Carboxylic Acids and NitrilesOrganic Chemisty 6e Chapter 20

Introduction to Chapter RCO 2 H – About Carboxylic Acids –Serve as starting materials for preparing acyl derivaties; Esters Amides Acid Chlorides –Many carboxylic acids are found in Nature Acetic Acid, CH 3 CO 2 H for vinegar Butanoic Acid, CH 3 (CH 2 ) 2 CO 2 H is the rancid oder from sour butter Palmitic Acid, CH 3 (CH 2 ) 14 CO 2 H is a biological precursor of fats and other lipids. –Approx. 2 million tons of acetic acid are produced annually in the United States C h a p t e r 2 0 I n t r o d u c t i o n

N a m i n g C a r b o x y l i c A c i d s a n d N i t r i l e s Nomencalture - RCOOH Two systems have been adopted by IUPAC: 1. Carboxylic acids derived from open-chain alkanes are named by replacing their terminal –e of the alkane with -oic acid 2. Compounds that have a –COOH group bonded to a ring are named using the suffix –carboylic acid Propanoic acid 4-Methylpentanoic acid 3-Bromocyclohexanecarboxylic acid 1-Cyclopentenecarboxylic acid

20.1 Naming Carboxylic Acids and Nitriles Nomencalture – RC N Two systems have been adopted by IUPAC: 1. Nitriles derived from open-chain alkanes are named by adding –nitrile as a suffix to the alkane name, with the nitrile carbon numbered C1: 2. Nitriles are named as derivatives of carboxylic acids by replacing the –ic acid or –oic acid with –onitrile, or replacing –carboxylic acid with -carbonitrile. Acetonitrile 4-Methylpentanenitrile 4,5-dimethylhexanenitrile Benzonitrile 3,3-Dimethylcyclohexanecarbonitrile

20.1 Naming Carboxylic Acids and Nitriles

S t r u c t u r e a n d P h y s i c a l P r o p e r t i e s Carboxyl carbon has sp 2 hybridization; carboxyl group is therefore planar with C C O and O C O bond angles of ~120° Carboxylic acids are strongly associated by hydrogen bonds, most existing as cyclic dimers held together by two hydrogen bods

20.2 Structure and Physical Properties Formic acidAcetic acid Propanoic acid Propenoic acid Benzoic acid

D i s s o c i a t i o n o f C a r b o x y l i c A c i d s Carboxylic acids are acidic, K a ~ (pKa ~5), and therefore react readily with a base such as NaOH to give a carboxylate salt. Metal-carboxylate salt H3O+H3O+ H2OH2O and pK a = - log K a H2OH2O

20.3 Dissociation of Carboxylic Acids Carboxylic acids are more acidic than alcohols by a factor of ~10 11 Relative Acidity of Carboxylic Acids Acidity CH 3 CH 2 OH pK a = 16 CH 3 COH pK a = 4.75 O HCl pK a = -7 Explanation: Acidity can be explained in terms of bonding H3O+H3O+ H2OH2O Not stabilized H2OH2O stabilized by resonance

S u b s t i t u e n t E f f e c t s o n A c i d i t y Acidity of carboxylic acids varies greatly according to the nature of the substituent attached to the carboxyl group Generally, any factor that STABILIZES the carboxylate group relative to the undissociated acid will drive the equilibrium toward increased dissociation and result in increased acidity. Key Points Electron-withdrawing groups stabilize carboxylate ions Electron-donating groups destabilize carboxylate ions EWG Electron-withdrawing group Stabilizes carboxylate and strengthens acid Electron-donating group Destabilizes carboxylate and weakens acid

20.4 Substituent Effects on Acidity Relative Strengths of Acetic Acid and Chloro- Derivatives Acidity pK a = 4.75pK a = 2.85pK a = 1.48pK a = 0.64 Acidity ClCH 2 CH 2 CH 2 COH pK a = 4.52 O CH 3 CHCH 2 COH pK a = 4.05 OCl CH 3 CH 2 CHCOH pK a = 2.86 OCl

S u b s t i t u e n t E f f e c t s i n S u b s t i r u t e d B e n z o i c A c i d s Acidity p-Methoxybenzoic acid (pK a = 4.46) Benzoic acid (pK a = 4.19) p-Nitrobenzoic acid (pK a = 3.41) Deactivating groups (electron-withdrawing) stabilize carboxylates Activating groups (electron-donating) destabilize carboxylates

P r e p a r a t i o n o f C a r b o x y l i c A c i d s Five methods of preparation of Carboxylic Acids I - Oxidation of a substituted alkylbenzene using KMnO 4 or Na 2 Cr 2 O 7 KMnO 4 H 2 O, 95°C p-Nitrotoluenep-Nitrobenzoic acid (88%) * Oxidation occurs for 1° & 2° alkyl groups only, not in 3° alkyl groups II – Oxidative cleavage of an alkene with KMnO 4 CH 3 (CH 2 ) 7 CH CH(CH 2 ) 7 COH Oleic acid O KMnO 4 H3O+H3O+ CH 3 (CH 2 ) 7 COH nonanoic acid O HOC(CH 2 ) 7 COH OO nonanedioic acid * Alkene must have at least one vinylic hydrogen

