Organic Chemistry – chemistry of aromatics

History
- discovery of benzene (M.Faraday – 1825)
- structure of benzene (F.A.Kekulé – 1864)
- conjugation, resonance structures
X X X

HA HB HA Y Y HB
C6H6 substitution
+

H
D
H H
α = 120 °
D C-H = 108,4 pm
C-C = 139,7 pm
H H
H
 Organic Chemistry – chemistry of aromatics

Aromaticity

H H
= 6x H H H

H H

Delocalisation of π – electrons
- is it favourfable process ???
 Organic Chemistry – chemistry of aromatics

energy

ΔHh =
estimated delocalisation energy
of benzene
ΔHh =
410 kJ mol-1

ΔHh =
208 kJ mol-1

ΔHh = ΔHh =
96 kJ mol-1 120 kJ mol-1
 Organic Chemistry – chemistry of aromatics

Aromaticity

„Hückel rule“
Aromatic compounds have to have
- cyclic structure
- conjugated systém of double bonds
- 4n + 2 (n = 1,2,3,4….. Π – electrons
- planar structure (shape) of aromatic part
 Organic Chemistry – chemistry of aromatics

Aromaticity – π - orbital picture

energy

antibonding MO
LUMO

HOMO bonding MO

benzene 1,3-cyclobutadiene
 Organic Chemistry – chemistry of aromatics

Aromatic compounds

[10]-annulene [18]-annulene naphthalene anthracene fenanthrene

H H
+
Fe
H H H H
 Organic Chemistry – chemistry of aromatics

Heteroaromatic compounds

N
N N
pyridine quinoline isoquinoline

N N
H
N O S
H H
N N
pyrrole furane thiophene

porfyrine
 Organic Chemistry – chemistry of aromatics

Aromatic compounds - reactivity

OH
OsO4 OsO4
no reaction
OH
H
RCO3H RCO3H
no reaction vs. O
H
Br2/CCl4 Br
Br2/CCl4
no reaction
Br
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – reactivity – SE aromatic

CH2=O/HCl Br2/FeBr3
ClCH2 Br
chloromethylation halogenation

SO3/H2SO4 HNO3/H2SO4
HO3S NO2
sulfonation nitration
CH3 (CH3)3CCl/AlCl3 CH3COCl3/AlCl3
H3C C CO-CH3
F-C alkylation F-C acylation
CH3
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – retention of aromatic character

Br
addition
H
Br
Br
+ Br-Br
+ Br
Br substitution
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – reactivity – SE aromatic

H
E+

"base"

H H H
+
E E E
+ +

σ-complex σ-complex

E
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – reactivity – SE aromatic

NO2
NC CN
X2
NC CN O2N NO2

π – complexes
C-T (charge-transfer) complexes
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – reactivity – SE aromatic

TS-1
TS-2

energy

σ - complex

Eactivation
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – reactivity – SE aromatic

TS1
TS2

energy
energie H Br

+ σσ--complex
complex

π -complex FeBr4- Br
HBr

+ FeBr3

C6H6 + Br2 + FeBr3 π -complex

Br2

+ FeBr3 C6H5Br + HBr + FeBr3

reakční koordináta
Reaction coordinate
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic - halogenation

FeBr3
+ -
Br Br Br Br FeBr3

H Br FeBr3- Br
Br
+ + FeBr3 + HBr

bromobenzene
Cl Cl2 I
I2
FeCl3 HNO3
chlorobenzene iodobenzene
(83%) (86%)
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic - nitration

H OSO3H
+
HO NO2
-H SO
H O NO2 NO2+ + H2O
2 4 H H
-OSO
3H
NO2
NO2
+

nitrobenzene

stable salts NO2+ X - (X = BF4 , ClO4 , PF6)

 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic - sulfonation

H OSO3H + H
O
+
HO SO3H H O SO2 OH
O
S
O
+ H2O
H
+ H
O
H O O O O
S -OSO
O O 3H S S +
SO3H OH NaCl O Na
+

benzenesulfonic acid natrium-benzenesulfonate

 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic – F-C alkylation

AlCl3
+ -
CH3CH2 Cl CH3CH2 Cl AlCl3 CH3 CH2 +[AlCl4]-

+
CH3CH2
H Cl AlCl3- CH2CH3
CH2CH3 + AlCl3 + HCl
+
ethylbenzene
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic – F-C alkylation

