The Aromatic Substitution Game
Murray anger,' Alfonso R. Gennaro, and James R. McKee
Philadelphia College of Pharmacy and Science, Philadelphia, PA
Electrophilic aromatic substitution is one of the few top-
ics in organic chemistry where the theory of the reactions
can be used to guide the syntheses of a particularly wide
varietv of substituted benzenes. The theory and synthetic
~ ~~~
schemes can be used to reinforce n mutuiliunder~tandin~
of the cornnlementarv methods. Unfortunately, in the typ-
ical s q u e k e of text6ook chapters, much of the hemi&&
needed to achieve these syntheses (e. g., amine diazotiza-
tion replacement reactions) has not yet been discussed.
When new substitution reactions are encountered subse-
quently, the student rarely is required to reconsider the
substitution theory learned in the earlier chapter. An im-
portant educational benefit is thus lost.
To redress this problem, the Aromatic Substitution
Game was developed. The student is given a Reaction
Table (see table), a Substitution Chart (see figure) and a
brief, limited set of Rules of the Game and Hints for the
Game. A review of several current orzanic chemistry texts
( 1 4 , was used to limit the number orreactions covered by
this game. Some simplification of the chemtstry was re-
For example, when a compound already bearing an
o-, p-orienting group is further substituted, the student
may choase either disubstituted isomer formed as the final
product. Not every possible substitution reaction is uti-
lized, only those that are found in typical organic texts.
The table shows which substitution reactions can occur
on substituted benzenes. For example, chlorobenzene can
be alkvlated. but nitrobenzene cannot. An alkvl proup can
be oxikzed k t h o u t affecting a bromo group-attachid a t
another position, hut n hydrnxy group is sensitive tooxida-
tion. Phenol cannot be ring-acylated directly.
I n the figure, all of the permitted syntheses are outlined.
Once one substituent is attached to the ring, the orients-
tion effect of introducing a second one is shown under each
Substitution Reactions
Reactions Carried Out to add a 2nd Substituent
Symbols:
(+) = readion works
-) = no readion
(+ I -) = different reaction occurs
( + I + ) = multiple substitution mun
(0) = oxidation ot an alkyl side chain
group, and the figure illustrates that certain wmplemen-
tary group pairs have opposite effects:
1. nitro (meta) can be reduced to amino (orthol~ara)
2. alkyl (ortholpara)can be oxidized to carboxyl (metal
3. acyl (mefa) can be reduced to alkyl (ortholpam)
These pairs when used in syntheses permit control of the
orientation of another incoming group. This is accom-
plished by converting the initial group to its subsequent
partner either before or after attaching the next substitu-
ent. In addition, the figure indicates the relative strengths
of the various activating groups. Information that is neces-
sary when placing a third substituent on a disubstituted
benzene.
The Rules are brief summations of concepts and limita-
tions that are extensively covered in standard organic
texts. Rules 7 and 8, for example, describe some limita-
tions of alkylation reactions. ~ i n t are
s suggestions de-
simed to prevent errors in proposed syntheses.
synthetic techniques cha~ac~eristic of aromatic substitu-
tion reactions are utilized. Among these is the use of an
amine as a group-orienting controller that is later removed
through diazotization. Another technique is the use of
acylaiion, followed by reduction a s the only practical
method for attaching unbranched alkyl groups longer than
two carbon atoms. Using the method described in this
. . . a student can undertake a l a r ~ variety
paper. e of syntheses
without having to know the actual reagents or-reaction
conditions reauired. When these methods are covered in
more detail in'later chapters, their application to
substitution reactions can be revisited.
Initially the student is permitted the use of the table and
figure supplied. The concepts must be learned, however, so
that additional synthetic schemes can be outlined without
the use of these materials. All syntheses begin with ben-
zene!
Rules of the Game
1. When the ring substituent is o-, p-orienting,choose either
disubstituted isomer formed as the product obtained from
a particular reaction.
2. Phenol and aniline are reactive and give poly-halogena-
tion. In order to monohalagenate phenol or aniline, the
ring first must be acylated (ta the ester or the amide),
then halogenated to either the ortho or para isomer. The
compound is then hydrolyzed to the halophenol or
haloaniline.
3. In Fnrdd-Crafrs nlkylations, the alkyl carbunlum ions
that form can rearrange to more stnhlr cnrborations (e. a.
n-propyl pelds isnpropyl and n-butyl gives ser-butyl,.
4. Acvlations do not lead to rearrangement of the acvl
. erouo.
. .
5. Oxdauon ofalkyl ride-chains or acyl groups remuvei all
of rhr carbon atom* except the one attached to rhc ring.
T h l ~carbon forms a cnrhoxylic acid
6. Rings that possess halogens, nitro, sulfonic acid, and car-
boxylic acid substituents survive side-chain oxidation.
Rings that contain amino and hydroxyl groups do not!
7. Rings substituted with m-orienting (deactivating)groups
cannot be alkylated or aqlated. Halobenzenes can be al-
kylated!
Author to whom correspondence should be addressed.
Volume 70 Number 12 December 1993 985
 2. If the alkyl group needed is longer than
two carbon atoms, aeylate and then
reduce to the alkyl group.
3. Remember. far these svntheses. the se-
quence of the reacttons determines
the suhstrtutlon pattern of the pmd-
uct.
sulfonate halogenate nitrate aimate acylate
Several synthetic examples a r e

1 1 1 R-?=O
given, illustrating the wide variety of
synthetic strategies that may be em-
ployed.

