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.