20.6 Preparation of Carboxylic Acids III – Oxidation of a 1° alcohol or an aldehyde IV – Hydrolysis of nitriles using strong, hot aquious acid or base CH 3 (CH 2 ) 8 CH 2 COH 1-Decanol CrO 3 H3O+H3O+ CH 3 (CH 2 ) 8 COH Decanoic acid (93%) O * 1° alcohols are oxidized with CrO 3 in aqueous acid, aldehydes are oxidized with either acidic CrO 3 OR Tollen’s reagent CH 3 (CH 2 ) 4 CH Hexanal Ag 2 O NH 4 OH CH 3 (CH 2 ) 4 COH Hexanoic acid (85%) OO RCH 2 Br Na + CN - (S N 2) RCH 2 C N H3O+H3O+ RCH 2 COH O NH3NH3 * Excellent two-step process for the preparation of carboxylic acids from 1° halides 1. NaCN 2. – OH/H 2 O 3. H 3 O Fenoprofen (an antiarthritic agent) * Product has one more carbon than the starting alkyl halide

20.6 Preparation of Carboxylic Acids V – Carboxylation (or carbonation) of Grignard reagents Reaction is limited to alkyl halides that can form Grignard reagents (i.e. reactants with specific functional groups) 1-Bromo-2,4,6-trimethyl-benzene Mg Ether 1. CO 2, ether 2. H 3 O + 2,4,6-Trimethylbenzoic acid (87%) R: -+ MgBr Reaction of Amide with SOCl 2

R N X o f C a r b o x y l i c A c i d s : A n O v e r v i e w Carboxylic acid Alpha substitution DeprotonatoinReduction Nucleophilic acyl substitution General Reactions of Carboxylic Acids

R e d u c t i o n o f C a r b o x y l i c A c i d s I – Using LiAlH 4 to give 1° alcohols II – Using borane (BH 3 ) to give 1° alcohols Carboxylic acids can be reduced using two approaches CH 3 (CH 2 ) 7 CH=CH(CH 2 ) 7 COH Oleic acid 1. LiAlH 4, THF 2. H 3 O + O CH 3 (CH 2 ) 7 CH=CH(CH 2 ) 7 CH 2 OH cis-9-Octadecen-1-ol (87%) * Reaction usually requires harsh conditions (i.e. heating) 1. BH 3, THF 2. H 3 O + p-Nitrophenylacetic acid 2-(p-Nitrophenyl)ethanol (94%) * Reaction is usually performed under mild conditions and can be used to selectively reduce carboxylic acid functionality

C h e m i s t r y o f N i t r i l e s The dehydration reaction occurs first with the nucleophilic amide oxygen atom reacting with SOCl 2, then a deprotonation of the molecule in a subsequent E2-like elimination reaction. Preparation of Nitriles Reaction of Amide with SOCl 2

20.9 Chemistry of Nitriles Nitrile groups are strongly polarized, thus resulting in a electrophilic carbon atom. Therefore they are attacked by nucleophiles and yield an sp 2 -hybridized imine anions. This reaction is analogous to the formation of an sp 3 -hybridized alkoxide ion by nucleophilic addition to a carbonyl group. Reactions of Nitriles δ+δ+ δ-δ- Products δ-δ- δ+δ+ Carbonyl Compound Nitrile Imine anion Nu --

20.9 Chemistry of Nitriles General Reactions of Nitriles Nitrile Amine Amide Carboxylic Acid Ketone H2OH2O H2OH2O LiAlH 4 R’MgX

20.9 Chemistry of Nitriles A nitrile can be hydrolyzed in either basic or acidic aqueous solution to yield a carboxylic acid and ammoniz or an amine Hydrolysis: Conversion of Nitriles into Carboxylic Acids H3O+H3O+ Basic hydrolysis of a nitrile Amide Or NaOH, H 2 O -- OH H2OH2O NH2-NH2- Carboxylate -- OH Dianion

20.9 Chemistry of Nitriles A nitrile can be reduced with LiAlH 4 to give a primary amine Reduction: Conversion of Nitriles into Amines o-Methylbenzonitrile 1. LiAlH 4, ether 2. H 2 O o-Methylbenzylamine The following example illistrates a reaction that occurs by nucleophilic addition of hydride ion to the polar C≡N bond, yielding an imine anion. The imine anion undergoes another nucleophilic addition to yield a dianion. LiAlH 4 ether LiAlH 4 ether H2OH2O NitrileImine anionDianionAmine

20.9 Chemistry of Nitriles A nitrile can add a Grignard reagent to give an intermediate imine anion that is further hydrolyzed by water to yield a ketone: Reaction of Nitriles with Organometallic Reagents :R’ - + MgX H2OH2O NitrileImine anionKetone NH3NH3 This type of reaction is similar to the reduction of a nitrile to an amine, however only one nucleophilic addition occurs and the nucleophile is a carbanion (R: - ) rather than a hydride ion: 1. CH 3 CH 2 MgBr, ether 2. H 3 O + BenzonitrilePropiophenone (89%)

S p e c t r o s c o p y o f C a r b o x y l i c A c i d s I. O-H gives broad band in the range of 2500 – 3300 cm -1 II. C=O gives band in the range 1710 – 1760 cm-1 Infrared Spectroscopy – Two characteristic IR absorptions Monomer Hydrogen-bonded dimer * Position depends on whether the acid exists as a monomer or hydrogen-bonded dimer IR Spectrum of Butanoic Acid

20.10 Spectroscopy of Carboxylic Acids NMR Spectroscopy Acidic –COOH proton absorbs as a singlet near 12 δ Carboxyl carbon atoms absorb in the range δ Aromatic / saturated near 165 ∂, aliphatic near 185 δ NMR spectrum of phenylacetic acid