Weaker bonds

Over the past two weeks I attended the Pacifichem meeting (http://www.pacifichem.org) in Honolulu and took a vacation with my wife. Several days ago I could not sleep because of the howling wind from the Pacific. Last night here in Oakville, it was a thunderous thump of a different kind – that of freezing rain – that kept me awake. Strangely, I have no longing for the tropical paradise my wife misses so much now. I feel in place in the midst of our barren winter landscapes, most likely because it is the climate I grew up in (granted, several thousand miles to the East of here).


Pacifichem was great, as it usually is. In the next few days, I will share some notable vignettes.

Due to my lab’s general interest in weak amide bonds, I have been trying to read about the imide functionality. The vast majority of known methods involve strong base-mediated acylation of NH amides. While attending the peptide section at the Pacifichem, I was intrigued by the presentation of Craig Hutton, who described his lab’s interests in building peptides. While Craig makes imides with the ultimate goal of hydrolyzing them post-coupling, my lab has been keen to study imides for a different reason (more on that later, I hope…). Craig’s method of synthesis involves a reaction between a silver carboxylate and an amide. The evidence collected by the Hutton lab points toward intramolecular attack shown below. The relatively weak linkage here is put together at the expense of the stable Ag-S bond. It remains for me to add that this peptide bond-forming method works in the so-called N-to-C direction, which is way less common than the other way around.



Type A problems

Here is something I have been ruminating over for quite some time. It relates to the pitfalls of interdisciplinary research. I will talk about collaborations with biologically minded colleagues, but you might probably find analogies in other cross-settings that involve chemistry.

If you look at the diagram below, you will see squares that correspond to four intersections between “type-A” and “type-B” chemistry and biology. I will define what I mean. Inevitably, exciting advances in synthesis are associated with interesting molecular structures (I refer to synthetically oriented students). If you think about synthesis, there is no doubt that these individuals are likely to be more excited about molecules that are complex and structurally intricate. Those who study method development are more likely to be interested in reactions that enable construction of relatively sophisticated structures. Let’s call this “type A” chemistry. Biologists would have their own “type A” problems and these might correspond to some exciting new proteins or a cellular pathways. The caveat is that biologists can address many of their “type A” challenges using molecules that are completely uninteresting to our students (they are in the “type B” category). For instance, thinking about a simple amide structure will not keep synthetic chemists up at night, although there is plethora of biological probes that are built around this trivial bond (and no other chemistry is involved in their syntheses, just “Acylate your amines, baby!”). There is a good explanation for this phenomenon from the standpoint of a biologist, who is the end user of chemical synthesis here: there is little reason to employ something elaborate if simple molecules do the trick. There are many landmark advances of this kind, yet our synthetic students have way more “firepower” as a result of their training. Consequently, they have no inclination to view these advances as interesting.

Conversely, there might be some complex and structurally interesting chemistry (“type A” chemistry) out there being applied to biological problems that are not exciting to biologists (“type B” biology). Typically, these proof of concept studies serve to highlight the perceived value of synthesis, yet they do not advance biology far enough.

I am not going to talk about the marriage of “type B” chemistry and “type B” biology because it is not interesting.

So herein we have a problem: an ideal scenario would combine exciting chemistry with exciting biology, but the corresponding examples are exceptionally rare. I am not sure what to do about this. I think that each of the three crossings I described has its reason to exist, but synthetically trained students surely prefer to be in the top left corner.