EP4652309A2 - Flow synthesis of amines - Google Patents

Abstract

A two step synthesis of electrochemical flow synthesis of nitroamines, comprising the method of electrochemical continuous flow nitrosylation of amines for the synthesis of N-nitrosamines, comprising the steps of: i). preparing input flow reagent A in a first solvent, comprising the amine compound of Formula (I), wherein R¹ and R² are independently selected fromialkyl, aryl, phenyl, cycloakyl, heterocyclic, heterocyclic aromatic, or together form cycloakyl, heterocyclic, heterocyclic aromatic; ii). preparing input flow reagent B a nitrite salt in aqueous solution; iii). causing the input flow reagents A and B to enter a continuous electrochemical flow reactor provided with electrodes for electrolysis, at a flow rate, to furnish a reaction solution comprising a N-Nitrosamines of Formula (II). and the subsequent step of causing the compound of Formula II to be subjected 20 to continuous flow electrochemical oxidation to form a compound of Formula (III).

Description

XA23231GB-SCD Spec for Filing - 1 - FLOW SYNTHESIS FIELD The present invention relates to compound synthesis, and specifically relates to electrochemical flow synthesis nitrosylation for the synthesis of N- nitrosamines and subsequent oxidation to N-nitramines. BACKGROUND The formation of explosive compounds typically involves the use of batch synthesis to form large quantities of explosive material, which presents a significant explosion hazard. SUMMARY Before the present invention is described in further detail, it is to be understood that the invention is not limited to the particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims According to the first aspect of the present invention, there is provided a method of electrochemical continuous flow nitrosylation of amines for the synthesis of N-nitrosamines, comprising the steps of: i). preparing input flow reagent A in a first solvent, comprising the amine compound of Formula (I), Formula wherein R¹ and R² are independently selected from H, alkyl, aryl, phenyl, cycloakyl, heterocyclic, heterocyclic aromatic, or together form heterocyclic, heterocyclic aromatic; ii). preparing input flow reagent B, a nitrite salt in aqueous solution; XA23231GB-SCD Spec for Filing - 2 - iii). causing the input flow reagents A and B to enter a continuous electrochemical flow reactor provided with electrodes for electrolysis, at a flow rate, to furnish a reaction solution comprising a N-Nitrosamines of Formula II. Formula II The nitrite salt may be any suitable nitrite salt, such as, for example tetrabutylammonium nitrite, group I metal nitrites, group II metal nitrites, preferably group I metal nitrites, such as KNO2 or NaNO2, more preferably NaNO2. The conditions are an acid-free, oxidant-free, electrolyte-free, continuous flow electrochemical strategy for the synthesis of N-nitrosamines from their corresponding primary or secondary amines. The first solvent may be any suitable solvent in which the amine of Formula I is soluble, preferably a polar organic solvent, more preferably the solvent may be MeCN or MeOH. The anode may be selected from any suitable anode, such as for example boron doped diamond (BDD) or graphite. The cathode may be any inert metal, preferably platinum. The reaction may be worked up by step iv) the reaction solution may be washed with dilute acid, such as for example HCl(aq). The products ie Formula II may be purified by any known purification means, such as, for example an in-line acidic extraction, chromatography or crystallisation. The input flow reagent A, an amine compound of Formula (I) may be present in a 0.01M to 5M solution in the first solvent. XA23231GB-SCD Spec for Filing - 3 - The input flow reagent B the nitrite salt in aqueous solution may be present in a 0.01M to 5M solution. Preferably the concentration of the nitrite salt in aqueous solution may be at least double the concentration of the amine compound of Formula (I). Preferably, Formula II R¹ and R² may be selected to form an N- Nitrosamines comprising at least two N-Nitrosamines groups. This allows the preparation of energetic material precursors, for highly nitrated nitramines. According to a further aspect of the invention there is provided a method of synthesising N- nitramines by electrochemical continuous flow comprising the steps of v) forming an N-Nitrosamines of Formula II, Formula II by any method or more preferably by a method as defined hereinbefore; vi) causing the compound of Formula II to