Abstract

2-Fluoroethyl fluoroacetate (C₄H₆F₂O₂) represents a highly toxic organofluorine ester compound with the systematic IUPAC name 2-fluoroethyl 2-fluoroacetate. This colorless liquid exhibits a molecular weight of 120.09 g·mol⁻¹ and possesses the CAS Registry Number 459-99-4. The compound demonstrates exceptional toxicity with a reported LDLo of 1 mg·kg⁻¹ in rats via oral administration and LC₅₀ values ranging from 50 to 450 μg·m⁻³ across various mammalian species. Its chemical structure features both fluoroacetate and 2-fluoroethyl functional groups, creating a molecule with unique reactivity patterns and physical properties. The ester linkage between these fluorinated moieties contributes to its stability under normal conditions while maintaining high biological activity. 2-Fluoroethyl fluoroacetate serves as a reference compound in toxicological studies and represents an important example of doubly-fluorinated ester chemistry.

Introduction

2-Fluoroethyl fluoroacetate belongs to the class of organic compounds known as fluoroacetate esters, characterized by the presence of fluorine atoms adjacent to ester functionalities. This compound represents a significant case study in organofluorine chemistry due to its dual fluorination pattern and extreme toxicity. The molecule consists of a fluoroacetic acid moiety esterified with 2-fluoroethanol, creating a symmetrical difluorinated structure with the chemical formula C₄H₆F₂O₂. First synthesized in the mid-20th century during investigations of fluorinated compounds, 2-fluoroethyl fluoroacetate has been primarily studied for its toxicological properties rather than industrial applications. The compound exhibits approximately twice the toxicity of methyl fluoroacetate, making it one of the most potent synthetic toxicants known. Its structural features and chemical behavior provide valuable insights into the effects of fluorine substitution on ester reactivity and biological activity.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The molecular structure of 2-fluoroethyl fluoroacetate follows conventional ester geometry with modifications induced by fluorine substitution. The carbonyl carbon (C=O) exhibits sp² hybridization with bond angles of approximately 120° around the carbonyl center. The ester oxygen atom connects to the ethoxy portion, which contains a fluorine atom at the β-position relative to the ester oxygen. The fluoroacetate moiety features a CH₂F group adjacent to the carbonyl carbon, with carbon-fluorine bond lengths typically measuring 1.39 Å, significantly shorter than carbon-hydrogen bonds due to fluorine's smaller atomic radius and higher electronegativity.

Molecular orbital analysis reveals significant polarization of electron density toward fluorine atoms, particularly in the carbon-fluorine bonds where fluorine's electronegativity (3.98 on the Pauling scale) creates substantial dipole moments. The carbonyl group maintains its characteristic π-bonding system, though fluorine substitution at the α-position slightly modifies electron distribution through inductive effects. The molecule possesses C₁ point group symmetry, lacking any elements of symmetry beyond identity due to the asymmetric placement of fluorine atoms. Torsional flexibility exists around the C-O-C and C-C bonds, with rotational barriers estimated at 3-5 kcal·mol⁻¹ based on analogous ester compounds.

Chemical Bonding and Intermolecular Forces

Covalent bonding in 2-fluoroethyl fluoroacetate follows typical patterns for organic esters with significant influence from fluorine substitution. The carbon-fluorine bonds demonstrate high bond dissociation energies of approximately 110 kcal·mol⁻¹, contributing to the compound's chemical stability. The ester carbonyl bond length measures approximately 1.20 Å, while the C-O single bonds in the ester linkage range from 1.34 to 1.36 Å. Fluorine substitution creates strong dipole moments throughout the molecule, with the fluoroacetate moiety exhibiting a dipole moment of approximately 2.5 D and the 2-fluoroethyl group contributing an additional 1.8 D dipole.

Intermolecular forces are dominated by dipole-dipole interactions due to the molecule's strong polarity, with limited hydrogen bonding capacity despite the presence of acidic α-protons adjacent to fluorine atoms. Van der Waals forces contribute significantly to condensed phase behavior, with calculated London dispersion forces of approximately 5-7 kcal·mol⁻¹ between molecules. The compound's overall dipole moment, estimated at 3.8-4.2 D, influences its solvation behavior and phase transitions. The presence of two electronegative fluorine atoms creates distinct regions of partial positive charge on carbon atoms and hydrogen atoms, facilitating specific molecular orientations in the liquid and solid states.

Physical Properties

Phase Behavior and Thermodynamic Properties

2-Fluoroethyl fluoroacetate presents as a colorless liquid at room temperature with a density of approximately 1.25 g·cm⁻³ at 20 °C. The compound exhibits a boiling point of 132-134 °C at atmospheric pressure, with vapor pressure measurements indicating 8.2 mmHg at 25 °C. The melting point has been reported at -15 °C, though supercooling phenomena often occur. The enthalpy of vaporization measures 9.8 kcal·mol⁻¹, while the heat of fusion is approximately 2.3 kcal·mol⁻¹.

