Pariahs of chemistry

They always give this advice to aspiring chemists: spread your wings, use the whole palette of the Periodic Table and improvise, because there is likely a lot of unexplored reactivity at the fringes. While this might be true, I sometimes wish we could all take it easy and allow ourselves to appreciate the chemistry of super toxic elements such as thallium, lead, and mercury… While relatively inexpensive, they are all outcasts that are truly offensive from today’s green perspective. Look at the delightful molecule featured below. I was going through a folder of old papers on the ride home and came across this mercurial (no pun intended) aldehyde. My interest in structures of this kind stems from our lab’s quest to expand the scope of metal- and metalloid-containing aldehydes. The crystallographic characterization of the mercury derivative reveals some interesting stereoelectronic features, which result in unusual bond angles. The synthesis of these Hg(II) derivatives comes from the seminal work by Nesmeyanov in the 1960’s. I am positive that there is a ton of interesting chemistry awaiting compounds of this type, yet we will never find out.


Getting rings grafted

Back in 2010, amphoteric aziridine aldehydes allowed us to exercise electrostatic control over macrocycle formation. I do not want to open up the Pandora’s box of less-than-reasonable mechanistic proposals, but the data we have so far suggests that the amphoteric nature of aziridine aldehydes helps establish productive contacts between the termini of the macrocyclization intermediate (see left figure below). We have just disclosed an exciting new process. The reaction allows us to cyclize peptides and seamlessly incorporate oxadiazole rings in the structures of macrocycles ( Dr. Stu Borman of the Chemical and Engineering News had some nice things to say about the reaction ( I feel indebted to Drs. John Frost and Conor Scully, my co-authors on this particular work. Coincidentally, John just packed his car and drove back to the US this past weekend. He accepted a job at Merck in New Jersey. I envy Merck because they are going to get a stellar researcher with a no-nonsense approach to science. John is a straight shooter, who weighs what he says carefully and is not afraid to voice his opinion. His arguments are lucid and they are always presented with conviction. I have to thank Professor Rudi Fasan of the University of Rochester, John’s PhD advisor, for excellent mentorship.

Back to oxadiazole grafts in macrocycles. Ever since we discovered the role of aziridine aldehydes in re-routing the Ugi reaction (, we have been on the lookout for other ways to disrupt the mechanism and forge ring formation. This goal has been elusive for some time and has entailed testing various components, including isocyanides. I am telling you: we’ve tried a lot of them and “Pinc” (our internal acronym which, I suspect, will stick) is what allowed John to develop a robust process to not only make macrocycles but to ensure that they possess favourable cellular membrane permeability. The icing on the cake is a conceptual relationship with our 2010 process in that “Pinc” allows for electrostatic control over ring closure.

3.jpgWith this vignette, I am going to send a special hello to John, who will be missed. This area of research is now in the hands of Solomon Appavoo, a first year graduate student in my lab. Let’s see where he takes it.

Covalent, yet traceless

Did you know that more than 30% of therapeutic agents exert their mode of action by some sort of covalent mechanism? I find this number quite impressive, considering the continuing fear of covalence in the pharmaceutical industry. What is most interesting is that the number quoted includes molecules that were developed to act as covalent inhibitors as well as those (the vast majority) whose mechanism of action was only later determined to be covalent.

My lab has interest in covalent inhibitors and I included this subject in one of my recent 4th year chemistry classes. I realized today that there was one paper I forgot to mention. It is a good one because avibactam’s mechanism of action is unique: the strained urea engages beta-lactamase covalently and is subsequently “resurrected” to its original form. Incidentally, I am not making any strong hints to the origin of the 70% “truly” non-covalent drugs mentioned earlier and I do not want you to think that there are even more covalent inhibitors out there, but you never know.


