Problems using either Solid Desiccants to Dry Organic Solutions or Charcoal to Decolorize when working At-Scale

Differing Time Requirements for Pilot Plant Operations

Neal G. Anderson in his book, Practical Process Research and Development, breaks down the time required to perform the operation of drying an organic solution with a solid inorganic desiccant such as sodium sulfate. He estimates that, including equipment preparation and equipment cleaning, the unit operation would take two operators 8 hours. Only three hours are actually spent performing the physical operations that parallel the laboratory manipulations. An additional one hour is spent assembling and testing the filter and its associated piping. At the end of the actual filtration, four hours are required to rinse, disassemble, clean, validate, and store the equipment ready for reuse.

These same times apply to the operation of treating an organic solution with decolorizing charcoal and filtering it off.

Chemists more accustomed to working at a laboratory scale cannot initially conceive how these preparation and cleaning phases can add up to so much time. In the lab, we are accustomed to using glassware that is cleaned with a quick acetone rinse, transferring liquids simply by gravity, pouring hot fluids through the air, and assessing cleanliness by visual inspection. On-scale, however, whether the solution is hot or cold, filtration needs to be done in a closed inert system. The generally uncomplicated pilot plant filtration compares more closely to working in the laboratory with a toxic liquid or a pyrophoric solid in Schlenk-tube equipment.

With regard to drying organic solvents, once it is grasped that removing water is a difficult and costly process, chemists who are trying to be process minded can try to avoid adding water into a reaction mixture or alternately think about ways to remove it without the complication of additional equipment. Pouring a reaction mixture into water or adding water into an organic reaction mixture is a frequent operation incorporated into a reaction step. We should be trying to rethink this standard approach, which often uses a humongous excess of water. To further complicate things this drown out is usually done rapidly, which again cannot be duplicated in the plant.

Reaction Quenching

Why is this done? One reason, as suggested above, is that it usually stops the reaction. This is why the operation is often called quenching the reaction. Water is an evaporable, cheap, low strength buffer. Since the strongest acid that can exist in a wet solution is H₃O⁺, and the strongest base  ^-OH, many reactions that require either more acidic or more basic conditions than these are stopped by adding water. Another mechanism also operates when a water quench is performed. The addition of sufficient water to produce two immiscible phases in the reactor quenches by phase separation of reaction participants. Some chemicals are much more soluble in the aqueous phase while others are much more soluble in the organic layer. Separation of reactants, reagents, products, co-products and byproducts into one or the other of water or organic usually reduces the rate of reaction among them to essentially zero. A third mode by which aqueous quenching works is the rapid decomposition of one of the reactants by water.

If we remove a water quenching step in a process, it is still usually necessary to stop the reaction at the correct endpoint by other means. Whatever that operation is, it must be rapid. What can be done depends upon the characteristics of the reaction itself. Whatever the quenching additive used it is very preferably inexpensive.

An option is to use some water, but not the large volumes that result in a second phase. In the laboratory, the volume of water used in a quench often doubles the total volume in the reaction vessel. When the quench is done by pouring, with vigorous stirring, the reaction mixture onto an ice-water slush, the final volume is usually still greater. Such large volumes are frequently used ‘just to be sure’ because the laboratory reactions are not investigated enough to figure out the actual lowest amount of water that is needed. At scale, the total reactor volume immediately after quenching, but before the separation of this water, is very often the point of maximum reactor volume and, as such, it controls the batch size. That is, using larger quench volumes than necessary immediately lowers the possible throughput for the process step. Increasing the volume at the point of maximum volume in the reactor increases the cost per kilogram of intermediate product from the step. Investigating the quench that is sufficient to do the job but keeps the lowest maximum reactor volume can pay off by keeping the throughput of the process step high. This is most critical for the early steps of a multistep process.

Increased Waste and Disposal Costs

Creating a large aqueous phase saturated with organic substances also creates a larger waste disposal cost. The water becomes a waste stream. Water contaminated with a saturation level of organic contaminants cannot be discharged to a municipal sewage treatment system. Moreover, it is one that cannot be treated inexpensively by burning. Reducing the amount of the water quench phase will greatly reduce the kilograms of waste produced per kilogram of product. It is an easy way to make a process step both more environmentally friendly and cheaper.

