Abstract

Pyrazinoic acid, systematically named pyrazine-2-carboxylic acid (C₅H₄N₂O₂), represents a significant heterocyclic carboxylic acid compound with distinctive chemical properties. This white to off-white crystalline solid exhibits a melting point range of 222-225°C and a density of 1.403 g/cm³. The compound demonstrates moderate water solubility and a characteristic pKa value of 2.9, classifying it as a weak organic acid. Its molecular structure incorporates a pyrazine ring system functionalized with a carboxylic acid group at the 2-position, creating a planar aromatic system with unique electronic properties. Pyrazinoic acid serves as a fundamental building block in synthetic organic chemistry and as a metabolite of the anti-tuberculosis prodrug pyrazinamide. The compound's chemical behavior is governed by the interplay between its aromatic heterocyclic system and carboxylic acid functionality.

Introduction

Pyrazinoic acid, known chemically as pyrazine-2-carboxylic acid, constitutes an important member of the heterocyclic carboxylic acid family. This organic compound belongs to the pyrazine class of nitrogen-containing heterocycles, characterized by a six-membered ring containing two nitrogen atoms at positions 1 and 4. The compound's significance stems from its dual functionality as both an aromatic heterocycle and carboxylic acid, creating a molecular system with distinctive electronic and chemical properties. First synthesized in the early 20th century through oxidation of pyrazine derivatives, pyrazinoic acid has established itself as a valuable intermediate in pharmaceutical chemistry and organic synthesis. The compound's molecular formula is C₅H₄N₂O₂ with a molar mass of 124.10 g/mol, and it is registered under CAS number 98-97-5.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

Pyrazinoic acid exhibits a planar molecular geometry with C_s point group symmetry. The pyrazine ring maintains perfect aromatic character with bond lengths of approximately 1.34 Å for C-N bonds and 1.39 Å for C-C bonds, consistent with delocalized π-electron systems in heteroaromatic compounds. The carboxylic acid group at the 2-position lies in the same plane as the pyrazine ring due to conjugation with the aromatic system. X-ray crystallographic analysis reveals bond angles of approximately 116° for the O-C-O moiety and 124° for the C-C-O arrangement. The nitrogen atoms in the pyrazine ring adopt sp² hybridization with lone pairs occupying orbitals perpendicular to the aromatic plane. Molecular orbital calculations indicate highest occupied molecular orbital (HOMO) localization on the pyrazine ring and lowest unoccupied molecular orbital (LUMO) character distributed across both ring and carboxyl group.

Chemical Bonding and Intermolecular Forces

The covalent bonding in pyrazinoic acid features extensive π-electron delocalization throughout the conjugated system. The C=O bond length measures 1.21 Å while the C-O bond extends to 1.36 Å, indicating partial double bond character in the carboxylic group due to resonance with the aromatic system. Intermolecular forces dominate the solid-state structure through hydrogen bonding networks. Carboxylic acid dimers form through strong O-H···O hydrogen bonds with distances of approximately 2.65 Å, creating characteristic centrosymmetric dimers. Additional weak C-H···O and C-H···N interactions contribute to crystal packing with distances around 3.2-3.5 Å. The molecular dipole moment measures 4.2 Debye with direction toward the carboxyl group, reflecting the electron-withdrawing nature of the pyrazine ring. The compound's polarity contributes to its solubility in polar solvents and melting characteristics.

Physical Properties

Phase Behavior and Thermodynamic Properties

Pyrazinoic acid presents as a white to off-white crystalline powder with monoclinic crystal structure belonging to space group P2₁/c. The compound melts at 222-225°C with decomposition, exhibiting a heat of fusion of 28.5 kJ/mol. The boiling point is reported as 313.1°C at 760 mmHg, though the compound typically undergoes decarboxylation before reaching this temperature. The density measures 1.403 g/cm³ at 20°C with a refractive index of 1.582. The specific heat capacity is 1.32 J/g·K at 25°C. The compound demonstrates moderate solubility in cold water (approximately 15 g/L at 20°C) with significantly higher solubility in hot water and polar organic solvents including ethanol, methanol, and dimethylformamide. The enthalpy of formation is -385.2 kJ/mol while the Gibbs free energy of formation is -295.4 kJ/mol at 298.15 K.

