John Congleton. Multistep Synthesis of Benzilic Acid:

Transcription

1 1 Multistep Synthesis of Benzilic Acid: Introduction Synthetic organic chemist often use the product of one reaction as the reactant in subsequent reaction (multistep synthesis). This situation occurs in biochemistry also. Various chemical pathways often use a newly synthesized product to be a reactant for the next reaction in that pathway. The first chemical transformation of this scheme uses a vitamin as the coenzyme for the synthesis of benzoin. A coenzyme is a non-protein organic molecule that binds with a protein to make an enzyme. Thiamine, vitamin B1, will be used in the current experiment to convert benzaldehyde into benzoin. The benzoin produced in the first experiment will then be used in the second to produce benzil. Lastly, the benzil will then be used to synthesize benzilic acid. Summary This experiment will have three separate reactions. First we will synthesize, purify, isolate and characterize benzoin and then we will use our prepared benzoin to synthesize, purify, isolate and characterize our final product benzil. Lastly, benzilic acid will be synthesized and anayzed. 2 Thiamine ydrochloride Step 1 Benzaldehyde Benzoin Step 2 N 3 1. K in Alcohol Step 3 Benzilic Acid Benzil

2 2 Step ne: Coenzyme Synthesis of Benzoin Introduction In step one of this sequence we will be synthesizing benzoin from the condensation of two benzaldehyde molecules. We will be using thiamine hydrochloride as a coenzyme for the synthesis. Prelab Assignment Your prelab should include the following: Date, Introduction, az-mat, Reactant Tables, Chemical Equation, and Procedures. Step ne: Coenzyme Synthesis of Benzoin Mechanism

3 3 Step ne Procedures Setting up the Reaction Weigh about 0.30 g of thiamine hydrochloride and place it in a clean 25-mL Erlenmeyer flask (the flask can be wet with deionized water). Measure about 0.5 ml of deionized water in a 10-mL graduated cylinder (cylinder can be wet with deionized water) and add it to the flask which contains thiamine hydrochloride. Swirl the flask until the thiamine hydrochloride dissolves. Measure about 3.0 ml of 95% ethanol in the wet 10-mL graduated cylinder and add it to the solution in the flask. Swirl the mixture until it is homogeneous. Measure about 1.0 ml of the provided Na solution and add it to the flask. Initially the color should change to a bright yellow; swirl the flask until it fades to a pale yellow color. If no yellow color is observed, the mixture should be discarded and prepared again. Weigh the flask and solution and record its weight. Measure about 0.9 ml of benzaldehyde, then add it to the flask. Swirl the flask until the mixture is homogeneous. Reweigh the flask and solution, record the new weight, and calculate the weight of benzaldehyde. Use a cork and Parafilm to seal the flask and place it in a dark place to react for at least two days. Reaction work-up and Purification After two days, crystals should have formed in the flask. If no crystals have formed, open the flask and scratch the inside of the flask with a glass stir rod, then allow to stand for five minutes. After crystals form, cool the flask in an ice-water bath for 10 min. Break up the crystal mass with a spatula, then vacuum filter the mixture using the irsch funnel. Use the spatula to help pull the crystals out of the flask as you pour. If a lot of crystals remain in the flask, add about 1 ml of ice-cold water and pour again. Rinse the crystals three times with 1 ml of icecold water. Leave the vacuum on for an additional 5 min to air-dry the crystals. Weigh the crude crystals, then transfer them to a clean, dry 25-mL Erlenmeyer flask. Add a boiling chip. Divide the mass (in grams) by 0.8, and obtain that many ml of 95% ethanol (i.e. 08 ml of 95% ethanol per 0.1 g of crude product). Add the ethanol to the flask with the crystals, then heat to boiling on the hot plate. Most of the crystals should dissolve. Remove the flask from the heat and leave it to cool slowly. Crystals should form. If no crystals have formed after about 5 min of cooling, seed the crystals by dipping your spatula in to the solution, evaporating the solvent from the spatula by gently blowing, scraping the spatula on the top rim of the flask, then dipping the spatula back into the solution. When the flask has reached room temperature and crystals have formed, cool the flask in an icewater bath for 5 min. Isolate the purified crystals by vacuum filtration using the irsch funnel. Rinse the crystals two times with 0.5 ml of ice-cold 95% ethanol. Use your spatula to break up the crystal mass, then stand the irsch funnel in a 100-mL beaker and leave in your lab drawer to air dry overnight. NTE: We will use g of our purified product in the next experiment. Yield Calculation and Melting-Point Determination nce your product is dry weigh the dry benzoin and calculate the percentage yield and percent recovery. Determine the melting point (lit value 135 C). btain the infrared spectrum of benzoin using the KBr disc method.