Replacements for copious amounts of water could be ammonium chloride or ammonium acetate both of which are quite soluble in lower alcohols and which only create volatile residues. These would also satisfy the buffering function. In other situations acetic acid or ammonia might work. Grignard reactions and hydride reduction reactions are often treated with ethyl acetate.

Even if water-organic partitioning in a liquid-liquid extraction cannot be avoided in the work-up procedure, using a minimum volume of quench can still be an advantage. Once the reaction has been stopped it may be possible to reduce the volume of the reaction mixture by distillation before adding the larger portion of the aqueous extraction phase. In this way, the volume/kg of product at the point of maximum volume will still be kept lower and the throughput maintained or increased.  For example, an alkylation under strongly basic anhydrous conditions could be quenched with ammonium chloride in methanol and then the volume of the reaction mixture could be reduced by half using vacuum distillation before adding water for an acid-base extraction to purify the product by phase shifting. The volume/kg at the point of maximum volume might thus be reduced by half and the number of runs required to meet a production target cut in half.

Scientists more accustomed to laboratory synthesis would benefit by recognizing that in a plant setting, one usually cannot do the equivalent of simply switching from a 500 ml to a 1-liter reaction flask when they want to make more material per run. The chemical reactors available are few in number and cannot be simply interchanged since, for example, some may be glass-lined and others stainless steel, or one may have a different heating/cooling capability than another.  In an environment with this rigidity, increasing the throughput per batch by increasing the starting materials charged becomes a big deal!

Alternative Methods for Drying an Organic Liquid

Herein, drying an organic liquid  means reducing the water content; most often to negligible or alternately to any other practically acceptable level.

Drying is often not necessary. In the laboratory drying an organic solution is conducted routinely. Most often no effort is made to determine whether it is useful or necessary. Drying may be performed because the cut between an aqueous and an immiscible organic phase may not be perfect and there may be a concern about small water droplets in the organic layer. In the lab, it is easier to be overly safe rather than sorry. In the plant, discovering that drying is not an operational concern can save significant time and money.

Drying a solution may be essential. The most widely known drying method in the plant setting is azeotropic distillation.  That the overall volume is reduced during the operation is an advantage. Also, because almost all multipurpose reactors have reflux and simple distillation capabilities, no additional equipment is contacted by the product. 

That the operation requires heating and also frequently a vacuum are disadvantages. Also, unfortunately, water is very often less volatile than the organic solvent used in reactions and many lower boiling solvents do not form water azeotropes. It is not much of an answer to suggest that the process step reaction solvent be switched to one that does form a useful azeotrope because this reduces solvent choice which is one of the most influential variables that can be used in reaction yield optimization. Choice of the reaction solvent should be kept as open as possible.

Where heating is a concern or where an azeotropic method is not possible, operators at scale have found that they can pass a solution through a fixed bed of molecular sieves to achieve drying. Molecular sieves that have absorbed water can be renewed by the passage of hot dry air once the sieves have been washed to remove external contamination. 

Another procedure that can remove water from a solution is to add a reagent that reacts preferentially with water and produces products that are more easily removed than water. Triethyl orthoformate or trimethyl orthoacetate, for example, can consume water and produce ester/alcohol products. DMF dimethylacetal can react with water to produce dimethylformamide and methanol. Bis-trimethylsilyl-trifluoracetamide can react with water to give Bis trimethylsilylether and trifluoracetamide.

Replacing Charcoal Treatment

Charcoal decolorizing treatment has even more severe time and equipment disadvantages than drying with inorganic salts. Because charcoal is insoluble and very finely divided in most cases, proper cleaning is harder and the evidence of inadequate cleaning (black particles) is embarrassingly obvious. Methods of purification of crude solids that are less burdensome are preferred but there are occasions when charcoaling cannot be replaced. At scale, producers often have dedicated charcoaling equipment so that most of their equipment is never contacted with charcoal. Sometimes pumping a solution through a fixed bed containing charcoal works just as well as adding it into the organic solution.

Reducing the extraneous color from process intermediates may be intellectually satisfying, but the question needs to be asked, "Is reducing the color a critical parameter of the process. Could the color be ignored? Would it be purged by further processing or removed closer to the end of the process?