Analysis method for tandem cyclization reaction mechanism of double-metal system catalyzed pyridyl homopropargyl alcohol and propargyl alcohol

Abstract

The invention belongs to the technical field of chemical reaction prediction, and discloses an analysis method for a tandem cyclization reaction mechanism of double-metal system catalyzed pyridyl homopropargyl alcohol and propargyl alcohol. The analysis method comprises the following steps: (1) respectively constructing calculation models of an Au (I) catalyst, a Cu (II) catalyst and a substrate pyridyl high-propargyl alcohol structure and a substrate pyridyl high-propargyl alcohol structure; (2) designing a reaction path under an Au (I) catalyst and a Cu (II) catalyst, and constructing an intermediate and a transition state; (3) screening a catalyst for catalytic synthesis of 2, 3-dihydrofuran and polycyclic dihydrobenzofuran; and (4) analyzing the reaction mechanism and path under the Au (I) catalyst and the Cu (II) catalyst. According to the invention, a highly coordinated bimetallic catalytic mechanism is emphasized by applying a density functional theory, and a valuable insight is provided for understanding and designing the bimetallic catalytic mechanism. The result obtained by the analysis method is very consistent with the experimental result, and the calculation result is accurate and reliable.

Description

Technical Field

[0001] This invention belongs to the field of chemical reaction prediction technology, and specifically relates to an analytical method for the tandem cyclization reaction mechanism of pyridyl-homyryl alcohol and propyryl alcohol catalyzed by a bimetallic system. Background Technology

[0002] Bimetallic catalysis, as an important strategy in synthetic chemistry, effectively overcomes the inherent limitations of monometallic systems by integrating the complementary properties of two metals. Bimetallic systems, with their unique synergistic effects, have become a highly efficient platform for constructing complex heterocyclic frameworks. Although this strategy is widely used in synthesis, the catalytic mechanism remains unclear, particularly the dynamic evolution of intermetallic interactions and the precise control mechanism of chemoselectivity. Relying on experimental verification would not only consume significant funds and time but also fail to identify optimal reaction conditions. Furthermore, the difficulty in directly detecting intermediate formation leads to a less in-depth understanding of the reaction mechanism, further hindering the selection of optimal reaction conditions.

[0003] Therefore, a new method is urgently needed to obtain a better reaction pathway and gain a deeper understanding of the reaction mechanism. Summary of the Invention

[0004] This invention aims to provide an analytical method for the tandem cyclization reaction mechanism of pyridyl-homoylated propanol and propargyl alcohol in a bimetallic system. It provides a profound understanding of the tandem cyclization reaction mechanism of pyridyl-homoylated propanol and propargyl alcohol in Au(I) / Cu(II) bimetallic system, and can screen out a reasonable reaction pathway without conducting experiments, which greatly reduces the cost and time required for experiments and has important application value.

[0005] To achieve the above objectives, the present invention provides the following technical solution:

[0006] An analytical method based on the synergistic catalytic mechanism of pyridyl-homoylated alcohols and propargyl alcohols in a bimetallic system has been developed. This method utilizes density functional theory (DFT) to systematically elucidate the mechanism and selectivity of the synergistic catalytic reaction of pyridyl-homoylated alcohols and propargyl alcohols in the Au(I) / Cu(II) bimetallic system. This is the first time that DFT has been applied to the study of the role of bimetals in tandem cyclization reactions. It not only elucidates the dynamic transformation mechanism of the active metal center during bimetallic catalysis but also reveals the differentiated functions of Au(I) and Cu(II) at different stages of the reaction. This significantly enhances the understanding of the synergistic catalytic effect of the Au(I) / Cu(II) bimetallic system, effectively overcoming the limitations of traditional single-metal catalysis techniques. It provides important insights for the efficient synthesis of complex heterocyclic compounds and offers effective guidance for the rational design of tandem cyclization reactions.

[0007] Specifically, this invention presents an analytical method for studying the reaction mechanism of the tandem cyclization reaction of pyridyl propargyl alcohol and propargyl alcohol to form polycyclic dihydrobenzofuran, involving a co-catalyzed Au(I) / Cu(II) bimetallic system. All calculations for this method were performed using Gaussian 16. In the reaction model, this invention employs the M06 / 6-31G(d,p) / SDD level to perform geometric optimization and calculate the frequencies of all intermediates and transition states.

[0008] Specifically, an analytical method for the tandem cyclization reaction mechanism of pyridyl-homoylated alcohol and propylated alcohol catalyzed by a bimetallic system includes the following steps:

[0009] (1) Computational models were constructed for the Au(I) catalyst and Cu(II) catalyst with the substrates pyridyl-homyne propanol and propyne propanol, respectively;

[0010] (3) Design reaction pathways under Au(I) catalyst and Cu(II) catalyst, and construct intermediates and transition states;

[0011] (3) Screening catalysts for the catalytic synthesis of 2,3-dihydrofuran and polycyclic dihydrobenzofuran;

[0012] (4) Analyze the reaction mechanism and pathway under Au(I) catalyst and Cu(II) catalyst.

[0013] Preferably, an analytical method for the tandem cyclization reaction mechanism of pyridyl-homoylated alcohol and propylated alcohol catalyzed by a bimetallic system comprises the following steps:

[0014] I. Constructing a computational model

[0015] Based on experimental conditions of the reaction of pyridine isopropanol and propargyl alcohol catalyzed by Au(I) and Cu(II) catalysts, 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.

[0016] II. Screening of Highly Efficient Catalysts

[0017] (1) Determine an efficient catalyst for the cyclization of pyridyl propargyl alcohol to 2,3-dihydrofuran;

[0018] ①When Au(I) is the catalyst;

[0019] (a) Constructing a precursor in which Au(I) is coordinated with the carbon-carbon triple bond of pyridyl-homyne propanol;

[0020] Precursor modeling: Au(I) was coordinated with the carbon-carbon triple bond of pyridylhopropynol 1a under the optimized model. The key bond lengths were adjusted, and the bond lengths of Au-C1 and Au-C2 were set to 1.80 Å and 1.93 Å, respectively. Other settings remained unchanged, and the structure was optimized to obtain the structure of the optimized precursor A-Au. The distances of the Au-C1 and Au-C2 bonds in the optimized precursor A-Au were 2.31 Å and 2.29 Å, respectively. Taking the energy of Au(I) and pyridylhopropynol under the optimized model as the reference zero point, 15.6 kcal / mol of energy was released when the precursor A-Au was generated.

[0021] (b) Constructing the transition state TS1-Au formed by C1-O bonds

[0022] Transition state modeling: Using a flexible scanning method, the structural changes that may result from changes in key chemical bonds are analyzed, and the energy of each step of the structure is calculated to obtain the potential energy curve of the key chemical bond change process. The structure corresponding to the highest energy point on the potential energy curve is used as the initial transition state structure to complete the preliminary modeling.

[0023] The structural bond length of the optimized precursor A-Au was adjusted, and the distance of the C2-O bond was adjusted to 1.86 Å. The adjusted transition state model was then optimized and its frequency was calculated. A transition state structure with only one imaginary frequency was obtained. The vibrational direction of this imaginary frequency was analyzed to be consistent with the formation of the C2-O bond, proving that the transition state was correctly found. Taking the energies of Au(I) and pyridylhopropynol under the optimized model as the reference zero point, the formation of the C2-O bond requires overcoming a free energy barrier of 15.6 kcal / mol.

[0024] (c) Visual analysis of TS1-Au

[0025] Prepare a TS1-Au input file containing wavefunction information (such as .fchk or .wfn), use software that supports IGMH analysis (such as Multiwfn), select the IGMH analysis function and set the parameters, and then run the VMD analysis to obtain the IGMH analysis results;

[0026] ②When Cu(II) is the catalyst

[0027] (a) Construction of a precursor with Cu(II) coordinated to the carbon-carbon triple bond of pyridylhopropynol

[0028] Precursor modeling: The carbon-carbon triple bond of Cu(II) was coordinated with the pyridylhomoylated alcohol 1a in the optimized model. The key bond lengths were adjusted, and the distances between Cu-C1 and Cu-C2 bonds were set to 2.14 Å and 2.25 Å, respectively, while other settings remained unchanged. Structural optimization was performed to obtain the optimized precursor A-Cu structure. The distances between Cu-C1 and Cu-C2 bonds in the optimized precursor A-Cu were 2.13 Å and 2.31 Å, respectively. Using the energy of Cu(II) and pyridylhomoylated alcohol in the optimized model as the reference zero point, 4.1 kcal / mol of energy was released when the precursor A-Cu was generated.

[0029] (b) Constructing the transition state TS1-Cu formed by C2-O bonds

[0030] Transition state modeling: Using a flexible scanning method, the structural changes that may result from changes in key chemical bonds are analyzed, and the energy of each step of the structure is calculated to obtain the potential energy curve of the key chemical bond change process. The structure corresponding to the highest energy point on the potential energy curve is used as the initial transition state structure to complete the preliminary modeling.

[0031] The bond lengths of the optimized precursor A-Cu were adjusted, and the distance of the C2-O bond was adjusted to 1.86 Å. The adjusted transition state model was then optimized and its frequency calculated, yielding a transition state structure with exactly one imaginary frequency. Analysis showed that the vibrational direction of this imaginary frequency conformed to the formation of the C2-O bond, proving that the correct transition state was found. Using the energies of Cu(II) and pyridylhopropynol under the optimized model as the reference zero point, the formation of the C2-O bond requires overcoming a free energy barrier of 14.7 kcal / mol.

[0032] (c) Visual analysis of TS1-Cu

[0033] Prepare a TS1-Cu input file (e.g., .fchk or .wfn) containing wavefunction information. Using software that supports IGMH analysis (e.g., Multiwfn), select the IGMH analysis function and set the parameters. Then, run the VMD analysis to obtain the IGMH analysis results.

[0034] From the perspective of thermodynamics and molecular structure, Au(I) has a significantly better activation ability for the carbon-carbon triple bond in pyridylpropargyl alcohol than Cu(II), and IGMH analysis of TS1-Au and TS1-Cu can further confirm this. Therefore, Au(I) is identified as a highly efficient catalyst for the formation of 2,3-dihydrofuran from pyridylpropargyl alcohol.

[0035] (2) Determine the catalyst for the formation of polycyclic dihydrobenzofuran from propargyl alcohol.

[0036] ①When Au(I) is the catalyst

[0037] (a) Construction of a precursor for Au(I) coordinated with the carbon-carbon triple bond of propargyl alcohol

[0038] Precursor modeling: Au(I) was coordinated with the carbon-carbon triple bond of propargyl alcohol 2a under the optimized model. The key bond lengths were adjusted, and the bond lengths of Au-C3 and Au-C4 were set to 2.19 Å and 1.82 Å, respectively, while other settings remained unchanged. Structural optimization was performed to obtain the optimized precursor D-Au structure. The distances of the Au-C3 and Au-C4 bonds in the optimized precursor D-Au were 2.42 Å and 2.25 Å, respectively. Using the energy of Au(I) and propargyl alcohol under the optimized model as the reference zero point, 17.4 kcal / mol of energy was released when the precursor D-Au was generated.

[0039] (b) Constructing the transition state TS2-Au formed by C1-C3 bonds

[0040] Transition state modeling: Using a flexible scanning method, the structural changes that may result from changes in key chemical bonds are analyzed, and the energy of each step of the structure is calculated to obtain the potential energy curve of the key chemical bond change process. The structure corresponding to the highest energy point on the potential energy curve is used as the initial transition state structure to complete the preliminary modeling.

[0041] The C1 atom of the generated dihydrofuran intermediate C was coordinated with the C3 atom of the precursor D-Au under the optimized model. The key bond length was adjusted, and the distance between the C1 and C3 bonds was adjusted to 2.30 Å. The adjusted transition state model was subjected to transition state geometry optimization and frequency calculation, resulting in a transition state structure with one and only one imaginary frequency. The vibrational direction of this imaginary frequency was analyzed to be consistent with the formation of the C1-C3 bond, proving that the transition state was correctly identified. Using the energies of Au(I) and propargyl alcohol under the optimized model as the reference zero point, the formation of the C1-C3 bond requires overcoming a free energy barrier of 15.1 kcal / mol.

[0042] (c) Constructing the intermediate E'-Au formed by C1-C3 bonds

[0043] Intermediate modeling: Based on the optimized transition state TS2-Au structure, the key bond lengths were adjusted, and the distance between C1-C3 bonds was adjusted to 1.55 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate E'-Au. After optimization, the distance between C1-C3 bonds in intermediate E'-Au was 1.54 Å. Using the energies of Au(I) and propargyl alcohol under the optimized model as the reference zero point, 4.0 kcal / mol of energy was released when intermediate E'-Au was generated.

