镍催化C(sp~3)-F键活化耦合反应机理的理论研究

【作者】 张晓敏；

【导师】 刘玉霞；

【作者基本信息】 曲阜师范大学 ， 物理化学， 2018， 硕士

【摘要】 过渡金属催化的有机反应,由于其高的反应活性、选择性,优良的官能团兼容性等优点,在药物开发和有机合成领域有着广泛的应用,其中过渡金属催化的C-F键活化占据重要的一席之地,备受瞩目。近十几年来,人们对芳基、乙烯基和烯丙基氟化物C-F键的交叉耦合反应进行了深入而系统的研究,但实现三氟甲基的C-F键活化仍然是一项极富挑战性的任务。通常,断裂C（sp³）-F键使用低价态过渡金属进行氧化加成来完成,但C（sp³）-F键本身强的键离解能以及在三个氟原子上孤对电子的屏蔽效应导致反应条件相对苛刻,这在一定程度上限制了该方法的潜在应用。相比之下,β-杂原子消除能够在温和的实验条件下进行,因此,通过β-F消除断裂C-F键是目前较为合理的合成方法。目前,相关反应的区域和立体选择性控制,不仅是实验化学家需要解决的问题,更引起理论化学家的关注,去探索实验现象背后的本质,因此具有非常重要的科学意义和应用前景。本文论文通过密度泛函理论（DFT）方法,研究了Ni（cod）₂/PCy₃催化2-三氟甲基-1-烯烃（1）和炔烃（2）的耦合反应。计算表明,反应经历配体交换→烯烃配位→氧化环化（1+Ni（0）+2）→第一个β-F（C（sp³））消除形成烯基镍（Ⅱ）中间体。从该中间体开始,反应要么生成计量的去氟化[3+2]环加成产物3,要么生成去氟化耦合产物（无甲基化产物5,单甲基化产物8或三甲基化产物9）,这取决于加入了何种额外试剂（Et₃SiH,ZnMe₂或AlMe₃）。Et₃SiH的加入诱导反应生成产物5,是其转位步骤比生成3的5-endo插入更容易进行的缘故;由于F→Zn/Al相互作用的存在,ZnMe₂/AlMe₃的使用将甲基引入到去氟化耦合产物中;在化学计量反应中,产物3而非C（sp³）-F氧化加成产物被捕捉的化学选择性源于吸电子–CF₃基团的存在。在Et₃Si H参与的催化反应中,产物只生成5的化学选择性有如下原因:（i）Et₃Si-H氧化加成产物的形成是热力学不可行的。（ii）大的空间位阻和相对弱的Ni-Si的σ键严重影响了炔烃硅氢化产物的生成。此外,Ni…Zn之间弱的相互作用阻碍了导致产物9的C（sp³）-F氧化加成决速步的进行,因而最终产生区域选择性的产物8。而强的Ni…Al相互作用促使产物8进一步转化为产物9。更多还原

【Abstract】 Transition-metal catalyzed organic reactions possess extensive applications due to their specific properties including high reactivity,high selectivity as well as excellent furnctional group compatibility.Among these transformations,transition-metal-mediated C-F bond activation has occupied a significant research area,establishing new synthetic methodologies.During the past few years,striking developments have been made on the C-F bond activaiton of aryl,vinyl,and allyl fluorides.In contrast,the C-F activation of the trifuloromethyl group remains a great challenge,which might be attributed not only to the high bond dissociation energies of the C（sp³）-F bond but also to the strong shielding effect of the three F atoms.Usually,the C（sp³）-F bond is broken by the oxidative addition using transitional-metal catalyst in low valence,in which,however,the harsh reaction conditions are required.This,to a certain extent,limited the application of the methodlology.Alternatively,under the milder conditions,the cleavage of the C（sp³）-F bond can be achieved by theβ-fluorine elimination,which is considered as a much more reasonable method.So far,the related selectivity control is not only challenging to experimental chemists but attracts extensive attention of theoretical chemists.Therefore,theoretical studies are of great significance on exploring the intrinsic reasons behind the reactions.In this dissertation,the mechanisms,chemo-and regioselectivities of divergent Ni（cod）₂/PCy₃ mediated/catalyzed C（sp³）-F bond activation of 2-trifluoromethyl-1-alkenes（1）with alkynes（2）were investigated by density functional theory（DFT）calculations.The nickel-mediated/catalyzed reaction involves sequential ligand exchange,alkene coordination,the oxidative cyclization（1+Ni（0）+2）,and firstβ-F（C（sp³））elimination to give a common and requisite alkenylnickel（Ⅱ）species,which bifurcates into either stoichiometric defluorinative[3+2]cycloaddition product 3 or catalytic defluorinative coupling products（no-methylated 5,mono-methylated 8 or triply-methylated 9）depending on the absence and presence of additional reagents（Et₃SiH,ZnMe₂ or AlMe₃）.The Et₃SiH-induced formation of 5 is found to be a result of facile metathesis relative to the 5-endo insertion leading to 3.Because of the presence of an F→Zn/Al interaction,ZnMe₂/AlMe₃ brings the methyl into defluorinative coupling products.In the stoichiometric reaction,the chemoselectivity of 3 over C（sp³）-F oxidative addition product originates from the presence of the electron-withdrawing–CF₃ group.Under the Et₃SiH-involved catalytic environment,the chemoselectivity of the formation of 5 can be explained as follow:（i）the formation of an Et₃Si-H oxidative addition product is thermodynamically infeasible and（ii）the large steric hindrance as well as the weak Ni-Siσ-bond heavily influences the generation of alkyne hydrosilylation complexes.In addition,the weak Ni…Zn interaction impedes the rate-determining C（sp³）-F oxidative addition leading to 9 and eventually provides regioselective product 8,while the strong Ni…Al interaction promotes the evolution of the initially formed 8further into 9.更多还原