ketone

Ketone group

Acetone

In organic chemistry, a ketone ( /ˈkiːtoʊn/) is an organic compound with the structure RC(=O)R', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group (C=O) bonded to two other carbon atoms.^[1] Many ketones are known and many are of great importance in industry and in biology. Examples include many sugars and the industrial solvent acetone.

Nomenclature and etymology

The word ketone derives its name from Aketon, an old German word for acetone.^[2]

According to the rules of IUPAC nomenclature, ketones are named by changing the suffix -e of the parent alkane to -one. For the most important ketones, however, traditional nonsystematic names are still generally used, for example acetone and benzophenone. These nonsystematic names are considered retained IUPAC names,^[3] although some introductory chemistry textbooks use names such as 2-propanone or propan-2-one instead of acetone, the simplest ketone (CH₃-CO-CH₃). The position of the carbonyl group is usually denoted by a number.

Although used infrequently, "oxo" is the IUPAC nomenclature for a ketone functional group. Other prefixes, however, are also used. For some common chemicals (mainly in biochemistry), "keto" or "oxo" is the term used to describe the ketone functional group. The term "oxo" is used widely through chemistry. For example, it also refers to an oxygen atom bonded to a transition metal (a metal oxo).

Structure and properties

Representative ketones, from the left: acetone, a common solvent; oxaloacetate, an intermediate in the metabolism of sugars; acetylacetone in its (mono) enol form (the enol highlighted in blue); cyclohexanone, precursor to Nylon; muscone, an animal scent; and tetracycline, an antibiotic.

The ketone carbon is often described as "sp² hybridized," terminology that describes both their electronic and molecular structure. Ketones are trigonal planar about the ketonic carbon, with C-C-O and C-C-C bond angles of approximately 120°. Ketones differ from aldehydes in that the carbonyl group (CO) is bonded to two carbons within a carbon skeleton. In aldehydes, the carbonyl is bonded to one carbon and one hydrogen and are located at the ends of carbon chains. Ketones are also distinct from other carbonyl-containing functional groups, such as carboxylic acids, esters and amides.^[4]

The carbonyl group is polar as a consequence of the fact that the electronegativity of the oxygen center is greater than that for carbonyl carbon. Thus, ketones are nucleophilic at oxygen and electrophilic at carbon. Because the carbonyl group interacts with water by hydrogen bonding, ketones are typically more soluble in water than the related methylene compounds. Ketones are hydrogen-bond acceptors. Ketones are not usually hydrogen-bond donors and cannot hydrogen-bond to itself. Because of their inability to serve both as hydrogen-bond donors and acceptors, ketones tend not to "self-associate" and are more volatile than alcohols and carboxylic acids of comparable molecular weights. These factors relate to pervasiveness of ketones in perfumery and as solvents.

A ketone that has an α-hydrogen participates in a so-called keto-enol tautomerism. The reaction with a strong base gives the corresponding enolate, often by deprotonation of the enol.

Classes of ketones

Ketones are classified on the basis of their substituents. One broad classification subdivides ketones into symmetrical and unsymmetrical derivatives, depending on the equivalency of the two organic substituents attached to the carbonyl center. Acetone and benzophenone (C₆H₅C(O)C₆H₅) are symmetrical ketones. Acetophenone (C₆H₅C(O)CH₃) is an unsymmetrical ketone. In the area of stereochemistry, unsymmetrical ketones are known for being prochiral.

Diketones

Many kinds of diketones are known, some with unusual properties. The simplest is diacetyl (CH₃C(O)C(O)CH₃), once used as butter-flavoring in popcorn. Acetylacetone (pentane-2,4-dione) is virtually a misnomer (inappropriate name) because this species exists mainly as the monoenol CH₃C(O)CH=C(OH)CH₃. Its enolate is a common ligand in coordination chemistry.

Unsaturated ketones

Ketones containing alkene and alkyne units are often called unsaturated ketones. The most widely used member of this class of compounds is methyl vinyl ketone, CH₃C(O)CH=CH₂, which is useful in Robinson annulation reaction. Lest there be confusion, a ketone itself is a site of unsaturation; that is, it can be hydrogenated.

Cyclic ketones

Many ketones are cyclic. The simplest class have the formula (CH₂)_nCO, where n varies from 3 for cyclopropanone to the teens. Larger derivatives exist. Cyclohexanone, a symmetrical cyclic ketone, is an important intermediate in the production of nylon. Isophorone, derived from acetone, is an unsaturated, unsymmetrical ketone that is the precursor to other polymers. Muscone, 3-methylpentadecanone, is an animal pheromone.

