The corresponding structure of the highest energy point on the potential energy curve is used as the initial transition state structure to complete the preliminary modeling;

[0152] Adjust the key bond length of the optimized precursor B1 structure and change C α -O key from Adjust to The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency. The vibration direction of the imaginary frequency is analyzed to be consistent with C α The -O bond breaks, proving that the transition state search is correct;

[0153] (b) Construct [BF 2 DMF]OH after leaving the intermediate B2

[0154] Intermediate modeling: After optimizing the transition state TS B1 Based on the structure, remove the [BF 2 DMF]OH part, other settings remain unchanged, and the adjusted structure is geometrically optimized to obtain the structure of the corresponding intermediate B2;

[0155] (c) Construction of SC γ Bond formation transition state TS B2

[0156] Transition state modeling: The tautomer 2a' of benzimidazole thiol was compared with the C of intermediate B2 in the optimized model. γ Coordinate, adjust key bond length, adjust SC γ The distance between the keys is The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency; and the vibration direction of the imaginary frequency is analyzed to be consistent with SC γ The bond is formed, proving that the transition state search is correct;

[0157] (d) Construction of SCγ Bond-forming intermediate B3

[0158] Intermediate modeling: After optimizing the transition state TS B2 Based on the structure, adjust the key bond length and adjust the SC γ The distance between the keys is The other settings remain unchanged, and the adjusted structure is geometrically optimized to obtain the structure of the corresponding intermediate B3. The SC of the optimized intermediate B3 γ The distance between the keys is

[0159] (e) Constructing BF 4 – Attack C β The transition state TS B3

[0160] Transition state modeling: Adjust the key bond length of the optimized intermediate B3 structure and adjust the distance of the BF bond to C β -The distance of the F key is The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency. The vibration direction of the imaginary frequency is consistent with BF fracture, C β -F bond formation proves that the transition state search is correct;

[0161] (f) Construction C β -F bond forming intermediate B4

[0162] After the optimization of the transition state TS B3 Based on the structure, adjust the key bond length and adjust the C β -The distance between F keys is The other settings remain unchanged, and the adjusted structure is geometrically optimized to obtain the structure of the corresponding intermediate B4. After optimization, the C β -The distance of the F key is

[0163] (g) Construction of the transition state TS of 1,6-HAT B4

[0164] Transition state modeling: Adjust the key bond length of the optimized intermediate B4 structure and adjust the distance of the NH bond to C α -The distance of the H bond is The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency. The vibration direction of the imaginary frequency is consistent with NH fracture, C α -H bond formation proves that the transition state search is correct;

[0165] (h) Construction C α -H bond forming intermediate B5

[0166] After the optimization of the transition state TS B4 Based on the structure, adjust the key bond length and adjust the C α -The distance between H bonds is The other settings remain unchanged, and the adjusted structure is geometrically optimized to obtain the structure of the corresponding intermediate B5. After optimization, the C α -The distance of the H bond is

[0167] (i) Construction of the product B6 with hydrogen proton leaving

[0168] Based on the optimized structure of intermediate B5, the hydrogen proton on nitrogen was removed, and other settings remained unchanged. The adjusted structure was geometrically optimized to obtain the structure of the corresponding product B6;

[0169] (j) Construction of NC β TS B6

[0170] Transition state modeling: Adjust the key bond length of the optimized intermediate B6 structure and adjust NC β The distance between the keys is C β -The distance of the F key is The distance of the BF bond is The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency; and the vibration direction of the imaginary frequency is analyzed to be consistent with NC β Bond formation, C β -F bond breaks and BF bond forms, proving that the transition state search is correct;

[0171] (k) Construct NC β The product of the ring bond B7

[0172] After the optimization of the transition state TS B6 Based on the structure, adjust the key bond length and adjust the NC β The distance between the keys is The other settings remain unchanged, and the adjusted structure is geometrically optimized to obtain the structure of the corresponding product B7. The NC β The distance between the keys is

[0173] 4. Analysis of reaction mechanism and path

[0174] Figure 1 (a) BF in DCM solvent at the M06-2X theoretical level3 ·OEt 2 and (b) BF 3 The optimized structure of the coordination with the hydroxyl group and the carbon-carbon triple bond of propargyl alcohol (the red italic numbers in the figure are the bond lengths in units of The black numbers are the relative Gibbs free energy ΔG, in kcal / mol).

