Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Products of Nitration CH 3 HNO 3 H 2 SO 4 CN HNO 3 H 2 SO 4 OH HNO 3 H 2 SO 4

63%

CH 3 + NO 2

17%

CN NO 2 +

50%

OH NO 2 + para

3%

NO 2 CH 3 + O 2 N

34%

CH 3 1 hr

81%

CN + O 2 N NO 2

2%

CN 48 hr

0%

NO 2 OH + O 2 N

50%

OH 0.0003 hr

Mechanism of Electrophilic Aromatic Substitution

E + E

H

E

H With a substituent group

G G E + G E

H

G E

H

E

H

G E

H Depending on the nature of the substituent, the substituent

G

may stabilize the carbocation intermediate and therefore speed the reaction , or it may raise the energy of the carbocation and slow the reaction . Substituents that make the ring react faster (than benzene) with electrophiles are called

activators

; those that make the ring react slower (than benzene) are called

deactivators

.

Substituent effects  All activators also direct incoming electrophiles to the

ortho

- and the

para

positions.

 Most deactivators direct incoming electrophiles to the

meta

position. The exceptions are the halogens, which are weakly deactivating yet ortho-para directing.

Classification of Substituents

Benzene NO 2 SO 3 H CO 2 H CHO

more deactivating

NR 3 + CN CR COR O m-directing deactivators O I Br Cl F o,p-directing deactivators R H Ar OR

more activating

NHCOCH o,p-directing activators 3 NH 2 OH

Product Distribution in Nitration

X ortho (Percent %) meta

(meta-directing Deactivators)

para X ortho (Percent %) meta para

(ortho- and para-directing Deactivators)

-N(CH 3 ) 3 -NO 2 -CO 2 H -CN 2 7 22 17 CO 2 CH 2 CH 3 28 -COCH -CHO 3 26 19 89 11 91 2 77 81 2 2 72 72 72 2 2 9 -F -Cl -Br -I 13 35 43 45 1 1 1 1

(ortho- and para-directing Activators)

-CH -OH 3 63 50 3 0 34 50 -NHCOCH 3 19 2 79 86 64 56 54

o,p-Activators (alkyl & aryl groups) CH 3 E CH 3 H CH 3 H CH 3 H E o E E H H 3º, especially stable CH 3 CH 3 CH 3 CH 3 H m E E H E H H E H CH 3 CH 3 CH 3 CH 3 p E H E H E H 3º, especially stable E H H

o m o,p-Activators with a lp of electrons OH E OH H OH H OH H OH H E E E E H H 4 resonance forms OH OH OH OH H E E H E H H E H OH OH OH OH OH p E H E H E H H E H 4 resonance forms

o m o,p-Deactivators (Halogens) Cl Cl Cl Cl E H H E E Cl E Cl Cl E H Cl E H H E E H Cl H E Cl 4 resonance forms Cl Cl Cl Cl p E E H E H E H 4 resonance forms

o meta-directing Deactivators CN E CN H E CN H E CN H E CN CN CN Especially UNSTABLE** CN m CN E H E H E H CN E CN CN p E E H Especially UNSTABLE** E H

Explanation of

meta

deactivators  Meta directors slow the reaction by raising the energy of the carbocation intermediate because they have (in

one resonance form

, shown below) a positively charged atom attached to the ring. Two positively charged atoms so close together is very high in energy (

especially unstable

).

O N O

E

H O O S OH

E

H O C CH 3

E

H N C

E

H

nitro group sulfonic acid ketone nitrile

Summary of Substituent Effects   When the substituent is R (alkyl) or Ar (aryl), the resonance hybrid cation intermediate has three resonance forms. For attack of the electrophile at the

ortho

or

para

positions, one of these is a

3º carbocation

, which is especially stable.

This lowers the energy of the intermediate, thus facilitates (speeds) the substitution reaction at the

o

- and

p

- positions.

When the substituent has a

lone pair of electrons

, such as the halogens, oxygen or nitrogen, the resonance hybrid for attack of the electrophile at the

ortho

and

para

positions has four resonance forms . This lowers the energy of the those intermediates, thus facilitates (speeds) the substitution reaction at the

o

- and

p

- positions.

Summary of Substituent Effects…  When the substituent has a

multiple bond conjugated with the ring

, and the second atom from the ring is more electronegative than the first, the substituent deactivates the ring and directs incoming electrophiles

meta

. It does this by raising the energy of the carbocation intermediates from

ortho

and

para

attack by an electrophile even more than it raises the energy of the intermediate resulting from

meta

attack.

Summary Energy Reactants -

NO 2 or -CO 2 H, ortho- and para -NO 2 or -CO 2 H, meta-

-

Cl or -Br, meta-

-

Cl or -Br, ortho- and para-

-

H (unsubstituted) -R or -Ar, meta- -R or -Ar, ortho- and para- Deactivators Activators -NH 2 or -OH, meta- -NH 2 or -OH, ortho- and para-

[Carbocation Intermediate] Reaction Progress

Additivity of substituent effects in disubstituted aromatic rings  Rule 1: If the directing effects of two substituents reinforce each other, the predicted product predominates.

CH 3 (o,p) CO 2 H (m) HNO 3 H 2 SO 4 CH 3 NO 2 CO 2 H

Additivity of substituent effects…  Rule 2: If the directing effects of two substituents oppose each other, the more activating group dominates, but mixtures often result.

NH 2 (o,p; STRONG activator) Br 2 CH 3 (FeBr 3 cat not needed) (o,p; weak activator) NH 2 Br CH 3

Additivity of substituent effects…  Rule 3: Substitution almost never occurs between two substituents

meta

to each other.

CH 3 (o,p)

X (too crowded)

SO 3 Cl (o,p) H 2 SO 4 CH 3 CH 3 + HO 3 S SO 3 H Cl but not: CH 3 SO 3 H Cl Cl

Additivity of substituent effects…  Rule 4: With a bulky o,p- director and/or a bulky electrophile,

para

substitution predominates.

O OCCH 3 (o,p; BULKY) SO 3 H 2 SO 4 (HSO 3 + is a BULKY electrophile) O OCCH 3 SO 3 H