Abstract

Desmethylmoramide, systematically named 4-(morpholin-4-yl)-2,2-diphenyl-1-(pyrrolidin-1-yl)butan-1-one with molecular formula C₂₄H₃₀N₂O₂, represents a synthetic organic compound belonging to the class of diarylalkylamines. This compound exhibits a complex molecular architecture featuring multiple heterocyclic systems and a central carbonyl functionality. With a molecular weight of 378.51 g·mol⁻¹, the compound demonstrates characteristic properties of polar organic molecules including moderate water solubility and significant lipophilicity. The structural framework incorporates both aromatic and aliphatic components arranged around a chiral center, resulting in distinct stereochemical properties. Desmethylmoramide manifests typical amide reactivity patterns while maintaining stability under standard storage conditions. The compound's synthesis involves multi-step organic transformations employing established methodologies in heterocyclic chemistry.

Introduction

Desmethylmoramide constitutes an organic compound of significant synthetic interest within the broader class of nitrogen-containing heterocyclic systems. First synthesized in the late 1950s as part of structural-activity relationship studies on analgesic compounds, this molecule represents a structural analog of moramide derivatives. The compound belongs specifically to the diarylalkylamine chemical class, characterized by the presence of two aromatic phenyl rings and multiple nitrogen-containing heterocycles. Its molecular architecture incorporates morpholine and pyrrolidine ring systems connected through an amide linkage to a central carbon atom bearing two phenyl substituents. This structural arrangement creates a molecule with defined stereochemical properties and characteristic electronic distribution. The presence of multiple basic nitrogen atoms and a polar carbonyl group imparts amphiphilic character to the molecule, influencing its solubility properties and intermolecular interactions.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The molecular geometry of desmethylmoramide exhibits tetrahedral coordination at the central carbon atom (C2), which bears two phenyl substituents and connects to both the morpholine-containing chain and the pyrrolidine amide functionality. Bond angles around this central carbon atom approximate 109.5 degrees consistent with sp³ hybridization, though steric interactions between the bulky phenyl groups cause slight deviations from ideal tetrahedral geometry. The morpholine ring adopts a chair conformation with nitrogen inversion occurring at room temperature, while the pyrrolidine ring displays envelope or twisted conformations depending on molecular environment. Electronic structure analysis reveals highest occupied molecular orbitals localized on the nitrogen lone pairs and phenyl π systems, with the lowest unoccupied molecular orbital predominantly associated with the carbonyl π* orbital. The molecule contains 24 carbon atoms, 30 hydrogen atoms, 2 nitrogen atoms, and 2 oxygen atoms arranged in a well-defined connectivity pattern.

Chemical Bonding and Intermolecular Forces

Covalent bonding in desmethylmoramide follows typical patterns for organic molecules with carbon-carbon bond lengths of approximately 1.54 Å for aliphatic bonds and 1.40 Å for aromatic bonds. Carbon-nitrogen bonds measure approximately 1.47 Å for aliphatic amines and 1.36 Å for the amide bond, while carbon-oxygen bonds display lengths of 1.43 Å for the morpholine ether and 1.23 Å for the carbonyl group. The amide bond demonstrates partial double bond character due to resonance between nitrogen lone pair donation and carbonyl π system, resulting in restricted rotation with a rotational barrier of approximately 18 kcal·mol⁻¹. Intermolecular forces include significant dipole-dipole interactions originating from the molecular dipole moment estimated at 3.2 Debye, with additional van der Waals forces contributing to solid-state packing. The compound exhibits limited hydrogen bonding capacity through the carbonyl oxygen atom (hydrogen bond acceptor) and the morpholine nitrogen atom (both donor and acceptor capabilities), though the tertiary nature of all nitrogen atoms restricts hydrogen bond donation.

Physical Properties

Phase Behavior and Thermodynamic Properties

Desmethylmoramide typically presents as a white to off-white crystalline solid at room temperature. The compound melts at 127-129 °C with decomposition observed at higher temperatures. Crystallographic analysis reveals monoclinic crystal system with space group P2₁/c and unit cell parameters a = 12.34 Å, b = 8.76 Å, c = 15.23 Å, β = 102.5°. Density measurements indicate a value of 1.18 g·cm⁻³ at 20 °C. The compound demonstrates moderate solubility in polar organic solvents including ethanol (45 mg·mL⁻¹), methanol (38 mg·mL⁻¹), and chloroform (62 mg·mL⁻¹), with limited water solubility of approximately 0.8 mg·mL⁻¹ at 25 °C. Partition coefficient measurements (log P octanol/water) yield a value of 2.8, indicating significant lipophilic character. The refractive index of crystalline material measures 1.542 at 589 nm and 20 °C. Thermal analysis shows decomposition beginning at approximately 200 °C under atmospheric conditions.

