1. Introduction to LEVOMENOL
Levomenol, also known as α-(-)-Bisabolol, is a naturally occurring monocyclic sesquiterpene alcohol that has gained substantial industrial significance in recent decades. With the CAS number 23089-26-1, this chiral compound is the optically active enantiomer of α-bisabolol, found predominantly in the essential oil of Matricaria chamomilla (German chamomile) and in several species of Vanillosmopsis and Eremanthus (particularly Eremanthus erythropappus, known as “Candeia” tree, native to Brazil).
Chemically, levomenol is valued for its pleasant floral aroma, biocompatibility, and biological activity, including anti-inflammatory, antimicrobial, antioxidant, and wound-healing properties. As a result, it has found wide-ranging applications in cosmetics, pharmaceuticals, personal care products, and functional materials.
From a chemical engineering perspective, α-(-)-Bisabolol represents an interesting case study of how natural product extraction, chiral separation, and biotechnological synthesis can intersect in modern industrial chemistry. The evolution of production technologies for levomenol exemplifies the global shift toward green chemistry and sustainable manufacturing.
2. Chemical Structure and Physicochemical Properties
2.1 Molecular Structure
- IUPAC name: (–)-(6-Methyl-2-(4-methyl-3-cyclohexen-1-yl)-5-hepten-2-ol)
- Molecular formula: C₁₅H₂₆O
- Molecular weight: 222.37 g/mol
- CAS number: 23089-26-1
- Structural class: Monocyclic sesquiterpene alcohol
- Chirality: The molecule is optically active with a single chiral center at the C-α carbon; levomenol is the levorotatory enantiomer (negative rotation).
2.2 Physical Properties
| Property | Value / Description |
| Appearance | Colorless to pale yellow viscous liquid |
| Odor | Sweet, floral, chamomile-like |
| Boiling point | 153–155 °C at 2.0 mmHg |
| Flash point | 105 °C |
| Density | 0.924–0.931 g/cm³ (at 25 °C) |
| Refractive index | nᴅ²⁵ ≈ 1.492–1.498 |
| Solubility | Insoluble in water; miscible with alcohols, oils, and organic solvents |
| Optical rotation | [α]ᴅ²⁰ = –68° to –70° (in ethanol) |
2.3 Chemical Behavior
Levomenol is relatively stable under mild conditions but sensitive to strong oxidation and acidic environments. The tertiary alcohol function makes it susceptible to dehydration under acidic catalysis, forming α-bisabolene and related terpenic hydrocarbons. Thermal degradation can occur at elevated temperatures, leading to rearrangement and loss of optical purity.
Owing to its hydrophobic nature, levomenol readily dissolves in lipidic and organic matrices, making it suitable for incorporation into cosmetic emulsions and oleogels. It is resistant to hydrolysis and compatible with surfactants and emulsifiers used in formulation chemistry.
3. Natural Occurrence and Sources
Levomenol occurs naturally in several plants, most notably:
- Matricaria chamomilla (German chamomile): Essential oil contains up to 50% α-bisabolol.
- Eremanthus erythropappus (Candeia tree): Wood oil contains up to 90% α-(-)-bisabolol (main industrial source today).
- Vanillosmopsis erythropappa and V. arborea: Secondary natural sources in South America.
Historically, chamomile oil extraction was the main route of obtaining bisabolol, but due to low yields (0.3–1% essential oil content in flowers) and sustainability concerns related to large-scale chamomile cultivation, modern production has shifted toward Candeia tree extraction and biotechnological synthesis.
4. Production Technologies
4.1 Overview
From an industrial chemical engineering perspective, the production of levomenol can be achieved through three main routes:
- Natural extraction from plant materials (Candeia or chamomile).
- Semisynthetic and total chemical synthesis, using terpenoid precursors.
- Biotechnological (fermentative or enzymatic) synthesis using engineered microbes.
