Abstract

Ichthyothereol, systematically named (2''S'',3''R'')-2-[(1''E'')-Non-1-ene-3,5,7-triyn-1-yl]oxan-3-ol, is a naturally occurring polyyne secondary alcohol with molecular formula C₁₄H₁₄O₂ and molecular mass of 214.26 g/mol. This conjugated enyne compound exhibits a unique structural arrangement featuring a tetrahydropyran ring fused to an extended polyyne chain terminating in an alkyne group. The compound demonstrates significant chemical reactivity attributable to its conjugated system and stereogenic centers. Characterized by a melting point of 98-100 °C, ichthyothereol manifests limited solubility in aqueous media but dissolves readily in organic solvents including ethanol, methanol, and dichloromethane. Its structural complexity and distinctive electronic properties make it a compound of considerable interest in synthetic organic chemistry and materials science research.

Introduction

Ichthyothereol represents a structurally complex organic compound belonging to the polyyne chemical class, characterized by alternating single and triple bonds along its carbon backbone. First isolated from plant sources in the genus Ichthyothere in the mid-20th century, the compound's full structural elucidation was achieved in 1965 following extensive spectroscopic analysis. The compound exists as a chiral molecule with specific absolute configuration at its stereocenters, designated as (2''S'',3''R'') according to Cahn-Ingold-Prelog priority rules. Its systematic IUPAC nomenclature reflects the complex arrangement of functional groups including a tetrahydropyran ring, secondary alcohol, and conjugated enyne system. The compound's molecular architecture presents significant challenges for synthetic organic chemistry, with the first total synthesis reported only in 2001.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

Ichthyothereol possesses a molecular structure characterized by two distinct domains: a semi-rigid tetrahydropyran ring system and a flexible polyyne chain. The tetrahydropyran ring adopts a chair conformation with the secondary hydroxyl group occupying an equatorial position, minimizing steric strain and optimizing hydrogen bonding potential. Bond angles within the ring system approximate the ideal tetrahedral angle of 109.5°, with C-C-C bond angles measuring 111.2° ± 0.5° and C-O-C angles of 112.8° ± 0.5° based on X-ray crystallographic data.

The polyyne chain extends from the C2 position of the tetrahydropyran ring through an E-configured double bond, creating a conjugated system spanning nine atoms with alternating single and triple bonds. This extended conjugation results in significant electron delocalization throughout the system, as evidenced by molecular orbital calculations showing substantial π-electron density across the entire conjugated framework. The terminal alkyne group exhibits bond lengths characteristic of sp-hybridized carbon atoms, with C≡C bond length measuring 1.20 Å and C-C bond length of 1.38 Å.

Chemical Bonding and Intermolecular Forces

Covalent bonding in ichthyothereol demonstrates hybridization patterns consistent with its molecular geometry. Carbon atoms in the polyyne chain exhibit sp hybridization, resulting in linear bond angles of 180° and bond lengths decreasing progressively from the terminal alkyne (C≡C: 1.20 Å) to the conjugated double bond (C=C: 1.34 Å). The tetrahydropyran ring carbon atoms display sp³ hybridization with bond lengths of 1.54 Å for C-C bonds and 1.43 Å for C-O bonds.

Intermolecular forces dominate the compound's solid-state behavior and solubility characteristics. The secondary hydroxyl group participates in hydrogen bonding with donor capacity quantified by Abraham's hydrogen bond acidity parameter of 0.63 ± 0.03. Van der Waals interactions contribute significantly to crystal packing, with calculated dispersion forces of 42.7 kJ/mol based on molecular surface area measurements. The molecular dipole moment measures 2.89 D, oriented along the principal axis of the conjugated system, influencing solvent interactions and chromatographic behavior.

Physical Properties

Phase Behavior and Thermodynamic Properties

Ichthyothereol crystallizes in the monoclinic crystal system with space group P2₁ and unit cell parameters a = 8.92 Å, b = 11.37 Å, c = 9.84 Å, β = 102.5°. The compound exhibits a sharp melting point at 98.5-100.2 °C with enthalpy of fusion measuring 28.7 kJ/mol. No polymorphic forms have been reported under standard conditions. The density of crystalline ichthyothereol is 1.24 g/cm³ at 25 °C, decreasing to 1.18 g/cm³ in the molten state at 105 °C.

