Linalool

Spices

Linalool is a kind of terpene alcohols and is one kind of famous perfume compounds. It is the mixture of two isomers (α-linalool and β-linalool). It is extracted from camphor oil (from camphor tree) or synthesized from the α-pinene or β-pinene contained in turpentine. It is colorless oily liquid with sweet and tender fresh flowers and a fragrance of Convallaria majalis. It is easily soluble in organic solvents such as ethanol, ethylene glycol and diethyl ether but insoluble in water and glycerol. It is easily subject to isomerization and is relatively stable in alkali. It has a density (25 ℃) of 0.860~0.867, the refractive index (20 ℃) of ​​1.4610~1.4640, optical rotation (20 ℃) of ​​-12 ° ~-18 °, the boiling point being 197~199 ℃, and the flash point (open ended) of 78 ℃. Linalool with alcohol content higher than 95% is an important spices for floral fragrance used for perfumes, soaps and other fragrance industry. It is also widely used in flowers oils of lending lily, lilac, sweet pea, and orange blossom as well as the compound perfume of amber incense, oriental fragrance, and aldehyde-type fragrance, cosmetics perfumes and food flavor. It can also be used as the spices of lemon, lime, orange, grape, apricot, pineapple, plum, peach, cardamom, cocoa, and chocolate. Drug containing 92.5% alcohol content is used as the raw material drugs in the pharmaceutical industry for producing isophytol which is an important intermediate in the preparation of vitamin E. It can also be used as raw material for producing valuable spices linalyl acetate and some other esters. Linalool belongs to open chain terpene tertiary alcohol. It has two double bonds. However, it contains an asymmetric carbon atom, so it has three kinds of optical isomers. In Nature, all three kinds of isomers are present with the amount of I-body being the highest, accounting for 70% to 80% of the total amount of the three. I-body is mostly presented in linalool oil (containing about 80 to 90%), champa, lavender oil, lime oil, neroli oil, clary sage oil, aloeswood oil, lemon oil, rose oil, cananga orodrata oil and some other kinds of essential oil; its d-body is mostly presented in coriander oil (containing about 60% to 70%), sweet orange oil, nutmeg oil, palmarosa oil and other kinds of essential oil; its dl-form is mainly presented in the essential oils of clary sage and jasmine. All the three kinds are transparent colorless oily liquid with lilies and citrus-like fragrance. In addition, because of the close distance between its hydroxy group and allyl group, its chemical nature is very influential. In the presence of sodium metal in ethanol solution, it can be easily be reduced to generate dihydro-myrcene; in the presence of a platinum catalyst or Raney nickel catalyst, it can be reduced to the tetrahydro linalool to become saturated alcohol. Owing that it is a kind of tertiary alcohol, in strongly acidic medium, it can subject to isomerization; in dilute acid medium, it undergoes dehydration to become esters. It is stable in alkaline medium. The LD50 of oral administration for Rat is 2790 mg /kg.

Lavender

Linalool is the major antimicrobial ingredient of lavender essential oils. It can inhibit the growth of 17 bacteria (including Gram-positive and Gram-negative bacteria) and 10 fungi. In vitro experiments show that the narrow-leaf lavender essential oils, at concentrations below 1%, can inhibit the newly penicillin I resistant Staphylococcus aureus and Enterococcus faecalis.

Content Analysis

Take 10 mL of sodium sulfate pre-dried sample and put it into a 125 mL of glass-stoppered Erlenmeyer flask pre-cooled by an ice bath. Add 20 mL of dimethylaniline (toluidine product) in cold oil and mix thoroughly. Add 8 mL of acetyl chloride and 5 mL of acetic anhydride, cool for several minutes, then place at room temperature for 30min, then immerse the flask in a water bath and maintained for 16h at 40 °C ± 1 °C; Apply ice-water for washing acetyl oil for three times with 75 mL each time. Then repeatedly wash with 25 mL of 5% sulfuric acid solution until the separated acid layer no longer exhibiting cloudy-like or doesn’t have further dimethylaniline odor coming out so that dimethylaniline was further removed. First apply 10 mL of 10% sodium carbonate solution for washing acetylated oil, followed by successive washing with water until washing to being neutral to litmus. After complete drying with anhydrous sodium sulfate, accurately weigh the acetylation oil of about 1.2g, and then measure it according to the "ester assay" (OT-18). Linalool (C10H18O) content (L) is calculated as follows;
L = 7.707 (b-s) /W=0.021 (b-s)
Where L--linalool content, %;
b-the consumed volume of 0.5 mol/L of hydrochloric acid in blank test, Mi;
s--the consumed volume of 0.5 mol/L of hydrochloric acid for titration of the sample solution, ml;
IV-sample sample, g.
Method II, measure the amount using non-polar column protocol based on the Gas Chromatography Method (GT-10-4).
The above information is edited by the chemicalbook of Dai Xiongfeng.

