Atomic chemical potential calculation method and method for predicting reaction site by using atomic chemical potential

Abstract

The invention provides an atomic chemical potential calculation method and a method for predicting a reaction site by using atomic chemical potential, and relates to the technical field of data operation, and the method comprises the following steps: obtaining molecular orbital information in a molecule; determining frontline molecular orbits, HOMO and LUMO according to the molecular orbital information, and calculating contribution of atoms in each frontline molecular orbital according to the HOMO and the LUMO; calculating frontline occupied layer energy and frontline unoccupied layer energy of the atoms according to the contribution of the atoms in each frontline molecular orbit; and calculating the atomic chemical potential based on the energy of the frontline occupied layer and the energy of the frontline unoccupied layer of the atoms. According to the method, the description amount of atomic chemical potential is put forward for the first time and used for describing the activity of reaction sites of various reactions, the atomic chemical potential is directly used for predicting the reaction sites, the prediction process is rapid and efficient, and the molecular weight lt is guaranteed; 1000, calculating a time lt at the reaction site of the molecule; 1s.

Description

Technical Field

[0001] The present invention relates to the technical field of data calculation, and in particular to a method for calculating atomic chemical potential and a method for predicting reaction sites using atomic chemical potential. Background Art

[0002] Single-step reactions in organic chemistry are the basic components of organic synthesis routes. The reaction site of a single step can directly affect the chemist's judgment of the previous and subsequent multi-step reactions, or even the entire route. For example: in the synthesis of polysubstituted aromatic hydrocarbons, it is necessary to judge which groups are electrophilic and which are nucleophilic, which leads to the swapping of steps; in nucleophilic substitution, it is necessary to consider a variety of attacking sites such as amines, amides, and hydrazines, and protect and weaken possible competitive sites to avoid side reactions. Such problems are directly related to the success or failure of the experiment, so chemists usually spend a lot of energy on manual judgment + literature research to determine the best route design plan. Even for experienced chemists, it is difficult to consider all types of chemical reactions that may occur.

[0003] Reaction site activity refers to the possibility of chemical reactions occurring in the various parts (sub)structures (sites) of a molecule under given reaction conditions. What is meaningful here is the relative value, that is, the relative activity order of each site. Theoretically, the reaction activity depends on the energy of the reaction transition state. A reliable transition state energy calculation often involves the sampling of molecular structures by molecular dynamics (metadynamics) and the energy calculation of each structure. This type of operation usually requires manual intervention analysis and takes from a few hours to several months, which far exceeds the feedback time that chemical synthesizers in industrial scenarios can accept when analyzing reactivity (usually the design of a route takes tens of minutes, including the judgment of reaction sites for dozens of molecules).

[0004] Currently, the faster reaction site prediction methods include:

[0005] 1. Nuclear Magnetic Resonance 13 C spectrum chemical shift prediction value (hereinafter referred to as 13 C spectrum). The chemical shift is used to characterize the electrophilic properties of the molecule and then determine the most likely reaction site in the aromatic electrophilic substitution reaction (SEAr).

[0006] 2. Atomic partial charge. Using the atomic charge distribution calculated in a single calculation, the positive and negative charges of each reaction site are compared to represent the site activity order in the chemical reaction. Atomic charge calculation methods include Mulliken, Hirshfeld, atom-in-molecule (AIM), etc.

[0007] 3. Fukui function: The difference in atomic charge distribution of a molecule under +1 charge, neutral, and -1 charge conditions is used to characterize the site activity order in aromatic electrophilic substitution and aromatic nucleophilic substitution (SNAr).

[0008] 4. Electrophilic superdelocalisability and nucleophilic superdelocalisability: The electron and empty orbital densities weighted by molecular orbital energy are used to characterize the site activity order in electrophilic and nucleophilic substitution.

[0009] 5. Use the energy of protonation reaction intermediates to determine the activity order of aromatic electrophilic substitution sites.

[0010] 6. Machine learning, such as WLN using Reaxys data to learn to determine the activity order of aromatic electrophilic substitution sites.

