Jones M., Fleming S.A. Organic Chemistry

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14.7 Synthetic Reactions We Can Do So Far 649

(67%)

CuCN

0 ⬚C, 5 h

CuBr

water/

acetone

–25 ⬚C

CuCl

CN,

65 ⬚C

(90%)

(98%)

FIGURE 14.54 Three Sandmeyer reactions. Decomposition of the diazonium ion with cuprous salts leads

to substitution.

Reagents other than cuprous salts are also effective. Figure 14.55 shows four

such reactions. Treatment with potassium iodide (KI) or fluoboric acid (HBF

)

gives the iodide or fluoride, respectively (the Schiemann reaction; G. Schiemann

1899–1969), and hydrolysis gives phenols (p. 231). Heating with hypophosphorous

acid (H

) removes the diazonium group and replaces it with hydrogen.

The diazonium ion is important because it is the critical intermediate in a num-

ber of transformations lumped under the heading of the Sandmeyer reaction,named

for Traugett Sandmeyer (1854–1922). Cuprous salts convert a diazonium ion into

the related cyanide or halide.In recent times, numerous variations on the basic theme

of the Sandmeyer reaction have improved yields and reduced side products.Figure 14.54

shows three typical Sandmeyer reactions.

(75%)

(85%)

25–100 ⬚C

100 ⬚C

(80%)

excess

HBF

0 ⬚C

Schiemann reaction

(68%)

FIGURE 14.55 Other substitution

reactions of diazonium ions.

650 CHAPTER 14 Substitution Reactions of Aromatic Compounds

CuCl

–

HCl H CuCl

Dichlorocuprate

ion

FIGURE 14.56 Formation of the

dichlorocuprate ion from CuCl

and HCl.

–

CuCl

Dichlorocuprate

ion

Benzenediazonium

ion

Phenyl

radical

Chlorobenzene

FIGURE 14.57 The mechanism of chlorobenzene formation.

PROBLEM 14.16 We reject out of hand the notion that any of these net displace-

ment reactions could go by something as simple as an S

2 reaction. Why?

–

Phenyl

cation

Fluorobenzene

FIGURE 14.58 Some reactions of

benzenediazonium chloride involve

a phenyl cation.

Some Sandmeyer reactions apparently involve a phenyl cation formed by the irre-

versible S

1 ionization of benzenediazonium chloride (Fig. 14.58).

In the Sandmeyer reactions involving copper, electron-transfer-mediated radi-

cal reactions are certainly involved. In HCl, cuprous chloride (CuCl) is in equilib-

rium with the dichlorocuprate ion



CuCl

(Fig.14.56).The dichlorocuprate ion can

transfer an electron to the diazonium ion, which can then lose molecular nitrogen

to give a phenyl radical. In turn, the phenyl radical can pluck a chlorine atom from

a copper chloride molecule to give the chlorobenzene and a molecule of cuprous

chloride.The mechanism for the formation of chlorobenzene in the Sandmeyer reac-

tion is shown in Figure 14.57.

Of course,you are now clamoring for the mechanisms for all these changes. Sadly,

only the outlines of the mechanisms are known, and much remains to be filled in.

The details of many reactions are imperfectly understood,and there remains a delight-

ful (to some) atmosphere of magic about parts of organic chemistry. What are we to

make of the admonition in one procedure for the Sandmeyer reaction to “stir the mix-

ture with a lead rod.”What happens if we use a glass rod? Although one would think

that the reaction might still succeed, there are examples to the contrary, and perhaps

microscopic pieces of lead do affect the success of the reaction. We’d use lead.

Speaking of lead and magic, two of MJ’s chemical relatives, Milton Farber (b.1925) and Adnan Abdul-rida

Sayigh (~1922–1980), once discovered a useful reaction of lead dioxide, and the work was duly published as

an effective way to make alkenes from 1,2-diacids. However, the reaction only worked when one particular

bottle of lead oxide was used, and once that bottle was used up no one could reproduce the yields achieved

earlier. All other sources of lead dioxide failed! Apparently, the particle size of the lead dioxide was critical.

(What’s a “chemical relation”? That’s someone who did his or her graduate work with the same professor as

you. Farber and Sayigh both worked with the same person as MJ and hence are his chemical brothers.)

14.7 Synthetic Reactions We Can Do So Far 651

NaNO

/HCl

An azo compound

WEB 3D

It doesn’t matter that some mechanistic details are sketchy; the formation of the

diazonium ion from aniline (and therefore ultimately from the easily made nitroben-

zene) and its further transformations give you the ability to make a great number

of substituted benzenes from very simple precursors.

