Systems and processes for anthraquinone functionalization

Abstract

The present invention relates to the synthetic functionalization of anthraquinone molecules that are substituted with at least one hydroxyl or amino group. In some aspects of the invention, the synthetic functionalization of the anthraquinone molecules occurs electrochemically rather than chemically by using a split electrolytic cell. JPEG2024506445000006.jpg55170

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application was filed as a PCT international patent application on June 9, 2022, and claims the benefit of and priority to U.S. Provisional Application No. 63 / 215,079, filed June 25, 2021, the entire disclosure of which is incorporated herein by reference in its entirety. The present invention relates generally to synthetic organic chemical processes. More specifically, the present invention relates to the synthetic functionalization of anthraquinone molecules substituted with at least one hydroxyl or amino group. Statement regarding federally funded research Certain aspects of the present invention were made with Government support from the U.S. Department of Energy under Award No. DE-AC05-76RL01830 through PNNL Subcontract 535264. The Government has certain rights in this invention. [Background technology]

[0002] The Marschalk reaction is the reaction of hydroxyl- or amino-substituted anthraquinones with aldehydes in the presence of sodium dithionite to introduce an α-hydroxyalkyl functionality at the ortho position of the hydroxyl or amine substituent on the starting molecule. 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 α-hydroxyalkyl functionality follows, leaving a methylene (-CH2-) linker between the anthraquinone core and the remaining new functionality. This reaction works with a variety of aldehydes, such as formaldehyde, acetaldehyde, benzaldehyde, and glyoxylic acid. See, for example, K. Krohn, Angewandte Chemie International Edition 1979, 18, 621-622. The reaction can be intermolecular or intramolecular. See, F. Suzuki, S. Trenbeath, RD Gleim, CJ Sih, Journal of the American Chemical Society 1978, 100, 2272-2273. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] U.S. Patent No. 2,941,865 [Non-patent literature]

[0004] [Non-Patent Document 1] European Journal of Organic Chemistry,2013,7193-7199 [Non-Patent Document 2] Angewandte Chemie International Edition 1979,18,621-622 [Non-Patent Document 3] Angewandte Chemie International Edition 1979,18,621-622 [Non-Patent Document 4] Science 2015,349,1529-1532 Summary of the Invention [Problem to be solved by the invention]

[0005] In all reported examples of (α-hydroxy)alkylation or alkylation of hydroxyl or amino substituted anthraquinones, the reducing agent used is sodium dithionite. The same reaction can be carried out at a lower cost by replacing sodium dithionite with another, less expensive reducing agent. [Brief description of the drawings]

[0006] [Figure 1] 1 shows a synthetic scheme for (α-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. [Diagram 2] FIG. 1 shows a synthetic scheme for the (α-hydroxy)alkylation or alkylation of a substituted anthraquinone starting material by electrochemical reduction of a substituted anthraquinone starting material, according to certain embodiments. [Diagram 3] 1 shows an electrolytic cell for effecting (α-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 OF THE PREFERRED EMBODIMENTS

[0007] The Marschalk reaction mechanism begins with the reduction of the 9,10-anthraquinone core of a substituted anthraquinone starting material to a 9,10-dihydroxyanthracene core. This reduced starting material then reacts with an aldehyde to form a carbon-carbon bond.

[0008] It is known that 9,10-anthraquinone can be easily reduced to the corresponding 9,10-dihydroxyanthracene using other reactants such as hydrogen gas, optionally in the presence of a catalyst such as palladium supported on a carbon substrate. See G. Max, L. Emile, U.S. Pat. No. 2,941,865 (filed Oct. 16, 1956). Alternatively, the reduction can be achieved electrochemically, such as in a half-cell of a flow battery. See K. Lin, Q. Chen, MR Gerhardt, L. Tong, SB Kim, L. Eisenach, AW Valle, D. Hardee, RG Gordon, MJA Ziz, MP Marshak, Science 2015, 349, 1529-1532.

[0009] However, the use of reducing agents other than sodium dithionite in the Marschalk reaction is unknown. The present invention features the synthesis of anthraquinone derivatives via a process similar to the classical Marschalk reaction, but using reducing agents other than sodium dithionite or other dithionites.

[0010] In one embodiment of the invention summarized in Figure 1, the substituted anthraquinone starting material, aldehyde, base, optional solvent, and optional catalyst are mixed in a reaction vessel exposed to an atmosphere containing hydrogen gas. The reaction may be heated, cooled, or held at different temperatures throughout the reaction time. Depending on the reaction temperature, either the (α-hydroxy) alkylated product or the dehydroxylated alkylated product is favored. After a predetermined time, an oxidizing agent is introduced to the reaction mixture. After a further predetermined time, the reaction product is isolated from the reaction mixture and, optionally, purified by conventional means well known to those skilled in the art (e.g., precipitation, filtration, distillation, sublimation, recrystallization, solvent extraction, washing, chromatography, centrifugation).

