during 
 the past few decades , tremendous progress has been described 
 in the development of transition - metal - catalyzed cross - coupling reactions . palladium - catalyzed processes have been the primary 
 focus of interest , mechanistic studies of which have established the 
 feasibility of an array of catalytic cycles , the predominant ones 
 involving palladium(0)/(ii ) . complexes of nickel , a congener 
 of palladium , have been less thoroughly 
 investigated as catalysts for cross - coupling reactions , although this 
 situation has begun to change in recent years . correspondingly , 
 the mechanisms of nickel - catalyzed couplings are also less well - studied , 
 and no single pathway has yet been shown to be especially common . during the past decade , we have pursued 
 the development of a wide 
 range of nickel - catalyzed cross - couplings of alkyl electrophiles , 
 including stereoconvergent reactions of racemic activated and unactivated 
 alkyl halides ( eq 1 ) . we 
 have postulated that cleavage of the c  x bond may occur via 
 a radical pathway , and vicic and phillips have reported experimental 
 and computational studies , respectively , that are consistent with 
 certain negishi couplings of unactivated alkyl electrophiles proceeding 
 through a transmetalation - first pathway ( figure 1 ) . recent mechanistic investigations by weix ( reductive coupling ) and hu ( kumada cross - coupling ) of nonasymmetric nickel - catalyzed couplings of unactivated 
 alkyl electrophiles have provided support for diverse reaction pathways.1 outline of one of the possible mechanisms for nickel - catalyzed 
 cross - coupling of unactivated alkyl electrophiles : transmetalation 
 before oxidative addition . to the best of our knowledge , to date there have been no 
 systematic 
 experimental investigations of the mechanism of nickel catalysts that 
 have been employed in enantioselective cross - couplings of alkyl electrophiles , 
 although there has been one computational study . in this report , we describe our examination of the pathway 
 for a stereoconvergent negishi arylation of racemic propargylic halides 
 that we reported in 2008 , catalyzed by nickel / pybox ( eq 2).2 x - ray 
 crystal structures of [ ( ( )-i - pr - pybox)niph]bar4 ( 1 ; left ; ni  pyridine 
 1.898(2 )  ; ni  ph 1.881(3 )  ) and ( ( )-i - pr - pybox)niph ( 2 ; right ; ni  pyridine 
 1.871(3 )  ; ni  ph 1.896(3 )  ) ( ellipsoids are shown 
 at 50% probability , and hydrogens , disordered fluorine atoms , and 
 additional molecules in the asymmetric unit are omitted for clarity ) . as part of 
 our initial investigation , we attempted to synthesize 
 and structurally characterize a ( pybox)niph complex , a 
 possible intermediate in the catalytic cycle for cross - couplings of 
 unactivated , as well as potentially for activated , electrophiles ( e.g. , 
 figure 1 ) . unfortunately , 
 our efforts with indanyl - pybox as the ligand were unsuccessful . however , 
 by instead employing i - pr - pybox , which furnishes 
 similar yield and ee in a negishi arylation of a propargylic bromide 
 ( eq 3 ) , we were able to achieve our objective.3 thus , treatment of ( ( )-i - pr - pybox)nibr2 with ph2zn and 
 then nabar4 ( bar4 = 
 tetrakis(3,5-bis(trifluoromethyl)phenyl)borate ) 
 provides [ ( ( )-i - pr - pybox)niph]bar4 ( 1 ) in good yield ( 70% ; eq 4 ) . a single - crystal x - ray diffraction study established 
 that this nickel complex adopts a square - planar geometry , consistent 
 with its formulation as a diamagnetic d ni(ii ) complex 
 ( figure 2 , left ) . electrochemical analysis 
 of complex 1 reveals two reversible reduction waves , 
 centered at 1.37 and 2.36 v versus fc / fc ( 0.10 m tbapf6 in thf).4 reduction of [ ( ( )-i - pr - pybox)niph]bar4 ( 1 ) with cp*2co ( 1.94 v versus fc / fc ) provides the desired phenylnickel(i ) 
 complex , ( ( )-i - pr - pybox)niph 
 ( 2 ; eq 5 ) . the solid - state structure 
 of nickel(i ) complex 2 is very similar to that of the 
 nickel(ii ) cation in [ ( ( )-i - pr - pybox)niph]bar4 ( 1 ; figure 2).5 the epr spectrum of ( ( )-i - pr - pybox)niph ( 2 ) displays an approximately 
 axial signal 
 centered at g = 2.00 that shows coupling to a single n atom in one g component ( figure 3 ) . this is consistent with a largely ligand - centered 
