Theoretical Studies On Copper-catalyzed Aerobic Amine Oxidation Of Olefins And Flavin-catalyzed Aerobic Epoxidation Of Olefin

Oxidation reaction is an important category of organic reaction.Traditional oxidation reactions rely on expensive,highly toxic and non-environmentally friendly oxidants such as metal salts,metal oxides,oxygen acids,peroxides and amine oxides.In contrast,dioxygen is cheap,easy to obtain,renewable and generates environment-friendly by-products,and has attracted much attention from researchers,being considered as an ideal oxidant for developing green oxidation reactions.However,dioxygen is a gas under normal conditions and has low solubility in organic solvents,which makes it less oxidative than traditional oxidants.In addition,dioxygen owns triplet ground state,making dioxygen prone to free radical reactions but difficult to participate electrophilic and nucleophilic organic reactions.Therefore,the development of aerobic reaction highly depends on efficient catalytic systems to activate and adjust the activity,reaction characteristics and selectivity of dioxygen.Deeper mechanistic investigation can provide valuable theoretical guidances for catalyst design.In this paper,the advances of recent experimental studies on copper-and flavin-type-small-molecular-catalyzed aerobic reactions and flavin were introduced first.Then,the mechanisms of copper-catalyzed amiooxygenation of alkene-tethered amides and flavin-catalyzed epoxidation of S-methyl cyclohepta-1,4,6-triene-1-carbothioate were by means of density functional theory（DFT）calculations.The mechanistic study on the mechanism of Cu-catalyzed aerobic aminooxygenation of alkene-tethered amides indicates that Cu（I）catalyst precursor is not active species,but can in situ generate two active mononuclear complexes LCu（OAc）OH and LCu（OAc）OOR via the formation of binuclear Cu（III）-oxo complexes,binuclear Cu（II）-OH complexes,heterobinuclear Cu（II）-Cu（I）complexes and the capture of alkyl peroxyradical by Cu（I）complex.LCu（OAc）OH is an active catalyst in the aminooxygenation reaction in which LCu（OAc）OOR is an active intermediate.In the aminooxygenation reaction,LCu（OAc）OH first converts alkene-tethered amide intoα-acylamino aldehyde,and then yields imide product.The formation ofα-acylamino aldehyde and imide is accomplished by two steps from LCu（OAc）OOR intermediate,including acetate-assisted proton coupled electron transfer（PCET）and concerted PCET/O-O bond cleavage among which the second steps are the rate-determining steps.During the conversion ofα-acylamino aldehyde to imide,the previously-proposed C_α-H activation pathway was found to produce CO₂as a byproduct,which is inconsistent with experimental observation.A more feasible C（O）-H activation pathway was located,and it produces CO as a byproduct and is consistent with experimental observation.The mechanistic study on the epoxidation of S-methyl cyclohepta-1,4,6-triene-1-carbothioate catalyzed by flavin-type small molecule indicates that the divalent anionic catalyst proposed in the previous study is not the active one while the active site for dioxygen binding was not the N5 site.A more plausible mechanism including hydride transfer from the C1 site of cyclohepta-1,4,6-triene-1-carbothioate anion to the N5 site of flavin catalyst,spin-state-change-promoted C-O bond formation at the C4a site of flavin catalyst,peroxyl radical addition to the C2 site of carbothioate,concerted O-O bond cleavage/epoxidation,nucleophilic substitution of methyl thiobate by alcoholate intermediate.Among these steps,the hydride transfer is the rate-determining step.It was also found that the C10a site of flavin catalyst is not the active site for O₂binding,and the addition of peroxyl radical to the C1 site or the carbonyl carbon of carbothioate are less favored mechanisms.The above theoretical studies have for the first time clarified the detailed reaction mechanisms of Cu-catalyzed aerobic aminooxygenation of alkene-tethered amides and the aerobic epoxidation of cyclohepta-1,4,6-triene-1-carbothioate catalyzed by flavin-type small molecule.A new mechanism involving acetate-assisted stepwise C-to-O hydrogen transfer,a new pathway starting from C（O）-H bond activation,the superoirty of hetero-counterionic Cu（II）catalysts and the active structure and the active O₂binding site of flavin-type small molecule catalyst were elucidated.The relevant results have modified and expanded the knowledge of aerobic reactions catalyzed by copper complexes and flavin,especially provided a deeper insights into the structural-activity relationship of catalysts,which has theoretical guiding value for the further experimental design.