1

more aromatic chemistry

� Aromatic substitution

� Electrophilic

� Nucleophilic

� Addition-Elimination Mechanism

� Benzyne Mechanism

� Other ring reactions

� Side-chain reactions

2

Benzyne Mechanism� Reactant is halobenzene with no

electron-withdrawing groups on the ring.

� Use a very strong base like NaNH2.

=>

Benzyne Intermediate

=>

3

Chlorination of Benzene

� Addition to the benzene ring may occur with high heat and pressure (or light).

� The first Cl2 addition is difficult, but the next 2 moles add rapidly.

� The product, benzene hexachloride, is an insecticide.

=>

Catalytic Hydrogenation

� Elevated heat and pressure is required.

� Possible catalysts: Pt, Pd, Ni, Ru, Rh.

� Reduction cannot be stopped at an

intermediate stage.

=>

CH3

CH3

Ru, 100°C

1000 psi3H2,

CH3

CH3

4

Reduction of Aromatic Compounds

� Aromatic rings are inert to catalytic hydrogenation under

conditions that reduce alkene double bonds

� Can selectively reduce an alkene double bond in the presence of an aromatic ring

� Reduction of an aromatic ring requires more powerful

reducing conditions (high pressure or rhodium catalysts)

Birch Reduction: Regiospecific

� A carbon with an electron-withdrawing group is reduced.

� A carbon with an electron-releasing group is not

reduced.

C

O

OH Na, NH3

CH3CH2OH

C

O

O

H

_

OCH3 Li, NH3

(CH3)3COH, THF

OCH3

=>

5

Birch Mechanism

=>

Side-Chain Oxidation� Alkyl side chains can be oxidized to CO2H by strong

reagents such as KMnO4 and Na2Cr2O7 if they have a C-H next to the ring

� Converts an alkylbenzene into a benzoic acid,

ArR → ArCO2H

6

Side-Chain Oxidation� Alkylbenzenes are oxidized to benzoic acid

by hot KMnO4 or Na2Cr2O7/H2SO4.

CH(CH3)2

CH CH2

KMnO4, OH-

H2O, heat

COO

COO

_

_

=>

Side-Chain Halogenation

� Benzylic position is the most reactive.

� Chlorination is not as selective as

bromination, results in mixtures.

� Br2 reacts only at the benzylic position.

=>

CHCH2CH3

Br

hνBr2,

CH2CH2CH3

7

Side-Chain Halogenation

� Reaction of an alkylbenzene with N-bromo-succinimide (NBS) and benzoyl peroxide (radical initiator) introduces Br into the side chain

SN1 Reactions

� Benzylic carbocations are resonance-

stabilized, easily formed.

� Benzyl halides undergo SN1 reactions.

CH2BrCH3CH2OH, heat

CH2OCH2CH3

=>

8

SN2 Reactions� Benzylic halides are 100 times more

reactive than primary halides via SN2.

� Transition state is stabilized by ring.

=>

Nitrobenzenes: Precursors to Anilines

� Nitric acid destroys alkenes through [O]

� In sulfuric acid, nitric acid reacts with benzene giving nitrobenzene

� Nitrobenzene may be reduced to aniline

� Aniline useful precursors to many industrially important organic compounds

NO2

NH2SnCl2/acid

9

Important Anilines

NH2

O

O Et

NH2

O

O NEt2

CH3

CH3

NH

O

NEt2

benzocaine procaine

lidocaine

Aromatic Dyes

� William Henry Perkin, Age 17

(1856)

� Undergraduate student in

medicine

� Reacted aniline with potassium

dichromate obtained a black

tarry mess

� Attempting to synthesize

quinine and instead discovered

how to make mauveine, a

purple dye - the first industrial

organic fine-chemical

http://www.ch.ic.ac.uk/motm/perkin.html

10

Aromatic Dyes

� Isolated

� Mauve - a purple color

� Dyed white cloth

� Patented material and process

� First chemical company

CH3

NH N

N

NH2

CH3

Some Aniline Chemistry

� Anilines readily react with

nitrous acid

� Diazonium salts

� Coupling reaction giving

an azo compound

� Dyes and sulfa drugs

NH2

N2

HONO

+

aryl diazonium salt

N2

X

NN

+

aryl diazonium salt

activated ring

azo compound

11

Aniline ChemistryH

I

CN

OH

N2+

H3PO3

N2+

NaI

N2+

KCN/CuCN

N2+

Cu2O/Cu(NO3)2

Phenols

� A phenol is a hydroxyl group directly bonded to a a

benzene ring.