 radical , i.e. , a nickel(ii ) center bound to a singly reduced ligand , 
 a description previously put forward by vicic to describe the electronic 
 structure of ( terpyridine)nime . epr spectrum of ( ( )-i - pr - pybox)niph ( 2 ; black ) and corresponding 
 fit ( red ) . fit 
 parameters : g1 = 2.0067 , g2 = 2.0075 , g3 = 1.9889 , n coupling ( mhz ) = 0.0205 , 0.0124 , 47.2047 , line width = 
 0.9929 . x - band epr spectra were collected at 77 k in a toluene glass 
 at  = 9.411 ghz at 2 mw power and a modulation amplitude of 
 2 g. in view of previous reports implicating 
 an organonickel(i ) complex 
 as a potential intermediate in cross - coupling reactions of alkyl electrophiles 
 ( e.g. , figure 1 ) , we examined the reactivity of ( ( )-i - pr - pybox)niph ( 2 ) toward a propargylic bromide . carbon 
 bond formation does indeed occur , although in modest yield and enantioselectivity 
 ( eq 6).6 under the same conditions , 
 the phenylnickel(ii ) complex , [ ( )-(i - pr - pybox)niph]bar4 ( 1 ) , reacts with 
 the propargylic bromide to furnish 
 the coupling product in substantially higher yield and ee than in 
 the case of the phenylnickel(i ) complex ( 2 ) ( eq 7 versus eq 6 ) . the results 
 for the phenylnickel(ii ) complex are more consistent with the efficiency 
 and the enantioselectivity of the catalyzed process ( eq 3).7 the reaction of the phenylnickel(ii ) complex ( 1 ) with 
 the propargylic bromide proceeds at the same rate in the dark as in 
 ambient light , and it is inhibited by a substoichiometric amount of 
 tempo ( 2,2,6,6-tetramethyl-1-piperidinyloxy ) . thus , in the presence 
 of 0.02 equiv of tempo , essentially no reaction between the phenylnickel(ii ) 
 complex and the propargylic bromide is observed after 4 h at room 
 temperature ( eq 8) , in contrast to the tempo - free 
 reaction ( eq 7 ) ; however , after 48 h , the coupling 
 has proceeded to completion , demonstrating a tempo - induced induction 
 period ( eq 8) . analysis of the reaction mixture 
 by esi+ms reveals a signal with m / z of 324.27 , the expected mass of the product of capture of the propargylic 
 radical by tempo . these data are consistent 
 with inhibition by tempo of a radical chain process that is subject 
 to slow , ongoing initiation , with product formation commencing only 
 after the tempo has been consumed ( tempo reacts with alkyl radicals 
 with rate constants of 1  10 m s to effect chain termination).8 we postulate that an odd - electron nickel(i ) 
 complex may be generated 
 slowly at room temperature and serves as an initiator for carbon carbon 
 bond formation through a radical chain process that includes an overall 
 bimetallic oxidative addition ( figure 4 ) . accordingly , 
 whereas there is essentially no reaction between phenylnickel(ii ) 
 complex ( 1 ) and the propargylic bromide after 4 h in 
 the presence of tempo , upon the addition of ( ( + ) -i - pr - pybox)nibr ( 3 ; 0.20 equiv ) , carbon  carbon 
 bond formation initiates and proceeds to completion within 0.5 h ( 83% 
 yield , 82% ee ; eq 9 ) . similarly , in the absence 
 of tempo , the addition of ( i - pr - pybox)nibr to a solution of phenylnickel(ii ) complex ( 1 ) and the propargylic 
 bromide leads to an enhanced rate of carbon  carbon bond formation . when the nickel(i ) complex ( 3 ) that is employed as 
 the initiator bears the opposite enantiomer of the pybox ligand as 
 compared with the phenylnickel(ii ) adduct ( 1 ) , there 
 is no change in the ee of the coupling product ( eq 9 ) , indicating that the enantioselectivity of the carbon  carbon 
 bond - forming process is determined by the configuration of the pybox 
 ligand bound to the phenylnickel(ii ) complex . two representations of a possible radical 
 chain mechanism for the 
 arylation of a propargylic bromide by an arylnickel(ii ) complex ( l 
 = pybox ) . treatment of a solution of ( i - pr - pybox)nibr ( 3 ) with the propargylic 
 bromide ( 1.0 equiv ) 
 leads to immediate bleaching ( violet  colorless ) and the formation 
 of ( i - pr - pybox)nibr2 ( identified 
 by uv  vis spectroscopy ) and a mixture of racemic and achiral 
 products derived from homocoupling of the propargylic radical , observations 
 consistent with the first step of the suggested propagation sequence 
 ( figure 4 ) . vis 
