Mechanochemical halogenation of unsymmetrically substituted azobenzenes

The direct and selective mechanochemical halogenation of C–H bonds in unsymmetrically substituted azobenzenes using N-halosuccinimides as the halogen source under neat grinding or liquid-assisted grinding conditions in a ball mill has been described. Depending on the azobenzene substrate used, halogenation of the C–H bonds occurs in the absence or only in the presence of PdII catalysts. Insight into the reaction dynamics and characterization of the products was achieved by in situ Raman and ex situ NMR spectroscopy and PXRD analysis. A strong influence of the different 4,4’-substituents of azobenzene on the halogenation time and mechanism was found.


General
Solvents and chemicals used in this study were of reagent grade and were not additionally purified. Ligands L6, L7, and L8 were prepared using the mechanochemical procedure. Complex Pd(OTs) 2 (MeCN) 2 was obtained according to the literature procedure [1]. Reactions were monitored by thin-layer chromatography on the silica gel 60 F254 aluminum sheets.
Mechanochemical experiments were performed at the ambient temperature of 23 ± 2 °C using an IST500 mixer mill with a built-in fan operating at 30 Hz (www.insolidotech.com/ist500.html). Reactions were conducted in 14 mL polymethyl methacrylate (PMMA) transparent jars that allowed for in situ Raman monitoring or in 14 mL polytetrafluoroethylene (PTFE) jars. One nickel bound tungsten carbide (WC, 7 mm in diameter, 3.9 g) or two zirconium oxide (ZrO 2 , 8 mm in diameter, 1.6 g) milling balls were used, and silica gel as a milling auxiliary.
NMR spectra were recorded on a Bruker Avance III HD 400 MHz/54 mm Ascend spectrometer. The temperature was kept constant at 25 °C and chemical shifts are reported in ppm and referenced to residual solvent signals.
HRMS spectra of novel compounds were obtained with a Bruker Microflex MALDI/TOF instrument.
Powder X-ray diffraction experiments that were used for crystal structure determination of compounds I6-I and I7-I were performed on a Panalytical Aeris desktop laboratory powder X-ray diffractometer in Bragg-Bretano geometry for 10 hours. Copper X-ray tube was operated at 40 kV and 7.5 mA, while the samples were prepared as thin films on zero-background silicon holders. Supplementary crystallographic data for the structures are available through the Cambridge Structural Database with deposition numbers 2159789 (I6-I) and 2159790 (I7-I).
Single crystals of L4-III were obtained by recrystallization of the purified product from hot ethyl acetate with a small amout of n-hexane (19:1). X-ray diffraction data of L4-III were collected by ω-scans on an XtaLAB Synergy diffractometer, Dualflex, HyPix using Cu Kα (λ = 1.54184 Å) radiation at ambient temperature (293.15 K). The CrysAlis software package [2,3] was used for data reduction, while programs incorporated in the OLEX2 system [4] were used for solution, structural refinement, and analysis of the structure. The structure was solved and refined with the SHELX programme suite [5,6]. Structural refinement was performed on F2 using all data. All hydrogen atoms were placed at calculated positions and treated as riding on their parent atoms. Crystal data and other crystallographic experimental details are summarized in Table S1.
Drawings of the structures were prepared using MERCURY programs [7]. Supplementary crystallographic data set for the structure is available through the Cambridge Structural Database with deposition number 2159788.
Raman experiments were performed by the portable Raman system with PD-LD (now Necsel) BlueBox laser source with the 785 nm excitation wavelength, equipped with B&W-Tek fiber optic Raman BAC102 probe and coupled to OceanOptics Maya2000Pro spectrometer. Details of Raman experiments and processing of data have been described previously [8].

