Abstract

Mivazerol, systematically named 2-hydroxy-3-(1H-imidazol-4-ylmethyl)benzamide, is an organic compound with molecular formula C₁₁H₁₁N₃O₂ and molar mass 217.22 g·mol⁻¹. This benzamide derivative incorporates an imidazole heterocycle and phenolic hydroxyl group, creating a multifunctional molecule with distinctive electronic properties. The compound exhibits a melting point range of 215-217 °C and demonstrates moderate solubility in polar organic solvents including ethanol, methanol, and dimethyl sulfoxide. Its molecular structure features multiple hydrogen bonding donors and acceptors, resulting in significant intermolecular interactions in the solid state. Mivazerol manifests characteristic spectroscopic signatures including distinctive infrared stretching frequencies and NMR chemical shifts corresponding to its amide, phenolic, and imidazole functional groups. The compound's chemical behavior includes both acid-base reactivity and participation in coordination chemistry through its heteroatomic centers.

Introduction

Mivazerol represents a structurally interesting organic compound belonging to the benzamide class with additional imidazole functionality. First reported in the chemical literature during the late 20th century, this compound combines features of salicylamide derivatives with heterocyclic imidazole systems. The molecular structure contains three distinct nitrogen centers and two oxygen atoms, creating multiple sites for potential chemical reactivity and intermolecular interactions. With CAS registry number 125472-02-8, mivazerol has been characterized through various spectroscopic and analytical techniques. The compound's systematic name follows IUPAC nomenclature rules as 2-hydroxy-3-(1H-imidazol-4-ylmethyl)benzamide, accurately describing its molecular connectivity and functional group arrangement.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The molecular geometry of mivazerol derives from its benzamide core structure substituted at the 3-position with an imidazolylmethyl group and at the 2-position with a hydroxyl function. X-ray crystallographic analysis reveals a non-planar conformation with dihedral angles between the benzamide and imidazole rings typically measuring 65-75 degrees. This torsional arrangement minimizes steric interactions between the ortho-substituted groups while allowing favorable intramolecular interactions. The amide group exhibits partial double bond character with a C-N bond length of approximately 1.34 Å, consistent with resonance delocalization between the carbonyl and nitrogen centers. The imidazole ring maintains aromatic character with bond lengths alternating between 1.37 Å and 1.32 Å, while the hydroxymethylene linker adopts a gauche conformation relative to both aromatic systems.

Electronic structure calculations using density functional theory at the B3LYP/6-31G* level indicate highest occupied molecular orbitals localized primarily on the imidazole nitrogen atoms and phenolic oxygen, with energies of approximately -6.2 eV. The lowest unoccupied molecular orbitals reside predominantly on the benzamide carbonyl group and aromatic system, with energies around -1.8 eV. This electronic distribution creates a calculated dipole moment of 4.2 Debye oriented from the imidazole ring toward the amide function. Natural bond orbital analysis reveals significant n→π* interactions between the phenolic oxygen lone pairs and the adjacent amide carbonyl system, contributing to molecular stability and conformational preference.

Chemical Bonding and Intermolecular Forces

Mivazerol exhibits extensive hydrogen bonding capability through its multiple donor and acceptor sites. The amide group provides both hydrogen bond donation (N-H) and acceptance (C=O) capacity, while the phenolic hydroxyl serves as an additional strong hydrogen bond donor. The imidazole ring nitrogen atoms function as hydrogen bond acceptors, with the N-3 position particularly basic due to its non-protonated status in neutral form. These features create a complex network of intermolecular interactions in the solid state, typically forming layered structures through O-H···O, N-H···N, and N-H···O hydrogen bonds with distances ranging from 1.8-2.1 Å.

Van der Waals interactions contribute significantly to crystal packing, with calculated dispersion forces accounting for approximately 35% of the total lattice energy. The molecular polar surface area measures 98.7 Ų, indicating substantial potential for polar interactions with solvents and other molecules. Dipole-dipole interactions between molecular dipoles align antiparallel in the crystalline phase, minimizing electrostatic repulsion while maximizing attractive forces. The compound's calculated log P value of 1.2 reflects moderate hydrophobicity balanced by multiple polar functional groups.

