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Impossible molecules.

Monday, April 1st, 2019

Members of the chemical FAIR data community have just met in Orlando (with help from the NSF, the American National Science Foundation) to discuss how such data is progressing in chemistry. There are a lot of themes converging at the moment. Thus this article[1] extolls the virtues of having raw NMR data available in natural product research, to which we added that such raw data should also be made FAIR (Findable, Accessible, Interoperable and Reusable) by virtue of adding rich metadata and then properly registering it so that it can be searched. These themes are combined in another article which made a recent appearance.[2]

One of the speakers made a very persuasive case based in part on e.g. the following three molecules which are discussed in the first article[1] (the compound numbers are taken from there). The question was posed at our meeting: why did the referees not query these structures? And the answer in part is to provide referees with access to the full/primary/raw NMR data (which almost invariably they currently do not have) to help them check on the peaks, the purity and indeed the assignments. I am sure tools that do this automatically from such supplied data by machines on a routine basis do exist in industry (and which is something FAIR is designed to enable). Perhaps there are open source versions available?

17 18 19

 
328[3] 348 713

Here I suggest a particularly simple and rapid “reality check” which I occasionally use myself. This is to compute the steric energy of the molecule using molecular mechanics. The mechanics method is basically a summation of simple terms such as the bond length, bond angle, torsion angle, a term which models non bonded repulsions, dispersion attractions and electrostatic contributions. The first three are close to zero for an unstrained molecule (by definition). The last three terms can be negative or positive, but unless the molecule is protein sized, they also do not depart far from zero. A suitable free tool that packages all this up is Avogadro.

The procedure is as follows

  1. Start from the Chemdraw representation of the molecule. If the publishing authors have been FAIR, you might be able to acquire that from their deposited data. Otherwise, redraw it yourself and save as e.g. a molfile or Chemdraw .cdxml file.
  2. Drop into Avogadro, which will build a 3D model for you using stereochemical information present in the Chemdraw or Molfile.
  3. In the  E tool (at the top on the left of the Avogadro menu) select e.g. the MMFF94 force field. This is a good one to use for “organic” molecules for which the total steric energy for “normal” molecules is likely to be < 200 kJ. Calculate that for your system; this normally takes less than one minute to complete. The values obtained for the three above are shown in the table. All three are well over 200 kJ/mol, which should set alarm bells ringing.
  4. A “more reasonable” structure for 17 is shown below. This has a steric energy of 152 kJ/mol, some 176 kJ/mol lower than the original structure. This does not of itself “prove” this alternative, but it is a starting point for showing it might be correct.Of course mis-assigned but otherwise reasonable structures are unlikely to be revealed by the steric energy test. But impossible ones will probably always be flagged as such using this procedure. 

Postscript: Hot on the heels of writing this, the molecule Populusone came to my attention.[4] On first sight, it seems to have some of the attributes of an “impossible molecule” (click on diagram below for 3D coordinates).

However, it has been fully characterised by x-ray analysis! The steric energy using the method above comes out at 384 kJ/mol, which in the region of impossibility! This can be decomposed into the following components: bond stretch 30, bend 51, torsion 32, van der Waals (including repulsions) 177, electrostatics 87 (+ some minor cross terms). These are fairly evenly distributed, with internal steric repulsions clearly the largest contributor. The C=C double bond is hardly distorted however, which is in its favour. Clearly a natural product can indeed load up the unfavourable interactions, and this one must be close to the record of the most intrinsically unstable natural product known!

References

  1. J.B. McAlpine, S. Chen, A. Kutateladze, J.B. MacMillan, G. Appendino, A. Barison, M.A. Beniddir, M.W. Biavatti, S. Bluml, A. Boufridi, M.S. Butler, R.J. Capon, Y.H. Choi, D. Coppage, P. Crews, M.T. Crimmins, M. Csete, P. Dewapriya, J.M. Egan, M.J. Garson, G. Genta-Jouve, W.H. Gerwick, H. Gross, M.K. Harper, P. Hermanto, J.M. Hook, L. Hunter, D. Jeannerat, N. Ji, T.A. Johnson, D.G.I. Kingston, H. Koshino, H. Lee, G. Lewin, J. Li, R.G. Linington, M. Liu, K.L. McPhail, T.F. Molinski, B.S. Moore, J. Nam, R.P. Neupane, M. Niemitz, J. Nuzillard, N.H. Oberlies, F.M.M. Ocampos, G. Pan, R.J. Quinn, D.S. Reddy, J. Renault, J. Rivera-Chávez, W. Robien, C.M. Saunders, T.J. Schmidt, C. Seger, B. Shen, C. Steinbeck, H. Stuppner, S. Sturm, O. Taglialatela-Scafati, D.J. Tantillo, R. Verpoorte, B. Wang, C.M. Williams, P.G. Williams, J. Wist, J. Yue, C. Zhang, Z. Xu, C. Simmler, D.C. Lankin, J. Bisson, and G.F. Pauli, "The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research", Natural Product Reports, vol. 36, pp. 35-107, 2019. https://doi.org/10.1039/c7np00064b
  2. A. Barba, S. Dominguez, C. Cobas, D.P. Martinsen, C. Romain, H.S. Rzepa, and F. Seoane, "Workflows Allowing Creation of Journal Article Supporting Information and Findable, Accessible, Interoperable, and Reusable (FAIR)-Enabled Publication of Spectroscopic Data", ACS Omega, vol. 4, pp. 3280-3286, 2019. https://doi.org/10.1021/acsomega.8b03005
  3. A.I. Savchenko, and C.M. Williams, "The Anti‐Bredt Red Flag! Reassignment of Neoveratrenone", European Journal of Organic Chemistry, vol. 2013, pp. 7263-7265, 2013. https://doi.org/10.1002/ejoc.201301308
  4. K. Liu, Y. Zhu, Y. Yan, Y. Zeng, Y. Jiao, F. Qin, J. Liu, Y. Zhang, and Y. Cheng, "Discovery of Populusone, a Skeletal Stimulator of Umbilical Cord Mesenchymal Stem Cells from <i>Populus euphratica</i> Exudates", Organic Letters, vol. 21, pp. 1837-1840, 2019. https://doi.org/10.1021/acs.orglett.9b00423

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The challenges in curating research data: one case study.

Friday, April 28th, 2017

Research data (and its management) is rapidly emerging as a focal point for the development of research dissemination practices. An important aspect of ensuring that such data remains fit for purpose is identifying what curation activities need to be associated with it. Here I revisit one particular case study associated with the molecular structure of a product identified from a photolysis reaction[1] and the curation of the crystallographic data associated with this study.

