Preferred Solvent for Synthesizing a Compound that can be Reversibly Extracted into Water.

 

Suppose I were presented with the problem of synthesising an organic compound that can be reversibly extracted into water at some pH (ie, an acid or base). Further, suppose that there is no powerful reason to use a particular solvent for the transformation, but I do know the plant reactor in which the reaction will likely be run in. What would my dream solvent be?

I know the minimum storable volume of the proposed reactor and the maximum volume of the reactor. So I would use a two-component solvent made up of o-dichlorobenzene and hexane. The ratio of hexane to o-dichlorobenzene would be (1/2 maximum volume - minimum stirrable volume) ÷ Minimum stirrable volume. 

Why o-dichlorobenzene? I want to be able to use enough o-dischlorobenzene to fully occupy the minimum storable volume in case it is necessary at some point to distil away all the hexane. Also, o-dichlorobenzene has a density of 1.31, so it will constitute the lower phase if I need to do a liquid-liquid extraction after distilling away hexane. Also, o-dichlorobenzene has a boiling point of 180 C, so it can serve as a chaser if I need to distil away any other solvents with significantly lower boiling points.

Why hexane? Hexane will ensure that the reaction temperature cannot, without resistance, go above 68.7 °C, the boiling point of hexane. I do not know what the optimal reaction temperature will be. A hydrocarbon cosolvent gives me the greatest number of very similar alternatives with different boiling points, which can serve as alternate stable reaction temperatures. Why the particular hexane: o-dichlorobenzene ratio? When I scale up, I want the o-dichlorobenzene to fill the minimum storable volume, while the reactor itself will be only half-filled in case I need to add more volume or perhaps an aqueous layer.

Hexane would be no more than my first choice for the second component of the solvent mixture, however, because any, preferably but not mandatory, water-immiscible solvent that can be distilled away from o-dichlorobenzene might function. I use a mixture of cosolvents because that makes the solvent composition adjustable during optimisation, knowing that waste solvents in the pharmaceutical and fine chemicals businesses are rarely recovered. 

The essential elements of this methodology for making a water-extractable product are (i) to use one cosolvent with a density greater than water and a boiling point distinctly different from that of the second solvent, and in a volume sufficient to occupy the minimum stirrable volume of the planned full-scale reactor and (ii) a final solvent that is immiscible with water.

The plan would be to conduct the chemical conversion at the best time-temperature combination studied. Then, optionally distil away the hexane, and add a water phase at the preferred pH to extract the desired product. Then drain away the lower chlorobenzene layer that contains any organically neutral & soluble co-products, byproducts, reagents or starting materials through the reactor’s bottom valve. Subsequently, any lighter than water organic solvent immiscible with water can be added into the reactor, and after adjusting the pH appropriately, the product will switch back into this upper organic layer, and the water can be drained off to waste. The product will remain partially worked-up, potentially in a solvent from which it can be crystallised or precipitated!

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 are contradictory teachings in the literature concerning the miscibility or immiscibility of ethanol and cyclohexane. This confusion may be 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 at any temperature less than 0℃  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 throughout under inert gas. Therefore, one could predict that two phases might not be seen in the laboratory but would be reasonably easily achieved with the more readily accessible plant peripherals.

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 any non-volatile substrates in either ethanol or cyclohexane depending upon what solvent predominated in the starting mix.

Alternatively, the reaction mixture can be cooled to below -16℃ to see whether or not two liquid phases separate and if so how the substrates of interest partition between them. It needs to be noted however that even if two liquid phases separate, that separation may be slow since these liquid layers are expected to have very close densities. A small addition of water may cause separation in cases where nothing is apparently happening.

As you can see, this binary solvent mixture provides options in the work-up and isolation.

The Advantage of Methanol-Hydrocarbon Solvent Mixtures for Organic Synthesis

This blog article is 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 was a poor use of reactor time and required extensive expensive analytical work to prove that the specifications were being consistently met.

KiloMentor thinks 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 a discrete variable in the process optimization. This does not rule out eventually finding a process step optimum that is 100% of one of your original solvent combinations.

