Isopropylidenecyclopentane -

PROBLEM Draw and name the eight isomeric alcohols with formula $\mathrm{C}_{5} \mathrm{H}_{12} \mathrm{O}$. 17-38


Isopropylidenecyclopentane -

PROBLEM Draw structures corresponding to the following IUPAC names:
17-39 (a) Trans-3-Chlorocycloheptanol
(b) 2-Ethyl-2-buten-1-ol
(c) o-(2-Hydroxyethyl)phenol
(d) 3-Methyl-1-phenyl-1-butanol


Isopropylidenecyclopentane -

PROBLEM Bombykol, the sex pheromone secreted by the female silkworm moth has the formula $\mathrm{C}_{16} \mathrm{H}_{28} \mathrm{O}$
17-40 and the systematic name ( $10 E, 12 Z$ )-10,12-hexadecadien-1-ol. Draw bombykol, showing the correct geometry for the two double bonds.


Isopropylidenecyclopentane -


Isopropylidenecyclopentane -

Carvacrol


Isopropylidenecyclopentane -

Reactions of Alcohols
PROBLEM What products would you obtain from reaction of 1-pentanol with the following reagents:
17-46
(a) $\mathrm{PBr}_{3}$
(b) $\mathrm{SOCl}_{2}$
(c) Dess-Martin periodinane


Isopropylidenecyclopentane -

PROBLEM How would you prepare the following compounds from 2-phenylethanol: More than one step may 17-47 be required.
(a) Styrene $\left(\mathrm{PhCH}=\mathrm{CH}_{2}\right)$ (b) Phenylacetaldehyde $\left(\mathrm{PhCH}_{2} \mathrm{CHO}\right)$
(c) Phenylacetic acid $\left(\mathrm{PhCH}_{2} \mathrm{CO}_{2} \mathrm{H}\right)$ (d) Benzoic acid (e) Ethylbenzene (f) Benzaldehyde
(g) 1-Phenylethanol (h) 1-Bromo-2-phenylethane

PROBLEM How would you prepare the following compounds from 1-phenylethanol: More than one step may 17-48 be required.
(a) Acetophenone $\left(\mathrm{PhCOCH}_{3}\right)$
(b) Benzyl alcohol
(c) m-Bromobenzoic acid
(d) 2-Phenyl-2-propanol


Isopropylidenecyclopentane -

PROBLEM How would you prepare the following substances from cyclopentanol: More than one step may be 17-49 required.
(a) Cyclopentanone
(b) Cyclopentene
(c) 1-Methylcyclopentanol
(d) trans-2-Methylcyclopentanol


Isopropylidenecyclopentane -

PROBLEM What products would you expect to obtain from reaction of 1-methylcyclohexanol with the 17-50 following reagents?
(a) HBr (b)
(b) NaH (c) $\mathrm{H}_{2} \mathrm{SO}_{4}$


Spectroscopy -

PROBLEM The following ${ }^{1} \mathrm{H}$ NMR spectrum is that of an alcohol, $\mathrm{C}_{8} \mathrm{H}_{10} \mathrm{O}$. Propose a structure.


17-51 -


17-51 -

PROBLEM Propose structures for alcohols that have the following ${ }^{1}$ H NMR spectra:
17-52
(a) $\mathrm{C}_{5} \mathrm{H}_{12} \mathrm{O}$
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0600.jpg?height=510&width=1402&top_left_y=252&top_left_x=481)
(b) $\mathrm{C}_{8} \mathrm{H}_{10} \mathrm{O}$
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0600.jpg?height=527&width=1410&top_left_y=815&top_left_x=474)


17-51 -

PROBLEM Propose a structure consistent with the following spectral data for a compound $\mathrm{C}_{8} \mathrm{H}_{18} \mathrm{O}_{2}$ :
17-53


17-51 -

> IR: $3350 \mathrm{~cm}^{-1}$
> ${ }^{1} \mathrm{H}$ NMR: $1.24 \delta(12 \mathrm{H}$, singlet $) ; 1.56 \delta(4 \mathrm{H}$, singlet $) ; 1.95 \delta(2 \mathrm{H}$, singlet $)$


17-51 -

PROBLEM The ${ }^{1} \mathrm{H}$ NMR spectrum shown is that of 3-methyl-3-buten-1-ol. Assign all the observed resonance
17-54 peaks to specific protons, and account for the splitting patterns.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0600.jpg?height=497&width=1397&top_left_y=1660&top_left_x=418)


