1490-04-6

Basic information

• Product Name: DL-Menthol
• Synonyms: (1RS,3RS,4SR)-4 MENTHAN-3-OL;2-ISOPROPYL-5-METHYLCYCLOHEXANOL;5-METHYL-2-(1-METHYETHYL)CYCLOHEXANOL;(+/-)-MENTHOL;MENTHOL;MENTHOL, DL-;DL-MENTHAN-3-OL;DL-4-MENTHAN-3-OL
• CAS NO: 1490-04-6
• Molecular Formula: C₁₀H₂₀O
• Molecular Weight: 156.27
• EINECS: 216-074-4
• Product Categories: Alphabetic;M;MEA - MESAnalytical Standards;NMR Reference Standards;NMRStable Isotopes;Spectroscopy;Flavor & essential oil
• Mol File: 1490-04-6.mol
• Article Data: 25

Chemical Properties

• Melting Point: 34-36 °C(lit.)
• Boiling Point: 216 °C(lit.)
• Flash Point: 200 °F
• Appearance: colourless crystals
• Density: 0.89 g/mL at 25 °C(lit.)
• Vapor Pressure: 0.8 mm Hg ( 20 °C)
• Storage Temp.: Sealed in dry,Room Temperature
• Solubility: Very soluble in ethanol (95%), chloroform, ether, fatty oils and liquid paraffin; freely soluble in glacial acetic acid;soluble in acetone and benzene; very slightly soluble in glycerin; practically insoluble in water.
• PKA: 15.30±0.60(Predicted)
• Stability: Stable. Combustible. Incompatible with strong oxidizing agents.
• CAS DataBase Reference: DL-Menthol(CAS DataBase Reference)
• NIST Chemistry Reference: DL-Menthol(1490-04-6)
• EPA Substance Registry System: DL-Menthol(1490-04-6)

Safety Data

• Hazard Codes: Xn,Xi
• Statements: 37/38-41-48/20/22-40-22
• Safety Statements: 36/37/39-36-26
• RIDADR: UN 1888 6.1/PG 3
• WGK Germany: 2
• RTECS: OT0525000
• Hazardous Substances Data: 1490-04-6(Hazardous Substances Data)

Usage

Uses

1. Used in Fragrance Industry:
DL-Menthol is used as a fragrance due to its strong characteristic odor and minty taste. It is commonly found in essential oils like peppermint oil.
2. Used in Pharmaceutical Industry:
DL-Menthol is used as an antiseptic, cooling agent, refreshing agent, and a blood-circulation stimulant in the pharmaceutical industry. It gives the skin a "cool" feeling after use and is used in oral gel patches or films containing herb extracts or Chinese medicine, fruit extract, spearmint, and menthol for smoking cessation.
3. Used in Confectionery and Perfumery:
DL-Menthol is used as a flavoring agent in the confectionery and perfumery industries due to its minty taste and strong characteristic odor.
4. Used in Cough Drops and Cigarettes:
DL-Menthol is used in cough drops for its cooling and refreshing properties, and it is also used in cigarettes to provide a minty flavor and cooling sensation.
5. Used in Liqueurs:
DL-Menthol is used as a flavoring agent in the production of certain liqueurs, adding a unique minty taste to the beverages.
6. Used as a Topical Antipruritic and Local Anesthetic:
DL-Menthol is used in the medical field as a topical antipruritic to relieve itching and as a local anesthetic to numb a specific area of the body.
7. Used as a Gastric Sedative:
DL-Menthol is used as a gastric sedative to help calm the stomach and alleviate symptoms of indigestion.
Brand Names:
1. Fisherman's Friend Lozenges (Bristol-Myers Products)
2. Therapeutic Mineral Ice (Bristol-Myers Products)

Production Methods

Menthol occurs widely in nature as l-menthol and is the principal component of peppermint and cornmint oils obtained from the Mentha piperita and Mentha arvensis species. Commercially, lmenthol is mainly produced by extraction from these volatile oils. It may also be prepared by partial or total synthetic methods. Racemic menthol is prepared synthetically via a number of routes, e.g. by hydrogenation of thymol.

