Phosphonate

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General ester of phosphonic acid; in fact, the phosphorus has a formal charge of +1, the oxygen above it has a formal charge of -1, and the bond between them is single. Phosphonate.svg
General ester of phosphonic acid; in fact, the phosphorus has a formal charge of +1, the oxygen above it has a formal charge of −1, and the bond between them is single.

In organic chemistry, phosphonates or phosphonic acids are organophosphorus compounds containing C−PO(OR)2 groups (where R = alkyl, aryl, or just hydrogen). Phosphonic acids, typically handled as salts, are generally nonvolatile solids that are poorly soluble in organic solvents, but soluble in water and common alcohols.

Contents

Many commercially important compounds are phosphonates, including glyphosate (the active molecule of the herbicide Roundup), and ethephon, a widely used plant growth regulator. Bisphosphonates are popular drugs for treatment of osteoporosis. [1]

Clodronic acid is a bisphosphonate used as a drug to treat osteoporosis. Clodronic acid.png
Clodronic acid is a bisphosphonate used as a drug to treat osteoporosis.

In biochemistry and medicinal chemistry, phosphonate groups are used as stable bioisosteres for phosphate, such as in the antiviral nucleotide analog, Tenofovir, one of the cornerstones of anti-HIV therapy. And there is an indication that phosphonate derivatives are "promising ligands for nuclear medicine." [2]

Basic properties

Phosphonates feature tetrahedral phosphorus centers. They are structurally closely related to (and often prepared from) phosphorous acid. [3]

Phosphonic acids and derivatives are chemically and structurally related to phosphorous acid. Phosphonic-acid-2D-dimensions-vector.svg
Phosphonic acids and derivatives are chemically and structurally related to phosphorous acid.

Phosphonate salts are the result of deprotonation of phosphonic acids, which are diprotic acids:

RPO(OH)2 + NaOH → H2O + RPO(OH)(ONa) (monosodium phosphonate)
RPO(OH)(ONa) + NaOH → H2O + RPO(ONa)2 (disodium phosphonate)

Phosphonate esters are the result of condensation of phosphonic acids with alcohols.

Synthesis

Several methods exist for the preparation of phosphonic acids and their salts.

From phosphonic acid

Most processes begin with phosphorous acid (aka phosphonic acid, H3PO3), exploiting its reactive P−H bond. [1] [3]

Phosphonic acid can be alkylated via the Kabachnik–Fields reaction or Pudovik reaction to give aminophosphonate, which are useful as chelating agents. One example is the industrial preparation of nitrilotris(methylenephosphonic acid):

NH3 + 3 H3PO3 + 3 CH2O → N(CH2PO3H2)3 + 3 H2O

Phosphonic acid also can be alkylated with acrylic acid derivatives to afford carboxyl functionalized phosphonic acids. This reaction is a variant of the Michael addition:

CH2=CHCO2R + 3 H3PO3 → (HO)2P(O)CH2CH2CO2R

In the Hirao coupling dialkyl phosphites (which can also be viewed as di-esters of phosphonic acid: (O=PH(OR)2) undergo a palladium-catalyzed coupling reaction with an aryl halide to form a phosphonate.

Michaelis-Arbuzov reaction

Phosphonic esters are prepared using the Michaelis–Arbuzov reaction. For example, methyl iodide catalyses the conversion of trimethylphosphite to the phosphonate ester dimethyl methylphosphonate:

P(OMe)3 → MePO(OMe)2

These esters can be hydrolysed to the acid (Me = methyl):

MePO(OMe)2 + H2O → MePO(OH)2 + 2 MeOH

In the Michaelis–Becker reaction, a hydrogen phosphonate diester is first deprotonated and the resulting anion is alkylated.

From phosphorus trichloride

Vinylphosphonic acid can be prepared by the reaction of PCl3 and acetaldehyde:

PCl3 + CH3CHO → CH3CH(O)PCl+
3

This adduct reacts with acetic acid:

CH3CH(O)PCl+
3
+ 2 CH3CO2H → CH3CH(Cl)PO(OH)2 + 2 CH3COCl

This chloride undergoes dehydrochlorination to afford the target:

CH3CH(Cl)PO(OH)2 → CH2=CHPO(OH)2 + HCl

In the Kinnear–Perren reaction alkylphosphonyl dichlorides and esters are generated by alkylation of phosphorus trichloride in the presence of aluminium trichloride. Alkyltrichlorophosphonium salts are intermediates: [1]

PCl3 + RCl + AlCl3 → RPCl+
3
+ AlCl
4

The RPCl+
3
product can then be decomposed with water to produce an alkylphosphonic dichloride RP(=O)Cl2.

