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1. OH O O Inlet 2 Inlet 6 N2H4 H20 Acetone CF3 Inlet 1 E Outlet 7 3223 Before starting the reaction a Check that the reactor holder contains reactor type 3223 consult a demonstrator if another reactor is installed b Fill two 1 ml glass gas tight syringes with absolute ethanol EtOH and attach the luer fittings connected to Inlets 1 and 2 Fill a third 1 ml glass gas tight syringe with acetone and attach to the luer fitting connected to Inlet 6 c Mount the two syringes filled with EtOH on Pump 1 the syringe filled with acetone on Pump 2 and set the pump rate of both pumps to 12 5 ul min collecting the solvent in a waste vial at the reactor outlet for 20 min Check that solvent is passing through the reactor and back pressure regulator into the waste vial if after 2 min no fluid is observed stop both pumps and consult a demonstrator d After 20 min stop the flow on both pumps and remove the syringes Empty the residual solvent into the appropriate waste container Setting up a reaction a Fill Syringe 1 with Stock Solution 1 see above to the 1 ml mark and attach to Inlet 1 before mounting on Pump 1 b Fill Syringe 2 with Stock Solution 2 see above to the 1 ml mark and attach to Inlet 2 before mounting on Pump 1 c Fill Syringe 3 with acetone to the 1 ml mark and attach to Inlet 6 mount on Pump 2 and place the outlet tube into a waste vial d Seta flow rate of 12 5 ul min on Pump 1 and 2 and start both pum2. D Personal Copy This document may not be distributed or resold by the recipient and may not be reproduced in a modified form Dr Charlotte Wiles CH SMTRIX APPENDIX III Model Answers Method 1 Synthesis of 3 Phenyl 5 trifluoromethyl 4 5 dihydro 1 H pyrazol 5 ol A TLC Analysis Substrate Ri 4 4 4 Trifluoro 1 phenyl 1 3 butanedione 0 62 3 Phenyl 5 trifluoromethyl 4 5 dihydro 1 H pyrazol 5 ol 0 21 B NMR Spectroscopy n 400 MHz CDCl and DMSO De 3 19 1H d J 17 8 CHH 3 36 2H m CHH and OH 7 26 1H brs NH 7 32 7 42 2H m 2 x ArH 7 62 2H m 2 x ArH and 7 88 1H s 1 x ArH Sc 100 MHz CDCl and DMSO De 41 2 CH2 90 9 q J 29 8 CoOH 124 2 q J 278 3 CFs 125 6 2 x CH 128 6 3 x CH 132 3 Co and 147 4 CoN C Reaction Yield Under the optimal conditions of a reaction time of 15 s and a reactor set temperature of 195 C 2 ml of collected reaction product will contain 0 153 g of 3 phenyl 5 trifluoromethyl 4 5 dihydro 1H pyrazol 5 ol assuming 100 conversion 7 673 x 10 g per ul D Time Taken The time taken to complete the reaction is estimated to be 5 h Experimental and Equipment Support For details on system assembly part numbers and trouble shooting please refer to the Labtrix Start user manual supplied with the system For any technical questions relating to the system or the development of additional teaching methods please contact us at info chemtri
3. in the Laboratory during the course of this experiment The substances especially harmful to health for this experiment are 6 ts 4 4 4 Trifluoro 1 phenyl 1 3 butanedione Harmful by inhalation in contact with skin and eyes Hydrazine monohydrate Flammable May cause cancer Toxic by inhalation in contact with skin and if swallowed May cause sensitization by skin contact Very toxic to aquatic organisms may cause long term adverse effects in the aquatic environment Exposure limits STEL 0 1 ppm Phenyl 5 trifluoromethy 4 5 dihydro 1H pyrazol 5 ol Harmful by inhalation and in contact with skin Ethanol Highly flammable liquid and vapour Harmful by inhalation and ingestion Delayed effects may include depression of the central nervous system narcosis and damage to the heart Exposure limits TWA 1000 ppm Acetone Highly flammable liquid Harmful by inhalation ingestion and contact with skin and eyes Exposure limits TWA 500 ppm Ethyl acetate Highly flammable Harmful by inhalation may cause drowsiness Exposure limits PEL 400 ppm Hexane Highly flammable May cause impaired fertility Irritating to the eyes skin and central nervous system Please refer to the material safety data sheet for each component to ensure the most up to date safety information is known and adhere to the following precautions Gloves safety glasses and a laboratory coat must be worn throughout the practical session The micro reaction e