PROBLEM 14.19 Suggest synthetic procedures leading to each of these compounds.

You may start with benzene, any inorganic reagent, and organic compounds con-

taining no more than four carbon atoms.

(a)

(e)

(f)

(g)

(h)

(i)

(b)

C(CH

)

(c)

(d)

CCH

PROBLEM 14.20 Phenols made by the Sandmeyer reaction can be used further

in synthesis. First, explain why phenol (pK

 10) is a much stronger acid than

cyclohexanol (pK

 16).

PROBLEM 14.17 Draw resonance forms for the phenyl radical, Ph (be careful).

PROBLEM 14.18 In the formation of diazonium ions from aromatic amines, side

products called azo compounds are occasionally encountered, as shown below.

Give a mechanism for the formation of these compounds.

652 CHAPTER 14 Substitution Reactions of Aromatic Compounds

NaH

0 ⬚C, THF

27 ⬚C, CH

OCH

Phenoxide 3-Phenoxypropene

(allyl phenyl ether)

(100%)

Phenol

–

PROBLEM 14.21 Aryl ethers can be made by the following reaction. Write an

arrow formalism mechanism for each step.

Pyridine Pyrrole

2-Substitution 3-Substitution 4-Substitution

2-Substitution 3-Substitution

H H

WEB 3DWEB 3D

FIGURE 14.59 Possible positions for electrophilic aromatic substitution in pyridine and pyrrole.

PROBLEM 14.22 A side product can be formed in the reaction in Problem

14.21, depending on the conditions. Explain the formation of the compound

A shown below in the reaction of phenoxide with allyl bromide. You will need

the additional information that in basic conditions ketones are transformed

into enolates and, after protonation, enols.

1. base

2. protonation

A Ketone Enol

14.8 Electrophilic Aromatic Substitution

of Heteroaromatic Compounds

Although heteroaromatic compounds generally have lower resonance energies than

benzene (Table 14.1, p. 629), they also undergo electrophilic aromatic substitution

rather than addition.

14.8a Reactions of Pyridine and Pyrrole The heteroatom introduces a

complication in aromatic substitution not present in benzene. Benzene has six

equivalent positions, but substitution could occur at two positions in pyrrole and

three in pyridine (Fig. 14.59).

14.8 Electrophilic Aromatic Substitution of Heteroaromatic Compounds 653

GENERAL CASES

SPECIFIC EXAMPLES

4-Position

2-Position

3-Position

+ +

Favored: No

on N!

AlCl

(30%)

(90%)

/SO

Bad!

FIGURE 14.60 In pyridine, substitution at the 3-position is favored, although the reaction is

slower than with benzene.

As with benzene, electrophilic attack on pyridine gives an intermediate in which

three atoms share the positive charge (Fig. 14.60). Substitution at the 2- or 4-position

(ortho or para to the nitrogen in pyridine) places a partial positive charge on the

relatively electronegative nitrogen atom. Substitution at the 3-position (meta to the

nitrogen) does not and is accordingly favored.

This rate-diminishing effect is accentuated if the nitrogen is protonated, as it

very often is under the strongly acid conditions necessary to carry out substitution

on pyridine. Therefore it is not surprising that substitution of pyridine takes place

more slowly than analogous reactions involving benzene. Pyridine itself substitutes

about as rapidly as nitrobenzene, 10

times more slowly than benzene. The pyri-

dinium ion substitutes an impressive 10

times more slowly than benzene.

A similar analysis serves to locate the more favorable position for substitution

on pyrrole. Addition at either carbon 2 or 3 (Fig. 14.59) allows the nitrogen to help

bear the positive charge. However, in the intermediate produced by substitution at

carbon 2, two ring carbons share the charge with the nitrogen, whereas substitution

at carbon 3 leads to an intermediate in which only one carbon shares the charge with

654 CHAPTER 14 Substitution Reactions of Aromatic Compounds

H H H

attack at

C(3)

attack at

C(2)

HNO

(80%) (20%)

A SPECIFIC EXAMPLE

GENERAL CASES

FIGURE 14.61 In pyrrole,

substitution at the 2-position

is favored.

ThiopheneFurfural

AlCl

(90%)

(43%)

CHO

FIGURE 14.62 Electrophilic substitution reactions of furan and thiophene.

PROBLEM 14.23 Explain why 2-substitution is preferred to 3-substitution in

electrophilic aromatic substitution of furan.

the nitrogen. Addition to the 2-position is favored, although the formation of mix-

tures is commonly observed (Fig. 14.61).

