aromatic substitution reactions · 2016. 3. 21. · p-substitution than o-substitution 5) the...
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AROMATIC SUBSTITUTIONAROMATIC SUBSTITUTION
REACTIONS REACTIONS
� Electrophilic
� Nucleophilic
Benzene undergoes substitution reactions instead of addition.It requires a strong electrophile
Cl2
FeCl3
Cl
ClH+ +
Benzene ReactivityBenzene Reactivity
Substitution
Cl2
Cl
Cl+
compare:
addition
Substitution….
Why??
How??
Influence of preexisting groups
Synthetic utility
+ Br2
Br
H
H
Br-
---------------------------------------------------------------------------
∆H
-27 kcal/mol
Br
H
HBr-
Br
Br
Br
+ HBr
-11 kcal/mol
Addition Substitution
Energy profile in the case of Olefins – Addition vs. Substitution
∆H
Addition Substitution
----------------
----------------
----------------
+9 kcal/mol-11 kcal/mol
+ Br2
Br
+ HBr
BrH
Br HBr
Br
BrH
Br-Br
H
Br-
AlCl3
Energy profile in the case of Benzene – Addition vs. Substitution
----------------
General reaction:
+ E B
H E
+ B
H E H E
Step 1:
a stabilized cyclohexadienyl cation
(also called a benzenonium ion)
Step 2:
H E
+ B
E
+ H-B
How???
Energy profile of aromatic substitution reactionEnergy profile of aromatic substitution reaction
H
E
E
+
Ea
H+
benzenonium
intermediateTransition
state 1
Transition
state 2
STEP 1 STEP 2
slowfast
activation
energy
intermediate
H E
The absence of
Kinetic isotope effect
shows that the second step
(that involves TS2) is not
Rate Determining
Substitution Reactions of BenzeneSubstitution Reactions of Benzene
Cl2
AlCl3
Cl
CH3Cl
AlCl3
CH3
CH3
CCl
O AlCl3
C CH3
O
OH N
O
O
H2SO
4
N O
O
S
O
OH
OOH S
O
O
OHSO
3
+
+
+
+
+
Halogenation
Friedel-Crafts
Alkylation
Friedel-Crafts
Acylation
Nitration
Sulfonation
+ +
-
-
Chlorination of BenzeneChlorination of Benzene
H
Cl
Cl
Cl
AlCl4
AlCl4
+ -
-
HCl + AlCl3
chloronium
ion complex
[ ] +Benzenonium ion
Cl2 + AlCl3
FriedelFriedel--Crafts AlkylationCrafts Alkylation
H
CH3
CH3
CH3
AlCl4
AlCl4
+ -[ ] +
CH3Cl + AlCl3
HCl + AlCl3
-
Consider all resonance
contributors
alkylation of benzene by alcohol
FC alkylations can give problems due to rearrangement FC alkylations can give problems due to rearrangement
of carbocations to more stable onesof carbocations to more stable ones
FriedelFriedel--Crafts AcylationCrafts Acylation
H
C CH3
O
C
O
CH3
C
O
CH3
AlCl4
AlCl4
+ -[ ] +
+ AlCl3
HCl + AlCl3
CH3
C
O
Cl
-
Since AlCl3 complexes with C=O group,
2 eq. of this reagent is required
C
O
CH2CH
3
C
O
CH3CH
2Cl
AlCl3
CH2CH
2CH
3
CH3CH
2CH
2Cl
AlCl3
Zn / HCl
X
Rearrangement is a
problem
AcylationAcylation followed by followed by ReductionReduction is a convenient routeis a convenient route
to introduce long alkyl chains on aromatic ring; Noto introduce long alkyl chains on aromatic ring; No
problem of rearrangement problem of rearrangement !!
