Abstract

4-Fluorobutan-1-ol (C₄H₉FO) represents a fluorinated primary alcohol with the systematic IUPAC name 4-fluorobutan-1-ol. This colorless liquid compound exhibits a boiling point of 129.3 °C and demonstrates complete miscibility with water and many organic solvents. The molecular structure features a terminal hydroxyl group separated from a fluorine substituent by a three-carbon alkyl chain, creating unique electronic and steric properties. 4-Fluorobutanol serves as a versatile synthetic intermediate in organofluorine chemistry, particularly for the preparation of fluorinated ethers, esters, and other functionalized molecules. The compound displays significant toxicity with an LD₅₀ value of 0.9 mg·kg⁻¹ in mice via intraperitoneal or subcutaneous injection, attributed to metabolic conversion to fluoroacetate. Its chemical behavior reflects the competing electronic influences of the strongly electronegative fluorine atom and the polar hydroxyl functionality.

Introduction

4-Fluorobutanol belongs to the class of organofluorine compounds, specifically fluorinated alcohols, which occupy an important position in modern synthetic chemistry. Fluorinated alcohols demonstrate altered physical and chemical properties compared to their non-fluorinated analogues, including enhanced acidity, increased stability, and modified solvation characteristics. The strategic placement of fluorine at the terminal position of the butanol chain creates a molecule with distinctive dipole characteristics and reactivity patterns. Although less extensively studied than shorter-chain fluorinated alcohols such as 2-fluoroethanol, 4-fluorobutanol presents particular interest due to its extended carbon chain, which moderates the electronic effects between the functional groups while maintaining significant biological activity. The compound serves primarily as a building block in pharmaceutical and agrochemical research where the introduction of fluorine atoms improves metabolic stability and modulates biological activity.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The molecular structure of 4-fluorobutanol follows conventional sp³ hybridization patterns for all carbon atoms. According to VSEPR theory, the carbon atoms adopt tetrahedral geometry with bond angles approximating 109.5°. The terminal carbon atoms bonded to oxygen and fluorine display slightly compressed bond angles due to the greater electronegativity of these heteroatoms. The C-F bond length measures approximately 1.39 Å, characteristic of carbon-fluorine single bonds, while the C-O bond length is approximately 1.43 Å. The four-carbon chain adopts a gauche conformation in the gas phase, minimizing dipole-dipole repulsion between the terminal functional groups. Molecular orbital analysis reveals highest occupied molecular orbitals localized primarily on the oxygen atom, while the lowest unoccupied molecular orbitals show significant contribution from the carbon-fluorine antibonding orbital. The fluorine atom exerts a strong inductive effect through the carbon chain, polarizing electron density toward itself and creating a molecular dipole moment estimated at 2.4 Debye.

Chemical Bonding and Intermolecular Forces

Covalent bonding in 4-fluorobutanol follows standard patterns for aliphatic compounds with heteroatom substituents. The C-F bond demonstrates high bond dissociation energy of approximately 116 kcal·mol⁻¹, contributing to the compound's thermal stability. The O-H bond dissociation energy is approximately 102 kcal·mol⁻¹. Intermolecular forces include strong hydrogen bonding capability through the hydroxyl group, with an O-H···O hydrogen bond energy of approximately 5.0 kcal·mol⁻¹. The presence of fluorine introduces additional dipole-dipole interactions and weak C-H···F hydrogen bonding with an energy of approximately 1.5 kcal·mol⁻¹. The compound's polarity, characterized by a calculated dielectric constant of approximately 15, enables solvation of both polar and moderately non-polar species. Van der Waals forces contribute significantly to the liquid-phase properties, with a calculated Lennard-Jones potential well depth of approximately 0.5 kcal·mol⁻¹.