[0011] The above existing technical solutions have problems with accuracy, scope of application or time cost.

[0012] Nuclear Magnetic Resonance 13 The prediction of chemical shifts in C spectra depends only on the surrounding chemical environment, so it is the fastest. However, its literature is limited to the discussion of aromatic electrophilic substitution reactions, which is only one of many types of reactions, resulting in a limited scope of application of this method. 13 The C spectrum has serious errors in some simple aromatic electrophilic substitution problems. For example, the electrophilic substitution site of nitrobenzene will give the wrong conclusion that ortho>meta>para (the correct answer is meta>para>ortho). For more complex condensed ring situations, 13 C spectrum often needs to be combined 1 The H spectrum comprehensive judgment and mixed judgment logic increase the uncertainty of site prediction.

[0013] The time cost of atomic charge, Fukui function, electrophilic / nucleophilic superdelocalization, and RegioSQM (20) is relatively high. Among them, the strict Fukui function requires multiple calculations, and the calculation of Fukui function with molecular orbital energy weight and electrophilic / nucleophilic superdelocalization requires the extraction of converged wave functions for analysis, which further increases the time cost. The process-optimized RegioSQM (20) also takes nearly 1 minute for small molecules. In terms of accuracy, the Fukui function is relatively accurate in judging aromatic electrophilicity / nucleophilicity, RegioSQM (20) is relatively accurate in judging aromatic electrophilicity, and electrophilic superdelocalization is relatively accurate in judging molecular electrophilicity; nucleophilic superdelocalization is unstable in judging molecular nucleophilicity, especially aromatic nucleophilic substitution, because its parameters contain contributions to the energy of all empty orbitals, and conventional ground state density functional theory (DFT) methods are difficult to accurately describe high-energy empty orbitals (more expensive methods do not have the possibility of obtaining results in a short time); atomic charge, no matter which charge partitioning method is used, is limited to the contribution of the overall charge, while ignoring the contribution of the more important frontier orbitals, resulting in errors in judging all aromatic sites. In terms of versatility, atomic charge and the two superdelocalizations are in principle universal for all types (but accuracy is not guaranteed), while the Fukui function's focus on frontier orbitals will make it unable to judge the reactivity of non-aromatic sites (some orbital energy-weighted Fukui function theories can solve the universality problem, but will have the same judgment accuracy problem as nucleophilic superdelocalization). RegioSQM (20) and the machine learning method WLN are limited to aromatic electrophilic substitutions. Summary of the invention

[0014] In view of this, the present invention provides a method for calculating atomic chemical potential and a method for using atomic chemical potential to predict reaction sites. The descriptive quantity "atomic chemical potential" is proposed for the first time to describe the activity of reaction sites for various reactions. This calculation method mainly targets frontier orbitals, but not the frontier orbitals of the entire molecule in the usual sense. Rather, it is the orbital with the highest atomic orbital component at the reaction site, so as to comprehensively consider all types of sites including aromatic sites (to ensure reactivity).

[0015] The technical purpose of the present invention is achieved in this way:

[0016] In one aspect, the present invention provides a method for calculating atomic chemical potential, the method comprising:

[0017] Get molecular orbital information in molecules;

[0018] Determine the frontier molecular orbital and HOMO and LUMO based on the molecular orbital information, and calculate the contribution of atoms in each frontier molecular orbital based on HOMO and LUMO;

[0019] Calculate the frontier occupied layer energy and frontier unoccupied layer energy of the atom according to the contribution of the atom in each frontier molecular orbital;

[0020] The atomic chemical potential is calculated based on the frontier occupied layer energy and frontier unoccupied layer energy of the atom.

[0021] On the basis of the above scheme, when calculating the atomic chemical potential, reaction parameters are introduced to balance the frontier occupied layer energy and the frontier unoccupied layer energy of the atoms, and the reaction parameters are related to the chemical reaction type.

[0022] On the basis of the above scheme, the molecular orbital information includes the electronic structure, molecular orbital coefficient and molecular orbital energy of the molecule, wherein the electronic structure of the molecule includes the number of electron occupancy of each molecular orbital.

