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Substitution & Elimination
R"
Base
Nucleophile
R
R
X
Nu
R'
t-BuOK
t-BuOH
H3C
H2
C Br
NaI
MeOH
Selectivity : SN or E, regioselectivity, stereoselectivity
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Chapter 9
Alcohols, Ethers and Epoxides
2
Alcohols, Ethers and Epoxides
Introduction—Structure and Bonding
• Alcohols contain a hydroxy group (OH) bonded to an sp3 hybridized
carbon.
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Alcohols, Ethers and Epoxides
Introduction—Structure and Bonding
• enols and phenols
Compounds having a hydroxy group on a sp2 hybridized carbon
undergo different reactions than alcohols.
• Will be discussed in chapter 11, 19
4
Alcohols, Ethers and Epoxides
Introduction—Structure and Bonding
• Ethers have two alkyl groups bonded to an oxygen atom.
5
Alcohols, Ethers and Epoxides
Introduction—Structure and Bonding
• Epoxides are ethers having the oxygen atom in a three-membered
ring.
Epoxides are also called oxiranes.
• The C—O—C bond angle for an epoxide must be 60°, a considerable
deviation from the tetrahedral bond angle of 109.5°. Thus, epoxides
have angle strain, making them much more reactive than other
ethers.
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Alcohols, Ethers and Epoxides
Introduction—Structure and Bonding
• The oxygen atom in alcohols, ethers and epoxides is sp3
hybridized. Alcohols and ethers have a bent shape like
that in H2O.
• The bond angle around the O atom in an alcohol or ether
is similar to the tetrahedral bond angle of 109.5°.
• Because the O atom is much more electronegative than
carbon or hydrogen, the C—O and O—H bonds are all
polar.
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Alcohols, Ethers and Epoxides
Nomenclature of Alcohols : -- ol
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Alcohols, Ethers and Epoxides
For cyclic compounds
• When an OH group is bonded to a ring, the ring is numbered
beginning with the OH group.
• Because the functional group is at C1, the 1 is usually omitted
from the name.
• The ring is then numbered in a clockwise or counterclockwise
fashion to give the next substituent the lowest number.
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Alcohols, Ethers and Epoxides
Nomenclature of Alcohols
• Common names are often used for simple alcohols.
Name all the carbon atoms of the molecule as a single
alkyl group.
Add the word alcohol, separating the words with a
space.
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Alcohols, Ethers and Epoxides
Nomenclature of Alcohols
• Compounds with two hydroxy groups : diols or glycols.
• Compounds with three hydroxy groups : triols
and so forth.
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Alcohols, Ethers and Epoxides
Nomenclature of Ethers
• Simple ethers are usually assigned common names. To
do so:
Name both alkyl groups bonded to the oxygen, arrange
these names alphabetically, and add the word ether.
For symmetrical ethers, name the alkyl group and add the
prefix “di-”.
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Alcohols, Ethers and Epoxides
• More complex ethers are named using the IUPAC system.
One alkyl group is named as a hydrocarbon chain, and the
other is named as part of a substituent bonded to that chain:
Name the simpler alkyl group as an alkoxy substituent by
changing the –yl ending of the alkyl group to –oxy.
Name the remaining alkyl group as an alkane, with the
alkoxy group as a substituent bonded to this chain.
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Alcohols, Ethers and Epoxides
• Cyclic ethers have an O atom in
the ring. A common example is
tetrahydrofuran (THF).
This name has a different origin
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Nomenclature of Epoxides
• Epoxides can be named in three different ways—As
epoxyalkanes, oxiranes, or alkene oxides.
• To name an epoxide as an epoxyalkane, first name the
alkane chain or ring to which the O atom is attached,
• and use the prefix “epoxy” to name the epoxide as a
substituent.
• Use two numbers to designate the location of the atoms
to which the O’s are bonded.
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•Epoxides can be named in three different ways—As
epoxyalkanes, oxiranes, or alkene oxides.
• Epoxides bonded to a chain of carbon atoms can also be
named as derivatives of oxirane, the simplest epoxide
having two carbons and one oxygen atom in a ring.
• The oxirane ring is numbered to put the O atom at
position one, and the first substituent at position two.
• No number is used for a substituent in a
monosubstituted oxirane.
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•Epoxides can be named in three different ways—As
epoxyalkanes, oxiranes, or alkene oxides.
