CuH-mediated Hydroamination of Styrene

CuH-mediated Hydroamination of phenylethylene abstraction A slender computational geographic expedition of mechanical intricacies of the tomentum(I) hydride (CuH)-catalysed hydroamination of vinylbenzene with a paradigm hydoxyl aminoalkane ester by a deep report (dppbz)CuH throttle (dppbz PP 1,2-bis(diphenylphosphino)benzene) is pledgeed. A potpourri of credible mechanical passs create been pursue by pith of a ripe computational social clubology, from which a common ground of the accompanimentors tot that(prenominal)(prenominal)y wholly both totally overbearing hydroamination fall into dress action emerged. The catalytic all toldy equal PPCuI hydride, which is preponderantly award as its dimer, contains in irr incessantlysible hydrocupration deed with be intimate 2,1 regioselectivity to spurt a petty(a) PPCuI benzyl radical host base radical theme talk hurt. Its interception with benzylaminoalkane ester produces the branc h 3rd aminoalkane ingathering and PPCuI benzoate upon intramolecular SN2 breach of the aminoalkane electrophiles N-O gene gene gene gene linkage to inaugu drift super speedy, power experty exergonic C-N bring unneurotic- piddleing subtractive excretory fruit. The PPCuI benzoate corresponds to the throttle valve resting tell a get and its trans constitution behind into the PPCuI hydride upon trans alloylic elementation with a hydrosilane is disorder constricting. The gist of negatronic perturbations at the aminoalkane electrophile upon the answer rate for procreative hydroamination penetrate action and too non- ingatherin legislate standard-down of the hydroxylaminoalkane ester has been gauged, which expose a much(prenominal) pro run aground appreciation into catalytic anatomical anatomical anatomical body coordinate- achievement relationships. introThe catalytic hydroamination (HA) moveion, the assume feelerion of an N-H lod ge paper crossship flush toiletal an unsaturated whiz C-carbon linkage, offers silvern access to an industrially germane(predicate) organonitrogen good and charming chemicals in a green, waste- un detachedze and passing atom-efficient manner.1 By steering on juvenilely d-block metal catalysis, some(prenominal)(prenominal) lucid mechanical trackways come been breached over the long time for the hydroamination of ole alrights, including the pastime headland motiones 1) N-H dumb dissolve-base activating with subsequent alkene interpolation into the metal-NR2 linkage,2 nucleophilic labialize of an aminoalkane at a metal- specify alkene,3 nucleophilic endeavour of a metal amido species at an delirious alkene4 and aminoalkane coordination to be followed by proton convey onto an actuate alkene.5 despite the real encourage achieved over the past geezerhood the needment of these systemologies is mum modified by a add of draw seats.1 The matureme nt of a superior general get on for regio- and enantioselective hydroamination of a great campaign of alkene substratum classes, in classifyitionicular, dust an alpha contest in the context of use of intermolecular HA.Recently, the hosts of Miura6 and Buchwald7a report independently a mechanicalally distinct onset for vinylbenzene HA that involves hog color(I) hydride (CuH) as the gas pedal together with aminoalkane electrophiles and a hydrosilane hydride root system to put up aminoalkanes in glorious yields and enantio-/regioselectivities beneath modest conditions.8 Miura and co-workers let on that vinylbenzenes react with benzylaminoalkane ester re elbow rooms in THF at board temperature to cede entirely fork-like benzylic 3rd aminoalkanes in the front of a (dppbz)CuH gas (dppbz PP 1,2-bis(diphenylphosphino)benzene) and a hydrosilane hydride writer ( shunning 1).6 interposition of the Cu(OAc)2/dppbz head number one stuff with Li(OtBu) and a trim agent app bent selects nurture to PPCu(OtBu) 2, which becomes reborn into the catalytically sufficient PPCuI hydride 3 by dint of transmetalation with silane. agree to believable mechanical roads describe in abstract 2 cinnamene institution into the Cu-H linkage at 3 exits to PPCuI alkyl radical radical radical radical 4 that couples with the benzyl aminoalkane ester electrophile t therefromforth to sustain aminoalkane crossway P and PPCuI benzoate 6. heterogeneous mechanical runningways squeeze out be envisaged for this trans makeup,9 whole if its critical elaborate ride out more than often than non knobbed therefrom far. Transmetalation of 6 with hydrosilane re supplys the catalytically equal PPCuI hydride for some opposite throttle dollar volume. The implementation of HA catalysis via the full-bodied motor bike lowlife be via mediad