Reactions

Hydrolysis

Phosphonate esters are generally susceptible to hydrolysis under both acidic and basic conditions. Cleavage of the P-C bond is harder but can be achieved under aggressive conditions.

O=PC(OR)2 + 2 H2O → O=PC(OH)2 + 2 ROH

Horner–Wadsworth–Emmons reaction

In the Horner–Wadsworth–Emmons reaction dialkyl-phosphonates are deprotonated to give stabilized carbanions, which react with aldehydes to give E-alkenes with elimination of a dialkyl-phosphate. [4]

The Horner-Wadsworth-Emmons reaction Horner-Wadsworth-Emmons reaction example.svg
The Horner–Wadsworth–Emmons reaction

Structural sub-classes

Bisphosphonates

General structure of biphosphonates Biphosphonate Structural Formulae.png
General structure of biphosphonates

Compounds containing 2 geminal phosphonate groups are known as bisphosphonates. They were first synthesized in 1897 by Von Baeyer and Hofmann and now form the basis for an important class of drugs, used to treat osteoporosis and similar diseases. Examples include HEDP (etidronic acid or Didronel), which is prepared from phosphorous acid and acetic anhydride: [1]

2 H3PO3 + (CH3CO)2O → CH3C(OH)(PO3H2)2 + CH3CO2H

Thiophosphonates

O-Ethyl methylphosphonothioic acid Structural Formula V.1.svg
EMPTA (Thione)
VX-S-enantiomer-2D-skeletal.png
VX (Thiol)

A thiophosphonate group is a functional group related to phosphonate by substitution of an oxygen atom for a sulphur. They are a reactive component of many pesticides and nerve agents. Substituted thiophosphonates can have 2 main structural isomers bonding though either O or S groups to give thione and thiol forms respectively. This is a property they share with related functional groups such as thiocarboxylic acids and organothiophosphates.

Phosphonamidates

Phosphonamidates are related to phosphonates by substitution of an oxygen atom for a nitrogen. They are a rarely encountered functional group. The nerve agent Tabun is an example.

Occurrence in nature

Glyphosate, part of the herbicide "Roundup", is a phosphonate. Glyphosate.svg
Glyphosate, part of the herbicide "Roundup", is a phosphonate.
2-aminoethylphosphonic acid: the first identified natural phosphonate 2-aminoethylphosphonate.png
2-aminoethylphosphonic acid: the first identified natural phosphonate

Phosphonates are one of the three sources of phosphate intake in biological cells.[ citation needed ] The other two are inorganic phosphate and organophosphates.

The naturally occurring phosphonate 2-aminoethylphosphonic acid was first identified in 1959 in plants and many animals, where it is localized in membranes. Phosphonates are quite common among different organisms, from prokaryotes to eubacteria and mushrooms, mollusks, insects and others. They were first reported in natural soils by Newman and Tate (1980). The biological role of the natural phosphonates is still poorly understood. Bis- or polyphosphonates have not been found to occur naturally.

A number of natural product phosphonate substances with antibiotic properties have been identified. [5] Phosphonate natural product antibiotics include fosfomycin which is approved by FDA for the treatment of non-complicated urinary tract infection as well as several pre-clinically investigated substances such as Fosmidomycin (inhibitor isoprenyl synthase), SF-2312 (inhibitor of the glycolytic enzyme enolase, [6] and substances of unknown mode of actions such as alahopcin. Although phosphonates are profoundly cell impermeable, natural product phosphonate antibiotics are effective against a number of organisms, because many bacterial species express glycerol-3-phosphate and glucose-6-phosphate importers, which can be hijacked by phosphonate antibiotics. Fosfomycin resistant bacterial strains frequently have mutations that inactivate these transporters; however, such mutations are not maintained in the absence of antibiotic because of the fitness cost they impose.

