Reaction Addition Modes: Controlling Chemical Reaction Stoichiometries

 

  A + B  Gives C + D

Most chemical reactions are either unimolecular or bimolecular in their kinetics. They are either addition/condensations where there is only one product, ie C and no D, or in other instances, some transformation also provides a coproduct, D, created along with C.

Reactions proceed when the energy supplied to a system is appropriate for the free energy of the reaction. More energy being supplied to the system can cause the reaction to proceed faster and/or it can promote alternative transformations that compete with the desired one. Applying excess energy for longer than necessary can degrade any of A, B, C, or D.

If any of the reactions

 C + (A or B) gives (E or H)

or 

A + A gives F  

or

B+ B gives G

can occur, then having the correct stoichiometry present throughout the time when the system experiences the required activation energy becomes important. If the stoichiometry is wrong then starting reactant polymerizations or overreaction modes can compete to the detriment of the desired outcome. A procedure that keeps the reactants in the correct stoichiometry throughout that period when adequate activation energy is supplied is likely to give a cleaner reaction.

Standard Chemical Processing

Now in the standard mixing procedure, a solution either of reactant A or B is added slowly to a solution of the complete charge of B or A already stirring in the reactor. If the reaction proceeds so quickly that it overheats, the addition is slowed or stopped allowing the rate of reaction to slow down as the reactant being added gets consumed and no more is being added. That is, the reaction is prevented from running out of control by letting the stoichiometry inside the reactor change radically. To control an exotherm the operators in such instances are forced to let the concentration of the reactant being added into the vessel fall towards zero.

For greater clarity and to emphasize the necessary safety issue let us perform the thought experiment of mixing all of the charge of these same A and B in methylene chloride and starting to heat the reactor. When the reaction between A and B sets in, the methylene chloride will start to reflux but as the temperature rises towards the boiling point of the methylene chloride the reaction between them goes faster and faster. The methylene chloride now boils faster than it can be condensed and gaseous methylene chloride blows liquid methylene chloride and all the rest of the reactor’s content out of the reactor and probably onto the roof of the plant building!

Identifying Reactions that Could be Affected by Stoichiometry

The standard mixing procedure is unlikely to be adversely affected by the ‘in situ’ stoichiometry if the reaction rates of all steps occurring in the reactor are slow compared to the addition time. This is easily determined. When one-half of the addition of the controlling reactant has been added, an in-process check should be done. If either the product or any reaction intermediates are significant compared with unreacted starting materials then the transformation is likely to be sensitive to the reaction’s stoichiometry. If nothing significant besides unreacted starting materials (or substances produced during the quenching of the reaction before analysis) are present, then it is very unlikely that the yield will be affected by stoichiometry. When hardly any change can be detected in this test it indicates that almost the reacting occurs mainly after the reactant being added is completely in the reactor and the stoichiometry is therefore essentially fixed throughout the actual reacting period.

Importance of the Enthalpy of Reaction Calculation

If you are going to perform experiments in which all the reactants are mixed together at once, you must take appropriate precautions. 

You must do a calculation of the enthalpy of reaction based on standard bond energies; however, the enthalpy of reaction (∆H) is only a crude approximation to the free energy of reaction (∆F) since ∆F = ∆H - T∆S. The change in entropy of the reaction (∆S) also contributes to the reaction’s driving force. For example, if the reaction leads to more moles of products than the moles of reactants, the entropy change is most likely going to be positive and the overall free energy decidedly more negative because of (-T∆S). The reaction will be faster than the approximation.  It will be necessary to absorb the net free energy of reaction through the agency of first- the temperature rise of the reactor contents ( mostly solvent),  then the energy absorbed in vaporizing some part of the reaction solvent, and finally by the energy drained off by the refluxing of a part of the solvent.

Absolute Necessity for Small Scale Trials in a Laboratory Fume Hood

Theory is just theory. If you are going to perform a reaction in which all the reactants are to be mixed together and then reaction initiated (either by heat or catalyst), you must try out the method at a scale where even if you have miscalculated there will be no more than a mess to clean up, not a laboratory disaster! The reaction which you have examined might not even be the reaction that occurs. Something much more energetic could surprise you.