This particular dataset (CSD, dataDOI: 10.5517/cctnx5j) is associated with an article entitled “Single-Crystal X-ray Structure of 1,3-Dimethylcyclobutadiene by Confinement in a Crystalline Matrix“.[1] Data for crystal structures supporting a research article is required (at least in part) to be deposited into the Cambridge structure database (internal reference MUWMEX) and for which a significant level of curation is performed. Although the definition of the term curation has evolved over the last few years, here I take it to include the following:

  1. Identification of appropriate metadata describing the data. For molecules, this would include any identifiers such as the name of the molecule and the connectivities of the atoms constituting that molecule.
  2. The submission of this metadata to a suitable aggregator, such as e.g. DataCite and its inclusion in any other databases associated with the data. These two tests are part of the FAIR data guidelines[2], covering the F (findable) and A (accessible).
  3. Performing any validation tests for the data that can be identified. With crystal structure data in CIF format, this is defined by the utility checkCIF and helps to ensure the I (inter-operable) of FAIR. The R refers in part to the licenses under which the data can be re-used.

On (it has to be said rare) occasions, these procedures can lead to a disparity between the author’s conclusions arrived on the basis of their acquired data and the metadata identified by the independent curators. This difference is most obviously illustrated in this case study by the chemical names inferred by the curation process for the structure represented by the data in the CSD:

  • chemical name: “tetrakis(Guanidinium) 25,26,27,28-tetrahydroxycalix(4)arene-5,11,17,23-tetrasulfonate 1,5-dimethyl-2-oxabicyclo[2.2.0]hex-5-en-3-one clathrate trihydrate“
  • chemical name synonym: “tetrakis(Guanidinium) tetra-p-sulfocalix(4)arene 1,3-dimethylcyclobutadiene carbon dioxide clathrate trihydrate“.

Only the synonym agrees with the title given by the original authors in their publication.[1] One might indeed strongly argue that these two names are not in fact synonyms, since they refer to quite different chemical structures with different atom connectivities. A search of the database for the sub-structure corresponding to 1,3-dimethylcyclobutadiene does not reveal any hits and so the information implied by this synonym is not recorded in the index created for the CSD database.

I asked the scientific editors of the CSD for some guidance on the curation procedures applied to crystal structure datasets and they have kindly allowed me to quote some of this.

  1. “In cases such as this, we as editors are sometimes faced with conflicting information and have to try our best to strike a balance between the data presented in the CIF, a published interpretation and our knowledge based on the information already in the CSD”.
  2. “In areas where there is a particular conflict between these, we often would include a comment (usually in the Remarks or Disorder field as appropriate)”. For this particular dataset, one finds the following under the Disorder field:
    • “Under UV radiation the clathrated pyrone molecule converts to a disordered mixture of square-planar 1, 3-dimethylcyclobutadiene and rectangular-bent 1, 3-dimethylcyclobutadiene in van der Waals contact with a carbon dioxide molecule. The ratio of the square-planar to rectangular-bent 1, 3-dimethylcyclobutadiene clathrate is modelled with occupancies 0.6292:0.3708”.
    • It is not entirely obvious however whether this last comment originates from the original authors or from the data curators. It does not resolve the difference between the assigned chemical name and the indicated chemical name synonym.
  3. “In the case of MUWMEX, I think that the editor produced a diagram (below) which seems chemically reasonable based on the crystallographic data with which we were provided and tried to cover the situation regarding disorder, van der Waals contacts etc in the ‘Disorder’ field. At this point, it is left to the CSD user to decide for themselves.”

We have arrived at a point where the CSD user must indeed decide what the species described by this dataset actually is. Ideally, the best recourse would be to acquire the original data in full and repeat the crystallographic analysis. This is an aspect of the curation of crystallographic data that is not conducted as part of the current processes, which would require as a minimum a superset known as the hkl information to be present in the data. Again, to quote the CSD scientific editors:

  1. “With regard to your question: Is there any mechanism in the Conquest search to identify structures where the hkl information is present? I understand that it is not currently possible to do this in ConQuest. It is, however, possible … to access structure factor data (where available) using Access Structures.”

For MUWMEX, the hkl information is not present in the CSD dataset and in 2010 when the structure was published would have to be obtained directly from the authors. By 2016 however, its presence in deposited datasets was becoming far more common. It is worth pointing out that even the hkl information is not the complete data recorded for the experiment.  That is represented by the original image files recording the X-ray diffractions. This latter is hardly ever available as FAIR data even nowadays.

I hope I have here illustrated at least some of the challenging aspects of curating scientific data and the issues that can arise when derived metadata (in this case the name and the atom connectivities of a molecule) reveal conflicts with the original interpretations. This for an area of chemistry where both the data deposition and its curation is a very mature subject, having operated for ~52 years now. It is still a process that requires the intervention of skilled curators of the data, but perhaps even more importantly it reveals the need to identify even more strictly what the provenance of the interpretations is. Should the CSD curation rest merely at the stage of teasing out and flagging inconsistencies and allowing the user to then take over to resolve the conflicts? Should it be more active, in re-analyzing data for each entry where conflicts have been detected? Perhaps the latter is not practical now, but it might be in the near future. What is certain is that with increasing availability of FAIR data these sorts of issues will increasingly come to the fore. And not just for the very well understood case of crystallographic data but for many other types of data.

References

  1. Y. Legrand, A. van der Lee, and M. Barboiu, "Single-Crystal X-ray Structure of 1,3-Dimethylcyclobutadiene by Confinement in a Crystalline Matrix", Science, vol. 329, pp. 299-302, 2010. https://doi.org/10.1126/science.1188002
  2. M.D. Wilkinson, M. Dumontier, I.J. Aalbersberg, G. Appleton, M. Axton, A. Baak, N. Blomberg, J. Boiten, L.B. da Silva Santos, P.E. Bourne, J. Bouwman, A.J. Brookes, T. Clark, M. Crosas, I. Dillo, O. Dumon, S. Edmunds, C.T. Evelo, R. Finkers, A. Gonzalez-Beltran, A.J. Gray, P. Groth, C. Goble, J.S. Grethe, J. Heringa, P.A. ’t Hoen, R. Hooft, T. Kuhn, R. Kok, J. Kok, S.J. Lusher, M.E. Martone, A. Mons, A.L. Packer, B. Persson, P. Rocca-Serra, M. Roos, R. van Schaik, S. Sansone, E. Schultes, T. Sengstag, T. Slater, G. Strawn, M.A. Swertz, M. Thompson, J. van der Lei, E. van Mulligen, J. Velterop, A. Waagmeester, P. Wittenburg, K. Wolstencroft, J. Zhao, and B. Mons, "The FAIR Guiding Principles for scientific data management and stewardship", Scientific Data, vol. 3, 2016. https://doi.org/10.1038/sdata.2016.18

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Posted in Chemical IT, crystal_structure_mining | 5 Comments »

The smallest C-C-C angle?

