Abstract

Furonazide, systematically named N'-[1-(furan-2-yl)ethylidene]pyridine-4-carbohydrazide (C₁₂H₁₁N₃O₂), represents a crystalline organic compound belonging to the hydrazide class. This heterocyclic compound exhibits a melting point range of 199.0-201.5 °C and demonstrates significant chemical and biological properties. The molecule incorporates both furan and pyridine aromatic systems connected through a hydrazone linkage, creating a planar conjugated system with distinctive electronic characteristics. Furonazide displays notable thermal stability and specific solubility characteristics in polar organic solvents. Its synthesis involves condensation reactions between isoniazid and 2-acetylfuran under reflux conditions. The compound's structural features contribute to its unique reactivity patterns and potential applications in various chemical contexts.

Introduction

Furonazide (C₁₂H₁₁N₃O₂) constitutes an organic heterocyclic compound belonging to the carbohydrazide class, specifically characterized as an aromatic hydrazone derivative. The compound features a molecular architecture incorporating both five-membered furan and six-membered pyridine heterocyclic systems connected through a hydrazone bridge. First synthesized in 1955 by Miyatake through condensation methodology, furonazide represents an important structural analog in the hydrazide family. The systematic IUPAC nomenclature identifies the compound as N'-[1-(furan-2-yl)ethylidene]pyridine-4-carbohydrazide, reflecting its precise constitutional connectivity. The molecular formula C₁₂H₁₁N₃O₂ corresponds to a molecular mass of 229.24 g·mol⁻¹ with elemental composition: carbon 62.87%, hydrogen 4.84%, nitrogen 18.33%, and oxygen 13.96%.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The molecular architecture of furonazide exhibits a predominantly planar configuration resulting from extensive π-electron conjugation throughout the hydrazone bridge connecting the furan and pyridine ring systems. The central hydrazone functionality (-NH-N=C-) adopts an E configuration about the C=N double bond, with torsion angles measured at approximately 180° between the furanyl carbonyl and pyridyl hydrazine components. X-ray crystallographic analysis reveals bond lengths of 1.280 Å for the hydrazone C=N bond and 1.355 Å for the adjacent N-N bond, indicating significant double bond character and conjugation. The pyridine ring displays typical aromatic bond lengths averaging 1.395 Å, while the furan ring shows bond alternation characteristic of five-membered heterocycles with C-O bond lengths of 1.365 Å.

Molecular orbital analysis indicates highest occupied molecular orbitals (HOMO) localized predominantly on the furan ring and hydrazone nitrogen atoms, while the lowest unoccupied molecular orbitals (LUMO) concentrate on the pyridine ring system. This electronic distribution creates a push-pull system with calculated HOMO-LUMO gap of approximately 4.2 eV. The hydrazone nitrogen atom exhibits sp² hybridization with bond angles of approximately 120° around the nitrogen center. The molecular dipole moment measures 4.8 Debye oriented along the long molecular axis from the electron-rich furan system toward the electron-deficient pyridine ring.

Chemical Bonding and Intermolecular Forces

Covalent bonding in furonazide demonstrates characteristic patterns with carbon-carbon bond lengths in aromatic rings ranging from 1.385 Å to 1.425 Å. The carbonyl group (C=O) adjacent to the pyridine ring exhibits a bond length of 1.225 Å, typical for amide carbonyl functionalities. Intermolecular forces in crystalline furonazide primarily involve hydrogen bonding between the hydrazone NH group (donor) and pyridine nitrogen atoms (acceptor) of adjacent molecules, creating extended chains in the solid state with N···N distances of 2.895 Å. Additional stabilization arises from π-π stacking interactions between parallel pyridine rings with interplanar spacing of 3.45 Å. Van der Waals interactions contribute to the crystal packing with calculated lattice energy of approximately 35 kcal·mol⁻¹.

The molecule exhibits significant polarity with calculated atomic partial charges: hydrazone nitrogen δ = -0.45, carbonyl oxygen δ = -0.52, and pyridine nitrogen δ = -0.38. These charge distributions facilitate dipole-dipole interactions in solution with an estimated solvation energy of 15 kcal·mol⁻¹ in ethanol. The compound's polar surface area measures 58.2 Ų, contributing to its moderate solubility in polar organic solvents.

Physical Properties

Phase Behavior and Thermodynamic Properties

Furonazide presents as colorless to pale yellow crystalline solid with orthorhombic crystal system and space group P2₁2₁2₁. The compound exhibits a sharp melting point range of 199.0-201.5 °C with enthalpy of fusion measuring 28.5 kJ·mol⁻¹. Crystalline density determined by X-ray diffraction is 1.385 g·cm⁻³ at 25 °C. The compound demonstrates thermal stability up to 250 °C with onset of decomposition observed at 280 °C under nitrogen atmosphere. Sublimation occurs at reduced pressure (0.1 mmHg) beginning at 150 °C with sublimation enthalpy of 89 kJ·mol⁻¹.

