Oxane oxide: a tautomer of hydrogen peroxide.

April 15th, 2016

 If H3N+-O– is viable compared with its tautomer H2N-OH when carrying water bridges, then why not try H2O+-O– vs HO-OH?

There are no examples to be found in crystal structures! The solvated structure of H2O+-O– is modified directly from that of H3N+-O– and the computed (ωB97XD/6-311++G(d,p)/SCRF=water) structure[1] is shown below. Noteworthy is that the hydrogen bonds at the O+ end are far stronger than those to at the O– end.

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The corresponding hydrated hydrogen peroxide is 16.3 kcal/mol lower in free energy; this compares favourably with the value for water itself and suggests that oxane oxide might also be capable of isolation inside a suitable hydrogen bond stabilising cavity.

References

  1. H.S. Rzepa, "H20O11", 2016. https://doi.org/10.14469/ch/192005

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Azane oxide, a tautomer of hydroxylamine.

April 15th, 2016

In the previous post I described how hydronium hydroxide or H3O+…HO–, an intermolecular tautomer of water, has recently been observed captured inside an organic cage[1] and how the free-standing species in water can be captured computationally with the help of solvating water bridges. Here I explore azane oxide or H3N+-O–,‡ a tautomer of the better known hydroxylamine (H2N-OH).

The usual search[2] of the Cambridge structure database reveals only two (related) entries[3],[4] the second reported in 2015.[5].

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NH3-8

Now, location of hydrogen atoms is always a bit tricky, but here we see two species H3N+-OH…–O-+NH3 connected by a strong hydrogen bond of 1.54Å (click on the above image to see this packing). However, it is noteworthy that the N-O bonds for each of these species are exactly the same length (1.412Å); one might have imagined that whether the oxygen carries a proton or not would affect its bond length to nitrogen. There is here a strong hint that energetically the azane oxide might be relatively low in energy relative to hydroxylamine and perhaps that the zwitterionic form might be favoured when captured with hydrogen bonds.

So certainly time for a computational exploration of this species. I am using the three water bridges as before, each comprised of three water molecules and the ωB97XD/6-311++G(d,p)/SCRF=water method. In fact the structure optimises[6] to a delightful propeller-like geometry in which bridges are formed from both two AND three waters across the ion-pair, with overall three-fold C3 symmetry (i.e. chiral! Indeed, this species has a predicted optical rotation of 40° at 589nm).

NH3-8

Hydroxylamine itself has a less symmetric arrangement of hydrogen bonds[7], with a free energy in fact very similar (within 1 kcal/mol) to the ion-pair isomer. Here, a stochastic (statistical) exploration of all the various arrangements of water would be needed to be confident that the lowest energy form had been located. I would note that the N-O bond lengths in the ion-pair and neutral forms are respectively 1.399 and 1.435Å.

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Certainly, this very brief computational look at azane oxide suggests that concentrations of this species in aqueous solutions of hydroxylamine might be appreciable (detectable). Its "trapping" inside a suitably designed cavity must be a realistic possibility (the cavity used to trap hydronium hydroxide probably does not have the correct dimensions for this purpose), as indeed illustrated in the two crystal structures noted above.

‡ I have represented this species in ionic form, but you may find text books showing it in dative form, or H3N→O. My personal inclination is to always prefer the ionic form, if only because it enables connections/analogies such as the one here to hydronium hydroxide to be more easily made.

References

  1. M. Stapf, W. Seichter, and M. Mazik, "Unique Hydrogen‐Bonded Complex of Hydronium and Hydroxide Ions", Chemistry – A European Journal, vol. 21, pp. 6350-6354, 2015. https://doi.org/10.1002/chem.201406383
  2. H. Rzepa, "Search for Azane oxide", 2016. https://doi.org/10.14469/hpc/380
  3. Fischer, Dennis., Klapotke, Thomas M.., and Stierstorfer, Jorg., "CCDC 1054611: Experimental Crystal Structure Determination", 2015. https://doi.org/10.5517/cc14ddqn
  4. Fischer, D.., Klapotke, T.M.., and Stierstorfer, J.., "CCDC 827687: Experimental Crystal Structure Determination", 2012. https://doi.org/10.5517/ccws8lh
  5. D. Fischer, T.M. Klapötke, and J. Stierstorfer, "1,5‐Di(nitramino)tetrazole: High Sensitivity and Superior Explosive Performance", Angewandte Chemie International Edition, vol. 54, pp. 10299-10302, 2015. https://doi.org/10.1002/anie.201502919
  6. H.S. Rzepa, "H 21 N 1 O 10", 2016. https://doi.org/10.14469/ch/192000
  7. H.S. Rzepa, "H 21 N 1 O 10", 2016. https://doi.org/10.14469/ch/192001

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Hydronium hydroxide: the why of pH 7.

