Isophorone

Isophorone[1]
Names
IUPAC name
3,5,5-Trimethyl-2-cyclohexene-1-one
Other names
1,1,3-Trimethyl-3-cyclohexene-5-one
Isoforone
Isoacetophorone
IP
Identifiers
78-59-1 YesY
ChemSpider 6296 YesY
EC Number 201-126-0
Jmol interactive 3D Image
KEGG C14743 YesY
PubChem 6544
Properties
C9H14O
Molar mass 138.21 g·mol−1
Appearance Colorless to white liquid
Odor Peppermint-like[2]
Density 0.9255 g/cm3
Melting point −8.1 °C (17.4 °F; 265.0 K)
Boiling point 215.32 °C (419.58 °F; 488.47 K)
1.2 g/100 mL
Solubility ether, acetone, hexane, dichloromethane, benzene, toluene, alcohol
Vapor pressure 0.3 mmHg (20°C)[2]
1.4766
Viscosity 2.62 cP
Thermochemistry
43.4 kJ/mol
Hazards
Flash point 84 °C (183 °F; 357 K)
460 °C (860 °F; 733 K)
Explosive limits 0.8%-3.8%[2]
Lethal dose or concentration (LD, LC):
2280 mg/kg (rat, oral)
2330 mg/kg (rat, oral)
2690 mg/kg (mouse, oral)[3]
4600 ppm (guinea pig, 8 hr)[3]
885 ppm (rat, 6 hr)
1840 ppm (rat, 4 hr)[3]
US health exposure limits (NIOSH):
TWA 25 ppm (140 mg/m3)[2]
TWA 4 ppm (23 mg/m3)[2]
200 ppm[2]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Isophorone is an α,β-unsaturated cyclic ketone, a colorless to yellowish liquid with a characteristic peppermint-like smell. It is used as a solvent and as an intermediate in organic synthesis.

Structure & reactivity

Isophorone is an α,β-unsaturated cyclic ketone (C9H14O). Isophorone can be degraded via a reaction with hydroxyl radicals which are formed via photochemistry. The half-life of the reaction is about five hours.[4]

Synthesis

Isophorone is not naturally available. Various techniques are available for obtaining isophorone. The most common and used method includes an self-condensation of acetone. For this reaction a dehydrogenated acetone allows one of the side faced carbon atoms to attack the central carbon atom (the carbonyl carbon) of another acetone molecule. Hereby a diacetone alcohol (4-hydroxy-4-methylpentan-2-one)(1) forms. A follow up dehydration reaction of diacetone alcohol yields (mesityl oxide)(2) and the rest product, water. Dehydrogenated acetone is then able to further react via an addition reaction with mesityl oxide (Michael reaction) to 4,4-dimethyl-2,6-dioxoheptan-1-ide (3), which successively attacks its own carbonyl carbon to form 3-hydroxy-3,5,5-trimethylcyclohexan-1-one(4). Finally a dehydration reaction of 3-hydroxy-3,5,5-trimethylcyclohexan-1-one forms isophorone.

For this reaction to occur in liquid phase mostly the catalyst magnesium aluminium double oxide is used. The magnesium aluminium double oxide has the following formula: Mg1-x Alx O1+x. Obtaining this molecule requires a, for example calcining hydrotalcites at temperatures lower than 800 °C. For the synthesis of isophorone to occur at vapor phase, the self-condensation reaction of acetone is carried out at temperatures above 200 °C.[5]

Available forms

Isophorone will be a vapor in the atmosphere mainly, due to the vapor pressure of 0.438 mm Hg at 25 °C.[4]

In aqueous solutions, isophorone forms different solvated species with various degrees of aggregation and hydration when exposed to direct sunlight. It especially forms three different tricyclic diketomers (Figure 1), when exposed to sunlight, a process known as photodimerization. The three tricyclic diketomers are cis-syn-cis head to tail (HT), cys-anti-cys (HT) and head-head (HH). The formation of HH photodimers is favored over HT photodimers with increasing polarity of the medium. The molecular weights of these compounds are twice of isophorone’s and the melting points range from 182 to 186.5 degrees Celcius.[6]

The proposed mechanism for the formation of the photodimers is that the oxygen of isophorone will be radicalized by the energy from the sunlight. The formed nucleophile will attack the double bound in the ringstructure from another isophorone, which will form a biradical and finally the HT or HH tricyclic diketomer.[6]

Derivatives

There are three different isophorone derivates, Isoa, Isob and Isoc.

