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 O
2
 addition of X
2
 loss of H
2
 Reductions
 loss of O or O
2
 loss of X
2
 addition of H
2 or H -

Classification of Reactions
 Neither an oxidation nor a reduction
 Addition or loss of H +
 Addition or loss of OH -
 Addition or loss of H
2
O
 Addition or loss of 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
O increasing level of oxidation
OH
OH
O
OH

Reactions of Alcohols -
Oxidation
 For alcohols, the oxidation comes from the loss of
H
2
.
 Oxidation of a 2° alcohol gives a ketone.
 Chromic acid reagent used in lab oxidations.
 Na
2
 CrO
Cr
3
2
O
7
+ H
+ H
2
SO
4
2
O (dil H
2
+ H
2
O  2H
2
SO
4
)  H
2
CrO
4
CrO
4
+ 2NaHSO
4

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:
 KMnO
4
 HNO
3
(will attack C=C, too)
 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 (CH
3
)
2
SCl + .
 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.
OH +
O
H
3
C S CH
3
+
O O
Cl C C Cl
(CH
3
CH
2
)
3
N
CH
2
Cl
2
-60°C
O
H
+ H
3
C S CH
3
+ CO
2
+ 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
OAc
OAc
..
I
O
O
O
H
+
OAc
..
I ..
O + 2HOAc
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 Cr 3+ ) 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 S
N
2 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
 H
2
O 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.

 As good as or better than a halide.


 S
N
2 reactions
 E2 reactions
 S
N
1 reactions
 E1 reactions


S
N
2 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 + NH
3
 RNH
3
+ OTs (amine salt)
 R-OTs + LiAlH
4
 RH (alkane) + OTs

S
N
2 Reactions of Tosylates -
Mechanism



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/H a good leaving group (H
2
O).
2
SO
4
 The H + is need to convert the -OH of the alcohol into
The reaction mechanism, S
N structure of the alcohol.
1 or S
N
2, depends on the

Alcohols to Alkyl Halides: Hydrohalic
Acids (HX)
 The structure of the alcohol dictates whether the mechanism is S
N
1 or S
N
2.

Alcohols to Alkyl Chlorides:
The Lucas Reagent
 Cl is a weaker nucleophile than Br .
 ZnCl
2 coordinates with the -OH of the alcohol (like H + does) to form a better leaving group (HOZnCl
2
) than water.
 ZnCl
2 is a better Lewis acid than H + .
 This promotes the S
N
1 reaction between
HCl and 2° and 3° alcohols.
 HCl/ZnCl
2 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 ZnCl added.
2
 Heating an alcohol with HCl or HBr can give the elimination product, an alkene.
 Rearrangements can occur with S
N
(this is not necessarily bad).
1
 HI does not give good yields of alkyl iodides, a valuable class of reagents.

Alcohols to Alkyl Halides: PBr
3 and P/I
2
 Can give good yields of 1° and 2° alkyl bromides and iodides without the acidic conditions that go with HX.
 3 R-OH + PBr
3
 PBr
3 and P/I alcohols.
2
 3RBr + P(OH)
3
 PI
3 is unstable and must be made in situ:
 6 R-OH + 2P + 3I
2
 6RI + 2P(OH)
3 do NOT work well with 3°

Alcohols to Alkyl Halides: PBr
3
Mechanism
A double S
N
2 mechanism, which is why it does not work on 3° alcohols.
Inversion of configuration, but no rearrangements.

2
 Often the best way to make an alkyl chloride from an alcohol.
ROH + SOCl
2 heat
 RCl + HCl(g) + SO
2 dioxane
(g)
 Gaseous by-products keep the equilibrium well to the right.

Alcohol
1°
Alkyl chloride
SOCl
2
Alkyl bromide
PBr
3
Alkyl iodide
P/I
2
2°
3°
SOCl
2
HCl
PBr
3
HBr
(P/I
2
)
(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 H
2
O

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.

 Competes with alkene formation.
 Lower temperatures favor ether formation, a ΔS thing.
 After protonation, the alcohol can undergo an S
N
2 attack by another alcohol molecule to form a symmetric ether.

 Acid-catalyzed dehydration of a 3° vicinal diol to form a ketone.
 Involves a methyl migration, ~CH
3

3° Vicinal Diols to Ketones:
The Pinacol Rearrangement
3° carbocation
resonance-stabilized carbocation

3° Vicinal Diols to Ketones:
The Pinacol Rearrangement

 Periodic acid is HIO
4
.
 Products are aldehydes and ketones.
 Products the same as for ozonolysis.
HIO
4

 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 propane-
1,2,3-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.

image from Wikipedia

Oxidation or Reduction?
O O
HO OH
OH
O
C
OH
CH
3
H
2
C
OH O
C
OH

Predict the Product
CH
2
OH
H
2
SO
4
, heat
OH
OH
Na
2
Cr
2
O
7
H
2
SO
4
SOCl
2

Predict the Product
OH
1.
TsCl/pyridine
2.
NaCN
OH
OH
1.
TsCl/pyridine
2.
NaOCH
3
/CH
3
OH
1.
TsCl / pyridine
2.
NaI / acetone

Predict the Product
CH
3
CH
2
OH
H
2
SO
4
140 °C
As opposed to 180°C.
OH
P/I
2

Predict the Product
O Cl
C
OH
+
O
C
OH
+
OH
H
+

Conversions
Br
O
C
H
Br
H
3
C
C
CH
3
OH
CH
3
Br
CH
3

Conversions
OH HO
CH
3
CH
2
OH CO
2
CH
2
CH
3