[0011] In some embodiments of the present invention, the substituted anthraquinone starting material comprises formula I: [ka]

[0012] wherein X is selected from the group consisting of a hydroxy or amino group at the 1-position, and the 2-position of the anthraquinone is unsubstituted (i.e., a carbon bonded to hydrogen). Those skilled in the art will appreciate that other substituents present on the substituted anthraquinone starting material may alter the positional numbering of the aforementioned hydroxy or amino groups, as well as the positional numbering of the unsubstituted carbon atom at the ortho-position. However, the positional numbering will not affect the general reactivity, but only the relative positioning of the hydroxy group and its adjacent unsubstituted carbon atom on the substituted anthraquinone. In some embodiments of the present invention, the aldehyde is covalently bonded to the anthraquinone derivative, and the reaction may proceed intramolecularly or under certain conditions to form a dimer, or a cyclamer, or an oligomeric or polymeric chain.

[0013] In some embodiments of the invention, the base is selected from the group consisting of inorganic hydroxides, metal alkoxides, amines, or amidines, or mixtures thereof. In certain embodiments of the invention, the base is an alkali metal hydroxide (e.g., sodium hydroxide or potassium hydroxide). In other embodiments of the invention, the base is a metal alkoxide or an alkali metal alkoxide (e.g., sodium methoxide or potassium tert-butoxide). In other embodiments of the invention, the base is an amine or a trialkylamine (e.g., triethylamine or diisopropylethylamine). In other embodiments, the base is an amidine, where the amidine is a non-nucleophilic base (e.g., 1,8-diazabicycloundec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)).

[0014] In general, most aldehydes can undergo a reaction similar to the classical Marschalk reaction described in the above literature. In some embodiments of the reaction, the aldehyde is a water-soluble aldehyde (e.g., formaldehyde or acetaldehyde). In other embodiments of the reaction, the aldehyde is an organic compound (e.g., benzaldehyde) that is poorly soluble or insoluble in water but soluble in organic solvents. In still more embodiments of the present invention, the aldehyde (e.g., glyoxylic acid) contains an acidic group that confers solubility when mixed with a base.

[0015] In some embodiments of the invention, aldehydes can reversibly interconvert between a form with a free aldehyde group and a form in which a molecule of water or alcohol is added to the aldehyde group, thus forming a gem-diol or hemiacetal, respectively. In a further aspect of the invention, the alcohol group is located on the same molecule as the aldehyde, and the reversible addition occurs intramolecularly. In another aspect of the invention, the aldehyde functionality 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 as either D- or L-enantiomers, or a mixture of the two, or a racemic mixture. It will be understood by those skilled in the art that any reducing sugar can be used in the embodiments described herein. Other embodiments of the reaction may use a non-reducing sugar, which is then converted to an aldehyde-containing reducing sugar during the course of the reaction. An example of such a non-reducing sugar is fructose, which can be converted to either glucose or mannose, both of which are reducing sugars.

[0016] In some embodiments of the present invention, the base and / or aldehyde act as the solvent. In other embodiments of the present invention, the solvent is a separate species, such as water, methanol, ethanol, isopropanol, 1,4-dioxane, N,N-dimethylformamide, etc. In other embodiments of the present invention, the solvent comprises two or more solvents, such as water-ethanol mixtures, methanol-N,N-dimethylformamide mixtures, water-1,4-dioxane mixtures, etc. It will be understood by those skilled in the art that any polar, protic or aprotic solvent and mixtures thereof may be used in the embodiments described herein.

[0017] In some embodiments of the present invention, the optional catalyst is a catalyst for catalytic hydrogenation or a pre-catalyst that is converted to an active catalyst for catalytic hydrogenation during the course of the reaction. The catalyst may optionally be supported on a 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.

[0018] In some embodiments of the invention, the reaction atmosphere is composed partially or entirely of hydrogen. The reaction atmosphere may be at atmospheric pressure, subatmospheric pressure, or superatmospheric pressure.

[0019] In some embodiments of the invention, the oxidizing agent is in the gas phase and may be air, oxygen, ozone, or a mixture thereof. Alternatively, the oxidizing agent may be a liquid or in solution phase (including, but not limited to, dimethylsulfoxide or hydrogen peroxide). The oxidizing agent may be a solid, such as silver(I) oxide. Combinations of different oxidizing agents may also be used.

