Carboxylic Acids and Their Derivatives (pp. 971-978)

Espacio deFormaciónMultimodal

Klein, D. (2012). Carboxylic Acids and Their Derivatives. En Organic Chemistry (pp. 971-976). USA: Wiley.

Carboxylic Acids and Their Derivatives

972 CHAPTER 21 Carboxylic Acids and Their Derivatives

21.2 Nomenclature of Carboxylic Acids

Monocarboxylic AcidsMonocarboxylic acids, compounds containing one carboxylic acid moiety, are named with the suffix “oic acid”.

Butanoic acid

OH

O

5-Hydroxy-4,4-dimethylpentanoic acid

OH

O

HO

The parent is the longest chain that includes the carbon atom of the carboxylic acid moiety. That carbon atom is always assigned number 1 when numbering the parent.

When a carboxylic acid moiety is connected to a ring, the compound is named as an alkane carboxylic acid, for example;

Cyclohexane carboxylic acid

OH

O

Many simple carboxylic acids have common names accepted by IUPAC. The examples shown here should be committed to memory, as they will appear frequently throughout the chapter.

Formic acid

H OH

O

Acetic acid

OH

O

Propionic acid

OH

O

Butyric acid

OH

O

Benzoic acid

OH

O

DiacidsDiacids, compounds containing two carboxylic acid moieties, are named with the suffix “dioic acid,” for example;

Pentanedioic acid

OH

O

HO

O

Many diacids have common names accepted by IUPAC.

Oxalic acid

O

HO

O

OH OH

O

HO

O

Malonic acid

OH

O

HO

O

Glutaric acidSuccinic acid

OHHO

OO

These compounds differ from each other only in the number of methylene (CH2) groups sepa-rating the carboxylic acid moieties. These names are used very often in the study of biochemical reactions and should therefore be committed to memory.

klein_c21_970-1029hr.indd 972 11/22/10 12:58 PM

21.1 Introduction to Carboxylic Acids 971

21.1 Introduction to Carboxylic Acids

Carboxylic acids, which were introduced in Section 3.4, are compounds with a COOH moiety. These compounds are abundant in nature, where they are responsible for some familiar odors.

Acetic acid(Responsible for

the pungent smellof vinegar)

OH

O

Butanoic acid(Responsible forthe rancid odorof sour butter)

OH

O

Hexanoic acid(Responsible for

the odor ofdirty socks)

OH

O

Lactic acid(Responsible for

the taste ofsour milk)

OH

O

OH

Carboxylic acids are also found in a wide range of pharmaceuticals that are used to treat a variety of conditions.

Acetylsalicylic acid(Aspirin, a widely used analgesic)

OHO

O

O4-Aminosalicylic acid(Used in the treatment

of tuberculosis)

HO

OHO

NH2

OHO

Isotretinoin(Used in the treatment of acne)

Each year the United States produces over 2.5 million tons of acetic acid from methanol and carbon monoxide. The primary use of acetic acid is in the synthesis of vinyl acetate, which is used in paints and adhesives.

OH

O

O

O

Acetic acid Vinyl acetate

CH3OH ± CO Rh catalyst

Vinyl acetate is a derivative of acetic acid and is therefore said to be a carboxylic acid derivative. Carboxylic acids and their derivatives occupy a central role in organic chemistry, as we will see throughout this chapter.

DO YOU REMEMBER?Before you go on, be sure you understand the following topics. If necessary, review the suggested sections to prepare for this chapter.

klein_c21_970-1029hr.indd 971 11/22/10 12:58 PM

976 CHAPTER 21 Carboxylic Acids and Their Derivatives

Pyruvic acid Pyruvate

OH

OO± H+

O

OO

–

Physiological pH

Carboxylate ions play vital roles in many biological processes, as we will see in Chapter 25.

Substituent Effects on AcidityThe presence of electron-withdrawing substituents can have a profound impact on the acidity of a carboxylic acid.

OH

O

pKa=4.8OH

OCl

pKa=2.9OH

OCl

ClpKa=1.3

OH

OCl

ClCl

pKa=0.9

Notice that the pKa decreases with each additional chlorine substituent. This trend is explained in terms of the inductive effects of the chlorine atoms, which can stabilize the conjugate base (as explained in Section 3.4). The effect of an electron-withdrawing group depends on its proximity to the carboxylic acid moiety.

pKa=4.1

OH

O

Clb

a

pKa=4.5

OH

O

Clb

g a

pKa=2.9

OH

O

Cla

The effect is most pronounced when the electron-withdrawing group is located at the posi-tion. As the distance between the chlorine atom and the carboxylic acid moiety increases, the effect of the chlorine atom becomes less pronounced.

The effects of electron-withdrawing substituents are also observed for substituted benzoic acids (Figure 21.3). In Sections 19.7–19.10, we discussed the electronic effects of each of the substitutents in Figure 21.3, and we saw that a nitro group is a powerful electron-withdrawing group. Consequently, the presence of the nitro group on the ring will stabilize the conjugate base, giving a low pKa value (relative to benzoic acid). In contrast, a hydroxy group is a powerful electron-donating group (Section 19.10), and therefore, the presence of the hydroxy group will destabilize the conjugate base, giving a high pKa value (relative to benzoic acid).

FIGURE 21.3K para

ZO

OH

NO2 ClCHO H CH3 OH

3.4 4.03.8 4.2 4.3 4.5pKa

Z

CONCEPTUAL CHECKPOINT

21.8 21.9

klein_c21_970-1029hr.indd 976 11/22/10 12:58 PM

21.4 Preparation of Carboxylic Acids 977

21.4 Preparation of Carboxylic Acids

In previous chapters, we studied a variety of methods for preparing carboxylic acids (Table 21.1). In addition to the methods we have already seen, there are many other ways of preparing carbox-ylic acids. We will examine two of them.

TABLE 21.1 A REVIEW OF METHODS FOR PREPARING CARBOXYLIC ACIDS

REACTION SECTION NUMBER COMMENTS

Oxidative Cleavage of Alkynes

R

HOO

OH

RO+

1) O3

2) H2OR R

Oxidation of Primary Alcohols

R OH R OH

O

H2SO4, H2ONa2Cr2O7

Oxidation of Alkylbenzenes

OH

O

H2SO4, H2ONa2Cr2O7

Hydrolysis of NitrilesWhen treated with aqueous acid, a nitrile (a compound with a cyano group) can be converted into a carboxylic acid.

RC

OH

OR C N H3O+

Heat

This process is called hydrolysis, and the mechanism for nitrile hydrolysis will be discussed later in this chapter. This reaction provides us with a two-step process for converting an alkyl halide to a carboxylic acid.

