EXPERIMENT 9 PREPARATION OF 3-NITROBENZAMIDE DANGER: Thionyl chloride is a colorless, volatile liquid with a suffocating odor. Both the vapors and the liquid are corrosive to skin. It also reacts vigorously with water to form HCI and SO. Under no circumstances should any glassware con- taining thionyl chloride be brought to a lab bench or sink. Rinse all contaminated glassware in the fume hood. Wear your gloves! BACKGROUND AND THEORY This reaction illustrates the greater nucleophilicity of ammonia (H¸N:) vs. water (H,O:). Commercial concentrated ammonium hydroxide is approximately 30% (15 M) ammonia. The remaining 70% is water (35 M). And yet, adding the acid chloride to aqueous ammonia at 0°C forms the amide almost exclusively. At higher reaction temperatures, this selectivity decreases, forming an increasing percentage of carboxylic acid. In the presence of excess ammonia, any acid so formed is converted to ammonium 3-nitrobenzoate, a water-soluble salt. In Figure 9.1, the overall reaction scheme for the synthesis of 3-nitrobenzamide is outlined. Note that both SO, and HCl gas are generated dur- ing the formation of the acid chloride. Both of these gases are highly toxic; make sure the hood is functioning properly. The generation of these gases makes the formation of the acid chloride irreversible, thus increasing the efficiency of the reaction. In the last step, HCl is also produced as a byproduct, but here due to the excess NH,OH present, it is quickly neutralized to NH,Cl + H₂O. Acids I-III: Carboxylic Acids O₂N- OH SOCI₂ DMF aqueous NH, O₂N- Cl དེགས་ ི་ ད་ལམ་ ་ ོ་ ིག་པ་ NH₂ + SO2(g) + HCl(gas) Figure 9.1. Preparation of an amide from a carboxylic acid. The mechanism for the formation of the acid chloride (Figure 9.2) begins with the attack by the oxy- gen of the hydroxyl group of the carboxylic acid (VI) on the sulfur of the thionyl chloride (SOCI). This is quickly followed by the loss of a proton to yield intermediate VIII, a chlorosulfite, plus HCI. Some of the HCl generated is lost as a gas and some reacts with dimethylformamide (DMF), the co-solvent, which also acts as a weak base. Chloride anion then attacks the chlorosulfite at the carbonyl carbon to yield intermediate IX. Loss of sulfur dioxide gas and chloride anion gives the final product acid chloride. The formation of gaseous SO, and HCI both serve to drive the reaction forward, as their escape makes the product formation irreversible. O₂N ork of VI H VII HCI (g) + SO2 (g) + Extremely poisonous gases IX ON- A tetrahedral intermediate Figure 9.2. Mechanism of acid chloride formation. VIII 115 116 Experiments 7-9 Amide formation (Figure 9.3) begins with nucleophilic attack by ammonia on the carbonyl carbon of the acid chloride followed by the ejection of the chloride anion to afford protonated amide X This intermediate is then deprotonated by chloride anion, acting as a base, to yield the final product amide XI. O₂N O₂N NH3 :NH₂ IX A tetrahedral intermediate XI ON NH₂ x NH₂ Figure 9.3. Mechanism of amide formation from an acid chloride This exercise also illustrates the use of safety equipment. Thionyl chloride-containing solutions emit noxious fumes. In addition, much dense white ammonium chloride smoke is formed when the reac- tion mixture is added to the ammonia. The circulation of this visible smoke shows the movement of all fumes within the hood. Note how the fumes move toward the front center of the hood. If you work with the sash raised, the fumes, whether visible or invisible, blow directly at you. With the sash lowered as much as possible, your face and body are protected from both fumes and unanticipated splashes. Both the original compound, 3-nitrobenzoic acid, and the final product, 3-nitrobenzamide, melt close to 130°C when pure and dry. However, an intimate mixture of the two compounds melts quite differently. This "mixed melting point" confirms that the two compounds are indeed different. EXPERIMENTAL PROCEDURE 1. Place 0.5 g of well-powdered 3-nitrobenzoic acid and a stirring bar into a 10 ml. round bottom flask. (The powdering is best done with a 25 ml. Erlenmeyer and smooth surfaced weighing paper.) 2. Attach a drying tube containing a wad of cotton and a one-inch layer of calcium chloride. 