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Citronellol

Citronellol is an acyclic monoterpenoid alcohol with the molecular formula C₁₀H₂₀O and the IUPAC name 3,7-dimethyloct-6-en-1-ol, existing as two enantiomers: (+)-citronellol and (–)-citronellol, which impart citrus and rose-like scents, respectively. It occurs naturally in essential oils from numerous aromatic plants, including roses (Rosa damascena, up to 35% in oil), geraniums (Pelargonium species), citronella grass (Cymbopogon nardus), and eucalyptus (Eucalyptus citriodora), often as a mixture of enantiomers or partial racemate. The compound is a pale yellow oily liquid with a density of 0.855 g/cm³ at 20°C, a boiling point of 224°C, and low water solubility (200 mg/L at 25°C), making it suitable for volatile applications. Citronellol's primary uses are in perfumery and , where it provides fresh, floral notes in fragrances, soaps, shampoos, and detergents; it is also employed as a agent in foods like , cherry, and products. In addition, it functions as an , particularly in formulations, and as a miticide in to attract pests for control. Emerging research highlights its biological activities, including anti-inflammatory, antinociceptive, and anticonvulsant effects, potentially via inhibition of and pro-inflammatory cytokines, though it can act as a skin sensitizer.

Properties

Chemical structure

Citronellol has the IUPAC name 3,7-dimethyloct-6-en-1-ol. Its molecular formula is C₁₀H₂₀O, and the molecular weight is 156.27 g/mol. This is an acyclic monoterpenoid consisting of an eight-carbon chain with a functional group (-CH₂OH) at position 1. A carbon-carbon is present between carbons 6 and 7, while methyl groups are attached to carbons 3 and 7, giving the structure HOCH₂CH₂CH(CH₃)CH₂CH₂CH=C(CH₃)CH₃. The of citronellol is represented below, showing the carbon chain with branches and the :
      CH₃
       |
HO-CH₂-CH₂-CH-CH₂-CH₂-CH=C-CH₃
            |
           CH₃
In line notation, citronellol is expressed using the SMILES string CC(CCC=C(C)C)CCO.

Physical properties

Citronellol is a colorless oily at . It has a of 224 °C at standard . The is below -20 °C, indicating it remains under typical ambient conditions. The density of citronellol is 0.855 /cm³ at 20 °C. It exhibits limited in water, approximately 200 mg/L at 25 °C, but is fully miscible with , , fixed oils, and . The (logP) is 3.91, reflecting its lipophilic nature primarily due to the extended nonpolar alkyl chain in its structure. Additional physical characteristics include a vapor pressure of 0.02 mm at 25 °C. The refractive index is 1.456 at 20 °C. Viscosity measures 11.1 ·s at 20 °C.
PropertyValueConditionsSource
Boiling point224 °C760 mm
Melting point< -20 °C-
Density0.855 g/cm³20 °C
Water solubility200 mg/L25 °C
LogP3.91-
Vapor pressure0.02 mm 25 °C
Refractive index1.45620 °CSigma-Aldrich
Viscosity11.1 ·s20 °C

Stereoisomers

Citronellol features a chiral center at the carbon atom in position 3 of its chain, giving rise to two enantiomers: (3R)-citronellol and (3S)-citronellol. These stereoisomers are non-superimposable mirror images, differing in their spatial arrangement around the chiral carbon, which influences their interactions with other chiral molecules. The (3R)-enantiomer, designated as (+)-citronellol, exhibits a specific optical rotation of [α]20D +5.3° (neat) and predominates in citronella oils extracted from Cymbopogon species, such as Cymbopogon nardus and Cymbopogon winterianus, where it can constitute up to 50% of the total citronellol content with notable enantiomeric excess favoring the (+) form. In contrast, the (3S)-enantiomer, known as (-)-citronellol, has a specific optical rotation of [α]20D -4.5° to -6.5° (neat) and is the primary form in rose (Rosa damascena) and geranium (Pelargonium graveolens) oils, often comprising 18–55% of the oil's composition. A of citronellol, consisting of equal proportions of both enantiomers, is optically inactive due to internal compensation of rotations and is commonly produced synthetically. Separation of these enantiomers can be achieved through methods like chiral or liquid using cyclodextrin-based stationary phases, enabling isolation for specific applications. In perfumery, the distinct enantiomers contribute subtle variations to floral and scent profiles.

