Posts Tagged ‘anomeric effects’

Spotting the unexpected. The trifluoromeric effect in the hydration of the carbonyl group.

Friday, March 9th, 2012

The equilibrium for the hydration of a ketone to form a gem-diol hydrate is known to be highly sensitive to substituents. Consider the two equilibria:

For propanone, it lies almost entirely on the left, whereas for the hexafluoro derivative it is almost entirely on the right. The standard answer to this is that electron-withdrawing substituents destabilize the carbonyl compound more than the hydrate. But could there be more to it than that? Might the converse also be true, that electron-withdrawing substituents stabilise the hydrate more than the carbonyl compound? To answer this last question, consider the anomeric interactions possible in the diol.

  1. There is the standard anomeric effect operating between the two hydroxy groups, whereby a lone pair donor on one oxygen interacts with the C-O acceptor bond of the other oxygen, and vice versa, a total of two stabilising interactions.
  2. But what if the C-CF3 group could also act as an acceptor instead of the C-O? That would give the trifluoromethyl system a total of four anomeric interactions, each of them stabilising, compared to only two for the methyl system.

Garnering evidence, firstly we compute (ωB97XD/6-311G(d,p) ) the free energy difference for the two equilibria above. These turn out to be +3.3 kcal/mol for the top equilibrium, and -9.0 kcal/mol for the bottom, which agrees with the assertions made earlier. The computed geometry looks as below.

Geometry of hydrate. Click for 3D.

We must now go hunting for anomeric interactions, and this is done using an NBO analysis. We look for large interactions between a donor (a lone pair on either oxygen) and an acceptor (which is conventionally the C-O anti-bonding NBO, but can now also be the C-CF3 anti-bonding NBO). Indeed exactly four large interactions are found, in pairs of E(2) = 17.5 and 9.8 kcal/mol. The former is common to both the systems above, but the latter is larger for the trifluoromethyl substituted equilibrium than the methyl system (for which E(2) is 6.2 kcal/mol), and therefore constitutes additional stabilisation by the electron-withdrawing groups of the diol.

Each oxygen has two lone pair NBO orbitals. The initial hypothesis is surely that it uses one of these to align with a C-O anti bonding acceptor, and the other to align with the C-CF3 anti bonding acceptor. The first of these is shown below.

The interaction between an O(Lp) and a O-C BD* orbital. Click for 3D.

  1. The colour code is that the two phases of the oxygen lone pair (Lp) are shown as purple/orange.
  2. These are superimposed upon the C-O anti bonding NBO (referred to as BD* in the output), which has the colours red and blue.
  3. I advise you now to click on the graphic above to load the 3D model and the orbital surfaces. You should spot the node along the C-O bond with a blue-red boundary.
  4. You will also spot that the orange phase of the Lp overlapping with the red phase of the C-O BD*. This is defined as a positive (stabilizing) overlap.
  5. Likewise the purple phase of the Lp overlaps with the blue phase of the C-O BD*. In other words orange=red, and purple=blue. I have made orange and red, and purple and blue deliberately different so that the origins of each NBO can be spotted.
  6. This combination therefore has good overlap, and this gives rise to the large E(2) interaction energy of 17.5 kcal/mol.
Now for the interaction with the C-CF3 BD*, the one with E(2) = 9.8 kcal/mol.

The interaction between an O(Lp) and a C-CF3 BD* orbital. Click for 3D.

  1. You can see the blue-red node along the C-CF3 bond quite clearly.
  2. But hang on, the O Lp orbital is the same as before! It is overlapping with BOTH the C-O and the C-CF3 BD* orbitals.

The other O Lp is shown below (viewed along the axis of the C-CF3 bond). Note how an equal proportion of the orange phase and the other purple phase of the O Lp overlap equally with the blue phase of the C-CF3 bond. In other words, one cancels the other.

The interaction between the other O(Lp) and a C-CF3 BD* orbital. Click for 3D.

So we have found that just one (of the two lone pairs) on each oxygen overlaps with both the C-O and the C-CF3 anti bonding NBOs, the latter giving a stabilisation not present when the group is instead C-CH3. We can attribute this to the far greater acceptor properties of the C-CF3 BD* because of the electronegative character of the fluorines.

This is an anomeric effect with a difference. The CF3 group is not normally associated with inducing such an effect (just as the CN group is not, see this post or this post where an alkene acts the donor instead of a lone pair). Also unusual (more accurately, I have not encountered it before) is the (apparent) use of the SAME donor lone pair to induce TWO quite different anomeric interactions. Before getting too excited by this unexpected effect, it it is worth taking a look at another technique for analysing lone pairs. The ELF (electron localisation function) can provide the centroid of what is referred to as a monosynaptic basin (a lone pair in other words).

EKF function, showing O Lone pairs (in yellow). Click for 3D.

You can see in yellow the oxygen lone pairs. Note how one of them aligns with the C-O bond, and the other with the C-CF3 bond. Unfortunately, the ELF method does not allow the strength of the interaction to be quantified, which is why the NBO analysis is preferred.

So we can conclude that not only might electron-withdrawing substituents destabilize the carbonyl compound more than the hydrate, but they certainly also stabilise the hydrate more than the carbonyl compound.

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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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