40
Electrophilic Electrophilic Aromatic Aromatic Substitution Substitution Lecture 5 Lecture 5 Chemistry 391 10/14/02
Electrophilic Electrophilic Aromatic Aromatic SubstitutionSubstitution
Lecture 5Lecture 5Chemistry 391 10/14/02
Chemistry 391 10/16/02
Diazonium Diazonium SaltsSalts
OH
+ H3O+N NNH2
H2O
HCl
ClNaNO2 Claq. HCl
Diazonium Diazonium SaltsSaltsThe The --NN22
++ group of angroup of an arenediazoniumarenediazonium salt can be salt can be replaced in areplaced in a regioselectiveregioselective manner by these groups manner by these groups
Ar-BrKCN, CuCN
Ar-H
HCl, CuCl
HBr, CuBr
KI
H3 PO2
HBF4
H2 O Ar-OHSchiemann reaction
Ar-F
Ar-ClSandmeyer reaction
(-N 2 )Ar-N 2+
Ar-CN
Ar-I
Chemistry 391 10/16/02
Vilsmeier Haack Reaction
NCH3
CH
Cl
R
NCH3
CH
Cl
H
R
Only “activated substrates!
Chemistry 391 10/16/02
Real FastReal Fast
Pretty fastPretty fast
KindaKinda slowslow
Pretty slowPretty slow
SlowSlow
Real SlowReal Slow
Chemistry 391 10/16/02
Effect onEffect on RegioselectivityRegioselectivity
•• OrthoOrtho--parapara directorsdirectors direct an incomingelectrophile to positions ortho and/or para to themselves.
• Meta directorsMeta directors direct an incoming electrophile to positions meta to themselves.
• All meta directorsAll meta directors are deactivating
•• AllAll orthoortho--parapara directors are activating except except halogen
Chemistry 391 10/16/02
Adding a Second Adding a Second SubstiuentSubstiuent
Methoxy Methoxy is is therefore an “ois is therefore an “o--p director”p director”
Chemistry 391 10/16/02
Adding a Second Adding a Second SubstiuentSubstiuent
Nitro is therefore a “meta director”Nitro is therefore a “meta director”
Chemistry 391 10/16/02
Problem: what reagents and experimental Problem: what reagents and experimental conditions will bring about this conversion?conditions will bring about this conversion?
(1) (2) (3) (4)
CO2 H CO2 HCH3 CO2 HCH3
NH2 OHNO2NO2
Can you fill in the blanks??Can you fill in the blanks??
NH2 CCH3
N CH2NH2CH3
NH2CH3 CH3
CH3Cl
CH3
Cl ClCl Cl
Chemistry 391 10/16/02
DiDi-- andand PolysubstitutionPolysubstitutionSequence matters!Sequence matters!
CH3 CO2H
HNO3H2 SO4
K2Cr 2O7H2SO4
K2Cr 2O7H2SO4
CH3 NO2pp-Nitrobenzoic
acid
NO2
mm-Nitrobenzoic acid
CO2H
NO2
CO2 HHNO3H2 SO4
Chemistry 391 10/16/02
How do you get there from here??How do you get there from here??
Cl
???
Br
Chemistry 391 10/16/02
One way to skin…the catOne way to skin…the cat
bbbbNO2
Br2
FeBr3
NO2
Br
NH2
BrH2
Pd/CNaNO2
HCl
Br
N2+Cl-
Br
Cl
HClCuCl
Chemistry 391 10/16/02
Let’s use it!!Let’s use it!!
NO2NO2HNO3
H2SO4CH3CH2Cl
l3AlC
CH2CH3
AlCl3CH3CH2Cl
NO2
CH2CH3
H2SO4
HNO3
CH2CH3
Is this ok???? Add this to your homework assignment
Multiple Substituent EffectsMultiple Substituent Effects
all possible EAS sites may be equivalentall possible EAS sites may be equivalent
The Simplest CaseThe Simplest Case
CHCH33
CCHCCH33
OO
AlClAlCl33OO
CHCH33COCCHCOCCH33
OO
++
CHCH33
CHCH33 CHCH33
99%99%
directing effects of substituents reinforcedirecting effects of substituents reinforceeach other; substitution takes placeeach other; substitution takes place orthoorthoto the methyl group and meta to the nitro groupto the methyl group and meta to the nitro group
Another Straightforward CaseAnother Straightforward Case
CHCH33 CHCH33
NONO22 NONO22
BrBrBrBr22
FeFe
8686--90%90%
GeneralizationGeneralization
regioselectivityregioselectivity is controlled by theis controlled by themost activating substituentmost activating substituent
all possible EAS sites may be equivalentall possible EAS sites may be equivalent
The Simplest CaseThe Simplest Case
aceticaceticacidacid
BrBr22
strongly strongly activating
NHCHNHCH33
ClCl
BrBr
NHCHNHCH33activating
ClCl
87%87%
substitution occurssubstitution occurs orthoortho to the smaller groupto the smaller group
When activating effects are similar...When activating effects are similar...
