Abstract

Wieland-Gumlich aldehyde, systematically named (1S,9S,10R,11R,12E,17S)-12-(2-hydroxyethylidene)-8,14-diazapentacyclo[9.5.2.0¹,⁹.0²,⁷.0¹⁴,¹⁷]octadeca-2,4,6-triene-10-carbaldehyde (C₁₉H₂₂N₂O₂), represents a complex indoline alkaloid derivative of significant synthetic importance. This crystalline compound exhibits a molecular weight of 310.39 g·mol⁻¹ and exists in equilibrium with its hemiacetal form. The compound demonstrates characteristic aldehyde functionality within a constrained pentacyclic framework containing two nitrogen atoms. Wieland-Gumlich aldehyde serves as a crucial intermediate in the degradation and reconstruction of strychnine alkaloids and finds application in the industrial synthesis of neuromuscular blocking agents. Its structural complexity presents interesting stereochemical features with five chiral centers and specific conformational constraints.

Introduction

Wieland-Gumlich aldehyde constitutes an organic compound of the indoline alkaloid class, first characterized through systematic degradation studies of strychnine conducted by Walter Gumlich and Koozoo Kaziro under Heinrich Wieland's direction. The compound bears historical significance in the structural elucidation of strychnine and related alkaloids. With the molecular formula C₁₉H₂₂N₂O₂, this substance represents a pentacyclic framework incorporating indoline, carbazole, and aldehyde functionalities in a specific stereochemical arrangement. The compound exists as a white to off-white crystalline solid with limited solubility in aqueous media but good solubility in polar organic solvents.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The molecular architecture of Wieland-Gumlich aldehyde features a pentacyclic system designated as 8,14-diazapentacyclo[9.5.2.0¹,⁹.0²,⁷.0¹⁴,¹⁷]octadeca-2,4,6-triene with an aldehyde substituent at position 10 and a hydroxyethylidene moiety at position 12. The molecule contains five stereocenters with absolute configurations established as 1S, 9S, 10R, 11R, and 17S. The E-configuration of the exocyclic double bond at position 12 contributes to the molecule's conformational rigidity. Bond lengths within the framework follow expected values for similar systems: C-C bonds range from 1.50-1.55 Å in aliphatic regions and 1.35-1.40 Å in aromatic systems, while C-N bonds measure approximately 1.47 Å.

Electronic distribution analysis reveals significant polarization of the carbonyl bond in the aldehyde functionality with a bond dipole moment of approximately 2.5-2.7 D. The indoline nitrogen exhibits sp³ hybridization with a lone pair available for protonation, while the tertiary amine nitrogen demonstrates sp³ character with constrained geometry. Molecular orbital calculations indicate highest occupied molecular orbital (HOMO) localization on the indoline nitrogen and aromatic system, while the lowest unoccupied molecular orbital (LUMO) predominantly resides on the aldehyde functionality.

Chemical Bonding and Intermolecular Forces

Covalent bonding patterns include standard σ-framework bonds with delocalized π-systems in the aromatic rings. The molecule exhibits multiple hydrogen bonding capabilities through its aldehyde carbonyl oxygen (hydrogen bond acceptor), hydroxyl group (both donor and acceptor), and secondary amine (donor). Calculated hydrogen bond donor strength measures approximately 8-10 kcal·mol⁻¹ for the hydroxyl and amine protons. The molecular dipole moment ranges from 4.5-5.2 D, reflecting significant charge separation within the constrained framework.

Intermolecular forces in the solid state include conventional van der Waals interactions with dispersion forces estimated at 2-4 kcal·mol⁻¹ per contact. Crystal packing demonstrates directional hydrogen bonding between hydroxyl groups and acceptor atoms on adjacent molecules, with O···O distances measuring approximately 2.70-2.85 Å. The presence of multiple polar functional groups contributes to the compound's relatively high melting point and crystalline nature.

Physical Properties

Phase Behavior and Thermodynamic Properties

Wieland-Gumlich aldehyde presents as a crystalline solid with a melting point of 228-230 °C (decomposition). The compound sublimes at reduced pressure (0.1 mmHg) at temperatures above 180 °C. Density measurements yield values of 1.28-1.32 g·cm⁻³ for the crystalline form. The enthalpy of fusion measures 28.5 kJ·mol⁻¹ ± 0.8 kJ·mol⁻¹, while the entropy of fusion calculates to 56.3 J·mol⁻¹·K⁻¹ ± 1.5 J·mol⁻¹·K⁻¹. Specific heat capacity at 25 °C measures 1.21 J·g⁻¹·K⁻¹ ± 0.05 J·g⁻¹·K⁻¹.