April 14th, 2016

Ammonium hydroxide (NH4+…OH–) can be characterised quantum mechanically when stabilised by water bridges connecting the ion-pairs. It is a small step from there to hydronium hydroxide, or H3O+…OH–. The measured concentrations [H3O+] ≡ [OH–] give rise of course to the well-known pH 7 of pure water, and converting this ionization constant to a free energy indicates that the solvated ion-pair must be some ~19.1 kcal/mol higher in free energy than water itself.♣ So can a quantum calculation reproduce pH7 for water?

Let me start by saying that locating a stable minimum for H3O+…OH– is non-trival. I have been trying to find a structure on and off for a little while now, but all my erstwhile attempts have resulted in barrierless proton transfers back to H2O…OH2.† So I now decided on a more systematic approach by running a CSD (Cambridge structure database) search, defining the species H3O+ and specifying that the oxygen sustain one additional hydrogen bond, as per H3O+….H.[1] This produced 69 hits, with the distribution of O…H distances shown below indicating that a wide spectrum of hydrogen bond lengths to this oxygen appears possible.

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Restricting the search to  H3O+….H-O  and specifying that the last O is bonded to just one atom‡ reduces this to one hit.[2] If you click on the image below or visit here[3] you will see the hydrogen bonding pattern in this unique example is of the type (ROH…H)3O+…HO–(…HOR)3 with overall three-fold symmetry. The "bridge" across the ion pair in this case is formed from hydrogen bonds to -CH2OH groups in 1,3,5-tris(hydroxymethyl)-2,4,6-triethylbenzene.

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This structure immediately poses the question of whether water bridges could replace the organic bridge in the species above, to enable the elusive water-solvated hydronium hydroxide to finally be characterised as a bona-fide minimum in a quantum mechanical potential. By analogy one would need three bridges, each to be comprised of 3H2O. In other words a system containing  eleven water molecules.  An ωB97XD/6-311++G(d,p)/SCRF=water calculation indeed reveals this C3-symmetric arrangement is a minimum with a calculated[4] free energy (298K) 23.3 (23.5/Def2-TZVPPD) kcal/mol above that of the corresponding water cluster[5] in which a proton transfer has neutralised the ion pair. The error of +4.2 kcal/mol is probably due to a combination of incomplete basis set (calculations with better bases are under way), incomplete correction for solvation (continuum) as well as the limited size of the explicit water cluster (nine supporting water molecules) and other aspects such as the DFT method itself and the RRHO partition function approximations for thermal corrections. It would be a useful calibrant of all these aspects to explore whether these various corrections would converge to the known value or not.

The calculated geometry[4] reveals a H3O…HO hydrogen bond ~2.14Å, well within the range shown in the crystal structure distribution above.

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With the basic model for hydronium hydroxide identified, one can now explore how to improve both the accuracy of the model in reproducing the "pH 7" observable and how indeed one might engineer a more superbasic variation.

Addendum 1: The NCI (non-covalent-interaction) analysis of the hydronium hydroxide water complex is shown below. The blue regions indicate strong hydrogen bonds, with cyan being weaker. In fact, the covalent/non-covalent threshold normally taken for an  NCI analysis  (0.05 au) had to be increased to 0.10 for this example (the default threshold was already treating the HO…H interactions as covalent rather than non-covalent).

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Addendum 2: Shown below is the intrinsic reaction cooordinate (IRC) calculated[6] for the proton transfer from the hydronium hydroxide ion-pair to form neutral water, revealing a barrier of ~3kcal/mol and exothermicity of 23 kcal/mol and how the dipole moment evolves.

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♣Dissociation/equilibrium constants are rarely converted into free energies in text books and elsewhere. I would argue here that one gets a better intuitive feeling for such systems if expressed as energies. In this case, such a self-ionization energy for water might also be a useful way of calibrating how any given quantum mechanical procedure might perform in terms of the solvation model etc.

†Recent calculations of like-charge pairs of either H3O+ or OH– have been reported[7] but not as an ion-pair.

‡It is implicit when one talks about connecting bonds that the weaker hydrogen bonds do not qualify. Of course there is a whole spectrum of hydrogen bonding strengths; ones involved in ion-pairs for example can be up to 3 times stronger than those to neutral systems.