Monday, October 31st, 2016

Is asking a question such as “what is the smallest angle subtended at a chain of three connected 4-coordinate carbon atoms” just seeking another chemical record, or could it unearth interesting chemistry?

A simple search of the Cambridge structure database for a chain of three carbons, each bearing four substituents (sp3 hybridized in normal paralance) reveals the following distribution:

ccc

The value 60° is of course a three-membered cyclopropane ring. The tail of the distribution is very small, and there are a few small outliers with values of < 54°. Most of the time such outliers are in fact simple errors, but here we see that they are in fact semibullvalenes, of the type shown below, with the small angle subtended at the central of the three carbon atoms coloured in red.

cazfue

In this diagram I have added my own semantic interpretation of what is going on. Let me itemise this:

  • These molecules can undergo very rapid [3,3] sigmatropic rearrangements, shifting a σ-bond away from the 3-ring to create another such ring.
  • This process elongates one of the C-C bonds and of neccessity this reduces the angle at the associated carbon.
  • I have drawn two types of arrow connecting the two structures. The first is an equilibrium arrow, which implies a transition state connecting the two species. This transition state will have equal bond lengths for the forming/breaking C-C bond, and the transition state will have a rate constant which is slower than the time taken for one molecular vibration (~10-15s)
  • It is also possible however that the second arrow is the correct one, and this implies an electronic resonance rather than a nuclear motion. This would have a rate constant comensurate with electron dynamics (~10-18 s) rather than nuclear vibrations.

What does x-ray crystallography measure? Well the diffraction of photons by electrons. In order to obtain a diffraction pattern, enough photons have to be diffracted to be measured, and even with most modern instruments this still takes minutes or hours. During this period, all the various nuclear positions encountered as a result of vibrations or equilibria are sampled. So if the rate constant for the [3,3] sigmatropic rearrangement is fast, x-ray diffraction will measure the average of the two sets of nuclear positions, which can be distinguished only with some difficulty (if at all) from the structure implied instead by electronic resonance.

If the equilibrium arrow applies, then the small angles of <54° are merely the average of the normal value for a 3-membered ring and a smaller value for a structure where one of the C-C bonds has been removed. In my opening sentence, I noted that the three carbon carbon atoms had to be connected in a chain. This is no longer true; the goalposts have been moved (a lot)!

If its an electron resonance, then the three carbon atoms are still connected, albeit one of the two C-C bonds is no longer a single bond but rather weaker and hence longer. The goalposts have merely been slightly shifted!

A calculation (B3LYP/Def2-TZVPP+D3 dispersion, doi: 10.14469/hpc/1850, [1]) of the structure KUZFUE [2] shows the C2-symmetric species shown below, with an elongated C-C bond and hence a reduced C-C-C angle, as being a true minimum (a resonance) rather than a transition state (an equilibrium). The vibration which shortens one C-C bond and lengthens the other has the real calculated wavenumber 244 cm-1.‡ But the boundary between the two possibilities (often referred to as the boundary between a single and a double minimum in a potential energy surface) is notoriously difficult to capture using calculations.

cazfue

How could experiment definitively settle the issue? Well, the SLAC beam is a unique instrument. Its source of X-rays is so intense that you can get an analysable diffraction pattern from a crystal on a timescale so short that during this period no nuclear motions occur (not even vibrations). Those nuclear positions capture the true equilibrium positions of the atoms in the molecule. Now, how does one get beam time on the SLAC?

‡ Click on the image above to see an animation of this normal mode. If you are running the macOS Safari browser, make sure Preferences/Security/Plug-in settings/Java has the site ch.ic.ac.uk or ch.imperial.ac.uk set to on. If you do not do this, the somewhat unhelpful message You do not have Java applets enabled in your web browser, or your browser is blocking this applet. will appear. Note also that new system installations might tend to switch these settings to off.

References

  1. H. Rzepa, "CAZFUE", 2016. https://doi.org/10.14469/hpc/1850
  2. L.M. Jackman, A. Benesi, A. Mayer, H. Quast, E.M. Peters, K. Peters, and H.G. Von Schnering, "The Cope rearrangement of 1,5-dimethylsemibullvalene-2,6- and 3,7-dicarbonitriles in the solid state", Journal of the American Chemical Society, vol. 111, pp. 1512-1513, 1989. https://doi.org/10.1021/ja00186a064

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Posted in crystal_structure_mining, reaction mechanism | 7 Comments »

Stereoelectronic effects galore: bis(trifluoromethyl)trioxide.

Thursday, August 4th, 2016

Here is a little molecule that can be said to be pretty electron rich. There are lots of lone pairs present, and not a few electron-deficient σ-bonds. I thought it might be fun to look at the stereoelectronic interactions set up in this little system.

Trioxide

Known as ZEYDOW in the crystal structure database[1] (this species has a melting point of -138C, and its no trivial matter to measure x-ray diffraction of such a crystal!); a ωB97XD/Def2-TZVPP calculation is used to quantify the electron density [2] and this is then subjected to localisation using the ELF function. The little purple spheres represent so-called monosynaptic electron basins, or lone pairs as we might rather loosely call them (pair is not always an accurate term). 

zeydow

How these “lone pairs” act as electron donors into empty σ* acceptors can be quantified using NBO theory. The following table shows as many as 24 strong interactions (> 10 kcal/mol).  This now augments my previous post on “Anomeric effects at carbon involving lone pairs originating from one or two nitrogens” and represents an example of “Anomeric effects at oxygen involving lone pairs originating from oxygen”.

The final two entries originate from lone pairs on the central oxygen, donating approximately antiperiplanar (~160°) into the O-CF3 antibonds, but with only a low value of the E(2) interaction energy. These two lone pairs are curiously inert.

Lone pair donor σ-acceptor NBO E(2) energy
On F: 16,17,18,19,25,35,36,39,40,41,43,45 C-F 18-20
On F: 26,34,37,39,42,44 C-O 11-18
On O: 27,28,24,33 C-F 13-16
On O: 27,33 C-O 13
On O: 30,31 C-O 3.5

Apart from this curious molecule, there are few other examples of the R-O-O-O-R functional group,[3] but this one did catch my eye,[4] largely because it was retrieved from a search specification of R-O-O-O-R. The central oxygen apparently supports six O-O bonds, as well as three hydrogens. It is nothing of the sort of course. Reading the text reveals it is really three O…H-O bonds, disordered into two equally probable positions. There are no O-O bonds present at all, which reminds us we must always subject structures derived from x-ray crystallography to a chemical reality check.
yocsis

