Theoretical Studies On The Mechanism Of Ni And Pd Catalyzed Several C-H Activation And C-C Coupling

Organometallic chemistry has been one of the most popular fields in modern organic chemistry.The core of its research is the transition metal compounds,which often used as catalysts for various organic synthesis and usually show high reactivity and high selectivity in the catalytic process.In many synthetic reactions catalyzed by organometallic compounds,there are still some phenomena where the mechanism is not clear enough and the results are difficult to understand,which to some extent restricts the development of organometallic chemistry.Using quantum chemistry methods to carry out relevant theoretical research,explore reaction mechanisms on the molecular level,and explain the microscopic nature of chemical reactions is of great significance for further promoting the development of organometallic chemistry.In this dissertation,we studied a series of C-H activation and C-C coupling reactions catalyzed by transition metals such as Ni and Pd transition metals by density functional theory(DFT)calculations.The microscopic mechanism of the reactions was clarified through our calculation,and the factors controlling chemo-,enantio-and regio-selectivities were revealed.Meanwhile,the effects of ligands,additives,solvents and other factors on the performance of the reaction were clarified,some novel experimental results were reasonably explained,and a series of innovative research results were obtained,which provided certain theoretical guidance for further improving the catalytic efficiency and designing new catalytic systems.The main contents and relevant innovative achievements of this dissertation are summarized as follows:1.Nonconventional meta-C-H arylation of electron-rich arenes via Pd/quinoxaline-based ligand/norbornene cooperative catalysis was studied.This reaction was reported by Yu et al.at the Scripps Research Institute in 2019 and published in J.Am.Chem.Soc..Experimental studies have shown that the exclusive non-directed meta-C-H activation of a variety of electron-rich alkoxy aromatics can be successfully achieved under the co-catalysis of palladium/ligand and norbornene.Our computational results can be summarized in the following three aspects:(1)The formation mechanism of mesa-mono-/bi-arylation products was clarified.The catalyst undergoes a Pd(Ⅱ)/Pd(Ⅳ)/Pd(Ⅱ)cycle,and successively undergoes elemental processes such as ortho-carbopalladylation.norbornene insertion,meta-C-H activation,oxidative addition,and reduction elimination to obtain meta-arylation products.The bi-arylation product begins with the para-carbopalladylation,and then undergoes two similar arylation processes to give the bi-arylation product.(2)The initial carbopalladation process is characterized as the rate-determining step.The calculated results show that the energy barrier for this step is 23.1 kcal/mol,which is consistent with the experimental conditions(95℃).(3)The co-catalysis of norbornene and quinoxaline-based ligand was revealed.Norbornene is used as a transient mediator to transfer the activation sites from ortho-and para-to meta-site,thereby obtaining meta-arylation products;the entire catalytic cycle is assisted by quinoxaline-based ligand:quinoxaline-based ligand always occupy a coordination vacancy of Pd center,maintaining it in a stable tetra-or six-coordinated form.2.We have investigated the prototype system of the palladium/chiral norbornene cooperative three-component cascade reaction.The reaction was developed by the Zhou’group of Wuhan University in 2020,and published in Nat.Catal..Using aryl iodide,aryl bromide and acrylate as substrates,they have successfully synthesized the axially S-chiral biaryl compounds with high yield and high enantioselectivity.Our theoretical calculations aim to understand the enantio-and regioselectivities of reaction and the reaction sequence of multi-component reaction.The main results are as follows:(1)The catalytic cycle is divided into three stages:(ⅰ)formation of the aryl-norbornyl-palladacycle intermediate via the oxidation addition of the aromatic iodine on the Pd(0)center,norbornene insertion,and the potassium carbonate assisted C-H activation,(Ⅱ)construction of C-C chiral axis,involving the oxidation addition of aryl bromide on the Pd(Ⅱ)and the C-C reduction elimination on Pd(Ⅳ),and(ⅲ)intermolecular termination via norbornene extrusion,alkene insertion,and β-H elimination.(2)The C-H activation is characterized as the rate-determining step,and the oxidative addition of aryl bromide on Pd(Ⅱ)control the enantioselectivity of the reaction.The energy barriers of the(S)-and(R)-products are 20.2 and 30.5 kcal/mol,respectively.The construction of more favorable(S)-C-C axial chirality is attributed to the smaller steric repulsion between the ortho-methyl group of aryl bromide and the norbornene moiety.The regioselective insertion of the terminating reagent in the final intermolecular termination stage originates from electronic effect and steric hindrance.