Pyrrole is more reactive than benzene or pyridine,because pyrrole is less well sta-

bilized by resonance than the six-membered ring molecules (Table 14.1).

14.8b Reactions of Furan and Thiophene These compounds are very

reactive toward electrophiles, E



. As in pyrrole, aromatic substitution is directed

first to the 2-position (Fig. 14.62), although mixtures are sometimes obtained in

which some 3-substitution appears.

PROBLEM SOLVING

All problems of this kind ask you to make comparisons, but they usually require

you to write mechanisms so that you can see the molecules that must be

compared. It may seem obvious, but attacking such problems is best done by

carefully writing out the mechanisms in parallel so that you can see the possible

points of comparison. Don’t just think, write.

14.9 Disubstituted Benzenes: Ortho, Meta, and Para Substitution 655

PROBLEM 14.24 In addition to the mechanism following the path shown for

pyrrole in Figure 14.61, there is another reasonable mechanism for aromatic

substitution of furan. Suggest one. Hint: Think simple! What are the possible

reactions between electrophiles and double bonds (Chapters 9 and 10)? Use the

chlorination of furan as an example.

PROBLEM 14.25 There is a difficulty with the answer to Problem 14.24. Find what

is wrong (or unlikely) and suggest an alternative mechanism. Hint: Recall what you

know of the stereoelectronic requirements of the E2 reaction (Section 7.9, p. 301).

14.9 Disubstituted Benzenes: Ortho, Meta,

and Para Substitution

We have already mentioned (Problem 14.9) that the synthesis of toluene from benzene

is made difficult because once a significant amount of toluene is formed, it competes

successfully with the unsubstituted benzene in further methylation reactions.Unless one

is careful to use a vast excess of benzene, the result is a horrible mixture of benzene,

toluene, dimethylbenzenes (xylenes), and even tri- and tetra-substituted molecules.

AlCl

repeat

three times

Toluene

Xylenes

Hexamethylbenzene

WORKED PROBLEM 14.26 If one attempts to methylate benzene completely with

Cl/AlCl

, the product is a greenish solid of the formula C

AlCl

Propose a structure for the compound and a mechanism for its formation.

ANSWER This problem involves a sequence of Friedel–Crafts alkylations.Toluene

is made first, then the xylenes, then trimethylbenzenes, and so on, until hexa-

methylbenzene is formed.

What happens if another Friedel–Crafts reaction occurs? The product is the

heptamethylcyclohexadienyl cation tetrachloroaluminate salt, and this material

is stable under the reaction conditions. Why? The resonance forms contributing

(continued)

656 CHAPTER 14 Substitution Reactions of Aromatic Compounds

The general question now arises of how the

substituted benzenes we have learned to make will

react with electrophilic reagents. What are the

possibilities? There are three isomers of disubsti-

tuted benzene, ortho, meta, and para, as shown in

Figure 14.63.

Substituents influence the distribution of the

three isomeric disubstituted products dramati-

cally. Further substitution of monosubstituted

benzenes by no means proceeds to give a statisti-

cal distribution of two parts ortho

product, two parts meta product,

and one part para product. In

fact, if one looks at the reactions

of a number of monosubstituted

benzenes, a pattern emerges. Some

groups (G) substitute predominant-

ly ortho and para, while for other

groups meta is dominant. There

is also a correlation between the

position of further substitution

and the rate of the reaction.

Monosubstituted benzenes that

give mainly ortho and para prod-

ucts usually react faster than ben-

zene. Monosubstituted benzenes

that give mainly meta product

react more slowly than benzene

(Table 14.2).

A look at the general mecha-

nism of substitution shows how

different groups influence the posi-

tion of subsequent reaction. We

can also see how these orientation

(regiochemical) effects are con-

nected to the rates of the reactions.

Let’s look first at methoxybenzene

(anisole). Methoxy (CH

O) is one

TABLE 14.2 Patterns of Further Reactions of Substituted Benzenes

G Position

o/p

Relative Rate

Very fast

o/p

Very fast

o/p

Very fast

o/p

Fast

Slow

Ortho = o, para = p, meta = m.

Slow

o/p

Fast

, NHR, NR

R (alkyl)

o/p

Slow

I, Cl, Br, F

H (benzene)

(R´ = OH, OR, NH2,

Cl, alkyl, aryl)

NH C

R´

Slow

SOH

Slow

–

ortho + para