Transcript Reactions of Alcohols Oxidation R-X, Ether, and Ester Preparation Protection of Alcohols Synthesis The Logic of Mechanisms.

Reactions of Alcohols
Oxidation
R-X, Ether, and Ester Preparation
Protection of Alcohols
Synthesis
The Logic of Mechanisms
Alcohols are Synthetically
Versatile
Oxidation levels of
oxygen- halogen- and nitrogencontaining molecules
CH2=CH2
CH3CH3
[O]
CH3CH2OH
HC
[O]
CH
CH
3CH=O
[O]
CH3CO2H
CH3CH2Cl
CH
3CHCl2
CH
3CCl3
CH3CH2NH2
CH
3CH=NH
CH
3CN
O xi dati on
Re du cti on
Oxidation - Reduction
Oxidation of 2o Alcohols with
Cr(VI)
Mechanism
Na2Cr2O7 + H2O + 2 H2SO 4
O
OH
+
HO
o
2 alcoh ol
O
Cr
OCrO 3H
OH
+ H2O
O
C h rom ic Acid (C r VI) C h rom ate e ste r
CrO3H
H
2 H2C rO4 + 2 NaHSO4
O
OH2
+ H3O + HCrO3
k e ton e
(C r IV)
Oxidation of 1o Alcohols
PCC oxidizes 1o Alcohols to
Aldehydes
CrO3Cl
N
PC C
H
pyri di n iu m ch l oroch rom ate
Pyridinium Chlorochromate (PCC)
• PCC is a complex of
chromium trioxide,
pyridine, and HCl.
• Oxidizes primary
alcohols to aldehydes.
• Oxidizes secondary
alcohols to ketones.
Oxidation of 1o Alcohols to
Aldehydes: PCC
3° Alcohols Cannot Be Oxidized
• Carbon does not have hydrogen, so
oxidation is difficult and involves the
breakage of a C—C bond.
• Chromic acid test is for primary and
secondary alcohols because tertiary alcohols
do not react. Orange color of Cr(VII) turns
green - Cr(III); 3o alcohol is not oxidized,
therefore no color change.
Sodium Hypochlorite (NaOCl)
• Sodium hypochlorite (household bleach) can
oxidize alcohols without heavy metals or
generating hazardous waste.
• This is a much better option for acid-sensitive
compounds.
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Swern Oxidation
• Dimethylsulfoxide (DMSO), with oxalyl chloride
and hindered base, oxidizes 2 alcohols to ketones
and 1 alcohols to aldehydes (same as PCC).
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Oxidation Summary
CH2CO2H
Na2Cr2O7
H2SO 4
CH2CH2OH
NH
CrO3Cl
OO
DMSO, ClCCCl
(CH3CH2)3N, in CH2Cl2
CH2CHO
CH2CHO
Reduction Summary
CH2CO2H
1) LiAlH4
+
2) H3O
CH2CH2OH 1) NaBH
4
CH2CHO
+
2) H3O
or
H2, Raney Ni
CH2CHO
Conversion of Alcohol into a
Leaving Group
• Form Tosylate (p-TsCl, pyridine)
• Use strong acid (H3O+)
• Convert to Alkyl Halide (HX, SOCl2, PBr3)
Formation of
p-Toluenesulfonate Esters
Substitution and Elimination
Reactions Using Tosylates
Summary of Tosylate Reactions
Best to use p-TsCl with
pyridine
CH3
OH
O
CH3
OS
N
CH3
+ ClS
O
p-tolue ne sulfonyl chloride
pyridine reacts with
HCl as it forms
O
O
N
H
Cl
CH3
Reactions of Tosylates:
Reduction, Substitution, Elimination
CH3
OH
CH3
O
+ ClS
O
CH3
O
OS
pyr:
CH3
O
1) LiAlH4
KI
NaOCH3
CH3
CH3
CH3
I
H
+ LiOT s
Reduction of Alcohols
• Dehydrate with concentrated H2SO4, then add H2.
