Carbonyl s
Short Description
reactions of carbonyl components...
Description
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
R
CH2 H
Aldehydes (R is H) or ketones (R is not H)
Reacts with bases
R
OH
-
O
O
Nu-
Nu
R 1
R 1 +
O
+
Nu
H
R
R
R 1 O
+
H
H
NuO
H
+
C R
R 1
R
R 1
R
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
R acetal 1 hemiacetal Stable at neutral conditions Stable at neutral and alkaline conditions
+
HO
OH
R 2
H
OH
+
O R
R
R 1
R 2
R 1
+
H
O
OH OR 2
H R
R 1
O
-
O -
O
R
R
R 1 hemiacetal
OR 2
R 2
R 2
H
+
H OR 2
O
OR 2
OR 2 +
OH
R
R
R 1
H
acetal
R 1 OR 2
+
OR 2
O OR 2
R
R 1 hemiacetal
H
+
R
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
R 1
H R
R 1
CH3 H
O
O
OH H
R
H
R 1
CH3 H
-
B H
R
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
R
+
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 +
R
H
+
O
R
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
<
R
< OH
pK a = 16
pK a = 10
pK a = 5
pK a = -1
O
+
O
+
H
H
+
R
R O
+
H
O R
H
+
R
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 +
+
R
H
R
CH3OH
O
OH
OCH3
+
H
R
H +
O
H
O
O
H
~H+ R
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
R -
+
O Na
OCH3
Alkylation of acids by diazomethane
solvent O
O
+
R
(C2H5) 2O CH2 N2
R
OH diazomethane (yellow gas)
+ OCH3
N2
Mild formation of esters DCC (dicyclohexylcarbodiimide)
O
O
+
R N
DCC
CH3OH
R
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
R +
O
H
CH3OH O
R
O
CH3 -
O
10. Conversion of carboxylic acids to acid chlorides and anhydrides O
O
+
R O
+
R
SOCl2
HCl
+
SO 2
Cl
H thionyl chloride O
O
+
R O
R
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 -
R
+ CO2
-
O
O slight heating CO2
O
R
+
R OH
H
O
~H+
R
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
+
R
X Nu
R
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
R
2. H+, H2O
OR 1
CH3 R
CH3
O
H
R
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
R
O
+ R
O
OR 1
R
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
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
R
C
acid
.
.
R
.
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
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
R COOEt
Br
-
C
COOEt
Synthesis of ketones from the b-ketoesters R
R
R O
O
+
H2O, H R 1
-CO2
R 2
R 2
COOEt
O
R 1
COOEt
Base
R 2
R
R
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
R
H2O
Nu
R
1,4-addition
OH Nu
-
R
O
O 1,2-addition
-
Nu
Irreversible and especially preferred by very strong nucleophiles
R
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
R
.
R
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)
View more...
Comments
