Jones M., Fleming S.A. Organic Chemistry

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6.3 Alkyl Halides as Sources of Organometallic Reagents: A Synthesis of Hydrocarbons 229

Li)

FIGURE 6.8 Organolithium reagents

are not monomeric, but oligomeric.

The exact value of n depends on the

solvent and the structure of R.

PROBLEM 6.3 Draw an interaction diagram to show the stabilization when two

methyl radicals combine. How great is that stabilization? For an example of an

interaction diagram see Figure 1.39, p. 33.

Coupling of R and MgX generates RMgX, and further radical reactions can

equilibrate this species with the dialkylmagnesium. Most halides (except fluorides)

can be made into Grignard reagents.

Organolithium reagents are even more complex. Here the ether solvent is not

essential, but the nature of the organolithium reagent does depend on the solvent.

Organolithium reagents are known not to be monomeric; they form aggregates the

size of which depends on the nature of the solvent and the structure of the R group.

As in RMgX, the representation of organolithium reagents as RLi, even with the

addition of the polar resonance form shown in Figure 6.5, is a convenient simplifi-

cation (Fig. 6.8).

R Li

LiOH

FIGURE 6.9 The powerfully basic

organometallic reagents are easily

protonated by water to give

hydrocarbons and metal hydroxides.

One of the end products of the reactions in Figure 6.9 is a hydrocarbon. This

sequence constitutes a synthesis of hydrocarbons from most halides. This reaction

can often be put to good use in the construction of isotopically labeled reagents,

because D

O can be used in place of H

O to produce a specifically deuteriolabeled

hydrocarbon (Fig. 6.10).

WEB 3D

ether

MgBr

CHBr

Cl Li D

FIGURE 6.10 Treatment of an

organometallic reagent with D

gives deuteriolabeled molecules.

Both of these organometallic reagents are extraordinarily strong bases, and they

must be carefully protected from moisture and oxygen. Chemists form them under

a strictly dry and inert atmosphere. Although these reagents do not contain free car-

banions, they act as if they did.They are sources of R



.The very polar carbon–metal

bond attacks all manner of Lewis and Brønsted acids. Water is more than strong

enough to protonate a Grignard or organolithium reagent (Fig. 6.9).

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

PROBLEM 6.4 Given inorganic reagents of your choice (including D

O), devise

syntheses of the following molecules from the indicated starting materials:

WEB 3D WEB 3D

Methanol

(methyl alcohol)

Ethanol

(ethyl alcohol)

1-Propanol

(propyl alcohol)

2-Propanol

(isopropyl alcohol)

1-Butanol

(butyl alcohol)

2-Methyl-1-propanol

(isobutyl alcohol)

CHOH

C OH

2-Methyl-2-propanol

(tert-butyl alcohol)

(CH

)

1-Pentanol

(amyl alcohol)

2-Chloro-1-butanol

3-Chloro-4-fluoro-

2-pentanol

2-Butanol

(sec-butyl alcohol)

Cyclopentanol

(cyclopentyl alcohol)

FIGURE 6.11 Some systematic and commonly used names for alcohols.

6.4 Alcohols

6.4a Nomenclature There are two ways to name alcohols: the IUPAC system-

atic way, and the way chemists often do it, by using the splendidly vulgar common

names. As usual, these common names are used only for the smaller members of the

class, and the system takes over as complexity increases.

Alcohols are named systematically by dropping the final “e” of the parent hydro-

carbon and adding the suffix “ol.” The functional group, OH, is given the lowest

number possible,taking precedence over other groups in the molecule including the

related thiol group, SH.The longest carbon chain is identified and the substituents

numbered appropriately (Fig. 6.11).

The smaller alcohols, however, are given common names with the word alcohol

written after the appropriate group name. Figure 6.11 gives some systematic and

common names for the smaller alcohols. When we get past approximately five car-

bons, the systematic naming protocol takes over completely, and even the delightful

6.4 Alcohols 231

name amyl for the five-carbon alcohols is disappearing.

However, some common

names seem to be quite hardy. For example, the correct IUPAC name for hydroxy-

benzene is benzenol, but the common name phenol is still accepted in the IUPAC

system and probably will survive for a long time (Fig. 6.12).

