Jones M., Fleming S.A. Organic Chemistry

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6.8 Ethers 249

PROBLEM 6.18 The stability of oxonium ions depends on the nature of the negatively

charged counterion. Fluoborate (



) is an especially favorable counterion. Why?

Hint: Lewis bases, B



, can transfer methyl (and other) groups through a process

called the S

2 reaction. You will learn all about it in Chapter 7, but you might

want to use it here in this problem.

–

Primary and secondary amines are Brønsted acids,but only very weak ones.Amines

are much weaker acids than alcohols. Removal of a proton from an alcohol gives an

alkoxide in which the negative charge is borne by oxygen. An amine forms an amide

in which the less electronegative nitrogen carries the negative charge (Fig. 6.49).

Be careful—there is another kind of amide that has the structure . There is no written or

verbal distinction made, so you need to know the context before you know which kind of amide is meant.

Amide ion

Primary amine

~ 36

–

Amide ion

Secondary amine

~ 36

–

R HB

Alcohol

~ 17

Alkoxide ion

–

FIGURE 6.49 Primary and secondary

amines are weak Brønsted acids.

It takes a very strong base indeed to remove a proton from an amine to give the

amide ion, which is itself a very strong base. Alkyllithium reagents (p. 228) are

typically used (Fig. 6.50).

LiBuH

BuLi

An amine (a good base

and a poor acid, pK

~ 36)

> 50 An amide ion (an even stronger

base than the related amine)

–

An exceptionally

strong base

FIGURE 6.50 Very strong bases,

such as alkyllithium reagents,

can remove a proton from an

amine to give an amide ion

(Bu  CH

So, amines are good bases, but relatively poor acids. Amides, the conjugate bases

of amines, are even stronger bases than the amines themselves (Fig. 6.50).

6.8 Ethers

Alcohol (ROH) and amine (RNH

) chemistry depends on both the OH or NH

and the OR or NR parts of the molecule. In this section, we look at molecules that

no longer have any OH groups,but retain the R group.These compounds are called

ethers, and have the structure or .R

R¿R

250 CHAPTER 6 Alkyl Halides, Alcohols, Amines, Ethers, and Their Sulfur-Containing Relatives

6.8a Nomenclature Naming ethers is simple. In the widely used common sys-

tem, the two groups joined by oxygen are named in alphabetical order, and the word

ether appended. In the IUPAC system, ethers are named as alkoxy (RO) alkanes.

Figure 6.51 gives some simple examples of both usages, IUPAC first.

WEB 3D

Methoxymethane

(dimethyl ether)

WEB 3D

Methoxyethane

(ethyl methyl ether)

Ethoxyethane

(diethyl ether or ether)

2-Methoxy-2-methylpropane

(tert-butyl methyl ether)

(CH

)

Ethoxyethene

(ethyl vinyl ether)

Furan

CH CH

Tetrahydrofuran (THF)

Anisole

(methyl phenyl ether)

FIGURE 6.51 Some ethers and their

common names.

6.8b Physical Properties Ethers are polar, but only for the smallest members

of the class does this polarity strongly affect physical properties. Other ethers are suf-

ficiently hydrocarbon-like so as to behave as their all-carbon relatives. For example,

diethyl ether has nearly the same boiling point as pentane and is only modestly

soluble in water.Table 6.10 gives some physical properties for a few common ethers.

TABLE 6.10 Some Physical Properties of Ethers

Compound bp (°C) mp (°C)

CCH

Dimethyl ether

–23 –138.5 0.668

34.6 –119.2

7.6 –139

Ethyl methyl ether

55.2 –109

Density (g/mL)

