Spring Organic Chemistry Experiment #3 Electrophilic Aromatic Substitution: An Investigation of Directing Effects in EAS Introduction Friedel-Crafts alkylation and acylation represent two examples of the electrophilic substitution reactions that are characteristic of aromatic compounds. The chemistry was discovered in 1877 by Charles Friedel at the Ecole des Mines in France and by James Crafts at M.I.T. Indeed, their discovery was groundbreaking because it has since led to one of the most useful C-C bond forming reactions involving aromatic systems. The original synthesis involved the alkylation of benzene by an alkyl chloride (e.g. 2-chloropropane) in the presence of aluminum chloride as a Lewis acid catalyst (shown below) to generate cumene as the only isolated product. The proposed mechanism (that is now widely accepted) that explains this outcome is as follows: Step #1 Cl Cl Cl Al Cl Al Cl + Cl AlCl4 Cl Cl Step #2 active electrophile (carbocation) H H H H (antiaromatic) (aromatic) Step #3 H H H H H H Step #4 H Cl H Cl Al Cl Cl The entire mechanism occurs in four steps: (1) generation of the active electrophile; (2) attack of the elctrophile by the pi electrons of the aromatic ring; (3) resonance stabilization of the resulting intermediate; and (4) regeneration of the aromatic system. The active electrophile in this alkylation process is a carbocation intermediate that is derived from an alkyl halide. You should read pages 679-696 in the Jones text before coming to lab. This groundbreaking work has spurned others to continue the original work of Friedel and Crafts. In particular, Professor George Olah at USC has derived most of the important details that we now know about the chemistry of the Friedel-Crafts reaction. In fact, Olah won the 1994 Nobel Prize for his pioneering efforts in the electrophilic aromatic substitution chemistry associated with the Friedel-Crafts reaction. Although this reaction is synthetically useful, it does suffer from a variety of limitations (see pages 690-691 of Jones). An important variation on the Friedel-Crafts alkylation is called a Friedel-Crafts acylation. In contrast, the electrophile for the Friedel-Crafts acylation is an acylium ion intermediate and it is derived from an acyl halide or an anhydride (i.e. acetyl chloride). The final product obtained in this reaction is an acylated aromatic ring (note: an acyl group contains a carbonyl and typically it’s a ketone). Objective In this experiment, we will be performing the Friedel-Crafts alkylation of m-xylene using 2-chloro-2-methylpropane in the presence of the Lewis acid catalyst, FeCl3. Our goal is to use proton NMR analysis in order to determine the structure of our product. However, we must first consider the possibilities. In other words, what structures are possible given these starting materials and the known mechanism of the reaction? Well, if you know something about the mechanism of the reaction and the effect that ring substituents can have on the course of further ring substitution, then you should be able to predict ALL of the possibilities (both favorable and unfavorable). I recommend that you check out Chemactivity #29 from the purple book (in particular, see pages 253-261 and Table 6 on page 259). Once you have the possibilities in front of you, you should be able to prioritize which ones are most favorable and which are least favorable. So, your job (before lab) is to work through the mechanism (as best you can) given the information above in order to derive all of the possible products. You should then establish a hypothesis predicting which of the possible products most likely would form. Finally, you should come to lab and conduct the experiment to either confirm or refute your hypothesis. Procedure Place 0.9 mL of m-xylene and 0.75 mL of 2-chloro-2-methylpropane in a dry reaction tube equipped with a rubber septum and the polyethylene tubing that leads to a second tube containing a small wad of moist cotton (2-3 drops of water). Cool the mixture in an ice bath and carefully add 40 mg of anhydrous iron (III) chloride. (Why does everything have to be dry/anhydrous?) Replace the septum and let the reaction proceed. Record your observations carefully. Once the reaction subsides, remove the ice bath and allow the reaction to warm to room temperature. Let the reaction go for an additional 15 minutes and then quench the reaction with 1.5 mL of water. Mix the solution well and then remove the aqueous layer with a Pasteur pipette. Repeat this procedure two more times using 1 mL of saturated NaHCO3 solution, followed by 1 mL of brine. Transfer the remaining solution to a clean reaction tube and dry with anhydrous MgSO4. Transfer the dried liquid to yet another reaction tube, add a small boiling chip, and heat the mixture to its boiling point. Heat so the vapors rise to a level of about 3 cm in the reaction tube. Draw the vapors into a Pasteur pipette and squirt this "distillate" into a final reaction tube that you a holding in the same hand (instant microscale distillation). Continue until you have distilled approximately half of the mixture. Analyze your product by preparing a 20-30 mg sample for NMR analysis (1H, 13C, 13C DEPT, and 1H-1H COSY) in the usual fashion using CDCl3/TMS as the solvent. In addition, use the Spartan 04 molecular modeling software to build each of your proposed reaction products and carry out molecular mechanics calculations to determine the relative steric energies for each product. Finally, during lab, work through the mechanism for the Friedel-Crafts acylation reaction (shown above) with your lab partner and discuss.