17-51 -

PROBLEM A compound of unknown structure gave the following spectroscopic data:
17-55
Mass spectrum: $\mathrm{M}^{+}=88.1$
IR: $3600 \mathrm{~cm}^{-1}$
${ }^{1} \mathrm{H}$ NMR: $1.4 \delta(2 \mathrm{H}$, quartet, $J=7 \mathrm{~Hz}) ; 1.2 \delta(6 \mathrm{H}$, singlet); $1.0 \delta(1 \mathrm{H}$, singlet); $0.9 \delta(3 \mathrm{H}$, triplet, $J=7 \mathrm{~Hz})$
${ }^{13}$ C NMR: 74, 35, 27, $25 \delta$
(a) Assuming that the compound contains C and H but may or may not contain O , give three possible molecular formulas.
(b) How many hydrogens does the compound contain?
(c) What functional group(s) does the compound contain?
(d) How many carbons does the compound contain?
(e) What is the molecular formula of the compound?
(f) What is the structure of the compound?
(g) Assign peaks in the molecule's ${ }^{1} \mathrm{H}$ NMR spectrum corresponding to specific protons.


17-51 -

PROBLEM Propose a structure for a compound $\mathrm{C}_{15} \mathrm{H}_{24} \mathrm{O}$ that has the following ${ }^{1} \mathrm{H}$ NMR spectrum. The peak 17-56 marked by an asterisk disappears when $\mathrm{D}_{2} \mathrm{O}$ is added to the sample.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0601.jpg?height=516&width=1403&top_left_y=669&top_left_x=418)


General Problems -

PROBLEM How would you carry out the following transformations?
17-57 (a)
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0601.jpg?height=147&width=785&top_left_y=1325&top_left_x=475)
(b)
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0601.jpg?height=142&width=789&top_left_y=1485&top_left_x=481)
(c)
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0601.jpg?height=150&width=795&top_left_y=1638&top_left_x=475)


General Problems -

PROBLEM Benzoquinone is an excellent dienophile in the Diels-Alder reaction. What product would you
17-58 expect from reaction of benzoquinone with 1 equivalent of 1,3-butadiene? From reaction with 2 equivalents of 1,3 -butadiene?


General Problems -


General Problems -

PROBLEM Benzyl chloride can be converted into benzaldehyde by treatment with nitromethane and base.
17-60 The reaction involves initial conversion of nitromethane into its anion, followed by $S_{N} 2$ reaction of the anion with benzyl chloride and subsequent E2 reaction. Write the mechanism in detail, using curved arrows to indicate the electron flow in each step.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0602.jpg?height=272&width=831&top_left_y=189&top_left_x=411)


General Problems -

PROBLEM Testosterone is one of the most important male steroid hormones. When testosterone is dehydrated
17-62 by treatment with acid, rearrangement occurs to yield the product shown. Propose a mechanism to account for this reaction.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0602.jpg?height=340&width=1021&top_left_y=968&top_left_x=411)


General Problems -

PROBLEM Starting from testosterone (Problem 17-62), how would you prepare the following substances?


General Problems -

PROBLEM Compound $\mathbf{A}, \mathrm{C}_{10} \mathrm{H}_{18} \mathrm{O}$, undergoes reaction with dilute $\mathrm{H}_{2} \mathrm{SO}_{4}$ at $25{ }^{\circ} \mathrm{C}$ to yield a mixture of two 17-65 alkenes, $\mathrm{C}_{10} \mathrm{H}_{16}$. The major alkene product, $\mathbf{B}$, gives only cyclopentanone after ozone treatment followed by reduction with zinc in acetic acid. Write the reactions involved, and identify $\mathbf{A}$ and $\mathbf{B}$.


General Problems -

PROBLEM Compound $\mathbf{A}, \mathrm{C}_{5} \mathrm{H}_{10} \mathrm{O}$, is one of the basic building blocks of nature. All steroids and many other 17-66 naturally occurring compounds are built from compound $\mathbf{A}$. Spectroscopic analysis of $\mathbf{A}$ yields the following information:


General Problems -

IR: $3400 \mathrm{~cm}^{-1} ; 1640 \mathrm{~cm}^{-1}$
${ }^{1} \mathrm{H}$ NMR: $1.63 \delta(3 \mathrm{H}$, singlet $) ; 1.70 \delta(3 \mathrm{H}$, singlet $) ; 3.83 \delta(1 \mathrm{H}$, broad singlet); $4.15 \delta(2 \mathrm{H}$, doublet, $J=7 \mathrm{~Hz}) ; 5.70 \delta(1 \mathrm{H}$, triplet, $J=7 \mathrm{~Hz})$
(a) How many double bonds and/or rings does $\mathbf{A}$ have?
(b) From the IR spectrum, what is the identity of the oxygen-containing functional group?
(c) What kinds of hydrogens are responsible for the NMR absorptions listed?
(d) Propose a structure for $\mathbf{A}$.


