Besides the substrate and the reagents involved in a reaction, the factor that has the greatest influence on the outcome is the solvent. The solvent is the only species typically intimately involved in the transition state other than the molecules that contribute bonds that are either formed or broken. I would say it is the only molecules except for catalysts. Changing the solvent is almost guaranteed to change the enthalpy and entropy of activation. As a consequence a reaction optimized in one solvent needs to be reoptimized when transferred to another. The changes are quite likely to be substantial even when the solvent change seems to be slight.
Effect on Process Step Throughput
It therefore follows that solvent choice is first based on net contributions to the maximizing yield and reducing the occurrence of impurities in the crude. If there is still room for choice among equally acceptable alternatives its contribution towards process throughput is often the next most significant consideration. Intuitively one might think that the most important consideration is the solubility of the pure product in the liquid reaction medium. In fact on more thoughtful consideration, it is probably the degree to which the reactor liquid can dissolve the starting material that is most important for processing. Think of it this way. It probably is not too important whether the product solidifies and falls out of the reaction mixture as the reaction proceeds. Indeed, one can think of equilibrium reactions that are only driven to good yields because the product or coproduct precipitates. The Finkelstein conversion of alkyl chlorides into iodides is driven by the insolubility of sodium chloride in the solvent acetone. In order to achieve the highest throughput and the highest initial reaction rate it is probably important to get as high a concentration of starting materials into solution as possible at the beginning of the reaction. If the product as it forms precipitates from solution that is just another opportunity for simplifying the isolation.
It is easy to mistake the rate of dissolution of a substrate or reagent for its equilibrium solubility and select a higher solvent dilution for a reaction than is actually necessary. A second mistake that is possible is to think what is important is the solubility of starting materials at ambient temperature rather than at the temperature at which the reaction is going to be conducted. Solubility of most materials increases markedly with increases in temperature. Finally, the mixture of substrates and reagents gives a mixture and mixtures of solutes typically dissolve more readily than a pure single solute. Furthermore, as the reaction gets started the presence of product and co-products in the mixture will likely increase the dissolving power of solvent yet again. The net result is that you would be surprised how little solvent is actually needed to produce a homogeneous reaction mixture for at least that portion of a reaction’s course required to give a good outcome. Particularly for the early reaction steps of a process getting high mass throughput can dramatically reduce costs by reducing the number of batches.
Reaction solvent selection in batch process chemistry campaigns does not need to be confined to single solvents; mixtures of solvents can be used. An argument often heard is that pure single solvents should be employed in order to facilitate recycling and reuse of solvent to reduce the overall cost. This seems simple and straightforward except that solvent recycling in fine chemical processing is surprisingly rare. One of the reasons for this is that using recycled solvents requires that the user validate the process for using recycled solvent and set and consistently meet some certificate of analysis requirements for the solvent stock. Yes, it is true that many generic API suppliers recycle solvents and even reuse some solvents without purification (ie for recrystallization) but these appear to be exceptions rather than the rule.
Theories of solvation recognize that certain portions of a substrate are better solvated by one solvent and other portions by a second solvent; as a consequence the overall solubility of a substrate can be enhanced in a judiciously selected mixture of these solvents. The widespread use of load cells to weigh solvents into a reactor has eliminated the problem of getting a consistent mixture of solvents at the beginning of reaction. On the other hand, a real downside of solvent mixtures is that the solvent composition in the reactor during the transformation varies somewhat depending upon the holdup of the reflux condenser and this holdup varies depending upon the particular equipment setup.
A reaction may proceed well even if there is no point during the processing when the reactor contents are homogeneous. This would seem to present a further opportunity to increase throughput by putting more substrate and reagents into each reactor load. The difficulty, that should not be overlooked, is that in-process checking for reaction completeness is typically made more difficult if the reactor contents are heterogeneous. If a starting material is not completely soluble how can one assay for it in the reactor? If the desired product is partially undissolved how does one assay the product in the reactor? A good assay is not possible. It is possible to perform quantitation upon both phases from a sample and this can tell something about reaction completeness but it cannot give a good assay and besides the procedure is more complex and less robust.
It is possible that no additional liquid medium at all may be needed for a reaction step. In some cases a liquid anti-solvent is sufficient to allow the reaction to proceed. In the case of reactions where substrate and reagents are insoluble in water, reaction ‘on water’ may be beneficial. The water drives the reactants together and serves as a medium for mass and heat transfer in the reaction vessel.
As the concentration in the reactor increases the rate is expected to increase. This may cause too exothermic a reaction or the reaction time may be so short that there is insufficient time to perform the in-process analysis to determine the best end point for the reaction period. Either of these can set a limit on the minimization of solvent and the throughput one can aim for.
Effect on Reaction Telescoping
Usually only when the yield and purity are acceptable from all the candidate solvents does one have the luxury of selecting from a group of possible solvents. In this fortunate circumstance one solvent may be preferable because it facilitates telescoping of reactions which can eliminate isolations that do nothing more than lose good material.
Solvent Additives to Improve Properties
Sometimes a second solvent is added to a first in small amount to change the physical properties of the liquid medium in some more desirable way rather than to change the bulk properties of the liquid. The addition of toluene in small amounts to DMSO for example is done to prevent it from freezing at such a high temperature when cooled. Something similar could be applied to cyclohexane, glacial acetic acid, or t-butyl alcohol solvent systems. The addition of a small amount of a lower boil solvent can assist in maintaining a predetermined maximum reaction temperature and to increase the apparent heat capacity.
