CHAPTER 14—ETHERS, EPOXIDES AND THIOETHERS

14-1
The four solvents decrease in polarity in this order: water, ethanol, ethyl ether, and dichloromethane. The
three solutes decrease in polarity in this order: sodium formate (ionic, most polar), 1-naphthol, and 2-
methylnaphthalene (no electronegative atoms). The guiding principle to determine solubility is, "Like
dissolves like." Compounds of similar polarity will dissolve (in) each other. Thus, sodium formate will
dissolve in water, will dissolve only slightly in ethanol, and will be virtually insoluble in ethyl ether and
dichloromethane. 1-Naphthol will be insoluble in water, somewhat soluble in ethanol, and soluble in ether
and dichloromethane. 2-methylnaphthalene will be insoluble in water, partially soluble in ethanol, and
soluble in ethyl ether and dichloromethane. (Actual solubilities are difficult to predict, but you should be
able to predict trends.)
14-2 Cl CH2CH3 Oxygen shares one of its electron pairs with aluminum; oxygen is the
Lewis base, and aluminum is the Lewis acid. An oxygen atom with three
Cl Al O bonds and one unshared pair has a positive formal charge. An aluminum
atom with four bonds has a negative formal charge.
Cl CH2CH3

14-3 The crown ether has two effects on KMnO4: first, it makes KMnO4 O O
much more soluble in benzene; second, it holds the potassium ion tightly,
making the permanganate more available for reaction. Chemists call this
a "naked anion" because it is not complexed with solvent molecules. Mn

O O
18-crown-6
a "crown ether"

O
O O
O O
O
K+ O O
benzene
+ KMnO4
O O O O

14-4 IUPAC name first; then common name (see Appendix 5 in the text for a summary of IUPAC
nomenclature). Current IUPAC recommendations place the position number immediately before the group
that it modifies.
(a) methoxyethene; methyl vinyl ether
(b) 2-ethoxypropane; ethyl isopropyl ether
(c) 1-chloro-2-methoxyethane; 2-chloroethyl methyl ether
(d) 2-ethoxy-2,3-dimethylpentane; no common name
(e) 1,1-dimethoxycyclopentane; no common name
(f) trans-2-methoxycyclohexan-1-ol; also possible: (1R,2R)-2-methoxycyclohexan-1-ol; no common name
(g) methoxycyclopropane; cyclopropyl methyl ether
(h) 1-methoxybut-2-yne; no common name
(i) (Z)-2-methoxypent-2-ene; no common name
14-5
OH HO O
H+
(a) + + 2 HO 2
OH HO O
The alcohol is ethane-1,2-diol; the common name is ethylene glycol.
351
Copyright © 2017 Pearson Education, Ltd.
14-5 continued
(b) H
H2O H3O+
HO OH HO OH HO HO
H A
H2C CH2 H2C CH2 H2C CH2 H2C CH2

HO O H HO O
HO OH
H2C CH2 H2C CH2
H2C CH2

HOH
H2O

H2C CH2 H2C CH2 H2C CH2

O
= O O H3O+ H O O HO O
O H2C CH2 H2C CH2 H2C CH2
The mechanism shows that the acid catalyst is regenerated at the end of the reaction.

14-6
(a) dihydropyran (b) 2-chloro-1,4-dioxane
(c) 3-isopropylpyran (d) trans-2,3-diethyloxirane; trans-3,4-epoxyhexane; trans-hex-3-ene oxide
(e) 3-bromo-2-ethoxyfuran (f) 3-bromo-2,2-dimethyloxetane

14-7 73 43

O
57 101
m/z 116
CH3
CH
CH3 CH3
CH3CH2CH3CH2
m/z 43
m/z 57 H2C CH
O O

CH3
H2C
O CH
O
m/z 73 m/z 101

352
Copyright © 2017 Pearson Education, Ltd.
14-8 SN2 reactions, including the Williamson ether synthesis, work best when the nucleophile attacks a
1° or methyl carbon. Instead of attempting to form the bond from oxygen to the 2° carbon on the ring,
form the bond from oxygen to the 1° carbon of the butyl group.
The OH must first be transformed into a good leaving group: either a tosylate, or one of the halides (not
fluoride).
TsCl
OH OTs
pyridine

OH O Na+ O
Na OTs

3-butoxy-1,1-
dimethylcyclohexane

14-9 Always put the leaving group on the less substituted carbon to maximize substitution: SN2 favors
methyl > 1° >> 2°.
OH O
Na CH3CH2CH2Br
(a)

