Well-Defined Aryl-FeII Complexes in Cross-Coupling and C–H Activation Processes

Herein we explore the intrinsic organometallic reactivity of iron embedded in a tetradentate N3C macrocyclic ligand scaffold that allows the stabilization of aryl-Fe species, which are key intermediates in Fe-catalyzed cross-coupling and C–H functionalization processes. This study covers C–H activation reactions using MeLH and FeCl2, biaryl C–C coupling product formation through reaction with Grignard reagents, and cross-coupling reactions using MeLBr or HLBr in combination with Fe0(CO)5. Synthesis under light irradiation and moderate heating (50 °C) affords the aryl-FeII complexes [FeII(Br)(MeL)(CO)] (1Me) and [FeII(HL)(CO)2]Br (1H). Exhaustive spectroscopic characterization of these rare low-spin diamagnetic species, including their crystal structures, allowed the investigation of their intrinsic reactivity.


General considerations Materials and methods
All reagents and solvents were purchased from Sigma Aldrich, Fisher Scientific or Fluorochem and used without further purification. NMR data concerning product identity were collected with a Bruker Ultrashield AVANCE III400 and a Bruker Ultrashield ASCEND Nanobay 400MHz (Serveis Tècnics, Universitat de Girona) spectrometers (CDCl3, THF-d8, CD3CN and DMSO-d6) and calibrated relative the residual protons of the solvent. All NMR experiments ( 1 H, 13 C 1 , COSY, HSQC, HMBC, NOESY and TOCSY) were recorded and processed using standard parameters and no more details are given, unless otherwise stated. Quantification of reaction yields through integration of peaks was performed using an internal standard (1,3,5-trimethoxybenzene). Preparation and handling of air-sensitive materials were carried out in a N2 drybox with O2 and H2O concentrations < 1 ppm. High resolution mass spectra (HRMS) were recorded on a Bruker MicrOTOF-Q IITM instrument using ESI as ionization source or CMS (cryospray ionization, for low temperature experiments) at Serveis Tècnics University of Girona. IR Spectra (FTIR) were recorded on a FT-IR Alpha spectrometer from Bruker with a PLATINUM-ATR attachment using OPUS software to process the data. UV-vis spectroscopy was performed with an Agilent 8453 UV-vis spectrophotometer with 1 cm quartz cells. Low temperature control was achieved with a cryostat from Unisoku Scientific Instruments, Japan. Monocrystal X-Ray diffraction was performed with a Bruker D8 QUEST ECO diffractometer. Ligands Me L H 2 and tBu L Br 3-4 were synthesized following previously described procedures. For Me L Br ligand, the synthesis was carried out following a slightly modified previously reported procedure. 2 Scheme S1. Synthesis protocol for Me L Br macrocyclic ligand.
Sodium azide (9.59 g, 146.0 mmol) and 2,6-bis(chloromethyl)pyridine (2.5 g, 14.0 mmol), were dissolved in DMF (130 ml) and refluxed overnight at 80 ºC. After that, the solvent was removed under reduced pressure, then the residue was extracted using water (4x60 ml) and EtOAc (100 ml). The organic layer was washed with brine (3x60 ml), dried over MgSO4, filtered and the solvent was removed under vacuum to yield a colorless oil corresponding to 2,6-bis(azidomethyl)pyridine (i) (2.56 g, 13.5 mmol, 97 %). Under N2, a 1 L round flask was charged with 2,6-bis(azidomethyl)pyridine (2.50 g, 13.2 mmol) and Pd/C (0.25 g, 10%) and then diluted in ethanol (280 ml). After that, the reaction was purged with H2 to remove N2. The reaction was left stirring at room temperature for 3 hours under a H2 atmosphere. The reaction solution was filtered using a celite® pad and rinsed with ethanol (the solid was discarded) and the filtrates were dried under reduced pressure to yield an orange oil corresponding to 2,6bis(aminomethyl)pyridine (ii) (1.75 g, 12.7 mmol, 96%).

