Introduction.
Just about 80% of the reactions in organic lab involve a step called refluxing. You use a reaction solvent to keep materials dissolved and at a constant temperature by boiling the solvent, condensing it, and returning it to the flask. The reflux method is also widely used in drug synthesis such as Amphetamine and Methamphetamine and other phenylethylamines, LSD, some synthetic cannabinoids, CBD isomerization, MDMA and many other cases. This technique quite simple but you haven't to underestimate its danger and take all precautions.
Overview of Reflux.
A reflux setup (Fig. 1) allows for liquid to boil and condense, with the condensed liquid returning to the original flask. A reflux setup is analogous to a distillation, with the main difference being the vertical placement of the condenser. The liquid remains at the boiling point of the solvent (or solution) during active reflux.
A reflux apparatus allows for facile heating of a solution, but without the loss of solvent that would result from heating in an open vessel. In a reflux setup, solvent vapors are trapped by the condenser, and the concentration of reactants remains constant throughout the process. The main purpose of refluxing a solution is to heat a solution in a controlled manner at a constant temperature. For example, imagine that you want to heat a solution to 60℃ for one hour in order to conduct a chemical reaction. It would be difficult to maintain a warm water bath at 60℃ without special equipment, and it would require regular monitoring. However, if methanol was the solvent, the solution could be heated to reflux, and it would maintain its temperature without regular maintenance at the boiling point of methanol (65℃). True, 65℃ is not 60℃ and if the specific temperature were crucial to the reaction, then specialized heating equipment would be necessary. But often the boiling point of the solvent is chosen as the reaction temperature because of its practicality.
Step-by-Step Procedures.
1. Pour the solution to be refluxed into a round bottomed flask, and clamp it to the ring stand or latticework with an extension clamp and small rubber gasket (Fig.2 a and video). The flask should be no more than half full. There aren't rubber gaskets in the figs for unknown reasons. If you are using high-temperature boiling (>150℃) or flame heating, they cannot be used.
2. Add a stir bar or few boiling stones for bump prevention. Boiling stones should not be used when refluxing concentrated solutions of sulfuric or phosphoric acid, as they will colorize the solution. For example, when a stir bar is used for bump prevention with concentrated sulfuric acid, the solution remains colorless (Fig.2 b). When the same reaction is conducted using a boiling stone, the solution darkens during heating (Fig.2 c) and eventually turns the entire solution a deep purple-brown color (Fig.2 d).
2. Add a stir bar or few boiling stones for bump prevention. Boiling stones should not be used when refluxing concentrated solutions of sulfuric or phosphoric acid, as they will colorize the solution. For example, when a stir bar is used for bump prevention with concentrated sulfuric acid, the solution remains colorless (Fig.2 b). When the same reaction is conducted using a boiling stone, the solution darkens during heating (Fig.2 c) and eventually turns the entire solution a deep purple-brown color (Fig.2 d).
3. Place rubber hoses on a condenser (wet the ends first to allow them to slide on), then attach the condenser vertically to the round bottomed flask. If using a tall condenser, clamp the condenser to the ring stand or latticework (Fig.3 a). Be sure the condenser fits snugly into the flask. Safety note: if the pieces are not properly connected and flammable vapors escape, they may be ignited by the heat source. Do not connect the round bottomed flask and condenser with a plastic clip, as shown in Fig.3 с. Plastic clips can sometimes fail (especially when they are heated), and this setup does not allow for the flask to be reliably removed from the heat source at the end of the reflux.
Note: The higher the boiling point of your solvent (solvent mixture), the shorter you need a reflux condenser. Conversely, if your solvent boils at low temperatures (ether), use the longest Liebig reflux condenser.
4. Connect the hose on the lower arm of the condenser to the water faucet and allow the hose on the upper arm to drain to the sink (Fig.3 b). It is important that water goes in the bottom of the condenser and out the top (so water flows against gravity) or else the condenser will be ineffective as it will not fill completely.
Note: The higher the boiling point of your solvent (solvent mixture), the shorter you need a reflux condenser. Conversely, if your solvent boils at low temperatures (ether), use the longest Liebig reflux condenser.
4. Connect the hose on the lower arm of the condenser to the water faucet and allow the hose on the upper arm to drain to the sink (Fig.3 b). It is important that water goes in the bottom of the condenser and out the top (so water flows against gravity) or else the condenser will be ineffective as it will not fill completely.
