Carbonyl s

Reactions of Carbonyl

Reactions of Carbonyl

Compounds

Compounds

  Outline

  Outline

1.

1. Addition to the Addition to the carbonyl group of aldehydes and carbonyl group of aldehydes and ketonesketones 2. Reduction of aldehydes and ketones

2. Reduction of aldehydes and ketones

3. Reaction of aldehydes and ketones with the

3. Reaction of aldehydes and ketones with the Gringard ReagentGringard Reagent 4. Reactions of aldehydes and ketones with ammonia and

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

derivatives

5. The Wittig Reaction 5. The Wittig Reaction

6. Oxidation of aldehydes and ketones 6. Oxidation of aldehydes and ketones 7. Alde

7. Aldehydes and ketohydes and ketones as electrophilesnes as electrophiles 8.

8. Acidity and basicity of Acidity and basicity of carboxylic acidscarboxylic acids 9. Conversion of carboxylic acids to esters 9. Conversion of carboxylic acids to esters 10. Conversion of carboxylic acids to acid

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

anhydrides 1

  Outline

  Outline

1.

1. Addition to the Addition to the carbonyl group of aldehydes and carbonyl group of aldehydes and ketonesketones 2. Reduction of aldehydes and ketones

2. Reduction of aldehydes and ketones

3. Reaction of aldehydes and ketones with the

3. Reaction of aldehydes and ketones with the Gringard ReagentGringard Reagent 4. Reactions of aldehydes and ketones with ammonia and

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

derivatives

5. The Wittig Reaction 5. The Wittig Reaction

6. Oxidation of aldehydes and ketones 6. Oxidation of aldehydes and ketones 7. Alde

7. Aldehydes and ketohydes and ketones as electrophilesnes as electrophiles 8.

8. Acidity and basicity of Acidity and basicity of carboxylic acidscarboxylic acids 9. Conversion of carboxylic acids to esters 9. Conversion of carboxylic acids to esters 10. Conversion of carboxylic acids to acid

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

anhydrides 1

12. Reactions of carboxylic acid derivatives with nucleophiles 12. Reactions of carboxylic acid derivatives with nucleophiles 13. Hydrolysis of carboxylic acid derivatives

13. Hydrolysis of carboxylic acid derivatives 14. Reduction of carboxylic acid derivatives 14. Reduction of carboxylic acid derivatives 15. Formation of enoles and enolates

15. Formation of enoles and enolates

16. Reactions of aldehydes and ketones, involving enolates 16. Reactions of aldehydes and ketones, involving enolates 17. Reactions of esters and acids, involving enolates

17. Reactions of esters and acids, involving enolates 18. Reactions of

18. Reactions of 19. Reactions of 19. Reactions of

a b

a b-unsaturated carbonyl compounds-unsaturated carbonyl compounds -halocarbonyl compounds

CH CH₂₂ H H₃₃CC HH O O H H₃₃CC HH 1.34 A 1.34 A _{1.21 A1.21 A}

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

CH CH₂₂ H H₃₃CC CHCH33 O O H H₃₃CC CHCH33  b.p. = -6.9  b.p. = -6.9 ooCC   = 0.5D = 0.5D Unsoluble in water  Unsoluble in water   b.p. = 56.5  b.p. = 56.5 ooCC   = 2.7D = 2.7D Soluble in water  Soluble in water  O O R  R  CHCH22 H H Aldehydes (R is H) or  Aldehydes (R is H) or  ketones (R is not H) ketones (R is not H)

Reacts with acids Reacts with acids

Reacts with nucleophiles Reacts with nucleophiles

Reacts with bases Reacts with bases

1.

R  R  _R R  1 1 O O  Nu  Nu --R  R  _R R  1 1 O O -- Nu  Nu R  R  _R R  1 1 O O

Activation of the carbonyl group Activation of the carbonyl group

R  R  _R R  1 1 O O++ HH R  R  C C++ R  R ₁₁ O O H H H H++ R  R  _R R  1 1 OH OH  Nu  Nu  Nu  Nu --H H++

Aldehydes are more reactive, than ketones due

Aldehydes are more reactive, than ketones due to the steric reasons and to the steric reasons and a largera larger  positive char

 positive charge on the ge on the carbonyl carbon carbonyl carbon in aldehydes.in aldehydes.