Get Emergency Control Means Ready

Of course, your reaction vessel must be equipped with a means to directly in real-time read the internal temperature. Otherwise, you won’t be alerted soon enough that you have a problem.

If despite your calculations the temperature of the reactor accelerates in an unexpected way you want to be prepared to intervene to slow things down. Having a cold -bath ready into which the reactor flask can be plunged often can tame a reaction that is misbehaving. The advantage of this form of moderation is that it can be removed when the danger passes and the experiment continued.

Some reactions need to be quenched by injection. In many cases that quench material can be as simple as water. Of course, such an experiment is wasted but a runaway condition is avoided. 

When a runaway reaction is the least bit possible, the experimentalist should both wear appropriate personal protective equipment and have a fire extinguisher handy. It is important to prepare by imagining what might happen. For example, are there other chemicals in the hood you will be using that could exacerbate your runaway? 

Well then—can we actually mix reactants A and B together safely so that the correct stoichiometric is maintained at all times and a runaway exotherm is prevented?

 Two Simultaneous but Separate Additions

Simple in concept but mechanically difficult would describe the simultaneous addition to one reactor of two separate solutions, one carrying the A reactant and the other carrying the B reactant. The two addition rates of each need to be controlled so that the same required molar amount of each reactant is delivered throughout the addition time. If unwanted exothermicity occurs in the reactor both reactant streams need to be slowed the same amount or stopped simultaneously. Technically this is a big ask and practically it will only be approximately successful but even if it is only achieved approximately it can provide a closer approximation to constant ideal stoichiometry. This method of reactant addition, even if performed somewhat imperfectly, can give the experimentalist an indication of whether getting better stoichiometry using a different but more practical method is likely to deliver a useful benefit.

Storage Solvent and Reaction Solvent Method

Both reactants can be dissolved together completely in a volatile solvent (storage solvent) at a temperature and concentration at which reaction will not proceed and that solution can be added in a controlled fashion to a higher boiling solvent (reaction solvent) preheated to below its own bp. but above the bp. of the addition solvent so that the storage solvent will flash distill as it is added and the reaction between A and B will occur at the set stoichiometry in the reaction solvent solution.

Flow System Method

A continuous flow system may be possible where the reactants are bled separately but in the proper stoichiometry into a heated reaction zone and the product is continuously removed from the reaction zone. The problem with the flow technique is that for many reactions operating at the lowest normal reaction temperature, the heated zone would be quite long. Such specially configured equipment is not typically available. This can be solved by operating at a higher temperature in a higher boiling solvent treated in the reaction zone near the higher boiling point of this alternative solvent. 

For example, suppose it is known that A will react with B in refluxing dichloromethane and the reaction is essentially complete in three hours. The same reaction however might proceed equally cleanly in hot propylene carbonate in one minute. Then mixing two solutions one of A and the other of B; each dissolved in hot propylene carbonate so that a correct stoichiometric ratio and delivering it into the hot reaction zone in a flow reactor so that the transition of material through that zone was one minute could produce C more cleanly than heating much longer in dichloromethane because the correct stoichiometry has been more faithfully observed and the reaction period is very abbreviated.  If the reaction time is lessened, the reaction zone length can be shortened and some standard equipment may suffice. Now, whether creating the advantage of having the correct stoichiometry throughout the reaction period outweighs the disadvantage of applying more energy to the system than is actually required to get reaction can only be answered by experiment.

Reactants- All-In Method

Another means to achieve the same result would be to mix the correct stoichiometric quantities of A and B in the bottom of a reactor and then add a high-boiling solvent to it; in our example above this would be the propylene carbonate. The reactor is then heated to start the reaction. Normally mixing all of the reactants together and then heating to start their reaction is never done at scale because, as already pointed out, the exothermicity of the reaction is likely to cause a runaway wherein the entire contents of the reactor including any solvent would overheat and potentially even explode; however, using a sufficient quantity of a high-boiling solvent with a significant heat capacity and large enough heat of vaporization will allow any exothermicity to be absorbed first by the heating of the high-boiling solvent and subsequently by the heat of vaporization (refluxing) of a small portion of this solvent.

