CHEM 231: Organic Form and Function
CHEM 231: Organic Form and Function
Laboratory 6 Multi-step Synthesis: Part B Specific Practical Goals
to prepare an alcohol from an aldehyde using hydride reduction to convert an intermediate to a final product in a multi-step procedure to heat a reaction using the reflux technique to isolate a product using aqueous extraction and rotary evaporation to determine the yield of a reaction based on the limiting reagent to characterize a product using TLC and IR spectroscopy
Background The 4-alkoxybenzyl alcohol motif has featured in synthetic biologically active compounds for some time. Over a 1 half century ago, 4-alkoxybenzyl alcohols were of interest as insecticides for body lice and repellants against salt2 marsh mosquitoes. More recently, 4-methoxybenzyl alcohol has been examined in crop protection as a 3 component in a composition to control fruit moths. And in the realm of human health, benzyl alcohol 1 has been 4 shown to be a potent histamine H3 receptor antagonist, while the closely related benzyloxybenzyl alcohol 2 5 exhibits antitubercular activity.
Figure 1. Some bioactive 4-alkoxybenzyl alcohol derivatives (4-alkoxybenzyl alcohol motif in red) This week, you will convert the 4-propoxybenzaldehyde (3) synthesized in Lab 5 into the corresponding 4-alkoxybenzyl alcohol derivative (4) by treatment with sodium borohydride in ethanol. The borohydride can be thought of as a source of hydride (H ), which engages in nucleophilic attack of the carbonyl group to produce an alkoxide; aqueous workup allows the alkoxide to become protonated and form the alcohol product. As in Lab 5, the product is characterized by TLC (vs. the starting material) and infrared (IR) analysis, which should reveal a new OH stretch.
Scheme 1. Borohydride reduction of 4-propoxybenzaldehyde to the corresponding benzyl alcohol
1
Eddy, G.W.; Carson, N.B., J. Econ. Entomol. 1948, 41, 31. Smith, C.N.; Burnett, Jr., D., J. Econ. Entomol. 1949, 42, 439. 3 Knudsen, G.K.; Tasin, M., European Patent Appl. EP2572579A1 (2012) 4 Labeeuw, O.; Levoin, N.; Poupardin-Olivier, O.; Calmels, T.; Ligneau, X.; Berrebi-Bertrand, I.; Robert, P.; Lecomte, J.-M.; Schwartz, J.-C.; Capet, M., Bioorg. Med. Chem. Lett. 2013, 23, 2548. 5 Tripathi, R.P.; Mishra, P.R.; Gupta, G.K.; Bisht, S.S.; Pandey, J.; Chaturvedi, V.; Sinha, S.; Gupta, V.; Dwivedi, A.K., Indian Patent Appl. IN2010DE00183A20120720 (2012). 2
Pre-lab Reading Technique Primers 1,3,5,6, & 8: TLC, Separatory Funnel, Reflux, Infrared Spectroscopy, & Yields Safety Considerations You must abide by all laboratory safety rules. Dichloromethane [75-09-2]. Harmful if swallowed. Causes skin and eye irritation. Suspected of causing cancer. May be harmful if inhaled. Causes respiratory tract irritation. Harmful if absorbed through skin. Causes skin irritation. Causes eye irritation. Harmful if swallowed. Ethanol [64-17-5]. Highly flammable liquid and vapor. Causes skin and eye irritation. May be harmful if inhaled. Causes respiratory tract irritation. May be harmful if absorbed through skin. Causes skin irritation. Causes eye irritation. May be harmful if swallowed. 4-Propoxybenzaldehyde [5736-85-6]. Harmful if swallowed or in contact with skin Causes skin irritation. Causes serious eye irritation. Harmful if inhaled. May cause respiratory irritation. 4-Propoxybenzyl alcohol [90925-43-2]. May be harmful if swallowed. Toxicity data have not been determined. Sodium borohydride [16940-66-2]. Flammable, toxic solid; contact with water liberates extremely flammable gases; toxic in contact with skin and if swallowed; causes burns. Keep away from water. Protect eyes and skin from exposure. Procedural Overview This reaction will be run in pairs. The two batches of 4-propoxybenzaldehyde can be combined, if necessary. Important Note: You will be evaluated on the amount of compound you recover. Therefore, make sure all transfers are quantitative. The final product must be transferred to a vial and turned in at the end of lab. In a 100 mL round-bottom flask, dissolve 492 mg of 4-propoxybenzaldehyde in 30 mL absolute ethanol. Add 126 mg sodium borohydride (make sure you keep the reagent bottle tightly closed!) and 2-3 boiling chips (IMPORTANT!). Attach a West condenser, heat at reflux for 15 min, and then remove the heat. Cool the flask in an ice bath while swirling until close to room temperature (2-3 min), and then remove the ethanol by rotary evaporation. Transfer the residue to a separatory funnel using 40 mL of dichloromethane and 75 mL of deionized water. Vigorously shake the funnel and let the phases separate. Collect the organic layer, dry over sodium sulfate, and remove the solvent using rotary evaporation. Weigh the isolated material to determine the yield of the reaction (note: to determine the theoretical yield, you must first identify the limiting reagent!). Prepare a TLC sample using a small amount of product, spot on a TLC plate alongside the starting material, and develop the plate in a mobile phase of ethyl acetate/hexane 1:3. Prepare a salt plate for IR analysis using a single small drop of neat (undiluted) product and collect an IR spectrum. Both samples can be washed back into the rotavap flask using a small amount of dichloromethane. Transfer the entire product to a sample vial with a minimum amount of dichloromethane. Clearly label the vial with your name and the product identity, and turn in to your instructor.