[0044] (d) Constructing the intermediate F'-Au after H2O departure

[0045] Based on the optimized intermediate E'-Au structure, the H atom on C1 and the H2O part generated by the OH group on C5 were removed, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate F'-Au. Using the energies of Au(I) and propargyl alcohol under the optimized model as the reference zero point, 22.7 kcal / mol of energy was released when intermediate F'-Au was generated.

[0046] (e) Constructing the transition state TS3-Au formed by C4-C6 bonds

[0047] The bond lengths of the optimized intermediate F'-Au were adjusted, and the distance between the C4 and C6 bonds was set to 1.90 Å. The adjusted transition state model was then optimized and its frequencies calculated, yielding a transition state structure with exactly one imaginary frequency. Analysis showed that the vibrational direction of this imaginary frequency conformed to the formation of the C4-C6 bond, proving that the correct transition state was found. Using the energies of Au(I) and propargyl alcohol under the optimized model as the reference zero point, the formation of the C4-C6 bond requires overcoming a free energy barrier of 23.6 kcal / mol.

[0048] (f) Constructing the intermediate G'-Au with C4-C6 bond cyclization

[0049] Based on the optimized transition state TS3-Au structure, the key bond lengths were adjusted, and the distance between C4-C6 bonds was adjusted to 1.63 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate G'-Au. The distance between the C4-C6 bonds in the optimized intermediate G'-Au was 1.60 Å. Using the energies of Au(I) and propargyl alcohol under the optimized model as the reference zero point, 20.4 kcal / mol of energy was absorbed when generating the intermediate G'-Au.

[0050] (g) Constructing the transition state TS4-Au formed by C5-C7 bonds

[0051] The bond lengths of the optimized intermediate G'-Au were adjusted, and the distance between the C5 and C7 bonds was set to 2.00 Å. The adjusted transition state model was then optimized and its frequencies calculated, yielding a transition state structure with exactly one imaginary frequency. Analysis showed that the vibrational direction of this imaginary frequency conformed to the formation of the C5-C7 bond, proving that the correct transition state was found. Using the energies of Au(I) and propargyl alcohol under the optimized model as the reference zero point, the formation of the C5-C7 bond requires overcoming a free energy barrier of 31.8 kcal / mol.

[0052] (h) Constructing the intermediate H'-Au with C5-C7 bond cyclization

[0053] Based on the optimized transition state TS4-Au structure, the key bond lengths were adjusted, and the distance between C5-C7 bonds was adjusted to 1.56 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate H'-Au. The distance between the C5-C7 bonds in the optimized intermediate H'-Au was 1.56 Å. Using the energies of Au(I) and propargyl alcohol under the optimized model as the reference zero point, 16.5 kcal / mol of energy was absorbed when generating the intermediate H'-Au.

[0054] (i) Visual analysis of TS4-Au

[0055] Prepare a TS4-Au input file (e.g., .fchk or .wfn) containing wavefunction information. Using software that supports IGMH analysis (e.g., Multiwfn), select the IGMH analysis function and set the parameters. Then, run the VMD analysis to obtain the IGMH analysis results.

[0056] ②When Cu(II) is the catalyst

[0057] (a) Construction of a precursor for Cu(II) coordinated with the carbon-carbon triple bond of propargyl alcohol

[0058] Precursor modeling: The carbon-carbon triple bond of Cu(II) was coordinated with propargyl 2a in the optimized model. The key bond lengths were adjusted, and the Cu-C3 and Cu-C4 bond lengths were set to 2.38 Å and 2.17 Å, respectively, while other settings remained unchanged. Structural optimization was performed to obtain the optimized precursor D-Au structure. The distances between the Cu-C3 and Cu-C4 bonds in the optimized precursor D-Cu were 2.37 Å and 2.17 Å, respectively. Using the energy of Cu(II) and propargyl 2a in the optimized model as the reference zero point, 8.2 kcal / mol of energy was released when the precursor D-Cu was generated.

[0059] (b) Constructing the transition state TS2-Cu formed by C1-C3 bonds

[0060] Transition state modeling: Using a flexible scanning method, the structural changes that may result from changes in key chemical bonds are analyzed, and the energy of each step of the structure is calculated to obtain the potential energy curve of the key chemical bond change process. The structure corresponding to the highest energy point on the potential energy curve is used as the initial transition state structure to complete the preliminary modeling.

[0061] The C1 atom of the generated dihydrofuran intermediate C was coordinated with the C3 atom of the precursor D-Cu under the optimized model. The key bond length was adjusted, and the distance of the C1-C3 bond was adjusted to 2.30 Å. The adjusted transition state model was subjected to transition state geometry optimization and frequency calculation, and a transition state structure with one and only one imaginary frequency was obtained. The vibration direction of this imaginary frequency was analyzed to be consistent with the formation of the C1-C3 bond, proving that the transition state was correctly found. With the energy of Cu(II) and propargyl alcohol under the optimized model as the reference zero point, the formation of the C1-C3 bond requires overcoming a free energy barrier of 10.8 kcal / mol.

[0062] (c) Constructing the intermediate E'-Cu formed by C1-C3 bonds

[0063] Intermediate modeling: Based on the optimized transition state TS2-Cu structure, the key bond lengths were adjusted, and the distance between C1-C3 bonds was adjusted to 1.54 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate E'-Cu. The distance between C1-C3 bonds in the optimized intermediate E'-Cu was 1.54 Å. Using the energies of Cu(II) and propargyl alcohol under the optimized model as the reference zero point, 9.5 kcal / mol of energy was released when the intermediate E'-Cu was generated.

[0064] (d) Construction of the intermediate F'-Cu after H2O departure

[0065] Based on the optimized intermediate E'-Cu structure, the H atom on C1 and the H2O part generated by the OH group on C5 were removed, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate F'-Cu. Using the energy of Cu(II) and propargyl alcohol under the optimized model as the reference zero point, 23.0 kcal / mol of energy was released when intermediate F'-Cu was generated.

[0066] (e) Constructing the transition state TS3-Cu with C4-C6 bonds

[0067] The bond lengths of the optimized intermediate F'-Cu were adjusted, and the distance between the C4 and C6 bonds was set to 2.00 Å. The adjusted transition state model was then optimized and its frequencies calculated, yielding a transition state structure with exactly one imaginary frequency. Analysis showed that the vibrational direction of this imaginary frequency conformed to the formation of the C4-C6 bond, proving that the correct transition state was found. Using the energies of Cu(II) and propargyl alcohol under the optimized model as the reference zero point, the formation of the C4-C6 bond requires overcoming a free energy barrier of 25.2 kcal / mol.

[0068] (f) Construction of the intermediate G'-Cu with C4-C6 bond cyclization

[0069] Based on the optimized transition state TS3-Cu structure, the key bond lengths were adjusted, and the distance between C4-C6 bonds was adjusted to 1.60 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate G'-Cu. The distance between C4-C6 bonds in the optimized intermediate G'-Cu was 1.63 Å. Using the energies of Cu(II) and propargyl alcohol under the optimized model as the reference zero point, 15.2 kcal / mol of energy was absorbed when generating the intermediate G'-Cu.

[0070] (g) Constructing the transition state TS4-Cu formed by C5-C7 bonds

[0071] The bond lengths of the optimized intermediate G'-Cu were adjusted, and the distance between the C5 and C7 bonds was set to 2.00 Å. The adjusted transition state model was then optimized and its frequencies calculated, yielding a transition state structure with exactly one imaginary frequency. Analysis showed that the vibrational direction of this imaginary frequency conformed to the formation of the C5-C7 bond, proving that the correct transition state was found. Using the energies of Cu(II) and propargyl alcohol in the optimized model as the reference zero point, the formation of the C5-C7 bond requires overcoming a free energy barrier of 20.9 kcal / mol.

[0072] (h) Constructing the intermediate H'-Cu with C5-C7 bond cyclization

[0073] Based on the optimized transition state TS4-Cu structure, the key bond lengths were adjusted, and the distance between C5-C7 bonds was adjusted to 1.54 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate G'-Cu. The distance between C4-C6 bonds in the optimized intermediate G'-Cu was 1.55 Å. Using the energies of Cu(II) and propargyl alcohol under the optimized model as the reference zero point, 5.0 kcal / mol of energy was absorbed when generating the intermediate H'-Cu.

[0074] (i) Visual analysis of TS4-Cu

[0075] Prepare a TS4-Cu input file (e.g., .fchk or .wfn) containing wavefunction information. Using software that supports IGMH analysis (e.g., Multiwfn), select the IGMH analysis function and set the parameters. Then, run the VMD analysis to obtain the IGMH analysis results.

[0076] From a thermodynamic and molecular structure perspective, in the D→G' conversion, the Au(I)-catalyzed pathway has a lower potential energy surface than the Cu(II)-catalyzed pathway. After the formation of intermediate G', the Friedel-Crafts cyclization reaction occurs. Au(I) catalysis requires overcoming an energy barrier of 31.8 kcal / mol, while Cu(II) catalysis requires overcoming an energy barrier of 20.9 kcal / mol. This indicates that Cu(II) catalysis of Friedel-Crafts cyclization is easier, and this is confirmed by IGMH analysis of TS4-Au and TS4-Cu. Therefore, a more accurate cyclic mechanism for the formation of polycyclic dihydrobenzofuran is proposed: in the D→G' conversion, the Au(I) catalyst plays a key role initially. It has a stronger interaction with the carbon-carbon triple bond of the substrate propargyl alcohol, enabling efficient activation of the substrate. Once intermediate G' is formed, the Au(I) catalyst dissociates from the reaction system, at which point the Cu(II) catalyst takes over and catalyzes the subsequent Friedel-Crafts cyclization reaction with even higher efficiency. This synergistic effect fully utilizes the properties of Au(I) and Cu(II) catalysts, achieving highly efficient reaction conversion.

[0077] III. Designing Reaction Pathways

[0078] (1) Design of the reaction pathway for Au(I) to generate 2,3-dihydrofuran

[0079] (a) Construction of a precursor with Au(I) coordinated to the carbon-carbon triple bond of pyridylhopropynol

[0080] Precursor modeling: Au(I) was coordinated with the carbon-carbon triple bond of pyridylhopropynol 1a in the optimized model. The key bond lengths were adjusted, and the bond lengths of Au-C1 and Au-C2 were set to 1.80 Å and 1.93 Å, respectively. Other settings remained unchanged, and the structure was optimized to obtain the structure of the optimized precursor A-Au. The distances between the Au-C1 and Au-C2 bonds in the optimized precursor A-Au were 2.31 Å and 2.29 Å, respectively.

[0081] (b) Constructing the transition state TS1-Au formed by C2-O bonds

[0082] Transition state modeling: Using a flexible scanning method, the structural changes that may result from changes in key chemical bonds are analyzed, and the energy of each step of the structure is calculated to obtain the potential energy curve of the key chemical bond change process. The structure corresponding to the highest energy point on the potential energy curve is used as the initial transition state structure to complete the preliminary modeling.

[0083] The structural bond length of the A-Au precursor was adjusted and optimized, and the distance of the C2-O bond was adjusted to 1.86 Å. The adjusted transition state model was then optimized and the frequency was calculated to obtain a transition state structure with one and only one imaginary frequency. Furthermore, the vibration direction of this imaginary frequency was analyzed to be consistent with the formation of the C2-O bond, proving that the transition state was correctly identified.

[0084] (c) Constructing the intermediate B-Au formed by C2-O bonds

[0085] Intermediate modeling: Based on the optimized transition state TS1-Au structure, the key bond lengths are adjusted, and the distance between C2-O bonds is adjusted to 1.53 Å, while other settings remain unchanged. The adjusted structure is then optimized to obtain the structure of the corresponding intermediate B-Au. The C2-O bond length of the optimized intermediate B-Au is 1.52 Å.

[0086] (d) Construction of the Au(I)-depleted product 2,3-dihydrofuran C

[0087] Based on the optimized intermediate B-Au structure, the Au(I) catalyst was removed, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate product C.

[0088] (2) Reaction pathway design for the co-catalytic formation of polycyclic dihydrobenzofuran by Au(I) and Cu(II)

[0089] (a) Construction of a precursor for Au(I) coordinated with the carbon-carbon triple bond of propargyl alcohol

[0090] Precursor modeling: Au(I) was coordinated with the carbon-carbon triple bond of propargyl alcohol 2a in the optimized model. The key bond lengths were adjusted, and the bond lengths of Au-C3 and Au-C4 were set to 2.19 Å and 1.82 Å, respectively. Other settings remained unchanged, and the structure was optimized to obtain the structure of the optimized precursor D-Au. The distances between the Au-C3 and Au-C4 bonds in the optimized precursor D-Au were 2.25 Å and 2.19 Å, respectively.

[0091] (b) Constructing the transition state TS2-Au formed by C1-C3 bonds

[0092] Transition state modeling: Using a flexible scanning method, the structural changes that may result from changes in key chemical bonds are analyzed, and the energy of each step of the structure is calculated to obtain the potential energy curve of the key chemical bond change process. The structure corresponding to the highest energy point on the potential energy curve is used as the initial transition state structure to complete the preliminary modeling.