 spectroscopy indicates that the second - order rate constant for the 
 halogen - atom abstraction is > 10 m s in dme at 20 c . no intermediates 
 are 
 observed by uv  vis or by epr spectroscopy.9 we hypothesize that , in the presence of an arylnickel(ii ) 
 complex , 
 e.g. , [ ( i - pr - pybox)niph]br , the propargylic radical is captured to form 
 [ ( i - pr - pybox)niph(propargyl)]br , which 
 can reductively eliminate to afford the coupling product and the chain - carrying 
 ( i - pr - pybox)nibr radical ( figure 4 ) . when the stoichiometric carbon  carbon 
 bond - forming process depicted in eq 7 is monitored 
 by epr spectroscopy , essentially no signal is observed , suggesting 
 that the postulated nickel(i ) and nickel(iii ) intermediates in the 
 chain - carrying steps are not present in significant quantities . consistent 
 with that conclusion , when the coupling illustrated in figure 5 is monitored by f nmr spectroscopy , 
 the consumption of the arylnickel(ii ) starting material correlates 
 directly with the formation of the coupling product , and no intermediates 
 are observed . progress of a stoichiometric arylation of a propargylic 
 bromide : 
 no evidence for the accumulation of an intermediate ( monitored by f nmr spectroscopy ) . on the basis of these observations for stoichiometric coupling 
 reactions of arylnickel complexes with a propargylic bromide , we propose 
 a pathway for nickel / pybox - catalyzed negishi arylations ( figure 6 ; through the use of uv  vis spectroscopy , 
 we have established that ( i - pr - pybox)nibr reacts much more rapidly with a propargylic bromide than with 
 ph2zn ) . the mechanism builds upon the radical chain process 
 depicted in figure 4 , but , rather than employing 
 [ lniar]br as a preformed stoichiometric arylating agent , 
 [ lniar]br is produced continuously in situ through the 
 reaction of arznar with lnibr2 , which is a 
 product of the chain reaction . a possible 
 catalytic cycle for the nickel / pybox - catalyzed negishi 
 arylation of a propargylic bromide . for the sake of simplicity , all 
 elementary steps are illustrated as being irreversible . with the aid of uv  vis spectroscopy and 
 esi mass spectrometry , 
 we have obtained data that support the viability of this key process 
 to regenerate [ lniar ] . thus , reaction of 
 ( i - pr - pybox)nibr2 with ph2zn leads to a uv  vis spectrum that is consistent with 
 independently synthesized [ ( i - pr - pybox)niph ] ( with bar4 as the counterion ; 
 figure 7 ) and to a mass spectrum in which the 
 major component has m / z = 436.1 , 
 again consistent with [ ( i - pr - pybox)niph ] ( positive - ion mode ; figure 8) . analysis via uv  vis spectroscopy of the reaction of ( i - pr - pybox)nibr2 with ph2zn to form [ ( i - pr - pybox)niph ] . in order for the proposed catalyzed 
 pathway ( figure 6 ) to lead to efficient cross - coupling , 
 during the reaction 
 the concentration of [ lniar]br should be substantially 
 higher than that of the propargylic radical ; otherwise , homocoupling 
 of the propargylic radical could occur to a significant extent . to 
 gain insight into the identity of the resting state of nickel during 
 a coupling process , we have employed f nmr spectroscopy 
 to investigate the negishi cross - coupling depicted in figure 9 . with the aid of an internal standard , we have 
 determined that , within 4 min , > 80% of the nickel that was originally 
 present has been transformed into [ ( i - pr - pybox)ni(4-fluorophenyl ) ] ( 121 ppm ; as expected , 
 the intensity of this signal is dependent on the loading of nickel ) . the structural assignment is based on comparison with the f nmr chemical shift of independently prepared [ ( i - pr - pybox)ni(4-fluorophenyl)]bar4 ( 120 ppm ) . analysis via esi - ms ( positive - ion mode ) of the reaction 
 of ( i - pr - pybox)nibr2 with 
 ph2zn to form [ ( i - pr - pybox)niph ] . analysis via f nmr spectroscopy of a catalyzed negishi 
 reaction in progress : (  ) [ ( i - pr - pybox)niar ] as a percentage of all nickel that is present ; 
 (  ) yield of cross - coupling product . similarly , the results of an investigation that employed 
 uv  vis 
 spectroscopy to monitor a catalyzed negishi arylation are consistent 
 with the rapid formation of [ ( i - pr - pybox)niph ] ( figure 10 ) . furthermore , 