OH CH3I OCH3
(b) Na

OH OCH3

NaOH CH3I
(c)

NO2 NO2

Na CH3CH2Br
(d) CH3CH2CH2OH CH3CH2CH2OCH2CH3 Both carbons bonded to
Na CH3CH2CH2Br oxygen are 1°, so either
CH3CH2OH CH3CH2CH2OCH2CH3 method will work.
CH3 CH3
Na PhCH2Br
(e) CH3 C OH CH3 C OCH2Ph
CH3 CH3

14-10
(a) (1)
Hg(OAc)2 NaBH4 OCH3
or
CH3OH

OH OCH3
(2) Na CH3I

353
Copyright © 2017 Pearson Education, Ltd.
14-10 continued
(b) (1) Hg(OAc)2 NaBH4 OCH2CH3

CH3CH2OH

(2) OH OCH2CH3
Na CH3CH2Br

(c) (1) Alkoxymercuration is not practical here; the product does not have Markovnikov orientation.

(2)
OH Na CH3I OCH3

OCH3
(d) (1) Hg(OAc)2 NaBH4
also possible as a starting material
CH3OH

(2) OH OCH3
Na CH3I

O
(e) (1) Hg(OAc)2 NaBH4
also possible as a starting material

OH
(2) Williamson ether synthesis would give a poor yield of product as the halide is on a 2° carbon.
2°
Br
OH O
Na

(f) (1)
Hg(OAc)2 NaBH4
O
OH

(2) Williamson ether synthesis is not feasible here. SN2 does not work on either a benzene or a
3° halide.
14-11 An important principle of synthesis is to avoid mixtures of isomers wherever possible; minimizing
separations increases recovery of products. Bimolecular condensation is a random process, assuming
similar structures for the two alkyl groups on the ether. Heating a mixture of ethanol and methanol with
acid will produce all possible combinations: dimethyl ether, ethyl methyl ether, and diethyl ether. This
mixture would be troublesome to separate.

354
Copyright © 2017 Pearson Education, Ltd.
14-12
Ether formation H
H A
CH3CH2CH2 OH CH3CH2CH2 O H

HO CH2CH2CH3

+ H3O+
H2O H

CH3CH2CH2 O CH2CH2CH3 CH3CH2CH2 O CH2CH2CH3

Dehydration H
H A
CH3CH2CH2 OH CH3CHCH2 O H CH3CH CH2
+ H2O
H
H2O
Remember ∆G = ∆H − T∆S ? Thermodynamics of a reaction depend on the sign and magnitude of ∆G. As
temperature increases, the entropy term grows in importance. In ether formation, the ∆S is small because
two molecules of alcohol give one molecule of ether plus one molecule of water—no net change in the
number of molecules. In dehydration, however, one molecule of alcohol generates one molecule of alkene
plus one molecule of water—a large increase in entropy. So T∆S is more important for dehydration than for
ether formation. As temperature increases, the competition will shift toward more dehydration (elimination).
14-13
(a) This symmetrical ether at 1° carbons could be produced in good yield by bimolecular condensation.
(b) This unsymmetrical ether could not be produced in high yield by bimolecular condensation. Williamson
synthesis would be preferred.
Na CH3CH2Br
OH O

Na CH3CH2CH2Br
O
OH
(c) Even though this ether is symmetrical, both
carbons are 2°, so bimolecular condensation would Hg(OAc)2 NaBH4
give low yields. Unimolecular dehydration to give or O
alkenes would be the dominant pathway.
Alkoxymercuration-demercuration is the preferred
route. OH
14-14

Br OH Br OH
O H Br O H Br
H
Br H Br

Br Br + H2O
355
Copyright © 2017 Pearson Education, Ltd.
14-15
HBr
(a) OCH2CH3 Br + Br CH2CH3 + H2O

O I I
HI HBr
(b) + H2O (c) OCH3 OH + CH3Br

no SN at sp2 carbon
HI
(d)
O OH I
no SN at sp2 carbon
HBr
(e) O CH2CH2 CH CH2 O CH2CH3
CH3

OH + BrCH2CH2 CH CH2 Br + BrCH2CH3 + H2O

no SN at sp2 carbon CH3
14-16 Br Br Br
O B O B Br O B + Br
Br Br
H3C Br H3C Br

H H H
O O
Bu Bu H2O Bu Br
BuOH O B Br O B Br O B + CH3Br
Two proton transfers happen Br
HOBBr2 H Br here: one H+ comes off of
Br
oxygen, another H+ goes on Nucleophilic attack on CH3
2 H2O the other oxygen; several is faster than on 1° carbon.
different scenarios of how
this happens could be
B(OH)3 + 2 HBr proposed.

