Abstract

N-Nitroso-N-methylurea (NMU, C₂H₅N₃O₂) is a nitrosated urea derivative with significant chemical and industrial importance. This yellow crystalline solid exhibits a melting point of 124 °C (with decomposition) and possesses limited stability at ambient temperatures. The compound serves as a potent methylating agent in organic synthesis, particularly for the generation of diazomethane. Its molecular structure features a planar nitroso group conjugated with the urea carbonyl, creating an electron-deficient system that facilitates nucleophilic attack. NMU demonstrates high reactivity toward nucleophiles through SN1 and SN2 mechanisms, with hydrolysis occurring rapidly in aqueous environments. Industrial applications focus primarily on its use as a specialized methylating reagent in fine chemical synthesis. The compound requires careful handling due to its thermal instability and shock-sensitive nature.

Introduction

N-Nitroso-N-methylurea represents an important class of N-nitrosourea compounds characterized by their reactivity as alkylating agents. First synthesized in the early 20th century, this organic compound has molecular formula C₂H₅N₃O₂ and molecular weight of 103.08 g/mol. The compound occupies a significant position in synthetic organic chemistry due to its ability to transfer methyl groups to nucleophilic centers. Although its practical applications have diminished over time due to stability concerns, NMU remains a compound of theoretical interest for studying nitrosation reactions and alkylation mechanisms. The structural features include a nitroso group attached to a methylated urea backbone, creating a molecule with distinctive electronic properties and reactivity patterns.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The molecular structure of N-nitroso-N-methylurea consists of a urea backbone with N-methyl and N-nitroso substituents. X-ray crystallography reveals a nearly planar arrangement around the central nitrogen atoms, with torsion angles indicating partial conjugation between the nitroso group and carbonyl function. The N-N bond between the methylurea and nitroso groups measures approximately 1.32 Å, characteristic of N-N bonds in nitrosamine compounds. Bond angle analysis shows ∠C-N-N approximately 115° and ∠N-N-O approximately 115°, consistent with sp² hybridization at the nitrogen atoms.

Electronic structure analysis indicates significant electron delocalization across the N-N=O moiety. The nitroso group exhibits partial double bond character with bond length of 1.21 Å, while the carbonyl bond measures 1.23 Å. Molecular orbital calculations demonstrate highest occupied molecular orbitals localized on the nitroso oxygen and carbonyl oxygen atoms, with lowest unoccupied molecular orbitals having significant antibonding character in the N-N bond region. This electronic configuration explains the compound's susceptibility to nucleophilic attack at the methyl carbon and nitroso nitrogen centers.

Chemical Bonding and Intermolecular Forces

Covalent bonding in NMU features polar bonds with calculated bond dipoles: C=O (2.4 D), N=O (1.8 D), and C-N (1.3 D). The molecular dipole moment measures 4.2 Debye in benzene solution, oriented toward the nitroso and carbonyl oxygen atoms. Intermolecular forces in the crystalline state include N-H···O hydrogen bonding between urea hydrogens and carbonyl oxygens of adjacent molecules, with bond distances of 2.01 Å. Van der Waals interactions between methyl groups contribute to crystal packing with spacing of 3.8 Å between methyl hydrogens.

The compound exhibits limited solubility in water (8.2 g/L at 20 °C) but high solubility in polar organic solvents including dimethylformamide (156 g/L) and acetone (98 g/L). Solubility parameters indicate δd = 18.2 MPa¹/², δp = 16.8 MPa¹/², and δh = 9.4 MPa¹/², consistent with moderately polar hydrogen-bonding compounds. The octanol-water partition coefficient (log P) measures -0.30, indicating slight hydrophilicity.

Physical Properties

Phase Behavior and Thermodynamic Properties

N-Nitroso-N-methylurea presents as pale yellow crystals with orthorhombic crystal structure belonging to space group P2₁2₁2₁. The compound melts with decomposition at 124 °C, precluding accurate determination of boiling point. Differential scanning calorimetry shows decomposition onset at 125 °C with exothermic peak at 135 °C (ΔHdec = -98 kJ/mol). The density of crystalline material measures 1.46 g/cm³ at 20 °C.

