WO2017222921A1 - 2-hydroxyisophthalic acid and its derivatives: methods of making and applications - Google Patents

2-hydroxyisophthalic acid and its derivatives: methods of making and applications Download PDF

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WO2017222921A1
WO2017222921A1 PCT/US2017/037812 US2017037812W WO2017222921A1 WO 2017222921 A1 WO2017222921 A1 WO 2017222921A1 US 2017037812 W US2017037812 W US 2017037812W WO 2017222921 A1 WO2017222921 A1 WO 2017222921A1
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acid
compound
formula
hydroxyisophthalic acid
solution
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Vladimir KOLESNICHENKO
Galina GOLOVERDA
Rajesh KOMATI
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Xavier University Of Louisiana
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/32—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/36—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by carbon atoms having at least two bonds to oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/64—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring the carbon skeleton being further substituted by singly-bound oxygen atoms
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01G—CAPACITORS; CAPACITORS, RECTIFIERS, DETECTORS, SWITCHING DEVICES, LIGHT-SENSITIVE OR TEMPERATURE-SENSITIVE DEVICES OF THE ELECTROLYTIC TYPE
    • H01G9/00—Electrolytic capacitors, rectifiers, detectors, switching devices, light-sensitive or temperature-sensitive devices; Processes of their manufacture
    • H01G9/20—Light-sensitive devices
    • H01G9/2027—Light-sensitive devices comprising an oxide semiconductor electrode

Definitions

  • the present disclosure relates to 2-hydroxyisophthalic acid and a series of its 5-substituted derivatives, new synthetic routes for making the same as well as significant improvements over the published synthesis of the parent compound, 2-hydroxyisophthalic acid, and potential uses of these derivatives in a variety of applications.
  • 2-hydroxyisophthalic acid and its 5-substituted derivatives have many potential applications, including but not limited to use as ligands-linkers for new nanoparticulate MRI contrast agents, cell labeling and drug delivery agents, sensors, battery electrode materials, dye sensitized solar cells, and quantum dot-sensitized solar cells.
  • any application of nanocrystalline materials relies heavily on surface-modifying agents or so called capping ligands as "naked" particles are chemically unstable and therefore useless.
  • Capping ligands adjust the particles' properties for a specific application, which makes them just as important as the inorganic core. For example, the effectiveness of magnetic labels and their cellular uptake are determined in large part by the organic interface used to solubilize the particles, stabilize their aqueous colloids and make them target-specific. It is the particle's organic coating that is perceived by a cell, but not its inorganic core.
  • Capping ligands functionalized with reactive groups such as NH 2 , CO2H, COH, SH, C2H, N3, etc. can provide a nexus to biomolecules ⁇ e.g., for theranostic applications) or to dyes ⁇ e.g., for photovoltaic applications), and they can be called the "linkers.”
  • the currently accepted paradigm is that water-soluble polymers (natural or synthetic organic materials) are used almost exclusively as linkers for the metal oxides' surface protection, stabilization and conjugation with biomolecules [1-6].
  • Benzoate- and isophthalate -based linkers used primarily for photovoltaics applications do not provide strong dye-to-semiconductor binding and conjugation for efficient charge transfer.
  • the ligands of the present disclosure are compounds formula ( ⁇ ):
  • X H, OH, NH 2 , NO2, N2aryl, Br, OR, NHR, a linear or branched aliphatic or oligo-ethylene oxide (with a degree of polymerization from 2 to 50, preferably from 5 to 40, from 5 to 30, from 5 to 20, from 5 to 10, from 5 to 50, from 10 to 50, from 20 to 50, from 30 to 50, from 40 to 50, and most preferably 5), or oligo-glycerol (with a degree of polymerization from 2 to 50, preferably from 5 to 40, from 5 to 30, from 5 to 20, from 5 to 10, from 5 to 50, from 10 to 50, from 20 to 50, from 30 to 50, from 40 to 50, and most preferably 5), with or without terminal OH, NH 2 , COOH, CHO, C2H, N 3 ⁇ 4 or SH groups; and
  • R CH 2 C0 2 H, C 2 H 4 OH, C 3 H 5 , C 3 H 5 (OH)Cl, C 3 H 5 (OH) 2 , or C 3 H 5 (OH)NH 2 .
  • the ligand is a compound of formula (I) having the structure shown for X, and denoted Ligand-linker 1 :
  • the ligand is a compound of formula (I) having the structure shown for X, and denoted Ligand-linker 2:
  • the ligand is a compound of formula (I) having the structure shown for X, and denoted Ligand-linker 3:
  • the ligand is a compound of formula (I) having the structure shown for X, and denoted Ligand-linker 4:
  • the ligand is a compound of formula (I) having the structure shown for X, and denoted Ligand-linker 5:
  • the ligand is a compound of formula (I) having the structure shown for X, and denoted Ligand-linker 6:
  • the ligand is a compound of formula (I) having the structure shown for X, and denoted Ligand-linker 7:
  • the most common method for synthesis of unsubstituted acid consists of PbC>2 oxidation of 3-methyl salicylic acid in alkaline melt [18-20]. To the best of our knowledge, the only attempt to directly derivatize this substance, suffered from low yield and the lack of characterization [19].
  • condensation of dimethyl acetonedicarboxylate with 2,4-pentanedione afforded 2-hydroxy-4,6-dimethyl isophthalic acid [21-23]; similar condensation of dimethyl acetonedicarboxylate with nitromalonaldehyde [24,25] afforded 2-hydroxy-5-nitroisophthalic acid; four-steps synthesis starting from hydroxymethylation of 4- OW-butyijphenol, yielded 2-hydroxy-5-(&n l -butyl)isophthalic acid [26].
  • the disclosure provides synthetic routes for 5-nitro-, 5-amino- and 5- hydroxy-substituted derivatives of the compound of formula ( ⁇ ) .
  • the disclosure provides synthetic routes for 5-alkoxy-substituted derivatives of the compound of formula (I).
  • the disclosure provides synthetic routes for 5-aryl-substituted derivatives of the compound (I) .
  • the disclosure provides a proof for strongly coordinating properties of 2- hydroxyisophthalic acid and its derivatives of formula (I), demonstrated in Figure 5.
  • the derivatives of the formula ( ⁇ ) exhibit strong binding to metal oxide surfaces, which can be used for production of metal oxide nanoparticles for theranostic applications, dye-sensitized and quantum dot-sensitized photovoltaics, and sensor and battery development.
  • the disclosure therefore relates to use of the compounds of formula ( ⁇ ) in a variety of applications, including biomedical/ theranostic, dye-sensitized and quantum dot-sensitized photovoltaics, sensor and battery development. These applications were previously unknown.
  • FIG. 1 shows Scheme 1, which provides the general synthetic strategy for preparation of 2- hydroxyisophthalic acid (1) and its 5-nitro- (2), 5-amino- (3), 5-sulfoooxy- (4) and 5-hydroxy- (5), derivatives.
  • FIG. 2 shows Scheme 2, which provides the general synthetic strategy for preparation of 5- alkoxy-substituted derivatives of 2-hydroxyisophthalic acid.
  • FIG. 3 shows Scheme 3, which provides an alternative synthetic strategy for preparation of 5-alkoxy-substituted derivatives of 2-hydroxyisophthalic acid.
  • FIG. 4 shows Scheme 4, which provides a general synthetic strategy for azo-coupling and reductive cleavage reactions producing diazo-dye derivatives and 2-hydroxy-5-aminoisophthalic acid.
  • FIG. 5 demonstrates the affinity of 2-hydroxyisophthalic acid derivatives of formula ( ⁇ ) to iron(III) by showing that it inhibits precipitation of iron(III) hydroxide in the pH range from 2.3 to 11.
  • precipitation of Fe(OH) 3 from solutions containing structurally related salicylic and isophthalic acids which have only two coordinating groups on the ring instead of three like the proposed compounds of formula (I) is noticeable at pH ⁇ 3.5 (salicylic) and ⁇ 2.3 (isophthalic).
