The mechanism of directed Ni(<scp>ii</scp>)-catalyzed C–H iodination with molecular iodine
The density functional theory method is used to elucidate the elementary steps of Ni(II)-catalyzed C(sp 2 )-H iodination with I 2 and substrates bearing N,N 0 -bidentate directing centers, amide-oxazoline (AO) and 8aminoquinoline (AQ). The relative stability of the lowest energy high-and low-spin electronic states of the catalyst and intermediates is found to be an important factor for all of the steps in the reaction. As a result, two-state reactivity for these systems is reported, where the reaction is initiated on the triplet surface and generates a high energy singlet nickelacycle. It is shown that the addition of Na 2 CO 3 base to the reaction mixture facilitates C-H activation. The presence of I 2 in the reaction provides the much needed driving force for the C-H activation and nickelacycle formation and ultimately reacts to form a new C-I bond through either a redox neutral electrophilic cleavage (EC) pathway or a one-electron reductive cleavage (REC) pathway. The previously proposed Ni(II)/Ni(IV) and homolytic cleavage pathways are found to be higher in energy. The nature of the substrate is found to have a large impact on the relative stability of the lowest electronic states and on the stability of the nickelacycle resulting from C-H activation.
Introduction<!>Results and discussion<!>Path<!>Ni(II)-catalyzed C-H iodination of 8-aminoquinoline (AQ) substrate with I 2<!>Conclusions<!>Computational details<!>Conflicts of interest
<p>Catalytic C-H functionalization-dened as the catalytic transformation of C-H bonds into C-B, C-C, C-N, C-O, C-S and C-halogen bonds-has inherent advantages for the development of environmentally friendly and sustainable synthetic routes to complex organic targets. [1][2][3][4][5][6][7] Currently, many of the developments in this eld rely on the use of expensive and rare noble metal catalysts, such as Au, [8][9][10] Pt, 11,12 Pd, 13,14 Rh, 5,[15][16][17][18] and Ir. 6,18,19 Therefore, the development of cost-effective earthabundant transition metal catalysts (such as Fe, Co, Ni and Cu) is an attractive strategy to further capitalize on the sustainable potential of catalytic C-H functionalization. [20][21][22] However, rst-row transition metals, compared with their heavier analogues, suffer from (a) more complex reactivity (i.e. more accessible oxidation states and intermediates) due to their tendency to be involved in single-electron redox processes along with two-electron redox processes 23 and (b) a lack of a driving force for insertion into C-H bonds because the resulting M-C and M-H bonds are weak. 24 Thus, innovative approaches are necessary to design earth-abundant transition metal catalysts for C-H functionalization.</p><p>Existing strategies in this eld of scientic research employ photoredox [25][26][27][28] or chelation assisted (i.e. directing group, DG, assisted) [29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] approaches. These studies have unambiguously demonstrated the effectiveness of substrates with two chelating centers, such as 8-aminoquinoline (AQ), picolinamide (PA) and others, to direct the C-H activation event. 48,49 It is believed that the bidentate coordination of the substrate to the metal center provides stability to the pre-reaction complex and brings the activated C-H bond in close proximity to the transition metal center. 50,51 Furthermore, these studies have identied the utmost importance of controlling the multitude of oxidation states of the transition metal centers in the course of the reaction, which may proceed via numerous pathways such as: (a) a two-electron redox pathway (i.e. oxidative addition and reductive elimination), (b) a single-electron oxidation/reduction pathway (for example, via reactive organic radical intermediate formation) and (c) redox neutral pathways. 23 Several recently reported computational studies have supported the above-mentioned complexity of Ni(II)-catalyzed C-H functionalization reactions. Omer and Liu have shown that while the C(sp 2 )-H and C(sp 3 )-H bond cleavage of substrates with an 8-aminoquinoline (AQ) group by Ni(II)-catalyst occurs via the concerted metalation-deprotonation (CMD) mechanism, 52,53 the mechanism of the subsequent C-C and C-X bond formation steps depends on the nature of the substrate and the coordination environment of the metal. They may occur via either radical mechanisms (involving Ni(III) complexes) when the coupling partners are substrates with steric hindrance and low X-Y/X bonding energies, such as dicumyl peroxide (O-O bond), heptauoroisopropyl iodide (3 alkyl C-I bond) and diphenyl disulde (S-S bond), or via an oxidative addition/ reductive elimination mechanism involving a Ni(IV) intermediate when the coupling partners are phenyl iodide (aryl C-I bond) and n-butyl bromide (1 alkyl C-Br bond). 