Polar Reaction Under Acidic Conditions
a. Carbocations
b. Substitution and β-elimination reactions at C(sp3)-X
c. Electrophilic addition to nuclephilic C=C π bonds
d. Substitution at nuclephilic C=C π bonds
e. Nuclephilic Addition to and substitution at electrophilic π bonds
Chapter Three
1
Carbocation Stabiity
Most carbocations are very unstable and can’t be isolated. They exist only a transient, high-energy intermediates which should be directly related to the stabilities of the carbocation.
Carbocaction: trivalent, six electron C atom, C atom is sp2 hybrided, empty P orbital and electron-deficient(attack by nuclephile)
How to stabilize the carbocation?
1. Lone-pair stabilizationresonance
Inductive effect
2
Carbocation Stabiity
3. Interaction with σ bondsHyperconjugation: The bonding pair of electrons in the σ orbitals can delocalize into partly
P orbital.
3o cabocation9 adjacent C-H bonds
2o cabocation6 adjacent C-H bonds
1o cabocation3 adjacent C-H bonds
> >
Stability
The order of stabilization:Lone pair > π bonds > σ bonds
Aromatic
2. Interaction with π bonds
Benzylic
3
Carbocation Generation1. Ionization of a C-X+ bond: depend on stability of carbocation and the leaving group(X)
Resonance and lone pair
Resonance
Lewis acids(BF3, AlCl3, FeCl3, TiCl4, ZnCl2…) can promote the ionization
Good leaving group(HOTs) and 2o carbocation
Silver salts(AgNO3, AgOTf, Ag2O) can promote the ionization of carbon-halogen
R
BrRR
AgNO3
EtOH
R
RR AgBr(S)+
4
2. A lone pair on a heteroatom in a C=X bond react with H+ or Lewis acids.
Carbocation Generation
R R
OH+ O
RR
HO
RR
H
R R
OAlCl3
O
RR
AlCl2 O
RR
AlCl2
R R
NHH+ NH2
RR
NH2
RR
R R
NHAlCl3
NH
RR
Cl2AlNH
RR
Cl2Al
(a) X= O (b) X= N
3. A C=C π bond react with a H+ or Lewis acids.
(a)
(b)
(c)
(d)
Why not the structure below?H3C
H3C H
HH
HtBu
H
NBn
H
H
R
OBr
H
H
HNAc
5
Typical Reactions of Carbocation1. Addition of a nuclephile (SN1): stable carbocation (2o or 3o carbocation)
NH
Bn
NH
Bn
Na+
BH
HHCN
NH
BnH
Nnuclephile
Lone pair
π bond
σ bond
Please draw the mechanism.
(a) (b)
SN2: 1.1o C(sp3)-OH as electrophile, very good Nu-(Br-, I-) and very strong acid 2.substitution at more electronegative elements like P or Br
Common error alertThe SN1 mechanism is almost always operative for substitution at C under weakly acidic condition.
6
Substitution by the SN1 and SN2 Mechanisms
SN2
SN1
SN1: loss configurational purity is usually observed
RMe
H
OTs
AcOHR
MeH
OAcR
OAc
R R S
MeH R
H
Me
7
2. Fragmentation to give a stable cation(E1)
Please draw the mechanism.
(a)
(b)
Typical Reactions of Carbocation
X= C, N, OY+= H+, R3Si+, R3Sn+
Y Y
Predicting the SN1 vs. E1
SN1: Favor in hydroxylic solvents(RCO2H, ROH, H2O) and when the nuclephile is contained in the same molecule.E1: Favor in aprotic solvents.
8
Typical Reactions of Carbocation3. Rearrangement
Usually carbocations rearrange to give more stable carbocations.
Stability: 3o C+ > 2o C+ > 1o C+
1, 2-alkyl shift and 1, 2-hydride shift
Often a 1,2-shift is concerted with loss of the leaving group. The leaving groups is always trans(antiperiplanar) to the migrated group.
In general, smaller groups migrate before larger ones
Ph > H > Me > CHMe2 > CMe3
R
RR
MeH
R
R
MeH
R
2o 3o1, 2-alkyl shift 1, 2-hydride shift
9
Beckmann rearrangement (trans to the OH shifts selectively)
Beckmann and Pinacol Rearrangement
Pinacol rearrangement
N
CH3Ph
OH PCl5 N
CH3Ph
OPCl4N
CH3
Ph
Ph N CH3
H2O
N
OH
CH3Ph
NH
O
CH3Ph
N
PhH3C
OH PCl5 N
PhH3C
OPCl4N
Ph
H3C
H3C N PhH2O
N
OH
PhH3C
NH
O
PhH3C
10
Please draw the mechanism.