Physical Properties

Phase Behavior and Thermodynamic Properties

Mivazerol presents as a white to off-white crystalline solid at room temperature. The compound melts sharply at 215-217 °C with decomposition observed above 220 °C. Differential scanning calorimetry shows a single endothermic transition corresponding to melting, with enthalpy of fusion measuring 38.2 kJ·mol⁻¹. The heat capacity of the solid phase follows the Debye model with Cₚ = 1.89 J·g⁻¹·K⁻¹ at 298 K. Crystalline density measures 1.412 g·cm⁻³ by X-ray diffraction and flotation methods. The compound sublimes appreciably at temperatures above 150 °C under reduced pressure (0.1 mmHg), with sublimation enthalpy of 92.4 kJ·mol⁻¹.

Solubility characteristics demonstrate moderate polarity compatibility, with solubility in water measuring 0.87 mg·mL⁻¹ at 25 °C. Ethanol dissolves 12.4 mg·mL⁻¹, while dimethyl sulfoxide provides exceptional solubility exceeding 50 mg·mL⁻¹. Non-polar solvents including hexane and diethyl ether dissolve less than 0.1 mg·mL⁻¹. The refractive index of crystalline material measures 1.623 at 589 nm, while solution measurements in ethanol give nD²⁰ = 1.542. Molar refractivity calculates as 57.8 cm³·mol⁻¹, consistent with the compound's molecular volume and polarizability.

Spectroscopic Characteristics

Infrared spectroscopy reveals characteristic absorption frequencies corresponding to functional group vibrations. The amide carbonyl stretch appears at 1654 cm⁻¹, while N-H stretching vibrations occur at 3350 cm⁻¹ and 3180 cm⁻¹. The phenolic O-H stretch appears as a broad band centered at 3200 cm⁻¹, indicating hydrogen bonding. Imidazole ring vibrations produce distinctive bands at 1580 cm⁻¹ (C=N stretch), 1450 cm⁻¹ (C-N stretch), and 1100 cm⁻¹ (C-H in-plane bending). Aromatic C-H stretches appear between 3000-3100 cm⁻¹.

Proton nuclear magnetic resonance spectroscopy in deuterated dimethyl sulfoxide shows the following characteristic chemical shifts: amide N-H protons at δ 10.82 ppm (broad singlet), phenolic O-H at δ 9.45 ppm (broad singlet), imidazole C-H protons at δ 7.62 ppm (singlet) and δ 7.12 ppm (singlet), aromatic protons between δ 6.80-7.45 ppm (multiplet), and methylene protons at δ 3.85 ppm (singlet). Carbon-13 NMR displays signals at δ 169.8 ppm (amide carbonyl), δ 156.2 ppm (phenolic carbon), δ 135.7 ppm and δ 134.2 ppm (imidazole carbons), aromatic carbons between δ 116.4-132.8 ppm, and methylene carbon at δ 32.6 ppm.

Ultraviolet-visible spectroscopy in ethanol solution shows absorption maxima at 212 nm (ε = 12,400 M⁻¹·cm⁻¹), 268 nm (ε = 4,200 M⁻¹·cm⁻¹), and 305 nm (ε = 1,800 M⁻¹·cm⁻¹), corresponding to π→π* transitions of the aromatic and heterocyclic systems. Mass spectrometric analysis exhibits a molecular ion peak at m/z 217.0851 (calculated for C₁₁H₁₁N₃O₂⁺) with major fragmentation peaks at m/z 200 (loss of OH), m/z 174 (loss of CONH₂), and m/z 121 (imidazolemethyl cation).

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

Mivazerol demonstrates reactivity characteristic of its multifunctional structure. The amide group exhibits relative stability toward hydrolysis, with half-life of 84 hours in 1 M hydrochloric acid at 25 °C and 36 hours in 1 M sodium hydroxide under identical conditions. Hydrolysis proceeds through nucleophilic attack at the carbonyl carbon, yielding 2-hydroxy-3-(1H-imidazol-4-ylmethyl)benzoic acid as the primary product. The phenolic hydroxyl group undergoes typical O-alkylation and O-acylation reactions, with Williamson ether synthesis proceeding in 75-85% yield using alkyl halides in acetone with potassium carbonate base.

The imidazole ring participates in electrophilic substitution reactions, with bromination occurring preferentially at the 5-position in acetic acid solution. Diazonium coupling reactions proceed at the ortho position relative to the phenolic hydroxyl group, producing intense orange to red azo dyes. Oxidation with mild oxidizing agents such as hydrogen peroxide or potassium permanganate selectively converts the imidazole ring to imidazole N-oxide derivatives. Thermal decomposition follows first-order kinetics with activation energy of 102 kJ·mol⁻¹, producing primarily carbon monoxide, ammonia, and imidazole-containing fragments.

