Facile access to nitroarenes and nitroheteroarenes using N-nitrosaccharin

Nitroaromatics and nitroheteroaromatics serve as key building blocks and intermediates in synthesis, and form the core scaffold of a vast number of materials, dyes, explosives, agrochemicals and pharmaceuticals. However, their synthesis relies on harsh methodologies involving excess mineral acids, which present a number of critical drawbacks in terms of functional group compatibility and environmental impact. Modern, alternative strategies still suffer from significant limitations in terms of practicality, and a general protocol amenable to the direct C-H functionalization of a broad range of aromatics has remained elusive. Herein we introduce a bench-stable, inexpensive, easy to synthesize and recyclable nitrating reagent based on saccharin. This reagent acts as a controllable source of the nitronium ion, allowing mild and practical nitration of both arenes and heteroarenes displaying an exceptional functional group tolerance.

Although we encountered no incidents while synthesizing this molecule or products reported herein, safety precautions must be taken such as wearing safety glasses, protected shield, full body protective clothing, etc. TGA-DSC profile of nitrating reagent 4a: Thermogravimetric and differential scanning calorimetry (TGA-DSC) measurments were performed in order to determine the melting point and decomposition temperature of 4a. Reagent 4a shows an exothermic decomposition at 173 °C, accompained with a mass loss of 87% . Representative procedure for synthesis of reagent 4b: In a 250 mL three necked round bottom flask equipped with a dropping funnel, air outlet and stirring bar was placed 6-nitrosaccharin (10.0 g, 36.63 mmol) in acetic anhydride (28.2 mL, 0.30 mol). The solution was cooled 5-10 °C with an ice-bath and concentrated fuming nitric acid (28.2 mL, 0.67 mol) was added dropwise to the solution during 30 minutes, while dry air was bubbled through the solution rapidly in order to remove excess nitrogen oxides. 6-Nitrosaccharin was completely dissolved once all nitric acid was added. The reaction mixture was stirred at 5-10 °C during 4 hours with constant bubbling of dry air through the liquid. The reaction mixture was placed in the freezer for 10 hours to complete precipitation of the product. The precipitate was collected on a sintered glass filter, washed with cold chloroform and dried under high vacuum until dryness (9.6 g, 96% yield). The mother liquor was quenched with a cold solution of 1N NaOH. The product is a light-yellow (off-white) crystalline compound. TGA-DSC profile of nitrating reagent 4b:TGA-DSC measurments were performed on reagent 4b, which was found to be stable unil 159 °C, whereby an exothermic event accompanied by a 9.4% mass loss was observed. This was followed by gradual decomposition between 166 °C -450 °C.

Stability of N-nitrosaccharins 4 in different solvents:
Reagents 4a and 4b were found to be stable in a variety of apolar and polar aprotic solvents including benzene, toluene, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, acetone, acetonitrile, hexafluoroisopropanol (HFIP), N-methyl-2pyrrolidinone (NMO) and cyclohexane, showing no signs of decomposition (Supplementary Table 1, entries 1-11). The reagents are not compatible with the use of highly polar solvents such as MeOH, DMF and DMSO and water, with hydrolysis and other decomposition products detected after 10 minutes or 24 hours (entries 12-15). [a] Reaction conditions: benzene (1.0 equiv), reagent (x equiv), solvent, Ar atmosphere, temperature. Yields were determined by GC-MS using decane as internal standard.
Optimization of the reaction conditions I: An oven-dried, 25 mL micro-vial was charged on the benchtop with a magnetic pTFE-coated stirbar and nitrating reagent 1-4 (x equiv.). The vial was sealed and the atmosphere was cycled three times with Ar/vac. Benzene (44.69 L, 0.5 mmol, 1.0 equiv.) in HFIP (1 mL) was added with a plastic syringe and the reaction mixture was heated at 40-85 °C with vigorous stirring for 1-8 hours. An internal standard of n-decane (97 L, 0.5 mmol, 1.0 equiv.) was added with a microsyringe. An aliquot was analyzed by GC-MS to obtain the calibrated yield of nitrobenzene.
Supplementary Figure 5. General procedure I for the nitration of (hetero)arenes.
General procedure I for the nitration of (hetero)arenes: An oven-dried, 25 mL micro-vial was charged on the benchtop with a magnetic pTFE-coated stirbar and 4a (148 mg, 0.65 mmol, 1.3 equiv.). The vial was sealed and the atmosphere was cycled 3x with Ar/vac. Hetero(arene) substrate (0.5 mmol, 1.0 equiv.) and HFIP (1 mL) were added and the reaction mixture was heated at 55 °C with vigorous stirring for 3 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the product was purified by flash column chromatography (SiO 2 , ethyl acetate/n-hexane gradient). hours. An internal standard of n-decane (97 L, 0.5 mmol, 1.0 equiv.) was added with a microsyringe. An aliquot was analyzed by GC-MS to obtain the calibrated yield of nitrobenzene.

