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Pinacolone
View on Wikipediafrom Wikipedia
| |||
| Names | |||
|---|---|---|---|
| Preferred IUPAC name
3,3-Dimethylbutan-2-one | |||
| Other names
t-Butyl methyl ketone
1,1,1-Trimethylacetone | |||
| Identifiers | |||
3D model (JSmol)
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| 1209331 | |||
| ChEBI | |||
| ChemSpider | |||
| ECHA InfoCard | 100.000.838 | ||
| EC Number |
| ||
| MeSH | Pinacolone | ||
PubChem CID
|
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| RTECS number |
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| UNII | |||
| UN number | 1224 | ||
CompTox Dashboard (EPA)
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| |||
| |||
| Properties | |||
| C6H12O | |||
| Molar mass | 100.161 g·mol−1 | ||
| Appearance | Colorless liquid | ||
| Density | 0.801 g cm−3 | ||
| Melting point | −52[1] °C (−62 °F; 221 K) | ||
| Boiling point | 103 to 106 °C (217 to 223 °F; 376 to 379 K) | ||
| −69.86·10−6 cm3/mol | |||
| Hazards | |||
| GHS labelling: | |||
 
| |||
| Danger | |||
| H225, H302, H315, H319, H332, H335, H412 | |||
| P210, P233, P240, P241, P242, P243, P261, P264, P270, P271, P273, P280, P301+P312, P302+P352, P303+P361+P353, P304+P312, P304+P340, P305+P351+P338, P312, P321, P330, P332+P313, P337+P313, P362, P370+P378, P403+P233, P403+P235, P405, P501 | |||
| NFPA 704 (fire diamond) | |||
| Flash point | 5 °C (41 °F; 278 K) | ||
| Safety data sheet (SDS) | External MSDS | ||
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Pinacolone (3,3-dimethyl-2-butanone) is an important ketone in organic chemistry. It is a colorless liquid with a slight peppermint or camphor odor. It is a precursor to triazolylpinacolone in the synthesis of the fungicide triadimefon and in synthesis of the herbicide metribuzin. The molecule is an unsymmetrical ketone. The α-methyl group can participate in condensation reactions. The carbonyl group can undergo the usual reactions (hydrogenation, reductive amination, etc.). It is a Schedule 3 compound under the Chemical Weapons Convention 1993, due to being related to pinacolyl alcohol, which is used in the production of soman.[2] It is also a controlled export in Australia Group member states.[3]
Preparation
[edit]Most famously, at least in the classroom, pinacolone arises by the pinacol rearrangement, which occurs by protonation of pinacol (2,3-dimethylbutane-2,3-diol).[4]
Industrially pinacolone is made by the hydrolysis of 4,4,5-trimethyl-1,3-dioxane, which is the product of isoprene and formaldehyde via the Prins reaction. It also is generated by ketonization of pivalic acid and acetic acid or acetone over metal oxide catalysts. 3-Methylbutanal is a starting material for 2,3-dimethyl-2-butene, which in turn is converted to pinacolone. Pinacolone can also be produced from 2-methy-2-butanol when reacted with C5 alcohols.[5]
Uses
[edit]Pinacolone is produced in large amounts for use in fungicides, herbicides, and pesticides. Some derivatives include:
- retrosynthetic analysis of vibunazole showed that it was derived from pinacolone.[original research?]
- It is also used to prepare pinacidil, as well as naminidil.
- Stiripentol
- Tribuzone
- Pivaloylacetonitrile is used in the synthesis of Doramapimod.
- Triadimefon
- Diclobutrazole
- Paclobutrazol
- Valconazole
- Diethylstilbestrol pinacolone [18922-13-9].[6]
- Some kind of Bisphenol A derivative also U.S. patent 4,599,463
- Thiofanox
See also
[edit]References
[edit]- ^ "Pinacolone | C6H12O | ChemSpider".
- ^ Handbook of chemical and biological warfare agents (2nd ed.). CRC Press. 24 August 2007. ISBN 9780849314346.
- ^ "Export Control List: Chemical Weapons Precursors". Australia Group. australiagroup.net. Retrieved 7 April 2017.
- ^ G. A. Hill and E. W. Flosdorf (1941). "Pinacolone". Organic Syntheses; Collected Volumes, vol. 1, p. 462.
- ^ Siegel, H; Eggersdorfer (2012). Ketones. 5. Vol. 20. doi:10.1002/14356007.a15_077. ISBN 9783527306732.
{{cite book}}:|journal=ignored (help) - ^ Oda, T; Sato, Y; Kodama, M; Kaneko, M (July 1993). "Inhibition of DNA topoisomerase I activity by diethylstilbestrol and its analogues". Biological & Pharmaceutical Bulletin. 16 (7): 708–10. doi:10.1248/bpb.16.708. PMID 8401407.