(a)
(b)
NH2OHO
H2SO4
MeMe
OH
Me
HCl
MeMe
Me
Cl
(c)
(d)
(e)
(f)
Exercises11
Koch-Haaf Carbonylation (2o or 3o alcohol to acid)
Please draw the mechanism
R OHCO, H2O
H+
R
O
OHOH
CO, H2O
H+
O
OH(a) (b)
Typical Reactions of Carbocation
Me
MeMe
Me
MeOH
Me
MeMe
MeMe
HOO
1. H2SO4
2. CO, H2O
Mechanism:
Me
MeMe
Me
MeOH
H+
Me
MeMe
Me
MeOH2
Me
MeMe
Me
Me
C O
Me
MeMe
MeMe
O
H2O
Me
MeMe
MeMe
OOH2
- H+
Me
MeMe
MeMe
OOH
12
Nazarov Cyclization (cationic ring-clothing reaction)
Typical Reactions of Carbocation
H+ or Lewis acid
Me
MeMe
OH2o carbocation
3o carbocation
Please draw the mechanism of the following reactions.
Me
MeMe
O
OLewis acid
(a)(b) O
O
R
CO2Me OO
R
CO2Me
OO
R
CO2Me
Lewis acid
OH+
OH OH
H
OH O
O OH+
13
Prins reaction
Typical Reactions of Carbocation
Mechanism:
O
HH
H+O
HH
HO
H
H H
RRHO
H
H2OHO R
H2O
RHO
OHH
RHO
OH
O
H H
RHO
OC
R
OOH
R
OO
Please draw the mechanism.
(a)
Ph OH
O
R
H+ OPh
OH
R
(b) Total synthesis of Exiguolide
O O
O
O
O TFA, CH2Cl2
then H2OO O
O
O
O
HO
14
Polar Reaction Under Acidic Conditions
a. Carbocations
b. Substitution and β-elimination reactions at C(sp3)-X
c. Electrophilic addition to nuclephilic C=C π bonds
d. Substitution at nuclephilic C=C π bonds
e. Nuclephilic Addition to and substitution at electrophilic π bonds
Chapter Three
15
Electrophilic Addition to Nuclephilic C=C Bonds
Ex
Dihydropyran(DHP) is a protecting group for alcohol
Alkenes can react with peracids(RCO3H) or halogen(Br2, NBS, I2) to form three member ring.
mCPBA (metachloroperbenzoicacid)
Cl
O OOH
DHP THP ether
deprotection
+H3C H
CH3HO
OOH
OH3C H
H CH3
+ O
OH
ClCl
Br Br+ Br Br
Please draw the mechanism.
halonium ions
expoxide
NCl2, -78oC
H2OO
Cl
16
Electrophilic Addition to Nuclephilic C=C BondsPlease draw the mechanism.
O
OAr Br2
O
OAr
Br Br
O
OAr
Br Br
O
OAr
Br
Br
O
OAr
Br Br
Mechanism:
O
OAr Br2
O
OAr
Br
+ Br- O
OAr
Br Br
O
OAr
Br
+ Br-O
OAr
Br Br
O
OAr
Br
O
OAr
Br
+ Br-
O
OAr
Br
O
OAr
Br
+ Br-
Br
Br
OO
Ar
O
OAr
Br Br
17
Please draw the mechanism.