Br CN

COH

OC N H3O+

Heat

–

The first step is an SN2 reaction in which cyanide acts as a nucleophile. The resulting nitrile is then hydrolyzed to yield a carboxylic acid that has one more carbon atom (shown in red) than the original alkyl halide. Since the first step is an SN2 process, the reaction cannot occur with tertiary alkyl halides.

Carboxylation of Grignard ReagentsCarboxylic acids can also be prepared by treating a Grignard reagent with carbon dioxide:

R MgBrR

COH

O1) CO22) H3O+

klein_c21_970-1029hr.indd 977 11/22/10 12:58 PM

978 CHAPTER 21 Carboxylic Acids and Their Derivatives

A mechanism for this process is shown below:

R–

RC –

O

O

RC

OH

OC OO

H OH

H±

In the first step, the Grignard reagent attacks the electrophilic center of carbon dioxide, gener-ating a carboxylate ion. Treating the carboxylate ion with a proton source affords the carboxylic acid. These two steps occur separately, as the proton source is not compatible with the Grignard reagent and can only be introduced after the Grignard reaction is complete. This reaction provides us with another two-step process for converting an alkyl (or vinyl or aryl) halide to a carboxylic acid.

Br MgBr COH

O

1) CO22) H3O+

Mg

O

We have now seen two new methods for preparing carboxylic acids, both of which involve the introduction of one carbon atom.

CONCEPTUAL CHECKPOINT

21.10

21.5 Reactions of Carboxylic Acids

Carboxylic acids are reduced to alcohols upon treatment with lithium aluminum hydride.

O

R OH R OH

H H1) LAH2) H3O+

The first step of the mechanism is likely a proton transfer, because LAH is not only a powerful nucleophile, but it can also function as a strong base, forming a carboxylate ion.

± ±± H Al

H

H

H

Li±

–AlH3 H2

RH

O

O R

O

O–

Li±

There are several possibilities for the rest of the mechanism. One possibility involves a reaction of the carboxylate ion with AlH3 followed by elimination to form an aldehyde:

Aldehyde

H

AlH H

R

O

O–

R

O

HRO

H

AlH2

–

O

klein_c21_970-1029hr.indd 978 11/22/10 12:58 PM

972 CHAPTER 21 Carboxylic Acids and Their Derivatives

21.2 Nomenclature of Carboxylic Acids

Monocarboxylic AcidsMonocarboxylic acids, compounds containing one carboxylic acid moiety, are named with the suffix “oic acid”.

Butanoic acid

OH

O

5-Hydroxy-4,4-dimethylpentanoic acid

OH

O

HO

The parent is the longest chain that includes the carbon atom of the carboxylic acid moiety. That carbon atom is always assigned number 1 when numbering the parent.

When a carboxylic acid moiety is connected to a ring, the compound is named as an alkane carboxylic acid, for example;

Cyclohexane carboxylic acid

OH

O

Many simple carboxylic acids have common names accepted by IUPAC. The examples shown here should be committed to memory, as they will appear frequently throughout the chapter.

Formic acid

H OH

O

Acetic acid

OH

O

Propionic acid

OH

O

Butyric acid

OH

O

Benzoic acid

OH

O

DiacidsDiacids, compounds containing two carboxylic acid moieties, are named with the suffix “dioic acid,” for example;

Pentanedioic acid

OH

O

HO

O

Many diacids have common names accepted by IUPAC.

Oxalic acid

O

HO

O

OH OH

O

HO

O

Malonic acid

OH

O

HO

O

Glutaric acidSuccinic acid

OHHO

OO

These compounds differ from each other only in the number of methylene (CH2) groups sepa-rating the carboxylic acid moieties. These names are used very often in the study of biochemical reactions and should therefore be committed to memory.

klein_c21_970-1029hr.indd 972 11/22/10 12:58 PM

21.1 Introduction to Carboxylic Acids 971

21.1 Introduction to Carboxylic Acids

Carboxylic acids, which were introduced in Section 3.4, are compounds with a COOH moiety. These compounds are abundant in nature, where they are responsible for some familiar odors.

Acetic acid(Responsible for

the pungent smellof vinegar)

OH

O

Butanoic acid(Responsible forthe rancid odorof sour butter)

OH

O

Hexanoic acid(Responsible for

the odor ofdirty socks)

OH

O

Lactic acid(Responsible for

the taste ofsour milk)

OH

O

OH

Carboxylic acids are also found in a wide range of pharmaceuticals that are used to treat a variety of conditions.

Acetylsalicylic acid(Aspirin, a widely used analgesic)

OHO

O

O4-Aminosalicylic acid(Used in the treatment

of tuberculosis)

HO

OHO

NH2

OHO

Isotretinoin(Used in the treatment of acne)

Each year the United States produces over 2.5 million tons of acetic acid from methanol and carbon monoxide. The primary use of acetic acid is in the synthesis of vinyl acetate, which is used in paints and adhesives.

OH

O

O

O

Acetic acid Vinyl acetate

CH3OH ± CO Rh catalyst

Vinyl acetate is a derivative of acetic acid and is therefore said to be a carboxylic acid derivative. Carboxylic acids and their derivatives occupy a central role in organic chemistry, as we will see throughout this chapter.

DO YOU REMEMBER?Before you go on, be sure you understand the following topics. If necessary, review the suggested sections to prepare for this chapter.

klein_c21_970-1029hr.indd 971 11/22/10 12:58 PM

21.3 Structure and Properties of Carboxylic Acids 973

21.3 Structure and Properties of Carboxylic Acids

StructureThe carbon atom of a carboxylic acid moiety is sp2 hybridized and therefore exhibits trigonal planar geometry with bond angles that are nearly 120 (Figure 21.1). Carboxylic acids can form two hydrogen-bonding interactions, allowing molecules to associate with each other in pairs.

RO

O

HR

O

O

H

These hydrogen-bonding interactions explain the relatively high boiling points of carboxylic acids. For example, compare the boiling points of acetic acid and ethanol. Acetic acid has a higher boiling point as a result of stronger intermolecular forces.

Acetic acidb.p.=118°C

OH

O

OHEthanol

b.p.=78°C

Acidity of Carboxylic AcidsAs their name implies, carboxylic acids exhibit mildly acidic protons. Treatment of a carboxylic acid with a strong base, such as sodium hydroxide, yields a carboxylate salt.

±±

A carboxylate salt

Na±–

OHR

O

O Na±– H2O

RH

O

O

Carboxylate salts are ionic and are therefore more soluble in water than their corresponding car-boxylic acids. Carboxylate ions are named by replacing the suffix “ic acid” with “ate”, for example:

CONCEPTUAL CHECKPOINT

LOOKING BACK

K

21.1

HO2 2 2 2 2 2

H5 2 2 2 2 2

2H

21.2

21.3 Provide an IUPAC name for each of the following compounds:

OH

O

(a)

O OH

(b)

OH

O

NH2(c)

FIGURE 21.1

OH

RO

klein_c21_970-1029hr.indd 973 11/22/10 12:58 PM

21.4 Preparation of Carboxylic Acids 977

21.4 Preparation of Carboxylic Acids

In previous chapters, we studied a variety of methods for preparing carboxylic acids (Table 21.1). In addition to the methods we have already seen, there are many other ways of preparing carbox-ylic acids. We will examine two of them.