Natural occurrence

In plants and essential oils

Citronellol occurs naturally in various plant families, with prominent sources in the Poaceae family, such as Cymbopogon nardus, where it contributes to the composition of citronella essential oil. In the Rosaceae family, it is found in Rosa damascena, forming a key component of rose essential oil, predominantly as the (-)-enantiomer. Similarly, the Geraniaceae family, particularly Pelargonium graveolens, yields geranium essential oil rich in citronellol, mainly the (-)-enantiomer. Additional sources include the family, exemplified by Eucalyptus citriodora, which produces eucalyptus containing citronellol, primarily the (+)-. In the family, officinale serves as a source, with citronellol present in ginger. Another species, mays, also harbors citronellol in its tissues. As a monoterpenoid , citronellol plays a role in the aromatic profiles of essential oils such as , , , and , enhancing their characteristic scents derived from . It has been detected in over 70 essential oils across diverse botanical origins. Beyond plants, citronellol is produced by certain microorganisms, such as the yeast Ambrosiozyma monospora, and via in .

Concentrations and sources

Citronellol is a major constituent in several oils derived from , with concentrations varying based on , methods, and environmental factors such as or growing conditions. In obtained from , the content of (+)-citronellol is typically 10-18%. Rose oil from typically contains 18-55% (-)-citronellol, contributing to its characteristic floral profile. In geranium oil extracted from , citronellol levels typically range from 20-40%. Eucalyptus oil from Eucalyptus citriodora includes approximately 4% citronellol. Beyond essential oils, higher concentrations are reported in other plant materials, such as 19,000 in leaves of Zea mays and 6,500 in the rhizome of officinale. Commercially, citronellol is primarily sourced from distilled essential oils like , , and , with global production from natural extraction estimated in the millions of kilograms annually, driven by demand in perfumery and related industries.

Biosynthesis

In plants

Citronellol, a monoterpenoid , is biosynthesized in primarily through the mevalonate (MVA) pathway in the cytosol or the 2-C-methyl-D-erythritol-4-phosphate () pathway in plastids, both of which converge to produce isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). These precursors are then condensed by geranyl diphosphate synthase (GPPS) to form (GPP), the universal C10 building block for monoterpenes such as citronellol. In many plant species, GPP undergoes hydrolysis to geraniol or isomerization to neryl pyrophosphate (NPP) followed by hydrolysis to nerol, catalyzed by terpene synthases, prenyl diphosphate isomerases, or Nudix hydrolases. These monoterpenols serve as immediate precursors and are oxidized to citral (a mixture of geranial and neral) by alcohol dehydrogenases (ADHs). Citral is then selectively reduced at the conjugated double bond to citronellal by specific reductases, followed by reduction of citronellal to citronellol via ADHs or related reductases, often in glandular trichomes where volatile terpenoids accumulate. The process typically involves stereospecific reductions, favoring the (R)- or (S)-enantiomer depending on the plant species. In species, such as rose-scented (), citronellol production follows a multi-step pathway initiated from GPP-derived , which is oxidized to (a mixture of geranial and neral) by geraniol dehydrogenases. is then reduced to by progesterone 5β-reductase and synthase-like enzymes (PRISE homologs, such as PhCIR1a/b and PhCIR2), which exhibit —PhCIR1a/b producing predominantly (S)- (92–97% enantiomeric excess), while PhCIR2 yields a . Finally, is reduced to citronellol by an , completing a net reductive transformation through three enzymatic steps localized in the of glandular trichomes. This pathway relies on a Nudix (PgNdx1) for dephosphorylation of geranyl monophosphate intermediates, bypassing traditional terpene synthase (TPS) activity. In roses (Rosa hybrida), belonging to the family, citronellol biosynthesis proceeds via a similar but independently evolved TPS-independent route starting from cytosolic GPP produced by G/FPPS1. Geraniol is sequentially oxidized to (geranial/neral) by geraniol dehydrogenase (RhGeDH1), reduced to by geranial reductase (RhGER2) or 12-oxophytodienoate reductase (RhOPR1), and further reduced to citronellol by citronellal reductase (RhCAR2) or RhGeDH1, all occurring in glandular trichomes. Unlike plastid-localized TPS pathways in other plants (e.g., geraniol synthase in ), roses utilize a cytosolic NUDX1-1a to generate from GPP. The citronellol biosynthetic pathways in (Geraniaceae) and roses (Rosaceae) exemplify independent evolution across angiosperm families, with convergent multi-step reductions from via intermediates despite distinct enzymatic recruitments—PRISE-like in and dehydrogenase/reductase combinations in roses—highlighting adaptive diversification of scent production.

