Systems and methods for anthraquinone functionalization

Abstract

The present invention relates to the synthetic functionalization of an anthraquinone molecule substituted with at least one hydroxyl or amino group. In some aspects of the invention, a mixture containing the anthraquinone starting material, an aldehyde, a base, an optional solvent, and an optional catalyst is reacted with hydrogen, and then with an oxidizing agent. In other aspects of the invention, the synthetic functionalization of the anthraquinone molecule is carried out electrochemically, rather than chemically, using a divided electrolytic cell.

Description

[0001] Cross Reference to Related Applications

[0002] This application is being filed on June 9, 2022 as a PCT International Patent Application and claims the benefit of and priority to U.S. Provisional Application No. 63 / 215,079, filed June 25, 2021, the disclosure of which is incorporated by reference herein in its entirety. TECHNICAL FIELD

[0003] The present invention relates generally to synthetic organic chemistry methods. More specifically, the present invention relates to the synthesis functionalization of anthraquinone molecules substituted with at least one hydroxyl or amino group.

[0004] Statement as to Federally Sponsored Research

[0005] Certain aspects of the present invention were made with government support under Award Number DE-AC05-76RL01830 by PNNL Subcontract 535264 with the U.S. Department of Energy. The government has certain rights in the present invention. BACKGROUND

[0006] The Marschalk Reaction is the reaction of a hydroxyl or amino substituted anthraquinone with an aldehyde in the presence of sodium hydrosulfite to introduce an a-hydroxyalkyl functionality on the starting molecule adjacent to the hydroxyl or amine substituent. See L.-M. Zhao, F.-Y. Ma, H.-S. Jin, J. Ma, H. Wang, C.-Z. Fu, European Journal of Organic Chemistry, 2013, 7193-7199. Under certain conditions, dehydroxylation of the a-hydroxyalkyl- functionality occurs, leaving a methylene (-CH2-) linker between the anthraquinone core of the new functionality and the rest of the molecule. The reaction works with a variety of aldehydes, including formaldehyde, acetaldehyde, benzaldehyde, glyoxylic acid, and the like. See, e.g., K. Krohn, Angewandte Chemie International Edition 1979, 18, 621-622. The reaction can be intermolecular or intramolecular. See F. Suzuki, S. Trenbeath, R. D. Gleim, C. J. Sih, Journal of the American Chemical Society 1978, 100, 2272-2273.

[0007] In all reported examples of (a-hydroxy)alkylation or alkylation of hydroxyl or amino substituted anthraquinones, the reducing agent used was sodium dithionite. Substitution of sodium dithionite with a different, cheaper reducing agent can allow the same reaction to be performed at lower cost. BRIEF DESCRIPTION OF DRAWINGS

[0008] Figure 1 Depicted is a synthesis scheme for (a-hydroxy)alkylation or alkylation of a substituted anthraquinone starting material by catalytic reduction of the substituted anthraquinone starting material with hydrogen gas, according to certain embodiments.

[0009] Figure 2 Depicted is a synthesis scheme for (a-hydroxy)alkylation or alkylation of a substituted anthraquinone starting material by electrochemical reduction of the substituted anthraquinone starting material, according to certain embodiments.

[0010] Figure 3 Depicted is an electrolytic cell for effecting (a-hydroxy)alkylation or alkylation of a substituted anthraquinone starting material by electrochemical reduction of the substituted anthraquinone starting material, according to certain embodiments. DETAILED DESCRIPTION

[0011] The mechanism of the Marshak reaction begins with reduction of the 9,10-anthraquinone core of the substituted anthraquinone starting material to a 9,10-dihydroanthracene core. This reduced starting material is the material that then reacts with an aldehyde to form a carbon-carbon bond.

[0012] It is well known that 9,10-anthraquinones can be reduced to the corresponding 9,10-dihydroanthracenes easily, optionally in the presence of a catalyst such as palladium on carbon substrate, using another reactant such as hydrogen gas. See G. Max, L. Emile, U.S. Patent 2,941,865, filed October 16, 1956. Alternatively, the reduction can be effected electrochemically, for example in a half-cell of a flow battery. See K. Lin, Q. Chen, M. R. Gerhardt, L. Tong, S. B. Kim, L. Eisenach, A. W. Valle, D. Hardee, R. G. Gordon, M. J. Aziz, M. P. Marshak, Science 2015, 349, 1529-1532.

[0013] However, the use of a reducing agent other than sodium dithionite in the Marshak reaction is unknown. The present invention features the synthesis of anthraquinone derivatives by a process analogous to the classic Marshak reaction, but utilizing a reducing agent other than sodium dithionite or other dithionite salt.

