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 topics 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 typical s q u e k e of text6ook chapters, much of the hemi&& needed to achieve these syntheses (e. g., amine diazotization replacement reactions) has not yet been discussed. When new substitution reactions are encountered subsequently, the student rarely is required to reconsider the substitution theory learned in the earlier chapter. An important 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 reFor 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 utilized, 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 tooxidation. 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 orientstion effect of introducing a second one is shown under each ~
~~~
Substitution Reactions Reactions Carried Out to add a 2nd Substituent
group, and the figure illustrates that certain wmplementary 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 accomplished by converting the initial group to its subsequent partner either before or after attaching the next substituent. In addition, the figure indicates the relative strengths of the various activating groups. Information that is necessary when placing a third substituent on a disubstituted benzene. The Rules are brief summations of concepts and limitations that are extensively covered in standard organic texts. Rules 7 and 8, for example, describe some limitations of alkylation reactions. ~ i n t are s suggestions desimed to prevent errors in proposed syntheses. synthetic techniques cha~ac~eristic of aromatic substitution 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 e of syntheses paper. . . . a student can undertake a l a r ~ variety 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 benzene!
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-halogenation. 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 3.
4. 5. 6.
Symbols: (+) = readion works -) = no readion (+ I -) = different reaction occurs ( + I + ) = multiple substitution mun (0) = oxidation ot an alkyl side chain
7.
compound is then hydrolyzed to the halophenol or haloaniline. 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,. Acvlations do not lead to rearrangement of the acvl . erouo. . . 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 Rings that possess halogens, nitro, sulfonic acid, and carboxylic acid substituents survive side-chain oxidation. Rings that contain amino and hydroxyl groups do not! Rings substituted with m-orienting (deactivating)groups cannot be alkylated or aqlated. Halobenzenes can be alkylated!
Author to whom correspondence should be addressed. Volume 70 Number 12 December 1993
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2. If the alkyl group needed is longer than
sulfonate
halogenate
two carbon atoms, aeylate and then reduce to the alkyl group. 3. Remember. far these svntheses. the sequence of the reacttons determines the suhstrtutlon pattern of the pmduct.
nitrate
aimate
1
1
acylate
1
(W
R-?=O
(*.F-) FA-haloe t i o n
I
reduce
Several synthetic examples a r e given, illustrating the wide variety of synthetic strategies that may be employed.
/
oxidize
+
Answer: Alkylate; brominate (halogenate); oxidize Discussion: Bromination must take place after alkylation has been carried out hut prior to oxidation. In this way the halogen is oriented para before the alkvl mu^ is oxidized to a m-onenting caFbox$ic acid.
(m)
reduce
R
I
y"'
YH-C=O
FHXR
F
FH2R
H
Example 2: Synthesize p-Chloroaniline
*
(*SF-)
F
-
(*)
(*&
Diazotize to
1 OH
I
1 CN
I
0
1 H
I
cyano (m-)
1 L I
1
1
Ci
Br
1
0
I
1 I
I
chlorine
(*P)
hydrolysis
Relative Strengthsof Activatina Grows Strong: NH,; NHR; NQOH Moderate: N+Ac;OR Weak: Me; Et: R; Ph 'Free Radical Aromatic Substitution Chart
Answer: Nitrate, reduce, N-acylate, chlorinate, hydrolyze Discussion: Aniline (nitration, reduction) must be deactivated by acylation to prevent polyhalogenation. An alternative synthesis is chlorinate; nitrate; reduce. Example 3: Synthesize 1,3,5-Tribromobenzene Answer: Nitrate, reduce, brominate 3x; diazotize to hydrogen Discussion: Bromo groups are o-, porienting and sequential halogenation cannot produce the required product. Aniline, however, can be polybrominated (2.4.6-tribromoaniline). The amine grobp is then removed by diazotization to hydrogen. The (3x1 notation is optional because the informed student will know that when brominated, aniline yields the polysubstituted product. Example 4: Synthesize m-HexyibenzenesulfonicAcid
Answer: Acylate; sulfonate; reduce Discussion: This synthesis illustrates the introduction of a six-carbon linear chain. After awlation, sulfonamtion is carried tn-nroduce - - - - -- --~ - - - - out ~- ~ ~ - the ~ ~- -isomer. The six carbon acyl group now can be reduced to a hexyl group. ~
8. Halobenzenes and vinyl halides cannot be used as alkylating 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.
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Journal of Chemical Education
~~~
L ~ -
~
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 prepared by dialkylation or oxidation. This would give the ortho or para product. Alkylation; oxidation; alkylation; oxidation is also incorrect since the second alkylation would not occur (a deactivated ring).
Example 6: Synthesize m-Fluorobromobenzene
Answer: Nitrate; brominate; reduce; diazotize to fluorine Discussion: Fluorination cannot typically be achieved directly. 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 attack; 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 synthesis before actuall~attemptinp . it. In addition. the directing 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 assigned 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. 3. M o m i ~ nR. , T;Boyd, R.
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;
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