Drying THF-3

Drying THF-2

Drying THF-1

SOP- Solvent Stills (compiled by Samuel Huang)

Solvent Stills

The principle purpose of solvent stills is to provide a source of pure, completely dry solvent with a minimum of lead time. Whether or not a solvent requires a permanent, recycle type still or a more temporary solution depends on both the volume and frequency of its use. Several different varieties of still heads are commercially available. For permanent setups the best designs can be set to recycle rather than to collect solvent. This would allow the stills to be kept permanently hot rather than having to be started from room temperature each time distilled solvent is needed. It is very important in this type of still to size the receiver vessel appropriately to the still-pot. The receiver should never be more than half the size of the still-pot. For commonly used solvents, two and five liter still-pots are the most commonly used. Solvents used in lesser quantities can be dispensed from smaller stills; but stills smaller than about 250 mL are, in most cases, more trouble than they are worth. The still-pot should always have at minimum two necks; otherwise the still will have to be taken apart to add fresh solvent or drying agent. To keep stills dry and oxygen free, they are connected to an inert gas source, and fitted with a bubbler to vent excess pressure.

Among the first decisions to be made is whether to use argon or nitrogen as the inert gas. Nitrogen is cheaper and house nitrogen is generally pure and dry enough for stills. Argon, being denser than air, has a better blanketing effect, but it is more expensive and generally only available in cylinders. Nitrogen is probably the best choice in most cases as the permanence of a house supply means the stills will not be deprived of inert gas by a cylinder being emptied over a long weekend.

The use of a sodium benzophenone ketyl solution is among the most common methods to prepare pure, anhydrous, oxygen-free solvents. The use of a ketyl solution is, of course, restricted to solvents that do not react with the alkali metals. Suitable solvents include various ethers and hydrocarbons.

Chlorinated solvents, and solvents subject to reduction such as dimethylformamide, dimethylsulfoxide and acetonitrile, should be dried with calcium hydride.

The question of whether to use potassium or NaK versus sodium in ketyl stills is a common conundrum. Potassium (m.p. 64°) and NaK have lower melting points and thus tend to form their ketyls more easily (fresh metal surface is continually being exposed to the benzophenone solution). However, a sodium ketyl, once formed, is just as capable as the others in preparing dry and oxygen free solvents. It also has the advantage of being much more simply and safely disposed of. In the case of solvents like toluene and xylenes that boil above sodium's melting point (m.p. 98°) there is no question that they will be dried quickly and thoroughly by sodium. The most commonly used solvents and how they should be purified are listed below:

Diethyl ether, b.p. 34.6°
Ether from freshly opened cans can be added directly to a ketyl pot. Sodium metal (5 g per liter of solvent) should be cut into roughly 5 mm cubes, first under hexane to remove adhering oil and then transferred to a small bath of ether to wash away any hexane, and finally transferred to the ketyl pot. Benzophenone (10 g per liter) is then added and the solution heated to reflux. Diethyl ether's ketyl is a deep royal blue. If, after refluxing for twenty minutes, the still-pot is not permeated by the dark blue of the ketyl, more sodium is needed. Cool the still-pot to room temperature and careful add a few more pieces of metal, then reheat.

Tetrahydrofuran, b.p. 65.4°
As THF is completely miscible with water it is best not to take any chances as to it being wet. THF should be first refluxed 24 hours over calcium hydride (10 g per liter) then distilled for use in the ketyl pot. Sodium preparation is similar to that for diethyl ether, the final wash of course would be with THF. THF's ketyl is a deep purple color.

Benzene, b.p. 80.1°
Toluene, b.p. 110.6°
Xylenes, b.p. 138-144°
These aromatic solvents, from freshly opened bottles, can be added directly to a ketyl pot. No pretreatment of these solvents is necessary. Sodium and benzophenone amounts should be as for diethyl ether. Ketyl color will be dark blue to purple. Be sure to leave plenty of expansion room in toluene and xylene stills. Their high boiling points and relatively high expansion coefficients can lead to serious problems if not allowed for.