[0014] In one aspect of the invention, it is summarized thatFigure 1 In some embodiments of the present application, the substituted anthraquinone starting material consists of Formula I:

[0015] In some embodiments of the present application, the substituted anthraquinone starting material consists of Formula I:

[0016]

[0017] wherein X is selected from the group consisting of a hydroxyl or an amino group in the 1 -position, and the anthraquinone is unsubstituted in the 2-position (i.e., the carbon is bonded to a hydrogen). Those skilled in the art will appreciate that other substituents present on the substituted anthraquinone starting material can change the position numbering of the aforementioned hydroxyl or amino group, as well as the unsubstituted carbon atom ortho thereto, but the position numbering will not affect the general reactivity, only the relative positioning of the hydroxyl group on the substituted anthraquinone and the immediately adjacent unsubstituted carbon atom. In some embodiments of the present application, the aldehyde is covalently attached to the anthraquinone derivative, and the reaction proceeds intramolecularly, or can continue under certain conditions to form a dimer, or a ring isomer, or an oligomeric or polymeric chain.

[0018] In some embodiments of the present application, the base is selected from the group consisting of an inorganic hydroxide, a metal alkoxide, an amine, or an amidine, or mixtures thereof. In particular embodiments of the present application, the base is an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide. In other embodiments of the present application, the base is a metal alkoxide or an alkali metal alkoxide, such as sodium methoxide or potassium tert-butoxide. In other embodiments of the present application, the base is an amine or a trialkylamine, such as triethylamine or diisopropylethylamine. In other embodiments, the base is an amidine, wherein the amidine is a non-nucleophilic base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).

[0019] In general, most aldehydes can undergo the reaction, similar to the traditional March reaction described in the literature above. In some embodiments of the reaction, the aldehyde is a water-soluble aldehyde, such as formaldehyde or acetaldehyde. In other embodiments of the reaction, the aldehyde is an organic compound that is only slightly soluble or insoluble in water but soluble in organic solvents, such as benzaldehyde. In yet more embodiments of the present application, the aldehyde, such as glyoxylic acid, contains an acidic group that imparts solubility when mixed with the base.

[0020] In some embodiments of the application, the aldehyde can reversibly interconvert between the form having a free aldehyde group and the form in which a molecule of water or alcohol has been added to the aldehyde group, thus forming dulcitol or a hemiacetal, respectively. In other aspects of the application, the alcohol group is on the same molecule as the aldehyde, and the reversible addition occurs intra-molecularly. In other aspects of the application, the aldehyde functional group forms an open chain form upon ring opening during the course of the reaction. Examples of such "transient" aldehydes are reducing sugars, including but not limited to glucose, galactose, fructose, mannose, xylose, arabinose, glyceraldehyde, lactose, cellobiose, and maltose. These reducing sugars can exist in the form of the D- or L- enantiomer, or a mixture of the two, or a racemic mixture. It will be appreciated by those skilled in the art that any reducing sugar can be used in the embodiments described herein. In other embodiments of the reaction, a non-reducing sugar can be used, which is then converted to a reducing sugar containing aldehyde during the course of the reaction. An example of such a non-reducing sugar is fructose, which can be converted to glucose or mannose, both of which are reducing sugars.

[0021] In some embodiments of the application, the base and / or the aldehyde act as the solvent. In other embodiments of the application, the solvent is a separate species, such as water, methanol, ethanol, isopropanol, 1,4-dioxane, N,N-dimethylformamide, and the like. In other embodiments of the application, the solvent includes more than one solvent, such as a water-ethanol mixture, a methanol-N,N-dimethylformamide mixture, a water-1,4-dioxane mixture, and the like. It will be appreciated by those skilled in the art that any polar, protic or aprotic solvent and mixtures thereof can be used in the embodiments described herein.

[0022] In some embodiments of the application, the optional catalyst is a catalyst for catalyzing hydrogenation, or a pre-catalyst that is converted to an active catalyst for catalyzing hydrogenation during the course of the reaction. The catalyst can optionally be supported on the substrate. Examples of catalysts include, but are not limited to, nickel on carbon, palladium on carbon, platinum on carbon, rhodium on carbon, palladium hydroxide, platinum black, platinum dioxide, Wilkinson's catalyst, Crabtree's catalyst, Shvo's catalyst, and the like.

[0023] In some embodiments of the application, the reaction atmosphere consists partially or entirely of hydrogen. The reaction atmosphere can be operated at atmospheric pressure, below atmospheric pressure, above atmospheric pressure.

[0024] In some embodiments of the invention, the oxidizing agent is present in the gas phase and can be air, oxygen, ozone, or mixtures thereof. The oxidizing agent can alternatively be liquid or present in solution phase, including but not limited to dimethyl sulfoxide or hydrogen peroxide. The oxidizing agent can be a solid, such as silver (I) oxide. Combinations of different oxidizing agents can also be employed.

[0025] In some embodiments of the invention, the catalyst is Raney nickel and hydrogen is already present on the surface of the catalyst and is not provided as a gas to the atmosphere of the reaction vessel.

[0026] In some embodiments of the invention, the aldehyde is introduced only after hydrogen has been vented from the reaction vessel but before the reduced, substituted anthraquinone starting material has been re-oxidized by the oxidizing agent.