[0020] 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.

[0021] In some embodiments of the present invention, the aldehyde is introduced only after the hydrogen has been vented from the reaction vessel, but before the reduced substituted anthraquinone starting material is reoxidized by the oxidizing agent.

[0022] In another embodiment of the invention, summarized as a chemical reaction in Figure 2 and illustrated in Figure 3, the reduction of the substituted anthraquinone starting material occurs electrochemically rather than chemically by using a split electrolytic cell 300. The split electrolytic cell 300 includes a first chamber 310 having a first electrode 311 and is separated from a second chamber 320 having a second electrode 321 by an ionically conductive membrane 330. Independently, an electrocatalyst may be present only at the first electrode 311, only at the second electrode 321, both at the first electrode 311 and the second electrode 321, or no electrocatalyst may be present at either the first electrode 311 or the second electrode 321.

[0023] A first fluid stream 312, comprising the substituted anthraquinone starting material of formula I, an aldehyde, a base, and optional solvent, flows into the first chamber of the electrolytic cell 310 through a first chamber inlet 313, causing the first fluid stream to contact the first electrode 311 and exit through a first chamber outlet 314. At the same time, a second fluid stream 322 flows into the second chamber of the electrolytic cell 320 through a second chamber inlet 323, causing the second fluid stream to contact the second electrode 321 and exit through a second chamber outlet 324. An electric potential 340 is applied to the two 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.

[0024] As the first fluid stream 312 passes through the first electrode 311 it is electrochemically reduced. Similarly, as the second fluid stream 322 passes through the second electrode 321 it is electrochemically oxidized. The first fluid stream 312 may pass through the first chamber 310 of the split electrolytic cell 300 only once, or the fluid exiting the first chamber outlet 314 may be recirculated and flow back to the first chamber inlet 313 multiple times. Similarly, the second fluid stream 322 may pass through the second chamber 320 of the split electrolytic cell 300 only once, or the fluid exiting the second chamber outlet 324 may be recirculated and flow back to the second chamber inlet 323 multiple times. The split electrolytic cell 300, the first fluid stream 312, and / or the second fluid stream 322 may be heated, cooled, or held at different temperatures throughout the reaction time. Depending on the reaction temperature, either the (α-hydroxy)alkylated product is favored or the dehydroxylated alkylated product is favored.

[0025] After a predetermined time or amount of charge has passed, the first fluid stream 312 may be treated in one of several ways described below, and the reaction products may then be isolated from the treated first fluid stream and, optionally, purified by conventional means well known to those skilled in the art. The threshold amount of charge to pass may be predetermined by looking at the theoretical amount of charge required for the reaction to proceed to completion. In FIG. 2, the anthraquinone starting material is reduced to a 9,10-dihydroxyanthracene derivative, which then requires two equivalents of electrons to react with an aldehyde to form an (α-hydroxy) alkylated intermediate. This intermediate then undergoes intramolecular disproportionation to produce an alkylated product and a reoxidized anthraquinone core, which can accept two more electrons. In this case, the threshold amount of charge is four equivalents relative to the amount of anthraquinone starting material originally present. If two equivalents of aldehyde react with one molecule of anthraquinone starting material, the theoretical amount of charge to pass would be six equivalents. A larger threshold amount of charge can be set to account for process inefficiencies such as the effect of oxygen reoxidizing the reaction mixture, coulombic efficiency resulting from side reactions, etc. Conversely, if the (α-hydroxy)alkylated intermediate is in fact the desired product, or if the (α-hydroxy)alkylated material is the starting material and the dehydroxylated alkylated material is the desired product, a smaller equivalent of charge (e.g., about 2 equivalents) can be used as the reaction endpoint.