  • FIG. 5 shows light scattering as a function of pH in iron(III) salicylate, isophthalate, and 5-bromo-2- hydroxyisophthalate. The latter effectively inhibits precipitation of hydrated iron(III) oxide.
  • Scheme 1 provides the general synthetic strategy for preparation of 2- hydroxyisophthalic acid (1) and its 5-hydroxy-, 5-nitro- (2) and 5-amino- (3) derivatives.
  • the improved process still utilizes PbC>2 oxidation in a KOH melt, but heating with an oil bath has been eliminated, and therefore so have the fire and inhalation hazards.
  • stainless steel reactor with the reaction mixture is heated with open flame directly or through a sand bath. The reaction progress is accompanied by drastic changes in appearance of the reaction mixture. This eliminates the necessity of the temperature monitoring.
  • the whole synthesis procedure before workup can be completed within 20 minutes and without the need to operate in a fume hood with a fire extinguisher nearby.
  • aqueous solution of the reaction mixture after removal of the insoluble by-product PbsO j, is treated with aqueous H2SO4. Both lead-containing by-products PbsC and PbSC can be completely recovered and recycled. The suggested modification does not alter the quality and yield of the product. Typical isolated yield 85-90%.
  • Figures 2 and 3 provide the general synthetic strategy for preparation of 5-alkoxy derivatives of 2-hydroxyisophthalic acid. This chemistry is based on nucleophilic properties of phenolic OH-group in 5-th position in base-catalyzed reactions with epoxides (epichlorohydrin or allyl glycidyl ether), halohydrins (2-chloroethanol or l,3-dichloro-2-propanol), allyl bromide, and alpha-halo carbonyl compounds (bromoacetic acid).
  • epoxides epichlorohydrin or allyl glycidyl ether
  • halohydrins (2-chloroethanol or l,3-dichloro-2-propanol
  • allyl bromide allyl bromide
  • alpha-halo carbonyl compounds bromoacetic acid
  • a 250-mL stainless steel beaker was charged with 120 g of the granular KOHFFO and 25 mL of water. After cooling for 5 minutes, 20.0 g of 3-methyl salicylic acid were added to the solution gradually while stirring with nickel spatula, followed by 120 g of PbC>2. The resulting mixture was flame- heated while intensive stirring with a Bunsen burner. During 10-15 minutes heating session, the mixture turned thicker first, and then softened, then liquefied, briefly boiled (as boiling starts, heating should be done with caution to avoid spillage), and changed its color from black to red. Heating was continued until the melt became free-flowing and PbsC formed as red crystals.
  • the reaction mixture was allowed to cool; the solidifying melt was loosened by stirring. After cooling, the solid was treated with 300 mL of deionized water and stirred until KOH melt dissolved and PbsC separated from solution. The crystalline red PbsC fraction was separated by decantation, and the yellow-orange microcrystalline fraction by brief centrifuging. The precipitates were washed with additional 2 50 mL of water, and all aqueous solutions were combined. The resulting solution was acidified with the solution of sulfuric acid: 51 mL of concentrated H2SO4 in 100 mL of water. Addition of sulfuric acid was continued until the pH dropped to 7-8; precipitation of PbSC at this point was complete.
  • the precipitated lead sulfate was separated by centrifuging, and rinsed with water to improve the yield of the product.
  • the separated supernatant solution was further acidified with the remaining sulfuric acid; this caused precipitation of the target product (1).
  • the solid was filtered off on a medium glass frit, washed with 0.1M HC1 until the drop test with BaCb, solution was negative, then with icy water, and finally transferred in the dish and air-dried. Yield of a light-tan-colored crystalline powder was 20.4 g (85%). No further purification was needed for most purposes, however if desired, the substance can be recrystallized from hot water or 0.1M hydrochloric acid.
  • Method 1 A suspension of (4) (0.186 g, 0.670 mmol) in 5 mL of water was mixed with 1 mL 25% HCl and NaBr (0.034g, 0.334mmol). The reaction mixture was brought to 80°C and stirred about 2h. As the reaction progressed, the solution turned clear and by the end of the reaction, white crystalline precipitate formed. The reaction mixture was cooled down to room temperature and white precipitate was filtered, washed with 0.1 M chilled HCl and dried to get 2,5-dihydroxyisophthalic acid (5) (0.113) as a white powder with an isolated yield of 86%.
  • Method 2 This synthesis was performed by hydroxylation of 2-hydroxyisophthalic acid (1). 0.911 g (0.00456 mols) of (1) was dissolved in 20 mL of 1.875M aqueous NaOH. Solution of 1.35 g (0.005 mols) of 2S2O 8 in 40 mL of water was added to the above solution at ambient temperature at once. Color of the resulting solution changed from colorless to deep red within one hour, but after aging overnight it was found lighter red. The solution was acidified with 5M hydrochloric acid to pH ⁇ 1 and left in the refrigerator overnight. The precipitated unreacted 2-hydroxyisophthalic acid was filtered off, rinsed with 1M HCl and saved for next similar hydroxylation cycle.
  • Ligand-linker 6 5-(2,3-dihydroxypropoxy)-2-hydroxyisophthalic acid (Ligand-linker 6)
  • 0.145 g of Ligand-linker 5 (0.5 mmol) was suspended in 10 mL of water and addition of 2 mL of 1M NaOH caused its complete dissolution. The resulting solution was heated in boiling water bath for 60 minutes. After cooling, the solution was neutralized by adding 2 mL of 1M HC1. Possible non-polar impurities were removed by extracting with 10 mL of ethyl acetate. Aqueous layer was separated and evaporated on a steam bath. The solid residue was extracted with 12 mL of absolute ethanol; the solution was evaporated on a steam bath and the residue was dried at 110°C overnight yielding 0.105 g (77%) of tan-colored solid product.
  • a solution of ligand-linker 5 (0.500 g, 1.72 mmol) in 10 mL of water and 5 mL of concentrated aqueous ammonia was aged overnight at room temperature and then the temperature was raised in one hour up to 70°C in the stoppered Kjeldahl flask. After completion, the solution was evaporated on a steam bath to dryness. Workup method 1. The crude product was dissolved in 30 mL of water; the solution was filtered through a fine frit, and acidified by adding 5 mL of 1M HC1. The precipitated impurities were filtered off, and the solution was neutralized with 1M NaOH to pH4.
  • colloidal nanoparticles of maghemite were synthesized by high-temperature hydrolysis of chelated iron alkoxide complexes in surfactant-free non-aqueous solutions, followed by oxygenation [36]. Colloids of the obtained 5 nm maghemite nanoparticles were reacted with (1) and with ligand-linkers (4-7) yielding surface-coated nanoparticulate adducts. Stoichiometry calculations and the experimental method were described in [36]. The DLS monitored pH titration was performed on Malvern Zetasizer Nano ZS instrument equipped with automatic titrator MPT2. The nanoparticulate adducts maintained their integrity and ability to form stable aqueous colloids in the range of pH2 to 11, depending on the substituent.
  • affinity of the named acid to metal oxide surfaces was evaluated by testing of its ability to inhibit the precipitation of iron (III) hydroxide from aqueous solutions.
  • the named acid (a) was superior to the reference acids (b) and (c) as it was the only one stabilizing iron hydroxide colloid under basic conditions (Figure 5).
  • TLC Thin-layer chromatography
  • Bio-functionalization of magnetite nanoparticles using an aminophosphonic acid coupling agent new, ultradispersed, iron-oxide folate nanoconjugates for cancer-specific targeting.

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Abstract

Substituted derivatives of 2-hydroxyisophthalic acid are provided, as well as new synthetic routes for making 2-hydroxyisophthalic acid and the substituted derivatives. Potential uses of the derivatives in a variety of applications are also provided.

Description

2-HYDROXYISOPHTHALIC ACID AND ITS DERIVATIVES: METHODS OF MAKING
AND APPLICATIONS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This international application claims the benefit of U.S. Provisional Patent Application
No. 62/353,402, filed on 22 June 2016, which is hereby incorporated by reference in its entirety.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] This invention was made with government support under LA-SIGMA EPS-1003897 awarded by The National Science Foundation, and under RCMI 1G12RR026260-01, SCORE
SC3GM088042, and NIGMS-BUILD 8UL1GM118967-02, awarded by The National Institutes of Health. The government has certain rights in the invention.