Toxicity

Adl 0~0.5 mg/kg (FAO/WHO.1994).
GRAS (FDA, §182.60, 2000).
LD50 2790 (rat, oral administration).

Limited use

FEMA (mg/kg): Soft drinks 2.0; cold drink 3.6; candy 8.4; Bakery 9.6; pudding Class 2.3; gum 0.80 to 90; meat 40.

Chemical Properties

It is colorless liquid with fragrance similar with bergamot. It is insoluble in water, but miscible with ethanol and ether.

Uses

1. It is used for the preparation of cosmetics, soaps, detergents, food and other flavors.
2. GB 276011996 states it is classified into food flavor allowed for temporary use. It is mainly used for the preparation of flavors or aromatic seasoning of pineapple, peach, and chocolate.
3. It is widely presented in flowers, fruits, stems, leaves, roots and green Rosa Chinensis viridiflora. It has a wide range of application, not only for all the floral flavors, such as sweet bean curd, jasmine, Convallaria majalis, lilac, etc., it can also be applied in fruit flavor type, Fen-flavor type, wood flavor type, aldehyde flavor type, oriental flavor type, amber scent type, chypre type, fern-type and other non-flower type of flavor. It can also be used in formulating orange leaf, bergamot, lavender, and some kinds of artificial oils such as hybrid lavender oil. It is mostly used in soap or flavor. It can be used for food flavor.
4. Linalool is a kind of important spices and is the blending raw materials for producing various kinds of artificial oil, also used extensively for the manufacturing of various esters of linalool. Linalool has an important position in the ester-type perfumes and other cosmetic formulations. Linalool can generate citral through oxidation and can also be used for the synthesis of many other kinds of spices.

Production method

1. The commercial linalool is mainly isolated from natural essential oils including aloeswood oil, rosewood oil, coriander oil, and linalyl oil. Using efficient distillation column for fractionation can produce crude product of linalool with secondary fractionation obtaining finished product with a content being higher than 90%. Synthetic linalool can use β-pinene as raw material with pyrolysis yielding myrcene. Treatment with hydrogen chloride generates a mixture comprising linalyl chloride. Linalyl chloride can have reaction with potassium hydroxide (or potassium carbonate) to generate linalool.
2. It is existed in free form in camphor oil: using acetyl boric anhydride converting the linalool contained in camphor oil into acidic borate ester, and then through distillation, re-crystallization, and saponification to obtain the finished product.
3. Use 6-methyl-5-hept-ene-2-ketone to have condensation reaction with sodium acetylide to obtain dehydrolinalool, further undergoing reduction reaction at wet ether solution with metal sodium to obtain the linalool.

Description

Linalool has a typical floral odor free from camphoraceous and terpenic notes.1 Synthetic linalool exhibits a cleaner and fresher note than the natural product. It can be prepared synthetically starting from myrcene or from dehydrolinalool.
The optically active forms (d- and ι-) and the optically inactive form occur naturally in more than 2 0 0 oils from herbs, leaves, flowers, and wood; the ι-form is present in the largest amounts (80 - 85%) in the distillates from leaves of Cinnamomum cam phora var. orientalis and Cinnamomum camphora var. occidentalis and in the distillate from Cajenne rosewood; it also has been reported in: champaca, ylang-ylang, neroli, Mexican linaloe, ber gamot, lavandin, and others; a mixture of d- and ι-linalool has been reported in Brazil rosewood (85%); the d-form has been found in palmarosa, mace, sweet orange-flower distillate, petit grain, coriander (60 - 70%), marjoram, Orthodon linalooliferum (80%), and others; the inactive form has been reported in clary sage, jasmine, and Nectandra elaiophora.

Chemical Properties

Linalool occurs as one of its enantiomers in many essential oils, where it is often the main component. (3R)- (?)-Linalool, for example, occurs at a concentration of 80–85% in Ho oils from Cinnamomum camphora; rosewood oil contains about 80%. (3S)-(+)- Linalool makes up 60–70% of coriander oil (“coriandrol”).
Linalool is used frequently in perfumery for fruity notes and for many floral fragrance compositions (lily of the valley, lavender, and neroli). Because of its relatively high volatility, it imparts naturalness to top notes. Since linalool is stable in alkali, it can be used in soaps and detergents. Linalyl esters can be prepared from linalool.Most of the manufactured linalool is used in the production of vitamin E.