General Problems -

PROBLEM Dehydration of trans-2-methylcyclopentanol with $\mathrm{POCl}_{3}$ in pyridine yields predominantly 17-67 3-methylcyclopentene. Is the stereochemistry of this dehydration syn or anti?


General Problems -

PROBLEM 2,3-Dimethyl-2,3-butanediol has the common name pinacol. On heating with aqueous acid, pinacol
17-68 rearranges to pinacolone, 3,3-dimethyl-2-butanone. Suggest a mechanism for this reaction.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0603.jpg?height=215&width=787&top_left_y=1058&top_left_x=409)


General Problems -

PROBLEM As a rule, axial alcohols oxidize somewhat faster than equatorial alcohols. Which would you expect
17-69 to oxidize faster, cis-4-tert-butylcyclohexanol or trans-4-tert-butylcyclohexanol? Draw the more stable chair conformation of each molecule.


Bicyclohexylidene -

PROBLEM A problem often encountered in the oxidation of primary alcohols to carboxylic acids is that esters
17-71 are sometimes produced as by-products. For example, oxidation of ethanol yields acetic acid and ethyl acetate:
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0603.jpg?height=109&width=730&top_left_y=1794&top_left_x=416)


Bicyclohexylidene -

Propose a mechanism to account for the formation of ethyl acetate. Take into account the reversible reaction between aldehydes and alcohols:
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0603.jpg?height=118&width=562&top_left_y=2012&top_left_x=413)


Bicyclohexylidene -

PROBLEM Identify the reagents a-f in the following scheme:
17-72
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0604.jpg?height=158&width=1153&top_left_y=176&top_left_x=410)
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0604.jpg?height=234&width=1265&top_left_y=344&top_left_x=430)


Bicyclohexylidene -

PROBLEM Galactose, a constituent of the disaccharide lactose found in dairy products, is metabolized by a
17-73 pathway that includes the isomerization of UDP-galactose to UDP-glucose, where UDP = uridylyl diphosphate. The enzyme responsible for the transformation uses $\mathrm{NAD}^{+}$as cofactor. Propose a mechanism.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0604.jpg?height=346&width=1416&top_left_y=781&top_left_x=409)


Bicyclohexylidene -

PROBLEM Propose structures for alcohols that have the following ${ }^{1} \mathrm{H}$ NMR spectra:
17-74 (a) $\mathrm{C}_{9} \mathrm{H}_{12} \mathrm{O}$
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0604.jpg?height=508&width=1405&top_left_y=1253&top_left_x=474)
(b) $\mathrm{C}_{8} \mathrm{H}_{10} \mathrm{O}_{2}$
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0604.jpg?height=513&width=1402&top_left_y=1820&top_left_x=475)


Bicyclohexylidene -

PROBLEM Compound $\mathbf{A}, \mathrm{C}_{8} \mathrm{H}_{10} \mathrm{O}$, has the IR and ${ }^{1} \mathrm{H}$ NMR spectra shown. Propose a structure consistent with
17-75 the observed spectra, and label each peak in the NMR spectrum. Note that the absorption at $5.5 \delta$ disappears when $\mathrm{D}_{2} \mathrm{O}$ is added.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0605.jpg?height=459&width=1397&top_left_y=193&top_left_x=413)
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0605.jpg?height=500&width=1397&top_left_y=647&top_left_x=418)


CHAPTER 18 <br> Ethers and Epoxides; Thiols and Sulfides -


FIGURE 18.1 The appalling and unforgettable odor of skunks is due to a mixture of several simple thiols. (credit: modification of work "Striped Skunk" by Tom Friedel/Wikimedia Commons, CC BY 3.0)


CHAPTER CONTENTS -

18.1 Names and Properties of Ethers
18.2 Preparing Ethers
18.3 Reactions of Ethers: Acidic Cleavage
18.4 Cyclic Ethers: Epoxides
18.5 Reactions of Epoxides: Ring-Opening
18.6 Crown Ethers
18.7 Thiols and Sulfides
18.8 Spectroscopy of Ethers


CHAPTER CONTENTS -

WHY THIS CHAPTER? This chapter finishes the coverage of functional groups with $\mathrm{C}-\mathrm{O}$ and $\mathrm{C}-\mathrm{S}$ single bonds that was begun in the chapter on Alcohols and Phenols. We'll focus primarily on ethers and take only a brief look at thiols and sulfides before going on to an extensive coverage of compounds with $\mathrm{C}=\mathrm{O}$ double bonds in Chapters 19 through 23.