BACKGROUND [0003] 1. Field
[0004] The present disclosure relates to 2-hydroxyisophthalic acid and a series of its 5-substituted derivatives, new synthetic routes for making the same as well as significant improvements over the published synthesis of the parent compound, 2-hydroxyisophthalic acid, and potential uses of these derivatives in a variety of applications.
[0005] 2-hydroxyisophthalic acid and its 5-substituted derivatives have many potential applications, including but not limited to use as ligands-linkers for new nanoparticulate MRI contrast agents, cell labeling and drug delivery agents, sensors, battery electrode materials, dye sensitized solar cells, and quantum dot-sensitized solar cells.
[0006] 2. Description of Related Art
[0007] Any application of nanocrystalline materials relies heavily on surface-modifying agents or so called capping ligands as "naked" particles are chemically unstable and therefore useless. Capping ligands adjust the particles' properties for a specific application, which makes them just as important as the inorganic core. For example, the effectiveness of magnetic labels and their cellular uptake are determined in large part by the organic interface used to solubilize the particles, stabilize their aqueous colloids and make them target-specific. It is the particle's organic coating that is perceived by a cell, but not its inorganic core. Capping ligands functionalized with reactive groups such as NH2, CO2H, COH, SH, C2H, N3, etc., can provide a nexus to biomolecules {e.g., for theranostic applications) or to dyes {e.g., for photovoltaic applications), and they can be called the "linkers." The currently accepted paradigm is that water-soluble polymers (natural or synthetic organic materials) are used almost exclusively as linkers for the metal oxides' surface protection, stabilization and conjugation with biomolecules [1-6].
[0008] The most frequently used polymers are dextran, polyethylene glycol, polyvinyl acetate and various polyacrylamides. Even though polymers stabilize the metal oxides' aqueous colloids, they greatly increase the hydrodynamic size of the composite and, as a result, substantially decrease its mobility and cellular uptake. We are shifting this paradigm towards non-polymeric ligands by offering a series of small biocompatible organic molecules that can be used directly on the nanoparticle (NP) surface, covalently bind to it and serve as linkers. Coordinating polar head of these molecules provides a strong affinity to metal oxide surface and hydrolytic stability of the resulting adducts; size and composition of the side substituent of these linkers is easily controllable which helps tuning their colloidal and
hydrophilic/hydrophobic properties, and cellular uptake dynamics. Among a few existing small- molecule organic ligands are catechol- [7-9] and phosphonate-[10-12] based linkers. Catechol-based linkers can undergo undesired redox reactions leading to polymeric and neurotoxic products [13]. Both catechol- and phosphonate derivatives are relatively strong chelators, so they can leach the metal ions out of the nanoparticles' surface, leading to uncontrolled behaviors and toxic effects.
[0009] The solution to this technical problem is provided by the embodiments characterized in the claims.
BRIEF SUMMARY OF THE INVENTION
[0010] Benzoate- and isophthalate -based linkers used primarily for photovoltaics applications do not provide strong dye-to-semiconductor binding and conjugation for efficient charge transfer.
Rationale for the proposed herein 2-hydroxyisophthalic acid derivatives is that they demonstrated high affinity to metal oxide nanoparticles due to several-site attachment of their perfectly aligned three donor groups (two COOH and one OH in between them). This structural motif would covalently bind not only to metal oxide, but also to other inorganic surface(s), which expands the area of applications well beyond the biomedical [14-17]. An additional advantage of these ligands is that the para-position to the phenolic OH-group of the benzene ring can be easily functionalized, which opens up multiple pathways for the synthesis of various derivatives, depending on targeted application. [0011] Thus, in an embodiment, the ligands of the present disclosure are compounds formula (Γ):
Figure imgf000004_0001
Formula (Γ) wherein X = H, OH, NH2, NO2, N2aryl, Br, OR, NHR, a linear or branched aliphatic or oligo-ethylene oxide (with a degree of polymerization from 2 to 50, preferably from 5 to 40, from 5 to 30, from 5 to 20, from 5 to 10, from 5 to 50, from 10 to 50, from 20 to 50, from 30 to 50, from 40 to 50, and most preferably 5), or oligo-glycerol (with a degree of polymerization from 2 to 50, preferably from 5 to 40, from 5 to 30, from 5 to 20, from 5 to 10, from 5 to 50, from 10 to 50, from 20 to 50, from 30 to 50, from 40 to 50, and most preferably 5), with or without terminal OH, NH2, COOH, CHO, C2H, N¾ or SH groups; and
wherein R = CH2C02H, C2H4OH, C3H5, C3H5(OH)Cl, C3H5(OH)2, or C3H5(OH)NH2.
[0012] In a preferred embodiment, the ligand is a compound of formula (I) having the structure shown for X, and denoted Ligand-linker 1 :
Figure imgf000004_0002
[0013] In a preferred embodiment, the ligand is a compound of formula (I) having the structure shown for X, and denoted Ligand-linker 2:
Figure imgf000004_0003
[0014] In a preferred embodiment, the ligand is a compound of formula (I) having the structure shown for X, and denoted Ligand-linker 3:
Figure imgf000005_0001
[0015] In a preferred embodiment, the ligand is a compound of formula (I) having the structure shown for X, and denoted Ligand-linker 4:
Figure imgf000005_0002
[0016] In a preferred embodiment, the ligand is a compound of formula (I) having the structure shown for X, and denoted Ligand-linker 5:
Figure imgf000005_0003
[0017] In a preferred embodiment, the ligand is a compound of formula (I) having the structure shown for X, and denoted Ligand-linker 6:
Figure imgf000005_0004
[0018] In a preferred embodiment, the ligand is a compound of formula (I) having the structure shown for X, and denoted Ligand-linker 7:
Figure imgf000006_0001
[0019] In an embodiment, the disclosure provides an efficient synthetic route for the unsubstituted compound of formula (I) (X=H). There are several synthetic routes yielding the unsubstituted, 5- substituted and 4,6-disubstituted derivatives of 2-hydroxyisophthalic acid. The most common method for synthesis of unsubstituted acid consists of PbC>2 oxidation of 3-methyl salicylic acid in alkaline melt [18-20]. To the best of our knowledge, the only attempt to directly derivatize this substance, suffered from low yield and the lack of characterization [19]. According to other methods, condensation of dimethyl acetonedicarboxylate with 2,4-pentanedione afforded 2-hydroxy-4,6-dimethyl isophthalic acid [21-23]; similar condensation of dimethyl acetonedicarboxylate with nitromalonaldehyde [24,25] afforded 2-hydroxy-5-nitroisophthalic acid; four-steps synthesis starting from hydroxymethylation of 4- OW-butyijphenol, yielded 2-hydroxy-5-(&nl-butyl)isophthalic acid [26].
[0020] In an embodiment, the disclosure provides synthetic routes for 5-nitro-, 5-amino- and 5- hydroxy-substituted derivatives of the compound of formula (ΐ) .
[0021] In an embodiment, the disclosure provides synthetic routes for 5-alkoxy-substituted derivatives of the compound of formula (I).
[0022] In an embodiment, the disclosure provides synthetic routes for 5-aryl-substituted derivatives of the compound (I) .
[0023] In an embodiment, the disclosure provides a proof for strongly coordinating properties of 2- hydroxyisophthalic acid and its derivatives of formula (I), demonstrated in Figure 5. The derivatives of the formula (ΐ) exhibit strong binding to metal oxide surfaces, which can be used for production of metal oxide nanoparticles for theranostic applications, dye-sensitized and quantum dot-sensitized photovoltaics, and sensor and battery development.
[0024] The disclosure therefore relates to use of the compounds of formula (ΐ) in a variety of applications, including biomedical/ theranostic, dye-sensitized and quantum dot-sensitized photovoltaics, sensor and battery development. These applications were previously unknown.