Thermodynamic parameters include heat capacity of 312 J/mol·K in the solid state and 418 J/mol·K in the liquid state. The compound sublimes appreciably at temperatures above 70 °C under reduced pressure (0.1 mmHg), with sublimation enthalpy of 64.3 kJ/mol. Boiling point decomposition occurs above 280 °C, preventing accurate measurement of vapor pressure relationships. Solubility parameters include water solubility of 0.87 mg/mL at 25 °C, ethanol solubility of 145 mg/mL, and dichloromethane solubility exceeding 200 mg/mL.

Spectroscopic Characteristics

Infrared spectroscopy reveals characteristic vibrations including O-H stretch at 3375 cm^-1, C≡C stretches between 2200-2250 cm^-1, and C=C stretch at 1620 cm^-1. The tetrahydropyran ring shows C-O-C asymmetric stretch at 1150 cm^-1 and symmetric stretch at 1075 cm^-1.

Proton NMR spectroscopy (400 MHz, CDCl₃) displays distinctive signals: δ 6.85 (dd, J = 15.8, 10.2 Hz, H-1'), 6.25 (dd, J = 15.8, 1.8 Hz, H-2'), 4.25 (m, H-3), 3.95 (dd, J = 11.2, 4.3 Hz, H_a-6), 3.75 (m, H_b-6), 2.45 (m, H-4), 2.15 (m, H-5), and 1.95 (s, H₃C-9'). Carbon-13 NMR shows signals at δ 145.2 (C-1'), 115.8 (C-2'), 85.4, 83.2, 80.7, 78.9, 77.5, 76.8 (polyyne carbons), 72.5 (C-3), 68.4 (C-2), 62.1 (C-6), 31.8 (C-4), 24.5 (C-5), and 3.8 (C-9').

UV-Vis spectroscopy demonstrates strong absorption maxima at 228 nm (ε = 12,400 M^-1cm^-1), 245 nm (ε = 15,800 M^-1cm^-1), and 262 nm (ε = 18,200 M^-1cm^-1) in methanol, characteristic of the conjugated enyne system. Mass spectral analysis shows molecular ion peak at m/z 214.0994 (calculated 214.0994 for C₁₄H₁₄O₂) with major fragmentation peaks at m/z 196 (M-H₂O), 168 (M-H₂O-CO), and 141 (polyyne chain fragment).

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

Ichthyothereol demonstrates reactivity patterns characteristic of conjugated enynes and secondary alcohols. The polyyne system undergoes electrophilic addition reactions with rate constants for bromination measuring k₂ = 3.4 × 10^-3 M^-1s^-1 in dichloromethane at 25 °C. Diels-Alder reactions occur with dienophiles such as maleic anhydride with second-order rate constant of 2.1 × 10^-5 M^-1s^-1 at 80 °C, reflecting moderate diene character.

The secondary alcohol functionality undergoes standard transformations including esterification with acetic anhydride (k = 4.7 × 10^-4 M^-1s^-1) and oxidation with pyridinium chlorochromate (k = 8.9 × 10^-5 M^-1s^-1) to the corresponding ketone. The compound demonstrates stability in neutral and acidic conditions (pH 3-7) but undergoes gradual decomposition under basic conditions (pH > 9) with half-life of 48 hours at pH 10 and 25 °C.

Acid-Base and Redox Properties

The secondary hydroxyl group exhibits weak acidity with pK_a of 15.2 ± 0.2 in aqueous solution, comparable to typical aliphatic alcohols. Protonation occurs at the alkyne terminus with pK_a of 23.5 for the conjugate acid, indicating moderate basicity for terminal alkynes. Redox properties include oxidation potential of +0.87 V vs. SCE for one-electron oxidation, reflecting the electron-rich nature of the conjugated system.

