Working on the microscale has many advantages. Workups take less time and are easy to do in parallel, heating and cooling is much more efficient, and 200 mg of intermediate lasts 10-20 reactions or more. I’ve already covered my favourite glassware for such reactions in an earlier post (vial chem), but there’s a whole set of skills necessary for measuring trace amounts of material that don’t come into play on the gram scale.
Solids
Solids to be weighed generally fall into one of three categories. The easiest to work with are small, free flowing granules that slide from spatula to weigh paper to vessel without leaving significant traces behind (potassium carbonate is a typical example). Crystalline materials are a little more challenging, as stray static charge usually holds them to both spatula and weigh paper, necessitating a quick rinse to “help” the residue into the reaction vessel. Gummy solids and hygroscopic materials are the worst, as both are difficult to scrape from their original container, and tend to hold tight to the weigh paper and spatula. With a gummy solid the usual solution is simply to dissolve the compound in a suitable solvent and transfer it via syringe or pipette.
Solids that weigh 15-150 milligrams
A good analytical balance (ideally with an error of ±0.1 mg) is required to accurately measure solids in this range. Luckily, these balances are not expensive, and most labs will have at least one. Weighing directly into your reaction vessel is viable for granular solids, but I generally use a 6 cm x 6 cm piece of weigh paper, torn into quarters and diagonally creased. The crease guides the solid into the reaction vessel, while the smaller size reduces overall surface area.
Solids that weigh less than 15 milligrams
With an analytical balance that measures to ±0.01 mg well-behaved solids less than 15 milligrams can be accurately weighed, though not without some difficulty. Slight breezes are enough to disturb the balance and prevent precise measurements, while a weak shake in the hand can spill the precious cargo en route to the reaction vessel. Work cautiously with plenty of room around you, and double check the number of grains before and after transfer to the reaction vessel.
Solids that are at all difficult to handle or precious should be dissolved in a carrier solvent at a known concentration, then transferred as a liquid (diethyl ether and dichloromethane good solvents, as they are relatively easy to remove under reduced pressure/nitrogen/argon [1]). If reactions are being set up in parallel the liquid transfer route is also significantly faster for more than ~2 samples.
Liquids of unknown density that weigh 50-200 milligrams
A 1 mL syringe with thin gauge needle (anywhere in the 19-22 range) is perfect for moving small quantities of poorly-characterized liquids. Weighing by difference, first measure the empty weight of the syringe, then draw up the liquid. Reweigh and repeat until the desired mass is achieved, then transfer the liquid to the reaction vessel. It’s necessary to rinse the syringe at least three times with a neutral carrier liquid to remove any residue, and thick oils may need to be adulturated with solvent prior to transfer.
Weighing via pipette: Measuring marker ink in acetone, for visibility.
Liquids of unknown density that weigh 10-50 milligrams
The standard pasteur pipette is your friend here. As above, tare an analytical balance with the empty pipette, then dab the pipette into your liquid/oil. Capillary action will draw up the liquid, which is then measured on the balance [2]. A thumb to the top of the pipette will eject the liquid, and solvent applied to the top (via a second pipette, now with bulb) will rinse any traces into the reaction vessel.
Liquids less than 10 milligrams and liquids of known density or concentration
As with solids in this range, dissolve the liquid to a known concentration in a neutral carrier solvent (ex. 1 mg/mL), and transfer with a 1 mL graduated pipette or hamilton microsyringe. The vials mentioned in this previous post will hold accurate concentrations for several months, provided the septa are not pierced.
Anhydrous conditions and the microscale
Maintaining an airfree environment is much more challenging on the microscale. Working with reactions that are at worst stoichiometrically sensitive to water, my practice has been to transfer solids to the reaction vessel under argon, then flush for ~10 minutes with argon before adding in solvent. Carrier liquids should be removed during the argon flush, rather than attempting to keep them dry outside of the fumehood/glovebox, and all glassware should be flame/oven dried. If any readers have expertise here, please speak up.
[1] In almost all cases the carrier liquid can also be your reaction solvent. With anhydrous reactions it’s probably easier to evaporate the solvent and purge/backfill with inert gas than keep the solvent dry though.
[2] As an aside, 1 cm of most oils in a standard pasteur pipette will give an acceptable NMR spectra.
Cutting two wedges 180 degrees apart from each other in the lip of a large-diameter rubber filter flask adapter (i.e. sigmaaldrich.com/catalog/product/aldrich/Z254312) makes a nice stage for your diagonally creased weigh paper. This allows you to avoid embarrassing spillage as you try to catch the corner of the weigh paper to pick it up.
I for one prefer weighing funnels (see, for example, http://www.chemglass.com/product_view.asp?pnr=CG-1760). They work well for BOTH liquid and solid reagents.
Converning footnote [2]:
I find that 1 cm will usually put way too much substance in your NMR tube. You can get signal broadening and couplings will just coalesce. I have had this problem many times already. Therefore, I usually use around 0.2-0.4 cm and get fine results. If there are certain peaks I don’t see in the 13C, then usually longer relaxation time solves this problem rather than adding more substance.
>Anhydrous conditions and the microscale
You forgot to mention the good ol’ high vac pump and Schlenk line (the default setup/apparatus in any synthetic lab). It will do wonders in respect to both convenience and working under anhydrous, mostly O2-free conditions. I’m sorry, this system won’t work with your screw-cap vial “reactor” system though.