Acid chlorides and anhydrides

Acid chlorides are made from fatty acids by reaction with phosphorus trichloride, phosphorus penta-chloride, phosphorus oxychloride, phosgene, oxalyl chloride, thionyl chloride or triphenylphosphine and carbon tetrachloride. Phosphorus trichloride is probably the most economical reagent for large-scale reaction. Improved yields have been claimed when the reaction is carried out in the absence of oxygen. The most common laboratory procedures require the acid to stand at room temperature for 

Dicyclohexylcarbodi-imide will dehydrate acids at room temperature to give the anhydride. 

Both the acid chlorides and anhydrides are effective acylating agents used in the synthesis of acylglycerols and phospholipids (Sections 7.4 and 7.5). 

Mixed anhydrides with methanesulphonic or toluene-4-sulphonic acid are also reported to be good acylating agents. They are made as indicated in the following equations  

3-5 days with thionyl chloride (2.4 mol) for saturated acids and with oxalyl chloride (1.8 mol) for unsaturated adds. 

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Esters can also be prepared by the action of alcohols on acid chlorides and anhydrides. 

The chemical reactions of the acid chlorides and anhydrides are so closely parallel that they are considered together. 

Acid chlorides and anhydrides give hydroxamic acids with... 

Reacts slowly on heating without evolution of gas. Esters some acid chlorides and anhydrides benzaldehyde (undergoes Cannizzaro s reaction, p. 342). 

Sulfur tetrafluoride [7783-60-0] SF, replaces halogen in haloalkanes, haloalkenes, and aryl chlorides, but is only effective (even at elevated temperatures) in the presence of a Lewis acid catalyst. The reagent is most often used in the replacement of carbonyl oxygen with fluorine (15,16). Aldehydes and ketones react readily, particularly if no alpha-hydrogen atoms are present (eg, benzal fluoride [455-31-2] from benzaldehyde), but acids, esters, acid chlorides, and anhydrides are very sluggish. However, these reactions can be catalyzed by Lewis acids (HP, BF, etc). 

Aldehyde Synthesis. Formylation would be expected to take place when formyl chloride or formic anhydride reacts with an aromatic compound ia the presence of aluminum chloride or other Friedel-Crafts catalysts. However, the acid chloride and anhydride of formic acid are both too unstable to be of preparative iaterest. 

The chemistry of benzenecarboxyUc acids generally is the same as that of other carboxyUc acids, which can be converted into esters, salts, acid chlorides, and anhydrides. Each carboxyl group can react separately, so that compounds in which carboxyl groups are converted into different derivatives can be prepared. Because there are aromatic hydrogens available in most of these acids, they also undergo reactions characteristic of the benzene nucleus. Some of the anhydrides have characteristic reactions. 

Acids and esters (see Esters, organic) are less easily brominated than aldehydes or ketones. Acid chlorides and anhydrides are more easily brominated (23). 

Acid moieties include formic acid itself, formates and orthoesters, formamide, DMF dimethyl acetal and ethyl diethoxyacetate, acids, acid chlorides and anhydrides, the last including a rare [3,4-oxalate esters, 2-acyl or 2-ethoxycar-bonyl derivatives e.g. 180) are formed. 

The most common O- and N-acylation procedures use acylating agents that are more reactive than caiboxylic acids or their esters. Carboxylic acid chlorides and anhydrides react rapidly with most unhindered hydroxy and amino groups to give esters and amides, respectively ... 

AkoJwIs may be obtained from aldehydes, ketones, esters, acid chlorides, and anhydrides,... 

At this stage, remember that carboxylic acids represent risks vis-a-vis esters, acid chlorides and anhydrides, amides or various sulphur-containing or phosphorated groups. 

Acid chlorides and anhydrides, especially the former, are the most reactive carbonyl compounds, hence the most dangerous. The dangerous reaction that is involved in accidents usually corresponds to the equation below, in which X is a chlorine atom or a O2C-R group and H-X a compound with a mobile hydrogen ... 

Thus acid chlorides and anhydrides react readily with ROH and NH3 to yield esters and amides, respectively, while esters react with NH3 or amines to give amides, but the simple reversal of any of these reactions on an amide, though not impossible, is usually pretty difficult. The relative reactivity will also depend on both the electronic and, more particularly, the steric effect of R. A slightly unusual leaving group is eCX3 (e.g. eCI3) in the haloform (158) reaction (cf. p. 297) ... 

Primary and secondary amines are acylated by acid chlorides and anhydrides, in particular also by the chloride of benzene sulphonic add (p. 192). The preparation of acetanilide has already been described (pp. 125, 128). The acetyl- and benzoyl-derivatives of all the simpler primary amines of the benzene and naphthalene series are known, so that these derivatives can always serve for purposes of identification. 

Catalysed reaction of acid chlorides and anhydrides with alcohols and phenols (Table 3.11)... 

Primary (RNH2) and secondary (R2NH) amines undergo nucleophilic acyl substitution with acid chlorides and anhydrides in pyridine or EtsN to give 2° and 3° amides (see Section 5.5.5). Primary amines (RNH2) react with... 

Allylic zinc reagents are highly reactive and add to acid chlorides and anhydrides. A double addition of the allylic moiety usually occurs, leading to tertiary alcohols . The double addition can be avoided by using a nitrile as substrate (Blaise reaction). By... 

Experimentally, it is preferable to add the alkene to the acylating agent under Friedel-Crafts conditions. Successful acylation is accomplished with both acid chlorides and anhydrides, though yields are higher with aliphatic rather than aromatic acid derivatives (61JCS3553). 

The formation of esters from acid chlorides and anhydrides according to the following equation has been discussed ... 

The physical properties of a number of carboxylic acid chlorides and anhydrides are given in Tables 10.22, 10.23 and 10.24. 

A review of solvent properties of, and organic reactivity in, ionic liquids demonstrates the relatively small number of quantitative studies of electrophilic aromatic substitution in these media.3 Studies mentioned in the review indicate conventional polar mechanisms. 1-Methylpyrrole reacts with acyl chlorides in the ionic liquid 1-butylpyridinium tetrafluoroborate to form the corresponding 2-acylpyrrole in the presence of a catalytic amount of ytterbium(III) trifluoromethanesulfonate.4 The ionic liquid-catalyst system is recyclable. Chloroindate(III) ionic liquids5 are catalytic media for the acylation, using acid chlorides and anhydrides, of naphthalene, benzene, and various substituted benzenes at 80-120 °C. Again the ionic liquid is recyclable. 

Figure 3.6 Examples of water solubilizing structures and the routes used to introduce them into the lead structures. O-alkylation, N-alkylation, O-acylation and N-acylation reactions are used to introduce both acidic and basic groups. Acetylation methods use both the appropriate acid chloride and anhydride.

Why acid chlorides and anhydrides undergo O-acylation has not been properly explained. According to one explanation, as the reactivity of the electrophile increases,... 

Sato et al. observed that the reaction of 2-phenyl-1-azirine with acid chlorides and anhydrides in the presence of triethylamine gives the oxazole directly.57 They have reported that azirines also react with carboxylic anhydrides to give oxazoles (136).57 Aziridine (135) is suggested as a likely intermediate in the reaction of acetic anhydride with azirine (42a), since carrying out the reaction at lower temperature and for a shorter reaction time gave a compound to which they assigned structure 135. 

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