Exploring Mechanisms in Ni Terpyridine Catalyzed C – C Cross-Coupling Reactions — A Review

In recent years, nickel has entered the stage for catalyzed C–C cross-coupling reactions, replacing expensive palladium, and in some cases enabling the use of new substrate classes. Polypyridine ligands have played an important role in this development, and the prototypical tridentate 2,2′:6′,2′ ′-terpyridine (tpy) stands as an excellent example of these ligands. This review summarizes research that has been devoted to exploring the mechanistic details in catalyzed C–C cross-coupling reactions using tpy-based nickel systems.

Out of the many applications of nickel(II) catalysts in C-C or C-E cross-coupling reactions, we will focus in this contribution on the Negishi-type reactions [15,18,19,25,26,33] using organometallic zinc reagents, and on electrochemically driven C-C cross-coupling reactions.Also, instead of providing a literature overview of the many transformation that have been achieved using these methods, we will focus on selected studies that have provided mechanistic insight into these reactions.
Inorganics 2018, 6, x FOR PEER REVIEW 2 of 18 of the three even electron oxidation states (0, +II, and +IV) during C-C coupling reactions, and twoelectron processes such as oxidative addition and reductive elimination are common mechanistic steps [14, 15,24,25].For nickel, single electron pathways between the oxidation states (0, +I, +II, +III, and +IV) often occur in addition to oxidative addition and reductive elimination [24][25][26]31,32].Out of the many applications of nickel(II) catalysts in C-C or C-E cross-coupling reactions, we will focus in this contribution on the Negishi-type reactions [15,18,19,25,26,33] using organometallic zinc reagents, and on electrochemically driven C-C cross-coupling reactions.Also, instead of providing a literature overview of the many transformation that have been achieved using these methods, we will focus on selected studies that have provided mechanistic insight into these reactions.

Nickel-tpy Catalyzed C-C Cross-Coupling
The simple organometallic low-valent species [Ni(tpy)(Me)] was reported to catalyze the crosscoupling of unactivated alkyl halides with primary alkylzinc reagents about 10 years ago (Scheme 3) [44][45][46][47].The fundamental studies on the electronic structures of terpyridine nickel complexes have also prompted others to explore details of related pybox complexes (pybox = pyridine-2,6-bisoxazolidine).Nickel pybox complexes are known to display high activity for alkyl-alkyl cross-coupling reactions, and can even promote stereoconvergent cross-couplings of racemic alkyl halides [26,42,43].Recently, Fu et al. found that upon reduction of the nickel(II) complex [Ni(i-Pr-pybox)(Ph)](BAr F 4 ), the reduced species [Ni(i-Pr-pybox)(Ph)] • 2 could be isolated and characterized (Scheme 2) [26].Spectroscopic studies of this complex in analogy to what was previously observed for related terpyridine complexes [44] indicated that the proper electronic structure consisted of a nickel(II) center bearing a reduced pybox ligand [Ni(II)(i-Pr-pybox of the three even electron oxidation states (0, +II, and +IV) during C-C coupling reactions, and twoelectron processes such as oxidative addition and reductive elimination are common mechanistic steps [14, 15,24,25].For nickel, single electron pathways between the oxidation states (0, +I, +II, +III, and +IV) often occur in addition to oxidative addition and reductive elimination [24][25][26]31,32].Out of the many applications of nickel(II) catalysts in C-C or C-E cross-coupling reactions, we will focus in this contribution on the Negishi-type reactions [15,18,19,25,26,33] using organometallic zinc reagents, and on electrochemically driven C-C cross-coupling reactions.Also, instead of providing a literature overview of the many transformation that have been achieved using these methods, we will focus on selected studies that have provided mechanistic insight into these reactions.
Non-innocent ligands [34-39] such as tpy contribute strongly to the electron inventory of such nickel complexes, and redox chemistry may often occur at the ligand in addition to the abovementioned oxidation states (0, +I, +II, +III, and +IV).For instance, since tpy is an excellent electron acceptor through its extended π system, a species resulting from the reduction of a nickel(II)tpy complex can be described in two different resonance forms: as a divalent nickel bound to a radical anionic (tpy) •− ligand [Ni(II)(tpy •− )] (n−1)+ (A), or as a monovalent nickel [Ni(I)(tpy)] (n−1)+ complex (B) (Scheme 1) [40,41].The fundamental studies on the electronic structures of terpyridine nickel complexes have also prompted others to explore details of related pybox complexes (pybox = pyridine-2,6-bisoxazolidine).Nickel pybox complexes are known to display high activity for alkyl-alkyl cross-coupling reactions, and can even promote stereoconvergent cross-couplings of racemic alkyl halides [26,42,43].Recently, Fu et al. found that upon reduction of the nickel(II) complex [Ni(i-Pr-pybox)(Ph)](BAr F 4), the reduced species [Ni(i-Pr-pybox)(Ph)] • 2 could be isolated and characterized (Scheme 2) [26].Spectroscopic studies of this complex in analogy to what was previously observed for related terpyridine complexes [44] indicated that the proper electronic structure consisted of a nickel(II) center bearing a reduced pybox ligand [Ni(II) F 4) (1) using pentamethyl cobaltocene, adapted from ref. [26].Copyright (2014) American Chemical Society.Further permissions related to the material excerpted must be directed to the ACS.
When propargylic secondary bromides and chlorides were used as the electrophiles, secondary alkylzinc reagents could be coupled, producing two adjacent secondary carbon centers using the nickel-terpyridine catalyst system (Scheme 4) [48].
Scheme 4. Cross-coupling of a secondary alkyl bromide with a secondary alkylzinc reagent, adopted from ref. [48].

