Flow Electrochemistry for the N -Nitrosation of Secondary Amines

: A flow electrochemical method towards the synthesis of N -nitroso compounds from secondary amines using cheap and readily available sodium nitrite has been developed. Sodium nitrite dissolved in aqueous acetonitrile made additional electrolytes unnecessary. This mild and straightforward approach made the use of acids or other harsh and toxic chemicals redundant. This procedure was applied to an assortment of cyclic and acyclic secondary amines (27 examples) resulting in yields of N -nitrosamines as high as 99%. To demonstrate the practicality of the process, scaled-up reactions were performed. Finally, selected products could be purified by using an in-line acidic extraction.

Electrochemistry is a promising alternative to the abovementioned processes as the use of toxic redox reagents can be eliminated and be replaced with electrons, a much greener and cheaper redox reagent.Flow chemistry in combination with electrochemistry is a great tool, as any short-lived intermediates generated from the electrolysis of chemicals can readily react with substrates due to the proximity of the electrodes.Additionally, multistep syntheses can be easily integrated into the system, products can be purified in-line, and reactions are easily scalable. [42]Several batch electrochemical processes towards the N-nitrosation of secondary amines have already been developed.The first electrochemical approach towards the synthesis of N-nitrosamines was performed by Masui and co-workers using sodium nitrite as the nitrosating source (Scheme 1). [43]Lu et al. used Fe(NO 3 ) • 9 H 2 O as a source of nitrate responsible for the N-nitrosation under electrochemical conditions. [44]Unfortunately, high temperatures of 70 °C were required for this reaction.Another electrochemical approach was described by Gao and co-workers, who used potassium nitrite as the nitrosating source (Scheme 1). [45]They also investigated sodium nitrite, a much cheaper source of nitrite ions, but this led to unacceptable yields.The latter two approaches require inert conditions for the reaction to proceed successfully.Additionally, all above methods suffer from the very low solubility of the nitrite salts in the organic reaction solvents, which must be addressed for developing suitable flow conditions.Herein, we report the development of an acid-and oxidantfree, continuous-flow electrochemical process towards the synthesis of N-nitrosamines from secondary amines.In this strategy, a one-electron anodic oxidation of the nitrite ion provides NO 2 * radicals, which dimerise and exist in equilibrium with dinitrogen tetroxide (N 2 O 4 ), [46][47][48] a known nitrosating agent for secondary amines under neutral or alkaline aqueous conditions and in organic media. [33,35]

Results and Discussion
The flow electrochemical experiments were carried out at ambient temperatures in an undivided, commercially available flow electrochemical reactor. [49]Constant current conditions were applied and a 500 μm FEP spacer was used to separate the electrodes, creating a channel with a 0.6 mL volume inside the reactor with an active surface area of 12 cm 2 for each electrode.N-Methylbenzylamine 1 a was employed as the substrate for the determination of the optimal conditions required for the electrolysis towards N-nitrosamine 2 a (Table 1).NaNO 2 was selected to be the source of nitrite ions as it is significantly cheaper than KNO 2 (NaNO 2 : £7.4/mol; [50] KNO 2 : £90.2/mol [51] ).As nitrite salts are insoluble in organic solvents, water must be used as the medium to dissolve the sodium nitrite, while the secondary amine was dissolved in acetonitrile owing to its miscibility with water.Due to the sufficient conductivity of the nitrite salt solutions and the small interelectrode distance, there was no need to add a supporting electrolyte.Using platinum as the cathode and graphite as the anode, an applied charge of 2 F mol À1 and a flow rate of 0.05 mL min À1 gave the desired product 2 a in 15 % yield (Table 1, entry 1).Using an excess NaNO 2 (5 equiv.)as shown in the recent batch reactions allowed the reaction to proceed efficiently. [45]This led to a dramatic increase in the yield (88 %, Table 1, entry 2).Changing the cathode material from platinum to nickel did not decrease the yield (Table 1, entry 6).Other cathodic materials were investigated and provided 2 a in 73 % (SS), 67 % (Cu), and 25 % (Gr) yield, respectively (Table 1, entries 3-5).Because Ni is considerably cheaper than Pt, Ni was chosen for the subsequent work.An increase in the concentrations of 1 a and NaNO 2 from 0.14 and 0.71 M to 0.2 and 1.0 M led to 2 a being formed in 81 % yield, showing a slight decrease (Table 1, entry 7).However, at the increased concentrations, reducing the amount of charge applied from 1.75 to 1.25 F mol À1 increased the yield of 2 a slightly to 89 % (Table 1, entry 8).Increased flow rates while keeping the charge applied constant at 1.25 F mol À1 , hence resulting in higher charge densities, led to a decrease in the observed yield (Table 1, entries 9 and 10).Finally, starting with even higher initial concentrations of 1 a and NaNO 2 unfortunately resulted in a decrease in the formation of 2 a (Table 1, entries 11 and 12).
With the optimised conditions in hand, the versatility of the procedure for converting cyclic and acyclic aliphatic secondary amines to their corresponding N-nitrosamines (Scheme 2) was explored.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 slightly decreased with increased steric bulk (2 a-2 d).Dibenzylamine produced the product 2 e with a very good yield of 92 %.The method was also efficient for piperidine and its 4substituted derivatives, as the products were obtained in yields Scheme 1. Synthesis of N-nitrosamines.