TABLE 21.1 A REVIEW OF METHODS FOR PREPARING CARBOXYLIC ACIDS

REACTION SECTION NUMBER COMMENTS

Oxidative Cleavage of Alkynes

R

HOO

OH

RO+

1) O3

2) H2OR R

Oxidation of Primary Alcohols

R OH R OH

O

H2SO4, H2ONa2Cr2O7

Oxidation of Alkylbenzenes

OH

O

H2SO4, H2ONa2Cr2O7

Hydrolysis of NitrilesWhen treated with aqueous acid, a nitrile (a compound with a cyano group) can be converted into a carboxylic acid.

RC

OH

OR C N H3O+

Heat

This process is called hydrolysis, and the mechanism for nitrile hydrolysis will be discussed later in this chapter. This reaction provides us with a two-step process for converting an alkyl halide to a carboxylic acid.

Br CN

COH

OC N H3O+

Heat

–

The first step is an SN2 reaction in which cyanide acts as a nucleophile. The resulting nitrile is then hydrolyzed to yield a carboxylic acid that has one more carbon atom (shown in red) than the original alkyl halide. Since the first step is an SN2 process, the reaction cannot occur with tertiary alkyl halides.

Carboxylation of Grignard ReagentsCarboxylic acids can also be prepared by treating a Grignard reagent with carbon dioxide:

R MgBrR

COH

O1) CO22) H3O+

klein_c21_970-1029hr.indd 977 11/22/10 12:58 PM

978 CHAPTER 21 Carboxylic Acids and Their Derivatives

A mechanism for this process is shown below:

R–

RC –

O

O

RC

OH

OC OO

H OH

H±

In the first step, the Grignard reagent attacks the electrophilic center of carbon dioxide, gener-ating a carboxylate ion. Treating the carboxylate ion with a proton source affords the carboxylic acid. These two steps occur separately, as the proton source is not compatible with the Grignard reagent and can only be introduced after the Grignard reaction is complete. This reaction provides us with another two-step process for converting an alkyl (or vinyl or aryl) halide to a carboxylic acid.

Br MgBr COH

O

1) CO22) H3O+

Mg

O

We have now seen two new methods for preparing carboxylic acids, both of which involve the introduction of one carbon atom.

CONCEPTUAL CHECKPOINT

21.10

21.5 Reactions of Carboxylic Acids

Carboxylic acids are reduced to alcohols upon treatment with lithium aluminum hydride.

O

R OH R OH

H H1) LAH2) H3O+

The first step of the mechanism is likely a proton transfer, because LAH is not only a powerful nucleophile, but it can also function as a strong base, forming a carboxylate ion.

± ±± H Al

H

H

H

Li±

–AlH3 H2

RH

O

O R

O

O–

Li±

There are several possibilities for the rest of the mechanism. One possibility involves a reaction of the carboxylate ion with AlH3 followed by elimination to form an aldehyde:

Aldehyde

H

AlH H

R

O

O–

R

O

HRO

H

AlH2

–

O

klein_c21_970-1029hr.indd 978 11/22/10 12:58 PM

972 CHAPTER 21 Carboxylic Acids and Their Derivatives

21.2 Nomenclature of Carboxylic Acids

Monocarboxylic AcidsMonocarboxylic acids, compounds containing one carboxylic acid moiety, are named with the suffix “oic acid”.

Butanoic acid

OH

O

5-Hydroxy-4,4-dimethylpentanoic acid

OH

O

HO

The parent is the longest chain that includes the carbon atom of the carboxylic acid moiety. That carbon atom is always assigned number 1 when numbering the parent.

When a carboxylic acid moiety is connected to a ring, the compound is named as an alkane carboxylic acid, for example;

Cyclohexane carboxylic acid

OH

O

Many simple carboxylic acids have common names accepted by IUPAC. The examples shown here should be committed to memory, as they will appear frequently throughout the chapter.

Formic acid

H OH

O

Acetic acid

OH

O

Propionic acid

OH

O

Butyric acid

OH

O

Benzoic acid

OH

O

DiacidsDiacids, compounds containing two carboxylic acid moieties, are named with the suffix “dioic acid,” for example;

Pentanedioic acid

OH

O

HO

O

Many diacids have common names accepted by IUPAC.

Oxalic acid

O

HO

O

OH OH

O

HO

O

Malonic acid

OH

O

HO

O

Glutaric acidSuccinic acid

OHHO

OO

These compounds differ from each other only in the number of methylene (CH2) groups sepa-rating the carboxylic acid moieties. These names are used very often in the study of biochemical reactions and should therefore be committed to memory.

klein_c21_970-1029hr.indd 972 11/22/10 12:58 PM

21.3 Structure and Properties of Carboxylic Acids 973

21.3 Structure and Properties of Carboxylic Acids

StructureThe carbon atom of a carboxylic acid moiety is sp2 hybridized and therefore exhibits trigonal planar geometry with bond angles that are nearly 120 (Figure 21.1). Carboxylic acids can form two hydrogen-bonding interactions, allowing molecules to associate with each other in pairs.

RO

O

HR

O

O

H

These hydrogen-bonding interactions explain the relatively high boiling points of carboxylic acids. For example, compare the boiling points of acetic acid and ethanol. Acetic acid has a higher boiling point as a result of stronger intermolecular forces.

Acetic acidb.p.=118°C

OH

O

OHEthanol

b.p.=78°C

Acidity of Carboxylic AcidsAs their name implies, carboxylic acids exhibit mildly acidic protons. Treatment of a carboxylic acid with a strong base, such as sodium hydroxide, yields a carboxylate salt.

±±

A carboxylate salt

Na±–

OHR

O

O Na±– H2O

RH

O

O

Carboxylate salts are ionic and are therefore more soluble in water than their corresponding car-boxylic acids. Carboxylate ions are named by replacing the suffix “ic acid” with “ate”, for example:

CONCEPTUAL CHECKPOINT

LOOKING BACK

K

21.1

HO2 2 2 2 2 2

H5 2 2 2 2 2

2H

21.2

21.3 Provide an IUPAC name for each of the following compounds:

OH

O

(a)

O OH

(b)

OH

O

NH2(c)

FIGURE 21.1

OH

RO

klein_c21_970-1029hr.indd 973 11/22/10 12:58 PM

974 CHAPTER 21 Carboxylic Acids and Their Derivatives

OH

O

Benzoic acid Sodium benzoate

O

O

Na±–

NaOH

You may recognize the name sodium benzoate, as it is commonly found in food products and beverages. It inhibits the growth of fungi and serves as a food preservative.

