Lecture Notes Chem 51C S. King

Chapter 25 Amines

Amines are widely found in nature. Many plants synthesize complex amines called alkaloids, some of which have medicinal or poisonous properties.

Some famous amines:

CH3 CH3 HO

HN HN NH2 CH3 H HO

O OCH3 OH OH C HO HO

HN NH2 HN HO CH3 HO O

OH CH3 CH CH 3 O 3 HN H3CO CH3 HN HN O CF CH3 CH3 3

N CH3 CH3 CH3

HN NH2 CH2CH3 N

CF3 O

127 Some Famous Heterocycles:

CH2CH2CH2N(CH3)2 O N CH2NHNH C CH3 N O Isocarboxazid Imipramine a monamine oxidase inhibitor a tricyclic antidepressant H3C N CH3 N O N N

N Cl N Cl N CH3 N Ph Ph Nicotine Diazepam (Valium) Aprazolam (Xanax) a benzodiazepine a benzodiazepine

O H CH3 CH2CH3 N HN CO2CH3 CHCH2CH3 Secobarbital CH3 O CPh O N O (Seconal) 2 H a barbituate Cocaine H an anesthetic HO O

N O H NH N N CH LSD HO 3 a hallucinogen CH3 Morphine a narcotic

128 I. Acid and Base Properties of Amines

A. Reaction of an Amine as a Base:

H O

H3C N + CH3CO H H

B. Reaction of an Amine as an Acid:

Ammonium ion acts as an acid:

H R N R + OH R

• Amines can also be deprotonated by very strong bases to make amides (not to be confused with amide derivatives of carboxylic acids)

N H + n-BuLi

Substituent Effects on Amine Acidity and Basicity:

The basicty of an amine depends on its structure. Factors that effect acidity basicity: 1. the effect of alkyl substitution 2. inductive effects 3. resonance effects

129 ☛ TEST YOUR KNOWLEDGE:

Q1: Which is the most acidic compound? Which is the least acidic?

H

NH4 CH3CH2NH3 H N CH2CH3

CH2CH3

Q2: Which amine is the most basic?

H H

H3C N N H H

130 Q3: Which amine is more acidic?

H H

CH3 N H N H H H

Always look at the conjugate base! If the conjugate base is more stable, then the compound is more acidic.

Q4: Which amine is more basic?

NH2 NH2 NH2

NO2 OCH3

Look at the pK ’s of the conjugate acids: a NH3 NH3 NH3

NO2 OCH3

131 Q5: Which nitrogen is the most basic?

H3C C N N N H

• electrons are held more tightly in orbitals with more “s” character.

N H

This is a large effect. Compare the pKa’s of of the conjugate acids:

H3C C NH N N H H H

132 Which is the most basic? Q6: O

CH CH NH CH CNH 3 2 2 3 2

II. Acidity & Basicity of Aromatic Heterocycles

When considering acidity & basicity of aromatic heterocycles, keep in mind:

• If N: is part of a double bond, then the lone pair is not part of the aromatic π- system.

N

N

133 • If N: is not part of a double bond, then the lone pair is part of the aromatic π- system.

H N

N H

• If oxygen is part of an aromatic ring, only one lone pair is part of the aromatic π-system.

O

O

Look @ pyrrole:

Q. Do you expect pyrrole to be very basic?

N H

134 Q. What about deprotonation of pyrrole?

N H N

Compare the pKa of pyrrole with that of ammonia:

Q. Why is pyrrole more acidic than ammonia? A.

Look @ Pyridine:

Q. Would you expect pyridine to be very basic?

N

135 Predict the relative acidity and basicity of imidazole (reactions of imidazole as an acid or base are important in many biological systems):

N

N H

N

N H

Summary of the pKa of Several Nitrogen Heterocycles:

H H N H N NH H N N N N N N H H H H H

pKa = !3.8 pKa = !2.4 pKa = 1.0 pKa = 2.5 pKa = 4.85

NH N

N N N N N N H H H H2 H H

pKa = 5.2 pKa = 6.8 pKa = 11.1 pKa = 14.4 pKa = 17 pKa = 36

136 III. Preparation of Amines

A. Alkylation of Amines

Amines are good nucleophiles and can react with primary alkyl halides to give alkylated ammonium halides. This is an SN2 reaction so 3° halides don’t work and 2° give mostly elimination reactions.

NH3 + H3C I

 Overalkylation! Big Problem: H NCH + H C I 2 3 3

Compare nucleophilicity:

NH H NCH 3 vs. 2 3

Even if only 1 equivalent of CH3I is used, you will get mixtures!

