1. Effective Quenching and Working-up of Reactions Advanced Research Techniques Workshop 18 th May 2011 David Molyneux 1

2. Quenching/Working-up of Reaction Mixtures Definitions Importance General comments/procedure Quenches for Various Reaction Types Strongly basic non-aqueous Neutral non-aqueous Strongly acidic non-aqueous Acidic or basic aqueous Liquid ammonia reactions Outline Formulas For Some Specific Reagents Cu salts Boron compounds R 3 SnX by-products Metal Salts Al based reductions Cr oxidation by-products m-CPBA Practical Considerations Techniques and apparatus Extraction Solvents Tips Troubleshooting 2

3. Definition: “The termination of a chemical reaction by the careful addition of a ‘quenching agent’ to react quickly and irreversibly with one or more of the substrates, thus preventing further reaction” David Molyneux (2011) Importance: Prevent generation of undesirable side products Removes excess reagent from the reaction mixture Makes the product stable Often makes the product safer to handle Often improves the yield of the product General Comments: If under inert atmosphere, quench before exposing to air Add quench as you would a reagent (i.e. drop-wise by syringe) If reaction run at low temp., add quench at low temp. and allow the mixture to warm to room temp. before exposing to air If reaction run at elevated temp., allow to cool to room temp. before adding the quench (still under inert atmosphere if used). Quenching of Reactions 3

4. Definition: “A series of manipulations required to isolate and purify the product(s) of a chemical reaction” Wikipedia Importance: Removes unreacted reagents Removes undesirable by-products Isolates desired product Dries organic products Quenches any charged species General Comments: Quick and easy form of purification Very inexpensive Reduces need for further purification (i.e. column etc.) Maximises yield Working-up of Reactions 4

5. A standard work-up typically involves: Quenching the reaction Separating the reaction mixture into organic and aqueous layers by liquid-liquid extraction Washing the product of any unreacted reagents/unwanted by- products Drying of the product (if organic) Filtration Removal of solvents by evaporation General Work-up Procedure 5

6. Examples: Alkylation using strong bases [BuLi, (i-Pr) 2 NLi, etc.] Organometallic reagents [MeLi, RMgBr, RZnX, etc.] Hydride reducing agents [LiAlH 4, Na(EtOCH 2 CH 2 O) 2 AlH 2, etc.] Cuprates [R 2 CuLi] Quench: Excess saturated aqueous NH 4 Cl - to protonate anions and destroy unreacted reagents Notes: Add slowly Can be used at low temp. (if concerned about the aqueous solution freezing out, use acetic acid as the quench) Don’t add too large an excess as this can make isolation difficult Non-Aqueous Strongly Basic Reactions 6

7. Exception (Aluminium Reagents): In the case of Al based reagents (e.g. LiAlH 4 ), alternative procedures are often used to prevent formation of a fine precipitate which is difficult to filter and can lead to emulsions Quench: Saturated aqueous sodium sulfate (dropwise with stirring and cooling) until a heavy precipitate is formed (N.B. Stop as soon as the precipitate is formed) Decant the supernant liquid Extract the solid at least 3 times with the reaction solvent DO NOT dispose of the solid until you are sure you have obtained a good recovery of material as further extraction may be necessary Non-Aqueous Strongly Basic Reactions 7

8. Neutral taken to mean neither strongly acidic or basic, but may be either: Slightly acidic (e.g. Acid catalysed ketalisation) Slightly basic (e.g. Tosylation of an alcohol using pyridine or NEt 3 ) Quench: Mildly basic reactions: sat. aq. NH 4 Cl or H 2 O Mildly acidic reactions: dilute NaHCO 3 Notes: If reagent used was fairly reactive, add quench carefully with cooling e.g. If p-toluenesulfonyl chloride has been used to prepare a tosylate, it is useful to add a small volume of water and stir for an hour to convert any remaining sulfonyl chloride to sulfonic acid (which will exist as a salt with the amine base). Non-Aqueous Neutral Reactions 8

9. Non-Aqueous Strongly Acidic Reactions Examples: Strong Lewis acids [TiCl 4, BF 3.OEt 2, etc.] (N.B. Quenching of these reagents will be exothermic and liberate strong protic acids) Quench: If the product is unlikely to be affected by the acid: H 2 O If the product is likely to be affected by the acid: NaHCO 3 Non-aqueous quench: NH 3 (g) in the reaction solvent Notes: Add slowly, with cooling The metals used (Ti, Al etc.) can give rise to insoluble precipitates 9

10. Aqueous Acidic or Basic Reactions Examples: Hydrolysis reactions Acid-base reactions Redox reactions Precipitation reactions Quench: For basic reactions: dilute acid For acidic solutions: dilute base Notes: Sometimes these reactions require no quench (e.g. Ester hydrolysis) 10

11. Liquid Ammonia Reactions Many synthetically useful reactions use this as a solvent and usually involve either the use, or generation of, strongly basic species. Quench: Excess solid NH 4 Cl and allow the ammonia to evaporate (in a fume hood) Notes: Add quench very slowly 11

12. Isolation of Product Procedure: Remove any solids by filtration Partition reaction mixture between an organic solvent and water (or other aqueous solutions) Wash desired layer Dry (if organic) Remove solvents by evaporation 12

13. Isolation of Product – Removal of Solids It’s important to remove any solids before partitioning the reaction mixture, as the presence of fine particlutaes can lead to the formation of an emulsion, making separation difficult. To remove fine particles: Dilute the quenched reaction mixture with the reaction solvent Make a Celite pad by packing Celite onto a sintered glass funnel Wash the pad with water and solvent to remove any impurities in the Celite Filter your mixture through the Celite pad, washing throughly with water and solvent 13

