Thymol

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Thymol
Thymol
Thymol3D.png
Names
Preferred IUPAC name
5-Methyl-2-(propan-2-yl)phenol
Other names
2-Isopropyl-5-methylphenol
Identifiers
89-83-8 YesY
ChEBI CHEBI:27607 YesY
ChEMBL ChEMBL29411 YesY
ChemSpider 21105998 YesY
DrugBank DB02513 YesY
ECHA InfoCard 100.001.768
2499
Jmol 3D model Interactive image
KEGG D01039 YesY
UNII 3J50XA376E YesY
Properties
C10H14O
Molar mass 150.22 g·mol−1
Density 0.96 g/cm3
Melting point 49 to 51 °C (120 to 124 °F; 322 to 324 K)
Boiling point 232 °C (450 °F; 505 K)
0.9 g/L (20 °C)[1]
Pharmacology
QP53AX22 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
YesY verify (what is YesYN ?)
Infobox references

Thymol (also known as 2-isopropyl-5-methylphenol, IPMP) is a natural monoterpene phenol derivative of cymene, C10H14O, isomeric with carvacrol, found in oil of thyme, and extracted from Thymus vulgaris (common thyme) and various other kinds of plants as a white crystalline substance of a pleasant aromatic odor and strong antiseptic properties. Thymol also provides the distinctive, strong flavor of the culinary herb thyme, also produced from T. vulgaris.

Biological activity[edit]

Thymol is part of a naturally occurring class of compounds known as biocides, with strong antimicrobial attributes when used alone or with other biocides such as carvacrol. In addition, naturally occurring biocidal agents such as thymol can reduce bacterial resistance to common drugs such as penicillin.[2] Numerous studies have demonstrated the antimicrobial effects of thymol, ranging from inducing antibiotic susceptibility in drug-resistant pathogens to powerful antioxidant properties.[3][4] Research demonstrates that naturally occurring biocides such as thymol and carvacrol reduce bacterial resistance to antibiotics through a synergistic effect,[2] and thymol has been shown to be an effective fungicide,[5] particularly against fluconazole-resistant strains. This is especially relevant to Candida infections. Compounds in the essential oils of one type of oregano have demonstrated antimutagenic effects, and in particular carvacrol (isomeric with thymol) and thymol were demonstrated to have a strong antimutagenic effect.[6] In addition, there is evidence that thymol has antitumor properties.[7] Though the exact mechanism is unknown, some evidence suggests thymol effects at least some of its biocidal properties by membrane disruption.[8]

Thymol has been shown to act as a positive allosteric modulator of GABAA in vitro.[9] Thymol is chemically related to the anesthetic propofol.

Chemistry[edit]

Thymol is only slightly soluble in water at neutral pH, but it is extremely soluble in alcohols and other organic solvents. It is also soluble in strongly alkaline aqueous solutions due to deprotonation of the phenol.

Synonyms include isopropyl-m-cresol, cymene,[10] 1-methyl-3-4-isopropylbenzene, 2--1-isopropyl-4-methylbenzene; 3-p-cymene, 3-methyl-6-isopropylphenol, 5-methyl-2-(1-methylethyl)phenol, 5-methyl-2-isopropyl-1-phenol, 5-methyl-2-isopropylphenol, 6-isopropyl-3-methylphenol, 6-isopropyl-m-cresol, Apiguard, NSC 11215, NSC 47821, NSC 49142, thyme camphor, m-thymol, and p-cymen-3-ol.[11]

Thymol has a refractive index of 1.5208[12] and an experimental dissociation exponent (pKa) of 10.59 ± 0.10.[13] Thymol absorbs maximum UV radiation at 274 nm.[14]

History[edit]

The Ancient Egyptians used thymol and carvacrol in the form of a preparation from the thyme plant (a member of the mint family) to preserve mummies.[citation needed] Thymol and carvacrol are now known to kill bacteria and fungi, making thyme well suited for such purposes.

In Ancient Greece, thyme was widely used for its aromatic qualities, being burned as incense in sacred temples. Thyme was also a symbol of courage and admiration, with the phrase "the smell of thyme" being a saying that reflected praise unto its subject. Thyme's association with bravery continued throughout medieval times, when it was a ritual for women to give their knights a scarf that had a sprig of thyme placed over an embroidered bee.[citation needed] Since the 16th century, thyme oil has been used for its antiseptic properties, both as mouthwash and for topical application.

