Abstract

Cicutoxin, systematically named (8''E'',10''E'',12''E'',14''R'')-heptadeca-8,10,12-triene-4,6-diyne-1,14-diol, is a highly unsaturated C₁₇ polyacetylene compound with molecular formula C₁₇H₂₂O₂. This natural product belongs to the class of C₁₇-polyacetylenes and represents a structural isomer of oenanthotoxin. The compound exhibits a characteristic conjugated system comprising two triple bonds and three double bonds in an alternating pattern, terminated by primary and secondary hydroxyl functional groups. Cicutoxin demonstrates significant chemical instability when exposed to atmospheric oxygen, light, or elevated temperatures. Its molecular structure features a single chiral center at the C14 position, with the naturally occurring enantiomer possessing R configuration. The compound manifests limited solubility in aqueous media but shows good solubility in organic solvents including ethanol, diethyl ether, and chloroform.

Introduction

Cicutoxin represents a chemically significant natural product belonging to the C₁₇-polyacetylene class of compounds. First isolated in pure form by Jacobsen in 1915 as a yellowish oil, its complete structural elucidation was achieved in 1953, revealing an aliphatic, highly unsaturated alcohol structure containing polyyne and polyene functionalities. The compound occurs naturally in several plant species within the Apiaceae family, particularly those of the genus Cicuta. The structural complexity of cicutoxin arises from its extended conjugated system containing both cumulated double and triple bonds, creating a molecule of considerable electronic interest. The presence of multiple functional groups and stereochemical elements makes cicutoxin a subject of continued research in organic chemistry and natural product synthesis.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The molecular structure of cicutoxin features an extended 17-carbon chain with precise stereochemical and geometric characteristics. The systematic IUPAC name (8''E'',10''E'',12''E'',14''R'')-heptadeca-8,10,12-triene-4,6-diyne-1,14-diol denotes the specific configuration of three trans double bonds at positions 8-9, 10-11, and 12-13, and a single chiral center at carbon 14 with R configuration. The carbon chain exhibits sp hybridization at positions 4,5,6, and 7 corresponding to the diyne system, while the triene system (positions 8-13) demonstrates sp² hybridization with bond angles approaching 180 degrees. The terminal carbon atoms at positions 1 and 14 show sp³ hybridization with characteristic tetrahedral geometry.

Molecular orbital analysis reveals an extensive conjugated π-system spanning carbon atoms 4 through 13, creating a delocalized electron system that significantly influences the compound's electronic properties. The HOMO-LUMO gap measures approximately 4.2 eV based on computational studies, indicating moderate electronic excitation requirements. The chiral center at C14 creates molecular asymmetry, with the naturally occurring enantiomer exhibiting specific optical rotation [α]_D²⁰ = -15.6° (c = 1.0 in ethanol).

Chemical Bonding and Intermolecular Forces

Cicutoxin exhibits predominantly covalent bonding throughout its molecular framework with bond lengths demonstrating characteristic values for the various hybridization states. The carbon-carbon triple bonds measure 1.20 Å, typical of alkynyl systems, while the double bonds in the triene system measure 1.34 Å. The single bonds adjacent to the conjugated system show slight shortening due to conjugation effects, with C7-C8 and C13-C14 bonds measuring 1.43 Å and 1.45 Å respectively.

Intermolecular forces are dominated by van der Waals interactions due to the largely hydrocarbon nature of the molecule. The hydroxyl groups provide limited capacity for hydrogen bonding, with the primary alcohol at C1 exhibiting stronger hydrogen bonding capability than the secondary alcohol at C14. The calculated dipole moment measures 2.8 Debye, oriented along the long molecular axis. The extensive conjugated system creates significant London dispersion forces, contributing to the compound's physical properties in condensed phases.

Physical Properties

Phase Behavior and Thermodynamic Properties

Cicutoxin exhibits distinct phase behavior dependent on its isomeric form. The naturally occurring (R)-enantiomer melts at 54 °C, while the racemic mixture demonstrates a higher melting point of 67 °C, indicative of racemic compound formation rather than a conglomerate system. The compound boils at 467.2 °C under atmospheric pressure, though thermal decomposition typically occurs before reaching this temperature. The density measures 1.025 g/mL at 20 °C for the pure compound.

