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Imaging vibrational normal modes of a single molecule.

Thursday, April 18th, 2019

The topic of this post originates from a recent article which is attracting much attention.[1] The technique uses confined light to both increase the spatial resolution by around three orders of magnitude and also to amplify the signal from individual molecules to the point it can be recorded. To me, Figure 3 in this article summarises it nicely (caption: visualization of vibrational normal modes). Here I intend to show selected modes as animated and rotatable 3D models with the help of their calculation using density functional theory (a mode of presentation that the confinement of Figure 3 to the pages of a conventional journal article does not enable).

I should start by quoting some pertinent aspects obtained from the article itself. The caption to Figure 3 includes assignments, which I presume were done with the help of Gaussian calculations. Thus in the Methods section, we find … The geometry of a free CoTPP molecule is optimized under tight convergence criteria using Gaussian 09 (ref. 33). The orientationally averaged Raman spectrum and vibrational normal modes are calculated with the geometry of a free molecule … All the calculations mentioned above are performed at the B3LYP/6-31G* level with the effective core potential at the cobalt centre. Armed with this information, I looked at the data included with the article (the data supporting the findings of this study are available within the paper. Experimental source data for Figs. 1–4 are provided with the paper) but did not spot any data specifically relating to those Gaussian 09 calculations; in particular any data that would allow me to animate some vibrational normal modes for display here. No matter, it is easy to re-calculate, although I had to obtain the basic 3D coordinates from the Cambridge crystal data base (e.g. entry IKUDOH, DOI: 10.5517/cc6hj4b) since they were unavailable from the article itself. At this point some decisions about molecular symmetry needed to be made (the symmetry is not mentioned in the article), since it is useful to attach the irreducible representations (IR) of each mode as a label♥ (lacking in Figure 3). The crystal structure I picked has idealised S4 symmetry, but it could be higher at D2d or lower at C2.

The next issue to be solved is how many electrons to associate with the molecule. Tetraphenylporphyrin has 347 electrons and the free molecule would be expected to be a doublet spin state (with the quartet as an excited state). Were the vibrational modes calculated for this state? Perhaps not since I then found this statement: The physisorbed CoTPP is positively charged on gold, as demonstrated through TERS measurements using CO-terminated tips24 and through the Smoluchowski effect29…. In contrast to gold, the Kondo resonance of cobalt disappears on Cu(100), suggesting that it acquires nearly a full electron from the metal (see Extended Data Fig. 2). So it seems worth calculating both the cation and the anion singlets as well as the neutral doublet. But at this stage we do not know for certain what spin state the Gaussian 09 assignments in Figure 3 were done for, since there is no data associated with the article to tell us, only that they were done for the free molecule (nominally a doublet).

There is one more remark made in the article we need to take into account: After lowering the sample bias to approach the molecule and scanning at close range, the molecule flattens. Its phenyl rings, which in the free molecule assume a dihedral angle of 72°, rotate to become coplanar (see Extended Data Fig. 1b). Evidently, the binding energy of the phenyl groups to copper overcomes the steric hindrance in the planar geometry. So it might be useful to calculate this “flattened” form to see how much steric repulsion energy needs to be overcome by that binding of the phenyl groups to the surface of the metal. 

Finally, I decided to not try to replicate exactly the reported calculations (B3LYP/6-31G(d)) since this type of DFT mode does not include any dispersion attraction terms; moreover by today’s standards the basis set is also rather small. So here you have an ωB97Xd/6-311G(d,p) calculation, with tight convergence criteria (integral accuracy 10-14 and SCF 10-9; again we do not know what values were used for the article). To ensure that my data is as FAIR as possible, here is its DOI: 10.14469/hpc/5461

charge Multiplicity ΔG, Twisted Ph
Hartree		 ΔG, Co-planar Ph
Hartree		 ΔΔG, kcal/mol
0 Doublet -3294.58693 -3294.48867 61.7
0 Quartet -3294.58777 -3294.51985 42.6
+1 Singlet -3294.35473 -3294.24973 65.9
+1 Triplet -3294.40821 -3294.33092 48.5
-1 Singlet -3294.67713 -3294.56652 69.4

Starting with a singlet cation as a model, the intent is to compare the “free molecule” energy with that of a flattened version where the dihedral angles of the phenyl rings relative to the porphyrin ring are constrained to ~0° rather than ~72°. This emerges as a 4th order saddle point (a stationary point with four negative roots for the force constant matrix). Such a property means that each co-planar phenyl group is independently a transition state for rotation. The calculated geometry overall is far from planar, having S4 symmetry. The image below in (a) shows how non-planar the molecule still is; (b) an attempt to orient it into the same position as is displayed in Figure 3 of the article.[1]

Singlet cation. Click on the image to get a rotatable model.

