Now I have been learning chemistry for five years. I remember when I started organic chemistry, it was fun to draw arrows between molecules to show, as if in a mathematical demonstration, how the reactions occurred. In every lesson I had, teachers explained to us how a specific reaction (for example the Shapiro reaction) occurs step by step, explaining the chemistry of each group in each intermediate as if things were obvious (you know how teachers are).


But I've been wondering for some weeks now how does a mechanism come to be considered as accepted or still discussed?

If they use some, what kind of spectrometry techniques are used to measure the amount of each intermediate? If not how do they proceed? Do they use computational chemistry? Because for example for a reaction such like a $\mathrm{S_N2}$ it doesn't look too tricky to find how it works, whereas for Fries rearrangement (I don't know if the mechanism is considered as accepted or not) it seems to be more tricky.

fries rearrangement

(Ref.)


So can you explain the methods (at least the most used) to confirm a mechanism? I am aware that "confirm" does not mean that we are 100% sure, but rather that it is simply the best we have found so far.

up vote 51 down vote accepted
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Great question!

When I was teaching, Anslyn and Dougherty was a decent text for this. Here are some general comments:

  1. First, please note that you cannot be sure about a mechanism. That's the real killer. You can devise experiments that are consistent with the mechanism but because you cannot devise and run all possible experiments, you can never be sure that your mechanism is correct.

  2. It only takes one good experiment to refute a mechanism. If it's inconsistent with your proposed mechanism, and you're unable to reconcile the differences, then your mechanism is wrong (or incomplete at best).

  3. Writing mechanisms for new reactions is hard. Good thing we have a whole slew of existing reactions that people already have established (highly probable, but not 100% guaranteed) mechanisms for.

  4. Computational chemistry is pretty awesome now and provide some really good insights into how a specific reaction tables place. It doesn't always capture all relevant factors so you need to be careful. Like any tool, it can be used incorrectly.


The types of reactions you run really depend heavily on the kind of reaction you're studying. Here are some typical ones:

  1. Labeling -- very good for complex rearrangements
  2. Kinetics (including kinetic isotope effects) -- good for figuring out rate-determining steps
  3. Stereochemistry -- Good for figuring out if steps are concerted (see this example mechanism I wrote for a different question)
  4. Capturing intermediates -- This can be pretty useful but some species that you capture aren't involved in the reaction, so be careful.
  5. Substitution effects and LFER studies -- Great for determining if charge build up is accounted for in your mechanism

For named reactions, the Kurti-Czako book generally has seminal references if you want to actually dig through the literature for experiments.

For your specific reaction, what do we think the rate-determining step is? Probably addition into the acylium? You could try capture the acylium intermediate.

You could run the reaction with reactants that have two labelled oxygens and reactants that have no labelled oxygens. Do they mix? If not, it's fully intramolecular. Otherwise, there's a intermolecular component and the mechanism as written is incomplete.

A quick Google search suggests that the boron trichloride mediated version has been studied via proton, deuterium, and boron NMR. I didn't follow up on this, but there's clearly some depth here.

When I was T.A.ing for Greg Fu, he really liked to use an example with the von Richter reaction. I might be able to find those references...

This doesn’t exactly concern the actual mechanism you asked for, but as part of my PhD thesis, I performed an amide alkyne coupling the mechanism of which had been researched by Arndt et al.[1] Analysing how they established an accepted mechanism may help understanding how these are accepted. The authors note five proposed mechanisms at the beginning of their paper and then proceed to state the implications of each mechanism concerning:

  • deuterium labelling of different reactants and how it affects the product
  • kinetic isotope effects when replacing protium with deuterium
  • whether certain ruthenium-hydride species should be observeable in NMR with either reactant
  • whether ruthenium-amide species should be observeable in ESI-MS
  • whether the intermediate species should be neutral, cationic or anionic.

After predicting the implications of each mechanism, they performed a number of experiments to prove either side of the story. Including:

  • Deuteration studies
  • Kinetic investigations via in situ IR spectroscopy; whether or not deuterium changed the picture
  • NMR studies of the catalyst system with one or the other reactant; and then NMR studies of all three species mixed ($\ce{^1H}$-NMR, $\ce{^31P}$-NMR, 2D-NMR, …)
  • MS experiments

Each of these methods has advantages and disadvantages. For example, NMR is a very slow method so one cannot expect to observe rapid transformations. However, it is a good structure determining tool, and if you ‘freeze’ the reaction (e.g. only one reactant added), you can draw good conclusions about the initial complexes by analysing the solution with NMR. Likewise, all methods have certain advantages that were used to their fullest.

At the end, the authors were able to deduce that a number of proposed mechanisms were incorrect (they did not fit the experiment) leaving one proposed mechanism that seemed plausible. Additionally, a number of MS peaks which could well represent different intermediates were discovered in the MS analyses.

The resulting most likely mechanism (mechanism D by the original numbering) was then further backed by computational studies showing the different energy differences and activation energies.

They still cannot be sure that their proposed mechanism is correct, but there is strong evidence pointing towards it.

Reference:

[1]: M. Arndt, K. S. M. Salih, A. Fromm, L. J. Goossen, F. Menges, G. Niedner-Schatteburg, J. Am. Chem. Soc. 2011, 133, 7428. DOI: 10.1021/ja111389r.

  • Is it true for canizzaro reaction too? The mechanism I study in A level textbook, isn't sure to be correct? – Mockingbird Mar 10 '17 at 10:32
  • @Mockingbird Mechanisms can never be proven, only disproven. At least, until we have the possibility to videotape molecules as they are reacting. – Jan Mar 15 '17 at 0:17

Nowadays, the popular well-known theory for kinetic chemistry called Transition State Theory has been recognised as a tool that can be used to 'judge' or 'verify' which reaction mechanism pathway will occur truly. The computational chemistry is be able to find where Transition State (TS) is, in which based on theory. Existing of TS implies to how difficulty of chemical reactions do.

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