[0023] On the basis of the above scheme, the contribution of the atom in each frontier molecular orbital refers to the number of electrons or empty orbitals belonging to the atom in each frontier molecular orbital.

[0024] Based on the above scheme, the frontier occupied layer energy of an atom refers to the average energy of the layer occupied by the atom in the frontier molecular orbital, and the frontier unoccupied layer energy of an atom refers to the average energy of the unoccupied layer of the atom in the frontier molecular orbital.

[0025] On the basis of the above scheme, the calculation of the frontier occupied layer energy and the frontier unoccupied layer energy of the atom according to the contribution of the atom in each frontier molecular orbital includes:

[0026] Set a predetermined occupation number threshold, and preset the starting frontier molecular orbital as j and the ending frontier molecular orbital as k;

[0027] Extract the number of electrons belonging to a single atom from the starting frontier molecular orbital j to HOMO, add them from near to far according to the molecular orbital energy from HOMO until the predetermined occupation number threshold is reached, and perform weighted average of the energy of the added electrons on the number of electrons to obtain the frontier occupation layer energy of the atom;

[0028] The number of empty orbitals belonging to a single atom from LUMO to the end frontier molecular orbital k is extracted, and the molecular orbital energies are added from near to far according to the distance from LUMO until the predetermined occupation number threshold is reached. The energy of the added empty orbitals is weighted averaged with the number of empty orbitals to obtain the frontier unoccupied layer energy of the atom.

[0029] On the basis of the above scheme, the starting frontier molecular orbital j=max{1,HOMO-9}, and the ending frontier molecular orbital k=min{LUMO+9,n}, where n is the total number of molecular orbitals.

[0030] On the other hand, the present invention also provides a method for predicting reaction sites using atomic chemical potential, the method comprising:

[0031] Obtain the SMILES information of the molecule and analyze it to obtain the three-dimensional molecular structure;

[0032] Perform single-point energy calculations on three-dimensional molecular structures and extract molecular orbital information;

[0033] Combined with the molecular orbital information, the atomic chemical potential is calculated using any of the calculation methods described above;

[0034] Atoms are sorted from large to small according to their chemical potential, and the atom corresponding to the maximum value is taken as the best reaction site.

[0035] Based on the above scheme, the three-dimensional molecular structure is one or more.

[0036] On the basis of the above scheme, when the three-dimensional molecular structure is multiple, the method further comprises:

[0037] The UFF force field was used for structural optimization, and the three-dimensional molecular structure with the lowest energy was selected for single-point energy calculation.

[0038] The method of the present invention has the following beneficial effects compared with the prior art:

[0039] (1) The present invention proposes for the first time the descriptive quantity "atomic chemical potential" to describe the activity of reaction sites for various reactions. In the calculation method of atomic chemical potential provided, the atomic chemical potential is calculated based on the energy localized to the atom as a parameter, rather than the energy-weighted charge, thus avoiding the huge uncertainty caused by high orbital energy.

[0040] (2) Based on the characteristic of the Fermi level that measures the difficulty of gaining or losing electrons, the present invention introduces the energy localized to the atom as a parameter, such as the frontier occupied layer energy and the frontier unoccupied layer energy of the atom, to calculate the atomic chemical potential, and uses the atomic chemical potential to reflect the tendency of electrophilic and nucleophilic reactions to occur at various reaction sites in the molecule;

[0041] (3) The calculation method provided by the present invention is aimed at the frontier orbital, but not the frontier orbital of the whole molecule in the usual sense, but the orbital with the highest atomic orbital component of the reaction site, so as to comprehensively consider all types of sites including aromatic sites (to ensure reactivity);

[0042] (4) The method for predicting reaction sites provided by the present invention directly uses atomic chemical potential to predict reaction sites. The prediction process is fast and efficient, ensuring that the reaction site calculation time for molecules with a molecular weight of <1000 is <1s (CPU 4 core 3.0GHz). BRIEF DESCRIPTION OF THE DRAWINGS

[0043] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0044] Figure 1 is a flow chart of a calculation method according to an embodiment of the present invention;

[0045] Figure 2 The figure is a flow chart of the prediction method according to an embodiment of the present invention. DETAILED DESCRIPTION

[0046] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0047] Terminology explanation:

[0048] Transition state: The highest energy (structural) state in the reaction path of a single-step elementary reaction in a chemical reaction.

