Researchers working in synthetic organic chemistry are under pressure to quickly develop innovative chemical reactions. But with methods largely unchanged over the last 50 years, synthesis possibilities are constrained by limited temperature ranges, demanding experiment supervision and lack of repeatability. New technology is enhancing synthesis by eliminating these challenges. Record-time process optimization is enabled, without the round-bottom flask.

The round-bottom flask has been the workhorse for synthesis laboratories since the 1950s. In fact, the flask is so ubiquitous that it has become the near-universal symbol for “chemistry happens here.”

But as anyone who has toiled over a Bunsen burner can tell you, the traditional round-bottom flask has its drawbacks. Heating and cooling can be awkward and imprecise, and maintaining set point can be outright difficult. Additionally, traditional synthesis needs a skilled operator present and laboratories lose productive time whenever researchers are focused on repetitive tasks.

Then the same human intervention required by traditional synthesis can make successful sequences hard to repeat—even when an operator issure he or she has followed a recipe to exacting standards. Unexpected exotherms also contribute to temperature deviations that may lead to unexpected side products or unstable compounds.

Can technology truly eliminate traditional synthesis challenges, such as temperature constants, process supervision and sequence repeatability, without adding even bigger headaches?  Chemists are applying established tools for understanding and controlling reactions. Worldwide, these technologies coming into their own, redefining organic synthesis while allowing chemists to maintain familiar workflows.


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Figure 1: Temperature profile of reaction showing attainment of -20 C. Figures: Mettler Toledo

Challenge one: Temperature
Organic chemists know that four temperatures have been consistently used for synthesis: -78 C, 0 C, room temperature and reflux. Many chemical reactions have been developed at these temperatures because they are easy to maintain. But reality involves many more temperatures; and innovative reactions may create better specificity or yield and avoid unwanted impurities when run at temperatures other than these classic values. By operating without temperature constraints, new synthetic steps may be discovered.

Next-generation synthesis workstations make it easy to attain and maintain a wide range of temperature. In Figure 1, for example, a decision was made to use Mettler Toledo’s EasyMax synthesis workstation and run the experiment at -20 C to prevent unwanted reactions and control a strong exotherm. Note the temperature trend, which tracks the reaction’s temperature progression.

The reaction was cooled simply by entering the desired temperature on the workstation’s touchpad. The temperature was then held for about two hours—with some minor fluctuations for reagent dosing—without human intervention. Side reactions and decompositions were avoided. With automated data logging, the successful scenario will be easy to repeat.

Challenge two: Continuous supervision
Temperature management becomes a non-issue with the right workstation. But what about the need for near-continuous supervision?

The right workstation can also eliminate the need for experiment babysitting. Imagine setting up a reaction and walking away. Temperature set points are controlled, ice and oil baths are no more and reagents are added according to an established sequence. No reaction event escapes detection. Researchers can even run reactions overnight.

To illustrate the “one touch” experiment run, we review a multi-step reactant addition over an experiment period of four hours. While not difficult, the dosing activities noted in the example would require constant watchfulness: For two hours, the ice bath would need to be maintained while reagent addition was performed by drop-funnel adjustment.

However, using a workstation, the temperature is set and reagents added according to recipe. The operator is now free to concentrate on something else, such as designing a new reaction sequence—or even heading home for the evening. Hold times can safely run overnight, so chemists return in the morning ready to review experiment results and move on to next steps.


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Figure 2: Reagent addition. All additions are executed by the workstation.

Challenge three: Repeatability
Perhaps the most valuable aspect of workstation use is the technology’s unwavering attention to reaction details which promote repeatability.

Nearly all chemists have experienced two apparently identical experiments producing markedly different outcomes. We might be tempted to accept the adage “chemistry is like that.” But certainly something happened that caused the difference in outcomes.

A synthesis workstation records reactor and jacket temperature, dosing, mixing and pH data during the entire synthesis sequence, and provides thorough insight into results. This data, combined with a recorded recipe, means a chemist can directly compare experiments side-by-side. If one reaction works and another doesn’t, differences in sequence are easily identified. Recreating the successful synthesis is simply a matter of copying the experiment and pressing “go.”

Bonus challenge: Training time
One final benefit to workstation synthesis should be noted: With a well-designed, usable system, training is minimal.

Using a simple touchscreen, experiments can be initiated and conditions changed to perform optimization exercises. Users are almost immediately productive. The resulting data capture means successful synthesis sequences can be repeated or even shared with colleagues around the world with little more than a single click.

Ultimately, with more consistent and wider range of temperature control, fewer supervisory duties, enhanced repeatability and reduced training needs, chemists can focus on chemistry instead of equipment and personnel management.

With challenges like these eliminated, chemists can continue to find new ways to push the bounds of synthetic chemistry. Now companies need to find new uses for round-bottom flasks.