Carboxylic acid derivatives chlorides Amides Anhydrides

The chemistry of the carbonyl group is probably the single most important aspect of organic chemical reactivity Classes of compounds that contain the carbonyl group include many derived from carboxylic acids (acyl chlorides acid anhydrides esters and amides) as well as the two related classes discussed m this chapter aldehydes and ketones... 

Conversions of acid anhydrides to other carboxylic acid derivatives are illustrated m Table 20 2 Because a more highly stabilized carbonyl group must result m order for nucleophilic acyl substitution to be effective acid anhydrides are readily converted to carboxylic acids esters and amides but not to acyl chlorides... 

This chapter concerns the preparation and reactions of acyl chlorides acid anhydrides thioesters esters amides and nitriles These com pounds are generally classified as carboxylic acid derivatives and their nomenclature is based on that of carboxylic acids... 

Carboxylic acid derivative (Section 20.1) Compound that yields a carboxylic acid on hydrolysis. Carboxylic acid derivatives include acyl chlorides, acid anhydrides, esters, and amides. 

Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. The halogen can be replaced by -OH to yield an acid, by —OCOR to yield an anhydride, by -OR to yield an ester, or by -NH2 to yield an amide. In addition, the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol. Although the reactions we ll be discussing in this section are illustrated only for acid chlorides, similar processes take place with other acid halides. 

Carboxylic acid derivatives are compounds that possess an acyl group (R—C=0) linked to an electronegative atom, e.g. —Cl, —CO2 R, —OR or —NH2. They can be converted to carboxylic acids via simple acidic or basic hydrolysis. The important acid derivatives are acid chlorides, acid anhydrides, esters and amides. Usually nitriles are also considered as carboxylic acid derivatives. Although nitriles are not directly carboxylic acid derivatives, they are conveniently hydrolysed to carboxylic acids by acid or base catalysts. Moreover, nitriles can be easily prepared through dehydration of amides, which are carboxylic acid derivatives. 

The carboxylic acid derivatives vary greatly in their reactivities in the acyl substitution reactions. In general, it is easy to convert more reactive derivatives into less reactive derivatives. Therefore, an acid chloride is easily converted to an anhydride, ester or amide, but an amide can only be hydrolysed to a carboxylic acid. Acid chlorides and acid anhydrides are hydrolysed easily, whereas amides are hydrolysed slowly in boiling alkaline water. 

Acid chlorides are the most reactive carboxylic acid derivatives, and easily converted to acid anhydrides, esters and amides via nucleophilic acyl substitutions (see Section 5.5.5). Acid chlorides are sufficiently reactive with H2O, and quite readily hydrolysed to carboxylic acid (see Section 5.6.1). 

Acid anhydrides are the second most reactive of the carboxylic acid derivatives. They are fairly readily converted to the other less reactive carboxylic acid derivatives, e.g. esters, carboxylic acids and amides. Acid anhydrides undergo many reactions similar to those of acid chlorides, and they can often be used interchangeably. 

Amides are the least reactive of the carboxylic acid derivatives, and undergo acid or base hydrolysis to produce the parent carboxylic acids, and reduction to appropriate amines (see Section 4.3.10). They can also be dehydrated to nitriles, most commonly with boiling acetic anhydride, (AcO)20, sulphonyl chloride (SOCI2) or phosphoms oxychloride (POCI3) (see Section 4.3.18). Amines (with one less carbon) are prepared from amides by the treatment of halides (Br2 or CI2) in aqueous NaOH or KOH. This reaction is known as Hofmann rearrangement (see Section 4.3.10). 

A number of other methods exist for the a halogenation of carboxylic acids or their derivatives.134 The acids or their chlorides or anhydrides can be a chlorinated by treatment with CuCl in polar inert solvents (e.g., sulfolane).135 Acyl halides can be a brominated or chlorinated by use of N-bromo- or N-chlorosuccinimide and HBr or HC1.136 The latter is an ionic, not a free-radical halogenation (see 4-2). Direct iodination of carboxylic acids has been achieved with L-Cu(II) acetate in HO Ac.137 Acyl chlorides can be a iodinated with L and a trace of HI.138 Carboxylic esters can be a halogenated by conversion to their enolate ions with lithium N-isopropylcyclohexylamide in THF and treatment of this solution at - 78° with I2138 or with a carbon tetrahalide.139 Carboxylic acids, esters, and amides have been a fluorinated at -78°C with F2 diluted in Ni.,4°... 

The carbonyl group of an amide is stabilized to a greater extent than that of an acyl chloride, acid anhydride, or ester amides are formed rapidly and in high yield from each of these carboxylic acid derivatives. 

Acid chlorides can be converted to acid anhydrides, esters, or amides. These reactions are possible because acid chlorides are the most reactive of the four carboxylic acid derivatives. Nucleophilic substitutions of the other acid derivatives are more limited because they are less reactive. For example, acid anhydrides can be used to synthesise esters and amides, but cannot be used to synthesise acid chlorides. 

Chapter 22 focuses on carbonyl compounds that contain an acyl group bonded to an electronegative atom. These include the carboxylic acids, as well as carboxylic acid derivatives that can be prepared from them acid chlorides, anhydrides, esters, and amides. 

Thus, the carbonyl group of an acid chloride and anhydride, which are least stabilized by resonance, absorb at higher frequency than the carbonyl group of an amide, which is more stabilized by resonance. Table 22.4 lists specific values for the carbonyl absorptions of the carboxylic acid derivatives. 

L22,13 and L24.12,14 Many carboxylic acid derivatives such as esters, amides, and chlorides or anhydrides may also be used. The same reaction conditions can be applied to the condensation reaction of aromatic nitriles with o-phenylenediamine for the synthesis of H2L8,15 H2L13, and L13a.16,17... 

A characteristic reaction of carboxylic acid derivatives is nucleophilic acyl substitution. In this reaction a negative or neutral nucleophile replaces a leaving group to form a substitution product. The leaving groups and nucleophiles are the groups that define the various acid derivatives as a result, the reaction usually involves the conversion of one acid derivative into another. The order of reactivity of acid derivatives is acid chloride > anhydride > acid or ester > amide. In general, reaction of any of these derivatives with water produces acids with alcohols, esters result and with amines, amides are formed. 

Since the discovery of the synthesis of 1,3,5-triazine-2,4-diamines from biguanide and its derivatives,328-329 a large variety of carboxylic acid derivatives, e.g. acid chlorides,332 342,346 lactones,333 amides,334,335 imides,336,337 ortho esters,338 amidines,338 esters334, 339- 343 and acid anhydrides,332,344,345 have been used as starting materials in the preparation of these triazines (Table 8).330,331 The preferred procedure is the reaction of biguanides 1 with esters 2 in alcoholic solution, sometimes in the presence of a basic catalyst. The reaction mechanism is thought to be as indicated.341... 

In Chapter 9 you see the basic structure of each of the carboxylic acids and carboxylic acid derivatives. In this chapter we focus on the carboxylic acids and related compounds, such as esters, acyl chlorides, and acid anhydrides, and we also include some information on amides (see Chapter 13 for an additional examination of amides). Before you can get into synthesis and reactions, though, you need to understand the structure and nomenclature of these compounds. 

The group shown in red is called the acyl group. The acyl group is part of the functional group of the carboxylic acid derivatives, including the esters, acid chlorides, acid anhydrides, and amides. 

Amides are prepared from carboxylic acid derivatives, either acid chlorides or acid anhydrides. Recall that acid chlorides are made from carboxylic acids by reaction with reagents such as PCI5. 

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