Keto-enol tautomerization

Keto-enol tautomerism. 1 is the keto form; 2 is the enol.

Ketones that have at least one alpha-hydrogen, undergo keto-enol tautomerization; the tautomer is an enol. Tautomerization is catalyzed by both acids and bases. Usually, the keto form is more stable than the enol. This equilibrium allows ketones to be prepared via the hydration of alkynes.

Acidity of ketones

Ketones are far more acidic (pKa ≈ 20) than a regular alkane (pKa ≈ 50). This difference reflects resonance stabilization of the enolate ion that is formed through dissociation. The relative acidity of the α-hydrogen is important in the enolization reactions of ketones and other carbonyl compounds. The acidity of the α-hydrogen also allows ketones and other carbonyl compounds to undergo nucleophilic reactions at that position, with either stoichiometric and catalytic base.

Characterization

Spectroscopy

Ketones and aldehydes absorb strongly in infra-red spectrum near 1700 cm⁻¹. The exact position of the peak depends on the substituents.

Whereas ¹H NMR spectroscopy is, in general, not useful for establishing the presence of a ketone, ¹³C NMR spectra exhibit signals somewhat downfield of 200 ppm depending on structure. Such signals are typically weak due to the absence of nuclear Overhauser effects. Since aldehydes resonate at similar chemical shifts, multiple resonance experiments are employed to definitively distinguish aldehydes and ketones.

Qualitative organic tests

Ketones give positive results in Brady's test, the reaction with 2,4-dinitrophenylhydrazine to give the corresponding hydrazone. Ketones may be distinguished from aldehydes by giving a negative result with Tollens' reagent or with the Fehling's solution. Methyl ketones give positive results for the iodoform test.^[5]

Synthesis

Many methods exist for the preparation of ketones in industrial scale, biology, and in academic laboratories. In industry, the most important method probably involves oxidation of hydrocarbons, often with air. For example, a billion kilograms of cyclohexanone are produced annually by aerobic oxidation of cyclohexane. Acetone is prepared by air-oxidation of cumene.

For specialized or small scale organic synthetic applications, ketones are often prepared by oxidation of secondary alcohols:

R₂CH(OH) + O → R₂C=O + H₂O

Typical strong oxidants (source of "O" in the above reaction) include potassium permanganate or a Cr(VI) compound. Milder conditions make use of the Dess-Martin periodinane or the Moffatt-Swern methods.

Many other methods have been developed including:^[6]

• By geminal halide hydrolysis.
• By hydration of alkynes. Such processes occur via enols and require the presence of an acid and HgSO₄. Subsequent enol-keto tautomerization gives a ketone. This reaction always produces a ketone, even with a terminal alkyne.
• From Weinreb Amides using stoichiometric organometallic reagents.
• Aromatic ketones can be prepared in the Friedel-Crafts acylation, the related Houben-Hoesch reaction and the Fries rearrangement.
• Ozonolysis, and related dihydroxylation/oxidative sequences, cleave alkenes to give aldehydes and/or ketones, depending on alkene substitution pattern.
• In the Kornblum–DeLaMare rearrangement ketones are prepared from peroxides and base.
• In the Ruzicka cyclization, cyclic ketones are prepared from dicarboxylic acids.
• In the Nef reaction, ketones form by hydrolysis of salts of secondary nitro compounds.
• In the Fukuyama coupling, ketones form from a thioester and an organozinc compound.
• By the reaction of an acid chloride with organocadmium compounds or organocopper compounds.
• The Dakin-West reaction provides an efficient method for preparation of certain methyl ketones from carboxylic acids.
• Ketones can also be prepared by the reaction of Grignard reagents with nitriles, followed by hydrolysis.
• By decarboxylation of carboxylic anhydride.
• Ketones can be prepared from haloketones in reductive dehalogenation of halo ketones.