[0093] The C1 atom of the generated dihydrofuran intermediate C was coordinated with the C3 atom of the intermediate D-Au under the optimized model. The key bond length was adjusted, and the distance between the C1 and C3 bonds was adjusted to 2.30 Å. The adjusted transition state model was subjected to transition state geometry optimization and frequency calculation, resulting in a transition state structure with one and only one imaginary frequency. The vibration direction of this imaginary frequency is consistent with the formation of the C1-C3 bond, proving that the transition state was correctly found.

[0094] (c) Constructing the intermediate E'-Au formed by C1-C3 bonds

[0095] Intermediate modeling: Based on the optimized transition state TS2-Au structure, the key bond lengths are adjusted, and the distance between C1-C3 bonds is adjusted to 1.55 Å, while other settings remain unchanged. The adjusted structure is then geometrically optimized to obtain the structure of the corresponding intermediate E'-Au. After optimization, the distance between C1-C3 bonds in intermediate E'-Au is 1.54 Å.

[0096] (d) Constructing the intermediate F'-Au after H2O departure

[0097] Based on the optimized intermediate E'-Au structure, the H atom on C1 atom and the H2O part generated by the OH group on C5 atom are removed, while other settings remain unchanged. The adjusted structure is then geometrically optimized to obtain the structure of the corresponding intermediate F'-Au.

[0098] (e) Constructing the transition state TS3-Au formed by C4-C6 bonds

[0099] The structural bond lengths of the optimized intermediate F'-Cu were adjusted, and the distance between the C4-C6 bonds was adjusted to 1.90 Å. The adjusted transition state model was then optimized and its frequency was calculated to obtain a transition state structure with only one imaginary frequency. Furthermore, the vibration direction of this imaginary frequency was analyzed to be consistent with the formation of the C4-C6 bonds, proving that the transition state was correctly identified.

[0100] (f) Constructing the intermediate G'-Au with C4-C6 bond cyclization

[0101] Based on the optimized transition state TS3-Au structure, the key bond lengths were adjusted, and the distance between C4-C6 bonds was adjusted to 1.63 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate G'-Au. The distance between C4-C6 bonds in the optimized intermediate G'-Au was 1.60 Å.

[0102] (g) Construction of the Cu(II) relay-catalyzed intermediate G''-Cu

[0103] Based on the optimized intermediate G'-Au structure, Au(I) catalyst at the C4 position was removed by hydrogen proton demetallization, and Cu(II) catalyst was coordinated at the C3 position. The C3-Cu bond distance was adjusted to 2.27 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate G''-Cu. The C3-Cu bond distance of the optimized intermediate G''-Cu was 2.10 Å.

[0104] (h) Constructing the transition state TS formed by C5-C7 bonds 4' -Cu

[0105] Transition state modeling: Adjust the bond length of the optimized precursor G''-Cu structure and adjust the distance of C5-C7 bonds to 2.05 Å. Perform transition state optimization and frequency calculation on the adjusted transition state model to obtain a transition state structure with one and only one imaginary frequency. The analysis shows that the vibration direction of this imaginary frequency is consistent with the formation of C5-C7 bonds, proving that the transition state was found correctly.

[0106] (i) Constructing the intermediate H''-Cu with C5-C7 bonded rings

[0107] In the optimized transition state TS 4' Based on the -Cu structure, the key bond lengths were adjusted, and the distance between C5-C7 bonds was adjusted to 1.57 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate H''-Cu. After optimization, the distance between C5-C7 bonds in the intermediate H''-Cu was 1.57 Å.

[0108] (j) Constructing the H2 departure transition state TS5-Cu

[0109] Transition state modeling: Adjust the structural bond length of the optimized precursor H''-Cu, and adjust the distance between CH and HH bonds to 1.50 Å and 1.15 Å, respectively. Perform transition state optimization and frequency calculation on the adjusted transition state model to obtain a transition state structure with one and only one imaginary frequency. Furthermore, the analysis shows that the vibration direction of this imaginary frequency conforms to the formation of CH and HH bonds, proving that the transition state was correctly found.

[0110] (k) Construct the product 3a after H2 removal.

[0111] Based on the optimized transition state TS5-Cu structure, the catalyst Cu(II) was removed. With other settings unchanged, the adjusted structure was geometrically optimized to obtain the structure of the corresponding product 3a.

[0112] Preferably, all calculations are performed using the Gaussian 16 program; the SMD-M06 / 6-31G(d,p) / SDD theoretical level is used to perform geometric optimization and calculate the frequencies of all intermediates and transition states.

[0113] Preferably, the intermediate optimization input file is: #M06 / 6-31G(d,p) / SDD opt freq scrf=(smd,solvent=1,4-dioxane).

[0114] Preferably, the transition state optimization input file is: #M06 / 6-31G(d,p) / SDD opt=(calcfc,ts,noeigentest,maxstep=3) freq scrf=(smd,solvent=1,4-dioxane).

[0115] Preferably, all intermediates have no imaginary frequency, the transition state has one and only one imaginary frequency, and the Gibbs thermodynamic correction value is extracted from the output file *.log file at the end of the optimization.

[0116] Preferably, in order to obtain more accurate energies, the large basis set solvation single-point energies of the intermediate and transition states are calculated using the M06 / 6-311+G(d,p) / SDD theoretical level and the SMD solvation model based on the optimized structure.

[0117] Preferably, the input file for higher-level single-point energy calculation is as follows: #M06 / 6-311+G(d,p) / SDD scrf=(smd,solvent=1,4-dioxane);

[0118] Preferably, the output file *.log of a single point is calculated using Gaussian16 software, and the single-point energy in the log file is read; the Gibbs free energy of each structure is obtained by adding the Gibbs thermal correction value to the single-point energy.

[0119] Preferably, the transition state structures were calculated using the intrinsic reaction coordinate method to ensure that they are connected to the corresponding reactants and products.

[0120] Furthermore, the input file for the optimization calculation is as follows:

[0121] Input file for intermediate optimization: The calculation settings for the Au(I) and Cu(II) catalytic system are as follows: #M06 / 6-31G(d,p) / SDD opt freq scrf=(smd,solvent=1,4-Dioxane).

[0122] Transition state optimization input file: The calculation settings for the Au(I) and Cu(II) catalytic system are as follows: #M06 / 6-311+G(d,p) / SDD opt=(calcfc,ts,noeigentest,maxstep=3) freq scrf=(smd,solvent=1,4-Dioxane).

[0123] All intermediates have no imaginary frequency, and the transition state has one and only one imaginary frequency. The Gibbs thermodynamic correction values ​​are extracted from the output file *.log after optimization. To obtain more accurate energies, the M06 / 6-311+G(d,p) / SDD level is used based on the optimized structure, and the SMD solvation model is used to calculate the large basis set solvation single-point energies of the intermediates and transition state.

[0124] The input file for high-level single-point energy calculations is as follows: For the Au(I) and Cu(II) catalytic systems, the calculation settings are as follows: #M06 / 6-311+G(d,p) / SDD scrf=(smd,solvent=1,4-Dioxane). The output file *.log is calculated using Gaussian16 software. The single-point energies in the log file are read; the Gibbs free energy for each structure is obtained by adding the Gibbs heat correction value to the single-point energy. The intrinsic reaction coordinate (IRC) theory is used to obtain the minimum energy path to determine the accuracy of the transition state.

[0125] This invention employs density functional theory to design reactants, intermediates, transition states, and products along each reaction pathway. The geometric structure of intermediates is adjusted based on the formation and breaking of chemical bonds and the coordination of key groups. Geometric optimization is then performed at the M06 / 6-31G(d,p) / SDD computational level, and single-point energies are calculated at the M06 / 6-311+G(d,p) / SDD computational level, yielding thermal corrections for vibrational harmonic frequencies and Gibbs free energy. All stationary points are identified as minimum values ​​(zero imaginary frequency) or transition states (one imaginary frequency). The activation energies of each elementary reaction are obtained, and corresponding potential energy surface diagrams are plotted. The optimal reaction pathway and its rate-determining step are determined. Reliability analysis, comparing with experimental results, determines the optimal active center structure of the catalyst and the reaction mechanism.

[0126] The beneficial effects achieved by this invention are as follows:

[0127] (1) This invention employs density functional theory under the M06 functional to study the reaction mechanism of the synergistic catalytic reaction of pyridylhopropargyl alcohol and propargyl alcohol to form polycyclic dihydrobenzofuran in the Au(I) / Cu(II) bimetallic system, proposing a new reaction mechanism that is more accurate and reasonable than experimental results. The results show that in the first catalytic cycle, Au(I) exhibits a significant catalytic advantage over Cu(II). The Au(I) catalyst effectively promotes the 5-endo-dig cyclization of pyridylhopropargyl alcohol to form the 2,3-dihydrofuran intermediate by π-acid activation of the substrate pyridylhopropargyl alcohol and stabilization of the key intermediate. The generated 2,3-dihydrofuran then enters the next catalytic cycle. In the second catalytic cycle, the Au(I) catalyst first activates the carbon-carbon triple bond in propargyl alcohol, promoting the C-C coupling reaction and triggering the initial cyclization process. This series of reactions provides ideal conditions for the subsequent intervention of Cu(II). Subsequently, the Cu(II) catalyst, through coordination, relays the catalytic process, significantly reducing the energy barrier of Friedel-Crafts cyclization and promoting the H2 elimination reaction, ultimately generating polycyclic dihydrobenzofuran products, thus achieving efficient advancement of the catalytic cycle.

[0128] (2) This invention fully investigates the reaction pathway of the Au(I) / Cu(II) bimetallic synergistic catalysis of the tandem cyclization reaction of pyridylhopropynol and propynol to form polycyclic dihydrobenzofuran. At the atomic level, it studies how the synergistic effect of Au(I) and Cu(II) catalysts can be precisely controlled to achieve maximum efficiency in the tandem cyclization reaction of pyridylhopropynol and propynol to form polycyclic dihydrobenzofuran. Exploring this reaction mechanism not only clarifies the reaction pathway but also provides theoretical research for designing more efficient catalysts, significantly reducing the cost and time required for experiments, and has important application value.

[0129] (3) This invention employs density functional theory to study in detail the reaction mechanism of the Au(I) / Cu(II) bimetallic system in the synergistic catalytic cascade cyclization reaction of pyridyl-hopropynol and propynol to form polycyclic dihydrobenzofuran. It identifies the possible intermediates and transition state structures obtained in the reaction. In the cyclic mechanism for the formation of 2,3-dihydrofuran, the carbon-carbon coupling step is the rate-determining step, with an activation energy barrier of 15.6 kcal / mol. In the process of forming polycyclic dihydrobenzofuran, the Friedel-Crafts cyclization step is the rate-determining step, with an activation energy barrier of 35.8 kcal / mol. This is largely consistent with the experimentally required reaction conditions.

[0130] (4) Due to current limitations in experimental resources, experimental methods alone cannot fully obtain the reaction mechanism and the configuration and energy of each initial substance, intermediate, transition state, and product. This invention, however, obtains the reaction mechanism at the atomic level using quantum chemical techniques. This research is the first to apply density functional theory to explore the role of bimetallic catalytic systems in cyclization reactions, providing valuable insights for understanding and designing bimetallic catalytic cyclization reactions. This method only requires a personal server, thus eliminating the need to purchase expensive large-scale computing equipment or incur high computational analysis costs, and also accelerating the development and synthesis process. The results are in excellent agreement with experimental results, demonstrating accurate and reliable calculations. Attached Figure Description

[0131] Figure 1 The graphs show the cycle diagrams and Gibbs free energy curves for the synthesis of 2,3-dihydrofuran from pyridylhopropanol using Au(I) / Cu(II) catalysts at the M06 theoretical level (the black curves represent the Au(I) catalytic synthesis pathway, and the red curves represent the Cu(II) catalytic synthesis pathway. The numbers represent the relative Gibbs free energy ΔG, in kcal / mol).

[0132] Figure 2 Independent gradient models for the three-dimensional structures of intermediates A-Au and A-Cu in the formation of 2,3-dihydrofuran from pyridylhopropynol catalyzed by Au(I) / Cu(II) catalyst and for IMH analysis (blue represents strong attraction interaction region, green represents weak attraction interaction region).

[0133] Figure 3 This is a Gibbs free energy curve for the reaction of propargyl alcohol and 2,3-dihydrofuran catalyzed by Au(I) / Cu(II) catalysts at the M06 theoretical level (the black curve represents the Au(I) catalytic synthesis route, and the red curve represents the Cu(II) catalytic synthesis route. The numbers represent the relative Gibbs free energy ΔG, in kcal / mol).

[0134] Figure 4 The three-dimensional structures of the transition states TS4-Au and TS4-Cu in the formation of polycyclic dihydrobenzofuran from propargyl alcohol by Au(I) / Cu(II) catalyst and the independent gradient model of IMH analysis (blue represents the region of strong attraction interaction and green represents the region of weak attraction interaction).