When dissolved in water, an equilibrium is established in which the carboxylic acid and the carboxylate ion are both present.

±±

O

O–H2OH

O

OH3O

±

In most cases, the equilibrium significantly favors the carboxylic acid with a Ka usually around 10-4 or 10-5. In other words, the pKa of most carboxylic acids is between 4 and 5.

OH

O

pKa=4.19 pKa=4.76OH

O

pKa=4.87OH

O

When compared to inorganic acids, such as HCl or H2SO4, carboxylic acids are extremely weak acids. But when compared to most classes of organic compounds, such as alcohols, they are relatively acidic. For example, compare the pKa values of acetic acid and ethanol.

O

O

H

pKa=4.76O

H

pKa=16

Acetic acid is 11 orders of magnitude more acidic than ethanol (over a hundred billion times more acidic). As explained in Section 3.4, the acidity of carboxylic acids is primarily due to the stability of the conjugate base, which is resonance stabilized.

O

O–

O

O–

In the conjugate base of acetic acid, the negative charge is delocalized over two oxygen atoms, and it is therefore more stable than the conjugate base of ethanol. The delocalized nature of the charge can be seen in an electrostatic potential map of the acetate ion (Figure 21.2).

FIGURE 21.2

klein_c21_970-1029hr.indd 974 11/22/10 12:58 PM

978 CHAPTER 21 Carboxylic Acids and Their Derivatives

A mechanism for this process is shown below:

R–

RC –

O

O

RC

OH

OC OO

H OH

H±

In the first step, the Grignard reagent attacks the electrophilic center of carbon dioxide, gener-ating a carboxylate ion. Treating the carboxylate ion with a proton source affords the carboxylic acid. These two steps occur separately, as the proton source is not compatible with the Grignard reagent and can only be introduced after the Grignard reaction is complete. This reaction provides us with another two-step process for converting an alkyl (or vinyl or aryl) halide to a carboxylic acid.

Br MgBr COH

O

1) CO22) H3O+

Mg

O

We have now seen two new methods for preparing carboxylic acids, both of which involve the introduction of one carbon atom.

CONCEPTUAL CHECKPOINT

21.10

21.5 Reactions of Carboxylic Acids

Carboxylic acids are reduced to alcohols upon treatment with lithium aluminum hydride.

O

R OH R OH

H H1) LAH2) H3O+

The first step of the mechanism is likely a proton transfer, because LAH is not only a powerful nucleophile, but it can also function as a strong base, forming a carboxylate ion.

± ±± H Al

H

H

H

Li±

–AlH3 H2

RH

O

O R

O

O–

Li±

There are several possibilities for the rest of the mechanism. One possibility involves a reaction of the carboxylate ion with AlH3 followed by elimination to form an aldehyde:

Aldehyde

H

AlH H

R

O

O–

R

O

HRO

H

AlH2

–

O

klein_c21_970-1029hr.indd 978 11/22/10 12:58 PM

21.3 Structure and Properties of Carboxylic Acids 973

21.3 Structure and Properties of Carboxylic Acids

StructureThe carbon atom of a carboxylic acid moiety is sp2 hybridized and therefore exhibits trigonal planar geometry with bond angles that are nearly 120 (Figure 21.1). Carboxylic acids can form two hydrogen-bonding interactions, allowing molecules to associate with each other in pairs.

RO

O

HR

O

O

H

These hydrogen-bonding interactions explain the relatively high boiling points of carboxylic acids. For example, compare the boiling points of acetic acid and ethanol. Acetic acid has a higher boiling point as a result of stronger intermolecular forces.

Acetic acidb.p.=118°C

OH

O

OHEthanol

b.p.=78°C

Acidity of Carboxylic AcidsAs their name implies, carboxylic acids exhibit mildly acidic protons. Treatment of a carboxylic acid with a strong base, such as sodium hydroxide, yields a carboxylate salt.

±±

A carboxylate salt

Na±–

OHR

O

O Na±– H2O

RH

O

O

Carboxylate salts are ionic and are therefore more soluble in water than their corresponding car-boxylic acids. Carboxylate ions are named by replacing the suffix “ic acid” with “ate”, for example:

CONCEPTUAL CHECKPOINT

LOOKING BACK

K

21.1

HO2 2 2 2 2 2

H5 2 2 2 2 2

2H

21.2

21.3 Provide an IUPAC name for each of the following compounds:

OH

O

(a)

O OH

(b)

OH

O

NH2(c)

FIGURE 21.1

OH

RO

klein_c21_970-1029hr.indd 973 11/22/10 12:58 PM

974 CHAPTER 21 Carboxylic Acids and Their Derivatives

OH

O

Benzoic acid Sodium benzoate

O

O

Na±–

NaOH

You may recognize the name sodium benzoate, as it is commonly found in food products and beverages. It inhibits the growth of fungi and serves as a food preservative.

When dissolved in water, an equilibrium is established in which the carboxylic acid and the carboxylate ion are both present.

±±

O

O–H2OH

O

OH3O

±

In most cases, the equilibrium significantly favors the carboxylic acid with a Ka usually around 10-4 or 10-5. In other words, the pKa of most carboxylic acids is between 4 and 5.

OH

O

pKa=4.19 pKa=4.76OH

O

pKa=4.87OH

O

When compared to inorganic acids, such as HCl or H2SO4, carboxylic acids are extremely weak acids. But when compared to most classes of organic compounds, such as alcohols, they are relatively acidic. For example, compare the pKa values of acetic acid and ethanol.

O

O

H

pKa=4.76O

H

pKa=16

Acetic acid is 11 orders of magnitude more acidic than ethanol (over a hundred billion times more acidic). As explained in Section 3.4, the acidity of carboxylic acids is primarily due to the stability of the conjugate base, which is resonance stabilized.

O

O–

O

O–

In the conjugate base of acetic acid, the negative charge is delocalized over two oxygen atoms, and it is therefore more stable than the conjugate base of ethanol. The delocalized nature of the charge can be seen in an electrostatic potential map of the acetate ion (Figure 21.2).

FIGURE 21.2

klein_c21_970-1029hr.indd 974 11/22/10 12:58 PM

21.3 Structure and Properties of Carboxylic Acids 975

Carboxylic Acids at Physiological pHOur blood is buffered to a pH of approximately 7.3, a value referred to as physiological pH. When dealing with buffered solutions, you may recall the Henderson-Hasselbalch equation from your general chemistry course.

pH p log[conjugate base]

[acid]aK

This equation is often employed to calculate the pH of buffered solutions, although for our purposes we will rearrange the equation in the following way:

[conjugate base][acid]

10(pH p aK )

This rearranged form of the Henderson-Hasselbalch equation provides a method for determining the extent to which an acid will dissociate to form its conjugate base in a buffered solution. When the pKa value of an acid is equivalent to the pH of a buffered solution into which it is dissolved, then

[conjugate base][acid]

(pH p a10 10 10K ) ( )

The ratio of the concentrations of conjugate base and acid will be 1. In other words, a carboxylic acid and its conjugate base will be present in approximately equal amounts when dissolved in a solution that is buffered such that pH pKa of the acid.