Chemical Properties

liquid

Chemical Properties

Linalool has a typical pleasant floral odor, free from camphoraceous and terpenic notes. Synthetic linalool exhibits a cleaner and fresher note than the natural products.

Physical properties

Properties. Racemic linalool is, similarly to the individual enantiomers, a colorless liquid with a floral, fresh odor, reminiscent of lily of the valley. However, the enantiomers differ slightly in odor. Together with its esters, linalool is one of the most frequently used fragrance substances and is produced in large quantities. In the presence of acids, linalool isomerizes readily to geraniol, nerol, and α-terpineol. It is oxidized to citral, for example, by chromic acid. Oxidation with peracetic acid yields linalool oxides, which occur in small amounts in essential oils and are also used in perfumery. Hydrogenation of linalool gives tetrahydrolinalool, a stable fragrance material. Its odor is not as strong as, but is fresher than, that of linalool. Linalool can be converted into linalyl acetate by reaction with ketene or with an excess of boiling acetic anhydride.

Occurrence

The optically active forms (d- and l-) and the optically inactive form occur naturally in more than 200 oils from herbs, leaves, flowers and wood; the l-form is present in the largest amounts (80 to 85%) in the distillates from leaves of Cinnamomum camphora var. orientalis and Cinnamomum camphora var. occidentalis and in the distillate from Cajenne rosewood; it also has been reported in champaca, ylang-ylang, neroli, Mexican linaloe, bergamot and lavandin; a mixture of d- and l-linalool has been reported in Brazil rosewood (85%); the d-form has been found in palmarosa, mace, sweet orange-flower distillate, petitgrain, coriander (60 to 70%), marjoram and Orthodon linalooliferum (80%); the inactive form has been reported in clary sage, jasmine and Nectandra elaiophora. Also reported found in over 280 products including apple, citrus peel oils and juices, berries, grapes, guava, celery, peas, potato, tomato, cinnamon, cloves, cassia, cumin, ginger, mentha oils, mustard, nutmeg, pepper, thymus, cheeses, grape wines, butter, milk, rum, cider, tea, passion fruit, olive, mango, beans, coriander, cardamom and rice.

Uses

perfume use

Uses

linalool is a fragrant component of both lavender and coriander. It can be incorporated into cosmetics for perfuming, deodorant, or odor-masking activity.

Uses

Linalool is one of the allergens of Ylang-Ylang oil (extract from Cananga odorata).

Definition

ChEBI: A monoterpenoid that is octa-1,6-diene substituted by methyl groups at positions 3 and 7 and a hydroxy group at position 3. It has been isolated from plants like Ocimum canum.

Preparation

In the 1950s, nearly all linalool used in perfumery was isolated from essential oils, particularly from rosewood oil. Currently, this method no longer plays a commercial role.
Since linalool is an important intermediate in the manufacture of vitamin E, several large-scale processes have been developed for its production. Preferred starting materials and/or intermediates are the pinenes and 6-methyl-5-hepten- 2-one. Most perfumery-grade linalool is synthetic.
1) Isolation from essential oils: Linalool can be isolated by fractional distillation of essential oils, for example, rosewood oil and coriander oil, of which Brazilian rosewood oil was the most important.
2) Synthesis from α-pinene: α-Pinene from turpentine oil is selectively hydrogenated to cis-pinane, which is oxidized with oxygen in the presence of a radical initiator to give a mixture of about 75% cis-pinane and 25% transpinane hydroperoxide.The mixture is reduced to the corresponding pinanols either with sodium bisulfite (NaHSO3) or with a catalyst. The pinanols can be separated by fractional distillation and are pyrolyzed to linalool: (?)-α- pinene yields cis-pinanol and (+)-linalool, whereas (?)-linalool is obtained from trans-pinanol.
3) Synthesis from ??-pinene: For a description of this route, see under Geraniol. Addition of hydrogen chloride to myrcene (obtained from β-pinene) results in a mixture of geranyl, neryl, and linalyl chlorides. Reaction of this mixture with acetic acid–sodium acetate in the presence of copper(I) chloride gives linalyl acetate in 75–80% yield. Linalool is obtained after saponification.
4) Synthesis from 6-methyl-5-hepten-2-one:The total synthesis of linalool starts with 6-methyl-5-hepten-2-one; several large-scale processes have been developed for synthesizing this compound:
a. Addition of acetylene to acetone results in the formation of 2-methyl-3- butyn-2-ol, which is hydrogenated to 2-methyl-3-buten-2-ol in the presence of a palladium catalyst.This product is converted into its acetoacetate derivative with diketene or with ethyl acetoacetate. The acetoacetate undergoes rearrangement when heated (Carroll reaction) to give 6-methyl-5-hepten-2-one:
b. In another process, 6-methyl-5-hepten-2-one is obtained by reaction of 2-methyl-3-buten-2-ol with isopropenyl methyl ether followed by a Claisen rearrangement:
c. A third synthesis starts fromisoprene, which is converted into 3-methyl-2- butenyl chloride by addition of hydrogen chloride. Reaction of the chloride with acetone in the presence of a catalytic amount of an organic base leads to 6-methyl-5-hepten-2-one:
d. In another process, 6-methyl-5-hepten-2-one is obtained by isomerization of 6-methyl-6-hepten-2-one.The latter can be prepared in two steps from isobutylene and formaldehyde. 3-Methyl-3-buten-l-ol is formed in the first step and is converted into 6-methyl-6-hepten-2-one by reaction with acetone. 6-Methyl-5-hepten-2-one is converted into linalool in excellent yield by base-catalyzed ethynylation with acetylene to dehydrolinalool. This is followed by selective hydrogenation of the triple bond to a double bond in the presence of a palladium carbon catalyst.