[0175] Figure 2 The optimized structures of (a) int1 and (b) int2 coordinated with the hydroxyl group and carbon-carbon triple bond of propargyl alcohol in DMF solvent at the M06-2X theoretical level (the red italic numbers in the figure are bond lengths in units of The black numbers are the relative Gibbs free energy ΔG, in kcal / mol).

[0176] Figure 3 This is the Gibbs free energy curve for the synthesis of benzimidazole thiazine in DCM solvent at the M06-2X theoretical level (the numbers in the figure are relative Gibbs free energy ΔG, in kcal / mol); Figure 3 In DCM solvent, “In DCM solvent” means in DCM solvent, “BF 3 coordination" means BF 3 coordination, "BF 3 OH – departure" means BF 3 OH – “Nucleophilic attack” means nucleophilic attack, “1,5-HAT” means 1,5-hydrogen atom transfer, “six-memberedcyclization” means six-membered cyclization, and “Deprotonation” means deprotonation.

[0177] Figure 4 The three-dimensional structure of the intermediate and transition state after optimization in DCM solvent (the numbers in the figure are bond lengths, in units of ).

[0178] Figure 5This is the Gibbs free energy curve of the synthesis of benzothiazole imidazole in DMF solvent at the M06-2X theoretical level (the numbers in the figure are Gibbs free energy ΔG, in kcal / mol); “In DMF solvent” means in DMF solvent, “int2 coordination” means int2 coordination, “int3 departure” means int3 departure, “Nucleophilicattack” means nucleophilic attack, “Fluorine migration” means fluorine migration, “1,6-HAT” means 1,6-hydrogen atom transfer, “Deprotonation” means deprotonation, and “Five-membered cyclization” means five-membered cyclization.

[0179] Figure 6 The three-dimensional structure of the intermediate and transition state after optimization in DMF solvent (the numbers in the figure are bond lengths, in units of ).

[0180] Figure 7 Schematic diagram of the reaction mechanism in different solvents (the numbers in the figure are relative Gibbs free energy ΔG, in kcal / mol); "Solvent" means solvent, and "Catalytic center" means catalytic center.

[0181] When drawing the Gibbs free energy curves for each reaction path, as shown in Tables 1 and 2, the catalytic active center BF is selected in DCM solvent. 3 The energy sum of propargyl alcohol and ethanol was used as the reference zero point, and the catalytic active center [BF 2 DMF] + The energy sum of propargyl alcohol is taken as the reference zero point. All energy values ​​on the Gibbs free energy curve are based on this reference. The energies used in the discussion are all relative Gibbs free energies.

[0182] Table 1: Gibbs free energy data of key intermediates and transition states in DCM solvent (“Hartree” in the table represents energy units)

[0183]

[0184] Table 2: Gibbs free energy data of key intermediates and transition states in DMF solvent

[0185]

[0186]

[0187] The specific analysis is as follows:

[0188] like Figure 3 As shown, in DCM solvent, BF 3 The hydroxyl group of propargyl alcohol is activated, releasing 7.2 kcal / mol of free energy and forming precursor A1. Subsequently, a dehydroxylation reaction is carried out to form the propargyl cation A2 and its resonance structure, BF 3 OH – This step requires overcoming an energy barrier of 13.5 kcal / mol. The tautomer 2a' of benzimidazole thiol passes through the transition state TS A2 The attack of propargyl cation A2 overcomes an energy barrier of 7.4 kcal / mol to form intermediate A3. Intermediate A3 then undergoes 1,5-HAT by overcoming an energy barrier of 24.6 kcal / mol to produce intermediate A4. The cyclization of intermediate A4 to form intermediate A5 requires crossing an energy barrier of 8.2 kcal / mol, releasing 28.6 kcal / mol. Finally, BF 3 OH – The hydrogen proton is captured, resulting in the formation of product A6. The whole process releases 25.8 kcal / mol of free energy. The optimized three-dimensional structures of the intermediate and transition state are as follows: Figure 4 shown.

