Reactionary Movement

The Gutenberg Press revolutionized efficiency; the once tedious transcription process was rendered obsolete, replaced by technology that facilitated a more open exchange of information. In an unassuming laboratory nestled in the basement of the Penn Chemistry building, a smaller—molecular—revolution is taking place.

Welcome to the High Throughput Experimentation (HTE) laboratory, a facility that has led to exponential improvements in the testing of chemical reactions and taken the study of organic synthesis to the next level. "It's really quite remarkable what we can achieve," says Penn postdoc, HTE expert, and graduate student-trainer Cornell Stanciu. "Before this technology, testing two or three reactions took an entire day. At that rate, publishable results could elude unlucky doctoral candidates completely. The lab allows for hundreds of these same reactions per day."

The HTE laboratory, a University of Penn and Merck and Co., Inc. collaboration, was made possible by National Science Foundation GOALI (Grant Opportunities for Academic Liaison with Industry) funds. Stanciu, who was trained on the equipment at Merck headquarters in New Jersey, is one of three postdocs working on a team led by four primary investigators, including: Gary Molander, Hirschmann-Makineni Professor of Organic Chemistry and Chair of the Department; Professor Marisa Kozlowski of Organic Chemistry; and Professor Patrick Walsh of Inorganic Chemistry; as well as Dr. Spencer Dreher from the Department of Process Research at Merck. The team also includes four Penn Chemistry doctoral candidates, referred to as "champions": Steven Wisniewski and Andreea Argintaru, who are part of Molander's group; Trung Cao, of the Kozlowski group; and Byeong Seon Kim, of the Walsh group. The other two postdocs, Dr. Simon Berritt and Dr. Jason Schmink, are still under training at Merck's headquarters in Rahway and will join the HTE Center early and mid-next year, respectively.

"Say divers have been sent to Australia to collect a rare sea sponge from the bottom of the ocean, a sponge that produces a certain biological compound that might be able to treat a disease. You might only have a very small amount of this reference material that can be used for testing. The HTE allows you to perform reactions with mere micromoles [one-millionth of a mole], so that less of the precious stock is wasted." – Cornell Stanciu

In addition to its superior speed and infrastructure, the HTE lab is vastly more efficient when it comes to the consumption of chemicals. Raw testing materials are often hard to come by, and even in an ideal open-air laboratory, significant amounts are needed to test reactions. To minimize depletion, the HTE laboratory voids the oxygen from glove boxes, replacing it with nitrogen. The chemicals are then transported inside through vacuum-sealed portals.

"Say divers have been sent to Australia to collect a rare sea sponge from the bottom of the ocean," Stanciu says, "a sponge that produces a certain biological compound that might be able to treat a disease. You might only have a very small amount of this reference material that can be used for testing. The HTE allows you to perform reactions with mere micromoles [one-millionth of a mole], so that less of the precious stock is wasted."

Typically, a team member first enters the "dry" glove box to weigh out compounds and solids and distribute them into the vials. The vials are then moved into the "wet" glove box where the solvents and solutions are made and added. Next, the 96 vial well plate is sealed off and brought outside the box where the reactions are stirred. The whole process consists of about 30 steps; in order to ensure accuracy, each must be strictly followed.

The next day, after the reactions have run their course and the vials are no longer vulnerable to air, samples are extracted and run through a high-performance liquid chromatography instrument that separates and identifies the resultant compounds. One team might be working to recreate an organic compound—the sea sponge active ingredient for instance—due to the determination that it might be useful in a medicine; while another team might be attempting to force two chemicals thought previously incapable of reaction, to react—a feat graduate student Wisniewski was able to accomplish using a carbamatotrifluoroborate and an aromatic chloride.

Ironically, the biggest drawback with the HTE technique, Stanciu says, is the speed at which one can run out of testing ideas. Hypotheses that would normally be tested over a year or two of work in the lab can now be sorted out within one or two weeks. The upside to this is that it translates into a much higher rate of success. The efficiency of the technology also frees up additional time for the team to research new experiments.

"Penn is one of only three non-industrial institutions using the HTE techniques, so the four graduate students I'm training have a great advantage in regards to significant discovery. Not only does the training translate into greater career opportunities, but it allows for them to train future generations, which will, over time, lead to greater collaboration throughout the field, and increased quality in industries across the board."