Amyl derives from the Latin word for starch, amylum. The first amyl alcohol was isolated from the fermen-

tation of potatoes.

WEB 3D

Allyl alcohol

Phenol Amyl alcohol Ethylene

col

Benzyl alcohol

trans-Crotyl alcohol

Glycerol

cerin

)

OH OH

FIGURE 6.12 Some widely used

common names for alcohols.

PROBLEM 6.5 Provide systematic names for the following alcohols:

OCH

6.4b Structure of Alcohols Alcohols are derivatives of water, and it will be no

surprise to see that they rather closely resemble water structurally. The bond angle

is expanded a bit from 104.5° in to approximately 109° in simple

alcohols .

The oxygen–hydrogen bond length is very little changed from that of water, but

the carbon–oxygen bond is a bit shorter and stronger than the carbon–carbon bond

in ethane (Fig. 6.13).

104.5⬚ 108.9⬚

0.96 A

⬚

1.43 A

⬚

0.96 A

⬚

1.54 A

⬚

FIGURE 6.13 Bond lengths and

angles for water, methyl alcohol,

and ethane.

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

PROBLEM 6.6 What is the approximate hybridization of the oxygen atom in

methyl alcohol ( angle  108.9°). How do you know?

(C)

Energy

C O

(O)

105 kcal/mol

92 kcal/mol

σ*

C Oσ

96 kcal/mol

FIGURE 6.14 A graphical description of the formation of the carbon–oxygen σ bond.

R = H (water) or alkyl (alcohols)

Here, an alcohol

acts as Brønsted

acid (proton donor)

etc.

An alcohol acts as

Brønsted base

(proton acceptor)

Hydrogen bonds

FIGURE 6.15 Water and alcohols are

both Brønsted acids and Brønsted

bases.This figure shows hydrogen

bonding between molecules of water

(R  H) and alcohols.

The orbital interaction diagram of Figure 6.14 shows the construction of the

carbon–oxygen bond, as well as typical bond energies. Notice that an electron in

an orbital near the very electronegative oxygen is more stable than it would be in an

orbital near carbon.

6.4c Physical Properties of Alcohols The presence of the electronegative

oxygen atom ensures that bonds will be strongly polarized in alcohols and that sub-

stantial dipole moments will exist. In the liquid phase, alcohols are strongly associ-

ated both because of dipole–dipole attractions and because of hydrogen bonding in

which the basic oxygen atoms form partial bonds to the acidic hydroxyl hydrogens.

Such bonds can be quite strong, on the order of 5 kcal/mol, a value not high enough

to make permanent dimeric or polymeric structures but quite sufficient to raise the

boiling points of alcohols far above those of the much less strongly associated

alkanes. Figure 6.15 shows an ordered, hydrogen-bonded structure for an alcohol.

In the absence of hydrogen bonding, water with a molecular weight of only 18, and

the low molecular weight alcohols, would surely be gases. The polarity of alcohols

6.4 Alcohols 233

makes them quite water soluble, and most of the smaller molecules are miscible

(soluble in all proportions) with, or at least highly soluble in, water. Table 6.3 gives

some physical properties of alcohols. For comparisons with the parent alkanes see

Table 2.4 (p. 79).

TABLE 6.3 Some Physical Properties of Alcohols

Compound bp (°C) mp (°C) Dipole Moment (D)

Methyl alcohol

65.15 –93.9 1.7

78.5 –117.3 1.69

(CH

)

CHOH 82.4 –89.5 1.68

Isopropyl alcohol

117.2 –89.5 1.66

Density (g/cm

)

0.79

0.80

0.81

Butyl alcohol

Ethyl alcohol

(CH

)

CHCH

OH –108 1.64108

99.5 –115

sec-Butyl alcohol

(CH

)

COH 82.3 25.5

181.7 43 1.45

0.80

0.81

0.79

1.06

Isobutyl alcohol

tert-Butyl alcohol

Phenol

CH(CH

)OH

Even though these intramolecular hydrogen bonds are relatively weak ( 5 kcal/mol)

they are critically important. For example, life as we know it is clearly not possible

without water and there would be no liquid water without hydrogen bonds.

