Abstract

3-Methyl-3-sulfanylhexan-1-ol (CAS Registry Number 307964-23-4) is an organosulfur compound with the molecular formula C₇H₁₆OS. This chiral thioalcohol features both hydroxyl and sulfhydryl functional groups attached to the same tertiary carbon center, creating a unique molecular architecture with distinctive chemical and physical properties. The compound exhibits a refractive index of 1.482 and manifests as a colorless to pale yellow liquid at ambient conditions. Its most notable characteristic is an intensely potent odor detectable at extremely low concentrations, contributing to its significance in olfactory chemistry. The molecule demonstrates complex hydrogen bonding capabilities due to its dual functional group arrangement, resulting in unusual solubility characteristics and reactivity patterns. 3-Methyl-3-sulfanylhexan-1-ol serves as an important reference compound in stereochemical studies and organosulfur chemistry research.

Introduction

3-Methyl-3-sulfanylhexan-1-ol represents a structurally distinctive class of organosulfur compounds characterized by the simultaneous presence of alcohol and thiol functional groups on a tertiary carbon center. This molecular arrangement creates a compound with unique electronic properties and reactivity patterns that differ significantly from either simple alcohols or thiols alone. The compound belongs to the broader category of thioalcohols, which have attracted considerable attention in synthetic chemistry due to their versatile reactivity and applications in materials science.

The molecular structure features a hexanol backbone with methyl and sulfanyl substituents at the 3-position, creating a chiral center with potential for enantiomeric separation. The presence of both oxygen and sulfur heteroatoms contributes to the compound's polar character and influences its intermolecular interaction capabilities. The compound's discovery and characterization emerged from research into sulfur-containing natural products and their olfactory properties.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The molecular geometry of 3-methyl-3-sulfanylhexan-1-ol is characterized by a tetrahedral carbon center at position 3, with bonds extending to methyl, ethyl, sulfhydryl, and hydroxymethyl groups. Bond angles approximate the ideal tetrahedral angle of 109.5°, with slight distortions due to differences in substituent electronegativity and steric requirements. The carbon-sulfur bond length measures approximately 1.81 Å, while carbon-oxygen bonds range from 1.42 to 1.46 Å depending on their position in the molecular framework.

Molecular orbital analysis reveals significant electron density redistribution between the sulfur and oxygen atoms. The highest occupied molecular orbital (HOMO) demonstrates substantial contribution from the sulfur 3p orbitals, while the lowest unoccupied molecular orbital (LUMO) shows antibonding character between carbon and oxygen atoms. This electronic configuration contributes to the compound's nucleophilic character at the sulfur center and electrophilic potential at the carbon atoms adjacent to heteroatoms.

Chemical Bonding and Intermolecular Forces

Covalent bonding in 3-methyl-3-sulfanylhexan-1-ol follows typical patterns for aliphatic compounds, with carbon-carbon bond energies averaging 347 kJ/mol and carbon-hydrogen bonds approximately 413 kJ/mol. The carbon-sulfur bond exhibits an energy of 272 kJ/mol, while the carbon-oxygen bond energy reaches 358 kJ/mol. These values reflect the relative bond strengths and influence the compound's thermal stability and fragmentation patterns.

Intermolecular forces dominate the physical behavior of 3-methyl-3-sulfanylhexan-1-ol. The molecule engages in hydrogen bonding through both hydroxyl (O-H...O) and thiol (S-H...S and S-H...O) interactions. The hydroxyl group serves as a strong hydrogen bond donor with a hydrogen bond energy of approximately 20 kJ/mol, while the thiol group participates in weaker hydrogen bonding with energies around 8 kJ/mol. Dipole-dipole interactions contribute significantly to intermolecular attraction, with the molecular dipole moment estimated at 2.1 Debye due to the electronegativity differences between sulfur (2.58), oxygen (3.44), and carbon (2.55).

Physical Properties

Phase Behavior and Thermodynamic Properties

3-Methyl-3-sulfanylhexan-1-ol exists as a liquid at standard temperature and pressure (25°C, 1 atm) with a boiling point range of 215-220°C and melting point between -5°C and 0°C. The compound demonstrates a density of 0.982 g/cm³ at 20°C and exhibits moderate viscosity of 15.2 cP at 25°C. The vapor pressure measures 0.15 mmHg at 25°C, reflecting the compound's relatively low volatility despite its potent odor characteristics.

Thermodynamic parameters include a heat of vaporization of 45.6 kJ/mol and heat of fusion of 12.3 kJ/mol. The specific heat capacity at constant pressure measures 2.1 J/g·K, while the thermal conductivity is 0.152 W/m·K. The compound displays a negative temperature coefficient of density of -0.00087 g/cm³·K over the liquid range. The surface tension measures 35.8 mN/m at 20°C, influenced by the polar functional groups and molecular architecture.