54 Sunoj and coworkers also report that aryl iodides react through a Ni(II)/ Ni(IV) mechanism with C(sp 3 )-H AQ substrates, where the regioselectivity is determined by the reductive elimination step. 55 Importantly, they demonstrate that the modeling of additives in the reaction can have a large impact on the computed pathways. Thus, the nature of the coupling partners (oxidants), transition metal centers and additives, as well as both the nature and number of chelating centers, are vital for C-H functionalization using rst-row transition metal catalysts.</p><p>C-H iodination with molecular I 2 under mild experimental conditions is a highly desirable process because it utilizes inexpensive I 2 as the sole oxidant and increases the accessibility of synthetically valuable aryl halide compounds. The design of the rst-row transition metal catalysts for this reaction is expected to be even more challenging because of the amphiphilic or "chameleon" nature of the I 2 molecule, which can act as either an electron-donor (L-type) or electron-acceptor (Z-type) ligand in transition metal complexes. [56][57][58] As a major advancement in this eld, the Ni(II)-catalyzed C-H iodination of an AQ substrate with I 2 with N,N 0 -directing groups was recently reported by both Chatani and coworkers 59 and Koley and coworkers 60 (Fig. 1). However, the mechanism of this reaction has not yet been studied in detail. Koley and coworkers proposed that either Ni(II)/Ni(IV) or redox-neutral Ni(II)/Ni(II) mechanisms could be operative (Fig. 2). In contrast, Chatani and coworkers settled on a Ni(II)/Ni(III) redox cycle that was previously proposed by Sanford and coworkers 61,62 for C-Br bond formation from the reaction of Br 2 and Ni(II)(phpy)(Br)(pic), where phpy ¼ 2-phenylpyridine and pic ¼ 2-picoline. A notable computational study by Hall and coworkers predicted a Ni(II)/Ni(III) spin-crossover mechanism for the C-Ni bromination reaction. 63 To deal with the mechanistic complexity of Ni(II)-catalyzed C-H iodination with I 2 , the knowledge acquired from the analogous Pd(II)-catalyzed reaction 64 could be useful, despite known differences in the electronic structure and reactivity of the Ni(II) and Pd(II) species. 65,66 In their seminal work, Yu and coworkers used a commercially available monodentate acidic amide DG for the Pd(II)-catalyzed reaction, 64 as opposed to the N,N 0 -bidentate directing groups used for the Ni-catalyzed reaction (Fig. 1). Our following extensive computational study 56 of this reaction revealed that C-I bond formation proceeds via a redox-neutral electrophilic cleavage (EC) mechanism initiated by the coordination of I 2 as a Z-type ligand 57,67,68 to the axial position of the square-planar d 8 Ar-Pd(II) C-H activation intermediate. 56 Its two-electron Pd(II)/Pd(IV) oxidation mechanism, including (a) I-I oxidative addition to the Ar-Pd(II) intermediate and (b) C-I reductive elimination from the resulting Pd(IV) intermediate, is less favorable. [69][70][71] In addition, recently we have shown that the presence of a mono-N-protected amino acid ligand (MPAA) changes the mechanism by enabling the oxidation of the Pd(II) center by I 2 prior to C-H activation. 72 With this uncertainty surrounding the mechanism, its importance for rst-row transition metal catalyst design and the available knowledge in the literature, here we use computational methods to explore the possible mechanisms and  Fig. 3 The substrates, AO and AQ, with N,N 0 -bidentate directing groups investigated in this paper.</p><p>governing factors of Ni(II)-catalyzed C-H bond iodination by molecular I 2 for substrates with N,N 0 -bidentate chelating groups, amide-oxazoline (AO) and AQ substrates (see Fig. 3). One should note that the AO ligand, developed in the Yu group, was previously used successfully for Cu-catalyzed C-H functionalization. [73][74][75][76][77] Here, we chose a common Ni(II) source, Ni(OAc) 2 , as a model catalyst because we aim to answer general questions about the reactivity of Ni(II) catalysts in C-H activation and iodination with I 2 . It is recognized that the identity of the pre-catalyst and the mechanism for entering the catalytic cycle are critical aspects of a successful reaction, but this is not the major focus of this study. Therefore, we do not strive for direct correlation with all of the successful experimental reaction conditions but instead focus on the general conclusions for how the catalyst achieves the critical C-H activation and iodination steps.