The free energy ΔG is 65.9 kcal/mol higher than the twisted form, which means that according to the model proposed, the binding energy of the phenyl groups to copper must recover at least this much energy. If we consider a cationic porphyrin interacting with an anionic metal surface as an ion-pair, then this is perhaps feasible. It is difficult however to see how more than two of the phenyl rings can simultaneously interact with a flat metal surface.

Next, the triplet state of the cation, again a 4th-order saddle point with a rotational barrier of ΔG‡48.5 kcal/mol; the triplet being 33.6 kcal/mol lower than the singlet using this functional (singlet-triplet separations can be quite sensitive to the DFT functional used).

Triplet cation. Click on the image to get a rotatable model.

Next, the neutral doublet, another 4th-order saddle point and below it the quartet state, which this time is just a 2nd-order saddle point (an interesting observation in itself).

Neutral Doublet

Neutral Quartet

Finally, the “flattened” singlet anion, which also emerges as a 4th-order saddle point (the triplet state has SCF convergence issues which I am still grappling with).

Singlet anion

To inspect the vibrational modes of any of these species, click on the appropriate image to open a JSmol display. Then right-click in the molecule window, navigate to the 3rd menu down from the top (Model – 48/226), where the frames/vibrations are ordered in sets of 25. Open the appropriate set and select the vibration you want from the list of wavenumbers shown. The preselected normal mode is the one identified in Figure 3 as 388 cm-1, the symmetric N-Co stretch (I note the figure 3 caption refers to them as vibrational frequencies; they are of course vibrational wavenumbers!). You can also inspect the four modes shown as negative numbers (correctly as imaginary numbers) to see how the phenyl groups rotate. If you want to analyze the vibrational modes using other tools (the free Avogadro program is a good one), then download the appropriate log or checkpoint file from the FAIR data archives at 10.14469/hpc/5461.

I conclude by noting that the aspect of this article which I presume reports the Gaussian normal vibrational mode calculations (Figure 3, caption Bottom, assigned vibrational normal modes), has been a challenging one to analyse.† Neither the charge state nor the spin state of these calculations is clearly indicated in the article (unless I missed it somewhere). The barriers to flattening out the molecule by twisting all four phenyl groups are unreported in the article, but emerge as substantial from the calculations here. The various species I calculated (summarised in the table and figures above) are all predicted to be non-planar. In the absence of provided coordinates with the article, the visual appearances (bottom row, Figure 3) are the only information available. These certainly appear flat and rather different from my projections shown above or below.

All of which amounts to a plea for more data and especially FAIR data to be submitted, providing information such as the charge and spin states used for the calculations, along with a full listing of all the normal mode vectors and wavenumbers. The article is only a letter at this stage; perhaps this information will appear in due course!

†As noted above I have not attempted a direct replication, not least because there is no reported data to which any replication could be compared. ♥The IRs of each vibrational mode are displayed along with the wavenumber when the 3D JSmol display is shown with a right-mouse-click.

References

  1. J. Lee, K.T. Crampton, N. Tallarida, and V.A. Apkarian, "Visualizing vibrational normal modes of a single molecule with atomically confined light", Nature, vol. 568, pp. 78-82, 2019. https://doi.org/10.1038/s41586-019-1059-9

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Organocatalytic cyclopropanation of an enal: (computational) assignment of absolute configurations.

Saturday, September 1st, 2018

I am exploring the fascinating diverse facets of a recently published laboratory experiment for undergraduate students.[1] Previously I looked at a possible mechanistic route for the reaction between an enal (a conjugated aldehyde-alkene) and benzyl chloride catalysed by base and a chiral amine, followed by the use of NMR coupling constants to assign relative stereochemistries. Here I take a look at some chiroptical techniques which can be used to assign absolute stereochemistries (configurations).