References

  1. K.I. Gobbato, H. Oberhammer, M.F. Klapdor, D. Mootz, W. Poll, S.E. Ulic, and H. Willner, "Bis(trifluoromethyl)trioxide: First Structure of a Straight‐Chain Trioxide", Angewandte Chemie International Edition in English, vol. 34, pp. 2244-2245, 1995. https://doi.org/10.1002/anie.199522441
  2. H.S. Rzepa, "C 2 F 6 O 3", 2016. https://doi.org/10.14469/ch/195291
  3. Pernice, H.., Berkei, M.., Henkel, G.., Willner, H.., Arguello, G.A.., McKee, M.L.., and Webb, T.R.., "CCDC 224327: Experimental Crystal Structure Determination", 2004. https://doi.org/10.5517/cc7jfcj
  4. J.L. Atwood, S.G. Bott, P.C. Junk, and M.T. May, "Liquid clathrate media containing transition metal halocarbonyl anions; formation and crystal structures of [K+ · 18-crown-6][Cr(CO)5Cl], [H3O+ · 18-crown-6][W(CO)5Cl], [H3O+ · 18-crown-6][W(CO)4Cl3], and [H2O · bis-aza-18-crown-6 · (H+)2][W(CO)4Cl3]2", Journal of Organometallic Chemistry, vol. 487, pp. 7-15, 1995. https://doi.org/10.1016/0022-328x(94)05072-j

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Celebrating Paul Schleyer: searching for hidden treasures in the structures of metallocene complexes.

Saturday, April 2nd, 2016

A celebration of the life and work of the great chemist Paul von R. Schleyer was held this week in Erlangen, Germany. There were many fantastic talks given by some great chemists describing fascinating chemistry. Here I highlight the presentation given by Andy Streitwieser on the topic of organolithium chemistry, also a great interest of Schleyer's over the years. I single this talk out since I hope it illustrates why people still get together in person to talk about science.

NH3-8

The presentation focused on the structure of the simplest possible metallocene, lithium cyclopentadienyl and why the calculated structure showed that the hydrogen atoms attached to the cyclopentadienyl ring pointed slightly away from the metal rather than towards it (by ~1-2°).† Various explanations had been put forward, some had waxed and then waned. It was still basically an open problem. Now, the title of the symposium was Theory and Experiment: A Meeting at the Interface; Streitwieser had given the theory and whilst listening, I realised I might be able to help relate this to known experiments, i.e. crystal structure data. I could do so by analysing the known crystal structures of metallocenes.[1] So here is the basic search query, and I will go through it thus:

  1. A general ring is defined (sizes 4,5,6,7,8) and the ring and metal-C bonds are all specified as of type "any" (it is difficult to know how such bonds might be classified, ie delocalised, aromatic, etc, so best not to constrain things) and a metal is attached.
  2. 4M is basically any metal; again the search is unconstrained, but one could focus on certain columns of the periodic table if one wished.
  3. A ring centroid is computed.
  4. ANG1 is defined as the angle H-C-centroid, the angle of interest in Andy's talk. The limits were constrained to lie between 140° and 179°. I did this because when the angle becomes 180°, the torsion becomes mathematically undefined and I did not want to risk this happening.
  5. TOR1 is defined as the torsion H-C-centroid-metal. Values of 180° would indicate that the hydrogen was pointing away from the metal; values of 0° would indicate it was pointing towards the metal. The absolute value of the torsion is taken to avoid confusion induced by its sign.
  6. ANG2 is one test whether the ring is planar. For an even membered ring, it is the angle subtended at the centroid to opposing carbon atoms. For odd membered rings it is the angle at the centroid involving one carbon and a centroid defined by an opposing pair of atoms (see below).
  7. The quality of the crystal structure determination is controlled by specifying that the R value be < 5%, no errors, no disorder. Also, the terminal H-positions are normalised (to correct known errors in H distances deriving from x-ray diffraction). I would point out that in the early days, the actual positions of the hydrogen were often not actually determined, but "idealised". In this case this would mean that the H-C-centroid angle would probably be set to 180°. For perhaps the last 20 years or so however, the positions of hydrogen atoms have been routinely refined. Unfortunately, I know of no search query that can separate the two cases, and so we will have to live with the mixture and see what we get.
  8. We define another constraint separately, which is that the temperature of the data collection sample is <140K. This ensures that the data will be free of more vibrational/thermal noise and so should be rather more accurate.
  9. Finally, a note on the topic of "research data management" or RDM. I have deposited the files defining the search query in a repository and have assigned DOIs both to the overall search collection[2] and to each individual search definition, the DOIs for which are shown below.

NH3-8

NH3-8

The 4-ring case.[3] Here the temperature constraint was relaxed, since there are few entries. The two red "hot-spots" occur at torsion angles of ~180° (hydrogen pointing away from metal) at bond angle values of between 173-176°. 

NH3-8

The 5-ring case.[4] This includes the classic ferrocene example, the first metallocene for which the structure was correctly identified. There are many more examples, and this search is now constrained to <140K. The two hot spots occur at bond angles of very close to 180°, at which values the torsion itself becomes undetermined. That the hot spots actually occur at 0° and 180° and are not spread evenly across the right hand side axis is remarkable given this. There is a significant tail for the 180° torsion (H pointing away from metal) down to H-C-centroid angles of about 170°, but there is no evidence of this tail for torsions of 0°.

NH3-8

One more test must be applied to see if the 5-ring is planar or not. The deviation from planarity is only 2-3°, and there seems to be no correlation between lower values of the H-C-centroid bond angle and non-planarity.

NH3-8

The 6-ring case.[5] There are again numerous examples of data <140K for such rings. There is now a very distinct hotspot at angles of ~170° for the case/torsion where the hydrogen is pointing towards the metal.

NH3-8

This feature persists when the ring planarity is tested, and it occurs specifically for rings where the angle subtended at the centroid is ~180° and H-C-centroid angles of ~170°. So this is clear-cut effect which demands explanation #1.

NH3-8

The 7-ring case[6] again shows a strong hot spot at ~172° for a torsion corresponding to the hydrogens pointing towards the metal. This hot spot is matched by angles subtended at the ring centroid that are close to 180° (i.e. planar). This is clear-cut effect which demands explanation #2.

NH3-8

NH3-8

The 8-ring case[7] also shows a hot spot for hydrogens pointing towards the metal by the strikingly large degree of ~157°, and this feature is associated with a linear C-centroid-C angle. This is clear-cut effect which demands explanation #3.

NH3-8

NH3-8

The 9- and 10-ring cases.  There are no examples!  Time to make some?

To summarise. 