</p><p>In general, the results of this study align with those reported by Liu 54 and Sunoj 55 but the reactivity of I 2 and the redox neutral EC pathway were not previously studied computationally. Furthermore, the previously reported studies 50,51,54,55 did not fully elaborate on the impact of the lowest-lying electronic states of the catalyst and intermediates in the mechanism. Therefore, here, for the rst time in the literature, we carefully analyze the impact of the lowest-lying singlet and triplet electronic states in Ni-catalyzed C-H functionalization. It is expected that this fundamental understanding of Ni-catalyzed C-H iodination reactions and the comparison of the acquired knowledge with that from the previously studied Pd-catalyzed reaction will enhance our ability to design cost-effective and environmentally friendly Ni-catalyzed C-H functionalization reactions and open new avenues for the design of rst-row transition metal catalysts for C-H halogenation.</p><!><p>Ni(II)-catalyzed C-H iodination of the amide oxazoline (AO) substrate with I 2 Mechanism of C-H activation. Our extensive calculations (see Fig. 4 and the ESI †) show that the reaction of Ni(OAc) 2 with the AO substrate is a multi-step process that proceeds via a triplet ground electronic state for the reactants, intermediates and two concerted metalation-deprotonation (CMD) transition states (for the deprotonation of N-H and C-H bonds, sequentially) but leads to the singlet state nickelacycle (5-S). Thus, it is most likely that the singlet and triplet surfaces of the reaction cross and both of the electronic states of the system contribute to the reactivity.</p><p>The rst CMD process (i.e. the deprotonation of the amide, which was not calculated) and the subsequent dissociation of acetic acid completes the bidentate coordination of the substrate to the Ni center with its two chelating N-groups. In the resulting (AO-k 2 -N,N 0 ,CH)Ni(II)(OAc) complex, 3, the ortho-C-H bond of the phenyl group in the substrate is closely positioned to the Ni center. Subsequently, cleavage of this ortho-C-H bond by the second acetate ligand through the CMD transition state, TS1, leads to the formation of the nickelacycle (AO-k 3 -N,N 0 ,C) Ni(II)(AcOH), 5, with two Ni-N bonds and one Ni-C bond. C-H bond deprotonation at the transition state TS1 is found to be the rate-limiting step of the process and occurs with a 31.8 kcal mol À1 free energy barrier (on the triplet state PES). Since the ground electronic state of TS1 is a triplet state, but that of nickelacycle 5 is a singlet state, it is most likely that the singlet and triplet surfaces of the reaction cross aer the triplet state C-H activation transition state. Thus, this process involves two lower-lying electronic states of the reactants, intermediates and transition states (i.e. shows two-state reactivity 78 ). Thus, the formation of nickelacycle 5 is endergonic by 25.9 kcal mol À1 (Fig. 4).</p><p>The computed thermodynamic instability of the nickelacycle (AO-k 3 -N,N 0 ,C)Ni(II)(AcOH) relative to reactants Ni(OAc) 2 (triplet) + AO is consistent with a previous computational study on the oxidative addition of C-H bonds to Ni(0) complexes. 79 This is also consistent with the deuterium labeling experiments performed by Chatani and coworkers, 59 the experiments of Koley and coworkers demonstrating that the nickelacycle formed by C-H activation cannot be isolated in the absence of I 2 , 60 as well as the computational ndings by Chen 50,51 and Liu. 54 Additional support for this conclusion comes from the fact that nickelacycles achieved via C-H activation are rare in the literature. 