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Aromatic Chemistry (Level 2)

Pavel Koovsk
E-mail: P.Kocovsky@chem.gla.ac.uk Office: A4-08 Introduction 1. Aromatic Compounds and the Structure of Benzene [Bruice: Ch. 6; McM: Ch. 15] 1.1. Comparison of Alkenes and Aromatic Compounds 1.2. Structure of Benzene 1.3. Aromaticity When is a compound aromatic? Hckel rule. Antiaromaticity. 2. Reactivity of Aromatic Compounds 2.1. Electrophilic Aromatic Substitution [Bruice: Ch. 14; McM: Ch. 16] (a) Bromination/Chlorination (b) Nitration (c) Sulfonation (d) Friedel-Crafts Alkylation (e) Friedel-Crafts Acylation 2.2. Substituent Effects in Electrophilic Aromatic Substitution (a) The effects on reactivity (inductive and resonance effects) (b) The effects on orientation (o/p- and m-directing groups) 2.3. Nucleophilic Aromatic Substitution (a) Mechanism (b) Applications in herbicide chemistry (c) Applications in heterocyclic chemistry 3. Synthesis of Substituted Benzene Derivatives 3.1. Synthetic Strategy 3.2. Electrophilic Substitution of Disubstituted Benzenes 3.3. Modifying Reactivity of Substituted Benzenes 3.4. Aromatic Amines and their Use in Synthesis (a) Amine synthesis (b) Diazonium salts (generatin, reaction with Nucl, Sandmeyer)

Introduction
Aromatic: Originally, aromatic came from aroma of some natural products. Later: aromatic = derivative of benzene Current: aromatic = compound with one or more benzene or benzene-like rings
Examples OH CH3 O2N OH CH3 Benzene Phenol (antiseptic) CH3 NO2 TNT HO Estrone O O O O Piperine (major constituent of black peper) CH3CO2 Heroin N CH3CO2 C2H5O HN CH3 NO2 O O Ecstasy NH2 O

Thymol (mouthwash ingredient)

CH3 N N CH2CH2CH3

O NCH3 O S O N N

CH3

Viagra

1. Aromatic Compounds and the Structure of Benzene


1.1. Comparison of Alkenes and Aromatic Compounds
Difference between alkenes and aromatics: Alkenes (unsaturated aliphatic hydrocarbons) undergo addition reactions to the double bond very rapidly. Aromatic hydrocarbons are more unsaturated yet undergo ionic substitution arather than addition.
Br + Br2 Br C6H10 C6H10Br2 C6H6 C6H5Br + Br2 catalyst Br + HBr

1.2. Structure of Benzene


Benzene is a flat, regular hexagon and bond angles equal 120. There are six sp carbons in the ring. All C-C bonds are the same length which is midway between a single and a double carbon-carbon bond. The six electrons are delocalised around the ring.
H H H H H H H H H H H Draw MO H H H H H H H
2

Benzene is 150 kJ/mol more stable than the calculated value for 'cyclohexatriene'; this is known as the delocalisation energy - its source can be seen from consideration of the molecular orbital diagram for benzene.
6 antibonding 4 5

Energy

bonding

The 150 KJ/mol stabilisation comes from all electrons being in molecular orbitals of lower energy than the p atomic orbitals. The delocalisation energy can be measured by determining the heat of hydrogenation (i.e., how much energy is required to convert benzene into cyclohexane). This delocalisation means benzene is thermodynamically more stable than the hypothetical cyclohexatriene. It is often more convenient to use the Kekul representation:

This is only a representation - benzene is neither of the structures shown above but a single substance in between these two extremes with extensive p-electron delocalisation. The actual structure of benzene is a resonance hybrid of these two canonical forms.

1.3. Aromaticity
When is a compound aromatic? (a) Experimentally: the molecular formula suggests a high degree of unsaturation (double bonds etc.) but the compound does NOT undergo addition reactions (b) Theoretically: the molecule has a flat, cyclic structure with uninterrupted clouds of delocalised electrons above and below the plane. There must be 4n+2 electrons in the delocalised clouds where n is any integer (0,1,2,3.... AND NOT the number of rings) - in other words there must be 2,6,10,14..... electrons (Hckel's Rule). Compounds with 4n electrons CANNOT be aromatic but may be cyclic and conjugated.
Examples benzene 6 electrons 4n + 2 (where n = 1), therefore aromatic planar

pyrrole

N H cyclooctatetraene

..

4 electrons + 2 electrons of the lone pair 4n + 2 (where n = 1), therefore aromatic planar 8 electrons 4n (where n = 2), therefore not aromatic non-planar

cyclobutadiene

4 electrons 4n (where n = 1), planar, but antiaromatic [appl. Hund rule]

Energy 6 antibonding 4 4 5 nonbonding 2 bonding 2 3 1 Cyclobutadiene 3

. . .

