ketone

Ketone group

In organic chemistry, a ketone (pronounced /ˈkiːtoʊn/ KEE-toan) is a type of compound that features a carbonyl group (C=O) bonded to two other carbon atoms, i.e., R₃CCO-CR₃ where R can be a variety of atoms and groups of atoms.^[1] With carbonyl carbon bonded to two carbon atoms, ketones are distinct from many other functional groups, such as carboxylic acids, aldehydes, esters, amides, and other oxygen-containing compounds. The double-bond of the carbonyl group distinguishes ketones from alcohols and ethers.

A carbon atom adjacent to a carbonyl group is called an α-carbon. Hydrogen atoms attached to these α-carbon centers are called α-hydrogens. Ketones with α-hydrogen centers participate in a so-called keto-enol tautomerism. The reaction with a strong base gives the corresponding enolate, often by deprotonation of the enol.

Nomenclature

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 used virtually exclusively, e.g. acetone and benzophenone. These nonsystematic names are considered retained IUPAC names.^[2], although some introductory chemistry textbooks use names such as 2-propanone instead of acetone, the simplest ketone (CH₃-CO-CH₃). The position of the carbonyl group is usually denoted by a number.

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 that describes the ketone functional group. The term "oxo" is used widely through chemistry, for example it also refers to a single oxygen atom coordinated to a transition metal (a metal oxo).

Structure and properties

Repesentative 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°.

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 a 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.

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 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 biacetyl (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 a animal pheromone.

Keto-enol tautomerization

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

Ketones that have at least one Éø-hydrogen center, undergo keto-enol tautomerization; the tautomer is an enol. Tautomerization may be 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 the a regular alkane (pKa ≈ 50). This difference reflects resonance stabilization of the enolate ion that is formed through dissociation. The relative acidity of the Éø-hydrogen is important in the enolization reactions of ketones and other carbonyl compounds. The acidity of the Éø-hydrogen also allows ketones and other carbonyl compounds to undergo nucleophilic reactions at that position, with either stoichiometric or catalytic base.

Characterization

Spectroscopy

Ketones and aldehydes display an intense absorption in infra-red spectrum near 1700 cm⁻¹. The peak can occur at slightly higher or lower energies, depending on the substituents.

Whereas ¹H NMR spectroscopy is generally 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 NoE 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. Methyl ketones give positive results for the iodoform test.

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. For example, billion kilograms of cyclohexanone are produced annually by aerobic oxidation of cyclohexane. The oxidation of secondary alcohols is also common:

H₃C-CH(OH)-CH₃ + O → H₃C-CO-CH₃ + H₂O

Typically, such oxidations employ air or oxygen for industrial processes. For specialized applications, such reactions rely on a strong oxidant such as potassium permanganate or a Cr(VI) compound. Milder conditions such as use of the Dess-Martin periodinane or the Moffatt-Swern oxidation are commonly employed in organic synthesis.

Many other methods have been developed including:

• Ketones can be prepared by geminal halide hydrolysis.
• Alkynes can be converted to enols through a hydration reaction in the presence of an acid and HgSO₄, and subsequent enol-keto tautomerization gives a ketone. This reaction always produces a ketone, even with a terminal alkyne.
• 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.
• Ketones can be prepared 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.

Reactions

Ketones engage in many organic reactions but 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:

• reaction with water (hydration) gives geminal diols
• the reaction with the anion of a terminal alkyne gives a hydroxyalkyne
• the reaction with ammonia or a primary amine gives an imine + water
• the reaction with secondary amine gives an enamine + water
• the reaction with a Grignard reagent or organolithium reagent to give, after aqueous workup, a tertiary alcohol
• the reaction with an alcohol, an acid or base gives a hemiketal and water and further reaction with an alcohol gives the ketal + water. This is a carbonyl-protecting reaction.
• reaction of RCOR' with sodium amide results in cleavage with formation of the amide RCONH2 and the alkane R'H, a reaction called the Haller-Bauer reaction.^[3]
• Electrophilic addition, reaction with an electrophile gives a resonance stabilized cation.
• the reaction with phosphonium ylides in the Wittig reaction gives alkenes
• reaction with thiols gives a thioacetal
• reaction with hydrazine or derivatives of hydrazine gives hydrazones
• reaction with a metal hydride gives a metal alkoxide salt and then with water an alcohol
• reaction of an enol with halogens to form α-haloketone
• a reaction at an α-carbon is the reaction of a ketone with heavy water to give a deuterated ketone-d.
• fragmentation in photochemical Norrish reaction
• reaction with halogens and base of methyl ketones in the Haloform reaction
• reaction of 1,4-aminodiketones to oxazoles by dehydration in the Robinson-Gabriel synthesis
• reaction of aryl alkyl ketones with sulfur and an amine to amides in the Willgerodt reaction

Biochemistry

Acetone, acetoacetate and beta-hydroxybutyrate are ketones (or ketone bodies) generated from carbohydrates, fatty acids and amino acids in humans and most vertebrates. 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. Acetoacetate and beta-hydroxybutyrate are an important fuel for many tissues, especially during fasting and starvation. The brain, in particular, relies heavily on ketone bodies as a substrate for lipid synthesis and for energy during times of reduced food intake. Ketones have been described as "magic" in their ability to increase metabolic efficiency, while decreasing production of free radicals, the damaging byproducts of normal metabolism. Ketone bodies are relevant to neurological diseases such as Alzheimer's and Parkinson's disease,^[4] and the heart and brain operate 25% more efficiently using ketones as a source of energy.^[5] Research has also shown ketones play a role in reducing epileptic seizures with the so-called high-fat, near-zero carbohydrate Ketogenic Diet. [1]

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. 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 give 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 generally not highly toxic. 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).

References

1. ^ International Union of Pure and Applied Chemistry. "ketones". Compendium of Chemical Terminology Internet edition.
2. ^ List of retained IUPAC names retained IUPAC names Link
3. ^ Haller-Bauer Reaction
4. ^ Y. Kashiwaya, T. Takeshima, N. Mori, K. Nakashima, K. Clarke and R. L. Veech (2000). "D-beta -Hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease". PNAS 97 (10): 5440–5444. doi:10.1073/pnas.97.10.5440. PMID 10805800. 
5. ^ Y. Kashiwaya, K. Sato, N. Tsuchiya, S. Thomas, D. A. Fell, R. L. Veech and J. V. Passonneau (1994). "Control of glucose utilization in working perfused rat heart". J. Biol. Chem. 269 (41): 25502–25514. PMID 7929251. http://www.jbc.org/cgi/content/abstract/269/41/25502. 

External links

• Berkeley Organic Chemistry Lecture on Aldehydes and Ketones