Tag Archives: Process Chemistry

Some Pragmatics of Green Chemistry

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After following a chat room discussion on process safety, I find myself mixed on the matter of what is called green chemistry. In the present example, a fellow wanted to methylate a phenol but didn’t want to use dimethylsulfate or some similar methylating agent. He wanted something that was “green”.

Suggestions were varied, including a recommendation on the use of dimethyl carbonate as methylating agent and a few other approaches through aromatic substitution. One contributor wisely reminded contributors about going into the weeds with low atom efficiency.

“Green chemistry is the design of chemical products and processes that reduce or eliminate the use or generation of hazardous substances. Green chemistry applies across the life cycle of a chemical product, including its design, manufacture, use, and ultimate disposal. Green chemistry is also known as sustainable chemistry.”  -EPA

When green organic chemistry is the goal in synthesis, it pays to be sure that there is an accepted definition of green chemistry on site.  The merits and definitions are explained elsewhere. Difficult questions come up when a non-green substance is replaced with something that may be “more green” but needs 2 steps instead of 1. Or when green but more expensive reagents and solvents are needed. What is best? In this case, greater safety, lower cost, higher space yields, reduced waste generation, and fastest reaction times will be the real drivers. The business to business market will not pay more for a green product while a cheaper non-green alternative is present. If you want to get an existing customer to requalify an existing product from a new green process, be prepared to discount the price in exchange for the customer having to go through a requalification process. Customers do not like change at all.

Under what conditions would management allow a process choice that is greenish but obviously more costly? Possibly never. A greener process needs to give a cost savings somewhere. Barring draconian regulation, a successful green process will have a cost benefit. The benefit may be in lower direct cost of manufacture, satisfaction of a process requirement by a customer, or a hedge against future regulatory restrictions.

Solvents may be one of the easier opportunities for green chemistry. For a given process, there may be a bit of latitude with the solvent. Sometimes the issue of solvent residues in the product may arise. Some solvents are easier to strip away than others. No one will choose a green solvent that is hard to remove from the product. Again, the drivers will be those mentioned above.

Another green opportunity is when we automatically choose a stoichiometric reducing agent when we could have looked at a catalytic system with hydrogen. Catalyst costs per kilogram of product can range from negligible to high. One advantage of using expensive platinum group metal catalysts is that the metal is usually recyclable, which is greenish. However, any organic ligand present does get incinerated producing non-green emissions in the process of energy intensive metal refining. If catalytic hydrogenation requires the installation of new capital equipment, then the installation costs in time and money may prevent a switch.

For green oxidation, oxygen in the air is cheap and abundant but carries a big problem. Using an oxidizing gas in the presence of a flammable liquid reaction mass can give rise to an explosive atmosphere in the headspace of the reactor. This is a non-starter in industry. Catalytic oxidation using a greenish primary oxidant in solution is a good place to start. I’ve heard of hydrogen peroxide or peroxyacetic acid referred to as greenish.

The big problem with green synthetic organic chemistry is that in order to synthesize a molecule, the structural precursors must be sufficiently green, reactive and selective to run on a reasonable timescale and at acceptable cost. And they must not produce non-green side products or wastes that spoil the advantage of the target green step. A weighing of the pros and cons of any attempt to do green chemistry will always be needed and subjective decisions will be made on what constitutes green.

While we are all struggling to be greener, let’s not forget to remind ourselves and others that reduced consumption of almost everything is a green step we can all take right now.

For Students. Thoughts on Chemical Process Scale-Up.

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Chemical process scale-up is a product development activity where a chemical or physical transformation is transferred from the laboratory to another location where larger equipment is used to run the operation at a larger scale. That is, the chemistry advances to bigger pots and pans, commonly of metal construction and with non-scientists running the process. A common sequence of development for a fine chemical batch operation in a suitably equipped organization might go as follows: Lab, kilo lab, pilot plant, production scale. This is an idealized sequence that depends on the product and value.