[0049] Molecular dynamics: A computer method for simulating the motion of molecular atomic systems.

[0050] Metadynamics: A method for enhanced sampling of molecular conformations in molecular dynamics.

[0051] Chemical shift: The phenomenon that atoms with nuclear spin produce absorption peaks at different positions in the nuclear magnetic resonance spectrum under different chemical environments.

[0052] Nucleophilic reaction: a reaction in which an electron-deficient molecule is attacked by an electron-rich molecule.

[0053] Electrophilic reaction: a reaction in which an electron-rich molecule attacks an electron-deficient molecule.

[0054] Aromatic electrophilic substitution reaction (SEAr): a substitution reaction in which the electron-rich aromatic site of a molecule is attacked. Aromatic nucleophilic substitution reaction (SNAr): a substitution reaction in which the electron-deficient aromatic site of a molecule is attacked. Protonation: the process in which a compound molecule absorbs a positive hydrogen ion.

[0055] Atomic charge: The projected charge distribution on the atoms in a chemical system.

[0056] Molecular orbital: A function of the combination of atomic orbitals in a molecule.

[0057] Wave function: A function that describes a system in quantum mechanics (eg electrons in chemistry).

[0058] Density functional theory: a quantum chemical approach to describing many-electron systems.

[0059] Ground state: the lowest energy state of a microscopic particle in quantum mechanics.

[0060] Frontier molecular orbital: The molecular orbital that has the greatest influence on chemical properties, usually including the highest occupied molecular orbital and the lowest unoccupied molecular orbital.

[0061] Highest occupied molecular orbital (HOMO): The orbital with the highest energy level that has electrons in a molecule Lowest unoccupied molecular orbital (LUMO): The orbital with the lowest energy level that has no electrons in a molecule

[0062] SMILES (Simplified Molecular Input Line Entry Specification): Simplified molecular linear input specification is a specification that uses ASCII strings to clearly describe molecular structures.

[0063] RDKit: an open source cheminformatics software.

[0064] UFF (Universal Force Field): A universal molecular force field model.

[0065] Overlap integral: the integral of two atomic orbital functions in three-dimensional space.

[0066] xTB (eXtended Tight Binding): A semi-empirical method of quantum chemistry based on tight binding theory.

[0067] GFN1-xTB: A method to implement xTB operations.

[0068] like Figure 1 As shown, the present invention provides a method for calculating atomic chemical potential, the method comprising:

[0069] Get molecular orbital information in molecules;

[0070] Determine the frontier molecular orbital and HOMO and LUMO based on the molecular orbital information, and calculate the contribution of atoms in each frontier molecular orbital based on HOMO and LUMO;

[0071] Calculate the frontier occupied layer energy and frontier unoccupied layer energy of the atom according to the contribution of the atom in each frontier molecular orbital;

[0072] The atomic chemical potential is calculated based on the frontier occupied layer energy and frontier unoccupied layer energy of the atom.

[0073] Specifically, when calculating the atomic chemical potential, reaction parameters are introduced to balance the frontier occupied layer energy and the frontier unoccupied layer energy of the atom, and the reaction parameters are related to the type of chemical reaction. For example, the reaction parameters of nucleophilic reaction and the reaction parameters of electrophilic reaction may be different.

[0074] Specifically, a molecular data model can be established to calculate and extract molecular orbital information, which includes the electronic structure, molecular orbital coefficients and molecular orbital energy of the molecule, wherein the electronic structure of the molecule includes the electron occupancy number of each molecular orbital.