0.725

0.714

0.740

(CH

)

tert-Butyl methyl ether

Diethyl ether

–115.8

–85.6

35.5

31.4

Furan

67 –108

155.0 –37.5

0.759

0.951

0.889

0.996

Ethyl vinyl ether

THF

Anisole

O CH

CCH

CHO CH

6.9 Special Topic: Thiols (Mercaptans) and Thioethers (Sulfides) 251

6.8c Structure The carbon–oxygen bond length in ethers is similar to that in

alcohols, and the opening of the angle as we go from (104.5°) to

( 109°) to ( 112°) continues. As the angle in ethers is

approximately 112°, the oxygen is hybridized approximately sp

6.8d Acidity and Basicity Of course, ethers lack the OH group of their rela-

tives water and the alcohols and so are not Brønsted acids. The oxygen atom has

two pairs of nonbonding electrons, however, and they make ethers weak Brønsted

and Lewis bases. Ethers can be protonated, and the protonated form has a pK

the same range as those of the protonated alcohols, which means that ethers and

alcohols are strong bases of similar strength (Fig. 6.52).

THE GENERAL CASE

A SPECIFIC EXAMPLE

~ – 3.5

= –1.74

–

CCH

~ – 3.8

FIGURE 6.52 Ethers are weak Brønsted bases and can be protonated. Protonated ethers (and protonated

alcohols) are strong acids.

We have already seen one instance in which the ability of ethers to donate

electrons, that is, to act as a Lewis base, was a critical property. Recall from p. 228

that an ether solvent is vital to success in the formation of the Grignard reagent

(Fig. 6.53). Ethers are stabilizing to Lewis acidic species. Boron trifluoride etherate

is a commercially available complex of BF

and ether that can even be distilled.

It is commonly used as a source of BF

. For similar reasons, the cyclic ether THF

(Fig. 6.51) is used to stabilize the highly reactive molecule BH

–

Boron trifluoride

etherate

RMg Cl

FIGURE 6.53 Ethers will react with

Lewis acids as well as Brønsted acids.

The BF

–etherate complex is a stable

source of boron trifluoride.

6.9 Special Topic: Thiols (Mercaptans) and

Thioethers (Sulfides)

Thiols (RSH) and thioethers (RSR′) are the sulfur-containing counterparts of

alcohols and ethers, and their chemistries are generally similar to those of their

oxygen-containing relatives.These sulfur compounds have a poor reputation,because

252 CHAPTER 6 Alkyl Halides, Alcohols, Amines, Ethers, and Their Sulfur-Containing Relatives

some are quite extraordinarily evil-smelling.The skunk uses a variety of four-carbon

thiols in its defense mechanism, for example. But this bad press is not entirely

deserved; not all sulfur compounds are malodorous. Garlic derives its odor from

small sulfur-containing compounds.You may never need to ward off a vampire with

it, but garlic contains many sulfur compounds that have quite remarkably positive

qualities. Figure 6.54 shows some of the sulfur-containing molecules that can be

found in garlic.

SOH SOH S

S S

Ajoene

FIGURE 6.54 Some of the sulfur-containing molecules in garlic.

AJOENE

Ajoene is only one of the beneficial compounds

present in garlic. Ajoene is lethal to certain tumor-prone

cells, promotes the antiaggregative action of some

molecules on human blood platelets, and seems to be

effective against viruses (including HIV) as well. It

appears to reduce repeat heart attacks among people who

have already suffered an initial attack. Garlic contains

many other compounds that also appear to have beneficial

medicinal properties. And, of course, if that vampire is hot

on your trail....

6.9a Nomenclature Thiols, also called mercaptans, are named by adding the

suffix “thiol”to the parent hydrocarbon name.Note that the final “e”is not dropped,

as it is, for example, in alcohol nomenclature (Fig. 6.55).

WEB 3D

Methanethiol

(methyl mercaptan)

CSH

1-Butanethiol

(butyl mercaptan)

S H

Cyclohexanethiol

Benzenethiol

(phenyl mercaptan)

(thiophenol)

FIGURE 6.55 Some thiols, or

mercaptans.

Thioethers, the sulfur counterparts of ethers, are also called sulfides, and are

named in the same way as ethers. The two groups attached to the sulfur atom are

6.9 Special Topic: Thiols (Mercaptans) and Thioethers (Sulfides) 253

followed by the word sulfide. Disulfides ( ) are the counterparts of

peroxides, , and have a significant biological role, which we will

discuss later. Peroxides are nastily unstable and tend to explode, but disulfides are

relatively benign.Disulfides are named in a similar fashion as are sulfides (Fig. 6.56).

