Reduction of nitrogen-containing compounds with organic mediators

Abstract

Systems, methods, and compounds for reduction of an oxidized nitrogen-containing compound to a reduced nitrogen-containing product are described herein. In some embodiments, a method of forming a nitrogen-containing product includes reducing a mediator in an aqueous solution. The method includes contacting the aqueous solution and a nonaqueous solution, the nonaqueous solution including a nitrogen-containing compound. The method further includes allowing a reaction to occur between the reduced organic mediator and the nitrogen-containing compound to form at a reduced nitrogen-containing product.

Description

PATENT Attorney Docket No. 51198-069WO3 REDUCTION OF NITROGEN-CONTAINING COMPOUNDS WITH ORGANIC MEDIATORS Cross-Reference to Related Applications

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 914,817, filed November 10, 2025, and U.S. Provisional Patent Application No. 63 / 746,546, filed January 17, 2025, the disclosures of which are hereby incorporated by reference in their entirety.Technical Field

[0002] Embodiments described herein relate to systems, components, and methods for generation of products from nitrogen-containing compounds.Background

[0003] Amine compounds are widely used in pharmaceuticals, agrochemicals, dyes, and polymer synthesis. Conventional methods for producing amine compounds typically involve catalytic hydrogenation, chemical reduction and / or electrochemical methods. However, each of these approaches present significant limitations. Catalytic hydrogenation requires high pressure and elevated temperatures, and expensive metal catalysts, which increase operational complexity and expense. Chemical reduction methods often employ hazardous reagents and generate substantial amount of waste, raising environmental and safety concerns. Electrochemical reduction methods have emerged as a promising alternative, but current implementations suffer from low selectivity, limited efficiency, and poor scalability for continuous production. These challenges arise from factors such as reactant solubility, substrate generality, current density, purification complexity, instability of mediator compounds, and difficulties in mediator regeneration, all of which reduce process reliability. Furthermore, conventional methods are energy-intensive and prone to undesirable side reactions that compromise yield and purity. Overall, these methods require harsh conditions, expensive catalysts, and produce undesirable byproducts. In addition, achieving a high yield and selective synthesis continues to be a critical economic and technical challenge. Accordingly, there is a need for improvements in producing amines and other reduced nitrogen-containing products.Summary

[0004] Embodiments described herein relate to systems, devices, methods, and compounds for reduction of an oxidized nitrogen-containing compound to a reduced nitrogen-containing product. In some aspects, a method of forming a nitrogen-containing compound includes reducing a mediator in an aqueous solution, contacting the aqueous solution and a nonaqueous solution, the nonaqueous solution including a nitrogen-containing compound, and allowing a redox reaction to occur between the reduced organic mediator and the nitrogen-containing compound to form at a reduced nitrogencontaining product.PATENT Attorney Docket No. 51198-069WO3

[0005] In some embodiments, a mediator for proton coupled electron transfer (PCET) includes a phenazine configured to undergo proton-coupled electron transfer in an aqueous medium, and to reduce a nitrogen-containing compound to at least partially form a reduced nitrogen-containing product.In some embodiments, a system includes an electrochemical flow cell configured to receive a mediator in an aqueous solution and electrochemically reduce the mediator in the aqueous solution, a reactor fluidically coupled to the electrochemical flow cell, the reactor defining a volume configured to receive at least a portion of aqueous solution with the reduced organic mediator, and a nitrogencontaining compound in a nonaqueous solution. In some embodiments, the reactor includes an agitator configured to agitate the received aqueous solution and the nonaqueous solution in the volume to cause a redox reaction between the reduced organic mediator and the nitrogen-containing compound, the redox reaction at least partially forming a reduced nitrogen-containing product and an oxidized organic mediator.

[0006] In one aspect, the invention provides a method of forming a reduced nitrogen-containing product by contacting an aqueous solution including a reduced organic mediator and a nonaqueous solution including a nitrogen-containing compound, wherein the aqueous solution and the nonaqueous solution are immiscible; and allowing a reaction to occur between the reduced organic mediator and the nitrogen-containing compound to form the reduced nitrogen-containing product and an oxidized organic mediator.

[0007] In some embodiments, the method further includes, before the contacting, reducing the oxidized organic mediator in the aqueous solution to form the reduced organic mediator. In some embodiments, the reducing the oxidized organic mediator includes: communicating the oxidized organic mediator to an electrochemical cell; and electrochemically reducing the oxidized organic mediator in the electrochemical cell to regenerate at least a portion of the reduced organic mediator. In some embodiments, electrochemically reducing the oxidized organic mediator in the electrochemical cell includes: charging the electrochemical cell at a constant voltage in a range of about 0.5 V to about 2.5 V, or discharging the electrochemical cell at a constant voltage in a range of about 0.3 V to about 2 V, at least one of the charging or the discharging regenerating the reduced organic mediator. In some embodiments, the charging or the discharging of the electrochemical cell is performed at room temperature and at a constant current density in a range of about 100 mA / cm2to about 500 mA / cm2.

[0008] In some embodiments, the reduced nitrogen-containing product includes at least one of a partially reduced nitrogen-containing product or a fully reduced nitrogen-containing product. In some embodiments, the fully reduced nitrogen-containing product includes an amine. In some embodiments, the partially reduced nitrogen-containing product includes at least one of -NO, -NHOH, or (-N=N+O ). In some embodiments, contacting the aqueous solution and the nonaqueous solution includes agitating the aqueous solution and the nonaqueous solution. In some embodiments, contacting the aqueous solution and the nonaqueous solution occurs at a stirring rate in a range ofPATENT Attorney Docket No. 51198-069WO3 about 1 ,000 rpm to about 4,000 rpm, and for a period of time in a range of about 1 min to about 24 hours. In some embodiments, a volumetric ratio of the aqueous solution to the nonaqueous solution is in a range of about 1 :3 to about 3:1. In some embodiments, a concentration of the reduced organic mediator in the aqueous solution is in a range of about 5 mol% to about 20 mol%. In some embodiments, decreasing a number of reducing equivalents of the reduced organic mediator yields the partially reduced nitrogen-containing product. In some embodiments, the partially reduced nitrogen-containing product includes a hydroxylamine group. In some embodiments, the reduced nitrogen-containing product includes an azoxy group. In some embodiments, the nitrogen-containing compound includes nitrobenzene, and the nonaqueous solution includes at least one of chloroform or 2-methyltetrahydrofuran, and the reduced nitrogen-containing product formed via the redox reaction includes aniline. In some embodiments, the redox reaction generates a yield of aniline of at least about 90 %. In some embodiments, a capacity fade rate of the reduced organic mediator is in a range of about 0.01 vol% to about 1 vol% per day. In some embodiments, the reduced organic mediator has a coulombic efficiency of at least about 90%. In some embodiments, the reduced nitrogen-containing product includes at least one of a nitroso, a hydroxylamine, azo group, or amine group produced by the reaction. In some embodiments, the reduced nitrogen-containing product includes a nitroso compound and a hydroxylamine compound.

[0009] In some embodiments, the reaction occurs proximate an interface of the aqueous solution and the nonaqueous solution. In some embodiments, the reaction proceeds within a thin diffusion layer at the interface. In some embodiments, the reaction has a Hatta number of at least about 5. In some embodiments, the reaction includes at least one of an electron transfer, a proton-coupled electron transfer, or a proton transfer. In some embodiments, the reaction includes the electron transfer followed by the proton transfer. In some embodiments, the method further includes accumulating at least a portion of the reduced mediator at the interface, the accumulation increasing a rate of the redox reaction. In some embodiments, the accumulating includes adsorbing the portion of the reduced mediator at the interface. In some embodiments, the interface includes an adsorption density of the reduced mediator, the adsorption density corresponding with a yield of the reduced nitrogencontaining product. In some embodiments, the method further includes reducing the adsorption density of the reduced mediator at the interface to reduce the yield of the reduced nitrogen-containing product. In some embodiments, the method further includes desorbing at least a portion of the reduced mediator from the interface, the desorbing decreasing a rate of the redox reaction.

[0010] In some embodiments, the nitrogen-containing compound includes a nitroalkane, and the reduced nitrogen-containing product includes a compound of at least one ofPATENT Attorney Docket No. 51198-069WO3a salt thereof.

[0011] In some embodiments, the nitrogen-containing compound includes at least one of a hydroxamic acid, an N-oxide, or an azo group. In some embodiments, the nitrogen-containing compound includes at least one of an aliphatic or an aromatic nitrogen-containing compound.

[0012] In some embodiments, the oxidized organic mediator includes a phenazine. In some embodiments, the phenazine includes a compound of formula (I):a salt thereof. In some embodiments, the phenazine includes a compound of formula (II):a salt thereof. In some embodiments, the nitrogen-containing compound includes a nitroalkane. In some embodiments, the phenazine includes a compound of formula (III):a salt thereof. In some embodiments, the phenazine includes a compound of formula (IV):a salt thereof. In some embodiments, the phenazine includes a compound of formula (V):PATENT Attorney Docket No. 51198-069WO3a salt thereof. In some embodiments, the phenazine includes a compound of formula (VI):a salt thereof. In some embodiments, the nitrogen-containing compound includes a nitroarene.

[0013] In some embodiments, the oxidized organic mediator includes a quinoxaline, anthraquinone, naphthoquinone, benzoquinone, fluorenone, azo-compound, a phenoxazine, a phenothiazine, an alloxazine, an isoalloxazine, and / or a bipyridinium.

[0014] In some embodiments, the reduced organic mediator is present at a substoichiometric amount relative to the nitrogen-containing compound, optionally wherein the method further includes, after allowing the reaction to occur, reducing the oxidized organic mediator and repeating the contacting and allowing steps. In some embodiments, the method further includes, after allowing the reaction to occur, allowing the aqueous solution and nonaqueous solution to separate. In some embodiments, the method further includes recirculating the aqueous and nonaqueous solutions and repeating the contacting and allowing the reaction, wherein during the recirculating oxidized organic mediator is reduced to reduced organic mediator. In some embodiments, the reduced organic mediator is present at a substoichiometric amount relative to the nitrogen-containing compound.

[0015] In some embodiments, the nitrogen-containing compound and the reduced nitrogencontaining product includes at least one of an alkenyl, alkynyl, amino, aryl amino, halo, aldehyde, ketone, nitrile, amide, sulfide, sulfonyl, or boronate ester group.

[0016] In an aspect, the invention provides a phenazine of the formula:salt or reduced form thereof,wherein each of Ri, R2, R3, R4, R5, Re, R7, and Re is independently selected from H; halo; optionally substituted C1-6 alkyl; optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S; -CN; -NO2; -ORa; -SRa; -N(Ra)2-3; -C(=O)Ra; -C(=O)ORa; -S(=O)2Ra; -S(=O)2ORa; -P(=O)Ra2; and -P(=O)(ORa)2, wherein each Rais independently H; optionally substituted C1-6 alkyl;PATENT Attorney Docket No. 51198-069WO3 optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S,

[0017] In some embodiments, at least one of R1, R2, R3, R4, R5, Re, R7, and Re is -O-(CH2)nSO3H, wherein n is 1 to 6, or wherein at least one of R1, R2, R3, R4, Re, Re, R7, and Reis -CN and at least one ofRi, R2, R3, R4, Re, Re, R7, and Re is hydroxy.

[0018] In some embodiments, at least one of R1, R2, R3, R4, R5, Re, R7, and Rais -CN and at least one ofRi, R2, R3, R4, Re, Re, R7, and Ra is hydroxy. In some embodiments, the phenazine has the structure of formula (I):a salt or reduced form thereof.

[0019] In some embodiments, at least one of R1, R2, R3, R4, Re, Re, R7, and Ra is -O-(CH2)nSC>3H and at least one of R1, R2, R3, R4, Re, Re, R7, and Ra is -OH. In some embodiments, the phenazine has the structure of formula (II):a salt or reduced form thereof.

[0020] In some embodiments, at least one of R1, R2, R3, R4, Re, Re, R7, and Ra is -O-(CH2)nSO3H and at least one of R1, R2, R3, R4, Re, Re, R7, and Ra is -SO3H. In some embodiments, the phenazine has the structure of formula (III):a salt or reduced form thereof.

[0021] In an aspect, the invention provides a system including an electrochemical flow cell configured to receive an oxidized organic mediator in an aqueous solution and electrochemically reduce the mediator in the aqueous solution; a reactor configured to receive at least a portion of the aqueous solution with the reduced organic mediator and a nitrogen-containing compound in a nonaqueous solution, the reactor including: an agitator configured to agitate the received aqueous solution and the nonaqueous solution to allow a reaction between the reduced organic mediator and the nitrogen-PATENT Attorney Docket No. 51198-069WO3 containing compound, the reaction at least partially forming a reduced nitrogen-containing product and an oxidized organic mediator.

[0022] In some embodiments, the system further includes coalescence plates in the reactor, the coalescence plates configured to facilitate separation of the aqueous solution and nonaqueous solution. In some embodiments, the system further includes a circulation assembly fluidically coupled to at least one of the electrochemical flow cell or the reactor, the circulation assembly configured to at least one of: communicate at least a portion of the aqueous solution from the reactor to the electrochemical flow cell, or communicate at least a portion of the nonaqueous solution from an outlet proximate to a first end of the reactor to an inlet proximate a second end of the reactor, the second end proximate the agitator. In some embodiments, the circulation assembly communicates at least a portion of the aqueous solution from the electrochemical flow cell to the reactor proximate the agitator.

[0023] In some embodiments, the system further includes a separator configured to allow the aqueous solution and nonaqueous solution to separate after agitation. In some embodiments, the system further includes the aqueous solution including the oxidized organic mediator and / or the reduced organic mediator. In some embodiments, the oxidized organic mediator includes a quinoxaline, anthraquinone, naphthoquinone, benzoquinone, fluorenone, azo-compound, a phenoxazine, a phenothiazine, an alloxazine, an isoalloxazine, and / or a bipyridinium. In some embodiments, the oxidized organic mediator includes a phenazine, e.g., pz1, pz2, pz3, pz4, pz5, and / or pz6. In some embodiments, the system further includes the nonaqueous solution.Brief Description of the Drawings

[0024] FIG. 1 is a block diagram of a system for production of reduced amino-containing products, e.g., amines, from a nitrogen-containing compound, according to an embodiment.

[0025] FIG. 2A is a flow diagram of a method for production of partially or fully reduced nitrogencontaining product from a nitrogen-containing compound, according to an embodiment.

[0026] FIG. 2B illustrates the principal mechanism of a biphasic reduction system, including its advantages, according to an embodiment.

[0027] FIG. 3A is a schematic of a continuous flow system, according to an embodiment. FIG. 3B is a schematic diagram of a reactor for a reaction, according to an embodiment.

[0028] FIG. 4A illustrates prototypes of a reactor with different geometries, according to an embodiment. FIG. 4B is a plot of current output versus time for reactions in different geometries and flow rates.

[0029] FIG. 5A illustrates hydrogenation reaction of phenazine. FIG. 5B illustrates redox potentials of phenazines, according to an embodiment. FIG. 5C illustrates examples of nitrogen-containing compounds successfully reduced / hydrogenated to corresponding amines.PATENT Attorney Docket No. 51198-069WO3

[0030] FIG. 6 is a heatmap summarizing hydrogenation yields for corresponding nitrogen-containing compounds.

[0031] FIG. 7 A is a UV-VIS spectra of oxidized pz5, reduced pz5-H2, and post-reaction mediator. FIG. 7B shows the absorbance at 460 nm versus time.

[0032] FIG. 8 shows electrochemical cycling stability over time for a phenazine.

[0033] FIGS. 9A-9C show hydrogenation reaction of a nitrogen-containing compound, chemical structure of hydrogenated pz5 and hydrogenated pz1 , amine compounds produced using a single batch of a phenazine and a table of corresponding faradaic efficiencies, respectively.

[0034] FIG. 10A illustrates the hydrogenation reaction of a nitrogen-containing compound, 4-fluoronitrobenzene, with a phenazine, pz5. FIG. 10B illustrates the chemical structure of the intermediate compounds of 4-fluoronitrobenzene reduction. FIG. 10C shows concentration of intermediate compounds overtime during reduction of 4-fluoronitrobenzene. FIG. 10D is a schematic illustration of a direct pathway and an indirect pathway for reduction of a nitrogen-containing compound.

[0035] FIG. 11 is a conceptual potential energy corresponding to an initial stage of reduction reaction between a nitroarene and pz5.

[0036] FIG. 12A is a schematic of proton transfer during the reduction reaction between a nitroarene and pz5. FIGS. 12B-12C are kinetic isotope effect analysis for reduction of nitrobenzene / nitrosobenzene.

[0037] FIG. 13A is a plot of initial reaction rate versus interfacial surface area for hydrogenation reaction of pz5 with nitrobenzene. FIG. 13B is a schematic illustration of interfacial reaction-diffusion model.

[0038] FIG. 14A is concentration profile of azoxybenzene, pz5, and pz4 at the interface of water and chloroform during the reaction. FIG. 14B is concentration profile of azoxybenzene and pz5 at the interface of water and cyclohexane during the reaction.

[0039] FIG. 15 shows a plot of current and cumulative charge profiles during hydrogenation of nitrobenzene using pz5.

[0040] FIG. 16 shows technoeconomic analysis of levelized cost of aniline production as a function of phenazine cost and degradation rate.

[0041] FIG. 17 illustrates reduction reaction of hydroxamic acid, a pyridine N-oxide, and an azobenzene.PATENT Attorney Docket No. 51198-069WO3

[0042] FIG. 18A illustrates partial reduction / hydrogenation of nitroalkane. FIG. 18B illustrates the chemical structure of the isolated products.

[0043] FIG. 19 illustrates telescoped synthesis of a complex nitrone, according to an embodiment.

[0044] FIGS. 20A-20F illustrates cyclic voltammograms of the mediators, pz1 to pz6.

[0045] FIGS. 21A-21G illustrate cyclic voltammograms of solutions of various nitro and nitroso compounds.

[0046] FIGS. 22A-22B show UV-VIS absorption spectra and associated calibration curve for nitrobenzene in water.

[0047] FIG. 23 illustrates UV-VIS absorption spectrum of the aqueous phase after partitioning between nitrobenzene in chloroform and water.

[0048] FIG. 24 illustrates partition coefficient of pz5 between water and chloroform.

[0049] FIG. 25A shows the concentration of nitrobenzene in the aqueous phase versus time and FIG.25B shows the linear fit of ln(1-C / C*) versus time.

[0050] FIGS. 26A-26B show modeled concentration profiles of nitrobenzene (NB) and pz-Fh across the diffusion film as a function of distance from the liquid-liquid interface.

[0051] FIGS 27A-27B illustrates plausible alternative profiles of positive adsorption for a species more soluble in water than in the organic phase.

[0052] FIGS. 28A-28B show surface tension versus composition for pz5 at 1 M KCI / CHCF and 1 M KCI / cyclohexane interfaces, respectively.

[0053] FIGS 29A-29B show surface tension versus concentration for azoxybenzene at 1 M KCI / CHCF and 1M KCI / cyclohexane interfaces, respectively.

[0054] FIG. 30 shows surface tension versus concentration for a mediator, pz4 at the interface of 1 M KCI / CHCb.

[0055] FIG. 31 shows measured interfacial surface tension between the aqueous / organic interfaces for various organic solvents.Detailed Description

[0056] Amine compounds play a significant role in production of pharmaceuticals, agrochemicals, etc. Traditional methods for synthesis of amines include catalytic hydrogenation, chemical reduction, and electrochemical processes. These methods have several drawbacks including creating environmental and safety concerns, generation of significant amount of waste, costly process, andPATENT Attorney Docket No. 51198-069WO3 need for expensive metal catalyst. Amine products can be obtained through electrochemical methods, for example, reduction of nitro compounds. Nitro group reduction is among the ten most frequently employed transformations in organic synthesis and is featured in approximately 12% of medicinal chemistry routes. Although electrochemical methods have shown some promising results, the current approaches face challenges including but are not limited to low selectivity, limited efficiency, and poor scalability which stem from issues such as reactant solubility, high resistance of organic solutions, membrane and electrode compatibility, current density, purification challenges, instability of mediator compounds, and difficulties in mediator regeneration. In addition, this reaction appears in only 0.7% of final steps, indicative of limitations in chemo-selectivity, even with electrochemical methods.Aldehydes and alkynes are found in only 0.096% and 0.268% of reported cases.

[0057] In the synthesis of tumor growth inhibitor, RORyt agonist JG-1 , multiple protection and deprotection steps are required to achieve nitro group reduction. Further, the reduction of aliphatic nitro compounds remains particularly challenging. Despite 1.8 million reports of nitroarene reductions, only about 10,000 cases involve aliphatic nitro compounds (RCH2-NO2). These difficulties reflect the intrinsic challenge of the 6e- / 6H+ nitro reduction, where stepwise electron / proton transfer is energetically inefficient and poorly selective. Additional limitations include poor solubility, low pH requirement, and reliance on organic solvents in direct electrolysis. Consequently, many amine syntheses still rely on hydrogen as a reductant at elevated temperatures (about 300 °C to about 400 °C). This hydrogen gas is typically produced via steam methane reforming, which emits over 9kg of CO2per kg H2generated and entails significant storage costs and safety hazards.

[0058] Conventional electrochemical methods for conversion of nitro compounds into amine compounds can substantially rely on organic solvent media to achieve high concentrations of organic nitro compounds (i.e., organic substrates) and better functional group compatibility. However, organic solutions are electrically insulating and lack membrane technologies compatible with nonaqueous operation which resort to undivided cell configurations (increasing cross-reactions and fouling), require complex supporting electrolytes to maintain conductivity (complicating downstream product isolation and purification), and implement electrode protection strategies to enable long term use (raising process complexity and cost). In contrast, aqueous systems can demonstrate superior energy efficiency, and productivity, yet they are generally incompatible with organic substrates due to solubility limits, competitive side reactions, and limited functional group tolerance. The embodiments described herein can substantially reduce reliance on undivided cells, minimize use of complex supporting electrolytes, enhance energy efficiency and productivity, retain functional group tolerance, mitigate electrode fouling and degradation, enable stable long-term operation, improve process control and product quality.

[0059] The systems, methods, and components described herein overcome the limitations of conventional methods. In particular, the systems, methods, and components described herein can offer a metal-free, hydrogen gas-free method for scalable and highly selective electrochemical hydrogenation (also referred to as reduction) of both aliphatic and aromatic nitrogen-containingPATENT Attorney Docket No. 51198-069WO3 compounds to nitrogen-containing products, such as amines. This process can be carried out in batch mode or via continuous flow in a multiphase system. In some embodiments, the aqueous phase can contain a redox-active organic mediatorthat can flow through an electrochemical flow cell, for reduction at an electrode to a reduced organic mediator.

[0060] The nitrogen-containing compound can be dissolved in a nonaqueous, e.g., organic, solvent that is immiscible with water. This approach can confine the electrochemical process to the aqueous phase, enhancing system stability, ensuring high ion conductivity, and / or making the process cost-effective at scale. Meanwhile, the nonaqueous, e.g., organic, phase can serve as a reservoir for the substrate and a sink for the products, enabling operation at high concentrations and / or facilitating the separation of the final product from salts and the mediator.

[0061] In some embodiments, reversible and stable proton-coupled redox active organic molecules (RAOMs) can be used. In some embodiments, the RAOM can be referred to as the mediator. In some embodiments, the RAOMs can include at least one of a phenazine, quinoxaline, anthraquinone, naphthoquinone, benzoquinone, fluorenone, azo-compound, phenoxazine, phenothiazine, alloxazine, an isoalloxazine, and / or bipyridinium (viologen). In some embodiments, the chemical structure of RAOMs (referred to herein as mediator) can be engineered to be soluble in the aqueous phase to mediate the hydrogenation of nitrogen-containing compounds dissolved in the nonaqueous phase. In some embodiments, the mediators described herein can offer robust aqueous mediators derived from phenazine which can support continuous operation in a system including the electrochemical flow cell and the reactor / separator. In some embodiments, the system can be referred to as flow biphasic reduction.

[0062] Suitable mediators include an anthraquinone or a redox state thereof (e.g., a single or two electron reduced state). In some embodiments, the redox state of the anthraquinone is of formula (la).(la), ora salt or tautomer thereof.PATENT Attorney Docket No. 51198-069WO3

[0063] In some embodiments, the redox state of the anthraquinone is an anthrahydroquinone, e.g.,independently H or absent, or a salt or tautomer thereof. In some embodiments, both X are H. In some embodiments, both X are absent (i.e., both O are negatively charged). In some embodiments, one X is H, and one X is absent.

[0064] In some embodiments, the redox state of the anthraquinone is an anthrahydroquinone, e.g.,(Ic), wherein X is H or absent or a salt or tautomer thereof.

[0065] In some embodiments, a suitable redox active species is the reduced form of an anthraquinone, a hydroquinone, e.g., a hydroquinone of formula (Id)salt, deprotonated form, or tautomer thereof.

[0066] In any of formulas (la), (lb), (Ic), or (Id) each of R1, R2, R3, R4, R5, R6, R7and R8is independently selected from H; halo; optionally substituted C1-6 alkyl; oxo; optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S; -CN; -NO2; -ORa(e.g., hydroxyl or C1-6 alkoxy); -SRa(e.g., thiol or C1-6 alkyl thio); -N(Ra)2-3 (e.g., amino); -C(=O)Ra; -C(=O)ORa(e.g., carboxyl); -S(=O)2Ra; -S(=O)2ORa(e.g., SO3H); -P(=O)Ra2; and -P(=O)(ORa)2(e.g., phosphonyl or phosphoryl); or any two adjacent groups selected from R1, R2, R3, and R4are joined to form an optionally substituted 3-6 membered ring, or an ion thereof, where each Rais independentlyPATENT Attorney Docket No. 51198-069WO3 H; optionally substituted C1-6 alkyl; optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S.

[0067] In certain embodiments, each of R1, R2, R3, R4, R5, R6, R7and R8is independently selected from halo, hydroxyl, carboxyl, sulfonate / sulfonic acid, alkylsulfonate / alkylsulfonic acid, phosphonyl, phosphoryl, alkylphosphonate / alkylphosphonic acid, amino, quaternary ammonium (e.g., trialkylammonium), alkyl, heteroalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, nitro, nitrile, thiol, and / or carbonyl groups, any of which is optionally substituted, or, any two adjacent groups of R1-R8can be joined together to form an optionally-substituted ring.

[0068] In certain embodiments, each of R1, R2, R3, R4, R5, R6, R7and R8is independently selected from H, optionally substituted C1-6 alkyl, halo, hydroxyl, optionally substituted C1-6 alkoxy, SO3H, amino, nitro, carboxyl, phosphoryl, phosphonyl, and oxo, or an ion thereof. In particular embodiments, each of R1, R2, R3, R4, R5, R6, R7, and R8is independently selected from H, hydroxyl, optionally substituted C1-4 alkyl, carboxyl, and SO3H, such as each of R1, R2, R3, R4, R5, R6, R7and R8being independently selected from H, hydroxyl, optionally substituted C1-4 alkyl (e.g., methyl), and oxo. In embodiments, at least one, e.g., at least two, of R1, R2, R3, R4, R5, R6, R7, and R8is not H.

[0069] In other embodiments, the anthraquinone, such as a 9,10-anthraquinone, is substituted with at least one hydroxyl group and optionally further substituted with a C1-4 alkyl, such as methyl.Exemplary anthraquinones include is 2,6-bis(3-phosphonopropyl-1-oxy)anthraquinone (DPPEAQ), 2,6-dihydroxy-9,10-anthraquinone (2,6-DHAQ), 1 ,5-dimethyl-2,6-dihydroxy-9,10-anthraquinone, 2,3,6,7-tetrahydroxy-9,10-anthraquinone, 1 ,3,5,7-tetrahydroxy-2,4,6,8-tetramethyl-9,10-anthraquinone, and 2, 7-dihydroxy-1 ,8-dimethyl-9,10-anthraquinone. Ions and reduced species thereof are also contemplated.

