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Effective Quenching and Working-up of Reactions

Advanced Research Techniques Workshop 18th May 2011

David Molyneux

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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• R3SnX by-products• Metal Salts

• Al based reductions• Cr oxidation by-products• m-CPBA

Practical Considerations• Techniques and apparatus• Extraction Solvents• Tips• Troubleshooting

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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

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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

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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

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Examples:

• Alkylation using strong bases [BuLi, (i-Pr)2NLi, etc.]• Organometallic reagents [MeLi, RMgBr, RZnX, etc.]• Hydride reducing agents [LiAlH4, Na(EtOCH2CH2O)2AlH2, etc.]

• Cuprates [R2CuLi]

Quench:

Excess saturated aqueous NH4Cl - 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

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Exception (Aluminium Reagents):

• In the case of Al based reagents (e.g. LiAlH4), 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

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• 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 NEt3)

Quench:

Mildly basic reactions: sat. aq. NH4Cl or H2O

Mildly acidic reactions: dilute NaHCO3

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 existas a salt with the amine base).

Non-Aqueous Neutral Reactions

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Non-Aqueous Strongly Acidic ReactionsExamples:

• Strong Lewis acids [TiCl4, BF3.OEt2, 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: H2O

If the product is likely to be affected by the acid: NaHCO3

Non-aqueous quench: NH3 (g) in the reaction solvent

Notes:

• Add slowly, with cooling• The metals used (Ti, Al etc.) can give rise to insoluble precipitates

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Aqueous Acidic or Basic Reactions

Examples:

• Hydrolysis reactions• Acid-base reactions• Redox reactions• Precipitation reactions

Quench:

For basic reactions: dilute acidFor acidic solutions: dilute base

Notes:

• Sometimes these reactions require no quench (e.g. Ester hydrolysis)

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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 NH4Cl and allow the ammonia to evaporate (in a fume hood)

Notes:

• Add quench very slowly

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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

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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

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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 UNTILYOU ARE SURE THAT YOUR PRODUCT HASBEEN RECOVERED!!!

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Isolation of Product – Extraction solvents

Solvent Specific gravityPentane 0.626

Petroleum ether 0.656Hexane 0.659

Diethyl ether 0.713Cyclohexane 0.779

Tert-butyl alcohol 0.781Isopropanol 0.785Acetonitrile 0.786

Ethanol 0.789Acetone 0.790

Methanol 0.7911-Octanol 0.826Toluene 0.867

Solvent Specific gravityBenzene 0.879

Tetrahydrofuran 0.889Ethyl acetate 0.895

N,N-Dimethylformamide 0.944Pyridine 0.982

Propanoic acid 0.993Water 1.000

Acetic acid 1.049Dimethyl sulfoxide 1.092Deuterium oxide 1.107Ethylene glycol 1.115

Propylene carbonate 1.21Chloroform 1.498

Specific gravity is often quoted in place of density: SG=density of solvent/density of water

SG<1.0 = float on H2O

SG>1.0 = sink under H2O

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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 MgSO4

• 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

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Reactions with PPh3OExamples:

• 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

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Copper Salts

Procedure:

• Quench reaction with NH4Cl 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 NH4Cl aq.• Isolate material• Filter through silica column

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Boron CompoundsExamples:

• Hydroboration• Allylation• Boron Redcution• Suzuki Couplings

Procedure:

• Concentrate the reaction mixture repeatedly from MeOH• This forms B(OMe)3 which is volatile

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R3Sn-X CompoundsExamples:

• Stannylation• Radical initinations• Stille Couplings

Procedure:

• Treat with AlMe3 to create non-polar Bu3SnMe

Or• Treat with NaOH to create polar Bu3SnOH• 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 MgSO4

• For Bu3SnH, , add I2 before KF treatment

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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 H2S• Some transition metals can be removed by aqueous extraction with

tris(hydroxymethyl)phosphine

See: R. H. Grubbs Tetrahedron Lett. 1999, 40, 4137

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Lithium aluminium Hydride

To work-up a reaction containing X g LiAlH4:

Procedure:

• Dilute with ether and cool to 0 oC• 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 MgSO4

• Stir 15 min and filter

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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 oC• 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 MgSO4

• Stir 15 min and filter

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Cr Oxidations

PCC/PDC:

Filter reaction mixture through a pad of florisil (make up pad as withthe Celite (page 13)

Jones:

Add isopropanol until reaction turns from orange/red to greenThis indicates that the oxidant has been consumed

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Meta Chloroperbenzoic Acid (m-CPBA)

Examples:

• Oxidations• Epoxidations

Procedure:

• If reaction done at reflux, cool reaction mixture to 0 oC to precipitate out all m-CPBA

• Add 10% solution of aq. Na2SO4

• 2 layers form• Separate and extract with DCM• Repeat addition of Na2SO4and extraction 3 times

• Wash organic layers with sat. aq. NaHCO3

• Wash organic layers with brine• Dry using MgSO4

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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• 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

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Acknowledgements

MAC Research Group

Dr. Stephen Hobson

MJH Research Group

Lynsey Cotterill

The Postgraduate Committee

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Other Workshops in the Series

Workshop Date

Recrystallisation and Growing Samples for X-Ray 15th June 2011

Industry Techniques 1: Flash Chromatography 13th July 2011

Air Sensitive Techniques 2: Using a Glove box 10th August 2011

Industry Techniques 2: Microwave Reactions 7th 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