[0075] Specifically, HOMO and LUMO can be distinguished based on the molecular orbital energy. HOMO refers to the highest occupied molecular orbital in a molecule. HOMO is the molecular orbital with the highest electron density in a molecule, usually filled with occupied electrons. LUMO refers to the lowest unoccupied molecular orbital in a molecule. LUMO is the lowest energy level molecular orbital that is not occupied in a molecule, usually an empty orbital. The set of molecular orbitals between HOMO and LUMO is the frontier molecular orbital.

[0076] Specifically, after obtaining the frontier molecular orbitals, for each atom, the contribution of a single atom to each frontier molecular orbital is calculated. The contribution refers to the number of electrons or empty orbitals belonging to the atom in each frontier molecular orbital. When it represents the number of electrons, its value is positive, and when it represents the number of empty orbitals, its value is negative.

[0077] Specifically, the calculating of the frontier occupied layer energy and the frontier unoccupied layer energy of the atom according to the contribution of the atom in each frontier molecular orbital comprises:

[0078] Set a predetermined occupation number threshold, and preset the starting frontier molecular orbital as j and the ending frontier molecular orbital as k;

[0079] Extract the number of electrons belonging to a single atom from the starting frontier molecular orbital j to HOMO, add them from near to far according to the molecular orbital energy from HOMO until the predetermined occupation number threshold is reached, and perform weighted average of the energy of the added electrons on the number of electrons to obtain the frontier occupation layer energy of the atom;

[0080] The number of empty orbitals belonging to a single atom from LUMO to the end frontier molecular orbital k is extracted, and the molecular orbital energies are added from near to far according to the distance from LUMO until the predetermined occupation number threshold is reached. The energy of the added empty orbitals is weighted averaged with the number of empty orbitals to obtain the frontier unoccupied layer energy of the atom.

[0081] Therefore, the frontier occupied layer energy of an atom can also be regarded as the average energy of the layer occupied by the atom in the frontier molecular orbital, while the frontier unoccupied layer energy of an atom can be regarded as the average energy of the unoccupied layer of the atom in the frontier molecular orbital.

[0082] Specifically, when calculating the frontier occupied layer energy and the frontier unoccupied layer energy of an atom, the calculation process is constrained by j and k. The constraint is reflected in that the frontier molecular orbitals involved in the calculation are constrained by [j, k]. Since j and k are both near the frontier molecular orbitals, the present invention sets a range for j and k, with the starting frontier molecular orbital j = max{1, HOMO-9} and the ending frontier molecular orbital k = min{LUMO+9, n}, where n is the total number of molecular orbitals.

[0083] Specifically, the present invention provides a specific embodiment to illustrate the process of the above-mentioned calculation method, but the formulas, parameters, etc. involved in this embodiment do not limit the protection scope of the present invention.

[0084] For an atom A in a molecule:

[0085] Defining ε A，FOS and ε A，FUS They are the frontier occupied shell energy and the frontier unoccupied shell energy of atom A. The calculation formula of atomic chemical potential is as follows:

[0086] η A =γε A，FOS +(1-γ)ε A，FUS (1);

[0087] Where η A is the atomic chemical potential of atom A, and γ represents the reaction parameter, which is an empirical parameter related to the reaction type. In particular, in aromatic electrophilic substitution, γ = 0.8-1.0.

[0088] Formula (1) defines the atomic chemical potential as the energy between the frontier occupied layer and the frontier unoccupied layer of electrons in an atom.

[0089] And ε A，FOS and ε A，FUS The calculation formula is as follows:

[0090]

[0091] In the formula, ε i is the energy of the ith frontier molecular orbital, ρ A，iIt refers to the contribution of atom A to the i-th frontier molecular orbital, x refers to the preset occupation number threshold, and in this embodiment, the effective range of x is set to 0-2, the starting frontier molecular orbital is i and the ending frontier molecular orbital is k.