Spectroscopic Characteristics

Infrared spectroscopy reveals characteristic vibrational modes including O-H stretching at 3000-2500 cm⁻¹ (broad), C=O stretching at 1690 cm⁻¹, and C-O stretching at 1290 cm⁻¹. The pyrazine ring shows aromatic C-H stretching at 3050 cm⁻¹ and ring vibrations at 1580, 1480, and 1410 cm⁻¹. Proton NMR spectroscopy in DMSO-d₆ displays three distinct signals: the carboxylic acid proton at δ 13.2 ppm (broad singlet), pyrazine ring protons at δ 8.75 ppm (d, J = 2.5 Hz, H-3), δ 8.85 ppm (d, J = 2.5 Hz, H-5), and δ 9.35 ppm (s, H-6). Carbon-13 NMR shows signals at δ 165.5 ppm (carboxyl carbon), δ 147.2 ppm (C-2), δ 144.5 ppm (C-6), δ 143.8 ppm (C-3), and δ 142.1 ppm (C-5). UV-Vis spectroscopy demonstrates absorption maxima at 265 nm (ε = 4500 M⁻¹cm⁻¹) and 320 nm (ε = 1200 M⁻¹cm⁻¹) corresponding to π→π* and n→π* transitions respectively. Mass spectrometry exhibits a molecular ion peak at m/z 124 with major fragmentation peaks at m/z 107 (M-OH), m/z 80 (M-CO₂), and m/z 52 (pyrazine ring fragment).

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

Pyrazinoic acid demonstrates typical carboxylic acid reactivity including formation of salts, esters, amides, and acid chlorides. Esterification reactions proceed with rate constants of approximately 2.3 × 10⁻⁴ L/mol·s in ethanol with acid catalysis. The compound undergoes decarboxylation at elevated temperatures (above 200°C) with an activation energy of 125 kJ/mol, producing pyrazine and carbon dioxide. Nucleophilic aromatic substitution occurs at the 3-position with halogens, demonstrating second-order kinetics with rate constants around 0.15 L/mol·s for chloride displacement. Reduction with lithium aluminum hydride yields the corresponding alcohol, pyrazine-2-methanol, with 85% yield. The compound forms stable complexes with metal ions including copper(II), zinc(II), and iron(III) through coordination at both carboxylate oxygen and ring nitrogen atoms. Oxidation with potassium permanganate cleaves the pyrazine ring, producing carbon dioxide and nitrogen oxides.

Acid-Base and Redox Properties

Pyrazinoic acid exhibits weak acid character with pK_a = 2.9 in aqueous solution at 25°C, making it approximately ten times stronger than benzoic acid (pK_a = 4.2) due to the electron-withdrawing pyrazine ring. The acid dissociation constant follows the relationship log K = -0.015T + 5.23 between 10-40°C. The compound forms stable buffer solutions in the pH range 2.0-3.8. Redox properties include a reduction potential of -0.85 V vs. SCE for the pyrazine ring reduction and oxidation potential of +1.25 V for carboxylic group oxidation. The compound demonstrates stability in reducing environments but undergoes gradual decomposition under strongly oxidizing conditions. Electrochemical studies reveal a one-electron transfer process for both oxidation and reduction with diffusion coefficients of 7.2 × 10⁻⁶ cm²/s for the reduced form and 6.8 × 10⁻⁶ cm²/s for the oxidized form.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

The most common laboratory synthesis involves oxidation of 2-methylpyrazine with potassium permanganate in aqueous solution at 60-80°C, yielding pyrazinoic acid with 70-75% efficiency after acidification and recrystallization from water. Alternative methods include hydrolysis of pyrazinonitrile with concentrated hydrochloric acid at reflux temperature for 6 hours, providing 85% yield after neutralization. Carboxylation of pyrazine via metallation with n-butyllithium followed by quenching with dry ice gives moderate yields of 50-60%. Electrochemical oxidation of 2-hydroxymethylpyrazine in alkaline medium represents an environmentally friendly approach with 80% yield and high purity. Purification typically involves recrystallization from water or ethanol-water mixtures, producing crystals with melting point 222-225°C. Analytical purity exceeding 99.5% is achievable through sublimation at 180°C under reduced pressure (0.1 mmHg).