Thermodynamic parameters include an enthalpy of fusion of 28.5 kJ/mol for the enantiopure material and 31.2 kJ/mol for the racemate. The heat of vaporization is estimated at 85.3 kJ/mol based on group contribution methods. The compound demonstrates limited thermal stability, with decomposition onset observed at approximately 120 °C under inert atmosphere. Solubility parameters indicate high solubility in polar organic solvents including ethanol (325 g/L), methanol (280 g/L), and acetone (410 g/L), but limited aqueous solubility of only 1.2 g/L at 25 °C.

Spectroscopic Characteristics

Infrared spectroscopy reveals characteristic vibrations including O-H stretch at 3350 cm^-1, ≡C-H stretch at 3310 cm^-1, C≡C stretch at 2250-2100 cm^-1, and C=C stretch at 1650-1600 cm^-1. The conjugated system produces distinctive pattern in the 1000-650 cm^-1 region corresponding to C-H bending vibrations.

Nuclear magnetic resonance spectroscopy shows distinctive signals: ¹H NMR (CDCl₃) displays the C14 methine proton at δ 4.25 ppm (multiplet, J = 6.2 Hz), terminal methyl protons at δ 0.92 ppm (triplet, J = 7.1 Hz), and olefinic protons between δ 5.70-6.40 ppm. ¹³C NMR reveals acetylenic carbon signals between δ 70-85 ppm and olefinic carbon signals between δ 120-140 ppm. UV-Vis spectroscopy shows strong absorption maxima at 235 nm (ε = 18,500 M^-1cm^-1) and 280 nm (ε = 12,300 M^-1cm^-1) corresponding to π→π* transitions of the conjugated system.

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

Cicutoxin demonstrates significant reactivity attributable to its extended conjugated system and multiple functional groups. The compound undergoes rapid oxidation upon exposure to atmospheric oxygen, particularly at the allylic and propargylic positions. Autoxidation proceeds with an initial rate constant of 0.15 h^-1 at 25 °C in solution phase. The hydroxyl groups undergo typical alcohol reactions including esterification with acetic anhydride (k = 2.3 × 10^-3 M^-1s^-1) and ether formation under Williamson conditions.

The conjugated enyne system participates in Diels-Alder reactions with dienophiles such as maleic anhydride, with second-order rate constants of approximately 0.08 M^-1s^-1 in benzene at 50 °C. Hydrogenation over palladium catalyst proceeds quantitatively to yield the fully saturated heptadecane-1,14-diol. Photochemical reactivity includes [2+2] cycloaddition reactions with activated alkenes upon irradiation at 350 nm.

Acid-Base and Redox Properties

The hydroxyl groups of cicutoxin exhibit typical alcohol acidity with estimated pK_a values of approximately 15-16 for the primary alcohol and 16-17 for the secondary alcohol. The compound shows no significant basic character. Redox properties include susceptibility to oxidation by common oxidizing agents including chromium(VI) reagents and manganese dioxide. The oxidation potential measured by cyclic voltammetry shows an irreversible oxidation wave at +0.85 V versus SCE in acetonitrile.

Electrochemical reduction occurs at -1.2 V versus SCE, corresponding to reduction of the conjugated system. The compound demonstrates stability in neutral aqueous solutions but undergoes hydrolysis under strongly acidic or basic conditions at elevated temperatures, with half-lives of 45 minutes in 1M HCl at 60 °C and 30 minutes in 1M NaOH at 60 °C.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

The first total synthesis of racemic cicutoxin was accomplished in 1955 through a multi-step sequence with overall yield of 4%. Modern synthetic approaches utilize palladium-catalyzed coupling reactions for efficient construction of the carbon framework. The enantioselective synthesis of natural (R)-cicutoxin was reported in 1999 employing a convergent strategy with four linear steps from three key fragments: (R)-1-hexyn-3-ol, 1,4-diiodo-1,3-butadiene, and THP-protected 4,6-heptadiyn-1-ol.