I will focus on the compound 4a, the major stereochemical product of this student laboratory reaction, with the stereochemistry as represented in e.g. the abstract of the main article[1] and shown below with added CIP (Cahn-Ingold-Prelog) notation as (1S,2R,3R);‡

Its enantiomer (not shown in the article) is of course;

In the article supporting information[1]), the major diasteromer of 4a deriving from use of the S stereoisomer of the prolinol catalyst is reported as having an optical rotation (ORP) [α]D25 of -62.4°, p6 or -58.1°, p5), but the stereo-labels are not added there. On  p1 (“based on a student report”) 4a was however labelled as (1R,2S,3S) and the chirality (S) of the catalyst used was also noted in the adjacent experimental procedure. One might then reasonably match (1R,2S,3S)-4a to the S-catalyst and hence (1S,2R,3R)-4a to the R-catalyst.  However, in a laboratory environment where both S and R catalysts are in circulation, it is always useful to have procedures available for independent checks.†

There are two methods of assigning absolute chirality, crystallography and chiroptical spectroscopy. The former does require crystalline samples; the latter can use solutions. To cut to the chase, the former method was used for a related compound where the n-heptyl group above is replaced by a p-chlorophenyl substituent (perhaps because the latter imparts suitable crystallinity). On p S123 of the SI of an earlier article[2] the assignment for the p-chlorophenyl derivative was as (1R,2S,3S)-4a for S-catalyst (see DOI: 10.5517/ccdc.csd.cc1mcqg5 OZAXEU). But this procedure is not entirely foolproof; the stereochemistry is decided by interactions between often bulky substituents at the transition state and it might be that here the p-chlorophenyl derivative has different properties from n-heptyl. Moreover bulk solutions may be different in their composition from single crystals. So it is useful to obtain independent proof.

An absolute assignment procedure based on chiroptical methods was first famously used by Kirkwood in 1951 (the Fischer convention is confirmed as a structurally correct representation of absolute configuration).[3] Such calculations need to take into account e.g. rotational conformers about the two bonds labelled in red above. In the previous post, I had noted variation of up to 2Hz in the calculated 3JHH coupling constants as a result of this mobility. This variation is probably too small to really influence any relative stereochemical interpretations, but is the same true for chiroptical assignments?

In Table 1 we can see whether this is still true for the predicted optical rotation of compound 4a, using two different functionals for the calculation (B3LYP and M062X respectively). The results rather surprised me; a simple bond rotation of an aryl or carbonyl group can invert the sign of the rotation. Clearly the observed optical rotation of -62.4° arises from a suitable combination of different Boltzmann populations of the individual bond rotamers, but to combine these accurately you would need to know the solution populations themselves very accurately and that is quite a challenge. So at this stage, we do not really have totally convincing independent evidence of whether the observed negative optical rotation corresponds to (1S,2R,3R)-4a or to its enantiomer (1R,2S,3S).

Table 1. Calculated Optical rotations for (1S,2R,3R)-4a. 

FAIR Data DOI: 10.14469/hpc/4678
Conformer

ORP [α]D, B3LYP+GD3BJ/Def2-TZVPP/SCRF=chloroform

ORP [α]D, M062X/Def2-TZVPP/SCRF=chloroform
4 +376 +238
3 -335 -301
2 -247 -223
1 +710 +522

Next, another chiroptical technique, electronic circular dichroism, or ECD. Here, the sign of the difference in absorption of polarized light (Δε), and known at the Cotton effect, characterises the specific enantiomer. The experimental Cotton effect for compound 4a obtained from S-catalyst (known as 3d in the SI, p S142[2]) can be simply summarised as +ve@315nm and -ve@275nm. Comparison with calculated spectra (Figure S17, p S146-7[2])♣  was performed using a Boltzmann-averaging (albeit based on enthalpies rather than the formally correct free energies), for three significant populations and this procedure matched to (1R,2S,3S).  Since the reported calculations were apparently for gas phase (and replacing n-heptyl with methyl) here I have repeated them in the actual solvent used (acetonitrile) and with the heptyl present. Although the ECD responses can still be severely dependent on the conformation, three of the spectra qualitatively agree that the responses at ~300nm♦ and 260 nm are respectively -ve and +ve. This confirms that (1S,2R,3R)-4a is the wrong enantiomer for S-catalyst and that the correct assignment is therefore (1R,2S,3S), as was indeed reported.[2]