Pharmaceutical Applications

Menthol is widely used in pharmaceuticals, confectionery, and toiletry products as a flavoring agent or odor enhancer. In addition to its characteristic peppermint flavor, l-menthol, which occurs naturally, also exerts a cooling or refreshing sensation that is exploited in many topical preparations. Unlike mannitol, which exerts a similar effect due to a negative heat of solution, l-menthol interacts directly with the body’s coldness receptors. d-Menthol has no cooling effect, while racemic menthol exerts an effect approximately half that of l-menthol. When used to flavor tablets, menthol is generally dissolved in ethanol (95%) and sprayed onto tablet granules and not used as a solid excipient. Menthol has been investigated as a skin-penetration enhancer and is also used in perfumery, tobacco products, chewing gum and as a therapeutic agent. When applied to the skin, menthol dilates the blood vessels, causing a sensation of coldness followed by an analgesic effect. It relieves itching and is used in creams, lotions, and ointments. When administered orally in small doses menthol has a carminative action.

Safety

Almost all toxicological data for menthol relate to its use as a therapeutic agent rather than as an excipient. Inhalation or ingestion of large quantities can result in serious adverse reactions such as ataxia and CNS depression,hypersensitivity reactions, severe abdominal pain, nausea, vomiting, vertigo, drowsiness, and coma.Although menthol is essentially nonirritant there have been some reports of hypersensitivity following topical application. In a Polish study approximately 1% of individuals were determined as being sensitive to menthol.There have been reports of apnea and instant collapse in infants after the local application of menthol to their nostrils. The WHO has set an acceptable daily intake of menthol at up to 0.4 mg/kg body-weight. LD50 (rat, IM): 10.0 g/kg LD50 (rat, oral): 3.18 g/kg

storage

A formulation containing menthol 1% w/w in aqueous cream has been reported to be stable for up to 18 months when stored at room temperature. Menthol should be stored in a well-closed container at a temperature not exceeding 25°C, since it sublimes readily.

Incompatibilities

Incompatible with: butylchloral hydrate; camphor; chloral hydrate; chromium trioxide; b-naphthol; phenol; potassium permanganate; pyrogallol; resorcinol; and thymol.

Regulatory Status

Included in the FDA Inactive Ingredients Database (dental preparations, inhalations, oral aerosols, capsules, solutions, suspensions, syrups, and tablets; also topical preparations). Included in nonparenteral medicines licensed in the UK. Accepted for use in foods and confectionery as a flavoring agent of natural origin. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

InChI:InChI=1/2C10H20O/c2*1-7(2)9-5-4-8(3)6-10(9)11/h2*7-11H,4-6H2,1-3H3

Upstream product

• 89-83-8 thymol 
• 1678-82-6 trans-1,4-menthane 
• 491-07-6 (+/-)-menthone 
• 611-70-1 phenyl isopropyl ketone 
• 2866-71-9 (1,1'-bicyclopentyl)-2-one 
• 535-13-7 2-chloro-propanoic acid, ethyl ester 
• 42411-39-2 (R)-ethyl 2-chloropropanoate 
• 89-78-1 menthol 
• 74497-15-7 (L) Ethyl 2-chloropropanoate 
• 2385-77-5 (R)-Citronellal 
• 89-82-7 pulegone 
• 5392-40-5 (E/Z)-3,7-dimethyl-2,6-octadienal 
• 10458-14-7 Menthone 
• 106-23-0 3,7-dimethyl-oct-6-enal 

