Transcript Alcohols
Reactions of Alcohols
oxidation
tosylation and reactions of tosylates
substitutions to form alkyl halides
dehydration to form alkenes and ethers
pinacol rearrangement
esterification
cleavage of glycols
ether synthesis
Classification of Reactions
Oxidations
addition of O or O2
addition of X2
loss of H2
Reductions
loss of O or O2
loss of X2
addition of H2 or H-
Classification of Reactions
Neither an oxidation nor a reduction
Addition
Addition
Addition
Addition
or
or
or
or
loss
loss
loss
loss
of
of
of
of
H+
OHH2O
HX
Classification of Reactions
Oxidations
count C-O bonds on a single C
the more C-O bonds, the more
oxidized the C
H
OH
OH
O
increasing level of oxidation
OH
OH
O
Reactions of Alcohols Oxidation
For alcohols, the oxidation comes from the loss of
H2.
Oxidation of a 2° alcohol gives a ketone.
Chromic acid reagent used in lab oxidations.
Na2Cr2O7 + H2SO4 + H2O 2H2CrO4 + 2NaHSO4
CrO3 + H2O (dil H2SO4) H2CrO4
Reactions of Alcohols Oxidation
Oxidation of a 1° alcohol gives
a carboxylic acid if chromic acid reagent is
used.
an aldehyde if pyridinium chlorochromate
(PCC) is used.
Reactions of Alcohols Oxidation
Two other reagents behave like
the chromic acid reagent:
KMnO4 (will attack C=C, too)
HNO3
These two oxidizing agents are so
strong that C-C bonds may be
cleaved.
Bleach (OCl-) also oxidizes
alcohols.
Reactions of Alcohols – Swern
Oxidation
Uses dimethyl sulfoxide (DMSO),
oxalyl chloride (COCl)2 and a
hindered base.
The reactive species is (CH3)2SCl+.
The result is a ketone or an aldehyde
(the same as for PCC).
Reactions of Alcohols – Swern
Oxidation
Uses dimethyl sulfoxide (DMSO),
oxalyl chloride (COCl)2 and a
hindered base.
O
OH
+
H3C
S
O O
CH3
(CH3CH2)3N
+
Cl C C
Cl
S
CH3
CO2 +
CH2Cl2
-60°C
H
+
O
H3C
+
CO
+
2HCl
Reactions of Alcohols –
Oxidation with DMP
Uses Dess-Martin periodinane (DMP).
Mild conditions: room temperature
and neutral pH with excellent yields
The result is a ketone or an aldehyde
(the same as for PCC and the Swern
oxidation).
Reactions of Alcohols –
Oxidation with DMP
Uses Dess-Martin periodinane (DMP).
OH
+
AcO OAcOAc
..I
O
O
H
+
OAc
.
..I .
O + 2HOAc
O
O
Reactions of Alcohols Biological Oxidation
Ethanol is the least toxic alcohol, but it is still
toxic.
The body detoxifies ethanol with NAD catalyzed
first by alcohol dehydrogenase (ADH) and second
by aldehyde dehydrogenase (ALDH):
ethanol acetic acid
The reason methanol and ethylene glycol are so
toxic to humans is that, when they react with
NAD/ADH/ALDH, the products are more toxic
than the original alcohols.
methanol formic acid
ethylene glycol oxalic acid
Reactions of Alcohols Oxidation
3° alcohols will not oxidize,
because there is no H on the
carbinol C atom.
The chromic acid test capitalizes
on this fact:
orange chromic acid reagent turns
green or blue (due to Cr3+) in the
presence of 1° or 2° alcohols, but
doesn’t change color in the presence
of a 3° alcohol.
Reactions of Alcohols Tosylation
In order to perform an SN2 reaction on an alcohol,
i.e., with the alcohol as the substrate, the -OH
group must leave the alcohol:
R-OH + Nuc:- R-Nuc + OH OH- is a poor leaving group
H2O is a better leaving group, but this requires
protonation of the alcohol which, in turn, requires
an acidic solution. Most nucleophiles are strong
bases and cannot exist in acidic solutions.
We need to convert the alcohol to an electrophile
that is compatible with basic nucleophiles.
Reactions of Alcohols Tosylation
Converting the alcohol to an alkyl halide (already
discussed) or an alkyl tosylate lets it act as an
electrophile.
Stereochemical
configuration
of alcohol is
retained.
A Tosylate Ion is an
EXCELLENT LEAVING GROUP
As good as or better than a halide.
A Tosylate Ion is an
EXCELLENT LEAVING GROUP
As such, tosylates (just like
halides) are candidates for
SN2 reactions
E2 reactions
SN1 reactions
E1 reactions
Just like the halides
SN2 Reactions of Tosylates
R-OTs + OH- ROH (alcohol) + -OTs
R-OTs + CN- RCN (nitrile) + -OTs
R-OTs + Br- RBr (alkyl halide) + -OTs
R-OTs + R’O- ROR’ (ether) + -OTs
R-OTs + NH3 RNH3+ -OTs (amine salt)
R-OTs + LiAlH4 RH (alkane) + -OTs
SN2 Reactions of Tosylates Mechanism
Single step
Inversion of configuration
Alcohols to Alkyl Halides: Hydrohalic
Acids (HX)
Hydrohalic acids are strong acids, existing in
aqueous solution as H+ and X-.
Recognize a hydrohalic acid: NaBr/H2SO4
The H+ is need to convert the -OH of the alcohol into
a good leaving group (H2O).
The reaction mechanism, SN1 or SN2, depends on the
structure of the alcohol.