Table 2. Calculated electronic circular dichroism for

 (1S,2R,3R)-4a. FAIR Data DOI: 10.14469/hpc/4678
Conformer

ECD calculation, ωB97XD/Def2-TZVPP
4
3
2
1

It is still true that the overall the fit between chiroptical experiment and theory can be sensitive to the Boltzmann population, as obtained from e.g. ΔΔG = -RT ln [1]/[2]), where 1 and 2 are two different conformers. ΔΔG is a difficult energy difference to compute accurately. Here is a suggested exercise in the statistics of error propagation. How does an error in ΔΔG propagate to the ratio of concentrations of two conformers [1]/[2]? Or, how accurately must ΔΔG be calculated in order to predict conformer populations to say better than 5%.

One more go at chiroptics, this time Vibrational Circular Dichroism, or VCD. The nature of the chromophore is different, but the principle is the same as ECD. I have deliberately truncated the spectrum to cut off all vibrations below 1000 cm-1 (these being the modes associated with group rotations) but to no avail, the four conformations all still look too different to avoid doing a Boltzmann averaging.

Table 3. Calculated VCD spectra for (1S,2R,3R)-4a. 
Conformer Spectrum
4
3
2
1

A modern VCD instrument does have one trick up its sleeve for coping with the conformer problem. The sample (as a thin-film) can be annealed down to very low temperatures before the spectrum is recorded. This effectively removes all higher energy forms, leaving just the most stable conformation as the only species present. However, that is an expensive experiment (and instrument!) to use.

There are perhaps some 2 million scalemic molecules (substances where one chiral form is in excess over the mirror image) for which chiroptical properties have been reported, but probably <50,000 crystal structures where absolute configurations have been assigned. Thus the vast majority of absolute configuration assignments have been done either chiroptically or by synthetic correlations (chemical transformations from molecules of known absolute configuration, with the assumption that you know how each transformation affects the chiral centres present). Given some of the difficulties and challenges noted above, it is tempting to conclude that a significant proportion of those 2 million molecules may have been mis-assigned (I once estimated up to 20%). However, we may conclude that the molecules discussed here are safely assigned correctly! 

‡No CIP-stereolabels appear in the article itself.[1] Perhaps this assignment is omitted in order to provide a student exercise? †There are many errors in stereochemical assignments in the literature. A good many of them may be the result of simple sample mis-labelling.[4] ♣The caption to Figure S17 states All the simulations are for the 1R,2R,3S absolute configuration. This is probably an error and should read 1R,2S,3S. ♦A correction of ~+15nm is sometimes applied to these values, but not done here.

 

References

  1. M. Meazza, A. Kowalczuk, S. Watkins, S. Holland, T.A. Logothetis, and R. Rios, "Organocatalytic Cyclopropanation of (<i>E</i>)-Dec-2-enal: Synthesis, Spectral Analysis and Mechanistic Understanding", Journal of Chemical Education, vol. 95, pp. 1832-1839, 2018. https://doi.org/10.1021/acs.jchemed.7b00566
  2. M. Meazza, M. Ashe, H.Y. Shin, H.S. Yang, A. Mazzanti, J.W. Yang, and R. Rios, "Enantioselective Organocatalytic Cyclopropanation of Enals Using Benzyl Chlorides", The Journal of Organic Chemistry, vol. 81, pp. 3488-3500, 2016. https://doi.org/10.1021/acs.joc.5b02801
  3. W.W. Wood, W. Fickett, and J.G. Kirkwood, "The Absolute Configuration of Optically Active Molecules", The Journal of Chemical Physics, vol. 20, pp. 561-568, 1952. https://doi.org/10.1063/1.1700491
  4. H.S. Rzepa, "The Chiro-optical Properties of a Lemniscular Octaphyrin", Organic Letters, vol. 11, 2009. https://doi.org/10.1021/ol901172g

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FAIR Data in Amsterdam – FAIR data points.

Wednesday, July 18th, 2018

FAIR is one of those acronyms that spreads rapidly, acquires a life of its own and can mean many things to different groups. A two-day event has just been held in Amsterdam to bring some of those groups from the chemical sciences together to better understand FAIR. Here I note a few items that caught my attention.