14-17 Begin by transforming the alcohols into good leaving groups like halides or tosylates:
PBr3 NaSH NaOH
OH Br SH S Na+
OH OTs
TsCl
pyridine
S
14-18 The sulfur at the center of mustard gas is an excellent nucleophile, and chloride is a decent leaving
group. Sulfur can do in internal nucleophilic subsitution to make a reactive sulfonium salt and the sulfur
equivalent of an epoxide. very reactive enzyme
(a) alkylating agent
SNi
Cl Cl Cl HN Cl
S S enzyme S
inactivated enzyme
NH2
356
Copyright © 2017 Pearson Education, Ltd.
14-18 continued
(b) NaOCl is a powerful oxidizing agent. It oxidizes sulfur to a sulfoxide or more likely a sulfone,
either of which is no longer nucleophilic, preventing formation of the cyclic sulfonium salt.

Cl Cl NaOCl Cl Cl Cl 2+ Cl
S S S
O O
O
sulfoxide sulfone
14-19 Br
new bond
starting from
H3C C C OH OH
4 2 4 2
3 1 3 1
desired target starting material
Analysis of the desired target structure shows that the new bond can be made from an acetylide ion plus
the given starting material, 4-bromobutan-1-ol. However, an acetylide ion is a strong base and will
remove H+ from the alcohol, making an alkyne that is no longer nucleophilic. The alcohol must be
protected before attempting the nucleophilic substitution.
protected—
Br Br no reaction
TIPSCl
OH O Si(i-Pr)3
Et3N
SN2
NaNH2
H3C C C H H3C C C Na+

Bu4N+ F–
H3C C C OH H3C C C O Si(i-Pr)3
H2O
remove silyl group
14-20
Generally, chemists prefer the peroxyacid method of epoxide formation to the halohydrin method. Reactions
(a) and (b) show the peroxyacid method, but the halohydrin method could also be used.
O HO O
mCPBA H2SO4 mCPBA
(a) (b)
CH2Cl2 ∆ CH2Cl2
Ph Ph Ph
Cl Cl HO O
BH3 • THF H2O2 2,6-lutidine
(c) 2,6-Lutidine is a non-
HO– nucleophilic base.

Cl Cl
Hg(OAc)2 NaBH4 OH 2,6-lutidine O
(d)
H2O

(e) NaOH NaOH can also do unwanted SN2

OH
O and E2 with the chloride.
Cl
357
Copyright © 2017 Pearson Education, Ltd.
14-21
(a) 1) tert-Butyl hydroperoxide is the oxidizing agent. The (CH3)3COOH contains the O—O bond just like
a peroxyacid. 2) Diethyl tartrate has two asymmetric carbons and is the source of asymmetry; its function is
to create a chiral transition state that is of lowest energy, leading to only one enantiomer of product. This
process is called chirality transfer. 3) The function of the titanium(IV) isopropoxide is to act as the glue
that holds all of the reagents together. The titanium holds an oxygen from each reactant—geraniol,
t-BuOOH, and diethyl tartrate—and tethers them so that they react together, rather than just having them in
solution and hoping that they will eventually collide.
(b) All three reactants are required to make Sharpless epoxidation work, but the key to enantioselective
epoxidation is the chiral molecule, diethyl tartrate. When it complexes (or chelates) with titanium, it forms a
large structure that is also chiral. As the t-BuOOH and geraniol approach the complex, the steric
requirements of the complex allow the approach in one preferred orientation. When the reaction between the
alkene and t-BuOOH occurs, it occurs preferentially from one face of the alkene, leading to one major
stereoisomer of the epoxide. Without the chiral diethyl tartrate in the complex, the alkene could approach
from one side just as easily as the other, and a racemic mixture would be formed.
(c) Using the enantiomer of diethyl L-tartrate, called diethyl D-tartrate, would give exactly the opposite
stereochemical results, i.e., the enantiomer of the first product.
t-BuOOH
Ti(Oi-Pr)4 O
OH COOCH2CH3 OH
HO H
H OH diethyl D-tartrate,
the enantiomer of diethyl L-tartrate
COOCH2CH3

14-22 R
O O H
C O
H3 O+
O H
O
H Me
C C H Me H Me
Me H Me H
Me H
trans-but-2-ene H O OR O H

