organic chemistry Organic chemistry is a subdiscipline within chemistry involving the science, scientific study of the structure, properties, and reactions of organic compounds and organic matter, organic materials, i.e., matter in its various forms that contain ...

, an α-halo ketone is a

functional group In organic chemistry, a functional group is any substituent or moiety (chemistry), moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions r ...

consisting of a

ketone In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...

group or more generally a

carbonyl In organic chemistry, a carbonyl group is a functional group with the formula , composed of a carbon atom double bond, double-bonded to an oxygen atom, and it is divalent at the C atom. It is common to several classes of organic compounds (such a ...

group with an α-

halogen The halogens () are a group in the periodic table consisting of six chemically related elements: fluorine (F), chlorine (Cl), bromine (Br), iodine (I), and the radioactive elements astatine (At) and tennessine (Ts), though some authors would ...

substituent In organic chemistry, a substituent is one or a group of atoms that replaces (one or more) atoms, thereby becoming a moiety in the resultant (new) molecule. The suffix ''-yl'' is used when naming organic compounds that contain a single bond r ...

. α-Halo ketones are

alkylating agent Alkylation is a chemical reaction that entails transfer of an alkyl group. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecting ...

s. Prominent α-halo ketones include

phenacyl bromide Phenacyl bromide is the organic compound with the formula C6H5C(O)CH2Br. This colourless solid is a powerful lachrymator as well as a useful precursor to other organic compounds. It is prepared by bromination of acetophenone Acetophenone is th ...

and

chloroacetone Chloroacetone is a chemical compound with the chemical formula, formula . At Standard temperature and pressure, STP it is a colorless liquid with a pungent odor. On exposure to light, it turns to a dark yellow-amber color. It was used as a lachry ...

Structure

The general structure is RR′C(X)C(=O)R where R is an alkyl or aryl residue and X any one of the halogens. The preferred conformation of a halo ketone is that of a cisoid with the halogen and carbonyl sharing the same plane as the

steric hindrance Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is generally a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivi ...

with the carbonyl alkyl group is generally larger.

Halo ketone synthesis

Halo ketones and halo carbonyl compounds in general are synthesized by reaction of

compounds with sources of X⁺ (X = halogen), which is provided using

s: :RC(O)CH₃ + X₂ → RC(O)CH₂X + HX Specialized sources of electrophilic halogenating agents include ''N''-Bromosuccinimide and 1,3-dibromo-5,5-dimethylhydantoin (DBDMH). In the

Nierenstein reaction The Nierenstein reaction is an organic reaction describing the conversion of an acid chloride into a haloketone with diazomethane. It is an insertion reaction in that the methylene group from the diazomethane is inserted into the carbon-chlorine b ...

an acyl chloride reacts with

diazomethane Diazomethane is an organic chemical compound with the formula CH2N2, discovered by German chemist Hans von Pechmann in 1894. It is the simplest diazo compound. In the pure form at room temperature, it is an extremely sensitive explosive yellow ga ...

Asymmetric synthesis

Efforts are reported in

asymmetric synthesis Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as "a chemical reaction (or reaction sequence) in which one or more new elements of chirality are formed in a substrate molecul ...

of halo carbonyls through

organocatalysis In organic chemistry, organocatalysis is a form of catalysis in which the rate of a chemical reaction is increased by an organic catalyst. This "organocatalyst" consists of carbon, hydrogen, sulfur and other nonmetal elements found in organic com ...

. In one study an

acid chloride In organic chemistry, an acyl chloride (or acid chloride) is an organic compound with the functional group . Their formula is usually written , where R is a side chain. They are reactive derivatives of carboxylic acids (). A specific example o ...

is converted into an α-halo ester with a strong base (

sodium hydride Sodium hydride is the chemical compound with the empirical formula Na H. This alkali metal hydride is primarily used as a strong yet combustible base in organic synthesis. NaH is a saline (salt-like) hydride, composed of Na+ and H− ions, in co ...

), a bromine donor and an organocatalyst based on

proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the p ...

and

quinine Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to ''Plasmodium falciparum'' that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal leg ...

In the proposed

reaction mechanism In chemistry, a reaction mechanism is the step by step sequence of elementary reactions by which overall chemical reaction occurs. A chemical mechanism is a theoretical conjecture that tries to describe in detail what takes place at each stage ...

the base first converts the acid chloride to the

ketene In organic chemistry, a ketene is an organic compound of the form , where R and R' are two arbitrary valence (chemistry), monovalent functional group, chemical groups (or two separate Substituent, substitution sites in the same molecule). The na ...

, the organocatalyst then introduces

chirality Chirality () is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is distinguishable fro ...

through its quinonoid

tertiary amine In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...

