Squaric acid, also called quadratic acid because its four carbon atoms approximately form a square, is a

diprotic In computer science, ACID ( atomicity, consistency, isolation, durability) is a set of properties of database transactions intended to guarantee data validity despite errors, power failures, and other mishaps. In the context of databases, a sequ ...

organic acid with the

chemical formula In chemistry, a chemical formula is a way of presenting information about the chemical proportions of atoms that constitute a particular chemical compound or molecule, using chemical element symbols, numbers, and sometimes also other symbol ...

C₄O₂(OH)₂. The

conjugate base A conjugate acid, within the Brønsted–Lowry acid–base theory, is a chemical compound formed when an acid donates a proton () to a base—in other words, it is a base with a hydrogen ion added to it, as in the reverse reaction it loses a ...

of squaric acid is the hydrogensquarate anion ; and the conjugate base of the hydrogensquarate anion is the divalent squarate anion . This is one of the

oxocarbon anion In chemistry, an oxocarbon anion is a negative ion consisting solely of carbon and oxygen atoms, and therefore having the general formula for some integers ''x'', ''y'', and ''n''. The most common oxocarbon anions are carbonate, , and oxalate, ...

s, which consist only of carbon and oxygen. Squaric acid is a reagent for

chemical synthesis As a topic of chemistry, chemical synthesis (or combination) is the artificial execution of chemical reactions to obtain one or several products. This occurs by physical and chemical manipulations usually involving one or more reactions. In mod ...

, used for instance to make

photosensitive Photosensitivity is the amount to which an object reacts upon receiving photons, especially visible light. In medicine, the term is principally used for abnormal reactions of the skin, and two types are distinguished, photoallergy and phototoxicit ...

squaraine dyes and inhibitors of

protein tyrosine phosphatase Protein tyrosine phosphatases (EC 3.1.3.48, systematic name protein-tyrosine-phosphate phosphohydrolase) are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins: : proteintyrosine phosphate + H2O = ...

Chemical properties

Squaric acid is a white crystalline powder. The onset of thermal decomposition depends on the different thermodynamic conditions such as heating rates. The structure of squaric acid is not a perfect square, as the carbon–carbon bond lengths are not quite equal. The high

acidity In computer science, ACID ( atomicity, consistency, isolation, durability) is a set of properties of database transactions intended to guarantee data validity despite errors, power failures, and other mishaps. In the context of databases, a ...

with p''K''_a = 1.5 for the first proton and p''K''_a = 3.4 for the second is attributable to

resonance stabilization In chemistry, resonance, also called mesomerism, is a way of describing bonding in certain molecules or polyatomic ions by the combination of several contributing structures (or ''forms'', also variously known as ''resonance structures'' or '' ...

of the

anion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...

. Because the negative charges are equally distributed between each oxygen atom, the dianion of squaric acid is completely symmetrical (unlike squaric acid itself) with all C−C

bond length In molecular geometry, bond length or bond distance is defined as the average distance between nuclei of two bonded atoms in a molecule. It is a transferable property of a bond between atoms of fixed types, relatively independent of the rest of ...

s identical and all C−O bond lengths identical.

Derivatives

Many of the reactions of squaric acid involve the OH groups. The molecule behaves similarly to a strong dicarboxylic acid. It is stronger acid than typical carboxylic acids. :C₄O₂(OH)₂ → ₄O₃(OH)sup>− + H⁺ pK = 1.5 : ₄O₃(OH)sup>− → ₄O₄sup>2- + H⁺ pK = 3.5 The OH groups are labile in squaric acid. It forms a dichloride with thionyl chloride: :C₄O₂(OH)₂ + 2 SOCl₂ → C₄O₂Cl₂ + 2 HCl + 2 SO₂ The chlorides are good leaving groups, reminiscent of

acid chloride In organic chemistry, an acyl chloride (or acid chloride) is an organic compound with the functional group . Their formula is usually written , where R is a side chain. They are reactive derivatives of carboxylic acids (). A specific example o ...

s. They are displaced by diverse nucleophiles. In this way dithiosquarate can be prepared. The bis(methylether) is prepared by alkylation with

trimethyl orthoformate Trimethyl orthoformate (TMOF) is the organic compound with the formula HC(OCH3)3. A colorless liquid, it is the simplest orthoester. It is a reagent used in organic synthesis for the formation of methyl ethers. The product of reaction of an ald ...

. Squaramides are prepared by displacement of alkoxy or chloride groups from C₄O₂X₂ (X = OR, Cl). One or both of the oxygen (=O) groups in the squarate anion can be replaced by dicyanomethylene =C(CN)₂. The resulting anions, such as 1,2-bis(dicyanomethylene)squarate and 1,3-bis(dicyanomethylene)squarate, retain the aromatic character of squarate and have been called

pseudo-oxocarbon anion In chemistry, the term pseudo-oxocarbon anion is used to refer to a anion, negative ion that is conceptually derived from an oxocarbon anion through replacement of one or more of the basic oxygen atoms by chemically similar elements or functional gr ...

s. Photolysis of squaric acid in a solid argon matrix at affords

acetylenediol Acetylenediol, or ethynediol, is a chemical substance with formula HO−C≡C−OH (an ynol). It is the diol of acetylene. Acetylenediol is unstable in the condensed phase, although its tautomer glyoxal (CHO)2 is well known. Detection Acetyl ...

