RNF 19-73-20085
«Highly efficient catalytic systems for C-H functionalization processes based on transition metal complexes with N-heterocyclic carbenes»
The project is aimed at solving the problem of efficient synthesis of complex organic molecules based on metal-catalyzed C-H functionalization reactions (C-H activation).
The classical strategy of organic synthesis is based on the use of functional groups to form new connections. As part of the classical strategy, a functional group must first be selectively introduced into a molecule and then used to modify a hydrocarbon, bioactive, or natural compound. The introduction of functional group X is a separate stage, sometimes difficult to implement, which involves the cost of time, special chemicals and energy, as well as the formation of waste. In addition, additional waste is generated in subsequent substitution or elimination reactions of functional groups X. Therefore, the classical strategy of functional groups has limited effectiveness.
The possibility of using C-H bonds instead of functional groups is very attractive, since it allows you to obtain valuable chemical compounds in one stage without first introducing functional groups. The advantage of the C-H activation strategy is the possibility of using more accessible starting materials (for example, hydrocarbons or natural compounds, relatively simple products of petrochemical synthesis, etc.), reducing the number of technological stages and capital intensity of production, and reducing waste.
However, conventional, i.e. inactive C-H bonds are quite inert (the C-H bond energy is about 110 kcal/mol), so strict reaction conditions are required, which does not allow the use of complex molecules containing labile groups. Another problem is the significant number of C-H groups in different places of the source substance molecule, which inevitably leads to the selectivity problem. In addition, the products of C-H functionalization often have a higher reactivity compared to the starting substances, and enter into adverse reactions.
Currently, one of the most effective ways to solve the problem is metal-complex catalysis, which allows selectively activating C-H bonds.
Works completed in 2019:
- Research on the first stage of the project included:
synthesis of libraries of structurally diverse metal complexes (M = Pd, Ni, Cu, Ru) with N-heterocyclic carbenes (NHC) and soligands of various types, including the development of methods for obtaining new types of functionally substituted NHC ligands and their complexes;
- Screening of the catalytic activity of the obtained m/NHC complexes in the reactions of C-H alkylation and alkenylation of heterocycles and aldehydes with alkenes and alkynes (C-H addition to carbon-carbon multiple bonds), investigation of the relationships "structure of M/NHC-catalytic activity»;
- Study of transformations of M/NHC complexes in the process of catalysis, determination of the nature of active centers and the main ways of activation and deactivation of the catalytic system;
- Development of new effective M/NHC catalytic systems for C-H alkylation and alkenylation reactions and optimization of conditions for the synthesis of alkyl and alkenyl derivatives of 1,3-benzoxazole, 1,3-benztiazole, benzimidazole and 1,2,4-triazole.
Results of the first stage of the project:
- A new reaction for the formation of 4,5-dialkoxy-4,5-dihydro-1,3-diaryl-1-N-imidazolium salts was discovered and investigated in the interaction of condensation products of glyoxal and aromatic amines with trialkylortoformates under acid catalysis conditions. A new type of NHC-proligands were synthesized and new Pd-PEPSI complexes with 4,5-dialkoxysubstituted imidazoline ligands were obtained by interaction with palladium salts.
- A method for the synthesis of NHC-proligands of a new type – imidazolium salts containing an electron-donating NH - acid amino or acylamine group in position 4 of the imidazole cycle has been developed. New Pd/NHC and Ni/NHC complexes, including the first representatives of M/NHC complexes with a free amino group in an imidazole NHC ligand, were obtained by the reaction of the obtained amino - and acylamino-imidazolium salts with palladium and Nickel-cene. A special feature of the obtained complexes is the presence of an NH-acid substituent capable of ionization in the presence of strong bases and the formation of m/NHC anionic complexes.
- More than eighty PD/NHC, Ni/NHC, Cu/NHC and Ru/NHC complexes were screened for catalytic activity in reactions of C-H addition of benzoxazole and aldehydes derivatives to alkenes and alkynes. It is shown that Ni/NHC complexes are most active in the catalysis of these reactions. The active centers are Ni(0)/NHC molecular complexes formed during the reduction of Ni(II)/NHC complexes by special activators (sodium hydride, sodium formate, etc.). The main ways to deactivate Ni/NHC catalysts include reduction elimination reactions of NHC ligands – H-NHC combination and R-NHC combination. It was found that the following factors have a determining influence on the catalytic activity of Ni/NHC complexes: (i) spatial influence of substituents in nitrogen atoms of the NHC ligand; (ii) electron-donating ability of the NHC ligand; (iii) mobility of soligands.
- A new effective catalytic system has been developed for the catalysis of C-H reactions of joining heterocycles to alkenes and international alkynes based on available and stable catalytic precursors — azolium salts, nickelocene and sodium formate. The efficiency of the developed catalytic system was demonstrated on the preparative synthesis of alkyl and alkenyl derivatives of 1,3-benzoxazole, 1,3-benztiazole, benzimidazole and 1,2,4-triazole.
