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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.

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.

• Advantages
• Cost of chemicals.
• Cost of solvents.
• Less risk.
• Less waste.
• Some things are faster.

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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 (RD) 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!
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SynMet microscale synthesis
Unit operations

• Reactions at room temperature or below
• Test-tubes with the possibility of attatcing a
  septum are useful if small less-than 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.

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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.

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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.

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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 N2. 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.

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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.

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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.

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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.

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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.

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SynMet microscale synthesis
Be gready!
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SynMet microscale synthesis
Purification techniques
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Equipment to show Kugelrohr apparatus. Test tube
for reaction at microscale. Small rbfs. 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. Pipettef
iltre. 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.
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Equipment to show Kugelrohr apparatus. Test tube
for reaction at microscale. Small rbfs. 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. Pipettef
iltre. 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. Ampuller. Værktøj til at åbne
ampuller. Sprøjter. Nåle. Trevejshaner. Teflondims
er til slib. NH3 refluxer system. Schlenklinje
udstyr.
Bøger tages med Diverse mikro-bøger. Houben-weil
. Purification of laboratory chemicals. Guide to
the perplexed Begtrups noter.
Tjek hvem der er overlap med og instruer i
fællesopgaver.
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