Carbonyl s

November 16, 2018 | Author: jonty777 | Category: Aldehyde, Ketone, Functional Group, Chemical Compounds, Physical Sciences
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reactions of carbonyl components...

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Reactions of Carbonyl Compounds

  Outline 1. Addition to the carbonyl group of aldehydes and ketones 2. Reduction of aldehydes and ketones 3. Reaction of aldehydes and ketones with the Gringard Reagent 4. Reactions of aldehydes and ketones with ammonia and its derivatives 5. The Wittig Reaction 6. Oxidation of aldehydes and ketones 7. Aldehydes Aldehydes and ketones keto nes as electrophiles 8. Acidity and basicity of carboxylic acids 9. Conversion of carboxylic acids to esters 10. Conversion of carboxylic acids to acid chlorides and anhydrides 11. Decarboxylation

  Outline 1. Addition to the carbonyl group of aldehydes and ketones 2. Reduction of aldehydes and ketones 3. Reaction of aldehydes and ketones with the Gringard Reagent 4. Reactions of aldehydes and ketones with ammonia and its derivatives 5. The Wittig Reaction 6. Oxidation of aldehydes and ketones 7. Aldehydes Aldehydes and ketones keto nes as electrophiles 8. Acidity and basicity of carboxylic acids 9. Conversion of carboxylic acids to esters 10. Conversion of carboxylic acids to acid chlorides and anhydrides 11. Decarboxylation

12. Reactions of carboxylic acid derivatives with nucleophiles 13. Hydrolysis of carboxylic acid derivatives 14. Reduction of carboxylic acid derivatives 15. Formation of enoles and enolates 16. Reactions of aldehydes and ketones, involving enolates 17. Reactions of esters and acids, involving enolates 18. Reactions of -unsaturated carbonyl compounds 19. Reactions of -halocarbonyl compounds

1. Addition to the carbonyl group of aldehydes and ketones CH2 1.34 A H3 C

O 1.21 A

H

H

H 3C

The carbonyl group (C=O bond) is shorter, stronger, and more polar, than the C=C bond CH2

Reacts with acids

O O

H3 C

CH3

H 3C

 b.p. = -6.9 oC

 b.p. = 56.5 oC

 = 0.5D

 = 2.7D

Unsoluble in water 

Reacts with nucleophiles

CH3

Soluble in water 



CH2 H

Aldehydes (R is H) or  ketones (R is not H)

Reacts with bases



OH

-

O

O

 Nu-

 Nu

R 1

R 1 +

O

+

 Nu

H





R 1 O

+

H

H

 NuO

H

+

C R 

R 1



R 1



R 1

Activation of the carbonyl group

Aldehydes are more reactive, than ketones due to the steric reasons and a larger  positive charge charge on the carbonyl carbon in aldehydes. Addition to C=O bonds is faster, than addition to C=C bonds due to the higher  polarity of the C=O bond, but less favorable thermodynamically thermodynamically due to the stronger C=O bond vs. the C=C bond. Example: Cyanohydrin synthesis

Acetals and their use in synthesis O

OH +

R 2OH, H  or OH R 

-

OR 2 R 

R 1

OR 2

R 2OH, H+

OR 2

R 1



R  acetal 1 hemiacetal Stable at neutral conditions Stable at neutral and alkaline conditions

+

HO

OH

R 2

H

OH

+

O R 



R 1

R 2

R 1

+

H

O

OH OR 2

H R 

R 1

O

-

O -

O





R 1 hemiacetal

OR 2

R 2

R 2

H

+

H OR 2

O

OR 2

OR 2 +

OH





R 1

H

acetal

R 1 OR 2

+

OR 2

O OR 2



R 1 hemiacetal

H

+



R  O

C

Examples:

H

R 2

R 1

OCH3

O

OCH3

+

CH3

CH3OH, H

CH3 Methyl phenyl ketone dimethylacet

O

O HOCH2CH2OH, H+

O

R 1

R 2

2. Reduction of aldehydes and ketones O

OH  NaBH 4 CH3OH



R 1

H R 

R 1

CH3 H

O

O

OH H



H

R 1

CH3 H

-

B H



H

R 1

O

+ H

-

B H

H This anion can reduce three more carbonyl gro

The carbonyl group can be reduced by catalytic hydrogenation, but it is less reactive, than the C=C bond OH

H H2, Ni Heat, pressure

O

H H2, Pd/C

O

Cannizzaro Reaction

Crossed Cannizzaro Reaction O

OH

H O

+

H

O

OH-, H2O H

+

H

-

O

3. Reaction of aldehydes and ketones with the Gringard Reagent (ORA 737) Synthesis of Grignard reagents Most hydrocarbons are so weak acids, that it is practical to substitute hydrogens with metals indirectly (ORA 737) Solvent CH2 H3C

(C2H5)2O

+

Mg Heat

Br 

CH2 H3C

MgBr 

Grignard's reagent Li

(C2H5)2O

Ethyl magnesium bromide

CH2 H3C

Li

 -

CH2

H3C

 + MgBr 

+

H2O

H3C

CH3

+

Mg(OH)Br

 Nucleophilic addition of Grignard reagents to the carbonyl group

Depending on R, R 1, and R 2, the reaction can produce primary, secondary or tertiary alcohols. R-Li is often used instead of R-MgBr. Example: O

OH 1. CH3(CH2)3Li

H3C

CH3

2. H+, H2O

H 3C

(CH2)3CH3 CH3

80%

If the ketyl radical is stabilized, the reaction switches to the redox-path

4. Reactions of aldehydes and ketones with ammonia and its derivatives

.

O

.

C

+

 N

.

R 2

O C

.

H

-

.

R 1

+

 N

H

R 3

R 1

.

R 2 R 3

if R 1 = H

.

.

.

.

. C

H

OH

if R 2 = H .  N

R 3

-H2O

imine, if R 3 starts from H or C oxime, if R  3  = OH hydrazone, if R  3 = NH2

C H

R 2

-H2O

.

C R 2

 N

. carbinolamine

 N R 3

. enamine

R 3

Examples:

O

H

H

 NH2 Heat

+

 N

-H2O  NH2

H3C

H N O

O2 N

 NO2

+

 N

-H2O

CH3

H3C

Heat H3C

 NO2

O2 N  NH

 NO2

O2 N H 3C

H3C

O

 NH

+

H3C

H+

 N

-H2O

H

H 3C

CH3

H

H3C H2 N

O

 N

+

H2 N

 NH2

KOH

Heat -N2

Imine formation (ORA 726)

82%

CH3 HN H3C

H3C

H+

O

+

H

H3C

H3C

- H 2O

N H

H3C

Enamine NH2

O N

CH3

+

CH3

KOH H2N

NH2

Hydrazone NH2 N CH3

CH3

KOH - H 2O 82% OH-

Wolff-Kishner reaction

- H2O

- OH-

-

NH N

CH3

H H

- OH

- N2

N

CH3

O

-

NH

OH-

-

-H O

N N

CH3 H O

H

5. The Wittig Reaction (ORA 745) O

Ph Ph

P Ph O

CH2

Ph

+

-

+

H2C

Ph

P

Ph

+

O

Ph

Ph

P Ph

 NaH Ph

Ph H 3C

+

Ph

P -

Br 

Br 

Ph

S N2

CH3

Ph

P Ph

This reaction is a common method for conversion of carbonyl compounds to alkenes

6. Oxidation of aldehydes and ketones O R  H

O

KMnO4, H2O, H+ or K 2Cr 2O7, H2O, H



+

OH

O

O

Silver mirror test

Ag2O, H2O, NH3 R 

+

R  H

-

Ag

O

Tollen’s

Reagent R  R 

O

O

+

O

+

KMnO4, H2O, H R 1

R 1

OH

OH

O

O

Heat R 1

+

+ OH

R  OH

Bayer-Villiger oxidation (ORA 989)

