Chemistry 262 Laboratory Experiment 3: Derivatization of the Grignard Product Formation of Ethyl and Propyl Benzoate 2/01/18, 2/08/18

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1 Chemistry 262 Laboratory Experiment 3: Derivatization of the Grignard Product Formation of Ethyl and Propyl Benzoate 2/01/18, 2/08/18 Objectives Explore methods of carrying out esterification reactions. In particular, investigate how to drive the reaction equilibrium towards products Gain experience assessing when a reaction has reached equilibrium Gain experience using derivatization techniques to establish the identity of a synthetic product Reading Please read section 20.8 in Loudon and Parise, 6 th ed. Introduction Now that we have successfully converted bromobenzene to benzoic acid, we will convert it to 2 esters: ethyl and propyl benzoate. We are doing this for 2 reasons (1) by successfully making this conversion, we corroborate the fact we made benzoic acid in the first place. As such, our esterification acts as a classic derivatization method for analysis, one which requires no expensive analytical instrumentation as we are making (2) pleasantly scented flavoring/perfumery agents. Once we learn how to conduct an electrophilic aromatic substitution, so we could convert benzene to bromobenzene, we would have the capacity to convert the inexpensive [albeit toxic] benzene (4L from Sigma-Aldrich $160) and n-propanol (2L from Sigma-Aldrich $115) to propyl benzoate (50.0 g from Sigma-Aldrich $34.70, d 25 = 1.03 g/ml, 4 L = $2.86 K); a definite value added product and a conversion from a noxious chemical feedstock to a sought after commodity in the consumer products sector pretty heady stuff. 1

2 The problem with esterifications is they are reactions with G o close to 0, which is not surprising given the ester may be best thought of as a condensation between carboxylic acid and alcohol with concomitant loss of water, and given the similarities between alcohols and water, the reverse reaction ester hydrolysis competes. Consequently, esterifications require a little coaxing towards completion. The Fischer esterification reaction, named after one of the giants of early organic and biochemistry, Hermann Emil Fischer ( ), requires the use of acid to promote nucleophilic attack by the alcohol, as shown below. Thinking in terms of LeChâtelier s Principle, we should minimize the amount of water, so using a small catalytic volume of H 2 SO 4 is fairly standard practice. We can also attempt to remove water from the reflux, and some fairly clever devises have been fashioned to this end (e.g. the Dean-Stark trap). We will take this tactic by providing an anhydrous salt to trap any water formed 2

3 Alternatively, one can drive the reaction be adding an excess of one of the reagents. This is wasteful if the excess reagents are not captured, and often the yields and reaction rates are not encouraging. While we will hedge our bets by using this tactic, the poor yields have led to the use of more reactive acid derivatives, typically an acyl chloride or acid anhydride. The relative reactivities of acid derivatives are shown below well worth knowing. Once a reactive acyl chloride has been generated the G o of the reaction is definitely << 0, and the reaction proceeds nicely. We will return to this approach early in Chem& 263 Tips & Precautions With the Fischer esterification, we want to keep water minimized. It is not critical the glassware be oven dried, but clean and dry is a good idea. It is important for our analysis that you purify the final product mixture directly, since leaving the mixture with acid raises the possibility of hydrolysis 3

4 Procedure The Fischer Esterification of Benzoic Acid to Form Ethyl Benzoate and Propyl Benzoate Prepare to assemble a typical reflux apparatus using a 50 ml round bottom flask (RBF) as the reaction flask, only insert a distillation head between the RBF and the condenser. Of course you won t actually assemble the apparatus until the reactants are in the reaction flask since you are only using a single neck RBF 1 Take a 25 ml RBF and add 5-6 g anhydrous MgSO 4. Fill the remainder of the RBF with glass beads to trap the salt and reduce the void volume. Connect this to the outlet of the distillation head To reduce vapors, place a drying tube filled with CaCl 2 on top of the condenser. Add 2 glass beads and a spin bar to the reaction flask Heat your reaction mixture using a heating mantle. If you find you are making poor contact between the RBF and the heating mantle, surround the setup (so you can still see) with some glass wool encased in Al foil You will also set the reflux on about a 30 o angle and angle the condenser so the condensate falls into the H 2 O trap Add 2.44 g (20 mmol) of benzoic acid crystals to the reaction flask, followed by a 20 fold excess (400 mmol) of the alcohol in question. This is a good example of a reactant also acting as a solvent. You must have the appropriate calculations completed before you enter the lab. Using an air displacement pipette, measure out 1 ml of concentrated sulfuric acid, and add to the mixture while it is stirring 1 You may insert a Claisen head, but this really is not necessary in this instance less to clean up, no? 4