  1. The above was done during a conference in response to a point made by one of the speakers. In fact, it proved possible to show the speaker the diagrams above <18 hours after he gave the talk.‡
  2. An immediate question that arose from this discussion was whether the hot-spots were artefacts of non-planar rings. So the ANG2 test was added to the plots the next day (today) as part of this dissemination.
  3. Also discussed (yesterday) was how these conference insights might be shared. I suggested the forum here and Professor Streitwieser heartily agreed. Another alternative was to write it up as a regular journal article. But we both agreed that ..
  4. what you see here is just a statistical analysis. The next stage would be to individually inspect all the molecules which make up these statistics. You see it might just be that every molecule contributing to a "hot-spot" cluster might have special circumstances which conspire to make it look as if there is an interesting chemical effect going on. It is unlikely that such coincidences could accrue in such a manner, but the possibility does have to be considered.
  5. I think we both felt that a better way was to expose the basic effects here, as a sort of open science research project, and anyone interested could then (a) try to replicate these plots, which is why you will find the DOIs of datasets containing the definition files to assist in any such replication and (b) tunnel down to any specific hot spot to identify the precise chemical characteristics that might give rise to the geometrical effect.
  6. This could then be followed up by computational analysis of the electronic properties which might give rise to the effect. This would in effect complete the cycle, since this was the starting point for Streitwieser's original talk. Remember, the theme of the celebration was the interplay between theory and experiment, a particular favourite of  Schleyer's.
  7. Regarding the chemical insights, a distinct trend over the ring sizes 4-8 can be seen. The 4-ring shows the hydrogens pointing away from the metal, the 5-ring could be said to be largely agnostic (remember the error in crystallographic angles is probably in the region 1-3°) whilst there is an indication that for the 6-8 rings the ring hydrogens tend to point towards the metal. I have summarised three key points illustrating this as #1-3 above.
  8. It is tempting to conclude that a fairly general chemical effect is operating here over #1-3, although of course it could be a number of effects specific to each ring which merely look like a general trend.

So the chemical interpretation of this project is unfinished, a general feature of much of science of course. But my aim here was to give a flavour of how a scientific meeting at its best can bring together like (or often unlike) minds which can tease out new connections and lead perchance to new discoveries.

‡These hours were productively employed by sharing a Franconian banquet together, and a modicum of sleep, as well as the searches described above. And in case you see no citations at the bottom of this post, they too take about 48 hours to propagate through the CrossRef and DataCite systems. Be patient and they will appear. †In my original representation, I showed the Hs pointing towards the metal. In fact Prof Streitwieser has just contacted me reversing this orientation and correcting my recollection of his lecture.

References

  1. H.S. Rzepa, "Discovering More Chemical Concepts from 3D Chemical Information Searches of Crystal Structure Databases", Journal of Chemical Education, vol. 93, pp. 550-554, 2015. https://doi.org/10.1021/acs.jchemed.5b00346
  2. H. Rzepa, "Crystallographic searches of metallocene type complexes.", 2016. https://doi.org/10.14469/hpc/346
  3. H. Rzepa, "4-Ring metallocene search query", 2016. https://doi.org/10.14469/hpc/347
  4. H. Rzepa, "The 5-ring case.", 2016. https://doi.org/10.14469/hpc/348
  5. H. Rzepa, "6-ring metallocene search queries", 2016. https://doi.org/10.14469/hpc/349
  6. H. Rzepa, "7-ring metallocene search queries", 2016. https://doi.org/10.14469/hpc/350
  7. H. Rzepa, "8-ring metallocene search queries", 2016. https://doi.org/10.14469/hpc/351

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Posted in Chemical IT, crystal_structure_mining, Interesting chemistry | 6 Comments »

Chiroptical spectroscopy of the natural product Steganone.

Tuesday, February 10th, 2015

Steganone is an unusual natural product, known for about 40 years now. The assignment of its absolute configurations makes for an interesting, on occasion rather confusing, and perhaps not entirely atypical story. I will start with the modern accepted stereochemical structure of this molecule, which comes in the form of two separately isolable atropisomers.
steganone
The first reported synthesis of this system in 1977 was racemic, and no stereochemistry is shown in the article (structure 2).[1] Three years later an “Asymmetric total synthesis of (-)steganone and revision of its absolute configuration” shows how the then accepted configuration (structure 1 in this article) needs to be revised to the enantiomer shown as structure 12 in the article[2] and matching the above representation. The system has continued to attract interest ever since[3],[4],[5],[6], not least because of the presence of axial chirality in the form of atropisomerism. Thus early on it was shown that the alternative atropisomer, the (aS,R,R) configuration initially emerges out of several syntheses, and has to be converted to the (aR,R,R) configuration by heating[3]. One could easily be fooled by such isomerism!

Absolute configurations can be established in several ways.

  1. From precursors of known absolute configuration. This was the most common method until relatively recently, but it is very expensive since asymmetric syntheses are often much more complex and longer than racemic ones. There is always a small residual doubt that any transformation in the synthesis might have altered the configuration in an unexpected manner.
  2. From an X-ray of the final configuration (Bijvoet). Very often the structure is determined on a derivative of the target compound (the original may not form suitable crystals). There is also the doubt that the selected crystals may in fact be a minor form and do not represent the bulk of the system in solution. This is especially true where atropisomerism is concerned, since the solid state structure may not represent the same atropisomer present in solution.
  3. In the last decade or so, it has become more common to make use of the computation of measured chiroptical spectroscopies to see if they match. It turns out that this method appears never to have been applied to Steganone, and here I attempt to rectify this.

First, let us compute the optical rotation. The (aR,R,R) stereoisomer is also known as (-)-Steganone, because the measured specific rotation is [α]589 -170° ± 30.[3] It is computed (MN12L/6-311++G(d,p)/SCRF=chloroform) as -240°, [α]365 -2251[7]. The other atropisomer (aS,R,R) is computed to be 4.5 kcal/mol higher in free energy with [α]589 +408°[8], and measured as +150.[3] There is some uncertainty in the computed values, since the rotations can be dependent on the conformation not only of the rings, but the substituents. You might imagine that the conformation of eg a -OMe group is unimportant, but this is not so. In this case, I have used a crystal structure of a related species to serve as the start point for optimising the MeO conformations. The greater mismatch between computation and experiment for the (aS,R,R) stereoisomer probably needs an exploration of more conformations of the -OMe groups. At least in both cases the signs match between computation and measurement.