[0027] In another aspect of the invention, the chemical reaction outlined in Figure 2 and Figure 3 is carried out electrochemically rather than chemically by using a divided electrolytic cell 300. The divided electrolytic cell 300 includes a first chamber 310 with a first electrode 311 and is separated from a second chamber 320 with a second electrode 321 by an ion-conducting membrane 330. An electrocatalyst can be present independently on only the first electrode 311, only the second electrode 321, both the first electrode 311 and the second electrode 321, or can be absent on either the first electrode 311 or the second electrode 321.

[0028] A first fluid stream 312 consisting of a substituted anthraquinone starting material of Formula I, an aldehyde, a base, and optionally a solvent is flowed through a first chamber inlet 313 into the first chamber of the electrolytic cell 310 such that the first fluid stream contacts the first electrode 311 and exits through a first chamber outlet 314. Simultaneously, a second fluid stream 322 is flowed through a second chamber inlet 323 into the second chamber of the electrolytic cell 320 such that the second fluid stream contacts the second electrode 321 and exits through a second chamber outlet 324. An electrical potential 340 is applied to both electrodes such that the first electrode is at a more negative potential relative to the second electrode. In some embodiments, the first electrode is a cathode and the second electrode is an anode.

[0029] When the first fluid flow 312 passes through the first electrode 311, the first fluid flow is reduced electrochemically. Similarly, when the second fluid flow 322 passes through the second electrode 321, the second fluid flow is oxidized electrochemically. The first fluid flow 312 may pass through the first chamber 310 of the partitioned electrolytic cell 300 in one pass, or the fluid exiting the first chamber outlet 314 may be recirculated multiple times and flow back to the first chamber inlet 313. Similarly, the second fluid flow 322 may pass through the second chamber 320 of the partitioned electrolytic cell 300 in one pass, or the fluid exiting the second chamber outlet 324 may be recirculated multiple times and flow back to the second chamber inlet 323. The partitioned electrolytic cell 300, the first fluid flow 312, and / or the second fluid flow 322 may be heated, cooled, or maintained at different temperatures throughout the reaction duration. Depending on the reaction temperature, (α-hydroxy)alkylation products or dehydroxylated alkylation products are advantageous.

[0030] After a predetermined time or after a predetermined amount of charge has passed, the first fluid stream 312 can be processed in one of several ways described below, and the reaction products can subsequently be separated from the processed first fluid stream and optionally purified by conventional methods familiar to those skilled in the art. The threshold amount of charge to be passed can be predetermined by examining the theoretical amount of charge required to continue the reaction. Figure 2 In this process, the anthraquinone starting material requires two equivalents of electrons to be reduced to a 9,10-dihydroxyanthracene derivative, which then reacts with an aldehyde to form an (α-hydroxy)alkylation intermediate. This intermediate then undergoes intramolecular disproportionation to produce an alkylated product and a re-oxidized anthraquinone core, which can accept more than two electrons. In this case, the charge threshold is 4 equivalents relative to the amount of initially present anthraquinone starting material. In the case of a two-equivalent aldehyde reacting with one molecule of anthraquinone starting material, the theoretical amount of charge to pass would be 6 equivalents. A larger charge threshold can be set to account for inefficiencies of the method, such as the effect of oxygen re-oxidation of the reaction mixture, coulombic efficiency caused by side reactions, etc. Conversely, if the (α-hydroxy)alkylation intermediate is actually the desired product, or if the (α-hydroxy)alkylation material is the starting material and the dehydrogenated alkylation material is the desired product, then a lower charge equivalent (e.g., about two equivalents) can be used as the reaction endpoint.