Pinacolone
View on Grokipediafrom Grokipedia
Pinacolone, systematically named 3,3-dimethylbutan-2-one, is an organic ketone with the molecular formula C₆H₁₂O and CAS number 75-97-8.[1] It appears as a colorless liquid with a characteristic odor reminiscent of camphor and is notable as the prototypical product of the pinacol-pinacolone rearrangement, an acid-catalyzed reaction converting vicinal diols to carbonyl compounds first observed in 1860.[2][3]
This rearrangement, involving the dehydration and 1,2-migration of a methyl group from pinacol (2,3-dimethylbutane-2,3-diol), exemplifies migratory aptitude in carbocation intermediates and remains a fundamental demonstration in organic chemistry education and synthesis.[4] Pinacolone functions primarily as a synthetic intermediate, employed in the production of pharmaceuticals with antibacterial, antifungal, antiviral, and antituberculous properties, as well as agrochemicals such as the fungicide triadimefon and the herbicide metribuzin.[5] Its simple structure and reactivity make it valuable for constructing more complex molecules, though industrial preparation often favors alternative routes like the reaction of acetone with acids for scalability.[6]
Pinacolone is classified as a flammable liquid under GHS criteria, with a flash point ranging from 5 °C to 23 °C and a boiling point of 106 °C, enabling vapors to form explosive mixtures with air at concentrations between 1.3% and 8.8% by volume.[1][5] Containers may rupture from pressure buildup under fire conditions, and vapors can travel to ignition sources, posing explosion risks indoors or in sewers.[28] The NFPA 704 rating assigns it a flammability hazard of 3 (serious fire risk), health hazard of 1 (slight acute toxicity), and reactivity of 0 (stable).[29] Exposure to pinacolone presents acute health risks primarily through ingestion and inhalation. Oral administration is harmful, evidenced by an LD50 of 610 mg/kg in rats, corresponding to GHS category 4 toxicity.[30][29] Inhalation of vapors may irritate the respiratory tract, with an LC50 of 5,700 mg/m³ in mice indicating moderate hazard potential.[29] Contact with skin or eyes can cause irritation, though no severe corrosive effects are reported.[28] No data indicate chronic effects, carcinogenicity, reproductive toxicity, or mutagenicity.[31] Safe handling protocols mandate use in well-ventilated areas or under fume hoods to minimize vapor exposure, with ignition sources prohibited. Personal protective equipment includes chemical-resistant gloves, safety goggles, and protective clothing; in case of fire, self-contained breathing apparatus and full protective gear are required.[30][31] Storage should occur in cool, grounded containers within approved flammable-liquid cabinets, away from incompatibles like strong oxidizers.[28]
Structure and Properties
Molecular Structure and Nomenclature
Pinacolone, with the molecular formula C₆H₁₂O, features a ketone functional group where the carbonyl carbon is bonded to a methyl group (CH₃) and a tert-butyl group (C(CH₃)₃), resulting in the condensed structural formula CH₃C(O)C(CH₃)₃.[1][7] This unsymmetrical structure places the carbonyl between a primary carbon chain and a branched tertiary carbon, contributing to its distinct reactivity profile as a methyl ketone.[1] The systematic IUPAC name for pinacolone is 3,3-dimethylbutan-2-one, derived from the parent butan-2-one chain with two methyl substituents at the 3-position to accommodate the branched tert-butyl moiety.[1][7] Alternative systematic nomenclature may refer to it as pinacolin in some contexts, though 3,3-dimethylbutan-2-one is the preferred IUPAC designation.[7] The retained trivial name "pinacolone" stems from its historical preparation via the pinacol rearrangement, but it lacks official IUPAC retention status for general use.[1]Physical Properties
Pinacolone appears as a colorless to light yellow liquid at room temperature, exhibiting a peppermint- or camphor-like odor.[1] Its melting point is reported as −52.5 °C, while the boiling point ranges from 103 to 106 °C at standard atmospheric pressure, with a literature value of 106 °C.[1][8][5] The density measures 0.801 g/mL at 25 °C, and the refractive index is 1.396 at 20 °C.[8][5] Pinacolone is sparingly soluble in water, with a solubility of approximately 2.44 g/100 mL at 15 °C, but it is miscible with common organic solvents such as alcohol, ether, acetone, benzene, and chloroform.[9][10] Vapor pressure is 33 hPa at 20 °C.[5]Chemical Properties and Reactivity
