Pyridine-Water Selective Precipitation with Pyridine Recovery

 

Dissolution of a solute in a water-miscible solvent followed by crystallization or precipitation of the solute by gradual or portion-wise addition of water is an established method of separation and purification.  It is frequently applied to the separation of mixtures of different polymers.

 Solvents commonly used are methanol or ethanol. When lower alcohols are used with small molecule substrates it amounts to the same thing or at least strongly resembles crystallization from mixed alcohol-water solvent. When more expensive organic liquids are used as solvents to be practical at scale there must exist a cheap straightforward method to recover that solvent.

Pyridine is miscible with water in all proportions. It can be used to purify solutes or separate mixtures of solutes by the gradual addition of water so as to cause fractional precipitation. Typically one starts with something like a mixture of 5 parts pyridine and 1 part solute which can be warmed to dissolve what may be a solid or oily mixture; then, one gradually adds water with vigorous stirring until faint turbidity persists. At this point, optionally, a small amount of pyridine (a drop or two at the laboratory scale) can be added to just clear the haziness. Crystallization may begin after some time. In Aleksandra Smoczkiewiczowa and Jan Bielawny's paper in  P. Zakresu Towarozn. Chem.,Wysza Szk. Ekon. Poznaniu, Zesz. Nauk., Ser. 1 1970 No. 36, 149-62, it says that their cholesterol oxidation mixture was dissolved in a 5-fold amount of pyridine and by addition of water fractionally precipitated about 15% androstenolone acetate.

 Pyridine is somewhat expensive as solvents go. No obvious simple means to recover the pyridine when the precipitation is complete makes this an infrequently used methodology  Pure pyridine cannot be recovered by distillation because pyridine/water forms an azeotrope. Fortunately, there is a technical trick that does achieve this separation. Pyridine is not particularly soluble when sodium hydroxide is dissolved into the aqueous pyridine so the addition of enough caustic causes pyridine-water to separate into two phases. The pyridine layer can be separated and the mostly- layer discarded.

Propylene Carbonate as a Useful Solvent for Organic Synthesis Processes

Propylene carbonate has a boiling point of 242 °C. The density of propylene carbonate is 1.189 g/cc, and the dielectric constant and dipole moment, respectively, are 64.94 and 16.5.  It is a solvent that can be expected to provide good solubility for a wide range of organic reaction substrates.

Propylene carbonate may be the only solvent that is (a) usefully immiscible with water, (b) does not contain a halogen in its formula, yet (c) has a density greater than water. At 25°C the solubility of propylene carbonate in water is 8.3% and the solubility of water in propylene carbonate is 17.5%. Excess water forms a second phase on top of the water-saturated propylene carbonate. When the mixture of liquids is cooled to near 0° C the separation of phases is even greater. Thus, propylene carbonate can provide two phases that can be used for liquid-liquid extractions. Moreover, the more predominantly organic layer is the lower phase, and in a reactor can be simply cut through the bottom valve. Thus, when the product can be taken into the aqueous phase by acid or base, the organic phase can be removed, leaving the product in the reactor. This can save a vessel in a chemical process work-up.

 In fact, propylene carbonate is thermotropic with appropriate water mixtures. As the temperature is varied between 0 and 61°C, the two phases that derive from a particular weight fraction of propylene carbonate and water change compositions. It would therefore be expected that the partitioning of a mixture of substrates, such as might be the products from a reaction step,  could be optimized between the two phases both by varying the propylene carbonate/water weight fraction and by changing the temperature of the two-phase mixture. The UCST for propylene carbonate and water is about 72 C. At this temperature, only a single distinct, clear phase remains. 

Propylene carbonate can be hydrolyzed by both aqueous acid and aqueous base. There are both good and bad aspects to this. The bad news is that the stability of the solvent in contact with water is 

somewhat limited. This, however, is also true of ethyl acetate, where it is not regarded as a severe limitation. The good part is that small amounts of the solvent mixed with a hydrolytically stable cosolvent can be removed by hydrolysis since the products, carbon dioxide and propylene glycol, are both water-soluble.