[0031] Alternatively, if the alkylated (non-α-hydroxylated) product is the desired product, then a threshold voltage (if the current is passed in a constant current fashion) or threshold current or current density (if the current is passed in a constant potential fashion) can be used in place of a predetermined amount of time or charge passed towards the end of the reaction, the increasingly fewer 9,10-anthracenequinone core in the reaction mixture remaining available to accept an electron. This is manifested as a sharp increase in voltage if the current is passed in a constant current fashion, or a decrease in current if the current is passed in a constant potential fashion. It is desirable to set a threshold upper voltage or threshold lower current (or current density) beyond which the current flow is stopped in order to minimize the amount of potential side reactions. The threshold voltage can be defined as a fixed number, e.g., > 0.5 volts / cell (V / cell), > 1.0 V / cell, > 1.5 V / cell, > 1.6 V / cell, > 1.7 V / cell, > 1.8 V / cell, > 1.9 V / cell, > 2.0 V / cell, > 2.1 V / cell, > 2.2 V / cell, > 2.3 V / cell, > 2.4 V / cell, > 2.5 V / cell, etc., or as a percentage increase in average voltage over a certain equivalent number of charges passed, e.g., > 10% greater than the average voltage during the first equivalent of charge passed, > 20% greater than the average voltage during the first 0.5 equivalents of charge passed, > 30% greater than the average voltage during the first 0.5 equivalents of charge passed, > 40% greater than the average voltage during the first 0.25 equivalents of charge passed, > 50% greater than the average voltage during the first 0.1 equivalents of charge passed, and various combinations thereof. For example, in the case where the theoretical amount of charge that can be passed is 4 equivalents and the average cell voltage is 1.5 V higher than the first equivalent of charge passed, a threshold voltage of > 30% greater than the starting voltage means that the current will stop once the voltage exceeds 1.95 V / cell when the current is applied in a constant current fashion. Similarly, the threshold current (or current density) can be defined as a number, e.g., < 10 A, < 1 A, < 0.1 A, < 0.01 A, < 10 mA / cm 2 , < 1 mA / cm 2 , < 0.1 mA / cm 2 , < 0.01 A / cm 2or can be defined as a percentage of the average current or current density over a certain equivalent amount of charge passed, such as <10% of the average current or current density over the first equivalent of charge passed, <5% of the average current or current density over the first 0.5 equivalent of charge passed, <2% of the average current or current density over the first 0.5 equivalent of charge passed, <1% of the average current or current density over the first 0.2 equivalent of charge passed, <0.5% of the average current or current density over the first 0.25 equivalent of charge passed, <0.2% of the average current or current density over the first 0.1 equivalent of charge passed, <0.1% of the average current or current density over the first 0.1 equivalent of charge passed, and various combinations of such. For example, where the theoretical amount of charge that can be passed is 4 equivalents and the average current density is 100 mA / cm 2 A threshold current density of <1% of the starting current density means that, when the current is applied in a constant potential manner, the current will stop once the current density drops below 1 mA / cm 2 In some embodiments, the current is passed in a constant current manner until the cell voltage hits a certain threshold, such as 1.2 V, 1.4 V, 1.6 V, 1.8 V, etc., and then the cell voltage is maintained until the current or current density drops below a threshold, as similarly specified for constant potential operation.

[0032] In some embodiments of the reaction, the substituted anthraquinone consists of Formula II:

[0033]

[0034] where X1and X2are hydroxyl or amino. In some embodiments, X1is the same as X2. In other embodiments, X1is different than X2. Examples of such include 1,5-dihydroxyanthraquinone, 1,5-diaminoanthraquinone, 1-hydroxy-5-aminoanthraquinone, etc.

[0035] In other embodiments of the reaction, the substituted anthraquinone consists of Formula III:

[0036]

[0037] where X1and X2are hydroxyl or amino. In some embodiments, X1is the same as X2. In other embodiments, X1is different than X2. Examples of such include 1,8-dihydroxyanthraquinone, 1,8-diaminoanthraquinone, 1-hydroxy-8-aminoanthraquinone, etc. Anthraquinones consisting of two X substituents on separate aromatic rings of the same molecule or two unsubstituted positions each adjacent to an X substituent of Formula II and Formula III will be capable of reacting with two equivalents of aldehyde to form a bis(alpha-hydroxy)alkylated product or a bisalkylated product.

[0038] In other embodiments of the reaction, the substituted anthraquinone consists of Formula IV:

[0039]

[0040] wherein X1and X2are hydroxyl or amino groups. In some embodiments, X1is the same as X2. In other embodiments, X1is different from X2. Examples of such include 1,4-dihydroxyanthraquinone, 1,4-diaminoanthraquinone, 1-hydroxy-4-aminoanthraquinone, and the like. Anthraquinones of Formula II, Formula III, and Formula IV consisting of two X substituents on separate aromatic rings of the same molecule or two unsubstituted positions each adjacent to an X substituent will be capable of reacting with two equivalents of aldehyde to form bis(alpha-hydroxy)alkylated products or bisalkylated products.

[0041] In some embodiments of the application, the base is selected from the group consisting of inorganic hydroxides, metal alkoxides, amines, and amidines, and mixtures thereof. In particular embodiments of the application, the base is an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide. In other embodiments of the application, the base is a metal or alkali metal alkoxide, such as sodium methoxide or potassium tert-butoxide. In other embodiments of the application, the base is an amine or trialkylamine, such as triethylamine or diisopropylethylamine. In other embodiments, the base is an amidine or non-nucleophilic base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).

[0042] In some embodiments of the application, the base and / or the aldehyde serve as the solvent. In other embodiments of the application, the solvent is a separate species, such as water, methanol, ethanol, isopropanol, 1,4-dioxane, N,N-dimethylformamide, and the like.

[0043] In some embodiments of the application, the first electrode 311 and the second electrode 321 can comprise defined flow channels to direct fluid.

[0044] In some embodiments of the application, the first electrode 311 and the second electrode 321 are conductive carbon electrodes. In other embodiments of the application, the first electrode 311 is a conductive carbon electrode and the second electrode 321 comprises nickel, cobalt, iron, stainless steel, or platinum.

