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CHEMISTRY MATTERS
Combinatorial Chemistry
Traditionally, organic compounds have been synthesized one at a time. This works well for preparing large
amounts of a few substances, but it doesn’t work so well for preparing small amounts of a great many
substances. This latter goal is particularly important in the pharmaceutical industry, where vast numbers of
structurally similar compounds must be synthesized and screened to find an optimum drug candidate.
To speed the process of drug discovery, combinatorial chemistry has been developed to prepare what are
called combinatorial libraries, in which anywhere from a few dozen to several hundred thousand substances
are prepared simultaneously. Among the early successes of combinatorial chemistry is the development of a
benzodiazepine library, a class of aromatic compounds commonly used as antianxiety agents.
Two main approaches to combinatorial chemistry are used—parallel synthesis and split synthesis. In parallel
synthesis, each compound is prepared independently. Typically, a reactant is first linked to the surface of
polymer beads, which are then placed into small wells on a 96-well glass plate. Programmable robotic
instruments add different sequences of building blocks to the different wells, thereby making 96 different
products. When the reaction sequences are complete, the polymer beads are washed and their products are
released.
In split synthesis, the initial reactant is again linked to the surface of polymer beads, which are then divided into
several groups. A different building block is added to each group of beads, the different groups are combined,
and the reassembled mix is again split to form new groups. Another building block is added to each group, the
groups are again combined and redivided, and the process continues. If, for example, the beads are divided into
four groups at each step, the number of compounds increases in the progression 4 → 16 → 64 → 256. After 10
steps, more than 1 million compounds have been prepared (FIGURE 16.23).
Of course, with so many different final products mixed together, the problem is to identify them. What structure
is linked to what bead? Several approaches to this problem have been developed, all of which involve the
attachment of encoding labels to each polymer bead to keep track of the chemistry each has undergone.
Encoding labels used thus far have included proteins, nucleic acids, halogenated aromatic compounds, and
even computer chips.
FIGURE 16.22 Organic chemistry by robot means no spilled flasks!
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FIGURE 16.23 The results of split combinatorial synthesis. Assuming that 4 different building blocks are used at each step, 64 compounds
result after 3 steps, and more than one million compounds result after 10 steps.
Key Terms
• acyl group
• acylation
• alkylation
• benzyne
• combinatorial chemistry
• electrophilic aromatic substitution
• Friedel–Crafts reaction
• inductive effect
• nucleophilic aromatic substitution
• resonance effect
Summary
We’ve continued the coverage of aromatic molecules in this chapter, shifting focus to concentrate on reactions.
In particular, we’ve looked at the relationship between aromatic structure and reactivity, a relationship critical
to understanding how numerous biological molecules and pharmaceutical agents are synthesized and why they
behave as they do.
An electrophilic aromatic substitution reaction takes place in two steps—initial reaction of an electrophile,
E+, with the aromatic ring, followed by loss of H+ from the resonance-stabilized carbocation intermediate to
regenerate the aromatic ring.
Many variations of the reaction can be carried out, including halogenation, nitration, and sulfonation.
Friedel–Crafts alkylation and acylation reactions, which involve reaction of an aromatic ring with carbocation
electrophiles, are particularly useful. They are limited, however, by the fact that the aromatic ring must be at
least as reactive as a halobenzene. In addition, polyalkylation and carbocation rearrangements often occur in
Friedel–Crafts alkylation.
Substituents on the benzene ring affect both the reactivity of the ring toward further substitution and the
orientation of that substitution. Groups can be classified as ortho- and para-directing activators, ortho- and
para-directing deactivators, or meta-directing deactivators. Substituents influence aromatic rings by a
combination of resonance and inductive effects. Resonance effects are transmitted through π bonds; inductive
effects are transmitted through σ bonds.
16 • Key Terms 559
Halobenzenes undergo nucleophilic aromatic substitution through either of two mechanisms. If the
halobenzene has a strongly electron-withdrawing substituent in the ortho or para position, substitution occurs
by addition of a nucleophile to the ring, followed by elimination of halide from the intermediate anion. If the
halobenzene is not activated by an electron-withdrawing substituent, substitution can occur by elimination of
HX to give a benzyne, followed by addition of a nucleophile.
The benzylic position of an alkylbenzene can be brominated by reaction with N-bromosuccinimide, and the
entire side chain can be degraded to a carboxyl group by oxidation with aqueous KMnO4. Aromatic rings can
also be reduced to cyclohexanes by hydrogenation over a platinum or rhodium catalyst, and aryl alkyl ketones
are reduced to alkylbenzenes by hydrogenation over a platinum catalyst.
Summary of Reactions
1. Electrophilic aromatic substitution
a. Fluorination (Section 16.2)
b. Bromination (Section 16.1)
c. Chlorination (Section 16.2)
d. Iodination (Section 16.2)
e. Nitration (Section 16.2)
f. Sulfonation (Section 16.2)
g. Friedel–Crafts alkylation (Section 16.3)
h. Friedel–Crafts acylation (Section 16.3)
2. Reduction of aromatic nitro groups (Section 16.2)
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3. Nucleophilic aromatic substitution
a. By addition to activated aryl halides (Section 16.6)
b. By formation of benzyne intermediate from unactivated aryl halide (Section 16.7)
4. Oxidation of alkylbenzene side chain (Section 16.8)
5. Benzylic bromination of alkylbenzene side chain (Section 16.8)
6. Catalytic hydrogenation of aromatic ring (Section 16.9)
7. Reduction of aryl alkyl ketones (Section 16.9)
Additional Problems
Visualizing Chemistry
PROBLEM
16-24
Draw the product from reaction of each of the following substances with (1) Br2, FeBr3 and (2)
CH3COCl, AlCl3.
(a) (b)
PROBLEM
16-25
The following molecular model of a dimethyl-substituted biphenyl represents the lowest-energy
conformation of the molecule. Why are the two benzene rings tilted at a 63° angle to each other
16 • Additional Problems 561
rather than being in the same plane so that their p orbitals overlap? Why doesn’t complete rotation
around the single bond joining the two rings occur?
PROBLEM
16-26
How would you synthesize the following compound starting from benzene? More than one step is
needed.
PROBLEM
16-27
The following compound can’t be synthesized using the methods discussed in this chapter. Why
not?
Mechanism Problems
Mechanisms of Electrophilic Substitutions
PROBLEM
16-28
Aromatic iodination can be carried out with a number of reagents, including iodine monochloride,
ICl. What is the direction of polarization of ICl? Propose a mechanism for the iodination of an
aromatic ring with ICl.
PROBLEM
16-29
The sulfonation of an aromatic ring with SO3 and H2SO4 is reversible. That is, heating
benzenesulfonic acid with H2SO4 yields benzene. Show the mechanism of the desulfonation
reaction. What is the electrophile?
PROBLEM
16-30
The carbocation electrophile in a Friedel–Crafts reaction can be generated by an alternate means
than reaction of an alkyl chloride with AlCl3. For example, reaction of benzene with
2-methylpropene in the presence of H3PO4 yields tert-butylbenzene. Propose a mechanism for this
reaction.
PROBLEM
16-31
The N,N,N-trimethylammoniumgroup, – (CH3)3, is one of the few groups that is a meta-directing
deactivator yet has no electron- withdrawing resonance effect. Explain.
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	Chapter 16 Chemistry of Benzene: Electrophilic Aromatic Substitution
	Chemistry Matters — Combinatorial Chemistry
	Key Terms
	Summary
	Summary of Reactions
	Additional Problems