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 is achieved for the step. This leads 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 fulfill the criteria of having both a polar and a non-polar component and being homogeneous at the azeotrope's 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 consistently 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 every 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 in every case maintain a single homogenous phase that 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,  when the reaction is complete and the reactor contents are 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 a specific gravity of 0.675 and the composition of the lower layer will be 42% hexane and 58% methanol with a specific gravity of 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, a UCST  is reported to occur at 51℃ but handbooks do not report separating phases on cooling. This is confusing 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 might 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 at least will dependably occur!

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

If an intermediate is being worked up, isolated, or 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 stirrable volume’ in the reactor contemplated for the eventual scale-up.

This will almost always involve replacing a traditional lower boiling solvent as part of the modifications of a literature example. These chaser phases must almost always be acceptable in cost to the solvents they replace. 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 so, using an appropriate chaser will save money that will only spent for 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 of a desired principal substrate in a hydrocarbon solution can be freed from more polar impurities by multiple extractions with an appropriately chosen combination of acetonitrile, ethylene glycol, and water.

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.

 

Using Chasers in the Work-up to make a High-boiling Solvent Practical

Importance of Solvent Choice

In the reaction of two generalized chemical species, A with B, the most significant variable invariably affecting the yield is the stoichiometry. The optimal stoichiometry is usually something close to the molecular proportions in the balanced chemical equation representing the desired reaction.  Certainly, these are the proportions that chemists hope will be best because any excess of either substrate will cost extra money.

Frequently, the second most significant variable is the choice of solvent. This makes intuitive sense. In an uncatalyzed reaction, the solvent is the only other chemical next to the reactants that is present within the transition state and it is the reduction of the transition state energy that makes the conversion to desired product preferred over unreacted starting materials or byproducts.

The more solvents to choose from, the greater the opportunity to improve a reaction’s selectivity. Of course, some solvents are preferred on the basis of cost per liter. Others are preferred for ease of removal in the isolation and purification of the product. Usually, this is because it is too high boiling/viscous for the work-up or makes drying tedious. Whatever it is, because solvent choice is a discrete variable, (if binary mixtures are off limits) there is a widespread tendency to quickly settle for one of those ‘old faithfuls’ and then systematically work with the continuous variables to ‘optimize’.

It is true that if 

• the substrate and reagent (A and B) are both soluble in a solvent and 
• that solvent has already been successfully used in an example in the literature 

your chance of successfully adapting it is substantially increased;

however, there are cases where benefits can accrue by looking beyond the ‘old faithful’ solvents. Those benefits are most likely to be realized

(a) if there is plenty of room to improve the reaction’s yield 

(b) if a good ‘in situ’ assay for the desired product is available, and 

(c) if one knows how to conduct an efficient search.

On the other hand, there are good reasons for not considering these less-utilized solvents.

 Reactions that cannot be totally quenched deteriorate during solvent switching. For example, if the substrate can over-react with excess of a reagent but excess reagent is necessary to give the required conversion, then tacking on a solvent switching operation to get rid of a higher-boiling reaction solvent, will most likely lead to overreaction and extra byproduct formation. Similarly, if the desired reaction product is thermally unstable, the extra heat input and time spent for solvent switching may prove deleterious.

 But if any excess reagent can be first completely destroyed or otherwise disabled, solvent switching to separate a higher boiling reaction solvent can still be considered.

It is not necessary to demonstrate the separation from a higher boiling reaction solvent unless such solvent actually seems to be delivering the required improvement in reaction yield. At this scouting stage in an ‘optimization’, improvement only needs to be hinted at by an improved assay for the desired product in the completed reaction mixture. This is why having a dependable product assay needs to be in hand before looking for a less-common reaction solvent. 

Switching from High-boiling Reaction Solvents for Work-up

A reaction solvent can be removed by distilling it away from an even higher-boiling solvent called the chaser solvent. I will consider five different chaser solvents: Acetic anhydride, Quinoline, Triethanolamine, PEG 400 (liquid polyethylene glycol), Glycerin, and Paraffin.

Each of these chasers has some unique feature that allows it to be in turn easily exchanged for something low-boiling to continue the isolation and purification.

 Acetic anhydride can only chase solvents of boiling point less than 140 C. It works because it can be converted to an aqueous acetic acid-water mixture that will be immiscible with many low-boiling, classic organic solvents that may be preferable for separation, purification, and isolation.