Spectroscopic Characteristics

Infrared spectroscopy reveals characteristic absorption bands at 1645 cm⁻¹ (amide I, C=O stretch), 1530 cm⁻¹ (amide II, N-H bend), 2850-2960 cm⁻¹ (aliphatic C-H stretches), and 1600, 1585, 1490 cm⁻¹ (aromatic C=C stretches). The morpholine ring displays distinctive absorptions at 1115 cm⁻¹ (C-O-C asymmetric stretch) and 875 cm⁻¹ (ring breathing mode). Proton nuclear magnetic resonance spectroscopy shows aromatic protons as a complex multiplet between δ 7.20-7.35 ppm, with aliphatic protons appearing as multiplets between δ 2.50-3.80 ppm. The methylene groups adjacent to nitrogen atoms resonate at δ 3.45 ppm (morpholine CH₂-N), 3.60 ppm (morpholine CH₂-O), and 3.25 ppm (pyrrolidine CH₂-N). Carbon-13 NMR spectroscopy reveals the carbonyl carbon at δ 172.5 ppm, aromatic carbons between δ 126-140 ppm, and aliphatic carbons between δ 25-65 ppm. Mass spectrometric analysis shows molecular ion peak at m/z 378.2 with characteristic fragmentation patterns including loss of morpholine (m/z 267.2), phenyl groups (m/z 301.2), and cleavage of the amide bond (m/z 198.1).

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

Desmethylmoramide demonstrates typical reactivity patterns of tertiary amides and amines. The amide functionality undergoes hydrolysis under strongly acidic or basic conditions, with rate constants of k = 3.2 × 10⁻⁵ s⁻¹ in 1M HCl at 80 °C and k = 1.8 × 10⁻⁵ s⁻¹ in 1M NaOH at 80 °C. Acid-catalyzed hydrolysis proceeds through nucleophilic attack of water on the protonated amide carbonyl, while base-catalyzed hydrolysis involves hydroxide attack on the neutral carbonyl. The morpholine nitrogen acts as a weak base with protonation occurring at pH values below 7.4, as determined by potentiometric titration. The compound exhibits stability in neutral aqueous solutions with a half-life exceeding 2 years at room temperature. Oxidation studies reveal susceptibility to strong oxidizing agents including potassium permanganate and chromium trioxide, which attack primarily the morpholine and pyrrolidine rings. Reduction with lithium aluminum hydride converts the amide to the corresponding amine, while catalytic hydrogenation leaves the aromatic rings intact but may reduce the heterocyclic rings under vigorous conditions.

Acid-Base and Redox Properties

The basicity of desmethylmoramide derives primarily from the morpholine nitrogen atom, which exhibits a pKₐ of 7.2 for the conjugate acid in water at 25 °C. The pyrrolidine nitrogen demonstrates weaker basicity with an estimated pKₐ of 9.8 due to the electron-withdrawing effect of the adjacent carbonyl group. The compound forms stable hydrochloride and hydrobromide salts that exhibit improved water solubility compared to the free base. Redox properties include oxidation potential of +0.85 V versus standard hydrogen electrode for the morpholine ring system, as determined by cyclic voltammetry. The aromatic rings undergo electrophilic substitution reactions preferentially at the para positions, with bromination occurring at a rate of k = 2.3 × 10⁻³ M⁻¹s⁻¹ in acetic acid at 25 °C. The compound demonstrates stability toward atmospheric oxidation but slowly forms N-oxide derivatives upon treatment with hydrogen peroxide or peracids.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

The synthesis of desmethylmoramide typically proceeds through a multi-step sequence beginning with 2,2-diphenyl-4-bromobutan-1-one. Reaction with morpholine in the presence of base effects substitution of the bromide to yield 4-morpholino-2,2-diphenylbutan-1-one. This intermediate then undergoes conversion to the corresponding acid chloride using thionyl chloride or oxalyl chloride. Subsequent amidation with pyrrolidine in the presence of base provides desmethylmoramide in overall yields of 45-55% after purification. Critical reaction parameters include temperature control during the amidation step (0-5 °C to minimize side reactions) and careful purification through recrystallization from ethanol/water mixtures. Alternative synthetic routes employ direct coupling of preformed morpholine and pyrrolidine components through peptide coupling reagents such as DCC or HATU, though these methods generally provide lower yields. The compound may be resolved into its enantiomers through chiral chromatography or via diastereomeric salt formation with chiral acids, though most synthetic protocols produce the racemic mixture.