Analytical Methods and Characterization

Identification and Quantification

High-performance liquid chromatography with UV detection at 265 nm provides reliable quantification with detection limits of 0.1 μg/mL using C18 reverse-phase columns and mobile phases of water-methanol-acetic acid (80:20:1). Gas chromatography with mass spectrometric detection requires derivatization with diazomethane to form the methyl ester, achieving detection limits of 0.5 ng/mL. Titrimetric analysis with standardized sodium hydroxide solution using phenolphthalein indicator allows determination with relative error less than 1% for samples above 100 mg. Spectrophotometric methods based on complex formation with iron(III) chloride provide detection at 480 nm with linear range 5-100 μg/mL. X-ray powder diffraction patterns show characteristic peaks at d-spacings of 5.82, 4.35, 3.72, and 3.21 Å for identification purposes.

Purity Assessment and Quality Control

Pharmaceutical-grade pyrazinoic acid must comply with purity specifications including not less than 99.0% assay by HPLC, loss on drying less than 0.5% at 105°C, sulfated ash less than 0.1%, and heavy metals content below 10 ppm. Common impurities include pyrazine-2,5-dicarboxylic acid (less than 0.2%), 2-methylpyrazine (less than 0.1%), and pyrazine (less than 0.05%). Residual solvent content must not exceed 500 ppm for methanol and 3000 ppm for ethanol according to ICH guidelines. Stability studies indicate shelf life of 36 months when stored in airtight containers protected from light at room temperature. Forced degradation studies show susceptibility to photodegradation with 5% decomposition after 24 hours under UV light at 254 nm.

Applications and Uses

Industrial and Commercial Applications

Pyrazinoic acid serves as a key intermediate in the manufacture of pharmaceuticals, particularly antituberculosis agents. The compound finds application in synthesis of corrosion inhibitors for metal surfaces, with effectiveness demonstrated at concentrations as low as 50 ppm in acidic environments. In polymer chemistry, it acts as a monomer for producing polyamides and polyesters with enhanced thermal stability, yielding materials with glass transition temperatures above 180°C. The compound's metal chelating properties make it valuable in water treatment formulations for sequestering heavy metals at neutral pH conditions. Agricultural applications include use as a precursor for synthesizing fungicides and herbicides with specific activity against soil-borne pathogens. The global production volume is estimated at 50-100 metric tons annually with market value of $2-5 million.

Research Applications and Emerging Uses

Recent research explores pyrazinoic acid as a building block for metal-organic frameworks (MOFs) with potential applications in gas storage and separation. The compound's ability to form stable complexes with lanthanide ions enables development of luminescent materials with quantum yields up to 45%. Catalytic applications include use as a ligand in transition metal complexes for oxidation reactions, demonstrating turnover numbers exceeding 1000 for cyclohexane oxidation. Electrochemical studies investigate its potential as an electrolyte additive for lithium-ion batteries to improve cycle life. The compound serves as a model system for studying proton transfer dynamics in heterogeneous catalysis with surface science techniques. Emerging applications in materials science include development of organic semiconductors with charge carrier mobility of 0.5 cm²/V·s in thin-film transistors.

Historical Development and Discovery

The history of pyrazinoic acid begins with the development of pyrazine chemistry in the late 19th century. Initial reports of pyrazine derivatives appeared in German chemical literature around 1900, with the first deliberate synthesis of pyrazinoic acid documented in 1928 through oxidation of 2-methylpyrazine. Systematic investigation of its properties commenced in the 1950s with the discovery that it represents the active metabolite of pyrazinamide, an antituberculosis drug introduced in 1952. Structural characterization advanced significantly with X-ray crystallographic studies in the 1960s that elucidated the hydrogen-bonded dimeric structure in solid state. The 1970s saw development of improved synthetic methods allowing larger-scale production. Recent decades have witnessed expanded applications in materials science and coordination chemistry, with over 200 scientific publications referencing the compound since 2000.

Conclusion

Pyrazinoic acid represents a chemically significant heterocyclic carboxylic acid with distinctive structural features and diverse applications. Its planar aromatic system combined with carboxylic acid functionality creates a molecule with unique electronic properties and reactivity patterns. The compound serves as an important intermediate in pharmaceutical synthesis and demonstrates potential in materials science applications. Current research continues to explore new derivatives and applications, particularly in coordination chemistry and materials design. Future investigations will likely focus on developing more efficient synthetic routes, exploring supramolecular chemistry applications, and investigating electrochemical properties for energy storage applications. The compound's fundamental chemical properties ensure its continued importance in both academic research and industrial chemistry.