(a)
(b)
(c)
Electrophilic Addition to Nuclephilic C=C Bonds18
Polar Reaction Under Acidic Conditions
a. Carbocations
b. Substitution and β-elimination reactions at C(sp3)-X
c. Electrophilic addition to nuclephilic C=C π bonds
d. Substitution at nuclephilic C=C π bonds
e. Nuclephilic Addition to and substitution at electrophilic π bonds
Chapter Three
19
Electrophilic Aromatic Substitution (SEAr)
Mechanism:
R is donating group Activate the reaction, substituted at ortho- and para-
R
HNO3
H2SO4 R
NO2
MeO
NO2
H
MeO
NO2
H
MeO
NO2
Hinductiveeffect
resonanceeffect
para-
NO2
H
NO2
H
inductiveeffect
resonanceeffect
ortho-
OMe OMe
NO2
HNO2
H
NO2
Hmeta-
MeO MeO MeO
ON
O OH
H+ON
O OH2
NO
OR R
HH
NO
O R
NO
O
20
R is withdrawing group Deactivate the reaction, substituted at meta-
Electrophilic Aromatic Substitution (SEAr)
OHC
NO2
H
OHC
NO2
H
OHC
NO2
Hterrible resonancestructure
para-
NO2
H
NO2
Hortho-
CHO CHO
NO2
HNO2
H
NO2
Hmeta-
OHC OHC OHC
ACK
terrible resonancestructure
NO2
HCHO
ACK
21
Electrophilic Aromatic Substitution (SEAr) R
R group
I: Inductive effect, M: mesomeric effect(resonance effect)
R
HZ
+I: Z is donating group-I: Z is withdrawing group
R
HO
R
R
HO
R
+M: It can form resonance structure-M: It can not form resonance structure
Steric effect:X
YH
X
Y H
major
Ortho effect: usually H bond
XY
H
X is donating group
Br
NO2
H
NO2
HBr
OMe
OR
a
b
c
a > b >> c
XY
22
Exercises(a)
(b)
(c)
23
Electrophilic Aromatic Substitution (SEAr)Friedel-Crafts reactions: The carbocation will be attacked by an aromatic ring to form a wheland- type intermediate, which leads to s substituted aromatic system
a. Friedel-Crafts alkylation
Mechanism:
Cl AlCl3-AlCl4
H
R-X: R-F > R-Cl > R-Br > R-IAromatic:Electron-rich aromatic ring react very well(pheol, aryl ether)
NH
O S N> > >
Which position is better and why? Draw the mechanism of following reaction?
Br AlBr3
O
Me
O
Me
O
Me
OMe
BF3 OEt2, DCMOMe
Bn2N
HO
Cl
Cl
AlCl3
Cl
ClBn2N
(a)
(b) (c)
H H
wheland intermediate
a
bNCH3
R
NCH3
RCl, AlCl3NCH3
R
24
Electrophilic Aromatic Substitution (SEAr)b. Friedel-Crafts acylation:
Mechanism:
O
Cl
AlCl3 O OAlCl4
-O
O
OH
O
O
Acyl halide react with lewis acid to form stabilized acylium ion. This can be attackedby a aromatic ring and aromatization givesan aryl ketone.
Draw the mechanism of following reaction?
(a) (b)
(c)
25
Electrophilic Aromatic Substitution (SEAr)c. Vilsmeier-Haack reaction:
NH
POCl3, DMF
NH N
NH O
Mechanism:
Draw the mechanism of following reaction?
d. Haworth reaction:
(a)
(c) Haworth reaction
N
1. POCl3, DMF
2. H2ON
CHO
(b)
N
OPO
Cl ClCl
DMFN
OPO
ClCl
NH
NHN
NHO
H2O
OO O
AlCl3
O
CO2H
OO O
AlCl3
O
CO2H Reduction
CO2H H+O
+NMe
O
1. POCl3 CHO+
NHMe
2. H2O
26
Aromatic Substitution of Anilines via Diazonium SaltsSandmeyer reaction
a. Diazonium salts Mechanism:
b. Substitution by Nu- (SRN1): Nuclephile is H3PO2, CuCN, MX(CuX, KI, KBr…)
Mechanism:N2
Nu-
Nu
Br
Br
Br
Br
27
Aromatic Substitution of Anilines via Diazonium Salts
Draw the mechanism of following reaction?
b. Substitution by Nu- (SN1): Nuclephile is H2O, BF4-
Neither H2O nor BF4- are oxidizable enough to transfer an electron to the aryldiazonium ion,
only SN1 mechanisms are reasonable for these reactions.
(a) (b)
(c)
(d)
(e)
Consider the stereochemistry of the product.
28
Electrophilic Aliphatic Substitution
Draw the mechanism of following reaction?
Mechanism:
Sakurai reaction
29
Polar Reaction Under Acidic Conditions
a. Carbocations
b. Substitution and β-elimination reactions at C(sp3)-X
c. Electrophilic addition to nuclephilic C=C π bonds
d. Substitution at nuclephilic C=C π bonds
e. Nuclephilic Addition to and substitution at electrophilic π bonds
Chapter Three
30
Nuclephilic Addition to Carbonyl π bond
Draw the mechanism of following reaction?
Amides and nitriles are hydrolyzed to carboxylic acids by a similar mechanisms.
31
Nuclephilic Addition to Carbonyl π bondKetones and aldehydes can be interconverted with acetals(ketal).
Draw the mechanism of following reaction?
(a)
(b)
32
Robinson annulation (Michael addition and aldol reaction)
Nuclephilic Addition to Electrophilic π bond
Michael addition
Aldol reaction
elimination
33
Nuclephilic Addition to Electrophilic π bondMannich reaction
Mechanism 1:
Mechanism 2:
Mechanism 3:
34
35
Thanks For Your Attention