Scale-up is where an optimized and validated chemical experimental procedure is taken out of the hands of R&D chemists and placed in the care of people who may adapt it to the specialized needs of large scale processing. There the scale-up folks may scale it up unchanged or more likely apply numerous tweaks to increase the space yield (kg product per liter of reaction mass), minimize the process time, minimize side products, and assure that the process will produce product on spec the first time with a maximum profit margin.

The path to full-scale processing depends on management policy as well. A highly risk-averse organization may make many runs at modest scale to assure quality and yield. Other organizations may allow the jump from lab bench to 50, 200, or more gallons, depending on safety and economic risk.

Process scale-up outside of the pharmaceutical industry is not a very standardized activity that is seamlessly transferable from one organization to another. Unit operations like heating, distillation, filtration, etc., are substantially the same everywhere. What differs is administration of this activity and the details of construction. Organizations have unique training programs, SOP’s, work instructions, and configurations of the physical plant. Even dead common equipment like a jacketed reactor will be plumbed into the plant and supplied with unique process controls, safety systems and heating/cooling capacity. A key element of scale-up is adjusting the process conditions to fit the constraints of the production equipment. Another element is to run just a few batches at full scale rather than many smaller scale reactions. Generally it costs only slightly more in manpower to run one large batch than a smaller batch, but will give a smaller cost per kilogram.

Every organization has a unique collection of equipment, utilities, product and process history, permits, market presence, and most critically, people. An organization is limited in a significant way by the abilities and experiences of the staff who can use the process equipment in a safe and profitable manner. Rest assured that every chemist, every R&D group, and every plant manager will have a bag of tricks they will turn to first to tackle a problem. Particular reagents, reaction parameters, solvents, or handling and analytical techniques will find favor for any group of workers. Some are fine examples of professional practice and are usually protected under trade secrecy. Other techniques may reveal themselves to be anecdotal and unfounded in reality. “It’s the way we’ve always done it” is a confounding attitude that may take firm hold of an organization. Be wary of anecdotal information. Define metrics and collect data.

Chemical plants perform particular chemical transformations or handle certain materials as the result of a business decision. A multi-purpose plant will have an equipment list that includes pots and pans of a variety of functions and sizes and be of general utility. The narrower the product list, the narrower the need for diverse equipment. A plant dedicated to just one or a few products will have a bare minimum of the most cost effective equipment for the process.

Scale-up is a challenging and very interesting activity that chemistry students rarely hear about in college. And there is little reason they should. While there is usually room in graduation requirements with the ACS standardized chemistry curriculum, industrial expertise among chemistry faculty is rare. A student’s academic years in chemistry are about the fundamentals of the 5 domains of the chemical sciences: Physical, inorganic, organic, analytical, and biochemistry. A chemistry degree is a credential stating that the holder is broadly educated in the field and is hopefully qualified to hold an entry level position in an organization. A business minor would be a good thing.

The business of running reactions at a larger scale puts the chemist in contact with the engineering profession and with the chemical supply chain universe. Scale-up activity involves the execution of reaction chemistry in larger scale equipment, greater energy inputs/outputs, and the application of engineering expertise. Working with chemical engineers is a fascinating experience. Pay close attention to them.

Who do you call if you want 5 kg or 5 metric tons of a starting material? Companies will have supply chain managers who will search for the chemicals with the specifications you define. Scale-up chemists may be involved in sourcing to some extent. Foremost, raw material specifications must be nailed down. Helpful would be some idea of the sensitivity of a process to impurities in the raw material. You can’t just wave your hand and specify 99.9 % purity. Wouldn’t that be nice. There is such a thing as excess purity and you’ll pay a premium for it. For the best price you have to determine what is the lowest purity that is tolerable. If it is only solvent residue, that may be simpler. But if there are side products or other contaminants you must decide whether or not they will be carried along in your process. Once you pick a supplier, you may be stuck with them for a very long time.

Finally, remember that the most important reaction in all of chemistry is the one where you turn chemicals into money. That is always the imperative.