Each route involves different trade-offs in cost, purity, sustainability, and scalability.
4.2 Extraction from Plant Material
4.2.1 Candeia Wood Extraction
The most common commercial process involves extraction of essential oil from the heartwood of Eremanthus erythropappus (Candeia), endemic to southeastern Brazil. The wood typically contains 5–10% essential oil, with 80–95% α-(-)-bisabolol.
Process steps:
- Raw Material Preparation:
The Candeia wood is chipped and air-dried to a moisture content below 10%. - Steam Distillation:
The dried wood chips undergo steam distillation at temperatures of 100–110 °C under atmospheric pressure.- Steam flow: 0.3–0.5 kg steam per kg wood.
- Distillation time: 4–6 hours.
The condensate separates into two layers: an aqueous phase and an oil phase.
- Oil Recovery:
The essential oil (crude Candeia oil) is separated and dried with anhydrous sodium sulfate. - Purification:
Fractional vacuum distillation is employed to obtain high-purity α-(-)-bisabolol (>95% purity).
Key parameters:- Pressure: 1–3 mmHg
- Temperature: 140–160 °C
- Distillation yield: 80–90%
- Quality Control:
Optical rotation, GC-MS, and IR spectroscopy are used to confirm enantiomeric purity and absence of degradation products.
Environmental Considerations:
Candeia harvesting is subject to environmental regulation to prevent deforestation. Sustainable sourcing programs, reforestation initiatives, and certification (e.g., FSC) are widely implemented.
4.2.2 Chamomile Oil Extraction
Extraction from chamomile flowers is performed via hydrodistillation or solvent extraction.
- Hydrodistillation yields an essential oil rich in α-bisabolol and bisabolol oxides.
- Solvent extraction using ethanol or supercritical CO₂ can increase recovery efficiency.
However, due to lower α-bisabolol concentration in chamomile oil and higher cost of cultivation, this route is mainly reserved for small-scale and high-end cosmetic applications.
4.3 Supercritical CO₂ Extraction
Supercritical CO₂ (scCO₂) extraction has become an environmentally preferred technique for isolating levomenol. The advantages include:
- No thermal degradation due to low temperature (35–50 °C)
- No solvent residues
- High selectivity and product purity
Typical process conditions:
- Pressure: 100–250 bar
- Temperature: 35–45 °C
- CO₂ flow: 0.1–0.3 kg CO₂/kg feed
- Extraction time: 2–4 h
Fractionation of the extract allows isolation of the bisabolol-rich fraction (>90%). The process can be integrated with in-line fractionation columns for continuous operation.
From a chemical engineering perspective, CO₂ extraction provides a clean, modular, and scalable technology that aligns with green chemistry principles.
4.4 Chemical Synthesis
4.4.1 Classical Synthetic Routes
Chemically, bisabolol can be synthesized from farnesol or nerolidol, both of which are commercially available sesquiterpene alcohols derived from isoprene units.
The process involves:
- Cyclization of farnesol or nerolidol under acidic catalysis to form bisabolene intermediates.
- Hydration or hydroboration-oxidation to introduce the hydroxyl group at the tertiary position.
However, chemical synthesis tends to produce racemic α-bisabolol (±), requiring optical resolution for obtaining the levorotatory isomer. Optical resolution is typically done using:
- Enzymatic ester hydrolysis (lipase-catalyzed kinetic resolution)
- Chiral chromatography
- Crystallization with chiral acids
Due to the complexity and cost, purely chemical synthesis is rarely used commercially but remains valuable for research and analytical standards.
4.5 Biotechnological Production
Recent advances in metabolic engineering and synthetic biology have enabled the microbial biosynthesis of α-(-)-bisabolol from renewable substrates such as glucose or glycerol.
4.5.1 Biosynthetic Pathway
The biosynthetic pathway of levomenol proceeds from farnesyl diphosphate (FPP), a key intermediate in the mevalonate (MVA) or methylerythritol phosphate (MEP) pathway.