Spectroscopic Characteristics

Infrared spectroscopy reveals characteristic absorption bands at 3350 cm⁻¹ (O-H stretch), 2570 cm⁻¹ (S-H stretch), 2920-2850 cm⁻¹ (C-H stretches), 1450 cm⁻¹ (CH₂ scissoring), and 1050 cm⁻¹ (C-O stretch). The S-H stretching frequency appears at lower wavenumbers than typical thiols due to hydrogen bonding interactions.

Proton NMR spectroscopy shows distinctive signals at δ 1.25 ppm (triplet, 3H, CH₃-CH₂), δ 1.45 ppm (singlet, 3H, CH₃-C), δ 1.55-1.75 ppm (multiplet, 4H, CH₂-CH₂), δ 2.65 ppm (broad singlet, 1H, SH), δ 3.55 ppm (triplet, 2H, CH₂-OH), and δ 3.85 ppm (broad singlet, 1H, OH). Carbon-13 NMR displays resonances at δ 13.8 ppm (CH₃-CH₂), δ 24.5 ppm (CH₃-C), δ 29.2 ppm (CH₂), δ 31.8 ppm (CH₂), δ 48.5 ppm (C-S), and δ 61.3 ppm (CH₂-OH).

Mass spectrometry exhibits a molecular ion peak at m/z 148 with characteristic fragmentation patterns including loss of water (m/z 130), loss of hydrogen sulfide (m/z 112), and cleavage of the carbon-carbon bond adjacent to the functionalized carbon center.

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

3-Methyl-3-sulfanylhexan-1-ol demonstrates bifunctional reactivity patterns characteristic of molecules containing both nucleophilic and protic functional groups. The thiol group exhibits typical nucleophilic behavior with second-order rate constants of 1.2 × 10⁻³ M⁻¹s⁻¹ for reaction with methyl iodide in ethanol at 25°C. The hydroxyl group participates in standard alcohol chemistry including esterification with acetic acid exhibiting a rate constant of 3.8 × 10⁻⁵ M⁻¹s⁻¹ under acid catalysis.

The proximity of functional groups enables unique intramolecular reactions. Under basic conditions, the thiolate anion can undergo intramolecular displacement of hydroxide, forming the corresponding episulfide with a rate constant of 8.9 × 10⁻⁴ s⁻¹ at pH 10. The compound demonstrates stability in neutral aqueous solutions with a hydrolysis half-life exceeding 100 hours at 25°C, but undergoes rapid oxidation in the presence of atmospheric oxygen with a half-life of approximately 4 hours, primarily forming the disulfide derivative.

Acid-Base and Redox Properties

The thiol group exhibits weak acidity with a pK_a of 10.3 ± 0.2, while the alcohol group shows minimal acidity with pK_a > 15. This differential acidity enables selective deprotonation under controlled conditions. The compound demonstrates buffering capacity in the pH range 9.5-11.0 due to the thiol/thiolate equilibrium.

Redox properties include a standard reduction potential of -0.32 V for the RS•/RSH couple versus the standard hydrogen electrode. The compound undergoes facile oxidation by common oxidizing agents including hydrogen peroxide (k = 12 M⁻¹s⁻¹), iodine (k = 280 M⁻¹s⁻¹), and atmospheric oxygen (k = 0.002 s⁻¹). Electrochemical studies reveal a reversible oxidation wave at +0.85 V versus Ag/AgCl in acetonitrile, corresponding to one-electron oxidation of the thiol functionality.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

The most efficient laboratory synthesis begins with 3-methylpent-2-enoic acid, which undergoes hydroalumination with diisobutylaluminum hydride followed by trapping with elemental sulfur to introduce the thiol functionality. The resulting thioacid is reduced with lithium aluminum hydride in anhydrous ether at 0°C to yield the target alcohol with overall yields of 65-70%.

An alternative route employs 3-methylhex-3-en-1-ol as starting material, which undergoes regioselective hydrothiolation with hydrogen sulfide under radical initiation conditions. This method proceeds with anti-Markovnikov selectivity and provides the target compound in 55% yield after purification by fractional distillation. Both synthetic routes produce racemic material due to the prochiral nature of the starting materials.

Industrial Production Methods

Industrial scale production utilizes continuous flow hydrogenation of 3-methyl-3-sulfanylhexanoic acid over nickel catalysts at 150°C and 50 atm pressure. The process achieves conversion rates exceeding 90% with space-time yields of 2.5 kg/L·h. Product separation employs fractional distillation under reduced pressure (50 mmHg) with reflux ratios of 8:1 to achieve pharmaceutical grade purity (>99.5%).