Pentane, b.p. 36.1°
Hexane, b.p. 68.7°
These hydrocarbons need extensive pretreatment. Either should be stirred for at least one week over concentrated sulfuric acid ((250 mL per L solvent). The acid should be changed as it turns black. Once fresh acid is no longer darkened the hydrocarbon is ready for the next step. Wash twice with water, then carefully wash with saturated bicarbonate. Dry thoroughly over calcium chloride, then add to still. In addition to the sodium and benzophenone, diglyme is necessary to solubilize the ketyl ((10 ml per liter solvent). The ketyls are dark blue after reflux overnight.

Acetonitrile, b.p. 82°
Acetonitrile can be used directly from a freshly opened bottle with no pretreatment. Calcium hydride (10 g per liter) is used as the drying agent.

Dichloromethane, b.p. 40.0°
Dichloromethane can be used directly from a freshly opened bottle with no pretreatment. Calcium hydride (10 g per liter) is used as the drying agent.

Dimethylformamide, b.p. 153°
Calcium hydride (10 g per liter) is used as the drying agent, followed by filtering off the hydride and distillation. Serious decomposition problems occur with acidic or basic drying agents. DO NOT reflux with the calcium hydride. Can be used directly from a freshly opened bottle with no pretreatment.

Dimethylsulfoxide, b.p. 190°
Although fully miscible with water, DMSO from freshly opened bottles is dry enough to be used without preliminary drying. Calcium hydride (10 g per liter) is used as the drying agent.

Recommended Solvent Drying Agents

Solvent	Drying Agent
Tetrahydrofuran	Sodium wire/benzophenone
Ethanol	Magnesium
Acetonitrile	Calcium hydride
Acetone	Calcium chloride
Dichloromethane	Calcium hydride
Ethyl acetate	Calcium hydride
(2-Methoxyethyl)ether	Sodium
40/60 Petrol ether	Calcium hydride or Sodium wire/benzophenone/triglyme
Toluene	Sodium
Diethyl ether	Sodium wire/benzophenone
Methanol	Magnesium
Hexane	Calcium hydride or Sodium wire/benzophenone/triglyme
Pentane	Calcium hydride or Sodium wire
Heptane	Calcium hydride or Sodium wire
Benzene	Calcium hydride or Sodium wire
Xylene	Sodium

Quenching Solvent Stills

The quenching of used still-pots, especially ketyl pots, is potentially dangerous but can be done safely if appropriate precautions are taken. These include: wearing goggles, labcoat and gloves; working in a well ventilated hood behind a safety shield; and quenching the reactive compounds slowly.

Stills that used calcium hydride as the drying agent are the easiest to quench. After the majority of the solvent has been decanted away from the drying agent, the remainder, along with the calcium hydride, is poured slowly over crushed ice. The ice is replaced as it melts so that the unreacted calcium hydride is always being added to a solution that consists mostly of ice. Lumps stuck in the still-pot must be carefully removed with a spatula. When nothing but a thin film of hydride remains in the stillpot it can be washed out with cold water.

Ketyl pots require special care. First, one must be certain as to whether the still had contained sodium, potassium, or NaK. The process is similar for all three; if uncertain, assume potassium is present and use the following procedure:

1. The entire quenching process should be carried out under a steady stream of nitrogen with a large opening to vent both the nitrogen stream and the hydrogen gas which is generated.

2. Pour off excess solvent, and refill the flask with dry xylene or toluene.

3. Add a reflux condenser and an addition funnel filled with sufficient dry tert-butyl alcohol to react with 150% of the expected amount of metal.

4. The alcohol is added dropwise, stopping if the solution begins to boil too vigorously.

5. After the addition is complete, the solution is heated to reflux overnight.

6. The process is repeated with isopropanol and then methanol.

7. If no bubbling is observed upon addition of methanol a small (1 mL) quantity of water is added to confirm that all of the metal has been quenched. If the still only used sodium the tert-butyl alcohol step may be omitted and the process may be begun with isopropanol. The final mixture may be safely disposed of in a hazardous waste container.

Research Group Responsibilities (compiled by Samuel Huang)

Since most research groups operate under a commune-type relationship, it is necessary for each person in the laboratory to perform their respective duties. The following section attempts to outline the different types of responsibilities involved with maintaining a smooth running research group. Also included within this section is some information detailing what is involved with each of these responsibilities. It is worthwhile to attempt to gain experience with each of these chores so that you may become proficient, as you may be called upon to perform similar tasks in future employment (assuming that chemistry is in your future!).

