It is known that the outcome of many chemical reactions is sensitive to trace amounts of water and this water often can arise as an impurity delivered from reagents and solvents. It is also known that removing the last vestiges of water from many solvents and reagents is both very difficult and time-consuming and furthermore, measuring low levels of residual water can be difficult. It is also true that in theory, it should be easier to dry and keep dry, larger amounts of materials in larger vessels than smaller amounts in smaller vessels. One reason for this is that the ratio of the surface of the containing vessels to the volume of these vessels is smaller as their size increases. Thus, for example, if water is adsorbed onto the wall of the vessel and from there contaminates the liquid, the amount of contaminant per unit volume of liquid will be smaller the larger the vessel.
A process chemist should certainly want to know what the effect of different levels of trace water would be on his process steps because this is a factor that can have profound effects but might still be within the accepted variance specification of his reagents or solvents. Put another way, the process chemist needs to know the effect of trace amounts of water in inputs so (s)he can set proper analytical specifications for the pilot plant or kilo lab.
Suppose the process chemist plans to use a reaction that is already known to be affected in terms of the yield and/or quality of the product by trace levels of moisture. That is, the moisture content of reagents and solvents are critical variables. Then, in costing the reaction step, the expense of buying such grades of inputs or of drying a cheaper grade to the higher specification must be included. In addition, consideration must be provided for the additional in-process testing that will be required to be assured that the correct anhydrous state is being maintained and to be aware of the heightened risk of process failure from this source. A reaction might prove just too persnickety to use if the requirement for being anhydrous is so strict.
High sensitivity to trace amounts of moisture increases risk. One of the ‘usual suspects’ that needs to be ‘rounded up’ when a process step is found to be irreproducible or that is out of control for no apparent reason, is the level of trace water in the reactor. One way to reduce somewhat such potential variation is by rigorous and effective drying of reagents and solvents. If a reaction behaves the same in terms of yield and product quality when performed with super-dry or regular reagent-grade solvents, then solvent moisture is most likely not going to be a critical variable. The drying of solvents rather than reagents is by far the more common difficulty because solvents are used in so much larger amounts compared with the reacting chemicals.
For drying any particular solvent the best drying agent and method of use of that agent has not been successfully predicted and needs to be empirically determined. The analysis to assess the residual trace level of water in the solvent is not simple so some literature guidance is valuable. David R. Burfield has written a series of papers that are authoritative on this question.
Acetone
Acetone is one of the trickiest solvents to dry thoroughly. The reason is that many of the agents that frequently are used to dry solvents cause condensation of acetone which produces water as a by-product. The preferred drying agent for acetone is boric anhydride. Using stirring and sequential drying, this agent gave less than 18 ppm of moisture in the acetone.
Acetonitrile
Acetonitrile is also most preferably dried with boric anhydride although this is not a particularly good agent for other solvents. The acetonitrile should be first distilled to remove gross water.
p-Dioxane
Calcium hydride is shown to be a good and rapid siccative for dioxane and this is assisted more by stirring the slurry rather than refluxing it. Calcium chloride is also a rather good desiccant, which is somewhat surprising in light of the fact that p-dioxane forms a strong complex with anhydrous calcium chloride.
Toluene
Burfield has not performed experiments with toluene; only with benzene. Toluene is expected to be, like benzene, an easy solvent to dry since water is immiscible with it. With benzene, azeotropic distillation followed by removing 20% of the benzene charge significantly dried benzene but nowhere near as dry as using an effective desiccant. This is important to recognize since distillation of a portion of solvent would be a preferred approach for drying at scale but would not be comparable in effectiveness with a chemical treatment.