 when this catalytic process was analyzed by epr spectroscopy , it was 
 found to be essentially epr silent , which is consistent with most 
 of the nickel being in the form of [ ( i - pr - pybox)niph ] . analysis 
 via uv  vis spectroscopy of a catalyzed negishi 
 reaction in progress : blue : ( i - pr - pybox)nibr2 ; red : cross - coupling reaction in progress ; purple : 
 [ ( i - pr - pybox)niph]bar4 . in a preliminary study , when the 
 propargylic bromide included an 
 olefin suitably positioned to trap the putative propargylic radical 
 through a 5-exo - trig cyclization , we observed more acyclic product 
 at higher catalyst loading , consistent with escape of the radical 
 from the solvent cage and coupling with a different nickel complex 
 to complete an overall bimetallic pathway for oxidative addition . we reported a similar trend in our recent report on catalytic asymmetric 
 negishi arylations of -bromosulfonamides . finally , we have examined the impact of tempo ( 4.5% ) 
 on a nickel - catalyzed 
 negishi arylation ( 3.0% catalyst loading ; figure 11 ) . during the first 60 min , essentially no carbon  carbon 
 bond formation is observed , and some of the [ ( i - pr - pybox)niph ] is consumed ( but less than the amount of 
 added tempo ) . then , presumably due to depletion of the tempo , the 
 cross - coupling proceeds at a substantial rate . analysis via f nmr spectroscopy of a catalyzed negishi 
 reaction in progress , in the presence of tempo : (  ) [ ( i - pr - pybox)niar ] as a percentage 
 of all nickel that is present ; (  ) yield of cross - coupling 
 product . this study represents 
 the first systematic mechanistic investigation 
 of a nickel - based catalyst that has been employed in stereoconvergent 
 cross - couplings of racemic alkyl electrophiles . specifically , we have 
 applied a wide array of tools to elucidate the pathway for the enantioselective 
 negishi arylation of propargylic bromides , examining both stoichiometric 
 and catalyzed processes . our observations are consistent with a radical 
 chain mechanism , wherein the c  br bond is cleaved during an 
 overall bimetallic oxidative addition that transiently generates a 
 propargylic radical ( which can account for the observed stereoconvergence ) , 
 as well as a series of nickel(i)/(ii)/(iii ) intermediates . independent 
 synthesis of an arylnickel(ii ) complex , combined with spectroscopic 
 analysis of stoichiometric reactions and of cross - couplings in progress , 
 supports the postulate that it is the predominant resting state of 
 nickel during a catalyzed process and that it is the species that 
 couples with the propargylic radical . our pathway differs from those 
 that have been proposed in recent studies of other nickel - catalyzed 
 cross - couplings , serving as another reminder that the use of different 
 ligands , coupling partners , and conditions can be expected to result 
 in substantial divergences in reaction mechanism . future investigations 
 will explore similarities and differences between this negishi arylation 
 of propargylic bromides and other nickel - catalyzed processes developed 
 in our laboratory .
although 
 nickel - catalyzed stereoconvergent couplings of racemic 
 alkyl electrophiles are emerging as a powerful tool in organic chemistry , 
 to date there have been no systematic mechanistic studies of such 
 processes . 
 herein , we examine the pathway for enantioselective negishi 
 arylations of secondary propargylic bromides , and we provide evidence 
 for an unanticipated radical chain pathway wherein oxidative addition 
 of the c  br bond occurs through a bimetallic mechanism . in 
 particular , we have crystallographically characterized a diamagnetic 
 arylnickel(ii ) complex , [ ( i - pr - pybox)niiiph]barf4 , and furnished support for [ ( i - pr - pybox)niiiph]+ being the predominant 
 nickel - containing species formed under the catalyzed conditions as 
 well as a key player in the cross - coupling mechanism . on the other 
 hand , our observations do not require a role for an organonickel(i ) 
 intermediate ( e.g. , ( i - pr - pybox)niiph ) , 
 which has previously been suggested to be an intermediate in nickel - catalyzed 
 cross - couplings , oxidatively adding alkyl electrophiles through a 
 monometallic pathway .