There is no free lunch

Earlier today, we had the first of a series of joint symposia between the University of Toronto and the University of Münster. Apart from MIT’s Mo Movassaghi (who gave a great lecture on his ongoing studies of alkaloid total synthesis), the speakers in the line-up were from Toronto and Münster. I thoroughly enjoyed the talks by the students as well as those by my colleague Mark Taylor and by Frank Glorious from Münster.

Frank and I discussed the following point I was trying to make. You see, I think there is a temptation to present some of the state of the art in the bustling area of transition metal-catalyzed C-H activation as breakthroughs that now allow one to carry out reactions at significantly lower temperatures than before. In general, mild reaction conditions run counter to what we have learned to expect from this field. Transformations, while often elegant and enabling, typically require a lot in terms of activation energy. As we all know, it is common to see temperatures well above 100 oC prescribed in C-H activation protocols. However, some of the processes that recently appeared from the labs of Cramer, Glorius, and others, suggest that significantly lower temperatures can now effect the desired transformations. This sounds really good and appears to formally represent a significant improvement.

Having said that, should we be so enthusiastic? If you consider the aforementioned studies, you will often note a common theme: a heteroatom-heteroatom bond as part of the substrate. The appearance of a lower temperature at which such substrates are activated is due to what I would call “energy front-loading”. I am showing a representative molecule that is commonly seen in these reports. It is perhaps not a surprise that an N-O containing substrate would require less activation energy than some other molecule. This is purely thermodynamic in nature: it all amounts to a clever redistribution of energy that gives us an illusion that the overall process is milder. Don’t get me wrong – the reaction conditions are relatively mild – but it is because you “front-load” the starting material with energy. I will make the following analogy: should we be touting epoxide ring-opening reactions as amazingly mild Sn2 processes? Epoxide ring-openings do appear to require less activation than other, strain-free, reactions with ordinary leaving groups, but they benefit from the energy embedded in 3-membered scaffolds.


I would be very impressed if someone came up with a ligand system to channel a relatively energy-costly metal catalyzed reaction into a more reasonable regime. This is very different from front-loading substrates with energy, but does this option even exist? After all, there is no free lunch and there is always a need to get energy from somewhere. We had a nice discussion with Frank. I think there are many interesting challenges that lie ahead in the field of C-H activation, yet I have my doubts that truly relevant energy barriers in this field will be coming down any time soon. These reactions seem to need special tricks to appear mild. For a number of years now, those who have acknowledged challenges associated with high barriers in this area, have been implying that solutions in the form of ligands might be in store. I have not seen these but, as George Olah would say, please forgive my ignorance. Do let me know if you have encountered such studies.

4 thoughts on “There is no free lunch

  1. There is always free lunch – you only have to make someone else to buy it for you.

    To answer many of your rhetorical questions: First, lets be honest, it isn’t likely these new catalytic systems will probably not used to manufacture commodity chemicals that already cost a dollar a pound when made by existing methods.

    As a process development chemist working for a small biotech, I care about practicality of the new methodology. So, I don’t give a hoot about whether using hydroxamide is cheating. The relevant questions are: Can you work with the precatalyst and ligands outside the glove box? Can you buy them from someone reliable, in less than 4 weeks? What is the substrate scope: If I have amide bond in the molecule, and Lewis acid-sensitive protecting group, and maybe even a tertiary amine sidechain, will the still reaction work? What is the solvent that I have to use (for the love of god, please not NMP), and can I use some milder base – say Cs2CO3 instead of tBuONa? How much heavy metal will carry over into my product and how do I get rid of it?

  2. Well, I do think that we need to consider fundamentals, elementary steps and, ultimately, mechanism. You might be right at the moment, but it is certainly possible that these reactions will eventually reach the regime of practicality. I think it is instructive to remember Pd-catalyzed amination of aryl halides: at the beginning it was all about R3Sn-NR2 reagents! People were emulating the Stille reaction as they were convinced amines would destroy Pd catalysts. We know what happened after that.

    It is still an interesting question – what do do with barriers of some inherently difficult reactions. My point is that chemists are rarely thinking about this (ironically). See my November 11, 2014 post…

  3. I think a typical energy front loading is something like using aryl diazoniums in place of aryl bromides for Pd-catayzed arylation. But in this case it is different: Intramolecular oxidant delivery is more akin to “entropy front-loading the rate-limiting step”. The other thing that is changed is the increased acidity of NH. It would be interesting in this respect to try a substrate like benzoyl azide, to see if instead of Curtius it could also this chemistry under very mild conditions.

  4. Well, I never said that it was purely enthalpic. I referred to energy as a whole. Of course, there would be both H and S components. H comes from energy-rich NO bond and S – from what you mentioned. But I think the H term predominates. As far as your comment – I am confident that azides would work in some capacity too. Not sure about selectivity and background reactions, but you are right.

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