First Mechanistic Investigations on the [Ni(tpy)(Me)] Catalyst
The reaction of a nickel(0) precursor with MeI in the presence of a tpy derivative provided the cationic methylnickel(II) complex 3 (Scheme 5).In a related reaction, the treatment of [Ni(tmeda)(Me)2] with the same terpyridine ligand gave the neutral complex 4 [45,46].Reaction of the cationic nickel(II) complex 3 with an alkylzinc reagent gave only a 8% yield of the cross-coupled product (Scheme 5).On the other hand, the neutral methylnickel(I) complex 4 reacted with nheptyliodide to give the corresponding coupling product in 90% yield (Scheme 6).These results suggest that the Ni-tpy catalytic system does not include a simple Ni(0)/Ni(II) mechanism comprising of an oxidative addition of alkyl halides at nickel(0), transmetalation of a nickel alkyl halide complex, and lastly, reductive elimination of carbon-carbon bonds (Scheme 7).
When propargylic secondary bromides and chlorides were used as the electrophiles, secondary alkylzinc reagents could be coupled, producing two adjacent secondary carbon centers using the nickel-terpyridine catalyst system (Scheme 4) [48].
When propargylic secondary bromides and chlorides were used as the electrophiles, secondary alkylzinc reagents could be coupled, producing two adjacent secondary carbon centers using the nickel-terpyridine catalyst system (Scheme 4) [48].Scheme 4. Cross-coupling of a secondary alkyl bromide with a secondary alkylzinc reagent, adopted from ref. [48].

First Mechanistic Investigations on the [Ni(tpy)(Me)] Catalyst
The reaction of a nickel(0) precursor with MeI in the presence of a tpy derivative provided the cationic methylnickel(II) complex 3 (Scheme 5).In a related reaction, the treatment of [Ni(tmeda)(Me)2] with the same terpyridine ligand gave the neutral complex 4 [45,46].Reaction of the cationic nickel(II) complex 3 with an alkylzinc reagent gave only a 8% yield of the cross-coupled product (Scheme 5).On the other hand, the neutral methylnickel(I) complex 4 reacted with nheptyliodide to give the corresponding coupling product in 90% yield (Scheme 6).These results suggest that the Ni-tpy catalytic system does not include a simple Ni(0)/Ni(II) mechanism comprising of an oxidative addition of alkyl halides at nickel(0), transmetalation of a nickel alkyl halide complex, and lastly, reductive elimination of carbon-carbon bonds (Scheme 7).

First Mechanistic Investigations on the [Ni(tpy)(Me)] Catalyst
The reaction of a nickel(0) precursor with MeI in the presence of a tpy derivative provided the cationic methylnickel(II) complex 3 (Scheme 5).In a related reaction, the treatment of [Ni(tmeda)(Me) 2 ] with the same terpyridine ligand gave the neutral complex 4 [45,46].Reaction of the cationic nickel(II) complex 3 with an alkylzinc reagent gave only a 8% yield of the cross-coupled product (Scheme 5).On the other hand, the neutral methylnickel(I) complex 4 reacted with n-heptyliodide to give the corresponding coupling product in 90% yield (Scheme 6).These results suggest that the Ni-tpy catalytic system does not include a simple Ni(0)/Ni(II) mechanism comprising of an oxidative addition of alkyl halides at nickel(0), transmetalation of a nickel alkyl halide complex, and lastly, reductive elimination of carbon-carbon bonds (Scheme 7).
When propargylic secondary bromides and chlorides were used as the electrophiles, secondary alkylzinc reagents could be coupled, producing two adjacent secondary carbon centers using the nickel-terpyridine catalyst system (Scheme 4) [48].Scheme 4. Cross-coupling of a secondary alkyl bromide with a secondary alkylzinc reagent, adopted from ref. [48].

First Mechanistic Investigations on the [Ni(tpy)(Me)] Catalyst
The reaction of a nickel(0) precursor with MeI in the presence of a tpy derivative provided the cationic methylnickel(II) complex 3 (Scheme 5).In a related reaction, the treatment of [Ni(tmeda)(Me)2] with the same terpyridine ligand gave the neutral complex 4 [45,46].Reaction of the cationic nickel(II) complex 3 with an alkylzinc reagent gave only a 8% yield of the cross-coupled product (Scheme 5).On the other hand, the neutral methylnickel(I) complex 4 reacted with nheptyliodide to give the corresponding coupling product in 90% yield (Scheme 6).These results suggest that the Ni-tpy catalytic system does not include a simple Ni(0)/Ni(II) mechanism comprising of an oxidative addition of alkyl halides at nickel(0), transmetalation of a nickel alkyl halide complex, and lastly, reductive elimination of carbon-carbon bonds (Scheme 7).
When propargylic secondary bromides and chlorides were used as the electrophiles, secondary alkylzinc reagents could be coupled, producing two adjacent secondary carbon centers using the nickel-terpyridine catalyst system (Scheme 4) [48].Scheme 4. Cross-coupling of a secondary alkyl bromide with a secondary alkylzinc reagent, adopted from ref. [48].