[0189] like Figure 5 As shown, in DMF solvent, [BF 2 DMF] + The hydroxyl group of propargyl alcohol is activated. Precursor B1 is formed, releasing 11.3 kcal / mol free energy. The subsequent cleavage of the CO bond in B1 requires 7.7 kcal / mol activation energy, generating the propargyl cation B2. The tautomer 2a' of benzimidazole thiol attacks B2, undergoing a 6.2 kcal / mol energy barrier to form B3, releasing 10.8 kcal / mol free energy in the process. Subsequently, BF 4 - The activation of the allenyl group of B3 overcomes the 13.8 kcal / mol energy barrier to form C β -F bond, thus forming B4. Subsequently, the 1,6-HAT process occurs, releasing 22.3 kcal / mol of free energy, which requires overcoming an energy barrier of 8.5 kcal / mol. Subsequently, the hydrogen proton is transferred to BF 4 - The intermediate B6 is captured, and finally the 5-exo-dig cyclization reaction occurs to form the product B7. This process needs to overcome a high barrier of 28.0 kcal / mol, and int2 is reduced to int1 to form the final product B7. The whole process is highly exothermic, releasing 125.0 kcal / mol of free energy. The optimized three-dimensional structure of the intermediate and transition state is shown in Figure 6 shown.

[0190] Comparison diagram of reaction mechanism under DCM solvent and DMF solvent, such as Figure 7 shown.

[0191] The above content describes the basic principle and main features of the present invention and the advantages of the present invention. It should be understood by those skilled in the art that protection scope of the present invention is not limited by the above-described embodiments. Without departing from the spirit and scope of the present invention, the present invention also has various changes and improvements, and these changes and improvements all fall within the scope of the present invention claimed for protection.

Claims

1. A method for analyzing the reaction mechanism between propargyl alcohol and benzimidazole mercaptan molecules, characterized in that: The specific steps are as follows:

1. Building a computational model Based on the experimental conditions of the reaction of propargyl alcohol and benzimidazole thiol catalyzed by BF3·OEt2, a computational model of the catalyst and the reaction substrate was constructed, and the density functional theory method was used to optimize the structure of the computational model to obtain the most stable configuration of the catalyst and the reaction substrate; 2. Searching for catalytically active components and activation sites in DCM and DMF solvents (1) Searching for catalytically active components in DCM solvent (a) Construction of precursors in which BF3·OEt2 is coordinated with the hydroxyl group and carbon-carbon triple bond of propargyl alcohol Precursor modeling: BF3·OEt2 was coordinated with the hydroxyl group of propargyl alcohol 1a under the optimized model, and the key bond length was adjusted to set the distance between the BO bonds to Keeping other settings unchanged, the structure is optimized to obtain the optimized structure of precursor A'. The distance between the BO bonds of the optimized precursor A' is Coordinate BF3·OEt2 with the carbon-carbon triple bond of propargyl alcohol in the optimized model, adjust the critical bond length, and set BC β , B.C. γ The distance between the keys is Keeping other settings unchanged, the structure is optimized to obtain the structure of the optimized precursor A". The BC of the optimized precursor A" β , B.C. γ The distances between the keys are (b) Construct a precursor in which BF3 is coordinated with the hydroxyl group and the carbon-carbon triple bond of propargyl alcohol respectively BF3·OEt2 is easily decomposed into BF3 and OEt2. BF3 is coordinated with the hydroxyl group of propargyl alcohol in the optimized model, and the key bond length is adjusted to set the distance between the BO bonds to The other settings remain unchanged, and the structure is optimized to obtain the optimized structure of precursor A1. The distance of the BO bond of the optimized precursor A1 is Taking the energy sum of propargyl alcohol and BF3 under the optimized model as the reference zero point, 7.2 kcal / mol of free energy is released when precursor A1 is generated; Coordinate BF3 with the carbon-carbon triple bond of propargyl alcohol in the optimized model, adjust the critical bond length, and set BC β , B.C. γ The distance between the keys is Keeping other settings unchanged, the structure is optimized to obtain the optimized structure of precursor A''. The BC β , B.C. γ The distances between the keys are Taking the energy sum of propargyl alcohol and BF3 under the optimized model as the reference zero point, the free energy of 5.7 kcal / mol is absorbed when the precursor A”’ is generated; From the perspective of thermodynamics and molecular structure, BF3 is more inclined to activate the hydroxyl group of propargyl alcohol. Therefore, BF3 is determined to be the catalytic active center in DCM solvent. (2) Searching for catalytically active components in DMF solvent (a) Constructing a precursor in which BF3DMF is coordinated with the hydroxyl group and the carbon-carbon triple bond of propargyl alcohol respectively Precursor modeling: BF3 easily reacts with DMF solvent to generate BF3DMF. BF3DMF is coordinated with the hydroxyl group of propargyl alcohol 1a under the optimized model, and the key bond length is adjusted to set the distance between the BO bonds to Keeping other settings unchanged, the structure was optimized to obtain the optimized structure of precursor B'. The distance between the BO bonds of the optimized precursor B' is Coordinate BF3DMF with the carbon-carbon triple bond of propargyl alcohol in the optimized model, adjust the critical bond length, and set BC β , B.C. γ The distance between the keys is Keeping other settings unchanged, the structure is optimized to obtain the structure of the optimized precursor B". The BC of the optimized precursor B" β , B.C. γ The distances between the keys are (b) Construction of [BF2DMF] + Precursors coordinated to the hydroxyl group and carbon-carbon triple bond of propargyl alcohol BF3DMF will further react to form [BF2DMF] + With BF4 – , [BF2DMF] + Coordinate with the hydroxyl group of propargyl alcohol in the optimized model, adjust the key bond length, and set the distance between the BO bonds to The other settings remain unchanged, and the structure is optimized to obtain the optimized structure of precursor B1. The distance of the BO bond of the optimized precursor B1 is The propargyl alcohol and [BF2DMF] + The energy sum of is taken as the reference zero point, and 11.3 kcal / mol of free energy is released when precursor B1 is generated; [BF2DMF] + Coordinate with the carbon-carbon triple bond of propargyl alcohol under the optimized model, adjust the key bond length, and set BC β , B.C. γ The distance between the keys is Keeping other settings unchanged, the structure is optimized to obtain the structure of the optimized precursor B''. The BC β , B.C. γ The distances between the keys are Taking the energy sum of propargyl alcohol and BF3 under the optimized model as the reference zero point, the free energy of 4.1 kcal / mol is absorbed when the precursor B"' is generated; From the perspective of thermodynamics and molecular structure, [BF2DMF] + It is obvious that it prefers to activate the hydroxyl group of propargyl alcohol, so it is determined that [BF2DMF] + It is the catalytic active center in DMF solvent; 3. Designing the reaction pathway (1) Reaction pathway design in DCM solvent (a) Construct C α -O cleavage transition state TS A1 Transition state modeling: Using the flexible scanning method, the structural changes that may be caused by the change of key chemical bonds are analyzed, and the energy of each step of the structure is further calculated to obtain the potential energy curve of the key chemical bond change process. The corresponding structure of the highest energy point on the potential energy curve is used as the initial transition state structure to complete the preliminary modeling; After adjusting the key bond length of the structure of the optimized precursor A1, C α -O key from Adjust to The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency. The vibration direction of the imaginary frequency is analyzed to be consistent with C α The -O bond breaks, proving that the transition state search is correct; (b) Construction of BF3OH – Intermediate A2 after leaving Intermediate modeling: After optimizing the transition state TS A1 Based on the structure, remove the BF3OH that is about to leave – part, other settings remain unchanged, and the adjusted structure is geometrically optimized to obtain the structure of the corresponding intermediate A2; (c) Construction of SC γ Bond formation transition state TS A2 Transition state modeling: The tautomer 2a' of benzimidazole thiol was compared with the C of intermediate A2 in the optimized model. γ Coordinate, adjust key bond length, adjust SC γ The distance between the keys is The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency; and the vibration direction of the imaginary frequency is analyzed to be consistent with SC γ The bond is formed, proving that the transition state search is correct; (d) Construction of SC γ Bond-forming intermediate A3 Intermediate modeling: After optimizing the transition state TS A2 Based on the structure, adjust the key bond length and adjust the SC γ The distance between the keys is With other settings unchanged, the adjusted structure was geometrically optimized to obtain the structure of the