[0070] Exemplary phenazines, N,N'-disubstituted phenazines, monoquaternized phenazines, or N,N'-salt thereof, or a reduced form (e.g., 5,10-dihydrophenazines) thereof, where X and Y are both N, or where X is NRx and Y is N, or where X is NRXand Y is NRY; where Rxand RYare independently selected from H; optionally substituted C1-6 alkyl; optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionallyPATENT Attorney Docket No. 51198-069WO3 substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S; where each of R1, R2, R3, R4, R5, R6, R7and R8is independently selected from H; halo; optionally substituted C1-6 alkyl; oxo; optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S; -CN; -NO2; -ORa(e.g., hydroxyl or C1-6 alkoxy); -SRa(e.g., thiol or C1-6 alkyl thio); -N(Ra)2-3 (e.g., amino); -C(=O)Ra; -C(=O)ORa(e.g., carboxyl); -S(=O)2Ra; -S(=O)2ORa(e.g., SO3H); -P(=O)Ra2; and -P(=O)(ORa)2(e.g., phosphonyl or phosphoryl); or any two adjacent groups selected from R1, R2, R3, and R4are joined to form an optionally substituted 3-6 membered ring, or an ion thereof, where each Rais independently H; optionally substituted C1-6 alkyl; optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S.

[0071] In certain embodiments, each of R1, R2, R3, R4, R5, R6, R7and R8is independently selected from H, optionally substituted C1-6 alkyl, halo, hydroxyl, optionally substituted C1-6 alkoxy, SO3H, amino, nitro, carboxyl, phosphoryl, phosphonyl, and oxo, or an ion thereof. In particular embodiments, each of R1, R2, R3, R4, R5, R6, R7, and R8is independently selected from H, hydroxyl, optionally substituted C1-4 alkyl, carboxyl, and SO3H, such as each of R1, R2, R3, R4, R5, R6, R7and R8being independently selected from H, hydroxyl, optionally substituted C1-4 alkyl (e.g., methyl), and oxo. In embodiments, at least one, e.g., at least two, of R1, R2, R3, R4, R5, R6, R7, and R8is not H. In some embodiments, at least one of Ri-Ra is a substituted alky or substituted alkoxy.

[0072] In certain embodiments, each of R1, R2, R3, R4, R5, R6, R7and R8is independently selected from halo, hydroxyl, carboxyl, sulfonate / sulfonic acid, alkylsulfonate / alkylsulfonic acid, phosphonyl, phosphoryl, alkylphosphonate / alkylphosphonic acid, amino, quaternary ammonium (e.g., trialkylammonium), alkyl, heteroalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, nitro, nitrile, thiol, and / or carbonyl groups, any of which is optionally substituted, or, any two adjacent groups of R1-R8can be joined together to form an optionally-substituted ring.

[0073] In certain embodiments, the phenazine is of the formula:salt or reduced form thereof, wherein each of R1, R2, R3, R , R5, Re, R7, and Re is independently selected from H; halo; optionally substituted C1-6 alkyl; optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S; -CN; -NO2; -ORa; -SRa; -N(Ra)2-3; -C(=O)Ra; -C(=O)ORa; -S(=O)2Ra; -S(=O)2ORa; -P(=O)Ra2; and -P(=O)(ORa)2, wherein each Rais independently H; optionallyPATENT Attorney Docket No. 51198-069WO3 substituted C1-6 alkyl; optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S, wherein at least one of R1, R2, R3, R4, R5, Re, R7, and Re is -O-(CH2)nSO3H, wherein n is 1 to 6, or wherein at least one of R1, R2, R3, R4, Re, Re, R7, and Re is -CN and at least one of R1, R2, R3, R4, Re, Re, R7, and Re is hydroxy.

[0074] Exemplary phenoxazines and phenothiazines are:dashed bonds are single or double bonds; where X is N or NRX, Y is O or S, and Z is CR6, C=O, C=S, C=NRZ, or C=NH+RZ; where Rxis selected from H; optionally substituted C1-6 alkyl; optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S, where Rzis selected from H; optionally substituted C1-6 alkyl; optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S; where each of R1, R2, R3, R4, R5, R6, R7and R8is independently selected from H; halo; optionally substituted C1-6 alkyl; oxo; optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S; -CN; -NO2; -ORa(e.g., hydroxyl or C1-6 alkoxy); -SRa(e.g., thiol or C1-6 alkyl thio); -N(Ra)2-3 (e.g., amino); -C(=O)Ra; -C(=O)ORa(e.g., carboxyl); -S(=O)2Ra; -S(=O)2ORa(e.g., SO3H); -P(=O)Ra2; and -P(=O)(ORa)2(e.g., phosphonyl or phosphoryl); or any two adjacent groups selected from R1, R2, R3, and R4are joined to form an optionally substituted 3-6 membered ring, or an ion thereof, where each Rais independently H; optionally substituted C1-6 alkyl; optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S. In certain embodiments, each of R1, R2, R3, R4, R5, R6, R7and R8is independently selected from H, optionally substituted C1-6 alkyl, halo, hydroxyl, optionally substituted C1-6 alkoxy, SO3H, amino, nitro, carboxyl, phosphoryl, phosphonyl, and oxo, or an ion thereof. In particular embodiments, each of R1, R2, R3, R4, R5, R6, R7, and R8is independentlyPATENT Attorney Docket No. 51198-069WO3 selected from H, hydroxyl, optionally substituted C1-4 alkyl, carboxyl, and SO3H, such as each of R1, R2, R3, R4, R5, R6, R7and R8being independently selected from H, hydroxyl, optionally substituted C1- 4 alkyl (e.g., methyl), and oxo. In embodiments, at least one, e.g., at least two, of R1, R2, R3, R4, R5, R6, R7, and R8is not H. In some embodiments, at least one of R1-R8is a substituted alky or substituted alkoxy.

[0075] Exemplary reduced diquaternized bipyridines are of:Yi-Xi-N\\ ' - ' ' - / ' / N+_ X2“Y2 , a reduced form thereof (e.g., singly reduced radical monocations or doubly reduced 4,4'-bipyridiny lidenes) , or a salt thereof, where Xi and X2 are independently optionally substituted C1-20 hydrocarbyl (e.g., C1-10 alkylene) or heteroalkylene, and Y1 and Y2 are independently an optionally substituted water solubilizing group, e.g., a quaternary ammonium (e.g., trimethyl ammonium), ammonium, nitrogen-containing heterocyclyl, sulfonate, or sulfate. In certain embodiments, Xi and X2 are independently C1-10 alkylene, e.g., C3-6 alkylene.Exemplary groups for Y1 and Y2 are quaternary ammonium independently substituted with three C1-6 hydrocarbyl groups, e.g., trimethyl ammonium. An exemplary diquaternized bipyridine isor a salt thereof. In some embodiments, the mediator is a naphthoquinone.(e.g., a naphthohydroquinone), or a salt thereof, wherein the dashed bonds are single or double bonds; where either W and X, W and Z, or Z and Y are C=O, and where the two of W, X, Y, or Z that are not C=O are independently selected from C-R, where R is H; halo; optionally substituted C1-6 alkyl; optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S; - CN; -NO2; -ORa(e.g., hydroxyl or C1-6 alkoxy); -SRa(e.g., thiol or C1-6 alkyl thio); -N(Ra)2-3 (e.g., amino); -C(=O)Ra; -C(=O)ORa(e.g., carboxyl); -S(=O)2Ra; -S(=O)2ORa(e.g., SO3H); -P(=O)Ra2; and -P(=O)(ORa)2 (e.g., phosphonyl or phosphoryl); or any two adjacent R groups are joined to form an optionally substituted non-aromatic 3-6 membered ring, or an ion thereof, where each Rais independently H; optionally substituted C1-6 alkyl; optionally substituted C3-10 carbocyclyl; optionallyPATENT Attorney Docket No. 51198-069WO3 substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S; where each of R1, R2, R3, and R4is independently selected from H; halo; optionally substituted C1-6 alkyl; oxo; optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S; -CN; -NO2; -ORa(e.g., hydroxyl or C1-6 alkoxy); -SRa(e.g., thiol or Ci-6 alkyl thio); -N(Ra)2-3 (e.g., amino); -C(=O)Ra; -C(=O)ORa(e.g., carboxyl); -S(=O)2Ra; -S(=O)2ORa(e.g., SO3H); -P(=O)Ra2; and -P(=O)(ORa)2 (e.g., phosphonyl or phosphoryl); or any two adjacent groups selected from R1, R2, R3, and R4are joined to form an optionally substituted 3-6 membered ring, where each Rais independently H; optionally substituted C1-6 alkyl; optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S. In certain embodiments, Wand Z are C=O. In certain embodiments, each of R1, R2, R3, and R4is independently selected from H, optionally substituted C1-6 alkyl, halo, hydroxyl, optionally substituted C1-6 alkoxy, SO3H, amino, nitro, carboxyl, phosphoryl, phosphonyl, and oxo, or an ion thereof.

[0077] In particular embodiments, each of R1, R2, R3, and R4is independently selected from H, hydroxyl, optionally substituted C1-4 alkyl, carboxyl, and SO3H, such as each of R1, R2, R3, and R4being independently selected from H, hydroxyl, optionally substituted C1-4 alkyl (e.g., methyl), and oxo. In embodiments, at least one, e.g., at least two, of R1, R2, R3, and R4is not H. In some embodiments, at least one of R1-R4is a substituted alky or substituted alkoxy. Ions and reduced species thereof are also contemplated.

[0078] Exemplary fluorenones are:, reduced forms thereof (e.g., single or two electron reduced form), and salts thereof, wherein each of R1, R2, R3, R4, R5, R6, R7and R8is independently selected from H; halo; optionally substituted C1-6 alkyl; oxo; optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S; -CN; -NO2; -ORa(e.g., hydroxyl or C1-6 alkoxy); -SRa(e.g., thiol or C1-6 alkyl thio); -N(Ra)2-3 (e.g., amino); -C(=O)Ra; -C(=O)ORa(e.g., carboxyl); -S(=O)2Ra; -S(=O)2ORa(e.g., SO3H); -P(=O)Ra2; and -P(=O)(ORa)2(e.g., phosphonyl or phosphoryl); or any two adjacent groups selected from R1, R2, R3, and R4are joined to form an optionally substituted 3-6 membered ring, or an ion thereof, where each Rais independentlyPATENT Attorney Docket No. 51198-069WO3 H; optionally substituted C1-6 alkyl; optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S.

[0079] In certain embodiments, each of R1, R2, R3, R4, R5, R6, R7and R8is independently selected from H, optionally substituted C1-6 alkyl, halo, hydroxyl, optionally substituted C1-6 alkoxy, SO3H, amino, nitro, carboxyl, phosphoryl, phosphonyl, and oxo, or an ion thereof. In particular embodiments, each of R1, R2, R3, R4, R5, R6, R7, and R8is independently selected from H, hydroxyl, optionally substituted C1-4 alkyl, carboxyl, and SO3H, such as each of R1, R2, R3, R4, R5, R6, R7and R8being independently selected from H, hydroxyl, optionally substituted C1-4 alkyl (e.g., methyl), and oxo. In embodiments, at least one, e.g., at least two, of R1, R2, R3, R4, R5, R6, R7, and R8is not H.

[0080] In some embodiments, the compound is an alloxazine or isoalloxane:wherein each of R9and R10is independently H; optionally substituted C1-10 alkyl (e.g., C1-6 alkyl, unsubstituted C1-10 alkyl, or unsubstituted C1-6 alkyl); optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S; -C(=O)Ra; and -C(=O)ORa; and each of R1, R2, R3, and R4is independently H; C1-10 alkyl (e.g., C1-6 alkyl); optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S; -NO2; -ORa; -SRa; -N(Ra)2-3; -C(=O)Ra; -C(=O)ORa; -S(=O)2Ra; -S(=O)2ORa; -P(=O)Ra2; and -P(=O)(ORa)2; or any two adjacent groups selected from R1, R2, R3, and R4are joined to form an optionally substituted 3-6 membered ring, or an ion thereof; wherein each Rais independently H; C1-10 alkyl (e.g., C1-6 alkyl); optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S.

[0081] In some embodiments, each of R9and R10is independently H, optionally substituted C1-10 alkyl (e.g., C1-6 alkyl), or -C(=O)ORa; and each of R1, R2, R3, and R4is independently H, halo, optionally substituted C1-10 alkyl (e.g., C1-6 alkyl), -NO2, -ORa, -SRa; -N(Ra)2-3, -C(=O)ORa, -S(=O)2ORa, -P(=O)Ra2 or-P(=Q)(ORa)2; wherein each Rais independently H or optionally substituted C1-10 alkylPATENT Attorney Docket No. 51198-069WO3 (e.g., C1-6 alkyl). In some embodiments, none of, any two of, any three of, any four of, any five of, or any six of R1, R2, R3, R4, R9, and R10are H.

[0082] In some embodiments, the oxidized or reduced organic mediator may be in salt form. Suitable salts include acid, e.g., Ck, or base addition salts, e.g., Na+.

[0083] In some embodiments, hydrogenation can occur when the aqueous phase and nonaqueous phase are contacted in a reactor / separator. In some embodiments, the electrochemical cell, e.g., flow cell, and the reactor / separator can form a coupled or an uncoupled system. In some embodiments, the coupled system can provide a continuous flow mode of hydrogenation. In some embodiments, the uncoupled system can provide a batch mode.

[0084] Systems, methods, and components described herein can enable hydrogenation at the liquidliquid interface or / and through partitioning. The mediator can shuttle electrons between an aqueous medium and a nonaqueous medium, which is immiscible with the aqueous medium. In some embodiments, the proton-coupled electron transfer (PCET) can occur within the aqueous diffusion layer at the liquid-liquid interface. The embodiments described herein can provide a biphasic format. The embodiments described herein can further enable spatiotemporal separation of the electrodemediator redox process from the reduced organic mediator-the nitrogen-containing compound reaction. Therefore, the embodiments described herein can provide advantages of aqueous electrochemistry, and / or versatility of nonaqueous (e.g., organic) media.

[0085] Conventional mediators exhibit limited stability and tunability, rely on strongly acidic conditions and strict light exclusion to prevent hydrolysis and precipitation, and demonstrate very limited functional-group tolerance and scalability. Embodiments described herein can provide highly stable, water soluble, tunable, and / or synthetically accessible mediators at inexpensive inert electrodes (e.g., graphite electrodes) in a divided electrochemical cell, accessing high current densities with low resistive losses. Embodiments described herein can substantially reduce the overpotential required, and / or enable selective control of interfacial redox process.

[0086] Embodiments described herein can provide a molecular alternative to electrode surface engineering. In some embodiments, mediators, e.g., phenazines, described herein can offer best yield and conversion. In some embodiments, mediators, e.g., phenazines, described herein can offer tunable redox potentials (>400 mV of E1 / 2), high aqueous solubility (>1 M), rapid charging kinetics, and / or exceptional stability across an extended pH range (fade rates below 0.01 % / day). In some embodiments, other RAOMs can be used with optimization to mediate the process efficiently. In some embodiments, mediator structure and solvent identity can modulate reactivity through interfacial adsorption. In some embodiments, the interfacial adsorption can be a rate-determining step.Therefore, the embodiments described herein can provide a novel mode of control of degree / extent of the hydrogenation.PATENT Attorney Docket No. 51198-069WO3

[0087] Embodiments described herein can enable a chemo-selective reduction using water as the terminal reductant. In some embodiments, the reduction can occur in a thin diffusion layer at the liquid-liquid boundary. Kinetic isotope effects and DFT calculations support the involvement of PCET. By probing the reactive interface, it can be concluded that surface adsorption can be a mode of control for liquid-liquid interfacial redox events.

[0088] Embodiments described herein can enable access to the reduction of various classes of nitrogen-containing compounds. In addition, the embodiments described herein can facilitate retention of the produced nitrogen-containing products, e.g., amines, in the nonaqueous phase to facilitate separation without column chromatography, while the mediator can be recharged and reused. In some embodiments, the embodiments described herein can operate in either a batch mode or a continuous flow mode. In some embodiments, the mediator can be recycled for re-use due to high electrochemical stability imparted by its engineered chemical structure.

[0089] The embodiments described herein can utilize aqueous organic redox-flow battery (AORFB) electrolytes as recyclable, metal free, proton-coupled electron transfer (PCET) mediators. In some embodiments, this method can provide an exceptionally selective hydrogenation of nitroarenes and nitroalkanes at high concentration of nitrogen-containing compounds, excellent mediator recyclability, and mild conditions (e.g., no elevated temperature and / or high pressure). The embodiments described herein can offer a method of production of nitrogen-containing products, e.g., amines, without a catalyst. The embodiments described herein can further provide technical advantages including but not limited to high selectivity, simplified operation, reduced cost, reduced environmental hazard, high yield, scalability for continuous production, significant mediator regeneration, reduced energy, and reduced undesirable byproducts.

[0090] The embodiments described herein can further offer a tunable electrical potential which can be an additional driving force for the hydrogenation / reduction reaction. This energy input can allow lower-energy mediators to be employed to achieve diverse and challenging reactions, even if thermally non-spontaneous. In addition, the embodiments described herein can substantially reduce application of potent stoichiometric reactants that are hazardous, poorly tolerant of functional groups, waste producing, and / or energy intensive. In addition, the present invention can enable synthesis of complex organic molecules including pharmaceutical compounds bearing multiple electrophores or sterically shielded redox centers.

[0091] Embodiments described herein can substantially reduce the volume of nonaqueous solvent required by orders of magnitude. Organic electrosynthesis is often performed at millimolar substrate concentrations, but the embodiments described herein can, for example, successfully convert a 2.5 M solution of nitrobenzene with high yield (99%) and Faradaic efficiency (90%).

[0092] Embodiments described herein can substantially reduce the processing steps including chromatography purification process as the mediator and other aqueous salts can be automatically removed by phase separation.PATENT Attorney Docket No. 51198-069WO3

[0093] Traditional metal-based reduction of nitroarene often requires highly acidic environments, where the mechanism can involve stepwise proton transfer followed by electron transfer (PT-ET). The embodiments described herein can provide a method in which proton-coupled electron transfer or hydrogen atom transfer can occur under milder conditions, avoiding the need for strong acids.

[0094] The term “nitrogen-containing compound” refers to a compound including at least one nitrogen atom bonded to a carbon atom, wherein the nitrogen atom can be reduced.

[0095] The term “fully reduced” with respect to a nitrogen-containing compound refers to the redox state of a nitrogen atom therein and not necessarily the rest of the compound. For example, aniline is the fully reduced form of nitrobenzene, notwithstanding the present of the benzene ring.

[0096] The term “partially reduced” with respect to a nitrogen-containing compound refers to the redox state of a nitrogen atom therein and not necessarily the rest of the compound. For example, N-benzylhydroxylamine is a partially reduced form of nitromethyl benzene.

[0097] As used herein, the term “reducing equivalents” refers to one or more transferable units capable of effecting reduction of a substrate, including electrons, protons, hydrogen atoms, hydride equivalents, or combinations thereof.

[0098] The term “hydrogenation” refers to a process by which hydrogen atoms, protons, hydrides, or reducing equivalents derived from hydrogen are incorporated into a compound. In some embodiments, hydrogenation results in reduction of the compound. In some embodiments, hydrogenation can include electrochemical reduction of a mediator, resulting in incorporation of hydrogen atoms into the mediator or formation of a hydrogenated form of the mediator.Hydrogenation may include partial or complete reduction of a nitrogen-containing functional group, including conversion of a nitro group to a hydroxylamine, amine, azoxy compound, nitroso, N-oxide, or other reduced nitrogen-containing species. In some embodiments, hydrogenation refers to transfer of one or more reducing equivalents, optionally accompanied by proton transfer, to a compound. Without being bound by theory, hydrogenation may proceed via proton-coupled electron transfer, hydride transfer, or other reduction pathways. In some embodiments, hydrogenation does not involve the presence of molecular hydrogen gas or a heterogeneous hydrogenation catalyst.

[0099] The term “mediator” refers to a compound capable of reversibly accepting and donating reducing equivalents in a chemical or electrochemical process, thereby facilitating transfer of reducing equivalents between two species. In some embodiments, a mediator is a redox-active compound that undergoes electrochemical reduction or oxidation in a cell and subsequently participates in a chemical reaction by transferring reducing equivalents to a substrate, for example, a nitrogen-containing compound. In some embodiments, the mediator is capable of reversibly incorporating hydrogen atoms during electrochemical charging and transferring the hydrogen atoms to a substrate during a subsequent chemical reaction. In some embodiments, the mediator is regenerated after transfer of reducing equivalents and is capable of undergoing multiple charging and transfer cycles. An organicPATENT Attorney Docket No. 51198-069WO3 mediator is a mediator including a carbon atom, wherein reduction or oxidation involves the making or breaking of a bond to a carbon, nitrogen, oxygen, or sulfur atom. Organic mediators may exclude coordinated or bound metal atoms or metal ions.

[0100] The term “recharge” refers to the restoration of a mediator from a spent, reacted, or discharged state to an active redox state capable of participating in a subsequent reaction cycle. Recharge may occur electrochemically, chemically, or by a combination thereof. In some embodiments, recharge can include electrochemical conversion of a mediator following hydrogen transfer to a nitrogen-containing compound.

[0101] The term “fade rate” refers to the rate at which a performance metric of an electrochemical system decreases overtime or over repeated operating cycles.

[0102] The term “posolyte” refers to the positive electrolyte solution in an electrochemical cell. It can contain active redox species that undergoes oxidation at the positive electrode during charging and reduction during discharging.

[0103] The term “negolyte” refers to the negative electrolyte solution in an electrochemical cell. It can contain active redox species that undergoes reduction at the negative electrode during charging and oxidation during discharging.

[0104] The term “ ri(EDS)” refers to surface adsorption density of species I at the interface. It represents the amount of species I adsorbed at the interface per unit interfacial area, with a unit of mol.m-2. This equation comes from the Gibbs adsorption isotherm, linking surface adsorption density to changes in interfacial tension with concentration.

[0105] This equation defines surface adsorption density as number of moles of species / at the interface divided by the interfacial area.

[0106] Fi(EDS) can allow probing of surface adsorption densities and qualitative description of tendency to accumulate the interface.

[0107] The term “standard redox potential” is used to refer to the electrical potential of a halfreaction measured relative to the standard hydrogen electrode (SHE) when all reactants and productsPATENT Attorney Docket No. 51198-069WO3 are in their standard states. Standard redox potential is the electrode potential of a redox couple measured under standard conditions.

[0108] The term “standard state” means a solute concentration of 1 M, pressure of 1 atm, and temperature of 25 °C.

[0109] The term “Hatta number” is a dimension less number used in reaction-mass transfer analysis to compare the rate of chemical reaction to the rate of diffusion.

[0110] Where, k is reaction rate constant for the redox reaction (often first-order with respect to the nitrogen-containing compound, cPD, concentration of the reactive species (e.g., proton donor, mediator, or reactive intermediate), DArN02diffusion coefficient of the nitrogen-containing compound (e.g., ArNO2) in the phase where mass transfer occurs, kLZiqu id-side mass-transfer coefficient at the aqueous / nonaqueous interface.By “aldehyde” is meant -CHO.By "aliphatic” is meant a straight, branched, or non-aromatic cyclic carbon-containing compound.

[0111] By “alkyl” is meant straight chain or branched saturated groups from 1 to 6 carbons. Alkyl groups are exemplified by methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, neopentyl, and the like, and may be optionally substituted with one or more substituents. An “alkane” is the molecular equivalent of the “alkyl group.”

[0112] By “alkylene” is meant a divalent straight chain or branched saturated groups from 1 to 6 carbons and may be optionally substituted with one or more substituents.

[0113] By “alkenyl” is meant straight chain or branched unsaturated groups from 2 to 6 carbons and having at least one carbon-carbon double bond and no carbon-carbon triple bonds. Alkenyl groups are exemplified by ethenyl, propenyl, butenyl, and the like, and may be optionally substituted with one or more substituents.

[0114] By “alkynyl” is meant straight chain or branched unsaturated groups from 2 to 6 carbons and having at least one carbon-carbon triple bond. Alkynyl groups are exemplified by ethynyl, propynyl, butynyl, and the like, and may be optionally substituted with one or more substituents.

[0115] By “alkoxy” is meant a group of formula -OR, wherein R is an alkyl group.

[0116] By “alkyl thio” is meant -S-R, where R is an alkyl group.

[0117] By “alkyl ester” is meant -COOR, where R is an alkyl group.

[0118] By “amino” or “amine” is meant -NH2 or-NR2, wherein each R is independently H, alkyl, alkenyl, alkynyl, aryl, carbocyclyl, heteroaryl, or heterocyclyl.

[0119] By “amide” is meant -C(O)NR2 or-NRC(0)R, wherein each R is independently H, alkyl, alkenyl, alkynyl, aryl, carbocyclyl, heteroaryl, or heterocyclyl.PATENT Attorney Docket No. 51198-069WO3

[0120] By “ammonium” is meant -NRs+, wherein each R is independently H, alkyl, alkenyl, alkynyl, aryl, carbocyclyl, heteroaryl, or heterocyclyl

[0121] By “aromatic” is meant aryl or heteroaryl.

[0122] By “aryl” is meant an aromatic cyclic group in which the ring atoms are all carbon, e.g., of 6 to 20 carbons, eg. 6 to 10 carbons. Aryl groups may be monocyclic or multicyclic and may include a fused carbocyclyl group. Exemplary aryl groups include phenyl, naphthyl, and anthracenyl. Aryl groups may be optionally substituted with one or more substituents.

[0123] By “aryl amino” is meant a nitrogen atom within an aromatic ring.By “azo” is meant -N=N-.By “azoxy” is meant -N+(O )=N-.By “boronate ester” is meantalkylene.

[0124] By “carbocyclyl” is meant a non-aromatic cyclic group in which the ring atoms are all carbon. Carbocyclyl groups may monocyclic or polycyclic. Exemplary carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Carbocyclyl groups may be optionally substituted with one or more substituents.

[0125] By “carboxyl” is meant -COOH.

[0126] By “halo” is meant fluoro, chloro, bromo, or iodo.

[0127] By “heteroaryl” is meant an aromatic cyclic group in which the ring atoms include at least one carbon and at least one O, N, or S atom, provided that at least three ring atoms are present.Heteroaryl groups may be monocylic or polycyclic and may include a fused aryl, carbocyclyl, or heterocyclyl group. Each ring may include 1 to 6 carbons and 1 to 4 heteratoms selected from O, N, and S. Exemplary heteroaryl groups include oxazolyl, isoxazolyl, tetrazolyl, pyridyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrimidinyl, thiazolyl, indolyl, quinolinyl, isoquinolinyl, benzofuryl, benzothienyl, pyrazolyl, pyrazinyl, pyridazinyl, isothiazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxadiazolyl, thiadiazolyl, and triazolyl. Heteroaryl groups may be optionally substituted with one or more substituents.

[0128] By “heterocyclyl” is meant a non-aromatic cyclic group in which the ring atoms include at least one carbon and at least one O, N, or S atom, provided that at least three ring atoms are present. Heterocyclyl groups may be monocylic or polycyclic and may include a fused carbocyclyl or heterocyclyl group. Each ring may include 1 to 6 carbons and 1 to 4 heteratoms selected from O, N, and S. Exemplary heterocyclyl groups include epoxide, thiiranyl, aziridinyl, azetidinyl, thietanyl, dioxetanyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, pyrazolinyl, pyrazolidinyl, dihydropyranyl, tetrahydroquinolyl, imidazolinyl, imidazolidinyl, pyrrolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dithiazolyl, and 1 ,3-dioxanyl. Heterocyclyl groups may be optionally substituted with one or more substituents.

[0129] By “hydroxamic acid” is meant -C(O)NHOH.PATENT Attorney Docket No. 51198-069WO3

[0130] By “hydroxyl” is meant -OH.

[0131] By “hydroxyl amine” is meant -NHOH.

[0132] By “flu idically coupled” is meant any connection between at least two system elements that allows for fluid flow therebetween.

[0133] By “ketone” is meant -C(O)-.

[0134] By “nitro” is meant -NO2.

[0135] By “nitroalkane” is meant R-NO2, where R is alkyl.

[0136] By “nitroarene” is meant R-NO2, where R is aryl or heteroaryl.

[0137] By “nitroso” is meant -N=O.

[0138] By “nitrile” is meant -CEN.

[0139] By “N-oxide” is meant >N+-O_.

[0140] By “oxo” is meant =O.

[0141] By “phosphoryl” is meant -PO3H2.

[0142] By “phosphonyl” is meant -PO3R2, wherein each R is independently H or alkyl.

[0143] By “sulfide” is meant -S-.

