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11.4 NUCLEOPHILIC SUBSTITUTION REACTIONS OF EPOXIDES 495
(d) When tert -butyl methyl ether is heated with sulfuric acid, methanol and 2-methylpropene
distill from the solution.
(e) Tert -butyl methyl ether cleaves much faster in HBr than its sulfur analog, tert -butyl
methyl sulfide. ( Hint: See Sec. 8.7.)
(f) When enantiomerically pure ( S )-2-methoxybutane is treated with HBr, the products are
enantiomerically pure ( S )-2-butanol and methyl bromide.
11.16 What products are formed when each of the following ethers reacts with concentrated aque-
ous HI?
(a) diisopropyl ether (b) 2-ethoxy-2,3-dimethylbutane
11.4 NUCLEOPHILIC SUBSTITUTION REACTIONS OF EPOXIDES
A. Ring-Opening Reactions under Basic Conditions
Epoxides readily undergo reactions in which the epoxide ring is opened by nucleophiles.
A reaction of this type is an S
N
2 reaction in which the epoxide oxygen serves as the leaving
group. In this reaction, though, the leaving group does not depart as a separate entity, but
rather remains within the same product molecule.
Because an epoxide is a type of ether, the ring opening of epoxides is an ether cleavage. Re-
call that ordinary ethers do not undergo cleavage in base (Eq. 11.23, p. 492). Epoxides, how-
ever, are opened readily by basic reagents. Epoxides are so reactive because they, like their
carbon analogs, the cyclopropanes, possess significant angle strain (Sec. 7.5B). Because of
this strain, the bonds of an epoxide are weaker than those of an ordinary ether, and are thus
more easily broken. The opening of an epoxide relieves the strain of the three-membered ring
just as the snapping of a twig relieves the strain of its bending.
In an unsymmetrical epoxide, two ring-opening products could be formed corresponding
to the reaction of the nucleophile at the two different carbons of the ring. As Eq. 11.30 illus-
trates, nucleophiles typically react with unsymmetrical epoxides at the carbon with fewer
alkyl substituents. This regioselectivity is expected from the effect of alkyl substitution on the
(11.30)
HL OC 2
H 5
nucleophile
leaving group
_
_
_
CH
2
O
CH
2
OC
2
H
5
OC
2
H
5
OC
2
H
5
O
L
L L L
CH
2
OC
2
H
5
OH
L
L L
2
2
an S
N
2 reaction
(CH
3
2
C (CH
3
2
C (CH
3
2
C
..
(11.29)
CH
2
O
C
2
H
5
OH OC
2
H
5
L
CH
2
OH
L
+ L L
Na
|
C 2
H 5
O
_
5 h, 80 °C
2,2-dimethyloxirane
(isobutylene oxide)
ethanol
(solvent)
1-ethoxy-2-methyl-2-propanol
(83% yield)
(CH
3
2
C (CH
3
2
C
496 CHAPTER 11 • THE CHEMISTRY OF ETHERS, EPOXIDES, GLYCOLS, AND SULFIDES
rates of S
N
2 reactions (Sec. 9.4D). Because alkyl substitution retards the S
N
2 reaction, the re-
action of a nucleophile at the unsubstituted carbon is faster and leads to the observed product.
Like other S
N
2 reactions, the ring opening of epoxides by bases involves backside substitu-
tion of the nucleophile on the epoxide carbon. When this carbon is a stereocenter, inversion of
configuration occurs, as illustrated by Study Problem 11.2.
Study Problem 11.
What is the stereochemistry of the 2,3-butanediol formed when meso -2,3-dimethyloxirane reacts
with aqueous sodium hydroxide?
Solution First draw the structure of the epoxide. The meso stereoisomer of 2,3-dimethyloxirane
has an internal plane of symmetry, and its two asymmetric carbons have opposite configurations.
Because the two different carbons of the epoxide ring are enantiotopic (Sec. 10.8A), the
hydroxide ion reacts at either one at the same rate. Backside substitution on each carbon should
occur with inversion of configuration.
The product shown is the 2 S ,3 S stereoisomer. Reaction at the other carbon gives the 2 R ,3 R
stereoisomer. (Verify this point!) Because the starting materials are achiral, the two enantiomers of
the product must be formed in equal amounts (Sec. 7.8A). Hence, the product of the reaction is
racemic 2,3-butanediol. (This predicted result is in fact observed in the laboratory.)
