Zeroing In on Electrophilic Aromatic Substitution


the preexisting substituents is nine. Only one ... The zeroing in effect is not evident in all nine ... Using dots and circles as symbols to represent...
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Zeroing In on Electrophilic Aromatic Substitution

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David C. Forbes,* Mohini Agarwal, Jordan L. Ciza, and Heather A. Landry Department of Chemistry, University of South Alabama, Mobile, AL 36688; *[email protected]

Electrophilic aromatic substitutions allow for the rapid assembly of substituted aromatic systems. Be it in the preparation of mono-, di-, or polysubstituted aromatic compounds, electrophiles not nucleophiles are the reagents of choice when considering the substitution of hydrogen on an aromatic ring. Open any mainstream organic textbook or research the literature on pedagogical advances in the lecture (1) or laboratory (2) and you will find a host of resources dedicated to the understanding and synthesis of substituted aromatic compounds. While often introduced because of its commercial and pharmaceutical impact, the concept of electrophilic aromatic substitution offers a unique opportunity to revisit several key concepts in organic chemistry. Typical analyses focus on how disubstituted benzene derivatives are formed using the electronic and steric effects of preexisting substituents. The depth of those analyses, however, is rarely duplicated when presenting the formation of trisubstituted systems.

While one can argue that the existing material equips the reader to explore additional substitution patterns, an opportunity exists to offer supplemental guidance in the formation of polysubstituted aromatic systems. Presented herein is a unique and novel illustration of reactivity trends in the formation of trisubstituted benzene derivatives from disubstituted systems using electrophilic aromatic substitution reactions. Method When considering reactions involving electrophilic aromatic substitutions, a significant quantity of time in lecture and space in a textbook are dedicated toward the mechanistic understanding of the transformation. As a result, a detailed analysis is rarely offered with all variants of the reaction. This offers the lecturer an opportunity to supplement infor-

Figure 1. Substitution guide in formation of trisubstituted benzene derivatives starting from disubstituted benzene derivatives: ERG is an + electron-releasing group; EWG is an electron-withdrawing group; and E or E is an electrophile. The check marks indicate the predicted location of the substitution.

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mation not extensively covered in the textbook. Our approach to illustrating the concept of electrophilic aromatic substitution in the formation of trisubstituted benzene derivatives is presented in Figures 1–5. Our method begins with reaction templates. The juxtaposition of two preexisting substituents creates three isomeric templates. Preexisting substituents in electrophilic aromatic substitutions can be classified as either an electron-releasing group (ERG) or an electron-withdrawing group (EWG). The number of templates to be considered when factoring both ERGs and EWGs and positions of the preexisting substituents is nine. Only one series containing both ERGs and EWGs was considered. Using a grid format (Figure 1), we developed a system by which all possible substitution patterns in the electrophilic aromatic substitution reactions of disubstituted systems can be surveyed. The zeroing in effect is not evident in all nine templates. Since each preexisting substituent plays an independent role in product formation, the net results may or may not lead to a cooperative effect in placement of the third substituent. Consequently, isomers may result. The reaction template located on the first row, third column of Figure 1 has as R an ERG and as R⬘ an EWG. The ERG is by definition an activating group and an ortho–para director. The EWG, by definition, is a deactivating group and a meta director. When two substituents are located 1,2 on the benzene ring, one being an ERG and the other an EWG, a cooperative effect exists in that what is meta to the R substituent is also ortho (and para) to the R⬘ substituent. Using dots and circles as symbols to represent where a third substituent will go, the template in Figure 1 has bull’s eyes (a dot inside a circle) in two locations because of the cooperative effects of both groups. With this example, one of the bull’s eyes is closer to a preexisting substituent than the other and to minimize steric congestion, the third substituent is predicted to react away from the preexisting groups. The predicted product is illustrated with a check mark. The reaction template located on the second row, third column of Figure 1 also has a ERG and EWG; however, the positions of the groups cause a different prediction. With this template, the dots are ortho and para to R and a circle is meta to R⬘. When considering where the third substituent will most likely react in an electrophilic aromatic substitution reaction, all four hydrogen atoms can be replaced. Given these options, the concept of activating and deactivating groups will dictate where the check mark(s) will be located: ortho and para to the ERG. An additional consideration here is avoiding a third substituent flanked by two preexisting substituents. The third template to be considered has both R and R⬘ as ERGs and is located on the third row, first column of Figure 1. As with the previous template, isomeric mixtures are predicted. That is, the dots and circles are ortho to both R and R⬘ and a zeroing in effect is not observed. The net result will most probably be dictated by sterics. Results and Discussion We have developed a method that illustrates substitution patterns associated with electrophilic aromatic substitution reactions of disubstituted benzene derivatives. Symbols were used to represent the directing effects of ERGs and www.JCE.DivCHED.org