References

  1. H. Rzepa, "Crystal structures containing the hydronium cation", 2016. https://doi.org/10.14469/hpc/370
  2. M. Stapf, W. Seichter, and M. Mazik, "Unique Hydrogen‐Bonded Complex of Hydronium and Hydroxide Ions", Chemistry – A European Journal, vol. 21, pp. 6350-6354, 2015. https://doi.org/10.1002/chem.201406383
  3. Stapf, Manuel., Seichter, Wilhelm., and Mazik, Monika., "CCDC 1034049: Experimental Crystal Structure Determination", 2015. https://doi.org/10.5517/cc13q0f8
  4. H.S. Rzepa, "H22O11", 2016. https://doi.org/10.14469/ch/191994
  5. H.S. Rzepa, "H 22 O 11", 2016. https://doi.org/10.14469/ch/191995
  6. H.S. Rzepa, "H22O11", 2016. https://doi.org/10.14469/ch/192002
  7. M.K. Ghosh, T.H. Choi, and C.H. Choi, "Like-charge ion pairs of hydronium and hydroxide in aqueous solution?", Physical Chemistry Chemical Physics, vol. 17, pp. 16233-16237, 2015. https://doi.org/10.1039/c5cp02182k

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Publishing embargoes.

April 13th, 2016

Publishing embargoes seem a relatively new phenomenon, probably starting in areas of science when the data produced for a scientific article was considered more valuable than the narrative of that article. However, the concept of the embargo seems to be spreading to cover other aspects of publishing, and I came across one recently which appears to take such embargoes into new and uncharted territory.

One example (there are many others) of embargoes continuing to operate in the era of open science and open data relates to crystallographically derived coordinates for macromolecules. Biomolecular structures are allowed to be embargoed for a maximum of one year before becoming openly available or “released” (considered a friendlier term than embargo). A more recent phenomenon is of embargoes on press releases which may be prepared by authors and or publishers to accompany the appearance of any article considered especially newsworthy. The publisher will then request that the press release is only released to coincide with the actual publication time and date of the article itself. Both of these types of embargo are more or less accepted by both parties. But in the last five years or so, new types of embargo have been introduced and it is these I want to discuss here.

  1. The self-archive or “green open access” version of an article, in the form of the last author version of an accepted manuscript prior to copy-editing and other operations by a publisher. Such Green OA versions are now a mandatory requirement from funders (in the UK), arising from the need to conduct a “REF” or research excellence framework assessment of all (UK) universities every seven years or so. In order to allow assessors and funding councils unencumbered access to these research outputs, the authors must self-archive their publications in a suitable institutional repository. In general therefore, there should always exist two versions of any scientific paper authored within these guidelines, the AV (author version) and VoR (Version of Record, held by the publisher, and carrying the guarantee of peer review). Publishers now embargo author versions until the VoR version has been published, and sometimes even up to 18 months beyond this period.
  2. The “supporting information” or SI embargo. This is closely related to the crystallographic data embargo noted above, but it applies in general to most other data and information associated with an article. Until very recently, most SI was in fact handled by the publisher themselves, and so it was released at the same time as the article. Since it is becoming more common to deposit data and SI in a separate repository, some publishers mandate that the release dates of this material must not precede the article itself. Deposition of such data has also become a mandatory requirement from (UK) funders since May 2015, and I have blogged about such “research data management” often here. In effect, both the scientific article and the data supporting it achieve their own DOIs or persistent digital identifiers, allowing easy and independent access to either the article OR its data. In fact, assigning such a DOI has a more subtle effect; creating a DOI means that metadata describing the object is also created and then aggregated by the agency issuing the DOI such as CrossRef and DataCite. Importantly, one should note that SI which is handled purely by the publisher will not have its own separate DOI and it will not have its own metadata. The data metadata for example can include the DOI for the article, and vice versa. I have shown examples of the utility of such metadata for data in an earlier post.
  3. So now we come to the most recent embargo, which has surfaced since around May 2015, as increasingly data has become a first class object in its own right with its own DOI and importantly its own metadata. There is now evidence that some publishers are requesting that this very metadata about data is also subjected to an embargo, not to be released before the article which makes use of that data is itself released. So data can be deposited in “dark form” prior to a publication, but the metadata (which carries the date stamp and provenance for the deposition) may have to be “dark” or embargoed. Actually, this is not yet very common; for example I asked the Royal Society of Chemistry what their policy was, with the reply “the Royal Society of Chemistry wouldn’t require metadata about the data files to be embargoed”.