revision 10-29-13
Laboratory 6 Multi-step Synthesis: Part B Specific Practical Goals
to prepare an alcohol from an aldehyde using hydride reduction to convert an intermediate to a final product in a multi-step procedure to heat a reaction using the reflux technique to isolate a product using aqueous extraction and rotary evaporation to determine the yield of a reaction based on the limiting reagent to characterize a product using TLC and IR spectroscopy
Background The 4-alkoxybenzyl alcohol motif has featured in synthetic biologically active compounds for some time. Over a 1 half century ago, 4-alkoxybenzyl alcohols were of interest as insecticides for body lice and repellants against salt2 marsh mosquitoes. More recently, 4-methoxybenzyl alcohol has been examined in crop protection as a 3 component in a composition to control fruit moths. And in the realm of human health, benzyl alcohol 1 has been 4 shown to be a potent histamine H3 receptor antagonist, while the closely related benzyloxybenzyl alcohol 2 5 exhibits antitubercular activity.
Figure 1. Some bioactive 4-alkoxybenzyl alcohol derivatives (4-alkoxybenzyl alcohol motif in red) This week, you will convert the 4-propoxybenzaldehyde (3) synthesized in Lab 5 into the corresponding 4-alkoxybenzyl alcohol derivative (4) by treatment with sodium borohydride in ethanol. The borohydride can be thought of as a source of hydride (H ), which engages in nucleophilic attack of the carbonyl group to produce an alkoxide; aqueous workup allows the alkoxide to become protonated and form the alcohol product. As in Lab 5, the product is characterized by TLC (vs. the starting material) and infrared (IR) analysis, which should reveal a new OH stretch.
Scheme 1. Borohydride reduction of 4-propoxybenzaldehyde to the corresponding benzyl alcohol
1
Eddy, G.W.; Carson, N.B., J. Econ. Entomol. 1948, 41, 31. Smith, C.N.; Burnett, Jr., D., J. Econ. Entomol. 1949, 42, 439. 3 Knudsen, G.K.; Tasin, M., European Patent Appl. EP2572579A1 (2012) 4 Labeeuw, O.; Levoin, N.; Poupardin-Olivier, O.; Calmels, T.; Ligneau, X.; Berrebi-Bertrand, I.; Robert, P.; Lecomte, J.-M.; Schwartz, J.-C.; Capet, M., Bioorg. Med. Chem. Lett. 2013, 23, 2548. 5 Tripathi, R.P.; Mishra, P.R.; Gupta, G.K.; Bisht, S.S.; Pandey, J.; Chaturvedi, V.; Sinha, S.; Gupta, V.; Dwivedi, A.K., Indian Patent Appl. IN2010DE00183A20120720 (2012). 2
Pre-lab Reading Technique Primers 1,3,5,6, & 8: TLC, Separatory Funnel, Reflux, Infrared Spectroscopy, & Yields Safety Considerations You must abide by all laboratory safety rules. Dichloromethane [75-09-2]. Harmful if swallowed. Causes skin and eye irritation. Suspected of causing cancer. May be harmful if inhaled. Causes respiratory tract irritation. Harmful if absorbed through skin. Causes skin irritation. Causes eye irritation. Harmful if swallowed. Ethanol [64-17-5]. Highly flammable liquid and vapor. Causes skin and eye irritation. May be harmful if inhaled. Causes respiratory tract irritation. May be harmful if absorbed through skin. Causes skin irritation. Causes eye irritation. May be harmful if swallowed. 4-Propoxybenzaldehyde [5736-85-6]. Harmful if swallowed or in contact with skin Causes skin irritation. Causes serious eye irritation. Harmful if inhaled. May cause respiratory irritation. 4-Propoxybenzyl alcohol [90925-43-2]. May be harmful if swallowed. Toxicity data have not been determined. Sodium borohydride [16940-66-2]. Flammable, toxic solid; contact with water liberates extremely flammable gases; toxic in contact with skin and if swallowed; causes burns. Keep away from water. Protect eyes and skin from exposure. Procedural Overview This reaction will be run in pairs. The two batches of 4-propoxybenzaldehyde can be combined, if necessary. Important Note: You will be evaluated on the amount of compound you recover. Therefore, make sure all transfers are quantitative. The final product must be transferred to a vial and turned in at the end of lab. In a 100 mL round-bottom flask, dissolve 492 mg of 4-propoxybenzaldehyde in 30 mL absolute ethanol. Add 126 mg sodium borohydride (make sure you keep the reagent bottle tightly closed!) and 2-3 boiling chips (IMPORTANT!). Attach a West condenser, heat at reflux for 15 min, and then remove the heat. Cool the flask in an ice bath while swirling until close to room temperature (2-3 min), and then remove the ethanol by rotary evaporation. Transfer the residue to a separatory funnel using 40 mL of dichloromethane and 75 mL of deionized water. Vigorously shake the funnel and let the phases separate. Collect the organic layer, dry over sodium sulfate, and remove the solvent using rotary evaporation. Weigh the isolated material to determine the yield of the reaction (note: to determine the theoretical yield, you must first identify the limiting reagent!). Prepare a TLC sample using a small amount of product, spot on a TLC plate alongside the starting material, and develop the plate in a mobile phase of ethyl acetate/hexane 1:3. Prepare a salt plate for IR analysis using a single small drop of neat (undiluted) product and collect an IR spectrum. Both samples can be washed back into the rotavap flask using a small amount of dichloromethane. Transfer the entire product to a sample vial with a minimum amount of dichloromethane. Clearly label the vial with your name and the product identity, and turn in to your instructor.
revision 10-29-13
