Carey - Organic Chemistry - chapt20

Carey - Organic Chemistry - chapt20

(Parte 1 de 6)


This chapter differs from preceding ones in that it deals with several related classes of compounds rather than just one. Included are

1.Acyl chlorides,

2.Carboxylic acid anhydrides, 3.Esters of carboxylic acids,

4.Carboxamides, ,,and

These classes of compounds are classified as carboxylic acid derivatives.All may be converted to carboxylic acids by hydrolysis.

Carboxylic acid derivative

H2OWater HX

Conjugate acidof leaving groupCarboxylic acid



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The hydrolysis of a carboxylic acid derivative is but one example of a nucleophilic acyl substitution.Nucleophilic acyl substitutions connect the various classes of carboxylic acid derivatives, with a reaction of one class often serving as preparation of another. These reactions provide the basis for a large number of functional group transformations both in synthetic organic chemistry and in biological chemistry.

Also included in this chapter is a discussion of the chemistry of nitriles,compounds of the type RCPN. Nitriles may be hydrolyzed to carboxylic acids or to amides and, so, are indirectly related to the other functional groups presented here.

20.1NOMENCLATURE OF CARBOXYLIC ACID DERIVATIVES With the exception of nitriles (RCPN), all carboxylic acid derivatives consist of an acyl group attached to an electronegative atom. Acyl groupsare named by replacing the -ic acidending of the corresponding carboxylic acid by -yl. Acyl halidesare named by placing the name of the appropriate halide after that of the acyl group.

Although acyl fluorides, bromides, and iodides are all known classes of organic compounds, they are encountered far less frequently than are acyl chlorides. Acyl chlorides will be the only acyl halides discussed in this chapter.

In naming carboxylic acid anhydridesin which both acyl groups are the same, we simply specify the acyl group and add the word “anhydride.” When the acyl groups are different, they are cited in alphabetical order.

The alkyl group and the acyl group of an esterare specified independently. Esters are named as alkyl alkanoates.The alkyl group R of is cited first, followed by the acyl portion . The acyl portion is named by substituting the suffix -atefor the -icending of the corresponding acid.

Ethyl acetate

Methyl propanoate


2-Chloroethyl benzoate


Acetic anhydride

Benzoic anhydride

Benzoic heptanoic anhydride

F CBr O p-Fluorobenzoyl bromide


3-Butenoyl chloride


Acetyl chloride

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Aryl esters, that is, compounds of the type , are named in an analogous way.

The names of amidesof the type are derived from carboxylic acids by replacing the suffix -oic acidor -ic acidby -amide.

We name compounds of the type and as N-alkyl- and N,N-dialkylsubstituted derivatives of a parent amide.

Substitutive IUPAC names for nitrilesadd the suffix -nitrileto the name of the parent hydrocarbon chain that includes the carbon of the cyano group. Nitriles may also be named by replacing the -ic acidor -oic acidending of the corresponding carboxylic acid with -onitrile.Alternatively, they are sometimes given functional class IUPAC names as alkyl cyanides.

PROBLEM 20.1Write a structural formula for each of the following compounds: (a) 2-Phenylbutanoyl bromide (e) 2-Phenylbutanamide (b) 2-Phenylbutanoic anhydride (f) N-Ethyl-2-phenylbutanamide (c) Butyl 2-phenylbutanoate (g) 2-Phenylbutanenitrile (d) 2-Phenylbutyl butanoate

SAMPLE SOLUTION(a) A 2-phenylbutanoyl group is a four-carbon acyl unit that bears a phenyl substituent at C-2. When the name of an acyl group is followed by the name of a halide, it designates an acyl halide.

2-Phenylbutanoyl bromide

Ethanenitrile (acetonitrile) CH3CN Benzonitrile

2-Methylpropanenitrile (isopropyl cyanide)










776CHAPTER TWENTYCarboxylic Acid Derivatives: Nucleophilic Acyl Substitution

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Figure 20.1 shows the structures and electrostatic potentials of the various derivatives of acetic acid–acetyl chloride, acetic anhydride, ethyl acetate, acetamide, and acetonitrile. Like the other carbonyl-containing compounds that we’ve studied, acyl chlorides, anhydrides, esters, and amides all have a planar arrangement of bonds to the carbonyl group.

An important structural feature of acyl chlorides, anhydrides, esters, and amides is that the atom attached to the acyl group bears an unshared pair of electrons that can interact with the carbonyl system, as shown in Figure 20.2.

This electron delocalization can be represented in resonance terms by contributions from the following resonance structures:

Electron release from the substituent stabilizes the carbonyl group and decreases its electrophilic character. The extent of this electron delocalization depends on the electron-



CH3CPN Acetyl chlorideAcetic anhydrideEthyl thioacetate

AcetonitrileAcetamideEthyl acetate

FIGURE 20.1 The structures and electrostatic potential maps of various derivatives of acetic acid. These models may be viewed on Learning By Modeling.