The bee balms Monarda fistulosa and Monarda didyma, North American wildflowers, are natural sources of thymol. The Blackfoot Native Americans recognized these plants' strong antiseptic action, and used poultices of the plants for skin infections and minor wounds. A tisane made from them was also used to treat mouth and throat infections caused by dental caries and gingivitis.[15]

Thymol was first isolated by the German chemist Caspar Neumann in 1719.[16] In 1853, the French chemist A. Lallemand named thymol and determined its empirical formula.[17] Thymol was first synthesized by the Swedish chemist Oskar Widman in 1882.[18] Alain Thozet and M. Perrin first published the crystal structure analysis with the exact determination of the structural atoms.

Uses[edit]

Thymol

Thymol has antimicrobial activity because of its phenolic structure, and has shown antibacterial activity against bacterial strains including Aeromonas hydrophila and Staphylococcus aureus.[19] In addition, thymol demonstrates considerable post antibacterial effect against some microorganisms.[3] This antibacterial activity is caused by inhibiting growth and lactate production, and by decreasing cellular glucose uptake.[20]

Thymol has been used in alcohol solutions and in dusting powders for the treatment of tinea or ringworm infections, and was used in the United States to treat hookworm infections.[21] People of the Middle East continue to use za'atar, a delicacy made with large amounts of Thyme, to reduce and eliminate internal parasites.[22]

It is also used as a preservative in halothane, an anaesthetic, and as an antiseptic in mouthwash. When used to reduce plaque and gingivitis, thymol has been found to be more effective when used in combination with chlorhexidine than when used purely by itself.[23] Thymol is also the active antiseptic ingredient in some toothpastes, such as Euthymol.

The antifungal nature of thymol is caused by thymol's ability to alter the hyphal morphology and cause hyphal aggregates, resulting in reduced hyphal diameters and lyses of hyphal wall.[24] Additionally, thymol is lipophilic, enabling it to interact with the cell membrane of fungus cells, altering cell membrane permeability permitting the loss of macromolecules.[25]

Recent medical research on rats concludes that "Thyme extract had relaxing effects on organs possessing β2-receptors (uterus and trachea)."[26]

In a 1994 report released by five major cigarette companies, thymol was listed as one of 599 additives to cigarettes.[27]

Thymol has been used to successfully control varroa mites and prevent fermentation and the growth of mold in bee colonies, methods developed by beekeeper R.O.B. Manley.[28]

Thymol is also used as a rapidly degrading, non-persisting pesticide.[29]

Derivatives of thymol and carvacrol with increased antimicrobial activities have been developed.[30] The preparation of methacrylic and p-styrenesulfonic acid esters of thymol could lead to less toxic macromolecular biocides, which can be attached to a polymeric backbone.[31]

A minor use of thymol is in book and paper conservation: Paper with mold damage can be sealed in bags with thymol crystals to kill fungal spores. However, this practice is not currently recommended due to apparent accelerated degradation suffered by these objects.[citation needed]

Thymol can also be used as a medical disinfectant and general purpose disinfectant.[32] For instance, thymol is used as the starting material used to synthesize biclotymol. Thymol can be brominated to Bromthymol (see [15062-34-7]), which is a recognized anthelmintic drug.

List of plants that contain thymol[edit]

Toxicology and environmental impacts[edit]

In 2009, the U.S. Environmental Protection Agency (EPA) reviewed the research literature on the toxicology and environmental impact of thymol and concluded that "thymol has minimal potential toxicity and poses minimal risk".[44]

Environmental breakdown and use as a pesticide[edit]

Studies have shown that hydrocarbon monoterpenes and thymol in particular degrade rapidly (DT50 16 days in water, 5 days in soil[29]) in the environment and are, thus, low risks because of rapid dissipation and low bound residues,[29] supporting the use of thymol as a pesticide agent that offers a safe alternative to other more persistent chemical pesticides that can be dispersed in runoff and produce subsequent contamination.

