Chapter 21: Amines and Their Derivatives

Medicines, amino acids, peptides, proteins, alkaloids, industrial materials

F F F

Fluoxetin (Prozac)

Polypeptide

Alkaloids (natural amines)

HO H NHCH3 H 2N H2C CH3 H NH2

HO OH

H3CO

OCH3 OCH3

Epinephrine (Adrenaline)

Amphetamine

Mescaline

Amines in Industry: Nylon

Nylon 6,6
Hosiery, gears, textile fiber,.......

Naming: Alkanamines
Primary amines

Secondary amines
N-alkyl, as
in amides

Tertiary amines

Substituent name: AminoHOOC NH2

4-(2-Aminoethyl)benzoic acid

Common names: Alkylamine

Physical Properties
1. Tetrahedral structure
Basic
Ea = 5-7 kcal mol-1

Inversion

2. Chiral amines racemize

3. Basicity-Nucleophilicity
RNH2
RNH2
:

HCl

Primary ammonium chloride

+ RNH3 +

: Cl: : :

CH3I

Secondary ammonium chloride

RNH2CH3 +

: I:

: :

Ammonium salts are configurationally stable

C6H5 CH2CH3

H3C

C6H5 CH2CH3 N CH2Cl + N

H3 C

:Cl: + H2C

+ N

: :

H3C

CH2CH3 C6H5

:Cl:

+ H3C

H2C N CH CH + C H 2 3 6 5

Can be resolved, e.g, by fractional crystallization of a salt with optically active anion

: :

4. Weaker hydrogen bonds than OH

Less electronegative than oxygen

H H H R

Only primary and secondary amines can function as proton donors

:
H

:
N

Spectroscopy
Infrared spectrum of cyclohexanamine

N-H IR stretch: 33003500 cm-1

1H

NMR spectrum of azacyclohexane

NH usually broad, variable, like OH

13C

Chemical Shifts (ppm)

N is less deshielding than O

Mass spectrum of N,N -diethylethanamine

Odd molecular weight

C : Mass 12 and tetravalent, e.g. CH4, results in even M+ N: Mass 14 and trivalent, e.g. NH3, results in odd M+ for N = 1,3,5... Preferred fragmentation bond cleavage (even fragments)

Acidity and Basicity

Acidity:

 Preparation of LDA:

Needs strong base

Preparation of Sodium Amide:

2Na + 2NH3
Catalytic Fe3+

2NaNH2 + H2

Basicity:

Ammonium ion

Kb =

[RNH3] [HO ] [RNH2]

~ 10-4 pK ~ 4 b

Recall:

pKa + pKb = 14

Thus, pKa of protonated amine ~ 10

Better (to compare with other pKa values):

H R O + H

pKa = -3

Synthesis
1. Alkylation of NH3, primary, and secondary amines

Problem: Overalkylation: Even though amine gets more hindered, it also gets more nucleophilic One solution is to have excess of RNH2 and use RX as limiting reagent

2. Via nitriles

3. Arenamine via nitroarene

NO2
HNO3,H2SO4 HNO3,H2SO4

NO2
H2,Ni

NH2

NO2

CF3CO3H

NH2
1,3-Benzenediamine

4. Gabriel Synthesis ( RX RNH2)

Solves problem of overalkylation

5. Reductive Amination

Primary amine

Secondary amine

Goes through iminium ion

Tertiary amine

Goes through iminium ion

Formaldehyde and a secondary amine:

Use of formaldehyde effects monomethylation of an amine.

RedAmin

6. Reduction of amides
O

RCNHR

LiAlH4

Recall:
O

RCH2NHR
O O

RCCl

Amide and RCNHR

RCNRR

7. Hofmann Rearrangement

August Wilhelm von Hofmann 1818-1892

Reactions of Amines
1. Hofmann Elimination
Recall:
ROH
H+

ROH2

Analogous (but attenuated) behavior in quaternary ammonium ions. Works for E2

: :

Oxonium ion

Hofmann eliminations are often used to break down larger amines, e.g., alkaloids, into smaller fragments. Procedure: First, methylate exhaustively to the quaternary ammonium salt; second, treat with base.

Degradation of a simple alkaloid

H H

Alkylation of Enols by Iminium Ions

2. Mannich Reaction

Carl Ulrich Franz Mannich 1877-1947

Form iminium ion

Form iminium ion

The enol is derived from an enolizable ketone/aldehyde and the iminium ion is formed in situ by condensation of a second, more reactive carbonyl component with an amine. The outcome is a aminocarbonyl product.

Net: Aminomethylation of enolizable aldehyde

Mannich

3. Reaction with nitrous acid

Nitrosyl cation: like :C O: , but more electrophilic (charged) and gets attacked by amines

Secondary amine

N Nitrosamines are
implicated in the carcinogenicity of cured meats (stable)

Tertiary amine

Primary N -nitrosamines decompose

R = Alkyl mess, R = Arene stable (Chapter 22)

4. Diazomethane CH2 N N

Amides are also subject to N -Nitrosation

N-Methyl-N-nitrosourea is a precursor to diazomethane

Mechanism:
Step 1: Hydroxide Addition
:O:
H3CN O N C

: :

NH2

:OH

:O:C

H3CN O

: : : :

N: OH

Step 2: Elimination
: :O
C NH2 CH3N N

: : : : : : : :

H3CN O

: O

:O: +
HO C

N::OH

HOH

CH3N NOH

+ :OH

: : :

CO2

HNH2

NH2

NH2

Step 3: Dehydration
:OH : :

-H2O

-:OH

: :

H 2C N

Diazomethane has two applications as a reagent: In esterifications and as a source of carbene CH2.

H2C N N

: : : : :

CH2N NOH

: : : :

-: H2C
OH

N N:

N:

 Formation of Esters
O R C O H

+ -:H C N 2

O N: R C O:

H3C

N N:

OCH3 N:

+
:N

Generation of Carbene
H2C N N :

: :

+ -

h or Cu or

:C

H H

Cyclopropanation
H2C N N :

+ -