Abstract

Oxipurinol (C₅H₄N₄O₂), systematically named as 1''H''-pyrazolo[3,4-''d'']pyrimidine-4,6(2''H'',5''H'')-dione, represents a heterocyclic organic compound with significant chemical interest. This bicyclic system exhibits a molecular mass of 152.11 g·mol⁻¹ and manifests as white crystalline solid material. The compound demonstrates tautomeric behavior between lactam and lactim forms, with the lactam tautomer predominating in aqueous solution. Oxipurinol displays amphoteric character with pKa values of 6.90 and 9.20, indicating both acidic and basic properties. The molecule exhibits strong hydrogen bonding capacity through its multiple hydrogen bond donor and acceptor sites. Spectroscopic characterization reveals distinctive infrared absorption bands at 1705 cm⁻¹ and 1660 cm⁻¹ corresponding to carbonyl stretching vibrations. Nuclear magnetic resonance spectroscopy shows characteristic proton signals at δ 11.25 ppm and δ 10.85 ppm for the imide protons. The compound's electronic structure features extensive π-conjugation across the fused ring system.

Introduction

Oxipurinol belongs to the class of fused heterocyclic compounds known as pyrazolopyrimidines, specifically functioning as a xanthine analog. First identified as a metabolite of allopurinol in the mid-20th century, this compound has attracted significant attention in synthetic organic chemistry due to its unique structural features. The molecular formula C₅H₄N₄O₂ represents a highly nitrogenated heterocyclic system with 52.63% nitrogen content by mass. This compound exemplifies the structural principles of purine-like systems with modified ring substitution patterns. The systematic IUPAC nomenclature identifies it as 1''H''-pyrazolo[3,4-''d'']pyrimidine-4,6(2''H'',5''H'')-dione, reflecting its bicyclic nature and functional group arrangement. Oxipurinol serves as a model compound for studying tautomerism in heterocyclic systems and demonstrates interesting electronic properties resulting from its conjugated system.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The molecular structure of oxipurinol features a fused bicyclic system consisting of a pyrazole ring annulated to a pyrimidine ring. X-ray crystallographic analysis reveals a nearly planar arrangement with maximum deviation from the mean plane of 0.032 Å. The pyrazole ring exhibits bond lengths of 1.365 Å for N1-N2 and 1.315 Å for C3-C4, while the pyrimidine ring shows characteristic bond lengths of 1.395 Å for C4-C5 and 1.435 Å for C5-C6. Bond angles within the rings range from 104.5° to 112.3°, consistent with sp² hybridization of all ring atoms. The carbonyl groups adopt typical bond lengths of 1.225 Å for C4=O and 1.231 Å for C6=O. Molecular orbital analysis indicates highest occupied molecular orbital (HOMO) localization on the pyrazole nitrogen atoms and lowest unoccupied molecular orbital (LUMO) distribution across the pyrimidine ring. The HOMO-LUMO gap measures approximately 4.2 eV, indicating moderate electronic stability.

Chemical Bonding and Intermolecular Forces

Oxipurinol exhibits extensive hydrogen bonding capabilities through its four hydrogen bond donors (two N-H and two O-H in lactim form) and multiple hydrogen bond acceptors. In the solid state, molecules form extended chains through N-H···O hydrogen bonds with donor-acceptor distances of 2.892 Å. Additional N-H···N hydrogen bonds with distances of 2.945 Å create a three-dimensional network. The calculated dipole moment measures 4.8 Debye in the gas phase, with the vector oriented along the molecular long axis. London dispersion forces contribute significantly to crystal packing, with calculated polarizability of 11.5 × 10⁻²⁴ cm³. The molecule demonstrates significant π-stacking interactions with interplanar distances of 3.354 Å in the crystalline form. Solvent interaction parameters indicate strong affinity for polar protic solvents with calculated log P value of -0.85.

Physical Properties

Phase Behavior and Thermodynamic Properties

Oxipurinol presents as a white crystalline solid with orthorhombic crystal structure belonging to space group P2₁2₁2₁. The compound decomposes before melting at temperatures above 350°C, with decomposition onset observed at 362°C under nitrogen atmosphere. The density measures 1.62 g·cm⁻³ at 25°C as determined by flotation method. Differential scanning calorimetry shows endothermic decomposition with enthalpy change of 185 kJ·mol⁻¹. The compound exhibits limited solubility in water (2.3 g·L⁻¹ at 25°C) but demonstrates increased solubility in basic aqueous solutions due to salt formation. Solubility parameters include δd = 18.2 MPa¹/², δp = 13.5 MPa¹/², and δh = 15.8 MPa¹/². The refractive index measures 1.682 at 589 nm and 20°C. Molar volume calculates to 93.8 cm³·mol⁻¹ with molecular volume of 155.7 ų.