• Make a tosylate, then reduce it with LiAlH4.
Alcohols to Alkyl Halides
OH
HX (HCl or HBr)
X
rapid SN1
+ HOH
o
3 alcoh ol
OH
o
2 alcoh ol
HX
moderat e SN1
X
+ HOH
Reaction of Alcohols with Acids
• The hydroxyl group is protonated by an acid to
convert it into a good leaving group (H2O).
• Once the alcohol is protonated, a substitution or
elimination reaction can take place.
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Reaction of Alcohols with HBr
•
•
•
•
–OH of alcohol is protonated.
–OH2+ is good leaving group.
3° and 2° alcohols react with Br– via SN1.
1° alcohols react via SN2.
SN1 Mechanism
Step 1: Protonation.
Step 2: Formation of the carbocation.
Step 3: Bromide attacks the carbocation.
SN1: Carbocations can Rearrange
HO
Br
Br
HBr
+
cis & trans
HO
Br
Br
H-Br
+
cis & trans
H
Br
HO
- H2O
H
Br
Solved Problem 2
When 3-methyl-2-butanol is treated with concentrated HBr, the major product is 2-bromo-2methylbutane. Propose a mechanism for the formation of this product.
Solution
The alcohol is protonated by the strong acid. This protonated secondary alcohol loses water to form a
secondary carbocation.
Solved Problem 2 (Continued)
Solution (Continued)
A hydride shift transforms the secondary carbocation into a more stable tertiary cation. Attack by
bromide leads to the observed product.
Lucas Test
CH3
ZnCl2
12M HCl
CH3COH
CH3
CH3CCl forms in seconds
CH3 + HOZnCl2
CH3
CH3
CH3C
CH3
OZnCl2
CH3 H
CH3C
CH3
Cl
SN2 Reaction with the Lucas Reagent
• Primary alcohols react with the Lucas reagent
(HCl and ZnCl2) by the SN2 mechanism.
• Reaction is very slow. The reaction can take from
several minutes to several days.
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Qualitative test for Alcohol
Characterization
primary
OH
Cl
>10 minutes
(if at all)
OH
ZnCl2, HCl
secondary
Cl
<5 minutes
OH
Cl
t ertiary
1-2 seconds
Other Simple Qualitative Tests
Alk e ne s
Br
Br2
re ddi sh -brown
OH
col orle ss
Br
O
Alcoh ols
Na2Cr2O7
OH
H2SO 4
orange
Cr(VI)
gre e n
Cr(IV)
CO2H
1o and 2o Alcohols: best to use
SOCl2, PBr3, or P/I2
All are SN2 Reactions
SOCl2
pyridine
OH
PBr3
P , I2
(in situ prep.
of PI3)
Cl
Br
I
Examples
Thionyl chloride mechanism
in Pyridine – SN2, Inversion
O
Cl
S
Cl
SOCl 2
OH
Cl + SO2 + HCl
pyridine
O
O
O
H
S
Cl
O
Cl
H
N
S
+
Cl
-H
O
Cl
O
S
Cl
Dehydration of Alcohols
• Alcohol dehydration generally takes place through the E1
mechanism.
• Rearrangements are possible.
• The rate of the reaction follows the same rate as the ease of
formation of carbocations: 3o > 2o > 1o.
• Primary alcohols rearrange, so this is not a good reaction
for converting 1° alcohols into alkenes.
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Dehydration of Alcohols – E1
OH
H
H2SO 4 (aq) cat .
