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Chapter 20: Carboxylic Acids and Nitriles

20.1 Naming Carboxylic Acids (please read) In general, the same for ; replace the terminal -e of the name with -oic acid The carboxyl atom is C1

Compounds with -CO2H group on a ring are named using the suffix -

The -CO2H carbon is not numbered in these cases

Many non-systematic names: Table 20.1

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20.1 Naming Nitriles (please read) If derived from open-chain alkanes, replace the terminal -e of the alkane name -nitrile as a suffix The nitrile carbon numbered C1 Complex nitriles are named as derivatives of carboxylic acids. Replace -ic acid or -oic acid ending with -onitrile

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88 20.2 Structure and properties of carboxylic acids The carboxylic acid function group contains both a hydrogen bond donor (-OH) and a hydrogen bond acceptor (C=O)

Carboxylic acids exist as hydrogen bonded dimers H-bond aceptor O O H O H-bond C H H3C C C CH3 H C O donor 3 O H O acetic acid

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20.3 Dissociation of Carboxylic acids

Acidity Constant and pKa Carboxylic acids react with base to give carboxylate salts

O O C H Na + NaOH C + H2O R O R O Bronsted Acidity (Chapter 2.7): + Carboxylic acids transfer a proton to water to give H3O and − carboxylate anions, RCO2

O O C + H2O C + H3O R OH R O

- + [RCO2 ] [H3O ] Ka= pKa= - log Ka [RCO2H]

typically ~ 10-5 typically ~ 5 for for carboxylic acid carboxylic acid 177

89 CH3CH3 CH3CH2OH PhOH CH3CO2H HCl pKa ~50-60 16 10 4.75 -7 Increasing acidity

The negative charge of a carboxylate is resonance stabilized

H2O H3C-H2C-OH H3C-H2C-O + H3O pKa~ 16

O H2O O O + H O C C C 3 H3C OH H3C O H C O pKa~ 4.7 3

! 4 electron delocalized O O C over three p-prbitals H3C C O O ! C-O bond length of a carboxylates are the same 178

20.4 Substituent Effects on Acidity

Substituents on the α-carbon influence the pKa of carboxylic acids largely through inductive effects. Electron-

withdrawing groups increase the acidity (lower pKa) and electron-donating groups decrease the acidity (higher pKa)

also see Table 20.4

Inductive effects work through σ-bonds, and the effect falls off dramatically with distance

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90 20.5 Substituent Effects in Substituted Benzoic Acids An aromatic or substituted aromatic rings has dramatically less

influence on the acidity of benzoic acids, pKa ~ 4.2 (when compared to acetic acid) than in the case of phenols

OH CO2H H3CH2C-OH H3C-CO2H R R

pKa ~ 16 R=H, pKa ~9.9 pKa ~ 4.75 R=H, pKa ~ 4.2 Cl 9.4 Cl 4.0

NO2 7.1 NO2 3.4 CH3 10.2 CH3 4.3 OCH3 10.2 OCH3 4.5 The charge of the carboxylate ion cannot be delocalize into the aromatic ring

Electron-donating groups decrease the acidity Electron-withdrawing groups increase the acidity 180

20.6 Preparation of carboxylic acids 1. Benzoic acids are prepared from the oxidation of

with KMnO4 (Chapter 16.10)

CH CH CH 2 3 3 CO2H KMnO4 O N 2 O2N Alkyl benzene

2. Oxidation of primary with chromic acid (CrO3/HCl) (Chapter 17.18)

3. Oxidation of with chromic acid or Ag2O (Chapter 19.3)

CrO3/HCl OH CO2H

1°

CrO3/HCl CHO CO2H -or- Ag O 2 181

91 20.6 Preparation of carboxylic acids 4. Acid or basic of a nitrile (mechanism, Fig. 20.4) ion is an excellent nucleophile and will react with 1° and 2° alkyl halides and tosylates to give nitriles. This reaction add one carbon. + NaC!N H3O H CH CH CH C-Br H3CH2CH2CH2C-C!N H3CH2CH2CH2C-CO2H 3 2 2 2 DMSO -or- NaOH C4 C5 C5

+ NaC!N H3O Br C!N CO2H DMSO -or- PhO NaOH PhO

+ O NaC!N H3O . . . and don’t forget HO CN HO CO2H

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20.6 Preparation of carboxylic acids 5. Carboxylation of Grignard reagents

Reaction of a Grignard reagent with CO2 gives a carboxylic acid

O O Br Mg(0) H O+ MgBr CO2 C 3 C O OH

MgBr O _ C O

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92 20.7 Reactions of carboxylic acids: an overview

O base Deprotonation H O (chapters 20.3 - 20.5)

H H [H] Reduction H OH (chapters 17.5 & 20.8) O H OH O α-Substitution R OH (chapter 22)

O Nucleophilic acyl H Y substitution (chapter 21)

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20.8 Reductions of carboxylic acids