4 4 Reference IR of Benzoin: (source SBDS) Postlab Questions Step ne Answer these questions in your lab notebook after your conclusions for Step ne in a section titled Postlab Questions Step ne 1. What is the impurity that must be removed from the benzaldehyde reagent before it can be used in this experiment? 2. Refer to the essay that precedes the experiment. It gives the structure of thiamine pyrophosphate. Draw a structure of thiamine hydrochloride. 3. What is the purpose of adding Na ot the reaction? 4. Using the information given in the essay that proceeds this experiment, formulate a complete mechanism for the thiamine-catalyzed conversion of benzaldehyde to benzoin. 5. What modifications of conditions would be appropriate if an enzyme was used for this reaction?

5 5 Step 2: Synthesis of Benzil Introduction In Step 2 of this reaction sequence you will oxidize benzoin to form benzil using nitric acid. Mechanism: N N N 2 N + 2 N

6 6 Step 2 Procedure: Synthesis of Benzil Caution: Use care when dispensing nitric acid. Vapors can irritate your eyes and be sure to avoid contact with your skin. It is important to wash your hands after dispensing the acid from the hood into your sample. In addition, the reaction generates noxious nitrogen oxide gases. Therefore, it is imperative that the reaction be performed under your hoods. Preparation of Reaction Mixture Place about 0.30 g of benzoin into a 5-mL conical vial and add 1.5 ml of concentrated nitric acid using the provided pipette in the hood. Check-out a magnetic spin vane from your instructor. In a hood, set up the apparatus for heating in a hot water bath, as in the diagram. eat the mixture in the hot water bath at ~70 C for 1 hour, with stirring. It is important to avoid over-heating the mixture. Be sure to keep the temperature at 70 o C and not to overheat. During the 1- hour heating period, red nitrogen oxide gases will be evolved. If it appears that gases are still being evolved after 1 hour, continue heating for another 15 minutes but then discontinue heating at that time. It is important to keep your reaction under the hood in order to avoid exposure to the nitrogen oxide fumes. Isolation of Crude Benzil After you are done heating you should cool the mixture to room temperature. Remove the air condenser and transfer the reaction mixture to a small beaker containing 4 ml of ice-cold water. Rinse the conical vial and spin vane with a small amount of water and combine the rinse in your small beaker. btain some ice in a larger beaker and cool the mixture in an ice bath until the crystals have formed. You should obtain crystals at this point. owever, if the material oils out rather than crystallizes, scratch the oil vigorously with a spatula until it does crystallize completely. Collect the crude product on a irsch funnel under vacuum. Wash it well with cold water (about 5 ml) to remove the nitric acid. Continue drawing air through the solid on the irsch funnel to help dry the solid. nce the solid is dry, weigh the solid. Crystallization of Product nce your crude product is dry you should recrystallize using 95% ethanol. Dissolve your crude benzil in hot 95% ethanol in a small Erlenmeyer flask (~5 ml per 0.5 g of product) using your hot plate. Add a small aliquot of 95% ethanol to your crude benzoin and a boiling stone. Incrementally add room temperature 95% ethanol to your crude product, bringing it to a boil. nce your product is dissolved in boiling solvent remove it from the heat source and allow it to cool slowly to room temperature. As the solution cools seed the solution using your glass stirring rod. Yellow crystals will precipitate as you cool. Further cool the mixture in an ice bath to complete the crystallization. Collect the product on a irsch funnel under vacuum. Rinse the flask with small amounts (about 1 ml total) of ice-cold 95% ethanol to complete the transfer of product to the irsch funnel. Continue drawing air through the crystals on the irsch funnel by suction for about 15 minutes or until your solid is dry. Yield Calculation and Melting-Point Determination nce your product is dry weigh the dry benzil and calculate the percentage yield and percent recovery. Determine the melting point (lit value 95 C). btain the infrared spectrum of benzil using the KBr disc method.

7 7 Reference IR of Benzil: (source SBDS) Postlab Questions for Step Two Answer these questions in your lab notebook after your conclusions for Step Two in a section titled Postlab Questions Step Two 1. The instructions in the lab text emphasize that the reaction mixture should not be heated above 70 o C. What could happen if the reaction temperature is too high? 2. Compare the IR spectrum of benzoin with the IR spectrum of benzil. Explain how the changes in the important peaks are related to the differences between the two structures.

