METHOD OF SYNTHESIZING A FUNCTIONALIZED BIPHENOL COMPOUND BY ELECTROCHEMICAL COUPLING

Description

FIELD OF THE DISCLOSURE

This invention relates to a method of synthesizing a functionalized biphenol compound, and in particular to a method of synthesizing a functionalized biphenol compound, wherein at least one of the functional groups comprises either an aldehyde group or a carboxylic acid group.

BACKGROUND OF THE DISCLOSURE

A functionalized biphenol refers to a molecule where a biphenol has one or more functional groups attached to its structure. The addition of functional groups can modify its properties and allow for further chemical reactions or applications in various fields like polymer synthesis, pharmaceuticals, and materials science. A functional group can be selected from various groups like halogens, alkyl chains, nitro groups, amino groups, or other aromatic rings, which are added to the biphenol molecule at different positions to achieve specific desired properties.

Functionalized biphenol compounds have a wide range of industrial uses. Symmetrical functionalized biphenol compounds are known, including biphenol dialdehydes and biphenol dicarboxylates. For example, the compounds 4,4′-dihydroxy-[1,1′-biphenyl-3,3′-dialdehyde](dobpda) and 4,4′-dihydroxy-[1,1′-biphenyl-3,3′-dicarboxylic acid](dobpdc) each have a range of industrial utilities.

Abatement of carbon emissions has emerged as a global environmental issue. Among many new developments directed at curtailing carbon emissions is the development of solid adsorbents capable of selectively adsorbing carbon oxides. Mg₂ (dobpdc), a metal-organic framework (MOF), and its derivatives functionalized with diamine can be very effective in capturing carbon oxide. To realize its application on a larger scale, the production of dobpdc would need to be scalable and economical.

Reported syntheses of dobpdc require challenging reaction conditions. For example, T. McDonald, Capture of Carbon Dioxide from Air and Flue Gas in the Alkylamine-appended Metal-organic Framework Mmen-Mg₂ (dobpdc), 134 J. Am. Chem. Soc. 7056 (2012) reports a synthesis in which 4,4′-biphenol is reacted with KHCO₃ in 1,2,4-trichlorobenzene in a steel reactor at 255° C. for 17 hours. In another method, 4,4-biphenol is reacted with KHCO₃ in 1,2,4-trichlorobenzene in the presence of carbon dioxide gas in a steel reactor at 250° C. for 72 hours. U.S. Pat. No. 11,465,959 discloses a dobpdc synthesis in which 4,4′-biphenol and K₂CO₃ are reacted in N,N-dimethylformamide (DMF), a harmful organic solvent, in a steel reactor at 200° C. for 70 hours to form a sludge of the product. That publication reports in Table 3 that no dobpdc was produced when the solvent was either methanol or a mixture of methanol and water.

It would be desirable to provide methods of synthesis of functionalized biphenol compounds such as dobpda and dobpdc that do not require expensive noble metal catalysts, potentially hazardous solvents, or elevated temperatures and pressures.

SUMMARY OF THE DISCLOSURE

Disclosed herein are methods of synthesizing functionalized biphenol compounds comprising a step wherein a phenol compound functionalized with at least one substituent which is-COOH or a non-halogen substituent that is convertible to a —COOH substituent is subjected to an electrochemical coupling reaction to form a functionalized biphenol compound having a C—C bond between two phenol rings. The electrochemical coupling reaction can be a reductive coupling reaction or an oxidative coupling reaction.

In one embodiment, a method of synthesizing a functionalized biphenol compound comprises the steps of

• • providing a solution comprising a functionalized phenol compound in a solvent, said phenol compound being functionalized with (a) at least one functional substituent which is —COOH or a non-halogen substituent that is convertible to a —COOH substituent; and (b) a leaving group; and
  • subjecting said functionalized phenol compound to an electrochemical reductive coupling reaction wherein the leaving group leaves the functionalized phenol compound to create a coupling site, whereby two functionalized phenol molecules couple together at their respective coupling sites thereby forming a functionalized biphenol compound having a C—C bond formed between two coupling sites.

The non-halogen substituent that is convertible to a —COOH substituent is selected from —CN or C(═O) R1, where R1 is selected from H, an alkyl, and an —O-alkyl. Optionally, if the non-halogen functional substituent is not —COOH, then after the electrochemical coupling reaction it can be converted to —COOH by subjecting the functionalized biphenol compound to an oxidation step or a hydrolysis step, to yield a biphenol dicarboxylate compound.