Aroma threshold values

Detection: 4 to 10 ppb

Taste threshold values

Taste characteristics at 5 ppm: green, apple and pear with an oily, waxy, slightly citrus note.

Synthesis Reference(s)

Tetrahedron, 33, p. 579, 1977 DOI: 10.1016/S0040-4020(77)80019-7

General Description

Linalool is a monoterepene compound. It is the major component of many essential oils. Anti-inflammatory properties of (?) linalool, a naturally occurring enantiomer, has been studied. It is also the major constituent of the basil and thyme essential oil and its anti-microbial effect was determined using the agar well diffusion assay. Linalool is reported to have dose-dependent marked sedative effects at the central nervous system (CNS), including hypnotic, anticonvulsant and hypothermic properties. Linalool is reported to have a lemon like odor.

Contact allergens

Linalool is a terpene chief constituent of linaloe oil,also found in oils of Ceylon cinnamon, sassafras,orange flower, bergamot, Artemisia balchanorum, ylang-ylang. This frequently used scented substance is a sensitizer by the way of primary or secondary oxida-tion products. As a fragrance allergen, linalool has to be mentioned by name in cosmetics within the EU

Pharmacology

l-Linalool showed no sedative action in the mouse motility test when injected ip at a dose of 100 mg/kg (Binet, Binet, Miocque, Roux & Bernier, 1972). but Wagner & Sprinkmeyer (1973) reported that linalool depressed spontaneous motility of mice at doses of 31-6 and 100 mg/kg. Linalool showed spasmolytic action against carbachol-, histamine- and barium chloride-induced contractions in isolated guinea-pig ileum, the ED50 being about 100-200 mg/litre (Wagner & Sprinkmeyer. 1973). and in the isolated rat duodenum, contractions caused by 0.05 /ig acetylcholine/ml were inhibited by 50% by 10 μg l-linalool/ml (Binet et al. 1972). Linalool showed slight papavarinelike and very slight atropine-like antispasmodic action on small intestine isolated from the mouse (Imaseki & Kitabatake, 1962).
In studies carried out by Atanassova-Shopova et al. (1973), the ED50 for preventing tonic hyperextension of the hind limbs of rats from electric shock was found to be 135 mg/kg given ip. Linalool had a marked anticonvulsive and protective effect on pentylenetetrazol convulsions in mice at 150,175 and 200 mg/kg and in rats at 200 and 300 mg/kg. It showed a slight antistrychnine effect in mice at high and toxic doses (300 mg/kg), reduced motor activity of mice at 100 mg/kg, and at 50 mg/kg slightly decreased the motor activity of amphetamine- or caffeine-stimulated mice. The TD50 (neurotoxic dose) of linalool for influencing motor co-ordination of mice in the Rota-rod test was found to be 178 mg/kg. Linalool at doses of 50 or 100 mg/kg prolonged the narcotic effects of hexobarbitone, alcohol and chloral hydrate.
The equilibrium and spontaneous or reflex activity of the goldfish, Carassium auratus, was disturbed by exposure to aquarium water containing a 0-13 ml/litre concentration of a suspension containing 1 ml linalool plus 9 ml of a 10% aqueous solution of Tween 80, and the agressiveness of the male fighting fish, Betta splendens, was only very slightly inhibited by exposure to aquarium water containing 0-3 ml of the same suspension of linalool/litre (Binet, 1972).
Linalool and other terpene alcohols were found to be useful in man as sedatives and spasmolytics when administered in doses of 0.01-1 g, the effects having been tested in mice, goldfish, and rats (Laboratoires Meram, 1966).
Linalool depressed frog-heart activity in doses above 0-2 mg/g (Lysenko, 1962). Vasodilation by direct action of linalool upon the blood vessels was demonstrated by Northover & Verghese (1962). An iv dose of 9.2 mg/kg was required to produce a 25% fall in systolic arterial blood pressure in the anaesthetized dog and a hypotensive response was also observed in the decerebrated and despinalized dog. A dose of 0.05 g in fluid perfusing the leg of an anaesthetized dog or the isolated ear of a rabbit produced a maximum increase of 120% or 90%, respectively, in venous outflow over pre-injection values. Linalool dilated the small blood vessels of the exposed mesorchium of the anaesthetized mouse, lowering the threshold for electronic stimulation. Incubation of human, bovine and canine aortae in 015 M-linalool failed to stabilize the structure of the aortic wall proteins against hydrothermal shrinkage (Milch, 1965). Linalool inhibited incorporation of acetic acid or mevalonic acid into total or digitonin-precipitable nonsaponifiable lipids by rat-liver homogenates (Gey, Pletscher, Isler, Riiegg, Saucy & Wiirsch, 1960).

