Abstract

Dihydrolipoic acid, systematically named 6,8-bis(sulfanyl)octanoic acid (CAS Registry Number: 462-20-4), represents a significant organosulfur compound with the molecular formula C₈H₁₆O₂S₂. This dithiol carboxylic acid serves as the reduced form of lipoic acid and exhibits distinctive chemical behavior due to its two thiol functional groups positioned at carbon atoms 6 and 8 of an octanoic acid backbone. The compound demonstrates optical activity with the R-enantiomer possessing particular biochemical relevance. Dihydrolipoic acid manifests moderate water solubility and undergoes characteristic thiol-based redox chemistry. Its physical properties include a melting point range of 46-48°C and characteristic spectroscopic signatures in both infrared and nuclear magnetic resonance spectra. The compound participates in various chemical transformations including disulfide bond formation, metal complexation, and nucleophilic substitution reactions.

Introduction

Dihydrolipoic acid belongs to the class of organosulfur compounds specifically categorized as dithiol carboxylic acids. This compound occupies a significant position in chemical research due to its role as the reduced member of the lipoic acid/dihydrolipoic acid redox pair. The systematic IUPAC nomenclature identifies the compound as 6,8-bis(sulfanyl)octanoic acid, while it is also known colloquially as 6,8-dimercaptooctanoic acid. The molecular structure incorporates an eight-carbon aliphatic chain terminating in a carboxylic acid group with thiol substituents at positions 6 and 8, creating a 1,3-dithiol arrangement along the carbon chain.

Chemical investigation of dihydrolipoic acid primarily focuses on its redox behavior, coordination chemistry with metal ions, and its participation in various organic transformations. The compound exhibits chirality at carbon atom 6, yielding two enantiomers with the R-configuration demonstrating specific chemical interactions in chiral environments. The presence of two thiol groups separated by a methylene unit creates unique chemical properties distinct from monothiol compounds or dithiols with different spacing between sulfur atoms.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The molecular structure of dihydrolipoic acid features an extended carbon chain with specific conformational preferences due to the presence of thiol substituents. The octanoic acid backbone adopts a zig-zag conformation with rotational freedom around carbon-carbon single bonds. The C6 and C8 carbon atoms bearing thiol groups are chiral centers, with the R-enantiomer exhibiting specific three-dimensional arrangement. Bond angles approximate tetrahedral geometry at all carbon atoms except the carbonyl carbon, which displays trigonal planar geometry with bond angles of approximately 120°.

Electronic structure analysis reveals that the highest occupied molecular orbitals primarily localize on the sulfur atoms of the thiol groups, with contributions from the π-system of the carbonyl group. The lowest unoccupied molecular orbitals demonstrate antibonding character between carbon and sulfur atoms. Molecular orbital theory predicts that the two sulfur atoms engage in weak through-space interactions despite their separation by a methylene group, influencing the compound's redox behavior and metal coordination properties.

Chemical Bonding and Intermolecular Forces

Covalent bonding in dihydrolipoic acid follows typical patterns for aliphatic carboxylic acids with thiol substituents. Carbon-sulfur bond lengths measure approximately 1.81 Å, consistent with single bond character. Carbon-carbon bonds in the alkyl chain range from 1.53-1.54 Å, while the carbonyl carbon-oxygen bond measures 1.21 Å. The carboxylic acid group exhibits typical bond lengths with C-O bonds of 1.36 Å and O-H bond of 0.97 Å.

Intermolecular forces include strong hydrogen bonding capability through both the carboxylic acid group and thiol functionalities. The compound forms dimers in solid state through carboxylic acid hydrogen bonding with O···O distances of approximately 2.64 Å. Thiol groups participate in weaker S-H···S hydrogen bonds with bond energies of approximately 4-8 kJ/mol. Van der Waals interactions between alkyl chains contribute to packing in crystalline forms. The molecular dipole moment measures approximately 2.8 Debye, primarily oriented along the carboxylic acid to terminal thiol vector.

Physical Properties

Phase Behavior and Thermodynamic Properties

Dihydrolipoic acid presents as a white to pale yellow crystalline solid at room temperature. The compound melts at 46-48°C with a heat of fusion of 28.5 kJ/mol. Boiling point occurs at 285°C at atmospheric pressure with decomposition observed above 200°C. The density of the solid compound measures 1.214 g/cm³ at 20°C. Specific heat capacity at constant pressure is 1.89 J/g·K at 25°C.

