Chapter 21: Amines and Chapter 21: Amines and Their DerivativesTheir Derivatives

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

materialsmaterials

Fluoxetin Fluoxetin (Prozac)(Prozac)

O

F

FF

PolypeptidePolypeptide

AmphetamineAmphetamine MescalineMescalineEpinephrineEpinephrine(Adrenaline)(Adrenaline)

Alkaloids (natural Alkaloids (natural amines)amines)

HO

OH

HOH

NHCH3H2C

H2N

H

CH3

H3CO

OCH3

OCH3

NH2

Amines in Industry: Nylon

Nylon 6,6Nylon 6,6

Hosiery, gears, textile fiber,.......

Primary aminesPrimary amines

Secondary aminesSecondary amines

TertiaryTertiary amines amines

Naming: Naming: AlkanaminesAlkanamines

NN--alkylalkyl, as , as in amidesin amides

Substituent name: Substituent name: Amino-Amino-

Common names: Common names: AlkylamineAlkylamine

4-(2-4-(2-AminoAminoethylethyl)benzoic acid)benzoic acid

HOOC

NH2

Physical PropertiesPhysical Properties

1.1.Tetrahedral structureTetrahedral structureBasicBasic

EEaa = 5-7 kcal mol = 5-7 kcal mol-1-1

InversionInversion

3. Basicity-Nucleophilicity3. Basicity-Nucleophilicity

RNHRNH22

:: HHClClRNHRNH33 + + ClCl

--++

Primary ammonium chloridePrimary ammonium chloride

:::::: ::

RNHRNH22

:: CHCH33II RNHRNH22CHCH33 + + II++ ::

:::: ::--

Secondary ammonium chlorideSecondary ammonium chloride

2. Chiral amines racemize2. Chiral amines racemize

Ammonium salts are configurationally stableAmmonium salts are configurationally stable

NH3C

C6H5CH2CH3

NH3C C6H5

CH2CH3

CH2Cl

NH3C C6H5

CH2CH3

H2C

NH3C

C6H5CH2CH3

H2C

+

Cl: :

::

-

Cl: ::

:

-+

+

+

+

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

4. Weaker hydrogen bonds than OH4. Weaker hydrogen bonds than OH

NRH

H

NHH

R:

:

Only primary and secondary amines can function Only primary and secondary amines can function as proton donorsas proton donors

Less electronegativeLess electronegativethan oxygenthan oxygen

SpectroscopySpectroscopyInfraredInfrared spectrum of spectrum of cyclohexanaminecyclohexanamine

N-H IR stretch: N-H IR stretch: 3300–35003300–3500 cm cm-1-1

11H NMRH NMR spectrum of azacyclohexane spectrum of azacyclohexane

NH usually broad, variable, like OH

13C Chemical Shifts (ppm)

N is N is lessless deshielding than O deshielding than O

Mass spectrumMass spectrum of of NN,,N N -diethylethanamine-diethylethanamine

Odd molecularweight

•C : Mass 12 and tetravalent, C : Mass 12 and tetravalent, e.g. CHe.g. CH44, results in , results in eveneven MM++

• N: Mass 14 and trivalent, N: Mass 14 and trivalent, e.g. NH e.g. NH33, results in odd , results in odd MM+ + for N = for N = 1,3,5...1,3,5...

• Preferred fragmentation Preferred fragmentation αα––ββ bond bond cleavage (even fragments)cleavage (even fragments)

Acidity and BasicityAcidity and Basicity

Acidity:Acidity:

• Preparation of Sodium Amide:Preparation of Sodium Amide:

• Preparation of LDA:Preparation of LDA:

Needs strong base

2Na + 2NH3 2NaNH2 + H2Catalytic Fe3+

Basicity:Basicity:

KKbb== [RNH[RNH33] [HO ]] [HO ]

[RNH[RNH22]]

++ --~~ 1010-4-4

Ammonium ion

ppKKbb ~ 4 ~ 4

Recall:Recall:ppKKaa + p + pKKbb = 14 = 14

Thus, pThus, pKKaa of protonated amine ~ of protonated amine ~ 1010

Better (to compare with other Better (to compare with other ppKKaa values): values):

O

H

H

R+

ppKKaa = = -3-3

SynthesisSynthesis1.1. AlkylationAlkylation of NH of NH33, primary, , primary,

and secondary amines and secondary amines

Problem: Problem: • OveralkylationOveralkylation: Even though amine gets more: Even though amine gets more hindered, it also gets more nucleophilichindered, it also gets more nucleophilic