In microorganisms

Citronellol production in microorganisms has been achieved through of biosynthetic pathways, often paralleling reduction steps observed in plant metabolism but adapted for microbial hosts. In , citronellol serves as a native formed via the of by the endogenous NADPH-dependent Oye2p during , acting as a cellular defense against toxicity. This native capability has been enhanced through overexpression of geraniol synthases and reductases, typically sourced from plants, to enable from central carbon precursors like glucose. For instance, truncated geraniol synthase (tCrGES) and citronellal reductase (CrIS) from have been expressed to convert geranyl diphosphate (GPP) to geraniol and subsequently to citronellol. Recent advances in S. cerevisiae engineering, including "push-pull-restrain" strategies, have significantly boosted yields by optimizing precursor supply (push), product formation (pull), and limiting competing pathways (restrain). These approaches involve upregulating enzymes (e.g., ERG10, ERG13) for GPP production, enhancing NADPH availability via genes (e.g., TAL1, TKL1), and integrating peroxisome-targeted plant-derived enzymes like tCrGES and CrIS. In fed-batch fermentation, such engineered strains have achieved titers exceeding 10 g/L, representing the highest reported for monoterpenes in yeast and demonstrating scalability. In , citronellol biosynthesis relies on bienzymatic cascades starting from exogenous , leveraging the host's endogenous geraniol dehydrogenase (GLDA, NAD+-dependent) to form , followed by reduction to citronellol using NADPH-dependent reductases such as AHR (endogenous) or plant-sourced CrIS from . These NAD(P)H-dependent dehydrogenases and reductases enable efficient, stereoselective conversion, with in vivo titers reaching 714 mg/L in optimized strains. Microbial production of citronellol offers a sustainable alternative to plant extraction, providing a carbon-neutral with reduced environmental impact compared to , as it operates under mild conditions without harsh or high inputs.

Chemical synthesis

From natural precursors

Citronellol is commonly produced through the reduction of , a monoterpenoid derived from natural sources such as essential oils of citriodora or species. This can be achieved using (NaBH₄) in a mild, selective that converts the group to the primary while preserving the molecule's if starting from enantiopure . Alternatively, catalytic with (Pd/C) under mild conditions provides an efficient route, often yielding high selectivity for the product. Another key method involves the selective of or —allylic alcohols obtained from natural oils like or —to racemic citronellol by reducing the allylic double bond. This is typically performed using a catalyst at temperatures of 100-150 °C, achieving substantial yields such as 82% with barium-promoted variants. For direct isolation, under reduced pressure is applied to or oils, separating citronellol fractions based on boiling points and enriching purity from complex mixtures. Enantioselective synthesis from these precursors employs with chiral ligands, such as cationic complexes bearing ligands, enabling production of (R)- or (S)-citronellol with enantiomeric excesses up to 84%.

Industrial methods

Citronellol is produced on an industrial scale, driven by demand in the fragrance and industries. The majority of commercial production relies on synthetic methods, with partial of and serving as the primary route. These unsaturated alcohols, often derived from distillates, are selectively hydrogenated to saturate the allylic while preserving the terminal , yielding racemic citronellol. The conventional process employs heterogeneous catalysts such as or Raney cobalt, which enable high selectivity under moderate conditions. For instance, using Raney cobalt, the proceeds at temperatures of 100–150 °C and pressures of 7–35 atm (100–500 psig), with catalyst loadings of 2–20% by weight relative to the substrate. Conversion rates exceed 95%, with selectivity to citronellol typically above 90%, though minor over-reduction to 3,7-dimethyloctanol (1–5%) can occur. Purification is achieved via , isolating citronellol at >95% purity suitable for commercial use. Challenges include maintaining selectivity to minimize unwanted saturation, often monitored by changes during the . For enantiopure citronellol, with or complexes and chiral ligands, such as cationic with diphosphines or ruthenium-BINAP systems, is employed. These enable of or , achieving enantiomeric excesses up to 95% under higher pressures (30–100 atm) and temperatures of 50–100 °C. Such methods are optimized for optical purity in high-value applications, with conversions >95%, though they represent a smaller fraction of total production due to cost. Recent sustainability efforts post-2023 have integrated biotechnological approaches, leveraging engineered microorganisms like for greener production via metabolic pathways from . These microbial systems aim to reduce reliance on precursors and metal catalysts, with lab-scale titers reaching 10 g/L, signaling potential industrial scale-up for eco-friendly citronellol.

Applications

In perfumery and flavors

Citronellol exhibits a sweet, rosy-citrus profile, characterized by fresh floral and green nuances. The (S)- contributes prominent rose-like notes with waxy, undertones, while the (R)- delivers a lighter, citronella-inspired freshness reminiscent of oily, leafy petals. In perfumery, citronellol functions as a foundational material in constructing , , and accords, where it provides depth and natural floral authenticity to synthetic blends. Its esters, particularly citronellyl acetate, are valued for imparting fruity-rosy facets with improved , extending the longevity of scents in formulations ranging from fine fragrances to household products. Since the early 20th century, following its synthesis, citronellol has been incorporated into soaps and candles to evoke clean, blooming floral impressions, with annual global volume of use surpassing 1,000 metric tons (as of 2019) in IFRA-compliant perfume mixtures. For flavor applications, citronellol imparts citrusy, fruity, and subtle rose-like tastes, enhancing profiles in beverages, candies, and desserts such as grapefruit, apple, and peach varieties. Its designation as (GRAS) by the FDA permits direct use as a synthetic substance in products at low concentrations. Additionally, citronellol acts as a precursor to , a metallic-green rose note, via selective photooxidation processes that generate key intermediates.

