12.15 multiple substituent effects. all possible eas sites may be equivalent the simplest case alcl...
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12.1512.15
Multiple Substituent EffectsMultiple Substituent Effects
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all possible EAS sites may be equivalentall possible EAS sites may be equivalent
The Simplest CaseThe Simplest Case
AlClAlCl33OO
CHCH33COCCHCOCCH33
OO
++
CHCH33
CHCH33
CHCH33
CHCH33
CCHCCH33
OO
99%99%
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directing effects of substituents reinforcedirecting effects of substituents reinforceeach other; substitution takes place orthoeach other; substitution takes place orthoto the methyl group and meta to the nitro groupto the methyl group and meta to the nitro group
Another Straightforward CaseAnother Straightforward Case
CHCH33
NONO22
CHCH33
NONO22
BrBr
86-90%86-90%
BrBr22
FeFe
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GeneralizationGeneralization
regioselectivity is controlled by regioselectivity is controlled by thethe
most activating substituentmost activating substituent
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all possible EAS sites may be equivalentall possible EAS sites may be equivalent
The Simplest CaseThe Simplest Case
BrBr22
NHCHNHCH33
ClCl
87%87%
aceticaceticacidacid
NHCHNHCH33
ClCl
BrBr
strongly strongly
activatingactivating
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substitution occurs ortho to the smaller groupsubstitution occurs ortho to the smaller group
When activating effects are similar...When activating effects are similar...
CHCH33
C(CHC(CH33))33
CHCH33
C(CHC(CH33))33
NONO22HNOHNO33
HH22SOSO44
88%88%
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position between two substituents is lastposition between two substituents is lastposition to be substitutedposition to be substituted
Steric effects control regioselectivity whenSteric effects control regioselectivity whenelectronic effects are similarelectronic effects are similar
HNOHNO33
HH22SOSO44
98%98%
CHCH33
CHCH33
NONO22
CHCH33
CHCH33
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12.16Regioselective Synthesis of Disubstituted
Aromatic Compounds
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Factors to ConsiderFactors to Consider
order of introduction of substituents to ensure order of introduction of substituents to ensure correct orientationcorrect orientation
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Synthesis of m-BromoacetophenoneSynthesis of m-Bromoacetophenone
BrBr
CCHCCH33
OO
Which substituent Which substituent should be should be introduced first?introduced first?
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Synthesis of m-BromoacetophenoneSynthesis of m-Bromoacetophenone
BrBr
CCHCCH33
OO
parapara
metameta
If bromine is introduced first, If bromine is introduced first, pp-bromoacetophenone is major -bromoacetophenone is major product.product.
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Synthesis of m-BromoacetophenoneSynthesis of m-Bromoacetophenone
CCHCCH33
OO
OO
CHCH33COCCHCOCCH33
OO
AlClAlCl33
BrBr22
AlClAlCl33
CCHCCH33
OOBrBr
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Factors to ConsiderFactors to Consider
order of introduction of substituents to ensure order of introduction of substituents to ensure correct orientationcorrect orientation
Friedel-Crafts reactions (alkylation, acylation) Friedel-Crafts reactions (alkylation, acylation) cannot be carried out on strongly deactivated cannot be carried out on strongly deactivated aromaticsaromatics
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Synthesis of m-NitroacetophenoneSynthesis of m-Nitroacetophenone
NONO22
CCHCCH33
OO
Which substituent Which substituent should be should be introduced first?introduced first?
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Synthesis of m-NitroacetophenoneSynthesis of m-Nitroacetophenone
NONO22
CCHCCH33
OO
If NOIf NO22 is introduced first, is introduced first,
the next step (Friedel-Crafts the next step (Friedel-Crafts acylation) fails.acylation) fails.