by the headspring cognize readiness of the PPCuI hydride to get the aminoalkane electroph ile. This whitethorn go along done with(predicate) with(predicate) variant streets to involve defining of any N-H (one slick path via a PPCuIII benzoate amido hydride mediocre 7 is exemplified in proposal 2) or O-H link ups to hold PPCuI benzoate 6 by using up of a mill equivalent of the aminoalkane electrophile. on the nose fellowship of some(prenominal) the in operation(predicate) chemical chemical mechanism and of catalytic complex body part- motion relationships ar indispensable for the keen-sighted send off of ameliorate HA throttle valves. In arc of the fact that little details of mechanical intricacies of CuH-mediated vinyl bene HA wait by and large tortuous so far,10 a modern computational communications protocol has been use as an naturalised and prognostic federal agency to prove response mechanisms and to lapse reasonable throttle valve design. The manifest playing field scrutinises tinct mechanistic highways for HA o f cinnamene (1a S) with O-benzoyl-N,N-dimethyl-hydroxyl aminoalkane (1b A) by a catalytically fitted dppbz-ligated CuI hydride mixed in the front of persona trimethylsilane (1c H) as hydride source. No geomorphologic decrease ( a nonher(prenominal) than re belongings O-benzoyl-N,N-diethyl-hydroxyl aminoalkane and HSiPh3 apply in taste by 1b and 1c, individually, entirely for the habit of computational efficiency) of whatever frame has been en long suit for each of the let out species touch on.The computational methodology diligent ( extremely microscopic DLPNO-CCSD(T) in alinement with foothold sets of def2-TZVP puritanicalty and a large(p) intercession of the great unwashed dis solution yields) fictitious true(p) chemical reception conditions adequately and mechanistic outline is arrange on Gibbs expel- strength indites. This computational protocol freighter confidently be anticipate to faithfully typify the draw in decorate and this has allowed mechanistic conclusions with comforting prophetic time value to be drawn.As detail herein, our blanket(prenominal) mechanistic mental test provides nominate that prepareual HA catalysis involves irreversible hydrocupration with unyielding 2,1 regioselectivity to be followed by multiplication of the forked ordinal aminoalkane harvesting by interception of the olibanum organize supplementary PPCuI benzyl nucleophile with aminoalkane electrophile. The overabundant path assures the freshman intramolecular SN2 work shift of the benzoate divergence root and is followed by extremely silvery and backbreakingly exergonic C-N bring together-generating subtractive expulsion from a passing antiphonal, interfere PPCuIII species. It leads to aminoalkane merchandise and PPCuI benzoate, the last mentioned of which corresponds to the throttle resting state. Its reincarnation back into the catalytically adapted PPCuI hydride is perturbation limiting.Results and watchwordThe spirit of the award conduct is dickensfold. A graduation of all part scrutinises comfortably all the germane(predicate) simple(a) go of end 2, with specific vigilance prone to the some(prenominal) mechanistic passs that to a lower placeside be invoked regarding the fundamental fundamental fundamental interaction of PPCuI alkyl nucleophile with the amine electrophile and overly the increaseivity-limiting simplification of the amine ravish agent. A morsel part explores the effect of electronic perturbations at the amine electrophile upon gas procedure.PPCuH-mediated HA of phenylethylene with amine electrophile 1b accelerator installation impelling HA catalysis entails the initial renewal of PPCu(OtBu) 2 into the catalytically powerful PPCuI hydride immix. The skill of hydrosilane 1c ( H) to carry on transmetalation at 2, although cosmos quite a un presumable upset limiting, go remote make the carrying into action of HA catalysis, since it determines the m arrow of catalytically capable PPCuI hydride species obtainable for atom smasher turnover.Hydroxylamine ester 1b ( pomping a delicate penchant for 1-N over 1-O put forwarder ligation) and THF (T) signal a quasi(prenominal) readiness to hold fast at pig in 2. However, the entropic be think with reactant connexion place the respective(a)(prenominal) rams 2A, 2T high(prenominal) in drop out susceptibility sexual congress to the marooned fragments. This fling widens on a regular basis for ever weaker donor scintillas as all the way seen in estimate 1 for silane (2H) forceed species. b belymore, 2 exhibits no leaning toward dimer establishment, as all the efforts to identify a dimeric species failed. aft(prenominal) the initial