Post on 24-Feb-2016
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17.4 How Aldehydes and Ketones React (Part III)
1
C
O
C
O
C
O
YR
d+
R = alkyl or aryl (C)Y = alkyl, aryl or H (class II) (No leaving group)
d-Electron rich (Lewis base, Nu)
Electron deficient (Lewis acid, E+)
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Nucleophilic Addition (Class II)
2
1. General mechanism in basic condition:
C
O
R'(H)R
+ Z+ H+
C
O
RC
O
R'(H)
R Z- H+
C
OH
R'(H)
R Z
2. General mechanism in acidic condition:
C
O
R'(H)RZ
+ H+
C
O
R- H+
C
OH
R'(H)
R ZC
O
R'(H)R
H
Important pKa to Remember
3
Names AcidsH-Z
Approx. pKa
Conjugate Base, :Z General Roles of :Z
Alkane (2°) 51 Base as Li+ saltNucleophile as Grignard reagent
Amine 38 Base and Nucleophile
Hydrogen 35Base in NaH, CaH2Nucleophile in LiAlH4, NaBH4
Alcohol water 15-16 Often as a base but can be a
nucleophile
Ammonium 10-11 Weak base, but can be a nucleophile
Thiol 10-11 Nucleophile
Carboxylic Acid 4-5 Weak base, poor leaving group
Hydrochloric Acid -7 Leaving group, poor nucleophile
H3CCH
H3CH
H3CCH
H3C
HN
HH
HN
H
H H H
R O H R O
RNH
HH
RNH
H
SR H R S
HRCO2 RCO2
HCl Cl
Types of Nucleophile for Class II Carbonyl Groups
4
1. Carbon as the nucleophilic atom
HC H+C +
pKa = 50
Basic condition
2. Hydrogen as the nucleophilic atom
carboanion
H hydride Mostly basic condition
3. Nitrogen as the nucleophilic atom1° and 2° amines Mostly acidic condition
4. Oxygen as the nucleophilic atomAcidic condition
NH2
1° alcoholsOH
HCC H+CC +pKa = 25 Acetylide ion
Oxygen as the Nucleophilic Atom
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pKa of alcohol.
HO H+O +
pKa = 15-16
1° and 2° Alcohols function as weak acids, weak bases or nucleophiles.
HO
HH+O
H+
pKa = -2
3° Alcohols function as weak acids or weak bases.
Reactions of Aldehydes and Ketones with Alcohols
6
General reaction with primary alcohols:
O
CR'(H)R
H+
HO CH2R"+OCH2R"
CR'(H)R + H2O
R"CH2O
1° AlcoholsKetal or acetal
H+
H2O+
Geminal diol (gem-diol)
O
CR'(H)R
2
OH
CR'(H)R
HO
General reaction with water:
2° and 3° Alcohols are too hindered to react.
Reactions of Aldehydes and Ketones with Water
7
Example:O
CCH3
H+
H2O+
HO
CCH3
OH
O
CCH3
H+
Mechanism:O
CCH3
H
O
HH
O
C CH3
H
O
H
H
HO
CCH3
OH
H+
Reactions of Aldehydes and Ketones with Alcohols
8
Examples:O
CH
H+
CH3OH+
CH3O
CH
OCH3
+ H2O2
O
CCH3
H+
CH3OH+
CH3O
CCH3
OCH3
+ H2O2
O
CH
H+
HOCH2CH2OH+
O
CH
O
+ H2O1
Reactions of Aldehydes and Ketones with Alcohols
9
O
CH
H+
Mechanism:
O
CH
H
O
HCH3
O
C CH3
H
O
H
CH3
CH3O
CCH3
O
H+
H
CH3O
CCH3
O
HH CH3O
CCH3
O
HCH3O
CH
CH3
H2OO
HCH3
CH3O
CH
OCH3
acetal
hemiacetal
Application of Ketal or Acetal
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Synthesis using protecting group
OMe
OO
OH
O
OMe
OOOO
H+
H2O
OMe
OOHHO 1) LiAlH4
2) H2O
OO
OH H+H2O
OHHO
OH
O
1 3 4 5
2
2
(Reaction 1)
(Reaction 2)
(Reaction 3)
? LiAlH4 or DIBAL will reduce the ketone as well.