• Epoxides are also named as alkene oxides, since they
are often prepared by adding an O atom to an alkene. To
name an epoxide in this way:
Mentally replace the epoxide oxygen with a double
bond.
Name the alkene.
Add the word oxide.
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Alcohols, Ethers and Epoxides
Physical Properties
• Alcohols, ethers and epoxides exhibit dipole-dipole interactions
because they have a bent structure with two polar bonds.
• Alcohols are capable of intermolecular hydrogen bonding. Thus,
alcohols are more polar than ethers and epoxides.
• Steric factors affect hydrogen bonding.
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Alcohols, Ethers and Epoxides
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Alcohols, Ethers and Epoxides
Interesting Alcohols
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Alcohols, Ethers and Epoxides
Interesting Alcohols
glycerol
Sugars, cellulose, starch etc.
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Alcohols, Ethers and Epoxides
Interesting Ethers
Diethyl ether is the best-known ether, first used as a general anesthetic in
the 1830s. Because of its high flammability and side-effects on some patients,
its place as an anesthetic has been taken by other substances.
Cyclic polyether : crown ether
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Alcohols, Ethers and Epoxides
Interesting Ethers
• The ability of crown ethers to complex cations can be
exploited in nucleophilic substitution reactions, as shown in
Figure 9.5.
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Alcohols, Ethers and Epoxides
Interesting Ethers : nature’s crown ether
• Brevetoxin B is a naturally occurring polyether that
interferes with Na+ ion transport across cell membranes.
“Red Tide”
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마산 앞바다 적조
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San Diego
Interesting Epoxides : epoxides are reactive!
• Ethylene oxide : precursor of ethylene glycol, polyethylene glycol
OH
O
O
*
O
HO
n
• Natural epoxides
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Preparation of Alcohols, Ethers, and Epoxides
• Alcohols and ethers are both common products of nucleophilic
substitution of alkyl halides.
Williamson ether synthesis.
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Preparation of Alcohols, Ethers, and Epoxides
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Williamson ether synthesis.
• SN2 reaction
Strong Nucleophile (An alkoxide salt) is needed to make
an ether.
• Cyclic ethers are formed through intramolecular reaction.
Br
NaH
HO
n
When n=
n
O
-2, epoxides
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Preparation of Epoxides
• Organic compounds that contain both a hydroxy group
and a halogen atom on adjacent carbons are called
halohydrins.
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Reactions of Alcohols
Substitution, elimination, oxidation
• The OH group in alcohols is a very poor leaving group.
• For an alcohol to undergo nucleophilic substitution, OH must be converted
into a better leaving group (activated).
• By using acid, ¯OH can be converted into H2O, a good leaving group.
• By converting to sulfonates, ¯OH can be converted into
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¯OSO2R, a good leaving group.
Reactions of Alcohols
Br
OH
HBr (for SN)
or H2SO4
(for E)
+
OH2
SN
Halide
E
Alkene
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Reactions of Ethers and Epoxides
Ethers do not have a good leaving group and are difficult to activate.
Epoxides are highly reactive due to high angle strain.
Ring-opening results in
relief of strain
O
C
C
O
C
_
C
Nu
_
Nu:
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Reactions of Alcohols—Dehydration
• Dehydration, like dehydrohalogenation, is a  elimination
reaction in which the elements of OH and H are removed from
the  and  carbon atoms respectively.
• Dehydration is typically carried out using H2SO4 and other
strong acids, or phosphorus oxychloride (POCl3) in the
presence of an amine base.
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Reactions of Alcohols—Dehydration
• Typical acids used for alcohol dehydration : H2SO4 or ptoluenesulfonic acid (TsOH).
strong organic acid
• More substituted alcohols dehydrate more easily, giving rise
to the following order of reactivity.
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Alcohols, Ethers and Epoxides
Reactions of Alcohols—Dehydration
•Dehydration follows the Zaitsev rule.
The more substituted alkene is the major product when a
mixture of constitutional isomers is possible.
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Alcohols, Ethers and Epoxides
Reactions of Alcohols—Dehydration
• Secondary and 3° alcohols react by an E1 mechanism
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Alcohols, Ethers and Epoxides
Reactions of Alcohols—Dehydration
• The E1 dehydration of 20 and 30 alcohols with acid gives clean elimination
products without any by-products formed from an SN1 reaction.