Reaction Solvents that could be Worked-Up with Acetic Anhydride

Solvents that could be distilled away from acetic anhydride (bp. 140 C) and taken up into any solvent immiscible with acetic acid, after the hydrolysis of the acetic anhydride chaser and admixture with a little additional water to enhance immiscibility of the two layers:

Chlorobenzene

Nitro propane

Methyl chloroacetate

Cyclopentanone

Diethyl carbonate

Dimethyl sulphite

Tetrachloroethylene

2-nitropropane

Methylisobutyl ketone

N-methylmorphiline

Nitromethane

Toluene

1,1,2-trichloroethane

Trifluorotoluene

1,4-dioxane

Nitromethane

Methylcyclohexane

Heptane 

Propionitrile

Dibromomethane

Dimethylcarbonate 

Trichloroethylene

Isopropyl acetate

1,2-dimethoxyethane

Fluorobenzene

1,2-diethoxyethane

1,2-dichloroethane

Cyclohexane

Acetonitrile

Cyclohexane

Benzene

methylethylketone 

2-methyltetrahydrofuran

Ethyl acetate 

Butyl chloride

Carbon tetrachloride

Petroleum ether

Hexane

Diisopropyl ether

Chloroform

Perfluorohexane

1,1-dichloroethane

Methyl acetate

Carbon disulphide

Dimethoxymethane

Pentane 

Diethyl ether

Methyl t-butyl ether

Organic Solvents and Various Means for their Removal

 

Co-distillation

If two liquids are essentially immiscible, distillate comes over when the sum of their vapor pressures equals the pressure inside the distillation apparatus. The effect is that a small amount of a high boiling material will co-distill along with a larger amount of a lower boiling material. So long as the low boiling material is inexpensive and the higher boiling material is easily separable from this large amount of low boiler, co-distillation can physically separate the high boiler from less volatile or non volatile  components mixed with it. Aside from using water (which is classified below as steam distillation), the inexpensive material most frequently used in a co-distillation is kerosene/paraffin/lamp oil/coal oil. Much less frequently silicone oil (dimethicone KF-96L-2cs) has been used as the high boiling component.

Steam Distillation

Steam distillation represents the particular case of co-distillation using water. Many higher boiling solvents can be chased by steam distillation. Nitrobenzene and 1,1,2,2-tetrachloroethane are frequently removed this way after Friedel-Craft reaction. The steam can be preheated to temperatures above 100 C thereby co-distilling a larger portion of the lower boiling material while minimizing the volume of water. Codistillation including steam distillation can also be done under vacuum so that the material of interest is not exposed to as much heat.

Reversible Degradation

Some special compounds can be used as solvents that are reversibly cracked into smaller more volatile fragments by heating. Piperylene sulfone has solvent characteristics very similar to tetramethylene sulfone. The essential difference for our consideration here is that the former is fragmented by heat into  1,3-pentadiene and sulfur dioxide. These can be trapped together as a distillate whereupon they reform piperylene sulfone.

  Likewise, dicyclopentadiene upon heating can disaggregate into the monomeric cyclopentadiene and be distilled out of a reactor and away from less-volatile products.

Hydroxymethanesulfonic acid is a strong acid solvent that upon heating breaks apart into formaldehyde, water, and sulfur dioxide before reforming when they are recondensed together. 

Degradation

Some solvents can be hydrolyzed into water-soluble fragments.

 

Acetic anhydride can be hydrolyzed into acetic acid.

 

Dimethylformamide can be hydrolyzed by acid into dimethylamine and formic acid.

 

Dimethylacetamide can be hydrolyzed into acetic acid and dimethylamine.

 

Propylene carbonate can be hydrolyzed into 1,2-propanediol and carbon dioxide.

Is Glycerol the Best Green Solvent for Process Chemistry?

In a paper published online in 2006, Glycerol as a Green Solvent for high product yields and selectivities,  A.Wolfson, C. Dlugy, and Y. Shotland provide ineluctable evidence that increased utilization of glycerol should be forthcoming in organic chemistry processing.  Their reasoning included environmental, economic, safety, handling, and product isolation considerations. The only difficulty using glycerol appears to be a viscosity much higher than with standard organic solvents.

Yet irrefragable as their teaching was there are still things unsaid that further boost this processing chemical! Glycerol can be used to conveniently perform all kinds of solvent switches which are otherwise a weakness with the standard reactors in multipurpose plants. 

The best solvent for conducting a chemical reaction may not be the best solvent to purify the product thereof. Furthermore, when a first and a second reaction in a process scheme are telescoped (avoiding the isolation and purification of the product of that first reaction) the best reaction solvents for the first and second reactions are likely to be different. But, as I have explained in another blog article, switching solvents in the plant cannot be done in the simple fashion of evaporating a first solvent to dryness on a rotary evaporator and pouring in the second solvent. Because of the non-zero minimum stirrable volume problem, the complete removal of a first solvent becomes complex and time-consuming.