corresponding intermediate A3. The SC γ The distance between the keys is (e) Construction of the transition state TS of 1,5-HAT A3 Transition state modeling: Adjust the key bond length of the optimized intermediate A3 structure and adjust the distance of the NH bond to C β -The distance of the H bond is The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency. The vibration direction of the imaginary frequency is consistent with NH fracture, C β -H bond formation proves that the transition state search is correct; (f) Construct C β -H bond forming intermediate A4 After the optimization of the transition state TS A3 Based on the structure, adjust the key bond length and adjust the C β -The distance between H bonds is The other settings remain unchanged, and the adjusted structure is geometrically optimized to obtain the structure of the corresponding intermediate A4. After optimization, the C β -The distance of the H bond is (g) Construction of NC α TS A4 Transition state modeling: Adjust the key bond length of the optimized intermediate A4 structure and adjust NC α The distance between the keys is The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency; and the vibration direction of the imaginary frequency is analyzed to be consistent with NC α The bond is formed, proving that the transition state search is correct; (h) Construction of NC α Ring-bonded intermediate A5 After the optimization of the transition state TS A4 Based on the structure, adjust the key bond length and adjust the NC α The distance between the keys is The other settings remain unchanged, and the adjusted structure is geometrically optimized to obtain the structure of the corresponding intermediate A5. The NC α The distance between the keys is (i) Constructing the product A6 with hydrogen proton leaving Based on the optimized structure of intermediate A5, the hydrogen proton on nitrogen was removed, and other settings remained unchanged. The adjusted structure was geometrically optimized to obtain the structure of the corresponding product A6; (2) Reaction pathway design in DMF solvent (a) Construct C α -O cleavage transition state TS B1 Transition state modeling: Using the flexible scanning method, the energy of each step structure is further calculated by analyzing the structural changes that may be caused by the change of key chemical bonds, and the potential energy curve of the key chemical bond change process is obtained. The corresponding structure of the highest energy point on the potential energy curve is used as the initial transition state structure to complete the preliminary modeling; Adjust the key bond length of the optimized precursor B1 structure and change C α -O key from Adjust to The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency. The vibration direction of the imaginary frequency is analyzed to be consistent with C α The -O bond breaks, proving that the transition state search is correct; (b) Construction of intermediate B2 after [BF2DMF]OH leaves Intermediate modeling: After optimizing the transition state TS B1 Based on the structure, the [BF2DMF]OH part that was about to leave was removed, and other settings remained unchanged. The adjusted structure was geometrically optimized to obtain the structure of the corresponding intermediate B2; (c) Construction of SC γ Bond formation transition state TS B2 Transition state modeling: The tautomer 2a' of benzimidazole thiol was compared with the C of intermediate B2 in the optimized model. γ Coordinate, adjust key bond length, adjust SC γ The distance between the keys is The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency; and the vibration direction of the imaginary frequency is analyzed to be consistent with SC γ The bond is formed, proving that the transition state search is correct; (d) Construction of SC γ Bond-forming intermediate B3 Intermediate modeling: After optimizing the transition state TS B2 Based on the structure, adjust the key bond length and adjust the SC γ The distance between the keys is The other settings remain unchanged, and the adjusted structure is geometrically optimized to obtain the structure of the corresponding intermediate B3. The SC of the optimized intermediate B3 γ The distance between the keys is (e) Building BF4 – Attack C β The transition state TS B3 Transition state modeling: Adjust the key bond length of the optimized intermediate B3 structure and adjust the distance of the BF bond to C β -The distance of the F key is The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency. The vibration direction of the imaginary frequency is consistent with BF fracture, C β -F bond formation proves that the transition state search is correct; (f) Construct C β -F bond forming intermediate B4 After the optimization of the transition state TS B3 Based on the structure, adjust the key bond length and adjust the C β -The distance between F keys is The other settings remain unchanged, and the adjusted structure is geometrically optimized to obtain the structure of the corresponding intermediate B4. After optimization, the C β -The distance of the F key is (g) Construction of the transition state TS of 1,6-HAT B4 Transition state modeling: Adjust the key bond length of the optimized intermediate B4 structure and adjust the distance of the NH bond to C α -The distance of the H bond is The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency. The vibration direction of the imaginary frequency is consistent with NH fracture, C α -H bond formation proves that the transition state search is correct; (h) Construction C α -H bond forming intermediate B5 After the optimization of the transition state TS B4 Based on the structure, adjust the key bond length and adjust the C α -The distance between H bonds is The other settings remain unchanged, and the adjusted structure is geometrically optimized to obtain the structure of the corresponding intermediate B5. After optimization, the C α -The distance of the H bond is (i) Construction of product B6 with hydrogen proton leaving Based on the optimized structure of intermediate B5, the hydrogen proton on nitrogen was removed, and other settings remained unchanged. The adjusted structure was geometrically optimized to obtain the structure of the corresponding product B6; (j) Construction of NC β TS B6 Transition state modeling: Adjust the key bond length of the optimized intermediate B6 structure and adjust NC β The distance between the keys is C β -The distance of the F key is The distance of the BF bond is The adjusted transition state model is subjected to transition state geometry optimization and frequency calculation to obtain a transition state structure with only one imaginary frequency; and the vibration direction of the imaginary frequency is analyzed to be consistent with NC β Bond formation, C β -F bond breaks and BF bond forms, proving that the transition state search is correct; (k) Construct NC β The product of the ring bond B7 After the optimization of the transition state TS B6 Based on the structure, adjust the key bond length and adjust the NC β The distance between the keys is The other settings remain unchanged, and the adjusted structure is geometrically optimized to obtain the structure of the corresponding product B7. The NC β The distance between the keys is 2. The analysis method according to claim 1, characterized in that All calculations were performed using Gaussian 16; the M06-2X / 6-31G(d,p) level of theory was used to perform geometry optimization and calculate the frequencies of all intermediates and transition states.