• Clean elimination takes place because the reaction mixture contains no good
nucleophile to react with the intermediate carbocation, so no competing SN1
reaction occurs.
• This makes the E1 dehydration of alcohols much more synthetically useful
than the E1 dehydrohalogenation of alkyl halides.
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Alcohols, Ethers and Epoxides
Reactions of Alcohols—Dehydration
• 1° alcohols undergo dehydration following an E2 mechanism.
• 1° carbocations are highly unstable, their dehydration cannot occur
by an E1 mechanism involving a carbocation intermediate.
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Reactions of Alcohols—Dehydration
While dehydrations have favorable entropy changes,
the position of equilibrium favors reactants.
Operation of the Principle of Le Châtelier in Alcohol Dehydrations
• removing a product from a reaction mixture as it is formed drives the
equilibrium to the right, forming more product.
• Thus, the alkene, which usually has a lower boiling point than the starting
alcohol, can be removed by distillation as it is formed, thus driving the
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equilibrium to the right to favor production of more product.
Carbocation Rearrangements
CH3 H
CH3
H2SO4
H3C
CH3
CH3 OH
CH3
H
H3C
H3C
CH3
CH2
CH3
CH3
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Alcohols, Ethers and Epoxides
Carbocation Rearrangements
• Often, when carbocations are intermediates, a less stable
carbocation will be converted into a more stable carbocation
by a shift of a hydrogen or an alkyl group. This is called a
rearrangement.
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Carbocation Rearrangements
• A 1,2-shift can convert a less stable carbocation into a
more stable carbocation.
• Rearrangements can occur whenever a carbocation is
formed as a reactive intermediate.
1,2-hydride shift
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Dehydration of Alcohols Using POCl3 and Pyridine
• Dehydration under basic condition
• A common method uses phosphorus oxychloride (POCl3) and
pyridine (an amine base) in place of H2SO4 or TsOH.
Dehydration proceeds by an E2 mechanism.
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Dehydration of Alcohols Using POCl3 and Pyridine
Mechanism : E2 mechanism
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Dehydration of Alcohols in the natural product synthesis
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Conversion of Alcohols to Alkyl Halides with HX
• Substitution reactions do not occur with alcohols unless ¯OH
is converted into a good leaving group.
• The reaction of alcohols with HX (X = Cl, Br, I) is a general
method to prepare 1°, 2°, and 3° alkyl halides.
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Conversion of Alcohols to Alkyl Halides with HX
• More substituted alcohols usually react more rapidly with HX:
• The mechanism depends on the structure of the R group.
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Conversion of Alcohols to Alkyl Halides with HX
1o alcohols and methanol react via an SN2 mechanism
1. Protonation
CH3
H
HX
C OH
D (S)
CH3
H
C
+
OH2
D
Primary alcohol
2. SN2 with inversion of configuration
_
X
CH3
+
H
H
C
D
+
OH2
CH3
X C
+
(R) D
OH2
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2o and 3o alcohols react via an SN1 mechanism
1. Protonation
CH3
CH3CH2
C
Ph (R)
OH
CH3
CH3CH2
C
Ph
HX
+
OH2
_
+
X
Tertiary alcohol
2. SN1 reaction with racemization
(a) Dissociation
CH3
CH3CH2
+
C OH2
Ph
CH3CH2
CH3
C+
+
OH2
Ph
Carbocation (planar)
(b) Attack of nucleophile
CH3
CH3CH2
C
Ph (R)
X
_
CH3CH2
X
Attack from
right
CH3
X
C+
Ph
_
X
Attack from
left
Racemate
CH3
CH2CH3
C
(S) Ph
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Alcohols, Ethers and Epoxides
Conversion of Alcohols to Alkyl Halides with HX
• The reactivity of hydrogen halides increases with increasing
acidity.
HI
RCH2
OH
RCH2
I
HCl
RCH2
OH
too slow to detect products
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Conversion of Alcohols to Alkyl Halides with HX
• 2o alcohols
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Conversion of Alcohols to Alkyl Halides
HI
RCH2
OH
RCH2
I
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Conversion of Alcohols to Alkyl Halides with SOCl2 and PBr3
• For primary and 2° alcohols
• SOCl2 (thionyl chloride) converts alcohols into alkyl chlorides.
