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.
http://pubs.acs.org/doi/abs/10.1021/ja109676d
http://www.sciencemag.org/content/338/6106/504
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.