Chapter 19 AMINESPROBLEMS 2a,b,e,3a,b,c,6a,c16b,c,17a,c,20b,d21b,25a,c,e,g,26a,c27b,36a,b,37ab,41c,d,I,

42a,b,c44a,c,g

INTRODUCTION

Organic derivatives of ammonia

70% of pharmaceuticals contain nitrogen

Alkaloids - obtained from plants and have strong biological properties

ExamplesPrimary RNH2

HO

HONH2

DOPAMINE

Parkinson's Disease - inadequate concentration of dopamine

Dopamine is a worthless drug since it can't cross blood-brain barrieri.e. can't get in cerebrospinal fluid

HO

HONH2

H CO2H

TYROSINE

An amino acid that can cross barrier

-CO2

Examples continuedSecondary Amines

NH

CH2CH2CH3

CONIINE - Hemlock SOCRATES CONIINE - Hemlock SOCRATES

NHMe

Me

methamphetaminespeed Tina

HO

HO NHMe

OH

epinephrine

Tertiary Amines

OHO

OHH

N

Me

OH3COCO

OCOCH3H

N

Me

HEROINMorphine

Me O Me

O O

Me OH

O

NomenclatureCommon Names - name radicals attached to nitrogen followed by amine

Nsec-butyldiethylamine

NH2 1-aminocyclopentene

N-Convention

N

Me

Me Me

N,N-dimethyl-4-methylaniline

IUPAC SystemALKANAMINE - Parent longest chain containing amine

CH3CH2CH2NHCH2CH2CH2CH2CH3

N-propyl-2-pentanamine

NH

ClCl

Me

3,4-dichloro-N-methybenzenamine

NH2

Basicity of aminesThe greater the availability of the lone pair electrons on nitrogen, the greater the base.

Kb = [RNH3+] [OH-] / RNH2

In the old days, pKb was a measure of base strength.

pKb = - log Kb

The stronger the base the lower the pKb

EFFECTS ON AMINE BASICITY

1. INDUCTIVE EFFECT - ALKYL SUBSTITUTION

CH3-NH2 < CH3-NH

CH3METHYL GROUP INCREASES ELECTRON DENSITY ON N

3.36 3.28 2 METHYLS ARE BETTER THAN ONE

WATCH OUT THREE METHYL GROUPS DECREASES BASICITY pKb = 4.26 - Steric inhibition of solvation of HOH with the NH+ of the R3NH+ cation.

The greater the availability of the lone pair electrons on nitrogen, the greater the base.

Kb = [RNH3+] [OH-] / RNH2

In the old days, pKb was a measure of base strength.

pKb = - log Kb

The stronger the base the lower the pKb

EFFECTS ON AMINE BASICITY

1. INDUCTIVE EFFECT - ALKYL SUBSTITUTION

CH3-NH2 < CH3-NH

CH3METHYL GROUP INCREASES ELECTRON DENSITY ON N

3.36 3.28 2 METHYLS ARE BETTER THAN ONE

WATCH OUT THREE METHYL GROUPS DECREASES BASICITY pKb = 4.26 - Steric inhibition of solvation of HOH with the NH+ of the R3NH+ cation.

2. RESONANCE EFFECT

Base weakening Why? Delocalizes electron pair on N!!

NH2

vs.

NH2

9.4 3.3

NH+

- N

aromatic 6 pi system

H

pKb = 15

N H

H+

not aromatic

HybridizationThe greater the % of s character The closer the lone pair is to N The weaker the base

N

H

N:H3CN

sp2

sp3

sp

8.75

242.88

Sections to be omitted

19-7 (salts of amines)19-8 (amines as PT catalysts)19-9 (Spectroscopy)

