Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at...

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Polar Reaction Under Acidic Conditions a. Carbocations b. Substitution and β-elimination reactions at C(sp 3 )-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
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Transcript of Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at...

Page 1: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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

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Page 2: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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

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Page 3: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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

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Page 4: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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)+

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Page 5: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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

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Page 6: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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.

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Page 7: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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

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Page 8: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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.

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Page 9: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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

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Page 10: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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

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Page 11: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

Please draw the mechanism.

(a)

(b)

NH2OHO

H2SO4

MeMe

OH

Me

HCl

MeMe

Me

Cl

(c)

(d)

(e)

(f)

Exercises11

Page 12: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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

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Page 13: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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+

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Page 14: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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

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Page 15: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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

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Page 16: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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

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Page 17: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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

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Page 18: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

Please draw the mechanism.

(a)

(b)

(c)

Electrophilic Addition to Nuclephilic C=C Bonds18

Page 19: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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

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Page 20: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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

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Page 21: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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

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Page 22: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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

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Page 23: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

Exercises(a)

(b)

(c)

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Page 24: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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

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Page 25: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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)

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Page 26: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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

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Page 27: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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

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Page 28: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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.

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Page 29: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

Electrophilic Aliphatic Substitution

Draw the mechanism of following reaction?

Mechanism:

Sakurai reaction

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Page 30: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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

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Page 31: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

Nuclephilic Addition to Carbonyl π bond

Draw the mechanism of following reaction?

Amides and nitriles are hydrolyzed to carboxylic acids by a similar mechanisms.

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Page 32: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

Nuclephilic Addition to Carbonyl π bondKetones and aldehydes can be interconverted with acetals(ketal).

Draw the mechanism of following reaction?

(a)

(b)

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Page 33: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

Robinson annulation (Michael addition and aldol reaction)

Nuclephilic Addition to Electrophilic π bond

Michael addition

Aldol reaction

elimination

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Page 34: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

Nuclephilic Addition to Electrophilic π bondMannich reaction

Mechanism 1:

Mechanism 2:

Mechanism 3:

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Page 35: Polar Reaction Under Acidic Conditions a.Carbocations b.Substitution and β-elimination reactions at C(sp 3 )-X c.Electrophilic addition to nuclephilic.

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Thanks For Your Attention