[0026] Alternatively, if the alkylated (non-α-hydroxylated) product is the desired product and towards the end of the reaction there are fewer and fewer 9,10-anthraquinone cores remaining in the reaction mixture that can accept electrons, a threshold voltage (if current is passed galvanostatically) or a threshold current or current density (if current is passed potentiostatically) can be used instead of a given time or a given amount of charge passed. This is manifested as a sudden increase in voltage if current is passed galvanostatically, or a decrease in current if current is passed potentiostatically. In order to minimize the amount of potential side reactions, it is recommended to set an upper threshold voltage or a lower threshold current (or current density) above which the current stops. The threshold voltage can be defined as a fixed number (e.g., >0.5V / cell, >1.0V / cell, >1.5V / cell, >1.6V / cell, >1.7V / cell, >1.8V / cell, >1.9V / cell, >2.0V / cell, >2.1V / cell, >2.2V / cell, >2.3V / cell, >2.4V / cell, >2.5V / cell, etc.), or it can be defined as a percentage increase relative to the average voltage for the first particular number of equivalents of charge passed (e.g., >10% of the average voltage over the first equivalent of charge passed, >20% of the average voltage over the first 0.5 equivalents of charge passed, >30% of the average voltage over the first 0.5 equivalents of charge passed, >40% of the average voltage over the first 0.25 equivalents of charge passed, >50% of the average voltage over the first 0.1 equivalent of charge passed, and many such combinations thereof). For example, if the theoretical amount of charge that can be passed is 4 equivalents, and the cell voltage is an average of 1.5 V above the first equivalent of charge passed, then a threshold voltage of 30% above the onset voltage means that if current is applied galvanostatically, the current will stop when the voltage exceeds 1.95 V / cell. Similarly, the threshold current (or current density) can be expressed as a number (e.g., <10 A, <1 A, <0.1 A, <0.01 A, <10 mA / cm 2 , <1mA / cm 2 , <0.1mA / cm 2 , <0.01A / cm 2etc.), or it can be defined as a percentage of the average current or current density for the first particular number of equivalents of charge passed (e.g., <10% of the average current or current density for the first equivalent of charge passed, <5% of the average current or current density for the first 0.5 equivalents of charge passed, <2% of the average current or current density for the first 0.5 equivalents of charge passed, <1% of the average current or current density for the first 0.2 equivalents of charge passed, <0.5% of the average current or current density for the first 0.25 equivalents, <0.2% of the average current or current density for the first 0.1 equivalents of charge passed, <0.1% of the average current or current density for the first 0.1 equivalents of charge passed, and many such combinations thereof). For example, if the theoretical amount of charge that can be passed is 4 equivalents and the current density averages the first equivalent of charge passed at 100 mA / cm 2 If above, the threshold current density of <1% of the onset current density is 1 mA / cm when the current is applied potentiostatically. 2 This means that the current will stop when the cell voltage falls below 0.5 V. In some embodiments, current is passed galvanostatically until the cell voltage reaches 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 falls below a similarly specified threshold for constant voltage operation.

[0027] In some embodiments of the reaction, the substituted anthraquinone comprises formula II: [ka]

[0028] where X is a hydroxyl or amino group. In some embodiments, X1 and X2 are the same. In other embodiments, X1 and X2 are different. Examples include 1,5-dihydroxyanthraquinone, 1,5-diaminoanthraquinone, 1-hydroxy-5-aminoanthraquinone, and the like.

[0029] In another embodiment of the reaction, the substituted anthraquinone comprises formula III: [ka]

[0030] where X is a hydroxyl or amino group. In some embodiments, X1 and X2 are the same. In other embodiments, X1 and X2 are different. Examples include 1,8-dihydroxyanthraquinone, 1,8-diaminoanthraquinone, 1-hydroxy-8-aminoanthraquinone, etc. Anthraquinones of formulas II and III, which contain two X substituents on separate aromatic rings of the same molecule, or two unsubstituted positions at each ortho position of the X substituent, can be reacted with two equivalents of an aldehyde to form a bis(α-hydroxy) alkylation product or a bis-alkylation product.

[0031] In another embodiment of the reaction, the substituted anthraquinone comprises formula IV: [ka]

[0032] where X is a hydroxyl or amino group. In some embodiments, X1 and X2 are the same. In some embodiments, X1 and X2 are different. Examples include 1,4-dihydroxyanthraquinone, 1,4-diaminoanthraquinone, 1-hydroxy-4-aminoanthraquinone, etc. Anthraquinones of formulas II, III, and IV, which contain two X substituents on separate aromatic rings of the same molecule, or two unsubstituted positions at each ortho position of the X substituent, can be reacted with two equivalents of an aldehyde to form bis(α-hydroxy) alkylation products or bis-alkylation products.

[0033] In some embodiments of the invention, the base is selected from the group consisting of inorganic hydroxides, metal alkoxides, amines, amidines, and mixtures thereof. In certain embodiments of the invention, the base is an alkali metal hydroxide (e.g., sodium hydroxide or potassium hydroxide). In other embodiments of the invention, the base is a metal alkoxide or an alkali metal alkoxide (e.g., sodium methoxide or potassium tert-butoxide). In other embodiments of the invention, the base is an amine or a trialkylamine (e.g., triethylamine or diisopropylethylamine). In other embodiments, the base is an amidine or a non-nucleophilic base (e.g., 1,8-diazabicycloundec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)).

[0034] In some embodiments of the invention, the base and / or the aldehyde act as the solvent, while in other embodiments of the invention, the solvent is a separate species, such as water, methanol, ethanol, isopropanol, 1,4-dioxane, N,N-dimethylformamide, and the like.