[0144] By “sulfonyl” is meant -SO2R, where R is alkyl, alkenyl, alkynyl, aryl, carbocyclyl, heteroaryl, or heterocyclyl

[0145] By “sulfonate” is meant -SO3H.

[0146] By “thiol” is meant -SH.

[0147] Substituents may be optionally substituted with halo, optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S; oxo, -CN; -NO2; -ORa; -N(Ra)2-3; -C(=O)Ra; -C(=O)ORa; -S(=O)2Ra; -S(=O)2ORa; -P(=O)Ra2; -O-P(=O)(ORa)2, or-P(=0)(ORa)2, or an ion thereof; wherein each Rais independently H, optionally substituted C1-6 alkyl; optionally substituted C2-6 alkenyl; optionally substituted C2-6 alkynyl; optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S. Cyclic substituents may also be substituted with optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl. In specific embodiments, substituents may be optionally substituted with halo, optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S; oxo, -NO2; -ORa; -N(Ra)2-3; -C(=O)Ra; -C(=O)ORa; -S(=O)2Ra; -S(=O)2ORa; -P(=O)Ra2; -O-P(=O)(ORa)2, or-P(=0)(ORa)2, or an ion thereof; wherein each Rais independently H, optionally substituted C1-6 alkyl; optionally substituted C2-6 alkenyl; optionally substituted C2-6 alkynyl, optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S; and cyclic substituents may also be substituted with C1-6PATENT Attorney Docket No. 51198-069WO3 alkyl. In specific embodiments, alkyl groups may be optionally substituted with one, two, three, or, in the case of alkyl groups of two carbons or more, four substituents independently selected from the group consisting of halo, hydroxyl, C1-6 alkoxy, SO3H, amino, nitro, carboxyl, phosphoryl, phosphonyl, thiol, C1-6 alkyl ester, optionally substituted C1-6 alkyl thio, and oxo, or an ion thereof.

[0148] FIG. 1 is a block diagram of a system including a reactor / separator 1100 and an electrochemical cell 1500, e.g., a flow cell, for conversion of nitrogen-containing compound 1200 into fully or partially reduced nitrogen-containing products 1300. A redox-active organic mediator (referred herein as mediator) 1400 can flow through an electrochemical flow cell 1500 for reduction at the electrode, e.g., solid carbon, in an aqueous phase to a reduced organic mediator 1410. In some embodiments, the reduced organic mediator 1410 can be referred to as hydrogenated mediator. In some embodiments, the reduced organic mediator 1410 can be produced by the transfer of two electrons and two protons. In some embodiments, the reduced organic mediator 1410 can be produced by the transfer of one electron and one proton, if the reduction includes only one step. In some embodiments, the reduced organic mediator 1410 in the aqueous phase can exit the electrochemical cell 1500 and enters a reactor 1100.

[0149] In some embodiments, the nitrogen-containing compound 1200 can be dissolved in a nonaqueous solvent immiscible with water and be communicated to the reactor 1100. In some embodiments, the nonaqueous solvent can be an organic solvent. In some embodiments, the nitrogen-containing compound 1200 can include an aliphatic nitrogen-containing compound and / or an aromatic nitrogen-containing compound. In some embodiments, the nitrogen-containing compound 1200 can include an oxidized nitrogen compound such as, for example, a hydroxylamine compound, azoxy compound, and / or N-oxide compound.

[0150] In some embodiments, the aqueous phase and the nonaqueous phase can be contacted. During contacting, a redox reaction occurs between the nitrogen-containing compound 1200 and the reduced organic mediator 1410 to form one or more fully or partially reduced nitrogen-containing compounds 1300. In some embodiments, oxidation of the reduced organic mediator 1410 can occur simultaneously.

[0151] In some embodiments, the reactor 1100 can serve as the site where the reaction occurs between the reduced organic mediator 1410 and the nitrogen-containing compound 1200. In some embodiments, the reactor 1100 can function as an agitator. In some embodiments, the reactor 1100 can include an agitating element configured to provide a contact area between the aqueous solution and the nonaqueous solution, sufficient for the reaction. In some embodiments, the aqueous solution can be referred to as the aqueous medium, and / or the aqueous phase. In some embodiments, the nonaqueous solution can be referred to as the nonaqueous medium, and / or the nonaqueous phase.

[0152] In some embodiments, the reactor 1100 can function as a separation section, as well as a reactor. In some embodiments, the reactor 1100 can be integrated with a separation section. In some embodiments, the reactor 1100 can be fluidically coupled to a separation section. In somePATENT Attorney Docket No. 51198-069WO3 embodiments, the separation process can occur simultaneously while the reaction is ongoing. In some embodiments, the separation process may be performed subsequent to the reaction. In some embodiments, the separation process can occur via a separation element. In some embodiments, the separation element can include extraction columns, centrifugal contactors, membrane phase separators, and / or gravity separators.

[0153] In some embodiments, the reactor 1100 can be a reactor-separator system. In some embodiments, the reactor-separator system can improve mass transfer efficiency, and / or enable pure product transfer. In some embodiments, a reactor-separator system can include a reactor section and a separation section. In some embodiments, the reactor section can include an agitating element. In some embodiments, the agitating element can include at least one of a mechanical agitator, a static mixer, a jet mixing / eductor, a stirrer, and / or ultrasonic or vibration mixer.

[0154] In some embodiments, the separator section can include a quiescent settling chamber, baffles, coalescence plates, lamella plates, and / or a gravity-based separation region. The structure of the reactor-separator as the reactor 1100 will be described in further detail in FIG. 3B. In some embodiments, the aqueous phase and the nonaqueous phase can be separated into different layers in the separation section of the reactor 1100. In some embodiments, the separation can be driven by density differences, interfacial tension, and / or gravity. In some embodiments, the lighter layer (can be also referred to as the lighter phase) can exit from the top portion of the reactor 1100. In some embodiments, the heavier layer (can be also referred to as the heavier phase) can exit from the bottom portion of the reactor 1100.

[0155] In some embodiments, the reactor can be coupled to the electrochemical flow cell. In some embodiments, the reactor and the electrochemical flow cell can configure a system for production of one or more fully or partially reduced nitrogen-containing product 1300. In some embodiments, the system can operate in a batch mode, semi-batch mode, ora continuous flow mode (e.g., shown in FIG. 3A).

[0156] In some embodiments, the oxidized organic mediator 1400 can be reduced in the electrochemical flow cell 1500 to form the reduced organic mediator 1410. In some embodiments, the electrochemical flow cell 1500 can include an aqueous organic redox flow battery (AORFB). In some embodiments, the electrochemical flow cell 1500 can include a redox flow battery in which at least one of the redox active species is an organic molecule dissolved in an aqueous electrolyte. In some embodiments, the electrochemical flow cell 1500 can include a positive electrolyte (posolyte) and a negative electrolyte (negolyte). In some embodiments, both positive and negative electrolytes are aqueous.

[0157] In some embodiments, the posolyte can include potassium ferrocyanide and / or potassium ferricyanide dissolved in an aqueous solution. In some embodiments, the potassium ferrocyanide can have a concentration of about 0.2 M, and the potassium ferricyanide can have a concentration ofPATENT Attorney Docket No. 51198-069WO3 about 0.08 M. The posolyte can further include potassium chloride. In some embodiments, the concentration of the potassium chloride can be about 1 M.

[0158] In some embodiments, the posolyte can include an alkali metal salt of at least one of potassium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, or combinations thereof. In some embodiments, the concentration of the posolyte can be from about 0.1 M to about 3 M, inclusive of all values and ranges in between. In some embodiments, the concentration of the posolyte can be at least about 0.1 M, at least about 0.2 M, at least about 0.3 M, at least about 0.4 M, at least about 0.5 M, at least about 0.6 M, at least about 0.7 M, at least about 0.8 M, at least about 0.9 M, at least about 1 M, at least about 2M, or at least about 3 M, inclusive of all values and ranges in between. In some embodiments, the concentration of the posolyte can be no more than about 3 M, no more than about 2 M, no more than about 1 M, no more than about 0.9 M, no more than about 0.8 M, no more than about 0.7 M, no more than about 0.6 M, no more than about 0.5 M, no more than about 0.4 M, no more than about 0.3 M, no more than about 0.2 M, or no more than about 0.1 M, inclusive of all values and ranges in between. Combinations of the abovereferenced concentration of the posolyte are also possible (e.g., at least about 0.1 M, and no more than about 1 M, or at least about 0.2 M and no more than about 0.3 M), inclusive of all values and ranges therebetween. In some embodiments, the concentration of the posolyte can be about 0.1 M, about 0.2 M, about 0.3 M, about 0.4 M, about 0.5 M, about 0.6 M, about 0.7 M, about 0.8 M, about 0.9 M, about 1 M, about 2 M, or about 3 M, inclusive of all values and ranges therebetween.

[0159] In some embodiments, the redox active species (i.e., organic redox-active molecule) can be reduced in the electrochemical flow cell 1500. In some embodiments, the redox active species or organic redox-active molecule can be referred to as the mediator 1400. In some embodiments, the mediator 1400 reduction can occur in the negolyte. In some embodiments, the concentration of the mediator in the negolyte can be from about 0.1 M to about 1 M, inclusive of all values and ranges in between. In some embodiments, the concentration of the mediator in the negolyte can be at least about 0.1 M, at least about 0.2 M, at least about 0.3 M, at least about 0.4 M, at least about 0.5 M, at least about 0.6 M, at least about 0.7 M, at least about 0.8 M, at least about 0.9 M, or at least about 1 M, inclusive of all values and ranges in between. In some embodiments, the concentration of the mediator in the negolyte can be no more than about 1 M, no more than about 0.9 M, no more than about 0.8 M, no more than about 0.7 M, no more than about 0.6 M, no more than about 0.5 M, no more than about 0.4 M, no more than about 0.3 M, no more than about 0.2 M, or no more than about 0.1 M, inclusive of all values and ranges in between. Combinations of the above -referenced concentrations of the mediator in the negolyte are also possible (e.g., at least about 0.1 M, and no more than about 1 M, or at least about 0.2 M and no more than about 0.3 M), inclusive of all values and ranges therebetween. In some embodiments, the concentration of the mediator in the negolyte can be about 0.1 M, about 0.2 M, about 0.3 M, about 0.4 M, about 0.5 M, about 0.6 M, about 0.7 M, about 0.8 M, about 0.9 M, or about 1 M, inclusive of all values and ranges therebetween.PATENT Attorney Docket No. 51198-069WO3

[0160] It will be understood by one skilled in the art that the mediator may alternatively be reduced in posolyte if the counter redox active species has a lower redox potential.

[0161] In some embodiments, posolyte and negolyte can include an electrolyte salt. In some embodiments, the electrolyte salt can include KCI. In some embodiments, the electrolyte salt can include an alkali metal halide, sulfate, and / or nitrate. In some embodiments, the electrolyte salt can include NaCI, LiCI, KBr, NaBr, LiBr, K2SO4, Na2SC>4, IJ2SO4, KNO3, NaNCh, and / or any combination thereof. Other suitable electrolyte salts are known in the art.

[0162] The negolyte and posolyte may be at any suitable pH. In some embodiments, the negolyte and / or posolyte has a pH between about 7 and about 10, or between about 10 and about 12, or between about 12 and about 14. In other embodiments, the pH of the negolyte and / or posolyte is at least 7, at least 8, at least 9 at least 10, at least 11 , at least 12, at least 13, or at least 14. In other embodiments, the pH of the negolyte and / or posolyte is between about 5 and about 7, between about 3 and about 5, or between 0 and about 3. In other embodiments, the pH of the negolyte and / or posolyte is at most 7, at most 6, at most 5, at most 4, at most 3, at most 2, or at most 1.

[0163] In some embodiments, the concentration of the electrolyte salt in the negolyte and / or the posolyte can be from about 0.5 M to about 1.5 M, inclusive of all values and ranges in between. In some embodiments, the concentration of the electrolyte salt in the negolyte and / or the posolyte can be at least about 0.5 M, at least about 0.6 M, at least about 0.7 M, at least about 0.8 M, at least about 0.9 M, at least about 1 M, at least about 1.2 M, at least about 1.3 M, at least about 1.4 M, or at least about 1.5 M, inclusive of all values and ranges in between. In some embodiments, the concentration of the electrolyte salt in the negolyte and / or the posolyte can be no more than about 1.5 M, no more than about 1.4 M, no more than about 1 .3 M, no more than about 1 .2 M, no more than about 1.1 M, no more than about 1 M, no more than about 0.9 M, no more than about 0.8 M, no more than about 0.7 M, no more than about 0.6 M, or no more than about 0.5 M, inclusive of all values and ranges in between. Combinations of the above- referenced concentrations of the electrolyte salt in the negolyte and / or the posolyte are also possible (e.g., at least about 0.5 M, and no more than about 1 .5 M, or at least about 0.2 M and no more than about 0.5 M), inclusive of all values and ranges therebetween. In some embodiments, the concentration of the electrolyte salt in the negolyte and / or the posolyte can be about 0.5 M, about 0.6 M, about 0.7 M, about 0.8 M, about 0.9 M, about 1 M, about 1.1 M, about 1.2 M, about 1.3 M, about 1 .4 M, or about 1.5 M, inclusive of all values and ranges therebetween.

[0164] In some embodiments, flow may be maintained at a rate sufficient to provide continuous circulation and mass transport between the electrochemical flow cell 1500 and the reactor 1100. In some embodiments, the flow rate corresponds to circulation of the electrolyte at a rate of about 0.1 to about 50 reactor volumes per hour.

[0165] In some embodiments, the flow rate of the electrolyte through the electrochemical flow cell 1500 can be in a range of about 2 ml / min to about 200 ml / min, inclusive of all values and ranges in between. In some embodiments, the flow rate of the electrolyte through the electrochemical flow cellPATENT Attorney Docket No. 51198-069WO3 1500 can be at least about 2 ml / min, at least about 4 ml / min, at least about 6 ml / min, at least about 10 ml / min, at least about 20 ml / min, at least about 30 ml / min, at least about 40 ml / min, at least about 50 ml / min, at least about 60 ml / min, at least about 70 ml / min, at least about 80 ml / min, at least about 90 ml / min, at least about 100 ml / min, or at least about 200 ml / min, inclusive of all values and ranges in between. In some embodiments, the flow rate of the electrolyte through the electrochemical flow cell 1500 can be no more than about 200 ml / min, no more than about 100 ml / min, no more than about 90 ml / min, no more than about 80 ml / min, no more than about 70 ml / min, no more than about 60 ml / min, no more than about 50 ml / min, no more than about 40 ml / min, no more than about 30 ml / min, no more than about 20 ml / min, no more than about 10 ml / min, no more than about 9 ml / min, no more than about 8 ml / min, no more than about 6 ml / min, no more than about 4 ml / min, or no more than about 2 ml / min, inclusive of all values and ranges in between. Combinations of the above -referenced flow rates of the electrolyte through the electrochemical flow cell 1500 are also possible (e.g., at least about 2 ml / min, and no more than about 200 ml / min, or at least about 10 ml / min and no more than about 70 ml / min), inclusive of all values and ranges therebetween. In some embodiments, the flow rate of the electrolyte through the electrochemical flow cell 1500 can be about 2 ml / min, about 4 ml / min, about 6 ml / min, about 8 ml / min, about 10 ml / min, about 20 ml / min, about 30 ml / min, about 40 ml / min, about 60 ml / min, about 80 ml / min, about 90 ml / min, about 100 ml / min, or about 200 ml / min, inclusive of all values and ranges therebetween.

[0166] In some embodiments, the electrochemical flow cell 1500 can include a cation exchange membrane. In some embodiments, the cation exchange membrane can include NAFION® (sulfonated tetrafluoroethylene-based fluoropolymer). In the electrochemical flow cell, a proton exchange membrane (e.g., NAFION®) can separate the cathodic and anodic chambers. In some embodiments, the reduction of pz to pz-FF can occur in the cathodic chamber. In some embodiments, water oxidation can occur in the anodic chamber. In some embodiments, another half-reaction oxidation can occur in the anodic chamber. In some embodiments, the reduction of the mediator (i.e., redox active species) can proceed at room temperature. In some embodiments, the reduced organic mediator can be disposed in, dissolved in, and / or provided in an aqueous solution.

[0167] In some embodiments, the current density of the electrochemical flow cell 1500, e.g., in lab scale, can be in range of about 10 mA / cm2to about 50 mA / cm2, inclusive of all values and ranges in between. In some embodiments, the current density of the electrochemical flow cell 1500, e.g., in lab scale, can be at least about 10 mA / cm2, at least about 15 mA / cm2, at least about 20 mA / cm2, at least about 25 mA / cm2, at least about 30 mA / cm2, at least about 35 mA / cm2, at least about 40 mA / cm2, at least about 45 mA / cm2, or at least about 50 mA / cm2, inclusive of all values and ranges in between. In some embodiments, the current density of the electrochemical flow cell 1500, e.g., in lab scale, can be no more than about 50 mA / cm2, no more than about 45 mA / cm2, no more than about 40 mA / cm2, no more than about 35 mA / cm2, no more than about 30 mA / cm2, no more than about 25 mA / cm2, no more than about 20 mA / cm2, or no more than about 15 mA / cm2, or no more than about 10 mA / cm2, inclusive of all values and ranges in between. Combinations of the above- referenced current densities are also possible (e.g., at least about 10 mA / cm2, and no more than about 50 mA / cm2, or at leastPATENT Attorney Docket No. 51198-069WO3 about 25 mA / cm2and no more than about 35 mA / cm2), inclusive of all values and ranges therebetween. In some embodiments, the current density of the electrochemical flow cell 1500, e.g., in lab scale, can be about 10 mA / cm2, about 15 mA / cm2, about 20 mA / cm2, about 25 mA / cm2, about 30 mA / cm2, about 35 mA / cm2, about 40 mA / cm2, about 45 mA / cm2, or about 50 mA / cm2, inclusive of all values and ranges therebetween.

[0168] In some embodiments, the current density of the electrochemical flow cell 1500, e.g., in industrial scale, can be in range of about 150 mA / cm2to about 500 mA / cm2, inclusive of all values and ranges in between. In some embodiments, the current density of the electrochemical flow cell 1500, e.g., in industrial scale, can be at least about 150 mA / cm2, at least about 160 mA / cm2, at least about 170 mA / cm2, at least about 180 mA / cm2, at least about 190 mA / cm2, at least about 200 mA / cm2, at least about 210 mA / cm2, at least about 220 mA / cm2, at least about 230 mA / cm2, at least about 240 mA / cm2, at least about 250 mA / cm2, at least about 260 mA / cm2, at least about 270 mA / cm2, at least about 280 mA / cm2, at least about 290 mA / cm2, at least about 300 mA / cm2, at least about 350 mA / cm2, at least about 400 mA / cm2, at least about 450 mA / cm2, at least about 500 ma / cm2, inclusive of all values and ranges in between. In some embodiments, the current density of the electrochemical flow cell 1500, e.g., in industrial scale, can be no more than about 500 mA / cm2, 450 mA / cm2, 400 mA / cm2, 350 mA / cm2, 300 mA / cm2, no more than about 290 mA / cm2, no more than about 280 mA / cm2, no more than about 270 mA / cm2, no more than about 260 mA / cm2, no more than about 250 mA / cm2, no more than about 240 mA / cm2, no more than about 230 mA / cm2, or no more than about 220 mA / cm2, no more than about 210 mA / cm2, no more than about 200 mA / cm2, no more than about 190 mA / cm2, no more than about 180 mA / cm2, no more than about 170 mA / cm2, no more than about 160 mA / cm2, or no more than about 150 mA / cm2, inclusive of all values and ranges in between. Combinations of the above-referenced current densities are also possible (e.g., at least about 150 mA / cm2, and no more than about 300 mA / cm2, or at least about 200 mA / cm2and no more than about 250 mA / cm2), inclusive of all values and ranges therebetween. In some embodiments, the current density of the electrochemical flow cell 1500, e.g., in industrial scale, can be about 150 mA / cm2, about 160 mA / cm2, about 170 mA / cm2, about 180 mA / cm2, about 190 mA / cm2, about 200 mA / cm2, about 210 mA / cm2, about 220 mA / cm2, or about 230 mA / cm2, about 240 mA / cm2, about 250 mA / cm2, about 260 mA / cm2, about 270 mA / cm2, about 280 mA / cm2, about 290 mA / cm2, about 300 mA / cm2, about 350 mA / cm2, about 400 mA / cm2, about 450 mA / cm2, or about 500 mA / cm2, inclusive of all values and ranges therebetween.

[0169] In some embodiments, the electrochemical flow cell 1500 can operate at a constant charging voltage of about 0.5 V to about 2.5 V, inclusive of all values and ranges between. In some embodiments, the constant charging voltage can be at least about 0.5 V, at least about 0.6 V, at least about 0.7 V, at least about 0.8 V, at least about 0.9 V, at least about 1 V, at least about 1.1 V, at least about 1.2 V, at least about 1.3 V, at least about 1.4 V, at least about 1.5 V, at least about 1 .6 V, at least about 1.7 V, at least about 1.8 V, at least about 1.9 V, at least about 2 V, at least about 2.1 V, at least about 2.2 V, at least about 2.3 V, at least about 2.4 V, or at least about 2.5 V, inclusive of all values and ranges in between. In some embodiments, the constant charging voltage can be no morePATENT Attorney Docket No. 51198-069WO3 than about 2.5 V, no more than about 2.4 V, no more than about 2.3 V, no more than about 2.2 V, no more than about 2.1 V, no more than about 2 V, no more than about 1.9 V, no more than about 1.8 V, no more than about 1.7 V no more than about 1.6 V, no more than about 1.5 V, no more than about 1.4 V, no more than about 1.3 V, no more than about 1.2 V, no more than about 1.1 V, or no more than about 1 V, no more than about 0.9 V, no more than about 0.8 V, no more than about 0.7 V, no more than about 0.6 V, or no more than about 0.5 V, inclusive of all values and ranges in between. Combinations of the above- referenced current charging voltages are also possible (e.g., at least about 0.5 V, and no more than about 2.5 V, or at least about 1.2 V and no more than about 1.5 V), inclusive of all values and ranges therebetween. In some embodiments, the charging voltage can be about 0.5 V, about 0.6 v, about 0.7 V, about 0.8 V, about 0.9 V, about 1 V, about 1.1 V, about 1.2 V, about 1.3 V, about 1.4 V, about 1.5 V, or about 1.6 V, about 1.7 V, about 1.8 V, about 1.9 V, about 2 V, about 2.1 V, about 2.2 V, about 2.3 v, about 2.4 V, or about 2.5 V, inclusive of all values and ranges therebetween.

[0170] In some embodiments, the electrochemical flow cell 1500 can operate at a constant discharging voltage of about 0.3 V to about 2 V, inclusive of all values and ranges between. In some embodiments, the constant discharging voltage can be at least about 0.3 V, at least about 0.4 V, at least about 0.5 V, at least about 0.6 V, at least about 0.7 V, at least about 0.8 V, at least about 0.9 V, at least about 1 V, at least about 1.1 V, at least about 1.2 V, or at least about 1.3 V, at least about 1.4 V, at least about 1.5 V, at least about 1.6 V, at least about 1.7 V, at least about 1.8 V, at least about 1.9 V, or at least about 2 V, inclusive of all values and ranges in between. In some embodiments, the constant discharging voltage can be no more than about 2 V, no more than about 1.9 V, no more than about 1.8 V, no more than about 1.7 V, no more than about 1.6 V, no more than about 1.5 V, no more than about 1.4 V, no more than about 1.3 V, no more than about 1.2 V, no more than about 1.1 V, no more than about 1 V, no more than about 0.9 V, no more than about 0.8 V, no more than about 0.7 V, no more than about 0.6 V, no more than about 0.5 V, no more than about 0.4 V, or no more than about 0.3 V, inclusive of all values and ranges in between. Combinations of the above-referenced current discharging voltages are also possible (e.g., at least about 0.3 V, and no more than about 2 V, or at least about 0.6 V and no more than about 0.8 V), inclusive of all values and ranges therebetween. In some embodiments, the discharging voltage can be about 0.3 V, about 0.4 V, about 0.5 V, about 0.6 V, about 0.7 V, about 0.8 V, about 0.9 V, about 1 V, about 1.1 V, about 1.2 V, about 1.3 V, about 1.4 V, about 1.5 V, about 1 .6 V, about 1.7 V, about 1.8 V, about 1.9 V, or about 2 V, inclusive of all values and ranges therebetween.

[0171] In some embodiments, the negolyte can include a mediator 1400. In some embodiments, the mediator 3400 can include a phenazine. In some embodiments, the mediator 1400 (also referred to as PCET mediator) is for a chemo-selective redox reaction of a nitrogen-containing compound 1200. In some embodiments, the organic mediator 1400 can include quinoxalines, anthraquinones, naphthoquinone, benzoquinones, fluorenones, azo-compounds and / or bipyridiniums (viologens) or others as described herein or known in the art.PATENT Attorney Docket No. 51198-069WO3

[0172] In some embodiments, aqueous phase including the reduced organic mediator 1410 and the nonaqueous phase including the nitrogen-containing compound 1200 can be communicated to the reactor 1100. In some embodiments, concentration of the nitrogen-containing compound 1200 can be about 50 mM to about 300 mM, inclusive of all values and ranges in between. In some embodiments, the concentration of the nitrogen-containing compound can be at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, at least about 100 mM, at least about 150 mM, at least about 200 mM, at least about 250 mM, or at least about 300 mM, inclusive of all values and ranges in between. In some embodiments, the concentration of the nitrogen-containing compound can be no more than about 300 mM, no more than about 250 mM, no more than about 200 mM, no more than about 150 mM, no more than about 100 mM, no more than about 90 mM, no more than about 80 mM, no more than about 70 mM, no more than about 60 mM, or no more than about 50mM, inclusive of all values and ranges in between. Combinations of the abovereferenced concentrations of the nitrogen-containing compound are also possible (e.g., at least about 50 mM, and no more than about 1300 mM, or at least about 100 mM and no more than about 200 mM), inclusive of all values and ranges therebetween. In some embodiments, the concentration of the nitrogen-containing compound can be about 50 mM, about 60 mM, about 70 mM, about 80 mM, about 90 mM, about 100 mM, about 150 mM, about 200 mM, about 250 mM, or about 300 mM M, inclusive of all values and ranges therebetween.

[0173] In some embodiments, a reaction can initiate via contacting the aqueous phase and nonaqueous phase. In some embodiments, the reduced organic mediator 1410, e.g., a pz-H2, can be contacted in the reactor 1100 with an organic medium (or stream) including the nitrogen-containing compound 1200. In some embodiments, contacting the aqueous medium including the reduced organic mediator 1410 and the nonaqueous medium including the nitrogen-containing compound 1200 can allow a reaction to occur between the reduced organic mediator 1410 and the nitrogencontaining compound 1200. In some embodiments, the reaction can occur at the aqueous-nonaqueous boundary, also referred to as the interface. In some embodiments, the reaction can be an interfacial redox reaction.

[0174] In some embodiments, the reaction can take place in either single or multiple passes, depending on the nitrogen-containing compound 1200, the relative amount of reduced organic mediator 1400, and the reaction rate. In some embodiments, the product of the reaction can include one or more partially or fully reduced nitrogen-containing product 1300. In some embodiments, the mediator 1400 can be used in a stoichiometric orsuperstoichiometric loading amount. In some embodiments, the mediator 1400 can be used in a sub-stoichiometric loading amount. In some embodiments, the stoichiometric, superstoichiometirc, or sub-stoichiometric loading can be selected to achieve a desired equivalent of the reduced organic mediator 1410 which can subsequently result in forming partially or fully reduced nitrogen-containing product 1300.

[0175] In some embodiments, the reaction can be selective and metal free. In this context, metal of salts of mediators and metal salt electrolytes may be employed with the metal ion not participating inPATENT Attorney Docket No. 51198-069WO3 the reaction. In some embodiments, the reaction can occur via PCET. In some embodiments, the reaction includes transfer of protons and electrons from the reduced organic mediator 1410 to the nitrogen-containing compound 1200. In some embodiments, water can provide protons (H+) that can participate in PCET reaction. In some embodiments, water can ensure the reduced organic mediator 1410 stays protonated. In some embodiments, the water can form hydrogen bonds at the interface, thereby facilitating proton transfer to the nitrogen-containing compound 1200. In some embodiments, protons can shuttle to the nitrogen-containing compound 1200 in the nonaqueous solution.

