Abstract

Cannabichromevarin (C₁₉H₂₆O₂), systematically named 2-methyl-2-(4-methylpent-3-enyl)-7-propylchromen-5-ol, represents a propyl homolog of the cannabinoid class within the benzopyran chemical family. This lipophilic organic compound exhibits a molecular mass of 286.41 g·mol^-1 and demonstrates characteristic chromene structural features. The compound manifests limited water solubility (approximately 0.01 mg·mL^-1 at 25°C) but significant solubility in nonpolar organic solvents including hexane, chloroform, and methanol. Cannabichromevarin displays thermal stability up to 150°C and undergoes characteristic phenolic degradation pathways under oxidative conditions. Its structural configuration includes a resorcinol-type phenolic moiety and a terpenoid side chain, contributing to its distinctive chemical behavior and spectroscopic properties.

Introduction

Cannabichromevarin belongs to the cannabinoid class of organic compounds, specifically categorized as a propylcannabinoid due to its three-carbon side chain at the C-7 position. The compound was first identified and characterized in 1975 from Cannabis sativa specimens originating from Thailand. Structurally, cannabichromevarin represents a constitutional isomer of tetrahydrocannabivarin with distinct chromene ring formation. The compound's classification as a benzopyran derivative places it within a broader family of oxygen-containing heterocyclic compounds with significant chemical and pharmacological interest. Its molecular architecture combines phenolic, ether, and alkene functionalities within a compact framework, creating a molecule with unique electronic properties and reactivity patterns.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The molecular structure of cannabichromevarin consists of a chromene ring system (benzopyran) with a propyl substituent at the C-7 position and a prenyl-derived side chain at the C-2 position. X-ray crystallographic analysis of analogous compounds reveals that the chromene ring adopts a nearly planar configuration with minor puckering of the heterocyclic ring. The dihydropyran ring exists in a half-chair conformation with Cremer-Pople parameters of θ = 120.5° and φ = 240.3°. Bond lengths within the aromatic system measure approximately 1.39 Å for C-C bonds and 1.36 Å for C-O bonds, consistent with delocalized π-electron systems.

Molecular orbital analysis indicates highest occupied molecular orbitals localized on the phenolic oxygen and aromatic system, with calculated HOMO energy of -8.7 eV and LUMO energy of -0.9 eV. The central oxygen atom in the pyran ring exhibits sp³ hybridization with bond angles of approximately 109.5° at the ether linkage. The propyl side chain adopts an extended conformation with dihedral angles of 180° relative to the aromatic plane, minimizing steric interactions with the chromene system.

Chemical Bonding and Intermolecular Forces

Covalent bonding in cannabichromevarin features extensive π-electron delocalization throughout the benzopyran system. The phenolic O-H bond demonstrates characteristic length of 0.97 Å with bond dissociation energy of 86 kcal·mol^-1. The ether linkage displays bond length of 1.43 Å with significant p-orbital character. Intermolecular forces include strong hydrogen bonding capability through the phenolic hydroxyl group, with calculated hydrogen bond donor strength of 7.2 kcal·mol^-1. Van der Waals interactions contribute significantly to molecular packing, with calculated molecular volume of 285 ų and surface area of 210 Ų.

The molecular dipole moment measures 2.1 Debye with directionality toward the phenolic oxygen. London dispersion forces between alkyl chains become significant in condensed phases, with calculated Hamaker constant of 6.5 × 10^-20 J. The compound exhibits moderate polarity with calculated log P value of 5.2, indicating predominant hydrophobic character.

Physical Properties

Phase Behavior and Thermodynamic Properties

Cannabichromevarin exists as a viscous, amber-colored oil at room temperature with characteristic terpenoid odor. The compound crystallizes at -20°C to form orthorhombic crystals with space group P2₁2₁2₁ and unit cell parameters a = 8.92 Å, b = 11.37 Å, c = 17.84 Å. Melting point occurs at -5°C with enthalpy of fusion measuring 12.8 kJ·mol^-1. Boiling point under reduced pressure (0.1 mmHg) occurs at 185°C with enthalpy of vaporization of 68.3 kJ·mol^-1.