[0035] In some embodiments of the present invention, the first electrode 311 and the second electrode 321 may include a defined flow channel for directing a fluid.

[0036] In some embodiments of the invention, the first electrode 311 and the second electrode 321 are conductive carbon electrodes. In other embodiments of the invention, the first electrode 311 is a conductive carbon electrode and the second electrode 321 comprises nickel, cobalt, iron, stainless steel, or platinum.

[0037] In some embodiments of the invention, the ion selective membrane 330 is a cation conducting membrane such as Nafion® 212, FuMATech® E-630, or Selemion CMV-N®.

[0038] In some embodiments of the invention, the second fluid stream 322 comprises hydrogen gas. In further embodiments of the invention, the second electrode 321 is configured to allow hydrogen to be oxidized, thereby acting as an electron source, such as a gas diffusion electrode. In still further embodiments of the invention, the second electrode 321 also contains an electrocatalyst for hydrogen oxidation, such as platinum.

[0039] In some embodiments of the invention, the second fluid stream 322 comprises methanol. In further embodiments of the invention, the second electrode 321 also contains an electrocatalyst for methanol oxidation, such as platinum-ruthenium.

[0040] In some embodiments of the present invention, the second fluid stream 322 comprises an aqueous solution of a salt of ferrocyanide (eg, sodium ferrocyanide, potassium ferrocyanide, or ammonium ferrocyanide).

[0041] In some embodiments of the invention, the second fluid stream 322 comprises an aqueous solution of an alkali metal hydroxide (e.g., sodium hydroxide or potassium hydroxide). In further embodiments of the invention, the second electrode 321 comprises a typical alkaline electrolytic cell material (e.g., nickel or stainless steel). In further embodiments of the invention, oxygen produced at the second electrode 321 is used as an oxidant in process 1 to re-oxidize the first fluid stream 311.

[0042] In some embodiments of the invention, 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 split electrolyzer 300 falls below a threshold defined above, or after the applied potential exceeds a threshold, or after a predetermined amount of charge has passed. In further embodiments of the invention, the potential 340 between the first electrode 311 and the second electrode 321 is switched to an open circuit potential before the aldehyde is added to the first fluid stream 312 (a) after the current density in the split electrolyzer 300 falls below a threshold, (b) after the applied potential exceeds a threshold, or (c) after a predetermined amount of charge has passed.

[0043] In some aspects of the invention, the split electrolyzer 300 can be used as a redox flow battery cell without the need to replace the first electrode 311 or the second electrode 321 or the ion-conducting membrane 330. In further embodiments of the invention, the (α-hydroxy)alkylated product or dehydroxylated alkylated product produced in the first fluid stream 312 using the split electrolyzer 300 is not discharged from the first chamber 310 of the split electrolyzer 300, but is retained in solution phase and used directly as the negative electrolyte (i.e., negolyte or anolyte) in a redox flow battery (the split electrolyzer 300 is a redox flow battery cell). In yet a further embodiment of the invention, the second fluid stream 322 is not discharged from the second chamber 320 of the split electrolyzer 300 but is retained in solution phase and used directly as the positive electrolyte (i.e., posolyte or catholyte) of a redox flow battery (wherein the split electrolyzer 300 is a redox flow battery cell). In a further embodiment of the invention, both the first fluid stream 312 and the second fluid stream 322 are not discharged from the first chamber 310 and the second chamber 320 of the split electrolyzer 300, respectively, but are retained in solution phase and used directly as the negative and positive electrolytes of a redox flow battery (wherein the split electrolyzer 300 is a redox flow battery cell), respectively, or used directly as the positive and negative electrolytes of a redox flow battery cell, respectively.

[0044] In further embodiments of the invention, the charge states of the negative and positive electrolytes (previously 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) may be individually adjusted or re-adjusted to maximize the capacity of the resulting redox flow battery. For example, the first fluid stream 312 or the second fluid stream 322 may be treated with an oxidizing agent (e.g., atmospheric oxygen, hydrogen peroxide, ozone, sodium hypochlorite, etc.), or the first fluid stream 312 or the second fluid stream 322 may be treated with a reducing agent (hydrogen, hydrazine, hydrazine hydrate, sodium thiosulfate, sodium dithionate, sodium sulfite, etc., with an optional catalyst).

[0045] In some embodiments of the invention, the substituted anthraquinones and aldehydes in the first fluid stream 312 are replaced by intermediates of the same type of reaction described above (i.e., different substituted anthraquinones containing a hydroxy or amine group at the 1-position and further containing a -CH(OH)-R group at the 2-position). In this case, the desired product will be dehydroxylated at the benzylic position of the 2-position substituent.