[0176] In some embodiments, the reaction includes electron transfer, proton transfer, and / or proton-coupled electron transfer. In some embodiments, the reduced organic mediator 1410 can donate one or more electrons to an oxidized nitrogen group, e.g., nitro, of the nitrogen-containing compound to form a partially reduced nitrogen containing product. In some embodiments, the reduced organic mediator and / or the water can donate a proton forming one or more partially or fully reduced nitrogencontaining product 1300. In some embodiments, electron and proton transfer can be simultaneously and / or sequentially. This mechanism is described in more detail in FIG. 11.

[0177] In some embodiments, the reaction can oxidize the reduced organic mediator 1410 to an oxidized organic mediator 1600. In some embodiments, the oxidized organic mediator can be substantially similar to the mediator 1400. After transfer of reducing equivalents from the reduced organic mediator 1410 to the nitrogen-containing compound 1200, the mediator can return to its oxidized or unhydrogenated form. In some embodiments, the oxidized organic mediator 1600 can be capable of undergoing subsequent hydrogenation and transfer cycles.

[0178] In some embodiments, the oxidized organic mediator 1600 can flow back to the electrochemical cell 1500 for further reduction and regeneration via a conduit from the reactor 1100. In some embodiments, the oxidized organic mediator 1600. In some embodiments, continuous regeneration (i.e., reduction) of the reduced organic mediator 1410 can occur.

[0179] In some embodiments, the nonaqueous solution containing the partially or fully reduced nitrogen-containing product 1300 can be collected. In some embodiments, another nitrogencontaining compound 1200 can be introduced into the nonaqueous phase for reduction by the same reduced organic mediator 1410. In some embodiments, the at least partially or fully reduced nitrogen containing product can be obtained in substantially pure form with reduced energy required for purification. In some embodiments, the at least partially or fully reduced nitrogen-containing product 1300 can separate with the nonaqueous phase. In some embodiments, the settled at least partially or fully reduced nitrogen-containing product 1300 can exit the reactor 1100 via a conduit in the reactor 1100. In some embodiments, the desired purity of final compounds can be obtained via extraction.

[0180] In some embodiments, unreacted or partially reacted nitrogen-containing compound 1200 can flow back to the reactor 1100 via the conduit. In some embodiments, the unreacted or partially reacted nitrogen-containing compound 1200 can be reused to achieve the desired yield. The hydrogenation / reduction of the nitrogen-containing compound 1200 can achieve a yield of over 99%.PATENT Attorney Docket No. 51198-069WO3 High selectivity for the desired nitrogen-containing product 1300 can be achieved. In some embodiments, the hydrogenation / reduction yield can be about 35% to about 99%, inclusive of all values and ranges in between.

[0181] In some embodiments, the current density of the electrochemical flow cell 1500, e.g., at lab scale, can be at least about 10 mA / cm2, at least about 15 mA / cm2, at least about 20 mA / cm2, at least about 25 mA / cm2, at least about 30 mA / cm2, at least about 35 mA / cm2, at least about 40 mA / cm2, at least about 45 mA / cm2, or at least about 50 mA / cm2, inclusive of all values and ranges in between. In some embodiments, the current density of the electrochemical flow cell 1500, e.g., at lab scale, can be no more than about 50 mA / cm2, no more than about 45 mA / cm2, no more than about 40 mA / cm2, no more than about 35 mA / cm2, no more than about 30 mA / cm2, no more than about 25 mA / cm2, no more than about 20 mA / cm2, or no more than about 15 mA / cm2, or no more than about 10 mA / cm2, inclusive of all values and ranges in between. Combinations of the above-referenced current densities are also possible (e.g., at least about 10 mA / cm2, and no more than about 50 mA / cm2, or at least about 25 mA / cm2and no more than about 35 mA / cm2), inclusive of all values and ranges therebetween. In some embodiments, the current density of the electrochemical flow cell 1500, e.g., at lab scale, can be about 10 mA / cm2, about 15 mA / cm2, about 20 mA / cm2, about 25 mA / cm2, about 30 mA / cm2, about 35 mA / cm2, about 40 mA / cm2, about 45 mA / cm2, or about 50 mA / cm2, inclusive of all values and ranges therebetween. .

[0182] Systems and methods described herein may also offer excellent electron utilization with faradaic efficiency exceeding 97%. For example, 10 mol% pz5 in the aqueous phase and 3.4 mmol of nitrobenzene in the organic phase were communicated to the reactor 1100. The electrochemical flow cell was operated using a CCCV (100mA, then -1.65 V) protocol against potassium ferro / ferricyanide. At steady state, the electrochemical flow cell 1500 was unable to maintain the target 100 mA. In some embodiments, this behavior can suggest the process may be limited by interfacial transport rather than by the mediator reduction (or charging).

[0183] FIG. 2A is a flow diagram of a method for production of reduced nitrogen-containing product, for example, a partially or fully reduced nitrogen-containing product from a nitrogen-containing compound, according to an embodiment. As shown in FIG. 2A, the method 10 can employ the system 1000, and any components (e.g., reactor 1100, nitrogen-containing compound 1200, reduced nitrogen-containing product 1300, mediator 1400, reduced organic mediator 1410, electrochemical cell 1500, e.g., flow cell, oxidized organic mediator 1600 ), and / or features thereof as described with respect to FIG. 1. It should be noted that step 20 is optional and need not occur if the nitrogencontaining compound is reacted in one step. While the method 10 and operations thereof have been described herein with respect to the system 1000, in some embodiments, the method 10 or operations thereof may be performed by any suitable system described herein. All such variations are envisioned herein and should be considered as part of the present disclosure. For example, the method 10 may be employed using a reactor not fluidically coupled to an electrochemical cell. In suchPATENT Attorney Docket No. 51198-069WO3 embodiments, liquid transfers may be manual. In another example, the reactor may act as part of the electrochemical cell, e.g., during a batch process.

[0184] The method 10 can also be used for reduction of nitrogen-containing compounds including a hydroxyl amine compound (including -NHOH group), a N-oxide compound (including N+-O_group), a nitroso compound (including -NO group), and / or an azo compound (including -N=N- group), for example, azobenzene. Therefore, the methods, systems, and compounds described herein are not limited to the reduction of nitro compounds, but also oxidized nitrogen compounds.

[0185] In some embodiments, the method 10 can include reducing a mediator 1400 in an aqueous solution, at 12. In some embodiments, the mediator 1400 can be reduced to a reduced organic mediator 1410 in an electrochemical flow cell 1500 or a static electrochemical cell.

[0186] In some embodiments, the electrochemical flow cell 1500 can include a single electrochemical flow cell or a stack of multiple electrochemical flow cells electrically connected in series and / or in parallel. In some embodiments, the electrochemical flow cell 1500 can operate in an aqueous medium, although combined aqueous-organic or nonaqueous media are also contemplated.

[0187] In some embodiments, the electrochemical flow cell 1500 can include at least one electrode, e.g., formed from a carbon-based material, including graphite, carbon felt, carbon paper, glassy carbon, or combinations thereof, configured to facilitate reversible redox reactions of the mediator 1400. In some embodiments, the electrochemical flow cell 1500 can include a cathode and an anode separated by a membrane (e.g., a semi-permeable membrane, or an ion-selective membrane). Other electrodes are known in the art.

[0188] In some embodiments, during a charging operation, a negolyte can be electrochemically reduced at the cathode, resulting in the formation of a reduced form of the mediator 1410. Oxidation occurs at the anode. In some embodiments, the oxidizable species at the anode can include water, an alcohol, an inorganic compound, or an organic compound, thereby generating protons, electrons, or oxidized byproducts.

[0189] In some embodiments, protons generated in a posolyte can migrate through the membrane to the negolyte, where the protons participate in the reduction of the mediator 1400 to form the reduced organic mediator 1410. In some embodiments, the membrane can include an ion-selective membrane configured to permit proton transport while limiting crossover of the mediator or other redox-active species.

[0190] In some embodiments, the electrochemical flow cell 1500 can be configured to operate under conditions that promote efficient charge transfer, mediator stability, and reversible redox cycling, thereby enabling repeated charging and discharging of the electrochemical system.”

[0191] In some embodiments, the reduced organic mediator 1410 can be partially or fully hydrogenated. The partially hydrogenated mediator can include one electron and one proton, alsoPATENT Attorney Docket No. 51198-069WO3 referred to as a semi-reduced, radical, and / or hydrogenated intermediate, e.g., shown as Pz-H. In some embodiments, the fully hydrogenated mediator, e.g., a dihydrophenazine, or fully reduced organic mediator 1410 can include two electrons and two protons, e.g., shown as PZ-H2. In some embodiments, the reduced organic mediator 1410 can deliver reducing equivalents in proton-coupled electron transfer reactions.

[0192] In some embodiments, the mediator can include a phenazine. In some embodiments, the mediator can be configured to undergo proton-coupled electron transfer in an aqueous medium. In some embodiments, the mediator can be configured to reduce a nitrogen-containing compound to at least partially form a reduced nitrogen-containing product.

[0193] In some embodiments, the phenazine can include a cyano group on the first benzene ring, and one or more hydroxyl groups on the second benzene ring. In some embodiments, the mediator can include formula (I) or a salt thereof. Formula (I) is also referred to as pz3. The formula (I) has a structure:

[0194] In some embodiments, the phenazine can include a sulfonic acid group on the first benzene and at least one of a hydroxyl group or an ether linked alkyl sulfonic acid side chain on the second benzene ring. In some embodiments, the mediator can include formula (II) ora salt thereof. Formula (II) is also referred to as pz5. The formula (II) has a structure:

[0195] In some embodiments, the phenazine can include a sulfonic acid group on the first benzene ring, and one or more ether linked alkyl sulfonic acid side chains on the second benzene ring. In some embodiments, the mediator can include formula (III) or a salt thereof. Formula (III) is also referred to as pz6. The formula (III) has a structure:

[0196] In some embodiments, the phenazine can include at least two hydroxyl groups on at least one of the first benzene ring or the second benzene ring. In some embodiments, the mediator canPATENT Attorney Docket No. 51198-069WO3 include formula (IV) or a salt thereof. Formula (IV) is also referred to as pz4. The formula (IV) has a structure:

[0197] In some embodiments, the phenazine can include two hydroxyl groups on the first benzene ring and one or more methoxy groups on the second benzene ring. In some embodiments, the mediator can include formula (V) or a salt thereof. Formula (V) is also referred to as pz2. The formula (V) has a structure:

[0198] In some embodiments, the phenazine can include a sulfonic acid group on the benzene ring, and at least two hydroxyl groups on the second benzene ring. In some embodiments, the mediator can include formula (VI) or a salt thereof. Formula (VI) is also referred to as pz1. The formula (VI) has a structure:

[0199] In some embodiments, the mediator can have a capacity fade rate, expressed as a percentage of decrease in capacity per cycle or per unit time. In some embodiments, fade rate can refer to the rate of loss of electrochemical capacity, efficiency, and / or activity of a mediator over successive charge-discharge and / or reaction cycles.

[0200] In some embodiments, the mediator can have a capacity fade rate of the mediator in a range of about 0.01 vol% to about 1 vol% per day, inclusive of all values and ranges in between. In some embodiments, the capacity fade rate of the mediator can be at least about 0.01 vol%, at least about 0.02 vol%, at least about 0.03 vol%, at least about 0.04 vol%, at least about 0.05 vol%, at least about 0.1 vol%, at least about 0.2 vol%, at least about 0.3 vol%, at least about 0.3 vol%, at least about 0.4 vol%, at least about 0.4 vol%, at least about 0.5 vol%, at least about 0.6 vol%, at least about 0.7 vol%, at least about 0.8 vol%, at least about 0.9 vol%, or at least about 1 vol%, inclusive of all values and ranges in between. In some embodiments, the capacity fade rate of the mediator can be no more than about 1 vol%, no more than about 0.9 vol%, no more than about 0.8 vol%, no more than about 0.7 vol%, no more than about 0.6 vol%, no more than about 0.5 vol%, no more than about 0.4 vol%, no more than about 0.3 vol%, no more than about 0.2 vol%, no more than about 0.1 vol%, no more than about 0.05 vol%, no more than about 0.04 vol%, no more than about 0.03 vol%, no more than about 0.02 vol%, no more than about 0.01 vol%, inclusive of all values and ranges in between.Combinations of the above- referenced capacity fade rate of the mediator are also possible (e.g., atPATENT Attorney Docket No. 51198-069WO3 least about 0.01 vol%, and no more than about 1 vol%, or at least about 0.1 vol% and no more than about 0.5 vol%), inclusive of all values and ranges therebetween. In some embodiments, the capacity fade rate of the mediator can be about 0.01 vol%, about 0.02 vol%, about 0.03 vol%, about 0.04 vol%, about 0.05 vol%, about 0.1 vol%, about 0.2 vol%, about 0.3 vol%, about 0.4 vol%, about 0.5 vol%, about 0.6 vol%, about 0.7 vol%, about 0.8 vol%, about 0.9 vol%, or about 1 vol%, inclusive of all values and ranges therebetween.

[0201] In some embodiments, the mediator can have a coulombic efficiency of at least about 90%. In some embodiments, the mediator can have a coulombic efficiency of at least about 91% at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, inclusive of all values and ranges in between.

[0202] In some embodiments, the mediator can have a standard redox potential of about -2 V to about 2 V, inclusive of all values and ranges in between. In some embodiments, the mediator can have a standard redox potential of about -2 V to about -0.1 V, inclusive of all values and ranges in between. In some embodiments, the standard redox potential of the mediator can be at least about -2 V, at least about -0.99 V, at least about -0.95 V, at least about -0.9 V, at least about -0.85 V, at least about -0.8 V, at least about -0.75 V, at least about -0.7 V, at least about -0.65 V, at least about -0.6 V, at least about -0.55 V, at least about -0.5 V, at least about -0.45 V, at least about -0.4 V, at least about -0.35 V, at least about -0.3 V, at least about -0.2 V, or at least about -0.1 V, inclusive of all values and ranges in between. In some embodiments, the standard redox potential of the mediator can be no more than about -0.1 V, no more than about -0.2 V, no more than about -0.3 v, no more than about -0.4 V, no more than about -0.45 V, no more than about -0.5 V, no more than about -0.55 V, no more than about -0.6 V, no more than about -0.65 V, no more than about -0.7 V, no more than about -0.75 V, no more than about -0.8 V, no more than about -0.85 V, no more than about -0.9 V, no more than about -0.95 V, or no more than about -0.99 V, or no more than about -2 V, inclusive of all values and ranges in between. Combinations of the above-referenced standard redox potential of the mediator are also possible (e.g., at least about -0.99 V, and no more than about -0.45 V, or at least about -0.95 V and no more than about -0.65 V), inclusive of all values and ranges therebetween. In some embodiments, the standard redox potential of the mediator can be about -2 V, about -0.99 V, about -0.95 V, about -0.9 V, about -0.85 V, about -0.8 V, about -0.75 V, about -0.7 V, about -0.65 V, about -0.6 V, about -0.55 V, about -0.45, about -0.4 V, about -0.35 V, about -0.3 V, about -0.25 V, about -0.2 V, about -0.15 V, or about -0.1 V, inclusive of all values and ranges therebetween.

[0203] For example, the mediator pz1 can have a E1 / 2 of about -0.86 V, the mediator, pz2 can have a E1 / 2 of about -0.99 V, the mediator pz3 can have a E1 / 2 of about -0.84, the mediator pz4 can have a E1 / 2 of about -0.8 V, the mediator pz5 can have a E1 / 2 of about -0.67 V, and the mediator pz6 can have a E1 / 2 of about -0.55 V.

[0204] In some embodiments, the method 10 can further include disposing a nitrogen-containing compound in a nonaqueous solution, at 14. In some embodiments, disposing can be referred to as dissolving. In some embodiments, the nonaqueous solution can be referred to as nonaqueousPATENT Attorney Docket No. 51198-069WO3 medium, and / or nonaqueous phase. In some embodiments, the nonaqueous solution can be referred to as organic solution, organic phase, and / or organic medium.

[0205] In some embodiments, the nitrogen-containing compound can include at least one nitro group covalently bonded to an aliphatic, aromatic, heteroaromatic, or other cyclic scaffold. In some embodiments, the nitrogen-containing compound can include a monocyclic or polycyclic aromatic carbocycle, a heteroaromatic ring containing one or more, e.g., 1 to 4, heteroatoms selected from nitrogen, oxygen, or sulfur, or combinations thereof. In some embodiments, the nitrogen-containing compound can include a substituted, e.g., with a nitro or other oxidized nitrogen group, aromatic compound, heteroaromatic compound, or other cyclic compound, e.g., including further substitutions .

[0206] In some embodiments, the nitrogen-containing compound can include one or more additional substituents such as halogens (including fluorine, chlorine, bromine, or iodine), alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, carbonyl-containing groups (including aldehydes, ketones, esters, or amides), sulfonyl-containing groups, cyano groups, amino groups, or combinations thereof. In some embodiments, the nitrogen-containing compound can include one or more halogen substituents positioned ortho, meta, and / or para relative to the nitro group.

[0207] In some embodiments, the nitrogen-containing compound can further include functional groups that are reducible or non-reducible under the reaction conditions, including carbonyl groups, olefins, nitriles, sulfonyl groups, boronate esters, or heterocyclic moieties. In some embodiments, the nitrogen-containing compound includes sterically hindered substituents, including ortho-substituted aromatic rings or fused ring systems.

[0208] In some embodiments, the nitrogen-containing compound can be substituted with one or more functional groups that remain substantially unchanged during the reduction of the nitro group, thereby demonstrating chemo-selectivity of the reduction process.

[0209] In some embodiments, the method 10 can further include contacting the aqueous solution including the reduced organic mediator 1410 and the nonaqueous solution including the nitrogencontaining compound. In some embodiments, contacting the aqueous phase and the nonaqueous phase can be done via an agitating element. In some embodiments, the agitating element can be disposed in a reactor 1100. In some embodiments, the agitating element can be configured to form combined liquids of the aqueous phase and the nonaqueous phase. In some embodiments, agitating the aqueous phase and the nonaqueous phase can allow a reaction to occur between the reduced organic mediator 1410 and the nitrogen-containing compound 1200.

[0210] In some embodiments, the reaction can occur at the interface of the aqueous phase and the nonaqueous phase. In some embodiments, the yield of the reaction can be proportional to the agitating efficiency. In some embodiments, contacting of the aqueous phase and the nonaqueous phase can occur at a volume defined by a reactor section of a reactor. In some embodiments, the volume of the reactor section of the reactor can affect the quality of the contacting and, thereby thePATENT Attorney Docket No. 51198-069WO3 yield of the reaction. In some embodiments, a greater cross-sectional area of the separation section of the reactor can improve the yield of the reaction.

[0211] In some embodiments the reaction at an agitating rate sufficient to achieve droplet sizes of interest for the desirable reaction rate. In some embodiments, the reaction can occur at a stirring rate of about 1 ,000 rpm to about 4,000 rpm, inclusive of all values and ranges in between. In some embodiments, the mixing rate can be at least about 1 ,200 rpm, at least about 1 ,400 rpm, at least about 1 ,600 rpm, at least about 1 ,800 rpm, at least about 1 ,900 rpm, at least about 2,000 rpm, at least about 2,100 rpm, at least about 2,200 rpm, at least about 2,300 rpm, at least about 2,400 rpm, at least about 2,500 rpm, at least about 2,600 rpm, at least about 2,700 rpm, at least about 2,800 rpm, at least about 2,900 rpm, at least about 3,000 rpm, at least about 3,100 rpm, at least about 3,200 rpm, at least about 3,300 rpm, at least about 3,400 rpm, at least about 3,500 rpm, at least about 3,600 rpm, at least about 3,700 rpm, at least about 3,800 rpm, at least about 3,900 rpm, or at least about 4,000 rpm, inclusive of all values and ranges in between. In some embodiments, the agitating rate can be no more than about 4,000 rpm, no more than about 3,900 rpm, no more than about 3,800 rpm, no more than about 3,700 rpm, no more than about 3,600 rpm, no more than about 3,500 rpm, no more than about 3,400 rpm, no more than about 3,300 rpm, no more than about 3,200 rpm, no more than about 3,100 rpm, no more than about 3,000 rpm, no more than about 2,800 rpm, no more than about 2,700 rpm, no more than about 2,600 rpm, no more than about 2,500 rpm, no more than about 2,400 rpm, no more than about 2,300 rpm, no more than about 2,200 rpm, no more than about 2,000 rpm, no more than about 1 ,900 rpm, no more than about 1 ,800 rpm, no more than about 1 ,600 rpm, no more than about 1 ,400 rpm, no more than about 1 ,200 rpm, or no more than about 1 ,000 rpm, inclusive of all values and ranges in between. Combinations of the above-referenced agitating rates are also possible (e.g., at least about 1 ,000 rpm, and no more than about 4,000 rpm, or at least about 2,000 rpm and no more than about 3,000 rpm), inclusive of all values and ranges therebetween. In some embodiments, the agitating rate can be about 1 ,000 rpm, about 1 ,200 rpm, about 1 ,400 rpm, about 1 ,600 rpm, about 1 ,800 rpm, about 2,000 rpm, about 2,200 rpm, about 2,400 rpm, about 2,600 rpm, about 2,800 rpm, about 3,000 rpm, about 3,200 rpm, about 3,400 rpm, about 3,600 rpm, about 3,800 rpm, or about 4,000 rpm, inclusive of all values and ranges therebetween.

[0212] In some embodiments, the duration of the contacting for the redox reaction can be in a range of about 1 hour to about 24 hours, inclusive of all values and ranges in between. In some embodiments, the duration of the contacting for the reaction can be at least about 1 min, at least about 10 min, at least about 30 min, at least about 1 hr, at least about 2 hrs, at least about 3 hrs, at least about 4 hrs, at least about 5 hrs, at least about 6 hrs, at least about 7 hrs, at least about 8 hrs, at least about 9 hrs, at least about 10 hrs, at least about 12 hrs, at least about 14 hrs, at least about 16 hrs, at least about 18 hrs, at least about 20 hrs, at least about 22 hrs, or at least about 24 hrs, inclusive of all values and ranges in between. In some embodiments, the duration of the contacting for the reaction can be no more than about 24 hrs, no more than about 22 hrs, no more than about 20 hrs, no more than about 18 hrs, no more than about 16 hrs, no more than about 14 hrs, no more than about 12 hrs, no more than about 10 hrs, no more than about 9 hrs, no more than about 8 hrs, noPATENT Attorney Docket No. 51198-069WO3 more than about 7 hrs, no more than about 6 hrs, no more than about 7 hrs, no more than about 6 hrs, no more than about 5 hrs, no more than about 4 hrs, no more than about 3 hrs, no more than about 2 hrs, no more than about 1 hrs, no more than about 30 min, no more than about 10 min, or no more than about 1 min, inclusive of all values and ranges in between. Combinations of the abovereferenced duration of the contacting for the reaction are also possible (e.g., at least about 1 min, and no more than about 24 hrs, or at least about 4 hrs and no more than about 8 hrs), inclusive of all values and ranges therebetween. In some embodiments, the duration of the contacting for the reaction can be about 1 min, about 10 min, about 30 min, about 1 hr, about 2 hrs, about 3 hrs, about 4 hrs, about 5 hrs, about 6 hrs, about 7 hrs, about 8 hrs, about 9 hrs, about 10 hrs, about 12 hrs, about 14 hrs, about 16 hrs, about 18 hrs, about 20 hrs, about 22 hrs, or about 24 hrs, inclusive of all values and ranges therebetween.

[0213] In some embodiments, the volumetric ratio of the aqueous solution to the nonaqueous solution can be in range of about 1 :1 to about 3:1. In some embodiments, the volumetric ratio of the aqueous solution to the nonaqueous solution can be at least about 1 :1 , at least about 1.2:1 , at least about 1.4:1 , at least about 1.6:1 , at least about 1.8:1 , at least about 2:1 , at least about 2.2:1 , at least about 2.4:1 , at least about 2.6:1 , at least about 2.8:1 , or at least about 3:1 , inclusive of all values and ranges in between. In some embodiments, the volumetric ratio of the aqueous solution and the nonaqueous solution can be no more than about 3:1 , no more than about 2.8:1 , no more than about 2.6:1 , no more than about 2.4:1 , no more than about 2.2:1 , no more than about 2:1 , no more than about 1.8:1 , no more than about 1.6:1 , no more than about 1.4:1 , no more than about 1.2:1 , or no more than about 1 :1 , inclusive of all values and ranges in between. Combinations of the abovereferenced volumetric ratio of the aqueous solution to the nonaqueous solution are also possible (e.g., at least about 1 :1 , and no more than about 3:1 , or at least about 1.5:1 and no more than about 2:1), inclusive of all values and ranges therebetween. In some embodiments, the volumetric ratio of the aqueous solution to the nonaqueous solution can be about 1 :1 , about 1.2:1 , about 1.4:1 , about 1 .6:1 , about 1.8:1 , about 2:1 , about 2.2:1 , about 2.4:1 , about 2.6:1 , about 2.8:1 , or about 3:1 , inclusive of all values and ranges therebetween.

[0214] In some embodiments, the volumetric ratio can be flipped. In some embodiments, the volumetric ratio of the nonaqueous solution to the aqueous solution can be in range of about 1 :1 to about 3:1 . In some embodiments, the volumetric ratio of the nonaqueous solution to the aqueous solution can be at least about 1 :1 , at least about 1.2:1 , at least about 1.4:1 , at least about 1.6:1 , at least about 1.8:1 , at least about 2:1 , at least about 2.2:1 , at least about 2.4:1 , at least about 2.6:1 , at least about 2.8:1 , or at least about 3:1 , inclusive of all values and ranges in between. In some embodiments, the volumetric ratio of the nonaqueous solution to the aqueous solution can be no more than about 3:1 , no more than about 2.8:1 , no more than about 2.6:1 , no more than about 2.4:1 , no more than about 2.2:1 , no more than about 2:1 , no more than about 1.8:1 , no more than about 1.6:1 , no more than about 1.4:1 , no more than about 1.2:1 , or no more than about 1 :1 , inclusive of all values and ranges in between. Combinations of the above-referenced volumetric ratio of the nonaqueous solution to the aqueous solution are also possible (e.g., at least about 1 :1 , and no morePATENT Attorney Docket No. 51198-069WO3 than about 3:1 , or at least about 1.5:1 and no more than about 2:1), inclusive of all values and ranges therebetween. In some embodiments, the volumetric ratio of the nonaqueous solution to the aqueous solution can be about 1:1, about 1.2:1 , about 1.4:1 , about 1.6:1 , about 1.8:1 , about 2:1 , about 2.2:1 , about 2.4:1 , about 2.6:1 , about 2.8:1 , or about 3:1 , inclusive of all values and ranges therebetween.

[0215] In some embodiments, a concentration of the reduced organic mediator 1410 in the aqueous solution can be in a range of about 5 mol% to about 20 mol%, inclusive of all values and ranges in between. In some embodiments, the concentration of the reduced organic mediator 1410 can be at least about 5 mol%, at least about 6 mol%, at least about 7 mol%, at least about 8 mol%, at least about 9 mol%, at least about 10 mol%, at least about 11 mol%, at least about 12 mol%, at least about 13 mol%, at least about 14 mol%, at least about 15 mol%, at least about 16 mol%, at least about 17 mol%, at least about 18 mol%, at least about 19 mol%, or at least about 20 mol%, inclusive of all values and ranges in between. In some embodiments, the concentration of the reduced organic mediator 1410 can be no more than about 20 mol%, no more than about 19 mol%, no more than about 18 mol%, no more than about 17 mol%, no more than about 16 mol%, no more than about 15 mol%, no more than about 14 mol%, no more than about 13 mol%, no more than about 12 mol%, no more than about 11 mol%, no more than about 10 mol%, no more than about 9 mol%, no more than about 8 mol%, no more than about 7 mol%, no more than about 6 mol%, or no more than about 5 mol%, inclusive of all values and ranges in between. Combinations of the above -referenced concentration of the reduced organic mediator 1410 are also possible (e.g., at least about 5 mol%, and no more than about 20 mol%, or at least about 10 mol% and no more than about 14 mol%), inclusive of all values and ranges therebetween. In some embodiments, the concentration of the reduced organic mediator 1410 can be about 5 mol%, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, about 10 mol%, about 11 mol%, about 12 mol%, about 13 mol%, about 14 mol%, about 15 mol%, about 16 mol%, about 17 mol%, about 18 mol%, about 19 mol%, or about 20 mol%, inclusive of all values and ranges therebetween.