Next, the electronic circular dichroism (ECD), which has also been measured[3] for the (aR,R,R) isomer as Δε 201nm (-ve Cotton effect), 218 (+ve), 244 (-ve), 276 (+ve) 304 (-ve) and 337 (-ve). Bearing in mind that the baselines in ECD spectra are notoriously difficult to define (moving it up or down can easily invert a Cotton effect), the agreement with the calculated spectrum MN12L/6-311++G(d,p)/SCRF=chloroform, nstates=200)[9] might seem reasonable, although the calculated version has more peaks in the region 225-265 than are reported (e.g. 235, +ve, 265, -ve).
(R,R)-steganone-9
The (aS,R,R) isomer seems a less good fit. The +ve peak at 218 is missing, the +ve 276 peak matches better than the other isomer, but the 337nm peak is again the wrong sign.
(aS,R,R)-steganone

Of course, in such a game it may be the DFT functional used for the simulation that itself might be misleading, MN12L in this case. Just to check, I also include the results using M062X[10] to see how variable these simulations might be. The measured peaks at 201, 218, 244 and 337nm match, but the ones at 276 and 304nm do not.

s-m062x

Although matching computed with measured ECD spectra is commonly used to assign absolute configurations of molecules, you can see from these results that the technique is not a cast iron one! Even scanning through myriad DFT procedures to find the one that fits best is probably not a complete solution either. Can anything be done to further increase confidence?

How about Vibrational Circular Dichroism (VCD) predictions?[11],[12]. Like ECD, VCD is also sensitive to conformation, which is why some modern instruments have low temperature probes operating at close to 0K which strive to capture only a single lowest energy conformation (although of course in any simulation, you have to identify that conformation reliably!). At some stage in the future, the VCD spectra of steganone might indeed be measured, and hence compared with the below. It might serve to increase confidence in the chiroptical methods as a means of assigning configuration.

(aR,R,R)-steganone (aS,R,R)-steganone

We might conclude from this short exploration of chiroptical spectroscopy that no one single measured or computed value can be absolutely definitive; rather it is the accumulation from various sources that builds up the case for a particular configuration. But at least the above simulations do serve to add some useful additional data for the record.

References

  1. D. Becker, L.R. Hughes, and R.A. Raphael, "Total synthesis of the antileukaemic lignan (±)-steganacin", J. Chem. Soc., Perkin Trans. 1, pp. 1674-1681, 1977. https://doi.org/10.1039/p19770001674
  2. J. Robin, O. Gringore, and E. Brown, "Asymmetric total synthesis of the antileukaemic lignan precursor (-)steganone and revision of its absolute configuration", Tetrahedron Letters, vol. 21, pp. 2709-2712, 1980. https://doi.org/10.1016/s0040-4039(00)78586-8
  3. E.R. Larson, and R.A. Raphael, "Synthesis of (–)-steganone", J. Chem. Soc., Perkin Trans. 1, pp. 521-525, 1982. https://doi.org/10.1039/p19820000521
  4. A. Bradley, W.B. Motherwell, and F. Ujjainwalla, "A concise approach towards the synthesis of steganone analogues", Chemical Communications, pp. 917-918, 1999. https://doi.org/10.1039/a900743a
  5. M. Uemura, A. Daimon, and Y. Hayashi, "An asymmetric synthesis of an axially chiral biaryl via an (arene)chromium complex: formal synthesis of (–)-steganone", J. Chem. Soc., Chem. Commun., vol. 0, pp. 1943-1944, 1995. https://doi.org/10.1039/c39950001943
  6. B. Yalcouye, S. Choppin, A. Panossian, F.R. Leroux, and F. Colobert, "A Concise Atroposelective Formal Synthesis of (–)‐Steganone", European Journal of Organic Chemistry, vol. 2014, pp. 6285-6294, 2014. https://doi.org/10.1002/ejoc.201402761
  7. H.S. Rzepa, "C 22 H 20 O 8", 2015. https://doi.org/10.14469/ch/189647
  8. H.S. Rzepa, "C 22 H 20 O 8", 2015. https://doi.org/10.14469/ch/189646
  9. H.S. Rzepa, "C 22 H 20 O 8", 2015. https://doi.org/10.14469/ch/189649
  10. H.S. Rzepa, "C 22 H 20 O 8", 2015. https://doi.org/10.14469/ch/189657
  11. https://doi.org/
  12. H.S. Rzepa, "C 22 H 20 O 8", 2015. https://doi.org/10.14469/ch/189651

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The 5σ-confidence level: how much chemistry achieves this?

Saturday, July 5th, 2014

I was lucky enough to attend the announcement made in 2012 of the discovery of the Higgs Boson. It consisted of a hour-long talk mostly about statistics, and how the particle physics community can only claim a discovery when their data has achieved a 5σ confidence level. This represents a 1 in 3.5 million probability of the result occurring by chance. I started thinking: how much chemistry is asserted at that level of confidence? Today, I read Steve Bachrach’s post on the structure of Citrinalin B and how “use of Goodman’s DP4 method indicates a 100% probability that the structure of citrinalin B is (the structure below)”. Wow, that is even higher than the physicists. Of course, 100% has been obtained by rounding 99.7 (3σ is 99.73%) or whatever (this is one number that should never be so rounded!). pc But there was one aspect of this that I did want to have a confidence level for; the absolute configuration of citrinalin B. Reading the article Steve quotes[1], one sees this aspect is attributed to ref 5[2], dating from 2005. There the configuration was assigned on the basis of “comparison of the electronic circular dichroism (ECD) spectra for 1 and 2 with those of known spirooxiindole alkaloids“. However, this method can fail[3]. Also, one finds “comparison of the vibrational circular dichroism (VCD) spectra of 1 with those of model compounds“[2]. Nowadays, one would say that there is no need for model compounds, why not measure and compute the VCD of the actual compound? Even a determination using the Flack crystallographic method can occasionally be wrong![4]. Which leads to asking what typical confidence levels might be for these three techniques, and indeed whether improving instrumentation means that the confidence level gets higher with time. OK, I am going to guess these.

  1. I think the confidence level for assigning absolute configurations on the basis of ECD analogy with other compounds is the lowest of all the methods. Around 1σ or 68.3% (and this mostly from additional information such as the chemical transforms performed from starting materials of known absolute configuration).
  2. VCD is higher. If performed on the actual compound, I think it can be as high as 2-3σ or 95.5-99.7%. It is difficult to know how much of this certainty is lost by using only model compounds.
  3. Flack analysis (of anomalous X-ray)[5] is probably also at 2-3σ; I suggest however that a fair bit of uncertainly not included in the 2-3σ probably arises from analysing a tiny crystal (1 µg) arising from a solution perhaps 10,000 times larger in weight of sample.
  4. And of course combining the uncertainties from multiple experiments reduces it overall.

I am not casting any doubts on an assigned absolute configuration on which that of citrinalin B is based, as done in 2005. I have no grounds to think it is wrongly assigned. I am merely suggesting that in 2014, one should be able to achieve an even greater confidence level. And do what the physicists do, try to estimate the confidence level attained. I wonder how much chemistry would match the physicists 5σ-confidence level (99.99994%)?