Ketal as the protecting group for ketone:
Ketals like ethers are relatively stable in basic condition.
Mechanism for the Formation of Cyclic Ketal
11
OMe
OOO
H
ORH
OMe
OO
OHHOH+
OMe
OO
HO
O
H
H
H
OR
OMe
OO
HO
O
H
H
ORH
H
OHR
OMe
OO
HO
O
HH
R
O H
OMe
OO
R
O H
HO
OMe
OOOH
R
O H
More Examples on the Use of Protecting Groups
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OH
O
OH
O
HO HO2C
? SOCl2 (PBr3 or PCl3) will convert carboxylic acids into acyl halides as well.
Ester as the protecting group for carboxylic acid:
OH
O
H+
H2O
OCH2CH3
OOH
SOCl2
H+, heatH2O
OH
13
4
6
2
2
(Reaction 1)
(Reaction 2)
(Reaction 4)
HO HO
OCH2CH3
O
Cl
NaCN
5
(Reaction 3)
OCH2CH3
O
NC
OH
O
HO2C
Ester will not react with SOCl2 (from compound 3 to compound 4).
More Examples on the Use of Protecting Groups
13
Amines under acidic condition may turn into an EWG in the form of ammoniim ions.
Amide as the protecting group for amine:
NEt3Cl
HNO3H2SO4
1 3 4
2
(Reaction 1) (Reaction 2)
NH2
O
HN
O
HN
OO2N
H+, heatH2O
OH
52
(Reaction 3)
O
NH3
O2N
Amide in compound 3 will act as EGD..
NH2?
NH2
NO2
Formation of Cyclic Hemiacetals or Ketals
14
HOH
O H+
removal of H2O HO O
Intramolecular reaction: formation of 5 or 6-membered rings
H
O H+
removal of H2O
HO
O OH
HO
O H+
removal of H2O HO O
H
O H+
removal of H2OOH
HO
O OHHO
Cyclic Hemiacetals in Carbohydrates
15
Intramolecular formation of 5 or 6-membered rings
CHO
OHH
HHO
OHH
OHH
CH2OH
1
2
3
4
5
6
5-OH OHO
OH
HOOH
OH15
+O
HO
OH
HOOH
OH
15
CHO
OHH
HHO
OHH
OHH
CH2OH
1
2
3
4
5
6
4-OH1 +
OOH
OH
HO
HOOH
41
O
OH
OH
HO
HOOH
4
D-Glucose
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Learning Check1. What could be the reagent and reaction condition for the following transformation?
2. What should be the product from the following reaction?
O
CH3
OCH2CH3
CH3
H3CH2CO?
(a) ethanol, NaOH(b) ethanol, H+
(c) methanol, NaOH(d) methanol, H+
(e) None of the above
O
OCH3
1) DIBAL, -78oC then H2O2) H+, removal of water
HO
OH
(a) (c)
product
(e) none of the above
O
H
(b) OOH O OH (d)
OH
OH
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Learning Check3. What could be the product for the following reaction?
H+
removal of water
(a) (b) (c) (d)
(e) None of the above
Product?
OOH
OH
O
O
O
O
OHO
O
O
O
O
OHOH
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Learning Check4. Which hydroxy group when added to the aldehyde functional group (C-1) of open chain glucose will produce the cyclic hemiacetal form shown below?
CHO
OHH
HHO
OHH
OHH
CH2OH
glucose (open chain)
glucose (cyclic hemiacetal)
1
2
3
4
5
6
OHO
HO
HO
OHOH
(a) The one that locates on C-2.(b) The one that locates on C-3.(c) The one that locates on C-4.(d) The one that locates on C-5.(e) None of the above
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Learning Check5. Which hydroxy group when added to the aldehyde functional group (C-1) of open chain glucose will produce the cyclic hemiacetal form shown below?
(a) The one that locates on C-2.(b) The one that locates on C-3.(c) The one that locates on C-4.(d) The one that locates on C-5.(e) None of the above
CHO
OHH
HHO
OHH
OHH
CH2OH
glucose (open chain)
glucose (cyclic hemiacetal)
1
2
3
4
5
6
O
OH
HO
HO
HO
OH
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