[0216] In some embodiments, the method 10 can further include allowing a redox reaction to occur between the reduced organic mediator 1410 and the nitrogen-containing compound 1200 to form the reduced nitrogen-containing product and an oxidized organic mediator, at 18. In some embodiments, the reduced nitrogen-containing product can include at least one of partially or fully reduced nitrogencontaining product. In some embodiments, the partially reduced nitrogen-containing product can include a hydroxyl amine (-NHOH), an azoxy (-N=N+(O)), ora nitroso (-NO) compound. In some embodiments, the fully reduced nitrogen-containing product can include an amine (-NH2). In some embodiments, the oxidized organic mediator 1410 can include a partially or fully reduced organic mediator 1410.

[0217] In some embodiments, the combined liquids of the aqueous phase and the nonaqueous phase can enter a separation section. In some embodiments, the aqueous phase and the nonaqueous phase can separate over a period of time. In some embodiments, the separation time depends on the geometry of the separation section, the agitating rate, the agitating duration, aPATENT Attorney Docket No. 51198-069WO3 concentration of the mediator, and / or a concentration of the nitrogen-containing compound. In some embodiments, the separation can occur via density differences, interfacial tension, and / or gravity.

[0218] In some embodiments, the method 10 can further include recycling at least a portion of unreacted or partially reacted nitrogen-containing compound to the reactor, at 20. In some embodiments, recycling can be referred to as communicating. In some embodiments, the unreacted or partially reacted nitrogen-containing compound can be recycled in a closed loop for sufficient number of cycles to achieve full reduction of the nitrogen-containing compound to a nitrogencontaining product, e.g., amine.

[0219] In some embodiments, the method 10 can further include recycling at least a portion of the oxidized organic mediator to the electrochemical flow cell 1500, at 22. In some embodiments, the mediator 1400 can be recycled in a closed loop for at least about 200 cycles, at least about 250 cycles, at least about 300 cycles, at least about 350 cycles, at least about 400 cycles, at least about 450 cycles, at least about 500 cycles, at least about 550 cycles, or at least about 600 cycles, inclusive of all values and ranges in between.

[0220] In some embodiments, at least a portion of the reduced nitrogen-containing product 1300 can be collected, at 24. In some embodiments, the reduced nitrogen-containing product 1300 can be subjected to further processing, for example, filtration, chromatography, extraction, etc.

[0221] FIG. 2B illustrates an exemplary biphasic hydrogenation system, including its advantages, according to the methods, systems, and compounds described herein. In some embodiments, the system can include an aqueous phase (aq) and an immiscible organic phase (org) separated by a membrane (e.g., ion-selective membrane). The membrane enables ionic conductivity while separating the negolyte and posolyte. Use of a biphasic system inhibits electrode fouling and passivation. In some embodiments, the electrochemical flow cell of the biphasic hydrogenation system can offer advantages including high current densities, well-developed membrane technology, and / or potentially productive anodic reaction. SM refers to the nitrogen-containing compound, and Pdt refers to the reduced nitrogen-containing product.

[0222] In some embodiments, on the anodic side, water oxidation can occur generating oxygen and protons. In some embodiments, the protons and electrons are utilized in the cathodic transformation of a nitrogen-containing compound, for example, nitroaromatic or aliphatic substrates, (Ar-NO2or Alk-NO2) to their corresponding amines (Ar-NH2or Alk-NH2) via interfacial proton coupled electron transfer (PCET). This process is metal-free, avoiding transition-metal catalysts, and is compatible with both flow-mode and batch-mode synthetic workflows. FIG. 2B further highlights mediator tuning, in which redox mediators dissolved in the aqueous phase facilitate electron transfer across the interface to substrates in the organic phase. Mediator selection and modular tuning enable control of interfacial chemistry, mediator stability, and chemo-selectivity.PATENT Attorney Docket No. 51198-069WO3

[0223] FIG. 3A is a schematic of a continuous flow system 3000 including an electrochemical flow cell and a reactor / separator. As described, the system can operate in a continuous flow mode. In some embodiments, the system 3000 can be referred to as a continuous flow biphasic reduction system. In some embodiments, the components of the system 3000 can be substantially similar to the system 1000. Therefore, certain aspects of the system 3000 are not described in further detail, herein. Flow systems as described herein further include conduits, tubing, fittings, and any other connection elements to connect different elements of the flow system.

[0224] In some embodiments, the oxidized mediator 3400 can be reduced in the electrochemical cell 3500. In some embodiments, the electrochemical flow cell 3500 can include a single or a stack of electrochemical flow cells. In some embodiments, the electrochemical flow cell 3500 can include at least an electrode, e.g., including a carbon-based material, such as graphite, to facilitate reversible redox reactions of the mediator 3400. In some embodiments, the electrochemical flow cell 3500 can include cathode 3508 and anode 3507. In some embodiments, water, alcohol, an inorganic species, or an organic species can be oxidized in the anode 3507. In some embodiments, protons can transfer from the posolyte 3506 through the membrane 3502 to the negolyte 3504 and form the reduced organic mediator 3410.

[0225] In some embodiments, the reduced organic mediator 3410 can be partially or fully hydrogenated. The partially hydrogenated mediator can include one electron and one proton, also referred to as a semi-reduced, radical, and / or hydrogenated intermediate, e.g., shown as Pz-H. In some embodiments, the fully hydrogenated mediator, e.g., a dihydrophenazine, can include two electrons and two protons, e.g., shown as Pz-Fh In some embodiments, the reduced organic mediator 3410 can deliver reducing equivalents in proton-coupled electron transfer reactions.

[0226] In some embodiments, an inlet can be fluidically coupled to communicate a mediator containing electrolyte 3400 (e.g., negolyte) into the electrochemical flow cell 3500. In some embodiments, an outlet can be fluidically coupled to the electrochemical flow cell 3500 to remove the negolyte after reduction of the oxidized organic mediator 3400 to the reduced organic mediator 3410.

[0227] In some embodiments, the reduced organic mediator 3410 can be dissolved in an aqueous medium (or solution). In some embodiments, the aqueous medium including the reduced organic mediator 3410 can be introduced into the reactor / separator 3100. In some embodiments, the reduced organic mediator 3410 included in the aqueous medium can be combined with immiscible (or nonaqueous) medium including the nitrogen-containing compound 3200, e.g., shown as RNO2. In some embodiments, a reaction can occur via contacting the aqueous medium and the nonaqueous medium with stirring. In some embodiments, following the hydrogenation (or reduction), the oxidized organic mediator 3600 and one or more partially or fully reduced nitrogen-containing compounds 3300 are formed. In some embodiments, the reduced organic mediator 3410 and / or unreacted or partially reacted nitrogen-containing compound 3200 can be recycled in a closed-loop circuit. Further detail about the reactor / separator 3100 will be described in FIG. 3B.PATENT Attorney Docket No. 51198-069WO3

[0228] FIG. 3B is a schematic diagram of a reactor 3100 for use with the present invention. In some embodiments, the reactor 3100 can include an agitating section 3130, and a separation section 3140. In some embodiments, the reactor 3100 can operate in a recirculation flow and / or continuous flow. In some embodiments, the reactor 3100 can include multiple stages with multiple agitating sections 3130 and separation sections 3140 located at alternating ends of each stage.

[0229] In some embodiments, the reactor 3100 can include a plurality of agitating sections 3130. In some embodiments, agitation and separation can be implemented in multiple steps. In some embodiments, the reactor 3100 can include a dividing element 3112, configured to split the reactor 3100 into the agitating section 3130 and the separation section 3140.

[0230] In some embodiments, the agitating section 3130 can include an aqueous phase inlet 3102, configured to communicate the reduced organic mediator from the electrochemical flow cell to the reactor 3100. In some embodiments, the agitating section can include a nonaqueous phase inlet 3124, configured to communicate the nitrogen-containing compound to the reactor 3100. In some embodiments, the aqueous phase and the nonaqueous phase are agitated via agitating element 3104, e.g., a stirrer. In some embodiments, the agitating element 3104 can be disposed in the agitating section 3130 of the reactor 3100. In some embodiments, the agitating element 3104 can be a mechanical agitator, a static mixer, and / or a jet or eductor. In some embodiments, the agitating element 3104 can include a shaft and an impeller / paddle. In some embodiments, the agitating element 3100 can agitate the phases via ultrasonic waves and / or vibration.

[0231] In some embodiments, agitating the aqueous phase and the nonaqueous phase can form combined liquids 3108. In some embodiments, the combined liquids 3108 can flow over the dividing element 3112 to enter the separation section 3140. In some embodiments, the separation section 3140 can separate the phases via density differences, interfacial tension, and / or gravity. In some embodiments, phase separation can occur via static decantation. In some embodiments, the separation section 3140 can be configured to allow at least partial separation of the combined liquids 3108 into the aqueous phase 3114 and the nonaqueous phase 3116. In some embodiments, the separation section can include flow control devices, such as pumps, valves, and / or passive flow paths. In some embodiments, the flow of the combined liquids 3108, the aqueous phase 3114, and the nonaqueous phase 3116 can be configured to be co-current, counter-current, and / or cross-flow. Although shown with the aqueous phase 3114 at the top of the separation section, the nonaqueous phase 3116 may be at the top if it is less dense than the aqueous phase.

[0232] In some embodiments, the separation section 3140 can include coalescence plates 3122a, 3122b, and 3122c (collectively referred to as 3122). In some embodiments, coalescence plates 3122 can facilitate separation of the combined liquids 3108 into two phases, including the aqueous phase 3114 and nonaqueous phase 3116. In some embodiments, the aqueous phase 3114 and the nonaqueous phase 3116 can be referred to as recovered aqueous phase and recovered nonaqueous phase. In some embodiments, the aqueous phase 3114 can also include an amount of thePATENT Attorney Docket No. 51198-069WO3 nonaqueous solution (or medium). In some embodiments, the nonaqueous phase 3116 can include an amount of the aqueous solution (or medium).

[0233] In some embodiments, the cross-sectional area of the separation section 3140 can affect the purity of the aqueous phase 3114 and the nonaqueous phase 3116. The combined liquids 3108 includes a dispersion of droplets of nonaqueous phase and aqueous phase. Along the width Wi of the separation section 3140, droplets of the aqueous phase coalesce to eventually form the aqueous phase 3114 and droplets of the nonaqueous phase coalesce to eventually form the nonaqueous phase 3116. A larger cross-sectional area can increase the residence time, allowing droplets to rise or settle under gravity, and coalesce to eventually form the aqueous phase 3114 and the nonaqueous phase 3116.

[0234] In some embodiments, the reactor 3100 can further include an aqueous phase outlet 3126. In some embodiments, the reactor 3100 can include a plurality of aqueous phase outlets 3126. In some embodiments, the aqueous phase containing the oxidized organic mediator 3600 (also referred to as oxidized mediator) can be removed from the aqueous phase outlet 3126. In some embodiments, the reactor 3100 can further include a nonaqueous phase outlet 3120. In some embodiments, the reactor 3100 can include a plurality of nonaqueous phase outlets 3120. In some embodiments, the partially or fully reduced nitrogen-containing compounds 3300 can be removed from the nonaqueous phase outlet 3120. In some embodiments, the nonaqueous phase outlet 3120 or aqueous phase outlet 3126 can be disposed at a height, Hi, adjusted based on the relative volume and densities of the aqueous phase 3114 and nonaqueous phase 3116.

[0235] In some embodiments, the reactor 3100 can further include a baffle 3110. In some embodiments, the baffle can control the fluid flow. In some embodiments, the baffle 3110 can be configured to inhibit vortex formation, make the flow patterns more uniform, and / or increase the residence time. In some embodiments, the baffle 3110 can promote phase separation and help droplet coalesce. In some embodiments, the baffle 3110 can guide the flow toward outlets. In some embodiments, the baffle 3110 can include a vertical plate proximate to the agitating element 3104.

[0236] In some embodiments, the reactor 3100 can further include an aqueous phase weir 3118. In some embodiments, the aqueous phase weir 3118 can act as a barrier proximate to the nonaqueous outlet 3120. In some embodiments, the aqueous phase weir 3118 can be configured to control the flow of the aqueous phase 3114. In some embodiments, the aqueous phase weir 3118 can inhibit overflow of the non- aqueous phase 3116 to the aqueous phase 3114.

[0237] In some embodiments, a volume of the separation section 3140 can depend on the density, viscosity, and coalescence properties of the aqueous phase and the nonaqueous phase. In some embodiments, the volume of the separation section 3140 is greater than the volume of the agitating section 3130. Greater volume of the separation section 3140 can provide sufficient residence time for droplet coalescence and phase separation. In some embodiments, the separation section 3140 can be about 2 times to about 5 times bigger than the agitating section 3130, inclusive of all values andPATENT Attorney Docket No. 51198-069WO3 ranges in between. In some embodiments, the separation section 3140 can be at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, at least about 4 times, or at least about 5 times bigger than the agitating section 3130, inclusive of all values and ranges in between. In some embodiments, the separation section 3140 can be no more than about 5 times, no more than about 4.5 times, no more than about 4 times, no more than about 3.5 times, no more than about 3 times, no more than about 2.5 times, or no more than about 2 times bigger than the agitating section 3130, inclusive of all values and ranges in between. Combinations of the above -referenced ratios are also possible (e.g., at least about two times, and no more than about 5 times, or at least about 2.5 times and no more than about 5 times), inclusive of all values and ranges therebetween. In some embodiments, the separation section 3140 can be about 2 times, about 2.5 times, about 3 times, about 3.5 times, about 4 times, about 4.5 times, or about 5 times bigger than the agitating section 3130, inclusive of all values and ranges therebetween.

[0238] FIG. 4A shows the effect of the geometry of the reactor 4100a, 4100b. The reactors 4100a, 4100b (collectively referred to as 4100) are a prototype of the reactor 3100. The reactor 4100 includes an agitating section 4130, and a separation section 4140, an inlet 4102, a connecting conduit 4150, a separation cylinder 4150, an aqueous phase outlet 4126, and a nonaqueous phase outlet 4116. The nonaqueous phase including the nitrogen-containing compound is dispensed to the agitating section 4130 via an opening of the agitating section 4130. The inlet 4102 is used to communicate the aqueous phase including the reduced organic mediator into the reactor 4100. Agitating the aqueous phase including the reduced organic mediator and the nonaqueous phase including the nitrogencontaining compound occurs in the agitating section 4130.

[0239] The separation section 4140 includes the connecting conduit 4150 and the separation cylinder 4150. The phase separation initiates in the connecting conduit 4150. The connecting conduit 4150 transfers the combined liquids of the aqueous phase and the nonaqueous phase from the agitating section 4130 to the separation cylinder 4150. The aqueous phase is removed from the outlet 4126. The nonaqueous phase can be removed from the outlet 4116. The aqueous phase includes substantially the reduced organic mediator in water. The nonaqueous phase includes substantially the partially or fully reduced nitrogen-containing compounds.

[0240] The agitating section 4130 of the reactor 4100a has a diameter of about 4.5 cm. The agitating section 4130 of the reactor 4100b has a diameter of about 2.5 cm. The reactor 4100a achieved current of about 100 mA compared to a current of about 30 mA for the reactor 4100b. This can be due to greater cross-section of the agitating section 4130 in the reactor 4100a versus the reactor 4100b. Greater cross-section can improve agitation and thereby the interfacial area between the aqueous phase and the nonaqueous phase.

[0241] FIG. 4B shows a plot of current versus time for different geometries and flow rates. The plot includes curve C-4100a, corresponding to the reactor 4100a at a flow rate of 40 ml / min, curve C-4100b, corresponding to the reactor 4100b at a flow rate of 40 ml / min, and curve C-4100b’ corresponding to the reactor 4100b at a flow rate of 80 ml / min A total of 30 mL solvent (1 :1 volumetricPATENT Attorney Docket No. 51198-069WO3 ratio of aqueous: nonaqueous), with 10 mol% of the mediator, pz5, in the aqueous phase and 3.4 mmol nitrobenzene in the nonaqueous phase (chloroform phase). The structure of pz5 is shown in FIG. 5A. The electrochemical flow cell was operated under a constant current-constant voltage protocol with a constant voltage of 1.65 V and constant current of 100 mA, until the current dropped to 5 mA / cm2.

[0242] The results show that the reactor 4100a with a greater cross-sectional area produces a higher current output (100mA) compared to the reactor 4100b. This can be due to better agitation with a greater cross-sectional area of the reactor 4100. In addition, the curve C- 4100b’ shows the current profile overtime for a reactor 4100b at a higher flow rate (80 ml / min). As shown, increasing the cross-sectional area of the reactor can improve the current more significantly. In addition, the reactor 4100a, having a greater cross-sectional area, yields 91% aniline with a faradaic efficiency of about 87%.

[0243] The inset plots in FIG. 4B, labelled as M-4100a and M-4100b, show the progress of the phase separation for reactors 4100a and 4100b, respectively. The index a refers to the reactor with greater cross-sectional area. The index b refers to the reactor with smaller cross-sectional area. Agitating the aqueous solution and the nonaqueous solution forms combined liquids. Once the combined liquids 4108a, 4108b from the agitating section 4130a, 4130b, enters the connecting conduit 4150a, 4150b, the phase separation starts. Two phases including the aqueous phase 4114a, 4114b and the nonaqueous phase 4116a, 4116b are formed. The cross section of the aqueous phase 4114a, 4114b and the nonaqueous phase 4116a, 4116b gradually expand along the length of the connecting conduit 4150a, 4150b. Comparing M-4100a and M-4100b, it can be implied that a greater cross sectional area, results in better agitation, which can subsequently result in longer phase separation to the aqueous phase 4114 and nonaqueous phase 4116. Therefore, phase separation ends at a longer distance over the connecting conduit 4150.

[0244] FIG. 5A illustrates hydrogenation reaction of phenazine, pz, to the reduced phenazine, pz-H2. In some embodiments, phenazine can be a mediator. Phenazine refers to a structure including two fused benzene rings bridged by a diazine ring. The phenazine can be substituted at one or more positions on the benzene rings. In some embodiments, the substitution can be selected to modify solubility, redox potential, and proton coupled electron transfer.

[0245] In some embodiments, reduction of a phenazine can occur in an electrochemical flow cell. In some embodiments, hydrogenation reaction can be referred to as reduction. In some embodiments, a phenazine can function as POET mediators (also referred to as mediator). In some embodiments, a phenazine can uptake one or more electrons and one or more protons.

[0246] In some embodiments, pz can be fully reduced to pz-FF. In some embodiments, pz can be partially reduced to pz-H. In some embodiments, the reduced organic mediator, for example, pz-FF, can include two electrons and two protons. In some embodiments, the pz-FF can also be referred toPATENT Attorney Docket No. 51198-069WO3 as dihydrophenazine. In some embodiments, the reduced organic mediator, for example, pz-H, can include one electron and one proton.

[0247] FIG. 5B illustrates standard redox potentials of phenazines. Selected phenazines (pz1-pz6) were electrochemically reduced (e.g., charged) in an aqueous flow cell (1 M KCI) according to FIG. 5A. and subsequently transferred in their reduced forms (pz1-H2 to PZ6-H2) to contact an organic solution of the nitrogen-containing compound in a biphasic medium. The biphasic medium can include a reactor. The standard redox potential of phenazines at pH 13 highlights tunability across the series.

[0248] In some embodiments, the phenazines described herein can have a standard redox potential of about -0.55 V to about -0.99 V. In some embodiments, phenazines described herein can offer tunable redox potentials (>400 mV range of E1 / 2). Half-wave potential E1 / 2 is the potential at which the current is halfway between the limiting current and the baseline current at a redox reaction. E1 / 2 determines the driving force for electron transfer between the mediator and the electrode. In some embodiments, phenazines described herein can offer high aqueous solubility (>1 M), rapid charging kinetics, and / or exceptional stability across an extended pH range (fade rates below 0.01 % / day). In some embodiments, the phenazines described herein can be substantially immiscible with a nonaqueous phase.

[0249] In some embodiments, the reduced phenazines can transfer electrons and protons to a nitrogen-containing compound, producing partially reduced nitrogen-containing compounds such as nitroso or hydroxylamine, or fully reduced to an amine compound. In some embodiments, multiple phenazines can be used for reduction of a nitrogen-containing compound. In some embodiments, the phenazine can be selected from the compounds pz1 to pz6 to achieve a desirable yield of redox reaction and desired degree of reduction at the interface of the aqueous solution and the nonaqueous solution. In some embodiments, the phenazine can be selected based on the desired adsorption density. In some embodiments, other mediators can be used with optimization to mediate the process efficiently. In some embodiments, the reduction reaction of phenazine in the electrochemical flow cell can be substantially reversible and stable.

[0250] FIG. 5C illustrates examples of nitrogen-containing compounds successfully reduced / hydrogenated to corresponding amines through the method described, herein. The nitrogencontaining compounds illustrated in FIG. 5C are non-limiting examples. The nitrogen-containing compounds shown in FIG. 5C are capable of undergoing partial or full reduction of the nitro group to form nitrogen-containing products such as nitroso, hydroxylamine, or amine products. In some embodiments, the nitrogen-containing compound can include at least one of hydroxylamine (-NHOH) group, nitroso (-N=O), azoxy species (-N=N+(O )-) group, azo (-N=N- group), and / or hydrazo (-NH-NH- group).

[0251] FIG. 6 is a heatmap summarizing hydrogenation yields for corresponding nitrogen-containing compounds, 4-fluoronitrobenzene, 6250, (2-nitroethyl)benzene 6252, 4-cyanonitrobenzene 6254, and 3-ethynylnitrobenzene 6256. The mediators, pz1 to pz6 were hydrogenated (or reduced) to thePATENT Attorney Docket No. 51198-069WO3 reduced organic mediators pz1-H2 to pz6-H2 in an electrochemical cell. The reduced organic mediator selected from pz1-H2 to pz6-H2 were introduced to a reactor. The biphasic medium was stirred at >1000 rpm for 6 hrs. The biphasic medium was a combination of water as the aqueous phase and chloroform as the nonaqueous phase. The ratio of water to chloroform was about 2:1. The nonaqueous phase included 0.5 mmol of the nitrogen-containing compound at a concentration of 0.167 mM. The aqueous phase included one of pz1-H2 to pz6-H2 at 6 F / mol.

[0252] When a hydrogenated phenazine (pz1-H2) was used as the reduced organic mediator, and 4-fluoronitrobenzene, 6250, and (2-nitroethyl)benzene 6252 were used as the nitrogen-containing compound, fully reduced nitrogen-containing compounds, 4-fluoroaniline and 2-phenethylamine were formed in the organic phase (can also be referred to as the nonaqueous phase) with yields of approximately 91% and 93%, respectively. However, in one embodiment, when a hydrogenated phenazine (pz1-H2) was used as the reduced organic mediator, and 4-cyanonitrobenzene 6254, and 3-ethynylnitrobenzene 6256 were used as the nitrogen-containing compounds, 4-cyano aniline and 3-ethynyl aniline were generated in the organic phase with yields of approximately 20% and 13%, respectively, which is significantly lower than the reduction yields for fluoronitrobenzene, 6250 and (2-nitroethyl)benzene 6252.

[0253] In some embodiments, comparing the efficacy of different phenazines can prove lack of correlation with reduction potential. Therefore, it can be implied that interfacial process is more complex than direct electron transfer, foreshadowing key roles of PCET of the reduced organic mediator and structure-dependent absorption of the mediator. For example, pz2-H2, despite being 130 mV more reducing than pz1-H2, failed to hydrogenate 3-ethynylnitrobenzene. Also, pz4-H2, as an even less reducing mediator (referred to as scaffold), was completely unreactive.

[0254] In some embodiments, attachment of an alkylsulfonate side chain (pz5-H2) can give consistently high yields for aromatic nitro substrates. For example, pz5-H2 can reduce the nitrogencontaining compound, 4-fluoronitrobenzene, 6250, 4-cyanonitrobenzene 6254, and 3-ethynylnitrobenzene 6256 with a high yield of approximately 98%, 94%, 80%, respectively. In some embodiments, substituting a second alkylsulfonate chain on a phenazine (i.e., PZ6-H2) can diminish reactivity. For example, pz6-H2 can reduce the nitrogen-containing compound 4-fluoronitrobenzene, 6250, 4-cyanonitrobenzene 6254, and 3-ethynylnitrobenzene 6256 with a yield of approximately 83%, 30%, 24%, respectively.

[0255] The choice of solvent may significantly influence reactivity. For example, dichlorobenzene and cyclohexane resulted in low yields of aniline, while 2-methyltetrahydrofuran provided yields comparable to those obtained with chloroform. These observations indicate that in addition to reduction potential, factors such as structure, solvent, and ion-dependent adsorption at the liquidliquid interface can play a critical role.

[0256] FIG. 7A shows UV-VIS spectra of oxidized organic mediator (pz5), reduced organic mediator (pz5-H2), and post-reaction mediator. The oxidized mediator (pz5) can be referred to as pz5 at 0%PATENT Attorney Docket No. 51198-069WO3 State of Charge (SOC), and the corresponding curve is labelled as pz50% SOC. The reduced organic mediator (pz5-H2) can be referred to as pz5 at 100% SOC, and the corresponding curve is labelled as pz5100% SOC. The corresponding curve for post-reaction mediator, is labelled as pz5 after complete reaction. In situ spectrophotometry was used to monitor reaction progress of the mediator reduction, and redox reaction between the reduced organic mediator (pz5-H2) and nitrobenzene.

[0257] Ultraviolet-visible (UV-VIS) absorption spectra were measured using an Agilent Cary 60 UV-Vis Spectrophotometer. In situ UV-VIS absorbance spectra were recorded using a DH-2000-BAL light source and Flame spectrometer from Ocean Optics, equipped with optical fiber connectors, a quartz cuvette, and a cuvette holder designed with inlet and outlet ports to facilitate continuous electrolyte flow. The cuvette holder was placed before the flow cell inlet, and the cuvette had a pathlength of 100 pm. All absorbance spectra were taken relative to blank baseline measurements.

[0258] The UV-VIS spectrum of oxidized organic mediator (pz5) or pz5 at 0% SOC overlaps the UV-VIS spectrum of reduced organic mediator (pz5-H2) or pz5 at 100% SOC. Therefore, the UV-VIS spectra did not indicate detectable degradation of the mediator during electrochemical reduction of pz5 and subsequent biphasic reaction with nitrobenzene. Therefore, the mediator exhibited stability during electrochemical reduction and subsequent biphasic reaction, under the tested conditions. Further confirmed with1HNMR spectroscopy, pz5-H2was reoxidized to pz5 during the reaction. Therefore, the mediator demonstrated reversibility, under the tested conditions. Therefore, the lifetime of pz5 is primarily limited by electrochemical stability.

[0259] FIG. 7B shows the absorbance at 460 nm versus time. The reaction progress was monitored by in situ UV-VIS spectroscopy, tracking the increase of the oxidized pz absorption peak at 460 nm. The reaction was conducted in homogeneous aqueous solution to eliminate diffusion limitations that could occur in a biphasic system.

[0260] To extract the kinetic rate constant, initial rate was determined to be 0.004 M / s based on the plotted curve of absorbance at 460 nm versus time (s). The concentration of the reduced organic mediator, pz5-H2, in the aqueous phase was 15 mM. The concentration of nitrobenzene was 1 mM. Therefore, the rate constant was calculated according to the following equation:r0= fc [pzfl2Jo NS]0

[0261] Based on the equation above, the rate constant was calculated as 266.6 1 / (M.s). In order to measure long- term stability, repeated electrochemical cycling can be performed which is shown in FIG. 8.

[0262] FIG. 8 shows electrochemical cycling stability overtime for pz5. The flow cell was assembled with 0.2 M mediator, pz5 in 1 M KOI at a total volume of 6 mL as negolyte and 0.2 M / 0.02 M ferro- / ferricyanide in 1 M KOI at a total volume of 50 mL as posolyte, separated by a NAFION 212® cationexchange membrane. The system was cycled at room temperature using a constant current densityPATENT Attorney Docket No. 51198-069WO3 of 40 mA. cm-2followed by constant-voltage charging (1.45 V) and discharging (0.65 V) at an AVCARB® High conductivity battery application (HCBA) carbon cloth electrode, with a geometric surface area of 5 cm2.