Due to its cyclic structure, isophorone has been assigned to DNA binding in various studies. The Isoc form was found to have the highest affinity to DNA. DNA was found to be modified upon binding of isophorone derivatives. The Isob derivative interacts with the DNA leading to deformation of the right handed double helical structure.[7]

Metabolism

Exposure to isophorone can be through three different forms of exposure: inhalation, dermal or oral via drinking water.

Isophorone is capable of passing across epithelial membranes by these three exposure forms and becomes toxic after crossing the epithelial membranes.

Isophorone is well absorbed and soluble in water.[8] This means that it is most likely to be found in the urine. The following results are all derived from studies with rats.

Almost 93% of the isophorone that was taken up by oral exposure was excreted unchanged within 24h, mainly in the urine and in expired air. The distribution of isophorone was measured with radiolabeled 14-C. This isotope was widely distributed through all tissues. The highest concentrations after 24h were found in the liver, kidney and preputial glands.[9]

The urine also contained the following metabolites of isophorone:

· 3-carboxy-5 (methyloxidation)

· 5-dimethyl-2-cyclohexene-1-one (methyloxidation)

· glucuronic conjugates of 3,3,5-trimyethyl-2-cychlohexene-1-ol (isophorol) (reduction of ketone group), 3,5,5,-trimethylcyclohexanone (dihydroisophorone) (reduction of the double bond), cis- and trans-3,5,5-trimethylcyclohexanols (dismutation of dihydroisiophorone)[9]

· 5,5-dimethylcyclohex-1-en-3-one-1-carboxylic acid, which is excreted in unrine as ester glucuronide.[10] The allylic methyl group of isophorone was oxidized to a carboxylic acid group when industrial isophorone was administered orally to rabbits. The product was detected in urine and no other products were identified.[11]

Isophorone reacts with strong oxidants, strong bases and amines.

Indications

The odor detection threshold is the lowest concentration of a certain odor (fragrance) compound that is perceivable by the human sense of smell.[11]

Odor detection in air= 2.00 ppm. Purity not specified.[12]

Odor recognition in air= 5.40 ppm. Purity not specified.[12]

The LD50 value of isophorone in rats and rabbits by oral exposure is around the 2.00 g/kg.[10]

Efficacy

Exposures of isophorone to F344/N rats and B6C3F1 mice indicates that the chemical has a rather low potential of causing non-neoplastic lesions in both short- and long term studies. The results also suggest that isophorone causes neoplasms in male rats and perhaps in male mice.[13]

Adverse effects & animal effects

In a 2 year study it was found that the body weight of male rats was decreased with 5% where the body weight of female rats was decreased with 8% with respect to the control group. Furthermore the kidneys of male rats exposed to isophorone showed a variety of proliferative lesions which were significantly different from the control group. These included hyperplasia, adenoma, adenocarcinoma of the proximal tubule and hyperplasia of the transitional cell epithelium in the renal pelvis. There were no kidney neoplasms diagnosed in females.[13]

Another difference between male and female rats found in the study was that the levels of isophorone per gram tissue wet weight declined rapidly in males and very little in females, three hours after exposure.[4]

Isophorone exposure with some tumor types showed in some examples a positive correlation. The correlation for hepatocellular neoplasms had a positive trend (P < 0.05) for the high dose exposure compared to the control group (control, 18/48; high dose, 29/50). Hepatocellular neoplasms were observed in high does males more frequently than in the control group. For mesenchymal tumors it holds that in the control group 6/48 were diagnosed and for the high dose 14/50. These tumors consist mainly of subcutaneous fibro sarcomas.[13]

The effects of isophorone on the eye have been tested in rabbits, with a drop of isophorone to rabbit corneas, which causes transient injury, graded on a scale of 1 to 10 after 24 hours. The effect of isophorone on the eye is reversible.[14]

Toxicity

Isophorone has high solvent power for vinyl resins, cellulose esters, ether, and many substances soluble with difficulty in other solvents.[15] The reactive groups of the molecule are the ketones, hydrocarbons and aliphatic unsaturated parts.