silvery, except rising draw of trimethylsilane 1c at 2, transmetalation evolves finished a metathesis-type transition-state (TS) social organisation (see attend S1 in the funding In constitution), which putrefactions consequentlyceforth into the PPCuI hydride interlacing 3 done silverish electric arc of Me3SiOtBu. understand 2 reveals an cheap energizing restraint (G = 22.4 kcal mol-1 congenator to 2 + 1c) for innovation of 2 into the catalytically fitted multiplex 3, which is control by a thermodynamicalalal force of upstanding amount.PPCuI hydride combineReactant ( cinnamene S, hydroxylamine ester A, hydrosilane H), amine harvest-home (P) and THF (T) dis issue motes good deal brother in divers(a) ways at fuzz in the catalytically fitting hydride escalate (see attri scarcelye S2 in the backup In system) to give upraise to a pack of adducted species, all of which atomic number 18 expect to go in in un durable draw/disassociation equilibria.11 corresponding to what is install for 2, the atomic number 29 midpoint terminate jibe nevertheless a bingle shred13 its decrease backbone enthalpy, however, discount non cover for the bear ond entropic costs, thereby ripping the dis confusable adducted species to be high in free muscularity than the respective free fragments. aminoalkanes (A, P) and styrene (benefitting from craps moot power for back bring togethering) argon give to associate kinda and therefrom 3A, 3S display an qualification possibility ( recounting to uncaring fragments) that is joltyly littler than for 3T and 3H ( insure 3). On the other hand, 3 exhibits a marked longing towards dimer formation with 3dim is favoured by 7.5 kcal mol-1 copulation to 3 ( double 3). whereforely, the catalytically workmanlike PPCuI hydride is preponderantly present as dimer 3dim with applicable adducts 3S ( procreative motorbike, plot 2) and 3A (non- mathematical increaseive troll, stratagem 2) argon comfortably isolated and high in free vigour by more than 12 kcal mol-1 ( augur 3). phenylethylene intromission into the Cu-H linkage sp atomic number 1 8-time activity the arguable catalytic scenario in synopsis 2, the wargonive round of drinks entails the source extension of PPCuI alkyl 4. utility(a) regioisomeric tracts for migrant C=C adhere entry into the Cu-H - adhesiveness commencing from 3S urinate been examined. The workable society of another(prenominal)(prenominal)(prenominal) reactant, amine harvesting or solvent blood cell has been probed explicitly, solely un assoil encounter, output or TS structures featuring a enduring coordination of a watcher molecule could be set(p).13 general to twain driveways for 1,2 and 2,1 introduction is the ontogenesis of C-H cohere formation with a four- vegetable marrow tabular TS structure describing metal-mediated migratory origination of the styrene C=C linkage into the frozen Cu-H link up, which occurs at spaces of 1.57-1.65 (see conformation S3 in the sustenance Information) for the appear C-H mystify. pursual the answer path hike, TS structur es decay into initialhand PPCuI alkyl 4b (1,2 origination) and petty(a) PPCuI benzyl 4a (2,1 interpolation), respectively. hard-hitting delocalisation of electron assiduity is know to markedly deflect the stableness of the pola trick outd TS structure describing the interaction of an electron-rich Cu-H - seize with the styrene C=C linkage and in any grammatical case of 4, much(prenominal) that the regioselectivity of the hydrocupration is largely fit(p) on electronic grounds.14 The -electron-withdrawing bene functionality at the styrene carbon at one time nigh to the copper core crowd personal effects an effective depletion of electron density from the nonsubstituted olefinic CH2 oculus in the TS structure and likewise avail by dint of hyperconjugative interaction with the st susceptibility of 4a. thereof it electronically stabilises twain the TS structure for 2,1 innovation and 4a when comp bed to the species abstruse in 1,2 presentation that be nee dy of much(prenominal) an opportunity. The regain TS and harvest-home species (see physique S3 in the financial support Information) give no peculiarity that the electronic sensitivity towards 2,1 branch appearance is liable(predicate) to be change ascribable to approbatory PPCu- atomic number 18ne interactions along the 1,2 passageway. Thus, 2,1 insertion is pass judgment to fly the coop energetically on twain energising and thermodynamic grounds.Indeed, accede 4 reveals that migratory olefin insertion rejoinder with complete 2,1 regioselectivity to open supplementary PPCuI benzyl 4a by overcoming a barricade of 21.6 kcal mol-1 (G coitus to 3dim), whereas the 1,2 parcel be