Using High-Boiling Solvents to Control Exothermic Reactions

The advantage to using a high-boiling solvent for such a reaction is not primarily its ability to dissolve the reactants and bring them together homogeneously. Good low-boiling solvents can do that. The high-boiling solvent can use its higher heat-of-vaporization, as well as its heat capacity, as a heat sink to soak up the exothermicity of the reaction.

In fact, the high-boiling liquid in which the reaction is being conducted does not need to be able to dissolve the reactants for it to be effective as a heat sink. So long as the reactants can blend together without solvation help the liquid medium does not have to dissolve them. Reactions ‘on-water’ for example are of this type. If at least one of the reactants is itself liquid there will be a reduced need for a dissolving type solvent. Another purpose for using a high-boiling liquid medium in which the reactants are insoluble is to provide sufficient bulk volume to satisfy the minimum stirrable volume requirement for the reactor.

Phenylboronic Acid: A Functional Tag to Enable Simple Removal of Excess Reagent or Coproduct using Chromotropic Acid

Chromotropic Acid for Extracting Boronates

The KiloMentor Blog articles emphasize ways to make the workup, separation, and purification of the product from organic reactions more cost-effective. Often this is enabled by phase switching methods that quickly take the desired material into one bulk phase and byproducts, coproduces, and the processing chemicals into another.

One way to dot this is to use a reagent or coreactant that has built into its structure some functionality that allows it to be subsequently extracted into an aqueous phase. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is an example of such a reagent. The pendant dimethylamino functional group makes an excess reagent or coproduce or byproduct basic and so soluble in aqueous acid.

A functional fragment that can be used in this way but has rarely been adopted is the p-dihydroxy-boryl benzyl function.  This substructure appears in the Dobz protecting group for peptide synthesis [D.S. Kemp and David C. Roberts, Tet. Lett. 52, 4629-4632, 1975]. The dihydroxyboryl group forms a strong covalent linkage with the sodium salt of chromotropic acid [1,8-dihydroxynaphthalene-3,6-disulfonic acid] which is very soluble in water.

In the absence of complexing species, boronic acids are in reversible equilibrium with their cyclic trimers and water. Other species containing the group may be partially converted to Boronic anhydrides.

Although many reactions can be conducted in the presence of the free Boronic acid function  as a second option the Boronic acid can itself be protected as the N-methyldiethanolamine complex. N-methylethanolamine is of course itself readily taken into water in a workup. 

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.

Pyridine-Water Selective Precipitation with Pyridine Recovery

 

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

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

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

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

Propylene Carbonate as a Useful Solvent for Organic Synthesis Processes

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

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

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

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

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

Reaction Solvents that could be Worked-Up with Acetic Anhydride

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

Chlorobenzene

Nitro propane

Methyl chloroacetate

Cyclopentanone

Diethyl carbonate

Dimethyl sulphite

Tetrachloroethylene

2-nitropropane

Methylisobutyl ketone

N-methylmorphiline

Nitromethane

Toluene

1,1,2-trichloroethane

Trifluorotoluene

1,4-dioxane

Nitromethane

Methylcyclohexane

Heptane 

Propionitrile

Dibromomethane

Dimethylcarbonate 

Trichloroethylene

Isopropyl acetate

1,2-dimethoxyethane

Fluorobenzene

1,2-diethoxyethane

1,2-dichloroethane

Cyclohexane

Acetonitrile

Cyclohexane

Benzene

methylethylketone 

2-methyltetrahydrofuran

Ethyl acetate 

Butyl chloride

Carbon tetrachloride

Petroleum ether

Hexane

Diisopropyl ether

Chloroform

Perfluorohexane

1,1-dichloroethane

Methyl acetate

Carbon disulphide

Dimethoxymethane

Pentane 

Diethyl ether

Methyl t-butyl ether