, forming a ketene adduct. AcidchlorideHalogenationReactionMechanism

Reactions

Illustrative of their alkylating activity are reactions with

potassium iodide Potassium iodide is a chemical compound, medication, and dietary supplement. It is a medication used for treating hyperthyroidism, in radiation emergencies, and for protecting the thyroid gland when certain types of radiopharmaceuticals are u ...

acetone Acetone (2-propanone or dimethyl ketone) is an organic compound with the chemical formula, formula . It is the simplest and smallest ketone (). It is a colorless, highly Volatile organic compound, volatile, and flammable liquid with a charact ...

reacts faster than 1-chloropropane by a factor of 36,000. Halo ketones react with phosphites in the

Perkow reaction The Perkow reaction is an organic reaction in which a trialkyl phosphite ester reacts with a haloketone to form a dialkyl vinyl group, vinyl phosphate and an alkyl halide. In the related Michaelis–Arbuzov reaction the same reactants are known ...

. The halo group can be removed in reductive dehalogenation of halo ketones. α-Halo ketones can also be converted to alkenes by treatment with hydrazine. Due to the presence of two

electron withdrawing group The electron (, or in nuclear reactions) is a subatomic particle with a negative one elementary electric charge. It is a fundamental particle that comprises the ordinary matter that makes up the universe, along with up and down quarks. E ...

s (carbonyl and halide), the α-hydrogen is acidic. This property is exploited in the

Favorskii rearrangement The Favorskii rearrangement is principally a rearrangement of cyclopropanones and α-halo ketones that leads to carboxylic acid derivatives. In the case of cyclic α-halo ketones, the Favorskii rearrangement constitutes a ring contraction. This ...

, where base abstracts first an acidic α-hydrogen and the resulting

carbanion In organic chemistry, a carbanion is an anion with a lone pair attached to a tervalent carbon atom. This gives the carbon atom a negative charge. Formally, a carbanion is the conjugate base of a carbon acid: : where B stands for the base (chemist ...

then displaces the halogen. In crossed

aldol reaction The aldol reaction (aldol addition) is a Chemical reaction, reaction in organic chemistry that combines two Carbonyl group, carbonyl compounds (e.g. aldehydes or ketones) to form a new β-hydroxy carbonyl compound. Its simplest form might invol ...

s between halo ketones and

aldehyde In organic chemistry, an aldehyde () (lat. ''al''cohol ''dehyd''rogenatum, dehydrogenated alcohol) is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred ...

s, the initial reaction product is a

halohydrin In organic chemistry a halohydrin (also a haloalcohol or β-halo alcohol) is a functional group in which a halogen and a hydroxyl are bonded to adjacent carbon atoms, which otherwise bear only hydrogen or hydrocarbyl groups (e.g. 2-chloroethanol ...

which can subsequently form an

oxirane Ethylene oxide is an organic compound with the formula . It is a cyclic ether and the simplest epoxide: a three-membered ring consisting of one oxygen atom and two carbon atoms. Ethylene oxide is a colorless and flammable gas with a faintly swe ...

in the presence of base. α-Halo ketones can react with amines to form an α-halo imine, which can be converted back to the parent halo ketone by

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...

, so that halo imines may be used as masked versions of halo ketones. This allows some chemical transformations to be achieved that are not possible with the parent halo ketones directly.

Precursors to heterocycles

Halo ketones take part in several reaction types, especially since they are bifunctional, with two electrophilic sites (α-carbon and carbonyl carbon). In one manifestation of this duality, they are precursors to heterocycles. Thiazoles arise from reaction of chloroacetone with thioamides.

2-Aminothiazole 2-Aminothiazole is a heterocyclic amine featuring a thiazole core. It can also be considered a cyclic isothiourea. It possesses an odor similar to pyridine and is soluble in water, alcohols and diethyl ether. 2-Aminothiazole itself is mainly of ...

s are similarly produced by reaction of 2-chloroketones with

thiourea Thiourea () is an organosulfur compound with the formula and the structure . It is structurally similar to urea (), with the oxygen atom replaced by sulfur atom (as implied by the '' thio-'' prefix). The properties of urea and thiourea differ s ...

s. Pyrroles may be synthesized by reaction of halo ketones with dicarbonyls and ammonia in the

Hantzsch pyrrole synthesis The Hantzsch Pyrrole Synthesis, named for Arthur Rudolf Hantzsch, is the chemical reaction of β-ketoesters (1) with ammonia (or primary amines) and α-haloketones (2) to give substituted pyrroles (3). Pyrroles are found in a variety of natural p ...

References

{{Reflist Functional groups