In another embodiment, a method of synthesizing a functionalized biphenol compound comprises the steps of providing a solution comprising a functionalized phenol compound in a solvent, said phenol compound being functionalized with at least one functional substituent which is —COOH or a non-halogen substituent that is convertible to a —COOH substituent; and subjecting said functionalized phenol compound to an electrochemical oxidative coupling reaction whereby two functionalized phenol molecules couple together thereby forming a functionalized biphenol compound having a C—C bond between two functionalized phenol rings.

In another embodiment of the present disclosure, a method of synthesizing a functionalized biphenol compound is disclosed, the method comprises the steps of providing a solution comprising a functionalized phenol compound, the functionalized phenol compound comprising a phenol compound functionalized with at least one substituent selected from a —COOH group and a non-halogen substituent that is convertible to a —COOH substituent in a solvent, wherein the non-halogen substituent is selected from —CN group or C(═O) R1, wherein R1 is selected from H, an alkyl, and an —O-alkyl; and treating the solution electrochemically to couple at least two of the functionalized phenol molecules in the solution to synthesize a functionalized biphenol compound having a C—C bond between two phenol rings. In an embodiment of the present disclosure, the electrochemical coupling reaction is a reductive coupling reaction. In an aspect, the functionalized phenol compound is further functionalized with a leaving group, which leaving group leaves the functionalized phenol compound to form a coupling site, such that a C—C bond is formed between two coupling sites. In an embodiment of the present disclosure, the R1 in the non-halogen substituent group C(═O) R1 is not —OH, and the symmetrical functionalized biphenol compound that is the product of the electrochemical reductive coupling step is subjected to an oxidation step to convert the non-halogen substituent to —C(═O) OH to produce a biphenol dicarboxylate compound. In another embodiment of the present disclosure, the electrochemical coupling reaction is an oxidative coupling reaction. In an exemplary embodiment, the functionalized phenol compound is salicylic acid.

In yet another embodiment of the present disclosure, a method of synthesizing a functionalized biphenol compound is disclosed, the method comprising the steps of providing a solution comprising a functionalized phenol compound, the functionalized phenol compound comprising a phenol compound functionalized with at least one substituent selected from a —COOH group and a non-halogen substituent that is convertible to a —COOH substituent by hydrolysis; and electrochemically treating the solution to couple at least two of the functionalized phenol molecules in the solution to synthesize a functionalized biphenol compound having a C—C bond between two phenol rings. In an embodiment of the present disclosure, the non-halogen substituent that is convertible to a —COOH substituent is —CN or C(═O) R1, wherein R1 is selected from H, an alkyl, and an —O-alkyl. In an aspect of the present disclosure, the electrochemical coupling reaction is a reductive coupling reaction. In another aspect of the present disclosure, the electrochemical coupling reaction is an oxidative coupling reaction.

The steps of each of the foregoing embodiments may be accomplished in alcoholic solvents, water, or a mixture of alcohol and water, thereby removing the need for undesirable organic solvents such as CCl₄, trichlorobenzene, amide solvents, and the like. Further, the electrochemical coupling steps can be performed at room temperature and at standard pressure, thereby enhancing safety and cost-effectiveness.

DETAILED DESCRIPTION

The term “alkyl” as used herein means a linear or branched saturated hydrocarbon group including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, up to 10 carbon atoms, more preferably one to six carbon atoms.

The term “substituent” as used herein means one or a group of atoms that replaces one or more atoms, thereby becoming a moiety in the resultant new molecule.

The term “functionalized compound” as used herein means a compound that has a specific “functional group” attached to it, meaning a distinct atom or group of atoms that gives the compound characteristic chemical properties and reactivity, allowing it to participate in specific chemical reactions.

The term “couple together” as used herein means joining together of two molecules by a chemical reaction to form a new, larger molecule.

The term “leaving group” as used herein means an atom or group of atoms that detaches from a molecule during a chemical reaction.

The present disclosure provides an effective solution of synthesizing functionalized biphenol compounds.

In an embodiment of the present disclosure, a first step of the method of synthesizing functionalized biphenol compounds comprises providing a solution comprising a functionalized phenol compound. The solution may comprise a functionalized phenol compound in a suitable solvent, preferably a polar solvent.

In an exemplary embodiment, the solution may comprise a functionalized phenol compound in a solvent selected from water, one or more alkyl alcohols, and a mixture of water and one or more alkyl alcohols.

In accordance with the present disclosure, the functionalized phenol compound may comprise a phenol compound functionalized with at least one substituent selected from a —COOH group and a non-halogen substituent that is convertible to a —COOH substituent.

