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Aldehydes and Ketones: Nucleophilic Addition to the Carbonyl ..., Study notes of Organic Chemistry

Carbonyl carbons are electrophilic sites and can be attacked by nucleophiles. The carbonyl oxygen is a basic site. Acetals are geminal diethers - structurally ...

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115
Chapter 17: Aldehydes and Ketones: Nucleophilic Addition
to the Carbonyl Group
17.1: Nomenclature (please read)
suffix: –al for aldehydes
–one for ketone
17.2: Structure and Bonding: The Carbonyl Group: Carbonyl
groups have a significant dipole moment
C
O
δ +
δ -
Aldehyde 2.72 D
Ketone 2.88
Carboxylic acid 1.74
Acid chloride 2.72
Ester 1.72
Amide 3.76
Nitrile 3.90
Water 1.85
C
O
C
O
Carbonyl carbons are electrophilic sites and can be attacked
by nucleophiles. The carbonyl oxygen is a basic site.
116
17.3: Physical Properties (please read)
17.4: Sources of Aldehydes and Ketones (Table 17.1, p. 693)
1. Oxidation of Alcohols
a. Oxidation of 1° and 2° alcohols (Chapter 15.9)
b. From carboxylic acids and esters (Chapter 15.3)
c. Ketones from aldehydes
pf3
pf4
pf5
pf8
pf9
pfa
pfd
pfe
pff

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Chapter 17: Aldehydes and Ketones: Nucleophilic Addition

to the Carbonyl Group

17.1: Nomenclature (please read)

suffix: –al for aldehydes

–one for ketone

17.2: Structure and Bonding: The Carbonyl Group: Carbonyl

groups have a significant dipole moment

C

O

Aldehyde 2.72 D

Ketone 2.

Carboxylic acid 1.

Acid chloride 2.

Ester 1.

Amide 3.

Nitrile 3.

Water 1.

C

O

C

O

Carbonyl carbons are electrophilic sites and can be attacked

by nucleophiles. The carbonyl oxygen is a basic site.

17.3: Physical Properties (please read)

17.4: Sources of Aldehydes and Ketones (Table 17.1, p. 693)

1. Oxidation of Alcohols

a. Oxidation of 1° and 2° alcohols (Chapter 15.9)

b. From carboxylic acids and esters (Chapter 15.3)

c. Ketones from aldehydes

2. Ozonolysis of alkenes (Chapter 6.12)

3. Hydration of alkynes (Chapter 9.12)

4. Friedel-Crafts Acylation – aryl ketones (Chapter 12.7)

17.5: Reactions of Aldehydes and Ketones: A Review and a Preview

Reactions of aldehydes and ketones (Table 17.2, p. 695)- Review:

1. Reduction to hydrocarbons (Chapter 12.8)

a. Clemmenson reduction (Zn-Hg, HCl)

b. Wolff-Kishner (H

NNH

, KOH, Δ)

Acid-catalyzed mechanism (p. 700):

protonated carbonyl is a better electrophile

Does adding acid or base change the amount of hydrate?

Does a catalysts affect ΔG

o

, ΔG

, both, or neither?

The hydration reaction is reversible

17.7: Cyanohydrin Formation

Addition of H-CN to the aldehydes and unhindered ketones.

(related to the hydration reaction)

The equilibrium favors cyanohydrin formation

Mechanism of cyanohydrin formation (p. 701)

17.8: Reaction with Alcohols: Acetals and Ketals

Acetals are geminal diethers - structurally related to hydrates,

which are geminal diols.

R R

C

O

OH

C

O H

R

R

+ H

2

O

- H

2

O

hydrate

(gem-diol)

aldehyde hemi-acetal acetal

(gem-diether)

ketone hemi-ketal ketal

(gem-diether)

R H

C

O

OR'

C

O H

R

H

+ R'OH

- R'OH

+ R'OH

- R'OH

OR'

C

OR'

R

H

+ H

O

R R

C

O

OR'

C

O H

R

R

+ R'OH

- R'OH

+ R'OH

- R'OH

OR'

C

OR'

R

R

+ H

O

Mechanism of acetal (ketal) formation is acid-catalyzed (p. 705)

The mechanism for acetal/ketal formation is reversible.

How is the direction of the reaction controlled?

Dean-Stark

Trap

O

a) NaNH 2

b) H

3

C-I

O

CH

3

The reaction cannot be done directly, as shown. Why?

Aldehyde

or ketone

hemi-acetal

or hemi-ketal

acetal

or ketal

17.10: Reaction with Primary Amines: Imines (Schiff base)

Aldehyde

or ketone carbinolamine Imine

O

C

R R

  • R'OH
  • R'OH

OH

C

OR'

R

R

  • R'OH
  • R'OH

OR'

C

OR'

R

R

  • H 2

O

  • H 2

O

OR'

C

R R

O

C

R R

  • R'NH

2

  • R'NH

2

OH

C

NHR'

R

R

  • R'NH 2
  • R'NH

2

NHR'

C

NHR'

R

R

  • H 2

O

  • H

2

O

N

C

R R

R'

Mechanism of imine formation (p. 709):

See Table 17.4 (p. 712) for the related carbonyl derivative,

oximes, hydrazone and semicarbazones (please read)

O

N

N-C 6

H 5

H 2

NOH

N

OH

phenylhydrazone oxime

C 6

H 2

NHNH 2

N

H 2

NHNCONH 2

N

H

NH

2

O

semicarbazide semicarbazone"