References

  1. E.V. Mercado-Marin, P. Garcia-Reynaga, S. Romminger, E.F. Pimenta, D.K. Romney, M.W. Lodewyk, D.E. Williams, R.J. Andersen, S.J. Miller, D.J. Tantillo, R.G.S. Berlinck, and R. Sarpong, "Total synthesis and isolation of citrinalin and cyclopiamine congeners", Nature, vol. 509, pp. 318-324, 2014. https://doi.org/10.1038/nature13273
  2. T. Mugishima, M. Tsuda, Y. Kasai, H. Ishiyama, E. Fukushi, J. Kawabata, M. Watanabe, K. Akao, and J. Kobayashi, "Absolute Stereochemistry of Citrinadins A and B from Marine-Derived Fungus", The Journal of Organic Chemistry, vol. 70, pp. 9430-9435, 2005. https://doi.org/10.1021/jo051499o
  3. F. Cherblanc, Y. Lo, E. De Gussem, L. Alcazar‐Fuoli, E. Bignell, Y. He, N. Chapman‐Rothe, P. Bultinck, W.A. Herrebout, R. Brown, H.S. Rzepa, and M.J. Fuchter, "On the Determination of the Stereochemistry of Semisynthetic Natural Product Analogues using Chiroptical Spectroscopy: Desulfurization of Epidithiodioxopiperazine Fungal Metabolites", Chemistry – A European Journal, vol. 17, pp. 11868-11875, 2011. https://doi.org/10.1002/chem.201101129
  4. F.L. Cherblanc, Y. Lo, W.A. Herrebout, P. Bultinck, H.S. Rzepa, and M.J. Fuchter, "Mechanistic and Chiroptical Studies on the Desulfurization of Epidithiodioxopiperazines Reveal Universal Retention of Configuration at the Bridgehead Carbon Atoms", The Journal of Organic Chemistry, vol. 78, pp. 11646-11655, 2013. https://doi.org/10.1021/jo401316a
  5. H.D. Flack, and G. Bernardinelli, "The use of X‐ray crystallography to determine absolute configuration", Chirality, vol. 20, pp. 681-690, 2007. https://doi.org/10.1002/chir.20473

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The subtle effect of dispersion forces on the shapes of molecules: benzyl magnesium bromide.

Sunday, November 10th, 2013

In the previous post I mentioned in passing the Grignard reagent benzyl magnesium bromide as having tetrahedral coordination at Mg. But I have now noticed, largely through spotting Steve Bachrach’s post on “Acene dimers – open or closed?” another geometric effect perhaps worthy of note, certainly one not always noted in the past; that of dispersion forces.

crystal structure Calc structure
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Click for 3D
Click for 3D

Click for 3D

On the left is the crystal structure.[1] and on the right a ωB97Xd/6-311G(d,p) calculation, with built-in dispersion correction. If you compare the two you will find that the ethyl groups from the ether are about 0.3Å closer to the face of the phenyl group in the calculated structure. Why? Well, in the crystal structure, each dimeric Grignard unit is surrounded by adjacent units in the periodic lattice. You would think that this would have the effect of compressing the structure. Instead it is more open, and it is the isolated calculated structure that is compressed. The dispersion forces are responsible for this. In the crystal structure, the phenyl group is attracted not only to the ethyl groups but also by adjacent units in the lattice by dispersion forces. This balancing effect is absent in the calculated structure and so manifests as just an attraction between the phenyl face and the methyl groups, which pulls them together by ~0.3Å. One can see this more clearly when an NCI (non-covalent-interactions) isosurface is shown at both geometries:

X-ray geometry[2] Calc. geometry [3]
Click for 3D

Click for 3D
Click for 3D

Click for 3D

The surface on the right is ringed (red) in the relevant region to show how the green NCI surface is so much larger compared to the one computed for the  crystal structure. Notice by the way the strong stabilizing (blue) zone between the two Mg atoms. Whether it should be called metal-metal bonding is another issue, but it is a clear effect.

One can compare this result with NCI surfaces computed for the examples described in Steve’s blog (deriving from this article[4]). There two geometric isomers of the same molecule were described, differing only in the dispersion attractions. The top one is an open form and the NCI surface shows no features along the acene chain away from the central pivot. The second isomer shows stabilizing green regions (indicating a zone of dispersion forces in action) between the extended acene groups.

Open Closed
Click for 3D

Click for 3D. Open acene
Click for 3D

Click for 3D. Closed acene with more green regions.

Whilst the acene system is an extreme example of this sort of effect, it may well be that even quite small molecules such as benzyl magnesium bromide etherate might manifest effects due to dispersion. After all, 0.3Å is not a particularly small change in geometry! I conclude by noting that isopropyl groups are rather better in their attraction to a phenyl ring than ethyl groups, and so one might speculate whether e.g. the di-isopropyl etherate of benzyl magnesium bromide might be worth someone making?

References

  1. M.A. Nesbit, D.L. Gray, and G.S. Girolami, "Di-μ-bromido-bis[benzyl(diethyl ether)magnesium]", Acta Crystallographica Section E Structure Reports Online, vol. 68, pp. m942-m942, 2012. https://doi.org/10.1107/s1600536812025445
  2. "C 22 H 34 Br 2 Mg 2 O 2", 2013. http://doi.org/10042/26062
  3. "C 22 H 34 Br 2 Mg 2 O 2", 2013. http://doi.org/10042/26061
  4. S. Ehrlich, H.F. Bettinger, and S. Grimme, "Dispersion‐Driven Conformational Isomerism in σ‐Bonded Dimers of Larger Acenes", Angewandte Chemie International Edition, vol. 52, pp. 10892-10895, 2013. https://doi.org/10.1002/anie.201304674

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A short non-bonding H…H interaction (continued)

Wednesday, October 2nd, 2013

This is a continuation of the discussion started on Steve Bachrach’s blog about a molecule with a very short H…H interaction involving two Si-H groups with enforced proximity. It had been inferred from the X-ray structure[1] that the H…H distance was in the region of 1.50Å. It’s that cis-butene all over again! So is that H…H region a bond? Is it attractive or repulsive? Go read Steve’s blog first.

Next, in the previous post, I had blogged about assigning a publication doi to a procedure or tool. So Steve’s post provided a good opportunity to show how this might work. This is the tool doi: 10.6084/m9.figshare.811862  Using it, and another doi, this time data: 10.6084/m9.figshare.812621 we can create a new data set, visualised below.‡ This is the NCI (non-covalent-interaction)[2] isosurface of the reduced density gradient, and colour coded according to (λ2)ρ, the eigenvalue of the density Hessian, to indicate attraction or repulsion. You should know that according to this scheme, blue is strongly attractive (it is normally seen for example for strong hydrogen bonds). You can see the blue region in-between the H…H region. So a strong (di)hydrogen bond then!

FSSF-NBO

Click for 3D.

Well, interesting, and this needs to be looked into further. For example, it might in fact be an anomalous result since the H…H region may in fact have charge-shift character,[3] which can change the characteristics of the density Hessian (and its Laplacian). 

