NCHE 222

Organic Chemistry II
(B.Sc.)

• Study Unit 3 – Aromatic Chemistry

NCHE222 overview SU3

Structure and Bonds

Organic reaction mechanisms

Aromatic Chemistry

Benzene derivatives

Aromatic nitrogen containing compounds

Aromatic multiple step synthesis

 Aromatic Chemistry

Benzene & Aromaticity Electrophilic Arom. Subst. Nucleophilic Arom. Subst.

(SEAr) (SNAr)

Benzene Mechanisms Mechanisms

MO of benzene Reactions Reactivity

Aromaticity Di- & Tri-substituted

Reactivity and
orientation
 Outcomes

• Know the basic principles of

aromaticity;
• Understand the reaction
mechanisms of electrophilic
and nucleophilic aromatic
substitutions and apply them
to given examples;
• Predict synthesis routes for
di- and tri-substituted
benzenes.
 Benzene & Aromaticity

3.1.1Introduction

3.1.2The structure of benzene

3.1.3The MO of benzene

3.1.4Aromaticity

3.1.5Aromatic ions

3.1.6Heterocyclic aromatic compounds

3.1.7Polycyclic aromatic compounds

3.1.8Determination of aromaticity
3.1.1 Introduction

• Alkenes

• Benzene
3.1.2 Structure of benzene

Lewis-model AO-model
P-orbitals

H H

H H
C = sp2

H H

???

MO-model
3.1.3 MO of benzene

• Remember

C C C C * CCCC * CCCC * C C C C *
2 2 2 2

C C C C * CCCC * C C C C * C C C C *
1 1 1 1

E E E E

C C C C  CCCC  CCCC  C C C C 2
p-atoomorbitale 2 p-atoomorbitale 2 p-ato morbitale 2 p-ato morbitale

C C C C  CCCC  CCCC  CCCC 

1 1 1 1

Molekuul= Grond= Aangeslane Molekuul= Grond= Aangeslane Moleku l= Grond= Aangeslane Moleku l= Grond= Aangeslane
orbitale toestand toestand orbitale toestand toestand orbitale toestand toestand orbitale toestand toestand

p-AO LCAO MO
 3.1.3 MO of benzene

LCAO
Energy
3.1.3 MO of benzene

• Remember

C C C C * CCCC * CCCC * C C C C *
2 2 2 2

C C C C * CCCC * C C C C * C C C C *
1 1 1 1

E E E E

C C C C  CCCC  CCCC  C C C C 2
p-atoomorbitale 2 p-atoomorbitale 2 p-ato morbitale 2 p-ato morbitale

C C C C  CCCC  CCCC  CCCC 

1 1 1 1

Molekuul= Grond= Aangeslane Molekuul= Grond= Aangeslane Moleku l= Grond= Aangeslane Moleku l= Grond= Aangeslane
orbitale toestand toestand orbitale toestand toestand orbitale toestand toestand orbitale toestand toestand

p-AO LCAO MO Node

3.1.3 MO of benzene

Energy LCAO Energy MO

Nodal planes
3.1.3 MO of benzene

Energy LCAO Energy MO

Nodal planes
3.1.3 MO of benzene
 3.1.3 MO of benzene

E E

Nodal planes
3.1.4 Aromaticity

What does aromatic mean?

Is benzene aromatic and why?

• Requirements for aromaticity

– cyclic
– Delocalisation of all p-electrons
– Planar (sp2)
– Obey's Hückel's rule
• (4n+2)p (n = 0,1,2,3…)
 3.1.4 Aromaticity

• Excercise – cyclic
– Delocalisation of all p-electrons
– Planar (sp2)
H H
– Obey's Hückel's rule
• (4n+2)p (n = 0,1,2,3…)
H H

H H

H
H =
H H H
+ H =
H H +
HH H
H H
H H H H
Siklopentadiënielanioon
H
Siklopentadiënielanioon
 Aromatic Chemistry

Benzene & Aromaticity Electrophilic Arom. Subst. Nucleophilic Arom. Subst.

SEAr SNAr

Benzene Mechanisms Mechanisms

MO of benzene Reactions Reactivity

Aromaticity Di- & Tri-substituted

Reactivity and
orientation
 3.2 Electrophilic Aromatic Substitution

3.2.1 Introduction

3.2.2

3.2.3
Nomenclature

Mechanism
SEAr
3.2.4 SEAr Reaction
3.2.5 Disubstituted benzene

3.2.6 Reactivity and orientation

3.2.7 Tri- and poli-substituted benzene

 3.2.1 Introduction

• Electrophilic aromatic substitution (SEAr)

Electrophilic: E+
Aromatic: benzene
Substitution: replace H with E
3.2.2 Nomenclature

Acylation
Nitration

Friedel-Crafts

Alkyation
Sulphonation
Halogenation
3.2.3 Mechanism

Nitration (HNO3, H2SO4)

No reaction

1.
2.