8. Acidity and basicity of carboxylic acids O

-

O +



H

+

O



R  -

OH

O

O

Carboxylic acids are stronger acids, than phenol, because the conjugate base (carboxylate) is stabilized by the delocalization of the negative charge between two electronegative oxygens.  Acidity trend:

OH

OH

<

HO 3S

O

<



< OH

 pK a = 16

 pK a = 10

 pK a = 5

 pK a = -1

O

+

O

+

H

H

+



R  O

+

H

O R 

H

+



OH

H

O C

H

OH

O

H

H

O R  O

+

H

9. Conversion of carboxylic acids to esters

Fischer esterification (ORA 896) O

O +

+



H



CH3OH

O

OH

OCH3

+

H



H +

O

H

O

O

H

~H+ R 



CH OH

R  +

OH

OH

O H

CH

C O

+

H

+

OH

O CH

CH3

H

Alkylation of salts O

H3 C

O

I



R  -

+

O  Na

OCH3

Alkylation of acids by diazomethane

solvent O

O

+



(C2H5) 2O CH2 N2



OH diazomethane (yellow gas)

+ OCH3

 N2

Mild formation of esters DCC (dicyclohexylcarbodiimide)

O

O

+

R   N

DCC

CH3OH



H

O

OCH3

C

-

H

H

 N

 N C

 N

O H -

 N

 N

H

 N

C

 N

 N

C ~H+

O

 N C

O

H

O +



R  +

O

H

CH3OH O



O

CH3 -

O

10. Conversion of carboxylic acids to acid chlorides and anhydrides O

O

+

R  O

+



SOCl2

HCl

+

SO 2

Cl

H thionyl chloride O

O

+

R  O



PCl5

+

HCl

+

Cl

H

O O

O

+ H3 C

H 3C O

H3C

P 2O 5

O O

H

H

acetic anhydride

H 3C O

O COOH P 2O 5

O

COOH

 phthalic anhydr ide O

POCl3

11. Decarboxylation (ORA 983) O  NaOH, melting R 

R  O

+  Na2CO3

H

H

 NaOH H2O

 NaOH

O R -



+ CO2

-

O

O slight heating CO2

O



+

R  OH

H

O

~H+



O

O slight heating O

HO O

H

CO2

+

~H+

HO

HO OH

O

12. Reactions of carboxylic acid derivatives with nucleophiles -



O

O

O



 Nu R 



X

+



X  Nu



 Nu

X

Reactions of acid chlorides (ORA 949)

O

O PhCH2CH2 NH2 Cl

 NH

Pyridine

H2 N

O

Py

-

O Cl +

 NH2

+

 NH2

O O

HO

CH3

CH3C(O)Cl CH3

H 3C

Pyridine

CH3

H3 C

75%

O

H3 C

O

OH

Py

Cl

+

H 3C CH3

CH3 CH3

O

CH3

O Cl

O

S

+ OH

O H 3C

O

O

+ Cl

+

O

Py

S O

TsCl

O

O

-

 Na O

90%

H3 C

O 60%

Reactions of anhydrides

O

 NH2

H N O

+

CH3

H2O

O O

Paracetamol

OH

OH O

OH

CH3

O COOH

+

O

COOH

H2O

O O

Aspirin O

O

O

O CH3OH, reflux

COOH O CH3 O

O

O

O

+

 NH2

Heat

O  NH OH

Acetic anhydride heat

 N

Reactions of esters

O  NH3

O

+

O

O  NH2OH O

OH

 NH2

O OH

+

 NH

OH

A hydroxamic acid (forms a red complex with Fe(II

Alkaline hydrolysis of esters (ORA 955)

Reaction of esters with Grignard reagent O

OH 1. 2CH3MgBr 



2. H+, H2O

OR 1

CH3 R 

CH3

O

H



OR 1

H3C

+

MgBr  

-

+

O Mg

Br 

CH3 R  -

+

O Mg

O

Br 

CH3 R 

OR 1

CH3

H3C R 

CH3

MgBr  

13. Hydrolysis of carboxylic acid derivatives -



O

O

O









O

+ R 

O

OR 1



R 

+ R 

OH

OH

R 1

R 

-

O

Acid-catalyzed hydrolysis of esters is the reaction of esterification, going backwards.

