Ch 16 Synthetic Strategies

I. Reactions of Disubstituted BenzenesA. The strongest activator wins

1) Ortho/para directors generally activate the ring, so these substituents should control the reactivity instead of a deactivation meta director

2) Steric considerations also play a role, especially when more than one location is equivalent by activation

B. Guidelines for predicting where a third substituent will go

1) The most powerful activator has primary control

OH

CH3

CH3

NO2

COOH

NH2

OCH3

Br

2) Substituent groups have been ranked

a) Group I = NR2, OR = most powerful activators

b) Group II = X, R

c) Group III = all of the other deactivators

d) I ~ I > II ~ II > III ~III

3) Ortho attack to a bulky group, or attack between 2 substituents is unlikely

Br

Br

CH3

CH2CH3

OCH3

OCH3

COOH

NO2

COOH

COOH

CH3

C(CH3)3

CH3

Cl OCH2CH3

OCH3 SO3H

SO3H

4) The same rules apply for higher substituted benzenes

II. Synthetic Strategies for Substituted BenzenesA. Reversibly Interchanging meta and ortho/para directors

1) Nitro (meta) and Amino (ortho/para) Interconversions

2) How could we prepare m-bromoaniline?

CH3

NH2

CH3

CH3

NO2

COOH

NH2

COOH

Br

Br

C(CH3)3

CH3

CH3

NO2 NH2Zn(Hg), HCl orH2, Ni orFe, HCl

CF3COOH

ONH2

Br

3) Use the NH2/NO2 interconversion:

4) Alkanoyl (meta) and Alkyl (ortho/para) Interconversion

NH2 NH2

Br

NH2

Br

Br Br

NO2

Br

NO2

Br2, FeBr3HNO3

H2SO4+ +

NO2 NO2

Br

NH2

Br

HNO3

H2SO4

Br2

FeBr3

FeHCl

CR

O

CH2RH2, Pd, EtOH orZn(Hg), HCl,

CrO3, H2SO4, H2O

5) How can we prepare m-chloroethylbenzene?

6) Use reduction of alkanoyl groups to give monosubstituted alkylbenzenes

B. Friedel-Crafts Electrophiles Don’t Attack Deactivated Benzenes

NO2 deactivates ring; electrophile not strong enough to react

O O

Cl

CH2CH3

Cl

CH3COClAlCl3

Cl2FeCl3

H2, PdEtOH

O

AlCl3HClZn(Hg)

Cl

O

O CH3

NO2

1. CH3COCl, AlCl3

2. H+, H2O3. HNO3, H2SO4

1. HNO3, H2SO4

2. CH3COCl, AlCl3

3. H+, H2O

C. Use of Reversible Sulfonation for Ortho Disubstitution

1) Para products are usually major when substituting a o,p directed benzene

2) We can block the para position with a sulfonate group. Steric bulk will lead to the para product as major

3) Nitration will then occur only at the original ortho site (meta to NO2) and deprotection yields the desired ortho product

C(CH3)3C(CH3)3

NO2

C(CH3)3

NO2

+HNO3, H2SO4

16%

73%

C(CH3)3C(CH3)3

SO3H

SO3, H2SO4

C(CH3)3

SO3H

HNO3, H2SO4

C(CH3)3

SO3H

NO2H+, H2O,

C(CH3)3

NO2

D. Moderation of Highly Activating Groups

1) NH2 and OH substituents “overactivate” benzene to multiple substitutions

2) The NH2 and OH groups can also react with electrophiles themselves

3) Amine moderation can be had through an acetyl protecting group

4) Phenols can be protected as the methyl ether

5) Di- or polysubstitution won’t occur with the less-activated derivatives

NH2 HN CH3

O

OH OCH3CH3COClpyridine

OH-, H2O

NaOH, CH3I

HI

CH3COClpyridine

NH2 NH2

NO2

HN CH3

O

HN CH3

O

SO3H

HN CH3

O

SO3H

NO2SO3

H2SO4 1. H+, H2O

2. OH-, H2O

HNO3

H2SO4

III. Polycyclic Aromatic Hydrocarbon ReactionsA. Naphthalene

1) Naphthalene undergoes electrophilic aromatic substitution very easily

2) Substitution is selective for C-1

3) Resonance forms determine higher reactivity at C-1

a) C-1 attack has 2 resonance structures with benzene rings

b) C-2 attack has only 1 resonance structure with a benzene ring

c) The most stable intermediate (C-1 attack) gives faster reaction

Br2

CCl4

Br

75%

HNO3

CH3COOH

NO2

major

12

3

44a

56

7

88a NO2

+

B. Electrophilic Attack of Substituted Naphthalenes

1) The ring carrying the substituent is most affected

a) Activating group puts the next substituent on the same ring

b) Deactivating group puts the next substituent on the other ring

E H E H E H E H E H

HHHHH

OH

HNO3

H2SO4

OH

NO2

OH

NO2

+

major

2) C-5 and C-8 are the preferred sites for deactivating groups

C. Larger PAH’s

1) Use resonance structures to predict substitution

2) Phenanthrene is monosubstituted preferentially at C-9

NO2

HNO3

H2SO4

NO2NO2 NO2

NO2

+

30%60%

1

2

34

56

7

8

9

10

E+

EH

EH

D. Carcinogenic PAH’s

1) Benzo[a]pyrene is a carcinogen

2) Many carcinogens are alkylating groups that alkylate DNA. This can lead to proliferating (cancerous) cells

OOH

HO

HOOH

NH

NH

N

N

N

O

DNA

HO

O

OH

oxidase hydratase

oxidase DNA-G

Br Br

OClCH2OCH3

dibromoethane oxacyclopropane chloromethoxymethane