CHAPTER CONTENTS -

Ethers ( $\mathbf{R} \mathbf{- 0}-\mathbf{R}^{\prime}$ ), like the alcohols we saw in the preceding chapter, are organic derivatives of water, but they have two organic groups bonded to the same oxygen atom rather than one. The organic groups might be alkyl, aryl, or vinylic, and the oxygen atom might be in an open chain or a ring.


CHAPTER CONTENTS -

Perhaps the most well-known ether is diethyl ether, which has a long history of medicinal use as an anesthetic and industrial use as a solvent. Other useful ethers include anisole, a pleasant-smelling aromatic ether used in perfumery, and tetrahydrofuran (THF), a cyclic ether often used as a solvent.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0607.jpg?height=237&width=427&top_left_y=218&top_left_x=418)
$\mathrm{CH}_{3} \mathrm{CH}_{2}, \mathrm{O}-\mathrm{CH}_{2} \mathrm{CH}_{3}$


CHAPTER CONTENTS -


CHAPTER CONTENTS -

Tetrahydrofuran


CHAPTER CONTENTS -

Thiols ( $\mathrm{R}-\mathrm{S}-\mathrm{H}$ ) and sulfides ( $\mathrm{R}-\mathrm{S}-\mathrm{R}^{\prime}$ ) are sulfur analogs of alcohols and ethers, respectively. Both functional groups are found in various biomolecules, although not as commonly as their oxygen-containing relatives.


CHAPTER CONTENTS - 18.1 Names and Properties of Ethers


Ethyl phenyl ether


Like alcohols, ethers have nearly the same geometry as water. The $\mathrm{R}-\mathrm{O}-\mathrm{R}$ bonds have an approximately tetrahedral bond angle ( $112^{\circ}$ in dimethyl ether), and the oxygen atom is $s p^{3}$-hybridized.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0607.jpg?height=271&width=1108&top_left_y=1761&top_left_x=490)


The electronegative oxygen atom gives ethers a slight dipole moment, and the boiling points of ethers are often slightly higher than the boiling points of comparable alkanes. TABLE 18.1 compares the boiling points of some common ethers and their corresponding hydrocarbons.


TABLE 18.1 Comparison of Boiling Points of Ethers and Hydrocarbons


| Ether | Boiling point ${ }^{\circ} \mathrm{C}$ | Hydrocarbon | Boiling point ${ }^{\circ} \mathrm{C}$ |
| :--- | :---: | :--- | :---: |
| $\mathrm{CH}_{3} \mathrm{OCH}_{3}$ | -25 | $\mathrm{CH}_{3} \mathrm{CH}_{2} \mathrm{CH}_{3}$ | -45 |
| $\mathrm{CH}_{3} \mathrm{CH}_{2} \mathrm{OCH}_{2} \mathrm{CH}_{3}$ | 34.6 | $\mathrm{CH}_{3} \mathrm{CH}_{2} \mathrm{CH}_{2} \mathrm{CH}_{2} \mathrm{CH}_{3}$ | 36 |


| Ether | Boiling point ${ }^{\circ} \mathrm{C}$ | Hydrocarbon | Boiling point ${ }^{\circ} \mathrm{C}$ |
| :---: | :---: | :---: | :---: |
|  | 65 | 49 |  |
|  |  |  |  |


Ethers are relatively stable and unreactive in many respects, but some ethers react slowly with the oxygen in air to give peroxides, compounds that contain an $\mathrm{O}-\mathrm{O}$ bond. The peroxides from low-molecular-weight ethers such as diisopropyl ether and tetrahydrofuran are explosive and extremely dangerous, even in small amounts. Ethers are very useful as solvents in the laboratory, but they must always be used cautiously and should not be stored for long periods of time.


PROBLEM Name the following ethers:


CHAPTER CONTENTS - 18.2 Preparing Ethers

Diethyl ether and other simple symmetrical ethers are prepared industrially by the sulfuric-acid-catalyzed reaction of alcohols. The reaction occurs by $\mathrm{S}_{\mathrm{N}} 2$ displacement of water from a protonated ethanol molecule by the oxygen atom of a second ethanol. Unfortunately, this method is limited to use with primary alcohols because secondary and tertiary alcohols dehydrate by an E1 mechanism to yield alkenes (Section 17.6).
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0608.jpg?height=430&width=578&top_left_y=1544&top_left_x=416)
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0608.jpg?height=283&width=703&top_left_y=1615&top_left_x=1004)