Quinoline is high boiling. It can be removed by steam distillation, even under vacuum for greater stability of the solutes. Trace residues can be removed by extraction with acidic water since quinoline is mildly basic.

Triethanolamine is very high boiling and can be a chaser for even rather high-boiling solvents. It is miscible with water. Traces that are carried over to a new lower boiling solvent can be extracted with aqueous acid.

PEG 400 is essentially nonvolatile. It can be a chaser for any organic solvent. It can be precipitated with diethyl ether.

Glycerin, although very viscous, can occupy the minimum stirrable volume in a reactor and allow another lower boiler to be distilled away. Glycerin is immiscible with a wide variety of regularly used organic solvents. Glycerin will keep polar solutes in solution.

Paraffin is the opposite polarity extreme to glycerin. It is essentially non-volatile straight-chain saturated hydrocarbons. It can occupy the minimum stirrable volume in a reactor allowing a reaction solvent to be completely replaced. Because paraffin is made up of long-chain hydrocarbons, it is immiscible with regular solvents which are themselves immiscible with hexane, heptane, cyclohexane, etc. Traces of paraffin, because they are straight chains in structure, can be removed as urea inclusion complexes that crystallize from methanol.

Mixed Xylenes as a Possible Extraction Solvent that is Immiscible with DMSO, DMF, and Trichloroethylene (TCE)

 In a chemical process step, the unseparated mixture of positional isomers of xylene is cheap enough to serve as either a reaction solvent or solvent for use in purification.

I am always on the lookout for pairs of organic solvents that can serve as immiscible phases for solute partitioning by liquid-liquid extraction since this is a very robust, simple, and scalable purification method.

Although toluene is immiscible with wet DMSO, it is miscible when thoroughly dried. However, the commercial xylene mixture is reported to be immiscible with even dry DMSO. This mixture of positional isomers also is reported to give two liquid phases with dimethylformamide and trichloroethylene. The extra saturated carbon apparently makes the difference. 

Of the three combinations:

xylenes/DMSO

xylenes/DMF

xylenes/ trichloroethylene

the final one seems the most remarkable.  I would appreciate it if someone who is actually in a lab (I am retired) would either confirm or disavow it in the comment section. It would be very interesting to see how different compounds are partitioned between these two.

Second Crops of Crystals are Easily Available from a Gas-Expanded, Mixed-Solvent System

 One of the advantages of performing crystallization of a substrate from a single solvent by cooling as opposed to causing crystallization by diluting a first solvent with a miscible anti-solvent is that one can try for a second crop simply by reducing the volume of the filtrate, recool the reduced volume to yield more solid. One can do this because the solvent composition isn't being modified. This advantage would be retained if the crystallizing solvent is a lower-boiling binary azeotrope.

In the alternative, where an anti-solvent is being mixed in to create the required supersaturation considerable tedious work is required to remove all the anti-solvent and concentrate that first pure solvent before a second crop can be attempted.

But if the anti-solvent is a gas under plant conditions, this re-establishment of a single solvent and its concentration is simple. Take for example a mixed-solvent recrystallization that was originally being performed by dissolving the substrate in toluene and then decreasing the overall solubility by adding hexane and then cooling. Suppose instead one dissolves the substrate in toluene cools the solution but instead now bubbles in butane gas. The butane will dissolve in the toluene but the solubility of the substrate will decline in just the same fashion that occurs by adding hexane. The product will crystallize. You cannot filter using a vacuum since this would drive off the butane. Filtration must instead be done by pushing the slurry through the filter cloth with pressure. When the crystallized substrate has been caught on a filter, evacuating the system will easily remove the butane from the filtrate leaving the toluene which can be further concentrated. A second crop can be isolated by repeating the gas expansion with butane.

Furthermore, although mixed solvents are not normally recycled and reused in multi-purpose fine chemical plants, Gas-expanded liquids are an exception since simple distillation rather than fractional distillation is sufficient to do the job.

Any mixed solvent recrystallization that uses cyclohexane, hexane, heptane or petroleum ether can be rejigged as a gas-expanded liquid mixed solvent recrystallization using butane thereby enabling taking a second crop of crystals to raise the yield.

Formamide: an Organic Reaction Solvent from which Product can be Easily Recovered

 Formamide is a clear, hygroscopic, oily liquid, miscible with water, methanol, acetone, acetic acid, dioxane, ethylene glycol, glycerol, and phenol. 