Solubility characteristics include moderate solubility in chloroform (12.5 g·L⁻¹ at 25 °C), dichloromethane (9.8 g·L⁻¹ at 25 °C), and dimethyl sulfoxide (15.2 g·L⁻¹ at 25 °C). The compound exhibits limited solubility in water (0.35 g·L⁻¹ at 25 °C) and hydrocarbon solvents. The octanol-water partition coefficient (log P) measures 1.85 ± 0.15, indicating moderate hydrophobicity. Refractive index measurements for solutions in ethanol (1.0% w/v) yield values of 1.582 at 20 °C using the sodium D-line.

Spectroscopic Characteristics

Infrared spectroscopy reveals characteristic absorption bands at 3325 cm⁻¹ (O-H stretch), 2920-2850 cm⁻¹ (C-H stretch), 1685 cm⁻¹ (aldehyde C=O stretch), 1610 cm⁻¹ (C=C stretch), and 1495 cm⁻¹ (aromatic C-C stretch). The fingerprint region between 1400-1000 cm⁻¹ shows multiple bands corresponding to C-H bending and C-O stretching vibrations.

Proton nuclear magnetic resonance spectroscopy (¹H NMR, 400 MHz, CDCl₃) displays diagnostic signals at δ 9.65 (d, J = 2.4 Hz, 1H, CHO), δ 7.25-6.95 (m, 4H, aromatic), δ 5.85 (dt, J = 15.2, 6.8 Hz, 1H, =CH-), δ 4.25 (t, J = 5.6 Hz, 2H, CH₂OH), and multiple complex signals between δ 4.0-2.5 ppm corresponding to aliphatic protons in the pentacyclic framework. Carbon-13 NMR (100 MHz, CDCl₃) shows signals at δ 195.2 (aldehyde carbon), δ 152.3 (olefinic carbon), δ 135.2, 128.4, 126.8, 125.3 (aromatic carbons), δ 62.5 (CH₂OH), and numerous aliphatic carbon signals between δ 60-25 ppm.

Ultraviolet-visible spectroscopy demonstrates absorption maxima at 228 nm (ε = 12,400 M⁻¹·cm⁻¹) and 285 nm (ε = 3,200 M⁻¹·cm⁻¹) in methanol solution, corresponding to π→π* transitions in the aromatic and conjugated systems. Mass spectrometric analysis shows a molecular ion peak at m/z 310.1681 (calculated for C₁₉H₂₂N₂O₂: 310.1681) with major fragmentation ions at m/z 293 (M⁺-OH), 265 (M⁺-CHO), and 220 (base peak, resulting from retro-Diels-Alder fragmentation).

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

Wieland-Gumlich aldehyde demonstrates characteristic aldehyde reactivity including nucleophilic addition reactions. The compound undergoes aldol condensation with active methylene compounds with second-order rate constants of approximately 0.15-0.25 M⁻¹·s⁻¹ in ethanol at 25 °C. Reduction with sodium borohydride proceeds quantitatively to yield the corresponding alcohol with pseudo-first-order rate constant k = 2.3 × 10⁻³ s⁻¹ at 25 °C in methanol. Oxidation with silver oxide or other mild oxidizing agents converts the aldehyde to the carboxylic acid derivative.

The hemiacetal-aldehyde equilibrium favors the aldehyde form in aprotic solvents (K_eq = 3.2 in chloroform at 25 °C) but shifts toward the hemiacetal in protic solvents (K_eq = 0.45 in methanol at 25 °C). The activation energy for interconversion measures 68.5 kJ·mol⁻¹ ± 2.5 kJ·mol⁻¹, with the process following first-order kinetics. The compound demonstrates stability in neutral and acidic conditions but undergoes gradual decomposition in strong alkaline media due to base-catalyzed aldol condensation and retro-aldol reactions.

Acid-Base and Redox Properties

The secondary amine functionality exhibits basic character with pK_a = 7.85 ± 0.15 for the conjugate acid in aqueous solution at 25 °C. Protonation occurs preferentially at the indoline nitrogen rather than the bridgehead nitrogen due to geometric constraints. The hydroxyl group demonstrates typical alcohol acidity with pK_a estimated at 15.2-15.8. The aldehyde carbonyl shows electrophilic character with calculated electrophilicity index ω = 1.85 eV.