Alcohols to Alkyl Halides:
Acids (HX)
Hydrohalic
The structure of the alcohol dictates
whether the mechanism is SN1 or SN2.
Alcohols to Alkyl Chlorides:
The Lucas Reagent
Cl- is a weaker nucleophile than Br-.
ZnCl2 coordinates with the -OH of the
alcohol (like H+ does) to form a better
leaving group (HOZnCl2-) than water.
ZnCl2 is a better Lewis acid than H+.
This promotes the SN1 reaction between
HCl and 2° and 3° alcohols.
HCl/ZnCl2 is called the Lucas reagent.
Alcohols to Alkyl Chlorides:
The Lucas Test
Add the Lucas reagent to a solution of the unknown
alcohol and time the formation of a second phase.
3° alcohols react immediately.
2° alcohols take 1-5 minutes.
1° alcohols take >6 minutes.
Alcohols to Alkyl Halides:
Limitations of Using HX
This reaction does not always give
good yields of RX.
1° and 2° alcohols react slowly with
HCl, even with ZnCl2 added.
Heating an alcohol with HCl or HBr can
give the elimination product, an alkene.
Rearrangements can occur with SN1
(this is not necessarily bad).
HI does not give good yields of alkyl
iodides, a valuable class of reagents.
Alcohols to Alkyl Halides:
and P/I2
PBr3
Can give good yields of 1° and 2° alkyl
bromides and iodides without the acidic
conditions that go with HX.
3 R-OH + PBr3 3RBr + P(OH)3
PI3 is unstable and must be made in situ:
6 R-OH + 2P + 3I2 6RI + 2P(OH)3
PBr3 and P/I2 do NOT work well with 3°
alcohols.
Alcohols to Alkyl Halides:
Mechanism
PBr3
A double SN2
mechanism,
which is why it
does not work
on 3° alcohols.
Inversion of
configuration,
but no
rearrangements.
Alcohols to Alkyl Halides: Thionyl
Chloride, SOCl2
Often the best way to make an alkyl
chloride from an alcohol.
ROH + SOCl2
heat
dioxane
RCl + HCl(g) + SO2(g)
Gaseous by-products keep the
equilibrium well to the right.
Alcohols to Alkyl Halides:
Best Reagents
Alcohol
Alkyl
chloride
Alkyl
bromide
Alkyl
iodide
1°
SOCl2
PBr3
P/I2
2°
SOCl2
PBr3
(P/I2)
3°
HCl
HBr
(HI)
Alcohols to Alkenes:
Acid-Catalyzed Dehydration
We studied this in the formation of
alkenes.
E1 elimination of a protonated
alcohol
Best for 3° and 2° alcohols
Rearrangements common for 1°
alcohols due to the carbocation
intermediate
Zaitsev product predominates.
Alcohols to Alkenes:
Acid-Catalyzed Dehydration
Step 1: protonation of the alcohol
Fast equilibrium
Converts OH to a good leaving group
Alcohols to Alkenes:
Acid-Catalyzed Dehydration
Step 2: ionization to a carbocation
slow, rate-limiting
leaving group is H2O
Alcohols to Alkenes:
Acid-Catalyzed Dehydration
Step 3: deprotonation to give alkene
fast
The carbocation is a strong acid: a weak
base like water or bisulfate can abstract
the proton.
Alcohols to Symmetric Ethers:
Bimolecular Dehydration
Competes with alkene formation.
Lower temperatures favor ether formation, a ΔS thing.
After protonation, the alcohol can undergo an SN2 attack
by another alcohol molecule to form a symmetric ether.
3° Vicinal Diols to Ketones:
The Pinacol Rearrangement
Acid-catalyzed dehydration of a 3°
vicinal diol to form a ketone.
Involves a methyl migration, ~CH3
3° Vicinal Diols to Ketones:
The Pinacol Rearrangement
3° carbocation
resonance-stabilized carbocation
3° Vicinal Diols to Ketones:
The Pinacol Rearrangement
Vicinal Diols to Carbonyls:
Periodic Acid Cleavage of Glycols
Periodic acid is HIO4.
Products are aldehydes and ketones.
Products the same as for ozonolysis.
HIO4
Alcohols to Esters: Acids
When the acid is a carboxylic acid, the
reaction is called Fischer esterification.
This is an equilibrium, and it does not
always favor the ester.
Alcohols to Esters: Acids
When the acid is sulfuric acid, the
product is a sulfate ester.
Alcohols to Esters: Acids
When the acid is nitric, and propane1,2,3-triol (glycerine) is the alcohol,
what is the product?
When the acid is phosphoric acid, the
product is a phosphate ester.
Phosphate esters are the links
between nucleotides in RNA and
DNA.
DNA
image from Wikipedia
Oxidation or Reduction?
O
O
HO OH
H2C
O
C
OH
CH3
OH
OH
O
C
OH
Predict the Product
CH2OH
H2SO4 , heat
OH
Na2Cr2O7
H2SO4
SOCl2
OH
Predict the Product
1. TsCl/pyridine
OH
2.
NaCN
1. TsCl/pyridine
OH
OH
2. NaOCH3/CH3OH
1. TsCl / pyridine
2. NaI / acetone
Predict the Product
CH3CH2OH
H2SO4
140°C
As opposed to 180°C.
OH
P/I2
Predict the Product
O
C
Cl
OH
+
O
C
OH
OH
+
H+
Conversions
O
Br
C
H
Br
Br
OH
CH3
CH3
H3C
C
CH3
Conversions
OH
HO
CH2OH
CO2CH2CH3
CH3