Table 1.
Optimisation studies for the N-nitrosation of N-methylbenzylamine 1 a. [a] [ 1 [b]   ranging from 68 to 99 % (2 f-2 k).Also, cis-2,6-dimethylpiperidine and 2,2,6,6-tetramethylpiperidine provided products 2 l and 2 m in 68 % and 72 % yield, respectively.N-Substituted piperazine derivatives were nitrosated successfully and products 2 n, 2 o, and 2 q were obtained in good to excellent yields, apart from 1-phenylpiperazine, which gave the product 2 p in only moderate yield of 46 %.Piperazine was dinitrosated in 30 % yield (2 r), however, for this reaction the solvent had to be changed to water only due to the formation of a biphasic system in the standard solvent system.Pyrrolidine and azepane were employed as other cyclic amines, affording the products in good yields of 75 % (2 s and 2 t).Morpholine and thiomorpholine furnished the nitrosated products in 78 and 63 % yield, respectively (2 u and 2 v).Fused bicyclic ring compounds such as cis-octahydroisoindole and 1,2,3,4-tetrahydroisoquinoline provided the products in 54 and 83 % yield, respectively (2 w and 2 x).Furthermore, several acyclic, symmetrical aliphatic amines such as dicyclohexylamine, diisopropylamine, and dibutylamine yielded the N-nitrosated amines in poor to moderate yields (2 y-2 aa).Unfortunately, secondary cyclic amides, such as δ-valerolactam (1 ab), were not nitrosated successfully under the given conditions, even at elevated temperatures of 80 °C.Finally, tributylamine resulted in trace amount of N-nitrosamine 2 aa, due to dealkylative nitrosation of tertiary amines being significantly slower than that of the corresponding secondary amine in aqueous media (see the Supporting Information). [52]Due to the hindered rotation around the NÀN bond resulting from its partial double bond character, the 1 H NMR spectra of all N-nitrosamines show the presence of configurational isomers. [53]nterestingly, several of the synthesised products did not require purification by column chromatography, and an in-line purification method was devised based on an acidic work-up protocol (Scheme 3a).This was achieved by including a commercially available in-line liquid-liquid extractor. [54]Here, 1 % aqueous HCl is pumped into the system to make sure any unreacted starting material, excess NaNO 2 , and species resulting from the electrolysis of NaNO 2 will be extracted into the aqueous phase.Subsequently, dichloromethane is added to extract the N-nitrosamine, and the two different solvent streams are passed into a phase separator.The products that were able to be purified using the in-line system were 2 a, 2 f, 2 g, 2 h, 2 i, 2 k, 2 l, 2 n, 2 o, and 2 u.To demonstrate the scalability of the procedure, N-methylbenzylamine 1 a and dicyclohexylamine 1 y were subjected to the reaction procedure with doubled flow rate to achieve a higher productivity (Scheme 3b).The products 2 a and 2 y were obtained in 65 and 41 % yield, respectively, after 16 and 24 h of reaction time.
To investigate the reaction mechanism, several mechanistic experiments were carried out.Cyclic voltammetry (CV) experiments were performed on both N-methylbenzylamine 1 a and NaNO 2 solutions, and the voltammograms showed the oxida- tion peaks to be 1.3 and 0.7 V (vs Ag/AgNO 3 ), respectively (see Figure S1 in the Supporting Information).The oxidation peak of NaNO 2 in the reaction mixture was seen at a lower oxidation potential of 0.4 V (vs Ag/AgNO 3 ).These results, in combination with past literature reports [45][46][47][48] allowed to propose a possible reaction mechanism (Scheme 4).Initially, NO 2 À anions undergo a one electron oxidation to the NO 2 * radical.This species can dimerise to form N 2 O 4 , which is in equilibrium with a NO + cation and NO 3 À anion in solution.The NO + cation and NO 3 À anion interact with the amine, which is followed by the introduction of a hydroxide anion, generated from the reduction of water at the cathode.This resulting intermediate allows the formation of the desired N-nitrosamines, with the release of one water molecule and a nitrate anion.Previously, it was shown that 5 equivalents of the nitrite source are necessary for the reaction to proceed efficiently.48] For further investigations of the mechanism, a series of density functional theory (DFT) calculations at the SMD/ωB97X-D/def2tzvp//B3LYP-D3/6-31G(d) level were studied with 1 e as the model substrate.The DFT results, presented in Figure 1, show that the reaction starts with three possible pathways for the formation of different forms of the NO 2 dimer: symmetric  N 2 O 4 , int-trans, and int-cis, from two monomers of NO 2 .The activation barrier for the formation of int-cis is 19.0 kcal mol À1 , while that for int-trans is 35.6 kcal mol À1 .However, attempts to locate the transition structure for symmetric N 2 O 4 were unsuccessful.The activation barrier for symmetric N 2 O 4 isomerising to int-trans was calculated to be 37.3 kcal mol À1 , making it an unlikely process in the NO 2 isomerisation.Thus, it is more favourable to first form int-cis and then convert it to int-trans where the activation barrier is 1.7 kcal mol À1 (TS4).These results align with the report by Goddard and Liu on the interconversion between the three isomers of dinitrogen tetroxide in chemical processes. [55]fter the formation of int-trans, the intermolecular Nnitrosation of the secondary amine 1 e will progress by forming adduct add-1.The subsequent generation of adduct add-2 occurs through transition structure TS5, which has an energy barrier of 1.0 kcal mol À1 .Subsequently, the formation of add-3 occurred without encountering any energy barrier.The presence of the hydroxide ion generated from the reduction of water at the cathode facilitated the deprotonation of add-3, leading to the production of the final product N-nitrosamine 2 e.This conversion proceeded through an exergonic process with a relative free energy of À82.0 kcal mol À1 , resulting in the release of NO 3 À and H 2 O.

