麻省理工学院：《有机化学基本实验操作技巧》教学资源（讲义）Original Research Project

Hal facilities and equip ment, and supervision by appropriate individual You bear the sole and risk for the implenentation of such safty procedures and measures. MIT shall have no or risk for the content or implemcatation of amy of the material presente 6. Introduction to Original research 6.1. Olefin Epoxidation with Mn(salen) Complexes Introduction: Your " advisor"has carefully monitored your progress in 5.301 and believes that you are ready to move from the technique modules to an actual project. This project will require you to use many of the skills that you have learned over the past three weeks to address a specific question. In addition, you and your labmates will learn to work as a research group in order to reach an ambitious goal in a short period of time Overview:(written by your advisor) Our group has had a longstanding interest in the epoxidation of olefins(eq 1), and would like to take another look at an important report from a decade ago. Eric Jacobsen (former MIT Post-doc and current Harvard Professor) showed that Mn(salen) complexes such as I are effective epoxidation catalysts(eq 1). Because Mn(salen) complexes are easy to make, I am interested probing the relative reactivity of a series of different Mn(salen) derivatives. A graduate student in the lab has investigated several Mn(salen) complexes, but I want you and your labmates to complete a more comprehensive study. So, look over the attached Jacobsen paper, talk to the graduate student on the project about the reactions you will be running, and be sure to organize your efforts with your fellow labmates. Let me know what trends you discover Epoxidation HO R (1) Reaction Olefin Epoxide H3C salen (one of Jacobsen's Mn(salen) catalysts bis(salicylaldehyde )ethylenediamine

6. Introduction to Original Research 6.1. Olefin Epoxidation with Mn(salen) Complexes Introduction: Your "advisor" has carefully monitored your progress in 5.301 and believes that you are ready to move from the technique modules to an actual project. This project will require you to use many of the skills that you have learned over the past three weeks to address a specific question. In addition, you and your labmates will learn to work as a research group in order to reach an ambitious goal in a short period of time. Overview: (written by your advisor) Our group has had a longstanding interest in the epoxidation of olefins (eq 1), and would like to take another look at an important report from a decade ago. Eric Jacobsen (former MIT Post-doc and current Harvard Professor) showed that Mn(salen) complexes such as 1 are effective epoxidation catalysts (eq 1). Because Mn(salen) complexes are easy to make, I am interested in probing the relative reactivity of a series of different Mn(salen) derivatives. A graduate student in the lab has investigated several Mn(salen) complexes, but I want you and your labmates to complete a more comprehensive study. So, look over the attached Jacobsen paper, talk to the graduate student on the project about the reactions you will be running, and be sure to organize your efforts with your fellow labmates. Let me know what trends you discover. H R Epoxidation H O R (1) Reaction R H R H Olefin Epoxide H3C tBu tBu 1 salen = (one of Jacobsen's Mn(salen) catalysts) bis(salicylaldehyde)ethylenediamine N N O O Mn Cl CH3 Ph Ph N N O O 37 WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. You bear the sole responsibility, liability, and risk for the implementation of such safety procedures and measures. MIT shall have no responsibility, liability, or risk for the content or implementation of any of the material presented. WARNING NOTICE: The experiments described in these materials are potentially hazardous and require a high level ofsafety training, special facilities and equipment, and supervision by appropriate individuals. 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Goals Synthesize a new salen complex (eq 2 ), and obtain a H NMR spectra Synthesize the corresponding Mn(salen) complex (eq 3) Compare isolated yields of the catalyst with your labmates Epoxidize stilbene using the published Jacobsen procedure and your catalyst(eq 4) Determine the conversion of your reaction using H NMR analysi Purify your crude reaction mixture by flash column chromatography, and obtain a yield. Obtain a HNMR spectrum of the pure epoxidation product. Compare conversions and isolated yields with your labmates. Use your results to make predictions about the correlation between catalyst structure and catalyst efficiency. This will help us to plan better catalysts in the future Hints from your graduate student mentor: 1. Making the Salen ligand (eq 2) Reactions that you shouldnt try: (I had problems making the Mn(salen) complex with these ligands. 1)ethylenediamine salicylaldehyde 2)trans-diaminocyclohexane +3, 5-di-tert-butyl, 2-hydroxybenzaldehyde 3)ethylenediamine nitrosalicylaldehyde 4)ethylenediamine chlorosalicylaldehyde You should aim to make 1.00 g of the Mn(salen)complex. Do your calculations based on the two reactions proceeding in 70%o overall yield Don't forget that after the reaction finishes you ll need to add water to precipitate therate There will be a large amount of solid produced, so use a large stir bar and fast stirring product, so dont start with too small a reaction flask When you first isolate the ligands(and later the metal complexes), they will be very wet, so dry them overnight in your desiccator before you determine their weight Note the difference between ethanol and absolute ethanol

