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Chapter Three
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
Carbocation Stabiity
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Carbocaction: trivalent, six electron C atom, C atom is sp2 hybrided, empty P orbital and
electron-deficient(attack by nuclephile)
Most carbocations are very unstable and can’t be isolated. They exist only a transient, highenergy intermediates which should be directly related to the stabilities of the carbocation.
How to stabilize the carbocation?
1. Lone-pair stabilization
resonance
Inductive effect
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Carbocation Stabiity
2. Interaction with π bonds
Benzylic
Aromatic
3. Interaction with σ bonds
Hyperconjugation: The bonding pair of electrons in the σ orbitals can delocalize into partly
P orbital.
Stability
>
>
1o cabocation
2o cabocation
6 adjacent C-H bonds 3 adjacent C-H bonds
3o cabocation
9 adjacent C-H bonds
The order of stabilization:
Lone pair > π bonds > σ bonds
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Carbocation Generation
1. Ionization of a C-X+ bond: depend on stability of carbocation and the leaving group(X)
Resonance and lone pair
Good leaving group(HOTs) and
2o carbocation
Resonance
Lewis acids(BF3, AlCl3, FeCl3, TiCl4, ZnCl2…) can promote the ionization
Silver salts(AgNO3, AgOTf, Ag2O) can promote the ionization of carbon-halogen
Carbocation Generation
2. A lone pair on a heteroatom in a C=X bond react with H+ or Lewis acids.
(a) X= O
(b) X= N
3. A C=C π bond react with a H+ or Lewis acids.
(a)
(b)
Why not the structure below?
(c)
(d)
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Typical Reactions of Carbocation
1. Addition of a nuclephile (SN1):
stable carbocation (2o or 3o carbocation)
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 alert
The SN1 mechanism is almost always operative for
substitution at C under weakly acidic condition.
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Substitution by the SN1 and SN2 Mechanisms
SN 2
SN1
SN1: loss configurational purity is usually observed
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Typical Reactions of Carbocation
2. Fragmentation to give a stable cation(E1)
Y
Y
X= C, N, O
Y+= H+, R3Si+, R3Sn+
Please draw the mechanism.
(a)
(b)
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.
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Typical Reactions of Carbocation
3. 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
In general, smaller groups migrate before larger ones
Ph > H > Me > CHMe2 > CMe3
1, 2-alkyl shift
1, 2-hydride shift
2o
3o
Often a 1,2-shift is concerted with loss of the leaving group. The leaving groups is always
trans(antiperiplanar) to the migrated group.
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Beckmann and Pinacol Rearrangement
Beckmann rearrangement (trans to the OH shifts selectively)
Pinacol rearrangement
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Exercises
Please draw the mechanism.
(a)
(e)
(b)
(f)
(c)
(d)
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Typical Reactions of Carbocation
Koch-Haaf Carbonylation (2o or 3o alcohol to acid)
1. H2SO4
2. CO, H2O
Mechanism:
Please draw the mechanism
(a)
(b)
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Typical Reactions of Carbocation
Nazarov Cyclization (cationic ring-clothing reaction)
H+ or Lewis acid
3o carbocation
2o carbocation
Please draw the mechanism of the following reactions.
(b)
(a)
Lewis acid
Lewis acid
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Typical Reactions of Carbocation
Prins reaction
Mechanism:
Please draw the mechanism.
(a)
(b) Total synthesis of Exiguolide
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Chapter Three
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
Electrophilic Addition to Nuclephilic C=C Bonds
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Ex
Dihydropyran(DHP) is a protecting group for alcohol
deprotection
DHP
THP ether
Alkenes can react with peracids(RCO3H) or halogen(Br2, NBS, I2) to form three member ring.
mCPBA (metachloroperbenzoicacid)
expoxide
halonium ions
Please draw the mechanism.
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Electrophilic Addition to Nuclephilic C=C Bonds
Please draw the mechanism.
Mechanism:
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Electrophilic Addition to Nuclephilic C=C Bonds
Please draw the mechanism.
(a)
(b)
(c)
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Chapter Three
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
Electrophilic Aromatic Substitution (SEAr)
Mechanism:
R is donating group
Activate the reaction, substituted at ortho- and para-
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Electrophilic Aromatic Substitution (SEAr)
R is withdrawing group
Deactivate the reaction, substituted at meta-
Electrophilic Aromatic Substitution (SEAr)
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R group
I: Inductive effect, M: mesomeric effect(resonance effect)
+I: Z is donating group
-I: Z is withdrawing group
+M: It can form resonance structure
-M: It can not form resonance structure
Steric effect:
Ortho effect: usually H bond
X is donating group
major
a > b >> c
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Exercises
(a)
(b)
(c)
Electrophilic Aromatic Substitution (SEAr)
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Friedel-Crafts reactions: The carbocation will be attacked by an aromatic ring to form a whelandtype intermediate, which leads to s substituted aromatic system
a. Friedel-Crafts alkylation
R-X:
wheland intermediate
R-F > R-Cl > R-Br > R-I
Aromatic:
Electron-rich aromatic ring react very well(pheol, aryl ether)
>
>
>
Mechanism:
Which position is better and why?
b
Draw the mechanism of following reaction?
(a)
a
(b)
(c)
Electrophilic Aromatic Substitution (SEAr)
b. Friedel-Crafts acylation:
Acyl halide react with lewis acid to form
stabilized acylium ion. This can be attacked
by a aromatic ring and aromatization gives
an aryl ketone.
Mechanism:
Draw the mechanism of following reaction?
(a)
(c)
(b)
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Electrophilic Aromatic Substitution (SEAr)
c. Vilsmeier-Haack reaction:
Mechanism:
d. Haworth reaction:
(b)
(c) Haworth reaction
Draw the mechanism of following reaction?
(a)
Aromatic Substitution of Anilines via Diazonium Salts
Sandmeyer reaction
a. Diazonium salts
Mechanism:
b. Substitution by Nu- (SRN1): Nuclephile is H3PO2, CuCN, MX(CuX, KI, KBr…)
Mechanism:
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Aromatic Substitution of Anilines via Diazonium Salts
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b. Substitution by Nu- (SN1): Nuclephile is H2O, BF4Neither H2O nor BF4- are oxidizable enough to transfer an electron to the aryldiazonium ion,
only SN1 mechanisms are reasonable for these reactions.
Draw the mechanism of following reaction?
(a)
(b)
(c)
(d) Consider the stereochemistry of the product.
(e)
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Electrophilic Aliphatic Substitution
Mechanism:
Draw the mechanism of following reaction?
Sakurai reaction
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Chapter Three
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
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Nuclephilic Addition to Carbonyl π bond
Amides and nitriles are hydrolyzed to carboxylic acids by a similar mechanisms.
Draw the mechanism of following reaction?
Nuclephilic Addition to Carbonyl π bond
Ketones and aldehydes can be interconverted with acetals(ketal).
Draw the mechanism of following reaction?
(a)
(b)
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Nuclephilic Addition to Electrophilic π bond
Robinson annulation (Michael addition and aldol reaction)
Michael addition
Aldol reaction
elimination
Nuclephilic Addition to Electrophilic π bond
Mannich reaction
Mechanism 1:
Mechanism 2:
Mechanism 3:
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Thanks For Your Attention
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