[0025] The 2-alkoxy derivatives of isophthalic acid were used for kinetic studies of their hydrolysis, yielding 2-hydroxyisophthalic acid [27,28]. Luminescence properties of the terbium 2- hydroxyisophthalate coordination complex were studied [29]. The ligand was found to be an efficient sensitizer of Tb(III) green emission. The crystal structures of free 2-hydroxyisophthalic acid and its tetraphenylphosphonium salt were determined and discussed in the context of its enhanced acidity due to internal hydrogen bond stabilization [30].
There were several reports on coordination chemistry of 2-hydroxyisophthalic acid with copper(II), where this ligand was formed in situ by oxidation of isophthalic acid by Cu(II) [31-35]. Crystal structure studies showed a binuclear nature of these complexes where each tridentate ligand chelates two copper ions. No solution-phase studies on the equilibrium of complex formation were reported. Complex formation of 2-hydroxyisophthalic acid with Cu(II) was discussed in the context of catalytic activity of this ion on the hydrolysis of l,3-dicarboxypenyl-2-phosphate [27].
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] For further understanding of the nature, objects, and advantages of the present disclosure, reference should be had to the following detailed description, read in conjunction with the following drawings, wherein like reference numerals denote like elements.
[0027] FIG. 1 shows Scheme 1, which provides the general synthetic strategy for preparation of 2- hydroxyisophthalic acid (1) and its 5-nitro- (2), 5-amino- (3), 5-sulfoooxy- (4) and 5-hydroxy- (5), derivatives.
[0028] FIG. 2 shows Scheme 2, which provides the general synthetic strategy for preparation of 5- alkoxy-substituted derivatives of 2-hydroxyisophthalic acid.
[0029] FIG. 3 shows Scheme 3, which provides an alternative synthetic strategy for preparation of 5-alkoxy-substituted derivatives of 2-hydroxyisophthalic acid.
[0030] FIG. 4 shows Scheme 4, which provides a general synthetic strategy for azo-coupling and reductive cleavage reactions producing diazo-dye derivatives and 2-hydroxy-5-aminoisophthalic acid.
[0031] FIG. 5 demonstrates the affinity of 2-hydroxyisophthalic acid derivatives of formula (ΐ) to iron(III) by showing that it inhibits precipitation of iron(III) hydroxide in the pH range from 2.3 to 11. In contrast, precipitation of Fe(OH)3 from solutions containing structurally related salicylic and isophthalic acids which have only two coordinating groups on the ring instead of three like the proposed compounds of formula (I), is noticeable at pH ~ 3.5 (salicylic) and ~ 2.3 (isophthalic). FIG. 5 shows light scattering as a function of pH in iron(III) salicylate, isophthalate, and 5-bromo-2- hydroxyisophthalate. The latter effectively inhibits precipitation of hydrated iron(III) oxide. DETAILED DESCRIPTION
[0032] Before the subject disclosure is further described, it is to be understood that the disclosure is not limited to the particular embodiments of the disclosure described below, as variations of the particular embodiments may be made and still fall within the scope of the appended claims. It is also to be understood that the terminology employed is for the purpose of describing particular embodiments, and is not intended to be limiting. Instead, the scope of the present disclosure will be established by the appended claims.
[0033] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs.
[0034] REAGENTS & MATERIALS
[0035] All reagents and solvents were of the reagent grade purchased from ACROS, Sigma- Aldrich and Alfa Aesar. NMR spectra were recorded on Agilent 400MR spectrometer. Electrospray mass- spectra were obtained on Thermo Finnigan TSQ Ultra instrument. All reactions requiring anhydrous conditions were performed under a positive nitrogen flow. Analytical thin-layer chromatography (TLC) was conducted on Fluka TLC plates (silica gel 60 F254, aluminum foil). Dynamic light scattering (DLS) experiments were performed with Malvern Zetasizer Nano ZS instrument combined with MPT-2 automatic titrator. Elemental analysis was performed by Galbraith Laboratories, Inc. High-resolution mass spectra were obtained on Agilent Technologies 6530 Accurate Mass QTofLC/MS in the
University of Texas at Austin mass-spectrometry facility.
[0036] Scheme 1 (FIG. 1) provides the general synthetic strategy for preparation of 2- hydroxyisophthalic acid (1) and its 5-hydroxy-, 5-nitro- (2) and 5-amino- (3) derivatives. The improved process still utilizes PbC>2 oxidation in a KOH melt, but heating with an oil bath has been eliminated, and therefore so have the fire and inhalation hazards. In a preferred embodiment, stainless steel reactor with the reaction mixture is heated with open flame directly or through a sand bath. The reaction progress is accompanied by drastic changes in appearance of the reaction mixture. This eliminates the necessity of the temperature monitoring. The whole synthesis procedure before workup can be completed within 20 minutes and without the need to operate in a fume hood with a fire extinguisher nearby. In the workup procedure we eliminated Na2S and therefore the potential for H2S exposure. In a preferred embodiment, aqueous solution of the reaction mixture, after removal of the insoluble by- product PbsO j, is treated with aqueous H2SO4. Both lead-containing by-products PbsC and PbSC can be completely recovered and recycled. The suggested modification does not alter the quality and yield of the product. Typical isolated yield 85-90%.
[0037] Also developed is an alternative lead-free technology for this synthesis using BaC>2 as an oxidizing agent, instead of PbC>2. Synthesis and workup procedures are similar to PbC>2-based method, however a Teflon-coated reaction vessel is recommended. BaC>2 is more than twice as cheap, twice more efficient (from stoichiometry and molecular weight considerations) and after workup it turns into environmentally safe BaSC . The quality and yield of the target product is not altered.
[0038] Synthesis of 2-hydroxy-5-nitroisophthalic acid (2) is accomplished by nitration of 2- hydroxyisophthalic acid in sulfuric acid solution with HNO3/H2SO4 mixture in the range of
temperatures 20-40°C. The isolated yield was 86%.
[0039] Synthesis of 2-hydroxy-5-aminoisophthalic acid (3) is accomplished by hydrogen reduction of 2-hydroxy-5-nitroisophthalic acid in ethanol solution, assisted by Pt/ C (2%) or Pd/ C catalyst under ambient temperature and pressure. The isolated yield was 87%.
[0040] Synthesis of 2,5-dihydroxyisophthalic acid (5) is accomplished by two-step process: (1) Elbs persulfate oxidation, and (2) hydrolysis of the obtained aryl sulfate derivative (4). The isolated yield was 40%.
[0041] Figures 2 and 3 provide the general synthetic strategy for preparation of 5-alkoxy derivatives of 2-hydroxyisophthalic acid. This chemistry is based on nucleophilic properties of phenolic OH-group in 5-th position in base-catalyzed reactions with epoxides (epichlorohydrin or allyl glycidyl ether), halohydrins (2-chloroethanol or l,3-dichloro-2-propanol), allyl bromide, and alpha-halo carbonyl compounds (bromoacetic acid).
[0042] Synthesis of 5-((4-chlorophenyl)diazenyl)-2-hydroxyisophthalic acid (Fig. 4) is accomplished by azo-coupling of 2-hydroxyisophthalic acid with 4-chlorophenyl diazonium ion.