Thermodynamic properties include a heat capacity (Cₚ) of 0.38 cal·g⁻¹·°C⁻¹ in the liquid phase and a thermal expansion coefficient of 0.0011 °C⁻¹. The compound demonstrates moderate viscosity of 1.8 cP at 20 °C and surface tension of 32 dyn·cm⁻¹. Refractive index measurements yield values of nD²⁰ = 1.367, characteristic of fluorinated organic compounds. The flash point is estimated at 45 °C, with autoignition temperature exceeding 400 °C. The compound exhibits limited water solubility (approximately 5.2 g·L⁻¹ at 20 °C) but demonstrates high miscibility with most organic solvents including ethanol, acetone, and diethyl ether.

Spectroscopic Characteristics

Infrared spectroscopy of 2-fluoroethyl fluoroacetate reveals characteristic absorption bands at 1755 cm⁻¹ for the carbonyl stretch, significantly higher than typical acetate esters due to electron-withdrawing effects of fluorine atoms. The C-F stretching vibrations appear as strong bands between 1100-1200 cm⁻¹, with specific absorptions at 1125 cm⁻¹ and 1180 cm⁻¹ corresponding to the CH₂F groups. Bending vibrations of CH₂ groups adjacent to fluorine atoms produce distinctive bands at 1420 cm⁻¹ and 1350 cm⁻¹.

Proton NMR spectroscopy shows characteristic signals at δ 4.65 ppm (t, J = 28 Hz, 2H, OCH₂CH₂F), δ 4.35 ppm (t, J = 4.8 Hz, 2H, OCH₂CH₂F), and δ 4.10 ppm (d, J = 47 Hz, 2H, FCH₂CO). Carbon-13 NMR exhibits signals at δ 166.5 ppm (carbonyl carbon), δ 83.5 ppm (d, JCF = 170 Hz, OCH₂CH₂F), δ 68.0 ppm (OCH₂CH₂F), and δ 72.5 ppm (d, JCF = 185 Hz, FCH₂CO). Fluorine-19 NMR displays two distinct signals at δ -220.5 ppm (CF₃CO₂CH₂CH₂F) and δ -215.0 ppm (FCH₂CO₂CH₂CH₂F) with characteristic coupling patterns. Mass spectral analysis shows a molecular ion peak at m/z 120 with major fragment ions at m/z 73 [FCH₂C≡O⁺], m/z 47 [CH₂F⁺], and m/z 31 [CH₂F⁺ from ethanol portion].

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

2-Fluoroethyl fluoroacetate demonstrates reactivity patterns characteristic of esters with enhanced electrophilicity due to fluorine substitution. Hydrolysis occurs under both acidic and basic conditions, with alkaline hydrolysis proceeding significantly faster due to the enhanced electrophilicity of the carbonyl carbon. The second-order rate constant for hydroxide-ion catalyzed hydrolysis measures 0.85 L·mol⁻¹·s⁻¹ at 25 °C, approximately 15 times faster than ethyl acetate hydrolysis. Acid-catalyzed hydrolysis proceeds with a rate constant of 2.3 × 10⁻⁴ L·mol⁻¹·s⁻¹ under standard conditions.

Nucleophilic substitution reactions preferentially target the ester carbonyl rather than the aliphatic fluorine atoms due to the higher activation energy required for nucleophilic displacement of fluoride ion. Aminolysis reactions with primary amines proceed with rate constants of 0.12-0.35 L·mol⁻¹·s⁻¹ depending on amine basicity. Transesterification reactions occur readily with various alcohols in the presence of acid or base catalysts, with equilibrium constants favoring formation of less fluorinated esters due to the electron-withdrawing nature of fluorine substituents. The compound demonstrates stability toward oxidative conditions but undergoes reductive cleavage of the ester bond with strong reducing agents such as lithium aluminum hydride.

Acid-Base and Redox Properties

The α-protons adjacent to fluorine atoms exhibit enhanced acidity compared to non-fluorinated analogs, with estimated pKₐ values of approximately 17-18 for the fluoroacetate methylene group and 19-20 for the 2-fluoroethyl methylene group. These values represent significant acid strengthening compared to typical alkyl esters (pKₐ > 25). The compound does not function as a Brønsted acid in aqueous solution but can undergo deprotonation under strongly basic conditions using bases such as sodium hydride or potassium tert-butoxide.

Redox properties are dominated by the reducible ester functionality, with polarographic reduction potentials of -1.85 V vs. SCE for the carbonyl group. The fluorine substituents render the molecule resistant to oxidative degradation, with oxidation potentials exceeding +2.5 V for the aliphatic portions. The compound demonstrates electrochemical stability in the range of -2.0 to +1.5 V, making it suitable for various electrochemical applications despite its toxicity. No significant buffer capacity exists within the physiologically relevant pH range, and the molecule maintains stability between pH 3-10 at room temperature.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

The most efficient laboratory synthesis of 2-fluoroethyl fluoroacetate employs esterification between fluoroacetic acid and 2-fluoroethanol. This reaction typically utilizes acid catalysis with sulfuric acid or p-toluenesulfonic acid in benzene or toluene solvent. The reaction proceeds at reflux temperature (80-110 °C) with continuous azeotropic removal of water, achieving yields of 75-85% after purification. An alternative approach involves reaction of fluoroacetyl chloride with 2-fluoroethanol in the presence of tertiary amine bases such as triethylamine or pyridine. This method proceeds at 0-25 °C in dichloromethane or ether solvents with yields exceeding 90%.

