I have not been able to write my posts for a while, which is partly due to travelling and partly to my attempts to finish up some papers while carrying on with teaching duties. I visited UC Davis and UC Merced two weeks ago. Dean Tantillo (Davis) and Ben Stokes (Merced) made this visit into a memorable stay. In the middle of that week came a dreadfully sad moment when I found out about the passing of George A. Olah, one of my PhD mentors. A lot has been said about George, particularly in recent weeks. His science has had transcending impact on organic chemistry and not a week goes by without me mentioning some of his insights in my 2nd year organic chemistry class. In particular, I refer to the concept of stable ion conditions. I cannot think of a more lucid idea that explains how an electron-poor intermediate such as carbocation can be made to persist in the liquid phase. I fondly recall our group meetings, where George’s lightning fast mind was on display. He was a towering figure and a true gentleman, who always came to lab impeccably dressed with a suite and tie, which is not something we do these days. Apart from this air of elegance, George was always eager to share his wisdom with students, who benefited tremendously from his wit. I could use many superlatives in describing George, but, upon reflection, one thing stands out: he was one of those people whom you do not want to disappoint. I will miss Professor Olah dearly.

George A. Olah (1927 – 2017)

Deciphering the structures of random reaction by-products is rarely on top of our “to do” list. This avoidance is understandable because constant pressure to move toward the stated goal makes us focused, which is both good and bad. Noticing reaction by-products is how one makes important breakthroughs, yet the chances of finding something truly spectacular in the “noise” are not in one’s favor.

As a research advisor, I love learning about crude NMRs. But I am also aware that our resources and bandwidth to pay attention to what comes our way are not limitless. This inevitably leads to (un)healthy skepticism. A recent paper in Organic Process Research and Development stopped in my tracks the other day because I clearly recall hearing about allene formation (by NMR) in one of our peptide coupling reactions. This observation was made while analyzing the reaction by-products and I dismissed it as “OK, the NMR might suggest there is something like an allene but it is unlikely, so let’s move on”. In the case of Knapp and colleagues, the acid used in the coupling process did lead to an allene. There is even a crystal structure of the product reported (it is a complex structure, so I am avoiding it here). The mechanism of allene formation is cool and involves ketene formation. I am not saying that definitive identification of a similar structure in our reaction several years ago would have affected the line of research we had been pursuing at that time, but I just wish we all had more time to dwell on what’s brewing in our flasks. Incidentally, I think it was BASF that has been pushing T3P as a fairly inexpensive reagent for amino acid coupling. It is a nice little molecule.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.7b00046

Here is a question for tonight: how many cases are out there where a single hydrogen bond dominates the regiochemical outcome of a chemical transformation? Let’s say we are comparing the protio version to its methylated congener, which is arguably the smallest steric perturbation that does not produce a confounding effect. Here is a case from Paul Carlier’s lab published some time ago in Organic Letters. If you look at the two epoxide-containing anilines depicted below, you will note that they differ by a methyl group. Their behavior is strikingly dissimilar, demonstrating how a single hydrogen bond can affect the reactive conformation. The reactions were run neat, by the way. Both outcomes are driven by the logic of trans-diaxial epoxide ring opening, yet the NH-to-O interaction flips the reactive conformation in the first case compared to the second one. If you are looking for a powerful demonstration of the Fürst-Plattner rule, there is probably no better way to show how a relatively weak interaction can control the reaction outcome.

http://pubs.acs.org/doi/abs/10.1021/ol902856b

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.

http://www.sciencedirect.com/science/article/pii/S0040402000003227

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 (http://cen.acs.org/articles/94/web/2016/12/Fluorinated-azides-click-make-triazoles.html?type=paidArticleContent) 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.

http://onlinelibrary.wiley.com/doi/10.1002/ange.201609715/abstract

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.

Jokes 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.

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 (http://pubs.acs.org/doi/abs/10.1021/ja055288c?journalCode=jacsat). 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.

http://pubs.acs.org/doi/abs/10.1021/acs.orglett.6b03407