Crospovidone or Popcorn Polymer for the Separation of Metal Salts and Phenolics

 Cross-linked polyvinylpyrrolidone also called crospovidone or popcorn polymer is a common pharmaceutical excipient used as a disintegrant in pharmaceutical tablets after they are ingested and come into contact with water. Consequently it is a relatively cheap, pure, and inert material. Cross-linked polyvinylpyrrolidone is insoluble in all solvents.  The metal complexing agent 8-quinolinol has a strong affinity for this polymeric material.  Its association is by strong hydrogen bonding between the phenolic OH of the agent and the lactam oxygen of the polymer. 

With 8-quinolinol bound to the surface of crospovidone, metals are readily retained such as cadmium, zinc, lead, copper, iron, manganese, nickel, cobalt and chromium salts. It would seem that the metal is being complexed by the neutral form of 8-hydroxyquinolinol since the hydrogen bond presumably must be preserved to bind with the polymer.

 This crospovidone polymer by itself might be applicable for separating phenols and polyphenols because in my notes it is written: Phloroglucinol>resorcinol>phenol and pyrogallol>catechol>phenol. The more phenols in the molecule the stronger we can imagine the molecule might bind to the polymer.

A lower than pharmaceutical grade of crospovidone might be available inexpensively from a manufacturer of this medicine excipient.

Cost Characteristics of a Linear Group of Chemical Reactions

In a linear chemical process, as opposed to a convergent one, the cost of an expensive starting material for the first transformation may become predominant as the number of linear steps rises.
A consequence is that the first reaction’s overall yield from a sophisticated starting material can easily become more important than the entire combined costs of reagents, catalysts, processing chemicals, and solvents for all the other steps. 

Since the overall yield for a reaction step is the product of the assay yield (the fraction of product in the reactor at quench ) and the isolation yield (the fraction of the assay material actually obtained separated pure ) expressed as a percentage, these two need to be optimized separately to raise the overall yield efficiently. Increasingly sophisticated (and more expensive) reagents, equipment and processing chemicals in the service of this first transformation usually lead to improved profits so long as they significantly improve either the assay yield or the isolation yield. Another consequence of the rapidly increasing value of the main input starting material for each subsequent step is that throughput becomes less important because the moles of starting material being processed are progressively being reduced while the capacities of the general-purpose reactors that are being used in the campaign remain the same. That is to say, for example, it might take 6 full load repeats of the first step of a sequence followed by three full-load repeats of the second step but the only one run of each of the third and fourth steps to produce a required amount of final product, because your reactor size is not big enough to do the first or second steps just once. So for the early steps in a linear process improving assay yield and/or isolation yield using inexpensive technology is key. 

Steps towards the end of the linear process chain batches are fewer in number and smaller in size. High assay and isolation yields remove key, but now this is where polymer-bound reagents, solid-state synthesis, and isolation by forming and then decomposing derivatives; technologies that may be too expensive to use in the early steps of a sequence or which temporarily increase the maximum stirrable volume of a batch, can lead to lower overall costs by using even more expensive means to raise these yields.

I do not usually think of it in this way but what the calculation shows is that using an expensive reagent should be placed as late in a process as possible because there will be fewer moles of intermediate to transform the later in the process the reagent is used. Just to illustrate, consider the synthesis of a molecule consisting of two functional groups that are not interacting but sit at the two ends of an alkyl chain. Each of the two functional groups is created by a chemical transformation from a different functional group in the starting material. The reagents and conditions required for the transformations, one at each end, do not interfere with each other. They could be conducted, either the left end first then the right end, or vice-versa. If the left end transformation uses much more expensive processing than the right end, the left end transformation should be done second, because it will that way use fewer molar equivalents of the processing chemicals since the overall yield in the first transformation is unlikely to be 100%.

A decision about positioning chiral resolution in a process chain is frequently required. The rule of thumb is to perform the resolution as early as possible in the synthesis because this decreases the amount of useless mass that is being carried through the synthetic stages wasting processing chemicals. When the resolving agent is very expensive, however, a confounding factor is at play. If the resolution is delayed more matter must be carried through more steps as we have noted, but when the resolution is done later in the sequence fewer moles of resolving agent will be used. So if throughput is not a problem and the processing chemicals that will be used going from the early resolvable intermediate to the later resolvable intermediate are relatively inexpensive, it could be worth holding off the resolution.

1-Butanol: Extraction Solvent for Removing Quite Polar Organic Substances from Dilute Aqueous Solutions

Ethyl acetate is the most polar organic solvent organic chemists use regularly in extractions from large volumes of water. 1-Butanol is more polar but still only partially miscible with water. It follows that it should be more effecient for taking up polar solutes from water. There is a further advantage. 1-Butanol distils with water as a lower boiling azeotrope and the azeotropic composition separates into layers upon cooling, allowing, as we shall propose, solvent recycling.

 According to the CRC Handbook of Chemistry and Physics 55^th Edition, at atmospheric pressure, the azeotrope boils at 93.0°C and separates on cooling into an upper phase that is, by volume, 71.5% of the total distillate. This layer is 79.9% by weight 1-butanol and 20.1% water.

The azeotropic behaviour varies little, whether the pressure is atmospheric or as low as 30 mm. of mercury. At 30 mm. pressure, this azeotrope boils at just 29.0°C. Again, two phases separate on cooling with the butanol rich upper phase constituting 59.0% by volume. The phase contains 79.9% by weight 1-butanol.

Despite these advantageous properties, this solvent is not popular, perhaps because this predominantly organic phase still contains 20.1 water weight % and would require special drying to get back pure 1-butanol. It would be interesting to see what the effect would be of adding 35 g of sodium chloride to 5 liters of this mixture of 1-butanol and water. I would not be surprised if most of the 1 liter of water separated as a brine!

My suggestion is to use the composition of the upper phase in the azeotrope’s distillate, which is 79.9%/20.1% 1-butanol/water by weight, as the original extraction phase for recovering polar organics from a dilute aqueous reaction mixture. First you would mix in about 35 g of salt for each liter of dilute aqueous solution to reduce partitioning of butanol into the material to be treated. Then you would perform multiple extractions on this mixture with this butanol-water composition. These would t be combined and distilled down to a convenient volume for product recovery by heating under 30 mm. vacuum to distil that azeotrope which comes over at the very moderate temperature of 29.0°C. After the distillate phases separate, the 59.0% percent by volume that constitutes the upper phase in the receiving vessel is of exactly the correct composition to be recycled as original extraction mixture in the next product batch!

This 79.9/20.1% 1-butanol/water composition might become so useful that it could end up commercially available!