It is dried with solid sodium sulfate or calcium oxide.  Activated alumina is also reported to be suitable for drying formamide. High-purity formamide is vacuum distilled and packaged under dry nitrogen. 

Many compounds such as tannins, starch, lignin, polyvinyl alcohol, cellulose acetate, and nylon, dissolve in it. It also dissolves many ionic compounds that are insoluble in water, making it a great solvent for salty/sugary reactions.  Chlorides of copper, lead, zinc, tin, cobalt, iron, aluminum, nickel, and the acetates of the alkali metals as well as some inorganic sulfates and nitrates dissolve. Zinc chloride, stannous and stannic chlorides, ferric and ferrous chlorides, aluminum chloride, and copper chloride are all organic chemistry reagents that might consequently benefit if used in formamide.

The Leuckart reaction necessarily uses formamide since it is required also as a reactant. Formamide should be considered a replacement for reactions more commonly conducted in water. It is polar, protic, and both a hydrogen bond donor and acceptor. It has been used in microwave-assisted syntheses. It degrades in a microwave at 170 °C to CO & NH3 which may be done deliberately as a source of reactant CO or NH3.

Similar to water, at temperatures close to 200ºC hot formamide begins to dissolve a wide variety of commonly functionalized organic compounds and thus can be used as a solvent for organic reactions. At 200ºC these reactions run exceptionally fast. When cooled to room temperature, the organic products become practically insoluble and can be easily separated. Unlike many organic solvents, but similar to water, formamide does not deteriorate at high temperatures. As a result, the formamide filtrate could be repeatedly used as the solvent in the same reaction.  

Its high BP and decomposition to small amounts of HCN at reflux lead chemists to often prefer dimethylformamide (DMF). Neither formamide nor DMF is easily removed with a vacuum, but formamide has the lower solubility in benzene/toluene compared to DMF so it's possible to remove an organic reaction product from formamide by benzene extraction. Extraction with toluene or xylene would also be expected to be OK although it is not documented.

BP: 210°C

Density: 1.133 g/mL

Acetic Acid-Cyclohexane a Solvent System that can be either one or two phases!

Acetic acid and cyclohexane are two very different substances that are nevertheless miscible above 3.9℃ (their UCST). In a cooled reactor, these will form two separate liquid layers allowing for liquid-liquid partitioning of any solutes therein. More easily than in the laboratory, in the plant the reactor can be kept closed and inerted; consequently, more easily water-free. The acetic acid in the lower layer will be glacial acetic acid so long as water is neither introduced into nor produced in the procedure. More polar components of a reaction conducted therein might be removed by simple phase separation. Glacial acetic acid will be much better at dissolving some substances than a mixture with water present to any extent.

After a cut, there will still be some acetic acid residue in the cyclohexane layer, but acetic acid and cyclohexane give an azeotrope bp. 79.6 ℃ that contains 2% acetic acid. Thus, the predominantly cyclohexane layer can be freed of even traces of acetic acid by distilling out from the reaction vessel a small first fraction. A work-up is possible, still without adding any water!

Where Could Such a Solvent System Be Useful?

This cyclohexane/glacial acetic acid solvent mixture, above 3.9℃ when it is a single-phase, might be a good candidate for conducting acetylations with either acetic anhydride or acetyl chloride reagents. The excess reagent might be removed without decomposing it by cooling to <0℃ and cutting the two phases.

This mixture of fluids might also serve for dehydrations or acid-catalyzed rearrangements. Adding anhydrous hydrogen halides would protonate acetic acid, giving rise to a very strong acid in situ. Excess hydrogen halide would be removed with the acetic acid-rich layer when the reactor was cooled. The system would protonate olefins perhaps inducing rearrangement but hydrogen halide would be unlikely to add across the unsaturation since the halide anion would be strongly solvated and deactivated by hydrogen bonds with the acetic acid.

Acetic acid might catalyze enol formation from ketones. Enols could react internally with a terminal double bone to give a cyclic product or they could be condensed, dehydrated, and so dimerized.

This post is speculative. It does not report experimental evidence.  

