reactions of alcohols oxidation r-x, ether, and ester preparation protection of alcohols synthesis...
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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 nitrogen-
containing molecules
Reduction
Oxidation
CH3CH3
CH2=CH2 HC CH
[O] [O]CH3CH2OH CH3CH=O CH3CO2H
CH3CH2Cl CH3CHCl2 CH3CCl3
CH3CH2NH2 CH3CH=NH CH3CN
[O]
Oxidation - Reduction
Oxidation of 2o Alcohols with Cr(VI)
Mechanism
OH+ Cr
O
O
OHHO
OCrO3H
Chromate ester
+ H2O
Na2Cr2O7 + H2O + 2 H2SO4 2 H2CrO4 + 2 NaHSO4
Chromic Acid (Cr VI)
H
OCrO3H
OH2
O
+ H3O + HCrO3
2 alcoholo
ketone (Cr IV)
Oxidation of 1o Alcohols
PCC oxidizes 1o Alcohols to Aldehydes
N
H
CrO3Cl
pyridinium chlorochromatePCC
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.
© 2013 Pearson Education, Inc. Chapter 11 12
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.
© 2013 Pearson Education, Inc. Chapter 11 13
Swern Oxidation
• Dimethylsulfoxide (DMSO), with oxalyl chloride and hindered base, oxidizes 2 alcohols to ketones and 1 alcohols to aldehydes (same as PCC).
Oxidation Summary
CH2CH2OHNHCrO3Cl
Na2Cr2O7
H2SO4
CH2CHO
CH2CO2H
DMSO, ClCCCl
OO
(CH3CH2)3N, in CH2Cl2
CH2CHO
Reduction Summary
CH2CH2OH CH2CHO
CH2CO2H
CH2CHO
1) LiAlH4
2) H3O+
2) H3O+
1) NaBH4
or
H2, Raney Ni
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
OH
CH3
CH3ClS
O
O
p-toluenesulfonyl chloride
OS
O
O
CH3
CH3
N
H
Clpyridine reacts with
HCl as it forms
N+
Reactions of Tosylates:Reduction, Substitution, Elimination
OH
CH3
CH3ClS
O
O
OS
O
O
CH3
CH3
+pyr:
1) LiAlH4
CH3
H+ LiOTs
KI
CH3
I
CH3
NaOCH3
Reduction of Alcohols• Dehydrate with concentrated H2SO4, then add H2.
• Make a tosylate, then reduce it with LiAlH4.
Alcohols to Alkyl Halides
OH
3 alcoholo
HX (HCl or HBr)X + HOH
rapid SN1
OH HX
moderate SN1
X+ HOH
2 alcoholo
© 2013 Pearson Education, Inc. Chapter 11 24
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.
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.
Step 1: Protonation.
Step 2: Formation of the carbocation.
Step 3: Bromide attacks the carbocation.
SN1 Mechanism
SN1: Carbocations can Rearrange
HO
HBrBr
+
Br
cis & trans
HO
H-BrBr
+
Br
cis & trans
HO
H
H- H2O
Br
Br
When 3-methyl-2-butanol is treated with concentrated HBr, the major product is 2-bromo-2-methylbutane. Propose a mechanism for the formation of this product.
The alcohol is protonated by the strong acid. This protonated secondary alcohol loses water to form a secondary carbocation.
Solved Problem 2
Solution
A hydride shift transforms the secondary carbocation into a more stable tertiary cation. Attack by bromide leads to the observed product.
Solved Problem 2 (Continued)
Solution (Continued)
Lucas Test
CH3COH
CH3
CH3
ZnCl212M HCl
CH3
CH3
CH3CCl
CH3
CH3
CH3C OZnCl2
H CH3
CH3
CH3CCl
forms in seconds
+ HOZnCl2
© 2013 Pearson Education, Inc. Chapter 11 32
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.
