Ketone Halogenation
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In
organic chemistry Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, J.; ...
, α-keto halogenation is a special type of halogenation. The reaction may be carried out under either acidic or basic conditions in an aqueous medium with the corresponding elemental halogen. In this way, chloride, bromide, and iodide (but notably not fluoride) functionality can be inserted selectively in the alpha position of a ketone. The position alpha to the
carbonyl In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containi ...
group in a ketone is easily halogenated. This is due to its ability to form an
enolate In organic chemistry, enolates are organic anions derived from the deprotonation of carbonyl () compounds. Rarely isolated, they are widely used as reagents in the synthesis of organic compounds. Bonding and structure Enolate anions are electr ...
in basic solution, or an
enol In organic chemistry, alkenols (shortened to enols) are a type of reactive structure or intermediate in organic chemistry that is represented as an alkene ( olefin) with a hydroxyl group attached to one end of the alkene double bond (). The t ...
in
acidic In computer science, ACID ( atomicity, consistency, isolation, durability) is a set of properties of database transactions intended to guarantee data validity despite errors, power failures, and other mishaps. In the context of databases, a ...
solution. An example of alpha halogenation is the mono-bromination of
acetone Acetone (2-propanone or dimethyl ketone), is an organic compound with the formula . It is the simplest and smallest ketone (). It is a colorless, highly volatile and flammable liquid with a characteristic pungent odour. Acetone is miscib ...
, carried out under either acidic or basic conditions, to give
bromoacetone Bromoacetone is an organic compound with the formula . It is a colorless liquid although impure samples appear yellow or even brown. It is a lachrymatory agent and a precursor to other organic compounds. Occurrence in nature Bromoacetone is pr ...
: Acidic (in acetic acid): Basic (in aqueous NaOH): In acidic solution, usually only one alpha hydrogen is replaced by a halogen, as each successive halogenation is slower than the first. The halogen decreases the basicity of the carbonyl oxygen, thus making protonation less favorable. However, in basic solutions, successive halogenation is more rapid due to inductive electron withdrawal by the halogen. This makes the remaining hydrogens more acidic. In the case of methyl ketones, this reaction often occurs a third time to form a ketone trihalide, which can undergo rapid substitution with water to form a carboxylate in what is known as the
haloform reaction In chemistry, the haloform reaction is a chemical reaction in which a haloform (, where X is a halogen The halogens () are a group in the periodic table consisting of five or six chemically related elements: fluorine (F), chlorine (Cl), ...
. The
regioselectivity In chemistry, regioselectivity is the preference of chemical bonding or breaking in one direction over all other possible directions. It can often apply to which of many possible positions a reagent will affect, such as which proton a strong base ...
also differs: The halogenation of an unsymmetrical ketone in acid results in the more substituted alkyl group being halogenated. A second equivalent of halogen results in the halogenation of the other alkyl substituent (without the halogen). In contrast, in basic solutions, an unsymmetrical ketone halogenates at the less substituted alkyl group. Subsequent halogenation (which usually cannot be stopped by control of stoichiometry) occurs at the position which already has a halogen substituent, until all hydrogens have been replaced by halogen atoms. For methyl alkyl ketones (2-alkanones), the haloform reaction proceeds to give the carboxylic acid selectively.


Halogenation of α,β-Unsaturated Ketones

On α,β-Unsaturated ketones or enones, it's possible to halogenate with
iodine Iodine is a chemical element with the symbol I and atomic number 53. The heaviest of the stable halogens, it exists as a semi-lustrous, non-metallic solid at standard conditions that melts to form a deep violet liquid at , and boils to a vi ...
selectively on the more saturated alpha on the ketone selectively over the unsaturated side. Iodine is preferred due to it being more reactive than alkyl bromides which makes this reaction quite useful. By using CuO in conjunction with I2, it is possible to achieve this reaction under relatively mild conditions. This reaction undergoes a very reactive
enol In organic chemistry, alkenols (shortened to enols) are a type of reactive structure or intermediate in organic chemistry that is represented as an alkene ( olefin) with a hydroxyl group attached to one end of the alkene double bond (). The t ...
mechanism, facilitated by the CuO, which allows for the selective addition of I2 on the saturated alpha carbon of the ketone. However, the effectiveness of this reaction depends on the presence of
aryl In organic chemistry, an aryl is any functional group or substituent derived from an aromaticity, aromatic ring, usually an aromatic hydrocarbon, such as phenyl and naphthyl. "Aryl" is used for the sake of abbreviation or generalization, and "Ar ...
functional groups.


Applications in Green Chemistry

Alpha halogenated products are very useful compounds as they have high reactivity which makes them very prone to reacting. Alpha halogenated ketones react with nucleophiles to create many valuable compounds. However, many of the current method for ketone halogenation use hazardous chemicals, have complex procedures, and/or require a long time to go to completion. Additionally, the polar solvents that are primarily used (DMF, DMSO, and CH3CN) are major environmental pollutants. An experiment conducted by Meshram et al. in 2005 investigated making ketone halogenation a greener reaction, according to the principles of
green chemistry Green chemistry, also called sustainable chemistry, is an area of chemistry and chemical engineering focused on the design of products and processes that minimize or eliminate the use and generation of hazardous substances. While environmental che ...
. Meshram et al. investigated alternatives to the hazardous chemicals that are primarily used in ketone halogenation, finding that room temperature ionic liquids were a promising option. Room temperature ionic liquids are interesting prospects as they have unique chemical and physical properties, and their properties can be modified by changing the cations that are attached. Additionally, these ionic liquids have high polarity and their ability to solubilize organic and inorganic molecules leads to enhanced reaction rates, which makes them more desirable. Many experiments found that ionic liquids with N-halosuccinimides as the solvent were an effective, greener alternative to conventional solvents. This process also resulted in enhanced yields, reduced reaction time, simplified the procedure, used less harmful chemicals (no strong acids), and did not require
catalysts Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
, all of which made the process greener.


References

{{Reflist Halogenation reactions