First Mechanistic Investigations on the [Ni(tpy)(Me)] Catalyst
The reaction of a nickel(0) precursor with MeI in the presence of a tpy derivative provided the cationic methylnickel(II) complex 3 (Scheme 5).In a related reaction, the treatment of [Ni(tmeda)(Me)2] with the same terpyridine ligand gave the neutral complex 4 [45,46].Reaction of the cationic nickel(II) complex 3 with an alkylzinc reagent gave only a 8% yield of the cross-coupled product (Scheme 5).On the other hand, the neutral methylnickel(I) complex 4 reacted with nheptyliodide to give the corresponding coupling product in 90% yield (Scheme 6).These results suggest that the Ni-tpy catalytic system does not include a simple Ni(0)/Ni(II) mechanism comprising of an oxidative addition of alkyl halides at nickel(0), transmetalation of a nickel alkyl halide complex, and lastly, reductive elimination of carbon-carbon bonds (Scheme 7).
Scheme 5. Control experiment of a cationic nickel(II) complex 1 with an alkylzinc reagent [46].Scheme 6. Intermediacy of a neutral nickel(I) complex 2 with an alkyl iodide, adopted from ref. [46].Scheme 6. Intermediacy of a neutral nickel(I) complex 2 with an alkyl iodide, adopted from ref. [46].Scheme 7. Proposed catalytic cycle of the nickel-tpy catalytic system in an alkyl-alkyl cross-coupling reaction, adopted from ref. [46], the oxidation states shown in red were the results of studies outlined in Sections 2.2 and 2.3.
A plausible catalytic cycle for the nickel-terpyridine-catalyzed cross-coupling reaction of alkyl iodides with alkylzinc reagents is shown in Scheme 7. The in situ-formed low-valent nickel complex 5 undergoes transmetalation with organozinc reagents to give the corresponding organonickel species 6. Single electron transfer (SET) from the nickel complex 6 to alkyl iodides forms alkyl radicals and the nickel(II) complex 7.These radicals add oxidatively [46,49] to the Ni(II) complex, giving a nickel(III) species 8 as an intermediate addition, which then undergoes reductive elimination to yield coupling products with generation of a nickel(I) species 5 to complete the catalytic cycle.

Investigations of the Low-Valent Systems
The low-temperature solid-state powder EPR spectrum of [Ni(tpy)Br] • exhibits an axial signal with g ║ = 2.256 and g⊥ = 2.091 consistent with a metal-centered d ground state [52].In DMF solution, an isotropic signal can be observed with giso = 2.139.Thus, both in the crystaline form and in solution, signals for a radical with substantial metal character are observed for [Ni(tpy)Br] • [52].In contrast to this, [Ni(tpy)(Me)] • , exhibits an isotropic signal at 298 K with giso = 2.021, and a rhombic spectrum with g1 = 2.056, g2 = 2.021, and g3 = 1.999 at 77 K in a glassy frozen solution [44].The spectra Scheme 7. Proposed catalytic cycle of the nickel-tpy catalytic system in an alkyl-alkyl cross-coupling reaction, adopted from ref. [46], the oxidation states shown in red were the results of studies outlined in Sections 2.2 and 2.3.
A plausible catalytic cycle for the nickel-terpyridine-catalyzed cross-coupling reaction of alkyl iodides with alkylzinc reagents is shown in Scheme 7. The in situ-formed low-valent nickel complex 5 undergoes transmetalation with organozinc reagents to give the corresponding organonickel species 6. Single electron transfer (SET) from the nickel complex 6 to alkyl iodides forms alkyl radicals and the nickel(II) complex 7.These radicals add oxidatively [46,49] to the Ni(II) complex, giving a nickel(III) species 8 as an intermediate addition, which then undergoes reductive elimination to yield coupling products with generation of a nickel(I) species 5 to complete the catalytic cycle.
Studies were performed on [Ni(tpy)(Me)] in order to determine its electronic structure.Electron paramagnetic resonance (EPR) spectroscopy, in combination with density functional theory (DFT) calculations on the electronic nature of the neutral complex [Ni(tpy)(Me)], revealed that the species should be described as divalent nickel bound to a radical anionic (tpy) [Ni(tpy)Br] was prepared in a comproportionation reaction from [Ni(II)(dme)Br 2 ] (dme = 1,2dimethoxy-ethane) and [Ni(0)(COD) 2 ] (COD = 1,5-cyclooctadiene) in the presence of the tpy ligand, and its structure was studied in detail.EPR and quantum chemical calculations clearly point to a complex containing monovalent nickel [Ni(I)(tpy)Br] and a neutral tpy ligand, in marked contrast to the methyl and aryl derivatives, as described above [52].
The low-temperature solid-state powder EPR spectrum of [Ni(tpy)Br] • exhibits an axial signal with g = 2.256 and g ⊥ = 2.091 consistent with a metal-centered d x 2 −y 2 ground state [52].In DMF solution, an isotropic signal can be observed with g iso = 2.139.Thus, both in the crystaline form and in solution, signals for a radical with substantial metal character are observed for [Ni(tpy)Br] • [52].
Two parameters in Table 1 are most revealing for the character of the complex radicals.Both the high g iso value and the high g anisotropy ∆g observed for [Ni(tpy)Br] • characterize this complex as having the unpaired electron largely centered at the metal in contrast to the Me and aryl derivatives [50,51].
Recently, the Cl derivative [Ni(tpy)Cl] was added to this list.The molecular structure from XRD clearly points to a Ni(I) description [Ni(I)(tpy)Cl] with neutral tpy, as for the Br derivative [41].Unfortunately, EPR spectra were not reported.For [Ni(tpy)I], quantum chemical calculations show similar electron distribution as that found for the Br derivative [52].In summary, it can be assumed that the largely superior σ-donor character of the Me or aryl coligands raise the d x 2 −y 2 orbital at the nickel above the lowest π* orbitals of the tpy ligand, and reduction leads to a (d 8 )(π* 1 ) configured species, while for the weaker ligands Cl, Br, and I, a (d 8 )(d x 2 −y 2 1 ) configuration is found [41,52].