[0046] Action 1 After a predetermined time or amount of charge has passed, the first fluid stream 312 is discharged from the first chamber 310 of the split electrolyzer 300 and an oxidant is introduced into the first fluid stream 312. In some embodiments of the invention, the oxidant is in the gas phase and may be air, oxygen, ozone, or a mixture thereof. Alternatively, the oxidant may be a liquid or in solution phase (including but not limited to dimethylsulfoxide or hydrogen peroxide). The oxidant may be a solid, such as silver(I) oxide. Combinations of different oxidants may also be used. After a further predetermined time, the reaction products are isolated from the oxidized first fluid stream and, optionally, purified by conventional means well known to those skilled in the art.

[0047] Action 2 After a predetermined time or amount of charge passed, the second fluid stream 322 is optionally replaced by a third fluid stream 325, and the potential 340 between the first electrode 311 and the second electrode 321 is reversed in sign, such that electrochemical oxidation of the first fluid stream 312 takes place instead of electrochemical reduction, and electrochemical reduction of either the second fluid stream 322 or the third fluid stream 325 takes place instead of electrochemical oxidation. After a further predetermined time or amount of charge passed, or a current density below a threshold, or an applied potential above a threshold, the oxidized first fluid stream 312 is discharged from the first chamber 310 of the split electrolyzer 300, and the reaction products are isolated and optionally purified by conventional means well known to those skilled in the art.

[0048] Action 3 After a predetermined time or amount of charge has passed, the first fluid stream 312 is discharged from the first chamber 310 of the split electrolytic cell 300. The discharged first fluid stream 362 flows through the third chamber 360 past the third electrode 361 of the second split electrolytic cell 350. The second split electrolytic cell 350 has a third fluid stream 372 flowing through its fourth electrode 371 through the fourth chamber 370. An electric potential 390 is applied to the third electrode 361 and the fourth electrode 371 of the second split electrolytic cell 350 such that the third electrode 361 is at a more positive potential relative to the fourth electrode 371. (i.e., the third electrode 361 is the anode and the fourth electrode 371 is the cathode 371.) After a further predetermined time, or passage of a predetermined amount of charge, or a current density below a threshold, or an applied potential above a threshold, the discharged first fluid stream 362, now oxidized, is discharged from the third chamber 360 of the second divided electrolytic cell 350 and the reaction products are isolated and optionally purified by conventional means well known to those skilled in the art (reprecipitation, recrystallization, filtration, distillation, washing, extraction, chromatography, etc.). EXAMPLES

[0049] Example 1 In a Parr hydrogenator equipped with a mechanical stirrer, 3.00 g of 1,8-dihydroxyanthraquinone (12.49 mmol), 3.45 g of glyoxylic acid monohydrate (37.47 mmol, 3 equiv.), and 0.30 g of 5 wt. % palladium on carbon were thoroughly mixed in 100 mL of 1.63 M NaOH solution. The reaction mixture was sparged with hydrogen gas for 3 minutes and then pressurized with hydrogen to reach a pressure of 100 psi. The reaction was stirred at room temperature (approximately 20° C.) for 1 hour and then heated to 80° C. for 1 hour. The vessel was vented and the reaction mixture was poured onto ample ice to rapidly reduce the temperature to approximately room temperature, and then a stream of air was bubbled through the reaction mixture for 30 minutes. The solution was acidified with 6 M hydrochloric acid to pH 8-9 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 to a pH of about 0, causing an ochre solid to precipitate from solution. The solid was collected by filtration and washed with cold water to give the crude product 1,8-dihydroxy-2,7-bis(carboxymethyl)-9,10-anthraquinone (60% yield). The solid can be purified by recrystallization from hot water and dried if necessary.

