Electrophilic Aromatic Substitution Discovery Lab Ronald M. ~arret,'Jamie New, and Cynthia Patraitis College of the Holy Cross, Worcester, MA01610
The chemistry department a t Holy Cross College has made a concerted effort to replace the traditional introductory chemistry courses with a lab-based four-semester curriculum we call Discovery Chemistry (1).Laboratory observations (made by s t u d e n t s ) a r e used, whenever ~ossible.to introduce topics of discussion. The most fruitFul l a b s i n Organic chemistry are those that lend themselves to mechanism elucidation. Such labs provide an exercise i n t h e scientific method a n d help s t u d e n t s differentiate fact from explanation (mechanism). Labs involving electrophilic aromatic substitution are particularly well suited for this approach. We currently perform two discovery labs on electrophilic aromatic substitution. The first one is based on the competitive nitration reaction of benzene and a mono-alkyl substituted benzene (methyl, ethyl, i-propyl, t-butyl) (2). We use this exoeriment to test our ~ronosedmechanism (based on polaAdditions to alkenes a'nd'knowledge of aromaticity) of a two-step reaction with a carbocation intermediate. (Its formation is the rate-determining step.) The results also allow students to discover the ortho-para directing nature of activating groups, with the ratio of orthopara being- d e-~ e n d e non t the size of the alkvl sub. ~roducts . stituent. The second discovew lab on electrophilic aromatic substitution is also a competitive nitration, this time between the activated and deactivated rings of a single compound. This lab also demonstrates the importance of reaction order i n a multi-step synthesis. All students start with methyl benzoate. Half of the class conducts a nitration reaction first (31, followed by benzamide formation (4);the 'Address to whom correspondence should be addressed.
Figure 1. GC trace and mass spectrum of A1
other half performs the reaction sequence in the reverse order. The lab handout consists prim&ily of the procedure for conducting each reaction. where ~ r o d u c t are s identified a s Al, A2, ~ C a n B2 d only ~ r o d u c t ~ amonitored re a t each stage by gc-mass spectrometry (with spectral data base) (5).When time constraint is a concern, necessary starting materials can be provided so that each student need only perform one step in a given sequence. Results and Discussion Each undermaduate will have generated a t least one gas chromatogram and corresponding mass spectrum ( ~ i ~ s : l 4); student results are pooled and discussed. Nitration of methyl benzoate generates methyl 3-nitrobenzoate (Al). While student inspection of the mass spectrum is not likely to differentiate between the various isomers. differences in the fragmentation patterns are readily matched through the spectral library (Fig. 1).Product identification can be corroborated by melting point. This reaction does not produce orthwpa=a substituted compounds (often expected by the students) a s the maior the fact that " oroduct. . ,des~ite tertiary cardocations would be generated. Students are forced to consider the electron-withdrawing nature of the carbonvl . a-o u v. more closelv in order to explain their discovery of its role as a meta-director. The idea of ring-deactivation is introduced, generalized, and compared with ring-activation (ortho-para-directors) discovered in the previous experiment. A derivative of A l , N-benzyl-3-nitrobenzamide (AZ),is formed in the second step of this two-step svnthesis. This serves as a suitable refeience for the alternate synthesis scheme. The base peak (at 150 amu) in the mass spectrum
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Figure 2. GC trace and mass spectrum of A2. Volume 72 Number 5 May 1995