H H

Me H OH HO Me
H Me H OH HO Me
H
+ +
Me H Me H
HO H Me OH H2O H Me OH2

H2O H2O
IDENTICAL—MESO
stereochemistry shown in Newman projections:
π bond O OH
OH OH
CH3 H
H CH3
rotate
H CH3 H3C H H3C H
H CH3 H2O H3C H H3C H
OH
trans MESO
See cis-but-2-ene on next page. 358
Copyright © 2017 Pearson Education, Ltd.
14-22 continued Me H OH HO
H Me
H H
C C +
Me Me H H
HO Me Me OH
cis-but-2-ene

ENANTIOMERS
stereochemistry shown in Newman projections:
O OH
π bond OH OH
H CH3
H CH3
rotate
H CH3 H CH3 H CH3
H CH3 H2O H CH3 H3C H
OH CHIRAL—
cis
RACEMIC
MIXTURE
14-23 H2SO4
H2C CH2 CH3CH2OH
H2O
H2SO4
CH3CH2OCH2CH2OH
RCO3H
H2C CH2 H2C CH2 Cellosolve®
O A peroxyacid is far too expensive to use on the industrial
scale. Ethylene oxide is produced in large quantity from
ethylene and oxygen using a metal catalyst.

14-24 The cyclization of squalene via the epoxide is an excellent (and extraordinary) example of how
Nature uses organic chemistry to its advantage. In one enzymatic step, Nature forms four rings and eight
chiral centers! Out of 256 possible stereoisomers, only one is formed!

CH3 CH3

H CH3
HO
A O = new bonds formed
H

14-25 H OCH3
O O H OH H + O CH3

O CH3
H H H OCH3 H OCH3
plus the other enantiomer
359
Copyright © 2017 Pearson Education, Ltd.
14-26
(a) (b) (c) S
O H2N O Na+
O Na+ O Na+

H
(d) N (e) (f)
OH N C N N N
O K+ O Na+

CH3
14-27 O HO H
(a) OH (b) 18OH
S R CH3O−
H18O HO (c)
CH3OH Et
Et CH3 OCH3
CH3 H CH3
Basic nucleophiles react at the less substituted carbon.
O Et OH
CH3
(d) S R H A
CH3OH CH3 In acid, nucleophiles react at
Et CH3 CH3O the more substituted carbon.
CH3 H H

14-28 Newly formed bonds are shown in bold. OH

(a) (b) (c)
OH HO

14-29
O
O O (c)
(a) (b)

(e) O
(d) O O (f)

H O
H3C
(g) (h) (i)
5
1 CH3
O O
H OH
14-30
(a) ethyl isopropyl ether (b) tert-butyl propyl ether
(c) methyl phenyl ether (d) chloromethyl ethyl ether
(e) methyl cis-2-hydroxycyclohexyl ether (f) cyclohexyl methyl ether
(g) 2,2,3-trimethyl oxirane (h) allyl cyclopropyl ether
(i) cyclohexene oxide (j) 2-methyltetrahydropyran

360
Copyright © 2017 Pearson Education, Ltd.
14-31
(a) 2-ethoxypropan-1-ol (b) methoxybenzene or phenoxymethane
(c) methoxycyclohexane (d) 2,2-dimethoxycyclohexan-1-ol
(e) cis-1-methoxy-2-methylcyclohexane (f) trans-3-chloro-1,2-epoxycyclohexane
(g) trans-1,2-epoxy-1-methoxypropane; or, (h) 3-chlorooxetane
trans-3-methoxy-2-methyloxirane (i) 1,4-dioxane
14-32 As is often true when explaining the properties of molecules, hydrogen bonding is the key.

HO OH Si Si
O O
OH
O
Si
glycerol
mol. wt. 92 g/mol mol. wt. 309 g/mol
b.p. 290 °C b.p. 180 °C
d 1.24 g/mL d 0.88 g/mL
Glycerol has extremely strong intermolecular hydrogen bonding because of the three OH groups per
molecule. Overcoming these intermolecular forces requires a lot of energy: thus, glycerol has a high
boiling point despite its fairly low molecular weight, and it flows slowly because hydrogen bonding must be
overcome in order for molecules to slide past each other. The density is high because these molecules pack
together tightly to maximize hydrogen bonding.
In contrast, the TMS (trimethylsilyl) ether of glycerol not only has no hydrogen bonding, but on each
end of the molecule, there is a nonpolar and essentially spherical group—this is like putting on boxing
gloves and trying to pick up a dime, or anything! So in spite of the high molecular weight, these molecules
tend to stay far apart, explaining the ease of flow, the low density, and the relatively low boiling point.
For a boiling point comparison, look up the structure of "isocetane," which is a highly branched alkane
of molecular weight 226 g/mol, with boiling point 240 °C. The van der Waals forces in the TMS ether
above must be even lower, despite it having a higher molecular weight than isocetane.
14-33 Br
(a) + + H2O (b) + + H2O
Br Br Br