Mechanism = 2-step
1. Generation of electrophile
2. Nucleophilic substitution
 3.2.3 Mechanism

Step 1: Generation of electrophile

Nitration:
HNO3, H2SO4

Sulfonation:
SO3, H2SO4

Alkyation:
RX, AlX3

Acylation:
RCOX, AlX3

Halogenation:
X2, AlX3
3.2.3 Mechanism

Step 2: Substitution

s
3.2.4 SEAr reactions

Nitration Acylation

Friedel-Crafts

Sulfonation Alkyation

Halogenation
3.2.3 Mechanism

Step 1: Generation of electrophile

Step 2: Substitution
 3.2.4 SEAr reactions

Step 1: E+ generation
 3.2.3 Mechanism

Step 2: Substitution
3.2.3 Mechanism

Step 1: Generation of electrophile

Step 2: Substitution
 3.2.4 SEAr reactions

Step 1: E+ generation

ens.
 3.2.4 SEAr reactions

Step 2: Substitution
3.2.4 SEAr reactions

Nitration Acylation

Friedel-Crafts

Sulphonation Alkyation

Halogenation
 3.2.4 SEAr reactions

MXn = AlCl3, FeCl3,

FeBr3, BF3, TICl3,
ZnCl2, SnCl4

Step 1: E+ generation

Step 2: Substitution
 3.2.4 SEAr reactions

MXn = AlCl3, FeCl3,

FeBr3, BF3, TICl3,
ZnCl2, SnCl4

Step 1: E+ generation

Step 2: Substitution
 3.2.4 SEAr reactions

MXn = AlCl3, FeCl3,

FeBr3, BF3, TICl3,
ZnCl2, SnCl4

Step 1: E+ generation

Step 2: Substitution
3.2.5 Di-substituted benzene
 3.2.5 Di-substituted benzene

- ortho (o): E is in the o-position w.t.o. A

- meta (m)
- para (p)
 By the way…

Use and meaning of the word “para” in English:

• Paramilitary Opposite of military

• Parachute Against falling
• Paradox Opposite of opinion
• Paragraph Break in sense
• Paranormal Opposite of normal
• Paradigm Show other side
• Paranoia Irregular mind

• Parasite Eating at another's table

 3.2.5 Di-substituted benzene

- ortho (o): E is in the o-position w.t.o. A chemically equivalent

??
- meta (m)
- para (p) ?
3.2.5 Di-substituted benzene

chemically equivalent

Nee / No
3.2.6 Reactivity and orientation

Influence of A?

influences i) reactivity and ii) orientation

3.2.6 Reactivity and orientation

A influences reactivity of SEAr

Slow reaction
-A = -NO2

Fast reaction
-A = -OH
 3.2.6 Reactivity and orientation

A influences orientation (position) of E

-A = -NO2

-A = -OH
3.2.6 Reactivity and orientation

Why does A influence reactivity & orientation?

3.2.6 Reactivity and orientation

Why?
Energy

NB: Energy of transition state

Reaction coordinates
3.2.6 Reactivity and orientation

How can we reduce energy of transition state?

Reduce effect of + charge

How?
I (inductive) and M (resonance) effect of A
3.2.6 Reactivity and orientation

Where does A have largest impact on + charge?

or
3.2.6 Reactivity and orientation
3.2.6 Reactivity and orientation
Energy

3 resonance

Reaction coordinates
3.2.6 Reactivity and orientation

ortho
3.2.6 Reactivity and orientation
3.2.6 Reactivity and orientation
Energy

o-, m- & p-

Reaction coordinates
3.2.6 Reactivity and orientation
 3.2.6 Reactivity and orientation

I Inductive effect N, O, X = -I effect

-I

+I -I
OH dstabilizes

ortho /
para +I

stabilizing CH3 stabilizes

destabilizing
3.2.6 Reactivity and orientation

M Resonance effect

+M

stabilizing
3.2.6 Reactivity and orientation
Energie / Energy

+M 3 resonance

4 resonance

Reaksie koördinate / Reaction coordinates

 3.2.6 Reactivity and orientation

4 resonance

+M

3 resonance

4 resonance
3.2.6 Reactivity and orientation

+M
Energy

m (3)
o,p (4)

Reaction coordinates
3.2.6 Reactivity and orientation

M Resonance effect

+M

stabilizing

-M

destabilizing
 3.2.6 Reactivity and orientation

3 resonance (1 unstable)
-M

3 resonance

3 resonance (1 unstable)
3.2.6 Reactivity and orientation

unstable

-M
Energy

o,p (3*)
m (3)

3 of which 1 is unstable

Reaction coordinates
 3.2.6 Reactivity and orientation

I Inductive effect
M Resonance effect

+M
+I -I

stabilizing
ortho /
para

-M

stabilizing

destabilizing
destabilizing
3.2.6 Reactivity and orientation

• Activation & Deactivation

I- & M-effect

A A

Nu

A has a +M or +I that dominates Activation

Thus benzene becomes a stronger Nu, and transition state less pos.
3.2.6 Reactivity and orientation

• Activation & Deactivation

I- & M-effek / I- & M-effect

A A

Nu

A has a -M or -I that dominates Deactivation

Thus benzene becomes a weaker Nu and transition state more pos.

