The Advantages of Ethanol-Cyclohexane Mixtures as Organic Reaction Solvent Media

In designing process steps for fine chemical synthesis a bias has existed against multi-component solvent systems. In the past, it was argued that using combinations of solvents meant that money would be lost because it would be necessary to separate these solvents in a recovery step. What was not then properly recognized was that recovery of solvents from mixtures for reuse was rarely undertaken in the fine chemical and pharmaceutical industries mainly because recovering and recycling solvents required extensive expensive analytical work to prove that the specifications were being consistently met.

Here I will look at combinations of cyclohexane and absolute ethanol.

There is a contradiction within the literature concerning the miscibility or immiscibility of ethanol and cyclohexane. This may be understandable because the UCST (upper critical solution temperature ) of the combination is reported to be -16℃. In the laboratory, it is difficult to maintain the contents of a separatory funnel even at a temperature less than 0℃ without special cooling but this should be much less a problem in the plant where extractions are conducted in a reactor completely surrounded by a heating/cooling jacket and the entire charge is maintained under inert gas throughout. Consequently one might expect that two phases would not be seen in the laboratory but are reasonably easily achieved with the more effective plant cooling systems.

Ethanol and cyclohexane do have an azeotrope ( bp 64.9℃ ) that boils significantly below the boiling point of either pure ethanol ( bp 78.5℃ ) or pure cyclohexane ( bp 81.4℃ ). Mixtures in any proportion of these two pure liquids will give a homogeneous reaction medium above -16℃ and fractional distillation of the reaction mixture will remove the azeotropic composition and leave the non-volatile substrates in either ethanol or cyclohexane depending upon what solvent predominated in the starting mix.

Alternatively, the reaction mixture could be cooled to below -16℃ and whether two liquid phases separate or not and if so how substrates partition between them. Unfortunately, these two have close to the same densities so separation of phases can be expected to be slow.

The Advantage of Methanol-Hydrocarbon Solvent Mixtures for Organic Synthesis

This blog article is somewhat speculative. It is not based on experimental data. However, the information about the compositions and boiling points of the hexane, cyclohexane, and heptane azeotropes with methanol are accurate as are the upper critical solution temperatures (UCSTs).

In designing process steps for fine chemical synthesis a bias has existed against multi-component solvent systems. In the past it was argued that using combinations of solvents meant that money would be lost because it would be necessary to separate these solvents in a recovery step. What was not then properly recognized was that recovery of solvents from mixtures for reuse was rare in the fine chemical and pharmaceutical industries mainly because recovering and recycling solvents required extensive expensive analytical work to prove that the specifications were being consistently met.

KiloMentor is of the opinion that using solvent mixtures has so many advantages that they should be considered more frequently than not. In particular mixtures of lower alcohols and various hydrocarbons that provide protic media of a wide range of polarities and dielectric constants should be among the first systems considered.

Utilizing multi-component solvent systems turns the solvent composition into a continuous rather than discrete variable in the process optimization. This does not rule out eventually find a process step optimum that is !00% of one of your original solvent combination.

If a lower proportion of solvent can be used in a chemical process step the the amount of material that can be processed in a single batch is increased and a higher throughput achieved for the step. This will lead to cost savings for a campaign that includes that step. 

It is often the case that a homogeneous mixture of polar and  non-polar solvent liquids that is homogeneous is better at dissolving a substrate that has distinct polar and apolar subdomains than either pure liquid alone. That would mean, mutatis mutandis, that such mixtures should increase the throughput in reactions of such substrates.

Specifically, this suggests that a homogeneous single phase mixture of a hydrocarbon and methanol could realistically be better at dissolving some reaction substrates and producing more concentrated solutions that give higher throughputs.

Hexane, cyclohexane, and heptane all give constant boiling binary azeotropes with methanol and these azeotropic compositions fulfil the criteria of having both a polar and a non-polar component and being homogeneous at the azeotropes boiling point. 

Reaction mixtures of the azeotropic compositions in each of these cases would be obtained by mixing a chosen hydrocarbon and methanol in their correct proportions but with a consistent biased slight excess of methanol, which has the lowest boiling point among these liquids. Thus, when any such mixture is brought to reflux the excess methanol will be distilled over first  before the refluxing settles at the actual constant boiling point of each particular azeotrope.

The upper critical solution temperature (UCST) designates the temperature above which the two pure solvents form a single liquid phase. In each case, whether cyclohexane, hexane, or heptane, is paired with methanol, the upper critical solution temperature  of  each azeotropic composition is below that azeotrope’s boiling point. That is to say, refluxing will maintain a single homogenous phase which can serve as a homogeneous reaction medium.

Besides potentially providing a throughput advantage these particular azeotropes offer something else. When these mixtures are cooled below their  UCSTs, as will occur when the reaction is complete and is cooled for quenching, work-up, separation and/or purification, two liquid layers are expected to separate. This might prove useful because it provides a ‘natural’ ‘free’ phase switching extraction which might simplify the work-up.

But let us not delude ourselves about how frequently this will be useful. Neither of these two phases is predominantly methanol or hydrocarbon. 