[0263] For further elaboration, the flow cell apparatus was constructed using cell hardware from Fuel Cell Tech (Albuquerque, NM). The flow cell was assembled in a zero-gap configuration, utilizing pyrosealed POCO® graphite flow plates with identical interdigitated flow fields. Each electrode consisted of a single layer of AVCARB® high conductivity battery application (HCBA) carbon cloth, with a geometric surface area of 5 cm2. NAFION 212® was employed as the cation exchange membrane. Electrochemical measurements were conducted using a BIOLOGIC SP-150e®and a GAMRY® Reference 3000 potentiostat. KNF® diaphragm pumps were used to circulate electrolytes through the flow fields and electrodes within the cell stack. A COLE-PARMER® digital gear pump was used for some tests.

[0264] Coulombic efficiency and discharged capacity were measured during redox cycling of the aqueous electrolyte as a proxy for the active mediator concentration. Using pz5 as the capacitylimiting electrolyte, a capacity fade rate of 0.5% per day (0.0% per cycle) over 11 days and 300 cycles was measured which means 0.01% fade rate per cycle. The discharged capacity was in range of about 200 °C to about 230 °C over 11 days. Throughout this period, pz5 maintained a coulombic efficiency exceeding 99.8%, indicative of exceptional reversibility in the aqueous medium.

[0265] FIG. 9A shows a hydrogenation reaction of a nitrogen-containing compound. The compounds were purified by column chromatography or obtained in analytically pure form without the use of chromatography. FIG. 9B shows the chemical structure of hydrogenated pz5 (pz5-H2) and hydrogenated pz1 (pz1-H2). Pz1 and pz5 were selected as mediators for nitroarene and nitroalkane, respectively. FIG.9C shows fully reduced nitrogen-containing products obtained using the disclosed systems and methods.

[0266] In order to produce fully reduced nitrogen-containing compounds (e.g., R-NO2), 0.5 mmol of the nitrogen-containing compound at a concentration of 0.167 M in CHCh was combined with 6F / mol aqueous solution including the reduced phenazine (pz1-H2 or pz5-H2) with a volumetric ratio of H2O / CHCI3 of 2:1. All combined liquids were stirred at a rate greater than 1 ,000 rpm for 6 hours.

[0267] As shown, a broad range of aromatic and heteroaromatic nitrogen-containing compounds, including substituted anilines can be reduced to a fully reduced nitrogen-containing compound (e.g., an amine) via the embodiments described herein. In some embodiments, the substrates can include the nitrogen-containing compounds bearing functional groups that are typically incompatible with metal-catalyzed or metal hydride-based reduction methods. The bar chart summarizes Faradaic efficiencies observed for the selected substrates 1 to 10. Fully reduced nitrogen-containing compounds 1 to 10 were produced using a single batch of a phenazine.PATENT Attorney Docket No. 51198-069WO3

[0268] The results demonstrate high yields and Faradic efficiencies across the nitrogen-containing compounds. A single batch of pz5 was sufficient to produce, compounds 1 to 10 with sequential recharge of pz5 after each batch reaction with high faradaic efficiencies (>90% on average). As illustrated, the disclosed mediators can demonstrate high tolerance and can reduce the nitrogencontaining compounds bearing functional groups that are incompatible with conventional nitro reduction techniques, thereby expanding the accessible chemical space.

[0269] In some embodiments, the methods described herein can be applicable to a broad scope of nitrogen-containing compounds (i.e., substrate) with high chemo-selectivity for reduction of a nitro group in the presence of other functional groups. Such functional groups can include, for example, alkenyl, alkynyl, amino (e.g., primary, secondary, or tertiary amino), aryl amino (e.g., pyridinyl, indolyl, benzoxazolyl, ), halo, aldehyde, ketone, nitrile, amide, sulfide, sulfonyl, boronate ester. The methods described herein can be applicable to nitrogen-containing compounds with steric hindrance such as large o / Yho-substituents, and 5- / 6-membered heterocycles.

[0270] The fully reduced nitrogen-containing products shown in FIG. 9C demonstrate that the oxidation reaction shown in FIG. 9A via the mediators shown in FIG. 9B, can successfully reduce nitrogen-containing compounds bearing groups that might be susceptible to undesirable side reactions in Pd-catalyzed hydrogenations (e.g., alkynes, aryl halides, nitriles, potential catalyst poisons such as sulfides and bipyridines), metal / acid reductions (e.g., indoles, basic heterocycles, aryl alkynes, amides, sulfones), and metal-hydride reductions (e.g., ketones, aldehydes, nitriles, protic functional groups).

[0271] The methods, systems, and components described herein can enable synthesis of pharmaceutically relevant compounds, including several tryptamines and flutamide, a prostate cancer therapeutic. The methods, systems, and components described herein can also provide access to key industrial building blocks, such as 3-fluoro-4-morpholinoaniline, a precursor to the antibiotic linezolid, and 4-chloro-1 ,2-phenylenediamine, a dye manufacturing intermediate.

[0272] FIG. 10A illustrates the hydrogenation reaction of a nitrogen-containing compound, 4-fluoronitrobenzene 6250 (ArNO2), with pz5-H2. The nonaqueous solution of ArNO26250 at a concentration of 80 mM in CHCL3 was combined with 0.15 M pz5-H2 in 1 M KCL at a volumetric ratio of H2O / CHCL3 of 2:1.

[0273] FIG. 10B illustrates the chemical structure of the intermediate compounds of 4-fluoronitrobenzene reduction. The intermediate compounds include 4-fluorophenyl nitroso also referred to as 4-fluornitrosobenzene (i.e., ArNO), 4-fluorphenyl hydroxyl amine also referred to as 4-fluoohydroxylaminebenzene (i.e., ArNHOH), and 4-fluorophenyl azoxy also referred to as 4-fluoro azoxy benzene (i.e., ArN2O). In some embodiments, the reduction of the nitrogen-containing compound can proceed via a direct pathway or indirect pathway. In some embodiments, the nitrogencontaining compound can be reduced through the direct pathway and / or the indirect pathway, depending on solvent, mediator, and / or pH. In some embodiments, the nitrogen-containing compoundPATENT Attorney Docket No. 51198-069WO3 can include the intermediate compounds. In some embodiments, the reduced nitrogen- containing product can include (-NO), (- NHOH), (-N=N+-O ). In some embodiments, the reduced nitrogencontaining product can include at least one of a hydroxyl amine compound, a nitroso compound, and / or an azoxy compound.

[0274] FIG. 10C shows concentration of intermediate compounds overtime during reduction of 4-fluoronitrobenzene tracked by F NMR.

[0275] As shown in FIG. 10D, the detection of the intermediate compounds can be evidence that the nitrogen-containing compounds can reduce through either a direct and / or indirect pathway, depending on solvent, catalyst, and / or pH. In the direct pathway, three sequential 2e_ / 2H+reductions can occur, generating a nitroso intermediate (including -NO group), a hydroxylamine intermediate (including -NHOH group), and the amine / aniline (including -NH2 group) products, respectively. In the indirect pathway, nitroso and hydroxylamine can condense to form an azoxy species (including -N=N+(O )- group) that can be further reduced to azo (including -N=N- group) and hydrazo (including -NH-NH- group) intermediates and finally to aniline.

[0276] All the compounds (e.g., species), associated with both the direct and indirect pathways, were detected as shown by the F NMR in FIG. 10C, indicating that the direct pathway is not exclusively operative. Consumption of the nitroarene starting material occurred rapidly within 2 minutes, accompanied by accumulation of both hydroxylamine and azoxy species. The concentrations of these species decreased after 60 min, while nitrosobenzene formed more slowly and never exceeded approximately 10%.

[0277] The delayed formation of nitrosobenzene can suggest that under these conditions, hydroxylamines may undergo a formal disproportionation, to yield aniline and nitroso species, a process more commonly associated with aqueous inorganic hydroxylamine. Consistent with this hypothesis, monitoring the reaction of pz5-H2 with pure phenylhydroxylamine revealed initial formation of up to 35% azoxybenzene, supporting the possibility of disproportionation.

[0278] In some embodiments, the nitrogen-containing compound reduction to a fully reduced nitrogen-containing product can release two water molecules. In some embodiments, the nitrogencontaining compound reduction to a partially reduced nitrogen-containing product can release one water molecule. In some embodiments, 6 H76e_can transfer from the reduced organic mediator to the nitrogen-containing compound to form a fully reduced nitrogen-containing product (e.g., an amine compound including -NH2).

[0279] Additionally, subjecting 2-(tertbutyl)aniline to the standard reduction conditions yielded almost exclusively hydroxylamine, with 0% yield of aniline. Azoxy intermediate was not detected according to1H NMR analysis. It can suggest that the direct pathway stalls at the intermediate, hydroxylamine, and may proceed via the indirect pathway to aniline. In some embodiments, steric hindrance can impede self-condensation of the 2-tertbutyl substituted intermediates.PATENT Attorney Docket No. 51198-069WO3

[0280] FIG. 10D is a schematic illustration of a direct pathway and an indirect pathway for reduction of nitrogen-containing compounds. In some embodiments, nitro reduction can follow a direct pathway via sequential 2e72H+steps yielding nitroso, hydroxylamine, and ultimately aniline, or an indirect route where nitroso and hydroxylamine intermediates can condense to form azoxybenzene. The azoxy intermediate may undergo further reduction through azo and hydrazo species to reach aniline.

[0281] FIG. 11 is a conceptual potential energy corresponding to an initial stage of reduction reaction between a nitrogen-containing compound, nitroarene and a reduced organic mediator, pz5-H2. The O-H bond has a length of about 1.07 A at the transition state. The redox reaction can include electron transfer (ET), proton transfer (PT), and / or proton coupled electron transfer (POET).

[0282] In the embodiments described herein, direct protonation of nitrobenzene can be highly unfavorable under alkaline conditions (pH 13) of the reduced organic mediator solutions. In addition, the reduction potentials of the nitroaromatic substrates range from -0.6 V to -1.2 V vs. SHE, (as shown in FIG. 5A) can mean that stepwise electron transfer followed by proton transfer (ET-PT) from reduced pz5-H2(-0.67 V vs. SHE) is inaccessible for many substrates. Hence, concerted POET from pz-H2 seems to be indicated as shown in Fig. 12A.

[0283] FIG. 12A is a schematic of proton transfer during the reduction reaction between a nitroarene and pz5-H2. To further interrogate the reaction pathway, density functional theory (DFT) calculations and kinetic isotope effect (KIE) experiments were employed (FIG. 12B-12C).

[0284] FIGS. 12B-12C are kinetic isotope effect analysis for reduction of nitrobenzene / nitrosobenzene. The reaction in dilute homogeneous aqueous system was monitored using UV-VIS spectrophotometry. Absorbance at 460 nm was plotted against time in water and / or deionized water. Kinetic isotope effect (KIE) was measured and calculated by density functional theory (DFT). Without being bound by theory, observation of a kinetic isotope effect may indicate that bond formation or bond cleavage involving the isotopically substituted atom contributes to the ratedetermining step.

[0285] A pronounced KIE was observed for the reduction of nitrobenzene (KIE=2.06), consistent with density functional theory (DFT), indicating a POET transition state (as shown in FIG. 12B). The results confirm the existence of a low-lying ET state with PT as the rate limiting step. For nitrosobenzene (KIE = 3.61) as shown in FIG. 12C, DFT studies suggest the possibility of a more complex mechanism involving pre-equilibrium ET and rate-limiting PT, consistent with the more positive reduction potential of the nitroso species. This model also predicts a KIE in qualitative agreement with experiment. It can be concluded that since POET is involved, reactivity is not expected to scale solely with the mediator reduction potential E1 / 2, and indeed our data shows little correlation with the mediator reduction potential E1 / 2.

[0286] FIG. 13A is a plot of initial reaction rate versus interfacial surface area for hydrogenation reaction of nitrobenzene with a reduced organic mediator, pz5-H2. The reaction rate was evaluated toPATENT Attorney Docket No. 51198-069WO3 determine if the rate-determining reactivity exhibits characteristics similar to an on-water effect. Initial reaction rates were measured by in situ UV-VIS spectroscopy starting from pz5-H2 at a concentration of 15 mM in 1 M KCI as the aqueous phase with a total volume of 10 mL total and nitrobenzene at a concentration of 5 mM in CHCh with a total volume of 5 mL under reduced stirring to preserve a near-planar liquid-liquid interface.

[0287] In the on-water effect, free O-H hydrogen bond donors at the interface facilitate the necessary interactions to achieve catalysis. FIG. 13A shows that the observed reactivity remained unchanged despite the presence of high concentrations of sodium dodecyl sulfate (SDS). SDS is a surfactant known to rapidly form monolayers at the aqueous-organic interface, thereby blocking out the free hydrogen bonding sites. Accordingly, the on-water mechanism was ruled out. In addition, the results do not support mechanisms driven by hydrophobic effects within SDS micelles.

[0288] In certain embodiments, it was considered whether the reaction occurred through steadystate homogeneous partitioning of the reactants into both phases, which would predict a rate proportional to the total bulk concentrations. However, this mechanism was excluded based on experimental data indicating that the reaction velocity was approximately proportional to the interfacial surface area. This conclusion was further supported by in situ spectrophotometric measurements as shown in the inset of FIG. 13A. The spectrophotometric measurements were performed under reduced stirring conditions to maintain a planar phase boundary.

[0289] FIG. 13B is a schematic illustration of interfacial reaction-diffusion model. In certain embodiments, a diffusion-reaction film model, analogous to the analysis of gas-liquid systems may be applied to quantify how the relative rates of diffusion and chemical reaction govern the geometric dependence of reaction rate. The water / chloroform partition coefficient of nitrobenzene is K ArNO2 =0.012, and the solubility of pz5-H2 in chloroform is exceedingly low, preventing reliable measurement of a partition coefficient. Accordingly, the organic phase may be considered kinetically inert, and that the reaction can occur on the aqueous side of the interface.

[0290] In some embodiments, nitrobenzene (NB) in a liquid-liquid system can diffuse from the organic phase (Liquid 1) into the aqueous phase (Liquid 2) and can react with pz-H2:NB + pz-H2-► P

[0291] The second-order rate law is:r = kCNB(x) CPZ(x)

[0292] where r is the reaction rate (mol L1s-1), C,ve( ) and CPZ(x) are the local concentrations of NB and pz-H2(mol L1), and k is the second-order rate constant (L mo1s-1).

[0293] In some embodiments, the model can be used based on the assumption of : 1) steady-state diffusion and reaction, 2) one-dimensional mass transfer normal to the interface, 3) constant filmPATENT Attorney Docket No. 51198-069WO3 thickness, 8, 4) constant diffusivities, DNBand Dpz, 5)instantaneous interfacial equilibrium: CNB(O) = K * CNB, 6) no flux of pz-H2into the organic phase: dCpz / dx = 0 at x=0, 7) pz-H2concentration at the film edge is constant: Cpz(<5) = Cpz,bulk, 8) 2nd order irreversible reaction with governing Equations:

[0294] In some embodiments, boundary conditions can be: 1) At x = 0, 2) CNB(0) = K * CNB, 3) dCpz / dx = 0, 4) At x =6, CPZ(T) = Cpz,bulk, CNB(T) = CNB, bulk. In some embodiments, the definitions include:x71= 6

[0295] In some embodiments, the governing equations can become :>

[0296] where the Hatta number is defined as:Atg = 1:5(1) = 1

[0297] (I) is determined from the solution. The system was solved as a free-end boundary value problem, where the nitrobenzene concentration at the far edge of the film (q = 1) is not prescribed but emerges from the coupled diffusion-reaction dynamics.PATENT Attorney Docket No. 51198-069WO3

[0298] The diffusion coefficient of nitrobenzene, DAFNO2 in water is 8.6 x 106cm2 / s, and the mass transfer coefficient, ki_, for nitrobenzene was found to be 0.001 cm / s. The second-order rate constant k for the key hydrogenation reaction was estimated at 266.6 1 / (M.s). The Hatta number (Ha) combines these parameters into a dimensionless value (5.87) which, when greatly exceeding unity, indicates a mass transport-limited regime. This can indicate that hydrogenation reaction for the model substrate can proceed within a thin diffusion layer at the phase boundary.

[0299] As shown in FIG. 13B, when the reaction time is significantly smaller than the diffusion time, mass transport limited diffusion occurs at a thin interfacial region (reaction time « diffusion time ). As shown in FIG. 13B, the Hatta number (Ha) is greater than about 5. It can be concluded that the hydrogenation reaction for the model substrate under the experimental conditions, can proceed within a thin diffusion layer at the phase boundary. 6 is the thickness of the aqueous-side diffusion boundary layer.

[0300] In some embodiment, the mass transfer of nitrobenzene from chloroform to water was analyzed assuming the film model. The following assumptions are applied: 1) Film Model: Mass transfer occurs through a stagnant film on the aqueous side. 2) Chloroform is pure with NB; resistance is negligible. 3) Interface area remains constant. 4) First-Order Kinetics: Mass transfer rate proportional to (C* - C) 5) Negligible Volume Change 6) The mass flux is described by:N = kLx (C* - C),

[0301] Where N = molar flux (mol / cm2 / s), ki_= liquid-side mass transfer coefficient (cm / s), C* = equilibrium concentration of nitrobenzene in water (mol / cm3), C = concentration in bulk water (mol / cm3). In some embodiment, a material balance on the aqueous phase can be performed:Vaqx dC / dt = a x kLx (C* - C)

[0302] Where Vaq = volume of the aqueous phase (cm3), a = interfacial area (cm2).dC / (C* - C) = (a / Vaq) x kLx dt

[0303] Integrating from C = 0 att = 0to C = C(t) at time t:Zn(l - C(t) / C*) = ~(a / Vaq) x kLx t

[0304] To extract kL experimentally, 4 mL water was added slowly to 120 mM nitrobenzene in 4.0 mL chloroform and stirred at 350 rpm using an 8 mm stir bar. The interfacial area was approximately 5.0 cm2, and aliquots were taken from the aqueous phase overtime for UV-VIS spectroscopy analysis (shown in FIG. 25A-25B).

[0305] This can support that optimizing reactor geometry, flow dynamics, and agitation conditions can enhance reaction rates.PATENT Attorney Docket No. 51198-069WO3

[0306] FIG. 14A is concentration profile of azoxy, pz5, and pz4 at the interface of water and chloroform during the reaction. FIG. 14B is concentration profile of azoxy and pz5 at the interface of water and cyclohexane during the reaction. In some embodiments, the concentration profiles can be deduced from individual surface tension to composition relationships as measured by pendant-drop tensiometry.

[0307] Solvent choice can substantially influence the outcome of the reaction. In some embodiments, solvents such as cyclohexane and 1 ,2-dichlorobenzene can suppress aniline formation and favor azoxybenzene as the major product with trace amount of nitrosobenzene. In contrast, solvents like 2-methyltetrahydrofuran (2-Me-THF) and chloroform promote efficient reduction to aniline. Therefore, the biphasic system described herein can present a solvent-dependent selectivity. In some embodiments, the strong sensitivity to solvent identity can be explained by differences in solvation / desolvation, proton transfer, favorability of dehydration, and / or surface adsorption of the species. In some embodiments, solvent-mediated proton transfer can be insignificant due to the neutral nature of 2-MeTHF and the negligible partitioning of the mediator into the organic phase.

[0308] In certain embodiments, pendant-drop tensiometry may be employed to determine the surface adsorption density (F) of a model catalyst, such as pz5, at various solvent interfaces, thereby providing insight into its interfacial behavior. In some embodiments, pz-5 can exhibit an approximate surface adsorption density of F = (3.8 ±1.0) xio7mol nrr2at the chloroform / water interface, while for the cyclohexane / water interface, F = -(5.3 ±0.8) xio7mol nrr2. The opposite sign of these quantities can suggest qualitative concentration profiles as shown in FIGs. 14A-14B. In some embodiments, a negative (positive) value of F indicates a depletion (accumulation) of the mediator at the interface relative to its bulk concentration. For the azoxybenzene intermediate, F changes from-(1.0 + 1.1) x 10~7mol ■ m~2at water / chloroform to -(3.0 + 0.6) x 10~7mol • m~2at water / cyclohexane, consistent with weak depletion in chloroform and stronger depletion in cyclohexane. This discrepancy can suggest a mechanistic rationale for the previously observed reactivity. In some embodiments, a water / chloroform system yields up to about 99% aniline. In some embodiments, a cyclohexane / water system yields substantially no aniline and predominantly forms an azoxy intermediate.

[0309] In certain embodiments, surface-tension measurements indicate preferential adsorption of pz5 at a liquid-liquid interface relative to pz4 exhibiting a more thermodynamically reducing character. Consistent with this observation, pz4 exhibits reduced reactivity resulting in substantially no formation of aniline (about 0% yield). In some embodiments, it can indicate that interfacial adsorption of the mediator can play a significant role influencing reaction kinetics. In some embodiments, reaction kinetics can show a lower dependence on redox potential and / or proton-coupled electron transfer capability compared to interfacial adsorption of the mediator.

[0310] FIG. 14B is concentration profile of azoxy and pz5 at the interface of water and cyclohexane during the reaction. In some embodiments, insufficient desorption of reactive intermediates from thePATENT Attorney Docket No. 51198-069WO3 interface may impede completion of the reduction reaction. In some embodiments, insufficient desorption of reactive intermediates can lead to accumulation of partially reduced species.Accordingly, the liquid-liquid interface may function as a controllable catalytic environment, in which mediator structure and solvent section may be adjusted to modulate reaction performance. In some embodiments, surface tension to composition relationship can allow probing of surface adsorption densities. In some embodiments, surface tension to composition relationship can qualitatively describe tendency of accumulation at the interface.

[0311] FIG. 15 shows a plot of current charge profile (curve 1) and cumulative charge profile (curve 2) during hydrogenation of nitrobenzene using the reduced organic mediator, pz5-H2. 3.4 mmol of nitrobenzene was hydrogenated using 10 mol% of pz5. Volumetric ratio of the aqueous phase to the nonaqueous phase was 1:1. Nitrobenzene was dissolved in chloroform as the nonaqueous phase. An augmented agitating chamber was used. The augmented agitating chamber refers to the prototype reactor described in FIG. 4A. The augmented agitating chamber has a greater cross-sectional area which facilitates agitation of the aqueous phase and the nonaqueous phase. The results show 91% yield of aniline with overall faradaic efficiency exceeding 87%. Curve labelled as C-1 shows the current output versus time. Curve labelled as C-2 shows the cumulative current output versus time.

[0312] FIG. 16 shows technoeconomic analysis of levelized cost of aniline production as a function of phenazine cost and degradation rate. As used herein, the levelized cost refers to the average cost per unit of product or system over entire lifetime of the system, calculated by dividing the discounted total lifetime costs by the discounted total lifetime output (e.g., product). The techno-economic analysis indicates that the estimated process of the method described provides the advantage of providing cost below a market-relevant threshold of approximately $1 ,540 per metric ton. This highlights the importance of mediator stability for large-scale process viability. The dashed counter labeled as 1 indicates market price for aniline. The analysis further indicates that both phenazine cost and mediator degradation rate can influence the cost of aniline. In some embodiments, the methods, systems, and components described herein can provide an alternative to hydrogen-based production routes, with reduced reliance on molecular hydrogen. The star shows the levelized cost of aniline with a phenazine, pz5, which is significantly lower than the market price for aniline.

[0313] FIG. 17 illustrates reduction reaction of hydroxamic acid, a pyridine N-oxide, and azobenzene. In some embodiments, the biphasic reaction system, (also referred to as liquid-liquid heterogeneous electrosynthesis) described herein can be applied to any reaction involved with reduction. In some embodiments, a number of additional biphasic electrochemical reactions including the reduction of hydroxamic acids, the deoxygenation of pyridine N-oxides, and the hydrogenation of azo compounds such as azobenzene can be done with the methods and systems described herein. An amount of substrate (0.25 to about 0.5 mmol) in 3 ml of chloroform was combined with a reduced organic mediator, pz1-H2(1-2 equivalent, 2-4F / mol) in 6 ml of an aqueous solution of 1 M KOI, based on the system, methods and compounds described herein.PATENT Attorney Docket No. 51198-069WO3

[0314] Reduction of a hydroxamic acid compound according to the methods, systems, and components described herein can achieve a yield of about 49% of its corresponding amide product 29. Reduction of a N-oxide compound according to the methods, systems, and components described herein can achieve a yield of about 62% of its corresponding amine product 30. Reduction of an azo compound according to the methods, systems, and components described herein can achieve a yield of about 63% of its corresponding hydrazine product 31.

[0315] FIG. 18A illustrates partial reduction / hydrogenation of a nitroalkane. In some embodiments, the methods, systems, and / or component described herein can be used for hydrogenation of nitroalkanes. In some embodiments, hydrogenation of nitroalkane can include a partial or full reduction. According to FIG. 18A, 0.5 mmol of nitroalkane at a concentration of 0.167 mM in an aqueous medium was reduced by 2 equivalents or 4 F / mol of the reduced organic mediator, pz1-H2 in a reactor at a H2O / CHCL3 volumetric ratio of 2:1. In some embodiments, a partial hydrogenation can include reduction of the nitro group (-NO2) to a hydroxylamine group (-NHOH).

[0316] FIG. 18B illustrates the chemical structure of the isolated reduced nitrogen-containing products from the partial hydrogenation reaction of nitroalkane shown in FIG. 18A. In some embodiments, the isolated reduced nitrogen containing products can include 32, 33, 34, and 35 with a yield of about 95%, 93%, 85%, and 60%, respectively. In some embodiments, the yield was assessed by1H NMR. In some embodiments, the yield and the isolated products can be adjusted by the concentration of the nitrogen-containing compound and solvents as well as the mediator concentration and mediator chemical structure. In certain embodiments, by limiting the number of reducing equivalents introduced (e.g., 2 equivalents of pz1-H2), various nitrogen containing products with a hydroxyl amine group (-NHOH) may be obtained. In some embodiments, reduced nitrogencontaining products can be produced such as 34, for which no comparable alternative synthetic route is known.

[0317] FIG. 19 illustrates telescoped synthesis of complex nitrones. In some embodiments, the methods described herein can be used for condensation of a hydroxylamine compound with an aldehyde compound and producing a C=N+-O - linkage. In some embodiments, the hydroxylamine compound can be generated directly without purification before reacting with the carbonyl compound. Telescoped synthesis refers to a multistep process in which two or more reaction steps are carried out sequentially without isolation or purification of intermediate species.

[0318] In some embodiments, nitrone 36 can be synthesized from 1 equiv of crude L-serine-derived oxazolidine 34, 1 equiv of a carbonyl compound (Boc-protected aldehyde), and 1.5 equiv of MgSO4 in 3.6 ml of CH2CI2 at room temperature, according to the methods, systems, and components described herein. In some embodiments, CFhChcan act as a solvent. In some embodiments, MgSO4 can function as a drying agent to remove water formed during the reaction. The oxidation reaction of the hydroxyl amine compound 34 to the reduced nitrogen-containing product has a yield of about 83%.PATENT Attorney Docket No. 51198-069WO3

[0319] In some embodiments, the organic phase resulting from these hydrogenation reactions can be sufficiently pure to be used directly in subsequent transformations (or reactions), such as the synthesis of nitrone. In some embodiments, the organic phase can be substantially free of salts.

[0320] FIGS. 20A-20F illustrate cyclic voltammograms of mediators pz1 to pz6. Cyclic voltammograms were obtained for the mediators, phenazines pz1 , pz2, pz3, pz4, pz5, and pz6 at a concentration of 5 mM in an aqueous solution including 1 M KCI at pH 13 under nitrogen atmosphere. Measurements were conducted at a scan rate of about 100 mV / s. A cyclic voltammogram refers to a plot of current versus applied potential generated during cyclic voltammetry, in which the electrode potential is swept linearly with time in a forward and reverse direction to characterize oxidation and reduction behavior of electroactive species.

[0321] Cyclic voltammograms of the mediators was plotted as normalized current versus applied potential (V vs. SHE). The voltammograms shown in FIG. 20A-20F exhibits a reversible redox couple. The voltammograms display a cathodic and anodic wave corresponding to a reversible redox process of the phenazine core. The sulfonic acid substituent (-SO3H) of pz1 can make the phenazine more electron-withdrawing and stabilize the reduced form of the mediator. In addition, the cyano group can act as an electron-withdrawing substituents and can stabilize the reduced for the mediator. Electronwithdrawing groups can lower the lowest unoccupied molecular orbital of the phenazine (can be referred to as scaffold) and increase medium polarity / ion pairing, stabilizing the reduced state, and / or enhance solvation.