[0092] According to x, the number of electrons belonging to atom A from the starting frontier molecular orbital j to HOMO is extracted, and the energy of the molecular orbital from the distance to HOMO is added from near to far until the value of x is reached, and the energy of the added electrons is weighted averaged to the number of electrons to obtain the frontier occupied layer energy of the atom. The number of empty orbitals belonging to atom A from LUMO to the ending frontier molecular orbital k is extracted, and the energy of the molecular orbital from the distance to LUMO is added from near to far until the value of x is reached, and the energy of the added empty orbitals is weighted averaged to the number of empty orbitals to obtain the frontier unoccupied layer energy of the atom.

[0093] ρ A，i The calculation formula is as follows:

[0094]

[0095] In the formula, f i is the number of electrons occupied by the i-th frontier molecular orbital, c is the molecular orbital coefficient, S is the overlap integral matrix under the atomic orbital basis, and the subscripts μ and v represent atomic orbitals. A，i Defines the number of electrons or empty orbitals belonging to atom A in the frontier molecular orbital i.

[0096] Specifically, in this embodiment, in order to increase the calculation speed during calculation, a matrix simplification operation may be used.

[0097] Specifically, ε A，FOS and ε A，FUS The calculation of is constrained by i∈[j, k], so ρ A，i The calculation and even the range of the input matrix can constrain i. Since j and k are both near the frontier molecular orbital, this patent uses j = max{1, HOMO-9}, k = min{LUMO+9, n} (n is the total number of molecular orbitals), that is, a maximum of 20 molecular orbitals are considered.

[0098] The present invention proposes an atomic chemical potential description quantity and provides a specific calculation method. The atomic chemical potential is a potential (energy) defined on an atom based on the proportion of the atom in the frontier molecular orbital. This definition ensures that the most reactive frontier orbitals are considered and minimizes the reliance on the accuracy of molecular data calculations.

[0099] Atomic chemical potential can be directly used to predict the reaction sites of the same type of chemical reactions. In electrophilic reactions, the larger the value, the stronger the reactivity; in nucleophilic reactions, the smaller the value, the stronger the reactivity. Figure 2As shown, based on the characteristics of atomic chemical potential, the present invention also provides a method for using atomic chemical potential to predict reaction sites, the method comprising:

[0100] Obtain the SMILES information of the molecule and analyze it to obtain the three-dimensional molecular structure;

[0101] Perform single-point energy calculations on three-dimensional molecular structures and extract molecular orbital information;

[0102] Combined with the molecular orbital information, the atomic chemical potential is calculated using any of the calculation methods described above;

[0103] Atoms are sorted from large to small according to their chemical potential, and the atom corresponding to the maximum value is taken as the best reaction site.

[0104] Wherein, the three-dimensional molecular structure is one or more types. When the three-dimensional molecular structure is multiple types, the method further comprises:

[0105] The UFF force field was used for structural optimization, and the three-dimensional molecular structure with the lowest energy was selected for single-point energy calculation.

[0106] Specifically, the present invention first obtains the SMILES information of the molecule, uses RDKit to generate one or more three-dimensional molecular structures from SMILES, and uses the UFF force field to optimize the three-dimensional molecular structure, and selects the three-dimensional molecular structure with the lowest energy. After that, the selected three-dimensional molecular structure is subjected to single-point energy calculation at the level of the semi-empirical method GFN1-xTB, and the converged wave function or the corresponding numerical integral is saved, and the molecular orbital coefficient, overlap integral, molecular orbital energy and molecular orbital electron occupancy number are extracted therefrom. According to the extracted molecular orbital information, the atomic chemical potential of each atom is calculated according to the atomic chemical potential calculation method described above, and in order to speed up the calculation speed, matrix simplification can be performed. Finally, the atomic chemical potential is used as the basis for determining the reaction activity of atoms at each reaction site, and the atoms are arranged from large to small according to their atomic chemical potential, and the one with the maximum atomic chemical potential is the best reaction site.

[0107] Specifically, the present invention provides a specific embodiment to illustrate the above prediction method:

[0108]

[0109] The above formula is the structural formula of an aromatic compound. The numbers marked in the formula are the numbers of the atoms at each reaction site. For this compound, its potential aromatic electrophilic sites are: 4, 5, 7, 8, 10, 15, 16, 17, 18, 19.