Studies on the Trivalent Species
Vicic showed that trifluoromethyl ligands can support the five-coordinate nickel(II) species 9, which can be chemically oxidized with [ferrocenium][PF 6 ] to generate the transient nickel(III) species 10 (Scheme 8) [54].Once formed, however, 10 undergoes a reductive homolysis of a trifluoromethyl ligand to afford the cationic nickel(II) species 11.Spectroelectrochemical EPR studies supported the intermediacy of 10, but its short-lived nature precluded any fundamental studies of its reactivity.Quite clearly, a • CF 3 radical is cleaved from 10, which was shown through spin-trapping studies using PBN (N-t-Bu-α-phenylnitrone) [54].Two parameters in Table 1 are most revealing for the character of the complex radicals.Both the high giso value and the high g anisotropy ∆g observed for [Ni(tpy)Br] • characterize this complex as having the unpaired electron largely centered at the metal in contrast to the Me and aryl derivatives [50,51].
Recently, the Cl derivative [Ni(tpy)Cl] was added to this list.The molecular structure from XRD clearly points to a Ni(I) description [Ni(I)(tpy)Cl] with neutral tpy, as for the Br derivative [41].Unfortunately, EPR spectra were not reported.For [Ni(tpy)I], quantum chemical calculations show similar electron distribution as that found for the Br derivative [52].In summary, it can be assumed that the largely superior σ-donor character of the Me or aryl coligands raise the d orbital at the nickel above the lowest π* orbitals of the tpy ligand, and reduction leads to a (d 8 )(π* 1 ) configured species, while for the weaker ligands Cl, Br, and I, a (d 8 )(d 1 ) configuration is found [41,52].

Studies on the Trivalent Species
Vicic showed that trifluoromethyl ligands can support the five-coordinate nickel(II) species 9, which can be chemically oxidized with [ferrocenium][PF6] to generate the transient nickel(III) species 10 (Scheme 8) [54].Once formed, however, 10 undergoes a reductive homolysis of a trifluoromethyl ligand to afford the cationic nickel(II) species 11.Spectroelectrochemical EPR studies supported the intermediacy of 10, but its short-lived nature precluded any fundamental studies of its reactivity.Quite clearly, a • CF3 radical is cleaved from 10, which was shown through spin-trapping studies using PBN (N-t-Bu-α-phenylnitrone) [54].Scheme 8. Oxidation of the isolated complex and follow-up reactions, adopted from ref. [54].

Electrochemistry and Character of the Trivalent Species [Ni(tpy)(C4F8)] +
It was found that the addition of terpyridine to [Ni(MeCN)2(C4F8)] 12 led cleanly to the formation of [Ni(tpy)(C4F8)] 14 (Scheme 9) [55].Surprisingly, in the solid state, the terpyridine ligand in 14 coordinates to nickel in a η 2 -fashion.However, solutions of 14 are paramagnetic, supporting an equilibrium with the η 3 -binding mode.Interestingly, when 0.5 equiv. of terpyridine is added to 12, the bimetallic species 13 can be isolated reproducibly, which is a testament to the lability of the acetonitrile ligands.Terpyridine is known to bind to more than one metal center [56][57][58][59][60][61], but 13 represented the first such adduct with nickel.Scheme 8. Oxidation of the isolated complex and follow-up reactions, adopted from ref. [54].[55].Surprisingly, in the solid state, the terpyridine ligand in 14 coordinates to nickel in a η 2 -fashion.However, solutions of 14 are paramagnetic, supporting an equilibrium with the η 3 -binding mode.Interestingly, when 0.5 equiv. of terpyridine is added to 12, the bimetallic species 13 can be isolated reproducibly, which is a testament to the lability of the acetonitrile ligands.Terpyridine is known to bind to more than one metal center [56][57][58][59][60][61], but 13 represented the first such adduct with nickel.
Oxidation of the [Ni(tpy)(C4F8)] complex 14 was explored.The η 3 -binding of the terpyridine ligand generates a high-spin nickel complex which, upon addition of Ag[BF4], affords the bluish/purple nickel(III) species 15 (Scheme 10).Unlike complex 10, which readily loses a trifluoromethyl radical, there is no evidence that 15 loses a perfluoroalkyl radical, even upon standing for hours in MeCN solution.The stability of 15 facilitated its characterization by X-ray crystallography, which identified the addition of an acetonitrile to the coordination sphere.Scheme 10.Stable terpyridine perfluoroalkylated Ni(III) species, adopted from ref. [55].
Variable temperature EPR spectra and magnetic moment data were obtained for 15, confirming its unpaired electron.Cyclic voltammetry experiments on 6 identifies a redox potential of +1.34 V for the Ni(III)/Ni(IV) couple.So, the [C4F8 2− ] ligand is exceptionally suitable for stabilizing high valent nickel.Unlike [Ni(tpy)(CF3)2] + complexes, which readily lose [ • CF3] radicals [54], the [Ni(tpy)(C4F8)] + analogue is solution stable, and can also be isolated in the solid state.The unique stability afforded by the [C4F8 2− ] ligand now provides a family of related fluoroalkyl nickel complexes spanning the +II to +IV oxidation states for future fundamental studies [55].

