Experiment V: Multistep Convergent Synthesis: Synthesis of Hexaphenylbenzene 1) Introduction CH H Thiamine HCl (V-02) ah (aq) Cu(Ac) 2 H 4 3 HAc V-01 V-03 V-04 Me 3 + H - V-05 V-06 Tetraphenylcyclopentadieneone V-07 nbu 4 + 3 - V-09 KH Diphenylacetylene V-08 V-10 V-11
+ V-07 V-11 + C (g) V-12 The conversion of benzaldehyde (V-01) to benzoin (V-03) is generally known as the typical benzoin condensation. The traditional reaction conditions for such a condensation take the advantage of cyanide anions which act as a good nucleophile on the aldehyde moiety. However, such a reagent is of course very toxic and should be avoided as much as possible. A quite similar type and less toxic reagent is thiamine hydrochloride (V-02). Step 2 is a simple and very mild redox reaction of V-03 to benzil (V-04) in which copper(ii) is reduced to copper(i) and nitrogen gas is evolved. The reaction between V-04 and carbonyl compound V-05 in the presence of a base is a double aldol condensation with elimination of two equivalents of water to give enone V-07. The other parallel synthesis toward V-12 involves the preparation of diphenylacetylene (V-11). Thus, the addition and subsequent elimination sequence starting with transstilbene yields V-08. Instead of using neat bromine in the reaction from V-08 to V-10, a much milder bromination reagent (V-09) is used here.
The last step is a Diels Alder reaction between diphenylacetylene (V-11) and tetraphenylcyclopentadienone (V-07) with loss of C to give hexaphenylbenzene (V-12). 2) Synthetic Procedures 2.1 Synthesis of Benzoin (V-03) Vitamin B 1, also known as thiamine pyrophosphate, is a coenzyme universally present in all living systems. It was discovered as a required nutritional factor in humans by its link to beriberi, a disease of the peripheral nervous system caused by a lack of vitamin B 1, in the diet. This substance catalyses several important biochemical reactions, including the conversion of aldehydes to α-hydroxyketones (acyloins). The related compound thiamine hydrochloride (V-02) can effect the same transformation in the absence of other biological substances. We will take the advantage of this reactivity to produce benzoin from benzaldehyde. You must understand the mechanism of this transformation. It can be found in various biochemistry textbooks, as well as in "Introduction to rganic Laboratory Techniques" by Pavia, Lampman, Kriz and Engel, from where this experiment was adapted. H 2 + H S P H P H H 2 H Cl + S HCl H Procedure: Thiamine Pyrophosphate CH Thiamine Hydrochloride (V-02) H Thiamine HCl (V-02) ah (aq) V-01 V-03 Add thiamine hydrochloride (V-02), (750 mg) to a suitable round bottom flask. Dissolve the solid in water (2.5 ml) by swirling, add 95% ethanol (7.5 ml) and cool the solution for a few minutes in an ice bath. Place a stir bar in the flask and, with stirring, add 2.5 ml of 2M ah. Weigh a dry vial and add benzaldehyde (V-01), (4.5 ml). Reweigh the vial and determine the exact mass of the benzaldehyde added. Attach an air condenser and heat the reaction mixture with stirring in a water bath at 60 o C for about 90 minutes.
At the end of the reaction time, remove the stir bar and allow the mixture to cool to ambient temperature. Induce crystallization of the benzoin by cooling the mixture in an ice bath. If the product separates as an oil, reheat the mixture and allow to cool more slowly than previously. It may be helpful to scratch the inside of the flask with a glass rod. Collect the product by on a Hirsch funnel by vacuum filtration and wash the crystals with two 5 ml portions of ice cooled water. Weigh the dry crude product, determine the melting point and calculate the yield. The benzoin obtained should be of sufficient purity to continue the next step. However, if the melting point is more than 5 C off the literature value, the product should be purified by recrystallization from 95% ethanol by using ~ 8 ml of ethanol per gram of benzoin. btain and record the following information in your notebook: 1. purified product description (color, physical state, etc.) 2. purified product weight/yield 5. IR of product (V-03) (interpret) 6. H 1 MR of the starting material (V-01) (interpret) 7. C 13 MR of the starting material (V-01) (interpret) 2.2 Synthesis of Benzil (V-04) H Cu(Ac) 2 H 4 3 HAc V-03 V-04 Dissolve cupric acetate (10 mg) and ammonium nitrate (500 mg) in deionized water (750 µl) and glacial acetic acid (2.8 ml) in a 10 ml round bottom flask containing a suitable stir bar. Attach a reflux condenser and slowly heat the flask if the salts are difficult to dissolve. As the reaction will evolve nitrogen gas, it is very important to keep the reaction apparatus open to the atmosphere at all times. nce a homogenous solution is obtained, cool the reaction flask to ambient temperature. Add benzoin (V-03, 1.00 g) to the stirred solution at room temperature, attach the condenser and start heating the mixture gently. Reflux the reaction mixture for 1 hr and the benzoin reaction mixture will become more homogenous and green. About 100 ml of nitrogen gas will evolve during this time!! Cool the reaction to ambient temperature and add water (5 ml). Cool the reaction flask in an ice/water bath around 10 minutes and collect the yellow crystals of benzil (V-04)
