Thoughtful polarity arguments

Last December, Dr. Steve Ritter of the Chemical and Engineering News asked me to comment on a paper from the lab of Prof. Petr Beier of the Czech Academy of Sciences. I gladly did ( and I just want to share my thoughts with you in the event you have not seen the Beier paper.

Every now and then we need a reminder of a rather straightforward kind: if we have trouble making a bond, just reverse the darn polarity of reagents! It is remarkable how infrequently this way of thinking pops into our heads, and I am judging from years of experience. Indeed, unless you are into radical reactions, there are always at least two ways to make a bond by a polar mechanism. In the example described by the Prague team in the Angewandte article, the curious CF3N3 molecule was the target. Attempts to forge the C-N bond using CF3I as the electrophile led nowhere, whereas using the fluoroalkyl portion as the nucleophile delivered CF3N3 and other uncommon azides without a glitch. I know this stuff ultimately relates to the well-known umpolung arguments, but those of us who are in the business of making bonds would still rather search “closer to the lamp post” than reverse reagent polarity. I am convinced that there are a lot of other previously “unmakable” molecules that might be made using this simple logic. We should keep this in mind.


We aren’t too smart, but we are doing our best

The evolutionary history of homo sapiens is likely going to be written some millions of years from now. Who knows where this will take place, perhaps on some other planet. I submit that we might not be treated too kindly in terms of our intelligence. I am not even going to elaborate on political matters because I not an expert. But I suppose I know chemistry reasonably well, so let’s stick to this craft. Below is a slide I used to show 14 years ago when my lab was entrenched in synthetic electrochemistry. The argument is that, if you pay your electricity bills, electrons cost about 0.6 cents per mole and just flow out of your electrical outlet if a wire is inserted. This was in 2003, so the prices might have gone up to, say, 0.8 cents per mole. You can also tune applied potential using a range of electrochemical techniques. But here is the best part: all of the reagents on the list below are ultimately produced using electrochemistry in the chemical industry… Those who will decide to evaluate us might have something to say about the way in which homo sapiens then had to deal with the atomic waste that came from all those reductants and oxidants. Maybe we won’t even have to wait for millennia to pass! Perhaps there will be a class action lawsuit against chemical industry, which knowingly butchered the mass balance and ignored investment toward direct use of electricity to make chemicals.

Screen Shot 2017-01-17 at 3.29.39 PM.pngJokes aside, there is always a counterargument, isn’t there? Here is one in defence of our species: constrained by the lack of a universal energy carrier, we had no choice but to resort to these “intermediary” products to move electrons around. This is also a reasonable thought, ladies and gentlemen. Capital investment in electrochemical plants is not a joke and some of the arguments for direct use of certain kinds of energy (for instance sun light everyone talks about) eventually run out of steam because it is simply more economically feasible to have a carrier, however imperfect it might be. I always remember Surya Prakash’s dictum: there is no problem with energy on this planet, but there is a problem with the energy carrier. So we might be doing our best, after all.

Palladium nuances

Years ago, when Iain Watson was in my lab, we looked at palladium-catalyzed allylic amination. We came to the conclusion that this reaction was far more nuanced than people had thought ( Under acidic conditions, the process is under thermodynamic control and linear product originates from isomerization of kinetically formed branched allyl amine. The addition of base naturally suppresses this process and one can then isolate the branched derivative. I asked our grad students to identify the origins of this selectivity as part of a cumulative examination last December. I received some very reasonable proposals, but none was close to what is actually at play in this system. This is fine, but it exposes an interesting pedagogical challenge: people rarely turn to thermodynamic control as their first choice for explaining reaction outcomes. I suppose we are “wired” to seek uniquely distinct product-specific pathways and do not like to offer explanations that are based on a “path continuum” that is traversed differently according to conditions.

That was a longish prelude to an outstanding paper by Breinbauer and colleagues. My PhD student Frank Lee discussed this work at one of our weekly research updates. Here is another nuance attributable to palladium. What you see is an initial formation of the N-allylated heterocycle, which is followed by an aza-Calisen rearrangement. As a result, the reaction provides access to some interesting side chain-allylated products.


Still looking for dyotropic reactions

Happy New Year, everyone! Lets kick 2017 by looking at what is up with dyotropic rearrangements. I mentioned them in the past, but still have trouble finding too many of these fascinating reactions in papers. Perhaps one of the reasons for this lack of occurrence is that substrates for dyotropic processes tend to be fairly complex. This naturally brings me to total synthesis, where the starting material complexity is a moot point. The example below comes from the lab of Professor Thomas Magauer. I met him last summer in Munich and became acquainted with his innovative program. Now that his paper dedicated to the synthesis of dictooxetane is out, you can also enjoy the rare case of a dyotropic process that has been put to good use here. In this case, an epoxide/oxetane system participates in a dyotropic rearrangement. As a result of the bond switch, the scaffold gets transformed into a tetrahydrofuran/oxetane, which represents a downhill process. Copper tetrafluoroborate was used as the Lewis acid to trigger this process.