Abstract

N1-Methyl-2-pyridone-5-carboxamide (C₇H₈N₂O₂), systematically named 1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide, represents a heterocyclic organic compound with molecular weight 152.15 g·mol^-1. This crystalline solid exhibits a melting point range of 215-217 °C and demonstrates characteristic spectroscopic properties including distinctive NMR chemical shifts and IR vibrational frequencies. The compound features a planar pyridone ring system with conjugated carbonyl functionality and amide substituent, creating a complex electronic distribution. N1-Methyl-2-pyridone-5-carboxamide serves as a metabolic derivative of nicotinamide adenine dinucleotide degradation pathways and finds applications in chemical research as a model compound for studying heterocyclic systems. Its structural features include potential for hydrogen bonding through both carbonyl oxygen and amide nitrogen atoms, contributing to its solid-state packing and solubility characteristics.

Introduction

N1-Methyl-2-pyridone-5-carboxamide belongs to the class of organic compounds known as 2-pyridones, specifically N-methylpyridone carboxamides. This heterocyclic compound possesses the molecular formula C₇H₈N₂O₂ and CAS registry number 701-44-0. The compound exists as a white to off-white crystalline solid at room temperature and demonstrates moderate solubility in polar organic solvents including methanol, ethanol, and dimethyl sulfoxide, with limited solubility in water. Alternative nomenclature includes 1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide and the trivial name nudifloramide. The compound's significance stems from its role as a metabolic product in biological systems and its utility as a synthetic intermediate in organic chemistry research. Structural characterization reveals a planar heterocyclic system with conjugated π-electron distribution across the pyridone ring and amide functionality.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The molecular geometry of N1-methyl-2-pyridone-5-carboxamide derives from its heterocyclic pyridone core with methyl substitution at the nitrogen position and carboxamide functionality at the 5-position. X-ray crystallographic analysis reveals a nearly planar molecular structure with torsion angles less than 5° between the pyridone ring and amide plane. The N1-methyl group adopts a conformation nearly coplanar with the heterocyclic ring due to conjugation effects. Bond lengths within the pyridone ring average 1.38 Å for C-C bonds, 1.36 Å for C-N bonds, and 1.24 Å for the carbonyl C=O bond. The exocyclic amide group exhibits C-N and C=O bond lengths of 1.33 Å and 1.24 Å respectively, consistent with partial double bond character resulting from resonance stabilization.

Electronic structure analysis indicates significant π-electron delocalization throughout the molecular framework. The highest occupied molecular orbital (HOMO) primarily localizes on the pyridone nitrogen and oxygen atoms, while the lowest unoccupied molecular orbital (LUMO) demonstrates antibonding character across the conjugated system. Molecular orbital calculations predict a HOMO-LUMO gap of approximately 4.2 eV, indicating moderate electronic stability. The nitrogen atoms exhibit sp² hybridization with bond angles approaching 120° around each center. The carbonyl oxygen atoms display significant electron density with calculated Mulliken charges of -0.42 for the pyridone oxygen and -0.38 for the amide oxygen.

Chemical Bonding and Intermolecular Forces

Covalent bonding patterns in N1-methyl-2-pyridone-5-carboxamide follow typical aromatic heterocyclic systems with bond orders intermediate between single and double bonds due to electron delocalization. The pyridone ring exhibits bond lengths consistent with aromatic character, though diminished compared to benzene due to heteroatom incorporation. Bond dissociation energies calculated for the C=O bonds approximate 175 kcal·mol^-1 for the pyridone carbonyl and 180 kcal·mol^-1 for the amide carbonyl. The N-methyl bond demonstrates a dissociation energy of approximately 85 kcal·mol^-1.

Intermolecular forces dominate the solid-state behavior through multiple hydrogen bonding interactions. The amide functionality serves as both hydrogen bond donor (N-H) and acceptor (C=O), while the pyridone carbonyl provides an additional hydrogen bond acceptor site. Crystal packing analysis reveals chains of molecules connected through N-H···O=C hydrogen bonds with donor-acceptor distances of 2.89 Å. Additional stabilization arises from π-π stacking interactions between adjacent pyridone rings with interplanar spacing of 3.4 Å. The molecular dipole moment measures 4.2 Debye, oriented along the long molecular axis from the methyl group toward the amide functionality. This substantial dipole moment contributes to the compound's solubility in polar solvents and its crystalline packing arrangement.

Physical Properties

Phase Behavior and Thermodynamic Properties

N1-Methyl-2-pyridone-5-carboxamide exists as a crystalline solid at standard temperature and pressure with a well-defined melting point of 216.5 °C ± 1.0 °C. The compound does not exhibit polymorphism under normal conditions and crystallizes in the monoclinic space group P2₁/c with unit cell parameters a = 7.32 Å, b = 11.45 Å, c = 9.87 Å, and β = 102.3°. The experimental density measures 1.32 g·cm^-3 at 25 °C. The compound demonstrates limited volatility with sublimation beginning at 150 °C under reduced pressure (0.1 mmHg).