Spectroscopic Characteristics

Infrared spectroscopy reveals characteristic absorption bands at 3150 cm⁻¹ (N-H stretch), 1705 cm⁻¹ (C=O symmetric stretch), 1660 cm⁻¹ (C=O asymmetric stretch), and 1580 cm⁻¹ (C=N stretch). The fingerprint region between 1400-800 cm⁻¹ shows multiple bands associated with ring vibrations and deformation modes. Proton nuclear magnetic resonance spectroscopy in DMSO-d₆ displays signals at δ 11.25 ppm (s, 1H, N-H), δ 10.85 ppm (s, 1H, N-H), and δ 7.95 ppm (s, 1H, C-H). Carbon-13 NMR exhibits resonances at δ 159.5 ppm (C=O), δ 155.8 ppm (C=O), δ 138.2 ppm (C-N), δ 135.6 ppm (C-N), and δ 104.3 ppm (C-H). Ultraviolet-visible spectroscopy in aqueous solution shows absorption maxima at 248 nm (ε = 12,400 M⁻¹·cm⁻¹) and 290 nm (ε = 8,700 M⁻¹·cm⁻¹) corresponding to π→π* transitions. Mass spectrometric analysis displays molecular ion peak at m/z 152 with characteristic fragmentation patterns including loss of CO (m/z 124) and CONH (m/z 109).

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

Oxipurinol demonstrates reactivity typical of cyclic imides with enhanced nucleophilic character at the carbonyl carbons. Hydrolysis under acidic conditions proceeds with rate constant k = 3.2 × 10⁻⁴ s⁻¹ at pH 2.0 and 25°C, following first-order kinetics. Alkaline hydrolysis occurs more rapidly with k = 8.9 × 10⁻³ s⁻¹ at pH 12.0 and 25°C. The compound undergoes electrophilic substitution reactions preferentially at position 7 with bromination yielding 7-bromooxipurinol. Reduction with sodium borohydride produces the dihydro derivative while catalytic hydrogenation leads to ring opening reactions. Photochemical degradation follows pseudo-first order kinetics with quantum yield Φ = 0.032 at 254 nm. Thermal decomposition kinetics show activation energy Ea = 145 kJ·mol⁻¹ with entropy of activation ΔS‡ = -35 J·mol⁻¹·K⁻¹. The compound demonstrates stability in aqueous solution between pH 4-8 with half-life exceeding 2 years at 25°C.

Acid-Base and Redox Properties

Oxipurinol exhibits amphoteric behavior with two ionization constants: pKa₁ = 6.90 ± 0.05 (deprotonation of N1-H) and pKa₂ = 9.20 ± 0.05 (deprotonation of N7-H). The isoelectric point occurs at pH 8.05. Potentiometric titration shows buffering capacity between pH 5.5-8.5. Redox properties include oxidation potential E° = +0.87 V versus standard hydrogen electrode for the two-electron oxidation process. Cyclic voltammetry reveals quasi-reversible redox behavior with peak separation ΔEp = 85 mV at scan rate 100 mV·s⁻¹. The compound demonstrates resistance to reduction with reduction potential E° = -1.23 V. Stability in oxidizing environments is limited with decomposition occurring in the presence of strong oxidizing agents such as potassium permanganate or hydrogen peroxide. The redox stability window spans from -0.5 V to +0.7 V versus Ag/AgCl reference electrode.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

The most efficient laboratory synthesis of oxipurinol proceeds through condensation of 5-amino-1H-pyrazole-4-carboxamide with urea at elevated temperature. This one-pot synthesis yields oxipurinol in 65-70% yield after recrystallization from water. Reaction conditions typically involve heating at 180°C for 4 hours under nitrogen atmosphere. Alternative routes include oxidation of allopurinol using potassium permanganate in acidic medium, achieving conversions of 85-90% with subsequent purification by column chromatography. Microwave-assisted synthesis reduces reaction time to 30 minutes with comparable yields. The synthetic pathway involves initial formation of the pyrazole ring followed by annulation with the pyrimidine ring. Purification methods include recrystallization from dimethylformamide/water mixtures or sublimation at reduced pressure (0.1 mmHg) at 280°C. The final product typically achieves purity exceeding 99.5% as determined by high-performance liquid chromatography.

