Unraveling the Mechanism of Hydrogen Atom Transfer by a Nickel-Hypochlorite Species and the Influence of Electronic Effects

The oxidation of hydrocarbons is an important chemical transformation with relevance to biology and industry. Ni-catalyzed transformations are more scarce compared to Mn or Fe but have gained attention in recent years, affording efficient oxidations. Understanding the mechanism of action of these catalysts, including the detection and characterization of the active nickel–oxygen species, is of interest to design better catalysts. In this work, we undertake a theoretical study to unravel the mechanism of formation of the previously reported [Ni(OCl)(HL)]+ (H2) and how it activates C–H bonds. We disclose that the active species is indeed compound [Ni(O)(HL)]+, formed after homolytic cleavage of the O–Cl bond in H2 assisted by a chlorine radical. [Ni(O)(HL)]+ mediates C–H activation through an asynchronous concerted mechanism, in which the transition state is given by hydrogen atom transfer. Moreover, the electronic tuning of the ligand has a very modest impact on the stability and reactivity of the corresponding X2 species. Effective oxidation state analysis reveals an intriguing electronic structure of H2 and [Ni(O)(HL)]+, in which both the macrocycic HL ligand and the OCl and O ligands behave as redox noninnocent. Such redox activity leads to a fully ambiguous oxidation state assignation.


Materials and methods
All reagents and solvents used were commercially available and purchased from Merck, Panreac, Scharlau and Fluorochem.Preparation and handling of air-sensitive materials was carried out in a N2 drybox (Jacomex) with O2 and H2O concentrations <1 ppm.(2-aminoethyl)(3aminopropyl)methylamine was synthesized as previously reported. 1 1 HNMR, 13 C-NMR and 19 F-NMR spectra were recorded in a Bruker Ultrashield Avance III400 and Ultrashield DPX300 spectrometers.Mass spectra were performed by electrospray ionization source in a high-resolution mass spectrometer Bruker micrOTOF QII (Q-TOF) with a quadrupole analyzer with positive ionization mode or in an Esquire 600 mass spectrometer with an ionic trap with positive ionization mode coupled to an HPLC UV-Vis Agilent 1200.UV/Vis spectroscopy was performed in an Agilent 8453 UV/Vis spectrophotometer with 1 cm quartz cells.Low temperature control was achieved with a cryostat from Unisoku Scientific Instruments, Japan.The X-ray intensity data were measured on a Bruker D8 QUEST ECO three-circle diffractometer system equipped with a Ceramic X-ray tube (Mo K,  = 0.71076 Å) and a doubly curved silicon crystal Bruker Triumph monochromato).
Cyclic voltammetries were performed with a CHI 620D Electrochemical Analyzer using a three electrode cell.The working electrode is a glassy carbon disk from BAS (0.07 cm 2 ), the reference electrode is a Ag/AgNO3 (10 mM) and the auxiliary electrode is platinum wire.All voltammetries have been carried out with nBu4NPF6 (TBAP) as supporting electrolyte (0.1 M ionic strength).All values are based on the Fc/Fc + redox couple as internal reference.

Synthesis of dimethyl 4-methoxypyridine-2,6-dicarboxylate (b). This compound was
prepared according to a literature procedure. 3In a 100 mL flask, product a (5.02 g, 23.8 mmol) was dissolved in CH3CN (50 mL) and potassium carbonate (4.93 g, 35.7 mmol) was added to the solution.Afterwards, methyl iodide (2.25 mL, 35.7 mmol) was carefully added to the reaction crude.The mixture was stirred and refluxed under N2 for 24 hours.Then, the reaction mixture was cooled down to room temperature and water (50 mL) was added.The CH3CN solvent was evaporated under reduced pressure and the aqueous phase was extracted with CH2Cl2 (4 x 50 mL).The organic phases were combined, dried over MgSO4 and filtered.The solvent was removed under reduced pressure to obtain compound b as a white solid (2.94 g, 13 mmol, 55% yield). 1 H-NMR (CDCl3, 300 MHz, 298 K) , ppm: 7.80 (s, 2H, HPy), 4.00 (s, 6H, CO-OCH3), 3.96 (s, 3H, CPy-OCH3). 13 Synthesis of 4-methoxy-2,6-pyridinedicarboxylic acid (c).This compound was prepared according to a modified literature procedure. 4In a two-necked flask, compound b (1.74 g, 7.73 mmol) was suspended in dry ethanol (100 mL) and stirred vigorously, followed by addition of NaOH (1.36 g, 100 mL, 34 mmol) in small portions over a period of 30 min.The mixture was stirred under N2 for 2 hours at room temperature.After this period the solvent was removed under vacuum.The resulting residue was then brought to pH = 1 by carefully adding the necessary amount of HCl 37% and then the product was extracted with ethyl acetate (4 x 100 mL).The organic phases were combined, dried over MgSO4 and concentrated until a white solid corresponding to c was obtained (1.49 g, 7.6 mmol, 98% yield). 1 H-NMR (CD3OD, 300 MHz, 298 K) , ppm: 7.85 (s, 2H, HPy), 3.99 (s, 3H, OCH3). 13