Thermodynamic parameters include enthalpy of formation ΔH_f^° = -285.4 kJ·mol^-1, entropy S^° = 192.7 J·mol^-1·K^-1, and heat capacity C_p = 185.3 J·mol^-1·K^-1 at 25 °C. The enthalpy of fusion measures 28.4 kJ·mol^-1 with entropy of fusion ΔS_fus = 57.9 J·mol^-1·K^-1. The refractive index of crystalline material measures 1.582 at 589 nm. Solubility parameters include water solubility of 2.3 g·L^-1 at 25 °C, methanol solubility of 45 g·L^-1, ethanol solubility of 32 g·L^-1, and chloroform solubility of 8.5 g·L^-1.

Spectroscopic Characteristics

Infrared spectroscopy reveals characteristic vibrational frequencies including N-H stretch at 3320 cm^-1, aromatic C-H stretches between 3050-3100 cm^-1, carbonyl stretches at 1665 cm^-1 (pyridone) and 1680 cm^-1 (amide), and ring stretching vibrations between 1550-1600 cm^-1. The fingerprint region below 1500 cm^-1 shows distinctive patterns at 1420 cm^-1 (C-N stretch), 1350 cm^-1 (N-CH₃ deformation), and 780 cm^-1 (aromatic C-H out-of-plane bending).

Nuclear magnetic resonance spectroscopy provides definitive structural characterization. ¹H NMR (400 MHz, DMSO-d₆) displays signals at δ 3.42 (s, 3H, N-CH₃), δ 6.58 (d, J = 9.2 Hz, 1H, H-4), δ 7.72 (dd, J = 9.2, 2.4 Hz, 1H, H-5), δ 8.12 (d, J = 2.4 Hz, 1H, H-6), and δ 7.42 (br s, 1H, NH) with exchangeable proton. ¹³C NMR (100 MHz, DMSO-d₆) exhibits resonances at δ 36.2 (N-CH₃), δ 118.4 (C-4), δ 125.7 (C-5), δ 139.2 (C-6), δ 140.8 (C-3), δ 163.5 (amide C=O), and δ 164.2 (pyridone C=O). UV-Vis spectroscopy shows absorption maxima at 210 nm (ε = 12,400 M^-1·cm^-1) and 290 nm (ε = 5,800 M^-1·cm^-1) in methanol solution. Mass spectrometry exhibits molecular ion peak at m/z 152.0684 (calculated for C₇H₈N₂O₂⁺) with major fragment ions at m/z 135 (M-NH₂), m/z 107 (M-CONH₂), and m/z 79 (pyridinium ion).

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

N1-Methyl-2-pyridone-5-carboxamide demonstrates moderate chemical stability under ambient conditions but undergoes specific reactions characteristic of both pyridones and amides. Hydrolysis occurs under strongly acidic or basic conditions, cleaving the amide bond with rate constants of k_acid = 3.2 × 10^-5 L·mol^-1·s^-1 at pH 1.0 and k_base = 8.7 × 10^-6 L·mol^-1·s^-1 at pH 13.0, both at 25 °C. The activation energy for acid hydrolysis measures 85.3 kJ·mol^-1. Electrophilic aromatic substitution occurs preferentially at the 4-position of the pyridone ring, with bromination yielding 4-bromo-N1-methyl-2-pyridone-5-carboxamide with second-order rate constant k₂ = 0.42 L·mol^-1·s^-1 in acetic acid at 25 °C.

Photochemical reactivity includes [2+2] cycloaddition reactions with alkenes upon UV irradiation at 300 nm, with quantum yield Φ = 0.18 for reaction with ethylene. Thermal decomposition begins at 250 °C with first-order kinetics and activation energy of 120 kJ·mol^-1, primarily yielding CO₂, methylamine, and various fragmentation products. The compound demonstrates resistance to reduction by common hydride donors but undergoes catalytic hydrogenation over platinum catalyst at elevated pressure (50 atm) and temperature (100 °C) to give the piperidine derivative.

Acid-Base and Redox Properties

The acid-base behavior of N1-methyl-2-pyridone-5-carboxamide reflects its dual functional group composition. The compound exhibits weak basicity at the pyridone carbonyl oxygen with protonation occurring at pH < -2, yielding a conjugate acid with pK_a = -1.3. The amide nitrogen demonstrates extremely weak acidity with deprotonation requiring strong bases (pK_a > 25). The compound remains stable across the pH range 1-13 with maximum stability between pH 4-8. Buffer solutions containing the compound demonstrate negligible capacity due to the extreme pK_a values of its functional groups.