Analytical Methods and Characterization

Identification and Quantification

High-performance liquid chromatography with ultraviolet detection provides the primary analytical method for oxipurinol quantification. Reverse-phase C18 columns with mobile phase consisting of methanol:water:acetic acid (15:84:1 v/v/v) achieve baseline separation with retention time of 6.8 minutes. Detection limits measure 0.1 μg·mL⁻¹ with linear response range from 0.5-100 μg·mL⁻¹. Capillary electrophoresis with ultraviolet detection at 248 nm offers alternative quantification with separation efficiency of 150,000 theoretical plates. Mass spectrometric detection using electrospray ionization in negative mode provides characteristic fragment ions at m/z 152 [M]⁻, m/z 124 [M-CO]⁻, and m/z 109 [M-CONH]⁻. Fourier transform infrared spectroscopy with attenuated total reflection sampling enables identification through characteristic carbonyl stretching vibrations at 1705 cm⁻¹ and 1660 cm⁻¹. X-ray powder diffraction patterns show characteristic peaks at 2θ = 12.5°, 15.8°, 18.2°, and 22.4° for crystalline identification.

Purity Assessment and Quality Control

Purity assessment typically employs differential scanning calorimetry to determine crystalline purity through melting point depression analysis. Impurity profiling identifies common impurities including allopurinol (≤0.2%), hypoxanthine (≤0.1%), and uric acid (≤0.05%). Karl Fischer titration determines water content typically less than 0.5% w/w. Residual solvent analysis by gas chromatography with flame ionization detection shows limits for common solvents: dimethylformamide (<500 ppm), methanol (<3000 ppm), and water (<5000 ppm). Elemental analysis conforms to theoretical values: C 39.48%, H 2.65%, N 36.83%, O 21.04% with acceptable deviation of ±0.3%. Heavy metal content determined by atomic absorption spectroscopy measures less than 10 ppm. Stability testing under accelerated conditions (40°C, 75% relative humidity) demonstrates no significant degradation over 6 months.

Applications and Uses

Industrial and Commercial Applications

Oxipurinol serves as a key intermediate in the synthesis of various heterocyclic compounds and pharmaceutical agents. The compound functions as a building block for modified nucleosides and nucleotides in synthetic chemistry. Industrial applications include use as a standard reference compound in analytical chemistry for method validation and quality control procedures. The chemical industry utilizes oxipurinol as a model compound for studying heterocyclic reactivity and tautomeric behavior. Specialty chemical manufacturers employ oxipurinol derivatives as ligands in coordination chemistry and as templates for molecular imprinting technologies. The compound finds application in electrochemical research as a redox-active species for studying electron transfer mechanisms. Materials science applications include incorporation into polymeric systems for creating functional materials with specific hydrogen bonding capabilities.

Research Applications and Emerging Uses

Oxipurinol represents a fundamental compound in research exploring purine analog chemistry and heterocyclic synthesis methodologies. Recent investigations focus on its potential as a ligand in coordination compounds with transition metals, forming complexes exhibiting interesting magnetic and catalytic properties. Materials science research explores incorporation of oxipurinol into metal-organic frameworks to create porous materials with specific molecular recognition capabilities. Electrochemical studies utilize oxipurinol as a model compound for investigating proton-coupled electron transfer reactions. Computational chemistry research employs oxipurinol as a test system for developing methods to predict tautomeric equilibria in complex heterocyclic systems. Emerging applications include use as a template molecule for developing molecularly imprinted polymers with specific binding properties. Research continues into modified derivatives with enhanced electronic properties for potential applications in organic electronics.

Historical Development and Discovery

Oxipurinol first emerged in chemical literature during the 1950s as researchers investigated the metabolism of allopurinol, a compound developed as a xanthine oxidase inhibitor. Initial structural characterization occurred through comparative analysis with known purine derivatives. The compound's systematic synthesis and full structural elucidation were accomplished by organic chemists specializing in heterocyclic systems during the 1960s. Early research focused on its tautomeric behavior and spectroscopic properties, with seminal papers appearing in Journal of Organic Chemistry and Tetrahedron. The development of modern synthetic routes in the 1970s enabled larger-scale production for detailed physicochemical studies. Advances in X-ray crystallography during the 1980s provided definitive structural information confirming the lactam tautomer predominance in the solid state. Recent research has focused on computational modeling of its electronic structure and exploration of its coordination chemistry with various metal ions.

Conclusion

Oxipurinol represents a chemically significant heterocyclic compound that exemplifies the structural and electronic complexity of fused pyrazolopyrimidine systems. Its well-characterized tautomeric behavior, amphoteric properties, and extensive hydrogen bonding capacity make it a valuable model compound for studying fundamental chemical principles. The compound's stability under various conditions, combined with its distinctive spectroscopic signatures, ensures its continued utility as a reference material in analytical chemistry. Ongoing research into its coordination chemistry and potential applications in materials science suggests expanding future relevance. The synthesis methodologies developed for oxipurinol provide important insights into heterocyclic formation reactions that benefit broader synthetic organic chemistry. Future research directions likely include exploration of its derivatives for specialized applications and further investigation of its fundamental physicochemical properties using advanced spectroscopic and computational methods.