Synthesis of 2,6-bis(aminomethyl)pyridine (ii)
Triethylamine (4.0 ml, 28.3 mmol) and 2,6-bis(aminomethyl)pyridine (1.85 g, 13.5 mmol) were dissolved in DCM (75 ml) and chilled to 0 °C. To this solution, TsCl (5.56 g, 28.6 mmol) diluted in DCM (100 ml) was added dropwise. During addition, the reaction mixture was vigorously stirred and maintained at 0 °C in an ice-bath. Upon completion of the addition, the reaction mixture was left stirring for an additional 24 hours allowing the solution to attain room temperature. The organic layer was washed with water and brine (2x175 ml each), dried with anhydrous MgSO4, and solvent was removed under reduced pressure to yield a brownish oil. The crude product was purified by silica gel column chromatography (DCM:EtOAc, 95:5) to obtain 2,6-bis(tosylmethylamine)pyridine (iii) as white powder ( In the Schlenk line, complex 1·Cl 2 (31.10 mg, 0.1 mmol) was dissolved in anhydrous THF (1.5 ml). The yellow suspension was stirred below -78 ºC and 3 equivalents of PhMgBr (236 μl of a 1.0 M solution in THF) were dropwise added via syringe. The mixture was left stirring below 78 ºC for 30 min and then the temperature was increased to 0 ºC for 1 hour. After that, the reaction was let to attain room temperature for 1 more hour and finally it was stirred under air for an additional hour. Next, concentrated HCl was added (together with the internal standard) and solvent was removed under reduced pressure. Ammonium hydroxide was used until pH >14 was reached, and extractions were performed using DCM. The product was dried over a MgSO4 plug and the solvent was removed. The final organic product was purified by silica gel chromatography using DCM:MeOH:NH3 (95:5:1) as eluent. Me  In the glovebox, tBu L Br (31.3 mg, 0.07 mmol) and Fe 0 (CO)5 (9.6 μl, 0.07 mmol) were dissolved in dry dioxane (1.0 ml). The mixture was left stirring for 24 hours at 100 ºC. After that, rapidly, vacuum was applied to remove any CO present in the atmosphere and to remove the solvent from the reaction mixture. 1 tBu (20.9 mg, 0.04 mmol, 58 %) was obtained as a greenish foam. inTHF) were dropwise added via syringe. The mixture was left stirring below 78 ºC for 30 min and then the temperature was increased to 0 ºC for 1 hour. After that, the reaction was let to attain room temperature for 1 more hour and finally it was stirred under air for an additional hour. Next, concentrated HCl was added (together with the internal standard) and solvent was removed under reduced pressure. Ammonium hydroxide was used until pH >14 was reached, and extractions were performed using DCM. The product was dried over a MgSO4 plug and the solvent was removed. The final organic product was purified by silica gel chromatography using DCM:MeOH:NH3 (95:5:1) as eluent. Me L COPh was obtained in a 38 % yield ( 1 H-NMR calculated using TMB as internal standard, 7% Me L Ph and 5% Me L H corresponding to the protodemetallation product).

A.
A UV-vis cell was charged with 2.2 ml of a 0.5 mM solution of 1·Cl 2 in anhydrous THF prepared in the glovebox. The quartz cell was capped with a septum, taken out of the glovebox, and placed in a Unisoku thermostated cell holder designed for low-temperature experiments at 273 K. Once the thermal equilibrium was reached, a UV-vis spectrum of the starting complex was recorded. PhMgBr (10 equiv) was injected into the cell through the septum causing immediate formation of two bands at λmax = 520 nm and λmax = 635 nm corresponding to the generation of the green (C) species proposed ( Figure S1).
Maximum formation of such species is formed after ca. 13 min. S10 Figure S1. UV-vis spectra of the reaction of 1·Cl 2 (yellow) towards PhMgBr at 0 ºC to form species C (green) with the corresponding bands at 520 and 635 nm. Scheme S15. Reaction of C towards dioxygen monitored by UV-vis spectroscopy at room temperature.

B.