In an exemplary embodiment, the non-halogen substituent that is convertible to a —COOH substituent may include-CN group or C(═O) R1 where R1 may be selected from H, an alkyl, and an —O-alkyl.

The solution comprising the functionalized phenol compound may be treated electrochemically under selected reaction conditions to couple at least two of the functionalized phenol molecules in the solution to synthesize a functionalized biphenol compound having a C—C bond between two phenol rings.

In an aspect of the present disclosure, the electrochemical treatment of the solution comprising the functionalized phenol compound may include an electrochemical coupling reaction selected from an oxidative coupling reaction and a reductive coupling reaction.

In the embodiment wherein the electrochemical treatment of the solution includes the reductive coupling reaction, the functionalized phenol compound may further be functionalized with a leaving group, which leaving group leaves the functionalized phenol compound to form a coupling site, such that a C—C bond is formed between two coupling sites.

In an exemplary embodiment, the leaving group may include one or more halogens.

In another exemplary embodiment, the leaving group is selected from a tosylate group and a mesylate group.

In an embodiment when the electrochemical treatment of the solution includes the reductive coupling reaction, the functionalized phenol may be 5-bromosalicylaldehyde.

In the embodiment, when the electrochemical treatment of the solution includes the reductive coupling reaction, the non-halogen substituent may comprise C(═O) R1 wherein R1 is not-OH. Further, the symmetrical functionalized biphenol compound that is the product of the electrochemical reductive coupling step is subjected to an oxidation step or a hydrolysis step to convert the non-halogen substituent to —C(═O) OH to produce a biphenol dicarboxylate compound.

In another embodiment when the electrochemical treatment of the solution includes the oxidative coupling reaction, the functionalized phenol compound may be salicylic acid.

In an exemplary embodiment of the present disclosure, the solution comprising the functionalized phenol compound may be treated electrochemically using the reductive coupling method as below:

In one embodiment, a method of synthesizing a functionalized biphenol compound comprises the steps of

• • providing a solution comprising a functionalized phenol compound in a solvent, said phenol compound functionalized with (a) at least one functional substituent which is —COOH or a non-halogen substituent that is convertible to a —COOH substituent; and (b) a leaving group; and
  • subjecting the functionalized phenol compound to an electrochemical reductive coupling reaction wherein the leaving group leaves the functionalized phenol compound to create a coupling site, whereby two functionalized phenol molecules couple together at their respective coupling sites thereby forming a functionalized biphenol compound having a C—C bond formed between two coupling sites.

The non-halogen substituent that is convertible to a —COOH substituent is —CN or C(═O) R1 where R1 is selected from H, an alkyl, and an —O-alkyl. Optionally, if the non-halogen functional substituent is not —COOH, it can be converted to —COOH after the electrochemical coupling step by subjecting the functionalized biphenol compound to an oxidation step or a hydrolysis step, to yield a biphenol dicarboxylate compound.

The functionalized phenol starting compound further comprises a leaving group that will cleave from the phenolic ring during the electrochemical reductive coupling to leave a reactive site on the ring, such that two rings can join to form a biphenol compound. In one embodiment the leaving group is a halide, such as F⁻, Cl⁻, or Br⁻. In one embodiment the leaving group is Br⁻. In one embodiment the leaving group is selected from a tosylate group and a mesylate group. Advantageously, the use of the leaving group at a predetermined location on the functionalized phenol ring assures that only the specific desired biphenol isomers will be formed, and that no unwanted regioisomers will be present in the reaction product. In one embodiment, if the leaving group is located para to the hydroxyl group on the functionalized phenol molecule, then only para biphenol molecules will be present in the reaction product, and the product will be a symmetrical phenol compound.

In one embodiment the —OH substituent of the phenol and the —COOH or non-halogen substituent that is convertible to a —COOH substituent are adjacent one another on the phenol ring. In one embodiment, the starting functionalized phenol compound is 5-bromosalicylic acid. In one embodiment, the starting functionalized phenol compound is 5-bromosalicylaldehyde (i.e., 5-bromo-2-hydroxy-benzaldehyde), and the biphenol compound made by the disclosed method is 4,4′-dihydroxy-[1,1′-biphenyl-3,3′-dialdehyde](dobpda).

In its simplest form, the reductive coupling pathway can be represented by Scheme I, wherein R is the non-halogen functional substituent and X is the leaving group.