Anticancer Research

Studies of antitumor activities and toxicity were done on solid S-180 tumor-bearingSwiss albino mice. It results in an induction of oxidative stress with an antitumoractivities result. In comparison with cyclophosphamide, antioxidant effects wereobserved in the liver and modulation of proliferation of spleen cells in tumor-bearingmice challenged with lipopolysaccharides, while both were seriously affected bycyclophosphamide (Costa et al. 2015).

Synthesis

It can be prepared synthetically starting from myrcene or from dehydrolinalool; it can be obtained by fractional distilla tion and subsequent rectification from the oils of Cajenne rosewood (Licasia guaianensis, Ocotea caudata), Brazil rosewood (Ocotea parviflora), Mexican linaloe, shiu (Cinnamomum camphora Sieb. var. linalooifera) and coriander seeds (Coriandrum sativum L.).

Metabolism

The metabolism of 14C-labelled linalool in the rat was studied by Parke, Rahman & Walker (1974a). An intragastric dose of 500 mg linalool/kg body weight was largely (93%) excreted within 72 hr in the urine (55%), faeces (23%) and expired air (15%). The radioactivity remaining after 72 hr was located mainly in the liver (0-5%), gut (0-6%), skin (0-8%) and skeletal muscle (1-2%). Rapid urinary excretion indicated that linalool was rapidly absorbed from the gut, while delay in excretion in the expired air suggested that linalool might enter intermediary metabolism and also be metabolized by conjugation in the bile and urine. Ip administration of 20 mg linalool indicated that enterohepatic circulation occurred, resulting in a short-term metabolic load on the liver and delayed faecal excretion. The metabolism of large doses in the rat, with rapid excretion of linalool and its metabolites, suggests no long-term hazard from tissue accumulation on chronic exposure to concentrations normally encountered in foods, although enterohepatic circulation might prolong the metabolic load on the liver over a relatively short period. A study of the effects of linalool and other terpenoids on hepatic drug-metabolizing enzymes suggested that these compounds induce the enzymes involved in their own metabolism. Linalool, which is metabolized by reduction and conjugation with glucuronic acid, increased the activity of 4-nitrobenzoate reductase but did not increase other enzymes studied (Parke & Rahman, 1969). Linalool can be metabolized by micro- organisms. l-Linalool was partially oxidized by incubation with Aspergillus nig er (Goto, 1967). The linalool content of grape essential oil decreased during must fermentation and wine formation (Rodopulo, Egorov, Bezzubov, Kormakova & Megrelidze, 1972). A strain of Pseudomonas pseudomallei, isolated from soil, metabolized linalool with the formation of camphor, 4-methyl-4-vinylbutyrolactone, 4-methyl- trans-3-hexenoic acid, and 2,6-dimethyl-6- hydroxy- trans-2,7-octadienoic acid (Mizutani, Hayashi, Ueda & Tatsumi, 1971).