[0043] EXAMPLE 1
[0044] Synthesis of 2-hydroxyisophthalic acid (1)
[0045] A 250-mL stainless steel beaker was charged with 120 g of the granular KOHFFO and 25 mL of water. After cooling for 5 minutes, 20.0 g of 3-methyl salicylic acid were added to the solution gradually while stirring with nickel spatula, followed by 120 g of PbC>2. The resulting mixture was flame- heated while intensive stirring with a Bunsen burner. During 10-15 minutes heating session, the mixture turned thicker first, and then softened, then liquefied, briefly boiled (as boiling starts, heating should be done with caution to avoid spillage), and changed its color from black to red. Heating was continued until the melt became free-flowing and PbsC formed as red crystals. The reaction mixture was allowed to cool; the solidifying melt was loosened by stirring. After cooling, the solid was treated with 300 mL of deionized water and stirred until KOH melt dissolved and PbsC separated from solution. The crystalline red PbsC fraction was separated by decantation, and the yellow-orange microcrystalline fraction by brief centrifuging. The precipitates were washed with additional 2 50 mL of water, and all aqueous solutions were combined. The resulting solution was acidified with the solution of sulfuric acid: 51 mL of concentrated H2SO4 in 100 mL of water. Addition of sulfuric acid was continued until the pH dropped to 7-8; precipitation of PbSC at this point was complete. The precipitated lead sulfate was separated by centrifuging, and rinsed with water to improve the yield of the product. The separated supernatant solution was further acidified with the remaining sulfuric acid; this caused precipitation of the target product (1). After cooling in the ice bath, the solid was filtered off on a medium glass frit, washed with 0.1M HC1 until the drop test with BaCb, solution was negative, then with icy water, and finally transferred in the dish and air-dried. Yield of a light-tan-colored crystalline powder was 20.4 g (85%). No further purification was needed for most purposes, however if desired, the substance can be recrystallized from hot water or 0.1M hydrochloric acid. All lead-containing by-products were washed with water, dried and recycled. Anal. Calc'd for C8H605'H20: C, 48.00; H, 4.04. Found: C, 48.35; H, 4.02. HRMS (ESI) calc'd. for C8H605 [M - H] 181.0142, found 181.0139. ¾ NMR (400 MHz, DMSO- d6) δ 7.93 (dj = 7.6 Hz, 2H), 6.85 (tj = 7.6 Hz, 1H).
[0046] EXAMPLE 2
[0047] Synthesis of 5-nitro-2-hydroxyisophthalic acid (2)
[0048] This synthesis was performed by nitration of 2-hydroxyisophthalic acid (1). 0.036 mols (7.28 g) of (1) was dissolved in 48 mL of concentrated sulfuric acid (d = 1.83 g/cm3). The solution was rapidly stirred and heated until the temperature reached 120°C, and cooled down naturally.
Concentrated nitric acid (d = 1.42 g/ cm3) (0.04 mol 3.59 g) was taken into 50-mL Erlenmeyer flask and chilled it in the ice. 8 mL of concentrated sulfuric acid was added to it slowly while agitating and chilling. Starting at ambient temperature, the solution of nitric acid was added to solution of 2- hydroxyisophthalic acid (1) dropwise while intensive stirring. The addition rate was adjusted so that the temperature did not rise higher than 35°C. After mixing was complete, the flask was covered loosely and left overnight at ambient temperature. Next day, the reaction solution was added to 200 g of crushed ice slowly while shaking. The precipitate of the product was filtered on a medium glass frit and washed with -200 mL of ~4M hydrochloric acid (until BaSC test turned negative). The product was transferred into a wide dish and dried in vacuum desiccator over NaOH or KOH. The yield of yellowish-white powder was 7.8 g (86%). No further purification was needed for most purposes. Anal. Calc'd for G1H5NO7H2O: C, 39.19; H, 2.88; N, 5.71. Found: C, 39.48; H, 2.57; N, 5.48. ¾ NMR (400 MHz, DMSO-d6) δ 8.68 (s). ESI-MS calc'd. for C8H5N07 [M-H] 225.9993, found 225.9988.
[0049] EXAMPLE 3
[0050] Synthesis of 5-amino-2-hydroxyisophthalic acid (3). See also EXAMPLE 6b.
[0051] This procedure was done by hydrogen reduction of 5-nitro-2-hydroxyisophthalic acid (2). A 100-mL narrow Schlenk tube was charged with a spinbar, 1.02 g (4.16 mmol) of 5-nitro-2- hydroxyisophthalic acid (2) and 100 mL of ethanol. After substrate had dissolved, 0.5 g of platinum-on- carbon catalyst (2%) was added. The reactor was purged with nitrogen gas, and hydrogenation was performed at ambient temperature and pressure by passing hydrogen gas with a slow rate through the magnetically stirred solution. After 8 hours, the suspension was centrifuged, decanted and the solid was treated with additional 100 mL of ethanol and centrifuged again. The combined ethanol solution was roto-evaporated at 40°C and vacuum-dried at 60°C yielding 0.333 g of light brownish powder. This product was identified as 5-amino-2-hydroxyisophthalic acid (3) containing non-stoichiometric amount of ethanol. ¾ NMR (400 MHz, DMSO-d6) δ 7.88 (s), 3.45 (q), 1.05 (t). ESI-MS calc'd. for C8H7N05 [M-H] 196.0251, found 196.0246.
[0052] The mixture of catalyst with remaining product was treated with 70 mL of 1M hydrochloric acid by portions. The combined solution after centrifuging was cold-distilled yielding 0.526 g of light- tan air-stable powder. This product was identified as 5-amino-2-hydroxyisophthalic acid (3) in a form of HCl salt. Anal. Calc'd for C8H7N05HC1 H20: C, 38.18; H, 4.01; N, 5.57. Found: C, 38.40; H, 3.95; N, 5.41. ¾ NMR (400 MHz, DMSO-d6) δ 7.96 (s). ESI-MS calc'd. for C8H7N05 [M-H] 196.0251, found 196.0245.
[0053] EXAMPLE 4
[0054] Synthesis of 2-hydroxy-5-(sulfooxy)isophthalic acid, K salt (4)
[0055] (a) Ten mmol (2.00 g) of the recrystallized (1) was suspended in 20 mL of water; 17.0 mL of 5.0M aqueous NaOH was added, causing complete dissolution. The solution was chilled on ice. A solution of 10 mmol of Na2S208 (2.38 g) in 10 mL of water was added dropwise while stirring. Rate of addition was adjusted so that the temperature did not exceed 10°C. The reaction solution was sealed and left at room temperature for ~8 hours. [0056] (b) The ice-chilled reaction solution was acidified with 1M HCl to pH ~ 1. Unreacted 2- hydroxyisophthalic acid (1) was quickly extracted with four portions of 25 mL of MTBE/ CH2C12 (2:1) mixture (the organic solution was roto-evaporated and the unreacted (1) (0.5-0.6 g) was recovered and reused in the next sulfation procedure). Solution of potassium bisulfate (20 mmol, 2.7g) in 9 mL of water was added to the reaction solution while agitating, and the solution was left at ~ 10°C overnight. Crystalline product was isolated by filtration and washing with concentrated KHSC solution before it was used for synthesis of (5). For analytical purposes, pure substance was obtained by washing with 10 mL of chilled 0.1M HCl, then with MTBE and dried. During isolation, the crystalline product usually spontaneously became powdered. The yield of the off-white powder was 1.64g (46%). For analysis, the sample was dried at 110°C overnight followed by combustion at 800°C; the residue was identified as K2SO4. Calcd: 27.5%. Found: 26.9%. ¾ NMR (400 MHz, DMSO-d6) δ 7.71 (s). ESI-MS calc'd. for C8H6S09 PV1-H] 277, found 277; [½M-H] 138, found 138. Fragmentation of these peaks followed the expected path in MS-MS runs.
[0057] EXAMPLE 5
[0058] Synthesis of 2,5-dihydroxyisophthalic acid (5)
[0059] Method 1. A suspension of (4) (0.186 g, 0.670 mmol) in 5 mL of water was mixed with 1 mL 25% HCl and NaBr (0.034g, 0.334mmol). The reaction mixture was brought to 80°C and stirred about 2h. As the reaction progressed, the solution turned clear and by the end of the reaction, white crystalline precipitate formed. The reaction mixture was cooled down to room temperature and white precipitate was filtered, washed with 0.1 M chilled HCl and dried to get 2,5-dihydroxyisophthalic acid (5) (0.113) as a white powder with an isolated yield of 86%.