Compendial status[edit]

See also[edit]

Notes and references[edit]

  1. ^ "Thymol". PubChem. Retrieved 1 April 2016. 
  2. ^ a b Palaniappan, Kavitha; Holley, Richard A. (2010). "Use of natural antimicrobials to increase antibiotic susceptibility of drug resistant bacteria". International Journal of Food Microbiology. 140 (2–3): 164–8. doi:10.1016/j.ijfoodmicro.2010.04.001. PMID 20457472. .
  3. ^ a b Zarrini G, Bahari-Delgosha Z, Mollazadeh-Moghaddam K, Shahverdi AR (2010). "Post-antibacterial effect of thymol". Pharmaceutical biology. 48 (6): 633–636. doi:10.3109/13880200903229098. PMID 20645735. 
  4. ^ Ündeğer, Ü.; Başaran, A.; Degen, G. H.; Başaran, N. (Aug 2009). "Antioxidant activities of major thyme ingredients and lack of (oxidative) DNA damage in V79 Chinese hamster lung fibroblast cells at low levels of carvacrol and thymol". Food and Chemical Toxicology. 47 (8): 2037–2043. doi:10.1016/j.fct.2009.05.020. PMID 19477215. 
  5. ^ Ahmad A, et al, Proton translocating ATPase mediated fungicidal activity of eugenol and thymol,Fitoterapia (2010), doi:10.1016/j.fitote.2010.07.020
  6. ^ Mezzoug, N.; Elhadri, A.; Dallouh, A.; Amkiss, S.; Skali, N.S.; Abrini, J.; Zhiri, A.; Baudoux, D.; Diallo, B.; El Jaziri, M.; Idaomar, M. (2007). "Investigation of the mutagenic and antimutagenic effects of Origanum compactum essential oil and some of its constituents". Mutation Research/Genetic Toxicology and Environmental Mutagenesis. 629 (2): 100. doi:10.1016/j.mrgentox.2007.01.011. 
  7. ^ Andersen, A (2006). "Final report on the safety assessment of sodium p-chloro-m-cresol, p-chloro-m-cresol, chlorothymol, mixed cresols, m-cresol, o-cresol, p-cresol, isopropyl cresols, thymol, o-cymen-5-ol, and carvacrol". International journal of toxicology. 25 Suppl 1: 29–127. doi:10.1080/10915810600716653. PMID 16835130. 
  8. ^ Trombetta, D.; Castelli, F.; Sarpietro, M. G.; Venuti, V.; Cristani, M.; Daniele, C.; Saija, A.; Mazzanti, G.; Bisignano, G. (2005). "Mechanisms of Antibacterial Action of Three Monoterpenes". Antimicrobial Agents and Chemotherapy. 49 (6): 2474–8. doi:10.1128/AAC.49.6.2474-2478.2005. PMC 1140516Freely accessible. PMID 15917549. 
  9. ^ García DA, Bujons J, Vale C, Suñol C (Sep 26, 2005). "Allosteric positive interaction of thymol with the GABAA receptor in primary cultures of mouse cortical neurons.". Neuropharmacology. 50 (1): 25–35. doi:10.1016/j.neuropharm.2005.07.009. PMID 16185724. 
  10. ^ Webster's 1913 dictionary
  11. ^ CAS Registry: Data were obtained from SciFinder
  12. ^ Mndzhoyan, A. L. Thymol from Thymus kotschyanus. Sbornik Trudov Armyanskogo Filial. Akad. Nauk. 1940, 25-28.
  13. ^ CAS Registry: Data were obtained from SciFinder
  14. ^ Norwitz, G.; Nataro, N.; Keliher, P. N. (1986). "Study of the Steam Distillation of Phenolic Compounds Using Ultraviolent Spectrometry". Anal. Chem. 58 (639–640): 641. doi:10.1021/ac00294a034. 
  15. ^ Tilford, Gregory L. (1997) Edible and Medicinal Plants of the West. Missoula, MT: Mountain Press Publishing. ISBN 0-87842-359-1