Qualitative test for Alcohol Characterization
OHprimary
OH
secondary
OH
tertiary
ZnCl2, HCl
Cl
Cl
Cl
1-2 seconds
<5 minutes
>10 minutes(if at all)
Other Simple Qualitative Tests
AlkenesBr2
reddish-brown
Br
Br
colorless
AlcoholsOH
OH
Na2Cr2O7
H2SO4orange
O
CO2HCr(VI)
greenCr(IV)
1o and 2o Alcohols: best to use SOCl2, PBr3, or P/I2
OH
SOCl2pyridine
PBr3Br
Cl
P, I2I(in situ prep.
of PI3)
All are SN2 Reactions
Examples
Thionyl chloride mechanism in Pyridine – SN2, Inversion
OH
S
O
ClCl
O
H
S
O
Cl
ClO
H
SCl
O
OS
Cl
O
-H+
ClSOCl2
pyridine
N
Cl
+ SO2 + HCl
© 2013 Pearson Education, Inc. Chapter 11 38
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.
Dehydration of Alcohols – E1
OH
H2SO4 (aq)
OHH
cat.
H
H
+ H2O
HSO4or H2O
-H2O
Hregenerated
Methide Shift is Faster than Loss of H+
OHCH3
CH3
H2SO4 (aq)
distill
CH3
CH3
+
CH3
CH3
major minor+ H2O
Dimerization of Alcohols:Symmetrical Ethers
2 CH3CH2CH2OHH2SO4, 125-140 C
o
CH3CH2CH2OCH2CH2CH3
+ H2O
Dehydration
Mechanism
2 CH3CH2CH2OHH2SO4, 125-140 C
o
CH3CH2CH2OCH2CH2CH3
+ H2O
Dehydration, Acid-Catalyzed
CH3CH2CH2-OH
CH3CH2CH2OH
H
CH3CH2CH2OCH2CH2CH3
HH2O
loss of H2O
Esterification
• Fischer: Alcohol + carboxylic acid
• Tosylate esters
• Sulfate esters
• Nitrate esters
• Phosphate esters
© 2013 Pearson Education, Inc. Chapter 11 44
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.
© 2013 Pearson Education, Inc. Chapter 11 45
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.
Phosphate Esters
Phosphate Esters in DNA
Protection of AlcoholsSuppose you wanted to carry out the following transformation:
CH2OH
O
1) CH3MgBr
2) H3O+
CH2OH
OHCH3
Would the following Grignard sequence work?
Nope.
Alcohol is acidic enough to react preferentially.
CH2OH
O
1) CH3MgBr
2) H3O+
CH2OMgBr
O
+ CH4
Chlorotrimethylsilane (TMS-Cl)
Protecting groups temporarily convert reactive functional
groups into unreactive groups in a simple, high-yielding reaction.
ROH + ClSi(CH3)3pyridine
TMS-ClROSi(CH3)3 + HCl
dilute H3O+
or Et3N
deprotection
Mechanism is SN2
OH Si Cl
CH3
CH3
CH3
OSi(CH3)3
H Cl
OSi(CH3)3
+ HCl
SN2
Protect as trimethylsilyl etherCH2OH
O
CH2OH
CH3
OH
1) ClSi(CH3)3in pyridine
CH2OSi(CH3)3
O
2) CH3MgBr
dry ether
CH2OSi(CH3)3
CH3
OMgBr
3) H3O+
protonates& deprotects
Give the Reagents…
O
OH OCH3
No Protection needed
O
OH OCH31) Na metal
2) CH3I
3) CH3CH2MgBr 4) H3O+
5) TsCl, pyridine6) LiAlH4 7) H3O+
Road Map Problem
Br MgBr
CH3CH2CH
O
A B
1)
2) H3O+ CNa2Cr2O7
H2SO4D
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.
CH3H3CCH3
OHH+, heat
CH3H3C
CH2
+ H2O
Only Five Arrows
CH3H3CCH3
OHH+, heat
CH3H3C
CH2
+ H2O
CH3H3CCH3
OH
H
CH3H3CCH3
CH3H3C
CH2HH2O
Propose a Mechanism
OCH2CH3 H3O+ O
+ CH3CH2OH
Where do you protonate?
Both approaches seem logical
OCH2CH3
H+
H+
OCH2CH3
H
OCH2CH3
H
OCH2CH3
H
Take the Blue Route
OCH2CH3
H+
OCH2CH3
H
O
H
CH2CH3
O
H
HOCH2CH3
H
OH2
H2O
H3O+ O
+ CH3CH2OH
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