OH OH OHOH OH

CH3

OH

OH

OHphenol

m-cresol3-methyl phenol

catechol1,2-benzenediol

resorcinol1,3-benzenediol hydroquinone

1,4-benzenediol

12

Phenols

� Phenol is a low melting solid that is soluble in water.

� It has antiseptic properties and was used in the 19th century in surgery. Its medical use is now limited as derivatives with fewer side effects have become available

� Phenols are found in coal tar as well as the cresols (o,m,p).

Some important phenols:

OH

H3C

CH

CH3

CH3

2-isopropyl-5-methylphenol

(Thymol an oil in thyme leaves)

OH

CHO

O

CH3

4-hydroxy-3-methoxybenzaldehyde

(Vanillin an important constituent of the vanilla bean)

Modern antiseptic phenols:

OH

OH

OH

H2C

O

CH3

CH

CH2

Eugenol

Hexylresorcinol

OH

OH

Urishol

Urishol is the active oil

ingredient in poison ivy.

Removing an OH gives a

lysol, a useful antiseptic.

13

Acidity of Phenols• Phenols and alcohols both contain hydroxyl groups however they

are classified as separate functional groups.

• Phenols have different properties than alcohols, most noteworthy is

their acidity (pKa difference of 106)

OH O

+ H2O + H3O+ pKa = 9.95

H3C

H2C

OH + H2O H3C

H2C

O+ H3O+ pKa = 15.9

Solutions of alcohols in water are neutral, whereas a solution of

0.1 M phenol is slightly acidic (pH 5.4).

• Why are phenols more acidic?

Resonance. The charge is delocalized around the ring.

O O O O

m-cresol and p-cresol are weaker acids than phenol with pKa’s

of 10.01 and 10.17 respectively.

OH OH

CH3CH3

m-cresolp-cresol

14

Alkyl groups decrease the acidity of phenol

halogens increase the acidity of phenol

O

CH3

Electron donating alkyl group destabilizesthis resonance structure

OH

X

X = F, Cl, Br

X

O

Electron withdrawing halogen groups stabilize the delocalized negative charge

Chlorine < fluorine < bromine < chlorine.

OH

Cl

m-chlorophenol

pKa = 8.85

OH

CH3

p-cresol

pKa = 10.17

Influence of substituents on the acidity of phenol

Nitro groups increase acidity by both inductive and resonance

effects. OH OH OH

NO2

NO2phenolpKa = 9.95

m-nitrophenolpKa = 8.28 p-nitrophenol

pKa = 7.15

p-Nitrophenol is more acidic than m-nitrophenol,

O

NOO

O

NOO

Delocalization of negative charge ontoocygen futher increases the resonancestabilization of the phenoxide ion

OH

NO2O2N

NO2

picric acid2,4,6-nitrophenol

pKa = 0.38

15

Acid-Base Reactions of PhenolWhen reacted with strong bases phenols are deprotonated to give

water-soluble salts. Phenols will not react with weak bases such as

sodium bicarbonate.

OH

+ NaOH

O

+ H2O (pKa = 15.7)

Na+

pKa = 9.95stronger acid

weaker acid

OH

+ NaHCO3

O

+ H2CO3 (pKa = 6.36)

Na+

pKa = 9.95weaker acid

stronger acid

OH

OH

CH3

NaOH+

dissolved in ethyl ether

ether

OH

O-Na+

CH3

evaporation

OH

+ H+

OH

CH3

Separation of alcohols from phenols

16

Preparation of Aryl EthersAryl ethers can be prepared from phenoxide salts and alkyl halides.