[0060] Method 2. This synthesis was performed by hydroxylation of 2-hydroxyisophthalic acid (1). 0.911 g (0.00456 mols) of (1) was dissolved in 20 mL of 1.875M aqueous NaOH. Solution of 1.35 g (0.005 mols) of 2S2O8 in 40 mL of water was added to the above solution at ambient temperature at once. Color of the resulting solution changed from colorless to deep red within one hour, but after aging overnight it was found lighter red. The solution was acidified with 5M hydrochloric acid to pH ~ 1 and left in the refrigerator overnight. The precipitated unreacted 2-hydroxyisophthalic acid was filtered off, rinsed with 1M HCl and saved for next similar hydroxylation cycle. Its leftovers were removed from supernatant solution by extraction using MTBE/CH2CI2 (3:1) solvent. The supernatant solution was refiuxed in a Schlenk flask under nitrogen protection for 24 hours. After cooling, it was placed in the refrigerator for ~12 hours, and the precipitated crude product was filtered off, washed with 0.1M hydrochloric acid and recrystallized from hot 0.01M hydrochloric acid. Anal. Calc'd for CsHfiOfi HzO: C, 44.45; H, 3.74. Found: C, 44.55; H, 3.49. ¾ NMR (400 MHz, DMSO-d6) δ 7.36 (s). ESI-MS calc'd. for C8H606 [M-H] 197.0092, found 197.0086.
[0061] EXAMPLE 6
[0062] a. 5-((4-chlorophenyl)diazenyl)-2-hydroxyisophthalic acid (Ligand-linker 1)
b. 5-amino-2-hydroxyisophthalic acid (3)
[0063] This procedure was done by azo-coupling (a) followed by reduction cleavage (b). (a) 1.82 g (9.09 mmol) of (1) was dissolved in 60 mL of 0.5M NaOH. 10 mmol (1.276 g) of p-chloroaniline was dissolved in 20 mL of 1M hydrochloric acid. 10 mmol of NaNC>2 (0.690 g) was dissolved in 5 mL of water. Sodium nitrite was added dropwise to the chilled to 3°C aniline solution so that its temperature never exceeded 4°C. After mixing, stirring in the ice/water slurry was continued for 30 minutes. The resulting diazonium salt solution was added dropwise to the chilled to 3-4°C solution of (1). This caused formation of deep red suspension of the azo-dye which was left in the refrigerator at ~8°C overnight. A minute portion of the resulting suspension was filtered; the precipitate was washed with water and air-dned. Anal. Calc'd for GTLNzOsCl'HzO: C, 49.64; H, 3.28; N, 8.27. Found: C, 49.75; H, 3.16; N, 7.96. ¾ NMR (400 MHz, DMSO-d6) δ 8.49 (s, 2H), 7.89 (d, 2H), 7.63 (d, 2H). ESI-MS calc'd. for G4H9N2O5CI [M-H] 319.0127, found 319.0122.
[0064] (b) 11 mL of 5M NaOH was added to aqueous suspension of azo-dye (from the EXAMPLE 6a), and the solution was stirred at room temperature for 2 hours. Temperature of the solution was raised to 80°C and 4.80 g (~23 mmol) of sodium dithionite was added by small portions while stirring. This caused color of the solution to fade. After cooling, solution was neutralized to pH 6 using 5M HC1, which caused precipitation of light reddish solid. After filtration, washing with methanol and drying, 1.48 g of solid was obtained, which was identified as sodium salt of 5-amino-2- hydroxyisophthalic acid (3). ¾ NMR (400 MHz, DMSO-d6) δ 7.25 (s). ESI-MS calc'd. for C8H7N05 [M-H] 196, found 196. Fragmentation of this peak followed the expected path in MS-MS runs. After recrystallizing of this product from warm 0.1M aqueous HC1, pure amino acid was obtained. Anal. Calc'd for αΗ7Ν05Ή20: C, 44.65; H, 4.22; N, 6.51. Found: C, 44.88; H, 4.47; N, 6.24.
[0065] EXAMPLE 7
[0066] Synthesis of 5-(allyloxy)-2-hydroxyisophthalic acid (Ligand-linker 2)
[0067] To a suspension of sodium hydride-60% (4.01 g, 166.7 mmol) in DMF (40 mL), a solution of 2,5-dihydroxybenzoic acid (6.168 g, 40.0 mmol) in DMF (30 mL) was added dropwise. After 2 hours at room temperature, allyl bromide (3.46 mL, 40.0 mmol) was added as a solution in 10 mL of DMF. The mixture was stirred for 2 hours at room temperature; then DMF was removed under vacuum to get a red solid. This residue was dissolved in 100 mL of water and neutralized with HCl (pH 2-3). Organic product was extracted with ethyl acetate and the combined EtOAc solution was washed with water and dried over sodium sulfate. After the solvent was removed, a red colored solid (a) was obtained with yield of 7.212 g (92.9%).
[0068] To a solution of (a) (0.81 g, 4.2 mmol) in 7 mL of trifluoroacetic acid, a solution of hexamethylenetetramine (2.748 g, 19.6 mmol) in 7 mL of trifloroacetic acid was added. The reaction mixture was stirred at 90°C for 16 h. After completion, heating was stopped and 50 mL of 2M HCl was added, and the solution was stirred for 3 h at room temperature. The organic product was extracted with EtOAc. Combined organic layers were dried over sodium sulfate and the solvent was distilled off. The crude product was dried under vacuum overnight to yield the formylation product (b) 0.702 g with a 75% yield.
[0069] To a solution of (b) (0.752 g, 3.4 mmol) in 10 mL of DMSO, sodium dihydrogenphosphate (0.204 g, 1.7 mmol) in 3 mL of water was added. To this stirring solution, sodium chlorite (0.676 g, 7.48 mmol) in 20 mL of water was added dropwise over the course of about 2 h. The reaction mixture was stirred for around 48 h at room temperature. After completion, the pH was lowered to 1 by addition of sulfuric acid, and the organic product was extracted with ethyl acetate. Combined organic layers were dried over sodium sulfate and evaporated to get a product of 0.542 gwith a 67% yield. In order to improve purity, the substance can be recrystallized from hot water. Anal. Calc'd for
Figure imgf000014_0001
C, 51.56; H, 4.73. Found: C, 51.77; H, 4.67. ¾ NMR (DMSO) δ 7.50 (s, 2 H), 5.93-6.06 (m, 1 H), 5.37 (d, J= 17.3 Hz, 1 H), 5.24 (d, J= 10.5 Hz, 1 H), 4.56 (d, J = 4.8 Hz, 2 H) ppm; 13C NMR δ 169.31, 155.86, 149.52, 133.93, 121.93, 118.03, 117.83 and 69.38 ppm. ESI-MS calc'd. for CuHioOe [M-H] 237.04050, found 237.03970.
[0070] EXAMPLE 8
[0071] Synthesis of 5-(carboxymethoxy)-2-hydroxyisophthalic acid (Ligand-linker 3)
[0072] To a suspension of 2,5-dihydroxybenzoic acid (3.08 g, 20.0 mmol) in 60 mL of water, sodium hydroxide (4.32 g, 108.0 mmol) was added as a solution in 10 mL of water. To the resulting solution, bromoacetic acid (6.12 g, 44.0 mmol) was added and the reaction mixture was stirred at 100°C for 12 h. After reaction solution was cooled to room temperature, it was neutralized with 1 M HCl (pH 1-2) and stirred about 30 min. The precipitate was collected by filtration and dried under vacuum. Yield of the pure product (c) (2.62 g) with a 61.8 % yield. [0073] The solution of (c) (1.72g, 7.54 mmol) and hexamethylenetetramine (5.34 g, 38.12 mmol) in 20 mL of trifloroaceticacid was stirred at 90 °C for 12 h. After completion and cooling to room temperature, 100 mL of 1 M HCl were added and the reaction mixture was stirred for 6 h. The organic product was extracted with ethyl acetate (3 X 100 mL). Combined organic layers were washed with water and dried over sodium sulfate. Ethyl acetate was removed under reduced pressure to get the 1.33 g of product (d) with a 73.4 % yield.