Reaction of Amines to be reviewed

Reaction with Aldehydes and Ketones - 19-10

Aromatic Substitution of Arylamines 19-11

Alkylation of AminesAlkylation of amines by alkyl halides -

Only two situations of importance

Excess Methyl iodide - all the way to quaternary salt

Excess ammonia - stops are monoalkylation stage

PhCH2Br + excess NH3 PhCH2NH2

Propyl-NH2 + ex MeI Propyl-N(Me)3+

Acylation of Amines

R Cl

O

HN

R

H+

R NHR

O

AMIDE

Ph Cl

O

HN

Me

H+

Ph NHMe

O

N-methylbenzamide

Mechanism

Ph Cl

O

HN

Me

H+

Ph NHMe

O-

Cl

Ph NHMe

O

H+

Amines as Leaving GroupsHofmann Elimination

R-NH2excess MeI

R-NMe3 I-+

Ag2OR-NMe3 OH-

+

H

N(Me)3

OH-

HEAT

ANTI ELIMINATION - Less stable (less substituted) alkene

StereochemistryCH3 CH2 CH CH3

N(Me)3+

1234

H CH3

N(Me)3+

H

CH3

H

looking down C2-C3

N(Me)3

H CH3

Me

H H

+

rotation about C-3 counterclockwise

More stable; not

Suitable for E-2

Suitable for E-2;less stable

Looking down C1-C2

H

H H

N(Me)3

H3CH2C H

+

looking down C1-C2

H

H H

CH2CH3

H N(Me)3+

Rotating clockwise about C-2

all suitable for E-2 CH2CH3

HH

H

Examples

NH2 1. excess MeI2. Ag2O

NMe3

+

H

OH_

heat

Note: NMe3 has no beta hydrogensthus complicating the E-2 process

Another example

1. excess MeI2. Ag2O

NH

NHO-

Me2+

H

h e a t

NMe2

H

Me2N

COPE REACTION

NR2

H2O2

NR2

O

+_

N-OXIDE

- HO-NR2

HR2NO-

LESS HINDERED BETA HYDROGENSYN ELIMINATION

COPE EXAMPLE

NMe2H2O2

H3C NMe2H2C

OH +

-

-HONMe2Mild conditions

Reaction of Primary Amines with HNO2

Preparation of HNO2

NaNO2+ HCl HNO2

NaCl+

Reaction

Aliphatic amines

RNH2NaNO2

HCl

RN2+

diazonium ion

RN2+ -N2R+

Hot carbocation

R+ SN1 mixture of products

Aromatic Primary Amines

ArNH2NaNO2

HClArN2

+

0 - 5 oCstable

undergoes SN1 withnucleophiles

Examples

ArN2+

K IArI

CuBr ArBr

CuCl

ArClHBF4

ArF

CuCNArCN

HO-ArOH

2 3

ArH

Conversion of NO2 to NH2

Good way to introduce NH2

ArHHNO3

H2SO4

ArNO2 ArNH2RED

RED = SnCl2/ HCl

Nice Synthesis

R

R Br

1. HNO3/H2SO4

2. SnCl2R

NH2

MeCOCl

R

NHCOMe

Br2 / Fe

R

NHCOMe

Br

HOH

heatR

NH2

Br

1. NaNO2 HCl

2. H2PO3 / ROH

Another one

CO2H

BrBr

I

CO2H

BrBr

NH2

1. NaNO3/HCl2. KI

CO2H

BrBr

NO2

CH3

BrBr

NO2

oxid

Red

CH3

NO2

Br2 / Fe CH3HNO3

H2SO4

CH3I / AlCl3

Synthesis of AminesReductive Amination

N H

C O

R'

R

1.

2. Reduction

N CHR

R'

NOTE: carbonyl has been reducedand aminated - most general method

Examples

Primary Amines

R

R

ONH2OH

R

R

NOH

OXIME

RedR

R

NH2H

Could use NH3 but it is a gas and inconvenient

LAH is usual reducing agent

Secondary AminesR

R

OR'NH2

R

R

NR Red

R

R

NHRHfrom carbonylcompound

fromamine

Note: Primary amine is convertedto secondary amine.

Tertiary AminesR

R

OR'R"NH2

R

R

NR'R"+

iminium saltVery unstabile

So reaction is run with reducing presence at all times.This means that there will both product and carbonyl compounds presence.

Must use reducing agent that only reduces iminium saltIt is: sodium triacetoxyborohydride!!

Preparation of Tertiary, Con’t

R

R

NR'R"+

Na(MeCOO)3)3BH

R

R

NR'R"H

tertiary amineNOTE: Secondary amine converts totertiary amine

Mechanism of iminium salts

R"'"R

ONRR'

H>

R"'R"

O-

NRR'

H

+

R"'"R

OH

NRR'PROTONATION

R"'"R

OH2NRR'

+

NRR'+

R"'

"R ..-H2O NRR'

R"'

"R +

EXAMPLE

O

+

N-CH3H

HOHN

CH3+

NCH3

+

Na(MeCOO)3BH

NCH3

H

Other Ways to Prepare Primary amines

REDUCTION OF NITROANILINES - as before

REDUCTION OF NITRILES

RCH2X RCH2CNCN-1

SN2 conditions

LAH RCH2CH2NH

essentially replaces halogen with a CH2NH2

group.Increases carbon chain length by one carbon

Don’t do problem 27b ch.19Please do problem 30b,

REDUCTION OF AZIDES

RCH2X N3-1

SN2 conditionsRCH2N3

LAH RCH2NH2

essentially replaces halogen with an NH2 group.

No increase in carbon chain length

NOTE 1-bromopentane to 1-pentanamine - azide

but 1-bromopentane to1-hexanamide - CN-