12.15 Multiple Substituent Effects

12.15Multiple Substituent Effects

O CH3 CH3 O O CCH3 AlCl3 + CH3COCCH3 CH3 CH3 99% The Simplest Case all possible EAS sites may be equivalent

CH3 CH3 Br Br2 Fe NO2 NO2 86-90% Another Straightforward Case directing effects of substituents reinforceeach other; substitution takes place orthoto the methyl group and meta to the nitro group

Generalization regioselectivity is controlled by themost activating substituent

NHCH3 NHCH3 Br Br2 aceticacid Cl Cl 87% Example strongly activating

CH3 CH3 HNO3 NO2 H2SO4 C(CH3)3 C(CH3)3 88% When activating effects are similar... substitution occurs ortho to the smaller group

CH3 CH3 HNO3 H2SO4 CH3 CH3 NO2 98% Steric effects control regioselectivity whenelectronic effects are similar position between two substituents is lastposition to be substituted

12.16Regioselective Synthesis of Disubstituted Aromatic Compounds

Factors to Consider order of introduction of substituents to ensure correct orientation

Br O CCH3 Synthesis of m-Bromoacetophenone Which substituent should be introduced first?

Br O CCH3 Synthesis of m-Bromoacetophenone If bromine is introduced first, p-bromoacetophenone is major product. para meta

Br O CCH3 O O Br2 CH3COCCH3 AlCl3 O CCH3 Synthesis of m-Bromoacetophenone AlCl3

Factors to Consider order of introduction of substituents to ensure correct orientation Friedel-Crafts reactions (alkylation, acylation) cannot be carried out on strongly deactivated aromatics

NO2 O CCH3 Synthesis of m-Nitroacetophenone Which substituent should be introduced first?

NO2 O CCH3 Synthesis of m-Nitroacetophenone If NO2 is introduced first, the next step (Friedel-Crafts acylation) fails.

O2N O CCH3 O O HNO3 CH3COCCH3 H2SO4 O CCH3 Synthesis of m-Nitroacetophenone AlCl3

Factors to Consider order of introduction of substituents to ensure correct orientation Friedel-Craftsreactions (alkylation, acylation) cannot be carried out on strongly deactivated aromatics sometimes electrophilic aromatic substitution must be combined with a functional group transformation

CO2H CH3 CH3 NO2 Synthesis of p-Nitrobenzoic Acid from Toluene Which first? (oxidation of methyl group or nitration of ring)

CO2H CH3 CH3 NO2 Synthesis of p-Nitrobenzoic Acid from Toluene nitration givesm-nitrobenzoicacid oxidation givesp-nitrobenzoicacid

CO2H CH3 CH3 NO2 Na2Cr2O7, H2O H2SO4, heat NO2 Synthesis of p-Nitrobenzoic Acid from Toluene HNO3 H2SO4

12.17Substitution in Naphthalene

Naphthalene H H 1 two sites possible for electrophilicaromatic substitution all other sites at which substitution can occurare equivalent to 1 and 2 H H 2 H H H H

O CCH3 O CH3CCl EAS in Naphthalene is faster at C-1 than at C-2 AlCl3 90%

EAS in Naphthalene E E H H when attack is at C-1 carbocation is stabilized by allylic resonance benzenoid character of other ring is maintained + +

E + H EAS in Naphthalene when attack is at C-2 in order for carbocation to be stabilized by allylic resonance, the benzenoid character of the other ring is sacrificed E H +

12.18Substitution inHeterocyclic Aromatic Compounds

Generalization There is none. There are so many different kinds of heterocyclicaromatic compounds that no generalizationis possible. Some heterocyclic aromatic compoundsare very reactive toward electrophilicaromatic substitution, others are very unreactive..

N Pyridine Pyridine is very unreactive; it resemblesnitrobenzene in its reactivity. Presence of electronegative atom (N) in ringcauses  electrons to be held more strongly thanin benzene.

SO3H N N Pyridine SO3, H2SO4 Pyridine can be sulfonated at high temperature. EAS takes place at C-3. HgSO4, 230°C 71%

•• •• •• O S N •• •• H Pyrrole, Furan, and Thiophene Have 1 less ring atom than benzene or pyridine to hold same number of  electrons (6).  electrons are held less strongly. These compounds are relatively reactive toward EAS.

O O O CH3COCCH3 Example: Furan undergoes EAS readilyC-2 is most reactive position BF3 + CCH3 O O 75-92%

12.15 Multiple Substituent Effects