17.11: Reaction with Secondary Amines: Enamines

R R

C

O

NHR'

C

O H

R

R

  • H 2

O

R R

C

N

R'

R'NH 2

1° amine:

2° amine:

Imine

Iminium ion

R R

C

O

N

C

O H

R

R

R'

N

H

R'

R'

R'

R R

C

N

R' R'

  • HO

_

iminium ion enamine

ketone with

α -protons

Mechanism of enamine formation (p. 713)

R

C

O

N

C

O H

R

- HO

R'

N

H

R'

R'

R'

R

C

N

R' R'

R

H H R

H

H

R

H H

R

C

N

R' R'

R

H

_

- H

17.12: The Wittig Reaction

1979 Nobel Prize in Chemistry: Georg Wittig (Wittig Reaction) and H.C. Brown (Hydroboration)

The synthesis of an alkene from the reaction of an aldehyde

or ketone and a phosphorus ylide (Wittig reagent), a dipolar

intermediate with formal opposite charges on adjacent atoms

(overall charge neutral).

R

1

C

R

2

O

R

4

Ph C

3

P

R

3

R

3

C C

R

2

R

1

R

4

+ Ph

3

P=O

aldehyde

or ketone

triphenylphosphonium

ylide (Wittig reagent)

alkene triphenylphosphine

oxide

Accepted mechanism (p. 716)

• There will be two possible Wittig routes to an alkene.

• Analyze the structure retrosynthetically , i.e., work the synthesis

out backwards.

• Disconnect (break the bond of the target that can be formed by

a known reaction) the doubly bonded carbons. One becomes

the aldehyde or ketone, the other the ylide.

R 3

C C

R

2

R

1

R 4

Disconnect

this bond

C

R 2

R 1

O

R 3

C

R 4

Ph

3

P

C

R 2

R 1

PPh

3

R

3

C

R

4

O

- OR -

C C

CH 3

CH 2

CH 2

H

CH

3

CH

2

CH

3

17.13: Stereoselective Addition to Carbonyl Groups

(please read)

17.14: Oxidation of Aldehydes

Increasing oxidation state

C C

C C

C C

C OH C O

C

O

OR

CO

2

C NH

2 C NH C N

C Cl C Cl

Cl

C Cl

Cl

Cl

C Cl

Cl

Cl

Cl

RCH

2

- OH

R H

O

R H

HO OH

R OH

O

hydration

H

3

O

acetone

H

2

Cr 2

O

7

1 ° alcohol

H

3

O

,

acetone

H

2

Cr

2

O

7

H

2

O

CH

2

Cl

2

PCC

OH

CO 2

H CHO

1 ° alcohol

H

3

O

acetone

H

2

Cr

2

O

7

Carboxylic Acid Aldehyde

Aldehydes are oxidized by Cr(VI) reagents to carboxylic acids

in aqueous acid. The reactions proceeds through the hydrate

See Chapter 15.

Baeyer-Villiger Oxidation of Ketones. Oxidation of ketones

with a peroxy acid to give as esters (p. 732)

R R'

O

O

O

Cl

O H

R O

O

R'

ester

OH

O

Cl

Oxygen insertion occurs between the carbonyl carbon and

the more substituted α-carbon

CH 3

O

H 3

C

O

mCPBA

mCPBA

O

O

O

O

H C

H NMR Spectra of Aldehydes and Ketones: The

H chemical shift

range for the aldehyde proton is δ 9-10 ppm

The aldehyde proton will couple to the protons on the α-carbon

with a typical coupling constant of J ≈ 2 Hz

A carbonyl will slightly deshield the protons on the α-carbon;

typical chemical shift range is δ 2.0 - 2.5 ppm

δ = 9.8, t,

J = 1.8, 1H

δ = 1.65, sextet,

J = 7.0, 2H

δ = 2.4, dt,

J = 1.8, 7.0, 2H

δ = 1.65, t,

J = 7.0, 3H

δ= 2.5 (2H, q, J = 7.3)

2.1 (3H, s)

1.1 (3H, t, J = 7.3)

H

C H

C C CH

O

δ 7.0 -6.0 δ 2.7 - 1.

δ= 6.8 (1H, dq, J = 15, 7.0)

6.1 (1H, d, J = 15)

2.6 (2H, q, J = 7.4)

1.9 (3H, d, J = 7.0 )

1.1 (3H, t, J = 7.4)

C

C

CH

2

CH

3

C

O

H

3

C

H

H

C NMR:

The intensity of the carbonyl resonance in the

C spectrum

usually weak and sometimes not observed.

The chemical shift range is diagnostic for the type of carbonyl

ketones & aldehydes: δ = ~ 190 - 220 ppm

carboxylic acids, esters, δ = ~ 165 - 185 ppm

and amides

CDCl 3

O

carbonyl

carbonyl

O

H C 3

CH 2

CH 2

C OCH 2

CH 3

C

9

H

10

O

2

1H

s

2H

d, J = 8.

2H

d, J = 8.

2H

q, J= 7.

3H

(t, J= 7.5)

IR: 1695 cm

13

C NMR: 191

2H

2H

(q, J = 7.3)

5H

C

10

H

12

O

IR: 1710 cm

13

C NMR: 207

3H

(t, J= 7.3)