H2SO4
+

cyclohexylbenzene

CH2OH
HF
+

diphenylmethane
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic – F-C alkylation

CH3
H3C CH CH2Cl C(CH3)3

AlCl3
tert-butylbenzene

H3C CH2 CH2Cl CH2CH2CH3 CH(CH3)2

AlCl3
+
propylbenzene isopropylbenzene
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic – F-C acylation

O δ+ δ− +
CH3CH2 C Cl AlCl3 CH3CH2 C O
O
AlCl3
CH3CH2 C Cl + AlCl4-
+
Cl δ+ δ− CH3CH2 C O
CH3CH2 C O AlCl3
stabilized acylium cation

+
O
O C CH3CH2 H -
Cl AlCl3 C CH2CH3
+ C CH2CH3
+ HCl + AlCl3
O 1-phenylpropane-1-one
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic – F-C acylation

O
CH3CH2CH2COCl C CH2CH2CH2CH3
CH2CH2CH3 Zn(Hg)x
AlCl3 HCl
1-phenylbutane-1-one butylbenzene

O
O O
O C CH2
reduction P2 O5
CH2 CH2
CH2 CH2 H3PO4
AlCl3
COOH COOH
O
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic – varia

electrophile formed
HCl CH=O +
H C O
+ C O
AlCl3, CuCl
H3C H3C
+
p-methylbenzaldehyde H C O

HO OH HO OH R C NH+
1) HCl/Zn(CN)2
+ H3C C N CH3
2) H2 O +
R C NH
OH OH O

2,4,6-trihydroxyacetophenone

CH2=O/HCl CH2OH HCl CH2Cl H2C OH+

H3C H3C H3C +

CH2 OH
p-methylbenzylchloride
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – varia

R2CuLi + R´X R-R + RCu + LiX

ether
(CH3)2CuLi + CH3(CH2)8CH2I CH3(CH2)8CH2CH3
-30 °C
lithiumdimethylcuprate 1-iododekane undekane (90%)

ether
(C6H5)2CuLi + CH3(CH2)6CH2I CH3(CH2)6CH2C6H5
lithiumdiphnylcuprate 1-iodooktane 1-phenyloktane (99%)

(CH3CH2CH2CH2)2CuLi + I ether
CH2CH2CH2CH3

lithiumdibutylcuprate butylbenzene (75%)

 Organic Chemistry – chemistry of aromatics

Aromatic compounds – varia

Negishi reaction:

Pd0[P(C6H5)3]4
I CO2CH3 + ZnI CO2CH3 + ZnI2

methyl-4-jodobenzoate phenylzinc iodide methyl-biphenyl-4-carboxylate

 Organic Chemistry – chemistry of aromatics

Aromatic compounds – varia

Pd0[P(C6H5)3]4

Catalytic circle: +2P(C6H5)3 -2P(C6H5)3

I CO2CH3 Pd0[P(C6H5)3]2 CO2CH3

oxidative reductive
addition elimination

P(C6H5)3 P(C6H5)3
II transmetallation
I Pd CO2CH3 Pd
II
CO2CH3
P(C6H5)3 P(C6H5)3

ZnI2
ZnI
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic – directive effect

NO2
H3C HNO3 H3C H3C NO2 H3C
+ +
H2SO4
NO2
2-nitrotoluene 3-nitrotoluene 4-nitrotoluene
(63%) (3%) (34%)
NO2
CF3 HNO3 CF3 CF3 NO2 CF3
+ +
H2SO4
NO2
2-nitro(trifluoro- 3-nitro(trifluoro- 4-nitro(trifluoro-
methyl)benzene methyl)benzene methyl)benzene
(6%) (91%) (3%)
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic – directive effect

1.0 CH3 CF3

44 4,6 x 10-6

2,4 69 x 10-6
relative velocity
of nitration 59 4,5 x 10-6
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic – directive effect

CH3 CH3 CH3
H H H
+
NO2 NO2 NO2 ortho substitution
+ +
+I
CH3 CH3 CH3
H3C Ar
+
+ + para substitution

H NO2 H NO2 H NO2

CH3 CH3 CH3

+ + H
H H meta substitution
+
NO2 NO2 NO2
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic – directive effect

CF3 CF3 CF3
H H H
+
NO2 NO2 NO2 ortho substitution
+ +
F -I
CF3 CF3 CF3 F C Ar
+ F
+ + para substitution