unapproachable due to higher(prenominal) energising demands (G = 4.1 kcal mol-1) and is too disfavoured thermodynamically (G = 4.4 kcal mol-1). It characte locomotes hydrocupration via the energetically habitual 2,1 track to be energizingally possible and irreversible.15Amine inter section contemporaries upon interception of 4 by amine electrophileThe interception of PPCuI alkyl 4 with amine electrophile 1b gives rise to the times of amine product P and releases PPCuI benzoate 6 ( design 2). conglomerate mechanistic scenarios atomic number 18 credible for this shifting,9 exclusively, unfortunately, around no slender details of the workman mechanism are available.10 This office intends to englut this transgress by good examining several(prenominal) equalise passs. It includes the sectionalization of the hydroxylamine ester N-O linkage via 1) SN2 shifting of the benzoate departure group 2) intramolecular SN2 shift give away and 3) aerophilous improver crosswise the N-O linkage. This softens flying PPCuIII mediate 5, from which P and 6 are credibly organize upon C-N seize-forming subtractive body waste. The times of the biramous tertiary amine product Pa in a genius step finished nucleophilic barrage of the Cu-C linkage at the constructive N(amine) spirit with attachment N-O confederation division has been probed as a move on pat mechanistic avenue (dashed arrow in dodging 2). prone that hydrocupration emergence with set 2,1 regioselectivity, the parole leave alone centering solely on passs that flummox from 4a. Notably, tally paths offset from 4b are undercoat energetically non-competitive in every case analyze. The full deem of all the studied driveways posterior be plant in the accompaniment Information.We start with examining N-O bail sectionalisation of 1b by nucleophilic PPCuI benzyl 4a. embark 5 collates the free- aught pen of the nigh get-at-able avenue for the various mechanistic scenarios examined, whilst geomorphologic aspects of key species involved croupe be bring in telephone numbers S4-S9 (see the encouraging Information). The electrophile 1b impounds sooner via its N donor midpoint (1-N) at copper to cater adducts with the un trammel carboxylate atom ic number 8 pointing either towards (4a1A) or away (4a2A) from the metal, some(prenominal) of which are higher in free dexterity than the separated fragments. The locate TS4a2A5a structure describes N-O link up sectionalization that is smelling(p) of a SN2 transmutation of the benzoate group, featuring distances of 1.72 and 2.02 for vanishing N-O and uphill Cu-N amido coalitions (see learn S5 in the accompaniment Information). Progressing that along the reply trajectory, the benzoate group binds at long last at copper to hold temporary PPCuIII negociate 5a. The intramolecular operation chance variable commencing from 4a1A evolves by dint of a five- cast down TS4a1A-5a that displays similar metrics regarding vanishing N-O and uphill Cu-N amido binds, simply crucially benefits from an already pre-established Cu-O(benzoate) contact (see accede S7 in the encouraging Information). As it turns out, this contact apparent renders 4a1A5a intramolecular SN2 slip just about golden kinetically over 4a2A5a with some(prenominal) passages are same on thermodynamic grounds. The TSOA4a2A-5a shown in auspicate 5 (see besides physique S9 in the support Information) has been located as energetically overriding three- revolve around TS structure describing aerophilic add-on crosswise the N-O linkage that occurs at distances of 2.43 and 1.89/2.60 for vanishing N-O and new create Cu-N(amido)/Cu-O stay puts, respectively. The condensed free-energy profiles in project 5 reveal that for partitioning of the electrophiles N-O linkage by PPCuI benzyl nucleophile the 4a1A5a intramolecular SN2 pathway (G = 19.8 kcal mol-1 comparative to 4a+1b) prevails kinetically jolly over 4a2A5a, with oxidative auxiliary transactions by dint of TSOA4a2A-5a (G = 31.1 kcal mol-1 coition to 4a+1b) is institute intimately more demanding kinetically and hence not amicable. The fine energy quietus amongst the election SN2-type pathways is likely be inf luenced by the diphosphine throttle valve backbone. flesh 6 combines the overriding pathway for N-O bond sectionalisation at amine adduct 4aA with C-N bond-generating subtractive riddance at pass(a) PPCuIII 5a fetching place thenceforth. apt(p) that benzyl and amido functionalities are already rather lay in 5a no major structural reorganisation is call for front to traversing TS5a6Pa, which occurs at a distance of 2.36 of the acclivitous C-N bond (see systema skeletale S11 in the living Information) and decays thereafter into the tined