5. If multiple solutions will be refluxed at the same time (e.g. if many students are performing a reflux side by side), the hoses from each reflux setup can be connected in series (Fig. 4). To accomplish this, the upper arm of "Setup A" which normally drains to the sink is instead connected to the lower arm of "Setup B." The upper arm of Setup B then drains to the sink. Connecting apparatuses in series minimizes the use of water, as water exiting one condenser enters the next. Several reflux setups can be connected in series, and the water flow should be monitored to ensure that all setups are adequately cooled.
6. Begin circulating a steady stream of water through the hoses (not so strong that the hose flops around from the high water pressure). Check again that the pieces of glassware securely fit together, then position the heat source under the flask. Turn on the stirring plate if using a stir bar.
a) If using a heating mantle, hold it in place with an adjustable platform (e.g. a wire mesh / ring clamp). Allow a few inches below the mantle so when the reaction is complete, the mantle can be lowered and the flask cooled. If the heating mantle is not a perfect fit for the size of the round bottomed flask, surround the flask with sand to create a better contact (Fig.5 a).
b) If using a sand bath, bury the flask in the sand so that the sand is at least as high as the level of liquid in the flask (Fig.5 b).
c) If the setup will eventually be left unattended for a long period of time (e.g. overnight), tighten copper wire over the hose attachments to the condenser to prevent changes in water pressure from causing them to pop off.
7. If the heat source was preheated (optional), the solution should begin to boil within five minutes. If it does not, increase the rate of heating. The appropriate heating rate occurs when the solution is vigorously boiling and a "reflux ring" is seen roughly one-third of the way up the condenser. A "reflux ring" is the upper limit of where hot vapors are actively condensing. With some solutions (e.g. aqueous solution), the reflux ring is obvious with easily visible droplets in the condenser (Fig.6 a+b). With other solutions (e.g. many organic solvents) the reflux ring is subtler, but can be seen with close observation (Fig.6 c). Subtle movement may be seen in the condenser as liquid drips down the sides of the condenser, or background objects may appear distorted from refraction of light through the condensing liquid (in Fig.6 d, the ring stand pole is distorted).
8. If following a procedure in which you are to reflux for a certain time period (e.g. "reflux for one hour"), the time period should begin when the solution is not just boiling but actively refluxing in the bottom third of the condenser.
9. The heat should be turned down if the reflux ring climbs to go half-way up the condenser or higher, or else vapors could escape the flask.
10. After the reflux is complete, turn off the heat source and remove the flask from the heat by either lifting the reflux apparatus up, or dropping the heat source down (Fig.7 a).
9. The heat should be turned down if the reflux ring climbs to go half-way up the condenser or higher, or else vapors could escape the flask.
10. After the reflux is complete, turn off the heat source and remove the flask from the heat by either lifting the reflux apparatus up, or dropping the heat source down (Fig.7 a).
Do not turn off the water flowing through the condenser until the solution is only warm to the touch. After a few minutes of air cooling, the round bottomed flask can be immersed in a tap water bath to accelerate the cooling process (Fig.7 b).
Dry reflux.
If you have to keep the atmospheric water vapor out of your reaction, you must use a drying tube and the inlet adapter in the reflux setup (Fig. 8). You can use these if you need to keep water vapor out of any system, not just the reflux setup.
1. If necessary, clean and dry the drying tube. You don’t have to do a thorough cleaning unless you suspect that the anhydrous drying agent is no longer anhydrous. If the stuff is caked inside the tube, it is probably dead. You should clean and recharge the tube at the beginning of the procedure. Be sure to use anhydrous calcium chloride or sulfate. It should stay okay in few usages. If you are fortunate, indicating Drierite, a specially prepared anhydrous calcium sulfate, might be mixed in with the white Drierite. If the color is blue, the drying agent is good; if red, the drying agent is no longer dry, and you should get rid of it (see Desiccants in “Vacuum desiccators”).
2. Put in a loose plug of glass wool or cotton to keep the drying agent from falling into the reaction flask.
3. Assemble the apparatus as shown, with the drying tube and adapter on top of the condenser.
4. At this point, reagents may be added to the flask and heated with the apparatus. Usually, the apparatus is heated while empty to drive water off the walls of the apparatus.
5. Heat the apparatus, typically empty, on a steam bath, giving the entire setup a quarter-turn every so often to heat it evenly. A burner can be used if there is no danger of fire and if heating is done carefully. The heavy ground glass joints will crack if heated too much.
6. Let the apparatus cool to room temperature. As it cools, air is drawn through the drying tube before it hits the apparatus. The moisture in the air is trapped by the drying agent.