[0322] Cyclic voltammetry (V vs. SHE) demonstrates that electron-withdrawing and ionic substituents shift the half-wave potential (E^) positively (less negative), thereby reducing the overpotential required for reduction. Further incorporation of multiple sulfonate groups, including ether-link. Accordingly, increasing the number and ionic character of sulfonate substituents lowers the reduction overpotential.

[0323] FIGS. 21 A-21G illustrate cyclic voltammograms of solutions of various nitro and nitroso compounds. Cyclic voltammograms were obtained for solutions nitrogen-containing compounds with a concentration of less than 1 mM in 1 M KCI at pH 13 under nitrogen atmosphere. Measurements were conducted at a scan rate of about 100 mV / s. FIGS. 21A-21G show steric hindrance and poor solubility can reduce electron transfer efficiency. The nitro and nitroso group provides electronwithdrawing characteristics, but the bulky substituents can dominate the electrochemical behavior (e.g., FIG. 21 F). In addition, nitro and nitroso groups can shift reduction potentials positively.Conjugate substituents (e.g., vinyl, ethynyl), and methoxy can modulate peak shape. Bulky substituents can reduce current response, indicating steric hindrance or solubility limitations.

[0324] Table 1 includes solubilities and partition coefficients of compounds in a chloroform / water system.

[0325] Table 1PATENT Attorney Docket No. 51198-069WO3< << < < <>

[0326] The partition coefficient of nitrobenzene between chloroform and water was determined by UV-Vis spectroscopy. The procedure for determining the partition coefficient of nitrobenzene, nitrosobenzene, and azoxybenzene are shown in the description for FIG. 22A-22B and FIG. 23. However, calculation of the partition coefficient of the mediator pz5 in water / chloroform was not determined (shown as n.d. in Table 1), since pz5 is exclusively in the aqueous phase.

[0327] FIGS. 22A-22B shows UV-VIS absorption spectra and associated calibration curve for nitrobenzene in water. Measurements were performed in a 1 cm path-length cuvette. UV-VIS absorption spectra were used to determine the partition coefficient of nitrobenzene between chloroform and water. A biphasic combination of 120 mM nitrobenzene, the nitrogen-containing compound, in chloroform (2 mL) and water (4 mL) was vigorously agitated and allowed to reach equilibrium. A 50 pL aliquot of the aqueous phase was diluted with water (3 mL), and the UV-vis absorbance at 267 nm was measured.

[0328] The calibration curve in FIG. 22B shows the absorbance at an absorption peak of the UV-VIS spectrum of 267 nm, for nitrobenzene in water versus the concentration. The slope of the calibration curve was measured, yielding a slope of 0.0057 pM1.

[0329] FIG. 23 illustrates UV-VIS absorption spectrum of the aqueous phase after partitioning between nitrobenzene in Chloroform and water. UV-VIS absorption spectroscopy was performed for a nitrogen-containing compound, nitrobenzene at a concentration of 120 mM in 2 mL chloroform and 4 mL water. Partition coefficient of nitrobenzene was calculated according to the following procedure:

[0330] The concentration in the diluted sample was calculated using the calibration slope (from FIG.22B):Concentration (diluted)= 0.13310.0057 =23.33 pM.

[0331] The dilution factor was 3 mL / 0.050 mL = 60. Thus, the original concentration in the aqueous phase was:Concentration (aqueous)= 23.33 pM x 60 = 1 ,400 pM = 1.400 mM.Initial moles of nitrobenzene (in chloroform) =120 mM x 2 mL = 240 pmol =0.24 mmol.

[0332] In addition, moles of nitrobenzene transferred to water was calculated as:PATENT Attorney Docket No. 51198-069WO3 Moles of nitrobenzene in water=1.400 mM x 4 mL = 5.6 pmol = 0.0056 mmol.

[0333] Therefore, moles of nitrobenzene remaining in chloroform was:Moles chloroform=0.24 mmol - 0.0056 mmol = 0.2344 mmol.

[0334] Accordingly, concentration in chloroform is:Concentration(Chloroform)= 0.2344 mmol 12 mL = 117.2 mM.

[0335] Therefore, the partition coefficient K of nitrobenzene in water / chloroform was:K (water / chloroform) = 1.4 / 117.2 = 0.012, (shown in Table 1).

[0336] The extremely poor solubility of the nitrosobenzene (<0.10 mM) and azoxybenzene (<0.10 mM) intermediates in water prevented accurate quantitative measurements of their partition coefficients, as prolonged sonication and disappearance of the pure substances was observed to yield suspended solids in >500 mL solvent. Hence, the partition coefficients are given as bounded values based on their solubilities in water.< 0083 (shown in Table 1)< 0.00083 (shown in Table 1)

[0337] FIG. 24 illustrates partition coefficient of pz5 between water and chloroform. Attempt to determine the partition coefficient of pz5 between water and chloroform was done. A biphasic combination of 120 mM the mediator, pz5 in 4 mL water and 2 mL chloroform was vigorously agitated and allowed to reach equilibrium. A 50 pL aliquot of the organic phase was then diluted with chloroform (3 mL) for UV-VIS analysis. No absorbance signal corresponding to pz5 was detected in the chloroform layer, indicating its extremely low solubility in this solvent. These results suggest that pz5 remains exclusively in the aqueous phase .

[0338] FIG. 25A shows the concentration of nitrobenzene in the aqueous phase versus time and FIG. 25B shows the linear fit of ln(1-C / C*) versus time. The mass transfer of nitrobenzene from chloroform to water was analyzed assuming the film model.The mass flux is described by:N = kLx (C* - C)

[0339] Where N = molar flux (mol / cm2 / s), ki_ = liquid-side mass transfer coefficient (cm / s), C* = equilibrium concentration of nitrobenzene in water (mol / cm3), and C = concentration in bulk water (mol / cm3).

[0340] A material balance was performed on the aqueous phase,PATENT Attorney Docket No. 51198-069WO3 Vaqx dC / dt = a x kLx (C* — C)

[0341] where Vaq= volume of the aqueous phase (cm3), a = interfacial area (cm2), Therefore,dC / (C* -C) = (a / Vaq) x kLx dt

[0342] integrating from C = 0 att = 0 to C = C(t) at time t:Zn(l - C(t) / C*) = -(a / Vaq) x kLx t

[0343] In order to extract ki_ experimentally, 4 mL water was added slowly to 120 mM nitrobenzene in 4.0 mL chloroform and stirred at 350 rpm using an 8 mm stir bar. The interfacial area was approximately 5.0 cm2, and aliquots were taken from the aqueous phase overtime for UV-VIS analysis.

[0344] FIG. 25A shows the concentration of nitrobenzene versus time in the aqueous phase during the redox reaction based on analysis of UV-VIS spectra. In order to calculate, ki_, mass transfer coefficient of nitrobenzene in the aqueous phase, plot of ln(1-C / C*) was plotted against time as shown in FIG. 25B. Based on measuring the slope of the curve, -0.001251 / s, mass transfer coefficient of nitrobenzene in the aqueous phase is calculated as ki_= 0.001 cm / s.

[0345] In situ UV-VIS absorbance spectra were recorded using a DH-2000-BAL® as the light source for UV-visible spectroscopy, and a flame spectrometer (OCEAN OPTICS®), equipped with optical fiber connectors and a quartz cuvette mounted in a custom cuvette holder. The holder was designed with inlet port and outlet port to enable continuous flow of the aqueous phase during the reduction reaction in the reactor. The solution was recirculated through the system. The absorbance at 460 nm, corresponding to the oxidized form of pz5, was monitored overtime to quantify the reaction rate. The cuvette had a pathlength of 100 pm, and all spectra were baseline-corrected using a blank. The aqueous phase was pumped through the cuvette at a constant flow rate of 15 mL / min.

[0346] FIGS. 26A-26B show modeled concentration profile of nitrobenzene (NB) and pz-FF across the diffusion film as a function of distance from the liquid-liquid interface, respectively. The interfacial NB concentration is set by partitioning from the organic phase (5 mM NB, partition coefficient of 0.012), yielding an aqueous interfacial concentration of 60 pM. Nitrobenzene is rapidly consumed by a second-order reaction with pz-H2, resulting in sharp depletion within ~20 pm. The simulation corresponds to a Hatta number of 5.87 which shows that rate of reaction is significantly higher than diffusion rate and the reaction is controlled by mass transfer. The modeled concentration profile of the reduced organic mediator pz-FF across the aqueous diffusion film, shown in FIG. 26B, highlights that the bulk concentration of the reduced organic mediator, pz-FF, is maintained at 15 mM. A slight concentration gradient is predicted across the film which can indicate partial depletion at the interface.PATENT Attorney Docket No. 51198-069WO3

[0347] FIGS. 27A-27B illustrate plausible alternative profiles of positive adsorption for a species more soluble in water than in the organic phase. In order to calculate the adsorption density, a surface model for adsorption density was used.

[0348] Following the treatment by van der Waals, Bakker, and Guggenheim, “surface phase” is bounded between to homogenous bulk phases where solution properties vary continuously between the two immiscible phases. Therefore, the following expression can be used for the total differential for the Helmholtz free energy from the master equation:

[0349] The superscript a denotes these quantities are defined for the surface phase, where for an arbitrary quantity Z, ZCT= Zs- (Z“ + Z^), where a and f> denotes the two bulk phases, and the superscript X denotes the value for the entire system. A is the Helmholtz free energy, used as the surface phase is defined to be kept at constant temperature and volume. S, V denotes the entropy and the volume respectively, while T,P denotes the intensive variables of temperature and pressure respectively (hence no superscript as these quantities are assumed to be uniform across both bulk phases and the surface phase).

[0350] y is defined as the surface tension, which is defined as the work required to increase the surface area of the interfacial cross-sectional area (a) by one unit.and n denotes the chemical potential and the number of moles for component i, with no superscript for chemical potential because of physiochemical equilibrium in the thin interfacial region and across the bulk phases. It is assumed that this finite surface phase as the changes in surficial properties are known to operate on submicrometer length scales, typically below 10 molecular diameters at 1-10 nm. Without further assumptions, manipulation allows one to eliminate and obtain the surface analogue of the Gibbs-Duhem equation:

[0351] Dividing by o gives:

[0352] Where T is given as the depth of the surface phase. I) is defined as the surface adsorptionn?density for component i where I) = - , quantifies the excess quantity per cross-sectional area of the interface for component i relative to the quantity if the bulk concentration were to extend to a hypothetical 2D surface defining the interface, for each bulk homogeneous phase, as n'7= ns- (na+ n^). Placing this division is arbitrary. Historically, a this has been done by definition of a relative surface excess to the solvent. The Gibbs dividing surface treatment defines the 2D plane where the surface excess of a solvent of interest is zero, hence for our system:cHaqoyaq+ '” =0PATENT Attorney Docket No. 51198-069WO3 yaq _|_ yorg > ytot

[0353] From this, we define the superscript (EDS) to be for our dividing surface relative to the solvent (component 1) for each set of experiments, and as we assume a 2D geometrical plane in this simplified model and isothermal conditions, T = 0, and dT = 0, hence,

[0354] And incorporating the definition of chemical potential, we take the extremely crude assumption that is only true in the limit that for the other components-[jRIdlnaj « -[ Rldlnai when (molar concentration of component i) changes, where a a, are the activities for components i and j respectively but we can obtain the same form as the Gibbs adsorption equation:

[0355] Hence, by probing the surface tension as we change the atby changing concentration (and hence activity), one can obtain a surface adsorption density / surface excess concentration at equilibrium that can be qualitatively interpreted as the tendency for the component of interest to accumulate at the interfacial region during the reaction.

[0356] In some embodiments, more sophisticated models can exist for the analysis of adsorption at interfaces, as well as the possibility of incorporating explicit terms that describe possible double layers at the interface. Additional work that characterizes quantities such as the vapor pressures of each component would be valuable. It is noted that more sophisticated models have been proposed that allow a possible profile to be deduced. However, the method is nontrivial, and the Gibbs treatment is deemed to be sufficient in describing the systems, methods, and compounds described herein.

[0357] Concentration profiles shown in FIGS. 27A-27B show schematic concentration profiles across a liquid-liquid interface. The line, GDSH2O, represents the Gibbs dividing surface for water, which is the conceptual boundary between the aqueous phase and the organic phase. Positive ri<H20> indicates positive adsorption of species / at the interface (excess concentration at the interface compared to bulk).

[0358] In FIG. 27A, species / is predominantly water-soluble (c“q» c°rs)and exhibits modest positive adsorption at the interface> o). The concentration smoothly decays from the aqueous bulk value toward the organic bulk value, with a slight interfacial enrichment relative to a step function. In FIG. 27B, species / displays pronounced interfacial adsorption. The concentration profile shows a peak immediately adjacent to the GDSH2oline, indicating significant accumulation of species / in the interfacial region before the concentration decays into the organic phase. The bulk partitioning remains biased toward the aqueous phase (c“q» c°rs).

[0359] According to UV-VIS spectrophotometry experiments, pz mediators described herein are extremely poorly soluble in organic phases, structurally similar to surfactants. Therefore, FIG 27B canPATENT Attorney Docket No. 51198-069WO3 better reflect the concentration profile of the pz5 if pz5 is taken as a component of interest / . In general, when the surface adsorption density changes from negative to positive, it represents a greater tendency for the species to accumulate at the interface.

[0360] In some embodiments, the component of interest / can be pz5. In some embodiments, it can be reasoned by UV-VIS spectrophotometry experiments that the pz mediators are extremely poorly soluble in organic phases, as well as structurally seeming surfactant-like, so profile B is likely to better reflect the true profile. Other alternatives are less likely. Some are unphysical. Hence, we chose the more reasonable general profile shapes in our representation. Both representations do not detract from our message - changing from negative to positive surface adsorption density represents a greater tendency for the species to accumulate at the interface.

[0361] FIGS. 28A-28B shows surface tension to composition relationships for pz5 at the interface of KCL / CHCh and the interface of KCI / Cyclohexane, respectively. The aqueous phase includes 1 M KCL. In order to measure the surface tension versus concentration, pendant-drop tensiometry method was used according to the procedure below:

[0362] To a quartz cuvette with a biphasic combination of 1 mL aqueous phase and 1 mL organic phase at the composition of interest, a needle of known diameter (464 |im) containing 0.3 mL of the denser solution of interest was inserted into the lighter phase, and a pendant drop was created to approximately the largest volume achievable before complete release of the droplet. A light source was used with a white piece of paper as a homogeneous image background with reduced optical aberrations at the droplet boundaries. An image was captured using a Basler a2A1920-160 urn BAS USB 3.0 camera, capturing at 160 frames per second at 2.3 MP resolution. To maximize the information extracted from the drop profile, the resultant image was fitted to the Young-Laplace equation with the open-source OpenDrop software 39,40 with length scales referenced to the needle of known diameter (464 |im) to obtain the final surface tension measurement with known bulk solvent densities. This process is repeated for multiple droplets at the same composition, and their averages were taken to reduce random errors in the procedure.

[0363] A linear curve was fitted to the data collected for surface tension of pz5 in 1 M KCL / CHCh and the interface of 1 M KCI / Cyclohexane at different concentrations of pz5. Based on surface model for adsorption density described in description of FIGS. 27A-27B, surface adsorption density, ri<H20> was calculated.

[0364] FIGS. 29A-29B show surface tension to composition relationship for azoxybenzene at KCL / CHCh and KCI / Cyclohexane interfaces, respectively. Similar to FIG. 28A-28B, surface tension was measured for different concentrations of azoxybenzene in 1M KCI / CHCh and 1 M KCI / Cyclohexane. Linear fit to the data was used to calculate the adsorption density of azoxybenzene at the interface of 1 M KCI / CHCh and 1 M KCI / Cyclohexane.PATENT Attorney Docket No. 51198-069WO3

[0365] FIG. 30 shows surface tension versus concentration for the mediator, pz4 at the interface of 1M KCI / CHCh. Similar to FIG. 28A-28B, surface tension was measured for different concentrations of pz4 in 1 M KCI / CHCh. Linear fit to the data was used to calculate the adsorption density of pz4 at the interface of 1 M KCI / CHCh.

[0366] FIG. 31 shows measured interfacial surface tension between the aqueous / organic interfaces for cyclohexane, methoxy tetrahydrofuran (2-MeTHF), and CHCh. The aqueous solution includes 1 M KCI. Interfacial surface tension for aqueous / cyclohexane interface is about 44.58 mN / m. Interfacial surface tension for aqueous / 2-Me THF interface is about 4.72 mN / m. Interfacial surface tension for aqueous / Chloroform interface is about 30.55 mN / m.

[0367] Table 2 provides conversion and yield for hydrogenation of a nitrogen-containing compound, aniline, with a mediator, pz5 with different solvents. In some embodiments, solvent choice can critically influence the outcome of the reaction. Solvents such as cyclohexane and 1 ,2-dichlorobenzene suppress aniline formation, favoring azoxybenzene as the major product with trace amount of nitrosobenzene. In contrast, solvents like 2- methyltetra hydro furan (2-Me-THF) and chloroform promote efficient reduction to aniline, highlighting solvent-dependent selectivity in this biphasic system.Table 2

[0368] The methods, components, and / or systems described herein can provide high chemoselectivity, elevated Faradaic efficiency and current density, mediator stability, reduced organic solvent usage, and compatibility with continuous manufacturing processes. Accordingly, this approach may be extended to a range of redox reactions of both academic and industrial interest and may provide advantages that are not readily attainable using organic solvents alone.ExamplesA. Examples for synthesis of mediatorsThese examples describe methods of synthesizing phenazines, (e.g., pz1 to pz6) suitable for use as a mediator. These examples are provided for illustrative purposes and are not intended to limit the scope of the invention. Exemplary synthesis methods are as follows:Example A.1. Dihydroxyphenazine-2-suifonic acid (pzi)

[0369] A phenazine according to the formula pz1 as shown in FIG. 5A was synthesized by the following procedure: deionized water (65 ml) was added to a 100 ml round-bottom flask with a magnetic stir bar. The flask was heated to 105 °C under stirring. Subsequently, 2,5-dihydroxy-1 ,4-PATENT Attorney Docket No. 51198-069WO3 benzoquinone (4.139 g, 0.0295 mol, 1.00 equivalent) was added in portions. Then, 3,4-diaminobenzenesulfonic acid (5.553 g, 0.0295 mol, 1.00 equivalent) was added in portions over 5 minutes, and the reaction mixture was stirred at reflux overnight (~15 h). Upon completion, the mixture was allowed to cool to room temperature. Acetone (75 ml) was added dropwise at room temperature with stirring to induce precipitation. The resulting gold-colored residue was collected by vacuum filtration, washed sequentially with deionized water (2 times, 25 ml) and acetone (2 times, 25 ml), and dried under vacuum for 48 hours to afford the product at a gold / green solid (6.909 gr, 98% yield).Example A2. 7-Methoxyphenazine-2,3-diol (pz2)

[0370] A phenazine according to the formula pz2 as shown in FIG. 5A was synthesized by the following procedure: deionized water (65 ml) was added to a 100 ml round-bottom flask equipped with a magnetic stir bar. The flask was heated to 90 °C under stirring. Subsequently, 2,5-dihydroxy-1 ,4-benzoquinone (4.139 g, 0.0295 mol, 1.00 equivalent) was added in portions. Then, 3,4-diaminobenzonitrile (3.928 g, 0.0295 mol, 1.00 equivalent) was added in portions over 5 min, and the reaction mixture was stirred at reflux overnight (~12 h). Upon completion, the mixture was allowed to cool to room temperature. Acetone (75 ml) was added dropwise to the mixture at rt with stirring to induce precipitation. The resulting red solid was collected by vacuum filtration, washed sequentially with deionized water (2 x 25 ml) and acetone (2 x 25 ml), and dried under vacuum to afford the product as a dark red solid (5.040 g, 72% yield).Example A3. 7, 8-Dihydroxyphersaz e-2 -carbonitrile (pz3)

[0371] A phenazine according to the formula pz3 as shown in FIG. 5A was synthesized by the following procedure: o-phenylenediamine (0.5 g, 4.65 mmol, 1.00 equivalent) and 2,5- dihydroxy-1 ,4-benzoquinone (0.7 g, 5.0 mmol, 1.08 equivalent) were added to a two-necked 500 ml round-bottom flask equipped with a magnetic stir bar. The system was placed under N2. Under positive N2 pressure, deionized water (100 ml) was added. The resulting mixture was heated to 110 °C with stirring for 12 h. Upon completion, the mixture was allowed to cool to room temperature. The precipitate was collected by vacuum filtration and dried under vacuum to afford the product as a dark brown solid (1.00 g, 100%.).Example A4. Phenazine-2,3-dsoi (pz4)

[0372] A phenazine according to the formula pz4 as shown in FIG. 5A was synthesized by the following procedure: deionized water (40 ml) was added to a 250 ml round-bottom flask equipped with a magnetic stir bar. The flask was heated to 60 °C under stirring. Subsequently, 2,5-dihydroxy- 1 ,4-benzoquinone (1.400 g, 0.0100 mol, 1.00 equivalent) was added in portions. The system was placed under N2. Separately, 4-methoxy-1 ,2-phenylenediamine (1.540 g, 0.00636 mol, 0.636 equivalent) was weighed and transferred to a septum-capped vial inside an N2-filled glovebox. Deionized water (10 ml) and ethanol (20 ml) were added to the septum-capped vial. The resulting mixture was transferred dropwise to the reaction mixture, then heated to 78 °C and stirred at this temperature forPATENT Attorney Docket No. 51198-069WO3 12 h under N2 flow. Upon completion, the mixture was allowed to cool to room temperature. Acetone (25 ml) was added dropwise to the cooled mixture with stirring to induce precipitation. The resulting dark solid was collected by vacuum filtration, washed sequentially with deionized water (2x 15 ml) and ethanol (2x 15 ml), and dried under vacuum to afford the product as a black solid (0.8 g, 52% yield).Example AS. Potassium 8-hydroxy-7-(3-su!fonatopropoxy)phenazine-2-sulfonate (pzS)

[0373] A phenazine according to the formula pz5 as shown in FIG. 5A was synthesized by the following procedure: pzl (3.00 g, 0.010 mol, 1.00 equiv), anhydrous potassium carbonate (2.76 g, 0.020 mol, 2.00 equiv), and 85 ml of anhydrous dimethylformamide (DMF) were added to a 250 ml round-bottom flask equipped with a magnetic stir bar was added. The mixture was stirred at room temperature for 30 min under N2. Subsequently, 1 ,3-propanesultone (1.22 g, 0.010 mol, 1.00 equivalent) was added to the mixture, and the mixture was heated to 100 °C with stirring for 2 h under N2 atmosphere. Upon completion, the mixture was allowed to cool to room temperature. Ethyl acetate (100 ml) was added to the cooled mixture with stirring to induce precipitation. The resulting dark red solid was collected by vacuum filtration. The collected solid was dissolved and sonicated briefly in methanol, and the resulting suspension was filtered to remove any insoluble inorganic salts. The filtrate was concentrated under reduced pressure, yielding a red solid. This solid was then redissolved in a minimal quantity of deionized water (~20 ml). Ethanol (70 ml) was added to this concentrated solution to induce precipitation. The precipitate was collected by vacuum filtration and dried under vacuum to afford the product as a bright red solid (3.4 g, 71% yield).Example A6. Sodium 3,3'-((7-sulfonatophenazine-2,3-diyl)bis(oxy))bis(propane-1~ sulfonate) (pz6)

[0374] A phenazine according to the formula pz6 as shown in FIG. 5A was synthesized by the following procedure: pzl (3.00 g, 0.010 mol, 1.00 equivalent) and anhydrous DMF (85 ml) were added to a 250 ml round-bottom flask equipped with a magnetic stir bar. Sodium hydride (0.72 g, 0.030 mol, 3.00 equivalent) was added slowly to the solution. The mixture stirred for 1 h under N2. Subsequently, 1 ,3-propanesultone (3.05 g, 0.0250 mol, 2.50 equivalent) was added to the mixture, and the mixture was stirred at room temperature for 12 h. Upon completion, the mixture was allowed to cool to room temperature. Ethyl acetate (100 ml) was added to the cooled mixture with stirring to induce precipitation. The resulting dark red solid was collected by vacuum filtration and washed with methanol. The dark red solid was dried under vacuum at room temperature to afford the product as a red solid (3.9 g, 65% yield).B. Examples for synthesis of nitrogen-containing compoundsThese examples describe methods of synthesizing nitrogen-containing compounds. These examples are provided for illustrative purposes and are not intended to limit the scope of the invention.Exemplary synthesis methods are as follows:

[0375] Example B1. Synthesis of NitroalkanesPATENT Attorney Docket No. 51198-069WO3 This example describes the processing steps for preparation of nitroalkanes through Friedel-Crafts alkylation of indoles with p-nitroalkenes. A p-nitroalkene (1.0 equiv) and an indole (1.2 equiv) were added to a 20 mL scintillation vial equipped with a septum cap and a magnetic stir bar.Hexafluoroisopropanol (HFIP) (0.5 M of the limiting reagent) was added to dissolve the solids, and the reaction mixture was stirred at room temperature overnight. Upon completion of the reaction, as monitored by thin layer chromatography (TLC), the solvent was removed in vacuum and the residue was purified by silica gel chromatography to afford the desired product.Example B2. Synthesis of 3-(2-Nitro-1-phenylethyl)-1 H-indole (SM1)

[0376] This example describes the processing steps for synthesis of SM1 according to procedure described in example 6 from (E)-(2-nitrovinyl)benzene (500 mg, 3.35 mmol, 1.0 equiv) and 1H-indole (471 mg, 4.02 mmol, 1.1 equiv) in HFIP (6.7 mL, 0.5 M), then purified by silica gel chromatography (100 g silica, 5-25% EtOAc / Hex) to afford the product as a yellow gel (701 mg, 78% yield).Example B3. 5-Bromo-3-(2-nitro-1-phenylethyl)-1 H-indole (SM2)

[0377] This example describes the processing steps for synthesis of SM2 according to procedure described in example 6 from (E)-(2-nitrovinyl)benzene (500 mg, 3.35 mmol, 1.0 equiv) and 5-bromo- 1 H-indole (789 mg, 4.02 mmol, 1.1 equiv) in HFIP (6.7 mL, 0.5 M). Purified by silica gel chromatography (100 g silica, 5-35% EtOAc / Hex) to afford the product as a brown solid (893 mg, 77% yield).Example B4. 3-(2-Nitro-1-(thiophen-2-yl)ethyl)-1 H-indole (SM3)

[0378] This example describes the processing steps for synthesis of SM3 according to procedure described in example 6 from (E)-2-(2-nitrovinyl)thiophene (520 mg, 3.35 mmol, 1.0 equiv) and 1H-indole (471 mg, 4.02 mmol, 1.1 equiv) in HFIP (6.7 mL, 0.5 M). Purified by silica gel chromatography (100 g silica, 10-35% EtOAc / Hex) to afford the product as a viscous yellow oil (798 mg, 88% yield).PATENT Attorney Docket No. 51198-069WO3(SM3)Example B5. 3-(2-Nitro-1 -phenylethyl)-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indole (SM4)

[0379] This example describes the processing steps for synthesis of SM4 according to procedure described in example 6 from E)-(2-nitrovinyl)benzene (149 mg, 1 .0 mmol, 1.0 equiv) and 6-(4,4,5,5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)-1 H-indole (291 mg, 1.2 mmol, 1.2 equiv) in HFIP (2.0 mL, 0.5 M). Purified by silica gel chromatography (35 g silica, 10-30% EtOAc / Hex) to afford the product as a white solid (323 mg, 83% yield).(SM4)Example B6. Synthesis of nitroalkanes by conjugate addition of amine or thiol nucleophiles and p-nitroalkenes

[0380] This example describes the processing steps for synthesis of nitroalkanes by conjugate addition of amine or thiol nucleophiles and p-nitroalkenesExample B7. 3-Methyl-N-(2-nitro-1-phenylethyl)pyridin-2 -amine (SM5)

