Electrophilic Aromatic Substitution Multiple Substituent Effects: Activation-Deactivation / Direction (Regio-selectivity) 1

Activation & all possible sites are equivalent The Simplest Case Activation & all possible sites are equivalent CH3 O AlCl3 CH3COCCH3 + CH3 CCH3 99% 2

Another Straightforward Case CH3 NO2 CH3 NO2 Br 86-90% Br2 Fe directing effects of substituents reinforce each other; substitution takes place ortho to the methyl group and meta to the nitro group 2

regioselectivity is controlled by the most activating substituent Generalization regioselectivity is controlled by the most activating substituent 6

Question Which positions are activated for chlorination on the compound shown below? A) 2 and 3 B) 1 and 3 C) 2 and 4 D) 1 and 4

Example strongly activating NHCH3 Cl Br2 87% acetic acid NHCH3 Cl Br 2

When activating effects are similar... CH3 C(CH3)3 CH3 C(CH3)3 NO2 HNO3 H2SO4 88% substitution occurs ortho to the smaller group 5

position between two substituents is last position to be substituted Steric effects control regioselectivity when electronic effects are similar CH3 HNO3 H2SO4 98% NO2 CH3 position between two substituents is last position to be substituted 5

Question Which compound undergoes electrophilic aromatic substitution with (CH3)3CCl and AlCl3 at the slowest rate (or not at all)? A) B) C) D) CH3

Regioselective Synthesis of Disubstituted Aromatic Compounds 7

Synthesis of m-Bromoacetophenone Which substituent should be introduced first? CCH3 O 8

Synthesis of m-Bromoacetophenone para If bromine is introduced first, p-bromoacetophenone is major product. CCH3 O meta 8

Synthesis of m-Bromoacetophenone AlCl3 CCH3 O Br O CH3COCCH3 CCH3 O AlCl3 8

order of introduction of substituents to ensure correct orientation 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 6

Synthesis of m-Nitroacetophenone Which substituent should be introduced first? CCH3 O 8

Synthesis of m-Nitroacetophenone If NO2 is introduced first, the next step (Friedel-Crafts acylation) fails. CCH3 O 8

Synthesis of m-Nitroacetophenone HNO3 H2SO4 CCH3 O O2N O CH3COCCH3 CCH3 O AlCl3 8

order of introduction of substituents to ensure correct orientation 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 sometimes electrophilic aromatic substitution must be combined with a functional group transformation 6

Question Which of the following is the most reasonable way to begin an effective synthesis of the compound shown? A) Treat benzene with isopropyl chloride and AlCl3. B) Treat chlorobenzene with propene and AlCl3. C) Treat benzene with 2-chloropropene and AlCl3. D) Treat benzene with 3-chloropropene and AlCl3.

Synthesis of p-Nitrobenzoic Acid from Toluene CO2H CH3 Which first? (oxidation of methyl group or nitration of ring) NO2 CH3 8

Synthesis of p-Nitrobenzoic Acid from Toluene CO2H nitration gives m-nitrobenzoic acid CH3 NO2 CH3 oxidation gives p-nitrobenzoic acid 8

Synthesis of p-Nitrobenzoic Acid from Toluene NO2 CO2H Na2Cr2O7, H2O H2SO4, heat CH3 NO2 CH3 HNO3 H2SO4 8

Substitution in Naphthalene 1

two sites possible for electrophilic aromatic substitution Naphthalene H H 1 H H 2 H H H H two sites possible for electrophilic aromatic substitution all other sites at which substitution can occur are equivalent to 1 and 2 2

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

carbocation is stabilized by allylic resonance EAS in Naphthalene E H E H + + when attack is at C-1 carbocation is stabilized by allylic resonance benzenoid character of other ring is maintained 2

EAS in Naphthalene E H + E H + 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 2

Substitution in Heterocyclic Aromatic Compounds 1

Generalization There is none. There are so many different kinds of heterocyclic aromatic compounds that no generalization is possible. Some heterocyclic aromatic compounds are very reactive toward electrophilic aromatic substitution, others are very unreactive.. 2

Pyridine N Pyridine is very unreactive; it resembles nitrobenzene in its reactivity. Presence of electronegative atom (N) in ring causes  electrons to be held more strongly than in benzene. 2

Pyridine can be sulfonated at high temperature. SO3, H2SO4 SO3H N N HgSO4, 230°C 71% Pyridine can be sulfonated at high temperature. EAS takes place at C-3. 2

Pyrrole, Furan, and Thiophene •• O •• S •• 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. 31

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