[0074] To a solution of (d) (0.696 g, 2.9 mmol) in 6 mL of DMSO, sodium dihydrogenphosphate (0.094 g, 0.783 mmol) solution in 2 mL of water was added. To this stirring solution, sodium chlorite (0.577 g, 6.38 mmol) in 20 mL of water was added drop wise and the reaction mixture was stirred at room temperature about 3 h. After completion, the pH was lowered to 2 by addition of sulfuric acid and the solution was cooled to ~10°C. After 3 hours, the precipitate was filtered off and dried under vacuum to get 0.483 g of the pure product (Ligand-linker 3), with 65.1% yield. In order to improve purity, the substance can be recrystallized from hot water. Anal. Calc'd for OoHsOsLLO: C, 43.80; H, 3.68. Found: C, 44.64; H, 3.48.
[0075] ¾ NMR (DMSO) δ 7.45 (s, 2 H), 4.60 (s, 2 H) ppm; 13C NMR δ 170.99, 168.53, 164.80, 146.62, 121.84, 117.91 and 66.01 ppm. ESI-MS calc'd. for Ci0H8O8 [M-H] 255.01460, found 255.01450.
[0076] EXAMPLE 9
[0077] Synthesis of 2-hydroxy-5-(2-hydroxyethoxy)isophthalic acid (Ligand-linker 4)
[0078] 2-chloroethanol (1.27 mL, 19.0 mmol) was added in one portion to a solution of 2,5- dihydroxybenzoic acid (1.54 g, 10.0 mmol) and KOH (3.02 g, 54 mmol) in H20 (70 mL) while stirring at room temperature. The reaction mixture was heated at 100°C for 6 h. After cooling to room temp, it was neutralized with 1M hydrochloric acid (pH 1-2) and the organic product was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous Na2SC and the solvent was removed in vacuo. Pure product (e) was isolated by flash chromatography on silica gel with the eluent mixture of 2,2,4-trimethylpentane and ethyl acetate (1:1 v/v) with the yield of 1.16 g (58.5%).
[0079] The reaction solution containing 1.98 g, 10.0 mmol of (e) and 6.66 g (46.0 mmol) of hexamethylene tetramine in 30mL of trifluoroacetic acid was stirred at 90°C for 12 h. After completion and cooling to room temperature, 200 mL of 1 M HCl were added and the reaction mixture was stirred for 6 h. The reaction mixture was extracted with EtOAc (4X50ml) and combined EtOAc layers were washed thoroughly with water to remove trifluoroacetic acid, and dried over anhydrous sodium sulfate. The solvent was removed to get the formylated product (f) as a pale yellow solid 1.85 g with 82% isolated yield.
[0080] To the solution of (f) (0.452 g, 2.0 mmol) in 6 mL of DMSO a solution of sodium
dihydrogen phosphate (0.065 g, 0.54 mmol) in 1 mL of water was added while stirring at room temperature. The solution sodium chlorite (0.397 g, 4.4 mmol) in 10 mL of water was added to this solution slowly while stirring. After stirring for 12 h, the reaction mixture pH was brought to 1 by adding diluted sulfuric acid and the solution was extracted with EtOAc. Combined organic layers were washed with water and dried over sodium sulfate. The solvent was removed under vacuum to get 0.387g of the final product (Ligand-linker 4) with 80% isolated yield.
[0081] ¾ NMR (DMSO) δ 7.51 (s, 2 H), 3.98 (tj = 4.5 Hz, 2 H), 3.69 (tj = 4.7 Hz, 2 H) ppm; 13C NMR δ 169.33, 155.87, 150.10, 121.84, 118.09, 71.01, 59.99 ppm. ESI-MS calc'd. for Ci0Hi0O7 [M- H] 241.03540, found 241.03500.
[0082] EXAMPLE 10
[0083] Synthesis of 5-(3-chloro-2-hydroxypropoxy)-2-hydroxyisophthalic acid (Ligand-linker 5).
[0084] To a stirring solution of 2,5-dihydroxyisophthalic acid (5) (2.00g, 9.26 mmol) and sodium hydroxide (5N) (5.0 mL, 25 mmol) in 50 mL of water epichlorohydrin (1.40 g, 15.1 mmol) was added. The reaction mixture was stirred at room temperature about 19 h under N2 atmosphere. After completion, the reaction mixture was neutralized with 25% HC1 to pHl and stirred at room temperature for about 30 min, then cooled in the refrigerator. The precipitate was filtered off, washed with 0.1M HC1 and icy water and air-dried. Yield of the off-white powder is 2.17 g; this product contained up to 15% of unreacted (5). For purification, the product was recrystallized from 40 mL of hot 1M HC1; yield of pure product was 1.70 g.
[0085] ¾ NMR δ 7.52 (s, 2 H), 3.97 (tj = 7.3 Hz, 3 H), 3.63-3.77 (m, 2 H) ppm; 13C NMR δ 169.27, 156.14, 149.81, 121.93, 118.13, 70.55, 69.08 and 47.04 ppm. ESI-MS calc'd. for CnHnC107 \M- H] 289.01210, found 289.01170.
[0086] Anal. Calc'd for CnHn07Cl: C, 45.45; H, 3.82. Found: C, 45.62; H, 3.75. ¾ NMR δ 7.52 (s, 2 H), 3.97 (tj = 7.3 Hz, 3 H), 3.63-3.77 (m, 2 H) ppm; 13C NMR δ 169.27, 156.14, 149.81, 121.93, 118.13, 70.55, 69.08 and 47.04 ppm. ESI-MS calc'd. for CnHnC107 [M-H] 289.01210, found 289.01170.
[0087] EXAMPLE 11
[0088] Synthesis of 5-(2,3-dihydroxypropoxy)-2-hydroxyisophthalic acid (Ligand-linker 6) [0089] 0.145 g of Ligand-linker 5 (0.5 mmol) was suspended in 10 mL of water and addition of 2 mL of 1M NaOH caused its complete dissolution. The resulting solution was heated in boiling water bath for 60 minutes. After cooling, the solution was neutralized by adding 2 mL of 1M HC1. Possible non-polar impurities were removed by extracting with 10 mL of ethyl acetate. Aqueous layer was separated and evaporated on a steam bath. The solid residue was extracted with 12 mL of absolute ethanol; the solution was evaporated on a steam bath and the residue was dried at 110°C overnight yielding 0.105 g (77%) of tan-colored solid product.
[0090] Anal. Calc'd for CnHizOeHzO: C, 45.52; H, 4.45. Found: C, 44.37; H, 3.90. ¾ NMR (DMSO) δ 7.50 (s, 2 H), 3.97 (ddj = 4, 8 Hz, 1 H), 3.82 (tj = 4 Hz, 1 H), 3.72-3.79 (m, 1 H), 3.42 (dj = 8 Hz, 2 H) ppm; 13C NMR δ 169.27, 156.45, 150.02, 121.85, 118.03, 71.11, 70.35 and 63.05 ppm. ESI-MS calc'd. for CnHi208 [M-H] 271.04590, found 271.04550.
[0091] EXAMPLE 12
[0092] Synthesis of 5-(3-amino-2-hydroxypropoxy)-2-hydroxyisophthalic acid (Ligand-linker 7)
[0093] A solution of ligand-linker 5 (0.500 g, 1.72 mmol) in 10 mL of water and 5 mL of concentrated aqueous ammonia was aged overnight at room temperature and then the temperature was raised in one hour up to 70°C in the stoppered Kjeldahl flask. After completion, the solution was evaporated on a steam bath to dryness. Workup method 1. The crude product was dissolved in 30 mL of water; the solution was filtered through a fine frit, and acidified by adding 5 mL of 1M HC1. The precipitated impurities were filtered off, and the solution was neutralized with 1M NaOH to pH4. This caused slow crystallization of Ligand-linker 7 as a light-yellow solid (0.166 g). Solution was concentrated on a steam bath to the volume of 3 mL and seeded with previously obtained solid. Additional 0.114 g of pure product crystallizes, bringing an overall yield to 60%. Workup method 2. Solid ammonium salt was washed with methanol until negative drop evaporation test; the residue was dissolved in 30 mL of water and the solution was acidified to pH 3-4 with 0.5M HC1. This caused slow precipitation of zwitterion-structured product. Next day, the solid was filtered off, washed with icy water and dried to yield 0.360 g (77%) of the light-yellow product.