Carboxylic acids are reduced to primary alcohols by LiAlH4 (Chapter 17.5) and borane (BH3) but not by NaBH4

a. LiAlH4, THF + b. H3O R-CO2H RCH2OH Lithium will also reduce , aldehydes , nitriles, , acid chlorides alkyl halides, and nitro groups Borane reacts most rapidly with carboxylic acids to give primary alcohols and it is possible to reduce carboxylic acids in the presence of some other functional groups

a. BH3 , THF + OH b. H3O CO2H

O2N O2N

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93 20.9 Chemistry of Nitriles: Preparation of nitriles

1. Reaction of cyanide ion with 1° and 2° alkyl halides- this is

an SN2 reaction. 2. - reaction of cyanide ion with ketones and aldehydes (Chapter 19.7)

3. Dehydration of primary amides with POCl3 or SOCl2

O SOCl2 -or- POCl C 3 Dehydration: formal loss R NH2 R C N benzene, 80°C of H2O from the substrate Primary nitrile Mechanism (p. 751, please read): the carbonyl oxygen of an amide is nucleophilic, and can react with

O O A very important resonance form of an C C amide, which contributes significantly R NH 2 R NH2 to their properties and reactivity

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O O O Cl S S S O O Cl Cl O Cl O Cl C C C C H R NH2 R NH2 R NH2 R N O H Cl S O Cl - HCl C - SO2, - HCl R N R C N H Cl - Cl - R C N H 20.9 Chemistry of Nitriles: Reactions of Nitriles The C≡N bond has a large dipole moment like carbonyls, making the carbon a potential site for nucleophilic attack

O O H-A OH aldehydes C C O ! - C Nu & ketones Nu ! + C µ~ 2.8 D :Nu

- N N N N NH2 N ! nitriles H-A C C C C C C ! + µ ~ 3.9 D :Nu Nu Nu R Nu R Nu :Nu R R R R Nu Nu

NH + O H-A H3O C -or- C 187 R Nu HO R Nu

94 1. Hydrolysis of nitriles to carboxylic acids and amides: Nitriles are hydrolyzed in either aqueous acid or aqueous base to give carboxylic acids. The corresponding primary amide is an intermediate in the reaction.

Mechanism of the base-promoted reaction (Figure 20.4) 188 Please try the acid-promoted mechanism

2. Reduction of nitriles to primary

Nitriles can be reduced by LiAlH4 or BH3 (but not NaBH4) to give primary amines

H 2 N N + NH2 LiAlH4 H3O R C N C C C R H R H R H H H H

Reduction of a nitrile with Diisobutylaluminium hydride (DIBAH) give an , which easily hydrolyzes to the aldehyde (not in book)

Al(iBu) H 2 DIBAH + NH O N H3O R C N C toluene C C R H R H R H

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95 3. Reaction of nitriles with Grignard reagents: general method for the preparation of ketones

H3C MgBr MgBr N + NH O THF H3O R C N C C C R CH R CH3 R CH3 3 Must consider compatibility; there is wide flexibility in the choice of Grignard reagents.

Summary: primary amines CH2NH2 CHO aldehydes

LiAlH4 DIBAH

Br C!N O Na+ -CN MgBr ketones SN2 + H3O

CO2H

190 carboxylic acids

20.10 Spectroscopy of Carboxylic Acids and Nitriles Infrared Spectroscopy Carboxylic acids: Very broad O-H absorption between 2500 - 3300 cm−1 Strong C=O absorption bond between 1710 - 1760 cm−1 Usually broader than the O-H absorption of an alcohol

H O

carboxylic acid alcohol

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96 Nitriles show an sharp C≡N absorption near 2250 cm−1 for alkyl nitriles and 2230 cm−1 for aromatic and conjugated nitriles (highly diagnostic)

C N H3CH2CH2C C N

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1H NMR

The -CO2H proton is a broad singlet near δ ~12 When D2O is added to the sample the -CO2H proton is replaced by D causing the resonance to disappear (same for alcohols)

-CO2H

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97 The nitrile function group is invisible in the proton NMR. The effect of a nitrile on the chemical shift of the protons on the α-carbon is similar to that of a .

H3CH2CH2C C N

δ= 2.3 (2H, t) 1.7 (2H, m) 1.1 (3H, t)

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13C NMR The chemical shift of the carbonyl carbon in the 13C spectrum is in the range of ~165-185. This range is distinct from the aldehyde and ketone range (~190 - 220) The chemical shift of the nitrile carbon in the 13C spectrum is in the range of ~115-130 (significant overlap with the aromatic region).

Ph-H2C-CO2H H3CH2CH2C C N 133.2 129.3 128.5 41.1 19.3, 13.3 127.3 19.0

CDCl3

CDCl 119.8 TMS 178.2 3

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98 1.92 C10H11N 3.72 (2H, dt, J=7.4, 7.1) (1H, t, J=7.1) 7.3 1.06 (5H, m) (3H, t, J=7.4)

129.0 128.0 127.3 29.2 38.9 11.4

CDCl3 135.8 120.7 TMS

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