The compound demonstrates limited solubility in water, approximately 0.5 g/L at 25°C, but exhibits good solubility in polar organic solvents including ethanol, acetone, and dimethyl sulfoxide. In ethanol, solubility reaches 85 g/L at 25°C. Partition coefficient (log P) between octanol and water measures 1.8, indicating moderate hydrophobicity. Refractive index of the pure liquid at 50°C is 1.528. The compound does not exhibit liquid crystalline behavior and forms a simple monoclinic crystal system upon solidification.

Spectroscopic Characteristics

Infrared spectroscopy reveals characteristic absorption bands including a broad O-H stretch at 3300-2500 cm⁻¹, carbonyl stretch at 1710 cm⁻¹, and S-H stretch at 2570 cm⁻¹. The alkyl chain shows C-H stretching vibrations between 2850-2960 cm⁻¹ and bending vibrations at 1465 cm⁻¹.

Proton nuclear magnetic resonance spectroscopy in deuterated chloroform displays the following chemical shifts: carboxylic acid proton at δ 11.5 ppm (singlet), thiol protons at δ 1.6 ppm (triplet, J = 8.2 Hz), methine proton at C6 at δ 3.1 ppm (multiplet), methylene protons adjacent to carbonyl at δ 2.35 ppm (triplet, J = 7.4 Hz), and aliphatic chain protons between δ 1.2-1.8 ppm. Carbon-13 NMR shows the carbonyl carbon at δ 178.5 ppm, methine carbon at C6 at δ 41.2 ppm, and other aliphatic carbons between δ 24-34 ppm.

Ultraviolet-visible spectroscopy demonstrates weak absorption maxima at 210 nm (ε = 1500 M⁻¹cm⁻¹) and 230 nm (ε = 900 M⁻¹cm⁻¹) corresponding to n→σ* transitions of the thiol groups. Mass spectrometry exhibits a molecular ion peak at m/z 208 with characteristic fragmentation patterns including loss of COOH (m/z 163), loss of SH (m/z 175), and cleavage between C6 and C7 (m/z 119 and 89).

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

Dihydrolipoic acid undergoes characteristic thiol chemistry including oxidation to form disulfide bonds. The oxidation reaction proceeds with second-order kinetics and a rate constant of 0.15 M⁻¹s⁻¹ in aqueous solution at pH 7.0 and 25°C. This oxidation yields the corresponding disulfide, lipoic acid, with a standard reduction potential of -0.32 V for the lipoic acid/dihydrolipoic acid couple.

The compound demonstrates nucleophilic character through its thiol groups, participating in SN2 reactions with alkyl halides with second-order rate constants typically between 0.01-0.5 M⁻¹s⁻¹ depending on the electrophile. Thiol-disulfide exchange reactions proceed with rate constants of approximately 10 M⁻¹s⁻¹ at pH 7.0. Metal complexation reactions with various transition metals form stable complexes with formation constants ranging from 10⁴ to 10¹² M⁻² for divalent metals.

Acid-Base and Redox Properties

Dihydrolipoic acid exhibits multiple acid-base equilibria. The carboxylic acid group has a pK_a of 4.7, while the thiol groups display pK_a values of 9.8 and 10.9 respectively. The difference in thiol pK_a values arises from through-bond electronic effects and hydrogen bonding interactions between the two thiol groups. The compound functions as a buffer in the pH range 4-5 and 9-11.

Redox properties include a standard reduction potential of -0.32 V versus standard hydrogen electrode for the two-electron reduction of lipoic acid to dihydrolipoic acid. The compound undergoes stepwise one-electron oxidation processes with formation of thiyl radical intermediates. The first one-electron oxidation potential measures -0.15 V, while the second measures -0.29 V. Electrochemical studies reveal quasi-reversible behavior at mercury electrodes with diffusion coefficients of 7.2 × 10⁻⁶ cm²/s.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

Laboratory synthesis of dihydrolipoic acid typically proceeds through reduction of commercially available lipoic acid. The most common method employs sodium borohydride reduction in ethanol/water mixture at 0°C for 2 hours, yielding dihydrolipoic acid with 85-90% efficiency. Alternative reducing agents include zinc dust in acidic media or catalytic hydrogenation using palladium on carbon.