[0110] The reaction site prediction process for this compound is as follows:

[0111] 1. First enter its SMILES: [CH3:1][O:2][C:3]1=[CH:4][CH:5]=[C:6]([CH:7]=[CH:8]1)[C:9]1=[CH:10][C:11](=[N:12][O:13]1)[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=[CH:19]1.

[0112] 2. Generate and optimize its three-dimensional molecular structure. Perform semi-empirical single-point energy calculations and extract wave functions for the constraints i∈[j, k] to obtain f i ,c,S,ε i Information: (c, S are matrices of 20×102 and 102×102 respectively, only part of them is shown)

[0113] f i =[222222222220000000000];

[0114] c=[[1.0000e+00 0.0000e+00 0.0000e+00...0.0000e+00 0.0000e+000.0000e+00]

[0115] [0.0000e+001.0000e+000.0000e+00...0.0000e+000.0000e+000.0000e+00]

[0116] [0.0000e+000.0000e+001.0000e+00...0.0000e+000.0000e+000.0000e+00] ...

[0118] [0.0000e+000.0000e+000.0000e+00...1.0000e+00-9.2614e-022.8119e-02]

[0119] [0.0000e+000.0000e+000.0000e+00...-9.2614e-021.0000e+008.5040e-10]

[0120] [0.0000e+00 0.0000e+00 0.0000e+00...2.8119e-02 8.5040e-101.0000e+00]];

[0121] S=[[-2.2911e-08 -1.7617e-03 -1.0107e-02...2.6000e-08 -1.3862e-06-1.0550e-07]

[0122] [-1.6535e-029.3436e-02-1.7022e-02...1.0670e-02-2.2597e-01-1.3703e-02]

[0123] [-1.9260e-021.1450e-01-2.0880e-02...-1.2099e-021.7289e-011.3317e-02] ...

[0125] [3.9265e-07-1.6070e-03-9.2193e-03...1.1771e-088.3252e-08-4.4874e-08]

[0126] [6.0615e-03-1.3256e-022.7534e-03...-2.7194e-021.4303e-02-6.3465e-02]

[0127] [4.6337e-08-5.7747e-04-3.3132e-03...1.9536e-07-1.4155e-071.5112e-07]];

[0128]

[0129] 3. Substitute the above data into formula (3) and formula (4) to calculate ε A，FOS for:

[0130] [-0.462,-0.428,-0.431,-0.438,-0.437,-0.427,-0.438,-0.437,-0.429,-0.42,-0.436,-0.409,-0.451,-0.426,-0.432,-0.435,-0.424,-0.436,-0.431,-0.446,-0.446,-0.471,-0.471,-0.471,-0.471,-0.471,-0.471,-0.453,-0.468,-0.47,-0.469,-0.468,-0.469];

[0131] ε A，FUS for:

[0132] [-0.152,-0.225,-0.288,-0.275,-0.28,-0.285,-0.284,-0.273,-0.269,-0.276,-0.254,-0.293,-0.268,-0.282,-0.275,-0.267,-0.283,-0.268,-0.274,-0.154,-0.154,-0.152,-0.151,-0.126,-0.125,-0.141,-0.125,-0.125,-0.125,-0.125,-0.125,-0.125].

[0133] 4. Select 4, 5, 7, 8, 10, 15, 16, 17, 18, 19 and calculate η using formula (1) A (take k=0.9):[-0.421,-0.421,-0.423,-0.421,-0.405,-0.416,-0.418,-0.41,-0.419,-0.415].

[0134] 5. Set η A After sorting from large to small, it was found that the maximum value was -0.405, corresponding to reaction site 10, that is, reaction site 10 was the best reaction site.

[0135] The calculation method and prediction method provided by the present invention are equivalent to or better than the known methods in terms of versatility. And their accuracy is better than that of atomic charge, nuclear magnetic resonance 13 C spectrum is superior to nucleophilic superdelocalization in nucleophilic reactions; it is similar to or better than Fukui function in aromatic site judgment, and is similar to electrophilic superdelocalization in electrophilic reactions; it is similar to RegioSQM20 in aromatic electrophilic substitution. Its calculation speed and prediction speed are better than atomic charge and nuclear magnetic resonance. 13 C spectra, Fukui functions, RegioSQM20 and machine learning methods, with calculation times <1s at reaction sites for molecules with molecular weight <1000.