• PBr3 (phosphorus tribromide) converts alcohols into alkyl bromides.
via an SN2 reaction
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Conversion of Alcohols to Alkyl Halides with SOCl2 and PBr3
• For primary and 2° alcohols
• SOCl2 (thionyl chloride) converts alcohols into alkyl chlorides.
• PBr3 (phosphorus tribromide) converts alcohols into alkyl bromides.
via an SN2 reaction
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Alcohols, Ethers and Epoxides
Conversion of Alcohols to Alkyl Halides with SOCl2
and PBr3
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Alcohols, Ethers and Epoxides
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Tosylate—Another Good Leaving Group
• An alkyl tosylate is composed of two parts: the alkyl group R,
derived from an alcohol; and the tosylate (short for ptoluenesulfonate), which is a good leaving group.
• A tosyl group, CH3C6H4SO2¯, is abbreviated Ts, so an alkyl
tosylate becomes ROTs.
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Tosylate—Another Good Leaving Group
• This process converts a poor leaving group (¯OH) into a good one
(¯OTs).
• Tosylate is a good leaving group because its conjugate acid, ptoluenesulfonic acid (CH3C6H4SO3H, TsOH) is a strong acid (pKa = -7).
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Tosylate—Another Good Leaving Group
• Because alkyl tosylates have good leaving groups, they
undergo both nucleophilic substitution and  elimination,
exactly as alkyl halides do.
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Tosylate—Another Good Leaving Group
• Substitution occurs via an SN2 mechanism.
• Tosylates are equivalent to halides.
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Example:
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Alcohols, Ethers and Epoxides
Reaction of Ethers with Strong Acid
cleavage occurs either side of the ether oxygen atom to give two alkyl
halide products, so ethers are not generally as useful as alcohols in
synthesis.
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Mechanism of
68
Mechanism of
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Reactions of Epoxides
• Nucleophilic attack opens the strained three-membered ring, making
it a favorable process even with a poor leaving group.
Reactions occur with strong nucleophiles (such as OH-, CH3S-, CH3O- or CN-),
in the absence of acid and with weaker nucleophiles (such as Cl-) in the presence
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of strong acid (such as HCl).
Reactions of Epoxides
• Common nucleophiles that open the epoxide ring include ¯OH, ¯OR,
¯CN, ¯SR and NH3. With these strong nucleophiles.
• The reaction occurs by an SN2 mechanism.
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Reactions of Epoxides : stereochemical consequences
Nucleophilic attack of ¯OCH3 occurs from the backside at
either C—O bond, because both ends are similarly
substituted. Since attack at either side occurs with equal
probability, an equal amount of the two enantiomers (i.e., a
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racemic mixture) is formed.
Alcohols, Ethers and Epoxides
Reactions of Epoxides
Optically inactive starting materials give optically inactive
products!
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Alcohols, Ethers and Epoxides
Reactions of Epoxides
• Acids HZ that contain a nucleophile Z also open epoxide rings by
a two-step sequence.
• HCl, HBr and HI, as well as H2O and ROH in the presence of acid,
all open an epoxide ring in this manner.
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Reactions of Epoxides
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Alcohols, Ethers and Epoxides
Reactions of Epoxides
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Reactions of Epoxides
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Leukotriene Synthesis and Asthma Drugs
OOH
CO2H
C5H11
CO2H
C5H11
C5H11
Lipoxygenase
Zileuton blocks
this step
Arachidonic acid
OH
CO2H
5-HPETE
Sulfur
.. nucleophile,
RSH
.. (glutathione)
O
CO2H
C5H11
SR
Leukotriene C4
Leukotriene A4
HO
N
CONH2
S
Zileuton
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Alcohols, Ethers and Epoxides
Important Epoxide Ring Opening Reactions
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Homework
9.48, 9.49, 9.50, 9.52, 9.56,
9.58, 9.66, 9.67, 9.70, 9.71,
9.76
Preview of Chapter 10
Alkenes
Preparation of alkenes
Dehydration, dehydrohalogenation
Reactions of alkenes
Addition reaction --- Markovnikov’s rule
-Hydrohalogenation, hydration, halogenantion, hydroboration
- stereochemistry of the reaction products
Write mechanisms for following reactions.
HI
RCH2
OH
RCH2
I
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