Addition to C=O bonds is faster, than addition to C=C bonds due to the higher Addition to C=O bonds is faster, than addition to C=C bonds due to the higher  polarity of

 polarity of the C=O bond, the C=O bond, but less favorable but less favorable thermodynamicthermodynamically due to ally due to thethe stronger C=O bond vs. the C=C bond. Example:

Acetals and their use in synthesis R  _R  1 O R  _R  1 OH OR ₂ R  _R  1 OR ₂ OR ₂ R ₂OH, H+ or OH- _R  2OH, H + hemiacetal acetal

Stable at neutral conditions Stable at neutral and alkaline conditions

R  _R  1 O R  _R  1 OH+ R  _R  1 OH O+ R ₂ H R  O -OR ₂ H+ O H R ₂ R  _R  1 OH OR ₂ O- R ₂ O R ₂ H hemiacetal

hemiacetal H+ O R ₂ H _R  R ₁ OR ₂ O+ H R ₂ acetal R  _R  1 OH OR ₂ R  _R  1 O+ OR ₂ H H R  C+ R ₁ OR ₂ R  _R  1 OR ₂ OR ₂ Examples: CH₃ O CH₃ OCH₃ OCH₃ CH₃OH, H+

Methyl phenyl ketone dimethylacet

O O

O HOCH₂CH₂OH, H+

2. Reduction of aldehydes and ketones R  _R  1 O  NaBH₄ CH₃OH R  _R  1 OH H R  _R  1 O B -H H H H O CH₃ H R  _R  1 OH H B -H H H O CH₃ +

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

O H OH H₂, Ni Heat, pressure H₂, Pd/C O H

Cannizzaro Reaction

Crossed Cannizzaro Reaction

O H

+

+

-Synthesis of Grignard reagents C H₃ CH₂ Br 

+

Ethyl magnesium bromide (C2H5)2O Li C H₃ CH₂ Li C H₃ CH2 MgBr 

+

+

Most hydrocarbons are so weak acids, that it is practical to substitute hydrogens with metals indirectly (ORA 737)

3. Reaction of aldehydes and ketones with the Gringard Reagent (ORA 737)

 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:

CH₃ H₃C O 1. CH₃(CH₂)₃Li 2. H+, H₂O CH₃ H₃C OH (CH₂)₃CH₃ 80%

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

C O . H . . +  _N R ₁ R ₂ R ₃  N+ R ₁ R ₂ R ₃ C O -. H . . if R ₁ = H  N R ₂ R ₃ C OH . H . . carbinolamine if R ₂ = H -H₂O  N R 3 C . H . .

imine, if R ₃ starts from H or C oxime, if R ₃ = OH hydrazone, if R ₃ = NH₂  N R ₂ R ₃ C . . . enamine -H₂O

Examples: O _H +  NH₂ Heat -H₂O H  N +  N H  NH₂  NO₂ O₂ N  NO₂ Heat -H₂O H₃C CH₃ O  NH  N O2 N O₂ N  NO₂ H₃C H₃C H₃C H₃C O H +  NH CH₃ H+ -H₂O H₃C H₃C  N H H₃C O + H₂ N  NH₂  N  N H₂ KOH _Heat -N₂ 82%

H+ - H₂O C H₃ C H₃ O H + N H CH₃ C H₃ C H₃ N H C H₃ Enamine KOH - H₂O + Hydrazone O CH₃ N H₂ NH₂ N CH₃ NH₂ KOH - H₂O 82% N CH₃ NH₂ CH₃ Wolff-Kishner reaction N CH₃ NH -N CH₃ NH N CH₃ N -OH -H O H - OH -- OH -H O H - H O OH -- N₂

O + H₂C- P+ Ph Ph Ph CH₂ + O P Ph Ph Ph H₃C P+ Ph Ph Ph P Ph Ph Ph  NaH Br  -CH₃ Br  S _N2 O P Ph Ph Ph

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

6. Oxidation of aldehydes and ketones R  O H R  O OH KMnO₄, H₂O, H+ or K ₂Cr ₂O₇, H₂O, H+ R  O H R  O O -O R  R ₁ O OH R  + Ag Ag₂O, H₂O, NH₃ KMnO₄, H₂O, H+ Heat R ₁ O OH O OH R ₁ R  O OH + + ₊ Silver mirror test Tollen’s Reagent

8. Acidity and basicity of carboxylic acids O OH R  _H+

+

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.

O OH R  OH OH HO₃S

<

<

_<

9. Conversion of carboxylic acids to esters Fischer esterification (ORA 896) O OH R  H + O OCH₃ R  + CH₃OH H+ O+ OH R  H CH OH O OH R  H O+ CH H ~H+ O+ OH R  H O CH H C+ O R  O CH₃ H O OH R  H+ O+ OH R  H C+ O O R  H H O O+ R  H H O O+ R  H H H+

Alkylation of salts

Alkylation of acids by diazomethane O O -R  O OCH₃ R   Na+ H₃C I O OH R  O OCH₃ R 