Moreover, hydrogen bonds are used to maintain the proper structures in proteins

and nucleic acids, polymeric structures essential to our existence that we will meet

later in this book.

6.4d Acid and Base Properties of Alcohols We have just seen water and

alcohols acting as Brønsted acids and bases. Hydrogen bonding is a perfect exam-

ple of such behavior. In Chapter 7, we are going to look closely at a number of

reactions of alcohols. These processes depend on the ability of alcohols to act as

both acids and bases. Accordingly, we first make sure that we can see these

roles clearly.

A Brønsted acid is any compound that can donate a proton. A Brønsted base

is any compound that can accept a proton. Let’s look first at a very simple process,

the reaction of solid potassium hydroxide (KOH) with gaseous hydrochloric acid

(HCl).This reaction is nothing but a competition of two Brønsted bases (Cl



and



) for a proton, H



. The stronger Brønsted base (HO



) wins the competi-

tion (Fig. 6.16).

HCl

HOH

–

FIGURE 6.16 Two Brønsted bases

(blue) competing for a proton.

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

Hydrochloric acid (HCl) is called the conjugate acid of Cl



, and Cl



is the

conjugate base of hydrochloric acid. Conjugate bases and acids are related to each

other through the gain and loss of a proton (Fig. 6.17).

Caution! This is a formalized picture and does not

imply the reaction of bases with a bare proton, H

Outside of the gas phase, bare protons do not exist

H B is the

conjugate

acid of B

B is the

conjugate

base of H B

–

FIGURE 6.17 Conjugate acids and

bases.

–

ClCl

–

H H

(a)

(b)

FIGURE 6.18 Water is both a

Brønsted acid and base.

PROBLEM 6.7 What are the conjugate acids of the following molecules?

(a) H

O (b)



OH (c) NH

(d) CH

OH (e) (f)



PROBLEM 6.8 What are the conjugate bases of the following molecules?

(a) H

O (b)



OH (c) NH

(d) CH

OH (e) CH

(f) HOSO

OH (g)



OSO

As we saw in Figure 6.15, a molecule may be both a Brønsted acid and a

Brønsted base. Consider water, for example. Water can both donate a proton (act

as a Brønsted acid) and accept a proton (act as a Brønsted base). Figure 6.18 shows

two reactions, (a) the protonation of water by hydrogen chloride, in which water

acts as a base, and (b) the protonation of hydroxide ion by water, in which water is

acting as the acid.

Many reactions begin with a protonation step. Because strong acids are better

able to donate a proton than weaker acids, it will be important for us to know which

molecules are strong acids and which are weak acids.The dissociation of an acid HA

in water can be described by the equation

HA  H



 A



This equation leads to an expression for the equilibrium constant, K.

Because it is present as solvent, in vast excess, the concentration of water remains

constant in the ionization reaction. This equation is usually rewritten to give the

acidity constant, K

where the square brackets indicate concentration.

] [A

]

[HA]

K =

] [A

]

[HA] [H

6.4 Alcohols 235

By analogy with pH, we can define a quantity pK

log K

The stronger the acid, the lower is its pK

. Table 6.4 gives pK

values for some

representative compounds. This short list spans about 80 powers of 10 (pK

is a log

function). In practice, any compound with a pK

lower than about 5 is regarded

as a reasonably strong acid; those with pK

values below 0 are very strong. As we

discuss new kinds of molecules, more pK

values will appear. Should you memorize

this list? We think not, but you will need to have a reasonable idea of the approxi-

mate acidity of different kinds of molecules.

TABLE 6.4 Some pK

Values for Assorted Molecules

Compound pK

HI 10 H



9.2

3CH

OH 15.5

HBr 9H

O 15.7

HCl 8ROH

16–18

224



1.7 NH

HNO

1.3 50

HF 3.2 (CH

)

(cyclopropane) 46

RCOOH

4–5 CH

50–60

S 7.0 (CH

)

CH 50–70

When there is a choice, it is the underlined H that is lost. A longer list is provided on the back inside cover.