Reactions

Ketones engage in many organic reactions. The most important reactions follow from the susceptibility of the carbonyl carbon toward nucleophilic addition and the tendency for the enolates to add to electrophiles. Nucleophilic additions include in approximate order of their generality:^[6]

• With water (hydration) gives geminal diols, which are usually not formed in appreciable (or observable) amounts
• With an acetylide to give the α-hydroxyalkyne
• With ammonia or a primary amine gives an imine
• With secondary amine gives an enamine
• With Grignard and organolithium reagents to give, after aqueous workup, a tertiary alcohol
• With an alcohols or alkoxides to gives the hemiketal or its conjugate base. With a diol to the ketal. This reaction is employed to protect ketones.
• With sodium amide resulting in C-C bond cleavage with formation of the amide RCONH₂ and the alkane R'H, a reaction called the Haller-Bauer reaction.^[7]

Electrophilic addition, reaction with an electrophile gives a resonance stabilized cation

• With phosphonium ylides in the Wittig reaction to give the alkenes
• With thiols to give the thioacetal
• With hydrazine or 1-disubstituted derivatives of hydrazine to give hydrazones.
• With a metal hydride gives a metal alkoxide salt, hydrolysis of which gives the alcohol, an example of ketone reduction
• With halogens to form α-haloketone, a reaction that proceeds via an enol (see Haloform reaction)
• With heavy water to give a α-deuterated ketone
• Fragmentation in photochemical Norrish reaction
• Reaction of 1,4-aminodiketones to oxazoles by dehydration in the Robinson-Gabriel synthesis
• In the case of aryl-alkyl ketones, with sulfur and an amine give amides in the Willgerodt reaction
• With hydroxylamine to produce oximes

Biochemistry

Ketones are pervasive in nature. The formation of organic compounds in photosynthesis occurs via the ketone ribulose-1,5-bisphosphate. Many sugars are ketones, known collectively as ketoses. The best known ketose is fructose, which exists as a cyclic hemiketal, which masks the ketone functional group. Fatty acid synthesis proceeds via ketones. Acetoacetate is an intermediate in the Kreb cycle which releases energy from sugars and carbohydrates.^[8]

In medicine, acetone, acetoacetate, and beta-hydroxybutyrate are collectively called ketone bodies, generated from carbohydrates, fatty acids, and amino acids in most vertebrates, including humans. Ketones are elevated in blood after fasting including a night of sleep, and in both blood and urine in starvation, hypoglycemia due to causes other than hyperinsulinism, various inborn errors of metabolism, and ketoacidosis (usually due to diabetes mellitus). Although ketoacidosis is characteristic of decompensated or untreated type 1 diabetes, ketosis or even ketoacidosis can occur in type 2 diabetes in some circumstances as well.

Applications

Ketones are produced on massive scales in industry as solvents, polymer precursors, and pharmaceuticals. In terms of scale, the most important ketones are acetone, methylethyl ketone, and cyclohexanone.^[9] They are also common in biochemistry, but less so than in organic chemistry in general. The combustion of hydrocarbons is an uncontrolled oxidation process that gives ketones as well as many other types of compounds.

Toxicity

Although it is difficult to generalize on the toxicity of such a broad class of compounds, simple ketones are, in general, not highly toxic (for instance, the sugar fructose is a ketone). This characteristic is one reason for their popularity as solvents. Exceptions to this rule are the unsaturated ketones such as methyl vinyl ketone with LD₅₀ of 7 mg/kg (oral).^[9]

See also

• Thioketone
• Ketone bodies

References

1. ^ IUPAC Gold Book ketones
2. ^ http://www.etymonline.com/index.php?term=ketone Online Etymology Dictionary
3. ^ List of retained IUPAC names retained IUPAC names Link
4. ^ McMurry, John E. (1992), Organic Chemistry (3rd ed.), Belmont: Wadsworth, ISBN 0-534-16218-5 
5. ^ Mendham, J.; Denney, R. C.; Barnes, J. D.; Thomas, M.J.K.; Denney, R. C.; Thomas, M. J. K. (2000), Vogel's Quantitative Chemical Analysis (6th ed.), New York: Prentice Hall, ISBN 0-582-22628-7 
6. ^ ^{a b} Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.), New York: Wiley-Interscience, ISBN 0-471-72091-7, http://books.google.com/books?id=JDR-nZpojeEC&printsec=frontcover 
7. ^ Haller-Bauer Reaction
8. ^ Nelson, D. L.; Cox, M. M. "Lehninger, Principles of Biochemistry" 3rd Ed. Worth Publishing: New York, 2000. ISBN 1-57259-153-6.
9. ^ ^{a b} Hardo Siegel, Manfred Eggersdorfer "Ketones" in Ullmann's Encyclopedia of Industrial Chemistry, 2005, Wiley-VCH, Weinheim.doi:10.1002/14356007.a15_077