H NO2 H NO2 H NO2

CF3 CF3 CF3

+ +
H H H meta substitution
+
NO2 NO2 NO2
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic – directive effect

CH3 CH2CH3 CH(CH3)2 C(CH3)3

61% 47% 31% 18%

39% 53% 69% 82%

Steric effect
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic – directive effect

OH OH OH +OH
H H H H
+
+ Br Br Br Br
+

OH OH OH +OH

+
+ +

H Br H Br H Br H Br

- I +M substituents
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic – directive effect

Velocity of SEAr Substituent Name Oriention
super activating NH2 amino ortho/para
R1 alkylamino (R1=H) ortho/para
N dialkylamino (R1,R2≠H)
R2

OH hydroxy ortho/para
Strongly activating O
HN C R acylamino ortho/para

O R alkoxy ortho/para
O
O C R
acyloxy ortho/para

activating -R, -Ar alkyl, aryl ortho/para

-CH=CR2 alkenyl ortho/para
reference H
 Organic Chemistry – chemistry of aromatics

Velocity SEAr Substituent Name Oriention

reference H
weakly deactivating X halogen ortho/para
(X=F, Cl, Br, I)
CH2 X halogenmethyl ortho/para
strongly deactivating acyl (Y=R) meta
O acylchloride (Y=Cl)
C Y carboxylic acid (Y=OH)
ester (Y=OR)
C N cyano meta
SO3H sulfonic acid meta
Very strongly deactivating CF3 trifluormethyl meta
O
+
N nitro meta
O -
Organic Chemistry – chemistry of aromatics

O O O O
N+ N+

O O O O
N+ N+

+
+
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic – directive effect

O O O O O O
N+ N+ N+
H H H
+
+ Br Br Br
+

O O O O O O
N+ N+ N+

+
+ +

H Br H Br H Br
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic – multiple effect

CH3 CH3 CH3 CH3

Br Br
Br2 Br2
FeBr3 FeBr3
CH3 CH3 C(CH3)3 C(CH3)3
a) b)
CH3 CH3 Cl Cl
NO2
HNO3 H2SO4
H2SO4
SO3H
NO2 NO2 NHCOCH3 NHCOCH3
c) d)
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic – naphthalene

Br
8 1
Br
7 2 Br2

6 3 FeBr3 +
5 4
1-bromonaphthalene 2-bromonaphthalene
(99 %) (1 %)
NO2
HNO3 NO2

H2SO4
+
1-nitronaphthalene 2-nitronaphthalene
(90 %) (10 %)
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic – naphthalene

SO3H

H2SO4 H2SO4 SO3H

75 °C 165 °C
naphthalene-1-sulfonic acid naphthalene-2-sulfonic
acid (98 %) acid (88 %)

H E
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic – naphthalene

OMe OMe OMe
SO3H
H2SO4
+

SO3H
this nucleus is activated

Me = CH3

NO2 SO3H NO2 NO2

H2SO4
+

SO3H
this nucleus is deactivated 8-nitronaphthalene-1- 5-nitronaphthalene-1-
sulfonic acid sulfonic acid
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic – reduction

3 H2 (0,3 MPa)/Pt

AcOH, 30 °C
(100%)

3 H2/Rh

30 °C
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic – reduction

H H H H H H H H
H - H H H H H H H
H H EtOH
Na Na -

H H H H -EtONa H H H - H H H

H H Na+ H H Na+ H Na+

EtOH -EtONa

H H H H
H
H H H
NH3 (l) H
+ 2 Na + 2 EtOH + 2 EtONa +
H H H H
overall reaction
H H H

Et = C2H5
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic – reduction

COOEt COOEt H COOEt

COOEt -

Na
-
H Na+ H Na+ H H

OMe OMe OMe OMe

H H
H -
Na H
-
H
H H
H
Na+ Na+

Me = CH3, Et = C2H5
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic – oxidation

O O

vzduch
O O
V2 O5 , 400 °C
O O
ftalanhydride maleinanhydride
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – SE aromatic – oxidation

CH3 COOH
Na2Cr2O7

O2N H2SO4/H2O
O2N

p-nitrobenzoic acid

CH2CH2CH3 COOH
Na2Cr2O7

H3C H2SO4/H2O
HOOC

benzene-1,4-dicarboxylic acid
(tereftaphthalic acid)
 Organic Chemistry – chemistry of aromatics