Clemmensons reduction
Alkylation of Benzene by AcylationAlkylation of Benzene by Acylation--ReductionReduction
Advantages :
(1) No rearrangement
(2) No multiple substitutions (acyl- group is de-activating)
Nitration of BenzeneNitration of Benzene
pKa = -5
pKa = -1.3
(consider all resonance forms)
Sulfonation of BenzeneSulfonation of Benzene
Concentrated
or Fuming
H2SO4.SO3
(Fuming sulfuric acid)
also can be used
(Consider all resonance forms)
Sulfonation of BenzeneSulfonation of Benzene
O
S
O
OH
H
S OH
O
O
S
O
OH
O
HSO4
+
-
H2SO4 SO3.
+ H2SO4
can be
reversed
in boiling water
or steam (acidic)
H3O+
∆∆∆∆
Look.. It is reversible
CH3CH3
D
?
How would you do the following
conversion
Energy profile in Sulfonation
Depending upon whether they are electron
donating or electron withdrawing,
substituents fall into one of the following
categories:
o,p - directors m- directors
activate the ring deactivate the ring
Substitution categoriesSubstitution categories
G
Ripso
ortho
meta
para
o-
m-
p-
1
2
3
4
5
6
Directing effect of groups,Directing effect of groups,ring activation and deactivationring activation and deactivation
O CH3
Example, Nitration of AnisoleExample, Nitration of Anisole
NO2
O CH3
NO2
O CH3
Reacts faster
than benzene
+
ortho para
= “activated”
The -OCH3 (or other electron donating groups) if present on the ring,
give preferentially ortho and para products, and no meta.
Substituents that cause this effect are called o,p directors
HNO3
H2SO4
anisole
ACTIVATED RING
and they usually activate the ring
C
OOMe
Example Nitration of Methyl BenzoateExample Nitration of Methyl Benzoate
CO
NO2
OMe
Reacts slower
than benzene
meta
HNO3
H2SO4
= “deactivated”
methyl benzoate
The -COOMe (or other electron withdrawing groups) if present
on the ring give only meta, and no ortho or para products.
Substituents that cause this result are called m directors
and they usually deactivate the ring.
DEACTIVATED RING
H
HNO
2
O CH3
+
H
H
NO2
O CH3
+
H NO2
H
O CH3
+
O CH3
+ N
O
O
+
Nitration of AnisoleNitration of Anisole
NO2
O CH3
NO2
O CH3
actual
products
Activated ringortho meta para
ortho para+
Benzenonium ion-resonance forms
H NO2
H
O CH3
+
H NO2
H
O CH3
+
H NO2
H
O CH3
+
H NO2
H
O CH3
+
H
H
NO2
O CH3
+
H
H
NO2
O CH3
+
H
H
NO2
O CH3
+H
H
NO2
O CH3
+
H
HNO
2
O CH3
+
H
HNO
2
O CH3
+
H
HNO
2
O CH3
+
ortho
meta
para :
:
Extra stabilization and extra resonance structure
Extra stabilization and extra resonance structure
H
H
C
O
NO2
OMe
+
H
C
O
H
OMe
NO2
+
C
OOMe
H NO2
H
+
CO
OMe
+ N
O
O
+
Nitration of Methyl BenzoateNitration of Methyl Benzoate
CO
NO2
OMe
actual
product
Deactivated ring ortho meta para
meta
Benzenonium ion-resonance forms
H
H
CO
NO2
OMe
+
H
H
C
O
NO2
OMe
+
H
H
C
O
NO2
OMe
+
ortho
meta
para
H
C
O
H
OMe
NO2
+
H
C
O
H
OMe
NO2
+
H
C
O
H
OMe
NO2
+
δ+δ+δ+δ+δδδδ−−−−
δ+δ+δ+δ+δδδδ−−−−
C
OOMe
H NO2
H
+
C
OOMe
H NO2
H
+
CO
OMe
H NO2
H
+
BAD!
BAD!
• Classification of Substitutents
Deactivators (m-directing)
Comparison of Activators and deactivatorsRelative energy states of intermediates with respect to that of benzene
Benzene
Activators (o/p directing)E
+
orthoortho, , parapara -- Directing GroupsDirecting Groups
X
Groups that donate
electron density
to the ring.XX :
+I Substituent +R Substituent
CH3-
R-
CH3-O-
CH3-N-
-NH2
-O-H
These groups
“activate” the ring, or
make it more reactive.