Synthesis of 4-methoxypyridine-2,6-dicarbonyl dichloride (d).
The synthesis of this compound was performed according to a modified literature procedure. 5A catalytic amount of DMF (ten drops) was added to compound f (1.98 g, 10.05 mol) followed by dropwise addition of thionyl chloride (25 mL, 341.7 mmol).After the addition, the solution was stirred and refluxed at 85 ºC under N2 atmosphere for 6 hours.The volatile components were evaporated.Then, the resulting residue was suspended in dry toluene and the solvent was distilled so that excess SOCl2 co-evaporates together with toluene.The process was repeated several times until a white-yellow crystalline solid corresponding to d was obtained (2.27 g, 9.7 mmol, 97% yield). 1 H-NMR (CDCl3, 300 MHz, 298 K) , ppm: 7.82 (s, 2H, HPy), 4.07 (s, 3H, OCH3).

Synthesis of H2
OMe L. On the one hand, compound d (855 mg, 3.67 mmol) was dissolved in toluene (83 mL) and dichloromethane (5 mL).On the other hand, (2-aminoethyl)(3aminopropyl)methylamine (573 mg, 4.37 mmol) was also dissolved in toluene (146 mL) and dichloromethane (7 mL).Afterwards, these two solutions were transferred to two separate dropping funnels, which were both connected to a three-necked round-bottom flask containing pure toluene (25 mL).Then, both solutions were added dropwise to the flask over a period of 7 hours under a N2 atmosphere, producing a yellow solution which was left stirring at room temperature overnight.The resulting solution was evaporated under reduced pressure, and NaOH 2 M (30 mL) was added.Finally, the solution was extracted with dichloromethane (4 x 30 mL).The organic layers were combined, dried over MgSO4 and filtered.The organic solvent was removed under reduced pressure to obtain a white solid.The solid was purified by column chromatography over silica using a 90:10 dichloromethane/methanol solution as eluent to obtain a white solid corresponding to H2 OMe L (220.8 mg, 0.76 mmol, 21% yield). 1

Synthesis of H2 CF3 L
Scheme S2.Synthetic route for the synthesis of H2 CF3 L. Synthesis of dimethyl 4-chloropyridine-2,6-dicarboxylate (e).This compound was synthesized following a modified literature procedure. 6In a 100 mL round-bottomed flask chelidamic acid hydrate (6.2 g, 30.6 mmol), thionyl chloride (20 mL, 275.7 mmol) and one drop DMF were mixed.The resulting white solution was stirred at 100 °C overnight.Afterwards, the resulting red solution was distilled at 100 °C to remove the excess of thionyl chloride.Afterwards, methanol (24 mL) was slowly added at 0 C under stirring, and the resulting mixture was further stirred for 1 hour at 0 °C.Then, methanol was evaporated under reduced pressure to dryness and a yellowish solid was obtained.The solid was dissolved in chloroform (40 mL) and extracted with water (2 x 40 mL) and brine (2 x 40 mL).The organic phase was dried with anhydrous MgSO4, filtered and the solvent was removed under reduced pressure giving a yellowish solid corresponding to e (4.8 g, 21.0 mmol, 68%). 1 H-NMR (CDCl3, 400 MHz, 298 K) , ppm: 8.32 (s, 2H, HPy), 4.06 (s, 6H, OCH3). 13

Synthesis of dimethyl 4-iodopyridine-2,6-dicarboxylate (f).
8] Under an inert atmosphere, compound e (3.1 g, 13.5 mmol), NaI (40.4 g, 269.6 mmol) and anhydrous CH3CN (120 mL) were mixed into a 500 mL twonecked Schlenk flask.Acetyl chloride (3 mL, 40.1 mmol) was then carefully added under a N2 atmosphere and stirring at 0 °C.The resulting mixture was sonicated for 30 min under a N2 atmosphere, checking that the bath temperature did not exceed 50 °C.Afterwards, the resulting crude was cooled at 0 °C and a red solution with a white precipitate was obtained.At this point, CH2Cl2 (120 mL) was added and the mixture was extracted with a saturated aqueous solution of Na2CO3 (60 mL).The organic phase was washed with a saturated solution of Na2S2O3 (100 mL) and water (2 x 100 mL).The organic phase was dried with anhydrous MgSO4, filtered and the solvent was evaporated under reduced pressure giving a yellowish-white solid.The solid was purified by recrystallization with hot methanol and pure product f was obtained as a white solid (3.4 g, 10.6 mmol, 78%).