(c) and (d) no reaction— (e) (f) OH

ethers are cleaved only OH + CH3CH2I
no SN at sp2 carbon
OCH3
under acid conditions
H OH (i)
(g) (h) OH O
NHCH3 Keep at low temperature to
HO H plus the enantiomer minimize the competing E2
reaction.
HO O Br
(j) OH
(k) (l)

CH3 OCH3
(m) OH plus the (n) CH3 plus the
enantiomer enantiomer
H OH
OCH3 H
361
Copyright © 2017 Pearson Education, Ltd.
14-34
(a) At least three possible methods:
Na
Method 1: CH3OH CH3O– Na+
O
TsCl CH3
OH OTs
py
Method 2: PBr3 (or HBr, ∆)
CH3O– Na+
Br PBr3
CH3Br CH3OH
Method 3:
OH Na O– Na+

less practical method by SN2,

(b) More practical way: requiring more steps:
H2SO4
+ HOCH2CH3 +
S N1 LG
OH OCH2CH3 O– Na+
LG = leaving group
3°—forms Bimolecular condensation like Br or OTs
carbocation works well on 3° carbons. Recall that ethoxide plus tert-butyl
bromide gives only E2! See Solved
Problem 14-1 in the text.
(c) More practical way:
H2SO4 less practical method by SN2,
OH O requiring more steps:
+ SN1
LG
HO +
benzylic—forms
carbocation Na+ –O
LG = leaving group
like Br or OTs
Also possible is alkoxymercuration-demercuration:
Hg(OAc)2 NaBH4 O
OH
+

OH
(d) O
O CH3 plus the
H2SO4 mCPBA CH3CH2O− C
enantiomer
H2
heat
OH Si(i-Pr)3
(e) OH O See the solution to 14-25.
O TIPSCl O
Et3N
362
Copyright © 2017 Pearson Education, Ltd.
14-34 continued
(f) Alkoxymercuration-demercuration is the more practical method. Williamson ether synthesis on 2°
carbons would not give good yields.
HO 1) Hg(OAc)2
OH 1) Hg(OAc)2
OR + 2) NaBH4
+ 2) NaBH4
O

14-35
(a) On long-term exposure to air, ethers form peroxides. Peroxides are explosive when concentrated or
heated. (For exactly this reason, ethers should never be distilled to dryness.)
(b) Peroxide formation can be prevented by excluding oxygen. Ethers can be checked for the presence of
peroxides, and peroxides can be destroyed safely by treatment with reducing agents.
14-36
(a) In each case, the new bond will be shown in bold.
(i) second method BrMg CH3
first method
O
Ph MgBr + Ph Ph

OH O

(ii) O OH
H3O+
+ BrMg

(b) In each case, the epoxide is derived from a tetrasubstituted double bond, far too hindered for the
Grignard reagent to approach. (ii)
(i)
MgBr + BrMg
O
+ O

14-37
(a) Beginning with (R)-pentan-2-ol and producing the (R)-sulfide requires two inversions of configuration.
HO H H Br H3C S H
PBr3 Na+ – SCH
3

R S R
An alternative approach would be to make the tosylate, displace with chloride or bromide (SN2 with
inversion), then do a second inversion with NaSCH3.
(b) Synthesis of the (S) isomer directly requires only one inversion.
HO H TsO H H S H3C
TsCl Na+ – SCH3

R pyridine
R S
363
Copyright © 2017 Pearson Education, Ltd.
14-38
43 73
(a)
O O O
CH2 CH2
m/z 73
molecular ion m/z 102
CH3CH2CH2
m/z 43
(b) 31 OCH3
H H
71 C O C O m/z 31
59
H H H H (after H migration)
87

molecular ion m/z 102

OCH3 OCH3
H CH CH m/z 59
C CH3 CH3

m/z 71
OCH3 OCH3
m/z 87
CH CH

14-39
OH OH CH2OH
O O H
H A CH2 CH2
CH2
CH2 CH2
CH2 H
C H2O C H2O CH3
C O
CH3 CH3 CH3 CH3 H OH
CH3 H3O+
14-40 O
(a)
Hg(OAc)2 NaBH4
You could also make pentan-2-ol,
CH3OH then Na followed by CH3I.

