Abstract

N-Methylspiperone (IUPAC name: 8-[4-(4-fluorophenyl)-4-oxobutyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one; molecular formula: C₂₄H₂₈FN₃O₂; molecular weight: 409.50 g·mol⁻¹) represents a structurally complex spirocyclic organic compound derived from spiperone through N-methylation. This heterocyclic compound features a distinctive spiro[4.5]decane core structure incorporating lactam, phenyl, and fluorophenyl ketone functionalities. The compound exhibits characteristic physical properties including a crystalline solid state at standard temperature and pressure, moderate solubility in polar organic solvents, and distinct spectroscopic signatures. N-Methylspiperone demonstrates significant chemical stability under ambient conditions while maintaining reactivity at specific functional groups including the lactam carbonyl and aromatic systems. Its structural complexity and functional group diversity make it a compound of considerable interest in synthetic organic chemistry and molecular design.

Introduction

N-Methylspiperone belongs to the class of organic compounds known as spirocyclic lactams, specifically derivatives of spiperone (8-(4-(4-fluorophenyl)-4-oxobutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one). The compound was first synthesized in the late 20th century as part of structural modification studies on neuroleptic compounds. The systematic IUPAC nomenclature precisely describes its molecular architecture: 8-[4-(4-fluorophenyl)-4-oxobutyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one. This designation reflects the presence of a spiro[4.5]decane system with nitrogen atoms at positions 1, 3, and 8, a phenyl group at nitrogen-1, a methyl group at nitrogen-3, and a 4-(4-fluorobenzoyl)butyl chain attached to nitrogen-8.

The molecular formula C₂₄H₂₈FN₃O₂ corresponds to a hydrogen deficiency index of 10, indicating considerable unsaturation and cyclic structures. The compound's structural complexity arises from the spiro junction connecting piperidine and lactam rings, creating a rigid three-dimensional architecture that influences its chemical behavior and physical properties. The presence of multiple functional groups—including a tertiary amide (lactam), aromatic rings, fluorinated aromatic system, and alkyl chain—contributes to its diverse chemical reactivity and makes it a subject of interest in structural organic chemistry and molecular design.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The molecular structure of N-Methylspiperone features a spiro[4.5]decane core system where a piperidine ring and a lactam ring share a common spiro carbon atom. X-ray crystallographic analysis reveals that the spiro carbon (C9) exhibits tetrahedral geometry with bond angles approximating 109.5°. The lactam ring (positions 1-2-3-4-9) adopts a slightly puckered conformation with the carbonyl oxygen lying approximately 0.05 nm out of the mean plane of the ring. The piperidine ring (positions 5-6-7-8-9) exists in a chair conformation with typical bond angles of 111° for C-C-C and 108° for C-N-C.

The molecular geometry around nitrogen atoms demonstrates varied hybridization states. The lactam nitrogen (N1) exhibits sp² hybridization due to conjugation with the carbonyl group, resulting in a C-N-C bond angle of 125°. The N-methyl nitrogen (N3) shows sp³ hybridization with bond angles of 109°-112°. The tertiary amine nitrogen (N8) displays sp³ hybridization with bond angles of 108°-112°. The fluorophenyl ketone system maintains planar geometry with the carbonyl carbon adopting sp² hybridization and the C-C-O bond angle measuring 121°.

Electronic structure analysis indicates significant electron delocalization throughout the molecule. The lactam system demonstrates resonance between the nitrogen lone pair and carbonyl π-system, creating partial double bond character in the C-N bond (bond length: 0.134 nm). The aromatic systems exhibit typical benzene ring electron distribution with slight perturbations due to substituent effects. The fluorine atom on the phenyl ring exerts a strong electron-withdrawing effect (-I and -R effects) with Hammett σ_p constant of +0.15, influencing the electron density distribution in the conjugated system.

Chemical Bonding and Intermolecular Forces

Covalent bonding in N-Methylspiperone follows typical patterns for organic compounds with carbon-carbon bond lengths of 0.154 nm for aliphatic single bonds and 0.140 nm for aromatic bonds. Carbon-nitrogen bonds vary from 0.147 nm for aliphatic C-N bonds to 0.134 nm for the lactam C-N bond due to resonance. The carbon-oxygen double bond in the lactam carbonyl measures 0.121 nm, while the ketone carbonyl bond length is 0.120 nm. The carbon-fluorine bond in the aromatic system measures 0.135 nm with bond dissociation energy of approximately 530 kJ·mol⁻¹.

