17.3 How Aldehydes and Ketones React (Part II)

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C

O

C

O

C

O

YR

d+

R = alkyl or aryl (C)Y = alkyl, aryl or H (class II) (No leaving group)

d-Electron rich (Lewis base, Nu)

Electron deficient (Lewis acid, E+)

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Nucleophilic Addition (Class II)

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1. General mechanism in basic condition:

C

O

R'(H)R

+ Z+ H+

C

O

RC

O

R'(H)

R Z- H+

C

OH

R'(H)

R Z

2. General mechanism in acidic condition:

C

O

R'(H)RZ

+ H+

C

O

R- H+

C

OH

R'(H)

R ZC

O

R'(H)R

H

Important pKa to Remember

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Names AcidsH-Z

Approx. pKa

Conjugate Base, :Z General Roles of :Z

Alkane (2°) 51 Base as Li+ saltNucleophile as Grignard reagent

Amine 38 Base and Nucleophile

Hydrogen 35Base in NaH, CaH2Nucleophile in LiAlH4, NaBH4

Alcohol water 15-16 Often as a base but can be a

nucleophile

Ammonium 10-11 Weak base, but can be a nucleophile

Thiol 10-11 Nucleophile

Carboxylic Acid 4-5 Weak base, poor leaving group

Hydrochloric Acid -7 Leaving group, poor nucleophile

H3CCH

H3CH

H3CCH

H3C

HN

HH

HN

H

H H H

R O H R O

RNH

HH

RNH

H

SR H R S

HRCO2 RCO2

HCl Cl

Types of Nucleophile for Class II Carbonyl Groups

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1. Carbon as the nucleophilic atom

HC H+C +

pKa = 50

Basic condition

2. Hydrogen as the nucleophilic atom

carboanion

H hydride Mostly basic condition

3. Nitrogen as the nucleophilic atom1° and 2° amines Mostly acidic condition

4. Oxygen as the nucleophilic atomAcidic condition

NH2

1° alcoholsOH

HCC H+CC +pKa = 25 Acetylide ion

Nitrogen as the Nucleophilic Atom

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pKa of amines.

HN H+N +

pKa = 38

1° and 2°Amines function as weak bases or nucleophiles.

HN H+N +

pKa = 9-10

3° Amines function as weak bases.

Reactions of Aldehydes and Ketones with Amines

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General Reactions:

O

CCR

H

H+

H2N R+

N

CCR

H

R

+ H2O1° Amines

imine (Schiff base)

O

CCR

H

H+

HN R+

R'

N

CCR

R

+ H2O

R'

2° Aminesenamine

Reactions of Aldehydes and Ketones with Primary Amines

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Examples:O

CCH3

H+

H2N CH2CH3+

NCH2CH3

CCH3 + H2O

NH2

OHC CH2CH3+H+ N

+ H2O

CH2CH3

Reactions of Aldehydes and Ketones with Secondary Amines

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Examples:

O

CCH3

H+N+

H

N

CCH2 + H2O

O+

NH

H+ N+ H2O

Mechanism for the formation of Imines

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C

O

CH3H3CPh

N

H H

C

O

NH3C

HH3C

Ph

H

C

O

NH3CH3C

Ph

H A-

H A

H

AH

A-

C

O

NH3CH3C

Ph

H

A-

H

H

C

O

N

H3C

H3C

Ph

H

A-

H

H

C

O

N

H3C

H3C

Ph

H

A

H

H

Mechanism for the formation of Enamines

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O

N

H

O

N

H

O

N

H A-

H A

AH

A-

O

N

H

A-

H

O

N

H

A-

H

H

O

N

H

A

H

H

Optimal pH for the Formation of Imines

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C

O

CH3H3CPh

N

H H

C

O

NH3C

HH3C

Ph

H

C

O

NH3CH3C

Ph

H A-

H A

H

AH

A-

C

O

NH3CH3C

Ph

H

A-

H

H

C

O

N

H3C

H3C

Ph

H

A

H

H

pKa = 9-10pKa = -2

The highlighted protons are quite acidic.

Strong acid will protonate the amines.