The Utility of Ether Solvents and Special Auxiliaries with Organometallic Reagents

Organometallic reagents, such as organolithium compounds and Grignard reagents, are not monomeric in solvents that cannot donate Lewis electron pairs; therefore, because they are self-associated they often are not as reactive with an organic substrate as the monomer would be.  Ether solvents, with or without other chemical auxiliaries, can often dissociate organometallic reagents into monomers without degrading them. Each useful ether has its own limited temperature range. At too low a temperature the solvent either solidifies or becomes too viscous to be worked with and at too high a temperature reaction between the organometallic and the ether destroys the reagent. These de-oligomerizing solvents vary in such important aspects as price per unit volume, ease of purification, and the simplicity with which they can be made effectively anhydrous. The extent to which each of the solvents is miscible with water and recoverable from water also plays a role in the practical usefulness of each.

Special Auxiliary Chemicals

Besides ethers and polyethers there are various other complexing additives that can be useful when added in some low multiple of the organometallic’s molarity. These also modify the reactivity and stability of an organometallic reagent already in one of these ethers.  Sometimes, one of these additives makes it possible to use an ether solvent that otherwise would fail when used alone. Sometimes,  one of these additives activates a reagent so effectively that a solvent that is even less complexing than an ether or not complexing at all (like toluene) can be employed successfully. Some of the additives used successfully are: N,N’-tetramethylethylenediamine; HMPA; N,N’-dimethyl- ethylenephosphoramide; triethylenediamine; or lithium bromide.

Because ethers have such useful properties in organometallic reactions and can be supplemented or replaced, associated special advantages and disadvantages are important to know. Solvent choice is in general the most important discrete, discontinuous element among reaction conditions ( time and temperature are continuous variables). Let us look at the various ether solvents.

Diethyl Ether

Diethyl ether is the most frequent solvent for making Grignard reagents in the laboratory. Butyllithium can also be prepared in diethyl ether in the laboratory. At scale diethyl ether’s dangerous flammability and its exceptional tendency to form peroxides makes it unsuitable for making organometallics of any kind without extraordinary costly precautions. It is simply not done. 

Tetrahydrofuran (THF)

THF is the most common replacement at scale when making both Grignard and organolithium reagents. When the combination of too high a temperature with too long a time organolithiums decompose THF.  For example, a molecule of butyllithium splits THF into one equivalent of ethylene and one equivalent of the anion of acetaldehyde. 

THF has the disadvantages that it is miscible with water and consequently is a problem to recover and it forms no azeotropes to help in solvent switches to remove water and to dry it.

2-Methyltetrahydrofuran

2-Methyl THF has become popular because it has the advantage of being largely immiscible with water, thus enabling its simpler recovery while retaining the ability to complex organometallic reagents. Its boiling point of 80.2ºC is still acceptable but of course, it is more expensive than THF.

Methyl Ethyl Ketone (2-Butanone) as a Uniquely Useful Solvent

Anhydrous Hydrochloride and Hydrobromide Salts

The reason that I write the blog KiloMentor is to pass along whatever ‘tricks of the trade’ I have picked up in my career doing organic synthesis. While I was Research Director and President at QuébéPharma Recherche Inc. in Montreal Canada, a consultant, Lars Svendsen, said in an aside to our discussions that methylethylketone (MEK, 2-butanone) was a particularly good solvent for making a hydrochloride or hydrobromide salt because the water could be removed by heating to distill the water azeotrope. 

The azeotrope between MEK and water boils at 73.4℃ and has 12% water in the distillate. Since MEK itself boils at 79.6℃ the temperature gap between it and the azeotrope will be sufficient that a distillation column will not be required to take off fairly uncontaminated azeotrope.

It is not clear whether this process of making the solution anhydrous is performed before or after adding the basic group that is to be formed into a salt. It would logically be more likely that the heating to distill the azeotropic composition would be done after the neutralization. Distilling first would likely drive off some of the volatile hydrogen chloride gas and could cause some degradation of the ketone solvent.

MEK/Water Liquid-Liquid Extractions

KiloMentor is always on the lookout for mixtures of two liquids that are not completely miscible but could partition similar solutes usefully between the two layers. This would make liquid-liquid partitioning a practicable separation method.  A mixture of methyl ethyl ketone and water might do that. I calculate that at 25℃, water will dissolve 18.2% of its weight of MEK while a MEK phase will dissolve 12.5% of its weight of water.