Synthesis of L6-8
General procedure for mechanochemical synthesis of L6-8 4-Halogenated aniline (0.8 mmol), nitrosobenzene (0.8 mmol), AcOH (20 μL), and silica gel (120 mg) were transferred to the 14 mL polytetrafluoroethylene (PTFE) jar loaded with two zirconium oxide (ZrO 2 , 8 mm in diameter, 1.6 g) milling balls. The milling jar was placed in the mixer mill operating at 30 Hz, and the reaction mixture was milled at ambient temperature (23 ± 2 °C) for 1 h. The reaction mixture was scratched off from the jar, suspended in DCM (10 mL), and filtered through a thin layer of Celite. The mother liquid was collected, and the solvent was evaporated. The crude product was purified by column chromatography on silica gel (hexane/ethyl acetate 19:1) to obtain the desired product.

Regioselective mechanochemical halogenation reactions with L2-5
General procedure for the regioselective mechanochemical halogenation reactions with L2-5 Azobenzene L2-5 (0.5 mmol), NXS (X = Cl, Br, I) (0.6 mmol), and silica gel (250 mg) were transferred to a 14 mL polymethyl methacrylate (PMMA) jar loaded with one nickel bound tungsten carbide (WC, 7 mm in diameter, 3.9 g) milling ball. The milling jar was placed in the mixer mill operating at 30 Hz, and the reaction mixture was milled at ambient temperature (23 ± 2 °C for 1-15 hours as specified in Table 1. The crude product was scratched off from the jar, and re-chromatographed on silica gel (hexane/ethyl acetate 19:1) to obtain the desired monohalogenated product (LnX-I), and in the case of the reaction of L5 with NCS and dihalogenated product (L5Cl-II) as a side product. NMR yield was calculated using 1,4-dinitrobenzene as an internal standard.

Synthesis of I6-I
Solution synthesis of I6-I 4-Chloroazobenzene (L6, 0.825 mmol) was added to a solution of palladium acetate (0.625 mmol) in DCM (3 mL), and the reaction mixture was stirred for 10 minutes at ambient temperature, after which a solution of TsOH (0.7 mmol) in DCM (3 mL) was added. The reaction mixture was stirred for 1 hour at ambient temperature, filtered through a thin layer of Celite, and washed with DCM. The mother liquid was collected and the solvent was evaporated. The remaining solid was dissolved in MeCN (1,5 mL), and the desired product began to precipitate as a yellow powder after successive addition of hexane followed by diethyl ether. The precipitate was filtered off, then washed with hexane, and dried under vacuum. The product I6-I was isolated as an orange powder (283.1 mg, 85% isolated yield). The crystal structure of I6-I was solved using powder X-ray diffraction.

S11
Mechanochemical synthesis of I6-I 4-Chloroazobenzene (L6, 0.4 mmol), palladium acetate (0.42 mmol), TsOH (0.42 mmol), MeCN (25 μL), and silica gel (400 mg) were transferred to a 14 mL polymethyl methacrylate (PMMA) jar loaded with one nickel bound tungsten carbide (WC, 7 mm in diameter, 3.9 g) milling ball. The milling jar was placed in the mixer mill operating at 30 Hz, and the reaction mixture was milled at ambient temperature (23 ± 2 °C) for 3 hours. The resulting reaction mixture was scratched off from the jar, and the crude product was suspended in DCM (10 mL), and filtered through a thin layer of Celite. The mother liquid was collected, and the solvent was evaporated. The remaining solid was dissolved in MeCN (3 mL), and the desired product began to precipitate as a yellow powder after successive addition of hexane followed by diethyl ether. The precipitate was filtered, then washed with hexane, and dried under vacuum. The product I6-I was isolated as an orange powder (46.2 mg, 22% isolated yield). Characterization data are in agreement with those obtained for the same compound synthesized by the solution procedure. S12

Synthesis of I7-I
Solution synthesis of I7-I 4-Bromoazobenzene (L7, 0.825 mmol) was added to a solution of palladium acetate (0.625 mmol) in DCM (3 mL), and the reaction mixture was stirred for 10 minutes at ambient temperature, after which a solution of TsOH (0.7 mmol) in DCM (3 mL) was added. The reaction mixture was stirred for 1 hour at ambient temperature, filtered through a thin layer of Celite, and washed with DCM. The mother liquid was collected and the solvent was evaporated.
The remaining solid was dissolved in MeCN (1,5 mL), and the desired product began to precipitate as a yellow powder after successive addition of hexane followed by diethyl ether. The precipitate was filtered off, then washed with hexane, and dried under vacuum. The product I7-I was isolated as an orange powder (201.6 mg, 56% isolated yield). The crystal structure of I7-I was solved using powder X-ray diffraction.

