α-Halo ketone

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Skeletal formula of a general α-haloketone

In

alkylating agents. Prominent α-halo ketones include phenacyl bromide and chloroacetone.[1]

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

steric hindrance with the carbonyl alkyl group is generally larger.[2]

Halo ketone synthesis

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

carbonyl compounds with sources of X+ (X = halogen), which is provided using halogens:[1]

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 an acyl chloride reacts with diazomethane

Asymmetric synthesis

Efforts are reported in

acid chloride is converted into an α-halo ester with a strong base (sodium hydride), a bromine donor and an organocatalyst based on proline and quinine:[3]

Acid chloride bromination Dogo-Isonagie et al. 2006
Acid chloride bromination Dogo-Isonagie et al. 2006

In the proposed

tertiary amine
, forming a ketene adduct.

Acid chloride bromination reaction mechanism Dogo-Isonagie 2006
Acid chloride bromination reaction mechanism Dogo-Isonagie 2006

Reactions

Illustrative of their alkylating activity are reactions with

1-chloropropane by a factor of 36,000. Halo ketones react with phosphites in the Perkow reaction
.

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 groups (carbonyl and halide), the α-hydrogen is acidic. This property is exploited in the Favorskii rearrangement, where base abstracts first an acidic α-hydrogen and the resulting carbanion
then displaces the halogen.

In crossed aldol reactions between halo ketones and aldehydes, the initial reaction product is a halohydrin which can subsequently form an oxirane 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, 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.[4]

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-Aminothiazoles are similarly produced by reaction of 2-chloroketones with thioureas.[5][6] Pyrroles may be synthesized by reaction of halo ketones with dicarbonyls and ammonia in the Hantzsch pyrrole synthesis.

References

  1. ^
    ISBN 9780470771716
    .
  2. S2CID 53951565
    .
  3. PMID 17081026
    .
  4. ISBN 9780470771716
    .
  5. doi:10.15227/orgsyn.019.0010
    .
  6. doi:10.15227/orgsyn.025.0035
    .
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