The Williamson Ether Synthesis -

The most generally useful method of preparing ethers is the Williamson ether synthesis, in which an alkoxide ion reacts with a primary alkyl halide or tosylate in an $\mathrm{S}_{\mathrm{N}} 2$ reaction. As we saw in Section 17.2, the alkoxide ion is normally prepared by reaction of an alcohol with a strong base such as sodium hydride, NaH .
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0608.jpg?height=126&width=315&top_left_y=2214&top_left_x=558)


The Williamson Ether Synthesis -

Cyclopentanol
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0608.jpg?height=125&width=408&top_left_y=2209&top_left_x=891)


The Williamson Ether Synthesis -


The Williamson Ether Synthesis -

Cyclopentyl methyl ether (74\%)


The Williamson Ether Synthesis -

A useful variation of the Williamson synthesis involves silver oxide, $\mathrm{Ag}_{2} \mathrm{O}$, as a mild base rather than NaH . Under these conditions, the free alcohol reacts directly with the alkyl halide, so there is no need to preform the metal
alkoxide intermediate. Sugars react particularly well; glucose, for example, reacts with excess iodomethane in the presence of $\mathrm{Ag}_{2} \mathrm{O}$ to generate a pentaether in $85 \%$ yield.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0609.jpg?height=308&width=1055&top_left_y=296&top_left_x=535)


The Williamson Ether Synthesis -

Because the Williamson synthesis is an $\mathrm{S}_{\mathrm{N}} 2$ reaction, it is subject to all the usual constraints, as discussed in Section 11.3. Primary halides and tosylates work best because competitive E2 elimination can occur with more hindered substrates. Unsymmetrical ethers should therefore be synthesized by reaction between the more hindered alkoxide partner and less hindered halide partner rather than vice versa. For example, tert-butyl methyl ether, a substance used in the 1990s as an octane booster in gasoline, is best prepared by reaction of tert-butoxide ion with iodomethane rather than by reaction of methoxide ion with 2-chloro-2-methylpropane.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0609.jpg?height=135&width=879&top_left_y=881&top_left_x=623)
tert-Butoxide Iodomethane tert-Butyl methyl ether
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0609.jpg?height=337&width=966&top_left_y=1100&top_left_x=577)


The Williamson Ether Synthesis -

PROBLEM Why do you suppose only symmetrical ethers are prepared by the sulfuric-acid-catalyzed 18-2 dehydration procedure? What product(s) would you expect if ethanol and 1-propanol were allowed to react together? In what ratio would the products be formed if the two alcohols were of equal reactivity?


The Williamson Ether Synthesis -

PROBLEM How would you prepare the following ethers using a Williamson synthesis?
18-3 (a) Methyl propyl ether (b) Anisole (methyl phenyl ether) (c) Benzyl isopropyl ether
(d) Ethyl 2,2-dimethylpropyl ether


Alkoxymercuration of Alkenes -

We saw in Section 8.4 that alkenes react with water in the presence of mercuric acetate to yield a hydroxymercuration product. Subsequent treatment with $\mathrm{NaBH}_{4}$ breaks the $\mathrm{C}-\mathrm{Hg}$ bond and yields the alcohol. A similar alkoxymercuration reaction occurs when an alkene is treated with an alcohol in the presence of mercuric acetate or, even better, mercuric trifluoroacetate, $\left(\mathrm{CF}_{3} \mathrm{CO}_{2}\right)_{2} \mathrm{Hg}$. Demercuration by reaction with $\mathrm{NaBH}_{4}$ then yields an ether. The net result is Markovnikov addition of the alcohol to the alkene.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0610.jpg?height=313&width=1411&top_left_y=185&top_left_x=349)
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0610.jpg?height=250&width=856&top_left_y=528&top_left_x=781)

The mechanism of the alkoxymercuration reaction is similar to that described in Section 8.4 for hydroxymercuration. The reaction is initiated by electrophilic addition of $\mathrm{Hg}^{2+}$ to the alkene, followed by reaction of the intermediate cation with alcohol and reduction of the $\mathrm{C}-\mathrm{Hg}$ bond by $\mathrm{NaBH}_{4}$. A variety of alcohols and alkenes can be used in alkoxymercuration. Primary, secondary, and even tertiary alcohols react well, but ditertiary ethers can't be prepared because of steric hindrance.


WORKED EXAMPLE 18.1 -


Synthesizing an Ether -

How would you prepare ethyl phenyl ether? Use whichever method you think is more appropriate, Williamson synthesis or the alkoxymercuration reaction.