Optimal pH: 4 – 5 (ex: acetic acid) pH

Rate of rxn

0 4 5 10

Formation of Imine Derivatives

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O

CR'(H)R

H+

H2N OH+N

CR'(H)R

OH

+ H2OHydroxylamineOxime

O

CR'(H)R

H+

H2N NH

+C

NH2

O

N

CR'(H)R

HN

+ H2O

CNH2

Osemicarbazidesemicarbazone

O

CR'(H)R

H+

H2N NH

+R"

N

CR'(H)R

HN

+ H2O

R"

hydrazine

hydrazone

Application of Imine: Reductive Amination

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General reaction

The reaction can be conducted in one-pot fashion.

O

CR'(H)R

H+

H2N R"+N

CR'R

R"

Generatedin situ

H2, Pd/C

NaBH3CN

HN

CR'R

R"

H

HN

CR'R

R"

H

The use of NaBH3CN is important since it can tolerate the acidic condition.

Examples of Reductive Amination

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O

H2NCH2CH3, H2/Pt/CHOAc

NH

H

O H2NC6H5NaBH3CN, HOAc

NH

H2NCH2C6H5, NaBH3CNHOAc

CHO

HN

Application of Oxime: Beckmann Rearrangement

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Developed by the German chemist Ernst Otto Beckmann (1853–1923)

O

H2NOH, H+

NOH

H+, heat

O

NH

2-azacycloheptanone(a lactam)

nylon

NH

HN

O

O

n

oxime

Beckmann Rearrangement: Synthesis of Azithromycin

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Developed by a team of researchers at the Croatian pharmaceutical company Pliva in 1980.

lactam Azithromycin

O

MeO

OH

O

OH

Me

Me

MeO

Me

OH

Me

Et

OO

OHNMe2

Me

O OH

OMe

Me

Me

H2NOHH+

NOH

MeO

OH

O

OH

Me

Me

MeO

Me

OH

Me

Et

OO

OHNMe2

Me

O OH

OMe

Me

Me

H+

heat

Erythromycin oxime

HN

MeO

OH

O

OH

Me

Me

MeO

Me

OH

Me

Et

OO

OHNMe2

Me

O OH

OMe

Me

Me

OHN

MeO

OH

O

OH

Me

Me

MeO

Me

OH

Me

Et

OO

OHNMe2

Me

O OH

OMe

Me

Me

Mechanism of Beckmann Rearrangement

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O

H2NOH, H+

NOH

+ H+

- H+

NO

H

H

O

NH

NH2O

O

N

H H

H+

+ H+

O

NH

H

- H+

Application of Hydrazone: Deoxygenation of Carbonyl Groups

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the Wolff–Kishner reduction

O

RH2NNH2, KOH

H2Oheating

R

Mechanism of the Wolff–Kishner Reduction

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CH3C

N N

H

H

HO

H

O H

C

O

H3C

H2N NH2

C

O

H3C

H2N N

H

O H

H

C

O

H3C

H2N NH

HO

H

C

O

H3C

H2N N

H OH

H

O H

CH3C

HN N

H

HO

H

O HHO

H

O H

CH3C

N N

H

H

O H

HO

H

Application of Hydrazone: Use of 2,4-DNP

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2,4-Dinitrophenylhydrazine (2,4-DNP)

R R'(H)

O

2,4-DNP

NO2

HN

N

R'(H)

R NO2

General reaction:NO2

HN

NH2 NO2

The hydrazones have specific m.p.

Aldehyde or ketone Acetone Diethyl

ketone Cyclohexanone Benzaldehyde

m.p. of hydrazone (°C) 126 156 162 237

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Learning Check1. What could be the best reagents for the following reaction?

O reagents(a) H2NEt and CH3CO2H

(e) None of the above

NCH2CH3(b) H2NEt and HCl

(c) H2NEt and NaOH (d) H2NEt and Na+-OCH3

2. What could be the product for the following reaction?

O

CH3

CH3NH2H+, removal of water

NCH3

CH3

Product ?

NHCH3

O

OH

O NHCH3

CH3

I II III IV

H3CHN

(a) I(b) II(c) III(d) IV(e) None of the

above

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Learning Check3. What could be the products for the following reaction?

O

CH2CH3 H+

, removal of waterProducts

NH

+

N N

I

N

IIIII

N N

IV

(a) I, II(b) I, II, IV(c) III, IV(d) II, III(e) None of the above

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Learning Check4. What could be the product for the following reaction?

O H2NOH, H+

heat

NHOH

(a)NOH

(b) (c)NH

O(d)

NH(e) None of the above

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