[0135] Figure 5 The figure shows the Gibbs free energy curves for the synergistic catalytic reaction of propargyl alcohol and 2,3-dihydrofuran to produce polycyclic dihydrobenzofuran under the theoretical level of M06 (the red curve in the figure represents the Au(I) catalytic synthesis pathway, and the green curve represents the Cu(II) relay catalytic synthesis pathway. The numbers represent the relative Gibbs free energy ΔG, in kcal / mol). Detailed Implementation

[0136] To enable those skilled in the art to more clearly understand the technical solutions described in this invention, the following examples are provided for illustration. It should be noted that these examples do not constitute a limitation on the scope of protection claimed by this invention.

[0137] This invention employs density functional theory to model the reaction pathways explored by Au(I) and Cu(II), as well as the reactants, intermediates, transition states, and products under the combined action of Au(I) and Cu(II), based on the formation and breaking of chemical bonds and coordination conditions. Then, structural optimization is performed at the M06 functional calculation level to obtain the activation energy and reaction free energy change of the elementary reaction, and finally, the corresponding Gibbs free energy curves are plotted.

[0138] The input file for the optimization calculation is as follows:

[0139] Input file for intermediate optimization: The calculation settings for the Au(I) and Cu(II) catalytic system are as follows: #M06 / 6-31G(d,p) / SDD opt freq scrf=(smd,solvent=1,4-Dioxane).

[0140] Transition state optimization input file: The calculation settings for the Au(I) and Cu(II) catalytic system are as follows: #M06 / 6-311+G(d,p) / SDD opt=(calcfc,ts,noeigentest,maxstep=3) freq scrf=(smd,solvent=1,4-Dioxane).

[0141] All intermediates have no imaginary frequency, and the transition state has one and only one imaginary frequency. The Gibbs thermodynamic correction values ​​are extracted from the output file *.log after optimization. To obtain more accurate energies, the M06 / 6-311+G(d,p) / SDD level is used based on the optimized structure, and the SMD solvation model is used to calculate the large basis set solvation single-point energies of the intermediates and transition state.

[0142] The input file for high-level single-point energy calculations is as follows: In 1,4-dioxane solvent, the calculation settings for the Au(I) and Cu(II) catalytic systems are as follows: #M06 / 6-311+G(d,p) / SDD scrf=(smd,solvent=1,4-Dioxane). The output file *.log is calculated using Gaussian16 software. The single-point energies in the log file are read; the Gibbs free energy for each structure is obtained by adding the Gibbs heat correction value to the single-point energy. The intrinsic reaction coordinate (IRC) theory is used to obtain the minimum energy path to determine the accuracy of the transition state.

[0143] This invention employs density functional theory to design reactants, intermediates, transition states, and products along various reaction pathways. The geometric structure of intermediates is adjusted based on the formation and breaking of chemical bonds and the coordination of key groups. Geometric optimization is then performed at the M06 / 6-31G(d,p) / SDD computational level, and single-point energies are calculated at the M06 / 6-311+G(d,p) / SDD computational level, yielding thermal corrections for vibrational harmonic frequencies and Gibbs free energy. All stationary points are identified as minimum values ​​(zero imaginary frequency) or transition states (one imaginary frequency). The activation energies of each elementary reaction are obtained, and corresponding potential energy surface diagrams are plotted. The optimal reaction pathway and its rate-determining step are determined. Reliability analysis, comparing with experimental results, confirms the optimal active center structure of the catalyst and the reaction mechanism.

[0144] In computational chemistry, frequency analysis is mainly used to determine the stability of free radicals, evaluate the catalytic performance of complexes, and determine the location of energy shells. All calculations use the same computational level as intermediate optimization to perform structural optimization of the transition state, followed by frequency calculations. The results must guarantee that there is one and only one imaginary frequency.

[0145] Intrinsic Reaction Coordinates (IRC) is a theoretical method used to study the kinetics of molecular reactions and to identify transition states. This method determines the energy barriers and pathways between reactants and products by tracking changes at various stages of a chemical reaction. Simply put, the IRC is a continuous curve connecting the initial structure and the transition state, representing all possible conformations along the reaction path. The transition state structures were also calculated using IRC to ensure they connected to their corresponding reactants and products. To simulate real reactions and obtain more accurate energies, single-point energy calculations were performed on the optimized stagnation points at the M06 / 6-311+G(d,p) / SDD level, which is essential in studying catalytic reaction mechanisms. For solvation effects, the SMD solvation model was used for single-point calculations, with 1,4-dioxane as the solvent corresponding to the experimental conditions. Therefore, unless otherwise specified, all values ​​reported in this article are Gibbs free energies at a temperature of 298.15 K, including calculations based on reactants, intermediates, and transition states at the M06 / 6-311+G(d,p) / SDD / / M06 / 6-31G(d,p) / SDD level, including solvation correction energy (ECPCM) after geometry optimization at the M06 / 6-31G(d,p) / SDD level, van der Waals effect correction (EVDW), and thermal correction to Gibbs free energy (Gtc). In all energy distribution diagrams, the unit for relative Gibbs free energy is kcal / mol.

[0146] This invention presents an analytical method for the tandem cyclization reaction mechanism of pyridyl-modified propargyl alcohol and propargyl alcohol catalyzed by a bimetallic system, specifically including the following steps:

[0147] I. Constructing a computational model

[0148] Based on experimental conditions of the reaction of pyridyl isopropanol and propargyl alcohol catalyzed by Au(I) and Cu(II) catalysts, a computational model of the catalyst and 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 reaction substrate.

[0149] II. Screening of Highly Efficient Catalysts

[0150] (1) Determining the catalyst for the cyclization of pyridylpropargyl alcohol to 2,3-dihydrofuran

[0151] ①When Au(I) is the catalyst

[0152] (a) Construction of a precursor with Au(I) coordinated to the carbon-carbon triple bond of pyridylhopropynol

[0153] Precursor modeling: Au(I) was coordinated with the carbon-carbon triple bond of pyridylhopropargyl alcohol 1a under the optimized model. The key bond lengths were adjusted, setting the Au-C1 and Au-C2 bond lengths to 1.80 Å and 1.93 Å, respectively, while keeping other settings unchanged. Structural optimization was then performed to obtain the optimized precursor A-Au structure. The distances between the Au-C1 and Au-C2 bonds in the optimized precursor A-Au were 2.31 Å and 2.29 Å, respectively. Using the energy of Au(I) and pyridylhopropargyl alcohol under the optimized model as a reference zero point, 15.6 kcal / mol of energy was released during the generation of precursor A-Au.

[0154] (b) Constructing the transition state TS1-Au formed by C1-O bonds

[0155] Transition state modeling: Using a flexible scanning method, the structural changes that may result from changes in key chemical bonds are analyzed, and the energy of each step of the structure is calculated to obtain the potential energy curve of the key chemical bond change process. The structure corresponding to the highest energy point on the potential energy curve is used as the initial transition state structure to complete the preliminary modeling.

[0156] The structural bond length of the optimized precursor A-Au was adjusted, and the distance of the C2-O bond was adjusted to 1.86 Å. The adjusted transition state model was then optimized and its frequency calculated, yielding a transition state structure with exactly one imaginary frequency. Analysis showed that the vibrational direction of this imaginary frequency conformed to the formation of the C2-O bond, proving that the correct transition state was found. Using the energies of Au(I) and pyridylhopropargyl alcohol under the optimized model as the reference zero point, the formation of the C2-O bond requires overcoming a free energy barrier of 15.6 kcal / mol.

[0157] (c) Visual analysis of TS1-Au

[0158] Prepare a TS1-Au input file (e.g., .fchk or .wfn) containing wavefunction information. Using software that supports IGMH analysis (e.g., Multiwfn), select the IGMH analysis function and set the parameters. Next, run the VMD analysis to obtain the IGMH analysis results. The blue area represents strong attractive interactions, and the green area represents weak attractive interactions.

[0159] ②When Cu(II) is the catalyst

[0160] (a) Construction of a precursor with Cu(II) coordinated to the carbon-carbon triple bond of pyridylhopropynol

[0161] Precursor modeling: The carbon-carbon triple bond of Cu(II) was coordinated with the pyridylhomoylated alcohol 1a in the optimized model. The key bond lengths were adjusted, and the distances between Cu-C1 and Cu-C2 bonds were set to 2.14 Å and 2.25 Å, respectively, while other settings remained unchanged. Structural optimization was performed to obtain the optimized precursor A-Cu structure. The distances between Cu-C1 and Cu-C2 bonds in the optimized precursor A-Cu were 2.13 Å and 2.31 Å, respectively. Using the energy of Cu(II) and pyridylhomoylated alcohol in the optimized model as the reference zero point, 4.1 kcal / mol of energy was released when the precursor A-Cu was generated.

[0162] (b) Constructing the transition state TS1-Cu formed by C2-O bonds

[0163] Transition state modeling: Using a flexible scanning method, the structural changes that may result from changes in key chemical bonds are analyzed, and the energy of each step of the structure is calculated to obtain the potential energy curve of the key chemical bond change process. The structure corresponding to the highest energy point on the potential energy curve is used as the initial transition state structure to complete the preliminary modeling.

[0164] The bond lengths of the optimized precursor A-Cu were adjusted, and the distance of the C2-O bond was adjusted to 1.86 Å. The adjusted transition state model was then optimized and its frequency calculated, yielding a transition state structure with exactly one imaginary frequency. Analysis showed that the vibrational direction of this imaginary frequency conformed to the formation of the C2-O bond, proving that the correct transition state was found. Using the energies of Cu(II) and pyridylhopropynol under the optimized model as the reference zero point, the formation of the C2-O bond requires overcoming a free energy barrier of 14.7 kcal / mol.

[0165] (c) Visual analysis of TS1-Cu

[0166] Prepare a TS1-Cu input file (e.g., .fchk or .wfn) containing wavefunction information. Using software that supports IGMH analysis (e.g., Multiwfn), select the IGMH analysis function and set the parameters. Next, run the VMD analysis to obtain the IGMH analysis results. The blue area represents strong attractive interactions, and the green area represents weak attractive interactions.

[0167] From the perspective of thermodynamics and molecular structure, Au(I) has a significantly better activation ability for the carbon-carbon triple bond in pyridylpropargyl alcohol than Cu(II), and IGMH analysis of TS1-Au and TS1-Cu can further confirm this. Therefore, Au(I) is identified as a highly efficient catalyst for the formation of 2,3-dihydrofuran from pyridylpropargyl alcohol.

[0168] (2) Determine the catalyst for the formation of polycyclic dihydrobenzofuran from propargyl alcohol.

[0169] ①When Au(I) is the catalyst

[0170] (a) Construction of a precursor for Au(I) coordinated with the carbon-carbon triple bond of propargyl alcohol

[0171] Precursor modeling: Au(I) was coordinated with the carbon-carbon triple bond of propargyl alcohol 2a under the optimized model. The key bond lengths were adjusted, and the bond lengths of Au-C3 and Au-C4 were set to 2.19 Å and 1.82 Å, respectively, while other settings remained unchanged. Structural optimization was performed to obtain the optimized precursor D-Au structure. The distances of the Au-C3 and Au-C4 bonds in the optimized precursor D-Au were 2.42 Å and 2.25 Å, respectively. Using the energy of Au(I) and propargyl alcohol under the optimized model as the reference zero point, 17.4 kcal / mol of energy was released when the precursor D-Au was generated.

[0172] (b) Constructing the transition state TS2-Au formed by C1-C3 bonds

[0173] Transition state modeling: Using a flexible scanning method, the structural changes that may result from changes in key chemical bonds are analyzed, and the energy of each step of the structure is calculated to obtain the potential energy curve of the key chemical bond change process. The structure corresponding to the highest energy point on the potential energy curve is used as the initial transition state structure to complete the preliminary modeling.

[0174] The C1 atom of the generated dihydrofuran intermediate C was coordinated with the C3 atom of the precursor D-Au under the optimized model. The key bond length was adjusted, and the distance between the C1 and C3 bonds was adjusted to 2.30 Å. The adjusted transition state model was subjected to transition state geometry optimization and frequency calculation, resulting in a transition state structure with one and only one imaginary frequency. The vibrational direction of this imaginary frequency was analyzed to be consistent with the formation of the C1-C3 bond, proving that the transition state was correctly identified. Using the energies of Au(I) and propargyl alcohol under the optimized model as the reference zero point, the formation of the C1-C3 bond requires overcoming a free energy barrier of 15.1 kcal / mol.