Synthesis of dimethyl 4-trifluoromethylpyridine-2,6-dicarboxylate (g).
Compound g was synthesized following a literature procedure. 9A 250 mL two-necked Schlenk flask containing product f (2.5 g, 7.8 mmol) was equipped with a reflux condenser and connected to a Schlenk line.[PdCl2(dppf)] (0.28 g, 0.40 mmol) and CuI (1.4 g, 7.4 mmol) were added under a nitrogen atmosphere.Afterwards, anhydrous DMF (120 mL) and a solution of FSO2CF2CO2CH3 (5 mL, 39.3 mmol) in anhydrous DMF (16 mL) were added under stirring.The resulting mixture was stirred at 100 °C overnight, under a N2 atmosphere.After cooling to room temperature, dichloromethane (250 mL) was added and the solution was filtered off.The resulting dark brown filtrate was extracted with water (2 x 250 mL), a 3.25 M solution of NaCl (2 x 250 mL) and brine (2 x 250 mL).The organic phase was dried with anhydrous MgSO4, filtered and the solvent was evaporated under reduced pressure, affording a black solid.The residue was purified by column chromatography over silica using AcOEt:hexane 3:7 as eluent.Product g was obtained as a crystalline white solid (1.4 g, 5.3 mmol, 68%).

Synthesis of 4-trifluoromethyl-2,6-pyridinedicarboxylic acid (h).
A solution of NaOH (0.41 g, 10.3 mmol) in water (47 mL) was added into a 100 mL round-bottomed flask containing product c (0.45 g, 1.7 mmol).The resulting mixture was stirred for 1 hour at 100 °C.Then, it was cooled to room temperature and acidified to pH = 1 by dropwise addition of HCl 37% at 0 °C under stirring.Upon acidification, a white precipitate was obtained, which was filtered under vacuum, washed with water and dried.Meanwhile, the filtrate solution was extracted with dichloromethane (3 x 50 mL).The organic layer was dried with anhydrous magnesium sulfate, filtered and the solvent was removed to dryness affording a white solid.Both white solids corresponded to the pure product h (0.36 g, 1.5 mmol, 90%). 1 H-NMR (CD3OD, 400 MHz, 298 K) , ppm: 8.57 (s, 2H).

Synthesis of 4-trifluoromethylpyridine-2,6-dicarbonyl dichloride (i).
In a 50 mL roundbottomed flask containing product h (1.12 g, 4.8 mmol), dry CH2Cl2 (60 mL) and a drop of anhydrous DMF were added under a N2 atmosphere and stirring.The solution was cooled to 0 °C in an ice bath and then oxalyl chloride (1.2 mL, 14.3 mmol) was carefully added.The mixture was stirred overnight at room temperature under a N2 atmosphere.Afterwards, the solvent was evaporated under reduced pressure to dryness and the resulting solid was extracted with anhydrous toluene (3 x 10 mL).The liquid was decanted, and the solvent was removed under reduced pressure obtaining product i as a yellowish oil that slowly solidified (1.19 g, 4.4 mmol, 92 %).This compound was used directly in the next step without further purification. 1H-NMR (CDCl3, 400 MHz, 298 K) , ppm: 8.56 (s, 2H). 13 Synthesis of H2 CF3 L. On the one hand, compound i (1.19 g, 4.37 mmol) was dissolved in toluene (100 mL).On the other hand, (2-aminoethyl)(3-aminopropyl)methylamine (0.65 g, 4.95 mol) was dissolved in toluene (174 mL) and dichloromethane (8 mL).Afterwards, the two solutions were transferred to two separate dropping funnels, which were connected to a three-necked roundbottom flask containing 25 mL of toluene.Then, both solutions were added dropwise into the flask over a period of 7 hours under a N2 atmosphere.After the addition, the resulting yellow solution was stirred at room temperature overnight.The final mixture was evaporated under reduced pressure, and NaOH 2 M (35 mL) was added.Finally, the solution was extracted with dichloromethane (4 x 35 mL).The organic layers were combined and dried with MgSO4 and filtered.The organic solvent was removed under reduced pressure to obtain a brown oil.