be subjected to continuous flow electrochemical oxidation to form a N-nitramine compound of Formula III, Formula III; wherein R1 and R2 are as hereinbefore defined. Preferably, Formula III R¹ and R² are selected to form an energetic material N-nitramine comprising at least two N-nitramine groups, such as for example RDX (cyclo-1,2,3-trimethylene-2,4,6-trinitramine, Hexogen), HMX (cyclo-1,3,5,7-tetramethylene-2,4,6,8-tetranitramine, Octogen, NTO (3-nitro- 1,2,4-triazol-5-one) or CL-20 (2,4,6,8,10,12-hexanitro-2,4,6,8,10,12- hexaazaisowurtzitane). XA23231GB-SCD Spec for Filing - 4 - Nitramine compounds are those containing at least one N-NO₂ group. Heteroalicyclic nitramines bear a ring containing N-NO₂ groups. Such ring or rings may contain for example from two to ten carbon atoms and from two to ten ring nitrogen atoms. The electrochemical oxidation is more green and environmentally friendly, in line with the development direction of green chemical synthesis. The continuous flow chemical oxidation may be carried out by any known process (1)Dissolving and mixing the compound of Formula II; (2)The reaction solution is pumped into a microchannel reaction device equipped with electrodes for electrolysis reaction, and the reaction product is collected to obtain a solution comprising the compound represented by Formula III; Common anions for the oxidation used as supporting electrolyte may be perchlorates, hexafluorophosphates, tetrafluoroborates or nitrites, since they have high discharge potential (the potential at which the anion will be oxidised at the electrode). As for the cation, their choice becomes more important when a cathodic reduction will be performed. The cationic parts may be tetraalkylammonium ions, lithium, sodium and magnesium ions. Preferably, in step (2), the microchannel reaction device provided with electrodes includes a syringe pump, a microchannel reactor, a negative electrode sheet, a positive electrode sheet, and a receiver; wherein, both sides of the microchannel reactor are respectively provided with cathodes. The sheet and the anode sheet; the injection pump, the microchannel reactor and the receiver are connected in series; the connection is a pipeline connection. Further preferably, the positive electrode sheet may be a carbon sheet electrode, and the negative electrode sheet may be a platinum-plated electrode. XA23231GB-SCD Spec for Filing - 5 - According to a further aspect of the invention there is provided a method of electrochemical continuous flow nitrosylation of amines for the synthesis of N- nitrosamines, comprising the steps of: xi). preparing input flow reagent A in a first solvent; xii). preparing input flow reagent B a nitrite salt in aqueous solution; xiii). causing the input flow reagents A and B to enter a continuous electrochemical flow reactor provided with electrodes for electrolysis, at a flow rate, to furnish a reaction solution comprising a N-nitrosamine. According to a further aspect of the invention there is provided a method of synthesising N-nitramines by electrochemical continuous flow comprising the steps of: xv) selecting an N-Nitrosamine in a first solvent; xvi) causing the N-Nitrosamine in a first solvent to be subjected to continuous flow electrochemical oxidation to form a N-nitramine. Experimental General All chemicals were purchased from Acros Organics, Alfa Aesar, Apollo Scientific Ltd, Fisher Scientific Ltd, Scientific Laboratory Supplies Ltd, Merck KGaA, Fluorochem Ltd, and Sigma- Aldrich. All purchased chemicals were used without further purification. Deuterated solvents for NMR analysis were purchased from Sigma-Aldrich. Reference electrode kit was purchased from Osilla Ltd. Room temperature (rt) stands for 20-25 °C. Thin layer chromatography (TLC) experiments were performed on aluminum plates c_{oated with silica} (TLC Silica gel 60 F²⁵⁴) purchased from Merck, and visualised b^{y UV light. Column} chromatography was carried out using silica gel (technical grade, pore size 60 Å, 230-400 mesh particle size, 40-63 µm particle size) purchased from Sigma-Aldrich, or by flash column chromatography on a Biotage^® Isolera^TM Four system using Biotage^® SNAP Ultra 25 g, or 50 g, or Biotage^® Sfär Silica D 25 g, or 50 g cartridges. XA23231GB-SCD Spec for Filing - 6 - Electrolysis: Flow electrochemical experiments were performed using a stand-alone Vapourtec Ion Electrochemical Reactor or integrated Vapourtec Ion Electrochemical Reactor for heated experiments, with an Aim-TTi EX354RD Dual Power Supply from