“Can Reaction Mechanisms Be Proven?” generated spirited responses from its reviewers. The reviews were approximately evenly divided, and all were of very high quality. The authors agreed with the editor’s proposal that the reviewers convert their reviews into rebuttals or affirmations of the authors’ position for publication along with the article, which has been revised based on the reviews. Most agreed to such a process and their comments appear here. We hope that publication of this paper and well-reasoned rebuttals such as those provided here will initiate a wide-ranging discussion. JCE will provide an online forum for further discussion of the issue. Our hope is that both faculty and students will contribute their opinions and ideas to this discussion. -JWM

Huh.  You don’t usually hear about that happening too often.  So now I had to read the article.  It’s pretty fascinating, and I encourage you to read it all.  I’ll summarize and give my thoughts below the jump

The paper starts out with a bit of philosophy: how do we know when we “know” something?  Note that textbooks routinely tell us  reaction mechanisms can never be proven.  That is, we always talk about the “proposed” mechanism, and we never leave out that adjective and refer in the definite to “the” mechanism.  The authors conclude this is ultimately a philosophical limitation to knowledge: inductive reasoning cannot actually prove the mechanism of a reaction.  Repeated observations may suggest a mechanism operates a certain way, but 100 observations does not guarantee the 101st observation will definitely be the same.

The only correct way to theorize and “prove” a reaction mechanism – according to this philosophy of knowledge – is to postulate all plausible mechanisms… then run experiments to refute as many as possible.  The last mechanism standing doesn’t even win, though, as it only claims the title of “proposed” mechanism.  This sort of Survivor: Mechanisms mentality implies that “all knowledge is negative.”  We cannot Know (capital K) the mechanism of a reaction, we can only Know every mechanism the reaction does not follow.

The authors criticize this theory of knowledge sometimes referred to as “strong inference.”  We as scientists might think about atoms and bonds and orbitals and electrons and trajectories and charges……. but these are all just pictorial metaphors and mental constructs of the physical attributes of molecules and molecular motion.  Thus, all mechanistic observations are made through these man-made representations.  Does a negative result really negate the hypothesis?  Or is there a flaw in our representation and interpretation of the data?  Furthermore, the “strong inference” model also downplays experiments supporting a proposed mechanism.  They do have merit and deserve to be supporting evidence for a mechanisms – not just a lack of evidence against a mechanism.

As to the history of the elucidation of a mechanism, early mechanistic studies certainly failed to offer conclusive proof of a mechanism – especially the structure and conformation of transition state species.  Steady-state kinetics rely on observations of reactants, intermediates and products.  With no direct observation of transition state species (which have lifetimes on the order of molecular vibrations, or dozens of femtoseconds), definitive conclusions about those species and their formation and subsequent degradation can only be speculative.

However, advances in technology are now allowing the ability to resolve molecular motion to the femtosecond scale.  The field of femtochemistry has allowed observation of some of these exceedingly short lived structures.  Zewail received the 1999 Nobel Prize in Chemistry for his work in femtochemistry utilizing ultra-short laser pulses.  His Nobel lecture is adapted into print here.

So what can we say about mechanisms?  Can we prove them?  The authors conclusion is ultimately a dogmatic one: reinforcing a negative view on the study of reactions and their mechanisms (all we can conclusively do is prove them false) potentially discourages aspiring students from utilizing all possible tools (and very powerful tools, at that) at their disposal.  But they also note that, philosophically speaking, “we can never “prove” a mechanism – or any other scientific theory – absolutely.” (emphasis added).

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I think I tend to agree with reviewer David Lewis of Wisconsin-Eau Claire.  In his review, his answer to the title question is: it depends on what your definition of the word “proof” is.  It’s basically semantics.  Do we mean “proof” in the mathematical, Absolute Certainty sense of the word; or do we mean “proof” in the jurisprudence, Beyond a Reasonable Doubt sense of the word?  The answer to the title question changes depending on how you mean “proof.”  A sufficient body of support gleaned from a series of properly constructed experiments can serve to “prove” a proposed mechanism beyond a reasonable doubt … until such time as new knowledge or new technology allows for the construction of more and more thorough experiments to be carried out.

Two interesting case studies: the SN2 and the Mitsunobu reaction.  We all know how the SN2 reaction works, right?  Or do we?  The nucleophile should approach the electrophile from the back face, and – to preserve momentum – the leaving group should continue along the same trajectory as the incoming nucleophile, right?  Well, new evidence from the Wester and Hase labs suggests there might be more to it than originally thought.  Certain leaving groups were travelling significantly slower than expected by conservation of momentum.  The research team concludes that the nucleophile spins the electrophile 360 degC before undergoing SN2 addition.

The Mitsunobu reaction is a favorite quiz question for first year organic graduate students.  Next time you get asked the Mitsunobu mechanisms, tell your inquisitor, “it depends.”  Really.  The mechanism (click image for larger) changes depending on the nature of the azodicarboxylate, the nature of the phosphine, the pKa of the acidic proton, the phase of the moon, and the record of the Cleveland Indians.  Who’s to say the mechanism of the Mitsunobu reaciton has been “proven?”

I guess my final point would involve the conditions under which a reaction mechanism was “proven.”  A good mechanistic study will survey pH, concentration, electronic effects of the reactant molecules, etc.  But even still, all we can say is this is the postulated mechanism under these conditions.  Or, more melodramatically, this is the postulated mechanism on Earth. Remember, a reaction can theoretically proceed under any number of ionic, radical, diradical, and fragmentation pathways.  The energy surface for a reaction to occur is more like a mountain range.  The pathway requiring the lowest energy is the “accepted” mechanism.  But given sufficient energy and reaction conditions, other mechanistic pathways are attainable.  Given that the possibility for alternative mechanistic pathways exists to me says we cannot “prove” one mechanism as the mechanism.

In fact, this is kinda what the paper is talking about when it discusses eliminating all other possible mechanisms.  We can think of all sorts of crazy mechanisms to get to the product, and each of them will take a different path through our mountanous region of the energy surface.  We probe each mechanism to test its validity, and only the strongest mechanism surives.  This is why I liken this approach to Survivor.

Ya, know, I think we need a logo for Survivor: Mechanisms.  I’m no good with photoshop (or GIMP, for the open-sourced among us). But if you are, and you want to put together a logo for our Survivor island, you can email it to me, and I’ll post them here on the blog.  We’ll also need a name for our Survivor island.  I suggest Gibbs Free Pass (slogan: Minimal Energy Required).

Oh, and what do you think?  Can a mechanism be proven given our advances in technology?  Or is this all just a semantic triviality?

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I notice Sabbaitcal Epistles also covered this paper