Strategy -

Draw the target ether, identify the two groups attached to oxygen, and recall the limitations of the two methods for preparing ethers. Williamson synthesis uses an $S_{N} 2$ reaction and requires that one of the two groups attached to oxygen be either secondary or (preferably) primary. The alkoxymercuration reaction requires that one of the two groups come from an alkene precursor. Ethyl phenyl ether could be made by either method.


Strategy -

Ethyl phenyl ether
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0610.jpg?height=275&width=711&top_left_y=1532&top_left_x=856)


Strategy -


Strategy -

Ethyl phenyl ether


Strategy -

PROBLEM Review the mechanism of oxymercuration shown in Figure 8.4, and then write the mechanism of 18-4 the alkoxymercuration reaction of 1-methylcyclopentene with ethanol. Use curved arrows to show the electron flow in each step.


Strategy -

PROBLEM How would you prepare the following ethers? Use whichever method you think is more appropriate, 18-5 Williamson synthesis or the alkoxymercuration reaction.
(a) Butyl cyclohexyl ether (b) Benzyl ethyl ether $\left(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{CH}_{2} \mathrm{OCH}_{2} \mathrm{CH}_{3}\right)$
(c) sec-Butyl tert-butyl ether (d) Tetrahydrofuran


Strategy -

PROBLEM Rank the following halides in order of their reactivity in the Williamson synthesis:
18-6 (a) Bromoethane, 2-bromopropane, bromobenzene
(b) Chloroethane, bromoethane, 1-Iodopropene


Strategy - 18.3 Reactions of Ethers: Acidic Cleavage

Ethers are unreactive to many reagents used in organic chemistry, a property that accounts for their wide use as reaction solvents. Halogens, dilute acids, bases, and nucleophiles have no effect on most ethers. In fact, ethers undergo only one truly general reaction-they are cleaved by strong acids. Aqueous HBr and HI both work well, but HCl does not cleave ethers.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0611.jpg?height=221&width=966&top_left_y=605&top_left_x=577)

Acidic ether cleavages are typical nucleophilic substitution reactions and take place by either $\mathrm{S}_{\mathrm{N}} 1$ or $\mathrm{S}_{\mathrm{N}} 2$ mechanisms, depending on the structure of the substrate. Ethers with only primary and secondary alkyl groups react by an $\mathrm{S}_{\mathrm{N}} 2$ mechanism, in which $\mathrm{I}^{-}$or $\mathrm{Br}^{-}$reacts with the protonated ether at the less hindered site. This usually results in a selective cleavage into a single alcohol and a single alkyl halide. For example, ethyl isopropyl ether exclusively yields isopropyl alcohol and iodoethane on cleavage by HI because nucleophilic attack by iodide ion occurs at the less hindered primary site rather than at the more hindered secondary site.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0611.jpg?height=285&width=1324&top_left_y=1099&top_left_x=398)

Ethers with a tertiary, benzylic, or allylic group cleave by either an $S_{N} 1$ or E1 mechanism because these substrates can produce stable intermediate carbocations. These reactions are often fast and take place at moderate temperatures. tert-Butyl ethers, for example, react by an E1 mechanism on treatment with trifluoroacetic acid at $0^{\circ} \mathrm{C}$. We'll see in Section 26.7 that this reaction is often used in the laboratory synthesis of peptides.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0611.jpg?height=250&width=1013&top_left_y=1623&top_left_x=556)


WORKED EXAMPLE 18.2 -


Predicting the Product of an Ether Cleavage Reaction -

Predict the products of the following reaction:
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0611.jpg?height=158&width=503&top_left_y=2103&top_left_x=811)


Strategy -

Identify the substitution pattern of the two groups attached to oxygen-in this case a tertiary alkyl group and a primary alkyl group. Then recall the guidelines for ether cleavages. An ether with only primary and secondary alkyl groups usually undergoes cleavage by $\mathrm{S}_{\mathrm{N}} 2$ attack of a nucleophile on the less hindered alkyl group, but an ether with a tertiary alkyl group usually undergoes cleavage by an $\mathrm{S}_{\mathrm{N}} 1$ mechanism. In this case, an $\mathrm{S}_{\mathrm{N}} 1$ cleavage
of the tertiary $\mathrm{C}-\mathrm{O}$ bond will occur, giving 1-propanol and a tertiary alkyl bromide. In addition, a competitive E1 reaction leading to alkene might occur.