Thurlby Thandar Instruments Ltd. Chemyx Fusion 100 Touch Syringe Pumps were used in the flow set-ups. Electrode materials employed were Graphite (Gr), Platinum (Pt), Nickel (Ni), Stainless Steel (SS), and Copper (Cu) purchased from Goodfellow and Boron Doped Diamond (BDD) purchased from Vapourtec. The electrodes (5 x 5 cm²) were separated by a 0.5 mm FEP spacer or a 1.0 mm PTFE spacer resulting in a reactor volume of 0.6 mL or 1.2 mL, respectively with an exposed electrode surface area of 12 cm². General Flow Electrolysis Procedure A: The electrolysis was performed in an undivided cell using a Vapourtec Ion Electrochemical Reactor¹ (FEP spacer = 0.5 mm, reactor volume = 0.6 mL), employing a graphite electrode as the anode and a nickel electrode as the cathode (active surface area = 12 cm² for each electrode). A solution of secondary amine (0.2 M, 1 equiv.) in acetonitrile and sodium nitrite (1.0 M, 5 equiv.) in distilled water were pumped with a flow rate of 0.025 mL min^-1 (combined flow rate of 0.05 mL min^-1) into the electrochemical reactor and were electrolysed under constant current conditions (50 mA, 1.25 F). The first one and a half reactor volumes were disposed to ensure a steady state of the system had been reached. After collection for a ^{known period of time, the} XA23231GB-SCD Spec for Filing - 7 - reaction mixture was treated with 1% HCl_(aq) and the aqueous _{phase was} extracted with dichloromethane (3 x 25 mL). The organic layers were combined, dried over MgSO4, filtered, and the solvent was removed in vacuo to yield the c^{rude product.} The crude product was purified by column chromatography. Procedure A was adapted in certain cases by combining both solutions into one syringe to overcome solubility issues. Note: the combined solutions in the syringe are pumped with a flow rate of 0.05 mL min^-1. Procedure A was adapted for piperazine by employing a water only system to avoid the formation of a biphasic system, by using sodium nitrite (2.0 M, 10 equiv.) in water and electrolysing the substrates under constant current conditions (100 mA, 1.25 F). N-nitrosylation The N-nitrosylation flow electrochemical experiments were carried out at ambient temperatures in an undivided, commercially available flow electrochemical reactor. Constant current conditions were applied and a 500 µm FEP spacer was used to separate the electrodes, creating a channel with a reactor volume of 0.6 mL, and an active surface area of 12 cm² for each electrode. N-Methylbenzylamine (1a) was the substrate employed for the purpose of reaction optimisation required for the electrolysis towards N- nitrosamine 1c (Fig 1). Sodium nitrite was selected to be the source of nitrite i_{ons as it is significantly cheaper than potassium} ^{nitrite. Since nitrite salts are insoluble in organic} solvents, water must be utilised as the medium to dissolve the sodium nitrite, while the secondary amine was dissolved in an organic solvent miscible with water such as acetonitrile. The use of additional supporting electrolytes could be omitted due to not only the conductivity of the nitrite salts in solution, but also the small interelectrode distance. Initially, equipping the reactor with Pt as the ^{cathode, Gr as the anode,} using 1.2 equiv. of NaNO₂, an applied charge of 2 F, a flow rate of XA23231GB-SCD Spec for Filing - 8 - 0.05 mL min^-1 gave the desired product 1c in 15% yield (Fig 1, entry 1). Next, changing the nature of the cathode material from Pt to cheaper Ni did not decrease the yield (Fig 1, entry 6). Other cathodic materials were tested and gave rise to 73% (SS), 67% (Cu), and 25% (Gr) yields (Fig 1, entries 3–5). Since Ni is considerably cheaper than Pt, Ni was selected as the cathodic material. An increase in the initial concentration of 1a and 1b from 0.14 M and 0.71 M to 0.2 M and 1.0 M led to 1c being formed in 81% yield, showing a slight decrease (Fig 1, entry 9). However, at the increased concentrations, reducing the amount of charge applied from 1.75 F to 1.25 F increased the yield of 1c to 89% (Fig 1, entry 10). Turning to fig 2, with the optimum conditions in hand, the procedure was applied to converting various cyclic and acyclic aliphatic secondary amines to their corresponding N- nitrosamines (Figure 2). Starting with N- methylbenzylamine and increasing the steric bulk to N-ethyl, N-isopropyl, and N-tert-butyl resulted in good to excellent yields of the product, although the yield decreased with increased steric bulk (2a-2d). Dibenzylamine produced the product with