8 8 Step Three: Synthesis of Benzilic Acid You will now react your benzil with potassium hydroxide followed by an acid work-up to produce benzilic acid. Instructor notes: The aqueous potassium hydroxide solution should be prepared for the class by dissolving 2.75 g of potassium hydroxide in 6.0 ml of water. This will provide enough solution for 20 students, assuming little solution is wasted. bserved Reaction 1. K Benzil (alpha-diketone) Benzilic Acid Mechanism

9 9 Procedure: Step Three Procedure Step Three Reaction Place g benzil of your purified benzil from step two into a 3-mL conical vial. Measure 0.30 ml 95% ethanol and add to the benzil. Check-out a spin vane from your instructor and place it into the conical vial. Attach an air condenser (see figure) and heat the mixture with aluminum shot ( o C) while stirring until the benzil has dissolved. Using a 9-inch Pasteur pipette, add dropwise 0.25 ml of an aqueous potassium hydroxide solution1 through the condenser into the vial. Gently boil the mixture while stirring for 20 minutes. During this heating time the reaction mixture will be blueish-black. As the reaction continues to heat, the color will turn to brown, and the solid should dissolve completely. In addition, note that potassium benzilate may precipitate during the heating period. At the end of the 20 minutes of heating, remove the assembly from the aluminum shot and allow it to cool for a few minutes. Crystallization of Potassium Benzilate nce the apparatus is cool enough to handle detach the air condenser and transfer the reaction mixture (may contain some solid) with a Pasteur pipette into a 10-mL beaker. Allow the mixture to cool to room temperature and then cool in an ice-water bath for about 15 minutes until crystallization is complete (scratch the inside of the beaker with a glass stirring rod to induce crystallization if necessary). In this case you will crystallization is complete when almost all of mixture has solidified. Collect the crystals on a irsch funnel by vacuum filtration and wash the crystals with three 1-mL portions of ice-cold 95% ethanol. After the cold ethanol rinse you will notice that most of the color from the crystals has been removed. Transfer the solid potassium benzilate, to a 10-mL Erlenmeyer flask containing 3 ml of hot (70 C) water. Stir the mixture until all solid has dissolved or until it appears that the remaining solid will not dissolve. Any remaining solid will likely form a fine suspension. If solid does remain in the flask perform the following procedure. Place about g of Celite (Filter Aid) in a beaker with about 5 ml of water. Stir the mixture vigorously and then pour the contents into a irsch funnel (with filter paper) while applying a vacuum. Be careful not to let the Celite dry completely. This procedure will cause a thin layer of Celite to be deposited on the filter paper. Discard the water that passes through this filter. Pass the mixture containing potassium benzilate through this filter, using gentle suction. The filtrate should be clear. Transfer the filtrate to a 10-mL Erlenmeyer flask. If no solid remains in the flask, the filtration step may be omitted. In either case, proceed to the next step. Acid Work-up to form Benzilic Acid Add dropwise 0.50 ml of 1M hydrochloric acid to the solution of potassium benzilate while stirring. Use p paper to adjust the p to 2. As the solution becomes acidic, solid benzilic acid will begin to precipitate. Allow the mixture to cool to room temperature and then complete the cooling in an ice bath. Collect the benzilic acid by vacuum filtration using a irsch funnel. Wash the crystals with 3 4 ml of ice cold water to remove potassium chloride salt that sometimes co-precipitates with benzilic acid during the neutralization with hydrochloric acid. Remove the wash water by drawing air through the filter. Dry the product on your irsch funnel for 15 minutes.

10 10 Melting Point and Crystallization of Benzilic Acid Weigh the dry benzilic acid and determine the percentage yield. Determine the melting point of the dry product. Pure benzilic acid melts at 150 C. Take the IR using the KBr disc method. Calculate percent yield ptional Recrystallization If necessary, crystallize the product from hot water using a Craig tube. If some impurities remain undissolved, filter the mixture using the following procedure. It will be necessary to keep the mixture hot during this filtration step. Transfer the hot mixture to a test tube with a Pasteur pipette. Clean the Craig tube and filter the mixture by transferring it back to the Craig tube with a filter-tip pipette. Cool the solution and induce crystallization, if necessary. Allow the mixture to stand at room temperature until crystallization is complete (about 15 minutes). Cool the mixture in an ice bath and collect the crystals by centrifugation. Determine the melting point of the crystallized product after it is thoroughly dry. At the instructor s option, determine the infrared spectrum of the benzilic acid in potassium bromide. Calculate the percentage yield. Submit the sample to your laboratory instructor in a labeled vial. Reference IR of Benzilic Acid: (source SBDS)