 3.2.6 Reactivity and orientation

• Activation & Deactivation

I- & M-effect that dominates

-I +M -I +M

OH has a +M or –I effect: +M dominates Br has a +M or –I effect: -I dominates

 3.2.6 Reactivity and orientation

• Activation & Deactivation

I- & M-effect that dominates

+M -I
-I +M

OH has a +M or –I effect: +M dominates Br has a +M or –I effect: -I dominates

Activation Deactivation
3.2.6 Reactivity and orientation

• o-, m- & p-directing effect

– Only M-effect

A A

Nu

o- & p- 4 resonance
+M o- & p-directing
m- 3 resonance
3.2.6 Reactivity and orientation

• o-, m- & p-directing effect

– Only M-effect

A A

Nu

o- & p- 3 destabilsation m-rigtend

-M m-directing
m- 3 resonance
3.2.6 Reactivity and orientation
+I or +M effect dominates 3.2.6 Reactivity and orientation

-I or -M effect dominates
 3.2.6 Reactivity and orientation

+M effect
+M effect

-M effect
Ortho/para
 3.2.7 Tri-substituted benzene

Rule 1: Activatingstrong > Activatingweak > Deactivating

o,p- / act. o,p- / act.

(weak) (strong)

Rule 2: If both deactivating then o-/p- > m-

o,p- / deact.

m- / deact.
 3.2.7 Tri-substituted benzene

Rule 3: between meta = no reaction

Rule 4: if strengthens = 1 product

o,p- / act.
m- / deact.
 Aromatic Chemistry

Benzene & Aromaticity Electrophilic Arom. Subst. Nucleophilic Arom. Subst.

SEAr SNAr

Benzene Mechanisms Mechanisms

MO of benzene Reactions Reactivity

Aromaticity Di- & Tri-

substituted

Reactivity and
orientation
 3.3 Nucleophilic Aromatic Substitution

3.3.1 Introduction

3.3.2 Mechanisms
SNAr
3.3.1 Introduction

SEAr

Nu

SNAr
?
E
Nucleophilic Aromatic Substitution
3.3.1 Mechanism

SN1 vs SN2
sp2

SN1
X unstable

SN2

sterical hindrance
X
 3.3.1 Mechanism

VS

X How benzene stronger E?

Benzene is a Nu Therefore benzene is a weak E

Why?
 3.3.1 Mechanism

-I effect

Pulls e- away

E
Elimination
2 Mechanisms
• Elimination-Addition

• Addition-Elimination
Addition
3.3.1 Mechanism

3.3.1.1 Elimination-Addition

-HNu

Benzyne Unstable
3.3.1 Mechanism

3.3.1.2 Addition-Elimination

Unstable
3.3.1 Mechanism

Benzene still weak E & unstable transition state

Both reactions not possible as is!

• Elimination-Addition

X
• Addition-Elimination

X
3.3.1 Mechanism

Benzene still weak E & unstable transition state

Both reactions not possible as is!

• Elimination-Addition

Drastic conditions (T,P)

• Addition-Elimination

???
 3.3.1 Mechanism

3.3.1.2 Addition-Elimination

Unstable

Remember
3.3.1 Mechanism

no resonance
Energy

3 resonance

How can we lower energy further?

Reaction coordinates
3.3.1 Mechanism

3.3.1.2 Addition-Elimination

Y = e- withdrawing group (-I / -M effect)

3.3.1 Mechanism

3.3.1.2 Addition-Elimination

On which position?

o m p
3.3.1 Mechanism

3.3.1.2 Addition-Elimination

ortho

Y = e- withdrawing group: -M effect)

3.3.1 Mechanism

no resonance

-M
Energy

3 resonance

4 resonance

Reaction coordinates
3.3.1 Mechanism

3.3.1.2 Addition-Elimination

meta
3.3.1 Mechanism

3.3.1.2 Addition-Elimination

para
3.3.1 Mechanism

ortho meta para

no resonance

-M
Energy

m (3)

o,p (4)

Reaction coordinates
3.3.1 Mechanism

3.3.1.2 Addition-Elimination

Yo,p = e- withdrawing group on o/p-position

3.3.1 Mechanism

Benzene still weak E & unstable transition state

• Elimination-Addition

Drastic conditions (T,P)

• Addition-Elimination
NCHE222 overview SU3

Structure and Bonds

Organic reaction mechanisms

Aromatic Chemistry

Benzene derivatives

Aromatic nitrogen containing compounds

Aromatic multiple step synthesis