5 Begin the flow of water through the condenser and heat the mixture to reflux. Continue refluxing for 1 hour, then shut off the heat and allow to cool to room temperature One of the key problems in carrying out small alcohol esterifications is extractions become difficult, owing to the ability of the alcohols to make good molecular diplomats, mixing freely with water as well as most organic solvents. On the upside, as small alcohols, they may be readily distilled, and this is exactly what you will do. o Our product esters have boiling points well over 200 o C (but of course you will know exactly what they are when you come in for lab) while EtOH BP = 78 o C and PrOH BP = 98 o C (say, that 20 o C per C rule of thumb is pretty handy) o Since we are only trying to remove the unreacted alcohol at this point, set up the shortest path distillation possible, using your initial reaction flask as the still pot while you are at it, you may as well use the distillation head and condenser you were already using o Putting the system under vacuum should speed the solvent removal nicely (make certain you use an ice cooled trap!), and with a little foresight you should be able to carry out both reactions, and distillations, at once o Make certain you do not distill to dryness this will mean carefully observing near the end of the distillation, since your theoretical yield will only be around 3 ml (but of course you will know exactly what the theoretical yield is when you come in for lab) o I anticipate you will need to stop with about 10 ml of liquid remaining 5

6 Having allowed the still pot to cool, transfer to a small separatory funnel and wash with 2 x 5 ml portions of saturated NaCl, making a note of the ph of the aqueous layer after each extraction o If you find you do not have an obvious organic layer add 10 ml of DCM o Be careful in this step it is well worth your while to look up the densities of the products in question, as well as that of saturated NaCl, but be wary of the influence of EtOH be ready to test the layers and do not throw anything away until you have isolated your product Wash the organic extract with 5 ml 5 % NaOH, being careful of pressure buildup. Carefully combine the washes o The first 2 washes should remove any remaining alcohol and H 2 SO 4, while the NaOH wash ensures any unreacted benzoic acid is removed as sodium benzoate o Make the wash a quick one, since esters also hydrolyze readily in hydroxide (if you are given to overkill, you could chill the NaOH 1 st In order to establish the efficiency of your esterification, we will isolate the unreacted benzoic acid. If necessary, adjust the ph of the combined washes to a ph 2, chill on ice, then collect the solid, dry in the oven (ca. 100 o C) and report the mass as the percentage of the starting benzoic acid mass Dry your ester product over ca. 0.2 g anhydrous Na 2 SO 4 for 15 minutes, transfer to a clean, dry, preweighed 25 ml beaker and heat gently on a hot plate to remove any residual alcohol or DCM you may have used. Report the recovered mass and percent yield, then proceed to analysis 6

7 Analysis Run your product as a 0.1 mg/ml solution in MeOH for the GC/MS and as a 1.0 mg/ml solution in MeOH for HPLC. If the purity is good, we will run an IR (neat liquid), and NMR (5 % in CDCl 3 ) Questions 1. In the introduction, 4 L of propyl benzoate was presumed to arise from 4 L of benzene, and 2 L of n-propanol. What is the % yield if 4 L of propyl benzoate were in fact isolated? 2. Please provide a mechanism for the formation of benzoyl chloride from benzoic acid and thionyl chloride 3. Mechanistically, why is benzoyl chloride so much easier to esterify than (1) benzoic acid (2) benzoic anhydride? 4. When kept in warm, humid environments, aspirin begins to smell of vinegar (why we keep medicines in the bathroom I will never know). Please provide a detailed mechanism for the decomposition 5. Why was it important to have the reaction mixture stirring before adding the 1.0 ml of H 2 SO 4? That is, what are potential side reactions from exposing your alcohol to a concentrated, strong acid known for its ability to turn sucrose into carbon? 7