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donating properties of the substituent X. Generally, the less electronegative X is, the better it donates electrons to the carbonyl group and the greater its stabilizing effect.

Resonance stabilization in acyl chlorides is not nearly as pronounced as in other derivatives of carboxylic acids:

Because the carbon–chlorine bond is so long—typically on the order of 180 pm for acyl chlorides—overlap between the 3porbitals of chlorine and the orbital of the carbonyl group is poor. Consequently, there is little delocalization of the electron pairs of chlorine into the system. The carbonyl group of an acyl chloride feels the normal electronwithdrawing inductive effect of a chlorine substituent without a significant compensating electron-releasing effect due to lone-pair donation by chlorine. This makes the carbonyl carbon of an acyl chloride more susceptible to attack by nucleophiles than that of other carboxylic acid derivatives.

Acid anhydrides are better stabilized by electron delocalization than are acyl chlorides. The lone-pair electrons of oxygen are delocalized more effectively into the carbonyl group. Resonance involves both carbonyl groups of an acid anhydride.

The carbonyl group of an ester is stabilized more than is that of an anhydride.

Since both acyl groups of an anhydride compete for the oxygen lone pair, each carbonyl is stabilized less than the single carbonyl group of an ester.

Esters are stabilized by resonance to about the same extent as carboxylic acids but not as much as amides. Nitrogen is less electronegative than oxygen and is a better electron-pair donor.

is more effective thanEster

O Acid anhydride

ClR Cl C

Weak resonance stabilization

778CHAPTER TWENTYCarboxylic Acid Derivatives: Nucleophilic Acyl Substitution

X OH; carboxylic acid X Cl; acyl chloride

X OCR; acid anhydride X

FIGURE 20.2The three bonds originating at the carbonyl carbon are coplanar. The porbital of the carbonyl carbon, its oxygen, and the atom by which group X is attached to the acyl group overlap to form an extended system through which the electrons are delocalized.

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Amide resonance is a powerful stabilizing force and gives rise to a number of structural effects. Unlike the pyramidal arrangement of bonds in ammonia and amines, the bonds to nitrogen in amides lie in the same plane. The carbon–nitrogen bond has considerable double-bond character and, at 135 pm, is substantially shorter than the normal 147-pm carbon–nitrogen single-bond distance observed in amines.

The barrier to rotation about the carbon–nitrogen bond in amides is 75 to 85 kJ/mol (18–20 kcal/mol).

This is an unusually high rotational energy barrier for a single bond and indicates that the carbon–nitrogen bond has significant double-bond character, as the resonance picture suggests.

PROBLEM 20.2The 1H NMR spectrum of N,N-dimethylformamide shows a separate signal for each of the two methyl groups. Can you explain why?

Electron release from nitrogen stabilizes the carbonyl group of amides and decreases the rate at which nucleophiles attack the carbonyl carbon. Nucleophilic reagents attack electrophilic sites in a molecule; if electrons are donated to an electrophilic site in a molecule by a substituent, then the tendency of that molecule to react with external nucleophiles is moderated. An extreme example of carbonyl group stabilization is seen in carboxylate anions:

The negatively charged oxygen substituent is a powerful electron donor to the carbonyl group. Resonance in carboxylate anions is more effective than resonance in carboxylic acids, acyl chlorides, anhydrides, esters, and amides.

Table 20.1 summarizes the stabilizing effects of substituents on carbonyl groups to which they are attached. In addition to a qualitative ranking, quantitative estimates of the relative rates of hydrolysis of the various classes of acyl derivatives are given. Aweakly stabilized carboxylic acid derivative reacts with water faster than does a more stabilized one.

Most methods for their preparation convert one class of carboxylic acid derivative to another, and the order of carbonyl group stabilization given in Table 20.1 bears directly on the means by which these transformations may be achieved. Areaction that converts one carboxylic acid derivative to another that lies below it in the table is practical; a reaction that converts it to one that lies above it in the table is not. This is another way of saying that one carboxylic acid derivative can be converted to another if the reaction

Very effective resonance stabilization

Recall that the rotational barrier in ethane is only 12 kJ/mol (3 kcal/mol).

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leads to a more stabilized carbonyl group.Numerous examples of reactions of this type will be presented in the sections that follow. We begin with reactions of acyl chlorides.


Acyl chlorides are readily prepared from carboxylic acids by reaction with thionyl chloride (Section 12.7).

