© 2006 Thomson Higher Education Chapter 15 Carboxylic Acids and Nitriles

Carboxylic Acids and Nitriles Carboxylic acids are present in most biological pathways and are the biological starting materials from which other acyl derivatives are made Cholic acid is a major component of human bile

15.1Naming Carboxylic Acids and Nitriles Carboxylic acids named by replacing –e of the corresponding alkane name with –oic acid –CO 2 H carbon atom is numbered C1

Naming Carboxylic Acids and Nitriles Name compounds with –CO 2 H group bonded to a ring using the suffix –carboxylic acid

Naming Carboxylic Acids and Nitriles

Compounds containing functional group are called nitriles Named by adding –nitrile as a suffix to the alkane name Nitrile carbon numbered C1

Naming Carboxylic Acids and Nitriles Nitriles also named as carboxylic acid derivatives by replacing –ic acid or –oic acid ending with –onitrile or by replacing the –carboxylic acid ending with –carbonitrile

15.2Structure and Properties of Carboxylic Acids Carboxyl carbon is sp 2 -hybridized Carboxylic acids are strongly associated because of hydrogen bonding Hydrogen bonding significantly increases boiling point Most carboxylic acids exist as cyclic dimers

Structure and Properties of Carboxylic Acids Carboxyic acids react with bases to give metal carboxylate salts, RCO 2 - M + Carboxylic acids slightly ionize in water

Structure and Properties of Carboxylic Acids

Carboxylic acids are much weaker acids than mineral acids but much stronger acids than alcohols

Structure and Properties of Carboxylic Acids Carboxylic acids ionize to give resonance stabilized carboxylate ions

Structure and Properties of Carboxylic Acids Both carbon-oxygen bonds in sodium formate are 127 pm in length, midway between the C=O bond (120 pm) and the C-O bond (134 pm) of formic acid

15.3Biological Acids and the Henderson-Hasselbalch Equation At pH = 7.3, a value known as physiological pH, both the carboxylic acid and its conjugate base are present The conjugate base form predominates at pH = 7.3 Percentages of carboxylic acid and conjugate base can be calculated from the pK a and the pH of the medium

15.4 Substituent Effects of Acidity Substituents that stabilize the conjugate base drive the equilibrium toward increased ionization resulting in increased acidity

Worked Example 15.1 Predicting the Effect of a Substituent on the Reactivity of an Aromatic Ring toward Electrophilic Substitution The pK a of p-(trifluoromethyl)benzoic acid is 3.6. Is the trifluoromethyl substituent an activating or deactivating group in electrophilic aromatic substitution?

Worked Example 15.1 Predicting the Effect of a Substituent on the Reactivity of an Aromatic Ring toward Electrophilic Substitution Strategy Decide whether p-(trifluoromethyl)benzoic acid is stronger of weaker than benzoic acid. A substituent that strengthens the acid is a deactivation group because it withdraws electrons, and a substituent that weakens the acid is an activating group because it donates electrons.

Worked Example 15.1 Predicting the Effect of a Substituent on the Reactivity of an Aromatic Ring toward Electrophilic Substitution Solution A pK a of 3.6 means that p-(trifluoromethyl)benzoic acid is stronger than benzoic acid, whose pK a is Thus, the trifluoromethyl substituent favors ionization by helping stabilize the negative charge. Trifluoromethyl must therefore be an electron- withdrawing, deactivating group.

15.5 Preparation of Carboxylic Acids Preparation of carboxylic acids: Oxidation of substituted alkyl benzenes Oxidation of primary alcohols or aldehydes

Preparation of Carboxylic Acids Hydrolysis of nitriles Nitriles hydrolyzed in hot aqueous acid or base Fenoprofen prepared in three steps: 1. S N 2 reaction of primary or secondary alkyl halide with CN - 2. Hot basic hydrolysis of nitrile 3. Neutralization with aqueous acid

Preparation of Carboxylic Acids Carboxylation of Grignard Reagents

Preparation of Carboxylic Acids Biological carboxylation of Acetyl CoA to give Malonyl CoA

Worked Example 15.2 Devising a Synthesis Route for a Carboxylic Acid How would you prepare phenylacetic acid (PhCH 2 CO 2 H) from benzyl bromide (PhCH 2 Br)?

Worked Example 15.2 Devising a Synthesis Route for a Carboxylic Acid Strategy We’ve seen two methods for preparing carboxylic acids from alkyl halides: 1. cyanide ion displacement followed by hydrolysis, and 2. formation of a Grignard reagent followed by carboxylation. The first method involves an SN2 reaction and is therefore limited to use with primary and some secondary alkyl halides. The second method involves formation of a Grignard reagent and is therefore limited to use with organic halides that have no acidic hydrogens or reactive functional groups. In the present instance, either method would work well.

Worked Example 15.2 Devising a Synthesis Route for a Carboxylic Acid Solution

15.6 Reactions of Carboxylic Acids: An Overview Reactions of carboxylic acids can be grouped into four categories:

15.7 Chemistry of Nitriles Nitriles exhibit similar chemistry to carboxylic acids because both have a carbon atom with three bonds to an electronegative atom containing  bonds

Chemistry of Nitriles Nitriles are not abundant in living organisms Cyanocycline A is an antimicrobial and antitumor agent Lotaustralin is poisonous to herbivores

Chemistry of Nitriles Laboratory preparations of nitriles: S N 2 reaction of CN - with primary or secondary alkyl halide (Section 15.5) Dehydration of primary amide, RCONH 2 Occurs by initial reaction of SOCl 2 on the nucleophilic amide oxygen atom, followed by deprotonation and E2-like elimination

Chemistry of Nitriles Reactions of nitriles:

Chemistry of Nitriles Hydrolysis

Chemistry of Nitriles Mechanism of basic hydrolysis Proceeds through amide At higher temperatures the amide hydrolyzes to the carboxylic acid

Chemistry of Nitriles Reduction of nitrile with LiAlH 4 yields an amine

15.8 Spectroscopy of Carboxylic Acids and Nitriles Infrared Spectroscopy Carboxylic acids have two characteristic absorptions: Broad –OH absorption over 2500 to 3300 cm -1 range Strong C=O absorption between 1710 and 1760 cm -1

Spectroscopy of Carboxylic Acids and Nitriles Nuclear Magnetic Resonance Spectroscopy 13 C NMR Carboxyl carbon atoms absorb in the 165 to 185  range Aromatic and  -unsaturated carboxyl carbon atoms absorb near upfield end (~ 165  ) Carboxyl carbon atoms of saturated aliphatic acids absorb near the downfield end (~ 185  ) Nitrile carbons absorb in range 115 to 130 

Spectroscopy of Carboxylic Acids and Nitriles 1 H NMR – CO 2 H proton normally absorbs as a singlet near 12 