3. Under a fume hood, clamp the assembly in a water bath, making sure the assembly is half submerged in the water, and a thermoprobe is clamped in the water as well. 4. Remove the flask assembly and set it aside for the moment. Adjust the hot plate to warm the water bath to 50°C. 5. Take the flask assembly to the chemical supply hood and temporarily remove the drying tube assembly and add 0.4 mL. of thionyl chloride (d = 1.63 g/mL.) using the attached 1.0 ml. cali- brated pipette. Then add 6 drops of dimethylformamide (DMF) to the flask and replace the drying tube. Do this entire step in the chemical supply hood only, do not remove the thionyl chloride bottle or its associated pipette from that hood. Acids I-III: Carboxylic Acids 117 6. Bring the flask back to the hood with your 50°C water bath, clamp the assembly in place and stir the mixture for 10 minutes at 50°C. It is essential to keep the temperature of the water bath at 50° ± 5°C. Do not start tining if the temperature is below 45°C. 7. After the flask assembly is warming in the water bath place a 50 ml. Erlenmeyer flask contain- ing 12 ml of concentrated ammonia (15 M) in an ice bath in the same hood, close to your water bath. Note: In research labs, often such water-sensitive reactions are performed under an inert atmosphere (argon or nitrogen gas) rather than using a drying tube. 8. If the entire sample has not liquified after approximately 10 minutes, remove the flask assembly from the water bath, take it to the chemical supply hood and add another 0.2 mL. of thionyl chloride to the mixture, as before. 9. Bring the flask assembly back to your water bath and continue heating until no solid remains. Continuous stirring also helps to complete the reaction. 10. Once the reaction is complete, raise the reaction flask above the water bath and remove the drying tube. Use an eyedropper to transfer the acid chloride solution dropwise (slowly, at a rate of I drop per two seconds) to the ice-cold flask of ammonia while stirring. Keep the ammonia solution in the ice bath during the addition of 3-nitrobenzoyl chloride. REMEMBER TO KEEP YOUR HEAD OUT OF THE EXHAUST HOODS AT ALL TIMES DURING THIS EXPERIMENT. BOTH HCI AND SO, ARE EXTREMELY POISONOUS GASES. 11. Maximum yields are obtained when the addition is performed with cold ammonia, which is stirred continuously. Keeping 1-2 pieces of ice in the ammonia solution during the addition will help keep the temperature close to 0°C. Inverting the eyedropper allows the acyl chloride to enter the rubber bulb, contaminating your product and destroying the rubber. Do not hold an eyedropper upside down. 12. When the addition is complete, rinse the round bottom flask and the eyedropper with some ammonia. The materials may now be safely removed from the hood if the ammonia flask is stoppered. Otherwise, cool it in the hood. 13. Cool the crude amide for a few minutes, and collect the solid by suction filtration on a Hirsch funnel. A 1.5 cm piece of filter paper should just cover the bottom of the funnel, the same as a Büchner funnel. 14. Wash the product well with water to remove a large amount of NH,CI. Pour this ammonia waste down the drain promptly, and rinse with water. 15. Use a 10 ml. pear-shaped flask to recrystallize the crude amide by dissolving it in a mini- mum amount of denatured ethanol with heating (1-2 mL depending on the yield of your 3-nitrobenzamide). 16. Then add enough water to just saturate (first cloudiness) the solution followed by addition of 1-2 drops of ethanol. Do not add more than 5 mL. of water in any case, as the product is also somewhat soluble in water. 3 Experiments 7-9 17. The above crystallization is a difficult one to perform successfully. It is always a good idea to keep a few crystals of the crude product for "seeding" in case you have trouble with the recrys- tallization. Remember, also, that a trace of ammonium chloride may be trapped in the crude amide it will be virtually insoluble in denatured ethanol so you may have to filter it. 18. Use your Hirsch funnel to collect the product by suction filtration after cooling the 10 mL. pear-shaped flask in an ice bath for five minutes. The mother liquor should be added to the Hazardous Waste Container. 19. If you have not already done so, return the calcium chloride to the solid waste container. Calcium chloride left in drying tubes will eventually form a solid cake that is almost impossible to remove. 20. Simultaneously determine the melting point of the starting 3-nitrobenzoic acid, the final amide, and an intimately ground mixture of the two solids. The amide and corresponding acid both melt near 130°C. The range is from the first appearance of liquid until the complete disappear- ance of solid. It should be quite wide for a mixed melting point. REPORT Calculate the percent yield for all three reactions. Show your work in detail. Submit all products in properly labeled vials for full credit. The glassware for next week's experiment must be completely dry. Clean the fol- lowing equipment and place them in a labeled 250 mL beaker with your name and section number written on it. Allow them to dry thoroughly in an oven for at least 30 minutes. Make sure to take the hot glassware out of the oven and place them in drawer before exiting from the lab; you may risk losing them forever. The estimated replacement cost is approximately $100. 8 mL vial, 5 mL vial, Claisen adapter, air condenser, drying tube, glass stirring rod, and triangular stir bar DO NOT PLACE O-RINGS OR PLASTIC CAPS IN THE OVENS; THEY WILL MELT! your