Snyder/Cook

Chapter 20: Carboxylic Acids and Nitriles

Chem C3444

Physical Properties of Carboxylic Acids

Carboxylic acids contain both carbonyl and alcohol-like functionalities, and they also have many properties in common with these functional groups. Chief among these traits is the presence of hydrogen bonding. The carbonyl lone pairs are particularly good hydrogen acceptors and the -OH is a good hydrogen bond donor, thus driving carboxylic acids to dimerize in solution.
O R C O H O H O C R

Just as with alcohols and all other protic functional groups, we can analyze the effects of substituents on the molecule's acidity.

(1) Electronegative Substituents at the Alpha Carbon Electronegative substituents at the carbon adjacent to the carboxylic acid functionality provide inductive stabilization of the conjugate base and therefore increase acidity.
O O Cl H3C OH Cl3C OH Cl C Cl O O

G = -15 kcal/mol
R C

O O H

H O C R O

This large degree of stabilization results in the dimeric form being almost the exclusive structure in solution. As it did for alcohols, this association leads to higher boiling points for carboxylic acids. We can also consider the acidity of these compounds. Like alcohols, carboxylic acids are weak acids (pKa > 0) and exist in an equilibrium with their conjugate base in solvent.
O R C O H O

pKa

4.76

0.6

(2) Electronegative Substituents at the Carbonyl

Inductive effects may also occur directly at the carbonyl carbon. Recall that sp hybridized carbons are more electronegative than sp3 hybridized carbons.
O H3C OH HC C O OH C O HC O

Solvent
R

Solvent(H)
O

pKa

4.9

1.9

Since the pKa is positive, we know that Ka (and therefore Keq) is less than unity. This means that the overall Go for the reaction is positive.
O R O C O

(3) Sterics at the Alpha Carbon

Steric effects at the alpha carbon still have some effect by limiting solvation of the anion, but the effect is far less important than it is for alcohols.
O H3C OH MeH2C O OH Me2HC O OH Me3C O OH

Energy

Go

pKa

4.76

4.9

4.9

5.0

Reaction Coordinate
The Go given by the free energy diagram above provides us with Keq [recall from general chemistry that Go = -RT ln(Keq)], and Keq allows us to calculate the pKa. The entire point of this discussion is simply to once again show that the pKa of an acid depends on the stability of its conjugate base, the higher energy state!

(4) Aryl Substituents Inductive effects can be passed through phenyl rings. Electron-donating groups destabilize the conjugate base and decrease acidity while electronwithdrawing substituents inductively stabilize the conjugate base and increase acidity.
O OH MeO H O OH O2N O OH

pKa

4.46

4.19

3.41

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Chapter 20: Carboxylic Acids and Nitriles Synthesis of Carboxylic Acids

Chem C3444

Nitriles may also be hydrolyzed in aqueous acid to generate carboxylic acids.

OH2 R C N H OH2 R C NH R OH2 NH

You've already seen several methods to generate carboxylic acids in the preceeding chapters. They are reviewed below.
H R R O OH

KMnO4, H2O

Only forms aryl ketones. There must be at least one hydrogen at the benzylic position.

H+ Transfer
OH R H3N OH
OH2 R R OH2 OH NH2

R H R H2 C R

1. O3 2. H2O2, NaOH
HO

R O O R O R C OH

CrO3, H2O
OH

Monosubstituted carbons are easily converted to carboxylic acids while disubstituted carbons are converted to ketones. Alcohol must be primary. Secondary alcohols are oxidized to ketones, and tertiary alcohols are not oxidized. A very general method, preferable to the chromic acid oxidation above. Useful way to extend an alkyl halide by one carbon.

H+ Transfer H2N

OH

R O

OH H

R O

OH

O R H

Ag2O, NH4OH
R

O OH O R OH

Reductions of Carboxylic Acids

Carboxylic acids may be reduced to primary alcohols using either of two reagents: lithium aluminum hydride (LAH) or borane (BH3). The mechanisms of these two reductions allow us to achieve functional group selectivity when designing syntheses. As you saw in the last chapter, the order of reactivity for carbonyls increases from carboxylic acids to aldehydes and acid chlorides:

R MgBr

1. CO2 2. H3O+

Mechanism:
O R MgBr O C O R OMgBr

H3O+
R

O OH

O R C O R

O C NR2 R

O C OR R

O C R R

O C H R

O C Cl

As a matter of style, remember that numbers must accompany your Grignard reagents if the reaction is written as one step. Only the following two formats are acceptable. 1. RMgBr 2. H3O+
R O OH

increasing rate of nucleophilic addition

The reason for this trend can be rationalized by considering the resonance forms of the carbonyl. As the partial positive charge on carbon is delocalized over more atoms, the carbonyl carbon becomes less electrophilic. Two simple examples are shown at the top of the next page.

CO2

CO2

RMgBr; H3O+
R

O OH

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O R C H R O C H O OH R C O H

Chapter 20: Carboxylic Acids and Nitriles

Partial positive charge only on carbonyl carbon.