. . .

MO levels for a polygonal molecule

1 Benzene

5
Q: Which of the following structures are aromatic?

H H

H H

H H O S N N H

2. Reactivity of Aromatic Compounds


2.1. Electrophilic Aromatic Substitution
[Bruice Sec 14.3] Despite delocalisation, the electrons of an aromatic compound are available to electrophiles (reagents seeking electrons). However, since the electrons are delocalised, a more reactive electrophile is often required (compared with an alkene). (a) Bromination [Sec 14.4] Add Br2 to benzene - no reaction! But add Br2 to a mixture of benzene and FeBr3 (a Lewis acid) and HBr is evolved and bromobenzene is formed.
Br + HBr bp 156 oC

+ Br2 bp 80 oC

FeBr3

Mechanism of bromination FeBr3 is a Lewis acid and it complexes with a bromine molecule to increase its electrophilicity. + Polarised bromine is the source of "Br ". (You may consider it as displacement of FeBr 4

from Br2FeBr3 complex by two electrons of the benzene ring). + Br (or its equivalent) forms a new bond to the ring using two of the electrons of the benzene ring. FeBr4- then acts as a base by abstracting a proton from the -complex. The two electrons from the C-H bond go back in to the ring and regenerate the delocalised -system.

Br Br ..

..

weak electrophile H H H H -complex


+

NB: Addition of Br- to the -complex is not favoured because the electron delocalisation (aromaticity) would be lost.
Generalisation and stereochemical view of aromatic electrophilic substitution (E = Electrophile, B = Base) E+ E H H H H B

..

FeBr 3

Br Br FeBr 3 strong electrophile FeBr 3 H H


+

Br Br H H

H H fast H H Br + HBr + FeBr3 H

Br [FeBr4]

slow

H H

H -complex

E H

+ HB

C C Energy H + G Alkene + Br2 H G + Br TS1 Br + H + +

Br

Br TS2 Br Br

-complex (intermediate)
G o Br + HBr

+ Br2

Transition State 1: The C-Br is forming as the aromaticity within the ring is being lost. Intermediate -complex: The C-Br bond is now fully formed and the carbon with H and Br 3 2 attached is sp -hybridised; the positive charge is delocalised over the remaining five sp carbon atoms, wich stabilises the intermediate. + Transition State 2: The C-H bond begins to break as H is lost from the intermediate, which results in the formations of the aromatic product (restoring aromaticity). The alternative addition of bromine in the second step (the blue pathway) does not restore aromaticity (the product would be much higher in energy).

Notes: G is the activation energy; it is reduced when an activating substituent is present and increased when a deactivating substituent is present. Compare the G for benzene with that of an alkene. (b) Chlorination and Iodination Use Cl2/FeCl3 or Cl2/AlCl3 for chlorination and I2/CuI2 or I2/CuCl2 for iodination - analogous to bromination. Chlorination is used in the synthesis of a number of pharmaceutical agents, including the tranquilizer diazepam (Valium).
CH3 N Cl N O

(c) Nitration [Bruice: Sect 14.5]


HNO3 H2SO4

NO2

Mechanism O HO N+ O H2SO4 H2O - HSO 4 Overall: O N+


+

O
+

O N+ - H 2O O NO2+ + H3O+ + 2 HSO4 NO2 - H2O

N+ O

HNO3 + 2 H2SO4 H
+

N O

Nitroderivatives synthetic avenue to aromatic amines (industrial dyes, pharmaceuticals)


SnCl2, H3O+ or NO2 Fe, H+ or H2/Pt NH2

8 (d) Sulfonation [Bruice: Sect 14.6]


SO3 H2SO4

SO3H

Mechanism O O S
+

O H2SO4 O - HSO4 O OH S
+

S+ O

OH
+

H
+

O OH - H2O

SO3H

S O

("Fuming" H2SO4: contains 1-30% SO3

Use: Sulfonamides (first useful antibiotics) and synthesis of phenols (Ar-OH)


O S H2N Sulfanilamide O
+

SO3H NH2 CH3

1. NaOH, 300 oC 2. H3O+ CH3

OH

p-cresol (a phenol)