A first UV-vis spectrum of the new formed species C was recorded. Dioxygen was bubbled into the cell through the septum causing immediate decay of the two bands at λmax = 520 nm and λmax = 635 assigned to green species (C). Subsequent formation of new species was rapidly observed (< 20 seconds, orange trace in Figure S2a) corresponding to the putative C + species that rapidly evolves (< 10 seconds) to the final reaction mixture (purple trace in Figure S2a). Attempts to characterize C + by Cryospray ionization/HR-MS In order to perform HR-MS analysis, in a typical UV-vis experiment, the generation of species C was monitored at 0 ºC. Once it was fully formed the sample was cooled down to -45 ºC. On a separated vial containing DCM, previously cooled down and purged with dioxygen, an aliquot from the UV-vis cuvette was added and then it was immediately injected into the mass spectrometer equipped with cryospray ionization at -45 ºC. However, all attempts to gain information about the nature of species C + were unfruitful due to its extremely high reactivity. Nevertheless, a clean mass spectrum of the final coupling biaryl product Me L Ph was obtained (m/z = 344.2128 corresponding to [C23H25N3+H] + ) as shown in Figure S2b. In the Schlenk line, complex 1·Cl 2 (12.00 mg, 0.03 mmol) was dissolved in anhydrous THF (1.0 ml). The yellow suspension was stirred at -78 ºC and 3 equivalents of PhMgBr (120 μl of a 1.0 M solution in THF) were dropwise added via syringe. The mixture was left stirring at -78 ºC for 30 min and then the temperature was increased to 0 ºC for 1 hour. After that, the reaction was let to attain room temperature for 1 more hour. Next, concentrated HCl was added (together with the internal standard) under N2 atmosphere and solvent was removed under vacuum. Ammonium hydroxide was used until pH >14 was reached, and extractions were performed using DCM. The product was dried over a MgSO4 plug, filtered and the solvent was removed. Me L Ph was obtained in a 2% yield ( 1 H-NMR calculated using TMB as internal standard, 85% Me LH corresponding to the protodemetallation product). In the Schlenk line, complex 1 Me (26.00 mg, 0.06 mmol) was dissolved in anhydrous THF (1.5 ml). The yellow suspension was stirred at -78 ºC and 3 equivalents of PhMgBr (181 μl of a 1.0 M solution in THF) were added dropwise. The mixture was left stirring at -78 ºC for 30 min and then the temperature was increased to 0 ºC for 1 hour. After that, the reaction was let to attain room temperature for 1 more hour. Next, concentrated HCl was added (together with the internal standard) under N2 atmosphere and solvent was removed under vacuum. Ammonium hydroxide was used until pH >14 was reached, and extractions were performed using DCM. The product was dried over a MgSO4 plug, filtered and the solvent was removed. Me L COPh was obtained in a trace amounts ( 1 H-NMR calculated using TMB as internal standard, 95% Me L H corresponding to the protodemetallation product). Scheme S18. Reaction of 1·Cl 2 towards PhMgBr in presence of DCIB as oxidant.
In a typical experiment, in the Schlenk line, complex 1·Cl 2 (32.90 mg, 0.08 mmol) was dissolved in anhydrous THF (1.6 ml). The yellow suspension was stirred below -78 ºC and 3 equivalents of PhMgBr (251 μl of a 1.0 M solution in THF) were added dropwise via syringe. The mixture was left stirring below 78 ºC for 30 min and then the temperature was increased to 0 ºC for 1.5 hour. After that, 2 equivalents of DCIB, 1,2-dichloroisobutane (20.4 μl), were added the reaction was let to attain room temperature for 1 more hour. Next, concentrated HCl was added (together with the internal standard) under N2 atmosphere and solvent was removed under vacuum. Ammonium hydroxide was used until pH >14 was reached, and extractions were performed using DCM. The product was dried over a MgSO4 plug, filtered and the solvent was removed. Me L Ph was obtained in a 45% yield ( 1 H-NMR calculated using TMB as internal standard, 55% Me L H corresponding to the protodemetallation product).
Noteworthy, addition of DCIB with the rest of reagents at the beginning of the reaction only afforded 9% yield of Me L Ph. Attempts to conduct a catalysis with DCIB under N2 using 20 mol% of FeCl2 were unfruitful, and only 4% yield of Me L Ph was obtained. In a typical experiment, in the Schlenk line, complex 1·Cl 2 (38.90 mg, 0.10 mmol) was dissolved in anhydrous THF (1.5 ml). Once dissolved, a CO atm was provided. The yellow suspension was stirred below -78 ºC and 3 equivalents of PhMgBr (300 μl of a 1.0 M solution in THF) were added dropwise via syringe. The mixture was left stirring below 78 ºC for 30 min and then the temperature was increased to 0 ºC for 1 hour. After that, the reaction was let to attain room temperature for 1 more hour and finally it was stirred under air for an additional hour. Next, concentrated HCl was added (together with the internal standard) and solvent was removed under reduced pressure. Ammonium hydroxide was used until pH >14 was reached, and extractions were performed using DCM. The product was dried over a S14 MgSO4 plug and the solvent was removed. Me L COPh was