Now let’s apply this equation to carboxylic acids at physiological pH (7.3), so that we can determine which form predominates (the carboxylic acid or the carboxylate ion). Recall that carboxylic acids generally have a pKa value between 4 and 5. Therefore, at physiological pH:

[conjugate base][acid]

10 10 1(pH p ) (7.3 p )a aK K 003

The ratio of the concentrations of the carboxylate ion and the carboxylic acid will be approximately 1000 : 1. That is, carboxylic acids will exist primarily as carboxylate salts at phys-iological pH. For example, pyruvic acid exists primarily as pyruvate ion at physiological pH.

CONCEPTUAL CHECKPOINT

21.4

H

O

OHH3C OH

O

21.5 paraK

para

HOO

para-HydroxyacetophenonepKa=4.2

21.6 meta

para

meta-Hydroxyacetophenone

O

HO

HO

O

para-Hydroxyacetophenone

21.7

klein_c21_970-1029hr.indd 975 11/22/10 12:58 PM

974 CHAPTER 21 Carboxylic Acids and Their Derivatives

OH

O

Benzoic acid Sodium benzoate

O

O

Na±–

NaOH

You may recognize the name sodium benzoate, as it is commonly found in food products and beverages. It inhibits the growth of fungi and serves as a food preservative.

When dissolved in water, an equilibrium is established in which the carboxylic acid and the carboxylate ion are both present.

±±

O

O–H2OH

O

OH3O

±

In most cases, the equilibrium significantly favors the carboxylic acid with a Ka usually around 10-4 or 10-5. In other words, the pKa of most carboxylic acids is between 4 and 5.

OH

O

pKa=4.19 pKa=4.76OH

O

pKa=4.87OH

O

When compared to inorganic acids, such as HCl or H2SO4, carboxylic acids are extremely weak acids. But when compared to most classes of organic compounds, such as alcohols, they are relatively acidic. For example, compare the pKa values of acetic acid and ethanol.

O

O

H

pKa=4.76O

H

pKa=16

Acetic acid is 11 orders of magnitude more acidic than ethanol (over a hundred billion times more acidic). As explained in Section 3.4, the acidity of carboxylic acids is primarily due to the stability of the conjugate base, which is resonance stabilized.

O

O–

O

O–

In the conjugate base of acetic acid, the negative charge is delocalized over two oxygen atoms, and it is therefore more stable than the conjugate base of ethanol. The delocalized nature of the charge can be seen in an electrostatic potential map of the acetate ion (Figure 21.2).

FIGURE 21.2

klein_c21_970-1029hr.indd 974 11/22/10 12:58 PM

21.3 Structure and Properties of Carboxylic Acids 975

Carboxylic Acids at Physiological pHOur blood is buffered to a pH of approximately 7.3, a value referred to as physiological pH. When dealing with buffered solutions, you may recall the Henderson-Hasselbalch equation from your general chemistry course.

pH p log[conjugate base]

[acid]aK

This equation is often employed to calculate the pH of buffered solutions, although for our purposes we will rearrange the equation in the following way:

[conjugate base][acid]

10(pH p aK )

This rearranged form of the Henderson-Hasselbalch equation provides a method for determining the extent to which an acid will dissociate to form its conjugate base in a buffered solution. When the pKa value of an acid is equivalent to the pH of a buffered solution into which it is dissolved, then

[conjugate base][acid]

(pH p a10 10 10K ) ( )

The ratio of the concentrations of conjugate base and acid will be 1. In other words, a carboxylic acid and its conjugate base will be present in approximately equal amounts when dissolved in a solution that is buffered such that pH pKa of the acid.

Now let’s apply this equation to carboxylic acids at physiological pH (7.3), so that we can determine which form predominates (the carboxylic acid or the carboxylate ion). Recall that carboxylic acids generally have a pKa value between 4 and 5. Therefore, at physiological pH:

[conjugate base][acid]

10 10 1(pH p ) (7.3 p )a aK K 003

The ratio of the concentrations of the carboxylate ion and the carboxylic acid will be approximately 1000 : 1. That is, carboxylic acids will exist primarily as carboxylate salts at phys-iological pH. For example, pyruvic acid exists primarily as pyruvate ion at physiological pH.

CONCEPTUAL CHECKPOINT

21.4

H

O

OHH3C OH

O

21.5 paraK

para

HOO

para-HydroxyacetophenonepKa=4.2

21.6 meta

para

meta-Hydroxyacetophenone

O

HO

HO

O

para-Hydroxyacetophenone

21.7

klein_c21_970-1029hr.indd 975 11/22/10 12:58 PM

21.1 Introduction to Carboxylic Acids 971

21.1 Introduction to Carboxylic Acids

Carboxylic acids, which were introduced in Section 3.4, are compounds with a COOH moiety. These compounds are abundant in nature, where they are responsible for some familiar odors.

Acetic acid(Responsible for

the pungent smellof vinegar)

OH

O

Butanoic acid(Responsible forthe rancid odorof sour butter)

OH

O

Hexanoic acid(Responsible for

the odor ofdirty socks)

OH

O

Lactic acid(Responsible for

the taste ofsour milk)

OH

O

OH

Carboxylic acids are also found in a wide range of pharmaceuticals that are used to treat a variety of conditions.

Acetylsalicylic acid(Aspirin, a widely used analgesic)

OHO

O

O4-Aminosalicylic acid(Used in the treatment

of tuberculosis)

HO

OHO

NH2

OHO

Isotretinoin(Used in the treatment of acne)

Each year the United States produces over 2.5 million tons of acetic acid from methanol and carbon monoxide. The primary use of acetic acid is in the synthesis of vinyl acetate, which is used in paints and adhesives.

OH

O

O

O

Acetic acid Vinyl acetate

CH3OH ± CO Rh catalyst

Vinyl acetate is a derivative of acetic acid and is therefore said to be a carboxylic acid derivative. Carboxylic acids and their derivatives occupy a central role in organic chemistry, as we will see throughout this chapter.

DO YOU REMEMBER?Before you go on, be sure you understand the following topics. If necessary, review the suggested sections to prepare for this chapter.

klein_c21_970-1029hr.indd 971 11/22/10 12:58 PM

976 CHAPTER 21 Carboxylic Acids and Their Derivatives

Pyruvic acid Pyruvate

OH

OO± H+

O

OO

–

Physiological pH

Carboxylate ions play vital roles in many biological processes, as we will see in Chapter 25.