Process economics favor the hydrogenation route due to lower catalyst costs and reduced waste generation compared to stoichiometric reduction methods. Environmental considerations include recycling of hydrogen streams and treatment of aqueous waste streams by activated carbon filtration to remove sulfur-containing byproducts.

Analytical Methods and Characterization

Identification and Quantification

Gas chromatography with flame ionization detection provides the primary method for quantification, with a detection limit of 0.1 μg/mL and linear range of 0.5-500 μg/mL. Capillary columns with moderate polarity stationary phases (DB-1701, 30 m × 0.32 mm × 1.0 μm) achieve complete separation from common impurities with retention indices of 1450 ± 10 under programmed temperature conditions from 60°C to 250°C at 10°C/min.

High-performance liquid chromatography with UV detection at 210 nm offers alternative quantification with reversed-phase C18 columns and acetonitrile/water mobile phases. Method validation demonstrates accuracy of 98.5-101.2% and precision of 1.5% RSD across the quantitative range. Mass spectrometric detection provides confirmatory analysis with selected ion monitoring of m/z 148, 130, and 112.

Purity Assessment and Quality Control

Purity specifications require minimum 98.5% chemical purity by GC-FID with limits for common impurities including the corresponding disulfide (<0.5%), dehydration products (<0.3%), and oxidation derivatives (<0.2%). Water content by Karl Fischer titration must not exceed 0.1%, while residual solvents are limited to 50 ppm for class 2 solvents and 500 ppm for class 3 solvents according to ICH guidelines.

Stability studies indicate satisfactory storage for 24 months at -20°C under nitrogen atmosphere in amber glass containers. Accelerated stability testing at 40°C and 75% relative humidity demonstrates decomposition rates of <0.5% per month, primarily through oxidation pathways.

Applications and Uses

Industrial and Commercial Applications

3-Methyl-3-sulfanylhexan-1-ol serves as a key intermediate in the synthesis of more complex organosulfur compounds, particularly those with chiral tertiary carbon centers. The compound finds application in asymmetric synthesis as a chiral building block for pharmaceuticals and agrochemicals. Its bifunctional nature enables simultaneous introduction of alcohol and thiol functionalities in target molecules.

In materials science, the compound functions as a chain transfer agent in radical polymerization processes, providing polymers with terminal thiol groups for subsequent functionalization. The transfer constant measures 0.85 for styrene polymerization at 60°C, indicating high efficiency in molecular weight control. The compound also serves as a precursor for self-assembled monolayers on gold surfaces through thiol-gold interactions.

Research Applications and Emerging Uses

Research applications focus on the compound's unique stereoelectronic properties and potential in catalysis. The molecule serves as a model system for studying gauche effects in molecules with adjacent heteroatoms and for investigating non-covalent interactions involving sulfur atoms. Recent investigations explore its use as a ligand in transition metal catalysis, particularly for asymmetric hydrogenation reactions where the chiral center and soft donor atom provide stereochemical control.

Emerging applications include use as a template for molecular imprinting polymers designed to recognize sulfur-containing compounds, and as a building block for functionalized dendrimers with tailored surface properties. The compound's strong odor characteristics have led to investigations in olfactory science as a reference compound for studying odor perception thresholds and structure-activity relationships.

Historical Development and Discovery

The initial synthesis and characterization of 3-methyl-3-sulfanylhexan-1-ol emerged from systematic investigations into sulfur-containing natural products during the 1990s. Early research focused on understanding the relationship between molecular structure and olfactory properties in sulfur compounds. The compound's identification coincided with advances in asymmetric synthesis methodologies that enabled preparation of enantiomerically pure thioalcohols.

Methodological developments in the 2000s, particularly in hydrothiolation chemistry and reduction methods, provided more efficient synthetic routes to this class of compounds. The growing interest in organosulfur chemistry for pharmaceutical applications during the 2010s further stimulated research into compounds with tertiary thioalcohol functionalities. Recent advances in computational chemistry have enabled detailed understanding of the compound's conformational preferences and reactivity patterns.

Conclusion

3-Methyl-3-sulfanylhexan-1-ol represents a structurally unique bifunctional compound that bridges the chemical space between alcohols and thiols. Its molecular architecture, featuring both hydroxyl and sulfhydryl groups on a tertiary carbon center, confers distinctive physical properties and reactivity patterns that differ from simpler monofunctional analogues. The compound serves as an important reference material in organosulfur chemistry and provides a versatile building block for synthetic applications.

Future research directions include development of more efficient asymmetric synthesis methods, exploration of catalytic applications leveraging the chiral environment, and investigation of materials science applications utilizing the compound's dual functionality. The fundamental understanding of structure-property relationships gained from studying this compound contributes to broader advances in the chemistry of multifunctional molecules and their applications across chemical disciplines.