[0175] (c) Constructing the intermediate E'-Au formed by C1-C3 bonds

[0176] Intermediate modeling: Based on the optimized transition state TS2-Au structure, the key bond lengths were adjusted, and the distance between C1-C3 bonds was adjusted to 1.55 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate E'-Au. After optimization, the distance between C1-C3 bonds in intermediate E'-Au was 1.54 Å. Using the energies of Au(I) and propargyl alcohol under the optimized model as the reference zero point, 4.0 kcal / mol of energy was released when intermediate E'-Au was generated.

[0177] (d) Constructing the intermediate F'-Au after H2O departure

[0178] Based on the optimized intermediate E'-Au structure, the H atom on C1 and the H2O part generated by the OH group on C5 were removed, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate F'-Au. Using the energies of Au(I) and propargyl alcohol under the optimized model as the reference zero point, 22.7 kcal / mol of energy was released when intermediate F'-Au was generated.

[0179] (e) Constructing the transition state TS3-Au formed by C4-C6 bonds

[0180] The bond lengths of the optimized intermediate F'-Au were adjusted, and the distance between the C4 and C6 bonds was set to 1.90 Å. The adjusted transition state model was then optimized and its frequencies calculated, yielding a transition state structure with exactly one imaginary frequency. Analysis showed that the vibrational direction of this imaginary frequency conformed to the formation of the C4-C6 bond, proving that the correct transition state was found. Using the energies of Au(I) and propargyl alcohol under the optimized model as the reference zero point, the formation of the C4-C6 bond requires overcoming a free energy barrier of 23.6 kcal / mol.

[0181] (f) Constructing the intermediate G'-Au with C4-C6 bond cyclization

[0182] Based on the optimized transition state TS3-Au structure, the key bond lengths were adjusted, and the distance between C4-C6 bonds was adjusted to 1.63 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate G'-Au. The distance between the C4-C6 bonds in the optimized intermediate G'-Au was 1.60 Å. Using the energies of Au(I) and propargyl alcohol under the optimized model as the reference zero point, 20.4 kcal / mol of energy was absorbed when generating the intermediate G'-Au.

[0183] (g) Constructing the transition state TS4-Au formed by C5-C7 bonds

[0184] The bond lengths of the optimized intermediate G'-Au were adjusted, and the distance between the C5 and C7 bonds was set to 2.00 Å. The adjusted transition state model was then optimized and its frequencies calculated, yielding a transition state structure with exactly one imaginary frequency. Analysis showed that the vibrational direction of this imaginary frequency conformed to the formation of the C5-C7 bond, proving that the correct transition state was found. Using the energies of Au(I) and propargyl alcohol under the optimized model as the reference zero point, the formation of the C5-C7 bond requires overcoming a free energy barrier of 31.8 kcal / mol.

[0185] (h) Constructing the intermediate H'-Au with C5-C7 bond cyclization

[0186] Based on the optimized transition state TS4-Au structure, the key bond lengths were adjusted, and the distance between C5-C7 bonds was adjusted to 1.56 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate H'-Au. The distance between the C5-C7 bonds in the optimized intermediate H'-Au was 1.56 Å. Using the energies of Au(I) and propargyl alcohol under the optimized model as the reference zero point, 16.5 kcal / mol of energy was absorbed when generating the intermediate H'-Au.

[0187] (i) Visual analysis of TS4-Au

[0188] Prepare a TS4-Au input file (e.g., .fchk or .wfn) containing wavefunction information. Using software that supports IGMH analysis (e.g., Multiwfn), select the IGMH analysis function and set the parameters. Then, run the VMD analysis to obtain the IGMH analysis results.

[0189] ②When Cu(II) is the catalyst

[0190] (a) Construction of a precursor for Cu(II) coordinated with the carbon-carbon triple bond of propargyl alcohol

[0191] Precursor modeling: The carbon-carbon triple bond of Cu(II) was coordinated with propargyl 2a in the optimized model. The key bond lengths were adjusted, and the Cu-C3 and Cu-C4 bond lengths were set to 2.38 Å and 2.17 Å, respectively, while other settings remained unchanged. Structural optimization was performed to obtain the optimized precursor D-Au structure. The distances between the Cu-C3 and Cu-C4 bonds in the optimized precursor D-Cu were 2.37 Å and 2.17 Å, respectively. Using the energy of Cu(II) and propargyl 2a in the optimized model as the reference zero point, 8.2 kcal / mol of energy was released when the precursor D-Cu was generated.

[0192] (b) Constructing the transition state TS2-Cu formed by C1-C3 bonds

[0193] Transition state modeling: Using a flexible scanning method, the structural changes that may result from changes in key chemical bonds are analyzed, and the energy of each step of the structure is calculated to obtain the potential energy curve of the key chemical bond change process. The structure corresponding to the highest energy point on the potential energy curve is used as the initial transition state structure to complete the preliminary modeling.

[0194] The C1 atom of the generated dihydrofuran intermediate C was coordinated with the C3 atom of the precursor D-Cu under the optimized model. The key bond length was adjusted, and the distance of the C1-C3 bond was adjusted to 2.30 Å. The adjusted transition state model was subjected to transition state geometry optimization and frequency calculation, and a transition state structure with one and only one imaginary frequency was obtained. The vibration direction of this imaginary frequency was analyzed to be consistent with the formation of the C1-C3 bond, proving that the transition state was correctly found. With the energy of Cu(II) and propargyl alcohol under the optimized model as the reference zero point, the formation of the C1-C3 bond requires overcoming a free energy barrier of 10.8 kcal / mol.

[0195] (c) Constructing the intermediate E'-Cu formed by C1-C3 bonds

[0196] Intermediate modeling: Based on the optimized transition state TS2-Cu structure, the key bond lengths were adjusted, and the distance between C1-C3 bonds was adjusted to 1.54 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate E'-Cu. The distance between C1-C3 bonds in the optimized intermediate E'-Cu was 1.54 Å. Using the energies of Cu(II) and propargyl alcohol under the optimized model as the reference zero point, 9.5 kcal / mol of energy was released when the intermediate E'-Cu was generated.

[0197] (d) Construction of the intermediate F'-Cu after H2O departure

[0198] Based on the optimized intermediate E'-Cu structure, the H atom on C1 and the H2O part generated by the OH group on C5 were removed, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate F'-Cu. Using the energy of Cu(II) and propargyl alcohol under the optimized model as the reference zero point, 23.0 kcal / mol of energy was released when intermediate F'-Cu was generated.

[0199] (e) Constructing the transition state TS3-Cu with C4-C6 bonds

[0200] The bond lengths of the optimized intermediate F'-Cu were adjusted, and the distance between the C4 and C6 bonds was set to 2.00 Å. The adjusted transition state model was then optimized and its frequencies calculated, yielding a transition state structure with exactly one imaginary frequency. Analysis showed that the vibrational direction of this imaginary frequency conformed to the formation of the C4-C6 bond, proving that the correct transition state was found. Using the energies of Cu(II) and propargyl alcohol under the optimized model as the reference zero point, the formation of the C4-C6 bond requires overcoming a free energy barrier of 25.2 kcal / mol.

[0201] (f) Construction of the intermediate G'-Cu with C4-C6 bond cyclization

[0202] Based on the optimized transition state TS3-Cu structure, the key bond lengths were adjusted, and the distance between C4-C6 bonds was adjusted to 1.60 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate G'-Cu. The distance between C4-C6 bonds in the optimized intermediate G'-Cu was 1.63 Å. Using the energies of Cu(II) and propargyl alcohol under the optimized model as the reference zero point, 15.2 kcal / mol of energy was absorbed when generating the intermediate G'-Cu.

[0203] (g) Constructing the transition state TS4-Cu formed by C5-C7 bonds

[0204] The bond lengths of the optimized intermediate G'-Cu were adjusted, and the distance between the C5 and C7 bonds was set to 2.00 Å. The adjusted transition state model was then optimized and its frequencies calculated, yielding a transition state structure with exactly one imaginary frequency. Analysis showed that the vibrational direction of this imaginary frequency conformed to the formation of the C5-C7 bond, proving that the correct transition state was found. Using the energies of Cu(II) and propargyl alcohol in the optimized model as the reference zero point, the formation of the C5-C7 bond requires overcoming a free energy barrier of 20.9 kcal / mol.

[0205] (h) Constructing the intermediate H'-Cu with C5-C7 bond cyclization

[0206] Based on the optimized transition state TS4-Cu structure, the key bond lengths were adjusted, and the distance between C5-C7 bonds was adjusted to 1.54 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate G'-Cu. The distance between C4-C6 bonds in the optimized intermediate G'-Cu was 1.55 Å. Using the energies of Cu(II) and propargyl alcohol under the optimized model as the reference zero point, 5.0 kcal / mol of energy was absorbed when generating the intermediate H'-Cu.

[0207] (i) Visual analysis of TS4-Cu

[0208] Prepare a TS4-Cu input file (e.g., .fchk or .wfn) containing wavefunction information. Using software that supports IGMH analysis (e.g., Multiwfn), select the IGMH analysis function and set the parameters. Then, run the VMD analysis to obtain the IGMH analysis results. The blue areas represent strong attractive interactions, and the green areas represent weak attractive interactions.

[0209] Based on thermodynamic and molecular structure analysis, the Au(I) catalytic pathway exhibits a lower potential energy surface than the Cu(II) catalytic pathway in the D→G' conversion. However, in the Friedel-Crafts cyclization reaction following the formation of intermediate G', energy barrier analysis shows that Au(I) catalysis requires overcoming an energy barrier of 31.8 kcal / mol, while Cu(II) catalysis only requires overcoming a barrier of 20.9 kcal / mol. This indicates that Cu(II) catalysis is more favorable for Friedel-Crafts cyclization, a finding corroborated by IGMH analysis results of TS4-Au and TS4-Cu. Therefore, this invention proposes a more accurate catalytic cycling mechanism for the formation of polycyclic dihydrobenzofurans, namely, in the D→G' conversion, the Au(I) catalyst initially dominates the catalytic activity, exhibiting a stronger interaction with the carbon-carbon triple bond in the substrate propargyl 2a, thus efficiently activating the substrate. After intermediate G' is formed, the Au(I) catalyst dissociates from the reaction system, at which point the Cu(II) catalyst takes over and efficiently catalyzes the crucial Friedel-Crafts cyclization reaction with a lower energy barrier. This synergistic effect fully utilizes the unique advantages of both Au(I) and Cu(II) catalysts, achieving high efficiency for the entire reaction.

[0210] III. Designing Reaction Pathways

[0211] (1) Design of the reaction pathway for Au(I) to generate 2,3-dihydrofuran

[0212] (a) Construction of a precursor with Au(I) coordinated to the carbon-carbon triple bond of pyridylhopropynol

[0213] Precursor modeling: Au(I) was coordinated with the carbon-carbon triple bond of pyridylhopropynol 1a in the optimized model. The key bond lengths were adjusted, and the bond lengths of Au-C1 and Au-C2 were set to 1.80 Å and 1.93 Å, respectively. Other settings remained unchanged, and the structure was optimized to obtain the structure of the optimized precursor A-Au. The distances between the Au-C1 and Au-C2 bonds in the optimized precursor A-Au were 2.31 Å and 2.29 Å, respectively.

[0214] (b) Constructing the transition state TS1-Au formed by C2-O bonds

[0215] Transition state modeling: Using a flexible scanning method, the structural changes that may result from changes in key chemical bonds are analyzed, and the energy of each step of the structure is calculated to obtain the potential energy curve of the key chemical bond change process. The structure corresponding to the highest energy point on the potential energy curve is used as the initial transition state structure to complete the preliminary modeling.

[0216] The structural bond length of the A-Au precursor was adjusted and optimized, and the distance of the C2-O bond was adjusted to 1.86 Å. The adjusted transition state model was then optimized and the frequency was calculated to obtain a transition state structure with one and only one imaginary frequency. Furthermore, the vibration direction of this imaginary frequency was analyzed to be consistent with the formation of the C2-O bond, proving that the transition state was correctly identified.

[0217] (c) Constructing the intermediate B-Au formed by C2-O bonds

[0218] Intermediate modeling: Based on the optimized transition state TS1-Au structure, the key bond lengths are adjusted, and the distance between C2-O bonds is adjusted to 1.53 Å, while other settings remain unchanged. The adjusted structure is then optimized to obtain the structure of the corresponding intermediate B-Au. The C2-O bond length of the optimized intermediate B-Au is 1.52 Å.

[0219] (d) Construction of the Au(I)-depleted product 2,3-dihydrofuran C

[0220] Based on the optimized intermediate B-Au structure, the Au(I) catalyst was removed, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate product C.

[0221] (2) Reaction pathway design for the co-catalytic formation of polycyclic dihydrobenzofuran by Au(I) and Cu(II)

[0222] (a) Construction of a precursor for Au(I) coordinated with the carbon-carbon triple bond of propargyl alcohol

[0223] Precursor modeling: Au(I) was coordinated with the carbon-carbon triple bond of propargyl alcohol 2a in the optimized model. The key bond lengths were adjusted, and the bond lengths of Au-C3 and Au-C4 were set to 2.19 Å and 1.82 Å, respectively. Other settings remained unchanged, and the structure was optimized to obtain the structure of the optimized precursor D-Au. The distances between the Au-C3 and Au-C4 bonds in the optimized precursor D-Au were 2.25 Å and 2.19 Å, respectively.