Physical Properties

Phase Behavior and Thermodynamic Properties

4-Fluorobutanol presents as a colorless liquid at room temperature with a characteristic mild odor. The compound exhibits a boiling point of 129.3 °C at atmospheric pressure, notably higher than that of butanol (117.7 °C) due to the additional mass and polarity of the fluorine substituent. The melting point has not been precisely determined but is estimated below -30 °C based on analogous compounds. The density of the liquid is approximately 1.06 g·mL⁻¹ at 20 °C, slightly higher than that of non-fluorinated butanol (0.81 g·mL⁻¹). The refractive index measures 1.392 at 20 °C and 589 nm wavelength. Thermodynamic parameters include an enthalpy of vaporization of approximately 45 kJ·mol⁻¹ and a heat capacity of approximately 220 J·mol⁻¹·K⁻¹ in the liquid phase. The compound demonstrates complete miscibility with water, ethanol, diethyl ether, and most common organic solvents, forming azeotropes with several hydrocarbons.

Spectroscopic Characteristics

Infrared spectroscopy reveals characteristic absorption bands at 3350 cm⁻¹ (broad, O-H stretch), 2950-2850 cm⁻¹ (C-H stretches), 1070 cm⁻¹ (C-O stretch), and 1020 cm⁻¹ (C-F stretch). Proton NMR spectroscopy (CDCl₃, 400 MHz) shows signals at δ 1.60-1.75 ppm (m, 2H, CH₂), δ 1.80-1.95 ppm (m, 2H, CH₂), δ 3.65 ppm (t, J = 6.2 Hz, 2H, CH₂OH), δ 4.45 ppm (dt, J = 47.2 Hz, 6.0 Hz, 2H, CH₂F), and δ 2.20 ppm (s, 1H, OH). Carbon-13 NMR displays resonances at δ 30.2 ppm (CH₂), δ 29.8 ppm (CH₂), δ 62.5 ppm (CH₂OH), and δ 83.5 ppm (d, J = 165 Hz, CH₂F). Fluorine-19 NMR shows a single peak at δ -218 ppm relative to CFCl₃. Mass spectrometry exhibits a molecular ion peak at m/z 92 with characteristic fragmentation patterns including loss of H₂O (m/z 74), loss of HF (m/z 72), and formation of CH₂F⁺ fragment (m/z 33).

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

4-Fluorobutanol demonstrates reactivity characteristic of both primary alcohols and alkyl fluorides. The hydroxyl group undergoes typical alcohol transformations including esterification with rate constants of approximately 10⁻³ L·mol⁻¹·s⁻¹ for acetylation, ether formation with second-order rate constants of approximately 10⁻⁴ L·mol⁻¹·s⁻¹, and oxidation to the corresponding aldehyde with chromic acid (k ≈ 10⁻² L·mol⁻¹·s⁻¹). The fluorine substituent exhibits nucleophilic substitution reactivity significantly slower than that of shorter-chain fluorinated compounds due to reduced strain and decreased activation by adjacent groups. Displacement reactions proceed via S_N2 mechanism with second-order rate constants of approximately 10⁻⁶ L·mol⁻¹·s⁻¹ for reactions with iodide ion. The compound demonstrates stability toward hydrolysis under neutral conditions (half-life >1000 hours at 25 °C) but undergoes rapid defluorination under strongly basic conditions (half-life ≈ 2 hours in 1M NaOH at 25 °C). Thermal decomposition begins at approximately 200 °C via elimination of HF to form butenal.

Acid-Base and Redox Properties

The hydroxyl group of 4-fluorobutanol exhibits typical alcohol acidity with a pK_a of approximately 15.5 in water, slightly lower than that of butanol (pK_a ≈ 16) due to the electron-withdrawing effect of the fluorine substituent. The compound functions as a weak hydrogen bond donor with a Kamlet-Taft α parameter of approximately 0.7. Redox properties include oxidation potential of approximately 1.8 V versus SCE for conversion to the aldehyde. The fluorine substituent demonstrates negligible influence on the redox behavior of the hydroxyl group beyond its inductive electron-withdrawing effect. The compound displays stability across a pH range of 3-10 at room temperature, with gradual decomposition observed outside this range. Electrochemical reduction occurs at potentials below -2.5 V versus SCE, primarily involving cleavage of the C-F bond.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