7. Quickly add the dry reagents or solvents to the reaction flask, and reassemble the system.
8. Carry out the reaction as usual as a standard reflux.
2. Put in a loose plug of glass wool or cotton to keep the drying agent from falling into the reaction flask.
3. Assemble the apparatus as shown, with the drying tube and adapter on top of the condenser.
4. At this point, reagents may be added to the flask and heated with the apparatus. Usually, the apparatus is heated while empty to drive water off the walls of the apparatus.
5. Heat the apparatus, typically empty, on a steam bath, giving the entire setup a quarter-turn every so often to heat it evenly. A burner can be used if there is no danger of fire and if heating is done carefully. The heavy ground glass joints will crack if heated too much.
6. Let the apparatus cool to room temperature. As it cools, air is drawn through the drying tube before it hits the apparatus. The moisture in the air is trapped by the drying agent.
7. Quickly add the dry reagents or solvents to the reaction flask, and reassemble the system.
8. Carry out the reaction as usual as a standard reflux.
Addition and reflux.
Every so often you have to add a compound to a setup while the reaction is going on, usually along with a reflux. Well, you don’t break open the system, let toxic fumes out, and make yourself sick to add new reagents. You use an addition funnel. Now, we talked about addition funnels back with separatory funnels (Laboratory glassware) when we were considering the stem, and that might have been confusing.
Funnel use.
Look at Fig.9 a. It is a true sep. funnel. You put liquids in here and shake and extract them. But could you use this funnel to add material to a setup? No. No ground glass joint on the end; and only glass joints fit glass joints. Fig.9 c shows a pressure-equalizing addition funnel. Remember when you were warned to remove the stopper of a separatory funnel, so you wouldn’t build up a vacuum inside the funnel as you emptied it? Anyway, the sidearm equalizes the pressure on both sides of the liquid you’re adding to the flask, so it’ll flow freely, without vacuum buildup and without you having to remove the stopper. This equipment is very nice, very expensive, very limited, and very rare. And if you try an extraction in one of these, all the liquid will run out the tube onto the floor as you shake the funnel. So, a compromise was reached (Fig.9 b). Since you’ll probably do more extractions than additions, with or without reflux, the pressure-equalizing tube went out, but the ground glass joint stayed on. Extractions; no problem. The nature of the stem is unimportant. But during additions, you’ll have to take the responsibility to see that nasty vacuum buildup doesn’t occur. You can remove the stopper every so often or put a drying tube and inlet adapter in place of the stopper. The latter keeps moisture out and prevents vacuum buildup inside the funnel.
How to Set Up
There are at least two ways to set up an addition and reflux, using either a three-neck flask or a Claisen adapter. I thought I’d show both these setups with drying tubes. They keep the moisture in the air from getting into your reaction. If you don’t need them, do without them.
Funnel use.
Look at Fig.9 a. It is a true sep. funnel. You put liquids in here and shake and extract them. But could you use this funnel to add material to a setup? No. No ground glass joint on the end; and only glass joints fit glass joints. Fig.9 c shows a pressure-equalizing addition funnel. Remember when you were warned to remove the stopper of a separatory funnel, so you wouldn’t build up a vacuum inside the funnel as you emptied it? Anyway, the sidearm equalizes the pressure on both sides of the liquid you’re adding to the flask, so it’ll flow freely, without vacuum buildup and without you having to remove the stopper. This equipment is very nice, very expensive, very limited, and very rare. And if you try an extraction in one of these, all the liquid will run out the tube onto the floor as you shake the funnel. So, a compromise was reached (Fig.9 b). Since you’ll probably do more extractions than additions, with or without reflux, the pressure-equalizing tube went out, but the ground glass joint stayed on. Extractions; no problem. The nature of the stem is unimportant. But during additions, you’ll have to take the responsibility to see that nasty vacuum buildup doesn’t occur. You can remove the stopper every so often or put a drying tube and inlet adapter in place of the stopper. The latter keeps moisture out and prevents vacuum buildup inside the funnel.
How to Set Up
There are at least two ways to set up an addition and reflux, using either a three-neck flask or a Claisen adapter. I thought I’d show both these setups with drying tubes. They keep the moisture in the air from getting into your reaction. If you don’t need them, do without them.
Boiling Stones (Boiling Chips).