The azeotrope between hexane and methanol has bp.50℃. The composition of the upper layer will be 85% hexane and 15% methanol with specific gravity 0.675 and the composition of the lower layer will be 42% hexane and 58% methanol with specific gravity 0.724. It is decidedly not upper almost pure hexane; lower mostly methanol.

The UCST of methanol with n-hexane is only 35℃. That means that the partitioning of a substrate between these solvents can be accelerated by heating above 35℃ where a single phase can be formed, then cooled down so that the phases separate as a lot of small bubbles with lots of surface area. There are 15 Cº between the azeotropic boiling point and the UCST.

With heptane and methanol  an UCST  is reported to occur at 51℃ but handbooks do not report any separation into separate phases on cooling. This is contradictory and needs to be examined experimentally. The azeotrope is reported to have bp. 59.1℃.

With cyclohexane and methanol the UCST is 45℃. The azeotrope bp. is 45.2℃. As you would expect the azeotrope separates into two phases in the receiver. There is essentially no point where we can exploit a single homogeneous liquid phase. 

Whether two liquid phases separate upon cooling a reaction mixture using one of these azeotropic systems and whether any two phases that do separate are useful for partitioning reaction mixture components, in every case adding a bit of water will cause the compositions of the two phases to shift- the methanol phase becoming more nearly essentially methanol and the hydrocarbon phase more nearly all hydrocarbon. This more definitely will be useful!

When Scaling Up a Synthetic Organic Intermediate that is being Purified by Distillation

If an intermediate is being worked up, isolated, and purified by distillation as part of developing a chemical process for synthesis at scale that should trigger consideration in its synthesis for using a high boiling solvent which can act as a chaser during the contemplated large-scale distilling.

The volume of this ‘chaser’ phase should be sufficient to completely occupy the ‘minimal storable volume’ in the reactor contemplated in the eventual scale-up.

This will almost always involve replacing a traditional lower boiling solvent as part of the modifications of a literature model example. These chaser phases must almost always be acceptable in cost to the solvents they replace. Because product is lost whenever it is essentially the highest boiling part of the reaction mixture because some material must always remain boiling in the still pot even at the end of the fractionation, using an appropriate chaser will save money that will be partially lost from whatever extra cost is involved in using the chaser.

Mixtures of Acetonitrile, Ethylene Glycol, and Water in a Liquid-Liquid Extraction of Polar Impurities from Mixtures in Hydrocarbon Solvents

 

It is quite well known that acetonitrile and any hydrocarbon liquid upon mixing together will separate into two layers. It is very much more poorly recognized that the polarity of the acetonitrile can be tweaked by the addition of either water (5-20%) or ethylene glycol (5-40%) or a more finely refined tertiary combination of these while not disturbing the separability of the two phases, which remain essentially immiscible. Furthermore, because all of the hydrocarbon solvents have lower densities than any of acetonitrile, ethylene glycol, or water, the hydrocarbon liquid phase will consistently be the top-most layer.

How can this be practically useful? Using a small amount of an appropriately designed immiscible polar liquid phase in this way, a mixture in a hydrocarbon solution can be freed from polar impurities by multiple extractions.

This could be much more efficient, not to mention simpler and faster, than crystallizing a product from a mixture that still contains such polar impurities.

The research upon which this suggestion is based is Leshchev S.M.; Rumyantsev, I. Yu. Zh. Prikl. Khim 1992, 65(6), 1332-6 identified in CA 118: 88569f.

 

The Portfolio Method of Chemical Process Development

More efficient chemical process development is possible but it requires the addition to the team of someone with an unusual combination of bench experience, book learning, creativity, electronic search skills, and communication. This person acts as an assembler of the initial literature folio.

The method would work as follows:

As soon as a Process Development Project has been accepted all the client’s pertinent information is provided to the folio assembler. The longer the period between project acceptance and the planned start of the bench-work the better. The shorter the period, the more critical the assembler’s timeline becomes. The folio assembler works with the senior research chemist for the project. It is the folio assembler’s job to provide a stack of pertinent literature to the senior research chemist as quickly as possible of such a quality that after reading through it the senior research chemist will say, “The solution is obvious.” 

The early bench work of junior team members should concentrate on the development of ‘in situ’ assays for product and starting materials and sometimes known impurities. 

The senior research chemist, the folio assembler, and often other senior scientists conceive and rank possible synthetic routes.

 By the time the actual process work begins at the bench, the senior research chemist has read a wide variety of articles pertinent to the various critical aspects of the process problem. Thus the early work period is not spent just keeping junior people busy or making mistakes that could have been avoided with basic literature familiarity. Once new pertinent literature examples become difficult to unearth, the folio assembler moves on to a different priority. Searching becomes more focussed once bench results start coming in and the Senior Research Chemist should decide what new information will address the problem.

This methodology will work efficiently because:

• Reliable chemical data is pains-taking to acquire at the bench.

• It is much faster to learn methodology from a publication than de novo.

• A comprehensive set of pertinent references would be useful as close to the beginning of the process development experiments as possible.

• Early experiments are usually poorly chosen and waste time

• It takes more time to find a key paper than to read it.