Substituent Effects on AcidityThe presence of electron-withdrawing substituents can have a profound impact on the acidity of a carboxylic acid.

OH

O

pKa=4.8OH

OCl

pKa=2.9OH

OCl

ClpKa=1.3

OH

OCl

ClCl

pKa=0.9

Notice that the pKa decreases with each additional chlorine substituent. This trend is explained in terms of the inductive effects of the chlorine atoms, which can stabilize the conjugate base (as explained in Section 3.4). The effect of an electron-withdrawing group depends on its proximity to the carboxylic acid moiety.

pKa=4.1

OH

O

Clb

a

pKa=4.5

OH

O

Clb

g a

pKa=2.9

OH

O

Cla

The effect is most pronounced when the electron-withdrawing group is located at the posi-tion. As the distance between the chlorine atom and the carboxylic acid moiety increases, the effect of the chlorine atom becomes less pronounced.

The effects of electron-withdrawing substituents are also observed for substituted benzoic acids (Figure 21.3). In Sections 19.7–19.10, we discussed the electronic effects of each of the substitutents in Figure 21.3, and we saw that a nitro group is a powerful electron-withdrawing group. Consequently, the presence of the nitro group on the ring will stabilize the conjugate base, giving a low pKa value (relative to benzoic acid). In contrast, a hydroxy group is a powerful electron-donating group (Section 19.10), and therefore, the presence of the hydroxy group will destabilize the conjugate base, giving a high pKa value (relative to benzoic acid).

FIGURE 21.3K para

ZO

OH

NO2 ClCHO H CH3 OH

3.4 4.03.8 4.2 4.3 4.5pKa

Z

CONCEPTUAL CHECKPOINT

21.8 21.9

klein_c21_970-1029hr.indd 976 11/22/10 12:58 PM

21.4 Preparation of Carboxylic Acids 977

21.4 Preparation of Carboxylic Acids

In previous chapters, we studied a variety of methods for preparing carboxylic acids (Table 21.1). In addition to the methods we have already seen, there are many other ways of preparing carbox-ylic acids. We will examine two of them.

TABLE 21.1 A REVIEW OF METHODS FOR PREPARING CARBOXYLIC ACIDS

REACTION SECTION NUMBER COMMENTS

Oxidative Cleavage of Alkynes

R

HOO

OH

RO+

1) O3

2) H2OR R

Oxidation of Primary Alcohols

R OH R OH

O

H2SO4, H2ONa2Cr2O7

Oxidation of Alkylbenzenes

OH

O

H2SO4, H2ONa2Cr2O7

Hydrolysis of NitrilesWhen treated with aqueous acid, a nitrile (a compound with a cyano group) can be converted into a carboxylic acid.

RC

OH

OR C N H3O+

Heat

This process is called hydrolysis, and the mechanism for nitrile hydrolysis will be discussed later in this chapter. This reaction provides us with a two-step process for converting an alkyl halide to a carboxylic acid.

Br CN

COH

OC N H3O+

Heat

–

The first step is an SN2 reaction in which cyanide acts as a nucleophile. The resulting nitrile is then hydrolyzed to yield a carboxylic acid that has one more carbon atom (shown in red) than the original alkyl halide. Since the first step is an SN2 process, the reaction cannot occur with tertiary alkyl halides.

Carboxylation of Grignard ReagentsCarboxylic acids can also be prepared by treating a Grignard reagent with carbon dioxide:

R MgBrR

COH

O1) CO22) H3O+

klein_c21_970-1029hr.indd 977 11/22/10 12:58 PM

972 CHAPTER 21 Carboxylic Acids and Their Derivatives

21.2 Nomenclature of Carboxylic Acids

Monocarboxylic AcidsMonocarboxylic acids, compounds containing one carboxylic acid moiety, are named with the suffix “oic acid”.

Butanoic acid

OH

O

5-Hydroxy-4,4-dimethylpentanoic acid

OH

O

HO

The parent is the longest chain that includes the carbon atom of the carboxylic acid moiety. That carbon atom is always assigned number 1 when numbering the parent.

When a carboxylic acid moiety is connected to a ring, the compound is named as an alkane carboxylic acid, for example;

Cyclohexane carboxylic acid

OH

O

Many simple carboxylic acids have common names accepted by IUPAC. The examples shown here should be committed to memory, as they will appear frequently throughout the chapter.

Formic acid

H OH

O

Acetic acid

OH

O

Propionic acid

OH

O

Butyric acid

OH

O

Benzoic acid

OH

O

DiacidsDiacids, compounds containing two carboxylic acid moieties, are named with the suffix “dioic acid,” for example;

Pentanedioic acid

OH

O

HO

O

Many diacids have common names accepted by IUPAC.

Oxalic acid

O

HO

O

OH OH

O

HO

O

Malonic acid

OH

O

HO

O

Glutaric acidSuccinic acid

OHHO

OO

These compounds differ from each other only in the number of methylene (CH2) groups sepa-rating the carboxylic acid moieties. These names are used very often in the study of biochemical reactions and should therefore be committed to memory.

klein_c21_970-1029hr.indd 972 11/22/10 12:58 PM

21.1 Introduction to Carboxylic Acids 971

21.1 Introduction to Carboxylic Acids

Carboxylic acids, which were introduced in Section 3.4, are compounds with a COOH moiety. These compounds are abundant in nature, where they are responsible for some familiar odors.

Acetic acid(Responsible for

the pungent smellof vinegar)

OH

O

Butanoic acid(Responsible forthe rancid odorof sour butter)

OH

O

Hexanoic acid(Responsible for

the odor ofdirty socks)

OH

O

Lactic acid(Responsible for

the taste ofsour milk)

OH

O

OH

Carboxylic acids are also found in a wide range of pharmaceuticals that are used to treat a variety of conditions.

Acetylsalicylic acid(Aspirin, a widely used analgesic)

OHO

O

O4-Aminosalicylic acid(Used in the treatment

of tuberculosis)

HO

OHO

NH2

OHO

Isotretinoin(Used in the treatment of acne)

Each year the United States produces over 2.5 million tons of acetic acid from methanol and carbon monoxide. The primary use of acetic acid is in the synthesis of vinyl acetate, which is used in paints and adhesives.

OH

O

O

O

Acetic acid Vinyl acetate

CH3OH ± CO Rh catalyst

Vinyl acetate is a derivative of acetic acid and is therefore said to be a carboxylic acid derivative. Carboxylic acids and their derivatives occupy a central role in organic chemistry, as we will see throughout this chapter.