E+
The +R groups activate
the ring more strongly
than +I groups.
..
..
..
..
..
..
increased
reactivity
PROFILE:
X YY
metameta -- Directing GroupsDirecting Groups
X
Groups that withdraw
electron density from
the ring.
These groups
“deactivate” the ring,
or make it less reactive.
E+
-I Substituent -R Substituent
δ+δ+δ+δ+ δδδδ−−−−
C
O
R
C
O
OR
C
O
OH
C N
N
O
O
N
R
R
R
CCl3
-SO3H
+
decreased
reactivity
+
-
PROFILE:
Halides Halides -- o,po,p Directors / Deactivating;Directors / Deactivating;an exception to the trend we saw in the previous slidean exception to the trend we saw in the previous slide
X
E+
: :..
Halides represent a special case:
They are o,p directors (+M effect )
They are deactivating ( -I effect )
-F
-Cl
-Br
-I
X =
OH OH
Br?
How would you bring about the following conversion efficiently?
Directing effect of groups: Application in synthesisDirecting effect of groups: Application in synthesis
NO2
NO2
Br
NO2
Br
NO2
How would you bring about the following conversions efficiently?
Br
CH2CH2CH3
CH3CH2 C
O
Cl
AlCl3
CO CH2CH3
Br2
FeBr3
CO CH2CH3
Br
CH2
CH2CH3
Br
Zn(Hg)HCl??
Br
Cl CH2CH2CH2CH2 ClAlCl3
junk!!
X
Cl CH2CH2CH2C OH
O
AlCl3
CH2CH2CH2C OH
O
SOCl2
CH2CH2CH2C Cl
O
O
AlCl3
HCl
Zn(Hg)
α-tetralone
You can also consider a route
through succinic anhydride
(draw the sequence)
?
Ref: Syn. Commun.,Vol. 34, No. 12, pp. 2301–2308, 2004
NH2 NH2
Cl
NH2 NH2
NO2
??
Example
??
NH2 NH2
SO
O
HN
R
Sulfa drugs (very important class of
Antibacterials)
Clue: steps in random order
chlorosulfonation, amination, N-acetylation, de-acetylation
Give reasons for N-acetylation????
?
COOH
CH3
COOH
COOH
NO2
NO2O2N
??
????
General rulesGeneral rules
1) Activating (o,p) groups (+R, +I) win over
deactivating (m) groups (-R,-I)
2) Resonance groups (+R) win over inductive (+I) groups
3) 1,2,3-Trisubstituted products rarely form due to
steric crowding
4) With bulky directing groups, there will usually be more
p-substitution than o-substitution
5) The incoming group replaces a hydrogen, it will not
usually displace a substituent already in place (in the case of
electrophilic aromatic substitution)
Directing effect if more than one substituent is presentDirecting effect if more than one substituent is present
Case 1. When two substituents direct to the same positionCase 1. When two substituents direct to the same position
O CH3
NO2
m-director
o,p director
HNO3
H2SO4
O CH3
NO2
NO2
major
product
CH3
NO2
NO2+
CH3
NO2
NO2
99.8%
CH3
NO2
0.2%
Why a mixture
in this case ??
(assuming 1:1)
o,p-directing groups win
over m-directing groups
HNO3
H2SO4
O CH3
NO2
NO2
O CH3
NO2
O2N
O CH3
NO2
Steric
crowding
+
Activation effect of o,p directors are stronger than the meta directing deactivators.
Case 2. When two substituents direct to the different positions Case 2. When two substituents direct to the different positions
(activation vs. deactivation)(activation vs. deactivation)
X
HNO3
H2SO4
O CH3
CH3
NO2
O CH3
CH3
+R
+I
resonance effects are more
important than inductive effects
major
product
Case 3. Resonance vs. inducting effectCase 3. Resonance vs. inducting effect
The alkyl groups and halides are in-between (mixture of products)
Steric and electronic effects can decide the outcome
O
O
??
