exp 4

Liquid-Liquid Extractions

As seen in Exp. 3, compounds can be separated on the basis of polarity.  Compounds that are less polar will be attracted to substances that are less polar, compounds that are more polar will be attracted to substances that are more polar.  Remember “like dissolves like”; substances of similar chemical affinity will mix.  Compounds that have dissimilar polarity will not mix (e.g., oil and water). 

In this experiment, we will first use two solvents, one more polar and one less polar, to extract (i.e., remove or separate) a drug (the solute) from a tablet.  Here, the drug is less soluble in the more polar (aqueous) solvent, and so when the two solvents are adjacent to one together, the drug will migrate or partition over to the less polar (organic) solvent, as shown in Figure 4.1.  This is referred to as a liquid-liquid extraction.  The efficiency of the extraction is dependent upon the relative polarities between the solvents and solute.

Figure 4.1 Acetaminophen Partitioning from the Aqueous to Organic Solvent

The solubility of certain molecules can be altered through acid-base reactions.  Although compounds that contain a phenol (like acetaminophen) are polar, the molecule has too many carbons to be water-soluble.  However, if a strong base is added to a phenol (a weak acid), the phenol is deprotonated, becoming a salt (refer to reaction in Figure 4.2), and it is no longer soluble in the organic layer.  As it is now an ion, its affinity changes and partitions to the aqueous layer.  This is because the attractive ion-dipole intermolecular forces between the water (highly polar) and the phenoxide salt is stronger than the attractive forces between it and the intermediate-polarity, organic solvent (ethyl acetate, which has intermediate polarity).  A second extraction of the organic layer with the strong base in this experiment is used to increase the amount of the potassium phenoxide salt in the aqueous layer. 

 Figure 4.2 Deprotonation of Acetaminophen and Subsequent Partitioning 



Next, the deprotonated acetaminophen will be re-protonated through the addition of an acid.

This will cause it to partition back to the organic layer once the layers are mixed.

Figure 4.3 Flow Chart Illustrating the Migration of the Solute in Each Extraction

Ideally, all of the acetaminophen molecules will partition to the correct layer in each step.  However, extractions are not perfect, and it is virtually impossible to transfer 100% from one layer to the next even if the separatory funnel was vigorously shaken.  You will notice that your percent recovery is not 100%!  To improve the extraction efficiency from the organic layer to the aqueous layer in Part 2, a second addition of KOH is used to deprotonate any residual acetaminophen molecules in the organic layer.  Similarly, in Part 3, an additional amount of ethyl acetate is added to extract the re-protonated acetaminophen back into the organic layer.

Separatory Funnel Technique

Partitioning is affected by the amount of surface area between the two solvent layers.  Gentle mixing of the layers increases the surface area and thus the amount of solute that partitions.  Rather than stirring, a separatory funnel is used to allow for complete inversion and better (temporary) mixing between these two immiscible layers.  Inversion serves as a method to mix sufficiently without creating a permanent emulsion (a mixture of organic and aqueous, will be visibly cloudy).  When inverting the separatory funnel, the glass stopper (on top) must be held in place.  Inversion does create another issue, as the organic layer is volatile, the separatory funnel must be vented periodically while inverting to prevent the risk of an explosion.  This is even more of an issue when conducting an acid-base reaction in the separatory funnel.  Generally, venting is done more easily through rotating the plastic stopcock and allowing gases to escape through the bottom, than by removing the stopper each time.

Figure 4.4 Layers in Separatory Funnel, and Inverting

Before dispensing the layers through the stopcock, the glass stopper on top must be removed to prevent a vacuum from forming.  If a vacuum forms, initially the flow rate will slow down.  Then eventually, air from the room will be sucked upwards through the stopcock and disrupt the layers.

Density and Identifying Layers

The order of the layers in the separatory funnel are based upon their densities.  Illustrations above have correctly labeled the layers as “organic” at the top and “aqueous” at the bottom; as typically water is the most dense layer present.  However, it is important to be aware of what determines the order, as there are some organic solvents that are more dense than water.  Mixing a droplet of the top (or bottom) layer in a test tube that contains water is an easy test (if it is miscible, it’s aqueous!).

Washing and Drying Agents 

Finally, the acetaminophen will be removed from the organic layer, but not before the organic layer is purified.  Brine, which is a saturated salt solution, is extremely polar and is used to “wash” the organic layer.  The purpose of this is to remove any dissolved water in the organic layer, and any other ions, such as residual acid, from the organic layer.  Highly polar molecules like water and acids will be attracted to the high ionic strength of the brine solution.

The last treatment is that of a solid drying agent, such as anhydrous MgSO4.  Typically this solid (an ionic compound) has low solubility in water, but is hygroscopic, so it is one last way of ensuring there is no water present in the organic layer.  The solid will clump (usually on the bottom of the flask)  if there is water present.  A sufficient amount should be added so that all water has been absorbed by the solid (indicated by there being excess freely floating solid that is not clumped).  Use an Erlenmeyer flask for this to facilitate swirling without splashing.

The removal of the organic solvent from the solute (acetaminophen) is expedited by use of a Rotavapor®.  This device uses a vacuum along with a warm water bath to remove the evaporated, gaseous solvent (vapor pressure) from the flask.  By doing so repeatedly, more and more solvent evaporates from the solution, and eventually only the solute remains.  A round bottomed flask is used to maximize the surface area to increase the rate of evaporation.

After the acetaminophen is extracted, its purity will be tested using TLC and MP.

Learning Goals

  • Use a separatory funnel.

  • Perform simple acid-base reactions.

  • Safety practices with solvents and snorkel.

  • Use a drying agent and perform a gravity filtration.

  • Learn how to prepare a sample for the Rotavapor ®