[0045] In some embodiments of the application, the ion-selective membrane 330 is a cation-conducting membrane, such as Nafion® 212, FuMATech® E-630, or Selemion CMV-N®.

[0046] In some embodiments of the application, the second fluid stream 322 comprises hydrogen. In other embodiments of the application, the second electrode 321 is configured such that hydrogen is oxidized and thereby acts as a source of electrons, e.g., a gas diffusion electrode. In yet other embodiments of the application, the second electrode 321 also contains an electrocatalyst for hydrogen oxidation, e.g., platinum.

[0047] In some embodiments of the application, the second fluid stream 322 comprises methanol. In other embodiments of the application, the second electrode 321 also contains an electrocatalyst for methanol oxidation, e.g., platinum-ruthenium.

[0048] In some embodiments of the application, the second fluid stream 322 comprises an aqueous solution of a ferrocyanide salt, e.g., sodium ferrocyanide, potassium ferrocyanide, or ammonium ferrocyanide.

[0049] In some embodiments of the application, the second fluid stream 322 comprises an aqueous solution of an alkali metal hydroxide, e.g., sodium hydroxide or potassium hydroxide. In other embodiments of the application, the second electrode 321 comprises a typical alkaline electrolyzer material, e.g., nickel or stainless steel. In other embodiments of the application, the oxygen generated at the second electrode 321 is used as an oxidizing agent to re-oxidize the first fluid stream 311 in process 1.

[0050] In some embodiments of the application, the aldehyde is not included in the first fluid stream 312, but is added to the first fluid stream 312 only after the current density in the divided electrolytic cell 300 has fallen below a threshold value (as defined above), or after the applied potential has risen above a threshold value, or after a predetermined amount of charge has passed. In other embodiments of the application, the potential 340 between the first electrode 311 and the second electrode 321 is switched to an open circuit potential after (a) the current density in the divided electrolytic cell 300 has fallen below a threshold value, (b) after the applied potential has risen above a threshold value, or (c) after a predetermined amount of charge has passed and before the aldehyde is added to the first fluid stream 312.

[0051] In some aspects of the application, the compartmentalized electrolytic cell 300 can be used as a redox flow battery cell without having to alter the first electrode 311 or the second electrode 321 or the ion-conducting membrane 330. In other embodiments of the application, the (a-hydroxy)alkylated product or the dehydroxylated alkylated product produced in the first fluid stream 312 using the compartmentalized electrolytic cell 300 is not discharged from the first chamber 310 of the compartmentalized electrolytic cell 300 but is maintained in solution phase and used directly as the negative electrolyte (i.e., the catholyte or the anolyte) of a redox flow battery, where the compartmentalized electrolytic cell 300 is a redox flow battery cell. In yet other embodiments of the application, the second fluid stream 322 is not discharged from the second chamber 320 of the compartmentalized electrolytic cell 300 but is maintained in solution phase and used directly as the positive electrolyte (i.e., the anolyte or the catholyte) of a redox flow battery, where the compartmentalized electrolytic cell 300 is a redox flow battery cell. In other embodiments of the application, neither the first fluid stream 312 nor the second fluid stream 322 is discharged from the respective first chamber 310 and second chamber 320 of the compartmentalized electrolytic cell 300 but is maintained in solution phase and used directly as the respective negative and positive electrolytes of a redox flow battery, or as the respective positive and negative electrolytes of a redox flow battery, where the compartmentalized electrolytic cell 300 is a redox flow battery cell.

[0052] In other embodiments of the application, the charge states of the negative and positive electrolytes (previously referred to as the first fluid stream 312 and the second fluid stream 322, or in some other embodiments, the second fluid stream 312 and the first fluid stream 322) can be individually adjusted or balanced to maximize the capacity of the resulting redox flow battery. For example, the first fluid stream 312 or the second fluid stream 322 can be treated with an oxidizing agent such as oxygen in the atmosphere, hydrogen peroxide, ozone, sodium hypochlorite, etc., or the first fluid stream 312 or the second fluid stream 322 can be treated with a reducing agent such as hydrogen, along with optional catalysts, hydrazine, hydrazine hydrate, sodium thiosulfate, sodium hydrosulfite, sodium sulfite, etc.

[0053] In some aspects of the application, the substituted anthraquinone and the aldehyde in the first fluid stream 312 are replaced by intermediates of the same type of reaction previously described; in other words, a different substituted anthraquinone includes a hydroxyl or amine group at the 1 -position, and further includes a -CH(OH)-R group at the 2-position. In this case, the desired product will be dehydroxylated at the benzyl position of the substituent in the 2-position.

