SynMet microscale synthesis
What is small scale synthesis?
Not always better – but worth considering and worth knowing about!
• Few milligrams of material (1-100 mg).
• Small amounts of solvents.
• Use of little flasks.
Advantages:
• Cost of chemicals.
• Cost of solvents.
• Less risk.
• Less waste.
• Some things are faster.
•
•
Be gready!
Disadvantages:
Cost of equipment.
Different, and sometimes difficult unit operations.
• Static electricity makes life at the small scale difficult.
• Use of extra clean chemicals, dry solvents (Karl-Fisher is valuble) and clean equipment is important.

SynMet microscale synthesis
Cute is not always better (but sometimes it is)!
Who needs it:
• Initial testing of reactions – especially useful for multistep sequences.
• If you do not have much material
(e.g. the Marine chemistry group at KIKU).
• Medicinal chemistry (R&D) often only needs a few milligrams.
General considerations:
• It is not always enough to just make the equipment smaller.
• It is not always nesecary to use the smallest possible piece of equipment.
• Use simple setups!
• Sometimes special equipment is an advantage.
• Minimize the number of operations (material is often lost during transfer).
• Consider the use of cheap single-use equipment (it is often more clean!).
Be gready!

SynMet microscale synthesis
Unit operations
Reactions at room temperature or below:
• Test-tubes with the possibility of attatcing a septum are useful if small lessthan 1 ml flasks are not (easily) availble.
• Schlenk flasks are often useful.
Reactions above room temperature:
• It is useful to use air-condenser to avoid solvent or reagents being lost in glass-joints.
• Consider using closed systems like MW tubes, small autoclaves or similar.
• Begtrup style reaction flasks.
• Consider using NMR tubes as reaction vessel for direct monitoring
(remember NO magnetic stirbar, careful choice of solvent, concentration, and homogenity of reaction mixture.
• LC/MS vials can also be used.

SynMet microscale synthesis
Unit operations
Extractions:
• Separation funnels are often big and loss of material can be a problem.
• Use tall thin separation funnel (be gready, extract several times).
• Extractions using test tubes or small vials.
Filtration:
• Be gready – wash drying agent with extra solvent (pure and dry).
• Consider to filter through a Pasteur pipette filled with cotton wool. Apply preasure with a pipette teat.
• Micro-scale trituation, or crystallisation directly in reaction container: remove solvent with Pasteur pipette (or similar).
• Use vacuum (or preasure as above) when filtering; this helps avoiding condensation of water during the filtration proces.

SynMet microscale synthesis
Unit operations
Drying:
• Be gready – wash drying agent with extra solvent (pure and dry).
• Consider to filter through a Pasteur pipette filled with cotton wool. Apply preasure with a pipette teat.
• Use vacuum (or preasure as above) when filtering off the drying agent; this helps avoiding condensation of water during the filtration proces. Especially important on the small scale.
• Try to use the same flask as for the reaction.
• Choose the drying agent with care – often it is a good idea to use a drying agent that comes in big granulates. This enables one to avoid a filtration.

SynMet microscale synthesis
Unit operations
Removing the solvent:
• Rotory evaporator: sometimes good on microscale. Splash guard is a good idea, especially on small scale. Do not put non-round bottom flasks on rotory evaporator.
• Remove solvent by a flow of N
2
. Practical and fast on small scale.
• After crystallisation: remove solvent with pipette and remove residual solvent
in vacuo.
• Consider use of ’dimsen’.
• Speed vac can be useful.
• Lyophilization.

SynMet microscale synthesis
Unit operations
How to meassure on a small scale?:
• A very good scale (minimum of four decimals needed)!
• Consider to dilute / use aliquots.
• Static electricity might be a problem.
• Use Hamilton pipettes.
• Use of single-use plastic synges is very useful.
• Motorised addition apparatus can be useful.
• Consider the use of canula technique for addition of small amounts under inert atmosphere.

SynMet microscale synthesis
Purification techniques
Destillation:
• Kugel-rohr (bulp-to-bulp) destillation.
• Normal destillation (not practical with less than 1-2 ml).
• Steam destillation.
• Small-scale azeotrop destillation.

SynMet microscale synthesis
Purification techniques
Crystallisation:
• General crystallisation considerations (seven steps: choose solvent, dissolve the material, decolourise the solution, remove suspended solids (syringe filter can be useful), crystallise the compound, collect and wash the crystals, dry the product).
• Grannulated charcoal and drying agent can be useful on small scale.
• Practical to use the reaction vessel to crystallise in to avoid mechanical loss.
• Hirsch funnel might be useful.
• Craig-tube.
• Growing crystals for single crystal X-ray analysis.

SynMet microscale synthesis
Purification techniques
Chromatography:
• Preperative tlc.
• Chromatography in tiny flash columns (or in pasteur pipette) (see pp 235 in leonards book).
• Dry column vacuum chromatography.
• Other types of chromatography: size-exclusion chromatography (bio-beads in organic solvents, sephadex in aqueous solution), ion exchange chromatography.
• Flash master (or similar). We have one in the department, ask a local if you wish to try it during the cours.
Sublimation.
• Can be useful on a small scale.
• Kugel-rohr apparatus can sometimes be used.

SynMet microscale synthesis
Be gready!

SynMet microscale synthesis
Purification techniques

Equipment to show:
Kugelrohr apparatus.
Test tube for reaction at microscale.
Small rbf’s.
MW vial, autoclaves, Begtrup vials, alu block + vials.
Hirsch funnel + setup.
NMR tubes (various).
Small splash gueards for rotovap.
Dimsen and N2 evaoopration system.
Hamilton pipetter.
Mikropitetter.
Pipettefiltre.
Syringe pump.
Canula equipment.
Microscale destillation equipment.
Dean-Stark apparatus.
Steam destillation using normal destillation setup.
Schlenk flask with small filter.
Sclenk flask with solid addition setup.
Craig setup.
Prep. Tlc.
Small column.
Small dry column.
Sublimation kit.

Equipment to show:
Kugelrohr apparatus.
Test tube for reaction at microscale.
Bøger tages med:
Small rbf’s.
Diverse mikrobøger.
MW vial, autoclaves, Begtrup vials, alu block + vials.
Hirsch funnel + setup.
Houben-weil.
NMR tubes (various).
Purification of laboratory chemicals.
Small splash gueards for rotovap.
Guide to the perplexed
…
Dimsen and N2 evaoopration system.
Begtrups noter.
Hamilton pipetter.
Mikropitetter.
Pipettefiltre.
Tjek hvem der er overlap
Syringe pump.
med og instruer i
Canula equipment.
fællesopgaver.
Microscale destillation equipment.
Dean-Stark apparatus.
Steam destillation using normal destillation setup.
Schlenk flask with small filter.
Sclenk flask with solid addition setup.
Craig setup.
Prep. Tlc.
Small column.
Small dry column.
Sublimation kit.
Ampuller.
Værktøj til at åbne ampuller.
Sprøjter.
Nåle.
Trevejshaner.
Teflondimser til slib.
NH3 refluxer system.
Schlenklinje udstyr.