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Scheme I. Summary of the literature search. The electrophilic reactions were nitrations, brominations, chlorinations, iodinations, Friedel–Crafts alkylations (Me, Et), and Friedel–Crafts acylations (acyl bound to H and Ak) of disubstituted aromatic systems.

EWGs. When the directing effects were cooperative, the dots and circles formed bull’s eyes and represented the highest probability of product outcomes. The zeroing in effect was validated with a check mark once the steric demands of the template were considered. Of the nine templates considered, four had cooperative directing effects. The remaining five templates were governed primarily by the activating and deactivating properties of the preexisting substituents. Our analysis was based upon a mechanistic argument of the reaction intermediates and major resonance contributors formed upon reactions with the electrophile. Because our analysis was theoretical, we felt the need to compare our hypothesis against the literature. Using SciFinder Scholar, we searched the literature using a sampling of established electrophilic aromatic substitution reactions. Scheme I summarizes the scope of our literature search. A total of six transformations were surveyed. The transformations were nitrations, brominations, chlorinations, iodinations, Friedel– Crafts alkylations, and Friedel–Crafts acylations of disubstituted aromatic systems. The substitution patterns were 1,2-, 1,3-, and 1,4-disubstituted benzene derivatives. The type of substitution, R and R⬘, was classified as either electron releasing (ERG) or electron withdrawing (EWG). Using the toolbar on SciFinder Scholar, Scheme I lists all the shortcuts and variables we used to define the two types of directors. The question we asked using SciFinder Scholar was how many reactions have been reported when considering substitution onto a disubstituted aromatic ring using the criteria in Scheme I. Four independent searches were performed for each template representing all isomeric products formed. A total of 2,579 reactions were found for all nine templates. Searches using SciFinder Scholar were performed in September and October of 2006. Exceptions to our model were found and most evident in the halogenation reactions of 1,3disubstituted benzene derivatives consisting of one ERG and one EWG of high electron density. In addition to the predicted model, a number of citations had the third substituent placed in between the two preexisting substituents. With metal-mediated reactions, a chelation-controlled transition state offers substitution in proximity to a preexisting substitu-

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Figure 2. Data obtained using SciFinder Scholar in the formation of trisubstituted benzene derivatives starting from the corresponding disubstituted systems.

ent of high electron density. This type of intramolecular assistance is commonly referred to as the ortho effect. We did not consider reactions involving formation of tetra- and higher-substituted systems. A summary of our findings is provided in Figure 2 and conceptually illustrated in Figures 3– 5. For the conceptual illustrations, light gray spheres represent ERGs and darker gray spheres represent EWGs. Considering 1,2-disubstituted benzene derivatives with two ERGs, a total of 656 reactions were identified placing a third substituent onto a disubstituted ring. Just over 70% of those reactions report placement of the electrophile opposite either ERG. When switching to systems containing one ERG and one EWG, the number of reactions dropped to 253. The bull’s eye analysis accounted for 86% of the reported reactions favoring substitution away from the two preexisting substituents. When both substituents were classified EWG, the total number of reactions dropped to 10. The placement of the third substituent followed the predicted pathway of meta to the preexisting substituent. Our method did not differentiate between identical and different preexisting substituents. The high number of reactions found represents systems containing identical substituents. When the two ERGs were not the same, the number of 1880