Aromatic compounds – technically important

CH2CH3 HC CH2
HF dehydrogenation
+ H2C CH2
Cr2O3.Al2O3
styrene
OH
HF
+ CH3CH CH2 + CH3COCH3

kumene
phenol

CH3

CH3 O2N CH3 CH3

HNO3/H2SO4 HNO3/H2SO4 NO2 HNO3/H2SO4 O2N NO2
+
30 °C CH3 65 °C 110 °C
NO2
NO2 NO2
TNT
 Organic Chemistry – chemistry of aromatics

Phenols - SN on aromatic halogen

1. NaOH, H2O, 370°C

Cl OH
2. H+
chlorobenzene phenol (97%)

CH3OH
O2N Cl + NaOCH3 O2N OCH3 +
85 °C NaCl

4-chloronitrobenzene methyl(4-nitrophenyl)ether (92%)

 Organic Chemistry – chemistry of aromatics

Phenols - SN on aromatic skeleton

Relative velocity
Cl Cl Cl
reaction with NaOCH3:
NO2 O2 N NO2

Cl

NO2 NO2 NO2

1-chloro- 1-chloro- 2,4,6-trinitro-

chlorobenzene 4-nitrobenzene 2,4-dinitrobenzene chlorobenzene

1,0 7x1010 2,4x1015 too high to be

determined
 Organic Chemistry – chemistry of aromatics

Phenols - SN on aromatic skeleton - mechanism

1. step:
Cl
Cl OCH3
H H slow H H
- -
+ OCH3
H H H H
NO2 NO2
4-chloronitrobenzene cyclohexadienyl anion
2. step:

Cl OCH3 OCH3
H H quick H H
- -
+ Cl
H H H H
NO2 NO2
cyclohexadienyl anion methyl(4-nitrophenyl)ether
 Organic Chemistry – chemistry of aromatics

Phenols - SN on aromatic skeleton - mechanism

4-nitrochlorobenzene:

Cl OCH3 Cl OCH3 Cl OCH3 H3CO Cl

H - H H H H H H - H

H H H - H H H H H
N+ N+ N+ N+
O O- O O- -O O- -O O

The most stable mesomeric structure

(negative charge on oxygen)
3-nitrochlorobenzene:

Cl OCH3 Cl OCH3 H3CO Cl

H H H H - H
- H

O- O- O-
H N+ H - N+ H N+

H O H O H O

Negative charge can be located on carbon atoms only

 Organic Chemistry – chemistry of aromatics

SN on aromatic skeleton – addition-elimination mechanism

Cl NH2
KNH2 , NH3
-33 °C

chlorobenzene aniline (52%)

 Organic Chemistry – chemistry of aromatics

CH3 CH3 CH3

Br NH2
KNH2 , NH3
+
-33 °C
NH2
o-bromotoluene o-methylaniline
m-methylaniline

CH3 CH3 CH3

KNH2 , NH3 +
-33 °C NH2
Br NH2 m-methylaniline
p-bromotoluene p-methylaniline

CH3 CH3 CH3 CH3

NH2
KNH2 , NH3
+ +
-33 °C
Br NH2
o-methylaniline m-methylaniline NH2
m-bromotoluene
p-methylaniline
 Organic Chemistry – chemistry of aromatics

SN on aromatic skeleton – addition-elimination mechanism

1. step - elimination:
H H
H Cl H
-
+ NH3 + Cl
H H H
-
H NH2 H
H
chlorobenzene benzyne
H

H
H
 Organic Chemistry – chemistry of aromatics

2. step - addition amide anion:

H H
H H -

H - H NH2
NH2
H H
benzyne aryl anion

3. step - protonation:
H H
H - H NH2 H H
-
+ NH2
H NH2 H NH2
H H
aryl anion aniline
 Organic Chemistry – chemistry of aromatics

SN on aromatic skeleton – addition-elimination mechanism

CH3 CH3 CH3 CH3

Cl NH2
KNH2 KNH2
NH3 +
NH3
NH2
o-chlorotoluene 3-methylbenzyne o-methylaniline m-methylaniline
 Organic Chemistry – chemistry of aromatics