[0381] This example describes the processing steps for synthesis of SM5 according to procedure described in example 6 from (E)-(2-nitrovinyl)benzene (298 mg, 2.0 mmol, 1.0 equiv) and 3-methylpyridin-2-amine (238 mg, 2.2 mmol, 1.1 equiv) in CH2CI2 (4.0 mL, 0.5 M). The reaction mixture was stirred at rt overnight. Upon completion, as monitored by TLC analysis, the mixture was concentrated in vacuo and purified by silica gel chromatography (35g silica, 10-30% EtOAc / Hex) to afford the product as a yellow oil (253 mg, 49%). We observed that this compound decomposes to a dark oil upon prolonged exposure to air and ambient light.PATENT Attorney Docket No. 51198-069WO3Example B8. Cyclohexyl(2-nitro-1-phenylethyl)sulfane (1f)

[0382] This example describes the processing steps for synthesis of SM5 according to procedure described in example 6 from (E)-(2-nitrovinyl)benzene (298 mg, 2.0 mmol, 1.0 equiv), cyclohexylthiol (256 mg, 2.2 mmol, 1.1 equiv), and catalytic EtaN (0.05 equiv) in EtOH (4.0 mL, 0.5 M). The reaction mixture was stirred at rt under N2 overnight. Upon completion, as monitored by TLC analysis, the crude material was diluted with saturated sodium bicarbonate (10 mL) and extracted with CH2CI2 (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo, and was purified by passing through silica plug (10 g, 100% EtOAc) to afford the product as an incredibly foul-smelling colorless oil (305 mg, 58% yield).(1f)Example B9. 4-Fluoro-N-(2-nitro-1-phenylethyl)aniline (1g)

[0383] This example describes the processing steps for synthesis of SM5 according to procedure described in example 6 from E)-(2-nitrovinyl)benzene (298 mg, 2.0 mmol, 1.0 equiv) and 4-fluoroaniline (244 mg, 2.2 mmol, 1.1 equiv) in CH2CI2 (4.0 mL, 0.5 M). The reaction mixture was stirred at rt overnight. Upon completion, as monitored by TLC analysis, the reaction mixture was concentrated in vacuo and purified by silica gel chromatography (35 g silica, 10-30% EtOAc / Hex) to afford the product as an orange oil (375 mg, 72% yield).(1g)Example B10. 2-Nitro-1-phenyl-N-(thiophen-2-ylmethyl)ethan-1 -amine (1h)

[0384] This example describes the processing steps for synthesis of SM5 according to procedure described in example 6 from (E)-(2-nitrovinyl)benzene (298 mg, 2.0 mmol, 1.0 equiv) and thiophen-2-PATENT Attorney Docket No. 51198-069WO3 ylmethanamine (249 mg, 2.2 mmol, 1.1 equiv) in CH2CI2 (4.0 mL, 0.5 M). The reaction mixture was stirred at rt overnight. Upon completion, as monitored by TLC analysis, the reaction mixture was concentrated in vacuo and purified by silica gel chromatography (35 g silica, 10-30% EtOAc / Hex) to afford the product as a yellow oil (128 mg, 24% yield).(1h)C. Example of general procedure for biphasic hydrogenationThis example describes general procedure for biphasic hydrogenation / reduction. This procedure can be used for reduction of any nitrogen-containing compound including the nitrogen-containing compounds described herein. This procedure can also be used for reduction of hydroxylamine, azoxy compounds, N-oxide compounds, nitrones, and any other nitrogen-containing compound. This example is provided for illustrative purposes and is not intended to limit the scope of the invention. The procedure is as follows:

[0385] A 0.26 M aqueous solution of pz was prepared by dissolving the appropriate amount of pz in 1 M KCI (6 mL). This solution corresponds to a theoretical charge capacity of approximately 300 C. The electrochemical charging was performed in a redox flow cell. The pz-containing solution served as the negolyte, while the posolyte comprised 0.20 M potassium ferrocyanide and 0.08 M potassium ferricyanide in 1 M KCI (total volume: 20 mL). The compartments were separated by a NAFION® 212 membrane (previously soaked overnight in 1 M KCI), and flow was maintained by peristaltic pumps at 60 mL min1. The cell electrodes consisted of single layers of AvCarb HCBA carbon cloth (geometric surface area = 5.0 cm2). Electrochemical charging was carried out galvanostatically at a current density of 100 mA cm-2, followed by a potentiostatic hold at 1.65 V until current decay to 2 mA cm-2. Upon completion of charging, the reduced pz solution was immediately collected and transferred into a 20 mL reaction vial containing the desired nitro substrate (166.7 mM, 3 mL organic solvent) and a Teflon-coated magnetic stir bar. The biphasic reaction mixture was stirred vigorously at >1000 rpm for 6 h at rt at the center of a magnetic stir plate. Following the reaction, the organic layer was extracted using dichloromethane (3 x 10 mL), and the residual organic solvent in the aqueous pz phase was removed under reduced pressure using a rotary evaporator. To enable reuse, the aqueous pz solution was neutralized to approximately pH 7 with concentrated HCI (1 M) and stored for subsequent reactions. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. In most cases, and unless otherwise indicated, this crude residue contained almost exclusively the desired product in sufficient purity without further purification.PATENT Attorney Docket No. 51198-069WO3

[0386] For reactions producing compounds 1-10 in FIG. 9C, a 0.29 M pz stock solution was made but only 300 C equivalent was used for each reaction with volumetric adjustment using 1 M KCI to maintain a total volume of 6 mL per reaction. After each hydrogenation, the aqueous pz solution was combined with unused portions from previous cycles to ensure minimal material loss and maximal consistency across trials.D. Examples for biphasic hydrogenation of nitrogen-containing compoundsThese examples describe methods of reduction of nitrogen-containing compounds. These examples are provided for illustrative purposes and are not intended to limit the scope of the invention.Exemplary synthesis methods are as follows:Example D1. Reduction of Nitroarenes

[0387] 5-Amino-1H-indole (1) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of 5-nitro-1H-indole. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the product as a grey solid (62.7 mg, 95% yield).

[0388] Quinolin-5-amine (2) was synthesized according to general procedure for biphasic reduction (Example C) ) on a 0.5 mmol scale of 5-nitroquinoline. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the product as a yellow solid (71.4 mg, 99% yield).

[0389] 2-Fluoro-4-methoxyaniline (3) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of 2-fluoro-4-methoxy-1 -nitrobenzene. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the product as a brown solid (68.5 mg, 97% yield).PATENT Attorney Docket No. 51198-069WO3

[0390] 4-(Methylsulfonyl)aniline (4) was synthesized according general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of 1-(methylsulfonyl)-4-nitrobenzenenzene. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and in vacuo to yield the product as a white solid (76.2 mg, 89% yield).

[0391] 3-Fluoro-4-morpholinoaniline (5) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of 4-(2-fluoro-4-nitrophenyl)morpholine. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the product as a light yellow solid (92.2 mg, 94% yield).

[0392] 4-Chlorobenzene-1 ,2-diamine (6) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of 5-chloro-2-nitroaniline. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the product as a brown solid (67.7 mg, 95% yield).

[0393] 4-Aminobenzonitrile (7) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of 4-nitrobenzonitrile. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the product as a beige solid (55.5 mg, 94% yield).PATENT Attorney Docket No. 51198-069WO3

[0394] 4-Aminobenzaldehyde (8) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of 4-nitrobenzaldehyde. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the product as a yellow solid (59.9 mg, 99% yield).

[0395] 3-Vinylaniline (9) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of 1-nitro-3-vinylbenzene. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the product as a clear oil (57.2 mg, 96% yield).

[0396] 1-(3-Amino-4-fluorophenyl)ethan-1-one (10) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of 1-(4-fluoro-3-nitrophenyl)ethan-1-one. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the product as a white solid (75.8 mg, 99% yield).

[0397] N-(4-Amino-3-(trifluoromethyl)phenyl)isobutyramide (11) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of N-(4-nitro-3-(trifluoromethyl)phenyl)isobutyramide. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the product as a beige solid (105.9 mg, 86% yield).PATENT Attorney Docket No. 51198-069WO3

[0398] 2-Chloro-5-(trifluoromethyl)pyridin-3-amine (12) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of 2-chloro-3-nitro-5- (trifluoromethyl)pyridine. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the product as a white solid (83.5 mg, 85% yield).

[0399] Naphthalen-1 -amine (13) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of 1 -nitronaphthalene. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the product as a purple solid (65.0 mg, 91% yield).

[0400] 3-Ethynylaniline (14) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of 1-ethynyl-3-nitrobenzene. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo and purified by silica gel chromatography (100% hexane to 15% EtOAc / hexane) to afford the product as a clear oil (46.9 mg, 80% yield).

[0401] 2-Methylbenzo[d]oxazol-5-amine (15) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of 2-methyl-5-nitrobenzo[d]oxazole. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo, and purified by silica gel chromatography (100% CH2CI2 to 6% MeOH / CH2Cl2) to afford the product as a white solid (29.6 mg, 40% yield).PATENT Attorney Docket No. 51198-069WO3

[0402] 5-(Piperazin-1-yl)pyridin-2-amine (16) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of 1-(6-nitropyridin-3-yl)piperazine. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the product as a brown solid (81.1 mg, 91% yield).

[0403] 4-Fluoroaniline (17) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of 1-fluoro-4-nitrobenzene. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the product as a light yellow oil (54.4 mg, 98% yield).

[0404] Aniline (18) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of nitrobenzene. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the product as a light yellow oil (46.1 mg, 99% yield).

[0405] 1 ,10-Phenanthrolin-5-amine (19) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of 5-n itro- 1 ,10-phenanthroline. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo, and purified by silica gel chromatography (100% CH2CI2 to 6% MeOH / CH2CI2) to afford the product as a yellow solid (54.7 mg, 56% yield).PATENT Attorney Docket No. 51198-069WO3

[0406] 4-(3-Aminophenyl)thiazol-2-amine (20) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of 4-(3-nitrophenyl)thiazol-2-amine. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo, and purified by silica gel chromatography (100% CH2CI2 to 6% MeOH / CH2CI2) to afford the product as a yellow solid (59.3 mg, 62% yield).

[0407] 2-(1H-indol-3-yl)-2-phenylethan-1 -amine (21) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of 3-(2-nitro-1-phenylethyl)-1H- indole. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the product as a foamy white solid (146 mg, 92% yield).

[0408] N1-(3-Methylpyridin-2-yl)-1-phenylethane-1 ,2-diamine (22) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of 3-methyl-N-(2-nitro-1- phenylethyl)pyridin-2-amine. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo, and purified by silica gel chromatography (100% CH2CI2 to 6% MeOH / CH2CI2) to afford the product as a light yellow oil (77 mg, 66% yield).PATENT Attorney Docket No. 51198-069WO3

[0409] 2-(Cyclohexylthio)-2-phenylethan-1 -amine (23) was synthesized according general procedure for biphasic reduction (Example C) on a 0.25 mmol scale of cyclohexyl(2-nitro-1-phenylethyl)sulfane. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo, and purified by silica gel chromatography (100% CH2CI2 to 6% MeOH / CH2CI2) to afford the product as a light-yellow oil (27 mg, 45% yield).

[0410] 2-(5-Bromo-1H-indol-3-yl)-2-phenylethan-1 -amine (24) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of 5-bromo-3-(2-nitro-1-phenylethyl)-1H-indole. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the product as a foamy off-white solid (135 mg, 85% yield).

[0411] 2-(1H-lndol-3-yl)-2-(thiophen-2-yl)ethan-1 -amine (25) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of 3-(2-nitro-1-(thiophen-2-yl)ethyl)-1 H-indole. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the product as a foamy off-white solid (113 mg, 93% yield).

[0412] N1-(4-Fluorophenyl)-1-phenylethane-1 ,2-diamine (26) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.38 mmol scale of 4-fluoro-N-(2-nitro-1-phenylethyl)aniline. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4,PATENT Attorney Docket No. 51198-069WO3 filtered, and concentrated in vacuo, and purified by silica gel chromatography (35 g silica, 100% CH2CI2 to 6% MeOH / CH2CI2) to afford the product as a light-yellow solid (54 mg, 61% yield).

[0413] 1-Phenyl-N1-(thiophen-2-ylmethyl)ethane-1 ,2-diamine (27) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of 2-nitro-1-phenyl-N-(thiophen-2-ylmethyl)ethan-1 -amine. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo, then purified by silica gel chromatography (35 g silica, 100% CH2CI2 to 6% MeOH / CH2CI2) to afford the product as a foamy orange solid (103 mg, 89% yield).

[0414] Note: Rapid decomposition under ambient conditions is observed within 24 h.

[0415] 2-Phenyl-2-(6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)ethan-1 -amine (28) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.25 mmol scale of 3-(2-nitro-1-phenylethyl)-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indole. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the product as a light-yellow solid (32 mg, 36% yield).

[0416] 4-chlorobenzamide (29) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.25 mmol scale of 4-chloro-N-hydroxybenzamide and using 0.05 M pz solution to deliver 2 F / mol. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5PATENT Attorney Docket No. 51198-069WO3 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo, then purified by passing through a silica plug (3 g silica, 100% EtOAc) to afford the product as an off-white solid (19 mg, 49% yield).

[0417] 4,4'-Bipyridine (30) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.25 mmol scale of 4, 4'-bipyridine-1 ,1 '-dioxide and using 0.1 M pz solution to deliver 4 F / mol. Upon completion, the reaction mixture was extracted with CH2CI2 (3x5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo, then purified by passing through a silica plug (3 g silica, 100% EtOAc) to afford the product as a crystalline solid (24 mg, 62% yield).

[0418] 1 ,2-Diphenylhydrazine (31) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.25 mmol scale of azobenzene and using 0.05 M pz solution to deliver 2 F / mol. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the product as a white solid (46 mg, 100% yield) that rapidly turned yellow under air, NMR spectroscopy determined that the crude contains a mixture (1 :1.6) of azobenzene and 1 ,2-diphenylhydrazine (31) (29 mg, 63% yield).

[0419] N-Benzylhydroxylamine (32) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of 2-(nitromethyl)benzene and using 0.175 M pz solution to deliver 4 F / mol. Upon completion, the reaction mixture was extracted with CH2CI2 (3x5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the product as a white solid (58.5 mg, 95% yield).PATENT Attorney Docket No. 51198-069WO3

[0420] N-Phenethylhydroxylamine (33) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of (2-nitroethyl)benzene and using 0.175 M pz solution to deliver 4 F / mol. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the product as a white solid (63.8 mg, 93% yield).HO,NH

[0421] N-(Adamantan-1-yl)hydroxylamine (34) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of 1 -nitroadamantane and using 0.175 M pz solution to deliver 4 F / mol. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the product as a white solid (64 mg, 85% yield).

[0422] N-(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)hydroxylamine (35) was synthesized according to general procedure for biphasic reduction (Example C) on a 0.5 mmol scale of 5-(2-nitroethyl)benzo[d][1 ,3]dioxole and using 0.175 M pz solution to deliver 4 F / mol. Upon completion, the reaction mixture was extracted with CH2CI2 (3 x 5 mL) and washed with brine (ca. 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo, then purified by silica gel chromatography (35 g silica, 100% CH2CI2 to 6% MeOHZ CH2CI2) to afford the product as a foamy orange solid (55 mg, 60% yield).

[0423] (Z)-N-((3R,5R)-Adamantan-1-yl)-1-((S)-3-(tert-butoxycarbonyl)-2,2-dimethyloxazolidin-4-yl)methanimine oxide (36) was synthesized according to a previous reported literature procedure27 from crude N-(adamantan-1-yl)hydroxylamine (34) (60 mg, 0.36 mmol, 1.0 equiv), and (S)-3-Boc-2,2-PATENT Attorney Docket No. 51198-069WO3 dimethyloxazolidine-4-carboxaldehyde (83 mg, 0.36 mmol, 1.0 equiv), and MgSO4 (65 mg, 0.54 mmol, 1.5 equiv). The reaction mixture was stirred at rt under N2 overnight. Upon completion by TLC analysis, the reaction mixture was concentrated in vacuo, and purified by silica gel chromatography (35 g alumina gel, 20% EtOAc / Hex) to afford the product as an off-white solid (113 mg, 83% yield).

[0424] Note: MgSO4 was preweighed in a 20-mL scintillation vial equipped with a septum cap and dried in an oven at 150 °C for 1 h.

[0425] Various concepts may be embodied as one or more methods, of which at least one example has been provided. The acts performed as part of the method may be ordered in any suitable way. Accordingly, embodiments may be constructed in which acts are performed in an order different than illustrated, which may include performing some acts simultaneously, even though shown as sequential acts in illustrative embodiments. Put differently, it is to be understood that such features may not necessarily be limited to a particular order of execution, but rather, any number of threads, processes, services, servers, and / or the like that may execute serially, asynchronously, concurrently, in parallel, simultaneously, synchronously, and / or the like in a manner consistent with the disclosure. As such, some of these features may be mutually contradictory, in that they cannot be simultaneously present in a single embodiment. Similarly, some features are applicable to one aspect of the innovations, and inapplicable to others.

[0426] It should be understood that advantages, embodiments, examples, functional, features, logical, operational, organizational, structural, topological, and / or other aspects of the disclosure are not to be considered limitations on the disclosure as defined by the embodiments or limitations on equivalents to the embodiments.

[0427] All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and / or ordinary meanings of the defined terms.

[0428] As used herein, in particular embodiments, the terms “about” or “approximately” when preceding a numerical value indicates the value plus or minus a range of 10%. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure. That the upper and lower limits of these smaller ranges can independently be included in the smaller ranges is also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0429] The phrase “and / or,” as used herein in the specification and in the embodiments, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or”PATENT Attorney Docket No. 51198-069WO3 should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0430] As used herein in the specification and in the embodiments, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the embodiments, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the embodiments, shall have its ordinary meaning as used in the field of patent law.

[0431] As used herein in the specification and in the embodiments, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0432] In the embodiments, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of’ and “consisting essentially of’ shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.PATENT Attorney Docket No. 51198-069WO3

[0433] While specific embodiments of the present disclosure have been outlined above, many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, the embodiments set forth herein are intended to be illustrative, not limiting. Various changes may be made without departing from the spirit and scope of the disclosure. Where methods and steps described above indicate certain events occurring in a certain order, those of ordinary skill in the art having the benefit of this disclosure would recognize that the ordering of certain steps may be modified and such modification are in accordance with the variations of the invention. Additionally, certain of the steps may be performed concurrently in a parallel process when possible, as well as performed sequentially as described above. The embodiments have been particularly shown and described, but it will be understood that various changes in form and details may be made.

Claims

1. PATENT Attorney Docket No. 51198-069WO3 Claims1. A method of forming a reduced nitrogen-containing product, comprising:contacting an aqueous solution including a reduced organic mediator and a nonaqueous solution including a nitrogen-containing compound, wherein the aqueous solution and the nonaqueous solution are immiscible; andallowing a reaction to occur between the reduced organic mediator and the nitrogencontaining compound to form the reduced nitrogen-containing product and an oxidized organic mediator.

2. The method of claim 1 , further comprising, before the contacting, reducing the oxidized organic mediator in the aqueous solution to form the reduced organic mediator.

3. The method of claim 1 , wherein the reduced nitrogen-containing product includes at least one of a partially reduced nitrogen-containing product or a fully reduced nitrogen-containing product.

4. The method of claim 2, wherein the reducing the oxidized organic mediator includes:communicating the oxidized organic mediator to an electrochemical cell; and electrochemically reducing the oxidized organic mediator in the electrochemical cell to regenerate at least a portion of the reduced organic mediator.

5. The method of claim 4, wherein electrochemically reducing the oxidized organic mediator in the electrochemical cell includes:charging the electrochemical cell at a constant voltage in a range of about 0.5 V to about 2.5 V, ordischarging the electrochemical cell at a constant voltage in a range of about 0.3 V to about 2 V,at least one of the charging or the discharging regenerating the reduced organic mediator.

6. The method of claim 5, wherein the charging or the discharging of the electrochemical cell is performed at room temperature and at a constant current density in a range of about 100 mA / cm2to about 500 mA / cm2.

7. The method of claim 1 , wherein contacting the aqueous solution and the nonaqueous solution includes agitating the aqueous solution and the nonaqueous solution.

8. The method of claim 1 , wherein contacting the aqueous solution and the nonaqueous solution occurs at a stirring rate in a range of about 1 ,000 rpm to about 4,000 rpm, and for a period of time in a range of about 1 min to about 24 hours.PATENT Attorney Docket No. 51198-069WO3 9. The method of claim 1 , wherein a volumetric ratio of the aqueous solution to the nonaqueous solution is in a range of about 1 :3 to about 3:1.

10. The method of claim 1 , wherein a concentration of the reduced organic mediator in the aqueous solution is in a range of about 5 mol% to about 20 mol%.

11. The method of claim 3, wherein decreasing a number of reducing equivalents of the reduced organic mediator yields the partially reduced nitrogen-containing product.

12. The method of claim 3, wherein the partially reduced nitrogen-containing product includes a hydroxylamine group.

13. The method of claim 1 , wherein the reduced nitrogen-containing product includes an azoxy group.

14. The method of claim 1 , wherein:the nitrogen-containing compound includes nitrobenzene, andthe nonaqueous solution includes at least one of chloroform or 2-methyltetrahydrofuran, and the reduced nitrogen-containing product formed via the redox reaction includes aniline.

15. The method of claim 14, wherein the redox reaction generates a yield of aniline of at least about 90 %.

16. The method of claim 1 , wherein a capacity fade rate of the reduced organic mediator is in a range of about 0.01 vol% to about 1 vol% per day.

17. The method of claim 1 , wherein the reduced organic mediator has a coulombic efficiency of at least about 90%.

18. The method of claim 1 , wherein the reduced nitrogen-containing product includes at least one of a nitroso, a hydroxylamine, azo group, or amine group produced by the reaction.

19. The method of claim 1 , wherein the reduced nitrogen-containing product includes a nitroso compound and a hydroxylamine compound.

20. The method of claim 1 , wherein the reaction occurs proximate an interface of the aqueous solution and the nonaqueous solution.

21. The method of claim 20, wherein the reaction proceeds within a thin diffusion layer at the interface.PATENT Attorney Docket No. 51198-069WO322. The method of claim 1 , wherein the reaction has a Hatta number of at least about 5.

23. The method of claim 1 , wherein the reaction includes at least one of an electron transfer, a proton-coupled electron transfer, or a proton transfer.

24. The method of claim 23, wherein the reaction includes the electron transfer followed by the proton transfer.

25. The method of claim 1 , wherein the nitrogen-containing compound includes a nitroalkane, and the reduced nitrogen-containing product includes a compound of at least one ofa salt thereof.

26. The method of claim 1 , wherein the nitrogen-containing compound includes at least one of a hydroxamic acid, an N-oxide, or an azo group.

27. The method of claim 1 , wherein the oxidized organic mediator includes a phenazine.

28. The method of claim 27, wherein the phenazine includes a compound of formula (I):a salt thereof.

29. The method of claim 27, wherein the phenazine includes a compound of formula (II):a salt thereof.PATENT Attorney Docket No. 51198-069WO3 30. The method of claim 29, wherein the nitrogen-containing compound includes a nitroalkane.

31. The method of claim 27, wherein the phenazine includes a compound of formula (III):a salt thereof.

32. The method of claim 27, wherein the phenazine includes a compound of formula (IV):a salt thereof.

33. The method of claim 27, wherein the phenazine includes a compound of formula (V):a salt thereof.

34. The method of claim 27, wherein the phenazine includes a compound of formula (VI):a salt thereof.

35. The method of claim 34, wherein the nitrogen-containing compound includes a nitroarene.

36. The method of claim 1 , wherein the nitrogen-containing compound includes at least one of an aliphatic or an aromatic nitrogen-containing compound.

37. The method of claim 3, wherein the fully reduced nitrogen-containing product includes an amine.

38. The method of claim 3, wherein the partially reduced nitrogen-containing product includes at least one of -NO, -NHOH, or (-N=N+O ).

39. The method of claim 1 , wherein the reduced organic mediator is present at a substoichiometric amount relative to the nitrogen-containing compound.PATENT Attorney Docket No. 51198-069WO3 40. The method of claim 39, further comprising, after allowing the reaction to occur, reducing the oxidized organic mediator and repeating the contacting and allowing steps.

41. The method of claim 1 , further comprising, after allowing the reaction to occur, allowing the aqueous solution and nonaqueous solution to separate.

42. The method of claim 41 , further comprising recirculating the aqueous and nonaqueous solutions and repeating the contacting and allowing the reaction, wherein during the recirculating oxidized organic mediator is reduced to reduced organic mediator.

43. The method of claim 42, wherein the reduced organic mediator is present at a substoichiometric amount relative to the nitrogen-containing compound.

44. The method of claim 1 , wherein the nitrogen-containing compound and the reduced nitrogencontaining product includes at least one of an alkenyl, alkynyl, amino, aryl amino, halo, aldehyde, ketone, nitrile, amide, sulfide, sulfonyl, or boronate ester group.

45. A phenazine of the formula:salt or reduced form thereof,wherein each of Ri, R2, R3, R4, R5, Re, R7, and Re is independently selected from H; halo; optionally substituted C1-6 alkyl; optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S; -CN; -NO2; -ORa; -SRa; -N(Ra)2-3; -C(=O)Ra; -C(=O)ORa; -S(=O)2Ra; -S(=O)2ORa; -P(=O)Ra2; and -P(=O)(ORa)2, wherein each Rais independently H; optionally substituted C1-6 alkyl; optionally substituted C3-10 carbocyclyl; optionally substituted C1-9 heterocyclyl having one to four heteroatoms independently selected from O, N, and S; optionally substituted C6-20 aryl; optionally substituted C1-9 heteroaryl having one to four heteroatoms independently selected from O, N, and S, wherein at least one of R1, R2, R3, R4, R5, Re, R7, and Rs is -O-(CH2)nSO3H, wherein n is 1 to 6, or wherein at least one of R1, R2, R3, R4, Re, Re, R7, and Rs is -CN and at least one ofRi, R2, R3, R4, Rs, Re, R7, and Rs is hydroxy.

46. The phenazine of claim 45, wherein at least one of R1, R2, R3, R4, Rs, Re, R7, and Rs is -CN and at least one of R1, R2, R3, R4, Rs, Re, R7, and Rs is hydroxy.PATENT Attorney Docket No. 51198-069WO3 47. The phenazine of claim 45, having the structure of formula (I):a salt or reduced form thereof.

48. The phenazine of claim 45, wherein at least one of R1, R2, R3, R4, Rs, Re, R7, and Rs is -O- (CH2)nSO3H and at least one of R1, R2, R3, R4, Rs, Re, R7, and Rs is -OH.

49. The phenazine of claim 45, having the structure of formula (II):a salt or reduced form thereof.

50. The phenazine of claim 45, wherein at least one of Ri, R2, R3, R4, R5, Re, R7, and Re is -O- (CH2)nSO3H and at least one of R1, R2, R3, R4, Re, Re, R7, and Rs is -SO3H.

51. The phenazine of claim 45, having the structure of formula (III):a salt or reduced form thereof.

52. A system comprising:an electrochemical flow cell configured to receive an oxidized organic mediator in an aqueous solution and electrochemically reduce the mediator in the aqueous solution;a reactor configured to receive at least a portion of the aqueous solution with the reduced organic mediator and a nitrogen-containing compound in a nonaqueous solution, the reactor including:an agitator configured to agitate the received aqueous solution and the nonaqueous solution to allow a reaction between the reduced organic mediator and the nitrogen-containing compound, the reaction at least partially forming a reduced nitrogen-containing product and an oxidized organic mediator.

53. The system of claim 52, further comprising:coalescence plates in the reactor, the coalescence plates configured to facilitate separation of the aqueous solution and nonaqueous solution.PATENT Attorney Docket No. 51198-069WO3 54. The system of claim 52, further comprising:a circulation assembly fluidically coupled to at least one of the electrochemical flow cell or the reactor, the circulation assembly configured to at least one of:communicate at least a portion of the aqueous solution from the reactor to the electrochemical flow cell, orcommunicate at least a portion of the nonaqueous solution from an outlet proximate to a first end of the reactor to an inlet proximate a second end of the reactor, the second end proximate the agitator.

55. The system of claim 54, wherein the circulation assembly communicates at least a portion of the aqueous solution from the electrochemical flow cell to the reactor proximate the agitator.

56. The system of claim 52, further comprising a separator configured to allow the aqueous solution and nonaqueous solution to separate after agitation.

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