Solution -


Solution -

PROBLEM Predict the products of the following reactions:


Solution -

PROBLEM Write the mechanism of the acid-induced cleavage of tert-butyl cyclohexyl ether to yield
18-8 cyclohexanol and 2-methylpropene.
PROBLEM Why are HI and HBr more effective than HCl in cleaving ethers? (See Section 11.3.)
18-9


Solution - 18.4 Cyclic Ethers: Epoxides

For the most part, cyclic ethers behave like acyclic ethers. The chemistry of the ether functional group is the same, whether it's in an open chain or in a ring. Common cyclic ethers such as tetrahydrofuran and dioxane are often used as solvents because of their inertness, yet they can be cleaved by strong acids.
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1,4-Dioxane
<img class="imgSvg" id = "m6sn3oiahuk6n234ch" 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Solution - 18.4 Cyclic Ethers: Epoxides

Tetrahydrofuran


Solution - 18.4 Cyclic Ethers: Epoxides

The one group of cyclic ethers that behaves differently from open-chain ethers are the three-membered-ring compounds called epoxides, or oxiranes, which we saw in Section 8.7. The strain of the three-membered ring gives epoxides unique chemical reactivity.


Solution - 18.4 Cyclic Ethers: Epoxides

Ethylene oxide, the simplest epoxide, is an intermediate in the manufacture of both ethylene glycol, used for automobile antifreeze, and polyester polymers. Approximately 37 million tons of ethylene oxide is produced worldwide each year, most of it by air oxidation of ethylene over a silver oxide catalyst at $300^{\circ} \mathrm{C}$. This process is not useful for other epoxides, however, and is of little value in the laboratory.


Solution - 18.4 Cyclic Ethers: Epoxides

Note that the name ethylene oxide is not a systematic one because the -ene ending implies the presence of a double bond in the molecule. The name is frequently used, however, because ethylene oxide is derived from ethylene by addition of an oxygen atom. Other simple epoxides are named similarly. The systematic name for ethylene oxide is 1,2-epoxyethane.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0612.jpg?height=315&width=912&top_left_y=2152&top_left_x=593)


Solution - 18.4 Cyclic Ethers: Epoxides

In the laboratory, as we saw in Section 8.7, epoxides are usually prepared by treatment of an alkene with a
peroxyacid $\left(\mathrm{RCO}_{3} \mathrm{H}\right)$, typically $m$-chloroperoxybenzoic acid.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0613.jpg?height=313&width=1359&top_left_y=250&top_left_x=388)


Solution - 18.4 Cyclic Ethers: Epoxides

Epoxides can also be prepared from halohydrins, themselves produced by electrophilic addition of $\mathrm{Cl}_{2}$ or Br 2 to an alkene in the presence of water (Section 8.3). When a halohydrin is treated with base, HX is eliminated and an epoxide is produced by an intramolecular Williamson ether synthesis. That is, the nucleophilic alkoxide ion and the electrophilic alkyl halide are in the same molecule.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0613.jpg?height=321&width=1212&top_left_y=756&top_left_x=451)


Solution - 18.4 Cyclic Ethers: Epoxides

PROBLEM What product would you expect from reaction of trans-2-butene with $m$-chloroperoxybenzoic acid?
18-10 Show the stereochemistry.
PROBLEM Reaction of cis-2-butene with m-chloroperoxybenzoic acid yields an epoxide different from that
18-11 obtained by reaction of the trans isomer. Explain.


Solution - 18.5 Reactions of Epoxides: Ring-Opening


Acid-Catalyzed Epoxide Opening -

Epoxides are cleaved by treatment with acid just as other ethers are, but under much milder conditions because of ring strain. As we saw in Section 8.7, dilute aqueous acid at room temperature is sufficient for facilitating the hydrolysis of epoxides to give 1,2-diols, also called vicinal glycols. (The word vicinal means "adjacent," and a glycol is a diol.) The epoxide cleavage takes place by $\mathrm{S}_{\mathrm{N}} 2$-like backside attack of a nucleophile on the protonated epoxide, giving a trans-1,2-diol as product.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0613.jpg?height=191&width=323&top_left_y=1672&top_left_x=348)


Acid-Catalyzed Epoxide Opening -


Acid-Catalyzed Epoxide Opening -

Epoxides can also be opened by reaction with acids other than $\mathrm{H}_{3} \mathrm{O}^{+}$. If anhydrous HX is used, for instance, an epoxide is converted into a trans halohydrin.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0614.jpg?height=198&width=519&top_left_y=191&top_left_x=749)