an outstanding yield of 92% (2e). The method was also efficient for piperidine and its 4-substituted derivatives, as the products were obtained in yields ranging from 68% to 99% (2f–2k). Also, cis-2,6-dimethylpiperidine and 2,2,6,6-tetramethylpiperidine gave products 2l and 2m in 68% and 72% yields, respectively. Mono N-substituted piperazine derivatives were nitrosated successfully at the other nitrogen atom and products were obtained in good to excellent yields (2n, 2o and 2q), apart from 1-phenylpiperazine, which gave the product 2p in only moderate yields of 46%. Piperazine was dinitrosated in poor yields of 30% (2r), however this reaction was performed with water as the only solvent, due to the formation of a biphasic system in the standard solvent system. Pyrrolidine and azepane were employed as amines in a five- membered and seven-membered ring system, affording the products in good yields of 75% (2s and 2t). Morpholine and thiomorpholine furnished the XA23231GB-SCD Spec for Filing - 9 - nitrosated products in 78% and 63%, respectively (2u and 2v). Fused bicyclic ring compounds such as cis-octahydroisoindole and 1,2,3,4- tetrahydroisoquinoline provided the products in 54% and 83%, respectively (2w and 2x). Moreover, several acyclic, symmetrical aliphatic amines such as dicyclohexylamine, diisopropylamine, and dibutylamine yielded the N- nitrosated amines in poor to moderate yields (2y-2aa). Characterisation of the Products A selection of characterization data is provided below. N-nitroso-N-methylbenzylamine (2a) Prepared according to the general procedure A from N- methylbenzylamine (54.5 mg, 58.0 µL, 0.45 mmol) over 1.5 h. The product was obtained as a yellow oil (61.7 mg, 0.41 mmol, 91%). 1H NMR (500 MHz, CDCl3): δ 7.41-7.26 (m, 4.60H), 7.14-7.13 (m, 0.46H), 5.31 (s, 1.55H), 4.81 (s, 0.44H), 3.69 (s, 0.66H), 2.95 (s, 2.34H). 13C NMR (126 MHz, CDCl3): δ 134.5, 133.8, 129.2, 129.0, 128.7, 128.5, 128.2, 128.1, 57.8, 48.0, 38.6, 31.1. HRMS (CI): m/z [M+H]⁺ calcd for C8H11ON2 151.08659, found 151.0865. Two configurational isomers, produced from the restricted rotation around the N-N partial double bond, were observed in the NMR spectra, with a ratio of 2:7. XA23231GB-SCD Spec for Filing - 10 - NMR data is identical to the literature data N-nitrosodicyclohexylamine (2y) Prepared according to the general procedure A from dicyclohexylamine (217.6 mg, 1.20 mmol) over 4 h. The crude product was purified by column chromatography on silica gel (DCM:cyclohexane = 3:7) to give 2y as yellow crystals (140.9 mg, 0.67 mmol, 56%). 1H NMR (500 MHz, CDCl3): δ 4.87 (tt, J = 11.7, 3.7 Hz, 1H), 3.71 (tt, J = 11.0, 4.5 Hz, 1H), 1.96-1.57 (m, 12H), 1.47-1.20 (m, 7H), 1.14 (qt, J = 12.9, 3.6 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 58.7, 52.3, 34.5, 29.5, 26.2, 25.6, 25.5, 25.4. HRMS (CI): m/z [M]⁺ calcd for C12H22ON2210.17266, found 210.1727. NMR data is identical to the literature data

XA23231GB-SCD Spec for Filing - 11 - In-line purification General Flow Electrolysis Procedure B: This procedure is analogous to the above procedure A, except for a second pump connected via a T-piece, employed to protonate any remaining s_{tarting material and take up} ^{excess NaNO} ₂ ^{and its intermediates, and a third pump connected via another T-piece,} _{utilised for extraction of the product into} the organic layer, where the layers are separated at the in-line liquid-liquid separator. After collection for a known period of time, the solvent was removed in vacuo to yield the pure product. An in-line purification method was devised which is based on acidic work-up. This was achieved by including a commercially ^{available in-line liquid-} liquid extractor. A 1% HCl_(aq) is pumped into the system to make sure any unreacted starting material, excess NaNO2, and species resulting from the electrolysis of NaNO2 will reside in the aqueous phase. Subsequently, d^{ichloromethane was} used to extract the N-nitrosamine from the aqueous phase, before the two different solvent streams are separated at the extractor. XA23231GB-SCD Spec for Filing - 12 - Nitrosyl to nitro conversion- single step synthesis Table 1 a Standard reaction conditions: undivided flow cell, Pt anode (active surface area: 12 cm2), Pt cathode, interelectrode distance: 0.5 mm, current: 16 mA, charge: 1 F mol-1, 1a (0.05 M, 1 equiv.), nBu4NClO4 (0.1 M) in MeCN. b Yield determined by GC-FID using benzonitrile as internal standard The use of very low flow rates of 0.05 mL min-1, 1 bar of back-pressure cannot be