Chem C3444

O R C OH R

O C

This product may react further with borane to yield the reduced alkoxyborane; this intermediate may then trimerize to give a stable (aromatic!) trialkoxyboroxine. This boroxine is simply a cyclic boronic ester, and it may undergo hydrolysis as you saw in the mechanism for hydroboration last semester.
O R O R O B O R O O B R O H B H R O B R O H+ H2O 3 R 3 OH BH3 R O B O O O B

Partial positive charge delocalized between carbon and oxygen.

Now consider the overall reaction for a hydride reduction of a carboxylic acid.
O R C OH "H-" O R C O "H-"

O R C H

"H-"

very fast

very slow

fast

H H C OH R

B O O B O R

B(OH)3

The first step, deprotonation, occurs very rapidly to yield the carboxylate. Carboxylates are very stable carbonyl compounds, and they have very little electrophilic character at the central carbon. This causes the second step to be very slow relative to the deprotonation. The third step of the reaction is the reduction of an aldehyde, a reaction that should proceed much faster than the second step because of the increased electrophilicity of the aldehyde relative to the carboxylate. This means that the rate determining step in the reaction is the reduction of the carboxylate, thus making it impossible to isolate the aldehyde in this reduction. This mechanism has important consequences for synthesis design. If an LAH reduction is being employed to reduce a carboxylic acid, all other electrophilic functionalities will be reduced. LAH reduction of a carboxylic acid is therefore incompatible with aldehydes, ketones, esters, amides, acid chlorides, tosylates, halides, and nitro groups. To get around this problem, we may use a second hydride reducing agent that is selective for carboxylic acids in the presence of other carbonyls. The reagent, BH3THF, initially forms a complex with the carboxylic acid to activate its carbonyl for nucleophilic attack.
O R O H BH3 R O O H H B H H

To understand why this reaction is selective for carboxylic acids, let's reconsider the acyloxyborane intermediate.
O R O H B H R O O H B H

acyloxyborane
Unlike carboxylic acids, the partial charge on the carbonyl carbon in this acyloxyborane complex cannot be effectively delocalized by resonance because the oxygen lone pairs are now being shared with the boron. This functionality is very strongly electron-withdrawing by induction, thus placing a significant amount of partial positive charge on the carbonyl. Boron therefore coordinates to the free oxygen and transfers its hydrogen via an intramolecular hydride shift. This difference in reactivity now allows us to reduce carboxylic acids in the presence of esters, amides, halides, and many other functional groups, but borane-THF possesses a new limitation that LAH did not - it cannot be used in the presence of alkenes. As you saw early last semester, borane-THF reacts with alkenes to form alkylboranes. While these compounds will not be further oxidized to the alcohols without the addition of peroxide, the isolated product will not contain the desired alkene.
O

O R O H

H B H H

Recall that borane is a powerful Lewis acid:

O H B H H R O H B H R O O H B H

BH3THF (excess)
OH

H2 B

OH

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Snyder/Cook

Chapter 20: Carboxylic Acids and Nitriles

Chem C3444

In summary, LAH and borane-THF display complementary reactivity.

Functional Group O C O C O C O C

The oxyanion in the dipolar resonance form behaves similarly to an alcohol upon exposure to POCl3.
O O Cl R P Cl Cl O H N H H O P Cl R Cl O O P Cl R Cl

LiAlH4
OH C R R H H2 C H2 C

BH3THF

Functional Group O C O C

LiAlH4
H2 C H2 C

BH3THF

N.R. R N.R.

N.R. OH N.R.

OR

N H

H+

OH H2 C

Cl

OH

N C R OH R X R H N.R.

- H+

H N C R

OH

R OH slow H2 C

A similar mechanism can be drawn using SOCl2 as the dehydrating reagent to expell SO2 gas.

N.R. NR2 R

R R R

NR2 H R

R NO2

R NH2

N.R. H

The Chemistry of Nitriles

The CN * orbital is similar in energy to the carbonyl C=O * orbital, so nitriles display many of the same reactivity trends as carbonyls. A summary is shown below. H2O, O O
R NH2 R OH O R R

N.R.

R R

BH2 R

N.R.

R H

BH2

The Preparation of Nitriles

Nitriles may be readily synthesized by two simple reactions: the SN2 reaction of an alkyl halide and cyanide anion and the deoxygenation of amides. 1. LiAlH4 2. H3O+

H2O,
R C N

(1) SN2 Substitution Using

-CN

NH2

1. RMgBr 2. H3O+

Cyanide anion is a particularly strong nucleophile with a pKb of +9. It is usually added as the sodium or potassium salt, and, as with all SN2 reactions, the displacement is carried out in a polar, aprotic solvent. NaCN
R Br

DMF

CN

(2) Deoxygenation of Amides

The deoxygenation of amides proceeds via a mechanism that is very similar to the dehydration of alcohols. Recall that amides have a very important dipolar resonance form.
O R N H H R O N H H

The conversion of nitriles to ketones merits further consideration. As expected, the first step is addition of the Grignard reagent to the electrophilic nitrile carbon. This reaction then forms the amide (that is, the deprotonated imine), but this is not polarized enough to undergo a second nucleophilic addition. The reaction stops at this point and the imine is hydrolyzed to the ketone upon acidic aqueous workup.

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