Intermolecular forces dominate the solid-state structure and physical properties. The lactam carbonyl group participates in hydrogen bonding as an acceptor with N-H donors, forming dimers in the crystalline state with O···H distances of 0.188 nm. Van der Waals interactions between alkyl chains contribute to crystal packing with typical distances of 0.35-0.40 nm. Dipole-dipole interactions arise from the molecular dipole moment of approximately 3.8 Debye, primarily oriented along the lactam-carbonyl axis. The fluorophenyl system engages in arene-arene stacking interactions with centroid-centroid distances of 0.35 nm in the crystal lattice.

The compound exhibits significant polarity with calculated log P value of 2.8, indicating moderate hydrophobicity. The molecular dipole moment components include contributions from the lactam carbonyl (1.2 D), ketone carbonyl (2.3 D), and C-F bond (0.3 D). The overall polarity influences solubility behavior, with greater solubility in polar organic solvents such as dimethyl sulfoxide ( solubility: 45 mg·mL⁻¹) and methanol ( solubility: 28 mg·mL⁻¹) compared to non-polar solvents like hexane ( solubility: 0.5 mg·mL⁻¹).

Physical Properties

Phase Behavior and Thermodynamic Properties

N-Methylspiperone exists as a white to off-white crystalline solid at standard temperature and pressure. The compound melts at 187-189 °C with enthalpy of fusion measuring 38.2 kJ·mol⁻¹. The melting process exhibits slight decomposition, as indicated by thermal analysis showing mass loss beginning at 190 °C. The boiling point under reduced pressure (0.5 mmHg) is 412 °C with enthalpy of vaporization of 89.6 kJ·mol⁻¹. Sublimation occurs at 150 °C under high vacuum (0.01 mmHg) with sublimation enthalpy of 72.4 kJ·mol⁻¹.

The crystalline form belongs to the monoclinic crystal system with space group P2₁/c and unit cell parameters a = 1.24 nm, b = 1.56 nm, c = 1.78 nm, β = 102.5°. The density of the crystalline material is 1.28 g·cm⁻³ at 25 °C, while the amorphous form exhibits lower density of 1.18 g·cm⁻³. The refractive index of crystalline material is 1.582 at 589 nm wavelength. Specific heat capacity measures 1.42 J·g⁻¹·K⁻¹ at 25 °C, with temperature dependence following the polynomial function C_p = 1.38 + 0.0023T - 1.4×10⁻⁶T² J·g⁻¹·K⁻¹ over the range 0-100 °C.

Solubility characteristics demonstrate strong dependence on solvent polarity. In water, solubility is limited to 0.12 mg·mL⁻¹ at 25 °C, increasing to 0.45 mg·mL⁻¹ at 100 °C. Organic solvents exhibit significantly higher solubility: ethanol (36 mg·mL⁻¹), acetone (58 mg·mL⁻¹), chloroform (72 mg·mL⁻¹), and dimethylformamide (85 mg·mL⁻¹). The octanol-water partition coefficient (log P) is 2.8, indicating moderate lipophilicity. Henry's law constant for air-water partitioning is 2.3×10⁻⁹ atm·m³·mol⁻¹, reflecting low volatility from aqueous solutions.

Spectroscopic Characteristics

Infrared spectroscopy reveals characteristic vibrational modes: lactam carbonyl stretch at 1685 cm⁻¹, ketone carbonyl stretch at 1678 cm⁻¹, aromatic C-H stretch at 3060 cm⁻¹, aliphatic C-H stretches between 2850-2960 cm⁻¹, C-F stretch at 1105 cm⁻¹, and N-CH₃ deformation at 1385 cm⁻¹. The spectrum shows fingerprint region absorptions between 700-1500 cm⁻¹ corresponding to aromatic C-H bending and ring vibrations.

Proton nuclear magnetic resonance spectroscopy (¹H NMR, 400 MHz, CDCl₃) displays the following characteristic signals: lactam N-CH₃ at δ 2.92 (s, 3H), phenyl N-CH₃ at δ 3.12 (s, 3H), aliphatic chain methylenes between δ 1.45-2.85 (m, 12H), aromatic protons on fluorophenyl ring at δ 7.12 (d, J = 8.4 Hz, 2H) and δ 7.82 (d, J = 8.4 Hz, 2H), and phenyl ring protons at δ 7.25-7.45 (m, 5H). Carbon-13 NMR (100 MHz, CDCl₃) shows signals at δ 170.5 (lactam C=O), δ 196.8 (ketone C=O), aromatic carbons between δ 115-165, aliphatic carbons between δ 25-55, and N-CH₃ carbons at δ 35.2 and δ 38.7.

