Posts Tagged ‘chiral’

Scalemic molecules: a cheminformatics challenge!

Wednesday, July 6th, 2011

A scalemic molecule is the term used by Eliel to describe any non-racemic chiral compound. Synthetic chemists imply it when they describe a synthetic product with an observable enantiomeric excess or ee (which can range from close to 0% to almost 100%). There are two cheminformatics questions of interest to me:

  1. How many non-trivial scalemic molecules have been reported in the literature (let’s assume their ee is significantly greater than 0%)?
    • The distribution function for the ee of these molecules would be most interesting!
  2. Of those, how many have the absolute configuration of the predominant enantiomer established with high confidence?
    • Or, to put this another way, how many may prove to be mis-assigned?

Note the careful qualification in the above questions. Thus by non-trivial, I mean compounds whose scalemic attributes persist in solution for a chemically useful duration. That could be taken to mean configurationally stable chiral molecules, rather than those that might be conformationally chiral (an example of a trivial scalemic molecule would be e.g. the twist-boat conformation of cyclohexane, which having D2 symmetry is dissymetric, but which would only retain its scalemic property for a trivially short timescale).

What are boundary values? These are some:

  • As I write this, CAS records 61,257,703 chemical substances. Needless to say (unless I missed it), the answer to my first question is not to be found there.
  • Beilstein (Reaxys) records 1,126,995 compounds as having one or more reported chiroptical properties (which is the most direct way of establishing a molecule is scalemic, although strictly, having say an optical rotation of 0° does not necessarily mean the molecule is not scalemic). We have no way of knowing how many molecules are scalemic for which no chiroptical measurement has been made (but one would hope its a small proportion). Perhaps that is a good answer to question 1?
    • of which 1,097,094 relate to optical rotatory power, 17,515 to optical rotatory dispersion and 62,248 to electronic circular dichroism.
    • it is more difficult to answer how many of these 1,126,995 substances have a firmly established absolute configuration. Measuring a chiroptical property per se does NOT in itself establish the absolute configuration. Doing so is a fascinating exercise in sequential logical argument, and how one does it has changed quite a lot over time. And what might I mean with high confidence? An older assignment (made say > 40 years ago) might be less confident than one established in 2011 (fortunately, we can probably trust the absolute configurations of the amino acids!). A bit of a can of worms, nevertheless. But it interests me because it is a good example of what the semantic web is supposed to be all about.
  • The Cambridge crystallographic database reports 560,307 entries, of which 72,340 are in chiral space groups (in which a chiral molecule can crystallise) and exhibit no disorder or other errors. We do not know how many of these are non-trivial, since all manner of small (and low energy) distortions can create a chiral species (in the solid state), but which would not persist  for a chemically useful duration in solution (i.e. it might for example immediately racemize and become non-scalemic).
  • The Flack parameter has been used since 1983 for enantiomorph estimation (a value of ~≤ 0.10(10) would be considered meaningful). This could in principle provide an answer of known confidence to my question 2 above (but would not address the issue of non-triviality).
    • The challenge now is to quantify how many compounds have a meaningful reported Flack parameter (presumably a sub-set of 72,340?)

Let me declare one personal interest. Over the last four years or so, we have been asked to confirm the absolute configuration of around eight scalemic molecules. After a detailed study, we concluded three were mis-assigned. Now this in no way implies anything about what the answer to question 2 above might be! But it does make one think!

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Do electrons prefer to move in packs of 4, 6 or 8 during proton exchange in a calixarene?

Friday, January 7th, 2011

This story starts with a calixarene, a molecule (suitably adorned with substituents) frequently used as a host to entrap a guest and perchance make the guest do something interesting. Such a calixarene was at the heart of a recent story where an attempt was made to induce it to capture cyclobutadiene in its cavity.

The basic skeleton of a calixarene

At the base of the calixarene are four hydroxyl groups, arranged in either a left or right handed manner. The molecule, in other words is chiral (C4 symmetry to be precise). As a chiral molecule, it might trap left and right-handed guests in a slightly different manner (forming two possible diastereomeric host-guest complexes).  As it happens, the guest in the cyclobutadiene story was just such a chiral molecule. But an essential question to ask is what the barrier to enantiomerization of such a calixarene might be?  One can envisage several ways of accomplishing such a conversion.

Enantiomerization pathways for a chiral calixarene

All four hydrogens can be moved in a single step, one might move two at a time in two steps, or one might move one at a time in four steps. These processes would involve respectively 8, 6 or 4 electrons in each step. There is a fundamental difference between the first pathway and the last two;  the latter involve  ionic intermediates (zwitterions) whereas the first is neutral. As such one might imagine the process would depend on the ability of the solvent to stabilize any such zwitterion.

Let us start with a gas phase model (ωB97XD/6-311G(d,p)), and a transition state with one negative force constant is indeed found with  C4v symmetry. The free energy barrier ΔG† for the process is 14.0 kcal/mol, which means the reaction will occur rapidly, even at lower temperatures of  ~200K. A pack size of 8 seems preferred for this model. This is hardly a surprise since the formation of ionic intermediates would not be expected. One might however speculate thus. In the schematic above, n=1 and one might be tempted to ask if higher values of n (lets say  n=2, a pack size of 10, or n=3, a pack size of 12, etc ) might exhibit similar behaviour. Is there any limit to the ring/pack size for this type of proton exchange?

Transition state for enantiomerization of a calixarene in the gas phase. Click for 3D.

What about in solution? Well, let us apply the mildest of solvents, benzene as a so-called continuum field. This has a very low dielectric (2.3) and you might imagine it would have hardly any effect. Well click on the below. The C4v geometry now has three computed negative force constants; the two additional ones are shown below (they are degenerate with a wavenumber of 101i cm-1).

C4v symmetric geometry for calixarene in benzene solvent, with three negative force constants. Click for animation of E mode.

C4v geometry for calixarene in benzene. Click for animation of second E mode.

Each of these additional two negative force constants shows a displacement heading towards the zwitterion shown in the scheme below. As one increases the polarity of the solvent, so the force constant becomes more negative. Thus for dichloromethane, it is now 322i cm-1 and with water it is 376i cm-1

So now the question is what happens when either of the two additional negative force constants is followed downhill? Will it form a true zwitterion (which would have Cs symmetry), in which case it would be (two) 6 electron processes to enantiomerize the calixarene instead of one 8 electron one.

True transition state for proton exchange in solution phase calixarene

In fact this geometry of Cs symmetry, which does resemble the zwitterion shown in the scheme above, is NOT a minimum but a true transition state itself (the free energy barrier hardly changed from the value for the gas phase). So the answer seems to be that a calixarene enantiomerizes via transition state not of C4v but of Cs symmetry, and which resembles a zwitterion but is not actually one. The 8-packof electrons was tempted to take a short rest-break on their way to shifting the four protons, but in the end did it in a single journey! So we have an unusual zwitterionic but nevertheless concerted transition state for the process.

Still unresolved is whether such cyclic transfer of four protons between four oxygen atoms continues to be concerted for larger rings, or whether the system is finally tempted to break up the transfer by resting with one or more discrete intermediates along the way. I finally note that in the calixarene reported which catalysed the thoughts above, the four oxygens are capped with a guanidinium cation sitting just above them, and this too may have an interesting effect on the proton transfer process.

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