Ch.20 Carboxylic Acids and Nitriles Carboxylic Acids: common in nature COOH CH COOH OH 3 CH3 vinegar CH H 3 Cholic acid COOH H (major component of human bile) odor of sour butter HO OH H

COOH COOH odor of goats, socks palmitic acid (precursor of fat)

Industrial synthesis of acetic acid:

cobalt acetate Rh catalyst CH3OH CH3CHO o CH3COOH O2 80 C CO 20.1 Nomenclature

Carboxylic Acids: RCO2H alkane (-e) → -oic acid - parent chain contains the -COOH group, - carboxyl carbon is numbered as 1

CO2HCO2H 1 1 Propanoic acid 4-Methylpentanoic acid

1 CO2H HO2C Et 3-Ethyl-6-methyloctanedioic acid -COOH is attached to a ring -carboxylic acid

Br 1 COOH

3-Bromocyclohexanecarboxylic acid

CO2H 1 1-Cyclopentenecarboxylic acid Common Names Acyl groups HCOOH Formic acid HCO- Formyl Acetyl H3C COOH Acetic acid H3CCO-

COOH Propionic acid CO- Propionyl

COOH Butyric acid CO- Butyryl

HOOC COOH Oxalic acid -OC CO- Oxalyl

HOOC COOH Malonic acid -OC CO- Malonyl

HOOC -OC COOH Succinic acid CO- Succinyl

COOH Acrylic acid CO- Acryloyl

COOH Benzoic acid CO- Benzoyl Nitrile: RCN - nitrile - CN carbon is numbered as 1

4 CN 1 4-Methylpentanenitrile

complex nitrile -(o)ic acid → onitrile -carboxylic acid → -carbonitrile

1 CN CN CH3 H3CCN 2 CH3

Acetonitrile Benzonitrile 2,2-Dimethylcyclohexanecarbonitrile 20.2 Structure and Physical Properties of Carboxylic Acids

Structure

2 O R sp H O O O H H RO RO 120o planar dimer: H-bonding (high b.p.)

- high b.p. and m.p. - b.p. of acetic acid: 118oC 20.3 Dissociation of Carboxylic Acids

Acidity: weak bases (NaOH, NaHCO3) generate carboxylate, - + RCO2 Na O O + NaOH + ROH RONa + H2O H2O water-insoluble water-soluble

Acetic acid: only 0.1% dissociate in 0.1M solution HCl: 100% dissociate

O HCl CH3CH2OH H3COH

pKa = 16 4.75 -7 Alkoxide / Carboxylate ion

H2 H2 C H C H3C O H3C O localized charge

O O O H H CO H CO 3 3 H3CO delocalized charge resonance-stabilized carboxylate ion 127 pm 120 pm O 134 pm O Na+ C C H O H H O Formic acid Sodium formate

purification of acid: dissolve salts in water, extract out organic impurities with organic solvent, acidify aqueous layer to obtain carboxylic acids 20.4 Substituent Effects on Acidity

Carboxylic acids with Acid pKa more than six carbons are insoluble in water CH3CH2OH 16 CH3CH2COOH 4.87 CH3COOH 4.75 H C=CHCO H 4.25 stronger 2 2 acid PhCO2H 4.19 HOCH2COOH 3.83 HCO2H 3.75 ICH2CO2H 3.12 BrCH2CO2H 2.68 ClCH2CO2H 2.85 FCH2CO2H 2.59 F3CCO2H 0.23 Acidity of chloroacetic acids: inductive effect

O O O O Cl Cl H COH Cl CH OH CH OH COH 3 2 Cl Cl Cl stronger acid

O

- Cl CH2 O

electronegative Cl stabilizes anion - inductive effect operates through σ-bond and depends on distance

Cl COOH COOH COOH Cl Cl COOH pKa = 2.86 4.05 4.52 4.82 20.5 Substituent Effects in Substituted Benzoic Acids

O O O

OH OH OH

MeO O2N

pKa = 4.46 4.19 3.41

stronger acid - acidity of substituted benzoic acid correlate reactivity of the substituted benzene