Pinacolone, systematically named 3,3-dimethylbutan-2-one, functions as a methyl ketone with the carbonyl group flanked by a methyl and a tert-butyl substituent, imparting asymmetry and steric bulk to its reactivity profile.[1] The electrophilic carbonyl carbon readily undergoes nucleophilic addition reactions, including reduction via hydrogenation or hydride reagents to yield the secondary alcohol pinacolyl alcohol, as well as reductive amination to form amines.[11] These additions are typical of ketones but moderated by the tert-butyl group's steric hindrance, which elevates the activation barrier for approaching nucleophiles compared to less substituted analogs like acetone.[12] The α-methyl group's three hydrogens enable enolization exclusively toward that side, as the tert-butyl lacks α-protons, directing subsequent reactivity such as aldol condensations or α-halogenations to the methyl substituent.[1] This regioselectivity arises from the absence of enolizable hydrogens on the quaternary carbon, limiting reactivity to the less hindered methyl flank. As a methyl ketone, pinacolone participates in the haloform reaction under halogenating conditions with base, cleaving to iodoform (or analogous haloform) and pivalic acid, exploiting the methyl group's susceptibility to trihalogenation followed by C-C bond fission.[1] Overall, pinacolone's reactivity balances standard ketone behavior with steric constraints that favor smaller reagents and suppress side reactions from the hindered face, rendering it useful in selective synthetic transformations.[11]Synthesis
Laboratory Synthesis via Pinacol Rearrangement
The pinacol rearrangement provides a straightforward laboratory route to pinacolone from pinacol (2,3-dimethylbutane-2,3-diol), involving acid-catalyzed dehydration and 1,2-methyl migration to form 3,3-dimethylbutan-2-one. First reported by Wilhelm Rudolph Fittig in 1860, this method exemplifies early observations of carbocation-mediated skeletal rearrangements in organic chemistry.[13] In a standard procedure, 1 kg of pinacol hydrate is distilled with 750 g of 6 N sulfuric acid in a 2-L round-bottom flask equipped with a dropping funnel and condenser, typically in multiple batches of 250 g pinacol hydrate each treated with 60 mL concentrated sulfuric acid. The mixture is heated until the upper pinacolone layer ceases to increase (15–20 minutes per batch), followed by separation of the organic layer, drying over calcium chloride, filtration, and fractional distillation at 103–107°C/760 mmHg. This yields 287–318 g (65–72% theoretical) of purified pinacolone, with redistillation to remove trace yellow impurities.[13] Alternative conditions employ 50% phosphoric acid or hydrated oxalic acid under reflux for 3–4 hours, affording 60–65% yields, while using recrystallized pinacol hydrate boosts efficiency by approximately 4%.[13] The mechanism initiates with protonation of one tertiary hydroxyl group, expelling water to generate a resonance-stabilized tertiary carbocation at the adjacent carbon. A methyl substituent then migrates antiperiplanar to the leaving group, with the shifting electrons forming the carbonyl bond as the oxygen deprotonates, favoring the product due to the stability of the tertiary carbocation and high migratory aptitude of methyl over hydrogen.[14] This process is reversible under acidic conditions, as pinacolone can dehydrate back to alkenes or reform diols, but equilibrium favors the ketone under distillation.[14]Industrial Production Methods
Pinacolone is manufactured industrially via the acid-catalyzed pinacol rearrangement, in which pinacol hydrate (2,3-dimethylbutane-2,3-diol monohydrate) is distilled with dilute sulfuric acid, typically achieving nearly quantitative yields after separation by distillation.[1] This method leverages the dehydration and 1,2-methyl migration inherent to the rearrangement, with reaction conditions involving heating to reflux in 10-20% H₂SO₄, followed by phase separation and purification.[5] To circumvent the multi-step synthesis of pinacol from acetone reduction (using aluminum or magnesium amalgam), which incurs high energy and reagent costs, alternative routes have been patented for direct production from alkenes. One process reacts 2-methylbut-2-ene (or 2-methylbut-1-ene) with 0.5-1.5 moles of formaldehyde (as aqueous solution or paraformaldehyde) in 15-40% aqueous HCl or H₂SO₄ at 50-200°C and 1-20 bar pressure, with yields reaching 75% of theory after azeotropic distillation.[15] This single-step approach accommodates industrial butene feedstocks, halves formaldehyde consumption relative to prior methods, and minimizes by-products for better economics and reduced waste.[15] Refinements include adding acid-soluble salts (e.g., NaCl or CaCl₂) to enhance solubility and reaction efficiency in similar alkene-formaldehyde-acid systems, enabling aqueous phase recycling and supporting batch or continuous operations with yields up to 75.8%.[16] These processes, developed in the late 1970s, prioritize scalability using commodity chemicals over the traditional diol route.[16]Applications
Use as a Synthetic Intermediate in Pharmaceuticals