WEB 3D

Dimethyl sulfide

CCH

Ethyl methyl sulfide

CCH

tert-Butyl cyclopentyl sulfide

Dicyclopropyl disulfide

FIGURE 6.56 Some thioethers (sulfides) and disulfides.

6.9b Acidity Thiols (pK

 9–12) are stronger acids than alcohols and form

mercaptides, the sulfur counterparts of alkoxides, when treated with base.The rel-

atively high acidity of thiols makes formation of the conjugate base more favorable

than formation of alkoxides from alcohols (Fig. 6.57).

H ++

= 10 Alkoxide

(conjugate base

of CH

OH)

Mercaptide

(conjugate base

of CH

SH)

= 15.5

C HO

CONa

–

FIGURE 6.57 Mercaptides are easier

to form than alkoxides because thiols

are much more acidic than alcohols.

RaNi

(80%)

(85%)

O/NaOH

40 ⬚C

RaNi

Et = CH

EtOH, 78 ⬚C, 2 h

FIGURE 6.58 Desulfuration with

Raney nickel (RaNi).

6.9c Reduction of Sulfur Compounds with Raney Nickel: A New

Alkane Synthesis

Thiols and thioethers are reduced by a catalyst called Raney

nickel (essentially just hydrogen adsorbed on finely divided nickel) to give hydro-

carbons (Fig. 6.58). This synthetic method, called desulfuration, gives you a second

way to make alkanes.

PROBLEM 6.19 What reagents would you use to convert the indicated starting

materials into cyclohexane?

(a) (b) (c)

254 CHAPTER 6 Alkyl Halides, Alcohols, Amines, Ethers, and Their Sulfur-Containing Relatives

6.10 Special Topic: Crown Ethers

Cyclic ethers are common solvents and, as we will see in Section 7.10, can often be

prepared rather easily (Williamson ether synthesis,p. 315).It is possible to make cyclic

polyethers, compounds in which there is more than one ether linkage. Figure 6.59

gives some examples of cyclic ethers and cyclic polyethers.

Ethylene oxide

(oxirane)

Trimethylene oxide

(oxacyclobutane

or oxetane)

Furan

1,4-Dioxan

(1,4-dioxacyclohexane)

1,3-Dioxolane

(1,3-dioxacyclopentane)

1,3,5-Trioxane

(1,3,5-trioxacyclohexane

or paraldehyde)

Tetrahydropyran

(pentamethylene oxide

or oxacyclohexane)

Tetrahydrofuran

(THF)

O O

FIGURE 6.59 Some cyclic ethers and

polyethers.

We have mentioned more than once the remarkable solvating powers of ethers.

Ethers are Lewis bases and can donate electrons to Lewis acids, thus stabilizing

them. One example of this stabilization is the requirement for an ether, usually

diethyl ether or THF, in the formation of a Grignard reagent. Ethers are also polar

compounds and therefore are able to stabilize other polar molecules through non-

covalent dipole–dipole interactions.

This stabilization was carried to extremes in work that ultimately led to the

1987 Nobel Prize in Chemistry for Charles J. Pedersen (1904–1989) of du Pont,

Donald J. Cram (1919–2001) of UCLA, and Jean-Marie Lehn (b. 1939) of

Université Louis Pasteur in Strasbourg for opening the field of “host–guest”chem-

istry. Pedersen discovered that certain cyclic polyethers (the hosts) had a remark-

able affinity for metal cations (the guests). Molecules were constructed whose

molecular shapes created different-sized cavities into which different metal ions

fit well. Because of their vaguely crown-shaped structures, these molecules came

to be called crown ethers. Figure 6.60 shows two of them.