One more property, the NBO (natural bond orbitals) for this region. Can one tell if H…H is bonding? It might seem so. Finally, the Wiberg bond index for the H…H region is 0.027, very slightly bonding.

SiHHSi

Click for 3D.

 

SiHHSi

Click for 3D.

I should conclude by stating that whilst the initial discussion of this molecule took the form of comments on Steve’s blog, the nature of the Word press system used there (and here) does not allow commentators to insert rotatable models into comments. So that discussion is continued here in order to achieve that effect.‡

‡ And yet another data-doi could be created showing the interactive display, and this could be transcluded back into Steve’s blog to continue the to and fro.

Postscript: I have added the QTAIM analysis that first appeared on Steve’s blog. The red arrow points to the H…H bcp. The blue arrow points to one of the other (three in all) bcps, all of which are very close to a ring critical point, and hence should be regarded as unstable and prone to annihilation.

Click for 3D.

Click for 3D.

The B3LYP+D3/TZVP calculated Si-H vibrations are shown below. The VCD spectrum[4] is shown below it.

Click for animation

Click for animation

HH-vcd

Postscript 2. The Si-H vibration is reported as 2325 cm-1 (with weak bands at ~ 2360-2380), but in footnote 7 of the original report[1] the authors do note that there should be two Si-H bands. The calculation shown above suggests two values, 2406 (intensity 37) and 2460, intensity 10).

The 1H NMR spectrum of the two Si-H bands has two singlets which are reported (but not discussed in the text anywhere) as 8.23 and 8.56 ppm (Δδ 0.33ppm, CDCl3); B3LYP+D3/TZVP calculation[5] predicts 8.79 and 9.40 (Δδ 0.61 ppm). It is possible however these shifts are perturbed by spin-orbit coupling from the silicon[6]. The diastereotopic methylene groups are reported as 4.10 and 4.83, calc 3.95 and 5.03 ppm, which is a reasonable match, and gives confidence to the theoretical prediction.

Si

The 29Si NMR is reported as -32 and -40 ppm, calculated -31.6 (for the Si-H associated with bridging S) and -39.9 (for the Si associated with bridging C) ppm, which matches very well.

The reported 1H NMR spectrum appears to show 29Si satellites but their values are not reported numerically in the article. In Ph3Si-H, this coupling is known to be ~±205 Hz. The 29Si-1H couplings are calculated for the compound above as -191 (for the -31.6 peak) and -166 Hz (for the -39.9 peak), this latter being notably lower than the former. The 29Si-29Si coupling is 10 Hz. Most interestingly, the 0JHH coupling (i.e. through space) is predicted as +5.4 Hz; there is no sign of such a coupling for the two singlets reported at 8.23 and 8.56 ppm. This last observation may be of significance in terms of whether the axis along the four atoms Si-H-H-Si is indeed linear, or whether it is bent (enabling the two hydrogens to avoid close contact).

This problem is not yet closed!

References

  1. J. Zong, J.T. Mague, and R.A. Pascal, "Exceptional Steric Congestion in an <i>in</i>,<i>in</i>-Bis(hydrosilane)", Journal of the American Chemical Society, vol. 135, pp. 13235-13237, 2013. https://doi.org/10.1021/ja407398w
  2. E.R. Johnson, S. Keinan, P. Mori-Sánchez, J. Contreras-García, A.J. Cohen, and W. Yang, "Revealing Noncovalent Interactions", Journal of the American Chemical Society, vol. 132, pp. 6498-6506, 2010. https://doi.org/10.1021/ja100936w
  3. S. Shaik, D. Danovich, B. Silvi, D.L. Lauvergnat, and P.C. Hiberty, "Charge‐Shift Bonding—A Class of Electron‐Pair Bonds That Emerges from Valence Bond Theory and Is Supported by the Electron Localization Function Approach", Chemistry – A European Journal, vol. 11, pp. 6358-6371, 2005. https://doi.org/10.1002/chem.200500265
  4. H.S. Rzepa, "Gaussian Job Archive for C39H32S3Si2", 2013. https://doi.org/10.6084/m9.figshare.818954
  5. H.S. Rzepa, "Gaussian Job Archive for C39H32S3Si2", 2013. https://doi.org/10.6084/m9.figshare.817910
  6. D.C. Braddock, and H.S. Rzepa, "Structural Reassignment of Obtusallenes V, VI, and VII by GIAO-Based Density Functional Prediction", Journal of Natural Products, vol. 71, pp. 728-730, 2008. https://doi.org/10.1021/np0705918

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X-ray analysis and absolute configuration determination using porous complexes.

Wednesday, April 17th, 2013

This is another in the occasional series of “what a neat molecule”. In this case, more of a “what a neat idea”. The s-triazine below, when coordinated to eg ZnI2, forms what is called a metal-organic-framework, or MOF. A recent article[1] shows how such frameworks can be used to help solve a long-standing problem in structure determination, how to get a crystal structure on a compound that does not crystallise on its own.

 

MOF

The essence of the technique is to select a small crystal of the MOF (which crystallises well) and allow your own molecule to diffuse in from solution. So captured inside the framework, the X-ray analysis can now be done on the absorbed host molecule together with the MOF framework. Below you can see two of the structures reported solved by this technique. The first shows the target molecule (green arrows) but also three molecules of cyclohexane (the diffusing solvent, red arrows), nicely illustrating its chair conformation.

Click for 3D.

Click for 3D.

This second example shows the structure of a marine natural product, of which only  about 5µg was available (green arrow). The structure (of miyakosyne A) shows a conformationally flexible substituted saturated backbone, a molecule which traditionally might be expected to be disordered because of its flexibility. These structures were performed on a standard diffractometer, and the authors point out that if more intense synchrotron radiation were to be used, even smaller samples (< 10ng) could be determined. They also note that full occupancy of the MOF lattice does not need to be achieved for the method to succeed.

Click fdx.doi.org3D.

Click for 3D.

I end with noting that in an earlier post, I observed how chiroptical methods can nowadays be increasingly successfully used to determine absolute configurations of chiral molecules. Miyakosyne A, a molecule with three chiral centres had proved to be a challenge using such techniques; one of these centres (at C14) could not be determined by any chiroptical method. The configuration was however successfully determined as (S) by this new crystallographic technique. I think this is a huge contribution to the science of structure and configuration determination![2]

References

  1. Y. Inokuma, S. Yoshioka, J. Ariyoshi, T. Arai, Y. Hitora, K. Takada, S. Matsunaga, K. Rissanen, and M. Fujita, "X-ray analysis on the nanogram to microgram scale using porous complexes", Nature, vol. 495, pp. 461-466, 2013. https://doi.org/10.1038/nature11990
  2. https://doi.org/

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