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Synthesis of m-NitroacetophenoneSynthesis of m-Nitroacetophenone
CCHCCH33
OO
OO
CHCH33COCCHCOCCH33
OO
AlClAlCl33
HNOHNO33
HH22SOSO44
CCHCCH33
OOOO22NN
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Factors to ConsiderFactors to Consider
order of introduction of substituents to ensure order of introduction of substituents to ensure correct orientationcorrect orientation
Friedel-CraftsFriedel-Crafts reactions (alkylation, acylation) reactions (alkylation, acylation) cannot be carried out on strongly deactivated cannot be carried out on strongly deactivated aromaticsaromatics
sometimes electrophilic aromatic substitution sometimes electrophilic aromatic substitution must be combined with a functional group must be combined with a functional group transformationtransformation
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Synthesis of p-Nitrobenzoic Acid from TolueneSynthesis of p-Nitrobenzoic Acid from Toluene
Which first? Which first? (oxidation of methyl (oxidation of methyl group or nitration of group or nitration of ring)ring)
CHCH33
COCO22HH
NONO22
CHCH33
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Synthesis of p-Nitrobenzoic Acid from TolueneSynthesis of p-Nitrobenzoic Acid from Toluene
CHCH33
COCO22HH
NONO22
CHCH33
nitration givesnitration givesmm-nitrobenzoic-nitrobenzoicacidacid
oxidation givesoxidation givespp-nitrobenzoic-nitrobenzoicacidacid
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Synthesis of p-Nitrobenzoic Acid from TolueneSynthesis of p-Nitrobenzoic Acid from Toluene
CHCH33
NONO22
CHCH33
HNOHNO33
HH22SOSO44
NONO22
COCO22HH
NaNa22CrCr22OO77, H, H22OOHH22SOSO44, heat, heat
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12.1712.17
Substitution in NaphthaleneSubstitution in Naphthalene
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two sites possible for electrophilictwo sites possible for electrophilicaromatic substitutionaromatic substitution
all other sites at which substitution can occurall other sites at which substitution can occurare equivalent to are equivalent to 11 and and 22
NaphthaleneNaphthalene
11
22
HHHH
HH HH
HHHH
HH HH
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EAS in NaphthaleneEAS in Naphthalene
AlClAlCl33
OO
CHCH33CClCCl
90%90%
CCHCCH33
OO
is faster at C-1 than at C-2is faster at C-1 than at C-2
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EAS in NaphthaleneEAS in Naphthalene
when attack is at C-1when attack is at C-1
carbocation is stabilized by allylic resonancecarbocation is stabilized by allylic resonance
benzenoid character of other ring is maintainedbenzenoid character of other ring is maintained
EE HH EE HH
++
++
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EAS in NaphthaleneEAS in Naphthalene
when attack is at C-2when attack is at C-2
in order for carbocation to be stabilized by allylic in order for carbocation to be stabilized by allylic resonance, the benzenoid character of the other resonance, the benzenoid character of the other ring is sacrificedring is sacrificed
EE
HH++
EE
HH++
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12.1812.18
Substitution inSubstitution in
Heterocyclic Aromatic Compounds Heterocyclic Aromatic Compounds
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There is none.There is none.
There are so many different kinds of heterocyclicThere are so many different kinds of heterocyclicaromatic compounds that no generalizationaromatic compounds that no generalizationis possible.is possible.
Some heterocyclic aromatic compoundsSome heterocyclic aromatic compoundsare very reactive toward electrophilicare very reactive toward electrophilicaromatic substitution, others are very unreactive..aromatic substitution, others are very unreactive..
GeneralizationGeneralization
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Pyridine is very unreactive; it resemblesPyridine is very unreactive; it resemblesnitrobenzene in its reactivity.nitrobenzene in its reactivity.
Presence of electronegative atom (N) in ringPresence of electronegative atom (N) in ringcauses causes electrons to be held more strongly than electrons to be held more strongly thanin benzene.in benzene.
PyridinePyridine
NN
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Pyridine can be sulfonated at high temperature.Pyridine can be sulfonated at high temperature.
EAS takes place at C-3.EAS takes place at C-3.
PyridinePyridine
NN
SOSO33, H, H22SOSO44
HgSOHgSO44, 230°C, 230°C
SOSO33HH
NN
71%71%
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Pyrrole, Furan, and ThiophenePyrrole, Furan, and Thiophene
OO••••
••••
SS••••
••••
NN
HH
••••
Have 1 less ring atom than benzene or Have 1 less ring atom than benzene or pyridine to hold same number of pyridine to hold same number of electrons electrons (6).(6).
electrons are held less strongly.electrons are held less strongly.
These compounds are relatively reactive These compounds are relatively reactive toward EAS..toward EAS..
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undergoes EAS readilyundergoes EAS readilyC-2 is most reactive positionC-2 is most reactive position
Example: FuranExample: Furan
BFBF33OO
CHCH33COCCHCOCCH33
OO
++ CCHCCH33
OO
75-92%75-92%
OO
OO