Models for Ideal Chemical Processes

Any process has the possibility of continual incremental improvement but practically a point will be reached when it is not worth further effort and one’s time and talents are better expended elsewhere. 

 In process development how does one judge the good and the better?  A good process meets its quality and quantity requirements. The better process does this and goes further. The better process must be rugged. In a rugged process, if human error, mechanical failure, or equipment inadequacy creates some small deviations from the prescribed procedure, the result does not suffer seriously either in quality or quantity.

We judge a process by its costs and these include the labor expended, the time utilized in the special equipment, the price of the starting materials, and the price of waste disposal or recycling. A costing not only provides an indication of the efficiency with which inputs are used but it also provides a running assessment on the specific shortcomings that contribute most to the overall expense. A preliminary costing is an important tool in developing any process because it ranks areas where one might invest whatever limited time one has to achieve improvement.  

Trost has philosophized that the ideal process would be a single step and that there should be no co-product. That is, all the atoms in the reacting substances are retained in the products. Nothing then is thrown away. This is an interesting idea to contemplate.  It dramatically highlights that atom economy, as he calls it. It has the benefit of high weight throughput and low waste disposal but it is far from reality in terms of what can be actually practiced.  Every process is indeed ideally only a single transformation but the problem is starting materials for this ideal process are not commercially available- and because of this, the process creator must move retro-synthetically one step at a time until we do reach such commercial precursors.

Another useful idealized conception of a process is a sequence of chemical steps in which the reaction mixture from each step is simply treated over and over again with the reagents for the next transformation until the material which is the synthetic goal is present in the mixture; then, in one isolation operation, this product is separated pure from the complete complex mixture containing all the by-products and co-products of all the prior steps. This model dramatizes that it is most important to eliminate isolations because it is isolations that usually consume the most time and resources in a process.   In practice, of course, there are very valid reasons for performing isolations before the final isolation.

Valid reasons for isolation are:

1. To remove non-productive mass (ballast)
2. To change solvent for reaction optimization
3. To achieve needed purification through phase shifting
4. To correct stoichiometry and so save reagents
5. To provide convenient stopping points for campaign processing
6. To provide rework opportunities for rugged processing

Isolating More Product in Organic Synthesis by Crystallization when the Most Significant Minor Impurity is More Polar:

Trituration with a Modified Water Phase as a Potential Chemical Process Development Method

A reaction may proceed quite well to give an 80% yield of the desired product but be very difficult to work up if it is a mixture of neutral compounds. In this situation, acid-base extraction cannot help to obtain some partitioning between organic and aqueous phases.

 Furthermore, most often the two compounds making up the reaction mixture are both essentially insoluble in water.  When there is 20% by weight of impurity, even when you can find a solvent that gets the major compound to selectively crystallize, the recovery is usually quite poor, simply because by the time you have crystallized 60% of the major compound the mother liquors are a 1:1 mixture of desired and undesired compounds. At this point, the rate of crystallization normally becomes impractically slow. The crystallization has essentially stopped. 

Usually, thin-layer chromatography in more than one solvent system can quickly tell you whether the main impurity, which most probably is the one blocking the crystallization, is, by and large, less polar or more polar than the desired major component.  When the minor component is the more polar, what we intuitively would like to do is triturate with water, modified so that it can dissolve more of the mixture, hoping that the additional material dissolved into the water-rich phase will be disproportionately the more polar impurity component. 

A co-solvent for water to be effective must prefer to mix with the water rather than forming an oily phase with the products.  Only experimentally can we find something guaranteed to work, but perhaps KiloMentor can propose a rule of thumb, that could increase the likelihood of success: this aqueous phase modifier should be completely miscible in all proportions with water.  If a diluent is only partially miscible with water it is more likely that when mixed with the neat reaction oil it will simply migrate into the oil. 

The most lipophilic solvents that are completely miscible in all proportions with water are acetone, methyl ethyl ether, methyl acetate, and t-butanol. The lower homologs of each of these function group types will also be completely miscible. That is: methanol, ethanol, propanol, and isopropanol are also completely miscible and could also be used as diluents. For esters, ethyl formate is not completely stable in water so it cannot be used. Acetonitrile is completely miscible but propionitrile is not. Nitromethane is not completely miscible, while dimethylformamide, N-methyl formamide, formamide, DMSO, and pyridine are.

In addition to adding small quantities of these solvents to a large excess of water to increase the leaching power of the polar phase, recrystallization from the less polar of these at least: acetone, t-butanol, pyridine or methyl acetate by the gradual addition of water could be fruitful.

Once the level of the impurity is reduced below 10% from the 20% range, crystallization in general can be expected to give a superior recovery.  From a mixture containing just 10% impurity, one could crystallize 80% before the mother liquors would be 50:50 product: impurity.  

Even at scale, a reaction mixture can be freed of organic solvent by concentration in the presence of a water phase to give a reaction product oil as an oil in water. The aqueous phase modifier could be added to this mixture.

When trituration is not working an alternative is to dissolve the compounds into isooctane and extract with some mixture of acetonitrile, water, and ethylene glycol.