(e) Friedel-Crafts Alkylation


AlCl 3 CH2CH3 + HCl No reaction: Cl Cl

CH2CH3 Cl

Mechanism CH2CH3 Cl AlCl 3


+ +

CH2CH3 AlCl 4 H

AlCl 4

SO3H + HCl + AlCl3

CH2CH3

Other options H3C H3C H3C H3C H3C or OH H+ H+ CH2 + H2SO4 C(CH3)3

Works well when a tertiary carbocation is generated

9
Appliaction C6H6 HF Linear alkene (available from petroleum industry) 1. H2SO4 / SO3 (sulfonation) 2. NaOH (neutralisation) SO3Na+

detergent

Problems: One akylation makes the benzene ring more reactive to Friedel-Crafts alkylation; hence, mixtures of multiply-alkylated products are often formed. Use of primary halides often results in the formation of product mixtures owing to the o o o rearrangement to a more stable cation (remember the stability: 3 > 2 > 1 ). (f) Friedel-Crafts Acylation Acyl group = RCOO O + CH3 Cl AlCl 3 CH3 + HCl

Mechanism O R Cl AlCl 3
+ + .. R C O ..

R C O .. H

AlCl4 O CH3 + HCl + AlCl3

AlCl 4 O

2.2. Substituent Effects in Electrophilic Aromatic Substitution


Toluene (methylbenzene) can be nitrated 25 times faster than benzene, whereas nitrobenzene is 6 nitrated 10 times more slowly than benzene. Implies - CH3 is an activating group NO2 is a deactivating group Substituents on a benzene ring can be classified into two groups: 1. Those that activate the ring - i.e., increase the reactivity of the benzene ring (e.g., NH2, OH, OCH3, CH3, C6H5). 2. Those that deactivate the ring - i.e., decrease the reactivity of the benzene ring (e.g., Cl, CO2Et, NO2)

10 As a result, when benzene is subjected to nitration, only one mono-substituted product (nitrobenzene) is formed (nitrobenzene is not further nitrated under mild conditions). By contrast, when toluene (methylbenzene) is nitrated, we can expect formation of mono-, di- and even tri-nitro products. Substituents also effect the position of substitution:
CH3 HNO3 H2SO4 20 oC CH3 NO2 + NO2 ortho Statistically expected: Experimentally found: NO2 HNO3 H2SO4 90 oC 40 62 NO2 NO2 + NO2 ortho Experimentally found:
+

CH3 +

CH3

meta 40 5 NO2 +

NO2 para 20 33 NO2

meta 93.2

NO2 para 0.3

6.5

Methyl group - directs the electrophile (NO2 ) mainly to the ortho and para positions Nitro group - directs mainly to meta position Reactivity and orientation are connected - both are a matter of relative reaction rates. Thus, CH3 makes the ring react slightly faster than benzene at all 5 positions but makes ortho and para positions on the ring react faster than meta. - therefore ortho and para products predominate (energy of TS and intermediate lower than for benzene). Nitro group makes ring react significantly slower than benzene at all 5 positions but the reaction at ortho and para positions is slower than meta position - therefore meta product predominates (energy of TS and intermediate higher than for benzene) Reaction rate is determined by rate of the slowest step, i.e., attack of electrophile on ring. If substituent X can release electrons into the ring this will help to stablise the positive charge developing in the ring. The energy of the intermediate will be lower, so that less activation energy will be required the reaction will be faster. If substituent that withdraws electrons from the ring this will destabilise the positively charged intermediate and hence make the activation energy higher and therefore the reaction slower.

11
Reactivity NH2 OCH3 CH3 F Br CH=O CO2H SO3H NO2

OH

NHCOCH3 C6H5 H

Cl I

CO2CH3

COCH3 CN deactivators m-directing

N+R3

activators o- / p-directing Inductve effect CH3

deactivators o- / p-directing Cl NO2

Resonance effect

.. H O

..

.. H O

.. H O

.. H O or

+ .. H O o- / p

.. Cl

+Cl

..

+ Cl

..

+ Cl

..

.. + Cl or
..

.. ..

..

..

..

o- / p-

+ or +

+ m-

Note: Resonance effect is stronger than inductive effect

Examples OH Br2 Br OH Br or Br Compare with: CH3 Br2 FeBr3 Br CH3 Br + NH2 Br2 Br NH2 Br

Br CH3

Inductive effect is weaker - need for catalyst - monobromination

12

2.3. Aromatic Nucleophilic Substitution


(a) Mechanism
Unlike benzyl chloride, chlorobenzene does not undergo nucleophilic substitution. Nu Cl Nu Cl SN2 not possible (steric hindrance) SN1 difficult (very high in energy)
Nu:

Cl

benzyl chloride

chlorobenzene

Instead, addition-elimination mechanism in activated systems (recall Michael addition)


Nu X NO2 NuX O N+ O O NO2 NO2 N O O NO2 Meisenheimer complex O N X Nu Nu
X O N+

Nu O - X NO2 NO2

(b) Applications in Herbicide Chemistry


Cl2 AlCl 3 Cl Cl Cl Cl Cl-CH2CO2Na OCH2CO2H Cl Cl Cl Cl 2,4-D Cl 2,4,5-T Cl OCH2CO2H HCl Cl Cl OCH2CO2Na Cl NaOH Cl Cl O Na+ heat Cl Cl O O Cl Cl

2,3,7,8-Tetrachlorodioxin (toxic!)