Further Ni-tpy Catalyzed C-C Cross-Coupling Reactions
In the last 10 years, nickel-tpy systems have been used successfully for a number of C-C crosscouplings and related reactions.
Recently, Han et al. reported on Ni-catalyzed reductive cross-coupling reactions between two electrophiles, amides and aryl iodides [62].The nickel-tpy catalysts system turned out to be superior to catalysts containing the bidentate ligands 2,2′-bipyridine, 2,2′-biquinoline, 1,10-phenanthroline, and its 5,6-dione.In a mechanistic proposal (Scheme 11), the starting NiI2 is reduced in the presence of tpy (L) to [Ni(0)(L)] by the added metallic Zn, and the encompassing C-N bond activation of the amide is described as an oxidative addition to yield an [Ni(II)(L)(acyl) (amide)] species 16.This complex reacts with an aryl radical stemming from the aryl iodide substrate, and forms the 2− ] ligand, adopted from ref. [55].
Oxidation of the [Ni(tpy)(C 4 F 8 )] complex 14 was explored.The η 3 -binding of the terpyridine ligand generates a high-spin nickel complex which, upon addition of Ag[BF 4 ], affords the bluish/purple nickel(III) species 15 (Scheme 10).Unlike complex 10, which readily loses a trifluoromethyl radical, there is no evidence that 15 loses a perfluoroalkyl radical, even upon standing for hours in MeCN solution.The stability of 15 facilitated its characterization by X-ray crystallography, which identified the addition of an acetonitrile to the coordination sphere.] ligand, adopted from ref. [55].
Oxidation of the [Ni(tpy)(C4F8)] complex 14 was explored.The η 3 -binding of the terpyridine ligand generates a high-spin nickel complex which, upon addition of Ag[BF4], affords the bluish/purple nickel(III) species 15 (Scheme 10).Unlike complex 10, which readily loses a trifluoromethyl radical, there is no evidence that 15 loses a perfluoroalkyl radical, even upon standing for hours in MeCN solution.The stability of 15 facilitated its characterization by X-ray crystallography, which identified the addition of an acetonitrile to the coordination sphere.Scheme 10.Stable terpyridine perfluoroalkylated Ni(III) species, adopted from ref. [55].
Variable temperature EPR spectra and magnetic moment data were obtained for 15, confirming its unpaired electron.Cyclic voltammetry experiments on 6 identifies a redox potential of +1.34 V for the Ni(III)/Ni(IV) couple.So, the [C4F8 2− ] ligand is exceptionally suitable for stabilizing high valent nickel.Unlike [Ni(tpy)(CF3)2] + complexes, which readily lose [ • CF3] radicals [54], the [Ni(tpy)(C4F8)] + analogue is solution stable, and can also be isolated in the solid state.The unique stability afforded by the [C4F8 2− ] ligand now provides a family of related fluoroalkyl nickel complexes spanning the +II to +IV oxidation states for future fundamental studies [55].

Further Ni-tpy Catalyzed C-C Cross-Coupling Reactions
In the last 10 years, nickel-tpy systems have been used successfully for a number of C-C crosscouplings and related reactions.
Recently, Han et al. reported on Ni-catalyzed reductive cross-coupling reactions between two electrophiles, amides and aryl iodides [62].The nickel-tpy catalysts system turned out to be superior to catalysts containing the bidentate ligands 2,2′-bipyridine, 2,2′-biquinoline, 1,10-phenanthroline, and its 5,6-dione.In a mechanistic proposal (Scheme 11), the starting NiI2 is reduced in the presence of tpy (L) to [Ni(0)(L)] by the added metallic Zn, and the encompassing C-N bond activation of the amide is described as an oxidative addition to yield an [Ni(II)(L)(acyl) (amide)] species 16.This complex reacts with an aryl radical stemming from the aryl iodide substrate, and forms the [Ni(III)(L)(acyl)(amide) (aryl)] species 17 through a radical oxidative addition.This species cleaves the C-C coupling product, leaving an [Ni(I)(L)(amide)] complex 18.The Ni(I) species reacts with aryl iodide to produce the aforementioned aryl radical, and the resulting [Ni(II)(L)(amide)I] 19 is subsequently reduced to [Ni(0)(L)] by metallic Zn to restart the cycle.In addition to the production of the aryl radical through complex 18, 16 could also react with Ph-I to yield this radical in an initiation step forming another Ni(III) species 20.As a proof for the radical oxidative addition

