Alcohols

Report
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

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