CHRO

In alcohols and water, Brønsted basicity is centered on the nonbonding elec-

trons of the oxygen atom, which form bonds with a variety of acids. Protonation

converts an alcohol, ROH, into an oxonium ion (RO



). This conversion will

have profound chemical consequences, which we can preview here. Breaking the

bond to form ions is very difficult, because both positive (R



) and

negative (HO



) ions must be formed.Hydroxide, HO



, is very difficult to form—

one says that hydroxide is a poor leaving group—and alcohols do not ionize easily

(Fig. 6.19). After protonation, however, the “leaving group” is no longer hydroxide,

but water. Formation of the neutral molecule water is a much easier process

(Fig. 6.19).

An oxonium ion

(a strong acid)

–

A very poor

leaving group

A good

leaving group

Leaving group

(

–

OH) is very poor

Now, leaving group

(OH

) is much better

FIGURE 6.19 Protonation of an

alcohol leads to an oxonium ion.

In this process, the very poor leaving

group OH is transformed into the

good leaving group OH

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

TABLE 6.5 Some pK

Values

for Simple Oxonium Ions

Compound pK

1.74

2.2

1.9

2.3

2.2

2.6

About 3.5RO

HR¿

(CH

)

CHO

HCH

Note that the acidity order in water is CH

OH  CH

OH 

(CH

)

CHOH  (CH

)

COH. Apparently, the more alkyl groups on the alcohol,

the weaker an acid it is. For many years, this pK

order was explained by assuming

that alkyl groups are intrinsically electron donating. If this were true, the product

alkoxides would be destabilized by alkyl groups and the acidity of the correspon-

ding alcohol would be reduced (Fig. 6.21).

–

Alkoxide

ion

Brønsted base

FIGURE 6.20 Loss of a proton to a general

Brønsted base leads to an alkoxide ion. Alkoxides

are named very simply as oxides of the parent

alcohol.Thus, methyl alcohol, CH

OH, is

deprotonated to give methoxide, CH



, ethyl

alcohol, CH

OH, is deprotonated to give

ethoxide, CH



, and so on.

TABLE 6.6 Some pK

Values for Simple Alcohols in Water

Compound pK

(loss of underlined H)

Water H

O 15.7 Strongest acid

Methyl alcohol CH

OH 15.5

Ethyl alcohol CH

OH 15.9

Isopropyl alcohol (CH

)

CHOH 16.5

tert-Butyl alcohol (CH

)

COH 17.0 Weakest acid

–

Destabilized

by dipole in

–––

C bond

–

FIGURE 6.21 If alkyl groups were

electron-releasing, formation of an

alkoxide from an alcohol would be

retarded by alkyl groups.

Protonated alcohols are very strong Brønsted acids. Therefore, in order

to protonate an alcohol, it takes a very strong acid indeed. The conjugate

base (B



) of the protonating acid (HB) must be a weaker base than the

alcohol. The base must be an ineffective competitor in the equilibrium of

Figure 6.19.

Oxonium ions are much better proton donors than are the alcohols themselves.

Table 6.5 gives the pK

values for a few protonated alcohols and water. Oxonium

ions formed from alcohols have pK

values in the 2 range, and those from ethers

( ) are even more acidic.

Brønsted acidity, of course, is centered on the hydroxyl hydrogen. Loss of this

hydrogen to an acceptor, a Brønsted base, leads to the conjugate base of the alcohol,

the alkoxide ion (RO



). The proton is not just lost as H



but removed by a base

(Fig. 6.20).

R¿

Alcohols are approximately as acidic as water.Table 6.6 gives the pK

values for

some simple alcohols in aqueous solution as well as water itself.

–

CCH

OHF

–

CCH

–

CCH

–

6.4 Alcohols 237

Inductive effects, the result of polarized sigma bonds, are important. For exam-

ple,the pK

of 2,2,2-trifluoroethanol (CF

OH) is 12.5,whereas the pK

of ethyl

alcohol is 15.9. The fluorinated alcohol is more than a thousand times as acidic as

ethyl alcohol (remember the pK

scale is logarithmic). Fluorinated alcohols are always

stronger acids than their hydrogen-substituted counterparts.