[0224] (b) Constructing the transition state TS2-Au formed by C1-C3 bonds

[0225] Transition state modeling: Using a flexible scanning method, the structural changes that may result from changes in key chemical bonds are analyzed, and the energy of each step of the structure is calculated to obtain the potential energy curve of the key chemical bond change process. The structure corresponding to the highest energy point on the potential energy curve is used as the initial transition state structure to complete the preliminary modeling.

[0226] The C1 atom of the generated dihydrofuran intermediate C was coordinated with the C3 atom of the intermediate D-Au under the optimized model. The key bond length was adjusted, and the distance between the C1 and C3 bonds was adjusted to 2.30 Å. The adjusted transition state model was subjected to transition state geometry optimization and frequency calculation, resulting in a transition state structure with one and only one imaginary frequency. The vibration direction of this imaginary frequency is consistent with the formation of the C1-C3 bond, proving that the transition state was correctly found.

[0227] (c) Constructing the intermediate E'-Au formed by C1-C3 bonds

[0228] Intermediate modeling: Based on the optimized transition state TS2-Au structure, the key bond lengths are adjusted, and the distance between C1-C3 bonds is adjusted to 1.55 Å, while other settings remain unchanged. The adjusted structure is then geometrically optimized to obtain the structure of the corresponding intermediate E'-Au. After optimization, the distance between C1-C3 bonds in intermediate E'-Au is 1.54 Å.

[0229] (d) Constructing the intermediate F'-Au after H2O departure

[0230] Based on the optimized intermediate E'-Au structure, the H atom on C1 atom and the H2O part generated by the OH group on C5 atom are removed, while other settings remain unchanged. The adjusted structure is then geometrically optimized to obtain the structure of the corresponding intermediate F'-Au.

[0231] (e) Constructing the transition state TS3-Au formed by C4-C6 bonds

[0232] The structural bond lengths of the optimized intermediate F'-Cu were adjusted, and the distance between the C4-C6 bonds was adjusted to 1.90 Å. The adjusted transition state model was then optimized and its frequency was calculated to obtain a transition state structure with only one imaginary frequency. Furthermore, the vibration direction of this imaginary frequency was analyzed to be consistent with the formation of the C4-C6 bonds, proving that the transition state was correctly identified.

[0233] (f) Constructing the intermediate G'-Au with C4-C6 bond cyclization

[0234] Based on the optimized transition state TS3-Au structure, the key bond lengths were adjusted, and the distance between C4-C6 bonds was adjusted to 1.63 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate G'-Au. The distance between C4-C6 bonds in the optimized intermediate G'-Au was 1.60 Å.

[0235] (g) Construction of the Cu(II) relay-catalyzed intermediate G''-Cu

[0236] Based on the optimized intermediate G'-Au structure, Au(I) catalyst at the C4 position was removed by hydrogen proton demetallization, and Cu(II) catalyst was coordinated at the C3 position. The C3-Cu bond distance was adjusted to 2.27 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate G''-Cu. The C3-Cu bond distance of the optimized intermediate G''-Cu was 2.10 Å.

[0237] (h) Constructing the transition state TS formed by C5-C7 bonds 4' -Cu

[0238] Transition state modeling: Adjust the bond length of the optimized precursor G''-Cu structure and adjust the distance of C5-C7 bonds to 2.05 Å. Perform transition state optimization and frequency calculation on the adjusted transition state model to obtain a transition state structure with one and only one imaginary frequency. The analysis shows that the vibration direction of this imaginary frequency is consistent with the formation of C5-C7 bonds, proving that the transition state was found correctly.

[0239] (i) Constructing the intermediate H''-Cu with C5-C7 bonded rings

[0240] In the optimized transition state TS 4' Based on the -Cu structure, the key bond lengths were adjusted, and the distance between C5-C7 bonds was adjusted to 1.57 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate H''-Cu. After optimization, the distance between C5-C7 bonds in the intermediate H''-Cu was 1.57 Å.

[0241] (j) Constructing the H2 departure transition state TS5-Cu

[0242] Transition state modeling: Adjust the structural bond length of the optimized precursor H''-Cu, and adjust the distance between CH and HH bonds to 1.50 Å and 1.15 Å, respectively. Perform transition state optimization and frequency calculation on the adjusted transition state model to obtain a transition state structure with one and only one imaginary frequency. Furthermore, the analysis shows that the vibration direction of this imaginary frequency conforms to the formation of CH and HH bonds, proving that the transition state was correctly found.

[0243] (k) Construct the product 3a after H2 removal.

[0244] Based on the optimized transition state TS5-Cu structure, the catalyst Cu(II) was removed. With other settings unchanged, the adjusted structure was geometrically optimized to obtain the structure of the corresponding product 3a.

[0245] IV. Analysis of reaction mechanism and pathway

[0246] Figure 1The graphs and Gibbs free energy curves for the synthesis of 2,3-dihydrofuran from pyridylhopropynol using Au(I) / Cu(II) catalysts at the M06 theoretical level are shown (the black curve represents the Au(I) catalytic synthesis route, and the red curve represents the Cu(II) catalytic synthesis route. The numbers represent the relative Gibbs free energy ΔG, in kcal / mol; "Catalysis" indicates catalysis).

[0247] Figure 2 Independent gradient models for the three-dimensional structures of intermediates A-Au and A-Cu in the formation of 2,3-dihydrofuran from pyridylpropargyl alcohol by Au(I) / Cu(II) catalyst and IMH analysis (blue represents strong attraction interaction region, green represents weak attraction interaction region); "Stronger attraction" indicates strong attraction, "Weaker attraction" indicates weak attraction.

[0248] Figure 3 This is a Gibbs free energy curve for the reaction of propargyl alcohol and 2,3-dihydrofuran catalyzed by Au(I) / Cu(II) catalysts at the M06 theoretical level (the black curve represents the Au(I) catalytic synthesis route, and the red curve represents the Cu(II) catalytic synthesis route. The numbers represent the relative Gibbs free energy ΔG, in kcal / mol).

[0249] Figure 4 The three-dimensional structures of the transition states TS4-Au and TS4-Cu in the formation of polycyclic dihydrobenzofuran from propargyl alcohol by Au(I) / Cu(II) catalyst and the independent gradient model of IMH analysis (blue represents the region of strong attraction interaction and green represents the region of weak attraction interaction).

[0250] Figure 5 This is a Gibbs free energy curve for the synergistic catalytic reaction of propargyl alcohol and 2,3-dihydrofuran to produce polycyclic dihydrobenzofuran under the M06 theoretical level, using Au(I) / Cu(II) catalysts (the red curve represents the Au(I) catalytic synthesis pathway, and the green curve represents the Cu(II) relay catalytic synthesis pathway. The numbers represent the relative Gibbs free energy ΔG, in kcal / mol).

[0251] When plotting the Gibbs free energy curves for each reaction pathway, as shown in Tables 1, 2, 3, 4, and 5, the sum of the energies of catalysts Au(I) and Cu(II) with pyridylpropargyl alcohol was selected as the reference zero point in the pathway for the formation of 2,3-dihydrofuran. In the pathway for the formation of polycyclic dihydrobenzofuran, the sum of the energies of catalysts Au(I) and Cu(II) with propargyl alcohol was selected as the reference zero point. All energy values ​​on the Gibbs free energy curves are based on these references, and the energies used in the discussion are relative Gibbs free energies.

[0252]

[0253]

[0254]

[0255]

[0256]

[0257] The specific analysis is as follows:

[0258] like Figure 1 As shown, the gold (I)-catalyzed formation of 2,3-dihydrofuran C begins with coordination with pyridylhopropargyl 1a, releasing 15.6 kcal / mol of free energy to form intermediate A-Au. This is followed by a 5-endo-dig cyclization reaction, overcoming the 15.6 kcal / mol energy barrier to generate intermediate B-Au, which is then protonally demetallized to yield 2,3-dihydrofuran C. The entire process releases a net 19.3 kcal / mol of free energy. In contrast, the Cu (II)-catalyzed formation of 2,3-dihydrofuran C releases only 4.1 kcal / mol of free energy in the initial coordination step with pyridylhopropargyl 1a, forming intermediate A-Cu. This is followed by a 5-endo-dig cyclization reaction overcoming the 14.7 kcal / mol energy barrier to generate intermediate B-Cu, which is also protonally demetallized to yield 2,3-dihydrofuran C. Calculations show that Au(I) is more efficient in catalyzing the reaction of pyridylhomopropanol 1a to 2,3-dihydrofuran C. The strong initial coordination between Au(I) and pyridylhomopropanol 1a provides a more favorable thermodynamic starting point for subsequent steps, thus promoting the overall high efficiency of the reaction.

[0259] like Figure 2 As shown, to investigate the difference in the catalytic activity of Au(I) and Cu(II) in the formation of 2,3-dihydrofuran C from the substrate pyridylhomoylated alcohol 1a, we performed IGMH analysis on intermediates A-Au and A-Cu. The blue and green regions represent strong and weak attraction interactions, respectively. In contrast, the blue regions representing strong attraction between Au(I) and pyridylhomoylated alcohol 1a are significantly more numerous than those representing Cu(II). The IGMH analysis results are consistent with the previously calculated energy change trend, further revealing the underlying reason why Au(I) is more active in catalyzing the formation of 2,3-dihydrofuran C from pyridylhomoylated alcohol 1a.

[0260] like Figure 3The diagram illustrates the difference in the roles of Au(I) and Cu(II) in the conversion of propargyl alcohol 2a to the polycyclic compound H′. Computational data show that Au(I) exhibits superior catalytic efficiency in the initial conversion from 2a to G′: its initial coordination release with substrate 2a is 17.4 kcal / mol, significantly higher than the 8.2 kcal / mol of the Cu(II) catalytic system. Although the energy barrier of Cu(II) in the C1-C3 bond formation step is slightly lower (ΔG(TS2-Cu)-ΔG(D-Cu) = 10.8 kcal / mol; ΔG(TS2-Au)-ΔG(D-Au) = 15.1 kcal / mol), the energy span of the multi-step reaction in the Au(I) catalytic pathway is lower (ΔG… Au =ΔG (F'-Au)-ΔG (TS2-Au) = 41.8 kcal / mol; ΔG Cu =ΔG(F'-Cu)-ΔG(TS2-Cu) = 43.3 kcal / mol), indicating that Au(I) has a stronger overall thermodynamic driving force in continuous reactions involving multiple intermediates and transition states. However, in the subsequent Friedel-Crafts cyclization step, Cu(II) exhibits a significant advantage. The activation barrier for Cu(II)-catalyzed Friedel-Crafts cyclization is only 20.9 kcal / mol, far lower than the 31.8 kcal / mol catalyzed by Au(I). This indicates that Cu(II) has higher catalytic activity in the Friedel-Crafts cyclization reaction. In summary, Au(I) is more advantageous in driving the pathway from 2a to G′, while Cu(II) performs better in the Friedel-Crafts cyclization reaction. This difference provides a key basis for understanding the Au(I) / Cu(II) bimetallic synergistic catalytic mechanism.

[0261] like Figure 4 To understand the energy barrier differences between Au(I) and Cu(II) catalysts in promoting the Friedel-Crafts cyclization reaction, we performed IGMH analysis on the transition states TS4-Au and TS4-Cu. In TS4-Cu, a significant mutual attraction was observed between the OTfˉ ligand and the hydrogen atoms on the benzene ring. This mutual attraction helps stabilize the transition state structure, which is consistent with the lower Gibbs free energy of TS4-Cu, further demonstrating that Cu(II) catalysis performs better in the Friedel-Crafts cyclization reaction.

[0262] like Figure 5As shown, the reaction begins with the coordination of Au(I) with the carbon-carbon triple bond in the substrate propargyl alcohol 2a to form the stable intermediate D-Au, releasing a free energy of 17.4 kcal / mol. Subsequently, intermediate C, generated from the previous step, reacts with D-Au, overcoming an energy barrier of 15.1 kcal / mol to form a new C-C bond, yielding intermediate E'-Au. Next, E'-Au undergoes dehydration, releasing a free energy of 22.7 kcal / mol to generate intermediate F'-Au. Under Au(I) catalysis, F'-Au undergoes a crucial cyclization reaction, overcoming an energy barrier of 23.6 kcal / mol to generate intermediate G'-Au. This step fully demonstrates the key role of Au(I) in promoting the reaction process. Subsequently, the Au(I) catalyst dissociates from the system through proton demetallization, marking the transition of the catalytic relay to Cu(II). Subsequently, Cu(II) enters the catalytic cycle, driving the key Friedel-Crafts cyclization reaction, overcoming the energy barrier of 21.6 kcal / mol, and forming the intermediate H''-Cu. Finally, under the action of Cu(II), H''-Cu undergoes a dehydrogenation process, accompanied by the release of H2, efficiently generating the target product 3a. The entire catalytic process demonstrates a dual-catalytic relay mechanism of Au(I) and Cu(II): Au(I) efficiently activates the alkyne bond and drives the initial transformation (D-Au to G'-Au), while Cu(II), with its lower energy barrier, efficiently catalyzes the key Friedel-Crafts cyclization ring closure and product formation steps (G''-Cu to 3a). This multi-step catalytic mechanism reveals the synergistic effect between Au(I) and Cu(II): their synergistic effect not only significantly reduces the reaction energy barrier but also ensures the efficient formation of the final product.

