Reactive halides and anhydrides

Reactive halides and anhydrides. Substances like acid chlorides, low molecular weight anhydrides and some inorganic halides (e.g. PCI3) can be highly toxic and lachrymatory affecting mucous membranes and lung tissues. Utmost care should be taken when working with these materials. Work should be carried out in a very efficient fnme cupboard. 

Compared with esters, acid halides and anhydrides are more reactive and are hydrolyzed more readily. It is interesting to note that there is a substantial lifetime for these acid derivatives in aqueous media. Acid halides dissolved in PhCl or in PhBr shaken at a constant rate with water shows that hydrolysis occurs at the boundary between the two liquid phases.35 The reaction of benzoyl chloride (PhCOCl) and benzoate ion with pyridine A-oxide (PNO) as the inverse phase-transfer catalyst yields both the substitution product (benzoic anhydride) and the... 

Acyl halides and anhydrides are the most reactive class of carboxylic acid derivatives, and readily react with amines to give amides. It should be noted that in both cases the leaving group is a conjugate base that, upon protonation during the reaction, will become an... 

Acid halides and anhydrides are so reactive that they react with water under neutral conditions. This can he a potential problem for the storage if these compounds since these compounds can he air (moisture) sensitive. Hydrolysis of these compounds can he avoided hy using dry nitrogen atmospheres and anhydrous solvents and reagents. 

Esters are less reactive than acid halides and anhydrides but undergo the same types of reactions. 

The interaction of certain electrophiles with an aromatic ring leads to substitution. These electrophilic reactions involve a carbocation intermediate that gives up a stable, positively charged species (usually a proton) to a base to regenerate the aromatic ring. Typical electrophiles include chlorine and bromine (activated by interaction with a Lewis acid for all but highly reactive aromatic compounds), nitronium ion, SO3, the complexes of acid halides and anhydrides with Lewis acids (see Example 4.5) or the cations formed when such complexes decompose (R— —O or Ar =0), and carbocations. 

The basic mechanisms are well known.The nucleophilic species undergoes addition at the carbonyl group, followed by elimination of the halide or carboxylate group. Acid halides and anhydrides are reactive acylating reagents because of a... 

Transformation of carboxylic acids into more reactive derivatives, particularly halides and anhydrides, is an activation of the carboxylic group. Formation of more reactive carboxylic acid derivatives may be described as moving the carboxylic group energetically uphill, from where it can be favorably transformed downhill into a less reactive congener. Activated carboxylic acid derivatives characterize the localized partial positive charge on the carbonyl C atom and reactivity against weak nucleophiles such as water, alcohols, ammonia or amines. 

How does the reactivity of an aldehyde or a ketone toward nucleophiles compare with the reactivity of the carbonyl compounds whose reactions you studied in Chapter 16 Aldehydes and ketones are in the middle—they are less reactive than acyl halides and anhydrides, but they are more reactive than esters, carboxylic acids, and amides. 

We begin with a comparison of the structures, properties, and relative reactivities of carboxylic acid derivatives. We then explore the chemistry of each type of compound. Halides and anhydrides are valuable reagents in the synthesis of other carbonyl compounds. Esters and amides are enormously important in nature for example, the esters include common flavoring agents, waxes, fats, and oils among the amides we find urea and penicillin. The alkanenitriles, RC=N, are also freated here because they have similar reactivity. 

Esters undergo nucleophilic substitution reactions by means of addition-elimination pathways, albeit with reduced reactivity relative to halides and anhydrides. Thus, catalysis by acid or base becomes a frequent necessity. For example, esters are cleaved to carboxylic acids and alcohols in the presence of excess water and strong acid, and the reaction requires heating to proceed at a reasonable rate. The mechanism of this transformation is the reverse of acid-catalyzed esterification (Section 19-9). As in esterification, the acid serves two purposes It protonates the carbonyl oxygen to make the ester more reactive toward nucleophilic attack, and it protonates the alkoxy oxygen in the tetrahedral intermediate to make it a better leaving group. 

Reactivity order Toward Nu addition/elimination of leaving group (bold) halides (and anhydrides)— no catalyst needed esters, amides—H or OH catalyst required (20-1)... 

Heating a carboxylic acid with ammonia or urea gives a carboxamide. For example, heptanoic acid plus urea at 140-180°C gives heptanamide in 75% yield plus CO and H O [17], The highly reactive acid halides and anhydrides combine with ammonia or primary or secondary amines to give amides at ordinary temperatures. Esters will react slowly with ammonia at room temperature (Eq. 6.12) [18]. Higher-boiling amines may be used if the alcohol is removed continuously by distillation. 

After acyl halides acid anhydrides are the most reactive carboxylic acid derivatives Three of them acetic anhydride phthahc anhydride and maleic anhydride are mdus trial chemicals and are encountered far more often than others Phthahc anhydride and maleic anhydride have their anhydride function incorporated into a nng and are referred to as cyclic anhydrides... 

Friedel-Crafts acylation reactions usually involve the interaction of an aromatic compound with an acyl halide or anhydride in the presence of a catalyst, to form a carbon-carbon bond [74, 75]. As the product of an acylation reaction is less reactive than its starting material, monoacylation usually occurs. The catalyst in the reaction is not a true catalyst, as it is often (but not always) required in stoichiometric quantities. For Friedel-Crafts acylation reactions in chloroaluminate(III) ionic liquids or molten salts, the ketone product of an acylation reaction forms a strong complex with the ionic liquid, and separation of the product from the ionic liquid can be extremely difficult. The products are usually isolated by quenching the ionic liquid in water. Current research is moving towards finding genuine catalysts for this reaction, some of which are described in this section. 

The reactivity of an acid derivative toward substitution depends both on the steric environment near the carbonyl group and on the electronic nature of the substituent, Y. The reactivity order is acid halide > acid anhydride > thioester > ester > amide. 

Recently, use of LiCl/DMAc and LiCl/l,3-dimethyl-2-imidazolidinone as solvent systems for acetylation of cellulose by acetic anhydride/pyridine has been compared. A DS of 1.4 was obtained the substituent distribution in the products synthesized in both solvents was found to be the same, with reactivity order Ce > C2 > C3. Therefore, the latter solvent system does not appear to be better than the much less expensive LiCl/DMAc, at least for this reaction. It appears, however, to be especially efficient for etherification reactions [178]. It is possible, however, that the effect of cellulose aggregation is more important for its reaction with the (less reactive) halides than with acid anhydrides this being the reason for the better performance of the latter solvent system in ether formation, since it is more efficient in cellulose dissolution. 

Catalytic amounts of I fCl4-AgC104 and Hf(OTf)4 are used for activation of acid halides and acid anhydrides for Friedel -Crafts acylation (Scheme 42) 178 the reactions of both reactive and unreactive aromatic substrates proceed smoothly in the presence of Hf(OTf)4. Furthermore, the Fries rearrangement179,180 and direct C-acylation of phenolic compounds181,182 take place using Hf(OTf)4. Formation of esters and Mannich-type reactions and allylation of imines have been also reported.152... 

Halo-lactonization of ketophosphoranes has been achieved via reaction with cyclic anhydrides and subsequent halogenation. " The products, halo enol lactones (75), are synthetically useful compounds, and an alternative synthesis via incorporation of the halogen at the ylid stage is also described. Mechanistic investigation of the Wittig reactions involved reveals subtle variations in pathway, allowing optimum experimental conditions to be selected to allow for the variation in reactivity of different anhydrides and halides. 

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