Carbonyl Chemistry IIII

1

• Carbonyl Chemistry IIII

Lecture 17
2
Keto-enol Tautomerism
O
H
O
C
C
H
C
3
C
H
H
C
C
H
2
3
3
E
n
o
l
K
e
t
o
n
e
H


O
H
O



R2C
CR'
H
O
H


H
3
Acid Catalyzed a Halogenation
O
O


R2CCR'
X2
R2CCR'
HX
H
X

• X2 can be Cl2, Br2, or I2.
• Substitution is specific for replacement of a
  hydrogen.
• Not a free-radical reaction. Rather, involves
  keto-enol equilibrium.

4
Mechanism of a Halogenation
Two stages

• first stage is slow conversion of aldehyde or
  ketone to the corresponding enol this step is
  rate-determining
• second stage is the fast reaction of the enol
  with halogen far faster than the first stage

5
Mechanism of a Halogenation
OH
O
O
H
X2
RCH2CR'
RCH
RCHCR'
CR'
slow
fast
enol
X

• Enol is the key intermediate

6
Acid catalyzed a-Halogenation
O
O
Br
Br2, H (cat.)
7
Base catalyzed ?-Halogenation

• Base-promoted ?-halogenation
• Step 1 formation of an enolate anion

8
Base catalyzed ?-Halogenation

• Base-promoted ?-halogenation
• Step 2 nucleophilic attack of the enolate anion
  on halogen

9
?-Halogenation

• Sothere are major differences between
  acid-catalyzed and base-promoted ?-halogenation
• Acid catalysis gives the most substituted product
• Under such conditions, the rate of acid-catalyzed
  introduction of a second halogen is slower than
  the first
• introduction of the electronegative halogen on
  the ?-carbon decreases the basicity of the
  carbonyl oxygen toward protonation

10
?-Halogenation

• In base catalyzed ?-halogenation, each successive
  halogenation is more rapid than the previous one
• the introduction of the electronegative halogen
  on the ?-carbon increases the acidity of the
  remaining ?-hydrogens and, thus, each successive
  ?-hydrogen is removed more rapidly than the
  previous one

11
Relative Rates Rule
What happens next, if anything?
12
The Haloform Reaction

• Under basic conditions, halogenation of a methyl
  ketone often leads to carbon-carbon bond
  cleavage.
• This is called the haloform reaction because
  chloroform, bromoform, or iodoform is one of the
  products.

13
Example
O
(CH3)3CCCH3
Br2, NaOH, H2O
O

CHBr3
(CH3)3CCONa
H
O
(CH3)3CCOH
14
The Haloform Reaction--Details

• First stage is substitution of all available a
  hydrogens by halogen

O
O
RCCH3
RCCX3
X2, HO
X2, HO
O
O
X2, HO
RCCH2X
RCCHX2
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Second Stage

• Formation of the trihalomethyl ketone is
  followed by its hydroxide-induced cleavage

O
O






CX3
CX3
RC
RC


O
O







HCX3
RC
OH
RC
O



16
Haloform Reaction

• Summary of Iodoform Reaction
• A qualitative test for methyl ketones
• A decent way to synthesize carboxylic acids

Note In addition to oxidation of 2o alcohols
bearing a methyl group, we can make methy ketones
from 1) reaction of aryls with acylium ions
derived from acetyl chloride or acetic anhydride
and 2) terminal alkynes via oxymercuration
(Markovnikov addition of water).
17
Oxidation and Reduction

• Aldehydes are oxidized to carboxylic acids by a
  variety of oxidizing agents, and it is possible
  to do some selective reduction reactions

-4
-2
0
2
4
18
Reduction of Aldehydes Gives Primary Alcohols
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Reduction of Ketones Gives Secondary Alcohols
R
C
O
R'
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Example Catalytic Hydrogenation
H
OH
O


Pt

H2
ethanol
(93-95)

Exception Benzyl ketones and alchols get
reduced all the way to the alkyl, as we learned
in our study of Friedel-Crafts acylation reactions
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Exception Benzyl ketones and alcohols get
reduced all the way to the alkyl, as we learned
in our study of Friedel-Crafts acylation reactions
For Example
O
H
H

/

P
d
(
C
)
2
O
O
H
H

/

P
d
(
C
)
2
22
Retrosynthetic Analysis
H
H
23
Metal Hydride Reducing Agents
Sodiumborohydride
Lithiumaluminum hydride

• act as hydride (H-) donors

24
Examples Sodium Borohydride
Aldehyde
O2N
O2N


O
NaBH4
CH2OH
CH
methanol
(82)
Ketone

H
OH
O
NaBH4


ethanol
(84)
25
Lithium aluminum hydride (LiAlH4 or LAH for
short)

• more reactive than sodium borohydride
• cannot use water, ethanol, methanol etc.as
  solvents
• diethyl ether is most commonly used solvent

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Examples Lithium Aluminum Hydride
Aldehyde
1. LiAlH4diethyl ether
O
CH3(CH2)5CH2OH
CH3(CH2)5CH
2. H2O
(86)
Ketone

O
1. LiAlH4diethyl ether
(C6H5)2CHCCH3
2. H2O
(84)
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Selectivity

• neither NaBH4 or LiAlH4reduces isolateddouble
  bonds

O
1. LiAlH4diethyl ether
2. H2O

(90)
H
OH
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Catalytic Reduction

• Catalytic reductions are generally carried out
  from 25 to 100C and from 1 to 5 atm H2
• Carbon-carbon double bonds can be selectively
  reduced using rhodium catalysts

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Second reminder that hydrogenolysis of benzylic
carbonyls is special

• Palladium catalysis of hydrogenation reduces
  benzylic C-O bonds to methylene groups.
• Benzyl ethers, aldehydes and alcohols are also
  reduced to the corresponding methylene group
• Other sites off aryl rings act in a normal way

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Clemmensen Reduction

• Refluxing an aldehyde or ketone with amalgamated
  zinc in concentrated HCl converts the carbonyl
  group to a methylene group
• Limitations?? --gt Can you think of any??

O
OH
Zn(Hg), HCl
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Wolff-Kishner Reduction

• If aldehydes or ketones are refluxed with
  hydrazine and KOH in a high-boiling solvent, the
  reaction converts carbonyls into methylenes.

Limitations?? --gt Can you think of any??
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Review of Oxidation Reactions

• Jones Reagent (H2CrO4 in wet acetone) takes
  primary alcohols to acids and secondary alcohols
  to ketones
• The Tollens Test Ag(NH3)2OHthe silver mirror
  reaction is a qualitative test for aldehydes and
  an efficient but expensive way to make acids form
  aldehydes

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Examples
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Review of Oxidation Reactions -- Cont.
Cr(III) in the absence of H2O (e.g., pyridinium
chlorochromate, PCC pyridinium dichromate, PDC)
allows primary alcohols to be take ONLY to the
aldehyde stage (cf. section 9.8.1 in B F)
PCC
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Okay, Time for a Public Service Announcement!
Happy Birthday Eric Bernal!
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Okay, Lets Quit Here For Today. Have a Great
Spring Break!!