[0136] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for calculating atomic chemical potential, characterized in that: The method comprises: Get molecular orbital information in molecules; Determine the frontier molecular orbital and HOMO and LUMO based on the molecular orbital information, and calculate the contribution of atoms in each frontier molecular orbital based on HOMO and LUMO; Calculate the frontier occupied layer energy and frontier unoccupied layer energy of the atom according to the contribution of the atom in each frontier molecular orbital; The atomic chemical potential is calculated based on the frontier occupied layer energy and frontier unoccupied layer energy of the atom.

2. A method for calculating atomic chemical potential according to claim 1, characterized in that: When calculating the atomic chemical potential, reaction parameters are introduced to balance the frontier occupied layer energy and the frontier unoccupied layer energy of the atoms, and the reaction parameters are related to the chemical reaction type.

3. A method for calculating atomic chemical potential according to claim 1, characterized in that: The molecular orbital information includes the electronic structure, molecular orbital coefficient and molecular orbital energy of the molecule, wherein the electronic structure of the molecule includes the number of electrons occupied in each molecular orbital.

4. A method for calculating atomic chemical potential according to claim 3, characterized in that: The contribution of the atom in each frontier molecular orbital refers to the number of electrons or empty orbitals belonging to the atom in each frontier molecular orbital.

5. A method for calculating atomic chemical potential according to claim 1, characterized in that: The frontier occupied layer energy of an atom refers to the average energy of the layer occupied by the atom in the frontier molecular orbital, and the frontier unoccupied layer energy of an atom refers to the average energy of the unoccupied layer of the atom in the frontier molecular orbital.

6. A method for calculating atomic chemical potential according to claim 5, characterized in that: The step of calculating the frontier occupied layer energy and the frontier unoccupied layer energy of the atom according to the contribution of the atom in each frontier molecular orbital comprises: Set a predetermined occupation number threshold, and preset the starting frontier molecular orbital as j and the ending frontier molecular orbital as k; Extract the number of electrons belonging to a single atom from the starting frontier molecular orbital j to HOMO, add them from near to far according to the molecular orbital energy from HOMO until the predetermined occupation number threshold is reached, and perform weighted average of the energy of the added electrons on the number of electrons to obtain the frontier occupation layer energy of the atom; The number of empty orbitals belonging to a single atom from LUMO to the end frontier molecular orbital k is extracted, and the molecular orbital energies are added from near to far according to the distance from LUMO until the predetermined occupation number threshold is reached. The energy of the added empty orbitals is weighted averaged with the number of empty orbitals to obtain the frontier unoccupied layer energy of the atom.

7. A method for calculating atomic chemical potential according to claim 6, characterized in that: The starting frontier molecular orbital j = max{1, HOMO-9}, and the ending frontier molecular orbital k = min{LUMO+9, n}, where n is the total number of molecular orbitals.

8. A method for predicting reaction sites using atomic chemical potential, characterized in that: The method comprises: Obtain the SMILES information of the molecule and analyze it to obtain the three-dimensional molecular structure; Perform single-point energy calculations on three-dimensional molecular structures and extract molecular orbital information; In combination with the molecular orbital information, the atomic chemical potential is calculated using the calculation method described in any one of claims 1 to 6; Atoms are sorted from large to small according to their chemical potential, and the atom corresponding to the maximum value is taken as the best reaction site.

9. The method for predicting reaction sites using atomic chemical potential according to claim 8, characterized in that: The three-dimensional molecular structure is one or more.

10. The method for predicting reaction sites using atomic chemical potential according to claim 9, characterized in that: When the three-dimensional molecular structure is multiple, the method further comprises: The UFF force field was used for structural optimization, and the three-dimensional molecular structure with the lowest energy was selected for single-point energy calculation.

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