achieved. Similarly, with 0.01 mL min-1, 2 bar of back-pressure cannot be achieved. Thus, 0.2 mL min-1 was used as the flow rate to investigate the effect of back-pressure on the system. As can be seen from Table 1, the effect of back pressure had little effect on the yield% of 2a. Preferably there is no back pressure regulator. The effect of different anodic and cathodic materials were tested for their efficiencies and the results can be seen below in Table 2. Changing the anode from platinum (entry 1) to glassy carbon (GC) (entry 2) and graphite (entry 3) showed that despite the higher yields of product obtained for Pt and GC as the anode, there is less decomposition observed when using Gr. Therefore, graphite is a preferable anodic material. Moreover, changing the cathode from platinum to XA23231GB-SCD Spec for Filing - 13 - nickel (entry 4), copper (entry 5), and stainless steel (entry 6) showed that platinum, nickel and copper resulted in similar yields of product and reactant. The metal cathode may be chosen such that it can efficiently allow O2 to chemisorb to the surface. The energy for this process should be around -0.5 to - 2 eV which can be achieved by numerous metals. Platinum, gold, and silver are further suitable metals for the cathode. Table 2 a Standard reaction conditions: undivided flow cell, x anode (active surface area: 12 cm²), x cathode, interelectrode distance: 0.5 mm, current: 16 mA, charge: 1 F mol-1, flow rate liquid: 0.2 mL min-1, flow rate O2: 0.2 mL min-1, 1a (0.05 M, 1 equiv.), nBu4NClO4 (0.1 M) in MeCN. b Yield determined by GC-FID using benzonitrile as internal standard. XA23231GB-SCD Spec for Filing - 14 - The increase in flow rate of the O₂ was examined. Flowing through O₂ at double and quadruple the flow rate of the liquid was also performed, to see whether an excess flow of oxygen gas will allow for more conversion of the starting material However, the yield of starting material and product in all cases was similar, indicating that flowing excess amount of gas has no impact on the results- this is beneficial as it is more cost effective to reduce the gas flow. The applied charge was varied from 1 F mol-1 to 2 F mol-1 in increments of 0.25 F mol-1. It was observed that the best results were obtained with an applied charge of 1.25 F mol-1 resulting in 21% yield of the product with 55% of the starting material left unreacted. Higher charge applied results in slightly higher yields, with more decomposition observed, thus showing to be incompatible with the system. Finally, the concentration of the solution was lowered from 0.05M to 0.025M to see whether this change will allow for more conversion of the starting material to occur, and whether decomposition will be less likely. However, several experiments were carried out for both concentrations and the results were nearly identical showing that this change had no impact on the results obtained. The reaction scheme below was repeated to achieve compounds 2a-e, as described in Figure 7 below. BRIEF DESCRIPTION OF THE FIGURES Embodiments of the invention will now be described by way of example only with reference to the figures, in which: Figure 1 shows the table of results for N-nitroso-N-methylbenzylamine XA23231GB-SCD Spec for Filing - 15 - Figure 2 shows the table of example synthesised N- nitrosamines; Figure 3 shows optimisation of the nitrite salt; Figure 4 shows the optimisation of the NaNO2; Figure 5 shows .optimisation of solvent and anodic materials Figure 6 shows the synthesis of N-nitramines in a multistep synthesis. Figure 7 shows synthesised N- nitrosamines. DETAILED DESCRIPTION Figures 1 and 2 have been discussed in the Experimental. Turning to Fig 3, shows the different yields of varying nitrite salts, conveniently low cost sodium nitrite provided excellent yields in comparison to other nitrites. However, other nitrites, particularly metal nitrites will provide similar results. Turning to Fig 4, shows that increasing the concentration of sodium nitrite increased the yield. Turning to Fig 5 alternative polar solvents will work, but MeCN which has a low hazard is highly suitable for large scale manufacture. Alternative carbon based electrodes provide results, graphite provides the best yield in comparative studies. Turning to figure 6 there is provided the two step pathway for the conversion of amines to nitramines, for the synthesis of energetic materials. Turning to figure 7 there is provided the electrochemical oxidation of nitrosylated amines to corresponding nitramines.