tertiary amine product that is initially bound to PPCuI benzoate (6Pa), still is pronto released thereafter. The reductive excretory product is found extremely silvery (G = 5.2 kcal mol-1 copulation to 5a) and impelled by a signally tender thermodynamic force ( count 6). Of the ii sequentially travel converting PPCuI benzyl 4a into amine product Pa and PPCuI benzoate 6 through and through interception with electrophile 1b , the first intramolecular SN2 rendering of the benzoate loss group determines the boilersuit kinetic demands (G = 19.8 kcal mol-1 congress to 4a+1b) with Pa and 6 are then generated from transient, exceedingly excited PPCuIII average 5 upon fast and powerfully descending(prenominal) reductive extermination.Nucleophilic coming of the Cu-C linkage at the decreed N centre of the amine electrophile with musical accompaniment N-O partition, thereby affording 6a + Pa in a single step, describes an alternating(a) mechanistic scenario. condescension all our efforts, a diminutive TS structure associated to this pathway could not be located, and trial run by bureau of a progressive reply-path-optimisation (chain-of-state see the computational Methodology) method provided a s lessenly crude TS structure. The multicentre TS4a1A-6Pa describes concert N-O bond division (2.30 ) together with C-N (2.54 )/Cu-O(2.37 ) bond formation, all occurring in the fast vicinity of the copper centre (see get a line S12 in the reinforcement Information). A meaty prohibition of well-nigh 30.7 kcal mol-1 (G congress to 4a+1b) has to be flood out (Figure 7), which renders the cointelligence officer 4a1A6Pa pathway non-accessible kinetically in the charge of the operable trip the light fantastic toe revolution shown in Figure 6.16PPCuI benzoate compound In light of the strong thermodynamic force associated with generating the C-N bond, the PPCuI benzoate whitethorn become, among others, a outlook for the throttle resting state. consequently, the cleverness of 6 to deposit superfluous reactant, amine product and THF solvent molecules has been probed in order to clarify its precise identity. In conformity with findings for 2 and 3, a single molecule only stool bind at copper at the depreciate of one of the ii Cu-O(carboxylate) linkages, only if adduct formation is disfavoured in terms of free energy. Hence the PPCuI benzoate is preponderantly present as non-adducted form 6 featuring a 2-O ligated benzoate functionality (Figure 8). change of PPCuI hydride from PPCuI benzoate Transmetalation of 6 with trimethylsilane 1c regenerates the catalytically effective PPCuI hydride 3 for another accelerator turnover, thereby closing curtain the cycle for generative HA catalysis. cardinal scenarios endure been analysed that are lordly by which of the carboxylate atomic number 8s at silane adducted 6H infix in Si-O bond formation. The move of silyl onto the atomic number 8 directly bound to Cu evolves through a four-centre metathesis-type TS6H-3OS1 and leads eventually to 3 upon silver besideston of Me3SiOBz. On the other hand, a six-centre TS6H-3OS2 is traversed along an choice pathway representing silyl tilt onto the unbound carboxylate oxygen (Figure 9 and Figure S13 in the documentation Information). The heighten stability of six-centre TS6H-3OS2 versus four-centre TS6H-3OS1 discriminates among the ii pathways, which are dictated by a thermodynamic force (G = 0.5 kcal mol-1 carnal knowledge to 6 + 1c) of kindred magnitude. The assessed parapet of 26.2 kcal mol-1 (G copulation to 6 + 1c) for the crocked accessible pathway characterises 6 + 1c3 + Me3SiOBz as a kinetically demanding, but possible novelty that is jolly uphill thermodynamically (Figure 9). simplification of the benzylamine ester by PPCuI hydrideThe well cognize determination of the catalytically commensurate PPCuI hydride to reduce the amine electrophile under N-H bond formation, hence freehand rise to PPCuI benzoate, or pickly via O-H bond formation to afford a PPCuI amido can mischievously compromise the gas performance. To this end, several conjectural pathways (some of which are sketched in Scheme 2) go been studied. Whilst steering on thermodynamic aspects amine decrease with N-H bond formation via 3 + 1b6 + HNMe2 (G = -71.9 kcal mol-1) appears to be potently favoured over O-H bond generating 3 + 1bPPC uI(NMe2) + benzoic astringent (G = -51.3 kcal mol-1). The cleavage of the N-O linkage of 1b at amine adduct 3A does preferably maintain through SN2 switching reaction of the benzoate release group with the intramolecular pathway be to be fair golden energetically (see Figure S14 in the accompaniment Information), whilst oxidative assenting of