Downstream Products

• 77341-67-4 L-menthylsuccinic acid 
• 3309-12-4 (+/-)-phthalic acid mono-neomenthyl ester 
• 1144-50-9 (+/-)-Neomenthyl-acetoacetat 
• 15356-70-4 menthol 
• 1124-26-1 (+/-)-(3R,6S)-3-isopropyl-6-methyl-1-cyclohexene 
• 14539-76-5 rac-neomenthyl-4-tolylsulfonate 
• 42411-39-2 (R)-ethyl 2-chloropropanoate 
• 55284-69-0 (1R)-Menthyl (L)-2-chloropropanoate 
• 55284-69-0 (1S)-Menthyl (L)-2-chloropropanoate 
• 80317-59-5 (-)-2-<2-(1-(1R,3R,4S)-menthoxynaphthyl)>-4,4-dimethyl-Δ²-oxazoline 
• 89-48-5 neomenthyl acetate 
• 2552-91-2 (1S)-(+)-neomenthol acetate 
• 146502-80-9 (-)-(1R)-menthyl acetate 
• 108293-34-1 (1R)-2-oxo-bornane-10-sulfonic acid-((1S)-neomenthyl ester) 

Relevant articles and documents

Domino-cyclisation and hydrogenation of citronellal to menthol over bifunctional Ni/Zr-Beta and Zr-beta/Ni-MCM-41 catalysts

The one-pot conversion of (±)-citronellal to menthol can be selectively catalysed by either a bifunctional Ni/Zr-zeolite beta catalyst or a dual catalyst system of Zr-beta and Ni/MCM-41, giving a high diastereoselectivity to (±)-menthol of 90-94%. The Royal Society of Chemistry 2006.

MOFs as multifunctional catalysts: One-pot synthesis of menthol from citronellal over a bifunctional MIL-101 catalyst

A bifunctional MOF catalyst containing coordinatively unsaturated Cr 3+ sites and palladium nanoparticles (Pd@MIL-101) has been used for the cyclization of citronellal to isopulegol and for the one-pot tandem isomerization/hydrogenation of citronellal to menthol. The MOF was found to be stable under the reaction conditions used, and the results obtained indicate that the performance of this bifunctional solid catalyst is comparable with other state-of-the-art materials for the tandem reaction: Full citronellal conversion was attained over Pd@MIL-101 in 18 h, with 86% selectivity to menthols and a diastereoselectivity of 81% to the desired (-)-menthol, while up to 30 h were necessary for attaining similar values over Ir/H-beta under analogous reaction conditions. The Royal Society of Chemistry 2012.

STEREOSELECTIVE HYDROGENATION OF A MENTHONE-ISOMENTHONE MIXTURE ON HETEROGENEOUS NICKEL, NICKEL-COBALT, AND COBALT CATALYSTS

A study was carried out on the effect of the nature of the catalysts, additives, and solvents on the stereoselectivity of the liquid-phase hydrogenation of an equilibrium menthone-isomenthone mixture to give menthols.Neoisomenthol, which is the least stable of all the menthol isomers, was predominantly formed on a cobalt catalyst modified by (+)-tartaric acid in ethyl acetate at 130 deg C and 10 MPa.

STEREOCHEMICAL EVIDENCE FOR SINGLE ELECTRON TRANSFER MECHANISM IN THE REDUCTION OF CYCLIC KETONES WITH ALKOXYALUMINIUM DICHLORIDES

The stereochemical results of the reduction of cyclic ketones with alkoxyaluminium dichlorides do not conform to the conventional polar cyclic mechanism and may be explained by a single electron transfer mechanism.

Continuous synthesis of menthol from citronellal and citral over Ni-beta-zeolite-sepiolite composite catalyst

One-pot continuous synthesis of menthols both from citronellal and citral was investigated over 5 wt% Ni supported on H-Beta-38-sepiolite composite catalyst at 60–70 °C under 10–29 bar hydrogen pressure. A relatively high menthols yield of 53% and 49% and stereoselectivity to menthol of 71–76% and 72–74% were obtained from citronellal and citral respectively at the contact time 4.2 min, 70 °C and 20 bar. Citral conversion noticeably decreased with time-on-stream under 10 and 15 bar of hydrogen pressure accompanied by accumulation of citronellal, the primary hydrogenation product of citral, practically not affecting selectivity to menthol. A substantial amount of defuctionalization products observed during citral conversion, especially at the beginning of the reaction (ca. 1 h), indicated that all intermediates could contribute to formation of menthanes. Ni/H-Beta-38-sepiolite composite material prepared by extrusion was characterized by TEM, SEM, XPS, XRD, ICP-OES, N2 physisorption and FTIR techniques to perceive the interrelation between the physico-chemical and catalytic properties.