The opposite case is not true (aryl halides are not good leaving

groups).

The phase transfer catalyst transports the phenoxide anion into the

organic layer.

OH

+

NaOH, H2O

CH2Cl2

Bu4N+Br-

OCl

• Anisole can be formed from phenol plus a methylating agent, CH3I

or dimethyl sulfate.

OH

+

NaOH, H2O

CH2Cl2

Bu4N+Br-

OCH3

O S O

O

O

CH3H3C + +Na-O S O-Na+

O

O

dimethyl sulfate

anisole

17

• Aryl ethers can be cleaved by hydrohalic acids, HX, to form

alkyl halides and phenol.

O

+ HBr

OH

+ Br

Kolbe Carboxylation; Synthesis of Salicyclic Acid

•This industrial method is called the high-pressure carboxylation

of sodium phenoxide.

OHNaOHH2O

O OH

O-Na+

O

CO2

H2O

OH

OH

O

HCl

H2Osalicylic acid

O O

C

O

O

O-

O

H

OH

O-

Oketo-enoltautomerism

Mech:

18

1,4-diketones� Some reactions like aliphatic alcohols:

� phenol + carboxylic acid → ester

� phenol + aq. NaOH → phenoxide ion

� Oxidation to quinones: 1,4-diketones.

OH

CH3

Na2Cr2O7, H2SO4

CH3

O

O

=>

hydroquinones

19

Quinones

� Hydroquinone is used as a developer for film. It reacts with light-

sensitized AgBr grains, converting it to black Ag.� (http://video.uni-regensburg.de:8080/ramgen/Fakultaeten/Chemie/Org_Chemie/Demonstrationsexperimente/benzoquinone_0.rm)

� Coenzyme Q is an oxidizing agent found in the mitochondria of

cells. =>

20

hydroquinone

2e(–)

Quinone + 2H(+) Hydroquinone

–2e(–)

The SkinSilk Color Restoration step

includes a Skin "Bleach" Cream

formulated using the innovative ingredient Hydroquinone 2.0%

Orto-ElectrophilicSubstitution of Phenols

� Phenols and phenoxides are highly reactive.

� Only a weak catalyst (HF) required for Friedel-

Crafts reaction.

� Tribromination occurs without catalyst.

� Even reacts with CO2.

O_

CO2, OH-

O

C

O

O_

_

H+

OH

C

O

OH

salicylic acid

=>

21

Biological Halogenation

� Accomplished during biosynthesis of

thyroxine

OH

NH3H OH

NH3H

I

I

CO2-

+

tyrosine

thyroid peroxidase

CO2-

+

Hydroxylation

� Ipso-substitution

� Direct hydroxylation is difficult in lab

� Indirect method uses sulfonic acid

SO

O

OH OH1. NaOH

2. 300 oC

phenol

22

Biological Hydroxylation

� Coenzyme necessary

O

O

OH

O

O

OH

OHO2

o-hydroxyphenylacetate-3-hydroxylase

FADH2

Biological Alkylations� No AlCl3 present

� Utilizes an organodiphosphate

� Dissociation is facilitated by Mg+2

� Important reaction in biosynthesis of Vitamin K1

OR P O P O

OO

O O

Mg+2

R+

23

Oxidation of Benzene

� Toluene is readily oxidized by reagents

� Benzene is inert to oxidizing agents

� Benzene is toxic to humans

� Benzene is a suspected carcinogen

� Cytochrom P

� strong oxidant in Liver

� Primary detoxification process used

Proposed Chemistry

CH3

CO2H

O

O

O

[O] in liverwater soluble

Toluene is non-toxic

Benzene is toxic

[O] in liver triepoxidelipid solublemutagen

24

Biological Oxidations of Side Chains

� Biosynthesis of norepinephrine

OH

OHNH

2

OH

OHNH

2

OHH

enzyme

enzyme = dopamine-beta-monooxygenase