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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:

HO

HONH2

CH3

HNCH3

CH3

HNH

OH

HNCH3

CH3

HNCH3

O

O

CH3

N

N

O

HO

HO

OH

HNCH3

HO

HONH2

OH

HNCH2CH3

CH3

CF3

NH2

CH3CH3

HN

COCH3O

HNCH3

CH3

CF3

O

H3CO

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Some Famous Heterocycles:

N

CH2CH2CH2N(CH3)2

Imipraminea tricyclic antidepressant

CH2NH

N O

C

O

NH CH3

Isocarboxazida monamine oxidase inhibitor

N

N

Cl

CH3O

PhDiazepam (Valium)

N

N

Cl

PhAprazolam (Xanax)

NNH3C

HN

NH

O

O O

CH2CH3CHCH2CH3CH3 Secobarbital

(Seconal)a barbituate

an anesthetic

NCH3

CO2CH3

O2CPh

H

H

Cocaine

a benzodiazepine

O

HO

HO

H

N

CH3Morphinea narcotic

N

NH

CH3

N

O

LSDa hallucinogen

a benzodiazepine

N

N

CH3

Nicotine

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I. Acid and Base Properties of Amines A. Reaction of an Amine as a Base:

B. Reaction of an Amine as an Acid:

Ammonium ion acts as an acid:

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

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

H3C NH

H O+ HCH3CO

H

N

R

RR + OH

N H + n-BuLi

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☛ TEST YOUR KNOWLEDGE: Q1: Which is the most acidic compound? Which is the least acidic?

Q2: Which amine is the most basic?

H

N

CH2CH3

CH2CH3HNH4 CH3CH2NH3

H3C N

H

H

N

H

H

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Q3: Which amine is more acidic?

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?

Look at the pKa’s of the conjugate acids:

CH3 N N

H

H

H

H

H

H

NH2 NH2

NO2

NH2

OCH3

NH3 NH3

NO2

NH3

OCH3

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Q5: Which nitrogen is the most basic?

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

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

N N

H3C C N

H

N

H

H3C C NHN

H

NH H

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Q6: Which is the most basic?

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.

O

CH3CH2NH2 CH3CNH2

N

N

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

• If oxygen is part of an aromatic ring, only one lone pair is part of the aromatic

π-system.

Look @ pyrrole: Q. Do you expect pyrrole to be very basic?

N

H

N H

O

O

NH

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Q. What about deprotonation of pyrrole?

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

NH

N

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

Summary of the pKa of Several Nitrogen Heterocycles:

N

NH

N

NH

NH

NH

NH

NH

N

N

NHN

NH

NH

NH

NH

NH

H

H

H H

NH

NH2

N

NH

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

pKa = 17

pKa = 4.85

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

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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. Big Problem: Overalkylation!

Compare nucleophilicity:

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

+NH3 H3C I

+ H3C IH2NCH3

vs.NH3 H2NCH3

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Solution:

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

B. Reduction of Azides - Another Route to Primary Amines

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

+NaN3 PhCH2Br

ONaN3H2O

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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.

• 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

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

NH

O

O

R Br

HCl,H2O

HO

!

HO

C NR1. LiAlH42. H2O

R C

O

N R'

R"

1. LiAlH42. H2O

Br NaCN

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

Example 1:

Example 2: Reductive Amination to make speed:

E. Reduction of Nitro Compounds

1) NaCN2) H3O+

CHO

R C

O

R'RNH2

O

H2, PtHN(CH3)2

O

CH3 CH3NH2

RNO2

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

Mechanism:

H

OO

O

NaOHCH3NO2

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IV. Reaction of Amines A. Amines are good nucleophiles

• 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.

Cl

O

O O

O

OR

O O

O

RNH2

H Cl + O N O

+ N OCH NH2

CH3H3C

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• 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, HClH2O

N

N Cl

CuBr

CuCl

KI

HBF4!

CuCN

H2OH2SO4

H3PO2

!

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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:

If toluene is brominated, you get:

Instead:

BrBr

CH3

CH3

Br2FeBr3

CH3

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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.

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.

NO2

NO2

Cl

100°NaNH2

C

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Mechanism: Addition Elimination:

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.

F

NO

O

NO

O

NH2+

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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.

CH3

O

CCH3

H2C O, (CH3)2NHHCl/EtOH

2. NaOH

1.

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

Synthesis:

NH

CH3

O

F3C

Prozac

H2C O, CH3NH2HCl/EtOHCH3

O