I n this chapter, we first discuss the structure, nomenclature, physical properties,and chemical properties of ethers and then compare their physical properties withthose ofisomeric alcohols. Next, we study the preparation and chemical propertiesof a group of cyclic ethers called epoxides. As we shall see, their most important reac-tions involve nucleophilic substitution. This chapter continues the discussion of ~1and ~2 reaction mechanisms begun in Chapter 9 and continued into Chapter 10.

11.1 Structure of EthersThe functional group of an ether is an atom of oxygen bonded to two carbonatoms. Figure 11.1 shows a Lewis structure and a ball-and-stick model of dimethylether, CH30CH3, the simplest ether. In dimethyl ether, two sf hybrid orbitals ofoxygen form u bonds to the two carbon atoms. The other two sf hybrid orbitals ofoxygen each contain an unshared pair of electrons. The C-O-C bond angle indimethyl ether is 110.3, a value close to the tetrahedral angle of 109.5.

In still other ethers, the ether oxygen is bonded to sf hybridized carbons. Inethoxyethene (ethyl vinyl ether), for example, the ether oxygen is bonded to onesf and one sf hybridized carbon.

CH3CH2-O-CH=CH2Ethoxyethene

(Ethyl vinyl ether)

11.2 Nomenclature of EthersIn the IUPAC system, ethers are named by selecting the longest carbon chain asthe parent alkane and naming the -OR group bonded to it as an aIkoxy substitu-ent. Common names are derived by listing the alkyl groups bonded to oxygen inalphabetical order and adding the word "ether." Following are the IUPAC namesand, in parentheses, the common names for three low-molecular-weight ethers.

The discovery that inhaling etherscould make a patient insensitiveto pain revolutionized the prac-tice of medicine. Inset: A model ofisoflurane. CF3CHCIOCHF2 a halo-genated ether widely used as aninhalation anesthetic in both humanand veterinary medicine.

OUTLINE11.1 Structure of Ethers11.2 Nomenclature of Ethers11.3 Physical Properties of

Ethers11.4 Preparation of Ethers11.5 Reactions of Ethers11.6 Silyl Ethers as Protecting

Groups11.7 Epoxides: Structure and

Nomenclature11.8 Synthesis of Epoxides11.9 Reactions of Epoxides11.10 Ethylene Oxide and

Epichlorohydrin: BuildingBlocks in OrganicSynthesis

11.11 Crown Ethers11.12 Sulfides

Online homework for thischapter may be assignedin Organic OWL.

11.2 Nomenclature of Ethers 419

Chemists almost invariably use common names for low-molecular-weight ethers. Forexample, although ethoxyethane is the IUPAC name for CH3CH20CH2CH3, it israrely called that; rather, it is called diethyl ether, ethyl ether, or even more commonly,simply ether. The abbreviation for ttm-butyl methyl ether is MTBE, after the commonname methyl ttm-butyl ether (incorrectly alphabetized, as you will recognize).

Three other ethers deserve special mention. 2-Methoxyethanol and 2-ethoxy-ethanol, more commonly known as Methyl Cellosolve and Cellosolve, are good polarprotic solvents in which to carry out organic reactions and are also used commerciallyin some paint strippers. Diethylene glycol dimethyl ether, more commonly known by itsacronym, diglyme, is a common solvent for hydroboration and NaBH4 reductions.

..........O/'-...../OH /"-O/'-...../OH /O~O/'-...../O..........

(1R,2R)-2-Ethoxycyclohexanol(trans-2-Ethoxycyclohexanol)

1H3CH301CH3

CH32-Methoxy-2-methylpropane

(tert-Butyl methyl ether)

Diethylene glycol dimethyl ether(DigIyme)

("Y0H

V"""'OCH CH2 3

2-Ethoxyethanol(Cellosolve)

Ethoxyethane(Diethyl ether)

2-Methoxyethanol(Methyl cellosolve)

(b)

H HI 00 I

H-C-O-C-HI 00 IH H

(a)

Figure 11.1Dimethyl ether, CH30CH3(a) Lewis structure and(b) ball-and-stick model.

EtherA compound containing an oxy-gen atom bonded to two carbonatoms.

Alkoxy groupAn -OR group, where R is analkyl group.

HeterocycleA cyclic compound whose ringcontains more than one kind ofatom.Oxirane (ethylene oxide),for example, is a heterocyclewhose ring contains two carbonatoms and one oxygen atom.

Cyclic ethers are given special names. The presence of an oxygen atom in a satu-rated ring is indicated by the prefix 0, and ring sizes from three to six are indicatedby the endings -irane, -etane, -olane, and -ane, respectively. Several of these smallerring cyclic ethers are more often referred to by their common names, here shownin parentheses. Numbering of the atoms of the ring begins with the oxygen atom.These compounds and others in which there is a heteroatom (noncarbon atom) inthe ring are called heterocycles. Heterocycles containing or N atoms are particu-larly common in organic chemistry, and several clinically important pharmaceuticalsare heterocycles.