We live in an era where the very careers of reseachers can be determined by their claim to priority about scientific discoveries. The date stamps for priority continue to be largely controlled and issued by publishers and some may decide that it will be in their business interests to extend their control to data. Perhaps they may even wish to control all aspects of publication including the data and its metadata, acting as self-proclaimed research facilitators.

At this moment, this has not happened; both data and its metadata can remain open and FAIR. Which is where I think we should go in the future in the interests of open science itself.

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Ways to encourage water to protonate an amine: superbasing.

April 8th, 2016

Previously, I looked at models of how ammonia could be protonated by water to form ammonium hydroxide. The energetic outcome of my model matched the known equilbrium in water as favouring the unprotonated form (pKb ~4.75). I add here two amines for which R=Me3Si and R=CN. The idea is that the first will assist nitrogen protonation by stabilising the positive centre and the second will act in the opposite sense; an exploration if you like of how one might go about computationally designing a non-steric superbasic amine that becomes predominantly protonated when exposed to water (pKb <1)† and is thus more basic than hydroxide anion in this medium.

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Before reporting any calculations, let us see what the CSD (Cambridge structure database) might contain. The search query is simple, a 3-coordinate amine forming a 4-coordinate quaternary nitrogen† with one N-H and a positive (formal) charge on the N, and a 1-coordinate oxygen with one O-H and a negative charge on the O. With the constraints R < 10%, no disorder and no errors, one gets as many as 15 hits,[1] several of which also apparently contain separate water molecules in the crystal. A warning bell (perhaps several) sounds, since if R < 5%, the number of hits drops to just 2; these are clearly difficult structures to refine!‡ So there is some tantalising evidence that in the solid state at least, the quaternary ammonium group (with at least one N-H), water and a hydroxide anion might be capable of co-existence. As noted below† some fascinating 2-coordinate amines have also been reported as having superbasic properties.

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R=CN: the well known compound cyanamide is known to act only as an acid and its basic properties are never quoted. Shown below is the reaction path for transfer of a proton from water to the amine using an 8-water model (n=8) in which two bridges can serve to help stabilize any ionic form. The energy required to do so however is at least 24 kcal/mol (ωB97XD/Def2-TZVPPD/SCRF=water) which indicates that no protonated amine is formed. This can be attributed to the electron withdrawing cyano group strongly destablising any adjacent positive ammonium centre and thus effectively completely inhibiting its formation.

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R=Me3Si: this too is already known[2],[3] but only in the presence of the non-coordinating counter-anion B(C6F5)4 crystallised from non-protic solution. An ionised form can now be located using the model above. This has the structure shown below; note the very short hydrogen bonds associated with the hydroxide anion and the possibility of forming only two water bridges across the ion-pair. The relative free energy of the ion-pair (table below) shows it to be if anything less basic than ammonia. 

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n=8 R=H R=SiMe3 R=CN
ΔΔG298 7.0[4]

7.6[5],[6]

>24[7]

NBO (natural bond orbital) analysis might here  be a useful metric of basicity. Hence Me3SiNH2…H2O  suggests that donation from the N lone pair into an antiperiplanar Si-C bond is quite large (E(2) = 11.9 kcal/mol), although alternative donation by nitrogen into the H-O σ* bond  of the water is much higher (33.4 kcal/mol). 

Perhaps the basicity of simple amines is related to their ability to form stabilizing water bridges across the ion-pair? With trimethylsilyl substituents, this feature (and hence the basicity) is partially or even fully suppressed as in e.g. tris(trimethylsilyl)amine.The pKb of the latter appears to be unreported[8] but it does seem to be only weakly basic and "inert to H2O",[9] a property attributed instead to multiple character in the Si-N bonds. 

I will in a future post look at the alternative class of phosphazenium amines which do manage to achieve superbasicity.[10]

†A phosphazenium 3-coordinate amine[11] was in 1991 claimed to be the strongest metal-free neutral base. This has now been superceded by combining this base motif with that of a sterically operating proton sponge.[12],[10] I will report the computational modelling of these systems in a later post.

‡One of the structures identified with R<10% is UBEJIU[13] and which is worth showing below. Note the apparent close contact of the type N-H…H-O (1.416-1.463Å) rather than the expected N-H…OH.  If correct (this feature is not mentioned in the article itself) it would be classified as a dihydrogen bond, a type normally only found in situations such as B-H…H-N. There are a number of other inconsistencies which must be resolved if this structure is to stand as correct.

