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

The Context of a Chemical Process Development Training Blog like KiloMentor

 

If the KiloMentor blog were being written twenty years ago it would be different.  If it had been written thirty years ago it would have been different again.  The progress of a technical art, such as process development, creates dramatic changes. The step which had been a bottle-neck in the creation of a process becomes less demanding and another aspect of the art becomes the chief challenge to the scientist.  Thus, if any of these documents were revised in another dozen years, the relative difficulties of different aspects of the challenge will have again changed and the reasons for the proposals made here may have evaporated and the advice provided may become completely wrong-headed.  With this in mind, an author should at the outset state what the status quo is in his field at the time of writing so that future readers can decide for themselves whether the same state of affairs still exists and if not what logical changes should be inferred in the recommendations being offered.

To illustrate this point, forty-three years ago, when I was just beginning my activities as a process chemist, devising the sequence of organic reactions that could lead from commercially available starting materials to the target product was the great challenge.  Dependable reactions were limited.  HPLC did not exist.  IR and UV measurements were just being replaced by NMR methods for following reactions and identifying products.  But the more important difference was that on-line database searching did not exist.  Most significant of all, electronic substructure searching did not exist.  A close analog of the relevant portion of a molecule you wanted to synthesize might be present in the literature, but there was no dependable way to find it.  

To-day, although many would disagree about the degree of change, creating a realistic synthesis scheme for substances of moderate complexity is no longer the most challenging step simply because we have replaced our memories and our punch cards with computer memories professionally indexed available on our desktops.

In this earlier period, when creating the process step flow sheet was the dominant challenge, we synthetic chemists got into the habit of measuring excellence in synthesis by measuring the number of sequential steps in the longest arm of the contemplated process or the total number of reaction steps.  We also calculated the overall yield although this could only be determined after the proposed sequence was converted to a real process.

Because this challenge strained our ability to approximate we made some rough assumptions in inaccuracies of which we hoped would balance out between competing processes and still allow us to make a valid judgment of which was the most promising. For example, we assumed that the amount of crude impure product which one got out from a reaction step was proportional to the quantity of product, which was present in crude form in the mixture after the reaction was complete.  Why do I say we made that assumption? Because we looked at the yield of model reactions for simple substrates with just one or two functional groups and assumed that the recovery of pure product from these would be about the same when we used complicated substrates with multiple functional groups.  In the terminology I will use herein, we assumed that the isolation yield- the yield of pure product as a percent of the assay yield (the amount of product in the reaction mixture) is consistent for a reaction type.  The corollary of this which we also adopted as a simplifying assumption was that isolation although it might be tedious was routine and could be taken for granted as generally of similar difficult when integrated over all the steps of a process.  That is isolations can be ignored so long as the total reaction steps are minimized.

Today, the focus of attention has shifted.  Scientists can gather large amounts of relevant data about the likely properties not just of substances that have been reported somewhere in the vast chemical literature, but even predicted properties of unknown molecules.  What the electronic databases have not been able to do is help us select the simplest and most rugged purification methods to use with reactions at scale.  What we as scientists have not tried to do is ask ourselves the question, “What kinds of functional groups do I want in my intermediates because they will simplify the isolation and purification of that step?”

An axiom of the approach to process development that will be found here is that there is an advantage in ranking the degree of difficulty of isolation/purification of each process step and using it as an additional criterion of selection of the most preferable paper chemistry route along with the traditional criteria: number of steps, number of steps in the longest branch of a convergent process, and the known approximate yields for the reaction type.  The result of this I predict will be that preferred processes may on average contain more process steps but the speed with which these steps can be carried out will be much higher, the overall purity will be much higher, and the cost will be much lower because the time spent in the isolation purification is typically much more than the actual reaction time.

Methods for Forming and Crystallizing Organic Salts particularly Pharmaceutical Salts

 

Most Common Method for Forming Salts

Mixing  stoichiometric proportions of acid and base in a suitable solvent; then

1. Cooling to a lower temperature
2. Adding a miscible anti-solvent or liquefied gas
3. Adding an immiscible  or partially miscible anti-solvent
4. Drowning out in a miscible anti-solvent
5. Slowly adjusting the pH
6. Use of the common ion effect to decrease the salt’s solubility

Other Methods

1. Exchange of Ammonium Salt with Nonvolatile Base

An exchange between ammonium salt and another non-volatile cation to give a more insoluble salt of an anionic drug.

2. Exchange of formate or acetate or thiocyanate salt with a non-volatile acid

3. Double Decomposition Reactions

Metathetical reactions between a salt solubilize by the presence of a particular cation and a second salt solubilized by the presence of a particular anion giving one insoluble salt and one soluble salt from which the insoluble salt is recovered by filtration and washing.  

The use of metal salts of 2-ethyl hexanoic acid for the basification of organic acids is an example.

Methods for 

1. Direct addition

Addition of a solution of the salt-forming acid or base slowly into a solution or slurry of the pharmaceutical product whose salt is sought.

2. Inverse addition

Addition of the pharmaceutical salt capable species, either as a solid or as a solution into at least a full equivalent quantity of the salt-forming reagent.

3. Slow addition of poorly soluble neutral species by extraction

Extraction of the pharmaceutical salt capable species from a Soxhlet extractor by hot solvent and quench of the extracted species by an excess of the salt-forming reagent in the boiler of the extraction apparatus.

4. Impinging Streams of Salt Solution and Anti-solvent

5. Impinging Streams of Acid and Base
   

Methods for Precipitating Pharmaceutical Salts

Crystallization by Diffusion of an Ant-iSolvent

Dissolution of the salt in a mixture of solvents followed by the addition of an immiscible third solvent creating two phases in both of which the salt is insoluble.

Partial Evaporation of a Single Volatile Solvent

Partial Evaporation of a Mixed Solvent System

      Dissolving the pharmaceutical salt in a mixed solvent of a less volatile poorer solvent and a more volatile better solvent and then removing the better solvent by distillation of evaporation..

Lyophilization/Inorganic Salt Removal

Lyophilisation (freeze-drying) of a solution. Dissolution in methanol and filtration to remove inorganic salts.

Slurry to Slurry

Transformation from a slurry of the slightly soluble pharmaceutical acid or base candidate into a slurry of the desired salt form until a method of solution analysis shows equilibrium.

Precipitation by pH Adjustment

Dissolving of the pharmaceutical candidate in a partially aqueous solution followed by adjustment of the pH gradually by the hydrolysis of a solution component. For example: methyl acetate and base giving acetate and methanol; ethyl carbamate and acid giving ammonium carbon dioxide and ethanol.

Solvent Expansion

Dissolving the pharmaceutical salt or making the pharmaceutical salt in solution and then exposing the solution to a volatile anti-solvent so that the composition slowly becomes more insoluble