4. Dr Charlotte Wiles CH SMTRIX FLOW CHEMISTRY TEACHING METHOD Personal Copy This document may not be distributed or resold by the recipient and may not be reproduced in a modified form Dr Charlotte Wiles Table of Contents Chapter 1 Safe Working in a Laboratory 1 Safe Working in a Laboratory 1 1 Pre laboratory Preparation 1 2 Personal Protective Equipment 1 3 General Safety Instructions 1 4 Labtrix Start Safety Instructions 1 5 Risk Assessment Chapter 2 Micro Reaction Technology 2 Introduction to Micro Reaction Technology 2 1 What is a Micro Reactor 2 2 Advantages of Micro Reactors 2 3 How are Reactions Performed 2 4 Aim of the Experiments 2 5 References Chapter 3 Labtrix Start Micro Reaction Screening Apparatus 3 General Labtrix Start Information 3 1 Micro Reactors 3 2 Reactor Holder and Peripherals 3 3 Liquid Handling 3 4 Thermal Control 3 5 Background Information 3 5 1 Reagent Preparation How to make a Volumetric Stock Solution 3 5 2 Loading the Solution into a Gas tight Syringe 3 5 3 Calculation of Reaction Time 3 5 4 Qualitative Analysis of Flow Reactions 3 5 5 Quantitative Analysis of Flow Reactions 3 5 6 Determination of Product Purity Chapter 4 Experimental Section Method 1 Synthesis of 3 Phenyl 5 trifluoromethyl 4 5 dihydro 1 H pyrazol 5 ol Method 2 Synthesis of Ethyl 2 cyano 3 3 5 dimethoxyphenyl acrylate Method 3 Synthesis of 3aR 7aS 5 Methyl 3a 4 7 7a tetrahydroisobenzofuran 1 3 dione Met
5. al procedure followed recording the appearance weight and percentage yield obtained for the material synthesised and interpret the spectra for the 3 phenyl 5 trifluoromethyl 4 5 dihydro 1H pyrazol 5 ol synthesised if NMR analysis is not available please refer to the model spectra provided Comment on the differences you would expect in the 1H NMR spectra for 4 4 4 trifluoro 1 pheyl 1 3 butanedione in the keto and enol forms Propose a synthetic method for the conversion of 3 phenyl 5 trifluoromethyl 4 5 dihydro 1H pyrazol 5 ol to 3 phenyl 5 trifluoromethyl 1H pyrazole N NH N NH an I JF cw802 4_PROTON 4 jdf Flow Reaction 3 0 NH i CF OH 4 0 3 0 2 0 1 0 Millions 9 0 8 0 7 0 6 0 5 0 4 0 3 0 2 0 1 0 0 FEER ares F4 N m 5 aner 228584 Suan 6 AAA a X parts per Million 1H 1H NMR 400 MHz spectra of 3 phenyl 5 trifluoromethy 4 5 dihydro 1H pyrazol 5 ol in CDCl and DMSO D Personal Copy This document may not be distributed or resold by the recipient and may not be reproduced in a modified form Dr Charlotte Wiles CH SMTRIX cw802 4_CARBON 4 jdf Flow Reaction fA Ss g Ss 150 0 140 0 130 0 120 0 110 0 100 0 90 0 80 0 70 0 60 0 50 0 40 0 30 0 20 0 10 0 0 g HEFER zag sgg i AEN age ARS SaRARARS REE F98 Sesaass X parts per Million 13C 13C NMR 100 MHz spectra of 3 phenyl 5 trifluoromethyl 4 5 dihydro 1H pyrazol 5 ol in CDClz and DMSO
6. alysis of the samples generated calculate the percentage conversion of 4 4 4 trifluoro 1 phenyl 1 3 butandione to 3 phenyl 5 trifluoromethyl 4 5 dihydro 1 H pyrazol 5 ol using peak area 3 2 TLC Analysis Thin layer chromatography is carried out using Kieselgel 60 HF254 alumina backed TLC plates with 80 20 hexane ethyl acetate used as eluent Visualisation is achieved using fluorescence on exposure to short wave ultra violet light 254 nm The solvent front is marked with a pencil and the Rf values for the starting material and product The effect of flow reaction conditions can be assessed qualitatively based on the appearance of the product and consumption of the starting material Personal Copy This document may not be distributed or resold by the recipient and may not be reproduced in a modified form