  16. ^ Carolo Neuman (1724) "De Camphora," Philosophical Transactions of the Royal Society of London, 33 (389) : 321-332. Available on-line at: Royal Society. On page 324, Neumann mentions that in 1719 (MDCCXIX) he distilled some essential oils from various herbs. On page 326, he mentions that during the course of these experiments, he obtained a crystalline substance from thyme oil, which he called "Camphora Thymi" (camphor of thyme). (Neumann gave the name "camphor" not only to the specific substance that today is called camphor, but to any crystalline substance that precipitated from a volatile, fragrant oil from some plant.)
  17. ^ A. Lallemand (1853) "Sur la composition de l'huile essentielle de thym" (On the composition of the essential oil of thyme), Comptes rendus, 37 : 498-500. (Note that Lallemand's empirical formula for thymol is incorrect because chemists at that time used the wrong atomic masses for carbon and oxygen.)
  18. ^ Oskar Widmann (1882) "Ueber eine Synthese von Thymol aus Cuminol" (On a synthesis of thymol from cuminol), Berichte der Deutschen chemischen Gesellschaft zu Berlin, 15 : 166-172.
  19. ^ Dorman, H.J.D.; Deans, S.G. (2000). "Antimicrobial agents from plants: antibacterial activity of plant volatile oils". J. Appl. Microbiol. 88 (2): 308–316. doi:10.1046/j.1365-2672.2000.00969.x. PMID 10736000. 
  20. ^ Evans, J.; Martin, J. D. (2000). "Effects of thymol on ruminal microorganisms". Curr. Microbiol. 41 (5): 336. doi:10.1007/s002840010145. 
  21. ^ Ferrell, John Atkinson (1914). The Rural School and Hookworm Disease. US Bureau of Education Bulletin. No. 20, Whole No. 593. Washington, DC: U.S. Government Printing Office. 
  22. ^ Marwat et al. 2009
  23. ^ Filoche, S.K.; Soma, K.; Sissons, C.H. (2005). "Antimicrobial effects of essential oils in combination with chlorhexidine digluconate". Oral Microbiol Immunol. 20 (4): 221–225. doi:10.1111/j.1399-302X.2005.00216.x. PMID 15943766. 
  24. ^ Numpaque, M. A.; Oviedo, L. A.; Gil, J. H.; García, C. M.; Durango, D. L. (2011). "Thymol and carvacrol: biotransformation and antifungal activity against the plant pathogenic fungi Colletotrichum acutatum and Botryodiplodia theobromae". Trop. Plant Pathol. 36: 3–13. doi:10.1590/S1982-56762011000100001. 
  25. ^ Segvic Klaric, M.; Kosalec, I.; Mastelic, J.; Pieckova, E.; Pepeljnak, S. Antifungal activity of thyme (Thymus vulgaris L.) essential oil and thymol against moulds from damp dwellings Lett. Appl. Microbiol. 2007, 44, 36-42.
  26. ^ Wienkötter, N.; F. Begrow; U. Kinzinger; D. Schierstedt; E.J. Verspohl (2007). "The Effect of Thyme Extract on β2-Receptors and Mucociliary Clearance". Planta Medica. 73 (7): 629–635. doi:10.1055/s-2007-981535. PMID 17564943. 
  27. ^ Big Tobacco's List of 599 Cigarette Additives. About.com.
  28. ^ Ward, Mark. (2006-03-08) Almond farmers seek healthy bees. BBC News.
  29. ^ a b c D. Hu and J. Coats, Evaluation of the environmental fate of thymol and phenethyl propionate in the laboratory, Pest Manag Sci 64:775–779 (2008) doi:10.1002/ps.1555
  30. ^ Mathela, CS; Singh, KK; Gupta, VK (2010). "Synthesis and in-vitro antibacterial activity of thymol and carvacrol derivatives" (PDF). Acta Poloniae Pharmaceutica. 67 (4): 375–380. PMID 20635533. 
  31. ^ N. Moszner, U. Salz, V. Rheinberger (1994) "Synthesis and polymerization of unsaturated derivatives of thymol". Polymer Bulletin 33 (1) 7-12. doi:10.1007/BF00313467
  32. ^ http://archive.epa.gov/pesticides/reregistration/web/pdf/3143fact.pdf