Effect on Process Step Throughput
It therefore follows that solvent choice is first based on net contributions to the maximizing yield and reducing the occurrence of impurities in the crude. If there is still room for choice among equally acceptable alternatives its contribution towards process throughput is often the next most significant consideration. Intuitively one might think that the most important consideration is the solubility of the pure product in the liquid reaction medium. In fact on more thoughtful consideration, it is probably the degree to which the reactor liquid can dissolve the starting material that is most important for processing. Think of it this way. It probably is not too important whether the product solidifies and falls out of the reaction mixture as the reaction proceeds. Indeed, one can think of equilibrium reactions that are only driven to good yields because the product or coproduct precipitates. The Finkelstein conversion of alkyl chlorides into iodides is driven by the insolubility of sodium chloride in the solvent acetone. In order to achieve the highest throughput and the highest initial reaction rate it is probably important to get as high a concentration of starting materials into solution as possible at the beginning of the reaction. If the product as it forms precipitates from solution that is just another opportunity for simplifying the isolation.
It is easy to mistake the rate of dissolution of a substrate or reagent for its equilibrium solubility and select a higher solvent dilution for a reaction than is actually necessary. A second mistake that is possible is to think what is important is the solubility of starting materials at ambient temperature rather than at the temperature at which the reaction is going to be conducted. Solubility of most materials increases markedly with increases in temperature. Finally, the mixture of substrates and reagents gives a mixture and mixtures of solutes typically dissolve more readily than a pure single solute. Furthermore, as the reaction gets started the presence of product and co-products in the mixture will likely increase the dissolving power of solvent yet again. The net result is that you would be surprised how little solvent is actually needed to produce a homogeneous reaction mixture for at least that portion of a reaction’s course required to give a good outcome. Particularly for the early reaction steps of a process getting high mass throughput can dramatically reduce costs by reducing the number of batches.
Reaction solvent selection in batch process chemistry campaigns does not need to be confined to single solvents; mixtures of solvents can be used. An argument often heard is that pure single solvents should be employed in order to facilitate recycling and reuse of solvent to reduce the overall cost. This seems simple and straightforward except that solvent recycling in fine chemical processing is surprisingly rare. One of the reasons for this is that using recycled solvents requires that the user validate the process for using recycled solvent and set and consistently meet some certificate of analysis requirements for the solvent stock. Yes, it is true that many generic API suppliers recycle solvents and even reuse some solvents without purification (ie for recrystallization) but these appear to be exceptions rather than the rule.
Theories of solvation recognize that certain portions of a substrate are better solvated by one solvent and other portions by a second solvent; as a consequence the overall solubility of a substrate can be enhanced in a judiciously selected mixture of these solvents. The widespread use of load cells to weigh solvents into a reactor has eliminated the problem of getting a consistent mixture of solvents at the beginning of reaction. On the other hand, a real downside of solvent mixtures is that the solvent composition in the reactor during the transformation varies somewhat depending upon the holdup of the reflux condenser and this holdup varies depending upon the particular equipment setup.
A reaction may proceed well even if there is no point during the processing when the reactor contents are homogeneous. This would seem to present a further opportunity to increase throughput by putting more substrate and reagents into each reactor load. The difficulty, that should not be overlooked, is that in-process checking for reaction completeness is typically made more difficult if the reactor contents are heterogeneous. If a starting material is not completely soluble how can one assay for it in the reactor? If the desired product is partially undissolved how does one assay the product in the reactor? A good assay is not possible. It is possible to perform quantitation upon both phases from a sample and this can tell something about reaction completeness but it cannot give a good assay and besides the procedure is more complex and less robust.
It is possible that no additional liquid medium at all may be needed for a reaction step. In some cases a liquid anti-solvent is sufficient to allow the reaction to proceed. In the case of reactions where substrate and reagents are insoluble in water, reaction ‘on water’ may be beneficial. The water drives the reactants together and serves as a medium for mass and heat transfer in the reaction vessel.
As the concentration in the reactor increases the rate is expected to increase. This may cause too exothermic a reaction or the reaction time may be so short that there is insufficient time to perform the in-process analysis to determine the best end point for the reaction period. Either of these can set a limit on the minimization of solvent and the throughput one can aim for.
Effect on Reaction Telescoping
Usually only when the yield and purity are acceptable from all the candidate solvents does one have the luxury of selecting from a group of possible solvents. In this fortunate circumstance one solvent may be preferable because it facilitates telescoping of reactions which can eliminate isolations that do nothing more than lose good material.
Solvent Additives to Improve Properties
Sometimes a second solvent is added to a first in small amount to change the physical properties of the liquid medium in some more desirable way rather than to change the bulk properties of the liquid. The addition of toluene in small amounts to DMSO for example is done to prevent it from freezing at such a high temperature when cooled. Something similar could be applied to cyclohexane, glacial acetic acid, or t-butyl alcohol solvent systems. The addition of a small amount of a lower boil solvent can assist in maintaining a predetermined maximum reaction temperature and to increase the apparent heat capacity.
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