Dr Charlotte Wiles CH SMTRIX 4 Experimental Conditions 4 1 Stock Solutions Using the following weights and volumes prepare the stock solutions volumetrically see introductory information for details of how to do this if unsure consult a demonstrator Stock No Solution Quantity Volumetric Flask Concentration ml M 1 4 4 4 Trifluoro 1 phenyl 1 3 butanedione 1 08g 5 00 1 00 2 Hydrazine monohydrate 0 27 ml 5 00 1 10 4 2 Micro Reactor Set up The reactions will be performed using reactor type 3223 Volume 10 ul and the reagents will be introduced into the reactor using the following inlets _ NH 1 CF
7. azol 5 ol and record the observations made DO NOT touch the micro reactor holder or heater unit until the temperature controller reaches a temperature of 25 C as there is a risk of injury 6 Determination of Reaction Yield Under the optimal reaction conditions identified from Section 5 operate the micro reactor for a period of time sufficient to collect 2 ml of reaction mixture collecting the reaction product into a pre weighed 10 ml round bottomed flask Evaporate to dryness on a rotary evaporator allow the flask to cool and weigh the flask Determine the mass of 3 phenyl 5 trifluoromethyl 4 5 dihydro 1H pyrazol 5 ol synthesised Reduce the set flow rate on each pump to 1 ul min and the temperature controller to 25 C Once cooled stop the pumps remove the syringes and empty any residual reagents into the correct waste container Wash the syringes with acetone fill to 1 ml and connect to inlets 1 2 and 6 pumping at 12 5 ul min for 20 min to clean the tubing and reactor in preparation for the next experiment 7 NMR Spectroscopic Analysis Personal Copy This document may not be distributed or resold by the recipient and may not be reproduced in a modified form Dr Charlotte Wiles CH SMTRIX Dissolve 10 mg of the reaction product in CDCls 2 drops of d DMSO and record a H and C NMR spectra where this service is unavailable interpret the model spectra provided 8 Experimental Write up Describe the experiment
8. erial Qualitatively determine the effect of reaction time on the formation of 3 phenyl 5 trifluoromethyl 4 5 dihydro 1H pyrazol 5 ol and record the observation made Having evaluated reaction time perform the following temperature evaluation for a fixed 15 s reaction time Re fill Syringes 1 2 and 3 with the respective Stock Solution or acetone and mount on the correct Pump Set Pumps 1 and 2 to 20 ul min and collect the reaction products in a waste vial for 2 min Set the temperature controller to 50 C and collect the reaction products in a waste vial for 5 min a 9 5 p After 5 min move the outlet tube to a clean labelled vial and collect for 1 min move the outlet tube to waste and set the temperature controller to 100 C e After 5 min move the outlet tube to a clean labelled vial and collect for 1 min move the outlet tube to waste and set the temperature controller to 150 C f After 5 min move the outlet tube to a clean labelled vial and collect for 1 min move the outlet tube to waste and set the temperature controller to 195 C g After 5 min move the outlet tube to a clean labelled vial and collect for 1 min move the outlet tube to waste leave the temperature controller set to 195 C and reduce the flow rate on all pumps to 1 pl min Analyse each sample generated by GC FID or TLC and qualitatively determine the effect of reactor temperature on the formation of 3 phenyl 5 trifluoromethyl 4 5 dihydro 1 H pyr