Pharmaceutical and other uses

Citronellol exhibits and properties, making it a candidate for pharmaceutical applications. Studies have demonstrated its ability to reduce in models by modulating pro-inflammatory cytokines and pathways. Additionally, citronellol displays antinociceptive effects, alleviating in experimental settings through mechanisms involving and adrenergic receptors. Its activity targets bacterial and fungal pathogens, potentially enhancing immune function in patients undergoing or radiotherapy by reducing leukocyte and depletion. In plant models, citronellol acts as a histone deacetylase (HDAC) inhibitor, specifically targeting AtSRT1 in to elevate histone H3K9 levels, which upregulates (IAA) biosynthesis and signaling genes, promoting root and shoot growth. As an , citronellol contributes to the efficacy of formulations by disrupting mosquito olfaction, particularly against , through interference with odorant receptors. It also serves as a miticide in products, where it repels and controls populations in agricultural and ornamental settings, as in products like BIOMITE™. In , citronellol is incorporated into shampoos, lotions, and aftershave products for its benefits and odor-masking capabilities, helping to preserve formulations and provide a subtle rose-like scent. Similarly, in cleaning products, it functions as a fragrance component to neutralize odors while offering mild preservative effects. Emerging biotechnological applications leverage citronellol in chiral as a key intermediate and auxiliary for producing enantiopure terpenoids, such as through engineered microbial cascades that enhance yields via optimization. Recent highlights its role in plant growth promotion, where HDAC inhibition by citronellol increases histone acetylation to boost IAA content and , suggesting potential as a natural agricultural regulator. In blends, citronellol provides protective effects against microbial contamination and oxidative degradation.

Safety and regulation

Toxicity profile

Citronellol demonstrates low acute toxicity via oral and dermal routes. The median lethal dose (LD50) for oral administration in rats is 3.45 g/kg, while the dermal LD50 in rabbits is 2.65 g/kg. It acts as a moderate irritant to both skin and eyes. In rabbit studies, undiluted citronellol induced moderate skin irritation under occluded conditions over 24 hours and moderate to severe eye irritation. Contact dermatitis can occur in sensitive individuals following dermal exposure. As a dermal , citronellol is associated with skin , eliciting positive reactions in individuals allergic to related compounds like . It contributes to , particularly in fragrance-exposed populations where fragrance allergies affect approximately 1-2% of individuals. Chronic exposure may pose risks as a potential , based on assessments of its bioactivity. In occupational settings, of vapors can lead to respiratory irritation or , though specific data are limited. Citronellol undergoes rapid in mammals, primarily through to citronellic acid and subsequent β-oxidation to dicarboxylic acids like 2,6-dimethyl-6-octendioic acid, which are excreted in . Its value of approximately 3.4 indicates moderate , resulting in low potential. Citronellol holds (GRAS) status for food flavoring use by the FDA, with caveats for potential sensitization in .

Regulatory status

In the United States, the (FDA) has classified citronellol as (GRAS) for use as a synthetic substance and in under 21 CFR 172.515, permitting its application at low levels typically below 0.1% to achieve the intended flavor effect. The International Fragrance Association (IFRA) imposes restrictions on citronellol in fragrance formulations due to its potential as a skin sensitizer, with maximum acceptable concentrations in leave-on products varying by category—for instance, 2.6% in body lotions (Category 5A), 0.39% in face moisturizers (Category 5B), 0.55% in hand creams (Category 5C), and 0.13% in baby products (Category 5D); these standards were last updated in the 51st Amendment notified on June 30, 2023. The U.S. Environmental Protection Agency (EPA) has approved citronellol as an in biochemical pesticides, including as a miticide for attracting and disrupting populations in agricultural and ornamental settings, and established a tolerance exemption for its residues in all food commodities since 2004. Under the European Union's REACH regulation, citronellol is registered (EC number 203-375-0) and classified as a skin sensitizer (Skin Sens. 1, H317: May cause an allergic skin reaction), requiring appropriate labeling and risk management measures for industrial and consumer uses. Globally, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) evaluates citronellol as a agent with an (ADI) of 0–0.5 mg/kg body weight in a group including related terpenoids; additionally, post-2023, biotechnologically produced variants fall under regulations in regions like the , necessitating pre-market authorization if not historically consumed.

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