Posts Tagged ‘stereoelectronic’

The mechanism of the Baeyer-Villiger rearrangement.

Monday, May 7th, 2012

The Baeyer-Villiger rearrangement was named after its discoverers, who in 1899 described the transformation of menthone into the corresponding lactone using Caro’s acid (peroxysulfuric acid). The mechanism is described in all text books of organic chemistry as involving an alkyl migration. Here I take a look at the scheme described by Alvarez-Idaboy, Reyes and Mora-Diez[1], and which may well not yet have made it to all the text books!

The text-book mechanism involves pathway (a, R=CF3) via species 1 and 2. A characteristic feature of many a mechanism of this type is the need for a step often labelled just PT (proton transfer). Very often, a proton will find itself attached to the wrong atom, and before the mechanism can be completed, it must be transferred to the correct location. Confusingly, there can be many ways of doing this, differing in the timing of the proton choreography. Deciding that running order can be perplexing to new students of chemistry. Tutors often will say that since PTs are very fast, it does not matter when this step occurs, since in effect all paths will lead to the final product. But we might imagine that the energies of all the various pathways can be (in principle) obtained from quantum calculations and that one will prevail over the others.

Path (b) is just one such variation, but with a twist, since it involves starting from 3 and proceeding via a cyclic transition state in which the migrating alkyl group (shown in red above) moves in concert with the relocating proton. I have repeated the original calculations (from 2007) using a somewhat updated procedure, much in the same way that the transition state for the aldol reaction was. A ωB97XD/6-311G(d,p)/SCRF=dichloromethane calculation of step (b) gives the transition state and associated intrinsic reaction coordinate (IRC) shown below.

Cyclic 7-ring mechanism for the Baeyer-Villiger. Click for 3D.

IRC for 7-ring TS, forward direction only.

Choreographically, this transition state is quite complex. Five bonds, all different in some aspect, are changing in asynchronous concert.

  1. Following the transition state towards the product, between IRC=0 and +4, we see the cleavage of the O-O bond occurring in synchrony with the migration of the alkyl (methyl) group towards the oxygen (think of it as an SN2 reaction at oxygen). Notice the antiperiplanar stereoelectronic alignment of the migrating (methyl) and the axis of the O-O bond, which strongly differentiates which of the two alkyl groups migrates. The non-migrating group is essentially orthogonal to the O-O bond.
  2. At IRC = +5 we see a sudden abrupt feature, which corresponds to transfer of the proton, and which is complete by IRC = +6. Protons, being light, do tend to move quickly when they decide to.
  3. The final noteworthy feature from IRC=+6 to >20 is the rotation of the newly formed methoxy group, starting from orthogonality with the carbonyl group (~IRC +6) to co-planarity (IRC > 20). The origins of this effect are associated with the same orthogonal/antiperiplanar stereoelectronic alignments that determined which alkyl group migrated earlier.
  4. Notice a minor feature, which is the rotation of the methyl groups to set up weaker stereoelectronic interactions.

Path (c) is another variation, where an extra molecule of acid (X1, 4) helps catalyse the reaction, this time by creating an 11-membered ring 4 leading to a transition state with potentially two proton transfers as well as the alkyl migration. By involving an additional second molecule of acid as catalyst, we now have seven participating bond changes. Whilst the original path (b) six endo and two exo electrons move in a cycle which is tantalisingly close to but not quite pericyclic (?), path (c) extends this by four electrons. It might be tempting to try to apply a selection rule here (such as 4n+2) but I am not sure it would be justified. 

Baeyer-Villiger, 11-ring transition state. Click for 3D
  1. IRC +3 represents the starting tetrahedral intermediate 4 hydrogen bonded to an extra (trifluoroacetic) acid molecule.
  2. The transition state occurs at IRC =0.
  3. By IRC -2, O-O cleavage and methyl migration are essentially complete, but no protons have moved.
  4. From IRC -2 to -5, the methoxy group rotates to adopt the planar conformation of an ester.
  5. Only after this rotation does the first proton transfer start, at IRC -6, and this is then followed in rapid succession by a second at  -7 to complete the reaction to form ethyl ethanoate and two molecules of (trifluoroacetic) acid. This is a reversal of the sequence seen with path (b). Because no intermediates are discernible in the IRC, one must describe this as a concerted rearrangement, but in fact the bond choreography is far from synchronous. This is one aspect which conventional  arrow pushing does not capture.

To directly compare the energies of paths (b) and (c), we can repeat (b) with the addition of a more passive acid catalyst, in four new positions 3, X2 – X5. None of these are lower than 4 itself. There is one more surprise. Species 1 is not actually a minimum, but rearranges to e.g. the cyclic ring shown below. Its free energy is still higher than that of 3.

I will end with the following speculation. The point of interest to most students of the Baeyer-Villiger reaction is not the nature of the actual transition state, but deciding which of the two possible alkyl groups will migrate (in the example above both are methyls, but if one were e.g. phenyl it would migrate in preference to the methyl). The transition state teaches us that the group antiperiplanar to the O-O bond migrates. Can a system be devised where the antiperiplanar preference takes precedence over the migratory aptitude? For example, based on the following (click to see 3D structure below in which one R group is clearly pre-disposed to migrate in preference to the other).

