Professor Kalberg has a hand in molecule exploration
By Sandy Coleman
In a third-floor Science Center chemistry lab, the smell of oranges perfumes the afternoon air as the students in Associate Professor of Chemistry Christopher Kalberg's "Organic Chemistry" class peel the zest from the fruit, weigh it and puree it in a blender containing water. They then boil the puree, collect the vapor using a distillation apparatus, and eventually analyze it.
They are not making some complex smoothie or glass of OJ, but rather trying to understand one of the most important and difficultto-comprehend properties of organic molecules: handedness or chirality (from the Greek word for hand).
Look at your hands. Really look at them. What is the relationship of one hand to the other? They are nonidentical mirror images of each other. This is the very definition of chirality. Many molecules have that same property, including the amino acid building blocks of proteins and the sugar building blocks of the DNA backbone. One of the mirror images is designated as left-handed, the other right-handed.
Handedness is important in biological molecules because it allows molecules to recognize one another and differentiate, the way a right glove only fits a right hand and a left glove only fits a left hand. Recognition is important because the cells in the body have to figure out how their various molecules have to interact.
It turns out that understanding this difference presented by chirality is critical when it relates to biological functions of the body. In fact, it could mean the difference between life and death because each "hand" of a molecule such as a pharmaceutical can have a dramatically different impact on the body.
Kalberg's lab experiment offers students a vivid, yet harmless, illustration of the difference. (The left-handed version of limonene gives the orange peel its characteristic smell. The right-handed version is found in lemon peels and has a much more bitter scent.)
But one needs only to look to the drug thalidomide to witness a dramatic example of the damage that can occur when chirality is not understood. The drug was given to pregnant women in the late '50s and early '60s for morning sickness. However, the makers did not realize the evil-twin aspect of the drug-one of its mirror-image molecules had a sedative and antinausea effect, the other caused horrific birth defects and stillbirths, and had no useful properties.
It took 10 years to figure out that only one of the handed thalidomide molecules was responsible for the birth defects, notes Kalberg. "If you could develop only one of them, then it could be given safely and there would be no undesired side effects. That happened in about the mid-'90s and it was approved by the FDA as an antinausal for some very specific groups of people, like end-stage cancer patients. But it is only the one-handed form of it that is given."
In fact, the U.S. Food and Drug Administration now demands that handed molecules be tested separately to avoid potentially problematic interactions when the mirror-image molecules are present.
The thalidomide case is one of the reasons that Kalberg first became intrigued with researching chirality. Now, not only is he teaching this principle, his research also is related to the development of synthetic single-handed molecules that would pose fewer hidden side effects and could potentially benefit the pharmaceutical industry. And he is doing it using the principles of green chemistry, which sets his work apart from many of the other chemists who are exploring chirality worldwide.
"It turns out that nature does an excellent job of making only one of the pair of molecules. We as chemists in the lab can't do that," he says. "Whenever we try to synthesize molecules we end up with a 50/50 mixture of both. So the goal of my work is to try to essentially mimic nature, to make only one of the two pairs of molecules, if possible."
Kalberg has been researching chirality since 1994 while in graduate school at Duke University. He began working with chirality using the principles of green chemistry when he first came to Wheaton nine years ago, often partnering with students.
Applying green chemistry carries an added benefit because it helps to protect the environment as well as offers the potential to keep down drug production costs if materials used to create the single-handed molecules can be recycled. This is the focus of Kalberg's current work.
He's seeking to minimize the impact of doing chemistry on the environment, which includes trying to minimize overall waste, generate less toxic waste, recycle materials, use the least amount of energy, and use catalysts (small amounts of material to generate larger amounts of desired material).
Virtually every chemical reaction requires a solvent in order for molecules to react properly, he explains. Most of those solvents are very toxic and are usually used only once and then disposed of as hazardous waste.
"What I'm trying to do is use something called ionic liquids to replace traditional solvents and then recycle them to use them again," he said. "We're not at the recycling stage yet, but we have shown that you can get the chemical reaction to work in the ionic liquid."
Kalberg, along with two then students, Katherine Boyle '04 and Emily Lipsky '06, published a paper in 2006 detailing the first positive results for doing the reaction in ionic liquids. The paper was published in the journal Tetrahedron Letters, which is part of ScienceDirect, one of the largest online collections of scientific research in the world.
"The ultimate goal of this project is to remove the product that we want, the single-handed molecule, and keep both the catalyst that helps to perform the reaction and the ionic liquid intact. And then we add more starting material to be able to make a second batch or a third. So that's where this is ultimately going.
"The question is: Can we keep both the ionic liquid and catalyst and recycle it to use it again to keep generating single-handed molecules? I think we can."
Kalberg plans to work on the recycling possibilities in the fall when he goes on sabbatical.