Phenols – acidity – stabilisation od anion by resonance

-
O O O O

- -

Compounds pKa Compounds pKa

Phenol 10,0 3-nitrophenol 8,4
2-methylphenol 10,3 4-nitrophenol 7,2
3-methylphenol 10,1 2.4-dinitrophenol 4,0
4-methylphenol 10,3 3,5-dinitrophenol 6,7
2-nitrophenol 7,2 2,4,6-trinitrophenol 0,4
 Organic Chemistry – chemistry of aromatics

Phenols – are extremely reactive aromatics

OH OH
Br Br
H2O
+ 3Br2 + 3 HBr
25°C

Br
phenol 2,4,6-tribromophenol

OH OH

ClCH2CH2Cl
+ Br2 + HBr
0°C

Br
phenol 4-bromophenol (93%)
 Organic Chemistry – chemistry of aromatics

Phenols – are extremely reactive aromatics

OH OH

NaNO2
H2SO4, H2O

N O
phenol 4-nitrosophenol

O
C
O CH3 O OH O OH OH O
H3C C H3C C
C
Cl Cl CH3
+
AlCl3

C
O CH3
phenyl-acetate phenol 4-hydroxyaceto- 2-hydroxyaceto-
phenone (74%) phenone (16%)
 Organic Chemistry – chemistry of aromatics

Phenols – are extremely reactive aromatics

ONa CO2 OH +
OH
H
125°C, 10 Mpa CO2Na CO2H
sodium phenoxide sodium salicylate salicylic acid (79%)

- - -
O O O O OH O

- O C C
O O
+ C H
O
phenoxide anion oxoform of salicylate anion
salicylate anion
 Organic Chemistry – chemistry of aromatics

Phenols – oxidation to quinones

OH O

Na2Cr2O7
H2SO4, H2O

OH O
hydroquinone p-benzoquinone (81%)

OH O
OH O
Ag2O

CH3 CH3
4-methylbenzene-1,2-diol 4-methylbenzo-1,2-quinone (68%)
 Organic Chemistry – chemistry of aromatics

Phenols – oxidation to quinones and cleavage of ethers

O O
CH3O CH3 CH3
CH3 CH3 CH3
CH3O (CH2CH CCH2)nH CH2CH CCH2(CH2CH2CHCH2)3H
O n = 6-10 O
ubiquinone (koenzyme Q) vitamine K

-
I
no reaction here SN2
CH3
HI
O CH3 O OH + CH3I
+
H
phenyl(methyl)ether
(anisole) phenol iodomethane
 Organic Chemistry – chemistry of aromatics

Phenols – Claisen rearrangement of allylarylethers

OCH2CH=CH2 OH
200°C

CH2CH=CH2
allyl(phenyl)ether 2-allylphenol (75%)

O O O oxo-enol OH

14 14 14 14
C C C C
H
allyl(phenyl)ether transition state 6-allylcyclohexa-2,4-diene-1-one 2-allylphenol
(enolform of product)
 Organic Chemistry – chemistry of aromatics

Aromatic amines – preparation –reduction of nitrocompounds

O
redukce redukce redukce
C6H5 N+ C6H5 N O C6H5 NH OH C6H5 NH2
O nitrosobenzene N-phenylhydroxylamine aniline
nitrobenzene

1. Fe, HCl
Cl NO2 Cl NH2
2. NaOH
4-chloronitrobenzene 4-chloroaniline (95%)

CH(CH3)2 CH(CH3)2
NO2 NH2
H2, Ni
methanol

2-isopropyl-1-nitrobenzene 2-isopropylaniline (92%)

 Organic Chemistry – chemistry of aromatics

Aromatic amines – preparation –reduction of nitrocompounds

Zn, NH4Cl
NO2 NHOH
H2O
N-phenylhydroxylamine

+ -H2O +
C6H5 NHOH C6H5 N H2 + O N C6H5 C6H5 N N C6H5
N-phenylhydroxylamine O nitrosobenzene O
azoxybenzene

+ Zn, OH Zn, OH
C6H5 N N C6H5 C6H5 N N C6H5 C6H5 NH NH C6H5
O azobenzene 1,2-diphenylhydrazine
azoxybenzene
 Organic Chemistry – chemistry of aromatics

Aromatic amines - structure

NH2
aniline
H H
benzenamine
aminobenzene
H H phenylamine
H

+ NH +NH +NH
H - H H H H - H

H H H - H H H
H H H
 Organic Chemistry – chemistry of aromatics

Aromatic amines - structure

N H
H N N
H H
142.5° H
H
aniline sp3 sp2
aniline - conjugation of nonbonded electrons