[0054] Treatment 1

[0055] After a predetermined amount of time or after a predetermined amount of charge has passed, the first fluid stream 312 is drained from the first chamber 310 of the compartmentalized electrolysis cell 300 and an oxidizing agent is introduced into the first fluid stream 312. In some embodiments of the present application, the oxidizing agent exists in the gas phase and can be air, oxygen, ozone, or mixtures thereof. The oxidizing agent can alternatively be a liquid or exist in solution phase, including but not limited to dimethyl sulfoxide or hydrogen peroxide. The oxidizing agent can be a solid, such as silver (I) oxide. Combinations of different oxidizing agents can also be employed. After another predetermined amount of time, the reaction product is separated from the oxidized first fluid stream and optionally purified by conventional means familiar to those skilled in the art.

[0056] Process 2

[0057] After a predetermined amount of time or after a predetermined amount of charge has passed, the second fluid stream 322 is optionally replaced by a third fluid stream 325 and the sign of the potential 340 across the first electrode 311 and the second electrode 321 is reversed, so that now the electrochemical oxidation of the first fluid stream 312 occurs instead of electrochemical reduction, and now the electrochemical reduction of the second or fluid stream 322 or the third fluid stream 325 occurs instead of electrochemical oxidation. After another predetermined amount of time, or after a predetermined amount of charge or current density drops below a threshold value, or after the applied potential rises above a threshold value, the oxidized first fluid stream 312 is drained from the first chamber 310 of the compartmentalized electrolysis cell 300 and the reaction product is separated and optionally purified by conventional means familiar to those skilled in the art.

[0058] Process 3

[0059] After a predetermined amount of time or after a predetermined amount of charge has passed, the first fluid stream 312 is drained from the first chamber 310 of the compartmentalized electrolysis cell 300. The drained first fluid stream 362 now flows through a third chamber 360 of a second compartmentalized electrolysis cell 350, through a third electrode 361, the second compartmentalized electrolysis cell having a third fluid stream 372 flowing through a fourth chamber 370 of the second compartmentalized electrolysis cell 350, through a fourth electrode 371. A potential 390 is applied to the third electrode 361 and the fourth electrode 371 of the second compartmentalized electrolysis cell 350, so that the third electrode 361 is at a more positive potential relative to the fourth electrode 371. (In other words, the third electrode 361 is the anode and the fourth electrode 371 is the cathode 371). After another predetermined amount of time, or after a predetermined amount of charge or current density drops below a threshold value, or after the applied potential rises above a threshold value, the now oxidized drained first fluid stream 362 is drained from the third chamber 360 of the second compartmentalized electrolysis cell 350 and the reaction product is separated and optionally purified by conventional means familiar to those skilled in the art (reprecipitation, recrystallization, filtration, distillation, washing, extraction, chromatography, etc.).

[0060] Example

[0061] Example 1

[0062] In a Parr hydrogenator, equipped with a mechanical stirrer, 3.00 grams of 1,8-dihydroxyanthraquinone (12.49 mmol), 3.45 grams of glyoxylic acid monohydrate (37.47 mmol, 3 equiv.) and 0.30 grams of 5 wt% palladium on carbon were thoroughly mixed in 100 mL of 1.63 M NaOH solution. Hydrogen gas was sparged into the reaction mixture for 3 minutes and then pressurized with hydrogen to reach a pressure of 100 psi. The reaction was stirred at room temperature (about 20 °C) for 1 hour and then heated to 80 °C for 1 hour. The vessel was vented and the reaction mixture was poured into enough ice to rapidly reduce the temperature to about room temperature and then air was flowed through the reaction mixture for 30 minutes. The solution was acidified with 6 M hydrochloric acid until pH 8 to 9 and then filtered to remove the palladium on carbon catalyst and unreacted 1,8-dihydroxyanthraquinone. The filtrate was then further treated with concentrated hydrochloric acid until pH about 0, causing a yellowish solid to precipitate from the solution. The solid was collected by filtration and washed with cold water to give crude 1,8-dihydroxy-2,7-bis(carboxymethyl)-9,10-anthraquinone in 60% yield. The solid can be purified by recrystallization from hot water and dried as needed.