WEB 3D

12-Crown-4 18-Crown-6

FIGURE 6.60 Two crown ethers.The

first number in the name shows the

number of atoms in the ring, and the

final number shows the number of

heteroatoms in the ring. In these

molecules the heteroatoms are all

oxygen, but others are possible.

6.11 Special Topic: Complex Nitrogen-Containing Biomolecules—Alkaloids 255

The molecule 12-crown-4 is the proper size to capture lithium ions, and

18-crown-6 has a remarkable affinity for potassium ions. These crown ethers

can stabilize positive ions of different sizes, depending on the size of the cavity

(Fig. 6.61).

Three-dimensional versions of these essentially two-dimensional molecules

have now also been made, using both oxygen and other heteroatoms, such as sul-

fur and nitrogen, as the Lewis bases. These host molecules are called cryptands

and can incorporate positive ions into the roughly spherical cavity within the cage

(Fig. 6.62).

FIGURE 6.61 Two crown ethers

stabilizing cations.

A cr

tand

S S S S

FIGURE 6.62 Three-dimensional cryptands can incorporate metal ions into a

central cavity.

There are chemical and larger implications of this work. Potassium perman-

ganate, KMnO

, is an effective oxidizing agent. Its great insolubility in organic

reagents limits its use, however. For example, the deep purple KMnO

completely insoluble in benzene. It simply forms a solid suspension when

added to benzene, which remains a colorless liquid. The addition of a little

18-crown-6 results in the dissolution of the permanganate, and the benzene

takes on the deep purple color of the permanganate ion. The potassium ion

has been effectively solvated by the crown ether and now dissolves in the

organic solvent.The permanganate counterion, though not solvated by the crown

compound, accompanies the positive ion into solution, as it must to preserve

electrical neutrality. The purple benzene solution can be used as an effective

oxidizing agent.

Schemes have been envisioned in which specially designed crown compounds

are used to scavenge poisonous heavy metal ions from water supplies.There have

been less humanitarian, though admittedly clever, schemes for extracting the

minute amounts of gold ions present in seawater by passing vast amounts of water

over a crown compound.

6.11 Special Topic: Complex Nitrogen-Containing

Biomolecules—Alkaloids

Alkaloids are naturally occurring amines that are powerfully active biologically.They

are among the most useful medicinal agents known. The painkiller morphine and

the antimalarial agent quinine are typical examples. At the same time, some of the

256 CHAPTER 6 Alkyl Halides, Alcohols, Amines, Ethers, and Their Sulfur-Containing Relatives

most destructively addictive substances known are also alkaloids. Heroin and cocaine

are examples from our own time, and anyone at all familiar with popular literature

knows of the notorious poison strychnine (Fig. 6.63).

Strychnine

Quinine

Heroin

COOCH

NCH

Cocaine

Morphine

FIGURE 6.63 Some alkaloids.

We have already seen strychnine and its close relative brucine in Figure 4.44,

where they served as reagents for the resolution of optically active carboxylic acids

into separate (R) and (S) enantiomers (p. 171). As we work through the book, alka-

loids will reappear now and again. The important thing to “take home” from this

picture is not the detail but rather a broad view of the great structural diversity—

molecular architecture—of these bioactive molecules.

A measure of a compound’s acidity—its pK

value—is

introduced. The lower the pK

value, the more acidic is the

compound in question.

Solvents appear as important players in questions of

stability. For example, both the conjugate bases of alcohols

(alkoxides) and the conjugate acids of amines (ammonium

ions) depend greatly on solvation for stabilization. In

assessing basicity or acidity, one must take account of the

solvent.

A general discussion of solvents and solvation also appears.

Protic solvents that can participate in hydrogen bonding

dissolve other protic, polar molecules well. By contrast, polar

solvents do a poor job of dissolving “greasy” nonpolar organic

molecules such as hydrocarbons, which are dissolved by

nonpolar, similarly “greasy” solvents. Like dissolves like—polar

solvents dissolve polar molecules, and nonpolar solvents dissolve

nonpolar molecules.

Organic halogenated molecules can be used to form

organometallic reagents. Many of the important synthetic

reactions of organic chemistry use organometallic reagents.