In one embodiment, the nonhalogen functional substituent R is an aldehyde group, and the product of the reaction of Scheme I is 4,4′-dihydroxy-[1,1′-biphenyl-3,3′-dialdehyde](dobpda). Scheme II illustrates an oxidation step wherein the aldehyde groups on the dobpda are converted to carboxylate groups to form 4,4′-dihydroxy-[1,1′-biphenyl-3,3′-dicarboxylic acid](dobpdc).

In one embodiment, the oxidation step of Scheme II can be achieved by reacting the dialdehyde (dobpda) with sodium chlorite and sodium methoxide in DMSO solvent. The reaction can be worked up by acidification and extraction to yield the dicarboxylate (dobpdc).

In another embodiment, the non-halogen functional substituent R on the functionalized phenol starting compound of Scheme I is either an ester group or a —CN group, either of which can be converted to a —COOH group by a hydrolysis step to form dobpdc. These alternatives are illustrated in Scheme III, in which the ester of substituent R is —COOMe.

The electrochemical reductive coupling reaction of Scheme I can be carried out in any suitable solvent. The solvent preferably comprises a polar solvent. While well-known organic solvents such as N-methyl pyrrolidone and dimethyl formamide can be used, as well as mixtures of solvents, advantageously, the solvent can be water, one or more alkyl alcohols, or a mixture of water and one or more alkyl alcohols.

In one embodiment the alcohol comprises one or more of methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol, and mixtures of any of the foregoing.

The electrochemical reductive reaction can be conducted in the presence of a catalyst. In one embodiment the catalyst is a metal halide-2,2′bipyridine compound, such as NiBr2bpy. An electrolyte such as a halide salt can be present to support the flow of current in the electrochemical cell. NaBr is one such suitable halide salt. Optionally a surfactant can be used.

The reactants and solvent are supplied to an electrochemical reaction cell equipped with an anode and a cathode. The anode and cathode can be independently selected from metals known to be useful in this regard; particularly suitable metals include Ni, Pt, and Pd. Metals such as iron or magnesium may also be used. The metals of the anode and cathode can be the same or different. Current is applied to the solution, typically until the functionalized phenol compound is consumed in the electrochemical reaction to form the functionalized biphenol compound. The solvent can be removed, such as by evaporation.

Advantageously the electrochemical reductive coupling reaction can be carried out at standard temperature and pressure. Selection of alternative reaction conditions can be based on the choice of solvents and reactants.

In an embodiment, the electrochemical reductive coupling reaction may be carried out at a temperature of about 0° C. to about 50° C. and a pressure of about 100 kPa to about 500 kPa.

In another exemplary embodiment of the present disclosure, the solution comprising the functionalized phenol compound may be treated electrochemically using the oxidative coupling method as below:

Oxidative coupling of phenols is known, such as described in A. Hay, P,p′-Biphenols, 34,4 Journal of Organic Chemistry 1160 (1969); however, it is believed that oxidative coupling has not been applied to make the functionalized biphenol compounds as described herein.

In this embodiment, a method of synthesizing a functionalized biphenol compound comprises the steps of

• • providing a solution comprising a functionalized phenol compound in a solvent, the phenol compound functionalized with at least one functional substituent which is —COOH or a non-halogen substituent that is convertible to a —COOH substituent; and
  • subjecting said functionalized phenol compound to an electrochemical oxidative coupling reaction whereby two functionalized phenol molecules couple together thereby forming a functionalized biphenol compound having a C—C bond between two functionalized phenol rings.

In one embodiment, at least some of the functionalized biphenol compound will be in the form of functionalized biphenol coupled at the para position of each functionalized phenol compound.

In its simplest form, the oxidative coupling pathway can be represented by Scheme IV, wherein R is the non-halogen functional substituent.

In one embodiment, the non-halogen functional substituent R is an aldehyde group, and the product of the reaction of Scheme IV is 4,4′-dihydroxy-[1,1′-biphenyl-3,3′-dialdehyde](dobpda). Optionally, the dobpda can be subjected to an oxidation step to form dobpdc, as illustrated in Scheme II, above. Alternatively, the non-halogen functional substituent R in the starting material of Scheme IV is either an ester or a —CN group, either of which can be converted to a —COOH group by a hydrolysis step to form dobpdc as illustrated in Scheme III above, in which the ester of substituent R is —COOMe.

In yet another embodiment, the non-halogen functional substituent R of Scheme IV is a carboxylic acid group.

In one embodiment, the starting functionalized phenol compound is salicylic acid.