CHCH33 CHCH33
C(CHC(CH33))33 C(CHC(CH33))33
HNOHNO33
HH22SOSO44
NONO22
88%88%
position between two substituents is lastposition between two substituents is lastposition to be substitutedposition to be substituted
StericSteric effects controleffects control regioselectivityregioselectivity whenwhenelectronic effects are similarelectronic effects are similar
CHCH33
HNOHNO33
HH22SOSO44
98%98%
CHCH33
NONO22
CHCH33
CHCH33
Chemistry 391 10/16/02
Chemistry 391 10/16/02
Chemistry 391 10/16/02
Chemistry 391 10/16/02
Chemistry 391 10/16/02
Chemistry 391 10/16/02
Substitution in NaphthaleneSubstitution in Naphthalene
11
22
HHHH
two sites possible fortwo sites possible for electrophilicelectrophilicaromatic 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
HH HH
HHHH
HH HH
EAS in NaphthaleneEAS in Naphthalene
AlClAlCl33
OO
CHCH33CClCCl
CCHCCH33
OO
90%90%
is faster at Cis faster at C--1 than at C1 than at C--22
EAS in NaphthaleneEAS in Naphthalene
EE HH
++
EE HH
++
when attack is at Cwhen attack is at C--11carbocation is stabilized bycarbocation is stabilized by allylicallylic resonanceresonancebenzenoidbenzenoid character of other ring is maintainedcharacter of other ring is maintained
EAS in NaphthaleneEAS in Naphthalene
EE
++
EE
when attack is at Cwhen attack is at C--22in order for carbocation to be stabilized byin order for carbocation to be stabilized by allylicallylicresonance, theresonance, the benzenoidbenzenoid character of the other ring is character of the other ring is sacrificedsacrificed
HHHH++
Substitution inSubstitution inHeterocyclicHeterocyclic Aromatic CompoundsAromatic Compounds
There is none.There is none.
There are so many different kinds ofThere are so many different kinds of heterocyclicheterocyclicaromatic compounds that no generalizationaromatic compounds that no generalizationis possible.is possible.
SomeSome heterocyclicheterocyclic aromatic compoundsaromatic compoundsare very reactive towardare very reactive toward electrophilicelectrophilicaromatic substitution, others are veryaromatic substitution, others are very unreactiveunreactive....
GeneralizationGeneralization
Pyridine is veryPyridine is very unreactiveunreactive; it resembles; it resemblesnitrobenzene in its reactivity.nitrobenzene in its reactivity.
Presence of electronegative atom (N) in ringPresence of electronegative atom (N) in ringcauses causes ππ electrons to be held more strongly thanelectrons to be held more strongly thanin benzene.in benzene.
PyridinePyridine
NN
PyridinePyridine
SOSO33, H, H22SOSO4
Pyridine can bePyridine can be sulfonatedsulfonated at high temperature.at high temperature.
EAS takes place at CEAS takes place at C--3.3.
NN
4
HgSOHgSO44, 230°C, 230°C
SOSO33HH
NN
71%71%
PyrrolePyrrole, Furan, and, Furan, and ThiopheneThiophene
OO••••••••
SS••••••••
NN
HH
••••
Have 1 less ring atom than benzene or pyridine to Have 1 less ring atom than benzene or pyridine to hold same number of hold same number of ππ electrons (6).electrons (6).ππ electrons are held less strongly.electrons are held less strongly.These compounds are relatively reactive toward These compounds are relatively reactive toward EAS..EAS..
undergoes EAS readilyundergoes EAS readilyCC--2 is most reactive position2 is most reactive position
Example: FuranExample: Furan
OO
CHCH33COCCHCOCCH33
OO
CCHCCH33
OOBFBF33++
7575--92%92%
OOOO
Chemistry 391 10/16/02
Find and write mechanisms for :Find and write mechanisms for :
Homework: Homework: Problem in notes and….Problem in notes and….
Hösch Reaction
Gatterman Reaction
Reimer –Tieman Reaction
Pschorr Synthesis