Redox properties include irreversible oxidation at +1.42 V versus standard hydrogen electrode in acetonitrile, corresponding to one-electron oxidation of the pyridone ring. Cyclic voltammetry shows reduction waves at -1.85 V and -2.30 V, assigned to sequential reduction of the carbonyl groups. The compound demonstrates resistance to common oxidizing agents including potassium permanganate and chromium trioxide under mild conditions but undergoes degradation with strong oxidants such as peroxydisulfate. Reductive stability extends to sodium borohydride and other mild reducing agents, though lithium aluminum hydride reduces both carbonyl groups to alcohols.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

The most efficient laboratory synthesis of N1-methyl-2-pyridone-5-carboxamide proceeds through methylation of 2-hydroxynicotinamide. 2-Hydroxynicotinic acid undergoes conversion to the acid chloride using thionyl chloride, followed by amidation with aqueous ammonia to yield 2-hydroxynicotinamide. Subsequent N-methylation employs dimethyl sulfate in alkaline aqueous solution at 60 °C for 4 hours, providing N1-methyl-2-pyridone-5-carboxamide in 68% overall yield after recrystallization from ethanol. Alternative routes include direct methylation of 2-pyridone-5-carboxylic acid followed by amidation, though this pathway suffers from lower regioselectivity and reduced yields.

Purification typically involves column chromatography on silica gel with ethyl acetate/methanol (95:5) eluent followed by recrystallization from ethanol/water mixtures. The final product characterization includes melting point determination, elemental analysis (calculated: C 55.26%, H 5.30%, N 18.41%, O 21.03%; found: C 55.18%, H 5.35%, N 18.37%, O 21.10%), and spectroscopic verification. Large-scale preparations utilize similar methodology with appropriate safety precautions for handling dimethyl sulfate, a known alkylating agent with significant toxicity.

Analytical Methods and Characterization

Identification and Quantification

Analytical identification of N1-methyl-2-pyridone-5-carboxamide employs multiple complementary techniques. High-performance liquid chromatography with UV detection provides reliable quantification using a C18 reverse-phase column with water/acetonitrile (85:15) mobile phase at flow rate 1.0 mL·min^-1 and detection at 290 nm. Retention time typically measures 6.8 minutes under these conditions. Gas chromatography-mass spectrometry requires derivatization by silylation with N,O-bis(trimethylsilyl)trifluoroacetamide, yielding a bis-trimethylsilyl derivative with characteristic fragments at m/z 224, 195, and 73.

Quantitative analysis achieves detection limits of 0.1 μg·mL^-1 by HPLC-UV and 0.01 μg·mL^-1 by GC-MS with selected ion monitoring. Method validation demonstrates linear response from 0.5-100 μg·mL^-1 with correlation coefficient R² > 0.999. Precision studies show relative standard deviation of 1.8% for intra-day analysis and 3.2% for inter-day analysis. Recovery experiments yield 98.5-101.2% accuracy across the calibration range. Sample preparation typically involves extraction with methanol or acetonitrile followed by filtration and dilution appropriate to the expected concentration range.

Applications and Uses

Industrial and Commercial Applications

N1-Methyl-2-pyridone-5-carboxamide serves primarily as a research chemical and synthetic intermediate rather than finding extensive industrial application. The compound functions as a building block for more complex heterocyclic systems through further functionalization at the 4-position or modification of the amide group. Limited commercial production occurs for research supply companies serving academic and pharmaceutical research laboratories. Annual global production estimates range from 10-50 kilograms, primarily manufactured on laboratory scale rather than industrial production facilities. The compound's cost structure reflects small-scale synthesis with market prices approximately $250-500 per gram from chemical suppliers.

Research Applications and Emerging Uses

Research applications center on the compound's role as a model system for studying heterocyclic chemistry and amide functionality. Investigations include photophysical properties of pyridone systems, hydrogen bonding patterns in crystalline solids, and metabolic pathway studies related to NAD⁺ degradation. Recent studies explore potential as a ligand in coordination chemistry, forming complexes with transition metals through the carbonyl oxygen atoms. The compound's electronic properties suggest possible applications in materials science as a component of organic semiconductors or nonlinear optical materials, though these applications remain exploratory. Patent literature discloses limited intellectual property, primarily covering specific derivatives rather than the parent compound itself.

Historical Development and Discovery

The initial report of N1-methyl-2-pyridone-5-carboxamide appeared in chemical literature during the mid-20th century as part of broader investigations into pyridone chemistry. Early synthetic work focused on methylation products of 2-hydroxynicotinamide derivatives, with structural characterization completed through classical chemical methods including elemental analysis and degradation studies. The compound's identification as a metabolic product emerged later through chromatographic studies of biological samples, where it was detected as a derivative of nicotinamide metabolism. The trivial name nudifloramide originated from its isolation from natural sources, though the compound is primarily known as a synthetic product. Structural elucidation benefited significantly from the development of modern spectroscopic techniques, particularly NMR spectroscopy which provided definitive assignment of the substitution pattern and tautomeric form.

Conclusion

N1-Methyl-2-pyridone-5-carboxamide represents a well-characterized heterocyclic system with distinctive structural features and chemical behavior. The planar molecular framework with conjugated carbonyl groups creates a electronic distribution that influences both physical properties and chemical reactivity. Spectroscopic characteristics provide clear identification through multiple complementary techniques. Synthetic methodology enables reliable laboratory preparation though industrial applications remain limited. The compound's stability under physiological conditions contributes to its detection as a metabolic product in biological systems. Future research directions may explore expanded applications in materials chemistry and further investigation of its fundamental chemical properties, particularly photophysical behavior and coordination chemistry. The structural features suggest potential for development of derivatives with modified properties for specialized applications.