06/12/13

Extraction in Theory and Practice (Part I)

last updated Mon, Jun 23, 2003

Extraction (Part 1)
After you carried out an reaction, the solution often times not only contains the desired product, but also undesired byproducts of the reactions, unreacted starting material(s) and the catalyst (if used). In order to isolate the target compound, these products have to be remove in one way of the other. A very useful method to do so is an extraction or often also referred to as washing. However, these two operations are targeting different parts in the mixture. While the extraction affords the 'good stuff' from an impure matrix, the washing removes impurities from the 'good stuff'. Most of the time, a liquid-liquid extraction is performed. This implies that the liquids used are immisciblein order to form two layers on contact. Since most of the extractions are performed using aqeuous solutions, the miscibility of the solvent with water is crucial point. a. Good solvents (because they form two layers in contact with aqueous solutions): dichloromethane (=methylene chloride), chloroform, diethyl ether, ethyl ester b. Bad solvents (because they are miscible with aqueous solutions): ethanol, methanol, tetrahydrofuran (THF), acetone Even diethyl ether and dichloromethane dissolved up to 5-7 % in water. Therefore it is not advisable to use small quantities of these solvents with large quantities of aqueous solution. The most important point to keep in mind throughout the extraction process is which layer contains the product. Generally, chlorinated solvents e.g. CH2Cl2, CHCl3, etc are heavier than water while ethers, hydrocarbons and esters usually possess a lower density than water (see solvent table). If you prepare an organic compound, it is relatively safe to assume that it will dissolve better in the organic layer than in the aqeuous layer except you convert it to something else which makes it more water soluble. Before going more into detail, here is a rule that you should always follow when performing a work-up process. Never, ever throw away any layer, until you are absolutely sure (=100%) that you will never need it again. And the only time that you can really be sure about that is if you isolated your final product and it has been identified as the correct product by melting point, IR spectrum, etc. Keep it mind that it is always easier to recover the product from a different layer than from the waste container or the sink. In this context it would be wise to label all layers as well in order to be able to identify them later on. What do I use when to extract? There are several standard solutions that are used for extraction: 5% hydrochloric acid, 5% sodium hydroxide solution, saturated sodium bicarbonate solution (~6%), water. In order to extract an organic compound it often has to be modified in order to make it more water soluble. a. Removal of an acid In order to remove an acid from your mixture, a base is required e.g. NaOH or NaHCO3. The acid and the base react to form a salt which is usually exhibits a high water solubility.

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Extraction in Theory and Practice (Part I)

Which of the two reagents should be used depends on the other compounds present in the mixture. Sodium hydroxide is usually easier to handle since it does not evolve carbon dioxide. The formation of carbon dioxide causes a pressure build-up in the separatory funnel. However, if compounds are present that are sensitive to strong bases or nucleophiles e.g. esters, ketones, etc, sodium bicarbonate should be used since it it is a weaker nucleophile (resonance stabilization). The acid can be recovered by adding a mineral acid to the basic extract. b. Removal of phenol Due to the fact that phenols are weak acids, they do not react with sodium bicarbonate, which is a weak base. This can be used to separate acids and phenols (see below).

The phenol can be recovered by adding a mineral acid to the basic extract. c. Removal of an amine Amines are basic and can be converted to salts using acids e.g. hydrochloric acid.

The amine can be recovered by adding a strong base like NaOH or KOH to the acidic extract. d. Isolation of a neutral species Most neutral compounds cannot be converted into salts without changing their chemical nature. A lot of these neutral compounds tend to react in undesired ways:.esters undergo hydrolysis upon contact with strong bases or acids . Other compounds e.g. epoxides rearrange catalyzed by acids. In order to separate these compounds, often times column chromatography is used.

e. General Separation Scheme Based the discussion above the following overall separation scheme can be outlined.

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Extraction in Theory and Practice (Part I)

The indivual steps can be exchanged in many cases. Which sequence is the most efficient one highly depends on the individual target molecule. There is obviously no reason to go through the entire process if you are only interested in one compound that can be isolated in the first step already.

Practical Aspects of Extraction An extraction can be carried out in macro-scale or in micro-scale. In macro-scale, usually separatory funnel is used. In micro-scale the extraction can be performed in a conical vial or a centrifuge tube. Here are the most common problems encountered in the lab: a. Which layer is the aqueous layer? As explained above (beginning of this handout), most solutions are relatively diluted and their density is not much different from that of water. Looking up the density of a solid e.g. sodium hydroxide does not give information that you are looking for. In summary, ether and esters are usually lighter than water, dichloromethane and chloroform are heavier. The density is determined by the major component of a layer. 5% of a solute does not usually change this too much. b. How comes I got three layers? It is not uncommon that a small amount of solvent ends up on top. Mixing with a stirring rod or gentle shaking usually takes care of the problem. c. Help, my layers don't separate! You probably overdid it with the shaking a little bit and formed an emulsion (not two distinct layers). In such a case, you need to have some patience. Stirr the mixture slowly with a glass rod to bring the small droplets faster together to form a new layer. In some cases, the phases have similar polarity or density. If this is one of those cases, the addition of more solvent can be helpful. Sometimes, the addition of a salt can also lead to a better phase separation ("Salting out"). d. How do I know that I am done extracting? In most cases, you will never really extract everything (keep in mind that you have finite distribution coefficients, see extraction II). As a general rule, use multiple extraction with small quantities of solvent instead of one extraction using a batch of solvent. The amount of material left behind after two or three extractions is usually very small and does not justify the effort (solvent and extra time). Excessive extraction can also lower the yield of your product, if it dissolves significantly in the other phase. e. Help, my extraction container (vial, centrifuge tube) makes funny noises! You are probably using sodium bicarbonate for the extraction to neutralize/remove an acid. The reaction leads to the formation of CO2 (which is a gas at ambient temperature). The systems builds up a pressure that
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Extraction in Theory and Practice (Part I)

pushes some of the gas out and probably some liquid as well. Make sure that you vent (open) the container immediately before the pressure build-up causes an explosion. f. My centrifuge tube leaks! Did you check before hand if the cap that you are using really belongs to the tube? Did you screw the cap all the way on? Do you use NaHCO3 for extraction and forgot to vent (see e.)? g. Why do we use a centrifuge tube or a concial vial for the extraction and not a beaker or test tube? The conical shape of these pieces of equipment makes it easier to collect the solution on the bottom using a Pasteur pipet. It is very difficult to collect a liquid if it is spread out over a large, flat area. h. Which layer to I remove? Top or Bottom? You always take out the bottom layer first since it is much easier to do independent if this is the one that you actually want to further use or not. i. How much solvent/solution do I use for the extraction? This highly depends if you want to remove a large quantity of a compound of not. For most washing processes, 10-20% of the volume of the solution to be washed will do a good job. If you have to transfer or neutralize a large amount of compound, you usually use more concentrated solutions and higher quantities. In either way, always use multiple extraction over one extraction with a large quantity of solution/solvent (see extration II). If you use more concentarted solutions, be aware that neutralization reactions evolve heat, which can be a serious problem when using low boiling solvents e.g. ether, dichloromethane, etc. UNDER CONSTRUCTION!

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