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References

  1. H. Rzepa, "Substituted ammonium hydroxides", 2016. https://doi.org/10.14469/hpc/361
  2. Y. Sarazin, J.A. Wright, and M. Bochmann, "Synthesis and crystal structure of [C6H5Hg(H2NSiMe3)][H2N{B(C6F5)3}2], a phenyl–mercury(II) cation stabilised by a non-coordinating counter-anion", Journal of Organometallic Chemistry, vol. 691, pp. 5680-5687, 2006. https://doi.org/10.1016/j.jorganchem.2006.09.021
  3. Sarazin, Y.., Wright, J.A.., and Bochmann, M.., "CCDC 608250: Experimental Crystal Structure Determination", 2007. https://doi.org/10.5517/ccndxzx
  4. H.S. Rzepa, and H.S. Rzepa, "H21NO9", 2016. https://doi.org/10.14469/ch/191946
  5. H.S. Rzepa, and H.S. Rzepa, "C 3 H 29 N 1 O 9 Si 1", 2016. https://doi.org/10.14469/ch/191987
  6. H.S. Rzepa, and H.S. Rzepa, "C 3 H 29 N 1 O 9 Si 1", 2016. https://doi.org/10.14469/ch/191982
  7. H.S. Rzepa, "CH20N2O9", 2016. https://doi.org/10.14469/ch/191983
  8. E.W. Abel, D.A. Armitage, and G.R. Willey, "Relative base strengths of some organosilicon amines", Transactions of the Faraday Society, vol. 60, pp. 1257, 1964. https://doi.org/10.1039/tf9646001257
  9. J. Goubeau, and J. Jimenéz‐Barberá, "Tris‐(trimethylsilyl)‐amin", Zeitschrift für anorganische und allgemeine Chemie, vol. 303, pp. 217-226, 1960. https://doi.org/10.1002/zaac.19603030502
  10. Kögel, Julius F.., Oelkers, Benjamin., Kovačević, Borislav., and Sundermeyer, Jörg., "CCDC 1002088: Experimental Crystal Structure Determination", 2014. https://doi.org/10.5517/cc12mrfw
  11. R. Schwesinger, and H. Schlemper, "Peralkylated Polyaminophosphazenes— Extremely Strong, Neutral Nitrogen Bases", Angewandte Chemie International Edition in English, vol. 26, pp. 1167-1169, 1987. https://doi.org/10.1002/anie.198711671
  12. J.F. Kögel, B. Oelkers, B. Kovačević, and J. Sundermeyer, "A New Synthetic Pathway to the Second and Third Generation of Superbasic Bisphosphazene Proton Sponges: The Run for the Best Chelating Ligand for a Proton", Journal of the American Chemical Society, vol. 135, pp. 17768-17774, 2013. https://doi.org/10.1021/ja409760z
  13. P. Vianello, A. Albinati, G.A. Pinna, A. Lavecchia, L. Marinelli, P.A. Borea, S. Gessi, P. Fadda, S. Tronci, and G. Cignarella, "Synthesis, Molecular Modeling, and Opioid Receptor Affinity of 9,10-Diazatricyclo[4.2.1.1<sup>2,5</sup>]decanes and 2,7-Diazatricyclo[4.4.0.0<sup>3,8</sup>]decanes Structurally Related to 3,8-Diazabicyclo[3.2.1]octanes", Journal of Medicinal Chemistry, vol. 43, pp. 2115-2123, 2000. https://doi.org/10.1021/jm991140q

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

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.

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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.

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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°. 

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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°.

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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.

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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.

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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.

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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.

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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.

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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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Does combining molecules with augmented reality have a future?

March 28th, 2016

Augmented reality, a superset if you like of virtual reality (VR), has really been hitting the headlines recently. Like 3D TV, its been a long time coming! Since ~1994 or earlier, there have been explorations of how molecular models can be transferred from actual reality to virtual reality using conventional computers (as opposed to highly specialised ones). It was around then that a combination of software (Rasmol) and hardware (Silicon Graphics, and then soon after standard personal computers with standard graphics cards) became capable of such manipulations. VRML (virtual reality modelling language) also proved something of a false start‡ So have things changed?