A mixture of 2,4,5-Trichlorophenoxyacetic acid (2,4,5-T) and 2,4-dichlorophenoxyacetic acid (2,4D) was used as a large-scale defoliant (Agent Orange) in the Vietnam war. (c) Applications in Heterocyclic Chemistry
Nu N Cl
_ _

Cl Nu

Cl

Nu

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3. Synthesis of Substituted Benzenes


3.1. Synthetic Strategy
Use retrosynthetic analysis: Tend to think backwards from product to starting material (use disconnections), e.g.:
Cl + "can be made from" Cl+

Example 1: Chloronitrobenzenes
p-Nitrochlorobenzene Cl C-N Cl C-Cl Note: Cl is o- / p-directing, hence the plan is good

NO2 Compare:

Cl C-Cl Note: NO2 is m-directing, hence the plan is bad NO2 NO2

m-Nitrochlorobenzene Cl C-Cl NO2 Compare: Cl C-N NO2 Actual synthesis Cl Cl2 FeCl3 NO2 HNO3 H2SO4 HNO3 H2SO4 Cl NO2 + 30% Cl2 FeCl3 heat NO2 NO2 60% Cl NO2 Note: Cl is o- / p-directing, hence the plan is bad NO2 C-N Note: NO2 is m-directing, hence the plan is good

Cl

14

Example 2: Nitrobenzoic Acids


CO2H HNO3, H2SO4 NO2 meta CH3 HNO3, H2SO4 CH3 NO2 + 62% KMnO4 CO2H NO2 + NO2 para CO2H Note: NO2 is stable to oxidation as it is at its highest oxidation level NO2 33% Separation by distillation CH3 CO2H Note: o- / p-iomers are not accessible directly

ortho

3.2. Electrophilic Substitution of Disubstituted Benzenes


With disubstituted benzenes, substituent can either work together or agains each other (i.e., both direct to the same position or attempt to direct to different positions).
OCH3 CH3 CH3 NO2 CH3 CH3 CH3O is a more powerful activator NO2 reinforcing groups reinforcing groups O - o- / p- director determines orientation - a mixture formed in this case OCH3

15

3.3. Modifying Reactivity of Substituted Benzenes


Problem: How to prepare p-bromoaniline, knowing that aniline only gives the tris-brominated product; note that bromination of aniline does not stop at the monobrominated stage and cannot be moderated by using only one equivalent of bromine.
NH2 Br2 NH2 + Br aniline NH2 Br Br 2 NH2 Br Br + NH2 Br Br2 Br NH2 Br

Br cannot be isolated

Br

Solution: Moderating the activity of NH2 O NH2 CH3 O O O CH3 HN CH3 Br2 HN O CH3 OH heat Br The activating influence of NH2has been reduced due to competing withdrawal of N-lone pair by carbonyl group: .. HN O CH3 Br
+

NH2

O HN CH3

3.4. Aromatic Amines and their Use in Synthesis


(a) Amine Synthesis Reduction of Ar-NO2 (with 6 e and 6 H ).
SnCl2, H3O+ or NO2 Fe, H+ or H2/Pt NH2
+

Chemical reduction is carried out in an acidic medium. The amine product is basic and + therefore the salt is actually formed (C6H5NH3 Cl ). The free amine can be obtained by neutralising the salt with alkali.

16

(b) Diazonium Salts Formation


NaNO2 HCl (dil.) 0 C
o +

NH2

N Cl

Overall: C6H5NH2 + HNO2 + H+ C6H5N2+ + 2 H2O

diazonium salt (water soluble, stable at low temp.)

Reactions with Nucleophiles


Reaction with KI NH2 O2N Hydrolysis to phenols NH2 CH3 NaNO2 H2SO4 (dil.) 0 oC N
+

NaNO2 H2SO4 (dil.) 0 oC O2N

N HSO4

N KI O2N I

non-nucleophilic anion N HSO4 H2O heat OH CH3

CH3

Replacement with Cl, Br, CN (Sandmeyer Reaction) NaNO2 HBr (dil.) Cl NH2 Cl NaNO2 HCl (dil.) N
+

Cl

N Br N Cl CuCN 60 oC N

N CuBr 60 oC CuCl 60 oC Cl Cl Cl Br

Cl

NaBH4

Cl

H3O+ heat

Cl

CO2H