References

  1. J.R. Alvarez-Idaboy, L. Reyes, and N. Mora-Diez, "The mechanism of the Baeyer–Villiger rearrangement: quantum chemistry and TST study supported by experimental kinetic data", Organic & Biomolecular Chemistry, vol. 5, pp. 3682, 2007. https://doi.org/10.1039/b712608e

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Combichem: an introductory example of the complexity of chemistry

Sunday, December 19th, 2010

Chemistry gets complex very rapidly. Consider the formula CH3NO as the topic for a tutorial in introductory chemistry. I challenge my group (of about 8 students) to draw as many different molecules as they can using exactly those atoms. I imply that perhaps each of them might find a different structure; this normally brings disbelieving expressions to their faces.

Click on image to see molecules constructed from these atoms. The list is not comprehensive!

Amongst the useful concepts that can be introduced are:

  1. How to determine how many double bond equivalents (or degrees of unsaturation) are implied by the formula.
    1. Students spot one dbe in the above formula, but can take a little longer to notice that it can reside in a ring.
    2. Few (and I count tutors in this) will add sub-valent atoms (here, the possibility of a carbene or a nitrene) to the list.
  2. What is meant by “different”? This can be reduced to the equations: Ln k/T = 23.76 – ΔG‡/RT; t1/2 = (Ln 2)/k, where t1/2 is the half life (in seconds) of any species constrained by a free energy barrier of ΔG‡. A nice illustration of this equation is to be found on Jan Jensen’s blog (and an worthwhile calculation would be to find the barrier required to achieve a half life based on the age of the universe). This can be boiled down to three ranges.
    1. Half lives of ~10-15 s, or vibrations (and this includes transition states themselves). Arguably, resonance isomers, which involve the (nominal) motions of electrons and not nuclei, fall into this class as well.
    2. Half lives of < 101 s, which would include most conformational isomers (excepting atropisomers) and highly unstable isomers, and which cannot be bottled and labelled as such.
    3. Compounds with half lives > 102 s, up to of course the age of the universe. This would include configurational isomers (and if the students are up to it, you can ask them to identify any compounds constructed above which can exhibit optical isomerism).
  3. One might be inclined to (approximately) use arrows to indicate the timescales above. Thus electronic resonance is represented by double-headed arrow, conformational and E/Z isomers by an equilibrium arrow, and a single headed arrow indicating a reaction (which may in fact have a very low barrier) connecting two isomers.
  4. Its normally now time to count the electrons. This includes the “invisible ones”, the lone pairs, and also the occasion to introduce the valence shell octet.
  5. Putting the appropriate charges onto any atoms which require them is always fun (the dative bond is avoided). The blue structure revealed in the click above is an extreme interpretation of this! Gernot Frenking has pioneered the class of compound he calls carbones. For his latest article on the theme, see DOI: 10.1002/anie.201002773. The green compound would belong to this class, if it did not fall apart (probably with no barrier) to something which is not actually one molecule, but two (separable) molecules (purple). This brings us into what a molecule actually is. Could it be two molecules unconected by any bonds, but nevertheless also inseparable (such as catenanes, rotaxanes, and many other entwined systems)? Two molecules can also interact weakly, which is not normally referred to as bonds. In this case, the two molecules would be bound by a hydrogen bond.
  6. Quite a number of the isomers can be also called tautomers. This involve the movement of one type of atom in particular, the hydrogen (or proton). In terms of lifetime, they would fall into class 2 above (although if one takes extreme care to remove all traces of acids or bases, particularly from the surface of any glass container, one can extend the lifetimes quite considerably).
  7. The peptide bond is included in the isomers, and its ionic resonance formulation, which can lead the discussion to the molecular basis of life and how finely-tuned this bond in fact is.
  8. One might speculate about what the most stable of all the isomers might be, and how many are indeed bottleable. One might introduce quantum mechanics as nowadays a very reliable way of estimating this (and whilst you are at it, introduce free energies, entropies etc). For example, which of the two red geometrical isomers is the more stable, and why? What is the best resonance representation (i.e. where does one put the charges? On this specific point, a CCSD/6-311G(d,p) ELF calculation does come up with a very definitive answer of on the nitrogen rather than the oxygen).
  9. This might be followed up by introducing arrow pushing as a means of interconverting two isomers, and with one of the pair of isomers, one can introduce pericyclic selection rules, transition state aromaticity and other advanced stereochemical concepts.
  10. Now we are well into to stereoelectronics. One can introduce anomeric effects via the NBO technique. Thus in the red compounds, there is an interesting interaction between the lone pair on carbon and the anti N-H bond (but, spectacularly, not the syn N-H bond). There is another particularly strong one between the oxygen lone pair and the C-N bond.

I dare say I have only picked at the surface, but covering the above should be enough for one tutorial I should imagine 🙂

PS For the (calculated) relative energies of some of these isomers, see DOI: 10.1021/jo010671v

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