Other Useful Methyl Ethyl Ketone Azeotropes

Besides its behavior with water, MEK  forms lower boiling azeotropes with ethyl acetate (77℃/18% in distillate) and cyclohexane (71.8℃/40.0% in distillate).  

A Trick for Using Acetone as a Crystallizing Solvent.

Acetone is a good solvent for many organic compounds. It would be advantageous if for crystallizations it could be diluted with a less volatile anti-solvent and then warmed at a low temperature to remove predominantly acetone to decrease the substrate’s overall solubility in the residual fluid so that it could be crystallized in good yield.

If this anti-solvent is higher boiling, however, the substrate is increasingly likely to oil out as the pot temperature rises. Preferably, therefore, the anti-solvent should form a lower boiling azeotrope with the acetone so that the acetone can be completely substituted at a temperature below acetone’s own boiling point of 56.2 ℃.

Fortunately, there are quite a few potential anti-solvents that form such azeotropes.

Low Boiling Binary Azeotropes of Acetone with Other Low-

Boiling, Organic Solvents

Azeotropes           v/v ratio b.p. ℃

Acetone/ 1-chloropropane    15/85         45.8

Acetone/ cyclohexane            67/33         53.0

Acetone/ cyclopentane            36/64 41.0

Acetone/ hexane           59/41          49.8

Acetone/ isobutyl chloride        73/27         55.8

Acetone/ diisopropyl ether        56.5/43.5 53.3

Acetone/ methanol          88/12         55.7

Note that the first five in the list lead to a less-polar mixture as acetone is removed. Diisopropyl ether leads to something of similar polarity while removing the azeotrope with methanol eventually gives a more polar medium as the acetone is driven off.

Using diisopropyl ether is to be discouraged since it can have such strict safety requirements.

A Quicker, More Thorough Method for Choosing a Solvent for Your Reaction

 

In Acta Chemica Scandinavia B 39 (1985) 79-91, lead author Rolf Carlson has made some suggestions for choosing a solvent for a reaction. He feels an important consideration will be to be sure that a sufficiently wide range of properties is explored. At the same time, he recognizes that solvents that have already been used successfully in the literature for similar or analogous reactions or those selected in the literature for reactions that seem likely to follow similar mechanisms will be attractive. Our experience also suggests that solvents that won’t dissolve the reactants usually fail. In most cases the liquid medium needs to be a single fluid. 

His proposal produces a two-dimensional map using Eigenvector projections of the solvent descriptor space. I do not adequately know what that means and I don’t suppose it matters whether you do either. What matters is that if you choose one solvent from the central regions of each quadrant, such as chlorobenzene, diisopropyl ether, nitromethane and N-methyl-2-pyrollidone, there will be less probability that you will miss out on being directed towards an especially advantageous but less-obvious solvent choice. If it is obvious that a particular solvent picked from one or more of the quadrants will be unsuitable, choosing another from the same region can still maintain a diversity of solvent properties.

Liquid Sulfur Dioxide as a Means to Switch Solvents

Liquid sulfur dioxide is immiscible with saturated hydrocarbon liquids and will form a separate lower phase when combined with them. Thus, if a saturated hydrocarbon solvent is used as a chaser to drive off the reaction solvent from a first reaction, sulfur dioxide can be added to extract the reaction mixture content into a lower phase provided the desired material is soluble in sulfur doxide. The viscosity of a hydrocarbon fraction that is sufficiently high boiling to work as a ‘chaser’ may mix only sluggishly with liquid sulfur dioxide at -10 C. If it proves necessary to decrease the viscosity of such a hydrocarbon solution it can be mixed with a lower molecular weight saturated hydrocarbon.

Because at 1.46 g/ml the density of liquid sulfur dioxide is almost twice that of a typical hydrocarbon and since saturated hydrocarbons have only a limited solubility in liquid sulfur dioxide, they will form a separate liquid phase from which the liquid sulfur dioxide lower layer can be cut away.

Therefore, liquid sulfur dioxide can be used to transfer a solute from a higher-boiling hydrocarbon solvent mixture to a lower-boiling solvent such as ethyl acetate by first extracting the solute into a liquid sulfur dioxide phase and then displacing the sulfur dioxide with the second solvent (such as ethyl acetate).