(b) HBr Br NaOCH3 O

HOOH CH3OH CH3
You could also make pentan-1-ol,
then Na followed by CH3I, similar to
OH the solution to 14-34(a).
(c) mCPBA O NaOCH3 O
CH2Cl2 CH3OH CH3

364
Copyright © 2017 Pearson Education, Ltd.
14-40 continued CH3
(d) mCPBA O H+ O
CH2Cl2 OH
CH3OH
OH
(e) mCPBA O 1) PhMgBr Ph
CH2Cl2 2) H2O
O– MgBr+
(f ) mCPBA O PhMgBr
Ph
CH2Cl2 do not perform
aqueous workup CH3I

CH3
O
Ph

14-41
Two hints for this problem: 1) the last step in each sequence is a Williamson ether synthesis which follows
an SN2 mechanism, so always try to do this substitution on a 1° carbon; 2) As you know more reactions,
there are often more than one option of how to perform a synthesis. In general, syntheses with fewer steps
are better.
In this problem, the abbreviation "LG" will indicate a "leaving group" = a halide or a tosylate.
(a)
LiAlH4 LG
+ O

O O
OR Li
LG
+
O H BrMg O
MgBr
(b) The intermediate alkoxide can be made by three different Grignard reactions. In this case, LiAlH4
is not an option because there is no H on the carbinol carbon.
O
+ CH3CH2MgBr

H3C LG
O O
MgBr + O
MgBr

O
+ 2 CH3CH2MgBr
Cl
or ester 365
Copyright © 2017 Pearson Education, Ltd.
14-41 continued
(c) O LG

LiAlH4
H O O

Li
aldehyde or ester

O
LG
MgBr
H H O

MgBr

14-42 All chiral products in this problem are racemic.

OH OH
H2SO4 H3O+
mCPBA
O
∆ MgBr
A F
E
1) Hg(OAc)2 G
CH3OH Mg
2) NaBH4 ether
OCH3 Br
HBr
CH3Br +
∆
C
B D

OH O Na+ CH3Br OCH3

Na C

G H

366
Copyright © 2017 Pearson Education, Ltd.
14-43 O OH OTs
LiAlH4 H3O+ TsCl
OCH3
ether pyridine
J L
1 equiv.
NaOCl KO-t-Bu
TEMPO
Br
O
Br2
H N OH H2O
K M
TIPS–Cl Et3N
MgBr Br

Mg
K +
O TIPS ether O TIPS
[P] O

ether
MgBr TIPS
Fluoride removes the Si group,
O O and water protonates the oxygens. OH OH

H3O+
new
bond
Q Bu4N+ F–

14-44 The student turned in the wrong product! Three pieces of information are consistent with the
desired product: molecular formula C4H10O; O—H stretch in the IR at 3300 cm–1 (although it should be
strong, not weak); and mass spectrum fragment at m/z 59 (loss of CH3). The NMR of the product should
have a 9H singlet at δ 1.0 and a 1H singlet between δ 2 and δ 5. Instead, the NMR shows CH3CH2 bonded
to oxygen. The student isolated diethyl ether, the typical solvent used in Grignard reactions.
Predicted product Isolated product
59 CH3
59
CH3 C OH H3C CH2 O CH2 CH3

CH3
C4H10O C4H10O
strong O—H at 3300 cm–1 weak O—H at 3300 cm–1 due to water contamination
14-45
OH Na O Na+
O
(a)
OH PBr3 Br

367
Copyright © 2017 Pearson Education, Ltd.
14-45 continued
NaOH
(b) OH O Na+
O

TsCl
OH OTs
pyridine

Hg(OAc)2 NaBH4
(c)
CH3CH2OH
OCH2CH3
1) BH3 • THF
(d)
2) H2O2, HO– OH
HBr, ROOR 1) Na
2) CH3I
NaOCH3
Br OCH3

(e) 1) Hg(OAc)2 OCH2CH3

OH CH3CH2OH
H2SO4 2) NaBH4
∆

trans
OH + cis
O The trans isomer would be the major product from the
(f) mCPBA dehydration because trans is more stable than cis.
H2SO4 Epoxidation with mCPBA is stereospecific and will retain
CH2Cl2
∆ the stereochemistry of the starting double bond. The major
product will be trans, with some cis as a contaminant.