[0063] Example 2

[0064] Example 3 2An electrochemical cell of electrode area ("MP Cell®", ElectroCell North America, Inc.) was configured with a graphite felt cathode, a stainless steel anode, a Nafion® 115 membrane, a polypropylene flow frame, an EPDM gasket, a cathode reservoir for holding catholyte, and an anode reservoir for holding anolyte. The cathode reservoir had a capacity of about 2 liters and was maintained under an inert nitrogen atmosphere to prevent reoxidation of the reaction mixture by atmospheric oxygen, while the anode reservoir had a capacity of about 10 liters and was open to the atmosphere. Both reservoirs were equipped with heating elements to heat the anolyte and catholyte as needed. First, the anode reservoir was filled with 2 liters of 3 M NaOH. The catholyte was first prepared outside the cathode reservoir by mixing 137 mL of a 50% NaOH solution, 33.8 g of glyoxylic acid monohydrate, and 30.0000 grams (124.89 mmol) of 1,8-dihydroxyanthraquinone in sufficient deionized water to bring the total volume of the catholyte to about 2.0 liters. The catholyte slurry was added to the cathode reservoir and the pump was started to circulate both the catholyte and the anolyte to the electrochemical cell. An additional 750 mL of deionized water was added to the catholyte to obtain a final catholyte volume of 2.75 liters. The catholyte and anolyte were warmed to 40 °C and circulated at 40 mA / cm 2A constant current of 4 A was passed while the temperature was slowly ramped to 50 °C. Throughout the operation, oxygen was evolved at the anode, while the catholyte solution was depleted. After 2 equivalents of charge (249.78 mmol, 24,100 Coulombs) relative to 1,8-dihydroxyanthraquinone had passed, the temperature was ramped to 65 °C and held until a total of 4.1 equivalents of charge (512.05 mmol, 49,405 Coulombs) had passed. HPLC analysis of a gassed aliquot showed no 1,8-dihydroxyanthraquinone remaining in solution, and the target molecule 2,7-bis(carboxymethyl)-1,8-dihydroxyanthraquinone (DCDHAQ) was present in approximately 86% purity. Some of the impurities observed by HPLC (British Pharmacopeia 2004, Dantron: C18 column eluted isocratically with a mixture of 2.5 volumes glacial acetic acid, 40 volumes tetrahydrofuran and 60 volumes water at a flow rate of 1 ml / min, 40 min run time, detection at 254 nm) included the intermediate compounds 2,7-bis(a-hydroxy-carboxymethyl)-1,8-dihydroxyanthraquinone and 2-(a-hydroxy-carboxymethyl)-7-carboxymethyl-1,8-dihydroxyanthraquinone, which can subsequently be converted to the target molecule DCDHAQ by reduction in an electrochemical cell or by a recycling process within the liquid flow battery cell. Other impurities included anthrones and di-anthrones, such as 2,2'-(1,8-dihydroxy-9-oxo-9,10-dihydroanthracen-2,7-diyl)diacetic acid, 2,2'-(1,8-dihydroxy-10-oxo-9,10-dihydroanthracen-2,7-diyl)diacetic acid, 2,2',2",2"'-(4,4',5,5'-tetrahydroxy-10,10'-dioxo-9,9',10,10'-tetrahydro-[9,9'-bianthracen]-3,3',6,6'-tetrayl)tetraacetic acid and related isomers. In general, anthrones and di-anthrones can subsequently be converted to the target molecule DCDHAQ by oxidation in an electrochemical cell, extended exposure to atmospheric oxygen or by a recycling process within the liquid flow battery cell; see ChemRxiv 2021, Digital Object Identifier: 10.26434 / chemrxiv-2021-x05x1. Thus, in addition to some optional concentration by solvent evaporation, the catholyte solution from this synthesis can be used directly as a liquid flow battery negative electrolyte reactant without any subsequent processing to save costs and to reduce chemical waste. To isolate the product DCDHAQ, the catholyte solution was drained through a filter, exposed to air to fully re-oxidise the solution, and re-filtered. The filtrate was acidified with 15% hydrochloric acid until pH <1, and then the precipitated solid was filtered off and dried at 45 °C overnight. After grinding, the dried solid was orange to deep red. Isolated yield: 30.1393 grams (67.7%), melting point 260 to 262 °C.Most of the loss appears to originate from hard nodules of unreacted, undissolved 1,8-dihydroxyanthraquinone, which remain unreacted and are subsequently removed by filtration. If desired, the solids can be repurified to >98% purity DCDHAQ (HPLC) by dissolving 1 gram of solids in 4 mL of dimethylsulfoxide, adding 12 mL of deionized water to form a precipitate, then filtering the precipitate, washing the precipitate with deionized water, and drying. The NMR spectrum of the DCDHAQ produced in this example is consistent with the literature; see J. Mater. Chem. A, 2021, 9, 26709-26716. 1 H NMR (500 MHz, DMSO-d6) δ 12.43 (s, 2H), 12.24 (s, 2H), 7.76 (dd, J = 7.5 Hz, 2H), 7.68 (dd, J = 7.5 Hz, 2H), 3.71 (s, 4H). Example 3