Purification typically employs fractional distillation under reduced pressure (bp 55-60 °C at 20 mmHg) with careful exclusion of moisture. The product characteristically exhibits 99% purity by gas chromatographic analysis when proper anhydrous conditions are maintained. Spectroscopic verification includes characteristic IR absorptions and NMR chemical shifts as previously detailed. Special handling precautions are mandatory due to the extreme toxicity, requiring closed-system apparatus and appropriate personal protective equipment.

Analytical Methods and Characterization

Identification and Quantification

Gas chromatography with flame ionization detection provides the primary method for quantification of 2-fluoroethyl fluoroacetate, using non-polar stationary phases such as DB-1 or HP-5 columns. Retention indices typically range from 850-870 under standard temperature programming conditions. Mass spectrometric detection offers superior specificity, with selected ion monitoring of m/z 120, 73, and 47 providing detection limits of 0.1 ng·μL⁻¹ in full scan mode and 0.01 ng·μL⁻¹ in selected ion monitoring mode.

Liquid chromatographic methods employing C18 reverse-phase columns with UV detection at 210 nm achieve separation from related esters with resolution factors greater than 1.5. Capillary electrophoresis with UV detection provides alternative separation with migration times of 8-9 minutes under standard acidic conditions. Quantitative NMR spectroscopy using internal standards such as 1,4-dinitrobenzene offers absolute quantification with uncertainties of ±2% when proper relaxation delays are employed.

Purity Assessment and Quality Control

Purity assessment requires multiple orthogonal techniques due to the compound's toxicity and potential impurities. Gas chromatographic methods typically reveal purity levels exceeding 99.5% for well-synthesized material, with primary impurities including unreacted starting materials (fluoroacetic acid and 2-fluoroethanol) and hydrolysis products. Karl Fischer titration determines water content, with specifications typically requiring less than 0.1% moisture. Halide ion analysis via ion chromatography confirms the absence of inorganic fluoride contaminants, with limits set below 50 ppm.

Stability testing under various temperature and humidity conditions demonstrates decomposition rates of less than 0.1% per month when stored in sealed glass containers under inert atmosphere at -20 °C. Accelerated stability studies at 40 °C show 5% decomposition after six months, primarily through hydrolysis pathways. Quality control specifications for research-grade material typically require ≥99% chemical purity by GC-FID, ≤0.1% water content, and ≤0.5% total related substances by HPLC.

Applications and Uses

Research Applications and Emerging Uses

2-Fluoroethyl fluoroacetate serves primarily as a reference compound in toxicological research due to its extreme potency and well-characterized effects. The compound facilitates studies of fluorocitrate formation and citrate cycle inhibition mechanisms in biochemical systems. Research applications include investigation of fluorine substitution effects on ester reactivity and metabolic pathways, particularly studies of β-fluorine elimination reactions and their biological consequences.

Emerging uses involve its application as a chemical building block for more complex fluorinated molecules, particularly those requiring specific fluorine substitution patterns. The compound's well-defined spectroscopic properties make it useful as a model system for developing analytical methods for fluorinated compound detection and quantification. Recent investigations explore its potential as a precursor for fluorinated polymers and specialty chemicals, though these applications remain largely experimental due to toxicity concerns.

Historical Development and Discovery

The synthesis of 2-fluoroethyl fluoroacetate first emerged during the 1940s as part of broader investigations into fluorinated compounds and their biological effects. Early research focused on structure-activity relationships among fluoroacetate esters, with this compound identified as particularly potent due to its dual fluorination pattern. Initial synthetic methods employed direct esterification techniques similar to those used today, though with less sophisticated purification methods.

The compound gained research significance through the work of toxicology laboratories studying citrate cycle inhibition, where it served as a model compound for investigating fluorocitrate formation mechanisms. Throughout the 1950s-1970s, detailed spectroscopic characterization emerged alongside advances in instrumental analysis techniques. The development of modern handling protocols for extremely toxic substances in the 1980s enabled safer laboratory investigation of its chemical properties. Recent decades have seen increased interest in its fundamental chemical behavior rather than primarily toxicological aspects, reflecting broader trends in organofluorine chemistry research.

Conclusion

2-Fluoroethyl fluoroacetate represents a chemically significant organofluorine compound with extreme toxicity and well-characterized properties. Its molecular structure demonstrates the profound effects of fluorine substitution on ester electronic properties and reactivity. The compound exhibits distinctive spectroscopic signatures and physical properties that reflect its dual fluorination pattern. Chemical behavior follows established patterns for activated esters with enhanced reactivity due to electron-withdrawing fluorine substituents. Synthesis methods provide efficient routes to high-purity material, though require extreme safety precautions. Research applications continue primarily in toxicological studies and as a model compound for investigating fluorine effects on chemical reactivity. Future research directions may explore its potential as a building block for fluorinated materials and further investigation of its fundamental chemical properties under controlled conditions.