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reactions reported dropped significantly, almost tenfold. This observation does not take away from the fact that the volume of electrophilic aromatic reactions favors systems containing activating groups and not deactivating groups. Figure 3 illustrates the data presented in Figure 2 for the series of 1,2-disubstituted benzene derivatives. Examining 1,3-disubstituted benzene derivatives, a similar outcome is observed in that the volume of reactions reported favor activating systems. A total of 495 reactions were found, which is a 25% drop when considering 1,2-disubstituted benzene derivatives containing two ERGs. This may be due to the availability of a second major isomer while electronically favored, is sterically disfavored. The bias of ortho and para directing effects is evident in the data and clearly illustrated in the conceptual representations of reaction outcome, Figure 4. A ratio of 3.7:1 is observed disfavoring formation of a 1,2,3-trisubstituted benzene derivative. When switching to systems containing one ERG and one EWG, the number of reactions reported dropped to 158. Given the absence of any bull’s eye and knowledge of the ortho effect, isomeric mixtures, as predicted, result. With systems containing two EWGs, the number of reactions dropped even further to 110, 74% favoring meta substitution.

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Figure 3. Electrophilic aromatic substitutions of 1,2-disubstituted benzene derivatives. Scaffolds represent substitution patterns of ERG– ERG (left), EWG–ERG (center), and EWG–EWG (right), respectively.



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Figure 5. Electrophilic aromatic substitutions of 1,4-disubstituted benzene derivatives. Scaffolds represent substitution patterns of ERG– ERG (left), EWG–ERG (center), and EWG–EWG (right), respectively.

tives was conducted. A total of 2,579 reactions were surveyed starting from 1,2-, 1,3-, and 1,4-disubstituted benzene derivatives consisting of electron-releasing and electron-withdrawing groups. The predicted reaction product was confirmed using SciFinder Scholar. In all nine reaction templates, the literature search matched that of our predicted model. This detailed analysis surpasses those found in mainstream organic textbooks. The zeroing in method offers students and lecturers alike an opportunity to advance the concepts of electrophilic aromatic substitution in the formation of trisubstituted benzene derivatives. Acknowledgments Figure 4. Electrophilic aromatic substitutions of 1,3-disubstituted benzene derivatives. Scaffolds represent substitution patterns of ERG– ERG (left), EWG–ERG (center), and EWG–EWG (right), respectively.

The total number of reactions and reactivity trends found within the 1,4-disubstituted series mimicked that of 1,2-disubstituted systems (Figure 5). Furthermore, the vast majority of the reactions reported had identical preexisting substituents. The major difference between the two series was observed when considering templates containing one ERG and one EWG. Just over 94% of all the reactions surveyed had placement of the third substituent ortho to the ERG and meta to the EWG. This strong bias was neither predicted nor observed when considering templates containing two EWGs. For this template, the number of reactions dropped from 337 to 23. This again reflects the reacting trends of performing electrophilic aromatic substitutions on electron deficient aryl systems. Summary An analysis of product formation in the electrophilic aromatic substitution reaction of disubstituted benzene derivawww.JCE.DivCHED.org



DCF would like to thank NSF (CHE 0514004) for partial funding of this research. DCF, MA, JLC, and HAL would like to thank Patricia Davis, James Davis, and Norris Hoffman for their input during the preparation stages of this manuscript. WSupplemental

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A catalog of the 2,579 reaction data obtained through the SciFinder Scholar searches are available in this issue of JCE Online. Literature Cited 1. (a) Nelson, D. J. Chem. Educator 2001, 6, 142. (b) Nelson, D. J. Proc. Okla. Acca. Sci. 2000, 80, 71. 2. (a) Holden, M. S.; Crouch, R. D.; Barker, K. A. J. Chem. Educ. 2005, 82, 934. (b) Jones-Wilson, T. M.; Burtch, E. A. J. Chem. Educ. 2005, 82, 616. (c) Bowman, D. C. Chem. Educator 2004, 9, 163. (d) Smith, R. E.; McKee, J. R.; Zanger, M. J. Chem. Educ. 2002, 79, 227. (e) French, L. G.; Stradling, S. S.; Dudley, M.; DeBottis, D.; Parisian, K. Chem. Educator 2001, 6, 25. (f ) Kesler, B. S.; Williams, S. E. Chem. Educator 2000, 5, 223.

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