3. The analysis method according to claim 1, characterized in that Intermediate optimization input file: #opt freq M06-2X / 6-31G(d,p)scrf=(smd,solvent=Dichloromethane) in DCM solvent; #opt freq M06-2X / 6-31G(d,p)scrf=(smd,solvent=n,n-DiMethylFormamide) in DMF solvent.

4. The analysis method according to claim 1, characterized in that Transition state optimization input file: in DCM solvent, #opt=(calcfc,ts,noeigentest,maxstep=3)freq M06-2X / 6-31G(d,p)scrf=(smd,solvent=Dichloromethane); in DMF solvent, #opt=(calcfc,ts,noeigentest,maxstep=3)freq M06-2X / 6-31G(d,p)scrf=(smd,solvent=n,n-DiMethylFormamide).

5. The analysis method according to claim 1, characterized in that All intermediates have no imaginary frequency, transition states have only one imaginary frequency, and the Gibbs thermodynamic correction value is extracted from the output file *.log file at the end of optimization.

6. The analysis method according to claim 1, characterized in that In order to obtain more accurate energies, the M06-2X / 6-311+G(d,p) theoretical level was adopted based on the optimized structure and the SMD solvation model was used to calculate the large basis set solvation single point energies of the intermediates and transition states.

7. The analysis method according to claim 1, characterized in that The input files for higher level single point energy calculations are as follows: #M06-2X / 6-311+G(d,p)scrf=(smd,solvent=Dichloromethane) in DCM solvent; #M06-2X / 6-311+G(d,p)scrf=(smd,solvent=n,n-DiMethylFormamide) in DMF solvent.

8. The analysis method according to claim 7, characterized in that Gaussian16 software was used to calculate the output file *.log of the single point, and the single point energy in the log file was read; the single point energy was added with the Gibbs thermal correction value to obtain the Gibbs free energy of each structure.

9. The analysis method according to claim 8, characterized in that The transition state structures were all subjected to intrinsic reaction coordinate (IRC) calculations to ensure that they connected the corresponding reactants and products.

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