The most efficient laboratory synthesis of 4-fluorobutanol proceeds through nucleophilic fluorination of 4-chlorobutanol or corresponding tosylate derivatives. A typical procedure involves reaction of 4-chlorobutanol with potassium fluoride in aprotic solvents such as dimethylformamide or dimethyl sulfoxide at temperatures of 120-150 °C for 12-24 hours, yielding 4-fluorobutanol with approximately 65% conversion. Alternative methods include hydrofluorination of 3-buten-1-ol using hydrogen fluoride or amine-HF complexes, though these methods typically give lower yields and require careful handling. More modern approaches employ fluorination using silver(I) fluoride or tetrabutylammonium fluoride in dichloromethane at room temperature, achieving yields up to 80% with reduced reaction times. Purification typically involves fractional distillation under reduced pressure (bp 45-50 °C at 20 mmHg) followed by drying over molecular sieves. The compound is hygroscopic and requires storage under anhydrous conditions.

Analytical Methods and Characterization

Identification and Quantification

Gas chromatography with flame ionization detection provides the primary method for quantification of 4-fluorobutanol, using polar stationary phases such as Carbowax 20M with retention indices of approximately 1250. Detection limits approach 0.1 μg·mL⁻¹ with linear response across concentration ranges of 0.5-500 μg·mL⁻¹. High-performance liquid chromatography with reverse-phase C18 columns and UV detection at 210 nm offers alternative quantification with similar sensitivity. Infrared spectroscopy provides confirmatory identification through characteristic fingerprint region absorptions between 1000-1100 cm⁻¹. Nuclear magnetic resonance spectroscopy, particularly ¹⁹F NMR, offers highly specific detection with limits of approximately 10 μg·mL⁻¹. Mass spectrometric detection using electron impact ionization provides unambiguous molecular weight confirmation through the molecular ion at m/z 92 and characteristic fragmentation pattern.

Purity Assessment and Quality Control

Commercial 4-fluorobutanol typically exhibits purity grades of 95-99% with major impurities including water, 4-chlorobutanol (from incomplete fluorination), and 4,4'-oxybisbutanol (from ether formation). Karl Fischer titration determines water content with detection limits of 0.01%. Gas chromatography with mass spectrometric detection identifies and quantifies organic impurities at levels as low as 0.05%. Acceptable quality specifications include water content below 0.5%, halogenated impurities below 0.2%, and ether impurities below 0.1%. The compound demonstrates stability for at least 12 months when stored under nitrogen in amber glass containers at temperatures below 25 °C. Degradation products include 4-hydroxybutanal and 4,4'-dihydroxydibutyl ether, detectable by HPLC at levels above 0.1%.

Applications and Uses

Industrial and Commercial Applications

4-Fluorobutanol serves primarily as a specialty chemical intermediate in the pharmaceutical and agrochemical industries. The compound functions as a building block for the synthesis of fluorinated ethers, esters, and other derivatives where the introduction of fluorine modulates biological activity and metabolic stability. In pharmaceutical research, 4-fluorobutanol derivatives appear in compounds targeting neurological disorders and cardiovascular diseases. The compound finds application in materials science as a precursor to fluorinated polymers and surfactants, where the combination of hydrophilicity and lipophilicity provides unique surface activity. Production volumes remain relatively small, estimated at 10-100 kilograms annually worldwide, with primary manufacturing occurring in specialized fine chemical facilities. Handling requires strict engineering controls due to the compound's toxicity and flammability characteristics.

Conclusion

4-Fluorobutanol represents a structurally interesting fluorinated alcohol that demonstrates the competing electronic influences of terminal fluorine and hydroxyl substituents separated by an alkyl chain. Its physical properties reflect significant hydrogen bonding capability moderated by the inductive effect of the fluorine atom. The compound's chemical reactivity encompasses both alcohol and alkyl fluoride functionality, though with attenuated reactivity compared to shorter-chain analogues. Synthetic applications primarily exploit its role as a bifunctional building block in organofluorine chemistry. The significant toxicity resulting from metabolic conversion to fluoroacetate necessitates careful handling procedures. Future research directions may explore its potential in materials science applications, particularly in the development of fluorinated surfactants and polymers, as well as expanded synthetic methodology for its preparation and transformation.