In this chapter, we see them only as very strong bases and as

sources of hydrocarbons through their reaction with water.

6.12 Summary

New Concepts

6.12 Summary 257

Amines, like alkanes with sp

-hybridized carbons, are tetra-

hedral. Unlike alkanes, amines invert their “umbrellas” through

an sp

-hybridized transition state.

The hydrogen bond is introduced. This kind of bond is

nothing more than a partially completed Brønsted acid–base

reaction in which a partial bond is formed between a pair of

electrons on one atom and a hydrogen on another (Fig. 6.64).

Hydrogen bond

FIGURE 6.64 A hydrogen bond.

alkoxide ion (p. 236)

alkyl halide (p. 225)

amide (p. 249)

amine (p. 240)

amine inversion (p. 243)

ammonia (p. 240)

ammonium ion (p. 240)

aprotic solvent (p. 238)

aziridine (p. 242)

conjugate acid (p. 234)

conjugate base (p. 234)

crown ether (p. 254)

cryptand (p. 255)

diol (p. 240)

ether (p. 249)

free radical (p. 228)

glycol (p. 240)

Grignard reagent (p. 228)

hydrogen bonding (p. 232)

mercaptan (p. 252)

mercaptide (p. 253)

organolithium reagent (p. 228)

organometallic reagent (p. 227)

peptide (p. 224)

(p. 235)

primary amine (p. 240)

protein (p. 224)

protic solvent (p. 238)

Raney nickel (p. 253)

secondary amine (p. 240)

solvation (p. 237)

sulfide (p. 252)

tertiary amine (p. 240)

thioether (p. 251)

thiol (p. 251)

Key Terms

People sometimes get the connection between pK

and acid

strength wrong. A strong acid has a low pK

; a weak acid has a

high pK

It is easy to get confused when using the pK

of an ammo-

nium ion as a measure of the acidity of the related amine.

Review the discussion (p. 246) or use the more direct (but less

common) pK

values.

Common Errors

1. Grignard Reagents 3. Organolithium Reagents

Syntheses

R MgX

R can be almost any organi

structure. X is I, Br, or Cl

R MgX

If D

O is used instead

of H

O, deuterated

hydrocarbons can

be made

RLi

RSH

Raney

nickel

Raney

nickel

Reduction of thiols by

Raney nickel

Reduction of sulfides

by Raney nickel

RSR 2 R H

2. Hydrocarbons

RLi

R can be almost any organi

structure. X is I, Br, or Cl

258 CHAPTER 6 Alkyl Halides, Alcohols, Amines, Ethers, and Their Sulfur-Containing Relatives

PROBLEM 6.20 Name the following compounds:

PROBLEM 6.21 Draw structures for the following compounds:

(a) 1,4-butanediol

(b) 3-amino-1-pentanol

(d) 2,2,4,4-tetramethyl-3-pentanol

(e) (R)-sec-butyl alcohol

(f) trans-3-chlorocyclohexanol

(g) tert-butyl cyclopentyl ether

PROBLEM 6.22 Draw structures for the following compounds:

(a) neopentyl alcohol

(b) 18-crown-6

(d) THF

(e) furan

PROBLEM 6.23 Draw structures for the following compounds:

(a) (R)-3-methyl-2-butanamine

(b) cis-2-ethylcyclopentanamine

(d) 3-methoxy-2-heptanamine

(e) N-methyl-3-hexanamine

6.13 Additional Problems

(a)

(b)

(d)

(c)

(e)

(h)

(i)

(g)

(f)

(m)

(l)

(k)

(j)

OCH

(a)

(c)

(b)

(d)

(e)

PROBLEM 6.24 Draw structures for the following compounds:

(a) N-ethyl-1-ethanamine

(b) N,N-diethyl-1-ethanamine

(d) (Z)-2-penten-2-amine

(e) 2,3-pentanediamine

PROBLEM 6.25 Name the following compounds according to

the official naming system (IUPAC):