DO YOU REMEMBER?Before you go on, be sure you understand the following topics. If necessary, review the suggested sections to prepare for this chapter.

klein_c21_970-1029hr.indd 971 11/22/10 12:58 PM

976 CHAPTER 21 Carboxylic Acids and Their Derivatives

Pyruvic acid Pyruvate

OH

OO± H+

O

OO

–

Physiological pH

Carboxylate ions play vital roles in many biological processes, as we will see in Chapter 25.

Substituent Effects on AcidityThe presence of electron-withdrawing substituents can have a profound impact on the acidity of a carboxylic acid.

OH

O

pKa=4.8OH

OCl

pKa=2.9OH

OCl

ClpKa=1.3

OH

OCl

ClCl

pKa=0.9

Notice that the pKa decreases with each additional chlorine substituent. This trend is explained in terms of the inductive effects of the chlorine atoms, which can stabilize the conjugate base (as explained in Section 3.4). The effect of an electron-withdrawing group depends on its proximity to the carboxylic acid moiety.

pKa=4.1

OH

O

Clb

a

pKa=4.5

OH

O

Clb

g a

pKa=2.9

OH

O

Cla

The effect is most pronounced when the electron-withdrawing group is located at the posi-tion. As the distance between the chlorine atom and the carboxylic acid moiety increases, the effect of the chlorine atom becomes less pronounced.

The effects of electron-withdrawing substituents are also observed for substituted benzoic acids (Figure 21.3). In Sections 19.7–19.10, we discussed the electronic effects of each of the substitutents in Figure 21.3, and we saw that a nitro group is a powerful electron-withdrawing group. Consequently, the presence of the nitro group on the ring will stabilize the conjugate base, giving a low pKa value (relative to benzoic acid). In contrast, a hydroxy group is a powerful electron-donating group (Section 19.10), and therefore, the presence of the hydroxy group will destabilize the conjugate base, giving a high pKa value (relative to benzoic acid).

FIGURE 21.3K para

ZO

OH

NO2 ClCHO H CH3 OH

3.4 4.03.8 4.2 4.3 4.5pKa

Z

CONCEPTUAL CHECKPOINT

21.8 21.9

klein_c21_970-1029hr.indd 976 11/22/10 12:58 PM

21.4 Preparation of Carboxylic Acids 977

21.4 Preparation of Carboxylic Acids

In previous chapters, we studied a variety of methods for preparing carboxylic acids (Table 21.1). In addition to the methods we have already seen, there are many other ways of preparing carbox-ylic acids. We will examine two of them.

TABLE 21.1 A REVIEW OF METHODS FOR PREPARING CARBOXYLIC ACIDS

REACTION SECTION NUMBER COMMENTS

Oxidative Cleavage of Alkynes

R

HOO

OH

RO+

1) O3

2) H2OR R

Oxidation of Primary Alcohols

R OH R OH

O

H2SO4, H2ONa2Cr2O7

Oxidation of Alkylbenzenes

OH

O

H2SO4, H2ONa2Cr2O7

Hydrolysis of NitrilesWhen treated with aqueous acid, a nitrile (a compound with a cyano group) can be converted into a carboxylic acid.

RC

OH

OR C N H3O+

Heat

This process is called hydrolysis, and the mechanism for nitrile hydrolysis will be discussed later in this chapter. This reaction provides us with a two-step process for converting an alkyl halide to a carboxylic acid.

Br CN

COH

OC N H3O+

Heat

–

The first step is an SN2 reaction in which cyanide acts as a nucleophile. The resulting nitrile is then hydrolyzed to yield a carboxylic acid that has one more carbon atom (shown in red) than the original alkyl halide. Since the first step is an SN2 process, the reaction cannot occur with tertiary alkyl halides.

Carboxylation of Grignard ReagentsCarboxylic acids can also be prepared by treating a Grignard reagent with carbon dioxide:

R MgBrR

COH

O1) CO22) H3O+

klein_c21_970-1029hr.indd 977 11/22/10 12:58 PM

978 CHAPTER 21 Carboxylic Acids and Their Derivatives

A mechanism for this process is shown below:

R–

RC –

O

O

RC

OH

OC OO

H OH

H±

In the first step, the Grignard reagent attacks the electrophilic center of carbon dioxide, gener-ating a carboxylate ion. Treating the carboxylate ion with a proton source affords the carboxylic acid. These two steps occur separately, as the proton source is not compatible with the Grignard reagent and can only be introduced after the Grignard reaction is complete. This reaction provides us with another two-step process for converting an alkyl (or vinyl or aryl) halide to a carboxylic acid.

Br MgBr COH

O

1) CO22) H3O+

Mg

O

We have now seen two new methods for preparing carboxylic acids, both of which involve the introduction of one carbon atom.

CONCEPTUAL CHECKPOINT

21.10

21.5 Reactions of Carboxylic Acids

Carboxylic acids are reduced to alcohols upon treatment with lithium aluminum hydride.

O

R OH R OH

H H1) LAH2) H3O+

The first step of the mechanism is likely a proton transfer, because LAH is not only a powerful nucleophile, but it can also function as a strong base, forming a carboxylate ion.

± ±± H Al

H

H

H

Li±

–AlH3 H2

RH

O

O R

O

O–

Li±

There are several possibilities for the rest of the mechanism. One possibility involves a reaction of the carboxylate ion with AlH3 followed by elimination to form an aldehyde:

Aldehyde

H

AlH H

R

O

O–

R

O

HRO

H

AlH2

–

O

klein_c21_970-1029hr.indd 978 11/22/10 12:58 PM

972 CHAPTER 21 Carboxylic Acids and Their Derivatives

21.2 Nomenclature of Carboxylic Acids

Monocarboxylic AcidsMonocarboxylic acids, compounds containing one carboxylic acid moiety, are named with the suffix “oic acid”.

Butanoic acid

OH

O

5-Hydroxy-4,4-dimethylpentanoic acid

OH

O

HO

The parent is the longest chain that includes the carbon atom of the carboxylic acid moiety. That carbon atom is always assigned number 1 when numbering the parent.

When a carboxylic acid moiety is connected to a ring, the compound is named as an alkane carboxylic acid, for example;

Cyclohexane carboxylic acid

OH

O

Many simple carboxylic acids have common names accepted by IUPAC. The examples shown here should be committed to memory, as they will appear frequently throughout the chapter.

Formic acid

H OH

O

Acetic acid

OH

O

Propionic acid

OH

O

Butyric acid

OH

O

Benzoic acid

OH

O

DiacidsDiacids, compounds containing two carboxylic acid moieties, are named with the suffix “dioic acid,” for example;

Pentanedioic acid

OH

O

HO

O

Many diacids have common names accepted by IUPAC.