  1. Fairsharing.org was the basis for several presentations. It serves as “a curated, informative and educational resource on data and metadata standards, inter-related to databases and data policies.” It promotes establishing metrics which strive to quantify how FAIR any given resource is.[1] Any site which achieves a good FAIR metric can be described as a FAIR data point (a term new to me), and which can serve as an exemplar of what FAIR data aspires to.
  2. Intrigued, I offered this page and hope to establish its FAIR metric in the near future, if only to understand how to improve its “score” so that future pages can be improved. It is based on the following Figure[2] which appeared in a recent article and appears to be a publishing “first” in as much as the figure contains hyperlinks directly to the data sources upon which it is based. The putative FAIR data point takes this a little further by wrapping the figure with visualisation tools which take the FAIR data and convert it to interactive models with the help of an added toolbox.
  3. Another topic for discussion was spectroscopy and a veritable file format for its distribution, JCAMP-DX. One emerging theme is the idea of promoting two types of spectral distribution. The first is the use of a common standard format (JCAMP-DX) which strives to eliminate much of the proprietary character associated with data emerging from instruments. At the other extreme is to to offer to readers the raw instrumental data,[3] which has the advantage of having none of the inevitable loss of information when transforming to standard formats. The downside is that it almost always can only be processed using proprietary software provided by the instrument vendor. One way of avoiding this is Mpublish (the topic of an earlier blog) and we heard interesting updates on progress from MestreLabs, the originators of this procedure. It is still my hope that more vendors (both of instruments and of software) will adopt such a model.
  4. A further topic was metadata, which is at the heart of each of the terms in FAIR (F = findable, A = accessible, I = interoperable and R = re-usable), which are all defined in part at least by the metadata associated with any item. The state of metadata associated with research data is often dire, and often too little resource has been assigned to its improvement. I presented an example of how richer metadata might be injected. The below is a snippet of the metadata associated with one entry in a data repository (download the metadata here and open the file with a text editor). An advantage of doing this is that rich searches against these terms become enabled.
  5. Finally, I note events such as e.g. Harnessing FAIR data are starting to spring up. This one is at Queen Mary University of London on 3rd September 2018, for which “PhDs and Post Docs from a range of disciplines” are welcomed, they of course being the pre-eminent generators of  data and often the ones in charge of making it “FAIR”.

References

  1. M.D. Wilkinson, S. Sansone, E. Schultes, P. Doorn, L.O. Bonino da Silva Santos, and M. Dumontier, "A design framework and exemplar metrics for FAIRness", Scientific Data, vol. 5, 2018. https://doi.org/10.1038/sdata.2018.118
  2. S. Arkhipenko, M.T. Sabatini, A.S. Batsanov, V. Karaluka, T.D. Sheppard, H.S. Rzepa, and A. Whiting, "Mechanistic insights into boron-catalysed direct amidation reactions", Chemical Science, vol. 9, pp. 1058-1072, 2018. https://doi.org/10.1039/c7sc03595k
  3. 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

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Why do flowers such as roses, peonies, dahlias, delphiniums (etc), exhibit so many shades of colours?

Monday, June 18th, 2018

It was about a year ago that I came across a profusion of colour in my local Park. Although colour in fact was the topic that sparked my interest in chemistry many years ago (the fantastic reds produced by diazocoupling reactions), I had never really tracked down the origin of colours in many flowers. It is of course a vast field. Here I take a look at just one class of molecule responsible for many flower colours, anthocyanidin, this being the sugar-free counterpart of the anthocyanins found in nature.

These vary widely in the substituent around the aromatic rings, but here I take a look at just three differing substitutions. Thus pelargonidin has just one OH on ring C (R1‘, R3‘=H, see crystal structure[1]), cyanidin has two (R5‘=H, see crystal structure[2]) and is found in red roses, dahlia, peonies etc. Finally delphinidin (no crystal structure available) has three OHs in that region and is found in yes, delphiniums but also grape skins etc. Below is a colour table that allows one to relate the electronic transitions in a molecule to the observed colour, which of course is due to removal (absorption) of wavelength of light leaving us to see all the remaining wavelengths.
colour table

Next I show the computed UV/visible spectra of these three species (ωB97XD/6-311G(d,p)/SCRF=water)‡. Click on any image to se a 3D model of the molecule.

