Gas-Expanded Liquids as Solvents in Organic Synthesis

A gas-expanded liquid solvent combines a component that is a liquid at the operating temperature and pressure with a second component that is a gas under these same conditions but which is held within the liquid phase by the pressure used in the reaction and its solubility in the liquid component.

Amines as Gas-Expander for other Solvent Liquids

There are polar substances that are easily fluidized gases: ammonia, methylamine, ethylamine, trimethylamine, sulfur dioxide, and dinitrogen tetroxide being examples.  Some polar solutes may dissolve in rather apolar solvents, with the assistance of a minor quantity of such a polar fluidized gas. 

For such a co-solvent mixture to retain a fixed composition, however, the dissolution needs to be done well below the boiling point of the fluidized gas.  Then, heating the gas-solvent combination or placing it under a vacuum or a combination of these will remove the fluidized gas leaving the polar substrate in an essentially apolar solvent from which it is likely to crystallize readily.

Fluorinated compounds can be made to dissolve in hydrocarbon liquids in the presence of liquid carbon dioxide under pressure from which they crystallize out when the pressure is released and the carbon dioxide vaporizes away.

If the fluidized gas can be effectively recovered in usable purity and if by distillation the apolar co-solvent can be purified, then both solvent components can be recycled for a green process.

The most common co-solvent pair in the chemical literature is ethanol-water. Since neither ethanol nor water is a gas at ambient temperatures ethanol/water is not a gas expanded liquid. Methylamine/ethanol or ammonia/ethanol would be gas expanded liquids and could be useful at low temperatures. In the first instance, the methylamine might be recoverable by recondensation causing the crystallization to be from ethanol alone. Recovering ammonia on the other hand would be too expensive to be justified.

Ammonia is quite likely to be a satisfactory replacement for water in mixtures with other organic solvents such as ethyl acetate, isopropyl acetate, isopropanol, t-butyl alcohol, MTBE, acetonitrile, dimethoxymethane, THF, diethoxymethane, dioxane, nitromethane, nitroethane, isoamyl alcohol, ethylene glycol or DMSO and would constitute gas expanded solvents.  Ammonia may also work with solvents immiscible with water that require a polar additive to dissolve a substrate, such as toluene, hexane, heptane, cyclohexane, dibutyl ether, trifluoromethyl benzene, MTBE, and ethylene carbonate.

Sulfur Dioxide as Gas-Expanding Agent for Solvents

Sulfur dioxide, bp. -10 C, is readily condensed and has intriguing solvent properties. It is a Lewis acid, meaning it can accept an electron pair. It forms a stable complex with p-dioxane for example. It can be scrubbed by ethanolamine. Because it is a liquid denser than water, it likely can be used to increase the density of other solvents with which it is miscible perhaps even to the point where they may become the lower layer in a mixture with other organic solvents.

Dinitrogen Tetroxide as Gas-Expanding Agent for Solvents 

Dinitrogen tetroxide is another candidate for expanding the solvating properties of other solvents. 

Choosing the Scale for Laboratory Project Management Directed towards Chemical Process Development

Deciding the scale at which laboratory work should be done is a project management determination not a scientific one. The proper answer depends upon the physical resources of the laboratory, the budget for the particular project, the scale required to meet the final objective and the time available to meet that objective.

Whether the economic unit is a business or an educational institution the most frequent size at which synthesis experiments are performed can be quickly gauged by looking at the most common sizes of reaction glassware in the drawers of people working at the lab bench. For research conducted in schools, small scale work is more typical because the cost of chemicals is a substantial part of the overall expense. There the cost of student labor is low so using more labor is not a hardship for the professor. An addition consideration that reinforces this tendency is that academic research often works on targets that are many steps away from commercial starting materials. These target materials are time consuming to prepare and so the objects upon which publishable experimentation are conducted are precious and need to be hoarded.

On the other hand, in company laboratories, where the object is to produce either processes for manufacturing or families of compounds for property testing and where the wages of the scientists are a substantial part of the overall cost, the cost of the chemicals is a smaller proportion and working at larger scale saves project time and budget. Again, this will be reflected in the size of standard equipment found in the laboratory.

Although it is most convenient to work at the normal average scale set by the laboratory facilities this can be trumped by a particular project’s requirements so long as that is reflected in the project’s budget. Where this might be true, a discussion of the scale at which different parts of the work are to be performed should take place with the project manager to avoid later misunderstandings.

 http://chemjobber.blogspot.com/2011/11/process-wednesday-rb-woodward-on-scale.html

What is more, when the final objective is to produce hundreds or thousands of kilograms, even more risk related to scale up differences would be introduced if one starts working with only milligram quantities. Besides, if the cost of starting material is so high as to limit the scale of experimentation to the milligram range, it is also quite likely to be too high for commercial implementation at all. Another consideration is that developing a process step requires that many test samples be taken during the run to follow the reaction and to assess the qualities of the intermediates. A non-micro scale of operations is required to allow for representative and meaningful sampling.

What Size Steps for a Process Scale Up?

Why not simply jump from the scale at which a process step was developed to the scale at which it is planned to operate commercially?   Risk of catastrophic failure is the answer. The near optimal conditions for operating in laboratory equipment can still be quite different with respect to a number of variables from what must be done in a pilot plant. Just for starters, some parameters such as heating, cooling, stirring and the times for reagent additions cannot be physically matched on scale because of equipment limitations. Also other surprises can occur as one increases the size of operations and these can lead to product of unacceptable properties. Perhaps one ought to ask instead, “How well have I been able to scale-down the pilot   plant environment and reproduce it in my laboratory equipment."

 ‘Scaling down’ is the exercise of selecting the laboratory scale equipment that can best model operating conditions and provide data for mathematical models that successfully simulate pilot or production scale operations. Risk can be reduced by performing appropriate testing on such equipment.. If the experimentation has been conducted using exactly the same quality for solvents, reagents, processing aids and catalysts, the biggest source of deviation in scale up is removed. 

If the processing times including times of addition, times for transfer and times for filtration are approximately the same as will be used in the pilot plant, risk is reduced. 

If the corrosiveness and abrasiveness of the reactants have been tested upon the reactor construction materials this reduces another risk.

 If the procedure is insensitive to the agitation rate over a wide range another sensitivity has been allowed for.

 If the sensitivity to traces of air and moisture is known and taken into consideration life is simpler.

Water/Organic Solvent Systems for Reaction Between Organic Substrates and Inorganic Reagents

Choosing Reaction Solvents

Aqueous acetonitrile and aqueous 1-propanol are two separate solvent systems which should be considered for reactions between organic substrates and inorganic reagents. To separate these reaction mixtures into two phases; an essentially aqueous one to extract the inorganic residuals  and the second to take up the organic products,T.Hori and T.Fujinaga [Talanta, 32, 8(2), 735-743, 1985] have developed a method that appears more practical than adding salts. This involves adding chloroform in the case of aqueous acetonitrile and cyclohexane in the case of aqueous 1-propanol. These additions of a third solvent component appear to be preferable to the usually large amount of a salt (impurities in which may cause undue contamination); also, the volume and composition of the organic phase can be predicted from phase diagrams and the overall composition of the solvent mixture. Volume-fraction diagrams are especially easy to use. Furthermore, equilibrium is attained in solvent mixtures more rapidly than in salting-out systems.

Reactions that require an aqueous-organic solvent are usually candidates for the application of phase transfer catalysis and this should be the first option because of cost and waste destruction considerations.