80 This is in contrast to analogous Pd-catalyzed reactions, where the palladacycles resulting from C-H activation are thermodynamically stable and can oen be isolated, characterized and used as pre-catalysts. [81][82][83] Thus, based on the results given above, we once again highlight one of the foremost difficulties for Ni(II)-catalyzed C-H functionalization as the lack of a thermodynamic driving force for C-H activation, 84 which is a major reason for the failure of the isolation and characterization of nickelacycles from C-H activation processes. Of course, in the presence of an oxidant/electrophile, for example I 2 , the C-H formation barrier (i.e. the reverse barrier for C-H activation) is expected to compete with either I-I bond activation (if the reaction proceeds via an oxidative addition mechanism) and/or C-I bond formation (if the reaction proceeds via an electrophilic addition mechanism) and/or radical formation barriers. These processes are discussed in the next section. As shown in Fig. 5, the electronic state of the system has a signicant impact not only on the energetics but also on the geometry of the C-H activation transition states and products. The most striking difference is in the angle of the acetate base relative to the substrate coordination plane: in the triplet structures, TS1-T and 5-T, the acetate is nearly perpendicular to the substrate coordination plane (N-Ni-OAc ¼ 104.8 and 99.4 , respectively), whereas in the singlet structures, TS1-S and 5-S, the acetate is in the plane of the substrate (N-Ni-OAc ¼ 167.4 and 174.1 , respectively). It is also noted that the AO substrate is capable of twisting slightly away from planarity (in 5-T, C-N-N-Ni ¼ À14 ), which may allow for some stabilization of the transition state toward the tetrahedral geometry favored on the triplet surface. 63 Role of sodium carbonate additive. Since available experiments 59,60 have shown that the addition of Na 2 CO 3 base into the reaction mixture improves both the reaction yield and reaction time of Ni(II)-catalyzed C-H iodination in substrates with N,N 0bidentate directing groups, here, we also investigated the ratelimiting C-H activation step of this reaction in the presence of Na 2 CO 3 . In general, previous studies have indicated that the base additive may inuence the C-H activation step through (a) ligand exchange reactions that lead to the in situ formation of a different catalyst, 85,86 (b) scavenging protons or acetic acid to drive the C-H activation, [87][88][89][90] and/or (c) the formation of a molecular cluster with other components (substrate, ligand, solvent, etc.) of the reaction that can promote the C-H activation step either via direct involvement in the CMD transition state or through non-covalent interactions with the substrate. 91,92 The results presented in Fig. 6 show that the addition of the Na 2 CO 3 molecule to complex 3 leads to the formation of (AO-k 2 -N,N 0 ,CH)Ni(II)(OAc/Na 2 CO 3 ), (3-clus) "(AcO/Na 2 CO 3 )-clustercomplex" (see ESI, Fig. S1, † for selected geometries); the calculated free energy of the reaction (AO-k 2 -N,N 0 ,CH) Ni(II)(OAc) + Na 2 CO 3 / (AO-k 2 -N,N 0 ,CH)Ni(II)(OAc/Na 2 CO 3 ) is À28.9 kcal mol À1 . This complex has a triplet ground electronic state with 1.61|e| alpha-spin density on the Ni centers. Its openshell singlet state (with an hS 2 i value of 0.63) is 11.0 kcal mol À1 higher in free energy. From the triplet "cluster-complex" 3-clus, the reaction may proceed either via C-H bond activation through the CMD triplet transition state TS1-clus by the (AcO/ Na 2 CO 3 ) ligand, or via ligand-exchange (i.e. NaOAc dissociation) where the subsequent C-H bond activation requires almost no barrier (we were not able to locate the associated transition state) and is exergonic by 11.5 kcal mol À1 . Thus, one may condently conclude that the addition of a Na 2 CO 3 molecule to the reaction mixture will produce AcO-to-NaCO 3 ligand exchange and will generate the new catalytically active species (AO-k 2 -N,N 0 ,CH)Ni(II)(NaCO 3 ). In this newly generated active species, C-H bond activation requires a 21.6 kcal mol À1 free energy barrier and is endergonic by 12.3 kcal mol À1 . A comparison of these energy parameters for active species (AOk 2 -N,N 0 ,CH)Ni(II)(NaCO 3 ) with those for (AO-k 2 -N,N 0 ,CH) Ni(II)(OAc) (calculated relative to 3-T), a 24.7 kcal mol À1 free energy barrier and 18.8 kcal mol À1 endergonicity, clearly demonstrates the benets of the presence of Na 2 CO 3 in the reaction conditions. This is consistent with the ndings of Liu and coworkers that a Ni(NaCO 3 ) 2 $4DMF catalyst is the likely active catalyst in their systems. 