Further Ni-tpy Catalyzed C-C Cross-Coupling Reactions
In the last 10 years, nickel-tpy systems have been used successfully for a number of C-C cross-couplings and related reactions.
Recently, Han et al. reported on Ni-catalyzed reductive cross-coupling reactions between two electrophiles, amides and aryl iodides [62].The nickel-tpy catalysts system turned out to be superior to catalysts containing the bidentate ligands 2,2 -bipyridine, 2,2 -biquinoline, 1,10-phenanthroline, and its 5,6-dione.In a mechanistic proposal (Scheme 11), the starting NiI 2 is reduced in the presence of tpy (L) to [Ni(0)(L)] by the added metallic Zn, and the encompassing C-N bond activation of the amide is described as an oxidative addition to yield an [Ni(II)(L)(acyl) (amide)] species 16.This complex reacts with an aryl radical stemming from the aryl iodide substrate, and forms the [Ni(III)(L)(acyl)(amide) (aryl)] species 17 through a radical oxidative addition.This species cleaves the C-C coupling product, leaving an [Ni(I)(L)(amide)] complex 18.The Ni(I) species reacts with aryl iodide to produce the aforementioned aryl radical, and the resulting [Ni(II)(L)(amide)I] 19 is subsequently reduced to [Ni(0)(L)] by metallic Zn to restart the cycle.In addition to the production of the aryl radical through complex 18, 16 could also react with Ph-I to yield this radical in an initiation step forming another Ni(III) species 20.As a proof for the radical oxidative addition reaction, the addition of TEMPO (TEMPO = 2,2,6,6-Tetramethylpiperidin-1-yl)oxyl) inhibited the reaction and yielded the acyl-TEMPO adduct.Furthermore, [Ni(COD) 2 ] was also successfully used as the catalyst precursor, underpinning the role of the metallic zinc [62].
Inorganics 2018, 6, x FOR PEER REVIEW 7 of 18 reaction and yielded the acyl-TEMPO adduct.Furthermore, [Ni(COD)2] was also successfully used as the catalyst precursor, underpinning the role of the metallic zinc [62].
Scheme 11.Proposed reaction mechanisms for the reductive cross-coupling reaction of amides and aryl iodides, adapted with permission from [62].Copyright (2017) American Chemical Society.
An earlier study using [Ni(glyme)Cl2] (glyme = ethyleneglycoldimethylether) and various biand tridentate aromatic imine ligands as catalysts systems for the Negishi-type cross-coupling of secondary alkylzinc halides and aryl/heteroaryl iodides also found terpyridines superior to bidentate bpy or phen ligands, but also slightly better than the tridentate 2,6-di(1H-pyrazol-1-yl)pyridine, with the exception of the 4′-NO2-and 4′-CF3-tpy derivatives [63].This indicates that the redox potentials of the various Ni-tpy species are important, which is in line with our observations.
An interesting Ni-catalyzed reductive Csp3-Csp3 homocoupling using elemental zinc was reported to yield an alkyl chain axle [2]rotaxane [65].The authors firstly optimized the homocoupling reaction of 1-bromo-3-phenoxypropane, and found the Ni-(R,R)-Ph-pybox system slightly superior to Ni-tpy (pybox = pyridine-2,6-bisoxazolidine, see also introduction).Then, they coordinated When using [Ni(tpy)(Py)(MeCN)2](PF6) as the catalyst precursor, Vannucci et al. were able to perform efficient photoredox-assisted reductive coupling of two carbon electrophiles [66].Their mechanistic proposal starts with two subsequent reductions of the catalyst precursor to Ni(I)-and Ni(0)-tpy species by the iridium/TEOA photosystem (TEOA = triethanolamine).The Ni(0) complex undergoes oxidative addition of aryl halides to yield a Ni(II)Br(aryl) complex.At the same time, this species is supposed to react with alkyl halides through single electron transfer (SET) under the formation of an alkyl radical and a halide, thus recovering the Ni(I) species.Very similar to the report by Han [62], and our findings [44], the next step comprises a radical oxidative addition of an alkyl radical [49] stemming from the second substrate to the Ni(II) complex.The resulting Ni(III) species Scheme 11.Proposed reaction mechanisms for the reductive cross-coupling reaction of amides and aryl iodides, adapted with permission from [62].Copyright (2017) American Chemical Society.
An earlier study using [Ni(glyme)Cl 2 ] (glyme = ethyleneglycoldimethylether) and various bi-and tridentate aromatic imine ligands as catalysts systems for the Negishi-type cross-coupling of secondary alkylzinc halides and aryl/heteroaryl iodides also found terpyridines superior to bidentate bpy or phen ligands, but also slightly better than the tridentate 2,6-di(1H-pyrazol-1-yl)pyridine, with the exception of the 4 -NO 2 -and 4 -CF 3 -tpy derivatives [63].This indicates that the redox potentials of the various Ni-tpy species are important, which is in line with our observations.Elemental manganese has been used in effective Ni-catalyzed reductive dimerization of alkyl halides, tosylates, and trifluoroacetates applying a [Ni(glyme)Cl 2 ]/4,4 ,4 -(t-Bu) 3 tpy catalyst system [64].Interestingly, the addition of NaI promotes the reaction, but the reason for this is not yet clear.
An interesting Ni-catalyzed reductive C sp3 -C sp3 homocoupling using elemental zinc was reported to yield an alkyl chain axle [2]rotaxane [65] When using [Ni(tpy)(Py)(MeCN) 2 ](PF 6 ) as the catalyst precursor, Vannucci et al. were able to perform efficient photoredox-assisted reductive coupling of two carbon electrophiles [66].Their mechanistic proposal starts with two subsequent reductions of the catalyst precursor to Ni(I)-and Ni(0)-tpy species by the iridium/TEOA photosystem (TEOA = triethanolamine).The Ni(0) complex undergoes oxidative addition of aryl halides to yield a Ni(II)Br(aryl) complex.At the same time, this species is supposed to react with alkyl halides through single electron transfer (SET) under the formation of an alkyl radical and a halide, thus recovering the Ni(I) species.Very similar to the report by Han [62], and our findings [44], the next step comprises a radical oxidative addition of an alkyl radical [49] stemming from the second substrate to the Ni(II) complex.The resulting Ni(III) species undergoes reductive elimination to yield the C-C coupling product and a Ni(I) species, which is then reduced by the photosystem to recover the active Ni(0) species [66].
In 2010, C-H alkylations of 1,3-azoles with alkyl halides were reported by Hirano and Miura (Scheme 12) [67].C-H functionalizations using alkyl halides as a coupling partner are relatively rare compared with using unsaturated reactants, because of the difficulty in suppressing the β-hydrogen elimination of the alkylmetal intermediates.The nickel-terpyridine combination, in the presence of LiOt-Bu, was effective at suppressing such β-hydrogen eliminations.undergoes reductive elimination to yield the C-C coupling product and a Ni(I) species, which is then reduced by the photosystem to recover the active Ni(0) species [66].
In 2010, C-H alkylations of 1,3-azoles with alkyl halides were reported by Hirano and Miura (Scheme 12) [67].C-H functionalizations using alkyl halides as a coupling partner are relatively rare compared with using unsaturated reactants, because of the difficulty in suppressing the β-hydrogen elimination of the alkylmetal intermediates.The nickel-terpyridine combination, in the presence of LiOt-Bu, was effective at suppressing such β-hydrogen eliminations.
Gagné et al. achieved a total synthesis of a family of salmochelins, which are metabolites of the ferric-binding siderophores produced by E. coli and S. enterica.A key step in the synthesis was the nickel-catalyzed cross-coupling reaction of a bromoglucose derivative with an arylzinc reagent employing the terpyridine ligand on nickel [68].The key coupling reaction proceeded with excellent diastereoselectivity in a good yield to give 21 (Scheme 13).The C-aryl glycoside 21 was successfully converted into salmochelin S1 23 and S2 24 by subsequent condensation and deprotection processes (Scheme 13) [69].Moreover, Gagné also found that the combination of terpyridine and [Ni(0)(COD)2] (COD = 1,5 cyclooctadiene) can catalyze the reductive coupling of glycosyl bromides with activated alkenes (Scheme 14) [70].
Gagné et al. achieved a total synthesis of a family of salmochelins, which are metabolites of the ferric-binding siderophores produced by E. coli and S. enterica.A key step in the synthesis was the nickel-catalyzed cross-coupling reaction of a bromoglucose derivative with an arylzinc reagent employing the terpyridine ligand on nickel [68].The key coupling reaction proceeded with excellent diastereoselectivity in a good yield to give 21 (Scheme 13).The C-aryl glycoside 21 was successfully converted into salmochelin S1 23 and S2 24 by subsequent condensation and deprotection processes (Scheme 13) [69].Moreover, Gagné also found that the combination of terpyridine and [Ni(0)(COD) 2 ] (COD = 1,5 cyclooctadiene) can catalyze the reductive coupling of glycosyl bromides with activated alkenes (Scheme 14) [70].
Inorganics 2018, 6, x FOR PEER REVIEW 8 of 18 undergoes reductive elimination to yield the C-C coupling product and a Ni(I) species, which is then reduced by the photosystem to recover the active Ni(0) species [66].
In 2010, C-H alkylations of 1,3-azoles with alkyl halides were reported by Hirano and Miura (Scheme 12) [67].C-H functionalizations using alkyl halides as a coupling partner are relatively rare compared with using unsaturated reactants, because of the difficulty in suppressing the β-hydrogen elimination of the alkylmetal intermediates.The nickel-terpyridine combination, in the presence of LiOt-Bu, was effective at suppressing such β-hydrogen eliminations.
Gagné et al. achieved a total synthesis of a family of salmochelins, which are metabolites of the ferric-binding siderophores produced by E. coli and S. enterica.A key step in the synthesis was the nickel-catalyzed cross-coupling reaction of a bromoglucose derivative with an arylzinc reagent employing the terpyridine ligand on nickel [68].The key coupling reaction proceeded with excellent diastereoselectivity in a good yield to give 21 (Scheme 13).The C-aryl glycoside 21 was successfully converted into salmochelin S1 23 and S2 24 by subsequent condensation and deprotection processes (Scheme 13) [69].Moreover, Gagné also found that the combination of terpyridine and [Ni(0)(COD)2] (COD = 1,5 cyclooctadiene) can catalyze the reductive coupling of glycosyl bromides with activated alkenes (Scheme 14) [70].
The most important features of such electrocatalytic reactions include the possibility of using stable, simple, commercially available precatalysts, their compatibility with organic halides, and high functional group tolerances.In addition, compared with the more conventional chemical cross-coupling methods, electrochemical reactions have the advantage of providing an additional driving force (cathodic potential) for the reaction processes, which thus limits the need for additional means of activation, such as heating of the reaction medium [85-89].