Supplementary
Supplementary Figure 6. General procedure II for the nitration of (hetero)arenes.
General procedure II for the nitration of (hetero)arenes: An oven-dried, 25 mL micro-vial was charged on the benchtop with a magnetic pTFE-coated stirbar, nitrating reagent 4a (148 mg, 0.65 mmol, 1.3 equiv.) and Mg(ClO 4 ) 2 (11.2 mg, 0.05 mmol, 10 mol%). The vial was sealed and the atmosphere was cycled 3x with Ar/vac. Hetero(arene) substrate (0.5 mmol, 1.0 equiv.) in MeCN (1 mL) was added with a plastic syringe, and the reaction mixture was heated at 85 °C with vigorous stirring for 5 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the product was purified by flash column chromatography (SiO 2 , ethyl acetate/n-hexane gradient). Note: Li, Mg, Zn and Ni perchlorates are not dangerous chemicals if not employed under extreme acidic conditions and not exposed to high temperatures (>300−500 °C) (40)(41).
Nitrobenzene (5)     An oven-dried 10 mL microvial was charged on the bench with a magnetic stir bar and 4a (114 mg, 0.5 mmol, 1 equiv.). The vial was sealed and. HFIP (1 mL) was added with a syringe followed by benzene (134 L, 1.5 mmol, 3 equiv.) and deuterated benzene (133 L, 1.5 mmol, 3 equiv.) with a microsyringe. The reaction was placed in a heating block at 55 °C and stirred vigorously for 1 h. An internal standard of decane (97 L, 0.5 mmol, 1.0 equiv.) was added and the reaction mixture was analyzed with GC-MS. As can be seen in the following figure (Supplementary Fig. 8), the observed ratio between C 6 H 5 NO 2 (8.349 min) and The induction period could be due to the formation of a π complex, however we did not observe such a species by DFT. Under these conditions the NO 2 group of 4a was found to interact with HFIP via a hydrogen bond prior to nitronium transfer. We hypothesize that the induction period is due to the breaking of this weak adduct. Nevertheless, autocatalysis cannot be excluded.   , and the procedure was repeated 6 times. Supplementary Fig. 11 shows the yield for the formation of nitrobenzene (%). These results show that the magnesium catalyst can be reused without loss of its efficiency. The slight loss of yield after 6 runs may be the result of a high concentration of saccharin as well as nitrobenzene in the reaction mixture accumulated after 6 consecutive loads. x (see Supplementary Fig. 12). The experiments were performed following the method described by Harper and coworkers (42)(43). A 25 mL round bottom flask was charged with reagent 4a (23 mg, 0.1 mmol) and sealed under nitrogen atmosphere. Subsequently a solution consisting of benzene (47 L, 0.525 mmol,), bromo-benzene (53L, 0.503 mmol), toluene (53 L, 0.500 mmol) and anisole (54L, 0.502 mmol) in HFIP (4 mL) was introduced via syringe. The final reaction mixture was vigorously stirred at 55 °C for 3 hours. After completion of the nitration reaction, decane (49 L, 0.25 mmol) was added to the vessel through a micro-syringe and the final solution was stirred for an additional 5 minutes. The amounts of the corresponding arenes were determined by GC-MS analysis with respect to decane. The experiment was repeated three times with the use of the same amounts of arenes. Radical trapping mechanistic experiment: A 25 mL round bottom flask was charged with reagent 4a (148 mg, 0.65 mmol, 1.3 equiv.) and sealed under nitrogen atmosphere. Benzene (44.69 L, 0.5 mmol, 1.0 equiv.), additive (0.6 mmol, 1.2 equiv.,) and HFIP (1 mL) were added via syringe and the reaction mixture was vigorously stirred at 55 °C. After 3 h the crude reaction mixture was directly analyzed with GC-MS using n-decane (97 L, 0.5 mmol, 1.0 equiv.) as analytical standard. Results are summarized in Supplementary Table 4. It has been experimentally demonstrated that TEMPO and BHT are not suitable radical inhibitors under these reaction conditions, since they participate in a background reaction with nitrating reagent 4a in HFIP. Figure 13. Radical clock experiment.

