Inorganic chemistry,α-keto halogenation is a special type ofhalogenation.The reaction may be carried out under either acidic or basic conditions in anaqueous medium with the corresponding elementalhalogen. In this way,chloride,bromide, andiodide (but notably notfluoride) functionality can be inserted selectively in thealpha position of aketone.
The position alpha to thecarbonyl group (C=O) in a ketone is easily halogenated. This is due to its ability to form anenolate (C=C−O−) inbasic solution, or anenol (C=C−OH) inacidic solution. An example of alpha halogenation is themono-bromination ofacetone ((CH3)2C=O), carried out under either acidic or basic conditions, to givebromoacetone:
Acidic (in acetic acid):
Basic (in aqueousNaOH):
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 makingprotonation 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 methylketones, this reaction often occurs a third time to form a ketone trihalide, which can undergo rapid substitution with water to form acarboxylate (−C(=O)O−) in what is known as thehaloform reaction.[1]
Theregioselectivity also differs: The halogenation of an unsymmetrical ketone in acid results in the more substitutedalkyl 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by control of stoichiometry) occurs at the position which already has a halogen substituent, until all hydrogens have been replaced by halogen atoms.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.[2]
On α,β-Unsaturated ketones or enones, it's possible to halogenate withiodine 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.[3] By usingCuO in conjunction with I2, it is possible to achieve this reaction under relatively mild conditions. This reaction undergoes a very reactiveenol mechanism, facilitated by the CuO, which allows for the selective addition of I2 on the saturated alpha carbon of the ketone.[4] However, the effectiveness of this reaction depends on the presence ofaryl functional groups.
Alpha halogenated products are very useful compounds as they have high reactivity which makes them very prone to reacting. Alpha halogenatedketones react withnucleophiles 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 ofgreen chemistry.[5][6] 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.[6] 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.[6] This process also resulted in enhanced yields, reduced reaction time, simplified the procedure, used less harmful chemicals (no strong acids), and did not requirecatalysts, all of which made the process greener.