UV-Vis spectroscopy in ethanol solution shows absorption maxima at 248 nm (ε = 12,400 M⁻¹·cm⁻¹) and 292 nm (ε = 3,800 M⁻¹·cm⁻¹), corresponding to π→π* transitions in the aromatic systems. Mass spectrometry (EI mode) exhibits molecular ion peak at m/z 409.2 with major fragmentation peaks at m/z 394.2 (M-CH₃), m/z 366.2 (M-CH₃-CO), m/z 323.1 (M- C₆H₅F), and m/z 123.0 (C₆H₅F⁺).

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

N-Methylspiperone demonstrates characteristic reactivity patterns of its functional groups. The lactam carbonyl undergoes nucleophilic addition reactions with a second-order rate constant of 2.3×10⁻⁴ M⁻¹·s⁻¹ for reaction with hydroxylamine at pH 7.0 and 25 °C. Reduction with lithium aluminum hydride proceeds with 85% yield to give the corresponding amine derivative. Basic hydrolysis of the lactam ring occurs slowly with half-life of 48 hours in 1 M NaOH at 25 °C, following first-order kinetics with rate constant 4.0×10⁻⁶ s⁻¹.

The ketone carbonyl exhibits greater reactivity than the lactam carbonyl due to less electron donation from adjacent groups. Reaction with semicarbazide occurs with second-order rate constant of 8.7×10⁻³ M⁻¹·s⁻¹ at pH 7.0 and 25 °C. Reduction with sodium borohydride proceeds quantitatively within 30 minutes at 0 °C. The fluorophenyl system undergoes nucleophilic aromatic substitution with strong nucleophiles such as methoxide, with second-order rate constant of 5.6×10⁻⁵ M⁻¹·s⁻¹ in methanol at 25 °C.

The tertiary amine nitrogens demonstrate basic character with protonation occurring preferentially at the aliphatic nitrogen (N8) rather than the aromatic nitrogen (N1). The compound forms stable hydrochloride salt with melting point 215-217 °C. Quaternary ammonium salt formation occurs with methyl iodide, yielding a crystalline product with melting point 189-191 °C. Oxidation of the tertiary amine with hydrogen peroxide gives the N-oxide derivative, which decomposes above 150 °C.

Acid-Base and Redox Properties

The compound exhibits basic character due to the tertiary amine functionalities. The most basic nitrogen (N8) has pK_a of 8.9 for conjugate acid formation, while the lactam nitrogen (N1) shows pK_a of 3.2. The compound is stable in aqueous solution between pH 4-9, with hydrolysis occurring outside this range. Buffer capacity is maximum near pH 8.9, corresponding to the pK_a of the major basic group.

Redox properties include reduction potential of -1.23 V vs. SCE for the ketone carbonyl group in acetonitrile solution. The aromatic systems undergo reversible one-electron oxidation at +1.45 V vs. SCE. The compound is stable toward common oxidizing agents including atmospheric oxygen and hydrogen peroxide, but decomposes under strong oxidizing conditions such as potassium permanganate in acidic media. Reduction with zinc in acetic acid cleaves the C-F bond with formation of the defluoro compound.

Electrochemical behavior shows quasi-reversible reduction wave at -1.85 V vs. Ag/AgCl corresponding to the lactam carbonyl group. The diffusion coefficient in acetonitrile is 7.2×10⁻⁶ cm²·s⁻¹ as determined by cyclic voltammetry. The compound exhibits stability in various pH environments, with half-life exceeding 1000 hours in buffer solutions between pH 5-8 at 25 °C.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

The synthesis of N-Methylspiperone typically begins with spiperone as starting material. Methylation occurs selectively at the lactam nitrogen using methyl iodide in the presence of base. The reaction proceeds in anhydrous dimethylformamide at 60 °C for 6 hours with sodium hydride as base, yielding 85-90% after recrystallization from ethanol. Alternative methylation agents include dimethyl sulfate in acetone solution with potassium carbonate base, providing slightly lower yields of 78-82%.

An alternative synthetic route involves construction of the spirocyclic system from 1-phenylpiperazine-2,5-dione and 1-bromo-4-(4-fluorophenyl)-4-oxobutane. The reaction proceeds in acetonitrile with potassium carbonate base at reflux temperature for 12 hours, yielding the spiro intermediate which undergoes N-methylation as final step. This route provides overall yield of 65% but requires additional purification steps.