Supplementary
A 25 mL round bottom flask was charged with reagent 4a (148 mg, 0.65 mmol, 1.3 equiv.) and sealed under nitrogen atmosphere. Cyclopropylbenzene (59 mg, 0.5 mmol, 1.0 equiv.) in HFIP (1 mL) was added via plastic syringe, and the reaction mixture was vigorously stirred at 55 °C for 3 h. The solvent was evaporated and the crude product was purified by flash column chromatography on silica gel (hexane/ethyl acetate 30:1) to afford 14a and 14b in 65.7% and 31.3% yield, respectively.  (52)(53) was used for all the atoms. The implicit solvation model IEF-PCM was used as implemented in Gaussian (54)(55), applying all the parameters of 2-propanol, apart from the dielectric constant (ε), which was modified to 16.70 (HFIP) (56) according to the literature for the description of HFIP as solvent (57)(58). Stationary points were characterized by vibrational analysis (only real frequencies for minima, one imaginary frequency for transition states (TSs)), and intrinsic reaction coordinate (IRC) calculations were carried out on the TSs in order to confirm their correct identification. Computed harmonic frequencies were used to calculate the thermal contribution to Gibbs free energy at 298 K and 1 atm. The thermochemistry analysis was performed as implemented in Gaussian09 software. TSs were modelled according to the literature by substitution of H 2 SO 4 (36) with the nitrating agent (1)(2)(3)(4) and by introduction of an explicit HFIP molecule (37).  Fig. 14C). According to the two torsion angles ( Supplementary Fig. 14C), TSs were calculated for 1-4 (see Supplementary Tables 9-13).  Figure 15, left structure). The reaction proceeds with a concerted and strongly asynchronous mechanism whereby the NO 2 + addition is the rate determining step, in agreeance with the first order reaction in benzene and the observed KIE. In this case, the σ complex was not located as a discreet intermediate, although it is observed in the reaction profile and is rapidly followed by H + elimination (Fig.  4E). The existence of the σ complex as an intermediate is strongly dependent on the applied hybrid functional, as already observed by Schaefer III (35-36, 42,59-60). Whereas such electrophilic addition mechanisms are generally described for polar solvents which facilitate H + elimination, this role is undertaken by saccharin in our transformation. The deprotonation is assisted by its sulfoxide group, generating the sulfenic acid derivative, followed by prototropic equilibrium to generate saccharin (Supplementary Figure 15). Figure 16. H + Transfer from benzene to 1 and 4a at O or N atom.

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transition state distribution. A good match was found between the experimental and calculated ratios, and the high para selectivity can be explained by steric hindrance in the transition state, whereby 4a shields one ortho position, and the HFIP molecule the other. The ortho:para selectivity is explained by the steric hindrance of the nitrating agent, which shields the ortho1 position, and HFIP, which shields the ortho2 position in the TS. Figure 23. Dissociation Gibbs free energies (ΔG°, in kcal mol -1 ) for 1-4.