1 H-NMR and UV-vis spectra of [Ni( OMe L)] and [Ni( CF3 L)]
The most relevant couplings for the assignment of the signals of OMe 1 have been highlighted in their corresponding spectra (Figures S3-S11).The observed couplings that were crucial for the assignment are: -1 H- 13 C HMBC (Figure S10): coupling of methyl hydrogens (CH3) with carbons 9/12.
-1 H-1 H COSY (Figure S6): couplings of hydrogens G with F, D with C, F with G/E, C with D, and E with F. These assignments were also analyzed by 1 H-1 H TOCSY (Figure S8), confirming which carbons are part of the three-carbon aliphatic chain (E, F, and G) and which ones are part of the two-carbon aliphatic chain (C, and D).
-1 H- 13 C HMBC: couplings of hydrogen C with carbon 6, carbon 6 with hydrogen A, hydrogen E with carbon 7, and carbon 7 with hydrogen B (Figure S10).Thanks to the ligand asymmetry, the two carbonyl carbons and pyridine hydrogens A and B could be distinguished (Figure S11).However, four-bond couplings between hydrogen A and carbon 5, and hydrogen B and carbon 3 were not detected.Thus, quaternary carbons 3 and 5 are detected as separate signals but cannot be assigned.

S17
The most relevant couplings for the assignment of the signals of CF3 1 have been highlighted in their corresponding spectra (Figures S12-S21).The observed couplings that were crucial for the assignment are: -1 H- 13 C HMBC (Figure S20): coupling of methyl hydrogens (CH3) with carbons 9/12.
-1 H-1 H COSY (Figure S16): couplings of hydrogens G with F, D with C, F with G/E, C with D, and E with F. These assignments were also analyzed by 1 H-1 H TOCSY (Figure S18), confirming which carbons are part of the three-carbon aliphatic chain (E, F, and G) and which ones are part of the two-carbon aliphatic chain (C, and D).
-1 H- 13 C HMBC (Figure S21): couplings hydrogen C with carbon 6, carbon 6 with hydrogen A, hydrogen E with carbon 7, and carbon 7 with hydrogen B. Due to the ligand asymmetry, the two carbonyl carbons and hydrogens A and B could be distinguished.Four-bond couplings between hydrogen A and carbon 5, and hydrogen B and carbon 3 were detected.However, these couplings appear very close one to the other.Thus, carbons 3 and 5 cannot be unequivocally assigned.

Generation and reactivity of X 2 4.1. Generation of X 2
The experimental procedure was analogous to the one previously reported for the generation of H 2. 1 In a typical experiment, 2.5 mL of a 0.15 mM soltuion of X 1 in CH3CN were placed in a 1 cm path-length cuvette (0.38 mols of X 1).The quartz cell was placed in the Unisoku cryostat of the UV-vis absorption spectrophotometer and cooled down to -30 ºC.After reaching thermal equilibrium an UV-vis absorption spectrum of the starting complex was recorded.Then, 19 L of

Kinetic analyses of the reaction of X 2 with organic substrates.
Once X 2 were fully formed (see above) the appropriate amount of substrate (1-octene or 1,4cyclohexadiene) dissolved in 100 L CH3CN was directly added into the UV-vis cuvette.Substrate concentration was always in pseudo-first order excess with respect to X 2. Reaction kinetics were monitored by following the decay of their absorption band at 470 nm for H 2, 467 nm for OMe 2 and 472 nm for CF3 2. In all cases, a satisfactory fit was obtained for the disappearance of X 2 using a