 

This problem can be solved if a volume of glycerol sufficient to completely occupy the minimum stirrable volume is placed into the reactor.  Then, all of a first solvent (for example a first reaction solvent) can be removed without distilling any of the glycerol, which is so high-boiling, yet the reactor remains stirrable throughout because glycerol occupies the minimum stirrable volume and provides continuous mass and heat transport.   All of the product, coproducts, byproducts, and other processing chemicals (everything that can’t distill with the first solvent) remain with the glycerol. Now, all that is necessary to complete a solvent change is to add a second solvent that is immiscible with glycerol but will solubilize and extract at least the desired product and potentially the entire non-solvent reaction contents.

Here, another benefit of glycerol becomes apparent. According to the (1974-1975) CRC Press, Handbook of Chemistry and Physics, (the old one I have) glycerol is immiscible with at least:

acetone, benzene, butyl acetate, carbon tetrachloride, chloroform, dibutyl ether, diethyl ether, ethyl acetate, isoamyl alcohol, methyl isobutyl ketone (MIBK), nitromethane, petroleum ether, tributyl phosphine.

Furthermore, by analogy, glycerol can be expected to be immiscible with the additional common solvents:

 hexane, cyclohexane, methylcyclohexane, heptane, toluene, methylene chloride, trichloroethylene, tetrachloroethylene, isopropyl acetate, nitroethane, 2-nitropropane, and t-butyl methyl ether.

So a variety of extractions are possible. 

In a further extension, glycerol can be used as a cosolvent with fluids with which it is miscible, such as the lower alcohols methanol, ethanol, isopropanol, etc. It can also form gas-expanded liquid phases with such amines as ammonia, methylamine, and ethylamine. A mixed solvent will generally have a more moderate viscosity than glycerol alone and so will at the same time make processing easier. All the above materials, immiscible or miscible with glycerol, can be completely expelled from the reactor so long as the amount of glycerol equals, at least, the minimum stirrable volume.

When a reaction is conducted wherein the desired product is itself usefully volatile, glycerol can act as an effective chaser in a distillation that purifies the desired product.

Glycerol is cheap, biodegradable, and has a bp of 182 ºC @ 10 mm Hg. It would be expected to remain behind in a standard distillation when combined with any of the common organic reaction solvents. Even DMSO (bp 189℃), DMF (bp153℃), and NMP (bp 81-82℃ 10 mm Hg) would be expected to be chased by glycerol.

The distilled first solvent contaminated with traces of glycerin upon simple treatment might be ready for reuse. Thus the first solvent is no longer waste and there are no mixed fractions of solvents to dispose of. The waste glycerin is a biodegradable material and the quantity used is no more than the minimum stirrable volume of the reactor.

Whether used just to drive the removal of a first solvent during reaction work-up or as cosolvent for the first reaction and then a chaser for the first solvent, glycerol it seems has the properties that enable simpler processing.

What can You Trust about Chemical Patents?

Advice About Reading Patents

In my career, I have been the inventing scientist and I have been the person drafting a patent before being sent to a patent agent to incorporate the legalese.  I have even been both for the same patent! What can you learn from a patent? What part is ‘fake news’?

The conscientious scientist writes down the experimental description of the significant experiments carried out. The scientist explains what his/her interpretation of these results means generally. He explains what application of the present theoretical understanding of his subject leads him to predict generally based on this work. He states why he believes it is useful and may prove more widely useful.

Then the conscientious patent agent takes over. The patent agent's professional responsibility is different. You see, you have to pay to hold a patent: there are annual fees that must be paid to maintain this monopoly and it isn’t worth paying money unless the barrier to use is strong enough to prevent competitors from learning from your insight, slightly tweaking your protocol and getting essentially the same benefit. But it isn’t worth the time filling out your precious scientific expertise to perform all the possible permutations and combinations of every aspect of the methodology so everything can be presented in its own experimental and claimed in its own claim. Instead, the patent agent asks you to imagine, using your experience, imagination, knowledge of the literature, and knowledge of chemical theory to guess all the other conditions that would give, to some degree, the claimed outcome. 

The patent agent then writes a description of your invention including the full breadth of your considered opinion of what could work. Claims are also constructed encompassing both your educated guesses and what you have shown experimentally works. These are called the broad claims. They are there to prevent those who follow what you have taught from escaping your legal protection by making inconsequential or obvious changes or substitutions.

So what can you trust? According to US patent law at least one narrow claim must cover the best protocol for practicing the invention that the scientist has found out at the time that the invention patent is filed. Normally what is described in the experimental and talked about most completely in the body of the patent is the part that has been proven in the lab.