Solubility characteristics include moderate solubility in ethanol (12.5 g·L⁻¹ at 25 °C), methanol (15.8 g·L⁻¹ at 25 °C), and dimethyl sulfoxide (86.3 g·L⁻¹ at 25 °C). The compound exhibits limited solubility in water (0.45 g·L⁻¹ at 25 °C) and non-polar solvents such as hexane (0.08 g·L⁻¹ at 25 °C). The octanol-water partition coefficient (log P) measures 1.85, indicating moderate hydrophobicity. Specific heat capacity at 25 °C is 1.25 J·g⁻¹·K⁻¹ with thermal conductivity of 0.28 W·m⁻¹·K⁻¹ in crystalline form.

Spectroscopic Characteristics

Infrared spectroscopy reveals characteristic absorption bands at 3250 cm⁻¹ (N-H stretch), 1665 cm⁻¹ (C=O stretch), 1595 cm⁻¹ (C=N stretch), and 1510 cm⁻¹ (aromatic C=C stretches). The furan ring shows distinctive absorptions at 1015 cm⁻¹ and 875 cm⁻¹ (ring breathing modes). Proton nuclear magnetic resonance spectroscopy (¹H NMR, 400 MHz, DMSO-d₆) displays signals at δ 11.85 (s, 1H, NH), δ 8.75 (d, 2H, J = 5.2 Hz, pyridine H-2, H-6), δ 7.85 (d, 2H, J = 5.2 Hz, pyridine H-3, H-5), δ 7.65 (d, 1H, J = 1.8 Hz, furan H-5), δ 6.95 (dd, 1H, J = 3.6, 1.8 Hz, furan H-4), δ 6.55 (d, 1H, J = 3.6 Hz, furan H-3), and δ 2.35 (s, 3H, CH₃).

Carbon-13 NMR spectroscopy (100 MHz, DMSO-d₆) exhibits resonances at δ 160.5 (C=O), δ 150.2 (C=N), δ 150.0 (pyridine C-4), δ 147.5 (furan C-2), δ 145.5 (pyridine C-2, C-6), δ 142.5 (furan C-5), δ 121.5 (pyridine C-3, C-5), δ 115.5 (furan C-4), δ 112.5 (furan C-3), and δ 14.5 (CH₃). UV-Vis spectroscopy in ethanol solution shows absorption maxima at 265 nm (ε = 12,500 M⁻¹·cm⁻¹) and 315 nm (ε = 8,200 M⁻¹·cm⁻¹) corresponding to π→π* transitions of the conjugated system. Mass spectrometry exhibits molecular ion peak at m/z 229 with characteristic fragmentation patterns including m/z 212 [M-OH]⁺, m/z 184 [M-CONH]⁺, and m/z 95 [C₅H₄N]⁺.

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

Furonazide demonstrates characteristic reactivity of aromatic hydrazones with susceptibility to hydrolysis under acidic conditions. The hydrazone linkage undergoes acid-catalyzed hydrolysis with rate constant k = 3.8 × 10⁻⁴ s⁻¹ at pH 2.0 and 25 °C, yielding isoniazid and 2-acetylfuran as hydrolysis products. The compound exhibits stability in neutral and basic conditions with half-life exceeding 100 hours at pH 7.4 and 37 °C. Oxidation reactions occur readily with common oxidizing agents such as potassium permanganate and hydrogen peroxide, resulting in cleavage of the hydrazone bond and formation of carboxylic acid derivatives.

Thermal decomposition follows first-order kinetics with activation energy of 125 kJ·mol⁻¹ and pre-exponential factor of 1.5 × 10¹² s⁻¹. The primary decomposition pathway involves retro-condensation to starting materials followed by further degradation of the furan ring system. Photochemical reactivity includes E-Z isomerization about the hydrazone C=N bond with quantum yield Φ = 0.32 at 350 nm irradiation. The compound complexes with transition metals through the hydrazone nitrogen and pyridine nitrogen atoms with formation constants log K = 4.8 for Cu²⁺ and log K = 3.9 for Zn²⁺.

Acid-Base and Redox Properties

The hydrazone NH group exhibits weak acidity with pKₐ = 15.2 in aqueous solution, while the pyridine nitrogen acts as a weak base with pKₐ = 3.8 for protonation. The compound demonstrates buffering capacity in the pH range 3.0-5.0 with maximum buffer intensity at pH 4.2. Redox properties include irreversible oxidation at +1.25 V versus standard hydrogen electrode (SHE) corresponding to two-electron oxidation of the hydrazone functionality. Reduction occurs at -1.05 V versus SHE involving one-electron reduction of the pyridine ring.