54 To summarize, the addition of Mechanism of iodination with I 2 . The next step of the reaction of the substrate AO with I 2 is the addition of the oxidant to nickelacycle 5-S. This process is found to be thermodynamically favorable, provides additional stabilization to the C-H activation product and, consequently, increases the barrier of the reverse reaction (i.e. C-H bond formation). A similar result was previously reported for I 2 addition to a palladacycle in our study  on the analogous Pd(II)-catalyzed reaction. 56 The coordination of I 2 to the axial position of nickelacycle 5-S to form 6-S is exergonic by 9.4 kcal mol À1 . However, it is still endergonic by 10.1 kcal mol À1 relative to the dissociation limit of 1-T + AO + I 2 . The geometric signatures of the resulting complex 6-S-the elongation of the I-I bond from 2.87 Å in free I 2 to 3.11 Å in 6-S and the linearity of the interaction between Ni and I 2 (with :Ni-I-I ¼ 167.2 )-imply the donation of a partial electron from the Ni d z 2 orbital into the I 2 s* orbital 56,58 (see Fig. 7).</p><p>Consistently, the triplet electronic state of the I 2 coordination complex (6-T) becomes only 0.7 kcal mol À1 higher in free energy than its singlet state counterpart 6-S. Analysis of unpaired spin densities (with 1.2|e| and 0.8|e| on the I 2 and Ni fragments, respectively) allows us to characterize 6-T as a Ni(III)-I 2 complex formed by one electron transfer from the Ni center to I 2 (the calculated Mulliken charges of the I 2 and Ni fragments are À0.5|e| and 0.5|e|, respectively). 63 As a result of this full (rather than partial) Ni-to-I 2 electron transfer, the elongation of the I-I bond (3.42 Å) becomes more pronounced than in 6-S and the :Ni-I-I angle becomes bent (101.1 ).</p><p>The accessibility of the triplet state complex 6-T upon single electron transfer from Ni to I 2 makes the reactivity of the nickelacycle with I 2 more complex than that of its Pd analogue. Indeed, as illustrated in Fig. 8, one can expect two distinct iodination pathways for each of the singlet and triplet state complexes 6-S and 6-T. For the singlet 6-S complex, the pathways are analogous to those studied for the Pd-catalyzed reaction: (A) a redox neutral Ni(II)/Ni(II) pathway proceeding through the concerted electrophilic cleavage (EC) of I 2 and concomitant C-I bond formation (black solid line in Fig. 8) and (B) a Ni(II)/ Ni(IV) pathway proceeding through I-I oxidative addition (OA) followed by C-I reductive elimination (black dashed line in Fig. 8). For the triplet state 6-T complex, these pathways are (C) a single electron reductive electrophilic cleavage (REC) Ni(III)/ Ni(II) process in which C-I bond formation and the one electron reduction of the Ni(III) center occur simultaneously (blue solid line in Fig. 8), and (D) a radical mechanism (RA) in which cleavage of the I-I bond forms a Ni(III) complex and iodine atom (blue dashed line in Fig. 8). It is possible that these pathways can interconvert into each other by crossing between the singlet and triplet surfaces. Below, we discuss these processes in more detail (for the sake of simplicity, the free energies discussed in this section are calculated relative to the singlet state complex 6-S).</p><p>Path    9). The free energy barrier associated with this oxidative addition transition state is 27.9 kcal mol À1 , which is 23.5 kcal mol À1 higher than that required for the electrophilic cleavage (EC) pathway (Path-A) (see Fig. 8). These conclusions for the EC and OA pathways are consistent with our previous study on Pd-catalyzed C-H iodination where the redox neutral Pd(II)/Pd(II) pathway is also shown to be more favorable than the Pd(II)/Pd(IV) mechanism. 56 Since the OA pathway cannot compete with the EC pathway, here we will not discuss this OA pathway in more detail, while we have included full computational data on the OA pathway in the ESI (see Fig. S2 †). We also investigated the possibility of dissociation of L, AcOH in this case, from 6-S to facilitate oxidative addition. We found this process to have a slightly lower overall barrier (6-S / TS3-S-I2, DG ‡ ¼ 25.2 kcal mol À1 ) than the reaction through TS3-S (see ESI for more details †). Regardless, this reaction pathway is much higher than the EC pathway.</p><p>Path shows spin density transfer from I 2 À to the Ni complex (Fig. 10).</p><p>Of particular interest is that the distal I has a signicant negative charge (À0.5|e|) while the proximal I does not (0.1|e|).