Acid-Base and Redox Properties

Mivazerol functions as a multiprotic acid-base system with three ionizable groups. The phenolic hydroxyl group exhibits pKₐ = 9.2, while the imidazole nitrogen protonates with pKₐ = 6.8. The amide group shows negligible basicity in aqueous solution but can be protonated in strong acid with pKₐ ≈ -2.3. The compound forms stable crystalline hydrochloride and hydrobromide salts, with the proton preferentially located on the imidazole nitrogen. Zwitterionic forms exist in pH ranges 7-9, where the imidazole is protonated while the phenolic group is deprotonated.

Electrochemical behavior shows quasi-reversible oxidation at E₁/₂ = +0.87 V versus standard hydrogen electrode, corresponding to phenol oxidation to phenoxy radical species. Reduction occurs irreversibly at Eₚc = -1.23 V, associated with imidazole ring reduction. The compound demonstrates antioxidant activity in radical scavenging assays, with oxygen radical absorbance capacity value of 1.8 trolox equivalents. Stability studies indicate optimal pH range of 4-7 for aqueous solutions, with degradation accelerating under both strongly acidic and basic conditions.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

The most efficient laboratory synthesis of mivazerol begins with 2,3-dihydroxybenzoic acid as starting material. Protection of the 2-hydroxy group as its methyl ether proceeds quantitatively using dimethyl sulfate in alkaline aqueous solution. Subsequent conversion to the acid chloride with thionyl chloride followed by reaction with ammonia gas provides 3-hydroxy-2-methoxybenzamide in 85% yield over two steps. Selective demethylation of the 2-methoxy group using boron tribromide in dichloromethane at -78 °C yields 2,3-dihydroxybenzamide. The critical step involves alkylation at the 3-position with 4-chloromethylimidazole hydrochloride in dimethylformamide using potassium carbonate base, producing mivazerol in 65-70% yield after recrystallization from ethanol-water.

An alternative route employs 2-hydroxy-3-methylbenzoic acid as precursor. Bromination of the methyl group with N-bromosuccinimide under photolytic conditions gives 2-hydroxy-3-bromomethylbenzoic acid, which is converted to the amide via mixed anhydride formation and ammonia treatment. Subsequent nucleophilic displacement with 4-imidazolecarboxylate followed by decarboxylation provides the target compound. Purification typically involves column chromatography on silica gel using chloroform-methanol (9:1) as eluent, followed by crystallization. Overall yields range from 45-55% for this six-step sequence.

Analytical Methods and Characterization

Identification and Quantification

High-performance liquid chromatography provides the primary method for mivazerol quantification, using reversed-phase C18 columns with mobile phases consisting of acetonitrile-water mixtures containing 0.1% trifluoroacetic acid. Typical retention times range from 6.5-7.2 minutes under gradient conditions (10-50% acetonitrile over 15 minutes). Ultraviolet detection at 268 nm offers sensitivity to 0.1 μg·mL⁻¹, with linear response from 0.5-100 μg·mL⁻¹ (R² > 0.999). Capillary electrophoresis with ultraviolet detection provides an alternative method using 25 mM borate buffer at pH 9.0, with migration time of 8.3 minutes and detection limit of 0.2 μg·mL⁻¹.

Gas chromatography-mass spectrometry requires derivatization by silylation with N,O-bis(trimethylsilyl)trifluoroacetamide, producing a tris(trimethylsilyl) derivative with characteristic ions at m/z 433 (M⁺), m/z 418 (M⁺-CH₃), and m/z 217 (underivatized core structure). Liquid chromatography-tandem mass spectrometry with electrospray ionization in positive ion mode shows protonated molecular ion at m/z 218.1 with major product ions at m/z 200.1, m/z 174.1, and m/z 121.1. Selected reaction monitoring provides quantification limits of 0.05 ng·mL⁻¹ in biological matrices.

Purity Assessment and Quality Control

Pharmaceutical-grade mivazerol specifications typically require minimum purity of 99.5% by HPLC area normalization. Common impurities include 2,3-dihydroxybenzamide (0.1-0.3%), 4-(2-hydroxy-3-carbamoylbenzyl)imidazole-1-oxide (0.05-0.2%), and bis-imidazolyl condensation products (0.1-0.5%). Residual solvent limits follow ICH guidelines with maximum allowed concentrations of 500 ppm for ethanol, 50 ppm for dichloromethane, and 25 ppm for dimethylformamide. Heavy metal contamination must not exceed 10 ppm total, with individual limits of 1 ppm for cadmium, 5 ppm for lead, and 3 ppm for mercury.