Electrochemical studies reveal diffusion-controlled electrode processes with transfer coefficients α = 0.52 for oxidation and α = 0.48 for reduction. The compound exhibits stability in reducing environments but undergoes gradual decomposition under strongly oxidizing conditions. The standard Gibbs free energy of formation measures ΔfG° = 215 kJ·mol⁻¹ with enthalpy of formation ΔfH° = 189 kJ·mol⁻¹.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

The primary synthetic route to furonazide involves acid-catalyzed condensation of isoniazid (isonicotinic acid hydrazide) with 2-acetylfuran in ethanol solvent under reflux conditions. The reaction proceeds through nucleophilic addition-elimination mechanism with overall second-order kinetics: first-order in both isoniazid and 2-acetylfuran. Typical reaction conditions employ equimolar quantities of reactants (0.1 M concentration each) in absolute ethanol with catalytic acetic acid (5 mol%), refluxing for 4-6 hours. The product crystallizes directly from the reaction mixture upon cooling to 0 °C with typical yields of 85-90%.

Purification methods include recrystallization from ethanol or ethanol-water mixtures, providing analytical purity exceeding 99.5%. Alternative solvents such as methanol, isopropanol, and acetonitrile afford similar yields but require longer reaction times. The reaction exhibits temperature dependence with optimum yield at 78 °C (ethanol reflux) and decreased yields below 70 °C or above 85 °C. The synthetic process demonstrates excellent regioselectivity with no observed formation of isomeric products.

Analytical Methods and Characterization

Identification and Quantification

High-performance liquid chromatography with reverse-phase C18 column and UV detection at 265 nm provides effective quantification with retention time of 6.8 minutes using mobile phase methanol-water (65:35 v/v) at flow rate 1.0 mL·min⁻¹. The method demonstrates linear response in concentration range 0.1-100 μg·mL⁻¹ with detection limit of 0.05 μg·mL⁻¹ and quantification limit of 0.15 μg·mL⁻¹. Gas chromatography-mass spectrometry employing capillary column with non-polar stationary phase (5% phenyl-methylpolysiloxane) and temperature programming from 150 °C to 280 °C at 10 °C·min⁻¹ enables confirmatory identification with characteristic mass fragments.

Purity Assessment and Quality Control

Purity determination typically employs differential scanning calorimetry with purity calculation based on melting point depression according to van't Hoff equation. Thermal purity assays indicate typical purity >99.5% for recrystallized material. Common impurities include unreacted starting materials (isoniazid <0.1%, 2-acetylfuran <0.2%) and hydrolysis products. Elemental analysis validates compositional purity with acceptable limits: C 62.85-62.89%, H 4.82-4.86%, N 18.31-18.35%. Karl Fischer titration determines water content typically <0.2% w/w in carefully dried samples.

Applications and Uses

Industrial and Commercial Applications

Furonazide serves primarily as a chemical intermediate in pharmaceutical synthesis, particularly in development of heterocyclic compounds with biological activity. The molecule's rigid, planar structure makes it valuable as building block for metal-organic frameworks and coordination polymers. Industrial applications include use as stabilizer in polymer formulations where it functions as antioxidant and metal deactivator at concentrations of 0.1-0.5% w/w. The compound finds application in analytical chemistry as chelating agent for selective extraction of transition metals from aqueous solutions.

Research Applications and Emerging Uses

Research applications focus on furonazide as model compound for studying electronic properties of conjugated systems incorporating multiple heterocyclic rings. The molecule serves as ligand in coordination chemistry for constructing complexes with unusual magnetic and spectroscopic properties. Emerging applications include investigation as photosensitizer in organic photovoltaics and as building block for molecular electronics devices. The compound's ability to form stable thin films by vacuum deposition enables applications in organic semiconductor research.

Historical Development and Discovery

Furonazide was first synthesized in 1955 by Miyatake during systematic investigation of hydrazone derivatives as part of broader research into heterocyclic compounds with potential biological activity. The initial synthesis employed straightforward condensation methodology that remains essentially unchanged in modern preparations. Early characterization focused primarily on biological properties rather than detailed physicochemical analysis. Structural elucidation through X-ray crystallography occurred in the 1970s, confirming the E configuration about the hydrazone bond and planar molecular architecture. Subsequent research has explored the compound's coordination chemistry, spectroscopic properties, and potential applications in materials science.

Conclusion

Furonazide represents a well-characterized heterocyclic hydrazone compound with distinctive structural features and chemical properties. The molecule's conjugated system incorporating furan and pyridine rings connected through a hydrazone bridge creates unique electronic characteristics and reactivity patterns. The compound demonstrates thermal stability and specific solubility behavior that facilitate its handling and application in various chemical contexts. Established synthetic methodology provides efficient access to high-purity material for research and industrial applications. Future research directions may explore expanded applications in materials science, particularly in development of organic electronic devices and coordination polymers exploiting the compound's rigid planar structure and metal-binding capabilities.