2 3 Q 0 ()\7 [110 0Omane Oxetane Oxolane Oxane 1,4-Dioxane

(Ethylene oxide) (Tetrahydrofuran) (Tetrahydropyran)

Example 11.1

(b) 0-0-0Write IUPAC and common names for these ethers.CH3I(a) CH310CH2CH3CH3

Solution(a) 2-Ethoxy-2-methylpropane. Its common name is tert-butyl ethyl ether.(b) Cyclohexoxycyclohexane. Its common name is dicyclohexyl ether.(c) Methoxyethene. Its common name is methyl vinyl ether.Problem 11.1Write IUPAC and common names for these ethers.

("Y0Et(c)~

OEt

420 Chapter 11 Ethers, Epoxides, and Sulfides

Only very weakdipole-dipoleinteraction

\

HH / H

H 8- H 'C;:\ /0, / /C C08-

H// 8+ 8+ \'H \ 8+H H /C,

H \ HH

11.3 Physical Properties of EthersEthers are polar molecules in which oxygen bears a partial negative charge andeach attached carbon bears a partial positive charge (Figure 11.2). However, onlyweak. dipole-dipole interactions exist between ether molecules in the liquid state.Consequently, boiling points of ethers are much lower than those of alcohols ofcomparable molecular weight (Table 11.1) and are close to those of hydrocarbonsof comparable molecular weight (Table 2.5).

Because ethers cannot act as hydrogen bond donors, they are much lesssoluble in water than alcohols. However, they can act as hydrogen bond accep-tors (Figure 11.3), which makes them more water-soluble than hydrocarbonsof comparable molecular weight and shape (compare data in Tables 2.5 and11.1).

Table 11.1 Boiling Points and Solubilities in Water of Some Ethersand Alcohols of Comparable Molecular Weight

Figure 11.2Although ethers are polarcompounds, there areonly weak dipole-dipoleinteractions between theirmolecules in the liquid state.

Figure 11.3Ethers are hydrogen bondacceptors only. They are nothydrogen bond donors.

Molecular bp SolubilityStructural Formula Name Weight rC) in WaterCH3CH2OH Ethanol 46 78 InfiniteCH3OCH3 Dimethyl ether 46 -24 7.8 g/100 g

CH3CH2CH2CH2OH I-Butanol 74 117 7.4 g/100 gCH3CH2OCH2CH3 Diethyl ether 74 35 8.0 g/100 g

HOCH2CH2CH2CH2OH 1,4-Butanediol 90 230 InfiniteCH3CH2CH2CH2CH20H I-Pentanol 88 138 2.3 g/100 gCH3OCH2CH2OCH3 Ethylene glycol 90 84 Infinite

dimethyl etherCH3CH2CH2CH20CH3 Butyl methyl ether 88 71 Slight

11.3 Physical Properties of Ethers 421

Nadolol(racemic)

A nucleophile derivedby removal of the acidicH from an -OH group

The nitrogennucleophileofa 1 amine

Crown etherA cyclic polyether derived fromethylene glycol and substitutedethylene glycols.

Members of this class of compounds have received enormous clinical attentionbecause of their effectiveness in treating hypertension (high blood pressure), mi-graine headaches, glaucoma, ischemic heart disease, and certain cardiac arrhyth-mias. Shown in this retrosynthetic analysis are the two nucleophiles used in thesynthesis of nadolol. We will show how to complete the synthesis of nadolol whenwe study the chemistry of benzene and its derivatives in Chapters 21 and 22.

We are not concerned at this stage with how these nucleophiles are generatedor, if there are two nucleophiles used, which nucleophile is added first or reacts atwhich site. Our concern with ethylene oxide and epichlorohydrin at this stage ofthe course is only that you recognize the structural features in a target moleculethat might be derived from these building blocks. Call it pattern recognition ifyou will. Later, after we study the chemistry of other functional groups, we willdiscuss in detail the chemistry of how the target molecules are synthesized in thelaboratory.

11.11 Crown EthersIn the early 1960s, Charles Pedersen of DuPont discovered a family of cyclic poly-ethers derived from ethylene glycol and substituted ethylene glycols. Compoundsof this structure are named crown ethers because one of their most stable confor-mations resembles the shape of a crown. These ethers are named by the system de-vised by Pedersen. The parent name crown is preceded by a number describing thesize of the ring and followed by a number describing the number of oxygen atomsin the ring, as for example, 18-erown-6.