[0263] The above description outlines the basic principles, main features, and advantages of this invention. Those skilled in the art should understand that the scope of protection of this invention is not limited to the above embodiments. Various changes and modifications can be made to this invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the invention as claimed.

Claims

1. An analytical method for the tandem cyclization reaction mechanism of pyridyl-modified propargyl alcohol and propargyl alcohol catalyzed by a bimetallic system, characterized in that, Specifically, the following steps are included: (1) Computational models were constructed for the Au(I) catalyst and Cu(II) catalyst with the substrates pyridyl-homyne propanol and propyne propanol, respectively; (2) Design reaction pathways under Au(I) catalyst and Cu(II) catalyst, and construct key intermediates and corresponding transition states; (3) Screening for true catalysts for the catalytic synthesis of 2,3-dihydrofuran and polycyclic dihydrobenzofuran; (4) Analyze the reaction mechanism and pathway under Au(I) catalyst and Cu(II) catalyst.

2. An analytical method for the tandem cyclization reaction mechanism of pyridyl-modified propargyl alcohol and propargyl alcohol catalyzed by a bimetallic system, characterized in that, The specific steps are as follows: I. Constructing a computational model Based on experimental conditions of the reaction of pyridylhopropynol with propynol catalyzed by Au(I) and Cu(II) catalysts, 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. II. Screening of Highly Efficient Catalysts (1) Determine the true catalyst for the cyclization of pyridyl propargyl alcohol to 2,3-dihydrofuran. ①When Au(I) is the catalyst (a) Construction of a precursor with Au(I) coordinated to the carbon-carbon triple bond of pyridylhopropynol Precursor modeling: Au(I) was coordinated with the carbon-carbon triple bond of pyridylhopropynol 1a under the optimized model. The key bond lengths were adjusted, and the bond lengths of Au-C1 and Au-C2 were set to 1.80 Å and 1.93 Å, respectively. Other settings remained unchanged, and the structure was optimized to obtain the structure of the optimized precursor A-Au. The distances of the Au-C1 and Au-C2 bonds in the optimized precursor A-Au were 2.31 Å and 2.29 Å, respectively. Taking the energy of Au(I) and pyridylhopropynol under the optimized model as the reference zero point, 15.6 kcal / mol of energy was released when the precursor A-Au was generated. (b) Constructing the transition state TS1-Au formed by C1-O bonds Transition state modeling: Using a flexible scanning method, the structural changes that may result from changes in key chemical bonds are analyzed, and the energy of each step of the structure is calculated to obtain the potential energy curve of the key chemical bond change process. The structure corresponding to the highest energy point on the potential energy curve is used as the initial transition state structure to complete the preliminary modeling. The structural bond length of the optimized precursor A-Au was adjusted, and the distance of the C2-O bond was adjusted to 1.86 Å. The adjusted transition state model was then optimized and its frequency was calculated. A transition state structure with only one imaginary frequency was obtained. The vibrational direction of this imaginary frequency was analyzed to be consistent with the formation of the C2-O bond, proving that the transition state was correctly found. Taking the energies of Au(I) and pyridylhopropynol under the optimized model as the reference zero point, the formation of the C2-O bond requires overcoming a free energy barrier of 15.6 kcal / mol. (c) Visual analysis of TS1-Au Prepare a TS1-Au input file containing wavefunction information. Use software that supports independent gradient model analysis based on Hirshfeld atomic space partitioning, select the IGMH analysis function and set the parameters. Then, run VMD analysis to obtain the IGMH analysis results. ②When Cu(II) is the catalyst (a) Construction of a precursor with Cu(II) coordinated to the carbon-carbon triple bond of pyridylhopropynol Precursor modeling: Cu(II) was coordinated with the carbon-carbon triple bond of pyridylhopropynol 1a under the optimized model. The key bond lengths were adjusted, and the distances of Cu-C1 and Cu-C2 bonds were set to 2.14 Å and 2.25 Å, respectively. Other settings remained unchanged, and the structure was optimized to obtain the structure of the optimized precursor A-Cu. The distances of Cu-C1 and Cu-C2 bonds in the optimized precursor A-Cu were 2.13 Å and 2.31 Å, respectively. With the energy of Cu(II) and pyridylhopropynol under the optimized model as the reference zero point, 4.1 kcal / mol of energy was released when the precursor A-Cu was generated. (b) Constructing the transition state TS1-Cu formed by C2-O bonds Transition state modeling: Using a flexible scanning method, the structural changes that may result from changes in key chemical bonds are analyzed, and the energy of each step of the structure is calculated to obtain the potential energy curve of the key chemical bond change process. The structure corresponding to the highest energy point on the potential energy curve is used as the initial transition state structure to complete the preliminary modeling. The structural bond length of the optimized precursor A-Cu was adjusted, and the distance of the C2-O bond was adjusted to 1.86 Å. The adjusted transition state model was then optimized and the frequency was calculated. A transition state structure with only one imaginary frequency was obtained. The vibration direction of the imaginary frequency was analyzed to be consistent with the formation of the C2-O bond, proving that the transition state was correctly found. With the energy of Cu(II) and pyridylhopropynol under the optimized model as the reference zero point, the formation of the C2-O bond requires overcoming a free energy barrier of 14.7 kcal / mol. (c) Visual analysis of TS1-Cu Prepare a TS1-Cu input file containing wavefunction information, use software that supports IGMH analysis, select the IGMH analysis function and set the parameters, and then run VMD analysis to obtain the IGMH analysis results; (2) Determine the catalyst for the formation of polycyclic dihydrobenzofuran from propargyl alcohol. ①When Au(I) is the catalyst (a) Construction of a precursor for Au(I) coordinated with the carbon-carbon triple bond of propargyl alcohol Precursor modeling: Au(I) was coordinated with the carbon-carbon triple bond of propargyl alcohol 2a under the optimized model. The key bond lengths were adjusted, and the bond lengths of Au-C3 and Au-C4 were set to 2.19 Å and 1.82 Å, respectively, while other settings remained unchanged. Structural optimization was performed to obtain the optimized structure of precursor D-Au. The distances of Au-C3 and Au-C4 bonds in the optimized precursor D-Au were 2.42 Å and 2.25 Å, respectively. Taking the energy of Au(I) and propargyl alcohol under the optimized model as the reference zero point, 17.4 kcal / mol of energy was released when the precursor D-Au was generated. (b) Constructing the transition state TS2-Au formed by C1-C3 bonds Transition state modeling: Using a flexible scanning method, the structural changes that may result from changes in key chemical bonds are analyzed, and the energy of each step of the structure is calculated to obtain the potential energy curve of the key chemical bond change process. The structure corresponding to the highest energy point on the potential energy curve is used as the initial transition state structure to complete the preliminary modeling. The C1 atom of the generated dihydrofuran intermediate C was coordinated with the C3 atom of the precursor D-Au under the optimized model. The key bond length was adjusted, and the distance between the C1 and C3 bonds was adjusted to 2.30 Å. The adjusted transition state model was subjected to transition state geometry optimization and frequency calculation, resulting in a transition state structure with one and only one imaginary frequency. The vibrational direction of this imaginary frequency was analyzed to be consistent with the formation of the C1-C3 bond, proving that the transition state was correctly identified. Using the energies of Au(I) and propargyl alcohol under the optimized model as the reference zero point, the formation of the C1-C3 bond requires overcoming a free energy barrier of 15.1 kcal / mol. (c) Constructing the intermediate E'-Au formed by C1-C3 bonds Intermediate modeling: Based on the optimized transition state TS2-Au structure, the key bond lengths were adjusted, and the distance between C1-C3 bonds was adjusted to 1.55 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate E'-Au. After optimization, the distance between C1-C3 bonds in intermediate E'-Au was 1.54 Å. Using the energies of Au(I) and propargyl alcohol under the optimized model as the reference zero point, 4.0 kcal / mol of energy was released when intermediate E'-Au was generated. (d) Constructing the intermediate F'-Au after H2O departure Based on the optimized intermediate E'-Au structure, the H atom on C1 atom and the H2O part generated by the OH group on C5 atom are removed, while other settings remain unchanged. The adjusted structure is then geometrically optimized to obtain the structure of the corresponding intermediate F'-Au. Using the energies of Au(I) and propargyl alcohol under the optimized model as the reference zero point, 22.7 kcal / mol of energy was released when the intermediate F'-Au was generated; (e) Constructing the transition state TS3-Au formed by C4-C6 bonds The structural bond lengths of the optimized intermediate F'-Au were adjusted, and the distance between the C4 and C6 bonds was adjusted to 1.90 Å. The adjusted transition state model was then optimized and its frequency was calculated, resulting in a transition state structure with exactly one imaginary frequency. Analysis showed that the vibrational direction of this imaginary frequency was consistent with the formation of the C4-C6 bond, proving that the transition state was correctly identified. Using the energies of Au(I) and propargyl alcohol under the optimized model as the reference zero point, the formation of the C4-C6 bond requires overcoming a free energy barrier of 23.6 kcal / mol. (f) Constructing the intermediate G'-Au with C4-C6 bond cyclization Based on the optimized transition state TS3-Au structure, the key bond lengths were adjusted, and the distance between C4-C6 bonds was adjusted to 1.63 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate G'-Au. The distance between the C4-C6 bonds in the optimized intermediate G'-Au was 1.60 Å. Using the energies of Au(I) and propargyl alcohol under the optimized model as the reference zero point, 20.4 kcal / mol of energy was absorbed when generating the intermediate G'-Au. (g) Constructing the transition state TS4-Au formed by C5-C7 bonds The structural bond lengths of the optimized intermediate G'-Au were adjusted, and the distance between the C5 and C7 bonds was adjusted to 2.00 Å. The adjusted transition state model was then optimized and its frequency was calculated, resulting in a transition state structure with exactly one imaginary frequency. Analysis showed that the vibrational direction of this imaginary frequency was consistent with the formation of the C5-C7 bond, proving that the transition state was correctly identified. Using the energies of Au(I) and propargyl alcohol under the optimized model as the reference zero point, the formation of the C5-C7 bond requires overcoming a free energy barrier of 31.8 kcal / mol. (h) Constructing the intermediate H'-Au with C5-C7 bond cyclization Based on the optimized transition state TS4-Au structure, the key bond lengths were adjusted, and the distance between C5-C7 bonds was adjusted to 1.56 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate H'-Au. The distance between the C5-C7 bonds in the optimized intermediate H'-Au was 1.56 Å. Using the energies of Au(I) and propargyl alcohol under the optimized model as the reference zero point, 16.5 kcal / mol of energy was absorbed when generating the intermediate H'-Au. (i) Visual analysis of TS4-Au Prepare a TS4-Au input file containing wavefunction information, use software that supports IGMH analysis, select the IGMH analysis function and set the parameters, and then run VMD analysis to obtain the IGMH analysis results; ②When Cu(II) is the catalyst (a) Construction of a precursor for Cu(II) coordinated with the carbon-carbon triple bond of propargyl alcohol Precursor modeling: Cu(II) was coordinated with the carbon-carbon triple bond of propargyl alcohol 2a under the optimized model. The key bond lengths were adjusted, and the bond lengths of Cu-C3 and Cu-C4 were set to 2.38 Å and 2.17 Å, respectively. Other settings remained unchanged, and the structure was optimized to obtain the structure of the optimized precursor D-Au. The distances of Cu-C3 and Cu-C4 bonds in the optimized precursor D-Cu were 2.37 Å and 2.17 Å, respectively. Taking the energy of Cu(II) and propargyl alcohol under the optimized model as the reference zero point, 8.2 kcal / mol of energy was released when the precursor D-Cu was generated. (b) Constructing the transition state TS2-Cu with C1-C3 bond formation Transition state modeling: Using a flexible scanning method, the structural changes that may result from changes in key chemical bonds are analyzed, and the energy of each step of the structure is calculated to obtain the potential energy curve of the key chemical bond change process. The structure corresponding to the highest energy point on the potential energy curve is used as the initial transition state structure to complete the preliminary modeling. The C1 atom of the generated dihydrofuran intermediate C was coordinated with the C3 atom of the precursor D-Cu under the optimized model. The key bond length was adjusted, and the distance of the C1-C3 bond was adjusted to 2.30 Å. The adjusted transition state model was subjected to transition state geometry optimization and frequency calculation, and a transition state structure with one and only one imaginary frequency was obtained. The vibration direction of this imaginary frequency was analyzed to be consistent with the formation of the C1-C3 bond, proving that the transition state was correctly found. With the energy of Cu(II) and propargyl alcohol under the optimized model as the reference zero point, the formation of the C1-C3 bond requires overcoming a free energy barrier of 10.8 kcal / mol. (c) Constructing the intermediate E'-Cu formed by C1-C3 bonds Intermediate modeling: Based on the optimized transition state TS2-Cu structure, the key bond lengths were adjusted, and the distance between C1-C3 bonds was adjusted to 1.54 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate E'-Cu. The distance between C1-C3 bonds in the optimized intermediate E'-Cu was 1.54 Å. Using the energies of Cu(II) and propargyl alcohol under the optimized model as the reference zero point, 9.5 kcal / mol of energy was released when the intermediate E'-Cu was generated. (d) Construction of the intermediate F'-Cu after H2O departure Based on the optimized intermediate E'-Cu structure, the H atom on C1 and the H2O part generated by the OH group on C5 were removed, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate F'-Cu. Using the energy of Cu(II) and propargyl alcohol under the optimized model as the reference zero point, 23.0 kcal / mol of energy was released when intermediate F'-Cu was generated. (e) Constructing the transition state TS3-Cu with C4-C6 bonds The bond lengths of the optimized intermediate F'-Cu were adjusted, and the distance between the C4 and C6 bonds was adjusted to 2.00 Å. The adjusted transition state model was then optimized and its frequency was calculated, resulting in a transition state structure with only one imaginary frequency. The vibrational direction of this imaginary frequency was analyzed to be consistent with the formation of the C4-C6 bond, proving that the transition state was correctly identified. Using the energies of Cu(II) and propargyl alcohol under the optimized model as the reference zero point, the formation of the C4-C6 bond requires overcoming a free energy barrier of 25.2 kcal / mol. (f) Construction of the intermediate G'-Cu with C4-C6 bond cyclization Based on the optimized transition state TS3-Cu structure, the key bond lengths were adjusted, and the distance between C4-C6 bonds was adjusted to 1.60 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate G'-Cu. The distance between C4-C6 bonds in the optimized intermediate G'-Cu was 1.63 Å. Using the energies of Cu(II) and propargyl alcohol under the optimized model as the reference zero point, 15.2 kcal / mol of energy was absorbed when generating the intermediate G'-Cu. (g) Constructing the transition state TS4-Cu formed by C5-C7 bonds The bond lengths of the optimized intermediate G'-Cu were adjusted, and the distance between the C5 and C7 bonds was adjusted to 2.00 Å. The adjusted transition state model was then optimized and its frequency was calculated, resulting in a transition state structure with only one imaginary frequency. Analysis showed that the vibrational direction of this imaginary frequency was consistent with the formation of the C5-C7 bond, proving that the transition state was correctly identified. Using the energies of Cu(II) and propargyl alcohol under the optimized model as the reference zero point, the formation of the C5-C7 bond requires overcoming a free energy barrier of 20.9 kcal / mol. (h) Constructing the intermediate H'-Cu with C5-C7 bond cyclization Based on the optimized transition state TS4-Cu structure, the key bond lengths were adjusted, and the distance between C5-C7 bonds was adjusted to 1.54 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate G'-Cu. The distance between C4-C6 bonds in the optimized intermediate G'-Cu was 1.55 Å. Using the energies of Cu(II) and propargyl alcohol under the optimized model as the reference zero point, 5.0 kcal / mol of energy was absorbed when generating the intermediate H'-Cu. (i) Visual analysis of TS4-Cu Prepare a TS4-Cu input file containing wavefunction information, use software that supports IGMH analysis, select the IGMH analysis function and set the parameters, and then run VMD analysis to obtain the IGMH analysis results; III. Designing Reaction Pathways (1) Design of the reaction pathway for Au(I) to generate 2,3-dihydrofuran (a) Construction of a precursor with Au(I) coordinated to the carbon-carbon triple bond of pyridylhopropynol Precursor modeling: Au(I) was coordinated with the carbon-carbon triple bond of pyridylhopropynol 1a in the optimized model. The key bond lengths were adjusted, and the bond lengths of Au-C1 and Au-C2 were set to 1.80 Å and 1.93 Å, respectively. Other settings remained unchanged, and the structure was optimized to obtain the structure of the optimized precursor A-Au. The distances between the Au-C1 and Au-C2 bonds in the optimized precursor A-Au were 2.31 Å and 2.29 Å, respectively. (b) Constructing the transition state TS1-Au formed by C2-O bonds Transition state modeling: Using a flexible scanning method, the structural changes that may result from changes in key chemical bonds are analyzed, and the energy of each step of the structure is calculated to obtain the potential energy curve of the key chemical bond change process. The structure corresponding to the highest energy point on the potential energy curve is used as the initial transition state structure to complete the preliminary modeling. The structural bond length of the A-Au precursor was adjusted and optimized, and the distance of the C2-O bond was adjusted to 1.86 Å. The adjusted transition state model was then optimized and the frequency was calculated to obtain a transition state structure with one and only one imaginary frequency. Furthermore, the vibration direction of this imaginary frequency was analyzed to be consistent with the formation of the C2-O bond, proving that the transition state was correctly identified. (c) Constructing the intermediate B-Au formed by C2-O bonds Intermediate modeling: Based on the optimized transition state TS1-Au structure, the key bond lengths are adjusted, and the distance between C2-O bonds is adjusted to 1.53 Å, while other settings remain unchanged. The adjusted structure is then optimized to obtain the structure of the corresponding intermediate B-Au. The C2-O bond length of the optimized intermediate B-Au is 1.52 Å. (d) Construction of the Au(I)-depleted product 2,3-dihydrofuran C Based on the optimized intermediate B-Au structure, the Au(I) catalyst was removed while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate product C. (2) Reaction pathway design for the co-catalytic formation of polycyclic dihydrobenzofuran by Au(I) and Cu(II) (a) Construction of a precursor for Au(I) coordinated with the carbon-carbon triple bond of propargyl alcohol Precursor modeling: Au(I) was coordinated with the carbon-carbon triple bond of propargyl alcohol 2a in the optimized model. The key bond lengths were adjusted, and the bond lengths of Au-C3 and Au-C4 were set to 2.19 Å and 1.82 Å, respectively. Other settings remained unchanged, and the structure was optimized to obtain the structure of the optimized precursor D-Au. The distances between the Au-C3 and Au-C4 bonds in the optimized precursor D-Au were 2.25 Å and 2.19 Å, respectively. (b) Constructing the transition state TS2-Au formed by C1-C3 bonds Transition state modeling: Using a flexible scanning method, the structural changes that may result from changes in key chemical bonds are analyzed, and the energy of each step of the structure is calculated to obtain the potential energy curve of the key chemical bond change process. The structure corresponding to the highest energy point on the potential energy curve is used as the initial transition state structure to complete the preliminary modeling. The C1 atom of the generated dihydrofuran intermediate C was coordinated with the C3 atom of the intermediate D-Au under the optimized model. The key bond length was adjusted, and the distance between the C1 and C3 bonds was adjusted to 2.30 Å. The adjusted transition state model was subjected to transition state geometry optimization and frequency calculation, resulting in a transition state structure with one and only one imaginary frequency. The vibration direction of this imaginary frequency is consistent with the formation of the C1-C3 bond, proving that the transition state was correctly found. (c) Constructing the intermediate E'-Au formed by C1-C3 bonds Intermediate modeling: Based on the optimized transition state TS2-Au structure, the key bond lengths are adjusted, and the distance between C1-C3 bonds is adjusted to 1.55 Å, while other settings remain unchanged. The adjusted structure is then geometrically optimized to obtain the structure of the corresponding intermediate E'-Au. After optimization, the distance between C1-C3 bonds in intermediate E'-Au is 1.54 Å. (d) Constructing the intermediate F'-Au after H2O departure Based on the optimized intermediate E'-Au structure, the H atom on C1 atom and the H2O part generated by the OH group on C5 atom are removed, while other settings remain unchanged. The adjusted structure is then geometrically optimized to obtain the structure of the corresponding intermediate F'-Au. (e) Constructing the transition state TS3-Au formed by C4-C6 bonds The structural bond lengths of the optimized intermediate F'-Cu were adjusted, and the distance between the C4-C6 bonds was adjusted to 1.90 Å. The adjusted transition state model was then optimized and its frequency was calculated to obtain a transition state structure with only one imaginary frequency. Furthermore, the vibration direction of this imaginary frequency was analyzed to be consistent with the formation of the C4-C6 bonds, proving that the transition state was correctly identified. (f) Constructing the intermediate G'-Au with C4-C6 bond cyclization Based on the optimized transition state TS3-Au structure, the key bond lengths were adjusted, and the distance between C4-C6 bonds was adjusted to 1.63 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate G'-Au. The distance between C4-C6 bonds in the optimized intermediate G'-Au was 1.60 Å. (g) Construction of the Cu(II) relay-catalyzed intermediate G''-Cu Based on the optimized intermediate G'-Au structure, Au(I) catalyst at the C4 position was removed by hydrogen proton demetallization, and Cu(II) catalyst was coordinated at the C3 position. The C3-Cu bond distance was adjusted to 2.27 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate G''-Cu. The C3-Cu bond distance of the optimized intermediate G''-Cu was 2.10 Å. (h) Constructing the transition state TS formed by C5-C7 bonds 4' -Cu Transition state modeling: Adjust the bond length of the optimized precursor G''-Cu structure and adjust the distance of C5-C7 bonds to 2.05 Å. Perform transition state optimization and frequency calculation on the adjusted transition state model to obtain a transition state structure with one and only one imaginary frequency. The analysis shows that the vibration direction of this imaginary frequency is consistent with the formation of C5-C7 bonds, proving that the transition state was found correctly. (i) Constructing the intermediate H''-Cu with C5-C7 bonded rings In the optimized transition state TS 4' Based on the -Cu structure, the key bond lengths were adjusted, and the distance between C5-C7 bonds was adjusted to 1.57 Å, while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding intermediate H''-Cu. After optimization, the distance between C5-C7 bonds in the intermediate H''-Cu was 1.57 Å. (j) Constructing the H2 departure transition state TS5-Cu Transition state modeling: Adjust the structural bond length of the optimized precursor H''-Cu, and adjust the distance between CH and HH bonds to 1.50 Å and 1.15 Å, respectively. Perform transition state optimization and frequency calculation on the adjusted transition state model to obtain a transition state structure with one and only one imaginary frequency. Furthermore, the analysis shows that the vibration direction of this imaginary frequency conforms to the formation of CH and HH bonds, proving that the transition state was correctly found. (k) Construct the product 3a after H2 removal. Based on the optimized transition state TS5-Cu structure, the catalyst Cu(II) was removed while other settings remained unchanged. The adjusted structure was then geometrically optimized to obtain the structure of the corresponding product 3a.