137 Solution:

• Use a very large excess of NH3 • Use alternative methods shown below.

B. Reduction of Azides - Another Route to Primary Amines

NaN PhCH Br 3 + 2

Advantages of using azide rather than ammonia to make primary amines:

Example:

O NaN3 H O 2

138 C. Hydrolysis of an Imide: The Gabriel Synthesis

An imide is a compound with two acyl groups bound to nitrogen. The Gabriel synthesis, which converts alkyl halides into primary amines, involves hydrolysis of an imide.

O

HO R Br NH

O HCl, ! H2O

HO

• The Gabriel Synthesis only gives one product, and therefore is a great way to synthesize primary amines.

D. Reduction of Carbon-Nitrogen Double & Triple Bonds

1. Reduction of Amides & Nitriles

1. LiAlH4 R C N 2. H O 2

O 1. LiAlH R C N R' 4 2. H2O R"

Reduction of nitriles provides a route to two types of β-phenethyl amines:

Br NaCN

139 CHO 1) NaCN + 2) H3O

2. Reductive Amination - Reduction of Imines and Iminium ions:

O RNH2 R C R'

Example 1:

O

HN(CH3)2

H2, Pt

Example 2: Reductive Amination to make speed:

CH3 CH3NH2 O

E. Reduction of Nitro Compounds

RNO 2

140 A great way to make β-phenethylamines is the Henry Reaction (similar to the aldol reaction):

O

H CH3NO2 NaOH O O

Mechanism:

141 IV. Reaction of Amines

A. Amines are good nucleophiles

O O O

O RNH 2 O O O Cl OR

• SN2 substitution with alkyl halides is problematic due to overalkylation • Amines are also strong bases so E2 competes with SN2

B. Reaction of 1° Amines with Nitrous Acid

Nitrous acid, HNO2, is a weak, unstable acid generated in situ by treating NaNO2 (sodium nitrite) with HCl. In the presence of acid, nitrous acid decomposes to a nitrosonium ion, a powerful electrophile, which reacts with 1° amines to form diazonium salts.

H Cl + O N O

CH3

H3C CH NH2 + N O

142 • The reaction of primary aliphatic amines with nitrous acid is not synthetically useful. • The reaction of nitrous acid with primary aromatic amines, however is very synthetically useful. When aniline is allowed to react with nitrous acid, diazotization occurs to form an arenediazonium salt. This diazonium salt, has a very good L.G. (molecular nitrogen) and undergoes substitution reactions in which nitrogen is replaced by a variety of substituents:

NH2

NaNO2, HCl H2O

CuBr

CuCl

N Cl KI N

HBF4 !

CuCN

H2O

H2SO4 !

H3PO2

143 V. Using Diazonium Salts in Synthesis

The amino group can be used to direct electrophilic aromatic substitution on the ring, and can be removed through diazotization and replacement by hydrogen in a reduction reaction.

Example: Synthesize the following compound from toluene:

Br Br

CH3

If toluene is brominated, you get:

Br2

FeBr3

CH3

Instead:

CH3

144 VI. Use of Nucleophilic Aromatic Substitution to Make Substituted Aniline Rings

Background (chapter 18, 4th ed):

Aromatic rings do not react easily with nucleophiles. Nucleophiles can displace aryl halides in highly deactivated benzene derivatives via an addition/elimination mechanism.

Cl

NO2 NaNH2 100°C

NO2

Characteristics of Reaction:

• Strong nucleophile required. • Reaction cannot proceed by SN1 (formation of an aryl cation) because the EWG would destabilize this intermediate.

• Reaction cannot proceed by SN2: Like vinyl halides, aryl halides cannot achieve the correct geometry for backside displacement (aromatic ring blocks approach of the nucleophile to the back of the carbon bearing the L.G

• Fluoride is a much better L.G. than iodide ion in this reaction.

145 Mechanism: Addition Elimination:

O N F O + NH2 N O O

Q. Why is fluoro a better L.G. in this reaction? A. Two reasons: 1. F is more electronegative than I.

2. F is much smaller ∴ there is less steric hindrance to the approaching nucleophile that will bond to carbon and give a tetrahedral intermediate.

146 VII. Amines in Condensation Reactions: The Mannich Reaction

When an aldehyde or ketone is heated with an acid catalyst in the presence of formaldehyde and an amine, the product is a B-amino carbonyl compound.

O 1. H2C O, (CH3)2NH C HCl/EtOH CH CH 3 3 2. NaOH

147 The Mannich Reaction is used as the key step in the synthesis of Prozac®:

F3C

O

CH3 N H Prozac

Synthesis: O H2C O, CH3NH2 HCl/EtOH CH3

148