18-Crown-6(a cyclic hexamer)

Space-filling model,viewed from above

Ball-and-stick model,viewed through an edge

Electrostatic potential map showingthe electron-rich interior and

the nonpolar exterior

For his work, Pedersen shared the 1987 Nobel Prize for chemistry with Donald J.Cram of the United States andJean-Marie Lehn of France.

The most significant structural feature of crown ethers is that the diameter ofthe cavity created by the repeating oxygen atoms of the ring is comparable to thediameter of alkali metal ions. The diameter of the cavity in 18-crown-6, for exam-ple, is approximately the diameter of a potassium ion. When a potassium ion is in-serted into the cavity of lS-crown-6, the unshared electron pairs on the six oxygens

440 Chapter 11 Ethers, Epoxides, and Sulfides

of the crown ether are close enough to the potassium ion to provide very effectivesolvation for K+:

Diameter ofK+ is 266 pm

Ion Diameter (pm)Li+ 136Na+ 194K+ 266Rb+ 294Mg2+ 164Ca2+ 286

A complex of K+and l8-crown-6

18-Crown-6 forms somewhat weaker complexes with rubidium ion (a somewhatlarger ion) and with sodium ion (a somewhat smaller ion). It does not coordinateto any appreciable degree with lithium ion (a considerably smaller ion). 12-Crown-4,however, with its smaller cavity, does form a strong complex with lithium ion.

The cavity ofa crown ether is a polar region, and the unshared pairs ofelectrons onthe oxygen atoms lining the cavity provide effective solvation for alkali metal ions. Theouter surface of the crown is nonpolar and hydrocarbon-like, and, thus, crown ethersand their alkali metal ion complexes dissolve readily in nonpolar organic solvents.

Crown ethers have proven to be particularly valuable because of their abilityto cause inorganic salts to dissolve in nonpolar aprotic organic solvents such asmethylene chloride, hexane, and benzene. Potassium permanganate, for example,does not dissolve in benzene. If 18-crown-6 is added to benzene, the solution takeson the purple color characteristic of permanganate ion. The crown-potassium ioncomplex is soluble in benzene and brings permanganate ion into solution with it.The resulting "purple benzene" is a valuable reagent for the oxidation of water-insoluble organic compounds.

Crown ethers have also proven valuable in nucleophilic displacement reactions.The cations of potassium salts, such as KF, KCN, or KN3, are very tightly bound withinthe solvation cavity of 18-crown-6 molecules. The anions, however, are only weakly sol-vated, and because of the geometry of cation binding within the cavity of the crown,only loose ion pairing occurs between the anion and cation. Thus, in nonpolar aproticsolvents, these anions are without any appreciable solvent shell and are, therefore,highly reactive as nucleophiles. The nucleophilicity ofF-, CN-, N3-, and other anionsin nonpolar aprotic solvents containing an 18-erown-6 equals and often exceeds theirnucleophilicity in polar aprotic solvents such as DM80 and acetonitrile.

11.12 SulfidesA. NomenclatureTo derive the IUPAC name of a sulfide (also called a thioether), select the longestcarbon chain as the parent alkane and name the sulfur-containing substituent asan alkylsulfanyl group. To derive a common name, list the groups bonded to sulfurand add the word sulfide to show the presence of the -8- group:

Ethylsulfanylethane 2-Ethylsulfanylpropane(Diethyl sulfide) (Ethyl isopropyl sulfide)

The functional group of a disulfide is an -8-8- group. IUPAC names of di-sulfides are derived by selecting the longest carbon chain as the parent alkaneand indicating the disulfide-containing substitutent as an alkyldisulfanyl group.

SulfideThe sulfur analog of an ether; amolecule containing a sulfur atombonded to two carbon atoms. Sul-fieds are also called thioethers.

DisulfideA molecule containing an-5-S- group.

11.12 Sulfides 441

(racemic)

(c) /"'O~OH

(b) trans-2,3-Diethyloxirane(d) Ethenyloxyethene(f) 3-Cyclopropyloxy-l-propene(h) 1,I-Dimethoxycyclohexane

(d) R 20 aId

(b) Et20 and EtOH

(e) 0o

(racemic)

(b) o-0CH3

(h)~O~

(a) CH2Cl2 and EtOHo

(c) A aId

(a) 2-(I-Methylethoxy)propane(c) trans-2-Ethoxycyclopentanol(e) Cyclohexene oxide(g) (R)-2-Methyloxirane

PROBLEMS

12. Oxidation of Sulfides (Section 11.12C) Oxidation of a sulfide gives either a sulfoxide ora sulfone, depending on the oxidizing agent and experimental conditions. Air oxidationof dimethyl sulfide is a commercial route to dimethyl sulfoxide, a polar aprotic solvent.

~res