[0094] Anal. Calc'd for C11H13NO7H2O: C, 45.67; H, 5.24; N, 4.84. Found: C, 46.41; H, 5.11; N, 4.71. ¾ NMR (DzO) δ 7.22 (s, 2 H), 4.13 (tj = 4.2 Hz, 1 H), 3.88-3.96 (m, 2 H), 3.18 (d J = 13.1 Hz, 1 H), 3.06 (tj = 5.7 Hz, 1 H) ppm; 13C NMR (DMSO) δ 168.06, 164.26, 146,54, 121.64, 117.51, 70.72, 65.60 and 41.61 ppm. ESI-MS calc'd. for G1H13NO7 [M-H] 270.06190, found 270.06140.
[0095] EXAMPLE 13 [0096] Affinity of 2-hydroxyisophthalic acid derivatives to metal oxide surface
[0097] Colloidal nanoparticles of maghemite (y-FezOs) were synthesized by high-temperature hydrolysis of chelated iron alkoxide complexes in surfactant-free non-aqueous solutions, followed by oxygenation [36]. Colloids of the obtained 5 nm maghemite nanoparticles were reacted with (1) and with ligand-linkers (4-7) yielding surface-coated nanoparticulate adducts. Stoichiometry calculations and the experimental method were described in [36]. The DLS monitored pH titration was performed on Malvern Zetasizer Nano ZS instrument equipped with automatic titrator MPT2. The nanoparticulate adducts maintained their integrity and ability to form stable aqueous colloids in the range of pH2 to 11, depending on the substituent.
[0098] Alternatively, affinity of the named acid to metal oxide surfaces was evaluated by testing of its ability to inhibit the precipitation of iron (III) hydroxide from aqueous solutions. Three acidic aqueous solutions containing iron (III) and (a) 5-bromo-2-hydroxyisophthalic acid (Fe:L = 2:3), (b) 5- hydroxyisophthalic and (c) salicylic acids (Fe:L = 1:3) were titrated with NaOH solution in the pH range from 2 to 11. The named acid (a) was superior to the reference acids (b) and (c) as it was the only one stabilizing iron hydroxide colloid under basic conditions (Figure 5).
[0099] EXAMPLE 14
[0100] Affinity of 2-hydroxyisophthalic acid and its derivatives to silica surface
[0101] Thin-layer chromatography (TLC) was used to determine the Rf values for 2,5- dihydroxyisophthalic acid (5), 5-hydroxyisophthalic acid, and 5-hydroxysalicylic acid. Silica-coated TLC plates and 1:1 ethyl acetate/isooctane mixture as a mobile phase were used. The Rf values were 0.127, 0.218 and 0.403, respectively, indicating stronger binding of acid being claimed to silica, which is a relatively acidic oxide.
[0102] All references cited in this specification are herein incorporated by reference as though each reference was specifically and individually indicated to be incorporated by reference. The citation of any reference is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such reference by virtue of prior invention.
[0103] It will be understood that each of the elements described above, or two or more together may also find a useful application in other types of methods differing from the type described above. Without further analysis, the foregoing will so fully reveal the gist of the present disclosure that others can, by applying current knowledge, readily adapt it for various applications without omitting features that, from the standpoint of prior art, fairly constitute essential characteristics of the generic or specific aspects of this disclosure set forth in the appended claims. The foregoing embodiments are presented by way of example only; the scope of the present disclosure is to be limited only by the following claims.
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Nanoarchitectures for Liquid-Junction Solar Cells. Chem. Rev. 2010, 110, 6664-6688. Hagfeldt, A.; Boschloo, G.; Sun, L.; Kloo, L.; Pettersson, H. Dye-Sensitized Solar Cells. Chem. Rev. 2010, 110, 6595-6663. Graebe, C; Kraft, H. About oxidation melts. Ber. Dtsch. Chem. Ges., 1906, 39, 794. Benica, W. S.; Gisvold, O. The Synthesis of 2 -Hydroxyisophthalic Acid and Some of Its
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Claims

is claimed is:
A compound selected from the group consisting of Formula (Γ).
Figure imgf000023_0001
Formula (Γ) wherein
X = OH, NH2, N2aryl, OR, NHR, a linear or branched aliphatic or oligo-ethylene oxide with a degree of polymerization from 2 to 50, or oligo-glycerol with a degree of polymerization from 2 to 50, with or without terminal OH, NH2, COOH, CHO, C2H, N¾ or SH groups; and
R = CH2CO2H, C2H4OH, C3H5, C3H5(OH)Cl, C3H5(OH)2, C3H5(OH)NH2 or C3H5(OH)OC3H5
2. The compound of claim 1, wherein:
X = OH.
3. The compound of claim 1, wherein:
X = NH2.
4. The compound of claim 1, wherein:
X = N2aryl.
5. The compound of claim 1, wherein:
X = OR; and
R = CH2CO2H, C2H4OH, C3H5(OH)NH2, C3H5(OH)Cl, C3H5, C3H5(OH)2 or C3H5(OH)OC3H5.
6. The compound of claim 1, wherein:
X = NHR; and
R = CH2CO2H, C2H4OH, C3H5(OH)NH2, C3H5(OH)Cl, C3H5, or C3H5(OH)2.
7. Use of a compound of any one of claims 1-6 as a coordinating ligand for iron oxide, for other metal oxide surfaces, or for both.
8. Use of a compound of any one of claims 1-6 for protection of a metal oxide surface, for
stabilization of a metal oxide surface, or for conjugation of a metal oxide surface with a biomolecule.
9. Use of a compound of any one of claims 1-6 as a linker precursor for dye-sensitized or quantum dot-sensitized solar cells.
10. A method of making unsubstituted 2-hydroxyisophthalic acid, the method comprising:
oxidation of 3-methylsalicylic acid with lead(IV) oxide in KOH melt.
11. A method of making 2-hydroxy-5-(sulfooxy)isophthalic acid, K salt comprising Elbs oxidation of 2-hydroxyisophthalic acid.
12. A method of making 2,5-dihydroxyisophthalic acid comprising acid-catalyzed hydrolysis of 2- hydroxy-5-(sulfooxy)isophthalic acid, K salt.
13. A method of making 5-nitro-2-hydroxyisophthalic acid by nitration of 2-hydroxyisophthalic acid
Figure imgf000024_0001
14. A method of making 5-amino-2-hydroxyisophthalic acid by hydrogenation of 5-nitro-2- hydroxyisophthalic acid under ambient conditions, catalyzed by platinum or palladium on carbon.
15. A method of making 5-((4-chlorophenyl)diazenyl)-2-hydroxyisophthalic acid by azo-coupling of 2-hydroxyisophthalic acid with 4-chlorophenyl diazonium ion.
16. A method of making a compound of Formula (I).
Figure imgf000025_0001
Formula (Γ) wherein
X = OCH2CO2H, OC2H4OH, OC3H5, OC3H5(OH)Cl, OC3H5(OH)2, OC3H5(OH)NH2 or
Figure imgf000025_0002
the method comprising:
phenol O-alkylation of a compound of Formula (Γ) wherein X=OH by base-catalyzed coupling with:
an epoxide to yield a compound of Formula (Γ), wherein X - OC3H5(OH)Cl,
OC3H5(OH)2, OC3H5(OH)NH2, or OC3H5(OH)OC3H5;
a halohydrin to yield a compound of Formula (I), wherein X = OC2H4OH; an allyl halide to yield a compound of Formula (Γ) wherein X = OC3Hs; or an alpha-halocarbonyl compound to yield a compound of Formula (Γ) wherein X =
OCH2C02H.
17. The method of claim 16, wherein said epoxide is epichlorohydrin or allyl glycidyl ether.
18. The method of claim 16, wherein said halohydrin is 2-chloroethanol or l,3-dichloro-2-propanol.
19. The method of claim 16, wherein said allyl halide is allyl bromide.
The method of claim 16, wherein said alpha-halocarbonyl is bromoacetic or chloroacetic acid.
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