14-46 Approaching a good synthesis problem begins with comparing the product to the starting material.
If new carbons appear in the product, then the synthesis must include a carbon-carbon bond-forming
reaction, of which there are very few.
new bond CH3 The new bond is
HO Br ? HO OH
CH2CH3
shown in bold.

continued on next page

368
Copyright © 2017 Pearson Education, Ltd.
14-46 continued
At first glance, this appears to require a simple Grignard reaction, but then we recall that a Grignard reagent
cannot coexist with an OH group in the same molecule. Aha! The OH group needs to be protected before
the Grignard can proceed.

HO Br TIPSCl (i-Pr)3Si O Br Mg (i-Pr)3Si O MgBr

Et3N ether
Grignard reagents are
This could be isolated. stable only in solution;
they cannot be isolated.

Fluoride removes the Si group,

CH3 and water protonates the oxygens. CH3
OH O MgBr
HO Bu4N+ F– (i-Pr)3Si O
CH2CH3 CH2CH3
H2O

14-47 In the first sequence, no bond is broken to the chiral center, so the configuration of the product is the
same as the configuration of the starting material.
H OH H O Na+ H OCH2CH3
Na
CH3CH2I
[α]D = − 8.24° [α]D = − 15.6°
(Assume the enantiomer
shown is levorotatory.)
In the second reaction sequence, however, a bond to the chiral carbon is broken once, so the stereochemistry
of the process will be a net inversion.
O O
H OH Cl S H O S
O
H O

N
H OTs O
H O S
Undoubtedly, some E2 O
products will also
form in this reaction. CH3CH2O Na+ RETENTION OF CONFIGURATION
SN2—INVERSION The second sequence involves retention followed by
inversion, thereby producing the enantiomer of the 2-
CH3CH2O H ethoxyoctane generated by the first sequence. The optical
rotation of the final product will have equal magnitude but
opposite sign, [α]D = + 15.6° .

369
Copyright © 2017 Pearson Education, Ltd.
14-48
(a)
anhydrous HBr—only Br– nucleophiles present Br

H2C CH2 H2C CH2 CH2CH2Br CH2CH2Br

Br
O H Br O O H H Br H O H
H

BrCH2CH2Br + H2O
aqueous HBr—many more H2O nucleophiles than Br– nucleophiles

H2C CH2 H2C CH2 H2C CH2 H2C CH2

O H
O H Br O HO O H HO OH
H H2O
H H H3O+

(b) CH3 CH3 CH3 CH3 CH3

HO H2C CH HO CH2 CH O H2C CH HO CH2 C O CH2 CH O
H
O O
CH3
CH3 CH3 CH3 H2C CH
HO CH2 CH O CH2 CH O CH2 CH O O

HO H

CH3 CH3 CH3

HO CH2 CH O CH2 CH O CH2 CH OH + HO–

14-49 methyl cellosolve® CH3OCH2CH2OH

To begin, what can be said about methyl cellosolve®? Its molecular weight is 76; its IR would show C—O
in the 1000–1200 cm–1 region and a strong O—H around 3300 cm–1; and its NMR would show four sets of
signals in the ratio of 3:2:2:1.
The unknown has molecular weight 134; this is double the weight of methyl cellosolve®, minus 18
(water). The IR shows no OH, only ether C—O. The NMR shows no OH, only H—C—O in the ratio of
3:2:2. Apparently, two molecules of methyl cellosolve® have combined in an acid-catalyzed, bimolecular
condensation.
H A
CHOCH2CH2OH CH3OCH2CH2 OH2

− H2O
CH3OCH2CH2OH

CH3OCH2CH2 O CH2CH2OCH3 CH3OCH2CH2 O CH2CH2OCH3

(This compound is called diethylene H2O H

glycol dimethyl ether, or a shortened,
common name is diglyme.) 370
Copyright © 2017 Pearson Education, Ltd.
14-50 O O
(a) H2C CH2
H H
S CH3 H3C R

(b) O O H
H A H OH H OH
H3C H3C
CH2 CH2 CH2 CH2
H H
H3C H3C O H2O HO S
R H2O H H
Attack of water gave inversion of
configuration at the chiral center; R became S.