</p><p>Overall, the geometry of TS2-T is similar to TS2-S except that the Ni center and The free energy barrier (calculated relative to complex 6-S) for the REC pathway is found to be 5.0 kcal mol À1 , which is 0.6 kcal mol À1 higher than the EC pathway on the singlet surface. The product complex, 7-T, is an ion-pair between Ni(II) + and iodide and is analogous of 7-S except that the Ni(II) is highspin (there is a spin density of 1.62|e| on the Ni center). The formation of 7-T is exergonic by 7.1 kcal mol À1 and the combination of the Ni(II) + and iodide ions to produce 8-T is exergonic by 18.7 kcal mol À1 . With the expulsion of I À during the reaction, we also investigated the role of I 3 À complex formation in the presence of excess I 2 . We compute I 3 À formation from I 2 and I À to be exergonic by 12.3 kcal mol À1 . This suggests that I 3 À complex formation could be playing the role of providing additional driving force for I À generation. Indeed, coordination of an additional molecule of I 2 to complexes 7-S and 7-T to form 7-S-I3 and 7-T-I3, respectively are exergonic by 15.6 and 13.0 kcal mol À1 , respectively. Thus, we propose that the EC and REC pathways can be facilitated by I 3 À formation. Here we refer to this pathway as the radical pathway (RA), but it is analogous to the homolytic cleavage pathway described by Liu. 54 In the associated transition state (TS3-T), Mulliken spin density analysis of the I 2 fragment shows that the distal I has signicant radical character (0.7|e|), while the proximal I has little (0.1|e|) (Fig. 10). In the TS, the bond between the proximal iodine atom and the Ni center is almost fully formed (I-Ni ¼ 2.66 Å) and the distal iodine atom does not form any strong interactions (I-I ¼ 4.03 Å, Ni-I ¼ 3.72 Å). The free energy barrier (calculated relative to complex 6-S) for the RA pathway is 11.0 kcal mol À1 , which is 6.6 kcal mol À1 higher than the EC pathway and 6.0 kcal mol À1 higher than the REC pathway. The RA pathway will not compete with the EC and REC pathways, so we will not discuss it in more detail, but we include its full computational data in the ESI (see Fig. S2 †). Catalytic cycle. Extensive analysis of these reaction pathways shows that they converge to common Ni(II)-I intermediates 8-S on the singlet surface and 8-T on the triplet surface (Fig. 8). The high spin Ni(II)-I intermediate 8-T is lower in free energy than its singlet analogue 8-S by 14.2 kcal mol À1 , indicating that the overall C-H iodination reaction has a much larger driving force on the triplet surface than on the singlet surface. From 8-T, the catalytic cycle is closed by (i) reprotonation of the amide substrate by acetic acid (i.e. (AO-k 3 -N,N 0 ,CI)Ni(II)(AcOH)(I) / (AO-k 3 -N,NH 0 ,CI)Ni(II)(OAc)(I)), and (ii) displacement of iodide and the iodinated product (AO-I) by acetates to regenerate the Ni(OAc) 2 catalyst. If we also invoke the role of the strong base, Na 2 CO 3 , to remove the C-H proton from solution then the overall reaction, Ni(OAc) 2 (1-T) + AO + I 2 + Na 2 CO 3 / Ni(OAc) 2 (1-T) + AO-I + NaI + NaHCO 3 , becomes exergonic by 20.8 kcal mol À1 .</p><!><p>In summary, consideration of several reaction pathways for Ni-C bond iodination with I 2 reveals that the redox neutral Ni(II)/Ni(II) electrophilic cleavage (EC) and Ni(II)/Ni(III) single electron reductive electrophilic cleavage (REC) pathways are the most likely mechanisms for this reaction. The computed barrier for the EC pathway is the lowest for the AO substrate, but the computed barrier for the REC pathway is only 0.6 kcal mol À1 higher. The previously studied 2-electron Ni(II)/Ni(IV) oxidative addition/reductive elimination (OA) and Ni(II)/Ni(III) radical (RA, homolytic cleavage) pathways are found to be higher in energy for I 2 . Given that the reactivity is highly dependent on the identity of the oxidant/electrophile, these results suggest that the EC and REC pathways should also be considered for Nicatalyzed C-H functionalization reactions.</p><!><p>To provide further validation and connection to experiments, we also studied the Ni(II)-catalyzed C-H bond iodination of the AQ substrate with I 2 . We believe that our calculated results are going to be helpful in understanding and rationalizing experimental ndings by Chatani 59 and Koley, 60 as well as in the prediction of novel ligands. In general, we nd that the AQ substrate gives qualitatively the same results as the AO substrate with a few interesting differences that will be discussed here briey. Full details of the calculations with the AQ substrate can be found in the ESI (see Fig. S3 †).