Oxalic acid

O

HO

O

OH OH

O

HO

O

Malonic acid

OH

O

HO

O

Glutaric acidSuccinic acid

OHHO

OO

These compounds differ from each other only in the number of methylene (CH2) groups sepa-rating the carboxylic acid moieties. These names are used very often in the study of biochemical reactions and should therefore be committed to memory.

klein_c21_970-1029hr.indd 972 11/22/10 12:58 PM

21.1 Introduction to Carboxylic Acids 971

21.1 Introduction to Carboxylic Acids

Carboxylic acids, which were introduced in Section 3.4, are compounds with a COOH moiety. These compounds are abundant in nature, where they are responsible for some familiar odors.

Acetic acid(Responsible for

the pungent smellof vinegar)

OH

O

Butanoic acid(Responsible forthe rancid odorof sour butter)

OH

O

Hexanoic acid(Responsible for

the odor ofdirty socks)

OH

O

Lactic acid(Responsible for

the taste ofsour milk)

OH

O

OH

Carboxylic acids are also found in a wide range of pharmaceuticals that are used to treat a variety of conditions.

Acetylsalicylic acid(Aspirin, a widely used analgesic)

OHO

O

O4-Aminosalicylic acid(Used in the treatment

of tuberculosis)

HO

OHO

NH2

OHO

Isotretinoin(Used in the treatment of acne)

Each year the United States produces over 2.5 million tons of acetic acid from methanol and carbon monoxide. The primary use of acetic acid is in the synthesis of vinyl acetate, which is used in paints and adhesives.

OH

O

O

O

Acetic acid Vinyl acetate

CH3OH ± CO Rh catalyst

Vinyl acetate is a derivative of acetic acid and is therefore said to be a carboxylic acid derivative. Carboxylic acids and their derivatives occupy a central role in organic chemistry, as we will see throughout this chapter.

DO YOU REMEMBER?Before you go on, be sure you understand the following topics. If necessary, review the suggested sections to prepare for this chapter.

klein_c21_970-1029hr.indd 971 11/22/10 12:58 PM

21.3 Structure and Properties of Carboxylic Acids 973

21.3 Structure and Properties of Carboxylic Acids

StructureThe carbon atom of a carboxylic acid moiety is sp2 hybridized and therefore exhibits trigonal planar geometry with bond angles that are nearly 120 (Figure 21.1). Carboxylic acids can form two hydrogen-bonding interactions, allowing molecules to associate with each other in pairs.

RO

O

HR

O

O

H

These hydrogen-bonding interactions explain the relatively high boiling points of carboxylic acids. For example, compare the boiling points of acetic acid and ethanol. Acetic acid has a higher boiling point as a result of stronger intermolecular forces.

Acetic acidb.p.=118°C

OH

O

OHEthanol

b.p.=78°C

Acidity of Carboxylic AcidsAs their name implies, carboxylic acids exhibit mildly acidic protons. Treatment of a carboxylic acid with a strong base, such as sodium hydroxide, yields a carboxylate salt.

±±

A carboxylate salt

Na±–

OHR

O

O Na±– H2O

RH

O

O

Carboxylate salts are ionic and are therefore more soluble in water than their corresponding car-boxylic acids. Carboxylate ions are named by replacing the suffix “ic acid” with “ate”, for example:

CONCEPTUAL CHECKPOINT

LOOKING BACK

K

21.1

HO2 2 2 2 2 2

H5 2 2 2 2 2

2H

21.2

21.3 Provide an IUPAC name for each of the following compounds:

OH

O

(a)

O OH

(b)

OH

O

NH2(c)

FIGURE 21.1

OH

RO

klein_c21_970-1029hr.indd 973 11/22/10 12:58 PM

21.4 Preparation of Carboxylic Acids 977

21.4 Preparation of Carboxylic Acids

In previous chapters, we studied a variety of methods for preparing carboxylic acids (Table 21.1). In addition to the methods we have already seen, there are many other ways of preparing carbox-ylic acids. We will examine two of them.

TABLE 21.1 A REVIEW OF METHODS FOR PREPARING CARBOXYLIC ACIDS

REACTION SECTION NUMBER COMMENTS

Oxidative Cleavage of Alkynes

R

HOO

OH

RO+

1) O3

2) H2OR R

Oxidation of Primary Alcohols

R OH R OH

O

H2SO4, H2ONa2Cr2O7

Oxidation of Alkylbenzenes

OH

O

H2SO4, H2ONa2Cr2O7

Hydrolysis of NitrilesWhen treated with aqueous acid, a nitrile (a compound with a cyano group) can be converted into a carboxylic acid.

RC

OH

OR C N H3O+

Heat

This process is called hydrolysis, and the mechanism for nitrile hydrolysis will be discussed later in this chapter. This reaction provides us with a two-step process for converting an alkyl halide to a carboxylic acid.

Br CN

COH

OC N H3O+

Heat

–

The first step is an SN2 reaction in which cyanide acts as a nucleophile. The resulting nitrile is then hydrolyzed to yield a carboxylic acid that has one more carbon atom (shown in red) than the original alkyl halide. Since the first step is an SN2 process, the reaction cannot occur with tertiary alkyl halides.

Carboxylation of Grignard ReagentsCarboxylic acids can also be prepared by treating a Grignard reagent with carbon dioxide:

R MgBrR

COH

O1) CO22) H3O+

klein_c21_970-1029hr.indd 977 11/22/10 12:58 PM

978 CHAPTER 21 Carboxylic Acids and Their Derivatives

A mechanism for this process is shown below:

R–

RC –

O

O

RC

OH

OC OO

H OH

H±

In the first step, the Grignard reagent attacks the electrophilic center of carbon dioxide, gener-ating a carboxylate ion. Treating the carboxylate ion with a proton source affords the carboxylic acid. These two steps occur separately, as the proton source is not compatible with the Grignard reagent and can only be introduced after the Grignard reaction is complete. This reaction provides us with another two-step process for converting an alkyl (or vinyl or aryl) halide to a carboxylic acid.

Br MgBr COH

O

1) CO22) H3O+

Mg

O

We have now seen two new methods for preparing carboxylic acids, both of which involve the introduction of one carbon atom.

CONCEPTUAL CHECKPOINT

21.10

21.5 Reactions of Carboxylic Acids

Carboxylic acids are reduced to alcohols upon treatment with lithium aluminum hydride.

O

R OH R OH

H H1) LAH2) H3O+

The first step of the mechanism is likely a proton transfer, because LAH is not only a powerful nucleophile, but it can also function as a strong base, forming a carboxylate ion.

± ±± H Al

H

H

H

Li±

–AlH3 H2

RH

O

O R

O

O–

Li±

There are several possibilities for the rest of the mechanism. One possibility involves a reaction of the carboxylate ion with AlH3 followed by elimination to form an aldehyde:

Aldehyde

H

AlH H

R

O

O–

R

O

HRO

H

AlH2

–

O

klein_c21_970-1029hr.indd 978 11/22/10 12:58 PM