obtained in less than a 3 % yield ( 1 H-NMR calculated using TMB as internal standard, >95 % Me L H corresponding to the protodemetallation product and Me L Ph was not observed). In the Schlenk line, complex 1 Me (31.9 mg, 0.07 mmol) was dissolved in anhydrous THF (1.5 ml). The solution was stirred at -78 ºC and 3 equivalents of PhMgBr (230 μl of a 1.0 M solution in THF) were added dropwise. The mixture was left stirring at -78 ºC for 30 min. After that, the mixture was irradiated with 254 nm lamps and then the temperature was increased to room temperature for 2 hours and opened to air for 1 more hour. Next, concentrated HCl was added (together with the internal standard) and solvent was removed under vacuum. Ammonium hydroxide was used until pH >14 was reached, and extractions were performed using DCM. The product was dried over a MgSO4 plug, filtered and the solvent was removed. Me L Ph was obtained in an 8 % yield ( 1 H-NMR calculated using TMB as internal standard, 52 % Me L H corresponding to the protodemetallation product and a 10 % corresponding to Me L COPh). Under a nitrogen atmosphere, 1·Cl 2 (37.4 mg, 0.09mmol) and THF (2 mL) were added to a 25 mL round bottom flask stirring at -78 ºC. Once thermal equilibrium was reached, PhMgBr (170 µL, 1.8 eq) was added dropwise and stirred for 30 min. Then temperature was increased to -40 ºC generating a redcolored solution. At this point 1.5 eq of PPh3 (37.7 mg in 0.5 mL THF) were added. After that, the solution was cannulated at -40 ºC to remove the precipitate salts. Crystallization by slow diffusion over hexane at -40 ºC did not afford crystalline material but decomposition of the complex. HR-ESI-MS of the crude shows the 344.21 peak corresponding to the Me L Ph biaryl formation via C-C reductive elimination. Under a nitrogen atmosphere, 1·Cl 2 (35.4 mg, 0.09mmol), PPh3 (35.4 mg, 1.5 eq) and THF (3 mL) were added to a 25 mL round bottom flask stirring at RT for 1 hour. Temperature was lowered to -78ºC. Once thermal equilibrium was reached, PhMgBr (150 µL, 1.8 eq) was added to the vial containing the iron/PPh3 solution dropwise generating a red-colored solution after heating at 65 ºC for 2 hours. After that, temperature was lowered to -40°C and the solution was cannulated to remove the precipitate salts. Crystallization by slow diffusion over hexane at -40 ºC. Compound C' was neither detected, although PPh4 + was detected by HR-ESI-MS, suggesting a P-C reductive elimination from C'. 8. Amine-to-amide CO insertion reactivity 8 In the glovebox, Me L Br (31.8 mg, 0.09 mmol) and Fe 0 (CO)5 (12.13 μl, 0.09 mmol) were dissolved in dry MeCN (1 ml). The mixture was left stirring for 24 hours at 100 ºC. After that, rapidly, vacuum was applied to remove any CO present in the atmosphere and to remove the solvent from the reaction mixture. 2 Me (CO) was obtained as a red-brown foam (33.7 mg, 0.07 mmol, 80 %).

S16 (ii)
To 2 Me (CO) HCl was added and the reaction was left stirring at 100 ºC for 3 additional hours. After that, NH4OH was added until pH 14. Then extractions were performed in Et2O. The organic layer was dried in MgSO4, filtered and solvent was removed under vacuum to obtain Me L-CO H (99 %, NMR yield). In the glovebox, 1 Me (19.6 mg, 0.05 mmol) were dissolved in dry DMSO-d6 (1 ml). The mixture was left stirring for 2 hours at 100 ºC under a CO atmosphere. After that, rapidly, vacuum was applied to remove any CO present in the atmosphere and the reaction crude was checked by 1 H-NMR. After only 2 hours of reaction a 14 % of 2 Me (CO) could be observed together with a 14 % of Me L H (protodemetallation byproduct) and 71 % of starting complex (1 Me ).  Figure S3). 9. Spectroscopic characterization Figure S4. 1 H-NMR spectrum of (i) in CDCl3 at room temperature (400 MHz). Figure S5. 1 H-NMR spectrum of (ii) in CD3OD at room temperature (400 MHz). S19 Figure S6. 1 H-NMR spectrum of (iii) in CDCl3 at room temperature (400 MHz).                   [M+H] + S36 Figure S40. ATR-FT-IR spectrum of Me L COPh at room temperature.          Fe II S47 Figure S60. Crystal structure of 1·Br 2 at 100 K (CCDC 2046156).  Figure S61. Crystal structure of 1 Me at 100 K (CCDC 2046157).  Figure S62. Crystal structure of 1 H at 100 K (CCDC 2046158).  8 Geometry optimizations were carried out using the long-range corrected ωB97X-D functional, 9 which includes empirical dispersion correction, along with the def2-SVP basis set. 10 Solvation effects were included as a Polarizable Continuum using the SMD model. 11 Subsequently, we performed frequency calculations to each of the optimized structures to ensure that all local minima have only real frequencies and compute the Gibbs energy (ΔG), i.e., to evaluate the entropic and enthalpic corrections, assuming temperature value of 298.15 K and a pressure of 1.0 atm. Finally, single point energy calculations on the equilibrium geometries, including solvent effects, were computed with the more flexible basis set def2-TZPV. 10 Therefore, the values of ΔG reported in the manuscript are calculated at ωB97X-D/def2TZVP//ωB97X-D/def2SVP level, including solvent effects (SMD) and empirical dispersion corrections.