</p><p>Firstly, as shown in the calculated potential energy surface in Fig. 11, the C-H activation of the AQ substrate by Ni(OAc) 2 requires an overall 33.8 kcal mol À1 free energy barrier (calculated relative to the triplet complex AQ-2-T) at the transition state AQ-TS1-S, which is ca. 2 kcal mol À1 larger than that reported for the AO substrate (Fig. 4). In contrast to the AO substrate, the rate-limiting C-H activation transition state for the AQ substrate, AQ-TS1-S, has a singlet ground electronic state; its triplet state counterpart AQ-TS1-T lies 2.3 kcal mol À1 higher. Thus, the singlet-triplet surface crossing likely occurs before the rate-limiting C-H activation transition state for the AQ substrate. Indeed, we were able to locate a minimum energy crossing point (AQ-mecp) that is close in energy (13.0 kcal mol À1 ) and geometry to the singlet reactant structure AQ-4-S (Fig. 11 and 12). The nature of the substrate also has a signicant impact on the stability of the nickelacycles resulting from the C-H activation. As mentioned above, for the AO substrate, the overall process, Ni(OAc) 2 (triplet) + AO / 5-S, is endergonic by 19.5 kcal mol À1 . In contrast, this process for the AQ substrate, i.e. the Ni(OAc) 2 (triplet) + AQ / AQ-5-S reaction, is endergonic only by 13.6 kcal mol À1 .</p><p>Thus, the replacement of the AO substrate by the AQ substrate (a) shis the C-H bond activation reaction to the singlet surface and the triplet-to-singlet surface crossing occurs before the C-H activation transition state, (b) makes the overall process thermodynamically more favorable by 5.9 kcal mol À1 and (c) only slightly (ca. 2 kcal mol À1 ) increases the rate-limiting C-H activation barrier. The thermodynamic preference of the C-H activation in AQ compared to AO can be explained by the careful analysis of the geometries in the corresponding nal products. Indeed, nickelacycle AQ-5-S has a square planar   geometry with a :(Ni-N-N-C) angle of À1 through the formation of a fused [3.3.0] ring system (Fig. 12), whereas the nickelacycle 5-S is more twisted out of plane (Ni-N-N-C ¼ À6 ) because of additional ring strain introduced by the larger [4.3.0] fused ring system (Fig. 6). This analysis is consistent with the ndings of Chen and coworkers. 50,51 Secondly, in contrast to the AO substrate, for the AQ substrate the triplet I 2 -coordination complex AQ-6-T, which lies 4.7 kcal mol À1 higher than reactants AQ-1-T + I 2 , is slightly lower (by 0.5 kcal mol À1 ) than its singlet counterpart AQ-6-S (see ESI, Fig. S3 †). Likewise, the Ni(II)/Ni(III) single electron reductive electrophilic cleavage (REC) free energy barrier (Path-C, initiated from the AQ-6-T complex) at the transition state AQ-TS2-T is calculated to be lower than the redox neutral Ni(II)/Ni(II) electrophilic cleavage (EC) free energy barrier (Path-A, initiated from the AQ-6-S complex and following via the transition state AQ-TS2-S). Based on these results, it appears that the C-H iodination reaction in the AQ substrate will revert back to the triplet surface much earlier on the reaction coordinate (i.e. during I 2 coordination) than that was the case with the AO substrate. However, like the AO substrate, the Ni(II)/Ni(III) single electron reductive electrophilic cleavage (REC) and redox neutral Ni(II)/Ni(II) electrophilic cleavage (EC) pathways remain close in energy for the AQ substrate. This suggests that one can switch between the substrate structures (or reaction conditions) and still achieve C-I bond formation. Signicantly, these data clearly demonstrate the importance of the availability of the lowest-lying electronic states of the rst-row transition metal centers for C-H iodination in substrates with an N,N 0 -bidentate chelating groups: the actual mechanism of the reaction directly relates to stability and the energy difference between lowest high-and low-spin electronic states.</p><!><p>Extensive calculations on the elementary steps of Ni(II)-catalyzed C-H iodination with I 2 and two substrates with N,N 0bidentate directing groups (AO and AQ) have revealed the most likely reaction mechanism as illustrated in Fig. 13.</p><p>Importantly, we found the relative stability of the lowest energy high-and low-spin electronic states to be an important factor for all of the steps in the reaction. We expect this to be a general feature of rst-row transition metal catalysts in C-H functionalization. We found that:</p><p>(1) The reaction is initiated by substrate coordination to the triplet Ni(OAc) 2 complex and N-H deprotonation to form a stable triplet (SUB-k 2 -N,N 0 ,CH)Ni(II)(OAc) complex. The calculated stabilization energies are 6.4 and 9.6 kcal mol À1 for the AO and AQ substrates, respectively.