using a Hirsch funnel. Wash the crystals with two portions of cooled water (10 ml). The benzil obtained often contain small amounts of unreacted benzoin. Take a TLC on the crude crystals using methylene chloride as the eluent. Recrystallize the crude material from methanol and perform another TLC analysis. The crude material of benzil can also be purified using column chromatography. It is very important that the benzil (V-04) obtained in this step is free from benzoin (V-03) before conducting the next step in the synthetic sequence. To test if your product is free of benzoin, take ca. 0.5 mg of your product, add 0.5 ml of 95% ethanol or methanol and add one drop of 10% ah. If benzoin is present, a purple color will form. This color comes from a complex that forms between benzil and the autooxidation product of benzoin). If you do not observe a purple color, add 0.5 mg of benzoin to see what a positive result would look like. btain and record the following information in your notebook: 1. purified product description (color, physical state, etc.) 2. purified product weight/yield 5. IR (interpret) 2.3 Synthesis of Tetraphenylcyclopentadienone (TPCPD) (V-07) V-05 Me + 3 H - V-06 V-04 V-07 Combine the purified benzil (V-04, 300 mg) obtained from the previous step with 1,3- diphenylacetone (V-05, 300 mg) and triethylene glycol (1.5 ml) in a 10 ml round bottom flask containing a stir bar. Attach an air condenser and heat the reaction at 135-145 C for 10 minutes, in which the added benzil should dissolve. nce a homogenous solution is obtained, the heat is removed and the reaction allowed to cool to 80-100 o C. While the reaction mixture is still hot, 300 µl of a 40% benzyltrimethylammonium hydroxide (V-06) solution in methanol is cautiously added with stirring (do this in the hood!). Allow the reaction mixture to cool to room temperature. While the reaction mixture is cooled, dark purple crystals of tetraphenylcyclopentadienone (V-07) should be
formed. Cooling the reaction flask with water could also facilitate the formation of the crystals. Add cold methanol (4.5 ml) and cool the mixture for 10 minutes on an ice/water bath. Collect the purple crystals by vacuum filtration using a Hirsch funnel and wash the crystals with a couple ml of cold methanol in order to remove the brown impurities. Let the crystals dry in a desiccator. btain and record the following information in your notebook: 1. purified product description (color, physical state, etc.) 2. purified product weight/yield 5. IR of product (V-07) (interpret) 6. H 1 MR of the reagent (V-05) (interpret) 7. C 13 MR of the reagent (V-05) (interpret) 2.4 Synthesis of meso-stilbene dibromide (V-10) nbu 4 + 3 - V-09 V-08 V-10 Transfer trans-stilbene (V-08) (6 mmole) and methylene chloride (20 ml) to a 50 ml Erlenmeyer flask and cool the contents to 0 o C in an ice water bath. Use a powder funnel to add tetrabutyl ammonium tribromide (V-09) (6.5 mmoles) to the reaction contents. Wash any tetrabutyl ammonium tribromide adhering to the inside of the flask with additional methylene chloride (5 ml). Remove the ice water bath and allow the reaction to gradually warm to room temperature. Be sure to cover the reaction vessel to prevent methylene chloride vapors from escaping (methylene chloride is quite volatile and hazardous!). Stir the reaction contents for an additional 45 minutes. During this time, the orange colored solution gradually changes to yellow. If time permits, a longer reaction time will result in better yields. You may set the reaction contents aside until the next laboratory period. If you do this, be sure to cover the flask securely so that the methylene chloride does not evaporate (hazardous vapors!). Filter the crystalline product from the reaction mixture by vacuum filtration using a Hirsh funnel. Wash the product with three portions of cold water (10 ml each) and then with two portions of acetone (10 ml each). Air dry the product on a filter paper. The product should be of sufficient purity to be used in the next step. btain and record the following information in your notebook:
1. crude product description (color, physical state, etc.) 2. crude weight/yield 5. IR 2.5 Synthesis of Diphenylacetylene (DPA) (V-11) KH Diphenylacetylene V-10 V-11 Transfer meso-stilbene dibromide (V-10, 800 mg) and KH (800 mg) to a 25 ml Erlenmeyer flask containing a stir bar. Add triethylene glycol (4 ml) and heat the reaction mixture at 195 o C for 10 minutes. Cool the resulting dark-colored reaction mixture to 45 o C in water bath. Add water (10 ml), swirl or stir until thoroughly mixed, and place the flask in an ice/water bath for 15 minutes. Collect the crystals obtained with vacuum filtration using a Hirsch funnel. Wash the crystals with cooled 70% ethanol (2 x 1 ml) and let them air dry on a filter paper. btain and record the following information in your notebook: 1. crude product description (color, physical state, etc.) 2. crude weight/yield 5. IR
2.6 Synthesis of Hexaphenylbenzene (V-12) + + C (g) V-07 V-11 V-12 Add tetraphenylcyclopentadienone (V-07, 100 mg), diphenylacetylene (V-11, 100 mg) and high-boiling silicon oil (2 ml) to a 13 x 100-mm disposable test tube. Clamp the test tube in an angle facing the opening away from all personnel. Heat the reaction mixture gently using a Bunsen burner and boil the mixture for 5 minutes. Make sure to remove all sources of solvents and perform this experiment in an assigned area in a solvent free hood. All reagents will dissolve in the hot silicon oil and a dark purple solution will be obtained. Continue boiling the reaction mixture for an additional 10 minutes and the product starts to crystallize as tan crystals. Cool the test tube at room temperature and add hexane (4 ml). Mix on a Vortex mixer and crude product (V-12) is collected by vacuum filtration using a Hirsch funnel. Wash the crystals with hexane (2 ml) and next with cooled toluene (2 x 2 ml) to yield white crystalline product. Let the product air dry on a filter paper. btain and record the following information in your notebook: 1. product description (color, physical state, etc.) 2. weight/yield 4. literature value for melting point 5. IR Do not try to determine the melting point for the product. Be sure to locate and record the reported melting of hexaphenylbenzene.