Computational details
All geometry optimizations were performed using the B3LYP [10][11] density functional in combination with the def2-SVP basis set, including empirical dispersion correction of Grimme (D3) 12 with the Becke-Johnson (BJ) 13 damping function.The nature of the stationary points was confirmed by harmonic frequency calculations in all cases.Gibb's free energy corrections were obtained using the standard statistical-mechanics relationships for an ideal gas at 243.15 K. Single-point calculations using the def2-TZVP basis were performed at all stationary points to improve the electronic energy.Solvation effects were included for both the geometry optimizations and single-point calculations using the implicit SMD solvation model with standard parameters for acetonitrile.
Spin-resolved effective fragment orbitals (EFOs) and subsequent EOS analysis were performed with the APOST-3D program 14 using the Topological Fuzzy Voronoi Cells (TFVC) 15 real-space atomic definition.
from which observed rate constants (kobs) were extracted.The linear variation of kobs with substrate concentration enabled the calculation of the second-order rate constants (k).
In the low spin (S=1/2) surface, the reaction proceeds via an asynchronous with no intermediate between the HAT and the subsequent rebound, as shown in the IRC path of FigureS34.The transfer of H takes place during the first seven steps of the IRC, going from an O-H distance of 1.53 Å down to 0.99 Å.The O-H distance then remains essentially unchanged while the Ni-OH bond gradually rotates to facilitate the rebound.We have followed the partial charge and condensed spin density of Ni, macrocyclic ligand, OH ligand, and the substrate along these first steps of the IRC.The results are depicted in FigureS35.Surprisingly, both the partial charge and spin of the C atom of the substrate are very close to zero during these steps.Indeed, it can be clearly seen that the LUMO corresponds to a lone pair sitting in the C atom.Still, the C atom remains neutral.If one instead considers the partial charge and spin of the whole substrate, not just the contact atom, the picture becomes more clear.The partial charge gradually increases as the H is transferred to the oxyl fragment and reaches a value of ca.+0.75, thus indicating a formal hydride transfer.The mechanism of this transfer is however difficult to discern because of the delocalized nature of the electronic state.One can see an early and sudden increase in the spin density of Ni in the very first steps, from -0.17 to 0.68.However, this does not translate into a change in its partial charge, which remains remarkably constant at ca +1.40.At the same time, the spin density on the OH group rapidly decreases from +0.85 to +0.19, while its partial charge remains again constant at ca. -0.50.This indicates that, on average, the alpha electron of the C-S31 H bond is transferred to the OH group, while the beta electron is transferred to the Ni.The excess charge that compensates for the cationic nature of the substrate is gained by the macrocyclic ligand.This significant electron flow between the fragments translates into huge changes in the projected dipole moment, as shown in FigureS36.On the other hand, FigureS37shows the evolution of the charge and spin densities of the fragments along the IRC of the quadruplet state.Contrary to the rather involved situation of the S=1/2 state, in the S=3/2 path, the substrate's spin density gradually increases as the O-H distance decreases, forming a clear radical substrate.At the same time, the charge and spin of the Ni center remain remarkably constant, and only the spin density of the OH moiety decreases by the transfer of a beta electron together with the H nucleus. Thus, the reaction follows a clear HAT mechanism, also supported by the much smaller change in the projected dipole moment, as compared to the low spin case (see FigureS38).

Figure S35 .
Figure S35.Evolution of the partial charges (solid lines) and condensed spin densities (dotted lines) of the Ni atom (blue), the OH fragment (orange), cyclohexane fragment (grey) and macrocyclic ligand (yellow) along the IRC path from TS(II-III)d to IIId for [Ni(O)( H L)] + species computed at the B3LYP-D3(BJ)/def2-svp level of theory for state S=1/2.

Figure S36 .Figure S37 .
Figure S36.Evolution of the total dipole moment (blue line) and the projection of the dipole moment along the O-H vector (orange line), expressed in Debye, along the IRC path from TS(II-III)d to IIId for [Ni(O)( H L)] + species computed at the B3LYP-D3(BJ)/def2-svp level of theory for state S=1/2.O-H distance (dotted black line) in Å.

Figure S38 Figure S39 . 2 and S = 3 Figure S40 .Figure S41 .
Figure S38Evolution of the total dipole moment (blue line) and the projection of the dipole moment along the O-H vector (orange line), expressed in Debye along the IRC path from TS(II-III)q to III a q for [Ni(O)( H L)] + species computed at the B3LYP-D3(BJ)/def2-svp level of theory for state S=3/2.O-H distance (dotted black line) in Å.

Figure S43 .
Figure S43.Relevant EFOs and their occupation numbers for the H 2 species in the triplet (S = 1) state.Occupations in bold indicate that the EFO is occupied in the EOS analysis.

Figure S44 .
Figure S44.Relevant EFOs and their occupation numbers for the H 2 species in the open-shell singlet (S = 0) state.Occupations in bold indicate that the EFO is occupied in the EOS analysis.

Figure S45 .
Figure S45.Relevant EFOs and their occupation numbers for the [Ni(O)( H L)] + species in the S=3/2 state.Occupations in bold indicate that the EFO is occupied in the EOS analysis.

Figure S46 .
Figure S46.Relevant EFOs and their occupation numbers for the [Ni(O)( H L)] + species in the S=1/2 state.Occupations in bold indicate that the EFO is occupied in the EOS analysis.