(3)The reaction sequence of aryl iodide and aryl bromide was rationalized.The Pd(0)catalyst selectively reacts with the aryl iodide than aryl bromide to provide the Pd(Ⅱ)species due to the weaker C-I bond and the oxidative addition of the aryl bromide on the Pd(Ⅱ)more facile than that of the aryl iodine due to the the 5/6-quasi-planar motif and the special fused bis-palladacyclic formed by the ortho-ester group of aryl with the Pd(Ⅱ)center.3.The palladium catalyzed γ-C(sp3)-H arylation of alkylamines with 2-iodobenzoic acid was studied.This representative reaction was conducted by the Gaunt et al.of Cambridge University in 2019,and published in Angew.Chem.Int.Ed..The author found that using iodobenzene as aryl transfer reagent,unable to form the arylation of alkylamine,but 2-iodobenzoic acid can successfully achieve arylation of specific γ-position.Through the calculation of two reactions,we have clarified the influence of different substrates on the reaction performance and revealed the origin of regionalselectivity.The key findings include:(1)A new reaction mechanism is proposed.The reaction undergoes a Pd(Ⅱ)/Pd(Ⅳ)/Pd(Ⅱ)cycle to achieve the target product.The ortho carboxyl group can form a quasi-planar 5/6 ring structure,which could facilitate the C(sp3)-C(sp2)reductive elimination.Decarboxylation occurs at the Pd(Ⅱ)center rather than the Pd(Ⅳ)center suggested by the authors.The 1,2-arylpalladium migration is achieved by a stepwise mechanism rather than a concerted mechanism suggested by the experimental authors.(2)The energy barriers of 2-iodobenzoic acid and iodobenzene substrates are 27.1 and 35.6 kcal/mol,respectively,indicating that the former can occur under experimental conditions(room temperature,16h),while the latter is difficult to occur,which is consistent with experimental results.(3)The regioselectivity of the reaction was reasonably explained.For complexes with flexible skeletons,the structural stability of the four-or six-membered chelating ring structure is lower than that of the five-membered chelating ring,thus facilitating the formation of y-arylation products.4.We have investigated the palladium/Xu-Phos-catalyzed cascade Heck/remote C(sp2)-H alkylation reaction.The reaction was presented by the Zhang et al.of Fudan University in 2022,and published in Chem..In this reaction,Zhang et al.made a breakthrough in catalyzing asymmetric synthesis of spirocycle compounds from the ortho-iodophenol-derived allyl ether via Pd-catalyzed cascade Heck/remote C(sp2)-H alkylations with the Xu-Phos ligand.achieving exclusive exo-selectivity and high enantiomeric ratio of 5,4-spirocycle without observation of other possible by-products.By performing the DFT calculations,we systematically investigated the detailed mechanism of reaction and identified the factors affecting the enantio-and chemo-selectivities.The calculation results are as follows:(1)The optimal coordination mode between catalyst and ligand is palladium with P and S atoms.This mode is different from the P and O coordination proposed by the authors.This mode can effectively reduce the steric hindrance between ligand and substrate.(2)The catalytic cycle for formation of spirocycle is divided into four steps:oxidative addition,intramolecular alkene insertion,C(sp2)-H activation,and C(sp2)-C(sp3)reductive elimination.The C(sp2)-C(sp3)reductive elimination with the enery barrier of 27.7 kcal/mol is identified as the rate-determining step.(3)In alkene insertion process,the high enantioselectivity of R-type intermediate originates from the stronger electronic interaction between the catalyst and substrate,the exclusive 5-exo-regioselectivity is due to the stronger nucleophilicity of the terminal alkene carbon atom,and the C-H activation is driven by thermodynamics.5.This work presents a theoretical study on the nickel/symmetric and asymmetric N-heterocyclic carbene catalyzed aldehyde-alkyne reductive couplings with silanes.The experimental literature was initiated published by Montgomery et al.of University of Michigan in 2008,and published in J.Am.Chem.Soc..Later,it was expanded by Shi et al.of the Shanghai Institute of Organic Chemistry to achieve the synthesis of asymmetric chiral allyl alcohols by nickel/asymmetric N-heterocyclic carbene catalyzed aldehyde-alkyne reductive couplings with silanes.We have conducted a systematic theoretical study of the two reactions in order to clarify the molecular mechanism and investigate the origins of the regio-,enantio-,and chemoselectivities.The findings can be summarized as follows:(1)The reaction with trialkylsilane is found to proceed through oxidative cyclization,Si-H/Ni-O σ-bond metathesis,and C(sp2)-H reductive elimination,and the initial aldehyde-alkyne oxidative cyclization is identified as the rate-,regio-and enantio-selectivities determining step.(2)While for the reaction with dialkylsilane,the present calculations identified a new favorable mechanism involving a Ni-C/Si-H σ-bond metathesis and dehydrogenation later.The catalytic pattern is different from the mechanism proposed by the authors.Our calculations also show that the steric hindrance is the key factor in controlling the regio-and enantio-selectivities.