+

₊

Mild formation of esters O O R  H DCC O OCH₃ R  + _CH 3OH O O+ R  C  N  N -H CH₃OH C  N  N DCC (dicyclohexylcarbodiimide) O O R  C  N  N H O O -R  C  N  N O+ CH₃ H H ~H+ O C  N  N H H

-10. Conversion of carboxylic acids to acid chlorides and anhydrides O O R  H O Cl R  + _{SOCl2 + HCl} thionyl chloride + SO₂ O O R  H O Cl R  + PCl_{5 + HCl + POCl} 3 O O H₃C H O O H₃C H₃C O + O O H₃C H P₂O₅ acetic anhydride COOH COOH P₂O₅ O O O

11. Decarboxylation (ORA 983) O O R  H H R  + O O H R  O  NaOH, melting  Na₂CO₃  NaOH O O -R  R - + CO₂  NaOH H₂O slight heating R  OH + CO₂ ~H+ R  O O O H O H O slight heating O H OH + CO₂ ~H+ O H O

12. Reactions of carboxylic acid derivatives with nucleophiles R  _X O    Nu R  _X O - Nu R   _Nu O + X

Reactions of acid chlorides (ORA 949) Cl O  N H₂ PhCH₂CH₂ NH₂ Pyridine Cl O - NH₂+ O  NH₂+ O  NH Py

O H H₃C CH₃ CH₃C(O)Cl Pyridine O H₃C CH₃ O CH₃ 75% H₃C H₃C CH₃ OH + O Cl Py O O CH₃ CH₃ CH₃ OH + H₃C S O O Cl Py TsCl _H 3C S O O O 90% O Cl + O O - Na+ O O O 60%

Reactions of anhydrides  NH₂ OH + O O O H₂O  N H OH CH₃ O Paracetamol OH COOH + O O O H₂O O CH3 O COOH Aspirin O O O CH₃OH, reflux COOH O CH₃ O O O O +  NH₂ Heat O  NH OH Acetic anhydride heat O  N

Reactions of esters O O  NH₃ O  NH₂

+

+

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

Reaction of esters with Grignard reagent R  _OR  1 O R  _CH 3 OH CH₃ R  _OR  1 O R  _OR  1 O -CH₃ 1. 2CH₃MgBr  2. H+, H₂O H₃C MgBr   R  _CH 3 O -CH₃ H+ R  O CH₃ H₃C MgBr   Mg+ Br  Mg+ Br 

R  _O O R ₁    R  _OR  1 O -OH R  _OH O + R _ R  _O -O + R _

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

13. Hydrolysis of carboxylic acid derivatives

O O O _H 2O 25 oC H H COOH COOH 94% O Cl H₂O, 0 oC 5 min CH3COOH

+

O  NH_{2 55% H} 2SO4 heat O OH +  NH₄HSO₄ 90% O  NO₂  N H O 30% KOH CH₃OH, H₂O, heat O  NO₂  NH₂ + CH₃COOK  97%

 Nitriles are less active for hydrolysis

CN 57% H2SO4 heat COOH +  NH₄HSO₄ CN _{KOH, H} 2O heat O O -O OH H+

OH -- OH -C N R _{C N} -R O H C NH R O -~ H+ H O H C NH₂ R O C N R _{C NH} O+ R H H H+ H O H C NH+ R ~ H + C NH₂+ O R H - H+  OH -R₂ H R₁ O S O O R

+

+

Hydrolysis of sulfonic esters

14. Reduction of carboxylic acid derivatives R  O OC₂H₅ 1. LiAlH₄ 2. H+, H₂O a source of H -R CH₂OH H -R  O -OC₂H₅ H R  O H H -R  O -H H H+

R  O  NH₂ R   NH₂ 1. LiAlH₄ 2. H₂O CN 1. LiAlH4 2. H₂O  NH₂ 74% H₂ / Ni R  O Cl Pd / C, H₂, quinoline R  O H -78% Al -H O O O Li+ O Cl O 1. (CH₃)₂CuLi, -78 oC 2. H₂O 81%

15. Formation of enoles and enolates R  O H . . C- R  O . . R  OH . . R  O -. .  base _acid enol

enolate (a common conjugate base) a strong and polar bond

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

H₃C H

O

H₂C H

OH K = 6.10-7

In esters, enolization is even less favorable due to stabilization of the carbonyl group. H₃C OC₂H₅ O H₂C OC₂H₅ OH K = 10-20 H₃C OC2H5 O -+

Stabilization of the carbonyl form decreases acidity of the compound

H₂C OC2H5 O H H₂C CH₂ H H H₂C O H H  pK _a = 42  pK _a = 25  _pK  a = 17

Stabilization of the double bond (by conjugation) shifts the equilibrium toward the enol. CH₂ CH₃ O H₃C O CH CH₃ O H₃C O H 92% in hexane K = 1014 O H O