O

O

O

H2O 25 oC

O

Cl

H

COOH

H

COOH 94%

H2O, 0 oC 5 min

CH3COOH

+

H

O

O  NH2

55% H2SO4

OH

+

heat

 NH4HSO 4

90% O H N

 NH2

30% KOH

 NO2

 NO2

CH3OH, H2O, heat O

O

+

CH3COOK 

97%

 Nitriles are less active for hydrolysis

57% H2SO4

CN

COOH

heat O CN

KOH, H2O heat

+

 NH4HSO4 O

-

O

H+

OH

Hydrolysis of sulfonic esters O

R2

R1 S

O

O

O

+

H

 S N2

 OH-

S

O

O

R

-

+

R1

R2

H

OH

R

Alkaline and acidic hydrolysis of nitriles R R

C

N

C

~ H+

-

N

C O

O +

H R

C

N

R

C

-

C

H O

H

- OH

NH

-

HO

OH-

R

R

O H

- H+

H H

H

O

+

NH

+

~ H+ C

R

NH2

H

O

NH

C R

+

NH2

14. Reduction of carboxylic acid derivatives

a source of H

O 1. LiAlH4 R  OC2H5

R

+

2. H , H2O

CH2OH

-

H

+

H -

O R 

O R 

H

OC2H5

-

-

O

H

R  H

H

H

CN

O 1. LiAlH4 R 

2. H2O

R   NH2

 NH2

1. LiAlH4

2. H2O

74%

 NH2 H2 / Ni O

O Pd / C, H2, quinoline



R  H

Cl -78%

H +

-

Li

Al O

O

O

O

O o

1. (CH3)2CuLi, -78 C Cl

2. H2O 81%

15. Formation of enoles and enolates O a strong and polar bond .

O

-

 base

.

OH



C

acid

.

.



.

R  -

O

H

.

enol

. R  . enolate (a common conjugate base)

The equilibrium is strongly shifted toward the carbonyl form, especially in polar solvents OH

O K = 6.10-7 H3C

H

H2 C

H

In esters, enolization is even less favorable due to stabilization of the carbonyl group. O OH OC2H5

H3C

K = 10-20 OC2H5

H2C

-

O

+

OC2H5

H3C

Stabilization of the carbonyl form decreases acidity of the compound CH2

H

H2C H

OC2H5

H2C H

 pK a = 42

O

O

H

H2C H

 pK a = 25

 pK a = 17

Stabilization of the double bond (by conjugation) shifts the equilibrium toward the enol. H O

O

CH3

CH2

H3 C

O

O

CH3

CH

H 3C

92% in hexane O

HO K = 10

14

Enolization, catalyzed by acids O

+

H

+

H2 O .

R  H

OH

O

. .

H

. R 



. H

.

enol

16. Reactions of aldehydes and ketones, involving enoles and enolates a-Monohalogenation (ORA 830) O

O CH3

+

Br 

CH3COOH

Br 2

25 oC

70%

+

H

-H

H OH

O Br CH2

Br  

+

Br 

C

CH2

+

The haloform reaction CHCl3 - chloroform

CHBr 3 - bromoform

CHI3 - iodoform

O

O 1. OH-

CH3

+

Br 2

OH

2. H+

+

H

+

CHBr 3 O

-

HO

-

O

-

O

OH Br 

O

Br 

-

CH2 Br

O

Br  Br  

-

OH

HO

O

+

O Br  CH2

Br 

Two more times

Br  Br 

The reaction also works with Cl2 and I2

-

CBr 3

Aldol reaction (acid catalyzed) R 4

R 1

H

+

O

O

R 2 R 3 H

+

H

R 2

+

-H2O

+

O R 2

R 1

OH

H

O R 3

+

R 4

R 1

R 4

R 1

+

OH

R 4

R 3 R 2

O R 3

R 1

OH R  4 -H H +

R 2

C R 

O

+

Aldol reaction (base catalyzed, ORA 840, 852) R 4 HO R 4

O

-

HO

-

R 4

R 1

-

R 2

R 3

O R 3

HC

O

-H2O

R 3 R 1

-

O

R 1

O

R 4

R 1

O R 3

R 4

H2O

R 2 R 2

OH

R 2

O R 3

Examples:

O O

O H

H2SO4

+

95%

OH

O

O Ba(OH) 2

KOH

heat

heat

O

17. Reactions of esters and acids, involving enolates Br  Br 2, PBr 3

a-Bromination of carboxylic acids

COOH

COOH

Br 

PBr 3

COOH

Br 

Br  +

H  or PBr 3

O

Br 2 Br 

O OH

-HBr 

At least two hydrogens must be there! R 2

H

1. R 3COOR 4, base

H R 2 -

2. H+

O  base

HC

R 2

O

R 3

O

R 1

H

R 1

Ketone or aldehyde or ester 

+

R 2

O -

C

O R 3

R 1

Highly acidic hydrogen R 3

-

O

R 3

O

R 2

O

H

R 2

Base

O R 4

O R 4

O R 1

R 3

O

R 1 b-Ketoester or b-diketone

O R 1

Claisen condensation O 1. NaOC2H5

O

O

2. H+

O

O 75% H

O -

H2C

+

O

O -

O

CH

O

O Base

O

-

O O

O

O O

O

O

Crossed Claisen condensation O

O

+ O

O

1. NaOC2H5 O

O

2. H+

O

H O -

CH

O O

O -

O

C

O

O O

O Base -

O O

O

O O

O

O O

O

+

O

O 86%

Dieckmann condensation O O

O

O

1. NaOC2H5 O

O

+

2. H

80%

O

Synthesis of carboxylic acids from the malonic ester R 1

COOEt R 

+

H2O, H -CO2

COOH

COOEt

COOEt

R  R 1

COOEt

Base

R 1

COOEt

COOEt R

-

HC

COOEt

Br 

COOEt

Base



R  COOEt

Br 

-

C

COOEt

Synthesis of ketones from the b-ketoesters R 



R  O

O

+

H2O, H R 1

-CO2

R 2

R 2

COOEt

O

R 1

COOEt

Base

R 2





R  O R 1

-

HC

COOEt

O

O

Br 

Br 

Base

R 1 COOEt

R 1

-

C

COOEt

18. Reactions of 

-unsaturated carbonyl compounds

Electrophilic addition O

Br 

HBr 

O

O

H

O 84%

+

~H+ O -

Br 

O

Br  +

O

H

O

H

 Nucleophilic (Michael) addition (ORA 858)  Nu  Nu-

R  O



H2O

 Nu



1,4-addition

OH  Nu

-



O

O 1,2-addition

-

 Nu

Irreversible and especially preferred by very strong nucleophiles



In most cases reversible

 Nu -

O

O

CN

O

HCN KCN OH

90% OH

O 1. (CH3)2CuLi 1. PhLi 2. H2O O

2. H2O

Selective reduction of a,b-unsaturated compounds O

O H2 Pt, 3 atm 90% O

HO 1. LiAlH4 2. H2O 98%

19. Reactions of halocarbonyl compounds O

O

 Nu-

Hal

 Nu S N2



.



Faster, than for alkyl halides

.

.

.

Slower, than for alkyl halidesS N1  NuO .

+

C

O

+

. R 

R  .

.

This structure has a little contribution to resonan 1. NaCN Cl

COOH

2. H+

 NC

COOH 80%

OH Cl

+ Cl

COOH

O 1. OHCl

COOH

Cl

2. H+ Cl

87%

(2,4-dichlorophenoxy)acetic acid

(a selective herbicide)

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