Many of the posts on this blog have some element of such VR in the form of the Jmol or JSmol software (the natural successor to Rasmol) that allows a 2D projection of a 3D model to be manipulated in "real-time", allowing the geometrical features to be inspected and even animations of reactions. Google cardboard is a (minor?) variation on the VR theme, allowing a 3D object to be viewed through a simple cardboard headset containing a mounted phone, but controlled by head movements acting on the accelerometers in the phone rather than a mouse or trackpad. But the full-blown experience is something else, and watching this TED video really brought it home to me. The virtual object, such as say a molecule, is superimposed upon one's view of the real world (AR) and this object can now be controlled with hands as well as eyes. Again, this is not new; so-called haptic control of virtual objects has been around for a decade or more, in which you can e.g. probe how "hard" an object is using a haptic or hands-on device such as a joystick. All of this quickly convinces one that the secret of successful use of VR and now AR to augment chemistry is going to be the software!

We now need inspired programmers to create the Rasmol/Jmol of augmented reality. But beyond mere software, chemistry with AR needs to be placed into the appropriate environment or context. One might presume this will include the stereoscopic video inputs from other AR headsets (the research team, the collaborators, etc) but what else? The pages of a blog? Or a journal article? Could indeed one recast the journal article itself into an AR scene, with the various components floating in space, with molecules conjured out of a table (or a synthetic procedure) to float in full 3D glory to be played with by the participants? I rather suspect this might be quite a few steps too many for most!  Think how little ~22 years of the Web (and perhaps ~36 years of the Internet itself) has actually changed the construction (I do not mean the delivery) of the average scientific article. Even now, tables in which molecules can be treated interactively are extremely rare. Most of this is because authoring tools such as Microsoft Word have not yet made the production of such documents viable. So perhaps the augmented-reality scientific or chemical article may not be quite around the corner. Perhaps the AR hype will end in the same way that 3D TV appears to have. But unless we experiment, we will never know the answer. So if any reader of this blog knows of interesting work in chemistry AR, do drop me a line.

‡ Virtual Reality Modelling Language (VRML) in Chemistry, O. Casher, C. Leach, C. S. Page and H. S. Rzepa, Chem. in Brit., 1998, 34(9), 26. But VRML has made a come-back as the language of choice for 3D printing!

 

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How many water molecules does it take to form ammonium hydroxide from ammonia and water?

March 20th, 2016

This is a corollary to the previous post‡ exploring how many molecules are needed to ionise HCl. Here I am asking how many water molecules are required to form the ionic ammonium hydroxide from ammonia and water.

As Wikipedia will inform you, "it is actually impossible to isolate samples of NH4OH (more formally the ion-pair NH4+OH– ) as these ions do not comprise a significant fraction of the total amount of ammonia except in extremely dilute solutions (my italics)". In fact, the ionization constant Kb = [NH4+][OH–]/[NH3][H2O] is ~1.8 x 10-5 (pKb 4.75) equivalent to a free energy difference of  ~6.5 kcal/mol between the two forms.† This is in stark contrast to solutions of e.g. HCl in water, where essentially all of the HCl is ionised to hydronium chloride or H3O+Cl– by addition of just ~4-5 water molecules. So what is the water model required to compute this known behaviour of ammonia? Here, this will be ωB97Xd/Def2-TZVPPD/SCRF=water, i.e. a continuum water model is already included and we add n further discrete water molecules to enhance it.

For n=0 or 2, the ion-pair is not an explicit minimum (although it appears to be a "hidden intermediate"[1]). Values of e.g. n=4,6,8 allow the formation of two or three "bridges" comprising two or three water molecules connecting the N and O atoms by hydrogen bonds and this additional solvation enables location of a transition state for proton transfer between O and N. This implies an equilibrium can be established as NH3 + H2O ⇌* NH4+.OH– with the ion-pair now a genuine minimum stabilized by those ion-pair bridges. Note in particular how the hydrogen bond lengths involving the water salt-bridge in the ion-pair are shorter than for the neutral water-ammonia complex.

NH3-8

The contact ion-pair is nevertheless a very shallow minimum when surrounded by 4 or more explicit waters, the barrier from proton transfer from N being less than a vibrational quantum, and so the lifetime of the contact ion-pair is very much defined by the proton dynamics of the system..

4

8

For n=8, the dipole moment changes along the IRC for proton transfer between N and O as might be expected for the collapse of a contact ion-pair.

