Methyl ketones halogenation

Hagemann s-ester a compound prepared by treating a mixture of formaldehyde and ethylacetoacetate with base and then with acid and heat, half-chair conformation the least stable conformation of cyclohexane, haloform reaction the reaction of a halogen and HO — with a methyl ketone, halogenation reaction with halogen (Br, Cl, Ij). 

Unlike Its acid catalyzed counterpart a halogenation m base cannot normally be limited to monohalogenation Methyl ketones for example undergo a novel polyhalo genation and cleavage on treatment with a halogen m aqueous base... 

Methyl ketones are cleaved on re action with excess halogen in the presence of base The products are a trihalomethane (haloform) and a carboxylate salt... 

In spite of these rationali2ations, the stereochemistry of ketone halogenation retains some puzzling features. For example, the effect of a 2-methyl substituent on the direction of bromination at C-2 is unexpected. 

In addition to the applications indicated on p. 858. hypohalous acids are useful halogenating agents for Ixjth aromatic and aliphatic compounds. HOBr and HOI are usually generated in silii. The ease of aromatic halogenation increa.ses in the sequence OCl < OBr < Ol and is facilitated by salts of Pb or Ag. Another well-known reaction of hypohalites is their cleavage of methyl ketones to form carboxylates and haloform ... 

Methyl ketones 1, as well as acetaldehyde, are cleaved into a carboxylate anion 2 and a trihalomethane 3 (a haloform) by the Haloform reaction The respective halogen can be chlorine, bromine or iodine. 

The methyl group of a methyl ketone is converted into an a ,a ,a -trihalomethyl group by three subsequent analogous halogenation steps, that involve formation of an intermediate enolate anion (4-6) by deprotonation in alkaline solution, and introduction of one halogen atom in each step by reaction with the halogen. A... 

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

If excess base and halogen are used, a methyl ketone is triply halogenated and then cleaved by base in the halofotm reaction. The products are a carboxylic add plus a so-called haioform (chloroform, CHCI3 bromoform,... 

Haloform reaction (Section 22.6) The reaction of a methyl ketone with halogen and base to yield a haloform (CHX3) and a carboxylic acid. 

In the haloform reaction, methyl ketones (and the only methyl aldehyde, acetaldehyde) are cleaved with halogen and a base. The halogen can be bromine, chlorine, or iodine. What takes place is actually a combination of two reactions. The first is an example of 12-4, in which, under the basic conditions employed, the methyl group is trihalogenated. Then the resulting trihalo ketone is attacked by hydroxide ion ... 

Methyl ketones are degraded to the next lower carboxylic acid by reaction with hypochlorite or hypobromite ions. The initial step in these reactions involves base-catalyzed halogenation. The a-haloketones are more reactive than their precursors, and rapid halogenation to the trihalo compound results. Trihalomethyl ketones are susceptible to alkaline cleavage because of the inductive stabilization provided by the halogen atoms. 

Any compound that oxidizes to a methyl ketone also gives a haloform reaction, because halogens are also oxidizing agents. For example, the compound shown in Figure 11-8 reacts. 

A ketone can be halogenated even when it isn t a methyl ketone. This process can be either acid or base catalyzed. The general mechanism is shown in Figure 11-10. 

In general, ketones don t undergo oxidation however, methyl ketones undergo a haloform reaction. In a haloform reaction, the oxidation converts the methyl group to a haloform molecule (usually iodoform (CHI3)), which leaves the Ccirbon backbone one carbon atom shorter. The oxidant in a haloform reaction is sodium hypohalite (NaOX), which forms by the reaction of sodium hydroxide (NaOH) with a halogen (X, where X = Cl, Br, or 1). 

In order to activate the 21 position to halogenation, it is hrst converted to an oxalate. Condensation of the triketone with ethyl oxalate in the presence of alkoxide proceeds preferentially at the 21 position to give (12-2) due to the well-known enhanced reactivity of methyl ketones. Reaction of the crude sodium enolate with bromine leads to the dibromide (12-3), the oxalate moiety being cleaved under the reaction conditions. The Favorskii rearrangement is then used to, in effect, oxidize the 17 position so as to provide a site for the future hydroxyl group. Thus, treatment of (12-3) with an excess of sodium methoxide hrst provides an anion at the 17 position (12-4). This then cyclizes to the transient cyclopropanone (12-5)... 

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