WORKED PROBLEM 6.9 Explain in detail why 2,2,2-trifluoroethanol is a stronger

acid than ethyl alcohol.

ANSWER As fluorine is very electronegative, the fluorines are strongly electron-

withdrawing and will help stabilize the alkoxide ion. They will also stabilize the

transition state leading to the alkoxide because partial negative charge has begun

to develop on the oxygen atom. So the fluorines will have an effect on both the

kinetic and thermodynamic properties of the alcohol.

Yet this traditional, and simple, explanation that treats alkyl groups as intrinsi-

cally electron-donating is not correct. In 1970, Professor John Brauman (b. 1937)

and his co-workers at Stanford University showed that in the gas phase the opposite

acidity order obtained.The intrinsic acidity of the four alcohols of Table 6.6 is exact-

ly opposite to that found in solution.The acidity order measured in solution reflects

a powerful effect of the solvent, not the natural acidities of the alcohols themselves.

Organic ions are almost all unstable species,and the formation of the alkoxide anions

depends critically on how easy it is to stabilize them through interaction with sol-

vent molecules, a process called solvation. tert-Butyl alcohol is a weaker acid in

solution than methyl alcohol because the large tert-butyl alkoxide ion is difficult to

solvate. The more alkyl groups, the more difficult it is for the stabilizing solvent

molecules to approach (Fig. 6.22). Of course, in the gas phase where solvation is

impossible, the natural acidity order is observed.

–

base

–

solvent

base

solvent

Difficult to

solvate

Easy to

solvate

FIGURE 6.22 The smaller the

alkoxide ion, the easier it is for

solvent molecules to approach and

stabilize it.

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

In the gas phase, the alkyl groups are actually operating so as to stabilize the

charged alkoxide ions, presumably by withdrawing electrons, exactly the opposite

from what had been thought (Fig. 6.23).

–

O H

FIGURE 6.23 Alkyl groups can be

electron-withdrawing.

WORKED PROBLEM 6.10 Can you describe this phenomenon—the stabilization of

a pair of electrons by an adjacent alkyl group—in orbital terms? No orbital con-

struction or complicated argument is necessary. A simple statement is all that is

needed.

ANSWER Alkyl groups have both filled and empty molecular orbitals (see the

problems at the end of Chapter 1 for several examples). A pair of electrons adja-

cent to an alkyl group can be stabilized through overlap with the LUMO of the

alkyl group. (Similarly, an alkyl group stabilizes an adjacent empty orbital through

overlap with the alkyl HOMO.)

What lessons are to be drawn from this discussion? First, solvation is important

and not completely understood. We are certain to find other phenomena best

explained in terms of solvation in the future.Second,the gas phase is the ideal medi-

um for revealing the intrinsic properties of molecules. (Some would go further and

say that calculation is the best way.) However, the practical world of solvated reac-

tions is certainly real, and for us to understand reactivity we can no longer afford to

ignore the solvent.

6.5 Solvents in Organic Chemistry

We have just seen an example of a solvent playing a crucial role in determining

the acidities of alcohols. The greater acidity of methyl alcohol over tert-butyl

alcohol in a polar solvent is a result of the greater ease of solvating the

conjugate base of methyl alcohol, the methoxide ion, over the tert-butoxide ion

(Fig. 6.22). Let’s take a quick look at the properties of solvents and the process

of solvation.

6.5a Polar Solvents We have seen that one kind of stabilization by solvent—

solvation—is a consequence of hydrogen bonding.For hydrogen bonding to be pos-

sible, there clearly must be both a proton donor (usually a hydroxy or amino group,

OH or NH

) and a proton acceptor available (a pair of electrons). Solvents that can

donate a proton are called protic solvents. Protic solvents are usually also quite

polar; that is, they have relatively high dielectric constants, ε, a measure of the

ability of a solvent to separate charges. Solvents without available protons—in other

words, solvents that are not proton donors—are aprotic solvents and can be either

polar or nonpolar. It is distinctly possible for a solvent to be quite polar, to have a

high ε, but not be a proton donor. Of course, many molecules are both nonpolar and