Although the examples in this section have involved hydroxide and alkoxides as nucle-
ophiles, the pattern of reactivity is the same with any nucleophile: The nucleophile reacts at
the carbon with no alkyl substituents and opens the epoxide to form an alkoxide, which then
reacts in a Brønsted acid–base reaction with a proton source to give an alcohol. Letting Nuc 3
_
be a general nucleophile, we can summarize this pattern of reactivity with Eq. 11.31:
(11.31)
CH
2
O
L
Nuc
Nuc
Nuc
..
..
.. ..
.. ..
R
2
C CH
2
O
L
R L L
2
C
..
H
Nuc
..
CH
2
L
R L L
2
C
..
OH
nucleophilic
substitution
proton
transfer
H
H
C L
%
%
C
CH
3
H
3
C
O
OH
CH
3
H
C L
%
%
C
H
H 3
C
O
H H
C L
% %
C
CH 3
H 3
C
31
OH
1
3 3 23
3 OH 2
_
OH
_
_
H 2
O
1
3 3
3 OH 1
inversion
of configuration
H
O
CH 3
C L C
meso -2,3-dimethyloxirane
H
S
R
) )
H
3
C
498 CHAPTER 11 • THE CHEMISTRY OF ETHERS, EPOXIDES, GLYCOLS, AND SULFIDES
The structural properties of the protonated epoxide show that it can be expected to behave like
a tertiary carbocation.
First, calculations show that the tertiary carbon bears about 0.7 of a positive charge. Second,
the geometry at the tertiary carbon is nearly trigonal planar. This means that the tertiary car-
bon and the groups around it are very nearly flattened into a common plane so that little or no
steric hindrance prevents the approach of a nucleophile to this carbon. Finally, the bond be-
tween the tertiary carbon and the LOH group is unusually long and weak. This means that
this bond is more easily broken than the other CLO bond. In fact, this cation resembles a car-
bocation solvated by the leaving group (see Fig. 9.13, p. 419). The LOH leaving group
blocks the front side of the carbocation so that the nucleophilic reaction must occur from the
back side with inversion of stereochemistry. In other words, we can think of this reaction as an
S
N
1 reaction with stereochemical inversion.
Thus, a solvent molecule reacts with the protonated epoxide at the tertiary carbon, and loss
of a proton to solvent gives the product.
It is a solvent molecule, not the alkoxide conjugate base of the solvent, that reacts with the pro-
tonated epoxide. The alkoxide conjugate base cannot exist in acidic solution; nor is it neces-
sary, because the protonated epoxide is very reactive and because the nucleophile is also the
solvent and is thus present in great excess.
When the carbons of an unsymmetrical epoxide are secondary or primary, there is much
less carbocation character at either carbon in the protonated epoxide, and acid-catalyzed ring-
opening reactions tend to give mixtures of products; the exact compositions of the mixtures
vary from case to case.
The mixture reflects the balance between opening of the weaker bond, which favors reaction
at the carbon with more substituents, and van der Waals repulsions with the nucleophile,
which favors reaction at the carbon with fewer substituents.
The regioselectivities of acid-catalyzed epoxide ring opening and the reactions of solvent nu-
cleophiles with bromonium ions are very similar (see Eq. 5.15, p. 184). This is not surprising, be-
cause both types of reactions involve the opening of strained rings containing positively charged,
electronegative leaving groups.
CH CH (11.34)
2
H
3
C
O
L L OH
H
3
C CH
2
OC
2
H
5
L
L
CH L L OC
2
H
5
H
3
C CH
2
OH
L
L
CH L L
0.8% H
2
SO
4
secondary primary
37% of the product 63% of the product
C 2
H 5
OH (solvent)
(11.33c)
CH
2
HOCH
3
HOCH 1
3
OH
3 OH
CH
3
CH
2
O
L
L
L
L
L L
3 OH 2
CH
2
L
L
|
|
H
HOCH
3
CH
3
O
L
L
L
H
(CH
3
2
C (CH
3
2
C (CH
3
2
C
(11.33b)
CH
2
H
3
C
H
3
C
C
OH
..
d +
d +
long, weak bond
a large amount of
positive charge
nearly trigonal
planar geometry
11.4 NUCLEOPHILIC SUBSTITUTION REACTIONS OF EPOXIDES 499
Acid-catalyzed ring-opening reactions of epoxides, like base-catalyzed ring-opening
reactions, occur with inversion of stereochemical configuration.
