Transcript Effective Quenching and Working-up of Reactions Advanced Research Techniques Workshop 18th May 2011 David Molyneux Outline Quenching/Working-up of Reaction Mixtures • Definitions • Importance • General comments/procedure Quenches for Various.

Effective Quenching and Working-up
of Reactions
Advanced Research Techniques Workshop
18th May 2011
David Molyneux
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Outline
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
Formulas For Some Specific Reagents
• Cu salts
• Boron compounds
• R3SnX by-products
• Metal Salts
Practical Considerations
• Techniques and apparatus
• Extraction Solvents
• Tips
• Troubleshooting
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Al based reductions
Cr oxidation by-products
m-CPBA
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Quenching of Reactions
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).
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Working-up of Reactions
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
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General Work-up Procedure
A standard work-up typically involves:
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Quenching the reaction
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Separating the reaction mixture into organic and aqueous layers by
liquid-liquid extraction
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Washing the product of any unreacted reagents/unwanted byproducts
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Drying of the product (if organic)
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Filtration
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Removal of solvents by evaporation
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Non-Aqueous Strongly Basic Reactions
Examples:
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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:
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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
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Non-Aqueous Strongly Basic Reactions
Exception (Aluminium Reagents):
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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)
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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
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Non-Aqueous Neutral 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:
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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).
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Non-Aqueous Strongly Acidic Reactions
Examples:
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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:
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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:
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Hydrolysis reactions
Acid-base reactions
Redox reactions
Precipitation reactions
Quench:
For basic reactions: dilute acid
For acidic solutions: dilute base
Notes:
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Sometimes these reactions require no quench (e.g. Ester hydrolysis)
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Liquid Ammonia Reactions
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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:
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Add quench very slowly
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Isolation of Product
Procedure:
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Remove any solids by filtration
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Partition reaction mixture between an organic solvent and water (or
other aqueous solutions)
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Wash desired layer
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Dry (if organic)
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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:
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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:
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Extract the desired layer a minimum of 3 times
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If product in organic layer, make final wash brine
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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)
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Densities can be found in Alrich catalogue
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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!!!
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Isolation of Product – Extraction solvents
Specific gravity is often quoted in place of density:
SG=density of solvent/density of water
Solvent
Pentane
Petroleum ether
Hexane
Diethyl ether
Cyclohexane
Tert-butyl alcohol
Isopropanol
Acetonitrile
Ethanol
Acetone
Methanol
1-Octanol
Toluene
Specific gravity
0.626
0.656
0.659
0.713
0.779
0.781
0.785
0.786
0.789
0.790
0.791
0.826
0.867
SG<1.0 = float on H2O
SG>1.0 = sink under H2O
Solvent
Specific gravity
Benzene
0.879
Tetrahydrofuran
0.889
Ethyl acetate
0.895
N,N-Dimethylformamide
0.944
Pyridine
0.982
Propanoic acid
0.993
Water
1.000
Acetic acid
1.049
Dimethyl sulfoxide
1.092
Deuterium oxide
1.107
Ethylene glycol
1.115
Propylene carbonate
1.21
Chloroform
1.498
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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:
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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.
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Remove solvent by rotary evaporation
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Reactions with PPh3O
Examples:
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Wittig Reactions
Misunobu Reactions
Brominations
Procedure:
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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:
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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 Compounds
Examples:
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Hydroboration
Allylation
Boron Redcution
Suzuki Couplings
Procedure:
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Concentrate the reaction mixture repeatedly from MeOH
This forms B(OMe)3 which is volatile
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R3Sn-X Compounds
Examples:
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Stannylation
Radical initinations
Stille Couplings
Procedure:
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Or
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Treat with AlMe3 to create non-polar Bu3SnMe
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:
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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:
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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:
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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 with
the Celite (page 13)
Jones:
Add isopropanol until reaction turns from orange/red to green
This indicates that the oxidant has been consumed
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Meta Chloroperbenzoic Acid (m-CPBA)
Examples:
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Oxidations
Epoxidations
Procedure:
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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
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Effective Quenching and purification is essential to ensure good purity
and maximum recovery of a product
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It is important to consider the side-products formed during a reaction,
and how these can be removed effectively
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Every system is different, but the examples given cover most eventualities
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Solvent selection is important
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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
Dates, locations and titles to be confirmed
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Sign-up sheet for each workshop will be available on the Postgraduate
Notice board two weeks in advance
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PhD students: record attendance at each workshop in your e-portfolio
1 school PGRDP credit is available per workshop
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