S13
Mechanochemical synthesis of I7-I 4-Bromoazobenzene (L7, 0.4 mmol), palladium acetate (0.42 mmol), TsOH (0.42 mmol), MeCN (25 μL), and silica gel (400 mg) were transferred to a 14 mL polymethyl methacrylate (PMMA) jar loaded with one nickel bound tungsten carbide (WC, 7 mm in diameter, 3.9 g) milling ball. The milling jar was placed in the mixer mill operating at 30 Hz, and the reaction mixture was milled at ambient temperature (23 ± 2 °C) for 3 hours. The resulting reaction mixture was scratched off from the jar, and the crude product was suspended in DCM (10 mL), and filtered through a thin layer of Celite. The mother liquid was collected, and the solvent was evaporated. The remaining solid was dissolved in MeCN (3 mL), and the desired product began to precipitate as a yellow powder after successive addition of hexane followed by diethyl ether. The precipitate was filtered, then washed with hexane, and dried under vacuum. The product I7-I was isolated as an orange powder (50.0 mg, 13.8% isolated yield). Characterization data are in agreement with those obtained for the same compound synthesized by the solution procedure. S14

In situ observation of I6-I -I8-I during the time-resolved Raman monitoring
4-Halogenated azobenzene L6-8 (0.5 mmol), NBS (0.6 mmol), Pd(OAc) 2 or Pd(OTs) 2 (MeCN) 2 (0.15 mmol), TsOH (0.25 mmol), MeCN (15 μL), and silica gel (250 mg) were transferred to a 14 mL polymethyl methacrylate (PMMA) jar loaded with one nickel bound tungsten carbide (WC, 7 mm in diameter, 3.9 g) milling ball. The milling jar was placed in the mixer mill operating at 30 Hz, and the reaction mixture was milled at ambient temperature (23 ± 2 °C) for 4 hours in the case of L6 and 8 hours in the case of L7 and L8. Experimental data were interpreted by in situ collected Raman spectra and NMR spectra of the crude reaction mixture. In situ Raman monitorings of these reactions are shown in Figure 4a and Figures S23-S27.

Mechanochemical formation of I6-I and I7-I
4-Chloroazobenzene L6 or 4-bromoazobenzene L7 (0.4 mmol), palladium acetate (0.42 mmol), TsOH (0.42 mmol), MeCN (25 μL), and silica gel (400 mg) were transferred to a 14 mL polymethyl methacrylate (PMMA) jar loaded with one nickel bound tungsten carbide (WC, 7 mm in diameter, 3.9 g) milling ball. The milling jar was placed in the mixer mill operating at 30 Hz, and the reaction mixture was milled at ambient temperature (23 ± 2 °C) for 3 hours. Experimental data were interpreted by analyzing in situ collected Raman spectra and NMR spectra of the crude reaction mixture. In situ Raman monitorings of these reactions are shown in Figure 4b and Figure S28. S15

Competition experiments
General procedure for competition experiments between azobenzenes L2-5 Azobenzene A (0.75 mmol), azobenzene B (0.75 mmol), NXS (X = Cl, Br or I, 0.5 mmol), and silica gel (250 mg) were transferred to a 14 mL polymethyl methacrylate (PMMA) jar loaded with one nickel bound tungsten carbide (WC, 7 mm in diameter, 3.9 g) milling ball. The milling jar was placed in the mixer mill operating at 30 Hz, and the reaction mixture was milled at ambient temperature (23 ± 2 °C) until full consumption of NXS was observed. The ratio of products was determined from the crude reaction mixture by 1 H NMR spectroscopy.
 Competition experiment between L4 and L3 with NCS Figure S1: Aromatic region of the 1 H NMR spectrum of the crude reaction mixture of the competition experiment between L4 and L3 with NCS in CDCl 3 (400 MHz).