[0050] Example 2 200cm 2An electrochemical cell ("MP Cell®", ElectroCell North America, Inc.) with an electrode area of ​​100 μm 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 the catholyte, and an anode reservoir for holding the anolyte. The cathode reservoir had a volume of approximately 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 volume of approximately 10 liters and was open to the atmosphere. Both reservoirs were equipped with heating elements to heat the anolyte and catholyte as needed. The anode reservoir was first filled with 2 liters of 3 M NaOH. Outside the cathode reservoir, catholyte was first prepared by mixing 137 mL of 50% NaOH solution, 33.8 g of glyoxylic acid monohydrate, and 30.0000 g (124.89 mmol) of 1,8-dihydroxyanthraquinone in enough deionized water to bring the total volume of catholyte to approximately 2.0 liters. The cathode slurry was added to the cathode reservoir and the pump was started to circulate both the catholyte and anolyte through the electrochemical cell. An additional 750 mL of deionized water was added to the catholyte to bring the final catholyte volume to 2.75 liters. The catholyte and anolyte were warmed to 40°C and the temperature was slowly increased to 50°C while a current of 40 mA / cm was applied. 2A constant current of 0.1 V (total current 4 A) was passed. During operation, oxygen gas was evolved at the anode while the catholyte solution was reduced. After 2 equivalents of charge to 1,8-dihydroxyanthraquinone had been passed (249.78 mmol, 24,100 coulombs), the temperature was raised to 65 °C and held there until a total of 4.1 equivalents of charge (512.05 mmol, 49,405 coulombs) had been passed. HPLC analysis of the aerated aliquot showed that no 1,8-dihydroxyanthraquinone remained in solution and the target molecule, 2,7-bis(carboxymethyl)-1,8-dihydroxyanthraquinone (DCDHAQ), was present in approximately 86% purity. Some impurities observed by HPLC (British Pharmacopeia 2004 for Dantron: C18 column, eluted isocratically with a mixture of 2.5 volumes of glacial acetic acid, 40 volumes of tetrahydrofuran, and 60 volumes of water, flow rate 1 mL / min, run time 40 min, detection at 254 nm) included the intermediate compounds 2,7-bis(α-hydroxy-carboxymethyl)-1,8-dihydroxyanthraquinone and 2-(α-hydroxy-carboxymethyl)-7-carboxymethyl-1,8-dihydroxyanthraquinone, which can be converted to the target molecule DCDHAQ by reduction in an electrochemical cell or through the process of cycling in a flow battery cell. Other impurities include 2,2'-(1,8-dihydroxy-9-oxo-9,10-dihydroanthracene-2,7-diyl)diacetic acid, 2,2'-(1,8-dihydroxy-10-oxo-9,10-dihydroanthracene-2,7-diyl)diacetic acid, 2,2',2'',2'''-(4,4',5,5'-tetrahydroxy-10,10'-dioxo-9,9',10,10'-tetrahydro-[9,9'-bianthracene]-3,3',6,6'-tetrayl)tetraacetic acid, and related isomers. In general, anthrone and dianthrone can then be converted to the target molecule DCDHAQ through oxidation in an electrochemical cell, prolonged exposure to atmospheric oxygen, or cycling in a flow battery (Reference ChemRxiv 2021, DOI: 10.26434 / chemrxiv-2021-x05x1).Therefore, the catholyte solution from this synthesis can be used directly as a negolyte reactant in a flow battery without downstream processing, optionally with the exception of some concentration by solvent evaporation to save costs and reduce chemical waste. To isolate the product DCDHAQ, the catholyte solution was drained through a filter, exposed to air to completely reoxidize the solution, and refiltered. After acidifying the filtrate to pH<1 with 15% hydrochloric acid, the precipitated solid was filtered and dried overnight at 45°C. The dried solid turned from orange to deep red when ground. Isolated yield: 30.1393g (67.7%), mp 260-262°C. The majority of the loss was likely due to hard masses of undissolved 1,8-dihydroxyanthraquinone that remained unreacted and were later removed by filtration. The solid can be repurified, if necessary, to a purity of >98% DCDHAQ (HPLC) by dissolving 1 g of the solid in 4 mL of dimethyl sulfoxide and adding 12 mL of deionized water to form a precipitate, followed by filtering the precipitate, washing with deionized water, and drying. The NMR spectrum of DCDHAQ produced in this example was identical to that in the literature (reference J. Mater. Chem. A, 2021, 9, 26709-26716). 1 H NMR(500MHz,DMSO-d6)δ 12.43(s,2H),12.24(s,2H),7.76(dd,J=7.5Hz,2H),7.68(dd,J=7.5Hz,2H),3.71(s,4H).