Continuous flow synthesis of menthol: Via tandem cyclisation-hydrogenation of citronellal catalysed by scrap catalytic converters

A continuous flow synthesis of menthol starting from citronellal catalysed by scrap catalytic converters is reported. The reaction was conducted in a tandem system connecting in series two catalytic systems, with the first having Lewis acid properties (favouring the cyclisation of citronellal to isopulegols) and the second having hydrogenation catalytic activity (catalysing the hydrogenation of isopulegols to menthols). A Lewis acid catalyst was prepared by supporting iron oxide nanoparticles over a waste material, i.e. the ceramic core of scrap catalytic converters (SCATs) via a microwave assisted method. Most importantly, SCATs, containing a low residual noble metal content, could be directly employed in the second step as hydrogenation catalysts. The reaction was performed studying the influence on the yield and selectivity to (-)-menthol of various reaction parameters (T, p and flow rate). Under the best reaction conditions (at a flow rate of 0.1 mL min-1 and at 373 K and 413 K for cyclisation and hydrogenation steps respectively) a conversion of >99% of (+)-citronellal to (-)-menthol with 77% final yield was achieved.

A synthetic process of L-menthol

The invention relates to the field of spice synthesis and particularly relates to a synthetic process of L-menthol. The process includes steps of d,l-menthol synthesizing, d,l-menthol rectification, d,l-menthol esterification, d,l-menthyl benzoate rectification, d,l-menthyl benzoate resolution, D-menthol synthesizing, menthol isomerization and L-menthol synthesizing. The process adopts thymol that is a simple, easily available and cheap chemical product as a raw material. Esterification conditions are optimized and the esterification and rectification are performed at the same time so as to allow the esterification to be converted into a way beneficial to d,l-menthyl benzoate production, thus increasing the esterification yield. Crystallization and resolution are optimized by utilization of the d,l-menthyl benzoate. Preparation of the L-menthol by the process is characterized by being high in yield, low in cost, simple and convenient in operation, suitable for continuous and large-scale production, and the like. According to the process, operation of the process is cyclic with a whole system being sealed, and the process is free of waste water, energy-saving and environmental friendly.

Facile Protocol for Catalytic Frustrated Lewis Pair Hydrogenation and Reductive Deoxygenation of Ketones and Aldehydes

A series of ketones and aldehydes are reduced in toluene under H2 in the presence of 5 mol % B(C6F5)3 and either cyclodextrin or molecular sieves affording a facile metal-free protocol for reduction to alcohols. Similar treatment of aryl ketones resulted in metal-free deoxygenation yielding aromatic hydrocarbons.

P450-catalyzed regio- and stereoselective oxidative hydroxylation of disubstituted cyclohexanes: Creation of three centers of chirality in a single CH-activation event This paper is dedicated to the memory of Harry H. Wasserman

Wild-type P450-BM3 is able to catalyze in a highly regio- and diastereoselective manner the oxidative hydroxylation of non-activated disubstituted cyclohexane derivatives lacking any functional groups, including cis- and trans-1,2-dimethylcyclohexane, cis- and trans-1,4-dimethylcyclohexane, and trans-1,4-methylisopropylcyclohexane. In all cases except chiral trans-1,2-dimethylcyclohexane as substrate, the single hydroxylation event at a methylene group induces desymmetrization with simultaneous creation of three centers of chirality. Certain mutants increase selectivity, setting the stage for future directed evolution work.

PROCESS FOR THE PREPARATION OF MENTHOL

The invention relates to a process for the preparation of 2-isopropyl-5-methylcyclohexanol (D,L-menthol) via the hydrogenation of thymol to menthone and subsequent further hydrogenation to give D,L-menthol.