Synthesis of Ketones and Aldehydes

Chem 360 Jasperse Ch. 18 Notes. Aldehydes and Ketones

Synthesis of Ketones and Aldehydes 1

OH

Ph

PCC

OH

2

3

4

Ph

1. BH3•THF

Ph

OH

H2O, H+ Ph

PCC

OH

Ph

2. NaOH, H2O2

Ph

Ph

8.15 O

2. Me2S

Ph

OH

1. RMgBr H

Ph

2. H+

H

+

O

Ph

R

OH

1. LiAlH4 Ph

OR 2. H+

H

NaOH Br Br

9

R

Ph

H

NaOH

10

Ph C C H H2SO4 Markovnikov Addition

11

Ph C C H

OH Ph "enol"

1. (Sia)2BH Ph 2. NaOH, H2O2 Anti-Markovnikov Addition

O

6.8

O

H2CrO4

Hg2+, H2O

6.8

H R

OH

H

aldehyde

PCC

OH

10.11

O

PCC

acid or ester

R

R

Ketone

O

8

10.9

O

H2CrO4

Aldehyde

Ph

8.7

8.4

1. O3

O

7

O

O

H2CrO4

Ph

5

6

11.2

O

H2CrO4

Ph

11.2

O

Ph

H+, H2O MECH

OH "enol"

9.9F

O Ph Ketone

OH, H2O MECH

9.9F O Ph Aldehyde

1


O

12

Ph OH Ph OLi 2. H+, H2O acid carboxylate anion O

13

O

1. 2 RLi

R

14

Ph

R

Cl

Ar-H, AlCl3

R

1. RMgBr Ph R CN Nitrile 2. H+, H2O N

H

18

S R

H

S H

Ph R ketone

18.9

18.11

Aromatic ketone (from the acyl group's perspective)

1. BuLi 2. R-Br (1º) 3. Hg2+, H+, H2O

1. BuLi 2. R-Br (1º) 3.

R

H+, H2O

NH "imine"

MECH

H+ Ph

1. KCN

Br

S

MECH

Aromatic ketone (from the aryl group's perspective)

Ph

S

R

O

18.11

R

Ph CN Nitrile Intermediate (after step 1)

Primary Bromide 2. RMgBr 3. H+, H2O

17

Ph

H+, H2O

O

R Cl acid chloride

16

OH

O

O

Ph

HO

tetrahedral "hydrate"

tetrahedral dianion

AlCl3

15

acid

Ph R ketone

O H

OLi

O

R2CuLi

Ph Cl acid chloride

LiO

2

Hg2+,

H+,

H2O

S

S

H

Li

Ph

R

HO NH2 tetrahedral "aminol"

Steps 2 + 3

Step 2, SN2

H+, H2O MECH

S

R

Li

18.10

18.10

O

Step 3, S

S

H

R

S

S

R

R

Step 2, SN2

deprotonated, carbanion

R

O ketone

R

Ph

Hydrolysis

deprotonated, carbanion

S

Ph

Step 3, Hydrolysis

O H R Aldehyde

18.8

O R R Ketone

18.8


3

Reactions of Ketones and Aldehydes 19

O

1. RMgBr

R' R aldehyde or ketone

H+

2.

O R'

OH

Protonate R

R'

R anion intermediate

R

R

18.12, 10.9

Anionic Mech: Addition-Protonation. Strong nucleophile, Strongly anionic. Irreversible.

20

O R' R aldehyde or ketone

O

NaBH4 or LiAlH4

OH

Protonate

R'

R H anion intermediate

R'

H

R

18.12, 10.11

Anionic Mech: Addition-Protonation. Strong nucleophile, Strongly anionic. Irreversible.

21

O

O

KCN, HCN


R'

CN R anion intermediate

Anionic Mech: Addition-Protonation. buffered. Reversible. O

22

R'

R

18.15

CN

Medium nucleophile, Weakly anionic; literally

OH

H2O, OH-


OH

Protonate

R'

OH

R tetrahedral "hydrate"

"Hydrates" are present only as transient equilibrium species. They never form to 100% and are never isolable. Always in equilbrium their aldehyde or ketone.

