Humulene
Humulene, also known as α-humulene or α-caryophyllene, is a naturally occurring monocyclic sesquiterpene with the molecular formula C₁₅H₂₄ and a molecular weight of 204.35 g/mol.[1][2] It consists of three isoprene units forming an 11-membered ring with three nonconjugated carbon-carbon double bonds, two of which are triply substituted and one doubly substituted.[2] This terpene is widely distributed in the essential oils of various plants, including Humulus lupulus (hops, where it can comprise up to 40% of the oil), Cannabis indica, pine trees, sage, ginseng, and citrus sources such as orange orchards.[2][3] In hops, humulene plays a key role in contributing to the earthy, woody aroma of beer and other brewed beverages.[2] Beyond its sensory properties, humulene is biosynthesized from farnesyl diphosphate in plants and has been isolated through methods like steam distillation, with yields varying significantly across species from negligible to over 60%.[3] Humulene demonstrates diverse pharmacological activities, including anti-inflammatory, analgesic, antimicrobial, antioxidant, and anticancer effects, partly through interactions with cannabinoid and adenosine receptors as well as modulation of pathways like NF-κB.[3][4] These properties position it as a promising natural compound for therapeutic applications, such as treating inflammatory disorders, bacterial infections, and certain cancers, though challenges like low bioavailability and variable natural yields limit its clinical translation.[3][5] Additionally, it serves as a precursor for synthetic anticancer agents and exhibits repellent and larvicidal activity against mosquitoes, supporting its potential in vector control.[5]Chemical Properties
Molecular Structure and Isomers
Humulene, also known as α-humulene, has the molecular formula C₁₅H₂₄ and a molecular weight of 204.35 g/mol.[1][6] It is classified as a monocyclic sesquiterpene, consisting of three isoprene units arranged in a single 11-membered carbon ring featuring three nonconjugated double bonds.[7] The systematic IUPAC name for humulene is (1E,4E,8E)-2,6,6,9-tetramethylcycloundeca-1,4,8-triene, which highlights its cyclic structure with methyl substituents at positions 2, 6 (geminal dimethyl), and 9.[1][8] Humulene is structurally related to other sesquiterpenes but distinguished by its monocyclic architecture, in contrast to bicyclic forms like β-caryophyllene, which shares the same molecular formula (C₁₅H₂₄) but incorporates a fused ring system with a cyclobutane and nine-membered ring.[3] This isomerism arises from differences in carbon skeleton closure, with humulene representing a ring-opened variant of the caryophyllene framework.[9] The compound was first isolated from the essential oils of Humulus lupulus (hops), from which it derives its name, underscoring its historical significance in plant-derived terpenoids.[10] The stereochemistry of humulene is characterized by all-E (trans) configurations at its three double bonds (positions 1, 4, and 8), contributing to its rigid yet flexible molecular geometry.[1] Conformational analysis reveals that the 11-membered ring adopts multiple stable conformers due to low ring strain, with empirical force field calculations identifying key low-energy structures that influence its reactivity in biosynthetic and chemical transformations.[11] These conformational features, including chiral enantiomeric forms in certain derivatives, distinguish humulene from more constrained sesquiterpenes and enable its diverse biological roles.[12]Physical and Chemical Characteristics
Humulene, also known as α-humulene or α-caryophyllene, is a colorless to pale yellowish liquid at room temperature with a melting point below 25 °C.[13] Its density is approximately 0.889 g/mL at 20 °C, and it has a boiling point of 166–168 °C at atmospheric pressure or 99–100 °C at reduced pressure (3 mm Hg).[13][14] The compound exhibits optical activity, with reported specific rotations ranging from -30° to +30° depending on the source and purity.[15] Humulene is insoluble in water but readily soluble in organic solvents such as ethanol, chloroform, and ether, reflecting its nonpolar sesquiterpene nature.[16] The aroma profile of humulene is characterized by earthy, woody, and spicy notes, often described as contributing to the "hoppy" scent in hops and cannabis.[14][17] This sensory quality arises from its volatile structure and makes it valuable in flavor and fragrance applications. Chemically, humulene demonstrates stability under neutral conditions but is susceptible to oxidation, particularly in the presence of air or ozone, leading to the formation of humulene epoxide I and II as primary products.[18] Its UV absorption spectrum features a peak around 190 nm, attributable to the π→π* transitions of its conjugated double bonds.[19] Key spectroscopic data aid in its identification: the electron impact mass spectrum shows a molecular ion at m/z 204 and a base peak at m/z 93, with additional fragments at m/z 133 and 119 characteristic of the humulene ring system.[20] The IR spectrum includes prominent absorptions for aliphatic C-H stretches (2950–2850 cm⁻¹) and C=C stretches (1640–1660 cm⁻¹).[21] In ¹H NMR (CDCl₃), diagnostic signals appear for vinyl protons at δ 5.0–6.0 ppm (multiplets) and methylene protons at δ 1.5–2.5 ppm, confirming the three double bonds and cyclic structure.[22]| Property | Value | Source |
|---|---|---|
| Appearance | Pale yellowish green liquid | [14] |
| Density | 0.889 g/mL at 20 °C | [13] |
| Boiling Point | 166–168 °C (atmospheric); 99–100 °C (3 mm Hg) | [13][14] |
| Solubility | Insoluble in water; soluble in ethanol and organic solvents | [16] |
| Optical Rotation | -30° to +30° | [15] |