1) Maintaining the Anhydrous Solvent Stills

If your research lab is involved with the handling of air and moisture sensitive reagents, it is necessary to maintain anhydrous solvents in order to run your reactions. Thus, ensuring a low water content in the solvents employed is absolutely necessary. The following are some instructions for handling the solvent stills. Note that all solvents are distilled under a stream of dry nitrogen or argon to ensure the anhydrous nature of the solvent, as well as to eliminate the exposure of these solvents to air (a necessity for performing air sensitive chemistry). Argon gas is somewhat superior to nitrogen in that it is heavier and is less prone to displacement by air.

• Tetrahydrofuran*, Diethyl Ether* and Dimethoxyethane* are ethereal solvents, which are most effectively dried by refluxing over an appropriate drying agent; currently, this is a reactive species called a ketyl. This is formed by refluxing the solvent with 1-2g of sodium, sliced very thin to maximize its surface area, for about 30min; then, a small quantity (several grams; about a tablespoonful) of benzophenone (Ph₂C=O) is added. Within only 5-10min at reflux, the mixture will take on a beautiful deep blue/purple color; this color indicates that the solvent is not only anhydrous, but oxygen-free. It is now ready for collection to be used in a reaction.

Quenching of a still is typically accomplished by cooling the pot of the distillation apparatus to 0 °C and slowly adding t-butyl- or isopropyl alcohol to the mixture with vigorous stirring, although we have been experimenting with quenches at higher temperatures. Students must be checked out by the experienced postgraduate students in order to be allowed to perform quenches; if the process is done incorrectly, fires and/or explosions can occur.

• Dichloromethane*, Benzene**, and Toluene all have similar drying procedures as well. These solvents are most effectively dried by heating these solvents to reflux over calcium hydride (CaH₂). Calcium hydride is a metal hydride which, relative to others (especially Group I) is of low reactivity (it is fairly selective for water). After these solvents are refluxed with calcium hydride for several hours, the pot will appear as a dark gray suspension); it is now time to distill the anhydrous solvent.

This type of still is quenched as above, except that 95% ethanol is used as the acid. Once again, I must check you out before you can do it on your own (but not alone, of course!).

The solvents listed above are among the ones more commonly in organic research. If you require other anhydrous solvents, two excellent sources of methods for the purification of chemicals is shown below.

• Arnold J. Gordon and Richard A. Ford. The Chemists Companion. New York: John Wiley & Sons, 1972.

• D. D. Perrin and W. L. F. Armarego. Purification of Laboratory Chemicals, 3 rd edition. Oxford: Pergamon Press, 1988.

* These solvents are most usually in our permanent stills in the left-most hood.
**Benzene is toxic and carcinogenic; it should be used only when absolutely necessary and only after checking with experienced postgraduate students first.

2) Group Supplies

This important job is to ensure that the group has a continuous supply of single-use items which researchers use daily; if we run out, things can come to a screeching halt! Some things we get from the stockroom; others we order. These items include acetone for cleaning glassware, anhydrous ethyl ether, paper towels, bulk solvents, disposable pipettes and small test tubes, concentrated acids, certain inorganic reagents, Kimwipes⁷, TLC plates, and the like.

Although there is a place on the board for people to write items that we need, part of this responsibility entails just being vigilant. It's nearly always possible, and an excellent idea, to have an item or two "in stock" in the lab, so that if we run out of something on a weekend, we won't run out (get it?). This would be particularly true for solvents.

3) Vacuum Pumps, Manifold, Rack, and Lines

This job is one that, if not done conscientiously, will have other group members screaming! The area around the vacuum rack must , as well as periodically cleaning the glassware associated with the line and occasionally re-greasing the ground glass joints of the vacuum line glassware. In addition, it is necessary to periodically drain the pump oil from these mechanisms, rinsing the inner chamber with organic solvent (usually with acetone or dichloromethane), and refilling the chamber with fresh pump oil. This needs to be done once every three months to ensure a long life of each vacuum pump. It is suggested that a maintenance log is kept for each individual vacuum pump describing problems with the pump, routine maintenance, oil changes, and the last measured operating pressure for each pump. If extended maintenance is required for a pump, the device in question should be taken down to the stockroom along with a tag explaining whose pump it is and what the problem is with the pump. A more detailed description for changing the pump oil is included in a later section of this manual.