There is a shortage of usable solvents that have a higher density than water since halogenated solvents have fallen under a regulatory cloud. Liquid SO2 is such a dense solvent.

Unjustified Shortcomings of DMSO as Reaction Solvent

 

 It is true that DMSO has no known azeotropes. This and its high boiling point account for the difficulty of removing it from reaction mixtures. 

It is not true that DMSO is difficult to dry. DMSO distilled under vacuum after taking a forerun is water-free. 

Whatever its disadvantages DMSO is too valuable a solvent to rule it out.

DMSO is reported to be immiscible with cyclohexane, heptane, hexane, pentane, 2,2,4-trimethylpentane, and diethyl ether, so these liquids can be used in solvent/solvent extractions. Silylation of the solutes in a reaction mixture should improve their extraction into these less polar solvents which can provide a second layer with DMSO.

DMSO is reported to be miscible with methyl t-butyl ether (MTBE). Based on the reported immiscibility with diethyl ether, this would not necessarily be expected. Perhaps adding a small amount of hydrocarbon to the MTBE could provide a two-phase mixture. An anhydrous DMSO produces a phase separation with diisopropyl ether (DIPE) according to the “Solvent of the Week” website. This would permit more flexible liquid/liquid extractions to separate a product from DMSO.

Another potential way to work up reactions done in DMSO could be to concentrate the solution as much as possible under vacuum, and then add the minimum stirrable volume of glycerol (enough to still provide some slight agitation even if the DMSO gets completely removed) and displace the remaining DMSO, still operating under vacuum. Then,  any suitable solvent that is immiscible with glycerol (there are many) could be added and the substrates of interest taken into it. Mixtures of solvents both immiscible with glycerol can be used to increase the extraction’s effectiveness.

Paraffin can also be used instead of glycerol as the chaser for DMSO and this could be useful if the substrate you are trying to recover is polar. Then, extraction from paraffin into lower alcohols becomes possible since these alcohols will be immiscible with the saturated hydrocarbon (paraffin) medium.

The Upper Critical Solution Temperature (UCST) between Acetonitrile and Water

I have always been unsure of the behaviour of mixtures of acetonitrile and water. In some places it is lauded for the usefulness of liquid-liquid partitioning between the two of them while I also see plenty of recrystallizations from homogeneous mixtures of acetonitrile and water. 

Recently in an old US Pat. 4,954,260 filed in 1989 I found the linking piece of data. Water and acetonitrile have an upper critical solution temperature (UCST) of -0.4 C. That is to say below -0.4 C they are generally immiscible  That is to say the two phases each contain both ingredients but they do give two liquid phases. Above this temperature, they constitute a single homogeneous phase. Thus, if you try a recrystallization by heating a mixture of acetonitrile and water you will be working with a homogeneous liquid and even if you cool the solution in ice there will still be one liquid phase.

Good Reasons for Solvent Mixtures for Chemical Reactions?

 

Why do process chemists regularly optimize a chemical step using only a single reaction solvent? Neal G. Anderson in his valuable text, Practical Process Research & Development, dedicates an entire chapter to solvent selection; however, all that he says about using mixtures of solvents is “Sometimes a mixture of solvents will dissolve a compound much better than any one solvent .....” Rather obliquely, regarding the goal of solvent selection, he writes, “[Other] important considerations are to decrease waste and allow for efficient solvent recovery and reuse.”

Although purifying and recycling solvent is almost certainly easier if it is a single substance; generally, in the fine chemical industries, including making pharmaceuticals and pharmaceutical intermediates, solvents are not reused. The exception would be some product that achieves a massive volume. Thus, it might make sense for the owner of a composition of matter patent for a major pharmaceutical to use a single-component solvent so that solvent recovery would be simpler if that product became a blockbuster drug. 

The reason recycling is rare is economic. In a multipurpose plant, batch sizes are too small and the number of different solvents used is too many to make it worthwhile accumulating and storing used solvents for delivery to a solvent recycling specialist. As for purifying solvents themselves, the reactors in a multipurpose plant are too costly to be used for solvent recycling. Finally, recycling solvent within a fine chemical facility would only be acceptable so long as the same strict specifications could be met for recycled solvent as for other input reactants and this testing brings its own costly analytical burden.