Goals: • Synthesize a new salen complex (eq 2), and obtain a 1 H NMR spectra. • Synthesize the corresponding Mn(salen) complex (eq 3). • Compare isolated yields of the catalyst with your labmates. • Epoxidize stilbene using the published Jacobsen procedure and your catalyst (eq 4). • Determine the conversion of your reaction using 1 H NMR analysis. • Purify your crude reaction mixture by flash column chromatography, and obtain a yield. • Obtain a 1 H NMR spectrum of the pure epoxidation product. • Compare conversions and isolated yields with your labmates. • Use your results to make predictions about the correlation between catalyst structure and catalyst efficiency. This will help us to plan better catalysts in the future. Hints from Your Graduate Student Mentor: 1. Making the Salen Ligand (eq 2) • Reactions that you shouldn't try: (I had problems making the Mn(salen) complex with these ligands.) 1) ethylenediamine + salicylaldehyde 2) trans-diaminocyclohexane + 3,5-di-tert-butyl, 2-hydroxybenzaldehyde 3) ethylenediamine + nitrosalicylaldehyde 4) ethylenediamine + chlorosalicylaldehyde • You should aim to make 1.00 g of the Mn(salen) complex. Do your calculations based on the two reactions proceeding in 70% overall yield. • There will be a large amount of solid produced, so use a large stir bar and fast stirring rate. • Don't forget that after the reaction finishes you'll need to add water to precipitate the product, so don't start with too small a reaction flask. • When you first isolate the ligands (and later the metal complexes), they will be very wet, so dry them overnight in your desiccator before you determine their weight. • Note the difference between ethanol and absolute ethanol. 38

Absolute Ethanol Reflux. 1h H HO R H2n NH2 R=H OMe. NO or Cl Starting Materials: Salicy aldehyde Derivatives Diamines OH O OH O OH O OH O H2n NH2 H2N NH FW=156.57FW=167.12FW=152.15FW=122.12 FW=114.19FW=60.10 d=1.219 d=1.146 d=0951 d=0899 2. Making the mn(salen) Complex (eq 3) Some of our salen ligands behave a little differently than the ones Jacobsen describes. For some cases toluene needs to be added to the hot ethanol solution to dissolve the ligand. After the reaction is complete, it is crucial to cool the solution down to promote the precipitation of the Mn(salen)complex. It's easiest to put the flask in an ice-bath for about an hour, then filter the mixture. If no solids form after the ice-bath cooling, it may be necessary to leave the solution in the fridge overnight. Air. Ethanol. Reflux. 1h oh Ho 2. LiCl Reflux. 30 min

OH O Absolute Ethanol N N H (2) Reflux, 1h R H2N NH2 R OH HO R R = H, OMe, NO2, or Cl Starting Materials: Salicylaldehyde Derivatives: Diamines: OH O OH O OH O OH O H H H H H2N NH2 H2N NH2 Cl NO2 OMe FW = 156.57 FW = 167.12 FW = 152.15 FW = 122.12 FW = 114.19 FW = 60.10 d = 1.219 d = 1.146 d = 0.951 d = 0.899 2. Making the Mn(salen) Complex (eq 3) • Some of our salen ligands behave a little differently than the ones Jacobsen describes. For some cases toluene needs to be added to the hot ethanol solution to dissolve the ligand. • After the reaction is complete, it is crucial to cool the solution down to promote the precipitation of the Mn(salen) complex. It's easiest to put the flask in an ice-bath for about an hour, then filter the mixture. If no solids form after the ice-bath cooling, it may be necessary to leave the solution in the fridge overnight. 1. Mn(OAc)2·4H2O Air, Ethanol, Reflux, 1h N N N N (3) Mn 2. LiCl, Reflux, 30 min R OH HO R R O O R Cl 39

3. Epoxidizing Stilbene (eq 4) The best way to get the proper pH for this reaction is to use a pH meter. When it comes time to do this step, the TAs can show you how to use our meter. Monitoring this reaction by tlC can be tricky since the organic layer is on the bottom. The best way to do it is to dip a pipet as deep as possible into the mixture. The liquid drawn into the pipet by capillary action can then be rinsed into a vial using pentane. The less dense organic phase will now be present on top of the aqueous phase and will be easy to obtain using your TLC spotter. Note: we are only using this extravagant dilution procedure because this is a biphasic solution in dichloromethane. Most homogeneous reaction solutions(or biphasic mixtures with less dense organic solvents) can be directly spotted onto tlC plates for analysis 0.5 M Na2HPO4, Clorox 0.10 equiv Mn(salen CH2Cla2,o°toRT

3. Epoxidizing Stilbene (eq 4) • The best way to get the proper pH for this reaction is to use a pH meter. When it comes time to do this step, the TAs can show you how to use our meter. • Monitoring this reaction by TLC can be tricky since the organic layer is on the bottom. The best way to do it is to dip a pipet as deep as possible into the mixture. The liquid drawn into the pipet by capillary action can then be rinsed into a vial using pentane. The less dense organic phase will now be present on top of the aqueous phase and will be easy to obtain using your TLC spotter. Note: we are only using this extravagant dilution procedure because this is a biphasic solution in dichloromethane. Most homogeneous reaction solutions (or biphasic mixtures with less dense organic solvents) can be directly spotted onto TLC plates for analysis. O 0.5 M Na2HPO4, Clorox 0.10 equiv. Mn(salen) CH2Cl2, 0 °C to RT (4) 40