When water is used as a nucleophile in acid-catalyzed epoxide ring opening, the product is
a 1,2-diol, or glycol. Acid-catalyzed epoxide hydrolysis is generally a useful way to prepare
glycols.
Notice the trans relationship of the two hydroxy groups in the product, which results from the
inversion of configuration that occurs when water reacts with the protonated epoxide. It fol-
lows that cis -1,2-cyclohexanediol cannot be prepared by epoxide opening. However, in Sec.
11.5A, you will learn how this stereoisomer can be prepared by another method.
Although base-catalyzed hydrolysis of epoxides also gives glycols (see Study Prob-
lem 11.2), polymerization sometimes occurs as a side reaction under the basic conditions (see
Problem 11.68). Consequently, acid-catalyzed hydrolysis of epoxides is generally preferred
for the preparation of glycols.
PROBLEM
11.19 Predict the major product(s) of each of the following transformations.
(a)
(b)
Let’s summarize the facts about the regioselectivity and stereoselectivity of epoxide ring-
opening reactions:
- Nucleophiles react with unsymmetrical epoxides under basic conditions at the less
branched carbon, and inversion of configuration is observed if reaction occurs at a stere-
ocenter.
- Nucleophiles react with unsymmetrical epoxides under acidic conditions at the tertiary
carbon. If neither carbon is tertiary, a mixture of products is formed in most cases.
Inversion of configuration is observed if reaction occurs at a stereocenter.
These facts are applied in Study Problem 11.3.
H 2
SO 4
(trace)
The enantiomer of the epoxide in part (a) + CH
3
OH
(solvent)
(optically active)
(solvent)
CH
3
OH
C
2
H
5
C
2
H
5
H
H
O
C C
H 2
SO 4
(trace)
(11.36)
O
H
H
2
O
HClO
4
(trace)
30 min
OH
OH
cyclohexene oxide (
|
)- trans -1,2-cyclohexanediol
(a glycol; 80% yield)
H
_
H
H
(solvent)
O (11.35)
H
H
CH
3
OH
H
2
SO
4
catalyst
OH
H
OCH
3
H
cyclohexene oxide
inversion of configuration
(
|
)- trans -2-methoxycyclohexanol
(82% yield)
_
(solvent)
11.4 NUCLEOPHILIC SUBSTITUTION REACTIONS OF EPOXIDES 501
This reaction is another epoxide ring-opening reaction. To understand this reaction, recall
that the carbon in the CLMg bond of the Grignard reagent has carbon-anion character and is
therefore a very basic carbon (Sec. 8.8B). This carbon is the nucleophile that reacts with the
epoxide. At the same time, the magnesium of the Grignard reagent, which is a Lewis acid, co-
ordinates to the epoxide oxygen. (Recall that Grignard reagents associate strongly with ether
oxygens; see Eq. 8.23, p. 362.) Just as protonation of an oxygen makes it a better leaving
group, coordination of an oxygen to a Lewis acid also makes it a better leaving group. Conse-
quently, this coordination assists the ring opening of the epoxide in much the same way that
Brønsted acids catalyze ring opening (Sec. 11.4B).
As Eq. 11.40a shows, this reaction yields an alkoxide, which is the conjugate base of an
alcohol (Sec. 8.6A). After the Grignard reagent has reacted, the alkoxide is converted into the
alcohol product in a separate step by the addition of water or dilute acid:
It would be reasonable to suppose that Grignard and organolithium reagents would react
with epoxides other than ethylene oxide, and they do. However, many reactions of Grignard
and lithium reagents with epoxides are unsatisfactory because they give not only the expected
products of ring opening but also rearrangements and other side reactions as well. (Grignard
reagents and organolithium reagents have some Lewis acid character that promotes such side
reactions.) However, another type of organometallic reagent, the lithium organocuprate, un-
dergoes useful ring-opening reactions with epoxides.