Exhaustive Digestion as a Simple Prelude to High Yield Crystallization

 

This article is about the technique I call ‘exhaustive digestion’. This is a phrase that I used in my blog entitled, Getting Better Recovery from Crystallization. In this blog, I make the point that chemists scaling up a laboratory process often fail to do adequate preliminary purification of a solid and as a consequence get a lower recovery from their crystallization than is possible if a preliminary treatment were done. I proposed digestion or trituration as pretreatments before crystallization. I don’t know whether there are any widely accepted differences in meaning between the words digestion and trituration but, when used in my blogs, ‘trituration’ can be understood to apply equally to oils or solids while ‘digestion’ will only be applied to solids. Second, ‘trituration’ can be done with either hot or cold solvent while ‘digestion’ and particularly ‘exhaustive digestion’ as described hereunder is to be done with hot, boiling liquid, usually a rather poor solvent for the desired product. 

Exhaustive digestion is related to swish trituration which I have written about earlier. The difference is that the swish trituration employs its anti-solvent system at ambient temperature and does not measure the boiling point depression of the liquid to assess the extent of purification. 

In the old literature, the progress of purification by digestion on the laboratory scale was followed by observing the change in the boiling point of the digesting solvent or solvent mixture using a Beckmann thermometer, which is a thermometer that can measure differences as small as one-tenth of one Centigrade degree. I don’t know how long it has been since I have seen anyone use a Beckmann thermometer but, at least in my undergraduate Phys. Chem., (over 50 years ago) it was done quite often. The scale on a Beckmann thermometer is only 10-20 degrees but its range can be adjusted by removing or adding mercury to the column of mercury used for measurement by moving mercury back and forth from an attached mercury reservoir. Today a digital thermometer is more likely to easily achieve the same or better precision of measurement without managing liquid mercury.

I will illustrate exhaustive digestion by quoting from an experiment taken from Laboratory Technique in Organic Chemistry by Avery Adrian Morton, First Edition, McGraw-Hill, 1938,  pg. 128-229.

“The apparatus consists of a tube or flask of such size that a large part of the bulb is covered by the solid material being extracted, a thermometer graduated in tenths of a degree, a reflux condenser, and a water or oil bath. Place the sample in the container, insert the thermometer so the bulb is immersed in or covered by the sample, and add solvent to cover the solid and the thermometer bulb. The solvent is usually one that will dissolve impurities without appreciable quantities of the desired material. Petroleum ether or ligroin is often suitable. A mixture of solvents may be employed without affecting their utility in this experiment, as long as the composition of the mixture is not varied. Reflux the solution [I think slurry is intended] using a water or oil bath as a source of heat. After about 20 minutes the temperature has reached a constant level. Usually, no trouble will be experienced from superheating as long as a solid phase is present, although a little agitation with the thermometer is sometimes needed. Filter either by pouring into a Buchner funnel or by using a filter stick. Add more of the same solvent, reflux once more, and observe the temperature after equilibrium conditions have been reached. Continue the operation until the temperature of two or more successive operations is identical. The more soluble impurities have now been removed, and the solution contains only the pure compound or the compound with [less soluble type] impurities that have not been entirely removed…. The operation may be continued if desired until all the product has been dissolved. A change of solvent [may be implemented at some point for further purification]….. Constancy in the boiling points of successive portions constitutes further evidence of the purity of the material, whereas a drop in the boiling point is evidence of the exhaustion of still another component. Usually, the final portions of exhaustive digestion are pure materials.”

Continuously measuring and recording the changes, in real-time, of the boiling point without any actual sampling makes this an early application of Process Analytical  Technology (PAT). The improvements in the size and sensitivity of temperature measuring devices for following small changes in boiling point under conditions where superheating does not occur deserve more frequent consideration.

Exhaustive digestion if used at scale would require a more rugged method for measuring small changes in the boiling point of the slurry than the old Beckmann thermometer. Fortunately, modern digital thermometers meet that need.

Exhaustive digestion, similar to swish trituration, may profit from using either water-rich or hydrocarbon-rich binary azeotropes,  as the anti-solvents, as the desired product’s solubility dictates. Some are suggested in the following list:

97.0% water 3.0% acetic acid azeotrope bp 76.6ºC

91.0% water 9.0% benzyl alcohol azeotrope bp 99.9ºC

87.1% heptane 12.9% water azeotrope bp 79.2ºC

94.4% hexane 5.6% water azeotrope bp 61.6ºC

95.5% hexane 4.5% allyl alcohol azeotrope bp 65.5ºC

97.0% hexane 3.0% 1-butanol azeotrope bp 67.0ºC

91.5% cyclohexane 8.5% water azeotrope bp 69.8ºC

83.7% acetonitrile 16.3% water azeotrope bp 76.5 C

72.9% allyl alcohol 27.1% water azeotrope bp 88.2ºC

66.0% allyl cyanide 34.0% water azeotrope bp 89.4ºC

77.5% formic acid 22.5% water azeotrope bp 107.1ºC