H3C N N N
H
125° H 125° 180°

methylamine sp3 hybridisationace on N sp2 hybridisation on N

 Organic Chemistry – chemistry of aromatics

Aromatic amines – structure, chirality

CH3CH2 CH2CH3 CH3CH2 CH2CH3 CH2CH3

N N N N N
H H H H
H3C CH3 H3C H CH3 CH3

mirror plane

CH2CH3 CH2CH3
I +N I
N+
C6H5CH2 CH2C6H5
CH3 H3C
C6H5 C6H5

mirror plane
 Organic Chemistry – chemistry of aromatics

Amines – natural compounds

H OCH3
O C
H N
N HO N
H H3C O C6H5
CH3 C
N
O
nicotine N quinine cocaine

HO H CH2CH2NH2
H HO
HO N CO2H
CH3
N H2N H
HO H

adrenaline serotonine L-phenylalanine

 Organic Chemistry – chemistry of aromatics

Amines – basicity
+ -
R3N + H O H R3N H + O H

[R3NH+][OH-]
Kb = pKb = -log Kb
[R3N]

Amine pKb Amine pKb

amoniak 4,7 secondary amines
primary amines (CH3)2NH 3,3
CH3NH2 3,4 (CH3CH2)NH 2,9
CH3CH2NH2 3,2 C6H5NHCH3 9,2
(CH3)2CHNH2 3,4 Tertiary amines
(CH3)3CNH2 3,6 (CH3)3N 4,3
C6H5NH2 9,4 (CH3CH2)3N 3,2
C6H5N(CH3)2 8,9
 Organic Chemistry – chemistry of aromatics

Aromatic amines – basicity – role of substituent

X pKb
H 9,4 O
+
O
+ +
X NH2 N NH2 N NH2
CH3 8,7
O O
CF3 11,5
O2N 13,0
 Organic Chemistry – chemistry of aromatics

Amines – as acids – deprotonation of them

Ka - H
R NH2 + H O H R NH + +
O
H H

[RNH-][H3O+]
Ka = = ~ 10-35 pKa = -log Ka = ~ 35
[RNH2]

Li+
CH3CH2CH2CH2Li
(CH3)2CH N CH(CH3)2 (CH3)2CH N CH(CH3)2
H - CH3CH2CH2CH3
diisopropylamine lithium-diisopropylamide, LDA
 Organic Chemistry – chemistry of aromatics

Aromatic amines – reactivity SEAr

NH2 NH2
Br Br
Br2
H2O

Br
aniline 2,4,6-tribromoaniline (quantitative)

O O
C C
NH2 HN CH3 HN CH3 NH2

CH3COCl Br2 NaOH

nebo acetic H2O
(CH3CO)2O acid
Br Br
acetanilide 4-bromoacetanilide 4-bromoaniline
(main product)
 Organic Chemistry – chemistry of aromatics

Aromatic amines – reactivity SEAr

NH2 NHCOCH3 NHCOCH3 NH2

(CH3 CO)2O NO2 NO2

HNO3 KOH
protection 20°C H2 O
protection group
CH(CH3)2 CH(CH3)2 CH(CH3)2 removal CH(CH3)2

4-isopropylaniline 4-isopropylacetanilide 4-isopropyl-2-nitroacetanilide 4-isopropyl-2-nitroaniline

(98%) (94%) (100%)

+ +
NH2 NH3 HSO4 NH3 HSO4 NH2

H2SO4 HNO3 NaOH

H2SO4 H2O
NO2 NO2
hydrogensulphate hydrogensulphate 3-nitroaniline
of aniline of 3-nitroaniline
 Organic Chemistry – chemistry of aromatics

Aromatic amines – reactivity SEAr

+ + H
H H -H2O +
O N O H O N O H O N O N O
+
nitrous anion nitrous acid nitrosyl cation

N(CH2CH3)2 N(CH2CH3)2

1. NaNO2, HCl, H2O, 8°C

2. OH
-

N,N-diethylaniline N
O
N,N-diethyl-4-nitrosoaniline (95%)
 Organic Chemistry – chemistry of aromatics

Aromatic amines – reactivity SEAr

+
+ + -H
R2N + N O R2N N O R2N N O
H H N-nitrosoamine

NaNO2, HCl
(CH3)2NH (CH3)2N N O
H2O
N-nitrosodimethylamine
(90%)