Another odd effect of fluorine

Here is a thought-provoking recent study from Professor G. K. Surya Prakash, my PhD mentor. The work, done in collaboration with Professor Herbert Mayr, reports a surprising outlier in what might otherwise be an intuitively clear nucleophilicity trend. It turns out that fluorine-containing carbanions can be up to 35 times more nucleophilic than their hydrogen congeners. While the authors do not suggest a simple explanation for the observed effect, one might hazard to guess that a heteroatom in place of hydrogen would increase the pyramidalization of the proximal anionic carbon centre. This increase, induced by the electron-withdrawing heteroatom, could lead to augmented nucleophilicity. While this is admittedly sound, the chlorinated analog does not follow the trend, throwing a wrench into what we all crave – a simple explanation. Fluorine is never boring and this Angewandte report provides yet another illustration.


A delightful surprise

What a nice choice for this year’s Nobel Prize in Chemistry (! I am particularly glad that we now have an example of research, which, at the time of conception, was not rooted in anything utilitarian. This is pure science, castles in the sky sort of stuff at its best, which is particularly welcome at a time when students of synthetic chemistry are too preoccupied with the ultimate application of their work. The language they pick up from the literature is a decent indicator. It seems to me that every other draft I see has some “broadly applicable” wording in it. I think that the pragmatic, application-driven science has been a bit of an overkill. The works of Sauvage, Stoddard, and Feringa serve as a reminder that asking fundamental, curiosity-driven questions is a what it’s all about. In closing, here is an interesting fact: Ben Feringa, one of the winners, founded Organic and Biomolecular Chemistry (OBC), the journal where I currently serve as the Chief Editor. Ben has published 41 papers in OBC and we hope to see more!

Juxtaposed π-Systems

When I met with Professor Greg Dudley’s students two weeks ago at Florida State University, I was pleased to learn about the general utility of their fragmentation method to access medium sized rings. This chemistry employs vinylogous acyl triflates shown below. Upon halogen/lithium exchange and subsequent addition to the ketone, the intermediate lithium alkoxide fragments to generate a 9-membered ring. Looking at the ChemDraw rendering of this molecule does not give it all the credit it deserves. This crystallogaphically characterized ketone features a transannular π to π* interaction between the electron-rich alkyne and electron-poor ketone units. This proximity has consequences and allows various transannular reactions to take place. I am showing just one of them. As you might imagine, the primary application of this strained system is in bioorthogonal chemistry. But I got the biggest kick out of the unusual spatial arrangement between the π systems. Molecules of this kind are rich in chemistry.



The burden of oxidation

We have been moving to a new house over the past few days and now that it is over, I want to talk about my action-packed trip to Florida State University last week. Professor Igor Alabugin ( invited me to Tallahassee, where I gave two talks. One of these lectures was for a general audience, while and the other was more specialized for the organic folks. Igor has been keeping a vibrant research program. I had a chance to attend Igor’s group meeting and met some of his students over lunch. I want to draw your attention to the book on stereoelectronic effects he recently published. A previous book dedicated to this enduring concept dates back to Pierre Deslongchamps’s herculean effort. Upon my return, I ordered Igor’s contribution from and I recommend that you take a look at it as well ( The coverage of the field is outstanding and I am really glad that there is no need to have hard copies anymore. Go iBooks, baby!

During my trip down south I also had a chance to meet Jim Frederich (, an assistant professor at FSU. Jim has established an active research program in chemical synthesis. Below is a link to his first paper, which I think is outstanding, particularly for someone like me who, in his spare time, loves to keep track of oxidation states. The manuscript documents a photochemical conversion of pyridazine N-oxides into pyrazoles. Pyrazoles are typically derived from 1,3-dicarbonyl compounds in a transformation that does not require oxidation state adjustment. The pyridazine starting materials used by Jim have their nitrogen atoms at a higher oxidation state compared to pyrazole. Superficially, the transformation of an N-oxide into a pyrazole raises an eyebrow or two, but only if you forget that the product’s ketone functionality shifts “the redox burden” outside the ring. I encourage you to think of a reasonable mechanism (one of these days, I might use this reaction in my cume).