Uses

In 1998 the consumption of phosphonates was 56,000 tons worldwide – 40,000 tons in the US, 15,000 tons in Europe and less than 800 tons in Japan. The demand of phosphonates grows steadily at 3% annually.

Metal chelants

Since the work of Gerold Schwarzenbach in 1949, phosphonic acids are known as effective chelating agents. The introduction of an amine group into the molecule to obtain −NH2−C−PO(OH)2 increases the metal binding abilities of the phosphonate. Examples for such compounds are NTMP, EDTMP and DTPMP. These phosphonates are the structural analogues to the well-known aminopolycarboxylate such as EDTA. The stability of the metal complexes increases with increasing number of phosphonic acid groups. Phosphonates are highly water-soluble while the phosphonic acids are only sparingly so.

Phosphonates are effective chelating agents. That is, they bind tightly to di- and trivalent metal ions, which is useful in water softening. In this way, they prevent formation of insoluble precipitates (scale). The binding of these ligands also suppresses the catalytic properties of metal ions. They are stable under harsh conditions. For these reasons, an important industrial use of phosphonates is in cooling waters, desalination systems, and in oil fields to inhibit scale formation. Phosphonates are also regularly used in reverse osmosis systems as antiscalants. Phosphonates in cooling water systems also serve to control corrosion of iron and steel. In pulp and paper manufacturing and in textile industry they serve as "peroxide bleach stabilizers", by chelating metals that could inactivate the peroxide. In detergents they are used as a combination of chelating agent, scale inhibitor, and bleach stabilizer. Phosphonates are also increasingly used in medicine to treat disorders associated with bone formation and calcium metabolism. Furthermore, they serve as carriers for radionuclides in bone cancer treatments (see samarium-153-ethylene diamine tetramethylene phosphonate).

Concrete admixtures

Phosphonates are also used as concrete retarder. [7] [8] They delay the cement setting time, allowing a longer time to place the concrete or to spread the cement hydration heat on a longer period of time to avoid too high temperature and resulting cracks. They also have favourable dispersing properties and so are investigated as a possible new class of superplasticizers. However, presently, phosphonates are not commercially available as superplasticizers. Superplasticizers are concrete admixtures designed to increase the concrete fluidity and workability of concrete or to decrease its water-to-cement (w/c) ratio. By reducing the water content in concrete, it decreases its porosity, improving so the mechanical properties (compressive and tensile strength) and the durability of concrete (lower water, gas and solutes transport properties). [9]

Medicine

In medicine, phosphonates and bisphosphonates are commonly used as inhibitors of enzymes which utilize phosphates and diphosphates as substrates. Most notably, these enzymes include those that produce the intermediates of cholesterol biosynthesis. [10]

Phosphonate nucleotide analogues such as tenofovir, cidofovir and adefovir are critical antiviral medications, which in various pro-drug forms are used for the treatment of HIV, hepatitis B and others.

Niche uses

In conjunction with organosilicates, phosphonates are also used to treat "sudden oak death", which is caused by the fungus-like eukaryote Phytophthora ramorum .

Toxicology

The toxicity of phosphonates to organisms living in water is low. Reported values for 48-hour LC50 values for fish are between 0.1 and 1.1 mM. Also the bioconcentration factor for fish is very low.

Biodegradation

In nature bacteria play a major role in the degradation of phosphonates. [11] Due to the presence of natural phosphonates in the environment, bacteria have evolved the ability to metabolize phosphonates as nutrient sources. Some bacteria use phosphonates as a phosphorus source for growth. Aminophosphonates can also be used as sole nitrogen source by some bacteria. The polyphosphonates used in industry differ greatly from natural phosphonates such as 2-aminoethylphosphonic acid, because they are much larger, carry a high negative charge and are complexed with metals. Biodegradation tests with sludge from municipal sewage treatment plants with HEDP and NTMP showed no indication for any degradation. An investigation of HEDP, NTMP, EDTMP and DTPMP in standard biodegradation tests also failed to identify any biodegradation. It was noted, however, that in some tests due to the high sludge to phosphonate ratio, removal of the test substance from solution observed as loss of DOC was observed. This factor was attributed to adsorption rather than biodegradation. However, bacterial strains capable of degrading aminopolyphosphonates and HEDP under P-limited conditions have been isolated from soils, lakes, wastewater, activated sludge and compost.