O
N
H
N N
CH3 NaNO2, HCl CH3
H2O, 10°C
N-methylaniline N-methyl-N-nitrosoaniline (90%)
 Organic Chemistry – chemistry of aromatics

Aromatic amines – reactivity SEAr

H3C O
N N
N N
N N
H3C O N O
N-nitrosodimethylamine N-nitrosopyrrolidine N-nitrosonornicotin
(found e.g. in beer) (in roasted beans) (i tobacco smoke)
 Organic Chemistry – chemistry of aromatics

Amines – reactivity – diazonium salt formation

NaNO2 H + H +
H -H
R NH2 R N R N R N N OH
H+ +
N O N O H alkyldiazohydroxide
N-nitrosoalkylamine
(not isolated) +
H

+ -H2O +
R N N R N N OH2
diazonium cation
 Organic Chemistry – chemistry of aromatics

Amines – reactivity – diazonium salt formation

NaNO2 + +
CH3CH2CH2NH2 - N N CH3CH2CH2
CH3CH2CH2 N N
HCl, H2O
Cl

H H
CH3CH2CH2Cl + H3C C CH3 + CH3CH2CH2OH + H3C C CH3 + H2C CHCH3
Cl OH

N
Cl
NH2 N+

NaNO2, HCl, H2O

0 - 5°C
benzendiazoniumchloride
 Organic Chemistry – chemistry of aromatics

Amines – reactivity - diazonium salt synthetic utilisation – SN(R)

+ -N2 + H2 O +
Ar N N Ar Ar OH + H

1. NaNO2, H2 SO4, H2O

(CH3)2CH NH2 (CH3)2CH OH
2. H2 O, zahřátí
4-isopropylaniline 4-isopropylphenol (73%)

1. NaNO2, HCl, H2O, 0-5°C

NH2 I
2. KI, ambient temperature

Br Br
2-bromoaniline 1-bromo-2-iodobenzene (72-83%)
 Organic Chemistry – chemistry of aromatics

Amines – reactivity - diazonium salt synthetic utilisation – SN(R)

CH3 CH3
NH2 Cl
1. NaNO2, HCl, 0°C
2. CuCl, 60°C

2-methylaniline 2-chlorotoluene (79%)

Cl Cl
1. NaNO2, HBr, 0°C
2. CuBr, 100°C
NH2 Br
2-chloroaniline 1-bromo-2-chlorobenzene (73%)
 Organic Chemistry – chemistry of aromatics

Amines – reactivity - diazonium salt synthetic utilisation – SN(R)

NH2 CN

1. NaNO2, HCl, 0°C

2. CuCN, NaCN, 50°C

CH3 CH3
4-methylaniline 4-methylbenzonitrile (70%)
+ Δ
Ar N N BF4 Ar F + BF3 + N2

NH2 F

1. NaNO2, H2O,
CH2CH3 2. HBF4 CH2CH3
3. Δ
O O
1-(3-aminophenyl)propane-1-one 1-(3-fluorophenyl)propane-1-one (68%)
 Organic Chemistry – chemistry of aromatics

Amines – reactivity - diazonium salt synthetic utilisation – SN(R)

+ H3PO2
Ar N N Ar H + N2

CH3 CH3

1. NaNO2, HCl, H2O

2. H3PO2, H2O
Br Br
NH2 3-bromotoluene (85%)
2-bromo-4-methylaniline

CH(CH3)2 CH(CH3)2

1. NaNO2, HCl, H2O

2. CH3CH2OH
NO2 NO2
NH2 1-isopropyl-3-nitrobenzene (59%)
4-isopropyl-2-nitroaniline
 Organic Chemistry – chemistry of aromatics

Amines – reactivity - diazonium salt synthetic utilisation – SN(R)

NH2 NH2
Br Br Br Br
Br2 1. NaNO2, H2SO4, H2O
H2O 2. CH3CH2OH

Br Br
2,4,6-tribromoaniline (100%) 1,3,5-tribromobenzene (75%)

OH
O2N N N OH
+ -
+ O2N N2 Cl

4-(4-nitrophenyldiazenyl)-1-naphtol
 Organic Chemistry – chemistry of aromatics

Amines – reactivity - diazonium salt synthetic utilisation – SN(R)

+ +
(CH3)2N H N N (CH3)2N N N
H

-H +

(CH3)2N N N

4-(dimethylamino)azobenzene