Reaction:
FPP → α-bisabolol + diphosphate
Catalyzed by α-bisabolol synthase (BBS), an enzyme encoded by Eremanthus erythropappus or Matricaria chamomilla.
4.5.2 Engineered Microbial Systems
Typical host organisms:
- Escherichia coli
- Saccharomyces cerevisiae
- Corynebacterium glutamicum
By integrating:
- Heterologous α-bisabolol synthase gene (BBS)
- Optimized MVA pathway enzymes
- Cofactor regeneration systems
Engineers have achieved yields exceeding 2–5 g/L in fed-batch fermentation systems.
4.5.3 Downstream Processing
After fermentation:
- The bisabolol is extracted from the culture broth using organic solvents (e.g., hexane or isopropyl myristate).
- Liquid-liquid extraction and vacuum distillation purify the product.
- Optical purity is ensured via enzyme selectivity, eliminating the need for further chiral separation.
Advantages:
- Renewable feedstocks
- Lower carbon footprint
- No dependence on plant sources
- High optical and chemical purity
This biotechnological route is now being commercialized by several global fragrance and cosmetic ingredient companies, marking a paradigm shift in terpenoid production.
5. Chemical Stability and Formulation Aspects
Levomenol is relatively stable but may undergo oxidative degradation upon prolonged exposure to air, light, or elevated temperature. To prevent oxidation, antioxidants such as tocopherol or BHT are often added during formulation.
In emulsions, levomenol tends to partition into the oil phase; proper emulsifier selection (e.g., nonionic surfactants) ensures homogeneous dispersion. Its lipophilic nature enhances dermal penetration, which is advantageous for topical pharmaceutical formulations.
In chemical compatibility studies, levomenol shows excellent stability with fatty acids, esters, glycerides, and silicones, making it an ideal ingredient for cosmetic and dermatological formulations.
6. Industrial and Commercial Applications
6.1 Cosmetics and Personal Care
The largest market for levomenol is in cosmetics, accounting for more than 80% of global demand.
Functional Roles:
- Soothing and anti-inflammatory agent: Reduces skin irritation caused by surfactants, UV exposure, or shaving.
- Moisturizing enhancer: Improves lipid layer formation and reduces transepidermal water loss (TEWL).
- Fragrance ingredient: Adds a soft, floral aroma with woody undertones.
- Skin-conditioning agent: Enhances smoothness and elasticity of skin.
Applications:
- Face creams and lotions
- After-shave products
- Baby care formulations
- Lip care and deodorants
- Sun care and after-sun lotions
The recommended concentration in formulations ranges from 0.1–1.0%, depending on product type and regulatory considerations.
6.2 Pharmaceutical and Therapeutic Uses
Levomenol exhibits a broad range of pharmacological activities, including:
- Anti-inflammatory:
Inhibits cyclooxygenase (COX) and lipoxygenase (LOX) pathways, reducing prostaglandin and leukotriene formation. - Antimicrobial:
Demonstrates bactericidal and fungicidal activity against Staphylococcus aureus, Candida albicans, and Pseudomonas aeruginosa. - Wound healing and tissue regeneration:
Stimulates fibroblast proliferation and collagen synthesis, accelerating epithelial repair. - Gastroprotective effects:
Reduces gastric mucosal damage and enhances mucin secretion in animal studies. - Analgesic and antispasmodic effects:
Modulates calcium channels and inflammatory mediators, providing local pain relief.
Formulations:
- Topical gels and ointments
- Mouthwash and oral gels
- Ophthalmic and nasal solutions (in low concentrations)
Its excellent biocompatibility and low irritancy profile make it an ideal bioactive compound for dermal and mucosal applications.
6.3 Fragrance and Flavor Industry
Due to its delicate floral scent, levomenol is employed as a fragrance modifier in perfumes, soaps, and detergents. It imparts warm, sweet, and slightly balsamic notes, enhancing the longevity and harmony of fragrance blends.