On treatment with the appropriate nucleophile, an acyl chloride may be converted to an acid anhydride, an ester, an amide, or a carboxylic acid. Examples are presented in Table 20.2.

PROBLEM 20.3Apply the knowledge gained by studying Table 20.2 to help you predict the major organic product obtained by reaction of benzoyl chloride with each of the following:

(a)Acetic acid(d)Methylamine, CH3NH2

(b) Benzoic acid (e) Dimethylamine, (CH3)2NH (c) Ethanol (f) Water

SAMPLE SOLUTION(a) As noted in Table 20.2, the reaction of an acyl chloride with a carboxylic acid yields an acid anhydride.

Carboxylic acid

Acyl chloride


Thionyl chloride

Sulfur dioxide

Hydrogen chloride


2-Methylpropanoic acid (CH3)2CHCOH

2-Methylpropanoyl chloride (90%) heat

780CHAPTER TWENTYCarboxylic Acid Derivatives: Nucleophilic Acyl Substitution

TABLE 20.1Relative Stability and Reactivity of Carboxylic Acid Derivatives

Relative rate of hydrolysis*

Acyl chloride


Ester Amide

Carboxylic acid derivativeCarboxylate anion


Very small



Large Very large


*Rates are approximate and are relative to ester as standard substrate at pH 7.

One of the most useful reactions of acyl chlorides was presented in Section 12.7. Friedel–Crafts acylation of aromatic rings takes place when arenes are treated with acyl chlorides in the presence of aluminum chloride.

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The product is a mixed anhydride. Acetic acid acts as a nucleophile and substitutes for chloride on the benzoyl group.

Acetic benzoic anhydride CH3COH

Acetic acid

TABLE 20.2Conversion of Acyl Chlorides to Other Carboxylic Acid Derivatives

Reaction (section) and comments

Reaction with carboxylic acids (Section 20.4) Acyl chlorides react with carboxylic acids to yield acid anhydrides. When this reaction is used for preparative purposes, a weak organic base such as pyridine is normally added. Pyridine is a catalyst for the reaction and also acts as a base to neutralize the hydrogen chloride that is formed.

Reaction with alcohols (Section 15.8) Acyl chlorides react with alcohols to form esters. The reaction is typically carried out in the presence of pyridine.

Reaction with ammonia and amines (Section 20.13) Acyl chlorides react with ammonia and amines to form amides. A base such as sodium hydroxide is normally added to react with the hydrogen chloride produced.

Hydrolysis (Section 20.3) Acyl chlorides react with water to yield carboxylic acids. In base, the acid is converted to its carboxylate salt. The reaction has little preparative value because the acyl chloride is nearly always prepared from the carboxylic acid rather than vice versa.

General equation and specific example

Acyl chloride


Carboxylic acid

Acid anhydride


Hydrogen chloride pyridine

Heptanoyl chloride

Heptanoic acid pyridine

Benzoyl chloride tert-Butyl alcohol tert-Butyl benzoate (80%)


Hydrogen chloride chloride


Chloride ion H2OWater

Ammonia or amine chloride


Carboxylic acid


Hydrogen chloride

H2OWater Acyl chloride



Benzoyl chloride

PiperidineHN N-Benzoylpiperidine

Phenylacetyl chloride

Phenylacetic acid

Hydrogen chloride


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The mechanisms of all the reactions cited in Table 20.2 are similar to the mechanism of hydrolysis of an acyl chloride outlined in Figure 20.3. They differ with respect to the nucleophile that attacks the carbonyl group.

In the first stage of the mechanism, water undergoes nucleophilic addition to the carbonyl group to form a tetrahedral intermediate. This stage of the process is analogous to the hydration of aldehydes and ketones discussed in Section 17.6.

The tetrahedral intermediate has three potential leaving groups on carbon: two hydroxyl groups and a chlorine. In the second stage of the reaction, the tetrahedral intermediate dissociates. Loss of chloride from the tetrahedral intermediate is faster than loss of hydroxide; chloride is less basic than hydroxide and is a better leaving group. The tetrahedral intermediate dissociates because this dissociation restores the resonancestabilized carbonyl group.

PROBLEM 20.4Write the structure of the tetrahedral intermediate formed in each of the reactions given in Problem 20.3. Using curved arrows, show how each tetrahedral intermediate dissociates to the appropriate products.

SAMPLE SOLUTION(a) The tetrahedral intermediate arises by nucleophilic addition of acetic acid to benzoyl chloride.

Loss of a proton and of chloride ion from the tetrahedral intermediate yields the mixed anhydride.

Benzoyl chloride

Tetrahedral intermediate


Acetic acid

782CHAPTER TWENTYCarboxylic Acid Derivatives: Nucleophilic Acyl Substitution

(Parte 1 de 6)