Two types of organocuprates are used most commonly in organic chemistry. The first type
is formed from the reaction of two equivalents of an alkyllithium reagent with copper(I) halide
in an ether solvent. The first equivalent reacts to form an alkylcopper reagent plus a lithium
halide. The driving force for the reaction is the greater tendency of lithium, the more elec-
tropositive metal, to exist as an ion.
Because the copper is a Lewis acid, the alkylcopper reagent reacts with a second equivalent of
the alkyllithium to give a lithium dialkylcuprate.
Li (11.42) CuCH
2
CH
3
Cu(CH
2
CH
3
2
Li
CH +
3
CH
2
lithium diethylcuprate
(a lithium dialkylcuprate)
CH Li + Cu Cl Cu +Li Cl (11.41)
3
CH
2
CH
3
CH
2
R CH (11.40b)
2
CH
2
CH
2
CH
2
H
2
Mg
2 |
Br
_
MgBr H
2
H R H
L
L L L L
_
O 3
O
O
O
|
|
(11.40a)
_
O
CH
2
MgBr
Mg
Br
2 R
CH O
2
L
L
L L
L
Mg Br
L LR
R
R LMgBr
_
a bromomagnesium alkoxide
MgBr RMgBr CH
2
CH O
2
L L L
R 3 +
|
|
H
2
C CH
2
L
(11.39)
H
2
C CH
2
O
CH
3
CH
2
CH
2
CH
2
CH
2
CH
2
MgBr CH
3
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
L OH
ether, heat
H
3
O
|
hexylmagnesium bromide
(a Grignard reagent)
ethylene oxide 1-octanol
(71% yield)
502 CHAPTER 11 • THE CHEMISTRY OF ETHERS, EPOXIDES, GLYCOLS, AND SULFIDES
(Aryllithium reagents such as phenyllithium, Ph LLi, can also be used to prepare lithium di-
arylcuprates.)
If copper(I) cyanide, CuCN, is used instead of a copper(I) halide, the cyanide group, which
is much more basic than halide, remains bound to the copper, and a more complex reagent is
formed:
Although Eq. 11.43 describes the stoichiometry of the reagent, it exists in a state (or states) of
higher aggregation. Such reagents are called higher-order organocuprates.
Both types of organocuprate reagents are useful in organic chemistry, and both react with
epoxides. However, the higher-order organocuprates are the preferred reagents for use with
epoxides because they react with a wider variety of epoxides and give fewer side reactions.
(We’ll see some important uses of lithium dialkylcuprates in later chapters.)
An organocuprate reagent reacts at the carbon of the epoxide with fewer alkyl substituents
to give products of ring opening. Protonolysis gives the alcohol.
Notice that the alkyl group from the reagent reacts at the epoxide carbon with inversion of
stereochemical configuration.
We can think of the reaction as an S
N
2 process in which a “carbon–anion” nucleophile is
delivered from the copper to the epoxide carbon electrophile with stereochemical inversion.
Epoxide opening is assisted by lithium ion, which is a “built-in” Lewis acid:
This mechanism doesn’t take into account the aggregated structure of the reagent, but it cor-
rectly predicts the chemical and stereochemical outcome of the reaction.
The reactions of organometallic reagents with epoxides provide other methods for the syn-
thesis of alcohols that can be added to the list in Sec. 10.10. You should ask yourself what lim-
its the types of alcohols that can be prepared by each method.
(11.45)
O
H H
CH
3
CH
2
CH
3
CH
2
C C
R R
CH
3
CH
2
Cu(CN)Li
CH
3
CH
2
Cu(CN)Li
Li
.. ..
O
H
H
C C
R
R
Li
.. ..
..
(11.44)
(CH
3
CH
2
2
Cu(CN)Li
2
O
CH
3
H
THF
O Li
CH
3
H
CH
3
CH
2
OH
CH
3
H
CH
3
CH
2
CH
3
CH
2
Cu(CN) Li
H
3
O
+ CH +
3
CH
3
CuCN
2 Li
(1 S ,2 S )-2-ethyl-1-methyl-1-cyclopentanol
(96% yield)
–20 °C
(11.43)
CuCN
2 CH
3
CH
2
Li (CH
3
CH
2
2
Cu(CN)Li
2
a higher-order organocuprate