Electrochemical Properties of Ni-tpy Complexes
Knowledge of mechanism and key intermediates is important for the rationalization and control of catalytic processes.In Ni-tpy catalyzed reactions, the nickel oxidation states +IV, +III, +II, +I and 0 have to be considered in combination with neutral (tpy) or reduced forms of the ligand (tpy •− or tpy 2− ).
The most important features of such electrocatalytic reactions include the possibility of using stable, simple, commercially available precatalysts, their compatibility with organic halides, and high functional group tolerances.In addition, compared with the more conventional chemical crosscoupling methods, electrochemical reactions have the advantage of providing an additional driving force (cathodic potential) for the reaction processes, which thus limits the need for additional means of activation, such as heating of the reaction medium [85-89].

Electrochemical Properties of Ni-tpy Complexes
Knowledge of mechanism and key intermediates is important for the rationalization and control of catalytic processes.In Ni-tpy catalyzed reactions, the nickel oxidation states +IV, +III, +II, +I and 0 have to be considered in combination with neutral (tpy) or reduced forms of the ligand (tpy •− or tpy 2− ).
On the other hand, a four-coordinate species [Ni(tpy) 2 ] 0 with two η 2 coordinating tpy ligands has been proposed for the doubly-reduced state [41,94].Quantum chemical calculations reveal two isomers with a pseudo-tetrahedral structure and an [Ni(I)(tpy •− )(tpy 0 )] electron configuration with an S = 0 ground state.This is due to an antiferromagnetic coupling of the Ni(I), and the tpy •− radical and the calculations are in agreement with magnetic data [41].
Thus, the number of tpy ligands and the way they coordinate to Ni determines the redox potentials, the character of the reduced species, and therefore the reactivity of catalytically relevant complex species [52].

Aromatic Perfluoroalkylation Using Ni-tpy Under Electrocatalytic Conditions
In recent years, extensive efforts have led to new methods for the introduction of the trifluoromethyl and perfluoroalkyl groups into aromatic and heteroaromatic ring systems.[Ni(II)(tpy)] complexes were found to be effective catalyst precursors in olefin fluoroalkylationns and cross-couplings of fluoroalkylhalides and arylhalides.
A one-step catalytic method for aromatic perfluoroalkylation catalyzed by electrochemically reduced metal complexes, including Ni(tpy), has recently been developed [72].Cross-coupling proceeds under mild conditions with the decisive role of the sacrificial anode metal.The reaction is successful with bromo-and iodobenzene and perfluoroalkyl iodides as substrates (Scheme 16).

Aromatic Perfluoroalkylation Using Ni-tpy Under Electrocatalytic Conditions
In recent years, extensive efforts have led to new methods for the introduction of the trifluoromethyl and perfluoroalkyl groups into aromatic and heteroaromatic ring systems.
[Ni(II)(tpy)] complexes were found to be effective catalyst precursors in olefin fluoroalkylationns and cross-couplings of fluoroalkylhalides and arylhalides.
A one-step catalytic method for aromatic perfluoroalkylation catalyzed by electrochemically reduced metal complexes, including Ni(tpy), has recently been developed [72].Cross-coupling proceeds under mild conditions with the decisive role of the sacrificial anode metal.The reaction is successful with bromo-and iodobenzene and perfluoroalkyl iodides as substrates (Scheme 16).