Boiling stones (or boiling chips) are small pieces of black porous rock (often silicon carbide) that are added to a solvent or solution. They contain trapped air that bubbles out as a liquid is heated, and have high surface area that can act as nucleation sites for formation of solvent bubbles. They should be added to a cool liquid, not one that is near its boiling point, or a vigorous eruption of bubbles may ensue. When a liquid is brought to a boil using boiling stones, the bubbles tend to originate primarily from the stones (Fig.11 b). Boiling stones cannot be reused, as after one use, their crevices fill with solvent, and they can no longer create bubbles.
Boiling stones should not be used when heating concentrated solutions of sulfuric or phosphoric acid, as they may degrade and contaminate the solution. For example, Fig.12 shows a Fischer esterification reaction that uses concentrated sulfuric acid. When a stir bar is used for bump prevention, the solution remains colorless (Fig.12 a). When the same reaction is conducted using a boiling stone, the solution darkens during heating (Fig.12 b) and eventually turns the entire solution a deep purple-brown color (Fig.12 c). Besides contaminating the solution, the dark color makes manipulation of the material with a separatory funnel difficult: two layers are present in Fig.12 d, although it is very difficult to see.
Heating methods and flammability:
- In some contexts, the choice of what heat source to use is critical, while in other contexts several could work equally well. The choice of which heat source to use depends on several factors:
- Availability (does your institution own the equipment?)
- Rate of heating (do you want to heat gradually or quickly?)
- Flexibility of heating (does the heat need to be waved around an apparatus?)
- Final temperature required (low boiling liquids require a different approach than high boiling liquids)
- Flammability of the content
As safety is an important factor in making laboratory choices, it's important to consider the flammability of the liquid to be heated. Almost all organic liquids are considered "flammable," meaning they are capable of catching on fire and sustaining combustion (an important exception is that halogenated solvents tend to be non-flammable). However, this doesn't mean that all organic liquids will immediately ignite if placed near a heat source. Many liquids require an ignition source (a spark, match, or flame) in order for their vapors to catch on fire, a property often described by the liquid's flash point. The flash point is the temperature where the vapors can be ignited with an ignition source. For example, the flash point of 70% ethanol is 16.6 ℃, meaning it can catch on fire at room temperature using a match. A Bunsen burner is an excellent ignition source (and can reach temperatures of approximately 1500 ℃), making burners a serious fire hazard with organic liquids, and a heat source that should often be avoided.
Another important property in discussing flammability is a liquid's autoignition temperature: the temperature where the substance spontaneously ignites under normal pressure and without the presence of an ignition source. This property is particularly insightful because it does not require a flame (which is frequently avoided in the organic lab), but only a hot area. A hotplate surface turned up to "high" can reach temperatures up to 350 ℃. Safety note: as diethyl ether, pentane, hexane, and low-boiling petroleum ether have autoignition temperatures below this value (Fig.14), it would be dangerous to boil these solvents on a hotplate as vapors could spill out of the container and ignite upon contact with the surface of the hotplate. In general, caution should be used when using a hotplate for heating any volatile, flammable liquid in an open vessel as it's possible that vapors can overrun the hotplate's ceramic covering and contact the heating element beneath, which may be hotter than 350oC. It is for this reason that hotplates are not the optimal choice when heating open vessels of volatile organic liquids, although in some cases they may be used cautiously when set to "low" and used in a well-ventilated fume hood.
Another important property in discussing flammability is a liquid's autoignition temperature: the temperature where the substance spontaneously ignites under normal pressure and without the presence of an ignition source. This property is particularly insightful because it does not require a flame (which is frequently avoided in the organic lab), but only a hot area. A hotplate surface turned up to "high" can reach temperatures up to 350 ℃. Safety note: as diethyl ether, pentane, hexane, and low-boiling petroleum ether have autoignition temperatures below this value (Fig.14), it would be dangerous to boil these solvents on a hotplate as vapors could spill out of the container and ignite upon contact with the surface of the hotplate. In general, caution should be used when using a hotplate for heating any volatile, flammable liquid in an open vessel as it's possible that vapors can overrun the hotplate's ceramic covering and contact the heating element beneath, which may be hotter than 350oC. It is for this reason that hotplates are not the optimal choice when heating open vessels of volatile organic liquids, although in some cases they may be used cautiously when set to "low" and used in a well-ventilated fume hood.
As combustion is a reaction in the vapor phase, liquids with low boiling points (< 40 ℃) tend to have low flash points and autoignition temperatures as they have significant vapor pressures (Fig.12). All low boiling liquids should be treated more cautiously than liquids with moderate boiling points (> 60 ℃).
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