The behind the scenes of "Stereoelectronic sources of the anomalous stability of bis-peroxides"

Gabriel Dos Passos Gomes
5 min readNov 25, 2015
Bisperoxides can be viewed as bis-acetals. These patterns of stabilization lead to a myriad of compounds

A few weeks ago, FSU's Alabugin group was contacted by an editor of RSC's Chemistry World who was interested in writing an article for CW's website (read it here) about our latest Chemical Science paper. I was super excited! This was my first first-author paper and it ended up much more influential than I had anticipated. The paper even made it to NBO's feature website! The editor sent over quite a few questions about the nature and impact of the paper, but due to limitations of the size of the article, many of our responses did not make it to the final edit. But no worries: the full interview is available here, so that you can catch a glimpse behind the scenes of this work.

Enjoy! :)

Could you briefly explain the focus of your article to a non-specialist and why it is of current interest?

We had three main goals: to understand the fundamental nature of instability of peroxides, to explain the counterintuitive stability of bis-peroxides and to use this knowledge for discovering new stereolectronic motifs that can be used for stabilizing these unstable functionality.

Could you explain the motivation behind the study?

3D model of Artemisinin and the orbital interactions that stabilize the peroxide moiety in this molecule.

First, the peroxide moiety is one of the most unusual organic functional groups that often balances on the very brink of stability. “Do not distill THF to dryness” has been the mantra of many safety-conscious chemists for decades. Not surprisingly, peroxide chemistry has the reputation of a playing field for those who love to live dangerously and develop radical initiators, explosives and other highly reactive chemical reagents. However, peroxides are much more than that! For example, when stabilized properly, they can offer new opportunities in the design of new medicinal agents. This is well-illustrated by the remarkable story of artemisinin, a molecule that went from a curiosity to a life-saving antimalarial medicine that brought Youyou Tu 2015 Nobel Prize in Physiology and Medicine.

In this context, it is important to understand the fundamental factors that control intrinsic stability of peroxides. Many secrets of peroxides are likely to be still unknown. This paper tells the story that sheds the new light on the peroxide mysteries.

The Florida State authors were puzzled and intrigued by the recent findings made by the group in the Institute of Organic Chemistry, Russian Academy of Sciences who reported that bringing together the unstable groups leads to surprisingly stable molecules that can melt well above 100 C without decomposition. These molecules have a broad spectrum of biological activity which made this study important from the practical point of view of developing bis-peroxides as medicinal agents.

The study was driven by the hypothesis that the reason for the observed increase in stability is the resurrection of the classical anomeric effect, which has been well known and important, particularly in carbohydrate chemistry. We think that finding a new connection between seeming disparate fields of chemistry is always pretty interesting.

What are the current limitations in the field on which your study is based and how does it solve some of them?

Often times, chemists designing synthetic routes would not even consider the bis-peroxides as an intermediate or targets in synthesis, fearing they could be too stable to be further used or even explosive. Indeed, that is not unreasonable. By recognizing the stereoelectronic equivalency of bis-peroxides with bis-acetals and the beneficial stabilization from anomeric effect, we hope that new applications of bis-peroxides will appear because these molecules can be designed in a rational fashion.

The importance of such factors is illustrated by the fact that artemisinin, the 2015 Nobel molecule, benefits from the same interaction since it has a C-O bond positioned at the right location and aligned properly with one of the peroxide lone pairs. Again, this structural feature opens open the possibility of stabilization via the anomeric effect.

What are the limitations of your study?

Although originating from the experimental observations, our study relied on computations and theory. We hope that future experiments will test and benchmark the quality of theoretical approaches.

Furthermore, our findings bring out even more questions for the future studies. “Stability” can have different meaning when applied to peroxides. How important is this thermodynamic stabilization effect from the practical point of view? How far does thermodynamics translate into kinetic stability? How important is anomeric stabilization for reactivity of peroxides? Those are complex questions and they will require further studies.

What is your particular interest in this area of research?

The Florida State lab is interested in stereoelectronic effects and the interplay between structure and reactivity. The Institute of Organic Chemistry team designs new peroxide molecules suitable for antimalarial, anticancer, antischitosomal drugs and the synthesis of bis-peroxides and other oxygen-rich organic molecules.

How big an impact could your results potentially have?

This work will hopefully change the way chemists think about unstable functionalities that contain bonds between two electronegative heteroatoms (peroxides, hydroxylamines, hydrazines). First, we have uncovered some of the hidden reasons for their instability and, based on this understanding, suggested new ways to stabilize these molecules, hopefully bringing them from the realm of exotic to the realm of convenient and useful.

Could you give some examples in which way the newly gained knowledge could be applied?

At first, this should open the doors for new designs of reactions that use bis-peroxides as synthetic intermediates. It will also contribute a key piece in the very old chemistry puzzle, the electronic reasons for the instability of peroxides.

From the drug design point of view, incorporation of heteroatoms at the right position can stabilize peroxides and can lead to new medicines with increased thermodynamic stability.

Which part of the work towards this paper proved to be most challenging?

The transition from computed numbers to underlying stereoelectronic factors and patterns was challenging but intellectually rewarding.

In addition, distilling the large body of computational data in a way that tells the story of these interesting molecules in a suitable way for the broad audience was a challenge as well.

Where you surprised about the result?

One would expect that combining two unstable functionalities in one molecule will produce something even more unstable. However, just the opposite happens in bis-peroxides where each peroxide gets a little help from its twin peroxide. Presence of the 2nd peroxide resurrect the anomeric effect, making the bis-peroxides to be stereoelectronic equivalent of bis-acetals. Much like life itself, Chemistry shows us that together we can go further, perhaps even happier.

Also, we expected to see a stabilizing effect of anomeric interactions on bis-peroxides, but it was surprising to see how weak anomeric effect was in mono-peroxides. It was also surprising that the reasons for such inefficiency have not been recognized before.

It was also surprising to see that similar interactions were hiding in the plain sight in many medicinally and commercially important mono-peroxides but the scope of this electronic effect (the anomeric stabilization in peroxides) has not been fully recognized.