3. The analytical method according to claim 1 or 2, characterized in that, All calculations were performed using the Gaussian 16 program; the SMD-M06 / 6-31G(d,p) / SDD theoretical level was used to perform geometric optimization and calculate the frequencies of all intermediates and transition states.

4. The analytical method according to claim 2, characterized in that, Intermediate optimization input file: #M06 / 6-31G(d,p) / SDD opt freq scrf=(smd,solvent=1,4-dioxane).

5. The analytical method according to claim 2, characterized in that, Transition state optimization input file: #M06 / 6-31G(d,p) / SDD opt=(calcfc,ts,noeigentest,maxstep=3) freq scrf=(smd,solvent=1,4-dioxane).

6. The analytical method according to claim 2, characterized in that, All intermediates have no imaginary frequency, the transition state has one and only one imaginary frequency, and the Gibbs thermodynamic correction value is extracted from the output file *.log file after optimization.

7. The analytical method according to claim 2, characterized in that, To obtain more accurate energies, based on the optimized structure, the M06 / 6-311+G(d,p) / SDD theoretical level was used, and the SMD solvation model was employed to calculate the large basis set solvation single-point energies of the intermediate and transition states.

8. The analytical method according to claim 2, characterized in that, The input file for higher-level single-point energy calculation is as follows: #M06 / 6-311+G(d,p) / SDD scrf=(smd,solvent=1,4-dioxane).

9. The analytical method according to claim 8, characterized in that, The output file *.log of a single point was calculated using Gaussian16 software, and the single-point energy in the log file was read. The Gibbs free energy of each structure was obtained by adding the Gibbs thermal correction value to the single-point energy.

10. The analytical method according to claim 9, characterized in that, The transition state structures were all calculated using the intrinsic reaction coordinate method to ensure that they are connected to the corresponding reactants and products.

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