Enolization, catalyzed by acids

R  O H . . R  O+ . . H H R  OH . . H+ _H 2O enol

16. Reactions of aldehydes and ketones, involving enoles and enolates CH₃ O + Br Br   CH₃COOH 25 oC O Br  H+ CH₂ OH C+ CH₂ O H Br  -H+ Br ₂ 70% a-Monohalogenation (ORA 830)

The haloform reaction

CHCl₃ - chloroform CHBr ₃ - bromoform CHI₃ - iodoform

CH₃ O + Br Br   OH O CH₂ -O CH₂ O Br  Br ₂ 1. OH -2. H+ + CHBr 3

The reaction also works with Cl₂ and I₂ O

H

-Two more times

O Br  Br  Br  O -Br  Br  Br  OH O H -O OH + -_CBr  3 O O -H+

Aldol reaction (acid catalyzed) R ₁ R ₂ O ₊ R ₃ O R ₄ H+ R 1 R ₂ R ₃ O R ₄ H+ R ₁ R ₂ O+ H R ₃ OH R ₄ H+ + R ₁ R _{2 C}+ R  O R ₄ OH H R ₁ R ₂ R ₃ O R ₄ OH -H₂O -H+

Aldol reaction (base catalyzed, ORA 840, 852) R ₁ R ₂ O R ₃ O R ₄ R ₁ R ₂ R ₃ O R ₄ C H -R ₃ O R ₄ R ₁ R ₂ R ₃ O R ₄ O- R ₁ R ₂ R ₃ O R ₄ OH -H₂O O H -O H -O H₂

Examples: O H ₊ O H₂SO₄ O 95% O Ba(OH)₂ heat KOH heat O OH O

17. Reactions of esters and acids, involving enolates

COOH Br ₂, PBr ₃ COOH Br  PBr ₃ O Br  OH Br  O Br  Br  H+ or PBr ₃ Br ₂ -HBr  COOH a-Bromination of carboxylic acids

R ₃ O O R ₄ R ₁ O R ₂ H H C H -R ₁ O R ₂ R ₃ O R ₁ O R ₂ O -R ₄  base R ₃ R ₁ O R ₂ O H R ₃ C -R ₁ O R ₂ O R ₃ R ₁ O R ₂ O 1. R ₃COOR ₄, base 2. H+ Base H+ At least two hydrogens must be there!

Ketone or aldehyde or ester 

b-Ketoester or b-diketone Highly acidic hydrogen

O O 1. NaOC₂H₅ 2. H+ O O O 75% C H₂ -O O O- O O O O O O CH -O O O O O Base H+ Claisen condensation

O O 1. NaOC₂H₅ 2. H+ _O O O O 86% CH -O O Base H+ + O O O O C -O O O O O O O O O- O O O O O O

O O O O 1. NaOC₂H₅ 2. H+ O O O 80% Dieckmann condensation

Synthesis of carboxylic acids from the malonic ester COOEt COOEt Base C H -COOEt COOEt R Br  COOEt COOEt R  _C -COOEt COOEt R  COOEt COOEt R  R ₁ R ₁ COOH R  Base R ₁ Br  H₂O, H+ -CO₂

Synthesis of ketones from the b-ketoesters COOEt O R  Base R ₁ Br  _Base R ₂ Br  H₂O, H+ -CO₂ C H -COOEt O R  COOEt O R  R ₁ C -COOEt O R  R ₁ COOEt O R  R ₁ R ₂ O R  R ₁ R ₂

18. Reactions of  Electrophilic addition O O _HBr  O O Br  84% H+ O+ O H O O H Br  Br  -~H+  a b-unsaturated carbonyl compounds

 Nucleophilic (Michael) addition (ORA 858) O R  O -R   Nu  Nu - Nu -O -R   Nu H₂O OH R   Nu 1,2-addition 1,4-addition

In most cases reversible

Irreversible and especially preferred by very strong nucleophiles O R   Nu O HCN KCN O CN 90% O 1. PhLi 2. H₂O 1. (CH₃)₂CuLi 2. H₂O OH OH O

Selective reduction of a,b-unsaturated compounds O _O 90% H₂ Pt, 3 atm O 1. LiAlH₄ 2. H₂O O H 98%

19. Reactions of halocarbonyl compounds R  Hal O . . R   Nu O . .  Nu -S _N2 S _N1

Slower, than for alkyl halides

Faster, than for alkyl halides

C+ _R  O . . R  O+ . .

This structure has a little contribution to resonan  Nu -Cl COOH 1. NaCN 2. H+  NC COOH 80% OH Cl Cl + Cl COOH O Cl Cl COOH 87% 1. OH -2. H+ (2,4-dichlorophenoxy)acetic acid (a selective herbicide)