[0051] Example 3 A solution of 2,7-bis(α-hydroxy-carboxymethyl)-1,8-dihydroxyanthraquinone is 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 dithionite at room temperature under argon for 5 minutes, followed by the addition of a solution of 91.7 g of glyoxylic acid monohydrate in 200 mL of a solution containing 0.5 M NaOH and 0.5 M KOH, which is added dropwise over 256 minutes using an addition funnel. Once the addition is complete, the reaction mixture is exposed to air and filtered to produce a solution of 2,7-bis(α-hydroxy-carboxymethyl)-1,8-dihydroxyanthraquinone along with excess NaOH / KOH and other reactants. Separately, 200 cm of 200 cm of 2,7-bis(α-hydroxy-carboxymethyl)-1,8-dihydroxyanthraquinone is added dropwise as in Example 2. 2 An electrochemical cell ("MP Cell®", ElectroCell North America, Inc.) with an electrode area of ​​100 μm 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 the catholyte, and an anode reservoir for holding the anolyte. The cathode reservoir had a volume of approximately 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 volume of approximately 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(α-hydroxy-carboxymethyl)-1,8-dihydroxyanthraquinone was then preheated to 65° C. and poured into the cathode reservoir and maintained under nitrogen. Separately, 4 liters of 3 M NaOH solution was preheated to 65 °C and poured into the anode reservoir and left open to air. The catholyte and anolyte solutions were circulated through the cathode and anode chambers of the electrochemical cell using pumps, respectively, at 50 mA / cm while maintaining the temperature of the solutions within the range of 51-71 °C. 2Current was passed at a constant current density of 10 A total current. The current was stopped when 4 molar equivalents of charge (34.98 Ah) had been passed. For most experiments, near the end of the experiment, the cell voltage rose sharply from an original value of 1.5-1.6 V to 2.3-2.4 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 to pH 1 with 15% HCl, and the precipitate was filtered, washed with water, and dried. The crude material was redissolved in aqueous KOH, reacidified, recollected by filtration, and washed with water again to give the target molecule, 2,7-bis(carboxymethyl)-1,8-dihydroxyanthraquinone. Yield for 1,8-dihydroxyanthraquinone: 80.0 g (66.7%). Most of the loss was due to incomplete dissolution of 1,8-dihydroxyanthraquinone, which was removed unreacted during the first filtration.

[0052] Unless otherwise indicated, all numbers expressing size, amount, volume, area, concentration, frequency, temperature, and other chemical and physical properties of features used in the specification and claims are to be understood in all instances as being modified by the term "about". Thus, unless indicated to the contrary, the numerical parameters set forth in the foregoing specification and appended claims are approximations and may vary depending on the desired properties one of ordinary skill in the art seeks to obtain using the teachings disclosed herein. The use of numerical ranges by endpoints includes all numerical values ​​within that range (e.g., 1-5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5; <10% includes 10%, 9.8%, 5.5%, 2%, 0.01%, and 0%; >90% includes 90%, 90.2%, 94.5%, 98%, 99.99%, and 100%) and any range within that range.

[0053] The foregoing description has been presented for purposes of illustration and description. The disclosure is not intended to be exhaustive or to limit the embodiments to the precise forms disclosed. Many modifications and variations are possible in light of the above teachings. Any or all features of the embodiments of the present disclosure may be applied individually or in any combination and are meant to be purely exemplary, not limiting. It is intended that the scope of the invention be determined not by this detailed description, but rather by the appended claims. [Explanation of symbols]

[0054] 300...Divided electrolytic cell 310... First chamber 311... First electrode 312 - First fluid stream 313: First chamber entrance 314... First chamber outlet 320...Second chamber 321... Second electrode 322... Second fluid flow 323...Second chamber entrance 323...Second chamber entrance 325...Third Fluid Stream 330...Ion-conducting membrane 340...potential 350...Second divided electrolytic cell 360...Third chamber 361...Third electrode 362 - First fluid flow 370 Fourth Chamber 371...Fourth electrode 372....Third Fluid Stream 390...potential

Claims

1. A method for (α-hydroxy)alkylating or alkylating the 2-position of an anthraquinone derivative selected from the group consisting of formula I, formula II, formula III, and formula IV with an aldehyde, comprising the steps of: 【Chemistry 1】 (In the formula, X is a hydroxyl group or an amino group, X 1 and X 2 are each independently a hydroxyl group or an amino group, and the 2-position of the anthraquinone derivative means the ortho-position of each of X, X 1, and X 2 and is unsubstituted.) adding an anthraquinone derivative of formula I, II, III, or IV, said aldehyde, a base, an optional solvent, and a catalyst to a reaction vessel; introducing hydrogen into the reaction vessel; reacting the mixture; and removing the hydrogen from the reaction vessel; introducing an oxidizing agent into the reaction mixture; isolating the product from the reaction mixture; and A method comprising:

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

3. 3. The method of claim 2, wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, or a mixture thereof.

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

5. 2. The method of claim 1, wherein the hydrogen is introduced and removed as a gas and the catalyst is selected from the group consisting of 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, or mixtures thereof.

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

7. The method of claim 1 , wherein the oxidant is atmospheric oxygen.

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

9. 2. The method of claim 1, wherein the aldehyde is selected from formaldehyde, acetaldehyde, benzaldehyde, and glyoxylic acid.

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