Human volunteers that were exposed at 40, 850 200 and 400 ppm isophorone experienced nose-, throat- and eye irritation.[15] The eyes of humans already get irritated at 25 ppm, but have no persistent discomfort at 40 to 80 ppm. Objectionable irritation of the eyes and nose is experience at 200 to 400 ppm. It appears that isophorone has adequate warning properties, since objectionable sensation of irritation is experienced at concentrations which are not definitely injurious.[14]

Long term exposure

Long-term exposure to isophorone in humans can cause dizziness, fatigue and depression. Animal studies indicated that long-term inhalation of high concentrations of isophorone caused central nervous system effects. Limited evidence in animal studies suggests that isophorone may cause birth defects such as fetal malformations and growth retardation from inhalation exposure to isophorone during pregnancy. No information is available on the reproductive, developmental, or carcinogenic effects of isophorone in humans. EPA has classified isophorone as a Group C, possible human carcinogen.[9] This is based on non-human data and limited animal data.[12]

History

The use of isophorone as a solvent resulted from the search for ways to dispose of or recycle acetone, which is a waste product of phenol synthesis by the Hock method.[16]

Uses

Isophorone is used as a solvent in some printing inks, paints, lacquers, adhesives, copolymers, coatings, finishings and pesticides.[17] It is also used as a chemical intermediate and as an ingredient in wood preservatives and floor sealants.

See also

References

  1. ↑ Merck Index, 13th Edition, 5215.
  2. 1 2 3 4 5 6 "NIOSH Pocket Guide to Chemical Hazards #0355". National Institute for Occupational Safety and Health (NIOSH).
  3. 1 2 3 "Isophorone". Immediately Dangerous to Life and Health. National Institute for Occupational Safety and Health (NIOSH).
  4. 1 2 3 "TOXNET". toxnet.nlm.nih.gov. Retrieved 2016-03-11.
  5. ↑ Teissier, Remy; Kervennal, Jacques (15 Dec 1998), Process for obtaining isophorone, retrieved 2016-03-11
  6. 1 2 Gonçalves, Huguette; Robinet, Germaine; Barthelat, Michèle; Lattes, Armand (1998-01-28). "Supramolecularity and Photodimerization of Isophorone: FTIR and Molecular Mechanics Studies". The Journal of Physical Chemistry A 102 (8): 1279–1287. doi:10.1021/jp9729270.
  7. ↑ Deiana, Marco; Matczyszyn, Katarzyna; Massin, Julien; Olesiak-Banska, Joanna; Andraud, Chantal; Samoc, Marek (2015-06-12). "Interactions of Isophorone Derivatives with DNA: Spectroscopic Studies". PLoS ONE 10 (6). doi:10.1371/journal.pone.0129817. ISSN 1932-6203. PMC 4466397. PMID 26069963.
  8. ↑ Quincy. "National Fire Protection Association" (PDF). Retrieved 11 March 2016.
  9. 1 2 3 "ISOPHORONE - National Library of Medicine HSDB Database". toxnet.nlm.nih.gov. Retrieved 2016-03-11.
  10. 1 2 "Toxicity Effects". tools.niehs.nih.gov. Retrieved 2016-03-11.
  11. 1 2 "Odor detection threshold". Wikipedia, the free encyclopedia.
  12. 1 2 3 Pubchem. "ISOPHORONE | C9H14O - PubChem". pubchem.ncbi.nlm.nih.gov. Retrieved 2016-03-11.
  13. 1 2 3 Bucher, John R.; Huff, James; Kluwe, William M. (1986-05-01). "Toxicology and carcinogenesis studies of isophorone in F344 rats and B6C3F1 mice". Toxicology 39 (2): 207–219. doi:10.1016/0300-483X(86)90137-X.
  14. 1 2 W. Morton Grant, Joel S. Schuman M.D (11 February 2016). "Toxicology of the Eye: Effects on the Eyes and Visual System from Chemicals, Drugs, Metals and Minerals, Plants, Toxins, and Venoms; Also, Systemic Side Effects from Eye". med (2-Volume Set) 4th Edition, page 863.
  15. 1 2 "Toxicity Effects". tools.niehs.nih.gov. Retrieved 2016-03-11.
  16. ↑ Isophorone history at Degussa
  17. ↑ Chronic Toxicity Summary
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