[0065] A solution of 2,7-bis(a-hydroxy-carboxymethyl)-1,8-dihydroxyanthraquinone was prepared by first stirring 2.60 liters of deionized water, 78 mL of 50% NaOH, 128 mL of 45% KOH, 80.9 g of 1,8-dihydroxyanthraquinone, and 70.6 g of sodium hydrosulfite under argon at room temperature for 5 minutes, then adding a solution of 91.7 g of glyoxylic acid monohydrate in 200 mL of a solution comprising 0.5 M NaOH and 0.5 M KOH, adding this solution dropwise over 256 minutes using an addition funnel. Once the addition was complete, the reaction mixture was exposed to air and filtered to produce a solution of 2,7-bis(a-hydroxy-carboxymethyl)-1,8-dihydroxyanthraquinone, as well as excess NaOH / KOH and other reactants. Separately, as in Example 2, a 200 cm 2An electrochemical cell ("MP Cell®", ElectroCell, Inc., USA) of electrode area was constructed with a graphite felt cathode, a stainless steel anode, a Nafion® 115 membrane, a polypropylene flow frame, an EPDM gasket, a cathode reservoir for holding catholyte, and an anode reservoir for holding anolyte. The cathode reservoir had a capacity of about 2 liters and was maintained under an inert nitrogen atmosphere to prevent reoxidation of the reaction mixture by atmospheric oxygen, while the anode reservoir had a capacity of about 10 liters and was open to the atmosphere. Both reservoirs were equipped with heating elements to heat the anolyte and catholyte as needed. A solution of 2,7-bis(a-hydroxy-carboxymethyl)-l,8-dihydroxyanthraquinone was then preheated to 65°C and poured into the cathode reservoir and maintained under nitrogen. Separately, a 4 liter solution of 3 M NaOH was preheated to 65°C and poured into the anode reservoir and left open to the air. Pumps were used to circulate the catholyte and anolyte solutions to the cathode and anode chambers of the electrochemical cell, respectively, and a constant current density of 50 mA / cm2was passed through the cell (10 A total current) while the temperature of the solutions was maintained in the range of 51 to 71 °C. When 4 molar equivalents of charge (34.98 Ah) had been passed, the current was stopped. Near the end of the experiment, the cell voltage rose sharply from the original value of 1.5 to 1.6 V, which had persisted for most of the experiment, to 2.3 to 2.4 V. The catholyte was drained from the cathode reservoir, reoxidized by exposure to atmospheric oxygen, and filtered to remove any solids. The filtrate was acidified with 15% HC1 until the pH was about 1, and the precipitated material was filtered, rinsed with water, and dried. The crude material was redissolved in aqueous KOH, reacidified, recollected by filtration, and washed again with water to give the target molecule, 2,7-bis(carboxymethyl)-l,8-dihydroxyanthraquinone. Yield relative to 1,8-dihydroxyanthraquinone: 80.0 g (66.7%). Most of the loss was from incomplete dissolution of the unreacted 1,8-dihydroxyanthraquinone removed in the first filtration. 2

[0066] ​Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as size, amount, volume, concentration, time, temperature, and so forth as used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless otherwise indicated, the numerical parameters set forth in the foregoing description and associated claims are approximations. Thus, unless otherwise indicated, the numerical parameters set forth in the foregoing description and associated claims are approximations. Variations are made to the specification and claims in terms of material and / or dimensions. These parameters and geometric configurations are by way of example and are susceptible to modification without departing from the spirit of the disclosure. All such modifications and variations are considered within the scope of the disclosure. It is intended, therefore, that the specification and examples be considered as illustrative and that the true scope of the disclosure be indicated by the appended claims.

[0067] The foregoing description has been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the embodiments to the precise form disclosed. Many modifications and variations are possible in light of the above teaching. Any or all features of the disclosed embodiments can be applied singly or in any combination. There is no intention to limit the scope of the application to the specified recreational vehicle only. The intention is to cover all logical, enhanced, additional, or alternate variations that are within the spirit and scope of the application, as defined by the claims. The specification is to be regarded as illustrative, rather than restrictive, and all modifications are intended to be included within the scope of the application.

Claims

1. A method for α-hydroxy alkylation or alkylation at the 2-position of an anthraquinone derivative selected from the group consisting of formulas I, II, III and IV, comprising: The anthraquinone derivative, aldehyde, base, optional solvent, and optional catalyst are added to the reaction vessel; Hydrogen gas is introduced into the reaction vessel; To cause the mixture to react; Remove the hydrogen gas from the reaction vessel; An oxidant is introduced into the reaction mixture, and Separate the product from the reaction mixture. Where X is a hydroxyl or amino group, and X1 and X2 are each independently a hydroxyl or amino group, and The catalyst is selected from the group consisting of: nickel / carbon, palladium / carbon, platinum / carbon, rhodium / carbon, palladium hydroxide, platinum black, platinum dioxide, Wilkinson catalyst, Crabbuter catalyst, Shvor catalyst, or mixtures thereof.

2. The method according to claim 1, wherein the base is selected from the group consisting of: inorganic hydroxides, metal alkoxides, amines, amidines, or mixtures thereof.

3. The method according to claim 2, wherein the alkali is selected from the group consisting of sodium hydroxide, potassium hydroxide, or mixtures thereof.

4. The method according to claim 1, wherein the solvent is water.

5. The method according to claim 1, wherein the hydrogen is introduced and removed as a gas.

6. The method of claim 1, wherein the catalyst is Raney nickel and the hydrogen is provided on the catalyst as an adsorbent.

7. The method according to claim 1, wherein the oxidant is oxygen from the atmosphere.

8. The method of claim 1, wherein the aldehyde is introduced only after the hydrogen has been vented from the reaction vessel but before the oxidant has been added.

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