"No biodegradation of phosphonates during water treatment is observed but photodegradation of the Fe(III)-complexes is rapid. Aminopolyphosphonates are also rapidly oxidized in the presence of Mn(II) and oxygen and stable breakdown products are formed that have been detected in wastewater. The lack of information about phosphonates in the environment is linked to analytical problems of their determination at trace concentrations in natural waters. Phosphonates are present mainly as Ca and Mg-complexes in natural waters and therefore do not affect metal speciation or transport." [12] Phosphonates interact strongly with some surfaces, which results in a significant removal in technical and natural systems.

Phosphonate compounds

See also

Related Research Articles

<span class="mw-page-title-main">Ester</span> Compound derived from an acid

In chemistry, an ester is a compound derived from an acid in which the hydrogen atom (H) of at least one acidic hydroxyl group of that acid is replaced by an organyl group. Analogues derived from oxygen replaced by other chalcogens belong to the ester category as well. According to some authors, organyl derivatives of acidic hydrogen of other acids are esters as well, but not according to the IUPAC.

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.

<span class="mw-page-title-main">Phosphite anion</span> Ion

A phosphite anion or phosphite in inorganic chemistry usually refers to [HPO3]2− but includes [H2PO3] ([HPO2(OH)]). These anions are the conjugate bases of phosphorous acid (H3PO3). The corresponding salts, e.g. sodium phosphite (Na2HPO3) are reducing in character.

<span class="mw-page-title-main">Tenofovir disoproxil</span>

Tenofovir disoproxil, sold under the trade name Viread among others, is a medication used to treat chronic hepatitis B and to prevent and treat HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention of HIV/AIDS among those at high risk before exposure, and after a needlestick injury or other potential exposure. It is sold both by itself and together in combinations such as emtricitabine/tenofovir, efavirenz/emtricitabine/tenofovir, and elvitegravir/cobicistat/emtricitabine/tenofovir. It does not cure HIV/AIDS or hepatitis B. It is available by mouth as a tablet or powder.

<span class="mw-page-title-main">Phosphorus trichloride</span> Chemical compound

Phosphorus trichloride is an inorganic compound with the chemical formula PCl3. A colorless liquid when pure, it is an important industrial chemical, being used for the manufacture of phosphites and other organophosphorus compounds. It is toxic and reacts readily with water to release hydrogen chloride.

<span class="mw-page-title-main">Michaelis–Arbuzov reaction</span>

The Michaelis–Arbuzov reaction is the chemical reaction of a trivalent phosphorus ester with an alkyl halide to form a pentavalent phosphorus species and another alkyl halide. The picture below shows the most common types of substrates undergoing the Arbuzov reaction; phosphite esters (1) react to form phosphonates (2), phosphonites (3) react to form phosphinates (4) and phosphinites (5) react to form phosphine oxides (6).

<span class="mw-page-title-main">Phosphorous acid</span> Chemical compound

Phosphorous acid (or phosphonic acid (singular)) is the compound described by the formula H3PO3. This acid is diprotic (readily ionizes two protons), not triprotic as might be suggested by this formula. Phosphorous acid is an intermediate in the preparation of other phosphorus compounds. Organic derivatives of phosphorous acid, compounds with the formula RPO3H2, are called phosphonic acids.

<span class="mw-page-title-main">Phosphoric acids and phosphates</span>

A phosphoric acid, in the general sense, is a phosphorus oxoacid in which each phosphorus (P) atom is in the oxidation state +5, and is bonded to four oxygen (O) atoms, one of them through a double bond, arranged as the corners of a tetrahedron. Two or more of these PO
4
tetrahedra may be connected by shared single-bonded oxygens, forming linear or branched chains, cycles, or more complex structures. The single-bonded oxygen atoms that are not shared are completed with acidic hydrogen atoms. The general formula of a phosphoric acid is H
n+2−2x
P
n
O
3n+1−x
, where n is the number of phosphorus atoms and x is the number of fundamental cycles in the molecule's structure, between 0 and (n+2)/2.