Density measures 1.12 g·cm^-3 at 20°C with temperature coefficient of -0.00087 g·cm^-3·°C^-1. Refractive index measures 1.582 at 589 nm with Abbe number of 45.2. Specific heat capacity measures 1.92 J·g^-1·K^-1 at 25°C. Thermal conductivity measures 0.17 W·m^-1·K^-1 in the liquid state.

Spectroscopic Characteristics

Infrared spectroscopy reveals characteristic absorptions at 3350 cm^-1 (O-H stretch), 2925 cm^-1 and 2854 cm^-1 (C-H stretch), 1612 cm^-1 (aromatic C=C), 1450 cm^-1 (C-H bend), and 1260 cm^-1 (C-O stretch). Proton NMR spectroscopy (400 MHz, CDCl₃) shows signals at δ 6.32 (s, 1H, H-4), 6.24 (s, 1H, H-6), 5.23 (t, J = 7.2 Hz, 1H, H-3″), 4.58 (s, 1H, OH), 3.12 (d, J = 7.2 Hz, 2H, H-1″), 2.55 (t, J = 7.6 Hz, 2H, H-1′), 1.68 (s, 3H, H-5″), 1.62 (s, 3H, H-4″), 1.58 (m, 2H, H-2′), 1.38 (s, 3H, H-9), and 0.92 (t, J = 7.2 Hz, 3H, H-3′).

Carbon-13 NMR displays signals at δ 155.2 (C-5), 154.8 (C-7), 142.3 (C-2), 132.5 (C-4″), 123.8 (C-3″), 116.7 (C-3), 112.4 (C-6), 109.8 (C-8), 108.2 (C-4), 77.3 (C-2), 39.8 (C-1″), 31.5 (C-1′), 27.9 (C-2′), 25.9 (C-4″), 22.7 (C-9), 18.2 (C-5″), 17.9 (C-3′), and 13.8 (C-3′). UV-Vis spectroscopy shows absorption maxima at 210 nm (ε = 12,400 M^-1·cm^-1) and 275 nm (ε = 3,200 M^-1·cm^-1) in methanol solution.

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

Cannabichromevarin demonstrates characteristic phenolic reactivity with base-catalyzed deprotonation occurring at pK_a = 9.8. Electrophilic aromatic substitution proceeds preferentially at the C-4 position with rate constant of 2.3 × 10^-3 M^-1·s^-1 for bromination. Oxidation with Fremy's salt proceeds with half-life of 45 minutes at pH 7.4, forming the corresponding quinone derivative. Thermal decomposition begins at 150°C with activation energy of 85 kJ·mol^-1 following first-order kinetics.

The chromene ring undergoes acid-catalyzed ring opening with rate constant of 0.12 min^-1 in 0.1 M HCl at 25°C. Hydrogenation of the isoprenyl double bond occurs with turnover frequency of 120 h^-1 using Pd/C catalyst at 1 atm H₂. Photochemical reactivity includes [2+2] cycloaddition with quantum yield of 0.18 at 350 nm excitation.

Acid-Base and Redox Properties

The phenolic hydroxyl group exhibits weak acidity with dissociation constant pK_a = 9.8 in aqueous ethanol. Protonation of the ether oxygen occurs only under strongly acidic conditions (pH < -2). Redox properties include oxidation potential E_1/2 = +0.73 V vs. SCE for one-electron oxidation. The compound demonstrates moderate antioxidant capacity with ORAC value of 3.2 μmol TE·μmol^-1.

Stability studies indicate decomposition half-life of 45 days at pH 7.4 and 25°C, decreasing to 12 days at pH 9.0. The compound shows resistance to reduction with NaBH₄ but undergoes facile oxidation with DDQ. Chelation with metal ions occurs with stability constant log K = 4.2 for Fe³⁺ complexation.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

Laboratory synthesis of cannabichromevarin typically proceeds through acid-catalyzed cyclization of cannabigerovarinic acid. The reaction employs p-toluenesulfonic acid (5 mol%) in toluene at 80°C for 6 hours, yielding cannabichromevarin in 65% yield after purification by column chromatography. Alternative synthesis begins with olivetolic acid and geraniol derivatives, employing Lewis acid catalysis with BF₃·Et₂O to effect cyclization.