Pinacolone serves as a versatile synthetic intermediate in the pharmaceutical sector, primarily due to its methyl ketone functionality and sterically hindered tert-butyl group, which enable the construction of complex molecular scaffolds resistant to metabolic degradation. Its applications include the formation of precursors for active pharmaceutical ingredients (APIs) exhibiting antibacterial, antiviral, and anti-inflammatory properties, as well as contributions to hormone-related therapies.[17][11] A specific historical example is its involvement in the synthesis of diethylstilbestrol, a nonsteroidal synthetic estrogen developed in the 1930s for menopausal symptoms and other endocrine treatments, achieved through a route leveraging pinacol-pinacolone rearrangement intermediates to assemble the central stilbene structure.[18] Pinacolone has also been employed as a building block for certain steroids and hormones, providing the necessary alkyl branching in their side chains.[19] While its pharmaceutical utility is documented, production volumes for such applications remain smaller compared to agrochemical uses, reflecting targeted rather than broad-scale adoption in drug manufacturing.[1]Role in Pesticide Synthesis
Pinacolone functions as a versatile synthetic intermediate in the production of triazole-based pesticides, where its ketone moiety facilitates key condensation and cyclization reactions to form heterocyclic structures essential for biological activity. It is employed in the manufacture of fungicides such as triadimefon and triadimenol, which inhibit ergosterol biosynthesis in fungi, and herbicides like metribuzin, which disrupt photosynthesis in target weeds.[20][21] In the synthesis of plant growth regulators with pesticidal applications, pinacolone serves as a building block for compounds including paclobutrazol and uniconazole, which modulate gibberellin levels to control excessive vegetative growth in crops while exhibiting indirect pest management benefits through enhanced plant resilience. These triazole derivatives are produced via reactions involving pinacolone's carbonyl group with hydrazines or azides, followed by chlorination and substitution steps.[9][21] Recent research has explored pinacolone-containing sulfonamide derivatives as potent antifungal agents against Botrytis cinerea, a fungal pathogen affecting grapes and other crops; structure-activity relationship studies indicate that the pinacolone scaffold enhances inhibitory efficacy comparable to commercial fungicides like boscalid, with EC50 values as low as 0.82 mg/L for select analogs.[22][23] However, these remain in the developmental stage and are not yet commercialized. Overall, pinacolone's industrial-scale production supports the synthesis of over 20 pesticide variants, underscoring its economic importance in agricultural chemistry.[22]Other Industrial and Research Applications
Pinacolone serves as a solvent in certain organic synthesis processes due to its low viscosity and compatibility with various reagents.[6] It has been investigated as a potential "green" solvent alternative, with studies examining its atmospheric oxidation pathways to assess environmental persistence. In the flavors and fragrances industry, pinacolone contributes to the production of specialty perfumes and food flavorings, leveraging its distinct aromatic properties, such as a peppermint-like odor.[17] [24] In organic chemistry research, pinacolone is frequently employed as a model compound to investigate the pinacol-pinacolone rearrangement, providing insights into carbocation migration and acid-catalyzed dehydration mechanisms.[14] Studies have optimized reaction conditions, such as acid concentration and solvent-free methods under microwave irradiation, to enhance selectivity and yield in this transformation.[25] [26] Its role extends to broader applications in semipinacol rearrangements for constructing quaternary carbon centers in complex molecules.[27]Safety, Toxicity, and Environmental Considerations
Health and Safety Hazards
Pinacolone is classified as a flammable liquid under GHS criteria, with a flash point ranging from 5 °C to 23 °C and a boiling point of 106 °C, enabling vapors to form explosive mixtures with air at concentrations between 1.3% and 8.8% by volume.[1][5] Containers may rupture from pressure buildup under fire conditions, and vapors can travel to ignition sources, posing explosion risks indoors or in sewers.[28] The NFPA 704 rating assigns it a flammability hazard of 3 (serious fire risk), health hazard of 1 (slight acute toxicity), and reactivity of 0 (stable).[29] Exposure to pinacolone presents acute health risks primarily through ingestion and inhalation. Oral administration is harmful, evidenced by an LD50 of 610 mg/kg in rats, corresponding to GHS category 4 toxicity.[30][29] Inhalation of vapors may irritate the respiratory tract, with an LC50 of 5,700 mg/m³ in mice indicating moderate hazard potential.[29] Contact with skin or eyes can cause irritation, though no severe corrosive effects are reported.[28] No data indicate chronic effects, carcinogenicity, reproductive toxicity, or mutagenicity.[31] Safe handling protocols mandate use in well-ventilated areas or under fume hoods to minimize vapor exposure, with ignition sources prohibited. Personal protective equipment includes chemical-resistant gloves, safety goggles, and protective clothing; in case of fire, self-contained breathing apparatus and full protective gear are required.[30][31] Storage should occur in cool, grounded containers within approved flammable-liquid cabinets, away from incompatibles like strong oxidizers.[28]