Substitution Reactions of Alcohols
We have looked at substitution reactions that take place via two
mechanisms:
SN1 - works for substrates that can form relatively stable carbocations...
SN2 - works best for substrates where the carbon that bears the leaving
group is sterically uncluttered.
Both mechanisms involve loss of the leaving group in the rate-determining step.
Good leaving groups are...
The problem with alcohols...
N
C
+
OH
OH
CN
+ HO
+ HO
So, if we want to use alcohols as substrates in these reactions, we must do
something to make the –OH group a better leaving group.
1
Substitution Reactions of Alcohols
3° alkyl halides via SN1
H3C
H3C
C
H3C
Conc. HBr
O
H3C
H3C
C
Br
H
H3C
Propose a mechanism for this reaction:
2
Substitution Reactions of Alcohols
1° alcohols are converted into alkyl halides via SN2
H2SO4, NaBr
CH3CH2CH2CH2OH
CH3CH2CH2CH2Br
Propose a mechanism for this reaction:
3
Substitution Reactions of Alcohols
Consider the following reaction. We doesn’t it proceed to products?
H2SO4, NaCN
CH3CH2CH2CH2OH
X
CH3CH2CH2CH2CN
OK, so what if we use HCN instead? The reaction still doesn’t proceed. Why?
HCN
CH3CH2CH2CH2OH
X
CH3CH2CH2CH2CN
4
Substitution Reactions of Alcohols
If we want to make nitriles, we will have to use a different approach. One method
is to convert the alcohol into a sulfonate ester. To make a sulfonate ester, you
react an alcohol with an appropriate sulfonyl chloride in the presence of an amine
(usually pyridine):
5
Some common Sulfonate Esters:
Ester
Generic Name
Abbreviation
Mesylate
R-OMs
CH3
Tosylate
R-OTs
Br
Brosylate
R-OBs
Triflate
R-OTf
Nonaflate
R-ONs
O
R
O
S
CH3
O
O
R
O
S
O
O
R
O
S
O
O
R
O
S
CF3
O
O
R
O
S
O
CF2CF2CF2CF3
6
Sulfonate Esters
An alternative approach would be to deprotonate the alcohol first, then react it
with the sulfonyl chloride:
H2
DMF
DMF
The alkoxides can be made by reacting an alcohol with NaH or with an alkali metal
(Na or K):
7
Sulfonate Esters
Once the alcohols have been converted to the sulfonate ester, it can then be used
in an SN2 reaction:
THF
THF
8
Substitution Reactions of Alcohols – Converting Alcohols to Alkyl Halides
Sulfonate esters make good leaving groups because the pKa of their conjugate
acids is ~-6.5, roughly the same as that for Cl-. As such, another strategy for
making alcohols a better leaving group is to convert them into a halide!
PBr3
OH
Br
60%
Thionyl chloride
SOCl2
OH
Cl
70%
9
Converting Alcohols to Alkyl Halides
Propose a mechanism for the following reaction:
PBr3
OH
P=O bonds are very strong, making this process favourable.
10
Converting Alcohols to Alkyl Halides
Propose a mechanism for the following reaction:
SOCl2
OH
11
Converting Alcohols to Alkyl Halides – The Mitsunobu Reaction
R
OH
PPh3
HX
EtO2C
N
N
R
X
O PPh3
EtO2C
H
N
H
N
CO2Et
CO2Et
A Mitsonobu reaction involves four main reactants:
The alcohol to be substituted
The conjugate acid of the desired nucleophile (e.g. HCl for Cl-)
Triphenylphosphine (Ph3P = (C6H5)3P)
Diethyl azodicarboxylate (DEAD = CH3CH2OC(O)NNC(O)OCH2CH3)
12
Converting Alcohols to Alkyl Halides – The Mitsunobu Reaction
R
OH
PPh3
HX
EtO2C
N
N
R
X
O PPh3
EtO2C
H
N
H
N
CO2Et
CO2Et
Propose a mechanism for the Mitsunobu reaction:
13
The Mitsunobu Reaction
O
O
OH
+
H3C
PPh3, DEAD
S
C
SH
THF, 25°C
C
CH3
HX can be a weak acid ... HCN, RCO2H, HN3, ArOH, ArSH
This is a very convenient technique for doing SN2 reactions with alcohols without
requiring the alkyl halide.
14
Converting Alcohols to Ethers
If you wanted to make an ether, you could imagine an alcohol reacting with itself.
What are the two main reasons why this reaction does not work?
H
H
C
H
OH
+
H
H
H
C
X
OH
H
H
C
H
C
H
H
O
H
The Williamson ether synthesis is a versatile method for making ethers.
O
H NaH, DMF
O
Na
Br
O
What kind of mechanism does this reaction follow?
15
Converting Alcohols to Ethers
It is also possible to prepare ethers via SN1 processes.
CH3CH2OH
Br

OCH2CH3
Keep in mind that the nucleophilic site and electrophile site don’t necessarily have
to be in different molecules. Propose a mechanism for the following reactions:
NaH
HO
Cl
H
H
O
R
H
H
Br
DMF
NaOH
H2O
16
Cleavage of Ethers
The cleavage of ethers also occurs via substitution reactions. Propose a mechanism
for the following reaction:
HI
O
2
I
17
Cleavage of Ethers
The cleavage of ethers can also be done using trimethylsilyl iodide (TMSI):
H 3C
H 3C
O
Si
CH3
CH3
H3C
Si
O
CH3
CH3
I
+
I
CH3
18
Epoxides – SN2 substrates
With good nucleophiles and under neutral or basic conditions, epoxides are
excellent substrates for SN2 reactions.
O
O
Nu:
Nu
OH
H+
Nu
This type of reaction does not proceed with other ethers. Why?
Nu:
O
no reaction
19
Epoxides – SN2 substrates
Like all SN2 reactions, epoxides react with inversion of stereochemistry at the least
hindered electrophilic carbon atom.
H
NaN3, CH3CH3OH, H2O
O
H
O
PhSH, PhS
H3C
H
20
Epoxides – SN1 substrates
Under acidic conditions, epoxides are good SN1 substrates.
O
CH3OH, H2SO4
H3C
H3C
21
Epoxides – SN1 substrates
To understand the reactivity of epoxides under acidic conditions, we have to
consider the intermediate that is formed:
H
H
O
H3C
O
H3C
CH2
H3C
H3C
H
H3C
O
=
CH2
H
O
CH2
H3C
H3C
H3C
H3C
H
O
H3C
H
=
CH2
O
H3C
H3C
22
Epoxides – SN1 substrates
So what does this mean in terms of product distribution?
23
Common Leaving Groups
NC:
NC
RH2C N N
Class of compound
RH2C S C4F9
O
O
RH2C S CH3
C4F9SO3-
Mesylate
CH3SO3-
I
Iodides
I-
RH2C Br
Bromides
Br-
H
RH2C O
Protonated alcohols
H2O
H
RH2C Cl
Chlorides
Cl-
H
RH2C O
Protonated ethers
CH3OH
CH3
CH3
RH2C N CH3
CH3
Good leaving groups
Nonaf late
O
RH2C
Leaving group
Leaving group
N2
N N
Excellent leaving groups
Diazonium salt
RH2C N N
O
CH2R
Quaternary Ammonium Salts N(CH3)3
24
Fluorides
F-
O
RH2C O
C
Acetates
Acetate anion, CH3CO2-
Alcohols
Hydrides
Amines
Hydroxide, HOHydride, HAmide, NH2-
Alkanes
CH3-
CH3
RH2C OH
RH2C H
RH2C NH2
RH2C CH3
Very poor leaving groups
RH2C F
25