14. Isolation of Product – Partitioning Partition the product between an organic solvent and water or another aqueous solution such as brine. Procedure: Extract the desired layer a minimum of 3 times If product in organic layer, make final wash brine Most dense solvent is the bottom layer (as a general rule of thumb, halogenated solvents such as DCM sit on the bottom, however, this is not always the case) Densities can be found in Alrich catalogue If densities of the two solvents is similar, a third layer may form. In this case, add salt (NaCl) to the mixture, as this will increase the density of the aqueous layer, giving a better partition DO NOT DISPOSE OF EITHER LAYER UNTIL YOU ARE SURE THAT YOUR PRODUCT HAS BEEN RECOVERED!!! 14

15. Isolation of Product – Extraction solvents Specific gravity is often quoted in place of density: SG=density of solvent/density of water SG<1.0 = float on H 2 O SG>1.0 = sink under H 2 O 15

16. Isolation of Product – Drying of Organic Layer If your product exists in the organic layer, make the final wash with brine, rather than water. As brine is saturated, any water in the organic layer is drawn to the aqueous layer by the change in concentration gradient. Procedure: Wash with brine Separate organic layer Add drying agent such as MgSO 4 Filter through a sinter funnel TIP: When filtering under vacuum, DO NOT leave the vacuum once the filtrate has come through, as the reduced pressure causes condensation from the air to form inside the flask, potentially wetting your freshly dried organic layer. Remove solvent by rotary evaporation 16

17. Reactions with PPh 3 O Examples: Wittig Reactions Misunobu Reactions Brominations Procedure: Concentrate the reaction mixture to a lower volume Suspend the residue in pentane or hexane/ether Filter over a silica plug Elute compound with ether leaving phosphine oxide on top of the column Sometimes necessary to repeat 17

18. Copper Salts Procedure: Quench reaction with NH 4 Cl aq. Solution Stir for a few hours at room temp or until the solution turns dark blue (complexation of the copper) Remove aqueous layer and wash organic 3 times with NH 4 Cl aq. Isolate material Filter through silica column 18

19. Boron Compounds Examples: Hydroboration Allylation Boron Redcution Suzuki Couplings Procedure: Concentrate the reaction mixture repeatedly from MeOH This forms B(OMe) 3 which is volatile 19

20. R 3 Sn-X Compounds Examples: Stannylation Radical initinations Stille Couplings Procedure: Treat with AlMe 3 to create non-polar Bu 3 SnMe Or Treat with NaOH to create polar Bu 3 SnOH Filter through a mixture of KF/Celite Dilute reaction with suitable organic solvent Add aqueous phase and extract Wash organic layer with 1M KF solution 3 times, shaking flask for 1 min for each wash Filter any precipitate through Celite Wash with brine and MgSO 4 For Bu 3 SnH,, add I 2 before KF treatment 20

21. Transition Metal Salts Many transition metals can be removed by precipitation of the sulfides Procedure: Wash with aqueous sodium sulfide If necessary, adjust the pH to create H 2 S Some transition metals can be removed by aqueous extraction with tris(hydroxymethyl)phosphine See: R. H. Grubbs Tetrahedron Lett. 1999, 40, 4137 21

22. Lithium aluminium Hydride To work-up a reaction containing X g LiAlH 4 : Procedure: Dilute with ether and cool to 0 o C Slowly add X ml water Add X ml 15% aq. NaOH Add 3X ml water Warm to RT and stir for 15 min Add anhydrous MgSO 4 Stir 15 min and filter 22

23. Diisobutyl Aluminium Hydride (DIBAL-H) To work-up a reaction containing X mmol of an agent such as DIBAL: Procedure: Dilute with ether and cool to 0 o C Slowly add 0.04X ml water Add 0.04X ml 15% aq. NaOH Add 0.1X ml water Warm to RT and stir for 15 min Add anhydrous MgSO 4 Stir 15 min and filter 23

24. Cr Oxidations PCC/PDC: Filter reaction mixture through a pad of florisil (make up pad as with the Celite (page 13) Jones: Add isopropanol until reaction turns from orange/red to green This indicates that the oxidant has been consumed 24

25. Meta Chloroperbenzoic Acid (m-CPBA) Examples: Oxidations Epoxidations Procedure: If reaction done at reflux, cool reaction mixture to 0 o C to precipitate out all m-CPBA Add 10% solution of aq. Na 2 SO 4 2 layers form Separate and extract with DCM Repeat addition of Na 2 SO 4 and extraction 3 times Wash organic layers with sat. aq. NaHCO 3 Wash organic layers with brine Dry using MgSO 4 25

26. Summary Effective Quenching and purification is essential to ensure good purity and maximum recovery of a product It is important to consider the side-products formed during a reaction, and how these can be removed effectively 26 Every system is different, but the examples given cover most eventualities Solvent selection is important Getting this right makes purification much easy, saving you time, effort and money

27. Acknowledgements MAC Research Group Dr. Stephen Hobson MJH Research Group Lynsey Cotterill The Postgraduate Committee 27

28. Other Workshops in the Series WorkshopDate Recrystallisation and Growing Samples for X-Ray15 th June 2011 Industry Techniques 1: Flash Chromatography13 th July 2011 Air Sensitive Techniques 2: Using a Glove box10 th August 2011 Industry Techniques 2: Microwave Reactions7 th September 2011 Sign-up sheet for each workshop will be available on the Postgraduate Notice board two weeks in advance Dates, locations and titles to be confirmed PhD students: record attendance at each workshop in your e-portfolio 1 school PGRDP credit is available per workshop 28