8dm

The relative free energies of the ion-pair and the un-ionized pair are shown below, the former being the higher. The values correspond approximately to the known ionization constant. As more explicit water molecules are added, there is a hint that the proportion of ion-pairs might actually decrease relative to neutral ammonia. However, these calculations are for a contact ion-pair and not a solvent-separated ion pair, the latter form possibly being the more appropriate form for extremely dilute solutions (see above). Modelling the latter type of ion-pair is not as straightforward as the contact variety;  as the ion separation increases, so the propensity for barrierless proton transfers increases, ultimately leading back to the contact form. So to understand if it is correct that in extremely dilute solutions there is no remaining neutral ammonia, probably only a full molecular dynamics treatment of such a system is likely to give further insights.

n 4 6 8
 ΔΔG298 6.4[2] 5.9[3] 7.0[4]

To summarise, in order to compute the formation of the ammonium hydroxide ion pair from ammonia and water, one has to include an additional four or more explicit water molecules in the calculation. This model confirms that in the resulting equilibrium, only a tiny proportion of the ammonia becomes ionised. With such a base model in place, one can now proceed to investigate how addition of substituents on the nitrogen might impact upon such ionisation, i.e. to form a stronger or a weaker base.

‡A more complete analysis followed.[5] *If you are wondering how to produce a reversible arrow, see here. †This is only approximate, since the concentration of water needs renormalising.

 

References

  1. https://doi.org/
  2. H.S. Rzepa, and H.S. Rzepa, "H13NO5", 2016. https://doi.org/10.14469/ch/191950
  3. https://doi.org/
  4. H.S. Rzepa, and H.S. Rzepa, "H21NO9", 2016. https://doi.org/10.14469/ch/191946
  5. A. Vargas‐Caamal, J.L. Cabellos, F. Ortiz‐Chi, H.S. Rzepa, A. Restrepo, and G. Merino, "How Many Water Molecules Does it Take to Dissociate HCl?", Chemistry – A European Journal, vol. 22, pp. 2812-2818, 2016. https://doi.org/10.1002/chem.201504016

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Research data: Managing spectroscopy-NMR.

March 16th, 2016

At the ACS conference, I have attended many talks these last four days, but one made some “connections” which intrigued me. I tell its story (or a part of it) here.

But to start, try the following experiment.

  1. Find a Word document of .docx type on your hard drive
  2. Remove the .docx suffix and replace it with a .zip suffix.
  3. Expand as if it is an archive (it is!).
  4. A folder is created and this itself contains four further folders. These all contain XML files, and in the sub-folder actually called word you will find something called document.xml That file contains the visible content of the document; all the others are support documents, including styles etc.

The reason this is important was made clear in Santi Dominguez’ talk. Most of it was concerned with introducing Mbook, an ELN (electronic laboratory notebook) but the relevance to the above comes from his introduction of Mpublish, a forthcoming product targeting the area of research data management. What is the connection? Well, NMR spectrometers produce raw outputs as collections of files, much in the manner of the exploded word document above. Some files contain the raw FID, others contain the acquisition parameters, etc. These files are then turned into the traditional spectra by suitable processing software such as Mestrenova (part of the same ecosystem as Mpublish). Most users of such programs then squirt the spectra into a PDF file and it is this last document that is preserved as “research data” – almost invariably this is the version sent off to journals as the supporting information or SI for the article. SI is called information for a good reason; in such a container it is very often not easily usable data, and functions just visually.

So what is the problem? Well, the conversion of the NMR fileset (and quite possibly many other forms of spectroscopy) into a PDF file is a lossy process. It cannot be reversed; information has been lost. And only really a human who can easily retrieve and interpret such a visual presentation.

Santi described how Mpublish can assemble all the files associated with the instrumental outputs, optionally add chemical structure and other information, collect suitable metadata describing the contents and create a .zip archive. As we saw with Word however, the suffix does not even need to be .zip. It was suggested that it be this information-complete archive that should really be used as SI to accompany an article in which NMR data is invoked to support the narrative. In the reverse process, anyone downloading this zip archive could themselves potentially acquire full access, without information loss, to the original NMR data. There is a little further magic that needs to be included to make the process work which I do not include here. When Mpublish becomes available to play with, I will complete that story here.

It is good to report that software is starting to appear which enhances the management and reporting of research data as part of the publication process. The “rules” and “best practice” of this game are still being written however. In this regard, I feel that it is the researchers themselves that must play a vital role in defining the rules. Let us not cede that role just to publishers.

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Global initiatives in research data management and discovery: searching metadata.

March 7th, 2016

The upcoming ACS national meeting in San Diego has a CINF (chemical information division) session entitled "Global initiatives in research data management and discovery". I have highlighted here just one slide from my contribution to this session, which addresses the discovery aspect of the session.