Claims

XA23231 Spec for Filing - 16 - CLAIMS 1. A method of electrochemical continuous flow nitrosylation of amines for the synthesis of N-nitrosamines, comprising the steps of: i). preparing input flow reagent A in a first solvent, comprising the amine compound of Formula (I), Formula I wherein R¹ and R² are independently selected from H, alkyl, aryl, phenyl, cycloakyl, heterocyclic, heterocyclic aromatic, or together form heterocyclic, heterocyclic aromatic; ii). preparing input flow reagent B a nitrite salt in aqueous solution; iii). causing the input flow reagents A and B to enter a continuous electrochemical flow reactor provided with electrodes for electrolysis, at a flow rate, to furnish a reaction solution comprising a N-nitrosamine of Formula II; Formula II. 2. The method according to claim 1, wherein the nitrite salt is tetrabutylammonium nitrite, group I metal nitrite, group II metal nitrite. 3. The method according to claim 1 or claim 2, wherein the first solvent is a polar organic solvent. 4 The method according to claim 3 wherein the solvent is MeCN or MeOH. 5. The method according to any one of the preceding claims, wherein the anode is BDD or graphite and the cathode is platinum. XA23231 Spec for Filing - 17 - 6. The method according to any one of the preceding claims wherein step iv) the reaction solution is washed with dilute acid. 7. The method according to any one of the preceding claims wherein the amine compound of Formula (I) is present in a 0.01M to 5M solution. 8. The method according to any one of the preceding claims wherein the nitrite salt in aqueous solution is present in a 0.01M to 5M solution. 9. The method according to any one of the preceding claims wherein the concentration of the nitrite salt in aqueous solution is at least double the concentration of the amine compound of Formula (I). 10. The method according to any one of the preceding claims wherein Formula II R¹ and R² form an N-Nitrosamine heterocycle comprising at least two N- nitrosamine groups. 11. A method of synthesising N-nitramines by electrochemical continuous flow comprising the steps of v) forming an N-Nitrosamine of Formula II; Formula II by a method as claimed in any one of the preceding claims: vi) causing the compound of Formula II to be subjected to continuous flow electrochemical oxidation to form a N-nitramine compound of Formula III, Formula III. wherein R¹ and R² are independently selected from H, alkyl, aryl, phenyl, cycloakyl, heterocyclic, heterocyclic aromatic, or together form heterocyclic, heterocyclic aromatic. XA23231 Spec for Filing - 18 - 12. The method according to claims wherein Formula III R¹ and R² form an energetic material N-nitramine comprising at least two N-nitramine groups. 13. The method according to claim 12 wherein energetic material is RDX, HMX, or CL20. 14. A method of electrochemical continuous flow nitrosylation of amines for the synthesis of N-nitrosamines, comprising the steps of: xi). preparing input flow reagent A in a first solvent; xii). preparing input flow reagent B a nitrite salt in aqueous solution; xiii). causing the input flow reagents A and B to enter a continuous electrochemical flow reactor provided with electrodes for electrolysis, at a flow rate, to furnish a reaction solution comprising a N-nitrosamine. 15. A method of synthesising N-nitramines by electrochemical continuous flow comprising the steps of: xv) selecting an N-Nitrosamine in a first solvent; xvi) causing the N-Nitrosamine in a first solvent to be subjected to continuous flow electrochemical oxidation to form a N-nitramine.