R
(W

I
reduce
(*.F-)
FA-halo-
e t i o n /
oxidize
+
(m)
reduce
Answer: Alkylate; brominate (halo-
genate); oxidize
Discussion: Bromination must take
place after alkylation has been carried
out hut prior to oxidation. In this way
I the halogen is oriented para before
YH-C=O y"' FHXR F H FH2R the alkvl mu^ is oxidized to a m-on-
enting caFbox$ic acid.
Example 2: Synthesize p-Chloroaniline
Answer: Nitrate, reduce, N-acylate,
(*SF-) * F - (*) (*& chlorinate, hydrolyze
Discussion: Aniline (nitration, re-
duction) must be deactivated by acyla-
tion to prevent polyhalogenation. An
Diazotize to alternative synthesis is chlorinate; ni-
1 1 1 1 1 1 1 trate; reduce.

OH CN H L Ci
1
Br
I
I
I
Example 3: Synthesize
I I I I 1,3,5-Tribromobenzene

0cyano

(m-)
0chlorine

(*P)
Answer: Nitrate, reduce, brominate
3x; diazotize to hydrogen
Discussion: Bromo groups are o-, p-
orienting and sequential halogenation
cannot produce the required product.
Aniline, however, can be poly-
hydrolysis brominated (2.4.6-tribromoaniline).
The amine grobp is then removed by
diazotization to hydrogen. The (3x1
notation is optional because the in-
formed student will know that when
Relative Strengthsof Activatina Grows brominated, aniline yields the poly-
substituted product.
Strong: NH,; NHR; NQOH
Moderate: N+Ac;OR Example 4: Synthesize
Weak: Me; Et: R; Ph m-HexyibenzenesulfonicAcid
'Free Radical Answer: Acylate; sulfonate; reduce
Discussion: This synthesis illus-
trates the introduction of a six-carbon
Aromatic Substitution Chart linear chain. After awlation, sulfona-
tion~ is carried
- - - - -- - - - - out
- --~ -
~~~ tn-nroduce
~- - ~ ~ - the
L ~ - ~~- -
--
~m-
-

8. Halobenzenes and vinyl halides cannot be used as alkyl-
ating agents. They don't form carhocations readily.
9. When attaching a suhstihmnt to a disubstituted benzene,
the strongest activating group (0-, p-orienting) controls
the position of entry of the third group. (See figure.)
10. If two ortho-orienting substituents are needed meta to
each other, the amine group can be used to place them
(ortho and para to the amine). The amine group can
then be removed by diazotizing it to a hydrogen. (See
Example 3.)
Hints for the Game
1. If an alkyl group is needed, it is beat to put it on the ring
first.
isomer. The six carbon acyl group now can be reduced to a
hexyl group.
Example 5: Synthesize lsophthalic Acid
Answer: Alkylate; oxidize; nitrate; reduce; diazotize to
cyano; hydrolyze
Discussion: This synthesis illustrates both methods for
introducing a carboxylic acid group. It muld not be pre-
pared by dialkylation or oxidation. This would give the
ortho or para product. Alkylation; oxidation; alkylation; ox-
idation is also incorrect since the second alkylation would
not occur (a deactivated ring).

986 Journal of Chemical Education

Example 6: Synthesize m-Fluorobromobenzene
Answer: Nitrate; brominate; reduce; diazotize to fluorine
Discussion: Fluorination cannot typically be achieved di-
rectly. In this synthesis, the only simple way of introducing
a fluoro group is illustrated; diazotization of an amine
group to fluorine.
Example 7: Synthesize m-Nitrotoluene
Answer: Alkylate; nitrate; reduce; nitrate; diazotize to
hydrogen
Discussion: p-Toluidine @-methylaniline)is prepared in
the first three steps. When a second nitration is carried
out, the stronger amine group controls the position of at-
tack; ortho to the amine rather than the methyl, ~h~
amine is then removed by diazotization.
Example 8: Synthesize 4-chloro-2-nitroaniline
Answer: See example 2 forp-chloroaniline. Nitrate
Discussion: In this example, both amino and chloro
groups are o-, p-orienting. The amino group, however, is
stronger and, thus, controls the position at which the nitro
group enters; in this case ortho to the amino group,
The use of the Aromatic Substitution Game enables a
student to develop a technique for thinking through a syn-
thesis before actuall~attemptinp -
. it. In addition. the direct-
ing effects and a c t k t y of common substitutents can be
learned without the additional burden of knowing a wide
variety of reaction conditions. The specific problems as-
signed can be tailored to the level of any individual class.
Literature Cited
1.CaresE A.O~ganicChmisby,Znded.;Mffiraw-Hill:NewYork, 1992: pp452498.
2. M e M w , J. O r s n i e Chpmislry, 3rd ed.; BmoksiCole: Panfie Gmve, CA, 1992; pp
551-514.
, T;Boyd, R.
3. M o m i ~ nR. N.Organic C h i s f r y , 6th ed.; RentitiHall: Englewmd
cliffs,NJ,1992:PP 511.548.
'
4. Salomona, W G..OIgonk Chmisfry, 5th ed.; John Wiley & Sons: New York,1992;
pp 6.3661%
Volume 70 Number 12 December 1993 987