One solution is to have One solution is to have excessexcess of RNH of RNH22 and and use RX as limiting reagentuse RX as limiting reagent

2. Via 2. Via nitrilesnitriles

3. Arenamine via 3. Arenamine via nitroarenenitroarene

1,3-Benzenediamine1,3-Benzenediamine

HNO3,H2SO4

NO2

HNO3,H2SO4

NO2

NO2

H2,Ni

CF3CO3H

NH2

NH2

4. 4. GabrielGabriel Synthesis ( R Synthesis ( RXX RNH RNH22))Solves problem of overalkylation

5. 5. ReductiveReductive Amination Amination Primary aminePrimary amine

Secondary amineSecondary amine

Tertiary amineTertiary amine

Goes through iminium ion

Goes through iminium ion

Formaldehyde and a secondary amine:Formaldehyde and a secondary amine:

Use of formaldehyde Use of formaldehyde effects effects monomethylation monomethylation of an of an amine.amine.

RedAminRedAmin

6. Reduction of 6. Reduction of amidesamides

RCNHR’RCNHR’LiAlHLiAlH44

OO

RCHRCH22NHR’NHR’

Recall:Recall:

7. 7. HofmannHofmann Rearrangement Rearrangement

RCClRCCl

OO

AmideAmide andand RCNHR’RCNHR’

OO

RCNR’’R’RCNR’’R’

OO

August Wilhelm von

Hofmann 1818-1892

Reactions of AminesReactions of Amines1.1. Hofmann EliminationHofmann Elimination

Recall:Recall: ::::

Oxonium ionOxonium ion

Analogous (but attenuated) behavior Analogous (but attenuated) behavior in quaternary ammonium ions. Works in quaternary ammonium ions. Works for E2for E2

ROHH+

R OH2+

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

Degradation of a simple alkaloidDegradation of a simple alkaloid

HH HH

2. 2. Mannich ReactionMannich ReactionAlkylation of Enols by Iminium Ions

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 β-aminocarbonyl product.

Form iminium ionForm iminium ion

Form iminium ionForm iminium ion

Carl Ulrich Franz

Mannich 1877-19471877-1947

Net: Net: αα–Amino- –Amino- methylation of methylation of enolizable enolizable alde- hydealde- hydeMannichMannich

3. Reaction with nitrous acid3. Reaction with nitrous acid

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

::::

TertiaryTertiaryamineamine (stable)(stable)

Secondary Secondary amineamine

NN –Nitrosamines are –Nitrosamines are implicated in the implicated in the carcinogenicity of carcinogenicity of cured meatscured meats

Primary Primary N N -nitrosamines -nitrosamines decomposedecompose

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

4. Diazomethane CH4. Diazomethane CH2 2 N NN NAmides are also subject to Amides are also subject to NN -Nitrosation -Nitrosation

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

――――――――

Step 1: Hydroxide AdditionStep 1: Hydroxide Addition

C

O

NH2H3CN

NO

OH C

O

NH2H3CN

NO

OH::

::::

::::

::::::

:: ::::

::

::

::

::::

::

--:: ::

:: --

Mechanism:Mechanism:

Step 2: EliminationStep 2: Elimination

C

O

NH2H3CN

NO

OH

CH3N N O CHO NH2

O

HOH

CH3N NOH OH CO2 HNH2

--:: ::

::::

:: ::

::

::

::

::::

::

::

::::

::

:::::: ::::

::::::

::

::::

::::--

++

++ ++

CH2N NOH OH-H2O

H2C N N OH

H2C N N

H2C N NH

Step 3: DehydrationStep 3: Dehydration

::

::

::::

::

::

::::

::::::::

::

::::::::::

- OH- OH

----

--

++-- ::

Diazomethane has two applications as a Diazomethane has two applications as a reagent: In esterifications and as a source of reagent: In esterifications and as a source of carbene CHcarbene CH22..

H2C N NC

O

OR HC

O

ORH3C N N

N N

C

O

OCH3R

• Formation of EstersFormation of Esters

• Generation of CarbeneGeneration of Carbene

• CyclopropanationCyclopropanation

H2C N N++ --::

H2C N N CH

H::::++ -- hhνν or Cu or or Cu or

::++

::::-- ++::

:: ::

++

::::

::

::

--