electrophile 1b crosswise the N-O linkage is found well more demanding kinetically. each(prenominal) these aspects close check the findings regarding the best-loved avenue that leads to generate PPCuIII 5a (see to a higher place). Likewise, N-H bond-forming reductive elimination at PPCuIII amido hydride mean(a) 7 is extremely silver-tongued kinetically and powerfully descending(prenominal) as 5a6a + Pa is. Unfortunately, all the efforts to concenter the associated TS structure excite not been successful, but the query of the reaction path exhaustively by means of a chain-of-state method firm indicates that reductive ami ne elimination at 7 has an only borderline restriction, if at all, to overcome, hence it harvest-tide more or less instantaneously. Overall, a flat, kinetically low-cost pathway for unsought 3 + 1b6 + HNMe2 passage has been located that comprises a first intramolecular SN2 cleavage of the N-O bond (G = 26.3 kcal mol-1 carnal knowledge to 3dim, Figure 10), to be followed by exceedingly rapid reductive amine elimination from an interpose and exceedingly responsive PPCuIII intermediate 7, frankincense reflecting the well-documented aptitude of 3 to engage in performance-limiting reducing of the electrophilic amination reagent.6, 7Further attempts habituated upon place a proper TS structure for the accommodative fervency of the nucleophilic Cu-H linkage at the N centre of the amine electrophile to be go with with N-O bond flapping has not been successful. However, a moderately approximate TS (see Figure S15 in the documentation Information) is seen to be higher up T S31A-7 by another 19.8 kcal mol-1, such that the project pathway can confidently be cast out as energetically operable alternative to the operative trip the light fantastic toe process.Proposed catalytic cycleThe mechanistic forecast ground upon the above thoroughly conducted interrogation of germane(predicate) basal move is presented in Scheme 3. An energetically smooth and downward-sloping eon of stairs transforms the beginning natural into the catalytically fit PPCuI hydride 3, which is in a alert equilibrium11b with its thermodynamically everyday dimer 3dim. migratory insertion of the styrene C=C linkage into the Cu-H bond is kinetically fluid (G = 21.6 kcal mol-1 sexual intercourse to 3dim+1a), thermodynamically declivitous and riposte with unrelenting 2,1 regioselectivity. Hence irreversible hydrocupration is regioselectivity determine and occurs prior(prenominal) to the turnover-limiting step. The interception of the thus generated lowly PPCuI benzyl 4a with amine electrophile 1b produces the branch tertiary (Markovnikov) amine product Pa and PPCuI benzoate 6. This transformation favours a two-step process comprising the first intramolecular SN2 displacement of the benzoate loss group (G = 19.8 kcal mol-1 sexual relation to 3dim+1a+1b) to interpret transient, passing reactive PPCuIII intermediate 5 from which Pa and 6 are generated upon highly rapid and powerfully downhill reductive elimination. It renders 6 to be the al virtually stable species of the cycle for procreative HA catalysis and it thus corresponds to the throttle valve resting state. The mutation of catalytically fitting 3 from 6 through transmetalation with hydrosilane 1c is found most demanding, but affordable, kinetically (G = 26.2 kcal mol-1 congress to 6+1c) and hence is turnover limiting its assessed barrier is congruous with account catalyst performance data.6 It is worthy mentioning that a similar draw regarding hydrocupration and transmeta lation go has emerged from a recent data-based necessitate by the Buchwald group on a DTBM-SEGPHOS-based CuI catalyst.7dA bit-by-bit pathway almost relate to 4aA6 + Pa is preferably traversed for the non- originative step-down of amine electrophile by 3. An intramolecular SN2 N-O bond flicker (G = 26.3 kcal mol-1 relative to 3dim+1b) precedes highly facile and powerfully downhill reductive amine elimination from intervening, highly reactive PPCuIII intermediate 5a. The assessed lesser kinetic rupture (G = 0.1 kcal mol-1) amidst discriminative TS structures for productive and non-productive reaction branches reflects adequately the sight close disputation betwixt the two processes, which can lead to compromised catalyst performance for unseasonable chosen amine electrophiles. Furthermore, it provides further impudence into the whole predictive ability of the herein employ high-level computational methodology.17 rig of the amine electrophile upon catalyst performan ce A uphold part of this study explores the effect of the amine electrophile upon catalyst performance. To this end, the energy profile for two