Thermodynamic parameters include standard enthalpy of formation ΔHf° = -215.6 kJ/mol and Gibbs free energy of formation ΔGf° = -120.4 kJ/mol. Entropy measures S° = 189.5 J/mol·K in the crystalline state. The heat capacity Cp measures 152.3 J/mol·K at 25 °C. The compound sublimes slowly under vacuum (0.1 mmHg) at 40 °C with sublimation enthalpy ΔHsub = 78.2 kJ/mol.

Spectroscopic Characteristics

Infrared spectroscopy reveals characteristic vibrations: N-H stretch at 3320 cm⁻¹, C=O stretch at 1695 cm⁻¹, N=O stretch at 1485 cm⁻¹, and C-N stretch at 1250 cm⁻¹. The N-N stretch appears as a medium intensity band at 940 cm⁻¹. Proton NMR spectroscopy (DMSO-d6) shows methyl protons at δ 3.17 ppm (s, 3H) and amide proton at δ 8.45 ppm (broad s, 1H). Carbon-13 NMR displays carbonyl carbon at δ 156.2 ppm and methyl carbon at δ 27.8 ppm.

UV-Vis spectroscopy in ethanol solution shows absorption maxima at 230 nm (ε = 5400 M⁻¹cm⁻¹) and 395 nm (ε = 85 M⁻¹cm⁻¹), corresponding to π→π* and n→π* transitions respectively. Mass spectrometry exhibits molecular ion peak at m/z 103 with major fragmentation peaks at m/z 75 (M-CO), m/z 59 (M-N₂O₂), and m/z 43 (CH₃N₂⁺).

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

N-Nitroso-N-methylurea functions primarily as a methylating agent through nucleophilic substitution reactions. Hydrolysis follows first-order kinetics with rate constant k = 2.3 × 10⁻³ s⁻¹ at pH 7 and 25 °C, producing methylamine, carbon dioxide, and nitrous acid. The reaction proceeds through diazonium ion intermediate with activation energy Ea = 85.4 kJ/mol. Alkaline conditions accelerate decomposition with half-life of 12 minutes at pH 9.

Methyl transfer reactions occur through both SN1 and SN2 mechanisms depending on nucleophile. Strong nucleophiles such as thiolates react via SN2 pathway with second-order rate constant k₂ = 4.8 × 10⁻² M⁻¹s⁻¹. Weak nucleophiles follow SN1 mechanism with rate-determining formation of methyldiazonium ion. The compound demonstrates particular reactivity toward heteroatom nucleophiles including sulfur, nitrogen, and oxygen centers.

Acid-Base and Redox Properties

The urea proton exhibits weak acidity with pKa = 12.4 in aqueous solution. Protonation occurs at the nitroso oxygen with pKa = -2.3 for the conjugate acid. Redox properties include irreversible reduction peak at -0.72 V vs. SCE in acetonitrile, corresponding to single-electron reduction of the nitroso group. Oxidation occurs at +1.45 V vs. SCE with two-electron process generating decomposition products.

The compound demonstrates limited stability across pH ranges, with maximum stability observed at pH 4-5. Decomposition accelerates under both acidic and basic conditions through different pathways: acid-catalyzed denitrosation and base-catalyzed hydrolysis respectively. No significant buffer capacity exists within the stability range due to the weak acid character.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

The synthesis of N-nitroso-N-methylurea proceeds through nitrosation of N-methylurea. N-methylurea (0.1 mol) dissolves in cooled 2N hydrochloric acid (100 mL) at 0 °C. Sodium nitrite (0.12 mol) in minimum water adds dropwise with maintaining temperature below 5 °C. The reaction mixture stirs for two hours, during which yellow crystals precipitate. The product collects by filtration, washes with cold water, and dries under vacuum. Typical yields range from 65-75% with purity exceeding 98% by HPLC analysis.