Coordination complexes

Squarate dianion behaves similarly to

oxalate Oxalate (IUPAC: ethanedioate) is an anion with the formula C2O42−. This dianion is colorless. It occurs naturally, including in some foods. It forms a variety of salts, for example sodium oxalate (Na2C2O4), and several esters such as dimethyl ...

, forming mono- and polynuclear complexes with hard metal ions.

Cobalt(II) squarate hydrate Cobalt is a chemical element with the symbol Co and atomic number 27. As with nickel, cobalt is found in the Earth's crust only in a chemically combined form, save for small deposits found in alloys of natural meteoric iron. The free element, p ...

Co(C₄O₄)(H₂O)₂ (yellow, cubic) can be prepared by

autoclaving An autoclave is a machine used to carry out industrial and scientific processes requiring elevated temperature and pressure in relation to ambient pressure and/or temperature. Autoclaves are used before surgical procedures to perform steriliza ...

cobalt(II) hydroxide Cobalt(II) hydroxide or cobaltous hydroxide is the inorganic compound with the formula , consisting of divalent cobalt cations and hydroxide anions . The pure compound, often called the "beta form" (β-) is a pink solid insoluble in water. The ...

and squaric acid in water at 200 °C. The water is bound to the

cobalt Cobalt is a chemical element with the symbol Co and atomic number 27. As with nickel, cobalt is found in the Earth's crust only in a chemically combined form, save for small deposits found in alloys of natural meteoric iron. The free element, p ...

atom, and the crystal structure consists of a cubic arrangement of hollow cells, whose walls are either six squarate anions (leaving a 7 Å wide void) or several water molecules (leaving a 5 Å void).

Cobalt(II) squarate dihydroxide Cobalt is a chemical element with the symbol Co and atomic number 27. As with nickel, cobalt is found in the Earth's crust only in a chemically combined form, save for small deposits found in alloys of natural meteoric iron. The free element, p ...

Co₃(OH)₂(C₄O₄)₂·3H₂O (brown) is obtained together with the previous compound. It has a columnar structure including channels filled with water molecules; these can be removed and replaced without destroying the crystal structure. The chains are ferromagnetic; they are coupled antiferromagnetically in the hydrated form, ferromagnetically in the anhydrous form. Copper(II) squarate monomeric and dimeric mixed-ligand complexes were synthesized and characterized. Infrared, electronic and Q-Band EPR spectra as well as magnetic susceptibilities are reported. The same method yields iron(II) squarate dihydroxide Fe₂(OH)₂(C₄O₄) (light brown).

Synthesis

The original synthesis started with the ethanolysis of perfluorocyclobutene to give 1,2-diethoxy-3,3,4,4-tetrafluoro-1-cyclobutene.

Hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolys ...

gives the squaric acid. Although impractical, squarate and related anions such as deltate and

acetylenediolate Acetylenediol, or ethynediol, is a chemical substance with formula HO−C≡C−OH (an ynol). It is the diol of acetylene. Acetylenediol is unstable in the condensed phase, although its tautomer glyoxal (CHO)2 is well known. Detection Acetyle ...

are obtainable by reductive coupling of carbon monoxide using organouranium complexes.

Medical uses

Medically, SADBE or squaric acid dibutyl ester or dibutyl squarate derives from a squaric acid. is used for the treatment of

warts Warts are typically small, rough, hard growths that are similar in color to the rest of the skin. They typically do not result in other symptoms, except when on the bottom of the feet, where they may be painful. While they usually occur on the ...

. Squaric acid dibutyl ester is also used for treating

alopecia areata Alopecia areata, also known as spot baldness, is a condition in which hair is lost from some or all areas of the body. Often, it results in a few bald spots on the scalp, each about the size of a coin. Psychological stress and illness are pos ...

or alopecia totalis (

autoimmune In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". ...

hair loss Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scar ...

) through topical

immunotherapy Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...

involving the production of an

allergic Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic der ...

rash. Squaric acid dibutylester is currently undergoing trials for use in treating

herpes labialis Herpes labialis, commonly known as cold sores or fever blisters, is a type of infection by the herpes simplex virus that affects primarily the lip. Symptoms typically include a burning pain followed by small blisters or sores. The first attack ...

(cold sores). Diethylsquarate was utilized in the synthesis of Perzinfotel. Attempts to capitalize on Squaric acid in the arena of drug chemistry had also led to BMS-181885.

References