Conclusions
In conclusion, a new continuous-flow electrochemical method has been developed to access N-nitrosamines from their corresponding secondary amines by using sodium nitrite as the nitrosating source.This is a non-hazardous, straightforward, and simple to set-up approach that avoids the use of any additional supporting electrolyte or other toxic reagents.Additionally, ambient temperatures and less hazardous solvents were employed for these reactions, thus harsh reaction conditions could be avoided.This method allowed the synthesis of a diverse scope of N-nitrosamines in good to excellent yields.One such reaction demonstrated the di-nitrosation of a substrate.Furthermore, great functional group tolerance was observed, and some of the products could be purified by using an in-line acidic extraction.This method proved to be easily scalable, an invaluable asset intrinsic of continuous-flow chemistry, demonstrating great applicability in both academic and industrial settings.

Experimental Section
General procedure for the flow electrochemical N-nitrosation of secondary amines: the electrolysis was performed in an undivided cell using a Vapourtec Ion electrochemical reactor [49] (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 cm 2 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 À1 (combined flow rate of 0.05 mL min À1 ) into the electrochemical reactor and were electrolysed under constant current conditions (50 mA, 1.25 F mol À1 ).1.5 reactor volumes were disposed to ensure a steady state of the system had been reached.After collection for a known period, the reaction mixture was treated with 1 % HCl (aq) and the aqueous phase was extracted with dichloromethane (3 × 25 mL).The organic layers were combined, dried over MgSO 4 , filtered, and the solvent was removed in vacuo to yield the crude product.The crude product was purified by column chromatography.

Scheme 2 .
Scheme 2. Substrate scope for the electrochemical synthesis of N-nitrosamines from aliphatic secondary amine derivatives in flow.Standard reaction conditions: undivided flow cell, Gr anode (active surface area: 12 cm 2 ), Ni cathode, amine (0.2 M) in MeCN, sodium nitrite (1.0 M) in H 2 O, combined flow rate of 0.05 mL min À1 , constant current of 50 mA.Isolated yields.[a] Amine and NaNO 2 solutions combined into one syringe to account for the poor solubility of the amine in MeCN only.[b] H 2 O as a solvent, constant current of 100 mA.

Figure 1 .
Figure 1.DFT reaction pathway for the formation of N-nitrosamine compound 2 e from the reaction of dinitrogen tetroxide and secondary amine 1 e computed at the SMD/ωB97X-D/def2tzvp//B3LYP-D3/6-31G(d) level of theory.The relative free energies are given in kcal mol À1 .