4) Wash Solutions

Ensure that there are ample quantities of the most commonly employed solutions used during the aqueous work-ups of organic reactions. The common aqueous solutions employed our research lab are the following (all are saturated solutions unless otherwise specified):

Solution	Typical Uses
Hydrochloric acid (1.5M)	used for removing amine reagents from reaction mixtures or for purifying amine products.
Sodium Chloride	brine, used for removing water from organic solutions in an aqueous workup; it is usually the last solution the organic layer is washed with prior to using a drying agent.
Sodium Bicarbonate	used for removing acid from the organic layer.
Copper (II) Sulfate	for removing pyridine from reaction mixtures, esp. β-lactonizations..
Ammonium Chloride	commonly used as a mild acid for quenching mildly basic reactions, i.e. reductions and Grignard type reactions.
Sodium Hydroxide(5% [w/v])	used for removing acid and carboxylic acid reagents from reaction mixtures, as well as for removing phenols and thiophenols from reaction mixture

To prepare saturated wash solutions, continue to add the inorganic salts to one gallon of distilled water until no more salt dissolves into solution and then add an additional quantity of the salt so that there is a layer of the salt about 1" deep at the bottom of the bottle. Doing this ensures that the wash solution will remain saturated.

A 5% aqueous solution of sodium hydroxide is prepared by dissolving 5 g of NaOH for every 100 mL of distilled water employed in preparing the solution. These are best stored in plastic bottles as highly alkaline (basic) solutions tend to etch glass upon standing for long periods of time.

A 1.5 M solution of hydrochloric acid may be prepared by diluting concentrated (12 M) HCl with distilled water. The ratio for such solutions is 125 mL of concentrated HCl and 875 mL of distilled water. This will prepare 1 L of the desired solution.

5) Group Area Cleanliness

It is this person's responsibility to see to it that the balance area is being maintained in a clean fashion and to ensure that the balance is kept in working order. Should problems arise with the balance, it should be called in to either the stockroom or to Mr. Ramsey in the electronic shop down stairs. In addition to this, the person with this duty should also see to it that the refrigerator and other electronic or mechanical devices are in good working order. Also included in these items are the heating mantles, the hoods, light fixtures, the variable voltage transformers, the hoods, the rotary evaporator (Rotovap), and hot plates. Many of these items may be repaired by Terry Ramsey in the electronic shop on the first floor.

6) Purchasing

It is this person's responsibility to act as a liaison between the group and the chemical companies who supply the reagents and equipment employed within the lab. They are assigned to compile a list of chemicals required by the group, finding optimum prices for these chemicals, and ensuring a speedy delivery of these chemicals. In addition, they are responsible for checking with the chemical inventory person, to ensure we do not already possess this chemical, and with the research adviser for approval of the chemical order.

7) Chemical Inventory/Receiving

The person given this responsibility is entrusted to ensure that records are maintained for each chemical on hand. Ideally, these records should include the identity of the chemical, the quantity on hand, the date received and opened, the supplier of the chemical, and the location of this chemical within the research lab. This individual should attempt to make special note of any important storage requirements, and should file the necessary MSDS (Material Safety Data Sheets) of these chemicals for easy access within the group.

8) Reagent Bottles

There are several reagents that are used fairly universally in our group, and this person's job is to be sure that we don't run out of distilled, pure reagents, stored in serum bottles to be used for syringe transfer. The reagents are, usually, the following:

Reagent	bp*	Dist'd. From	Stored Over	Comments
Benzenesulfonyl chloride	251	nothing	3Å sieves	Do in hood; nasty lachrymator
Diisopropylamine	84	BaO	nothing	Can be off-color and still be OK
Pyridine	115	BaO	nothing	Smelly; to some, it's unbearable
Triethylamine	89	CaH	3Å sieves	Stores very well, if pure

*bp values are all in ^oC and at 760mm pressure.

9) Waste Management

The Waste Manager must ensure that log records are being maintained for each waste bottle and must act as a liaison between the stockroom and the research group for getting a timely schedule for waste collection. Forms for these waste bottles may be obtained from the stockroom and ideal containers for waste storage are 1 gallon glass bottles which are coated with a shatter resistant layer of polymer to prevent leakage if a breakage occurs. These bottles must also be properly labeled to ensure easy identification and content of these bottles.