18.14

Anionic Mech Forward: Addition-Protonation. Nucleophile, anionic mechanism. Reversible. Mech Reverse: Deprotonation-Elimination. Anionic mechanism. Reversible. O

23


OH

H2O, H+ R'

OH

R tetrahedral "hydrate"

"Hydrates" are present only as transient equilibrium species. They never form to 100% and are never isolable. Always in equilbrium with their aldehyde or ketone.

Cationic Mech Forward: Protonation-Addition-deprotonation. Weakly nucleophile, cationic mechanism. Reversible. Mech Reverse: Protonation-Elimination-deprotonation. Cationic E1-type mechanism. Reversible.

18.14


24

O

OH

ROH, H+


H2O, H+

R'

OR

R tetrahedral "hemiacetal"

OR

ROH, H+ H2O, H+

4

18.18, 18.19

R'

OR R acetal

Cationic Mech Forward: Protonation-Addition-deprotonation (hemiacetal) Protonationelimination-addition-deprotonation (acetal). Weak nucleophile, cationic mechanism. Reversible. Mech Reverse: Protonation-Elimination-Addition-deprotonation. (hemiacetal) protonation-elimination-deprotonation (aldehyde or ketone). Reversible. Notes: • • • •

• • • •

25

O

Reactions are reversible The “hemiacetal” is an intermediate, and can never be isolated The acetal can be isolated. Equilibrium considerations (LeChatelier’s principle) apply. When water is plentiful, things go to the left. When water is scarce or removed, and alcohol is abundant, things drive to the right. Use H2O/H+ to hydrolyze an acetal back to an aldehyde or ketone Use MeOH/H+ to convert an aldehyde to an acetal Use HOCH2CH2OH/H+ to convert a ketone to an acetal Aldehydes or ketones can be temporarily “protected” as their acetals, then later “deprotected” by hydrolysis

OH

ZNH2, H+

R' R + aldehyde H2O, H , -ZNH2 or ketone

R'

NHZ

R tetrahedral "aminol"

NZ

H+, -H2O H2O, H+

R'

18.16, 18.17

R

imine

Cationic Mech Forward: Protonation-Addition-deprotonation (aminol) Protonationelimination- deprotonation (imine). Mild nucleophile, cationic mechanism, buffered conditions. Reversible. Note: sometimes addition precedes protonation, or is concerted with protonation. Mech Reverse: Protonation-Addition-deprotonation (aminol) elimination- deprotonation (aldehyde or ketone). Reversible.

Protonation-

Notes: • “Z” can be a carbon, nitrogen, oxygen, or hydrogen atom/group. • The “aminol” can’t be isolated, it’s only present at equilibrium. • Equilibrium factors apply. Water drives to the carbonyl side; removal of water drives to the imine side.

Chem 360 Jasperse Ch. 18 Notes. Aldehydes and Ketones O

26

R'

O

H2CrO4 or Ag+ etc. H

5

R'

18.20

OH

No Mech Responsibility “Tollens test” is a common chemical test for aldehydes. Ag+ undergoes redox reaction with aldeydes to produce shiny Ag metal, or a “silver mirror”. O

27

R'

Zn(Hg), HCl R'

R

R

Acidic! Works best for aromatic ketones.

18.21

Notes: • Acidic conditions. Doesn’t work well for molecules with acid-sensitive functionality. • Works best for aromatic carbonyls. Saturated carbonyls are slower and less efficient. • Acidic nature is complementary to the basic analog below. 1. H2N-NH2

O

28

R'

R

R'

2. KOH, heat

R

Basic!

18.21

No Mech Responsibility Notes: • Basic conditions. Doesn’t work well for molecules with base-sensitive functionality. Basic nature is complementary to the acidic analog above.

OH

29

R'

CN

OH

H+, H2O

R (for prep, see Rxn 21)

R'

OH R

O hydroxy-acid

No Mech Responsibility Notes: • Unique access to 2-hydroxyacids.. Used in combination with reaction 21, the formation of the hydroxy-nitrile.

18.15