</p><p>(2) From (SUB-k 2 -N,N 0 ,CH)Ni(II)(OAc), C-H activation occurs via the base-assisted CMD mechanism on either the triplet surface (for the AO substrate) or the singlet surface (for the AQ substrate) and generates singlet Ni(II)-nickelacycles. This process requires a signicant free energy barrier (31.8 kcal mol À1 for AO and 33.8 kcal mol À1 for AQ), occurs via triplet-to-singlet spin crossover and is endergonic by 19.5 kcal mol À1 for AO and 13.6 kcal mol À1 for AQ. Thus, in the absence of an oxidant (or coupling partners) this C-H activation process is not feasible, which is consistent with experiments. 60 (3) However, in the presence of I 2 as an oxidant, the coordination of I 2 to Ni(II)-nickelacycle provides additional stability to the C-H activation product. In both the singlet and triplet states of the resulting nickelacycle-I 2 complex 6, I 2 accepts electron density from the Ni complex. Since in the triplet state nickelacycle-I 2 complex 6-T almost one electron is transferred to I 2 , it was characterized as a [Ni(III) + -I 2 À ] ion pair complex. (4) The subsequent C-I bond formation is very fast through either the redox-neural EC pathway, if the reaction starts from the singlet 6-S complex, or the one-electron REC pathway, if the reaction starts from the triplet 6-T complex. Both pathways lead to the formation of a stable, high spin Ni(II)-I intermediate.</p><p>(5) The addition of basic Na 2 CO 3 to the reaction mixture initiates AcO-to-NaCO 3 ligand exchange and generates the (SUBk 2 -N,N 0 ,CH)Ni(II)(NaCO 3 ) active catalyst. This ligand exchange reaction is exergonic for the AO substrate and requires an insignicant energy barrier. Furthermore, the involvement of a new base, i.e. Na 2 CO 3 , reduces the rate-limiting C-H activation barrier by 3.1 kcal mol À1 and stabilizes the C-H activation product by 6.3 kcal mol À1 . These ndings are consistent with experiments, showing that Na 2 CO 3 helps facilitate Ni-catalyzed C-H iodination with I 2 . 59,60 (6) The replacement of the AO substrate by the AQ substrate affects the energy difference between the lowest high-and lowspin electronic states of the systems in several places along the reaction pathway. It makes the C-H activation step thermodynamically more favorable by 5.9 kcal mol À1 and only slightly (ca. 2 kcal mol À1 ) increases the rate-limiting C-H activation barrier. Thus, the computations indicate that the AO substrate is also viable for Ni(II)-catalyzed C-H iodination with I 2 .</p><!><p>The calculations were performed with the Gaussian 09 (G09) program. 93 The geometry optimizations and frequency calculations for all of the reported structures were performed at the B3LYP-D3/[6-31G(d,p) + Lanl2dz (Pd, I)] level of theory with the corresponding Hay-Wadt effective core potential for Pd and I, [94][95][96] and Grimme's empirical dispersion-correction (D3) for B3LYP. 97 Each reported minimum has zero imaginary frequencies and each transition state (TS) structure has only one imaginary frequency. Intrinsic reaction coordinate (IRC) calculations were performed for selected transition state structures to conrm their identity. Bulk solvent effects were incorporated for all of the calculations using the self-consistent reaction eld polarizable continuum model (IEF-PCM) [98][99][100] with dimethylsulfoxide (DMSO) as the solvent. The calculated Gibbs free energies were corrected to a solution standard state of 1 M at room temperature (298.15 K). 101,102 It is known that Ni-complexes may have several energetically close lower-lying electronic states, 63 therefore, here we investigated both the ground and rst excited states of the reactants, intermediates, transition states and products of the reaction. Some of the structures on the singlet potential energy surface had lower energy open-shell singlet electronic states. In these cases, we re-calculated the geometries and energies of the structures at their open-shell singlet electronic states using unrestricted DFT (UB3LYP-D3). 103,104 The minimum energy crossing points (MECP) between singlet and triplet states were located using the MECPro program (v. 1.0.3) developed by Ess and coworkers 105 with G09.</p><!><p>There are no conicts to declare.</p>