Dimethylsulfoxide
Dimethylsulfoxide can be dried by combining it with an immiscible hydrocarbon and codistilling the mixture. When heptanes are used, for example, an azeotrope of heptanes and water distills and the heptanes can be returned to the still pot, and the water separated. In this way, the level of water can be reduced to about 0.2%. To proceed further one can fractionally distill through a packed column with variable takeoff and reduce the water content by another factor of 10 by discarding about 20% of the charge. Further drying with 4A molecular sieves can reduce the level to 10 ppm.
https://patents.google.com/patent/US6939962B2/en
“Many solvents are capable of removing water by co-distillation, and any solvent that can achieve this can be used in the method of the present invention. Preferred solvents are those which are immiscible with water and form a constant-composition minimum-boiling azeotrope with water. Exemplary classes of solvents are saturated hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons, ketones, and ethers. As for the polar aprotic solvent, safety and toxicity considerations will also affect the choice of an appropriate solvent. Hydrocarbons are preferred, and cyclohexane, n-heptane, toluene, and isooctane (2,2,4-trimethylpentane) are particularly preferred The most preferred solvent is cyclohexane.
The codistillation solvent is added to the mixture substantially continuously and is conveniently also added at a substantially constant rate. However, changes in the rate of addition and even stopping the addition altogether for a portion of the reaction are also possible.
The prior art EP-0776903-A prescribes that the solvent capable of removing water by codistillation be added in gaseous form. That is, the solvent, typically cyclohexane, is preheated, and vapors of the solvent are added to the reaction mixture. While this procedure can be used in the method of the present invention, it has been found that it is also possible to add the solvent directly as a liquid, without pre-heating. Typically, the solvent will be added through a polytetrafluoroethylene (PTFE) tube, into the mixture, preferably close to the agitator of the reaction vessel. It will be appreciated that, under these conditions, the solvent will then vaporize rapidly.
It is preferred to recover and re-use the codistillation solvent. This can easily be achieved by condensing the vapors from the reaction vessel and then washing and drying the condensate. More preferably, the codistillation solvent is recycled during the reaction. This can be achieved by condensing the codistillation solvent into a reservoir during the reaction and using that reservoir as the supply for the codistillation solvent to be added to the reaction mixture. In the case that the polar aprotic solvent is DMF and the codistillation solvent is cyclohexane, it has been found that it is best to add a small amount of water to the reservoir. This is because a small amount of DMF co-distills from the reaction vessel with the water and the cyclohexane. The DMF can dissolve in the cyclohexane in the reservoir, and thereby solubilize water in the cyclohexane. When water is already present in the reservoir, most of the DMF is taken into the aqueous layer, reducing the solubility of water in the cyclohexane, and thereby affording drier cyclohexane.”
Dimethylformamide
Type 3A molecular sieves used sequentially are the best drying agent. Phosphorus pentoxide is the best agent that operates by the reaction. Phosphorus pentoxide probably phosphorylates the oxygen of DMF and water is destroyed as it is hydrolyzed. Codistillation with heptanes or cyclohexane as for DMSO would also work but the level of drying is not reported.
Methanol
Water is the most significant impurity in methanol. Exposure of methanol to air increases the moisture content of each exposure. Methanol is often used as the drying agent for the walls of large-scale reactors. Clearly, the extent of drying there will be limited by the water content of the methanol.
Burfield and Smithers have noted that in contrast to ethanol for which there are many warnings in the literature that improperly dried ethanol will give lower yields the same is rarely noted for methanol even though its capacity to get contaminated is as great or greater. Methanol is best dried by stirring with magnesium or magnesium with some iodine and then distilling. 3A molecular sieves have pore sizes small enough that methanol can compete with water to enter. Nevertheless, it is useful to distill methanol from magnesium and store it over 3A sieves.
Ethanol
The best agent for ethanol is 3A molecular sieve powder. Treatment with sodium followed by addition and refluxing with a high molecular weight ethyl ester is effective because any sodium hydroxide formed reacts irreversibly to form ester carboxylate. Without the ester addition, sodium hydroxide removes protons from methanol to recreate water to some extent.
No comments:
Post a Comment