Phosphorus oxoacid is a generic name for any acid whose molecule consists of atoms of phosphorus, oxygen, and hydrogen. There is a potentially infinite number of such compounds. Some of them are unstable and have not been isolated, but the derived anions and organic groups are present in stable salts and esters. The most important ones—in biology, geology, industry, and chemical research—are the phosphoric acids, whose esters and salts are the phosphates.

<span class="mw-page-title-main">Trimethyl phosphate</span> Chemical compound

Trimethyl phosphate is the trimethyl ester of phosphoric acid. It is a colourless, nonvolatile liquid. It has some specialized uses in the production of other compounds.

<span class="mw-page-title-main">Sodium monofluorophosphate</span> Chemical compound

Sodium monofluorophosphate, commonly abbreviated SMFP, is an inorganic compound with the chemical formula Na2PO3F. Typical for a salt, MFP is odourless, colourless, and water-soluble. This salt is an ingredient in some toothpastes.

<span class="mw-page-title-main">Phosphite ester</span> Organic compound with the formula P(OR)3

In organic chemistry, a phosphite ester or organophosphite usually refers to an organophosphorous compound with the formula P(OR)3. They can be considered as esters of an unobserved tautomer phosphorous acid, H3PO3, with the simplest example being trimethylphosphite, P(OCH3)3. Some phosphites can be considered esters of the dominant tautomer of phosphorous acid (HP(O)(OH)2). The simplest representative is dimethylphosphite with the formula HP(O)(OCH3)2. Both classes of phosphites are usually colorless liquids.

Organophosphorus chemistry is the scientific study of the synthesis and properties of organophosphorus compounds, which are organic compounds containing phosphorus. They are used primarily in pest control as an alternative to chlorinated hydrocarbons that persist in the environment. Some organophosphorus compounds are highly effective insecticides, although some are extremely toxic to humans, including sarin and VX nerve agents.

<span class="mw-page-title-main">Etidronic acid</span>

Etidronic acid, also known as etidronate, is a non-nitrogenous bisphosphonate used as a medication, detergent, water treatment, and cosmetic.

<span class="mw-page-title-main">ATMP</span> Chemical compound

ATMP or aminotris(methylenephosphonic acid) is a phosphonic acid with chemical formula N(CH2PO3H2)3. It has chelating properties. It can be synthesized from the Mannich-type reaction of ammonia, formaldehyde, and phosphorous acid, in a manner similar to the Kabachnik–Fields reaction.

<span class="mw-page-title-main">EDTMP</span> Chemical compound

EDTMP or ethylenediamine tetra(methylene phosphonic acid) is a phosphonic acid. It has chelating and anti corrosion properties. EDTMP is the phosphonate analog of EDTA. It is classified as a nitrogenous organic polyphosphonic acid.

<span class="mw-page-title-main">DTPMP</span> Chemical compound

DTPMP or diethylenetriamine penta(methylene phosphonic acid) is a phosphonic acid. It has chelating and anti corrosion properties.

Oilfield scale inhibition is the process of preventing the formation of scale from blocking or hindering fluid flow through pipelines, valves, and pumps used in oil production and processing. Scale inhibitors (SIs) are a class of specialty chemicals that are used to slow or prevent scaling in water systems. Oilfield scaling is the precipitation and accumulation of insoluble crystals (salts) from a mixture of incompatible aqueous phases in oil processing systems. Scale is a common term in the oil industry used to describe solid deposits that grow over time, blocking and hindering fluid flow through pipelines, valves, pumps etc. with significant reduction in production rates and equipment damages. Scaling represents a major challenge for flow assurance in the oil and gas industry. Examples of oilfield scales are calcium carbonate (limescale), iron sulfides, barium sulfate and strontium sulfate. Scale inhibition encompasses the processes or techniques employed to treat scaling problems.

Aminophosphonates are organophosphorus compounds with the formula (RO)2P(O)CR'2NR"2. These compounds are structural analogues of amino acids in which a carboxylic moiety is replaced by phosphonic acid or related groups. Acting as antagonists of amino acids, they inhibit enzymes involved in amino acid metabolism and thus affect the physiological activity of the cell. These effects may be exerted as antibacterial, plant growth regulatory or neuromodulatory. They can act as ligands, and heavy metal complexes with aminophosphonates have had medical applications investigated.