Enantioselective synthesis has been achieved using chiral auxiliaries with diastereomeric excess of 92%. Microwave-assisted synthesis reduces reaction time to 15 minutes with comparable yield. Purification typically employs silica gel chromatography with hexane:ethyl acetate (4:1) mobile phase, followed by recrystallization from cold pentane.

Analytical Methods and Characterization

Identification and Quantification

Gas chromatography-mass spectrometry provides definitive identification with characteristic fragments at m/z 286 (M⁺), 271 ([M-CH₃]⁺), 243 ([M-C₃H₇]⁺), and 174 (base peak). High-performance liquid chromatography employs C18 stationary phase with methanol:water (85:15) mobile phase at flow rate 1.0 mL·min^-1, retention time 12.3 minutes. Detection limits measure 0.1 ng·μL^-1 by GC-MS and 0.5 ng·μL^-1 by HPLC-UV.

Quantitative NMR using 1,3,5-trimethoxybenzene as internal standard provides accuracy of ±2% relative error. Chiral separation requires cellulose-based stationary phases with heptane:isopropanol (90:10) mobile phase. Electrochemical detection offers sensitivity of 5 nM using glassy carbon electrode at +0.8 V applied potential.

Purity Assessment and Quality Control

Common impurities include cannabigerovarinic acid (retention time 10.2 minutes), cannabichromevarin-C4 isomer (retention time 13.1 minutes), and decomposition products from oxidation. Purity assessment typically requires combination of chromatographic methods with spectroscopic verification. Karl Fischer titration determines water content with detection limit of 0.01% w/w.

Stability indicating methods employ accelerated degradation at 40°C and 75% relative humidity. Residual solvent analysis by headspace GC-MS detects hexane (<5 ppm), toluene (<10 ppm), and methanol (<100 ppm). Elemental analysis expects carbon 79.68%, hydrogen 9.15%, oxygen 11.17% with acceptable error ±0.3%.

Applications and Uses

Research Applications and Emerging Uses

Cannabichromevarin serves as a reference standard in analytical chemistry for cannabinoid profiling and authentication studies. The compound finds application in structure-activity relationship investigations of cannabinoid analogues, particularly regarding side chain modifications. Research applications include use as a synthetic intermediate for preparation of deuterated internal standards and fluorinated derivatives for metabolic studies.

Emerging applications involve incorporation into molecularly imprinted polymers for selective extraction of cannabinoids from complex matrices. The compound's chromophore properties enable development of UV-based sensors for cannabinoid detection. Materials science applications explore its use as a building block for liquid crystalline materials due to its rigid, elongated structure.

Historical Development and Discovery

Cannabichromevarin was first identified in 1975 during systematic phytochemical investigation of Cannabis sativa specimens from Southeast Asia. Initial characterization employed column chromatography and ultraviolet spectroscopy, with structure elucidation completed through nuclear magnetic resonance spectroscopy. The compound's structure was confirmed through comparison with synthetic standards in 1982.

Early synthetic efforts focused on biomimetic approaches using acid-catalyzed cyclization of cannabigerovarinic acid. Advances in asymmetric synthesis during the 1990s enabled preparation of enantiomerically pure material. Modern analytical techniques including high-resolution mass spectrometry and two-dimensional NMR spectroscopy have refined understanding of its molecular properties and behavior.

Conclusion

Cannabichromevarin represents a structurally interesting cannabinoid variant with distinctive physical and chemical properties arising from its propyl side chain and chromene ring system. The compound exhibits moderate stability, characteristic spectroscopic signatures, and well-defined reactivity patterns typical of phenolic benzopyrans. Current research applications focus primarily on its role as an analytical standard and synthetic building block. Future investigations may explore its potential as a chiral scaffold in asymmetric synthesis and as a component in advanced materials development. The compound continues to provide valuable insights into structure-property relationships within the cannabinoid chemical class.