2-Phosphonobutyric acid triethyl ester
[CAS# 17145-91-4]

Identification

• Classification: Chemical reagent >> Organic reagent >> Phosphorous compound
• Name: 2-Phosphonobutyric acid triethyl ester
• Synonyms: Ethyl 2-(diethoxyphosphinyl)butanoate; Ethyl 2-(diethoxyphosphoryl)butanoate; Ethyl 2-(diethylphosphono)butyrate; NSC 22423; Triethyl 2-phosphonobutanoate; Triethyl 2-phosphonobutyrate; Triethyl alpha-phosphonobutyrate; alpha-Diethylphosphonobutanoic acid ethyl ester
• Molecular Formula: C₁₀H₂₁O₅P
• Molecular Weight: 252.24
• CAS Registry Number: 17145-91-4
• EC Number: 627-866-8
• SMILES: CCC(C(=O)OCC)P(=O)(OCC)OCC

Properties

• Density: 1.1±0.1 g/cm³ Calc.^*, 1.064 g/mL (Expl.)
• Boiling point: 315.2±25.0 ºC 760 mmHg (Calc.)^*, 309.7 - 312.4 ºC (Expl.)
• Flash point: 158.3±43.5 ºC (Calc.)^*, 113 ºC (Expl.)
• Solubility: water: Sparingly soluble (11 g/L) (25 ºC), Calc.
• Index of refraction: 1.43 (Calc.)^*, 1.4296 (589.3 nm 20 ºC) (Expl.)^**

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software V11.02 (©1994-2013 ACD/Labs)

^** Fiszer, Bernard; Roczniki Chemii 1954, V28, P185-95.

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H315-H319-H335
• Precautionary Statements: P261-P264-P264+P265-P271-P280-P302+P352-P304+P340-P305+P351+P338-P319-P321-P332+P317-P337+P317-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Specific target organ toxicity - single exposure	STOT SE	3	H335
Eye irritation	Eye Irrit.	2	H319
Skin irritation	Skin Irrit.	2	H315

Discovory and Applicatios

2-Phosphonobutyric acid triethyl ester is an organophosphorus compound in which the carboxylic acid of 2-phosphonobutyric acid is esterified with three ethyl groups, forming a triethyl ester. The molecule contains a four-carbon backbone, with a phosphonic acid group substituted at the α-position relative to the carboxyl group. In the triethyl ester form, the acidic hydrogens of the phosphonic acid are replaced by ethyl groups, resulting in the molecular formula C₁₀H₂₃O₅P and a molecular weight of approximately 246.25 g/mol. The presence of both phosphonate and ester functionalities imparts lipophilicity to the molecule while maintaining a reactive phosphorus center for subsequent chemical transformations.

This compound has been of interest primarily in the field of medicinal chemistry and organic synthesis. The phosphonate ester moiety is an analog of the naturally occurring phosphonic acids and can act as a bioisostere of carboxylic acids or phosphates in enzyme substrates and inhibitors. By modifying the phosphonic acid as a triethyl ester, solubility in organic solvents is increased, facilitating its use in synthetic sequences where the free phosphonic acid would be poorly soluble. In biological contexts, triethyl esters are often used as prodrugs that can release the active phosphonic acid in vivo through enzymatic or chemical hydrolysis.

The synthesis of 2-phosphonobutyric acid triethyl ester typically begins with 2-bromobutyric acid or a related α-halo carboxylic acid. This intermediate undergoes nucleophilic substitution with triethyl phosphite via a Michaelis–Arbuzov reaction to introduce the phosphonate moiety. The resulting phosphonate ester can then be purified by distillation or chromatography. Careful control of reaction temperature and stoichiometry is important to minimize side reactions such as over-alkylation or decomposition of the phosphonate. Alternative synthetic routes include phosphonylation of activated carboxylic acid derivatives with phosphorus trichloride followed by esterification with ethanol.

In terms of chemical properties, 2-phosphonobutyric acid triethyl ester is a colorless to pale yellow liquid or low-melting solid, depending on purity and preparation. It is stable under standard storage conditions, but it can hydrolyze slowly in the presence of water or acids to generate the corresponding phosphonic acid. The compound is soluble in common organic solvents such as dichloromethane, chloroform, and acetonitrile, which allows its use in multi-step organic synthesis. The triethyl ester groups are susceptible to cleavage under acidic or basic conditions, making them useful for controlled deprotection strategies in synthetic chemistry.

Applications of this compound are largely based on its role as a phosphonate ester building block. In medicinal chemistry, 2-phosphonobutyric acid triethyl ester can be employed in the synthesis of nucleotide analogs, enzyme inhibitors, and antiviral agents. The phosphonate group mimics the transition state of phosphate ester hydrolysis, which is useful for designing inhibitors of enzymes such as phosphatases or kinases. The triethyl ester form allows the molecule to cross cell membranes more readily than the free phosphonic acid, increasing its utility in cell-based assays or prodrug design.

In synthetic methodology, the triethyl ester serves as a protected form of the phosphonic acid, enabling selective reactions at other sites of the molecule. After the desired transformations, the ester can be hydrolyzed under acidic or basic conditions to regenerate the free phosphonic acid for further use. This strategy is commonly employed in the preparation of biologically active phosphonates and in the study of phosphonate-containing intermediates in organic synthesis.

Overall, 2-phosphonobutyric acid triethyl ester is a versatile organophosphorus compound that combines reactivity, solubility, and functional versatility. Its structural features—an α-phosphonate group adjacent to a carboxyl-derived ester—make it a valuable intermediate in both chemical synthesis and the development of biologically active molecules. The esterified form enhances handling and solubility while preserving the potential for controlled release of the active phosphonic acid in subsequent reactions or biological environments. Its combination of chemical stability, synthetic accessibility, and biological relevance ensures continued use in research and development contexts.

References

2022. Horner�Wadsworth�Emmons Olefination in Flow System by Photocatalysis. Synfacts.
DOI: 10.1055/s-0041-1738548

2021. Synthesis of PARP1�DNA Trapper AZD5305. Synfacts.
DOI: 10.1055/s-0041-1737091

2017. Advantages of the Microwave Tool in Organophosphorus Syntheses. Synthesis.
DOI: 10.1055/s-0036-1589031