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Figure 3. GC trace and mass spectrum of 61 ofA2 (Fig. 2) corresponds to the nitrophenyl acyl cation (as found for All. Benzylbenzamide ( B l ) is formed readily from methyl benzoate. The base peak in the mass spectrum of B 1 corresponds to the phenyl acyl cation (Fig. 3). This fragment has a mass of 105 amu (as compared to 150 amu for A1 andA2) because of the lack of nitro group on the benzamide ring. This (along with the spectra of A1 and A21 provides ample reference material to determine the regiochemistry in the nitration of B1 and test student predictions. B2 is the major product isolated from the nitration of B1. Inspection of the mass spectrum of B2 (Fig. 4) identifies the base peak a t 105 amu (not 150 amu), which corresponds to the phenyl acyl cation (i.e., not the nitrophenyl acyl cation). Thus, nitration has taken place on the benzyl ring. Because the mass spectrum is dominated by the acyl cation and its fragmentation, the students cannot identify that substitution has taken place a t the para position without additional information (e.g., mp or 'H NMR). The spectrum of B2 is clearly different from that of A2, indicating that the order of reactions in this two-step sequence affects the final product obtained. Conclusion The nitration of benzylhenzamide can be used to introduce the ideas of ring activation-deactivation in electrophilic aromatic substitution. Comparison of the reaction ~ r o d u c with t those obtained from (1)nitration of methvl henaoate and 121 htmzamide forniat~onof methyl benzoste and of methvl 3-nitrobenloate leads to student-discovc,w of ~ r t h o - ~ a rand a meta directors. These reactions also iilustrate the importance of overall planning in a multi-step synthesis. That is, the final product depends on whether the nitration or the benzamide formation is done first. Experimental Procedure The reported yields and melting points are those typically obtained by undergraduates. Recrystallization is not necessary if products are to he identified solely with gcmass spectrometry. Methyl-3-nitrobenzoate (Al). Methylbenzoate (6.8 g, 50 mmol) was added slowly to a stirred mixture of concen-
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Journal of Chemical Education
trated nitric acid (6.2 mL) and concentrated sulfuric acid (7.5 mL) a t 0 "C. The mixture was stirred for 15 min a t 80 'C. The reaction flask was cooled to 0 'C and water (25 mL) was added. The solid was collected by vacuum filtration and washed with cold distilled water. Recrystallization (methanol) gave A1 (1.8 g, 20%): mp 74-75 "C (lit. 78-80 T)(6a). N-Benzyl-3-nitrobenzamide (A2). Benzylamine (6.6 mL) was added to a mixture of A1 (3.6 g, 20 mmol) and ammonium chloride (0.4 g) a t 21 OC. The reaction mixture was under reflux for 30 min. The reaction flask was cooled to 0 'C by vacuum filtr;nim and aashtrd and the solid was c~~llc:cted with a few d r o ~ofi hmoin. Rccwstallizatinn rcthan~rl-water gave A2 (0.9 g; 18%):-mp 93-95'~ (lit. 100-101 'C) (7). N-Benzylbenzamide (Bl). The same reaction conditions as those described for the preparation of A2 were followed except that methyl benzoate (2.7 g, 20 mmol) gave B l ( 0 . 8 g, 19%): mp 103-104 "C (lit. 104-106 "C (6b). N-4-Nitrobenzylbenzamide(B2). The same reaction conditions as those described for the preparation of A1 were followed except t h a t the amount of each reagent was scaled down by a factor of 14 and that N-benzylhenzamide (B1) (0.76 g, 3.6 mmol) gave B2 (0.18 g, 20%): mp 145-148 OC (lit. 155-156 "C), after recrystallization (ethanol) ( 6 ~ ) . Safety and Disposal Nitric acid: highly toxic, oxidizer; sulfuric acid: corrosive, oxidizer: methvl benzoate: irritant. sensitizer: benzvInmint:: srren: irritant; mrthimol: highly toxic, flamm:~ble; liaroin: Irritant, flammable: ethanol: flammable; ammonium chloride: i m t a n t . Filtration waste (methanol, ethanol, ligroin, nitric acid, sulfuric acid, and ammonium chloride) is disposed (bulk quantities, 55-gal drum) according to CMR 310,000. Water is added to A2 and B2 and disposed (lab pack) according to CMR 310,000. A1 and B1 are recycled. Acknowledgment We wish to acknowledge the Pew Charitable Trust (through NECUSE) for support of laboratory development. R. M. J. is grateful to the National Science Foundation Instrument and Laboratory Improvement Program (USE-
90523181, Hewlett-l'ackard tI05261 and the College of the Holy Crosi for support of instrumentation I'acilities. Literature Cited
4. Shriner,R. L.;Fuaon,R. C.;Curtm,D.Y.;Modl,D. C. nisSyrlemolici&nlificalion ofOrg.nic Compoundr:Wiley & Sons: New Yark, 1980: p 300. 5. Three HewletbPackard ec-mass snedmmeters (HP-5971AMSD *th HP-6890 GC) are used for up to 30 students in a four-hour laboratoly period. 6. Buckingham,A., Ed. Dictionary ofOrgonic Compounds. 5th ed.: Chapman and HaU: New York, 1982, (a1 Vol. 4, p 4230; lb) Val. 1, p 604; ( c ) Vol. 4, p 4235. I. Lehman, J.W Operatiomi O'gmniiChhhiit'y.2nd ~ ~ . : A ~ I ~ " Y " Y " he.: ~ B BBoston, BBB, 1988; p A-24.
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