9. hod 4 Synthesis of Coumarins under Continuous Flow Method 5 Synthesis of 1 Phenylpropan 1 ol via a Continuous Flow Grignard Reaction APPENDIX Labtrix Start Spare Parts Part Number List APPENDIX II Material Compatibilities APPENDIX III Model Answers 10 10 11 13 14 14 14 15 15 16 16 17 18 19 25 31 37 44 51 52 53 CH MTRIX Personal Copy This document may not be distributed or resold by the recipient and may not be reproduced in a modified form Dr Charlotte Wiles CH MTRIX CHAPTER 4 EXPERIMENTAL SECTION Personal Copy This document may not be distributed or resold by the recipient and may not be reproduced in a modified form Dr Charlotte Wiles CH SMTRIX Method 1 Synthesis of 3 Phenyl 5 trifluoromethyl 4 5 dihydro 1H pyrazol 5 ol 5 y NH CF3 CFs NoH4 H20 Om abs EtOH sg ll Introduction The aim of the experiment is to optimise the reaction time and temperature to maximise the proportion of 3 phenyl 5 trifluoromethyl 4 5 dihydro 1H pyrazol 5 ol prior to synthesising 100 mg of material for analysis by NMR spectroscopy Depending on equipment availability reaction success will be determined using Gas Chromatography GC FID analysis or Thin Layer Chromatography TLC 1 Risk Assessment Students are reminded that they have a legal responsibility to take all necessary precautions to ensure the safety of themselves and others
10. ps at the same time collecting the reaction products into a waste vial before proceeding to optimise the reaction conditions see below Personal Copy This document may not be distributed or resold by the recipient and may not be reproduced in a modified form Dr Charlotte Wiles CH SMTRIX 5 Optimising a Continuous Flow Reaction In order to identify the best reaction conditions to use for the synthesis of 3 phenyl 5 trifluoromethyl 4 5 dihydro 1 H pyrazol 5 ol the reaction time and temperature must firstly be optimised To do this perform the following steps Set the temperature controller to 25 C and collect the reaction products in a waste vial for 5 min After 5 min move the outlet tube from the waste vial to a clean labelled vial and collect for 1 min Move the outlet tube to waste and set the flow rate on Pumps 1 and 2 to 5 ul min for 5 min After 5 min move the outlet tube from the waste vial to a clean labelled vial and collect for 2 min Move the outlet tube to waste and set the flow rate on Pumps 1 and 2 to 2 5 pl min 9 209 5 p After 5 min move the outlet tube from the waste vial to a clean labelled vial and collect for 5 min Move the outlet tube to waste and set the flow rate on Pumps 1 and 2 to 1 ul min gt After 10 min move the outlet tube from the waste vial to a clean labelled vial and collect for 10 min Analyse each sample generated by GC FID or TLC using Stock Solution 1 as the reference mat
11. quipment must be set up within a fume cupboard and used with the sash closed The preparation of stock solutions must be conducted within a fume cupboard Good laboratory practise should be employed throughout the practical session All waste generated from this reaction must be placed in an appropriate labelled waste container Personal Copy This document may not be distributed or resold by the recipient and may not be reproduced in a modified form Dr Charlotte Wiles CH SMTRIX 2 Reagents and Solvents N me Purity Molecular Weight Density g mol gm 4 4 4 Trifluoro 1 phenyl 1 3 butanedione 99 216 16 N A Hydrazine monohydrate 98 50 06 1 027 Ethanol Laboratory reagent grade 46 06 0 780 Acetone Laboratory reagent grade 58 08 0 790 Ethyl acetate Laboratory reagent grade 88 10 0 897 Hexane Laboratory reagent grade 86 18 0 655 Deuterated dimethyl sulfoxide 99 9 N A N A 3 Analysis Conditions Depending on equipment availability the micro reactions will be quantified using GC FID or qualified using TLC under the conditions outlined below 3 1 GC FID Methodology Using a gas chromatography GC FID operated under the conditions outlined in Chapter 3 Section 1 5 5 the following retention times are obtained for the solvents reagents and reaction product Retention Time Name min 4 4 4 Trifluoro 1 phenyl 1 3 butanedione 2 82 Ethanol 1 42 3 Phenyl 5 trifluoromethyl 4 5 dihydro 1 H pyrazol 5 ol 3 52 Upon an
12. x com 10 Personal Copy This document may not be distributed or resold by the recipient and may not be reproduced in a modified form
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