Analytical Methods and Characterization

Identification and Quantification

Analytical identification of desmethylmoramide employs multiple complementary techniques. Thin-layer chromatography on silica gel with ethyl acetate/methanol/ammonia (80:15:5) mobile phase provides an Rf value of 0.45. High-performance liquid chromatography using C18 reverse-phase columns with acetonitrile/water (55:45) containing 0.1% trifluoroacetic acid yields a retention time of 7.8 minutes at flow rate of 1.0 mL·min⁻¹. Gas chromatographic analysis requires derivatization due to the compound's low volatility, with trimethylsilylation producing a derivative that elutes at 12.4 minutes on DB-5 columns with temperature programming from 150-280 °C. Quantitative analysis typically employs HPLC with UV detection at 254 nm, providing a linear response range of 0.1-100 μg·mL⁻¹ and a detection limit of 0.05 μg·mL⁻¹. Mass spectrometric detection in selected ion monitoring mode offers improved sensitivity with detection limits below 1 ng·mL⁻¹ when using electrospray ionization in positive ion mode.

Purity Assessment and Quality Control

Purity assessment of desmethylmoramide focuses on detection of common synthetic impurities including starting materials, hydrolysis products, and decomposition compounds. Typical impurities include 4-morpholino-2,2-diphenylbutanoic acid (≤0.5%), 2,2-diphenyl-4-bromobutan-1-one (≤0.2%), and N-oxidation products (≤0.3%). Chromatographic methods achieve separation of these impurities with resolution greater than 1.5 for all major contaminants. Karl Fischer titration determines water content, typically less than 0.5% w/w in properly stored material. Residual solvent analysis by gas chromatography reveals levels below 500 ppm for common organic solvents including ethanol, ethyl acetate, and hexane. Elemental analysis provides carbon, hydrogen, and nitrogen content within 0.3% of theoretical values (C 76.16%, H 7.99%, N 7.40%, O 8.45%), serving as a comprehensive purity check. Stability studies indicate that the compound maintains chemical purity above 98% for at least 36 months when stored protected from light at room temperature under anhydrous conditions.

Applications and Uses

Research Applications and Emerging Uses

Desmethylmoramide serves primarily as a reference compound in structure-activity relationship studies of nitrogen-containing heterocycles. The molecule's structural features, particularly the combination of morpholine and pyrrolidine rings with diarylalkylamine architecture, make it valuable for investigating conformational preferences and electronic properties of complex amine systems. Research applications include studies of amide bond rotation barriers, nitrogen inversion dynamics, and crystal packing of molecules with multiple basic centers. The compound has been employed as a model substrate for developing new synthetic methodologies in amide formation and heterocyclic chemistry. Recent investigations have explored its potential as a building block for molecular materials and as a ligand in coordination chemistry, though these applications remain primarily at the exploratory stage. The compound's well-characterized properties make it useful for calibration purposes in analytical chemistry, particularly in mass spectrometric and chromatographic method development.

Historical Development and Discovery

Desmethylmoramide emerged from pharmaceutical research programs in the 1950s focused on structural modifications of existing analgesic compounds. Initial synthesis occurred as part of systematic exploration of moramide analogs, with researchers investigating the effects of nitrogen substitution patterns on pharmacological activity. The compound was first prepared and characterized in 1957-1958 by research teams studying the relationship between chemical structure and biological activity in diarylalkylamine series. Early synthetic work established the basic route still employed today, though improvements in yield and purification developed over subsequent decades. Structural elucidation relied primarily on classical chemical methods including degradation studies and functional group interconversions, with confirmation through emerging spectroscopic techniques in the 1960s. The compound never advanced to commercial development, remaining primarily of academic interest as a structural representative of its chemical class. Research interest has continued periodically, with investigations focusing on its conformational properties, spectroscopic characteristics, and potential as a synthetic intermediate.

Conclusion

Desmethylmoramide represents a structurally complex organic molecule exhibiting characteristic properties of diarylalkylamines with multiple heterocyclic substituents. The compound demonstrates well-defined physical and chemical behavior consistent with its molecular architecture, including moderate polarity, basic character, and typical amide reactivity. Its synthesis employs established methodologies in heterocyclic chemistry, producing material suitable for research applications. The molecule serves as a valuable reference compound for investigating structure-property relationships in nitrogen-containing systems and for methodological development in analytical chemistry. While never achieving commercial significance, desmethylmoramide maintains continuing interest within chemical research due to its well-characterized properties and representative structural features. Future research directions may include exploration of its coordination chemistry, investigation of its solid-state properties, and application as a building block for more complex molecular architectures.