  33. ^ P. Novy, H. Davidova, C. S. Serrano-Rojero, J. Rondevaldova, J. Pulkrabek, L. Kokoska, "Composition and Antimicrobial Activity of Euphrasia rostkoviana Hayne Essential Oil." Evididence Based Complementary and Alternative Medicine, April 27, 2015.
  34. ^ V. A. Zamureenko, N. A. Klyuev, B. V. Bocharov, V. S. Kabanov and A. M. Zakharov, "An investigation of the component composition of the essential oil of Monarda fistulosa", Chemistry of Natural Compounds, Vol. 25, No. 5, Sep. 1989.
  35. ^ a b Bouchra, Chebli; Achouri, Mohamed; Idrissi Hassani, L.M; Hmamouchi, Mohamed; et al. (2003). "Chemical composition and antifungal activity of essential oils of seven Moroccan Labiatae against Botrytis cinerea Pers: Fr". Journal of Ethnopharmacology. 89 (1): 165–169. doi:10.1016/S0378-8741(03)00275-7. PMID 14522450. 
  36. ^ Liolios, C.C.; Gortzi, O; Lalas, S; Tsaknis, J; Chinou, I; et al. (2009). "Liposomal incorporation of carvacrol and thymol isolated from the essential oil of Origanum dictamnus L. and in vitro antimicrobial activity". Food Chemistry. Elsevier. 112 (1): 77–83. doi:10.1016/j.foodchem.2008.05.060. 
  37. ^ Ozkan, Gulcan; Baydar, H; Erbas, S; et al. (2009). "The influence of harvest time on essential oil composition, phenolic constituents and antioxidant properties of Turkish oregano (Origanum onites L.)". Journal of the Science of Food and Agriculture. 90 (2): 205–209. doi:10.1002/jsfa.3788. PMID 20355032. 
  38. ^ Lagouri, Vasiliki; Blekas, George; Tsimidou, Maria; Kokkini, Stella; Boskou, Dimitrios; et al. (1993). "Composition and antioxidant activity of essential oils from Oregano plants grown wild in Greece". Zeitschrift für Lebensmittel-Untersuchung und -Forschung A. 197 (1): 1431–4630. doi:10.1007/BF01202694. 
  39. ^ Kanias, G. D.; Souleles, C.; Loukis, A.; Philotheou-Panou, E.; et al. (1998). "Trace elements and essential oil composition in chemotypes of the aromatic plant Origanum vulgare". Journal of Radioanalytical and Nuclear Chemistry. 227 (1 – 2): 23–31. doi:10.1007/BF02386426. 
  40. ^ Figiel, Adam; Szumny, Antoni; Gutiérrez-Ortíz, Antonio; Carbonell-Barrachina, ÁNgel A.; et al. (2010). "Composition of oregano essential oil (Origanum vulgare) as affected by drying method". Journal of Food Engineering. 98 (2): 240–247. doi:10.1016/j.jfoodeng.2010.01.002. 
  41. ^ a b Goodner, K.L.; Mahattanatawee, K; Plotto, A; Sotomayor, J; Jordan, M; et al. (2006). "Aromatic profiles of Thymus hyemalis and Spanish T. vulgaris essential oils by GC–MS/GC–O". Industrial Crops and Products. 24 (3): 264–268. doi:10.1016/j.indcrop.2006.06.006. 
  42. ^ Lee, Seung-Joo; Umano, K; Shibamoto, T; Lee, K; et al. (2005). "Identification of volatile components in basil (Ocimum basilicum L.) and thyme leaves (Thymus vulgaris L.) and their antioxidant properties". Food Chemistry. 91 (1): 131–137. doi:10.1016/j.foodchem.2004.05.056. 
  43. ^ Moldão-Martins, M.; Palavra, A; Beiraodacosta, M; Bernardogil, M; et al. (2000). "Supercritical CO2 extraction of Thymus zygis L. subsp. sylvestris aroma". The Journal of Supercritical Fluids. 18 (1): 25–34. doi:10.1016/S0896-8446(00)00047-4. 
  44. ^ 74 FR 12613
  45. ^ The British Pharmacopoeia Secretariat (2009). "Index, BP 2009" (PDF). Retrieved 5 July 2009. 
  46. ^ "Japanese Pharmacopoeia" (PDF). Retrieved 21 April 2010. 

External links[edit]

Media related to Thymol at Wikimedia Commons


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