(c) O + HO–
O HO
H OH No bond to the chiral center
CH2 CH2 CH2 was broken. Configuration
H R H H R is retained; R stays as R.
H3C OH H3C OH H3C OH

(d) The difference in these mechanisms lies in where the nucleophile attacks. Attack at the chiral carbon
gives inversion; attack at the achiral carbon retains the configuration at the chiral carbon. These products
are enantiomers and must necessarily have optical rotations of opposite sign. The lower enantiomeric
excess in the acid catalyzed mechanism probably comes from some opening of the epoxide ring to form a
secondary carbocation that can be attacked from either top or bottom by the water nucleophile, producing a
mixture of R and S configuration.

14-51
The formula C8H8O has five elements of unsaturation (enough (4) for a benzene ring). The IR is useful for
what it does not show. There is neither OH nor C=O, so the oxygen must be an ether functional group.
The HNMR shows a 5H signal at δ 7.2, a monosubstituted benzene. No peaks in the δ 4.5-6.0 range
indicate the absence of an alkene, so the remaining element of unsaturation must be a ring. The three
protons are non-equivalent, with complex splitting.

+ 2 C + O + 3 H + ring
ether

H H (Note that the CH2 hydrogens are not

These pieces can be assembled in only
one manner consistent with the data. equivalent (one is cis and one is trans
O H to the phenyl) and therefore have
distinct chemical shifts.)

371
Copyright © 2017 Pearson Education, Ltd.
14-52
(a) The product has a new pi bond so this must be an elimination reaction. The strong base tert-butoxide
points to E2 as the probable mechanism.
CH3 CH3
H
O O C CH3 O H O C CH3
H3C CH2 H3C CH2
CH3 CH3

H3C CH3 H3C CH3

The epoxide oxygen is the leaving group in this

elimination. Ordinarily, ether oxygens are not
leaving groups; in epoxides, however, the severe OH CH3
ring strain makes the ring open fairly readily. H3C CH2 O C CH3

CH3
H3C CH3

(b) This result does not occur with dimethyloxirane in acidic conditions; something must be special about
the two phenyl groups.
many resonance forms

H H
O O O
H H H
H+
C

H H H

hydride shift

conjugate
base of H
O H acid O H
A–
C C
H H

What's different because of the phenyl groups is that a free carbocation is present because it is doubly
benzylic. Once the free carbocation is present, it can undergo a hydride shift to form a protonated carbonyl.

372
Copyright © 2017 Pearson Education, Ltd.
14-53 HA is an acid; A– is the conjugate base.

3° carbocation!
C
H A
O O H C OH

+ A
This process resembles the A
cyclization of squalene oxide to
lanosterol. (See the solution to H
problem 14-24.) In fact, C
pharmaceutical synthesis of C
steroids uses the same type of OH
reaction called a biomimetic OH
cyclization.
+ H A
3° carbocation!

14-54
(a) There is only one true ether in Byrostatin 1, although there are two groups called a hemiacetal that
include an ether portion, so the answer that you might have given is "three".
(b) The other oxygen-containing functional groups are indicated in italics: five esters and two alcohols,
although you likely included the two OH groups in the hemiacetals as alcohols.
(c) The minimum number of atoms making a continuous path around the large ring is 20 (numbered).
(d) Chiral centers around the main ring are at carbons 4, 6, 8, 10, 12, 16, and 18, plus three more at atoms
outside of the main ring (indicated by a large dot •): total of 10 chiral centers.
(e) From section 5-12: "A compound with n asymmetric carbon atoms might have as many as 2n
stereoisomers." For 10 chiral centers, 210 = 1024 possible stereoisomers! Nature makes only one!

ester 9 HO ester
O O
10 8

O
11
O O
7
O hemiacetal—these are not
12
true ethers, as you will see
6
ether OH alcohol in Ch 18; if you identified
13 5
3
O these as "ether and
14 4 2
alcohol", that is fine for
OH 17 H 19 ester this chapter.
15 1
O 20 O
16 18
alcohol
O OH
ester
O
O
ester
O

373
Copyright © 2017 Pearson Education, Ltd.
14-55
(a) The ether groups are marked with a large dot •. The count is 24.
(b) The alcohols are indicated as OH. There are thirteen 2° alcohols and no 1° or 3° alcohols.
(c) There is one aldehyde.
This record-setting structure containing 17 fused (contiguous) rings, plus 7 other rings! Remember that
this structure is made by an algae.
2°
OH 2°
O OH
O
2°
O O
OH O 2°
O O O OH
O O O O HO
2°
OH 2°
O O O O
O O OH 2° HO
OH 2° OH 2°
H O
2° O
aldehyde OH 2°
O
2° O
O
HO O
O
OH
2°

374
Copyright © 2017 Pearson Education, Ltd.