Enolate ion halogenation

This section examines a reaction of the carbonyl gronp that can proceed through the intermediacy of either enols or enolate ions—halogenation. Aldehydes and ketones react with halogens at the a-carbon. In contrast with deuteration, which proceeds to completion with either acid or base, the extent of halogenation depends on whether acid or base catalysis has been nsed. 

Rapid halogenation of the a carbon atom takes place when an enolate ion is generated m the presence of chlorine bromine or iodine... 

As m the acid catalyzed halogenation of aldehydes and ketones the reaction rate is mde pendent of the concentration of the halogen chlorination brommation and lodmation all occur at the same rate Formation of the enolate is rate determining and once formed the enolate ion reacts rapidly with the halogen... 

As an example of enolate-ion reactivity, aldehydes and ketones undergo base-promoted o halogenation. Even relatively weak bases such as hydroxide ion are effective for halogenation because it s not necessary to convert the ketone completely into its enolate ion. As soon as a small amount of enolate is generated, it reacts immediately with the halogen, removing it from the reaction and driving the equilibrium for further enolate ion formation. 

It becomes clear that in all these compounds it is the conjugate base that takes part in the substitution proper. For mono- and particularly 1,3-dicarbonyl compounds this result actually removes the problem of whether it is the keto or the enol form which enters into an electrophilic substitution by diazonium ions, halogenating agents, and many other reagents. The keto and the enol form are distinct species, but they have one (common) conjugate base This was made clear quite early, but even today there are many chemists who seem not to be aware of it. 

It is not the aldehyde or ketone itself that is halogenated, but the corresponding enol or enolate ion. The purpose of the catalyst is to provide a small amount of enol or enolate. The reaction is often done without addition of acid or base, but traces of acid or base are always present, and these are enough to catalyze formation of the enol or enolate. With acid catalysis the mechanism is... 

A number of other methods exist for the a halogenation of carboxylic acids or their derivatives. Acyl halides can be a brominated or chlorinated by use of NBS or NCS and HBr or HCl. The latter is an ionic, not a free-radical halogenation (see 14-2). Direct iodination of carboxylic acids has been achieved with I2—Cu acetate in HOAc. " ° Acyl chlorides can be a iodinated with I2 and a trace of HI. Carboxylic esters can be a halogenated by conversion to their enolate ions with lithium A-isopropylcyclohexylamide in THF and treatment of this solution at -78°C with... 

The same products are obtained (though in different proportions) when Na or K is omitted but the solution is irradiated with near-UV light.In either case other leaving groups can be used instead of halogens (e.g., NR3, SAr) and the mechanism is the SrnI mechanism. Iron(II) salts have also been used to initiate this reaction. The reaction can also take place without an added initiator Enolate ions of ketones react with Phi in the dark. " In this case, it has been suggested that initiation... 

Aryl methyl ketones can only give a single enol (or enolate ion) and subsequent reactions are therefore entirely regioselective. These include halogenation (cf. Section 5.11.1, p. 667), and the Mannich reaction (cf. Section 5.18.2, p. 801). 

Rate coefficients (eqn 36) for the halogenation of enols, enol ethers and enolate ions in aqueous media at 25°C... 

Because acid conditions are used so this process does not involve an enolate ion. Instead, the reaction occurs through the enol tautomers of the carbonyl compound. The enol tautomer acts as a nucleophile with a halogen by the mechanism shown below. In the final step, the solvent acts as a base to remove the proton. 

However, it is difficult to stop the reaction at mono-halogenation because the product formed is generally more acidic than the starting ketone because of the electron-withdrawing effect of the halogen. Due to this, another enolate ion is quickly formed leading to further halogenation. 

When dihalobenzenes (Cl, Br, I) react with aliphatic ketone enolate ions, disubstitution products are furnished. On the other hand, mainly monosubstitution with retention of one halogen is obtained in the photostimulated reactions of o-iodohalobenzenes (X = I, Br, Cl) with the enolate ions of aromatic ketones, such as acetophenone, propiophenone, and l-(2-naphthyl)ethanone in DMSO. These results are explained in terms of the energetics of the intramolecular ET from the ArCO-7i system to the C-X a bond in the monosubstituted radical anions proposed as intermediates [81]. For example see Sch. 13. 

The substitution products, formed in the reaction of acetone or pinacolone enolate ions with aromatic substrates bearing a F3C group either ortho or para to the halogen, undergo reactions in which fluoride ions are eliminated. In the case of the ortho-isomer 310, a ring closure product 311 is formed by intramolecular reaction (equation 186)334. 

Mechanism 22-4 Base-Catalyzed Keto-EnolTautomerism 1047 Mechanism 22-5 Acid-Catalyzed Keto-EnolTautomerism 1047 22-3 Alkylation of Enolate Ions 1050 22-4 Formation and Alkylation of Enamines 1051 22-5 Alpha Halogenation of Ketones 1054... 

Q Show how enols, enolate ions, and enamines act as nucleophiles. Predict the products of their reactions with halogens, alkyl halides, and other electrophiles. Show how they are useful in synthesis. 

The base-promoted halogenation takes place by a nucleophilic attack of an enolate ion on the electrophilic halogen molecule. The products are the halogenated ketone and a halide ion. 

For example, bromination of pentan-3-one gives mostly 2,2-dibromopentan-3-one. After one hydrogen is replaced by bromine, the enolate ion is stabilized by both the carbonyl group and the bromine atom. A second bromination takes place faster than the first. Notice that the second substitution takes place at the same carbon atom as the first, because that carbon atom bears the enolate-stabilizing halogen. 

This is different and more complicated because it usually won t stop at the introduction of one halogen atom. If we go back to the bromination of acetone, the first step will now be a base-catalysed eno-lization to give the enolate ion instead of the enol. The enolate ion can attack a bromine molecule in a very similar way to the attack of the enol on bromine. The enolate will, of course, be even more reactive than the enol was (the enolate carries a negative charge). 

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