The classical strategy of organic synthesis is based on the use of functional groups to form new connections. As part of the classical strategy, a functional group must first be selectively introduced into a molecule and then used to modify a hydrocarbon, bioactive, or natural compound. The introduction of functional group X is a separate stage, sometimes difficult to implement, which involves the cost of time, special chemicals and energy, as well as the formation of waste. In addition, additional waste is generated in subsequent substitution or elimination reactions of functional groups X. Therefore, the classical strategy of functional groups has limited effectiveness.
The possibility of using C-H bonds instead of functional groups is very attractive, since it allows you to obtain valuable chemical compounds in one stage without first introducing functional groups. The advantage of the C-H activation strategy is the possibility of using more accessible starting materials (for example, hydrocarbons or natural compounds, relatively simple products of petrochemical synthesis, etc.), reducing the number of technological stages and capital intensity of production, and reducing waste.
However, conventional, i.e. inactive C-H bonds are quite inert (the C-H bond energy is about 110 kcal/mol), so strict reaction conditions are required, which does not allow the use of complex molecules containing labile groups. Another problem is the significant number of C-H groups in different places of the source substance molecule, which inevitably leads to the selectivity problem. In addition, the products of C-H functionalization often have a higher reactivity compared to the starting substances, and enter into adverse reactions.
Currently, one of the most effective ways to solve the problem is metal-complex catalysis, which allows selectively activating C-H bonds.
Works completed in 2019:
- Research on the first stage of the project included:
synthesis of libraries of structurally diverse metal complexes (M = Pd, Ni, Cu, Ru) with N-heterocyclic carbenes (NHC) and soligands of various types, including the development of methods for obtaining new types of functionally substituted NHC ligands and their complexes;
- Screening of the catalytic activity of the obtained m/NHC complexes in the reactions of C-H alkylation and alkenylation of heterocycles and aldehydes with alkenes and alkynes (C-H addition to carbon-carbon multiple bonds), investigation of the relationships "structure of M/NHC-catalytic activity»;
- Study of transformations of M/NHC complexes in the process of catalysis, determination of the nature of active centers and the main ways of activation and deactivation of the catalytic system;
- Development of new effective M/NHC catalytic systems for C-H alkylation and alkenylation reactions and optimization of conditions for the synthesis of alkyl and alkenyl derivatives of 1,3-benzoxazole, 1,3-benztiazole, benzimidazole and 1,2,4-triazole.
Results of the first stage of the project:
- A new reaction for the formation of 4,5-dialkoxy-4,5-dihydro-1,3-diaryl-1-N-imidazolium salts was discovered and investigated in the interaction of condensation products of glyoxal and aromatic amines with trialkylortoformates under acid catalysis conditions. A new type of NHC-proligands were synthesized and new Pd-PEPSI complexes with 4,5-dialkoxysubstituted imidazoline ligands were obtained by interaction with palladium salts.
- A method for the synthesis of NHC-proligands of a new type – imidazolium salts containing an electron-donating NH - acid amino or acylamine group in position 4 of the imidazole cycle has been developed. New Pd/NHC and Ni/NHC complexes, including the first representatives of M/NHC complexes with a free amino group in an imidazole NHC ligand, were obtained by the reaction of the obtained amino - and acylamino-imidazolium salts with palladium and Nickel-cene. A special feature of the obtained complexes is the presence of an NH-acid substituent capable of ionization in the presence of strong bases and the formation of m/NHC anionic complexes.
- More than eighty PD/NHC, Ni/NHC, Cu/NHC and Ru/NHC complexes were screened for catalytic activity in reactions of C-H addition of benzoxazole and aldehydes derivatives to alkenes and alkynes. It is shown that Ni/NHC complexes are most active in the catalysis of these reactions. The active centers are Ni(0)/NHC molecular complexes formed during the reduction of Ni(II)/NHC complexes by special activators (sodium hydride, sodium formate, etc.). The main ways to deactivate Ni/NHC catalysts include reduction elimination reactions of NHC ligands – H-NHC combination and R-NHC combination. It was found that the following factors have a determining influence on the catalytic activity of Ni/NHC complexes: (i) spatial influence of substituents in nitrogen atoms of the NHC ligand; (ii) electron-donating ability of the NHC ligand; (iii) mobility of soligands.
- A new effective catalytic system has been developed for the catalysis of C-H reactions of joining heterocycles to alkenes and international alkynes based on available and stable catalytic precursors — azolium salts, nickelocene and sodium formate. The efficiency of the developed catalytic system was demonstrated on the preparative synthesis of alkyl and alkenyl derivatives of 1,3-benzoxazole, 1,3-benztiazole, benzimidazole and 1,2,4-triazole.
Main publications on the results of the project:
1) Astakhov A.V. et al. Relative stabilities of M/NHC complexes (M = Ni, Pd, Pt) against R–NHC, X–NHC and X–X couplings in M(0)/M(II) and M(II)/M(IV) catalytic cycles: a theoretical study Dalton Trans., 2019, 48, p. 17052-17062 (doi: 10.1039/C9DT03266E).
1) Astakhov A.V. et al. Relative stabilities of M/NHC complexes (M = Ni, Pd, Pt) against R–NHC, X–NHC and X–X couplings in M(0)/M(II) and M(II)/M(IV) catalytic cycles: a theoretical study Dalton Trans., 2019, 48, p. 17052-17062 (doi: 10.1039/C9DT03266E).