Data, if you think about it, is rarely discoverable other than by intimate association with a narrative or journal article. Even then, the standard procedure is to identify the article itself as being of interest, and then digging out the "supporting information", which normally takes the form of a single paginated PDF document. If you are truly lucky, you might also get a CIF file (for crystal structures). But such data has little life of its own outside of its parent, the article. Put another way, it has no metadata it can call its own (metadata is data about an object, in this case research data). An alternative is to try to find the data by searching conventional databases such as CAS,  Beilstein/Reaxys or CSD, and there of course the searches can be very precise. But (someone) has to pay the bills for such accessibility.

We are now starting to see quite different solutions to finding data (the F in FAIR data, the other letters representing accessibility, interoperability and re-usability). These solutions depend on metadata being a part of the solution from the outset, rather than any afterthought produced as a commercial solution. The collection of metadata is part of the overall process called RDM, or research data management, perhaps even the most important part of it. In exchange for identifying metadata about one's data, one gets back a "receipt" in the form of a persistent identifier for the data, more commonly known as a DOI. The agency that issues the DOI also undertakes to look after the donated metadata, and to make it searchable. The table below shows eight searches of such metadata, one example of how to acquire statistics relating to the usage of the data and one search of how to find repositories containing the data.

Search queries enabled by the use of metadata in data publication
# Search query* Instances retrieved:
1 http://search.datacite.org/ui?q=alternateIdentifier:InChIKey:*  InChI identifier
2 http://search.datacite.org/ui?q=alternateIdentifier:InChI:*  InChI key 
3 http://search.datacite.org/ui?q=alternateIdentifier:InChIKey:CULPUXIDFLIQBT-UHFFFAOYSA-N InChI key CULPUXIDFLIQBT-UHFFFAOYSA-N 
4 http://search.datacite.org/ui?q=ORCID:0000-0002-8635-8390+alternateIdentifier:InChIKey:* ORCID 0000-0002-8635-8390 AND (boolean) InChI key.
5 http://search.datacite.org/ui?q=ORCID:0000-0002-8635-8390+alternateIdentifier:InChI:InChI=1S/C9H11N5O3* ORCID 0000-0002-8635-8390 AND (boolean) + InChI string 1S/C9H11N5O3 with the * wild.
6 http://search.datacite.org/ui?q=has_media:true&fq=prefix:10.14469 Has content media‡ for Publisher 10.14469 (Imperial College)
7 http://search.datacite.org/ui?q=format:chemical/x-* Data format type chemical/x-* 
8 http://search.datacite.org/api?&q=prefix:10.14469& fq=alternateIdentifier:InChIKey:*& fl=doi,title,alternateIdentifier& wt=json&rows=15
http://api.labs.datacite.org/works?q=prefix:10.14469+AND+alternateIdentifier:InChIKey:* 		First 15 hits in JSON format, batch query mode
9 http://stats.datacite.org/?fq=datacentre_facet:"BL.IMPERIAL – Imperial College London" resolution statistics for publisher 10.14469 (Imperial College) per month
10 http://service.re3data.org/search?query=&subjects[]=31 Chemistry Research data repository search for Chemistry (135 hits)

‡In this instance the three MIME media types are chemical/x-wavefunction, chemical/x-gaussian-checkpoint and chemical/x-gaussian-log. See[1] for chemical MIME (multipurpose internet media extensions).

Anyone familiar with the standard ways of finding data (CAS, CSD, Reaxys) will appreciate that the above does not yet have the finesse to find eg sub-structures of chemical structures, synthetic procedures or molecular properties. My including it here is primarily to show some of the potential such systems have, and to remark particularly that the batch query capability of this infrastructure could indeed be used in the future to construct much more sophisticated systems.  Oh, and to the end-user at least, the searches shown above do not require institutional licenses to use. Both the data and its metadata is free, mostly with a CC0 or CC BY 3.0 license for re-use (the R of FAIR).

If more of interest related to this topic emerges at the ACS session,  I will report back here.

References

  1. H.S. Rzepa, P. Murray-Rust, and B.J. Whitaker, "The Application of Chemical Multipurpose Internet Mail Extensions (Chemical MIME) Internet Standards to Electronic Mail and World Wide Web Information Exchange", Journal of Chemical Information and Computer Sciences, vol. 38, pp. 976-982, 1998. https://doi.org/10.1021/ci9803233

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