+ H2O
H
regenerat ed
H
O
HSO 4
or H2O
H
-H2O
H
Methide Shift is Faster than
Loss of H+
CH3
OH
CH3
CH3
CH3
H2SO 4 (aq)
+
distill
major
CH3
CH3
+ H2O
minor
Dimerization of Alcohols:
Symmetrical Ethers
De h ydrati on
o
2 CH3CH2CH2OH
H2SO 4, 125-140 C
CH3CH2CH2OCH2CH2CH3
+ H2O
Mechanism
Dehydration, Acid-Catalyzed
o
H2SO 4, 125-140 C
2 CH3CH2CH2OH
CH3CH2CH2OCH2CH2CH3
+ H2O
H
CH3CH2CH2-OH
CH3CH2CH2OH
loss of H2O
CH3CH2CH2OCH2CH2CH3
H2O
H
Esterification
•
•
•
•
•
Fischer: Alcohol + carboxylic acid
Tosylate esters
Sulfate esters
Nitrate esters
Phosphate esters
Fischer Esterification
• Reaction of an alcohol and a carboxylic acid produces an
ester.
• Sulfuric acid is a catalyst.
• The reaction is an equilibrium between starting materials
and products, and for this reason the Fischer esterification
is seldom used to prepare esters.
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Nitrate Esters
• The best-known nitrate ester is nitroglycerine, whose
systematic name is glyceryl trinitrate.
• Glyceryl nitrate results from the reaction of glycerol
(1,2,3-propanetriol) with three molecules of nitric acid.
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Phosphate Esters
Phosphate Esters in DNA
Protection of Alcohols
S u ppose you wan te d to carry ou t th e foll owi n g tran sform at
CH2OH
CH2OH
CH3
O
OH
W ou ld th e fol lowin g Gri gn ard se qu e n ce work ?
1) CH3MgBr
2) H3O
Nope .
+
Alcohol is acidic enough to
react preferentially.
CH2OH
CH2OMgBr
1) CH3MgBr
+ CH4
+
2) H3O
O
O
Chlorotrimethylsilane (TMS-Cl)
Protecting groups te m porari l y con ve rt re acti ve fu n cti on
grou ps i n to u n re acti ve grou ps i n a si m pl e , h i gh -yi e l di n g r
ROH + ClSi(CH3)3
T MS-Cl
pyridine
or Et3N
dilut e H3O
+
deprot ect ion
ROSi(CH3)3 + HCl
Mechanism is SN2
OH
H
CH3
CH3
Si
Cl
O
SN2
Cl
Si(CH3)3
CH3
OSi(CH3)3
+ HCl
Protect as trimethylsilyl ether
CH2OH
CH2OH
OH
CH3
O
+
3) H3O
protonat es
& deprot ects
1) ClSi(CH3)3
in pyridine
CH2OSi(CH3)3
CH2OSi(CH3)3
2) CH3MgBr
dry ether
OMgBr
O
CH3
Give the Reagents…
OH
O
OCH3
No Protection needed
OH
1) Na met al
2) CH3I
OCH3
+
O
3) CH3CH2MgBr 4) H3O
5) T sCl, pyridine
+
6) LiAlH4 7) H3O
Road Map Problem
Br
A
MgBr
B
O
1) CH3CH2CH
2) H3O
+
C
Na2Cr2O7
H2SO 4
D
1) CH3MgBr
2) H3O
+
E
Mechanisms
Thinking Logically
• Do not use reagents that are not given.
• Is the product a result of a rearrangement? Only
intermediates can rearrange.
• Is one of the reagents H3O+? If so, use it in the 1st
step. Do not create negatively charged species in
acid.
CH
2
H3C
CH3
CH3
OH
+
H , heat
H3C
CH3
+ H2O
Only Five Arrows
CH2
H3C
CH3
CH3
+
H , heat
CH3
H3C
+ H2O
OH
H 2O
H3C
CH3
CH3
OH
H
H3C
CH3
CH3
H
H3C
CH2
CH3
Propose a Mechanism
OCH2CH3
+
H3O
W h e re do you proton ate ?
O
+ CH3CH2OH
Both approaches seem logical
H
H
OCH2CH3
+
OCH2CH3
OCH2CH3
H
+
H
OCH2CH3
H
Take the Blue Route
OCH2CH3
H 3O
H
O
+
+ CH3CH2OH
+
OCH2CH3
H2O
H
H
O
OH2
O
H
CH2CH3
HOCH2CH3
H