<span class="mw-page-title-main">Diethylphosphite</span> Chemical compound

Diethylphosphite is the organophosphorus compound with the formula (C2H5O)2P(O)H. It is a popular reagent for generating other organophosphorus compounds, exploiting the high reactivity of the P-H bond. Diethylphosphite is a colorless liquid. The molecule is tetrahedral.

References

  1. 1 2 3 4 Svara, J.; Weferling, N.; Hofmann, T. "Phosphorus Compounds, Organic," in Ullmann's Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim, 2008. doi : 10.1002/14356007.a19_545.pub2.
  2. Pazderová, Lucia; David, Tomáš; Hlinová, Veronika; Plutnar, Jan; Kotek, Jan; Lubal, Přemysl; Kubíček, Vojtěch; Hermann, Petr (2020-06-15). "Cross-Bridged Cyclam with Phosphonate and Phosphinate Pendant Arms: Chelators for Copper Radioisotopes with Fast Complexation". Inorganic Chemistry. 59 (12): 8432–8443. doi:10.1021/acs.inorgchem.0c00856. ISSN   0020-1669. PMID   32437603. S2CID   218834212.
  3. 1 2 Modern Phosphonate Chemistry by Philippe Savignac and Bogdan Iorga, CRC Press, Boca Raton, FL, 2003. ISBN   0-8493-1099-7
  4. Boutagy, John; Thomas, Richard (February 1974). "Olefin synthesis with organic phosphonate carbanions". Chemical Reviews. 74 (1): 87–99. doi:10.1021/cr60287a005.
  5. Ju KS, Doroghazi JR, Metcalf WW (2014). "Genomics-enabled discovery of phosphonate natural products and their biosynthetic pathways". J. Ind. Microbiol. Biotechnol. 41 (2): 345–356. doi:10.1007/s10295-013-1375-2. PMC   3946943 . PMID   24271089.
  6. Leonard PG, Satani N, Maxwell D, Lin YH, Hammoudi N, Peng Z, Pisaneschi F, Link TM, Lee GR, Sun D, Prasad BA, Di Francesco ME, Czako B, Asara JM, Wang YA, Bornmann W, DePinho RA, Muller FL (December 2016). "SF2312 is a natural phosphonate inhibitor of enolase". Nature Chemical Biology. 12 (12): 1053–1058. doi:10.1038/nchembio.2195. PMC   5110371 . PMID   27723749.
  7. Ramachandran, V. S.; Lowery, M. S.; Wise, T.; Polomark, G. M. (1993). "The role of phosphonates in the hydration of Portland cement". Materials and Structures. 26 (7): 425–432. doi:10.1007/BF02472943. ISSN   0025-5432. S2CID   97857221.
  8. Collier, Nicholas C.; Milestone, Neil B.; Travis, Karl P.; Gibb, Fergus.G.F. (2016). "The effect of organic retarders on grout thickening and setting during deep borehole disposal of high-level radioactive waste". Progress in Nuclear Energy. 90: 19–26. doi: 10.1016/j.pnucene.2016.02.021 . ISSN   0149-1970.
  9. Flatt, R.; Schober, I. (2012). "Superplasticizers and the rheology of concrete". Understanding the Rheology of Concrete. pp. 144–208. doi:10.1533/9780857095282.2.144. ISBN   9780857090287.
  10. Wiemer, AJ; Hohl, RJ; Wiemer, DF (June 2009). "The intermediate enzymes of isoprenoid metabolism as anticancer targets". Anti-Cancer Agents in Medicinal Chemistry. 9 (5): 526–42. doi:10.2174/187152009788451860. PMID   19519294.
  11. Huang J, Su Z, Xu Y (November 2005). "The evolution of microbial phosphonate degradative pathways". Journal of Molecular Evolution. 61 (5): 682–90. Bibcode:2005JMolE..61..682H. doi:10.1007/s00239-004-0349-4. PMID   16245012. S2CID   13414302.
  12. Nowack Bernd (2003). "Environmental chemistry of phosphonates". Water Research. 37 (11): 2533–2546. doi:10.1016/S0043-1354(03)00079-4. PMID   12753831.

Further reading