I have always been interested in how intermediates with supposedly well-understood behaviour take an occasional detour. At the moment, I am collecting papers of this kind with the goal of writing a review article at some point. There is a lot to talk about here, particularly because the “roads less travelled” are often influenced by subtle structural changes in reaction components. The trouble is that it is not easy to find these cases. Let me illustrate what I mean by using a process you all probably know – the Staudinger reduction of azides. The example below is not new, but is nonetheless instructive because it shows a rare departure from the accepted reaction course. Depending on the group on the phosphorus centre, the reduction of the indole-derived azide proceeds to the well expected iminophosphorane outcome or to the less common triazine heterocycle, whose ring system features three contiguous nitrogen atoms. The mechanism is fascinating, especially if you are programmed to see nitrogen extrusion whenever phosphorus meets azide. I thought this reduction was largely predictable, but I was wrong. Let me know if you are aware of other interesting cases.22.jpg

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.


Tie that binds

A couple of weeks ago I gave a talk at the Scripps Research Institute. My visit was superbly organized by Professor Phil Dawson, for which I am thankful. The highlight for me was to interact with my mentor, Professor Barry Sharpless, who celebrated his 75th birthday earlier this year. We have not seen each other for a while, but we picked back up as if we never parted. As much as ever, I felt energized after our long meeting, where we shared some memories from days past. Barry told me about his new passion, which is the SuFEx reaction for stitching molecules together. SuFEx is a “click” process, with Barry’s well-known stamp written all over it. There are some spectacular new papers about to come out of the Sharpless lab on the subject, but you can take a look at this published one for starters: Speaking of Barry’s other famously known click transformation, I received a sweet present – a set of copper balls, in association with the copper catalysts used in the azide-alkyne cycloaddition. Barry told me: “Andrei, now you need to shine your new balls”. By the way, these things are heavy, about a pound or so each. The most memorable part of this trip, though, came during Q & A session after my talk. A good chunk of the lecture was related to one of my lab’s current interests, namely the relationship between hydrolase inhibitor design and boron / oxygen reversible interactions (we have an interesting paper with Professor Ben Cravatt’s lab that will be sent out soon). Toward the end, Barry made some insightful remarks related to the boron work and one of them has stuck with me. On the pervasive coordination of oxygen to boron in some of our systems, Barry quipped: “…these two deserve each other”. What can I say? This was vintage Barry.2.jpg

A nice way to transfer difluoroethyl groups

I have been intrigued by a series of papers from the lab of Professor Xiao of SIOC. The latest one just appeared in JOC and followed the Nat. Comm. report, which came out earlier this year. The reaction described in the JOC paper offers a route to difluoroethylated alcohols and amines. While it is easy to see why difluoroethylated molecules might be of interest in drug discovery programs, I am particularly intrigued by the mechanistic underpinnings of the Xiao process. Positively charged phosphonium cation is the source of the nucleophilic difluoroethyl group. The reaction appears to involve carbonate addition to phosphorous, at which points the “baton” is passed to the thermodynamics of the phosphorus-oxygen bond. This strong link is the reason why a nucleophile emerges from what is originally an electrophilic phosphorus component. By the way, this gives me an opportunity to lament, once again, on the ultimate origin of some common chemicals we take for granted. Take the venerable triphenylphosphine. Out of curiosity, I peeked into the Encyclopedia of Industrial Chemicals only to find out that this molecule is still produced from chlorobenene, sodium, and phosphorus tricholoride under intensive cooling. The corresponding oxide, which is made in almost all applications of triphenylphosphine in organic chemistry, is recycled by the likes of BASF using phosgene to first generate the Ph3PClderivative, which is then reduced with aluminum. Wow. Talk about tracing common chemicals to their metallic origins (see my previous post).