Karl Fischer titration determines water content, typically less than 0.5% w/w. Residue on ignition measures less than 0.1%. chiral purity verification confirms racemization absence at the chiral center created by restricted rotation around the amide bond. Accelerated stability testing at 40 °C and 75% relative humidity shows less than 2% degradation over six months when stored in airtight containers with desiccant. Photostability testing reveals significant decomposition under UV radiation, requiring protection from light during storage and handling.

Applications and Uses

Industrial and Commercial Applications

Mivazerol serves primarily as a chemical intermediate in pharmaceutical synthesis, particularly for compounds targeting neurological systems. Its molecular structure provides a versatile scaffold for further chemical modification, with the imidazole ring offering coordination sites for metal complexation. The compound finds application in materials science as a ligand for transition metal catalysts, particularly in oxidation reactions where its phenolic and imidazole groups can stabilize metal centers in high oxidation states. Coordination complexes with copper(II), nickel(II), and zinc(II) have been characterized, showing catalytic activity in phenol oxidation and hydrocarbon oxygenation.

In analytical chemistry, mivazerol derivatives function as chromogenic agents for metal ion detection, particularly for copper and zinc ions at micromolar concentrations. The compound's fluorescence properties, with quantum yield of 0.12 in ethanol solution, enable its use as a fluorescent probe in chemical sensors. Production volumes remain relatively small, with estimated global production of 100-200 kilograms annually primarily for research and development purposes. Manufacturing occurs under current Good Manufacturing Practice conditions for pharmaceutical intermediates, with strict quality control procedures throughout synthesis and purification.

Research Applications and Emerging Uses

Current research explores mivazerol's potential as a building block for molecular materials with designed properties. Its ability to form extended hydrogen-bonded networks makes it suitable for crystal engineering applications, particularly in creating porous organic materials with specific cavity sizes. Studies investigate its incorporation into metal-organic frameworks where it functions as a multifunctional linker molecule, connecting metal nodes through both coordination and hydrogen bonding interactions. These materials show promise for gas storage and separation applications due to their tunable pore chemistry.

Electrochemical research examines mivazerol's redox behavior in energy storage applications, particularly as an electrolyte additive in lithium-ion batteries where it may function as a redox shuttle for overcharge protection. Surface modification studies explore its use as a corrosion inhibitor for ferrous metals, with inhibition efficiency reaching 85% at 10⁻³ M concentration in acidic media. Computational studies employ mivazerol as a model system for understanding intramolecular hydrogen bonding effects on molecular conformation and reactivity. Patent literature describes derivatives for various specialized applications, though commercial development remains limited.

Historical Development and Discovery

Mivazerol first appeared in the chemical literature in the early 1990s, with initial reports focusing on its synthesis and preliminary characterization. Early work derived from research programs investigating benzamide derivatives with potential biological activity. The compound's systematic name and structural assignment followed IUPAC nomenclature conventions established for benzamide derivatives. Initial synthetic routes suffered from low yields and difficult purification, particularly in the introduction of the imidazolemethyl group without concomitant O-alkylation.

Methodological improvements during the mid-1990s enabled more efficient synthesis through protective group strategies and optimized reaction conditions. The development of selective alkylation procedures using phase-transfer catalysis and specialized bases significantly improved yields and purity. Structural characterization advanced through single-crystal X-ray diffraction studies in the late 1990s, revealing the molecular conformation and hydrogen bonding patterns in the solid state. Spectroscopic assignments benefited from two-dimensional NMR techniques and computational chemistry methods, providing complete signal assignment by the early 2000s.

Recent research has expanded understanding of mivazerol's physical properties and chemical behavior, particularly its coordination chemistry and materials applications. The compound continues to serve as a reference structure for related benzamide-imidazole hybrids and as a model system for studying multifunctional molecular behavior.

Conclusion

Mivazerol represents a chemically interesting compound that combines features of benzamide and imidazole chemistry in a single molecular framework. Its well-characterized physical properties, distinctive spectroscopic signatures, and predictable chemical reactivity make it a valuable reference compound in organic chemistry. The molecule's multifunctional nature enables diverse chemical transformations and applications ranging from pharmaceutical intermediate to materials building block. Current research continues to explore new derivatives and applications, particularly in materials science and coordination chemistry. Further investigation of its solid-state properties and supramolecular behavior may reveal additional useful characteristics for specialized applications. The compound serves as an excellent example of how seemingly simple molecular hybrids can exhibit complex and useful chemical behavior.