Acid-Catalyzed Epoxide Opening -

A trans 2-halocyclohexanol
where $X=\mathrm{F}, \mathrm{Br}, \mathrm{Cl}$, or I
The regiochemistry of acid-catalyzed ring-opening depends on the epoxide's structure, and a mixture of products is often formed. When both epoxide carbon atoms are either primary or secondary, attack of the nucleophile occurs primarily at the less highly substituted site: an $\mathrm{S}_{\mathrm{N}} 2$-like result. When one of the epoxide carbon atoms is tertiary, however, nucleophilic attack occurs primarily at the more highly substituted site-an $\mathrm{S}_{\mathrm{N}} 1$-like result. Thus, 1,2-epoxypropane reacts with HCl to give primarily 1-chloro-2-propanol, but 2-methyl-1,2-epoxypropane gives 2-chloro-2-methyl-1- propanol as the major product.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0614.jpg?height=210&width=386&top_left_y=806&top_left_x=607)


Acid-Catalyzed Epoxide Opening -

1,2-Epoxypropane
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0614.jpg?height=215&width=364&top_left_y=1166&top_left_x=626)


Acid-Catalyzed Epoxide Opening -

1-Chloro-2-propanol 2-Chloro-1-propanol (90\%)
2-Chloro-2-methyl- 1-Chloro-2-methyl-1-propanol (60\%) 2-propanol (40\%)


Acid-Catalyzed Epoxide Opening -

The mechanisms of these acid-catalyzed epoxide openings are more complex than they initially appear. They seem to be neither purely $\mathrm{S}_{\mathrm{N}} 1$ nor $\mathrm{S}_{\mathrm{N}} 2$ but instead to be midway between the two extremes and to have characteristics of both. For instance, take the reaction of 1,2-epoxy-1-methylcyclohexane with HBr, shown in FIGURE 18.2. The reaction yields only a single stereoisomer of 2-bromo-2-methylcyclohexanol in which the -Br and -OH groups are trans, an $\mathrm{S}_{\mathrm{N}} 2$-like result caused by backside displacement of the epoxide oxygen. But the fact that $\mathrm{Br}^{-}$attacks the more hindered tertiary side of the epoxide rather than the less hindered secondary side is an $\mathrm{S}_{\mathrm{N}} 1$-like result in which the more stable, tertiary carbocation is involved.

Evidently, the transition state for acid-catalyzed epoxide opening has an $\mathrm{S}_{\mathrm{N}}$ 2-like geometry but also has a high degree of $\mathrm{S}_{\mathrm{N}} 1$-like carbocationic character. Because the positive charge in the protonated epoxide is shared by the more highly substituted carbon atom, backside attack of $\mathrm{Br}^{-}$occurs at the more highly substituted site.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0615.jpg?height=765&width=953&top_left_y=195&top_left_x=586)

FIGURE 18.2 Ring-opening of 1,2-epoxy-1-methylcyclohexane with $\mathbf{H B r}$. There is a high degree of $\mathrm{S}_{\mathrm{N}} 1$-like carbocation character in the transition state, which leads to backside attack of the nucleophile at the tertiary center and to formation of a product isomer that has -Br and -OH groups trans.


WORKED EXAMPLE 18.3 -


Predicting the Product of Epoxide Ring-Opening -

Predict the major product of the following reaction:
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0615.jpg?height=175&width=415&top_left_y=1311&top_left_x=855)


Strategy -

Identify the substitution pattern of the two epoxide carbon atoms. In this case, one carbon is secondary and one is primary. Then recall the guidelines for epoxide cleavages. An epoxide with only primary and secondary carbons usually undergoes cleavage by $\mathrm{S}_{\mathrm{N}} 2$-like attack of a nucleophile on the less hindered carbon, but an epoxide with a tertiary carbon atom usually undergoes cleavage by backside attack on the more hindered carbon. In this case, an $\mathrm{S}_{\mathrm{N}} 2$ cleavage of the primary $\mathrm{C}-\mathrm{O}$ epoxide bond will occur.


Solution -


Solution -

PROBLEM Predict the major product of each of the following reactions:
18-12 (a)
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0615.jpg?height=174&width=451&top_left_y=2217&top_left_x=482)
(b)
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0615.jpg?height=169&width=363&top_left_y=2217&top_left_x=1049)


Solution -

PROBLEM How would you prepare the following diols?
18-13
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0616.jpg?height=420&width=1155&top_left_y=175&top_left_x=401)


Base-Catalyzed Epoxide Opening -

Unlike other ethers, epoxide rings can be cleaved by bases and nucleophiles as well as by acid. Although an ether oxygen is normally a poor leaving group in an $\mathrm{S}_{\mathrm{N}} 2$ reaction (Section 11.3), the strain of the threemembered ring causes epoxides to react with hydroxide ion at elevated temperatures.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0616.jpg?height=186&width=1270&top_left_y=823&top_left_x=449)