| Synthesis of the carbon-nitrogen(C-N) bond is a very important area of research in organic chemistry. As an attractive candidate for the synthesis of C-N bond, transition metal complex-catalyzed N-alkylation of amines with alcohols has attracted considerable attention since it was first reported in 1981. In this paper, DFT methods and the SMD solvation model in Gaussian 09 programs together with the energetic span model have been used to study the mechanisms of the N-alkylation of amines with alcohols catalyzed by the transition metal Cu(Ⅱ), Cp~*Ir(ⅡI) and Pd(Ⅱ) complexes. The active catalysts are postulated by considering the reaction free energies of yielding the possible catalytically active species. For the possible active catalysts, we calculate all the possible reaction pathways including inner-sphere and outer-sphere hydrogen transfer pathways. On the basis of the apparent activation energy of each pathway, we identify the most favourable reaction pathways. Moreover, a Fortran program based on the energetic span model is employed to calculate the turnover frequencies(TOFs) of some lower-energy catalytic cycles. By comparing the relative TOFs, we give the most favorable catalytic cycles. The main results are summarized as follows:1. DFT calculations at the level of M06//B3 LYP have been carried out to study the mechanism of Cu(Ⅱ)-catalyzed N-alkylation of amino derivatives with primary alcohols. The calculations indicate that t Bu OK is necessary for the generation of the active catalyst from Cu(Ac O)2 and that the catalytic cycle involves three sequential steps:(i) Cu(Ⅱ)-catalyzed alcohol oxidation to give the corresponding aldehyde and copper hydride,(ii) aldehyde-amine condensation to generate an imine,(iii) imine reduction to yield the expected N-alkylation secondary amine product and to regenerate the active catalyst. Based on the comparison of different reaction pathways, we conclude that the outer-sphere hydrogen transfer in a stepwise manner is the most favorable pathway for both alcohol oxidation and imine reduction. Thermodynamically, alcohol oxidation and imine formation are all uphill, but imine reduction is downhill significantly, which is the driving force for the catalytic transformation. Using the energetic span model, we find that the TOF-determining transition state(TDTS) and the TOF-determining intermediate(TDI) are the hydride transfer transition state for imine reduction and the active catalyst, respectively.2. DFT calculations at the level of M06//B3 LYP have been performed to study the mechanism of the N-alkylation of amines with alcohols catalyzed by [Cp~*Ir Cl2]2(Cp~* = η5-C5Me5) in the presence of K2CO3. The energetic results show that this N-alkylation reaction proceeds via the hydrogen autotransfer mechanism and the catalytic cycle includes three sequential stages:(i) alcohol oxidation to produce aldehyde,(ii) aldehyde–amine condensation to form an imine, and(iii) imine reduction to afford the secondary amine product. For stages(i) and(iii), the most favorable pathways are the inner-sphere hydrogen transfer pathway under the catalysis of Cp~*Ir(NHPh)Cl and the inner-sphere hydrogen transfer pathway with KHCO3 as the proton donor. Thermodynamically, both stages(i) and(ii) are endergonic, but stage(iii) is highly exergonic. Thus stage(iii) is the driving force for the catalytic cycle. The energetic span model has also been used to assess the catalytic cycle, and it is found that the TDI and TDTS are the 18 e complex Cp~*Ir(κ2-CO3K)Cl and the transition state for β-H elimination, respectively. Our calculation results show that Eisenstein and coworkers’ proposed favorable reaction pathways for alcohol oxidation and imine reduction are not true, so this mechanistic study can provide important insights for correctly understanding the N-alkylation of amines with alcohols catalyzed by the Cp~*Ir(ⅡI) complex.3. DFT methods and the energetic span model have been used to study the mechanism of the N-alkylation of amines with alcohols catalyzed by the Pd Cl2/dppe/Li OH system(dppe = 1,2-bis(diphenylphosphino)ethane). The energetic results indicate that the most favorable pathway is the inner-sphere hydrogen transfer pathway, which consists of initiation of the three-coordinated active alkoxide complex [Pd(Ph CH2O)(dppe)]+ and the catalytic cycle CC1. Initiation of the active alkoxide complex includes two sequential steps:(i) generation of the three-coordinated active species [Pd(OH)(dppe)]+ and [Pd(Ph NH)(dppe)]+ and(ii) Ph CH2 OH deprotonation to afford the active alkoxide complex. Catalytic cycle CC1 includes three sequential steps:(i) β-H elimination of the active alkoxide complex to generate benzaldehyde and the Pd(Ⅱ) hydride species,(ii) condensation of benzaldehyde with aniline to give the imine, and(iii) imine reduction to supply the amine product and to regenerate the active alkoxide complex. The TOF of this proposed catalytic cycle is inhibited by the reverse process of Ph CH2 OH deprotonation, but the calculated TOFs still support that the catalytic cycle CC1 is the most favorable. By calculating the degree of TOF control, we identify the TDI(the Li Cl2--coordinated alkoxide complex) and the TDTS(the transition state for the β-H elimination) in the catalytic cycle, and find that all the influential intermediates are the off-cycle Li Cl2--coordinated complexes in the overall reaction pathway, which leads us to conclude that Li Cl2- is the TOF-affecting key species. Our additional calculations show that the TOF may be improved by the addition of Ag OTf or Ag BF4, which can scavenge the Cl- and supply the weak ligand OTf- or BF4-.In the above mechanistic studies, the experimental substrates and catalyst without any simplificaion are used for the calculations, so our theoretical studies are much closer to the factual reactions. The calculated TOFs roughly agree with the experimental observation,which confirms that the validity of our proposed reaction mechanisms. Thus, our studies not only reveal the mechanism of the N-alkylation of amines with alcohols catalyzed by the transition metal Cu(Ⅱ), Cp~*Ir(ⅡI) and Pd(Ⅱ) complexes, but also can provide important insights for the development of more efficient catalyst systerm. |
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