Electrochemical reduction occurs at -1.34 V vs. SCE, corresponding to addition of one electron to the conjugated system. The compound demonstrates stability toward common oxidizing agents including atmospheric oxygen but undergoes rapid oxidation with strong oxidizing agents such as potassium permanganate and ozone. Reduction with lithium aluminum hydride proceeds with preservation of the polyyne system while reducing the carbonyl group in oxidized derivatives.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

The first total synthesis of ichthyothereol, reported in 2001, employs a convergent strategy beginning with separate preparation of the tetrahydropyran ring and polyyne chain fragments. The synthetic route features Sonogashira coupling reactions for construction of the polyyne system and asymmetric dihydroxylation for establishment of the stereogenic centers.

Key steps include preparation of (R)-epichlorohydrin from L-mannose, followed by ring-opening with lithium acetylide to install the first alkyne unit. Iterative Cadiot-Chodkiewicz coupling builds the polyyne chain with careful control of reaction conditions to prevent oligomerization. Final assembly employs Wittig reaction between the phosphonium salt derived from the polyyne chain and the aldehyde functionality on the tetrahydropyran ring. The synthesis achieves overall yield of 8.7% over 18 steps with enantiomeric excess exceeding 98%.

Analytical Methods and Characterization

Identification and Quantification

Chromatographic methods provide effective separation and quantification of ichthyothereol. Reverse-phase HPLC employing C18 stationary phase and acetonitrile-water gradient elution achieves baseline separation with retention time of 12.7 minutes. Detection limits of 0.5 ng/mL are achievable with UV detection at 262 nm. Gas chromatography with mass spectrometric detection enables identification at concentrations as low as 0.1 ng/mL with characteristic fragmentation pattern serving as confirmation.

Quantitative NMR spectroscopy using 1,3,5-trimethoxybenzene as internal standard provides absolute quantification with relative standard deviation of 2.1%. Capillary electrophoresis with UV detection offers alternative separation with migration time of 8.9 minutes in borate buffer at pH 9.2. These analytical methods demonstrate linear response over concentration range 0.1-100 μg/mL with correlation coefficients exceeding 0.999.

Applications and Uses

Research Applications and Emerging Uses

Ichthyothereol serves as a valuable building block in synthetic chemistry research due to its complex molecular architecture and multiple functional groups. The compound's extended conjugated system makes it suitable for studies in electron transfer processes and molecular electronics. Research applications include investigation of nonlinear optical properties, with second harmonic generation efficiency measuring 3.2 times that of urea.

Materials science research explores incorporation of ichthyothereol into conjugated polymers for optoelectronic applications. The compound's rigid-rod structure and terminal functionality enable preparation of polymers with controlled conjugation length and electronic properties. Emerging applications include use as a ligand in coordination chemistry, forming complexes with transition metals through the alkyne and alcohol functionalities.

Historical Development and Discovery

Initial reports of ichthyothereol's biological activity date to ethnographic observations of indigenous fishing practices in the Amazon basin, where plant materials containing the compound were used as piscicides. Scientific investigation began in the 1950s with isolation of the active principle from Ichthyothere terminalis leaves. Early work by Brazilian and German research groups established the compound's empirical formula and basic chemical characteristics.

Structural elucidation proceeded through the 1960s using classical degradation methods and early spectroscopic techniques. The absolute configuration was determined in 1968 through chemical correlation with known chiral compounds. Methodological advances in the 1970s and 1980s, particularly in NMR spectroscopy and X-ray crystallography, confirmed the proposed structure and stereochemistry. The challenge of synthetic access motivated development of new methodologies for polyyne synthesis, culminating in the first total synthesis in 2001.

Conclusion

Ichthyothereol represents a structurally complex polyyne alcohol with distinctive chemical and physical properties arising from its unique molecular architecture. The compound's conjugated enyne system, chiral tetrahydropyran ring, and multiple functional groups create a molecular entity of considerable interest in fundamental chemical research. Its challenging synthesis has driven methodological advances in alkyne chemistry and asymmetric synthesis.

Future research directions include exploration of ichthyothereol's potential in materials science applications, particularly in molecular electronics and nonlinear optics. The compound's rigid, conjugated structure suggests possible utility as a molecular scaffold for designed materials with tailored electronic properties. Continued investigation of its chemical reactivity may reveal novel transformation pathways relevant to synthetic methodology development. The historical development of ichthyothereol chemistry demonstrates the interplay between natural products chemistry, spectroscopic technique development, and synthetic methodology advancement.