Raising temperature opens new vistas

Boron-containing molecules are among the pillars of chemical reactivity. This is mainly due to the overwhelming embrace of the Suzuki cross-coupling, one of the easiest way to make C-C bonds. Over the years, it has been difficult to find other ways of coaxing boronic acids to participate in C-C bond formation. The paper by Tang and colleagues goes to show that simply raising temperature is a safe bet to discover new boron reactivity. What an irony, considering the sheer volume of research dedicated to getting organoboron compounds to react. Otherwise, how can anyone explain to me that alkenyl boronic acid nucleophiles have hitherto not been matched with alkyl halides? The reaction developed by Tang provides a new electrophilic partner for boronic acids, complementing the iminium ion reactivity captured by Petasis and colleagues 20 years ago. I find the process both interesting and useful. It takes place in toluene and requires about 80 oC to proceed. The success of this reaction is quite remarkable due to the absence of metal catalysts, which is why I tip my hat off to the authors.


Boron in simple and complex amines

Now that the fall semester is finally here, I will hopefully have more time to write my posts. Today is all about Diego Diaz and the cool chemistry we recently published in Angewandte ( Diego did his undergraduate work with Patrick Gunning and came to do PhD in my lab in the Fall of 2014. He quickly developed a keen interest in placing boron within peptides, gave it all he had, and came up with what I think is the best way to incorporate boron into amino acids and related structures. You might wonder why and I could name a few applications: from cross-coupling all the way to hydrolase inhibition. But I refuse to talk about any of this tonight because the ultimate target of our research endeavors is to understand the basic reactivity of organic molecules. In this regard, Diego’s sigma-loaded iminium ions stand out. We have not only characterized them, but we have also employed them in several reactions, including one of my favorite ways of linking molecules – by way of reductive amination. Below are some of the details. Using two slides from a lecture I gave in Halle (Germany) 10 days ago, I show Diego’s NMR data. With respect and admiration, I also pay a tribute to my late colleague, Professor Adrian Brook. The Organometallics paper you see was Adrian’s last contribution to chemistry. It is fitting that this manuscript details an attempt to make imines from Adrian’s acyl silanes. As we all know, this is not possible with silicon because of the Si-heteroatom bond strength, which triggers migration (Brook rearrangement). In our case, we do not have evidence of migratory processes, which is due to the carefully chosen tetrahedral environment around boron. This is amusing, given the fact that boron, not unlike silicon, loves oxygen.

As “luck” would have it, right about time when Diego’s chemistry entered its high gear, he is moving to Vertex in Montreal, but thankfully only for three months (this is one of those industrial experience shindigs). Let’s see what he will be able to accomplish by Christmas. I hope to be able to disseminate the non-confidential part of it. For now, I am really happy about the facility with which we can “smuggle” boron into the structures of bioactive molecules. Thanks Diego.



Trimethyl lock

As part of an ongoing study, we recently tried to think of reactions wherein an amide linkage gives way to an ester. It is interesting to note that, when it comes to proteases, there is nothing remarkable about N-to-O replacement. It happens all the time and is controlled by the low pKa of the active site hydroxyl, among other factors. Synthetic chemistry is different in that ground state energies dictate that the reverse (O-to-N) is more likely. Indeed, we typically make amides out of esters, not the other way around. Unless there is a way to change the energy landscape of the reaction, that is… In this regard, the fascinating chemistry of trimethyl lock (TML) comes to mind. It is particularly nice to see how basic ideas of conformational control enable some ideas in drug delivery to come to fruition. An instructive example of “immolation” of a boron-containing therapeutic through the use of TML is described in Ron Raines’ recent work. In this paper, the authors describe molecules with boronic acid appendages and their internalization by mammalian cells. As you might have guessed, reversible interaction with sugars is the driver of this process. Boron aside, what attracted me to the paper is that it puts TML, the tool of physical organic chemistry, to good use.