Chemistry - How do organic chemistry mechanisms become accepted?

Solution 1:

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 provides 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 to 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 an 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...

Solution 2:

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:

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.

Solution 3:

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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