De novo synthesis begins with 6,8-dibromooctanoic acid, which undergoes nucleophilic substitution with thiourea followed by hydrolysis to install the thiol groups. This method proceeds with overall yields of 60-65% and allows for the preparation of isotopically labeled derivatives. The synthetic route requires careful control of reaction conditions to prevent disulfide formation during the final hydrolysis step. Purification typically involves column chromatography on silica gel or recrystallization from hexane/ethyl acetate mixtures.

Analytical Methods and Characterization

Identification and Quantification

High-performance liquid chromatography with ultraviolet detection at 210 nm provides effective separation and quantification of dihydrolipoic acid. Reverse-phase C18 columns with mobile phases consisting of water/acetonitrile mixtures containing 0.1% trifluoroacetic acid achieve baseline separation from related compounds. Retention times typically range from 8-10 minutes under gradient elution conditions.

Gas chromatography-mass spectrometry after derivatization with N-methyl-N-(tert-butyldimethylsilyl)trifluoroacetamide provides sensitive detection limits of 0.1 ng/mL. Capillary electrophoresis with ultraviolet detection offers an alternative separation method with migration times of 12-14 minutes using borate buffer at pH 9.2. Quantification methods demonstrate linear response from 0.1-100 μg/mL with correlation coefficients exceeding 0.999.

Purity Assessment and Quality Control

Purity assessment typically employs chromatographic methods with detection of common impurities including lipoic acid (oxidation product), 6-mercaptooctanoic acid, and 8-mercaptooctanoic acid (partial reduction products). Acceptable purity standards require less than 2% total impurities by chromatographic area percentage. Water content by Karl Fischer titration should not exceed 0.5% w/w. Residual solvent levels must conform to ICH guidelines with limits of 500 ppm for ethanol and 50 ppm for hexane.

Applications and Uses

Industrial and Commercial Applications

Dihydrolipoic acid serves as a versatile reducing agent in specialized chemical synthesis, particularly for the reduction of disulfide bonds in complex molecules. The compound finds application in the production of certain pharmaceuticals where controlled reduction of disulfide linkages is required. In materials science, dihydrolipoic acid functions as a ligand for the stabilization of metal nanoparticles, particularly gold and silver nanoparticles with diameters between 2-10 nm.

The compound acts as a chain transfer agent in certain radical polymerization processes, influencing molecular weight distributions in resulting polymers. Industrial production remains limited to specialty chemical manufacturers with annual global production estimated at 5-10 metric tons. Current market prices range from $200-500 per gram for research-grade material, with bulk quantities available at reduced prices.

Research Applications and Emerging Uses

Research applications primarily focus on the compound's role as a model dithiol system for studying thiol-disulfide exchange kinetics and mechanisms. The compound serves as a reference standard in electrochemical studies of thiol-based redox systems. Emerging applications include use as a building block for the synthesis of complex molecular architectures through disulfide bond formation and thiol-ene click chemistry.

Investigations continue into the compound's potential as a ligand for metal extraction and separation processes, particularly for precious metals. Research explores its incorporation into supramolecular structures and self-assembled monolayers on metal surfaces. Patent literature describes uses in specialized electronic materials and as a component in certain energy storage systems.

Historical Development and Discovery

The discovery of dihydrolipoic acid followed the identification of lipoic acid as a growth factor for certain microorganisms in the 1930s. Initial chemical characterization occurred during the 1950s when researchers established the relationship between lipoic acid and its reduced form. The compound's structure was elucidated through chemical degradation studies and confirmed by synthesis in 1954.

Development of analytical methods for dihydrolipoic acid progressed throughout the 1960s-1980s with advances in chromatography and spectroscopy enabling precise characterization of its chemical properties. The late 20th century saw increased interest in the compound's coordination chemistry and its potential applications in various chemical processes. Recent research focuses on its fundamental chemical behavior and specialized applications in nanotechnology and materials science.

Conclusion

Dihydrolipoic acid represents a chemically significant dithiol carboxylic acid with distinctive properties arising from its molecular structure. The compound exhibits characteristic thiol reactivity, redox activity, and metal coordination behavior that make it valuable for various chemical applications. Its well-defined chemical properties and synthetic accessibility continue to make it a subject of ongoing research in fundamental chemistry and applied materials science. Future investigations will likely explore new synthetic methodologies, advanced applications in nanotechnology, and further elaboration of its fundamental chemical behavior under various conditions.