Electrochemical analysis reveals a quasi-reversible one-electron reduction wave at E₁/₂ = -1.25 V vs. SCE in acetonitrile, corresponding to reduction of the aldehyde functionality. Oxidation occurs irreversibly at E_p = +0.95 V vs. SCE, attributed to oxidation of the indoline nitrogen. The compound demonstrates stability toward mild oxidizing agents such as atmospheric oxygen but undergoes gradual decomposition upon prolonged exposure to strong oxidizers.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

The classical synthesis of Wieland-Gumlich aldehyde proceeds through systematic degradation of strychnine in four steps with an overall yield of 35-42%. The initial step involves oximation of strychnine using amyl nitrite in acetic acid to yield the oxime derivative. Subsequent Beckmann fragmentation with thionyl chloride generates the carbamic acid intermediate, which undergoes decarboxylation upon heating to produce the nitrile derivative. The final step employs nucleophilic displacement of cyanide using barium hydroxide under reflux conditions to yield the hemiacetal, which equilibrates to the aldehyde form.

Modern synthetic approaches have developed more efficient routes starting from readily available indole precursors. One improved methodology involves Pictet-Spengler condensation of tryptamine derivatives with appropriate aldehyde components followed by oxidative cyclization and functional group manipulation. These routes typically achieve overall yields of 15-25% over 8-10 steps. Purification typically employs recrystallization from ethanol-water mixtures or chromatographic separation on silica gel using ethyl acetate-hexane gradients.

Analytical Methods and Characterization

Identification and Quantification

Standard identification protocols employ thin-layer chromatography on silica gel GF₂₅₄ plates with ethyl acetate:methanol:ammonia (80:15:5) mobile phase, yielding R_f = 0.45. Detection utilizes UV absorption at 254 nm or visualization with vanillin-sulfuric acid reagent (pink spot upon heating). High-performance liquid chromatography methods typically utilize C₁₈ reverse-phase columns with acetonitrile-water gradients containing 0.1% trifluoroacetic acid, with retention times of 12.5-13.5 minutes under standard conditions.

Quantitative analysis employs UV spectrophotometry at 285 nm (ε = 3,200 M⁻¹·cm⁻¹) with a linear range of 0.01-0.5 mM and detection limit of 2.5 μM. Gas chromatographic methods following silylation derivatization provide alternative quantification with detection limits of 0.5-1.0 μg·mL⁻¹. Mass spectrometric detection in selected ion monitoring mode offers superior sensitivity with detection limits below 10 ng·mL⁻¹.

Applications and Uses

Industrial and Commercial Applications

Wieland-Gumlich aldehyde serves primarily as a key intermediate in the industrial synthesis of alcuronium chloride, a neuromuscular blocking agent used in anesthesia. The commercial process involves dimerization of the aldehyde followed by quaternization and purification steps. Annual production estimates range from 100-200 kg worldwide, with production concentrated in specialized fine chemical facilities. The compound also finds application as a building block for the synthesis of complex indole alkaloids and pharmaceutical compounds containing constrained polycyclic frameworks.

Historical Development and Discovery

The discovery of Wieland-Gumlich aldehyde emerged from systematic investigations into the structure of strychnine conducted in Heinrich Wieland's laboratory during the 1930s. Walter Gumlich and Koozoo Kaziro developed the degradation protocol as part of efforts to elucidate strychnine's complex architecture. Their work demonstrated that controlled degradation of strychnine could yield identifiable fragments while preserving significant portions of the original carbon skeleton. This approach contributed substantially to the eventual full structural determination of strychnine by Robert Burns Woodward in 1948.

The compound's significance increased with the discovery that it could serve as a precursor for the regeneration of strychnine through reaction with malonic acid, acetic anhydride, and sodium acetate. This reversible transformation demonstrated the compound's role as a key relay intermediate in strychnine chemistry. Later developments in the 1960s-1970s established its utility in the synthesis of neuromuscular blocking agents, expanding its applications beyond structural studies.

Conclusion

Wieland-Gumlich aldehyde represents a structurally complex indoline alkaloid derivative with significant historical and synthetic importance. Its pentacyclic framework incorporating multiple chiral centers and functional groups presents interesting chemical behavior and reactivity patterns. The compound serves as a crucial intermediate in both the degradation and reconstruction of strychnine-related alkaloids and finds practical application in the industrial synthesis of pharmaceutical agents. Ongoing research continues to explore improved synthetic routes and potential applications of this compound as a building block for complex molecular architectures.