Problem
Electrophile
Ar-NH2 ArN2+
A different electrophile
Show how ArN2+ is formed
There are two resonance structures which retain fully conjugated aromatic ring
in the case of substitution at position 1.
Naphthalene- electrophilic substitution
Electrophilic substitution of Naphthalene
H
Peri interaction
Allura Red
A red azo dye, used in many food, drug and cosmetic products
Synthesis of Shaffer acid required for the synthesis of Allura red
Method: Sulfonate 2-naphthol twice (ie. 1,6-disulfonate) and then desulfonate once.
Why desulfonation happens only at position 1?
SO3H
OH
HO3S
12
6
HO3S
O
HO3S
12
6
H
H
Consider other resonance forms also
OH
HO3S
22
6
+SO3HH2O
-H+H2SO4
2-hydroxynaphthalene-6-sulfonic acid (shaffer acid)
(irreversible
in dil H2SO4)
(First Sulfonation of 2-naphthol
goes to position 1 and the second goes to
position 2; First desulfonation happens at position1)
Neither true SN1 or SN2 is energetically feasible in
aromatic Systems
1. pi electrons in conjugation
2. Back side attack (as in SN2) and inversion is precluded by the
geometry of the ring
1. SN1 leads to phenyl cation which is less stable than a primary carbocation
Two types of mechanisms that operate in Nucleophilic substitutions are,
1. Addition-Elimination
2. Elimination-Addition
Nucleophilic Aromatic Substitution
X
Nu
X
Nu
Nu + X-
Nu X
1. Addition-Elimination (SNAr)
Groups which favor substitution
NO2, CN, -CO-
The formation of the addition intermediate is usually the RDS
For halogens, the order of reactivity is F > Cl > Br> I(stronger bond dipoles associated with the more electronegative atom favor the
addition step)
Meisenheimer complex
EWGEWG
EWG
leaving groups Halogens, Alkoxy, NO2, Sulfonyl
Examples
Nucleophiles in aromatic substitution
Alkoxides, Phenoxides, Sulfides, fluoride ion or amines
(similar to that in SN2)
The rate of the reaction gets enhanced on using
Dipolar aprotic solvents, crown ethers or other phase transfer catalysts
(by providing the nucleophile in a reactive state with minimum solvation)
Cl
+ OH-< 300oC
No reaction
Electron withdrawing groups stabilize Meisenheimer complex and favor the reaction
Energy profile
Which among these
Substrates undergo
the reaction efficientlyWhich chloride will
be nucleophilically
Substituted?H3C
Cl
CH3
Cl
NO2O2N
Cl
NO2
NO2
Cl
Meisenheimer complex
It is possible to isolate the Meisenheimer complex in some cases! Stable!
O2N
NO2
F
OHNO
R1
H2N R2
OHNO
R1
HN
R2O2N
NO2
+
O
R1
HNO2N
NO2
OH
HYDROLYSIS
Sanger’s Method of N-terminal Amino acid determination in proteins
One important application of nucleophilic aromatic substitution reaction
�The 2,4-dinitrofluorobenxene (2,4-DNP)
is treated with the protein of interest
under mild alkaline conditions (doesn't
cause cleavage of peptide bonds)
�The DNP-protein adduct is then
subjected to acid hydrolysis which lead
to the cleavage of peptide bonds,
leaving the N-terminal residue in the
form of its DNP-derivative
�This derivative can be identified by
chromatographic methods
Elimination-Addition (Benzyne mechanism)
14C
14C14C
14C
‘Cine’ Mechanism- evidence
What is the electrophilic species generated from HNO2/H2SO4 ?
Some functional group
Inter-conversions you can
consider while writing
a sequence
S
NH
O
OO
Br
NO2
SO3
H2SO4
NO2
O2N
How would you make this compound
Predict the product
Predict the product
Which among these products are most likely to be formed?
Answer by analyzing resonance structures of intermediates
O
HN
H2SO4
HNO3
H2SO4
HNO3
H2SO4
HNO3
How??
NHAc
Cl
O
Cl+
What is the product if 1 eq. of AlCl3 is used
Which is kinetic and which
is thermodynamic product?