O

OH Y Y predict reactivity of pK a electrophilic attack

"inverse relationship" 20.6 Preparation of Carboxylic Acids

Oxidation of benzylic C-H

CH3 COOH KMnO4

H2O 95oC

H KMnO4 O +CO2 H + H H3O HO Oxidation of alcohol/aldehyde

CrO3 RCH2OH RCOOH H2SO4, H2O

AgNO3 R CHO R COOH NH4OH Hydrolysis of nitrile

- 1. H2O, OH RCN R COOH + 2. H3O

N + NH + O H3O H3O RCN OH- ROH ROH ROH

- a typical way to introduce one carbon fragment from alkyl halides

1. KCN

Br - COOH O 2. H2O, OH O + 3. H3O Carboxylation of Grignard reagents

O + CO2 H3O RCH2MgX RCH2 C O MgX RCH2 COOH O CO

Br MgBr COOH

Mg 1. CO2

ether + 2. H3O 20.7 Reactions of Carboxylic Acids: An Overview General reactions of carboxylic acids O H H H C H C C O C OH

Deprotonation O Reduction H C C OH

O O R C H C C OH C Y

Alpha-substitution Nucleophilic acyl substitution 20.8 Reduction of Carboxylic Acids

LiAlH4: alkenes are not reduced

O 1. LiAlH 4 OH + 2. H3O OH

BH3: alkenes can be hydroborated, esters are not reduced

O2N O2N O 1. BH3, THF + OH 2. H3O OH

- LiAlH4 reduces both nitro and acid 20.9 Chemistry of Nitriles

O R C N C R OH

same oxidation level

Preparation

- SN2 substitution by CN

NaCN R CH2 Br R CH2 CN From amide: SOCl2, POCl3

O SOCl2 + R CH2 CN + SO2 2 HCl RNH2 benzene 80oC

O O O S S S O Cl Cl O Cl O Cl

RNH2 RNH2 RN H

SO2 + HCl + RCN Reactions of Nitriles

- O O R R products RR Nu- Nu

alkoxide ion

N products R CN R Nu Nu- imine ion 1. R'MgX + O H2O 2. H3O O RCN R OH R R' - 1. [H-] 1. [H ] + 2. H O+ 2. H3O 3 O R NH 2 R H Hydrolysis: acidic or basic conditions

- H2O, OH RCN R COOH + or H3O

N NH H2O O R CN - R R OH OH OH R NH2 imine anion

O

R OH Reduction: LiAlH4, DIBAL

to primary amine:

1. LiAlH 4 R CN RNH2 + 2. H3O

to aldehyde:

1. DIBAL CN CHO 2. H2O 1. LiAlH NH LiAlH 4 N 4 2 R CN - R + R H H H 2. H3O H imine anion

DIBAL toluene O N H2O R R H H imine anion Grignard addition: ketone formation

N +MgX H O+ O 3 + NH R CN R 3 R'MgX R' R R'

imine anion

O CN 1. EtMgBr

+ 2. H3O 20.9 Spectroscopy of Carboxylic Acids and Nitriles

IR Spectroscopy 1760 cm-1 free carboxyl (uncommon) C=O 1710 cm-1 associated carboxyl (usual case) O-H 2500-3300 cm-1 very broad

O R H O O O H H RO RO -1 1760 cm 1710 cm-1

RCN 2250 cm-1 IR Spectrum of n-Butanoic acid NMR Spectroscopy

1H NMR COO-H ~ 12 ppm, 13C NMR C=O 165-185 ppm

CH3CH2CN 10 11 121 1H NMR Spectrum Chemistry @ Work Vitamin C

Vitamin C: ascorbic acid

OH OH H O O HO O HO H HO OH HO OH OH Vitamin C Glucose (Ascorbic acid) Chemistry @ Work Industrial synthesis of ascorbic acid from glucose Problem Sets

Chapter 20

20, 26, 35, 39, 45