The synthetic sequence begins with Sonogashira coupling between (R)-1-hexyn-3-ol and 1,4-diiodo-1,3-butadiene, yielding the dienynol intermediate in 63% yield. Subsequent palladium-catalyzed coupling with the THP-protected diynol fragment constructs the complete 17-carbon skeleton in 74% yield. Selective reduction of the C5 triple bond using sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al), followed by tetrahydropyranyl group removal, affords (R)-cicutoxin with overall yield of 18%. The synthetic material exhibits identical spectroscopic properties to natural cicutoxin.

Analytical Methods and Characterization

Identification and Quantification

Analytical identification of cicutoxin primarily employs chromatographic and spectroscopic techniques. Gas chromatography-mass spectrometry shows characteristic molecular ion at m/z 258 and fragment ions at m/z 240 [M-H₂O]⁺, m/z 221 [M-H₂O-CH₃]⁺, and m/z 91 [C₇H₇]⁺. High-performance liquid chromatography with UV detection at 280 nm provides quantitative analysis with detection limit of 0.1 μg/mL and linear range of 0.5-100 μg/mL.

Thin-layer chromatography on silica gel with ethyl acetate:hexane (3:7) mobile phase gives R_f value of 0.45, visualized with vanillin-sulfuric acid reagent. Nuclear magnetic resonance spectroscopy provides definitive structural confirmation through characteristic coupling patterns and chemical shifts. Chiral HPLC methods employing amylose-based stationary phases resolve enantiomers with resolution factor of 2.3.

Purity Assessment and Quality Control

Purity assessment typically combines chromatographic and spectroscopic methods. Capillary gas chromatography with flame ionization detection achieves baseline separation from common impurities including isocicutoxin and oenanthotoxin. Quantitative ¹H NMR using internal standards provides absolute purity determination with uncertainty of ±1.5%. Water content by Karl Fischer titration should not exceed 0.5% for analytical standards.

Stability-indicating methods include accelerated degradation studies at 40 °C and 75% relative humidity, with monitoring of decomposition products by LC-MS. The compound requires storage under inert atmosphere at -20 °C to prevent oxidation and polymerization. Recommended handling procedures include use of amber glassware and oxygen-free solvents for quantitative work.

Applications and Uses

Research Applications and Emerging Uses

Cicutoxin serves as a valuable reference compound in natural product chemistry and toxicology research. The compound's extended conjugated system makes it of interest in materials science research concerning molecular electronics and nonlinear optical materials. Studies have investigated its potential as a building block for conjugated polymers with unique electronic properties.

The structural complexity and stereochemical features of cicutoxin make it a challenging target for synthetic organic chemistry, serving as a testbed for developing new methodologies in alkyne chemistry and cross-coupling reactions. Research continues into structure-activity relationships among C₁₇-polyacetylenes to understand how structural variations affect chemical and biological properties.

Historical Development and Discovery

The history of cicutoxin begins with early observations of poisoning by plants of the genus Cicuta, documented systematically by Johann Jakob Wepfer in 1679. The name cicutoxin was coined by Boehm in 1876 during investigations of Cicuta virosa. Initial isolation of the pure compound was achieved by Jacobsen in 1915, who obtained it as a yellowish oil. Structural elucidation proved challenging due to the compound's instability and complexity, with the correct molecular structure finally established in 1953 through degradative studies and synthetic work.

The first total synthesis of racemic cicutoxin in 1955 represented a significant achievement in natural product synthesis, accomplished without modern coupling methodologies. Determination of the absolute configuration awaited developments in stereochemical analysis, finally established in 1999 as (14R) through synthesis of both enantiomers and comparison with natural material. Throughout its history, cicutoxin has remained a compound of interest due to its structural features and biological significance.

Conclusion

Cicutoxin represents a chemically significant natural product with unique structural characteristics including an extended conjugated system comprising both polyyne and polyene functionalities. The compound exhibits distinctive physical and chemical properties derived from its molecular structure, particularly its sensitivity to oxygen, light, and heat. Synthetic methodologies have advanced from the initial low-yielding racemic synthesis to efficient enantioselective routes employing modern coupling strategies. Analytical methods provide comprehensive characterization and quantification, though special handling requirements remain necessary due to the compound's instability. Continued research interest focuses on the compound's potential applications in materials science and as a scaffold for further chemical exploration.