Aromatic Perfluoroalkylation Using Ni-tpy Under Electrocatalytic Conditions
In recent years, extensive efforts have led to new methods for the introduction of the trifluoromethyl and perfluoroalkyl groups into aromatic and heteroaromatic ring systems.
[Ni(II)(tpy)] complexes were found to be effective catalyst precursors in olefin fluoroalkylationns and cross-couplings of fluoroalkylhalides and arylhalides.
A one-step catalytic method for aromatic perfluoroalkylation catalyzed by electrochemically reduced metal complexes, including Ni(tpy), has recently been developed [72].Cross-coupling proceeds under mild conditions with the decisive role of the sacrificial anode metal.The reaction is successful with bromo-and iodobenzene and perfluoroalkyl iodides as substrates (Scheme 16).(dppe = 1,2-bis(diphenylphosphano)ethane) under reductive conditions do not react with the R F -I with a noticeable rate, and their reduction behavior (potentials, reversibility) is not changed by the addition of R F -I.In contrast to this, the CVs of the corresponding nickel and cobalt complexes are sensitive to the presence of R F -I.The reduction wave of M(II) to M(I) for both Ni and Co complexes experienced a twofold increase in current with a loss of reversibility [52,72], which indicates the occurrence of oxidative addition R F -X to [M(I)(L)] without the cyclic regeneration of the catalyst.Regeneration of the catalyst would have led to a strong catalytic current in the presence of substrate [97,98], but this was not observed.Thus, the observed changes in CVs can be described by an ECE (electrochemical-chemical-electrochemical) scheme [50,52].
The advantages of this Cu-assisted method are as follows: it is a one-step catalytic reaction carrying out under mild conditions, at room temperature, and the cross-couplings are successful not only with iodobenzene, but also with bromobenzene and perfluoroalkyl iodides.
Later, the method was extended to various aromatic halides (Scheme 18) [71].So, the single-stage synthesis of perfluoroalkylated arenes via the cross-coupling of bromo (in some cases, chloro) arenes or heteroarenes (derivatives of benzene, pyridine, and furan) and organic perfluoroalkyl halides involving [Ni(tpy)] complexes (and other metal and α-diimines ligands) in a low oxidation state under mild conditions was achieved.Perfluoroalkylated products are obtained in good yields in the presence of the [Ni(I)(L)] catalyst (1-10%) that was electrochemically generated from [Ni(II)(L)] at room temperature without chemical reductant.In the general case, it has been found that the success of the catalytic process depends on the reduction potential of the catalyst.The more negative reduction potential, the more effective the catalyst.[97,98], but this was not observed.Thus, the observed changes in CVs can be described by an ECE (electrochemicalchemical-electrochemical) scheme [50,52].The advantages of this Cu-assisted method are as follows: it is a one-step catalytic reaction carrying out under mild conditions, at room temperature, and the cross-couplings are successful not only with iodobenzene, but also with bromobenzene and perfluoroalkyl iodides.
Later, the method was extended to various aromatic halides (Scheme 18) [71].So, the singlestage synthesis of perfluoroalkylated arenes via the cross-coupling of bromo (in some cases, chloro) arenes or heteroarenes (derivatives of benzene, pyridine, and furan) and organic perfluoroalkyl halides involving [Ni(tpy)] complexes (and other metal and α-diimines ligands) in a low oxidation state under mild conditions was achieved.Perfluoroalkylated products are obtained in good yields in the presence of the [Ni(I)(L)] catalyst (1-10%) that was electrochemically generated from [Ni(II)(L)] at room temperature without chemical reductant.In the general case, it has been found that the success of the catalytic process depends on the reduction potential of the catalyst.The more negative reduction potential, the more effective the catalyst.Scheme 18. Ni-catalyzed cross-coupling of perfluoroalkyl halides and aromatic halides, adopted from ref. [71].
The proposed mechanism of the process involves electrochemical reduction of the [Ni(II)(L)Br2] complex to [Ni(I)(L)Br], followed by an oxidation by the fluoroorganic halide to regenerate [Ni(II)(L)BrX] (Scheme 20).The perfluoroalkyl radicals produced by these redox events react with α- Reproduced from ref. [53] with permission form The Royal Society of Chemistry.
The proposed mechanism of the process involves electrochemical reduction of the [Ni(II)(L)Br 2 ] complex to [Ni(I)(L)Br], followed by an oxidation by the fluoroorganic halide to regenerate [Ni(II)(L)BrX] (Scheme 20).The perfluoroalkyl radicals produced by these redox events react with α-methyl styrene to form an addition product, which undergoes either a dimerization process or forms the monomer product under the treatment of tributyltin hydride.An alternative and more complex mechanism would involve coordination of the olefinic substrate [53].

Inorganics 2018 , 18 [
6, x FOR PEER REVIEW 11 of Cu(dmphen)Cl2] (dmphen = 2,9-dimethyl-1,10-phenanthroline), or [Cu(dppe)Cl2] (dppe = 1,2bis(diphenylphosphano)ethane) under reductive conditions do not react with the RF-I with a noticeable rate, and their reduction behavior (potentials, reversibility) is not changed by the addition of RF-I.In contrast to this, the CVs of the corresponding nickel and cobalt complexes are sensitive to the presence of RF-I.The reduction wave of M(II) to M(I) for both Ni and Co complexes experienced a twofold increase in current with a loss of reversibility [52,72], which indicates the occurrence of oxidative addition RF-X to [M(I)(L)] without the cyclic regeneration of the catalyst.Regeneration of the catalyst would have led to a strong catalytic current in the presence of substrate

Table 1 .
). Selected EPR data of reduced nickel tpy complexes a .