My conclusion: most of the time using mixtures of solvents as the reaction medium is just as practical as using a single solvent. That is despite the almost universal traditional practice of using a single component solvent without asking the reason why it must be so. 

Let us examine some of the reasons solvent mixtures could be advantageous.

Throughput

A solvent mixture may well dissolve more substrate per liter than any single component medium can. Getting more substrate dissolved homogeneously in a reactor can improve the economics by increasing throughput, especially in early process steps which need to be run multiple times. (Solubility is the single advantage that Neal Anderson did mention.)

Cost

One particular solvent may possess a specially advantageous property while, at the same time, being prohibitively expensive. Using a mixture of this expensive solvent and a cheaper cosolvent may adequately preserve the special property while reducing the overall cost.

 

Increasing the Heat Capacity

The preferred solvent for yield optimization may be one that boils substantially above the best reaction temperature. Adding a co-solvent that boils at the desired reaction temperature can increase the heat capacity of the medium at the reaction temperature. The lower boiling solvent’s vaporization into the condenser and the returning condensate will stabilize the reactor temperature. Consequently, the addition rates of reactants can be higher without overshooting the optimum reaction temperature.

Changing a Phase’s Density

Some solvents are more dense, and some less dense than water.  In work-ups with water, sometimes having the product-containing liquid phase more or less dense than water can have an advantage. There can be fewer transfers between vessels. The number of large vessels needed to execute a process step may depend upon it. Processing times can be reduced and throughput increased. Fewer vessels mean less cleaning and a smaller burden on plant facilities.

Reducing the Solubility of a Product or Co-product

Decreasing the solubility of a product or co-product can cause it to precipitate as the reaction proceeds. This can drive an equilibrium towards completion, simplify isolation or raise the overall yield.

Making Telescoping Reactions Easier

Sometimes it is not useful to isolate a process intermediate but the solvents appropriate for the present and subsequent process steps are not the same. A solvent switch is required. Evaporation to dryness is not possible at scale. It would be advantageous if the second step in the telescoped pair was optimized in a solvent mixture consisting of a minor amount of the first solvent and a majority of the second solvent. If this were done it would not be required to substantially remove the first solvent. This might save substantial time and substantially reduce waste.

Because the Solvent Mixture Selected is a Constant Boiling Azeotrope

A constant boiling azeotrope has a fixed composition and it boils at a constant boiling point. In these respects, it is the same as a pure single molecular species. It can usually be purified by simple distillation. However, many azeotropes have the advantage that by changing the pressure-usually by reducing the pressure- the azeotrope can be split into its component substances for distillation. This distillation at a different pressure can potentially remove the better solvent and lead to the precipitation or crystallization of a solute.  

To Reduce Solvent Viscosity

Viscous solvents are often usefully high boiling but their viscosity is a problem for stirring and for heat conduction. Mixing with another solvent can reduce the viscosity of the reaction medium.

To Provide a Distillation Chaser

Adding a higher boiling solvent into a reaction solvent mixture can provide a chaser for reaction mixtures that are subsequently worked up by distillation. In ordinary distillation, sometimes a substantial amount of product is lost in the still pot and the distillation column. A solvent component that can act as a chaser can eliminate this loss. Of course, such a chaser could also be added after the reaction is over but before the distillation step.

Drying Simplicity 

Drying solvents at scale with inorganic salts followed by filtration of the inorganic salt hydrates uses labor, equipment, and time inefficiently.  It is greatly disfavoured for work at scale. The preferred method for solvent drying selects a solvent that forms an azeotrope with water and distills a portion of the solvent as the azeotrope. Such a solvent may usefully be part of the original reaction solvent liquid.

Raising the Freezing Point 

At what temperature does the solvent that is being considered solidify or become highly viscous? The freezing point can limit the range of temperatures that can be used in the optimization.  Lowering the temperature is often the best option for increasing the selectivity of the desired reaction versus competing reactions that produce by-products. If low temperatures create vicious reaction mixtures, these can result in hot spots during reagent additions. Inadequate mixing leads to incorrect stoichiometry, creating in turn by-products, and poor crystallization control. For example, DMSO when diluted with a small amount of toluene is more resistant to freezing and so can be cooled to a lower reaction temperature.