Purification employs recrystallization from ethanol-water mixture (3:1) at -10 °C. The crystalline product exhibits melting point of 123-124 °C with decomposition. Alternative synthesis routes include reaction of methylamine with nitrosating agents in presence of urea, but this method gives lower yields and requires extensive purification. Storage conditions necessitate temperatures below 0 °C in amber containers with desiccant to prevent decomposition.

Analytical Methods and Characterization

Identification and Quantification

Chromatographic analysis utilizes reverse-phase HPLC with C18 column and UV detection at 230 nm. Mobile phase consists of methanol-water (30:70) with flow rate 1.0 mL/min. Retention time measures 6.8 minutes under these conditions. Quantification employs external standard method with detection limit of 0.1 μg/mL and linear range 0.5-100 μg/mL (R² > 0.999).

Spectroscopic identification combines IR spectroscopy with characteristic carbonyl and nitroso stretches, complemented by NMR spectroscopy showing distinctive methyl and amide proton signals. Mass spectrometry provides confirmation of molecular weight and fragmentation pattern. Chemical tests include formation of diazomethane upon treatment with base, detected by yellow color and ether formation.

Purity Assessment and Quality Control

Common impurities include N-methylurea (retention time 3.2 minutes), methylnitramine (retention time 5.1 minutes), and decomposition products. Acceptable purity standards require less than 0.5% total impurities by HPLC area normalization. Water content by Karl Fischer titration should not exceed 0.2%. Residual solvents including ethanol must be below 0.1% by gas chromatography.

Stability testing indicates 5% decomposition after six months at -20 °C in sealed containers. Accelerated stability testing at 40 °C shows 50% decomposition after two weeks. Quality control specifications include assay value between 98.0-102.0% and melting point range 122-125 °C with decomposition.

Applications and Uses

Industrial and Commercial Applications

N-Nitroso-N-methylurea serves as a specialized methylating agent in pharmaceutical and fine chemical synthesis. The compound finds application in methylation of sensitive compounds where conventional methylating agents prove too vigorous. Production volumes remain limited due to stability concerns, with global production estimated at 100-200 kg annually. Primary industrial use focuses on small-scale methylation reactions in research and development settings.

The compound historically served as a precursor for diazomethane generation, though this application has largely been supplanted by safer alternatives such as Diazald® (N-methyl-N-nitroso-p-toluenesulfonamide). Current industrial applications remain niche due to the compound's thermal instability and handling difficulties. Economic factors limit large-scale application, with cost analysis indicating approximately $500-1000 per kilogram for research quantities.

Historical Development and Discovery

The synthesis of N-nitroso-N-methylurea was first reported in the chemical literature during the early 20th century as part of broader investigations into nitrosation reactions. Initial studies focused on the compound's ability to generate diazomethane, which represented a significant advancement in methylating methodology. Throughout the mid-20th century, research expanded to understand its decomposition mechanisms and alkylation properties.

Methodological advances in the 1960s improved synthesis and purification techniques, yielding material of higher purity and stability. The compound's thermal instability and shock sensitivity eventually led to declining use in favor of safer alternatives. Current research focuses primarily on fundamental reaction mechanisms rather than practical applications, representing a shift from applied to theoretical interest in this compound.

Conclusion

N-Nitroso-N-methylurea represents a chemically significant compound with distinctive structural features and reactivity patterns. Its planar conjugated system facilitates methyl transfer reactions through both SN1 and SN2 mechanisms. The compound's thermal instability and limited shelf life restrict practical applications despite its effectiveness as a methylating agent. Future research directions may explore stabilized formulations or encapsulated forms that could mitigate decomposition issues while preserving reactivity. The compound continues to serve as a model system for studying nitrosourea chemistry and alkylation mechanisms, maintaining its position in the chemical literature as a compound of theoretical importance.