The electrochemical oxidative coupling reaction can be carried out in any suitable solvent. The solvent preferably comprises a polar solvent. While well-known organic solvents such as N-methyl pyrrolidone and dimethyl formamide can be used, as well as mixtures of solvents, advantageously the solvent can be water, one or more alkyl alcohols, or a mixture of water and one or more alkyl alcohols. In one embodiment the alcohol comprises one or more of methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol, and mixtures of any of the foregoing.

Optionally, the electrochemical oxidative reaction can be conducted in the presence of a catalyst, such as a catalyst that includes any of Mn, V, or Cr. Optionally, the oxidative coupling reaction can be accomplished in the presence of an electrolyte; NaBr is one such suitable electrolyte. Optionally a surfactant can be used.

The reactants and solvent are supplied to an electrochemical reaction cell equipped with an anode and a cathode. The anode and cathode can be independently selected. Particularly suitable materials for the anode and cathode include Ni, Pt, carbon or boron-doped diamond electrodes. The materials of the anode and cathode can be the same or different. Current is applied to the solution, typically until the first functionalized phenol compound is consumed in the electrochemical reaction to form the functionalized biphenol compound. The solvent can be removed, such as by evaporation.

Advantageously the electrochemical oxidative coupling reaction can be carried out at standard temperature and pressure. Selection of alternative reaction conditions can be based on the choice of solvents and reactants.

In an embodiment, the electrochemical oxidative coupling reaction may be carried out at a temperature of 0° C. to about 50° C. and a pressure of about 100 kPa to about 500 kPa.

The methods as disclosed herein are shown in the following examples, which are presented by way of illustration and not by way of limitation.

EXAMPLES

Example 1

Reductive Coupling of Functionalized Phenol with Leaving Group.

In a 10 mL electrochemical synthesis vial, 5-bromosalicylaldehyde (i.e., 5-bromo-2-hydroxy-benzaldehyde) (3 mmol, 0.6 g), NaBr (0.4 mmol, 41 mg), and NiBr2bpy (0.3 mmol, 113 mg) were added along with a magnetic stir bar. Anhydrous, degassed MeOH (5 mL) and EtOH (5 mL) were added as the solvent. Nickel rod electrodes (10 cm²) were used as both cathode and anode. A constant current of 40 mA was applied, with the polarity switching every 30 seconds. A total faradic equivalent of 3 e⁻ (based on the 5-bromosalicylaldehyde) was dosed in the reaction. After the completion of the synthesis, the solvent was evaporated. HCl (6 M, 15 mL) was added to the reaction mixture and sonicated to ensure the mixing of the suspension. A yellow precipitate was filtered and characterized with TLC (Hex/EA=3:1). The solid was then dried under vacuum and analyzed with NMR. High purity 4,4′-dihydroxy-[1,1′-biphenyl-3,3′-dialdehyde](dobpda) (210 mg, 58%) was recovered without any additional purification step.

Example 2

Oxidation of Dobpda to Dobpde

NaOMe (1.1 eq.) is added to a stirred solution of dobpda (1 eq.) in DMSO followed by portion-wise addition of NaOCIO (2.2 eq.). The resulting mixture is stirred at room temperature for 4 hours. The mixture is then cooled to 0° C., and water is added slowly. The mixture is then acidified with 1 N aq. HCl solution to pH=2 and the mixture is extracted with EtOAc twice. The combined organic layers are washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue is purified by column chromatography on silica gel (eluted with DCM:MeOH=100:1 to 20:1) to give dobpdc as a white solid.

Example 3

Oxidative Electrochemical Coupling of Functionalized Phenol

345 mg (2.5 mmol) of salicylic acid and 0.25 mL of 4-Dimethylaminopyridine (396 mg, 3.24 mmol) are dissolved in 4.75 mL 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP). The solution is transferred into a 5 mL beaker-type electrochemical cell equipped with boron-doped diamond electrodes. A constant current electrolysis with a current density of 7.2 mA/cm² (1.8 cm² immersed anode surface, 13 mA) is performed at 50° C. After application of 242 C (1.0 F per mole of salicylic acid), the electrolysis is stopped and the solvent is recovered in vacuo (50° C., 200-70 mbar). The crude coupling product is purified by column chromatography (SiO₂, cyclohexane/ethyl acetate) and dried under reduced pressure to obtain the pure product.

Without further elaboration, it is believed that using the preceding description that one skilled in the art can utilize the present invention to its fullest extent and easily ascertain the essential characteristics of the invention, without departing from the spirit and scope thereof, and the foregoing description and examples are intended to cover various modifications and equivalent arrangements included within the scope of the appended claims.