Section 9: Amines – Chapter 20

Practice Problems:None! (yay!)

N

Amines: Nomenclature

H3CN

HH

H3CN

HCH3

H3CN

CH3CH3

1o amine 2o amine 3o amine

H3CN

CH3CH3

CH3X

a quaternary ammonium salt

NH2

t-butylamine

NH2

cyclohexylamine

NH2

aniline

N

diisopropylethylamine( Hünig's base )

OHH3C

H3CH3C NH2

H3C

H3CH3C

a 3o alcohol a 1o amine

Don't be confused...

Amines: Heterocyclic Amines

NNH

N

N

NH

NH

N

N

NH

NH

Pyridine Pyrrole

QuinolineImidazole

Indole

Pyrimidine

Pyrrolidine

Piperidine

Amines: Structure

RN

R''R'

close to 109o

sp3 ~ tetrahedral

note: if R, R’, R’’ are different, the amine is technically chiral, but…

RN

R''R'

fast RN

R''R'

Amines: Smell

Et3Ntriethylamine - "fishy smell"

H2N NH2

cadaverineH2N

NH2

putrescine

H2NHN NH2

spermidine

Amines: Basicity

N H A N H A

RNH3+ + H2O RNH2 + H3O+

K a =[RNH2][H3O+]

[RNH3+]

pK a = log K a

Basicity is often reported as the pKa of the conjugate acid:

Amines: Basicity

Some representative pKa values:

Et3N NH3 Ph NH2 NH

10.8 9.3 4.6 0.4pKa of

conjugate acid:

triethylamine ammonia aniline pyrrole

Don't be confused...

N H

pKa of the amineitself ~ 35

pKa of theconjugate acid

~ 11

Amines: in Biology

NH3C OCH3

O

O

OCocaine

N

NN

NH3C

CH3

CH3

O

O

Caffeine

O

NH

HN

HN

ONH

O

O

HN

O

NH

HN

ONH

O

O

HN

NH

O HN

O

O

NH O

OHNH

OH

OH

NH2

NH

NH2HN

NH2O

NNH

OHO

Protein

N

S

OOH

OO

HN

Penicillin

Amines: in Biology

N

NH

CH3

N O

H

Lysergic acid diethylamide

N

NN

N

NH H

O

O

O

P OON N

H

O

O

CH3

N

NO

O

O

P OO

N

N

OH

NH

H

N N

N

O

H

Hadenine

thymine

guanine

cytosineO

O

O

PO O

O

O

O

PO O

DNA

NH

OH H

H

NHO

Propecia

O

HO

HO

H

H H

NCH3

Morphine

OCH3

H

NH3C

Dextromethorphan

Amines: PreparationA. Reduction of nitriles / amides / nitro compounds

RC

N 1. LiAlH4

2. H3OR NH2

R N

OR'

R''

1. LiAlH4

2. H3OR N

R''

R'

NO2SnCl2

H3ONH2

Amines: PreparationB. SN2 reactions

H3N + R X R NH3

X

baseR NH2

X = Cl, Br, I...

H2N + R X R NH2

X

baseR NH

R R R

But...

Hard to stop here!!R X

NRR

R

OK to stop here

R XR4N

X

If you want to go from a 2o amine to a 3o amine, rxn with R-X is usually OK. Otherwise, consider an alternative approach.

Amines: PreparationC. Attack with NaN3

R X

X = Cl, Br, I...

Na N3+ SN2R N

NN R NH2or

LiAlH4

PPh3

D. Gabriel Synthesis

R X

X = Cl, Br, I...

+SN2

NH

O

Ophthalimide

N

O

O

KOH

R N

O

OR NH2or

H2NNH2

MeOH

NaOHH2O

Amines: PreparationE. Reductive amination

R R'

O

ketoneor aldehyde

H2NR''

NaBH3CNCH3OH

R R'

NR''H

BH2CNH (i.e. "H ")

R H

N HHR'

Great reaction!!

e.g.

H

O

NaBH3CNCH3OH

NH

CH3H2NCH3

O

NaBH3CNCH3OH

H3NNH2

O

HNH

CH3H3C

NaBH3CNCH3OH

N

H

H3C CH3

CH3

CH3

Ch. 20 - 14

4D. Preparation of Primary Amines through the Hofmann and Curtius Rearrangements

O

R NH2

Br2, NaOHH2O

R NH2

+ NaBr + Na2CO3

Hofmann rearrangement

Ch. 20 - 15

(1) NH2

OBr2

NaOHNH2

Examples

(2)NH2

ONH2

Br2NaOH

Ch. 20 - 16

Mechanism

O

R NH

HOH O

R NH

Br Br O

R NH

Br

HOO

R NBr

O C NR (Hofmann

rearr.)(isocyanate)

HOO C

N

OH

R

O CN

O

RH

+ CO2HN

RH OH

R NH2

Ch. 20 - 17

Curtius rearrangement

O

R ClNaN3

O

R N N NO C N

R+ N2 (g)

heat

R NH2

H2O

CO2 (g) +

O

Cl 1. NaN32. heat3. H2O

NH2

e.g.