S16
 Competition experiment between L3 and L5 with NCS Figure S2: Aromatic region of the 1 H NMR spectrum of the crude reaction mixture of the competition experiment between L3 and L5 with NCS in CDCl 3 (400 MHz).

S17
 Competition experiment between L4 and L2 with NBS Figure S3: Aromatic region of the 1 H NMR spectrum of the crude reaction mixture of the competition experiment between L4 and L2 with NBS in CDCl 3 (400 MHz).

S18
 Competition experiment between L4 and L3 with NBS Figure S4: Aromatic region of the 1 H NMR spectrum of the crude reaction mixture of the competition experiment between L4 and L3 with NBS in CDCl 3 (400 MHz).

S19
 Competition experiment between L3 and L5 with NBS Figure S5: Aromatic region of the 1 H NMR spectrum of the crude reaction mixture of the competition experiment between L3 and L5 with NBS in CDCl 3 (400 MHz).

S20
 Competition experiment between L5 and L2 with NBS Figure S6: Aromatic region of the 1 H NMR spectrum of the crude reaction mixture of the competition experiment between L5 and L2 with NBS in CDCl 3 (400 MHz).

S21
 Competition experiment between L5 and L4 with NIS Figure S7: Aromatic region of the 1 H NMR spectrum of the crude reaction mixture of the competition experiment between L5 and L4 with NIS in CDCl 3 (400 MHz).
 Competition experiment between L1 and L6 with NBS Figure S8: Aromatic region of the 1 H NMR spectrum of the crude reaction mixture of the competition experiment between L1 and L6 with NBS in CDCl 3 (400 MHz).

S23
 Competition experiment between L1 and L7 with NBS Figure S9: Aromatic region of the 1 H NMR spectrum of the crude reaction mixture of the competition experiment between L1 and L7 with NBS in CDCl 3 (400 MHz).

S24
 Competition experiment between L1 and L8 with NBS Figure S10: Aromatic region of the 1 H NMR spectrum of the crude reaction mixture of the competition experiment between L1 and L8 with NBS in CDCl 3 (400 MHz). Overlapping of the characteristic signals of L1 and L8.

S25
 Competition experiment between L1 and L6 with NIS Figure S11: Aromatic region of the 1 H NMR spectrum of the crude reaction mixture of the competition experiment between L1 and L6 with NIS in CDCl 3 (400 MHz).

S26
 Competition experiment between L1 and L7 with NIS Figure S12: Aromatic region of the 1 H NMR spectrum of the crude reaction mixture of the competition experiment between L1 and L7 with NIS in CDCl 3 (400 MHz).

S27
 Competition experiment between L1 and L8 with NIS Figure S13: Aromatic region of the 1 H NMR spectrum of the crude reaction mixture of the competition experiment between L1 and L8 with NIS in CDCl 3 (400 MHz).

Powder X-ray diffraction
Crystal structure of compound I6-I The collected powder pattern was indexed using a monoclinic unit cell (a = 7.138 Å, b = 10.491 Å, c = 29.761 Å, a = 87.76°, b = 90.88°, g = 101.54°) with the volume of 2182 Å 3 . Solved by simulated annealing in direct space with rigid-body Rietveld refinement. The P-1 space group was chosen because cell volume indicated two independent molecules in the asymmetric unit with an inversion center. Molecules in the asymmetric unit were treated independently in simulated annealing with torsions included in optimization. The starting molecular geometry was optimized in vaccuo and represented in Topas as a Z-matrix. Errors on atomic coordinates were estimated using bootstraping. Structure solution agreed with experimental PXRD data. Presented geometry had no overlap between neighboring molecules.
The crystal structure is isostructural to the Cl-substituted analogue (I6-I). The Z-matrix describing the molecules of I6-I were modified to account for longer C-Br bond distances and such a structure model was the initial point for Rietveld refinement. Errors on atomic coordinates were estimated using bootstraping. Structure solution agreed with experimental PXRD data. Presented geometry had no overlap between neighboring molecules. Figure S32: Rietveld plot for the crystal structure solution of compound I7-I.