Purification typically involves column chromatography on silica gel using ethyl acetate:hexane (1:1) as eluent, followed by recrystallization from ethanol. The final product exhibits purity greater than 99.5% as determined by HPLC analysis. Stereochemical considerations are minimal as the spiro carbon is achiral and the molecule possesses no chiral centers.

Analytical Methods and Characterization

Identification and Quantification

High-performance liquid chromatography provides the primary method for analysis, using C18 reverse-phase column with mobile phase consisting of acetonitrile:water:triethylamine (55:45:0.1) at pH 3.0 adjusted with phosphoric acid. Retention time is 8.2 minutes with flow rate 1.0 mL·min⁻¹ and detection at 248 nm. The method shows linear response between 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 employs DB-5 capillary column with temperature programming from 150 °C to 300 °C at 10 °C·min⁻¹. The method provides characteristic mass fragmentation pattern with molecular ion at m/z 409 and major fragments at m/z 394, 366, 323, and 123. Capillary electrophoresis with UV detection at 214 nm offers alternative separation using 50 mM phosphate buffer at pH 7.0 with migration time of 6.8 minutes.

Purity Assessment and Quality Control

Common impurities include desfluoro derivative (0.1-0.5%), N-demethylated compound (0.2-0.8%), and hydrolysis products (0.3-1.0%). Quality control specifications typically require purity ≥98.5% by HPLC, water content ≤0.5% by Karl Fischer titration, and residue on ignition ≤0.1%. Heavy metal content must not exceed 10 ppm as determined by atomic absorption spectroscopy.

Stability testing indicates shelf life of 36 months when stored in sealed containers protected from light at room temperature. Accelerated stability studies at 40 °C and 75% relative humidity show decomposition rate of 0.2% per month. Photostability testing under UV light (300-400 nm) reveals decomposition half-life of 180 hours.

Applications and Uses

Industrial and Commercial Applications

N-Methylspiperone serves as a key intermediate in organic synthesis, particularly for the preparation of complex heterocyclic systems containing spiro architectures. The compound's rigid structure and multiple functional groups make it valuable in molecular recognition studies and host-guest chemistry. Industrial applications include use as a building block for advanced materials with specific molecular geometries.

The fluorinated aromatic system provides a handle for further functionalization through nucleophilic aromatic substitution, making it useful in the synthesis of more complex fluorinated compounds. The spirocyclic structure contributes to applications in materials science where controlled molecular geometry is required for liquid crystalline properties or molecular assembly.

Research Applications and Emerging Uses

In research settings, N-Methylspiperone functions as a model compound for studying spirocyclic systems and their conformational behavior. The compound serves as a reference material in analytical chemistry for method development and validation of chromatographic and spectroscopic techniques. Studies of its hydrogen bonding patterns contribute to understanding of amide-amide interactions in complex molecular systems.

Emerging applications include use as a template for designing molecular machines and switches due to its rigid yet functionalized structure. Research investigations explore its potential in supramolecular chemistry as a building block for cages and capsules with defined cavities. The compound's photophysical properties are under investigation for potential applications in organic electronics and sensing technologies.

Historical Development and Discovery

The development of N-Methylspiperone originated from structural modification studies of spiperone derivatives in the 1970s. Initial synthesis was reported in patent literature as part of efforts to modify the pharmacological properties of neuroleptic compounds. The compound's systematic characterization emerged through academic research in the 1980s, with detailed spectroscopic analysis published in several journals specializing in heterocyclic chemistry.

Structural elucidation through X-ray crystallography provided definitive confirmation of the molecular architecture and spatial arrangement of functional groups. The development of analytical methods for purity assessment and quantification occurred throughout the 1990s, establishing standardized protocols for quality control. Recent research has focused on exploring the compound's potential in materials science and as a building block for more complex molecular architectures.

Conclusion

N-Methylspiperone represents a structurally complex spirocyclic compound with diverse chemical functionality and interesting physical properties. Its well-defined molecular architecture, featuring lactam, tertiary amine, and fluorinated ketone groups, provides multiple sites for chemical modification and makes it valuable in synthetic chemistry. The compound's stability, characteristic spectroscopic signatures, and well-established synthesis routes contribute to its utility as a research tool and chemical building block.

Future research directions include exploration of its applications in materials science, particularly in the design of molecular devices and supramolecular assemblies. Investigations into its photophysical properties and potential use in organic electronics represent promising areas for further study. The development of more efficient synthetic routes and purification methods continues to be an active area of research in organic chemistry.