In the flavor industry, although less common, it is occasionally used as a flavor enhancer in herbal teas, alcoholic beverages, and confectioneries, owing to its chamomile-like aroma.
6.4 Emerging Technical Applications
Beyond cosmetics and pharmaceuticals, levomenol has been explored in functional materials and biopolymer systems:
- Antioxidant additive in biodegradable polymers (e.g., PLA, PHB).
- Active agent in antimicrobial coatings and wound dressings.
- Carrier molecule for drug delivery systems, due to its lipophilicity and dermal permeation enhancement.
These applications highlight levomenol’s potential as a multifunctional bio-based chemical in emerging green technologies.
7. Safety, Toxicology, and Regulatory Status
Levomenol is considered non-toxic, non-sensitizing, and non-irritant at standard cosmetic and pharmaceutical concentrations.
- LD₅₀ (oral, rat): >15,000 mg/kg
- Dermal irritation (human): None observed at 1% concentration
- Mutagenicity: Negative in Ames test
- Phototoxicity: Not phototoxic
It is listed in major regulatory frameworks:
- INCI Name: Bisabolol
- EINECS No.: 245-872-3
- EU Cosmetic Regulation (EC) No. 1223/2009: Approved for unrestricted use
- US FDA: Generally Recognized as Safe (GRAS) for topical application
Sustainability and ethical sourcing (e.g., from certified Candeia plantations or microbial fermentation) are increasingly required by major cosmetic brands.
8. Economic and Market Considerations
Global demand for α-(-)-bisabolol has grown steadily due to its use in high-end personal care products. Market estimates suggest:
- Global market size (2025): >$70 million
- Major producers: Brazil, Germany, China, and the USA
- Price range: $300–800 per kg (depending on purity and source)
With the rise of biotechnological routes, prices are expected to stabilize, and the dependence on natural Candeia wood will decrease, reducing deforestation pressures.
9. Future Perspectives and Research Directions
9.1 Process Intensification
Efforts are ongoing to enhance the yield and efficiency of levomenol production using continuous extraction, membrane-assisted distillation, and reactive separation. Integration of in situ product removal (ISPR) in fermentation systems could significantly improve productivity.
9.2 Synthetic Biology Advancements
Metabolic pathway optimization in engineered microbes offers the potential to produce not only levomenol but also structural analogs with tailored biological activity. Synthetic biology platforms may soon achieve >10 g/L titers, making biotechnological bisabolol fully competitive with plant extraction.
9.3 New Derivatives and Formulations
Chemical modification of the bisabolol backbone—such as esterification, etherification, or oxidation—can yield derivatives with enhanced stability or solubility, expanding applications in pharmaceuticals and nanocosmetics.
9.4 Sustainability and Circular Chemistry
In line with green chemistry principles, industries are adopting zero-waste valorization of Candeia biomass and utilizing renewable carbon sources (sugarcane, lignocellulosic feedstocks) for fermentation processes. Life-cycle assessments (LCA) show up to 70% reduction in CO₂ footprint compared to traditional extraction.
10. Conclusion
Levomenol (α-(-)-Bisabolol, CAS 23089-26-1) stands as a prime example of a natural compound whose chemical elegance, biological functionality, and industrial relevance converge in modern chemical engineering. From its origins in chamomile and Candeia wood to its emerging biotechnological synthesis in microbial systems, levomenol embodies the transformation of natural product chemistry into a sustainable, scalable, and high-value industrial discipline. Its unique combination of chemical stability, biocompatibility, and multifunctionality ensures continued demand across the cosmetics, pharmaceutical, and fragrance sectors. With ongoing innovations in process engineering, biocatalysis, and sustainable sourcing, α-(-)-bisabolol will likely remain an essential benchmark compound in the evolution of bio-based fine chemicals.