Note how in the visible region, all have a very simple (monochromatic) single electronic transition comprising mostly the HOMO→LUMO excitation.

Click to view 3D model of the HOMO

Click to view 3D model of the LUMO

Now, λmax can be predicted quite poorly using most DFT methods, but the trends should be better predicted. Thus the change induced by adding two hydroxy groups is ~7nm, which is in effect how the colour seen in a flower can be tuned to display different shades.

Next, pH. Using delphinidin, under basic conditions one can remove a proton from the cationic species to produce a neutral quinone. In fact, any one of five OH groups could have its proton removed and so it is of some interest to compare the relative energies of the five isomers so produced.

Position proton removed Relative ΔG298, kcal/mol
4′ 0.0
5 3.8
7 4.7
3′ 11.8
5′ 22.2

In fact, one species only would have the major Boltzmann population (4′) and so we need only look at its UV/Visible predicted spectrum. This is shifted 17nm towards the red, thus producing a blue colour in what remains after it is absorbed. The absorption (ε) also increases significantly. Indeed the very striking colour of blue delphiniums (one of my favourite flowers) must be produced by such pH control in the plant. Given the presence of delphinidin in many grape skins, the next time I drink a glass of red wine, I will see if it turns blue upon adding some NaOH!

‡FAIR data doi: 10.14469/hpc/4473

References

  1. N. Saito, and K. Ueno, "The Crystal and Molecular Structure of Pelargonindin Bromide Monohydrate", HETEROCYCLES, vol. 23, pp. 2709, 1985. https://doi.org/10.3987/r-1985-10-2709
  2. K. Ueno, and N. Saito, "Cyanidin bromide monohydrate (3,5,7,3',4'-pentahydroxyflavylium bromide monohydrate)", Acta Crystallographica Section B Structural Crystallography and Crystal Chemistry, vol. 33, pp. 114-116, 1977. https://doi.org/10.1107/s0567740877002702

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Multispectral Chiral Imaging with a Metalens.

Saturday, January 6th, 2018

The title here is from an article on metalenses[1] which caught my eye.

Metalenses are planar and optically thin layers which can be manufactured using a single-step lithographic process. This contrasts with traditional lenses that are not flat and where the optical properties result from very accurately engineered curvatures, which in turn are expensive to manufacture. Metalenses can have built into them many interesting optical properties, including light polarisation and dispersion. Nanoengineering has now resulted[1] in a metalens which can simultaneously present two images of opposite helicity of an object within the same field of view.

What is the relevance to chemistry? Well, a well-known chiroptical technique is known as electronic circular dichroism (ECD). At its simplest, it probes the difference in absorption by a chiral molecule of UV and visible light with opposite circular polarisation. This difference plotted as a function of the wavelength of the light is known as the ECD response. Importantly, this response can also be calculated for either enantiomer of the chiral molecule and hence the absolute configuration can be assigned on the basis of which calculated response matches the observed spectrum. Because the difference in response to the two polarisations of the light (Δε) is actually very small, the ECD technique is intrinsically less sensitive than e.g. normal UV/Visible spectra and this requires the use of expensive instruments to record that small difference. Chiral metalenses offer an interesting future opportunity to create new forms of ECD instrument, perhaps ones that are far more sensitive. In turn, this could lower the costs of acquiring ECD functionality in the standard laboratory (see [2] for an application in teaching laboratories). Very possibly, the most expensive component would in fact then be the computational simulations required to match up with the experimental spectrum!

When metalenses were first introduced, they were only able to lens a limited range of wavelengths. In another article by the same group[3] they now announce a new generation of metalens that covers the region 470 to 670 nm. This excludes the UV regions (<300nm) or the IR regions (>1200nm). The latter covers another important chiroptical instrumental technique known as vibrational circular dichroism, or VCD. As with ECD, the VCD response of a chiral molecule can be pretty well calculated using quantum chemistry and indeed often the VCD method is the only one that can successfully be used to assign absolute molecular configurations.[4] Unfortunately, VCD instruments are even more expensive than ECD ones, again largely due to the intrinsic insensitivity and the need to accumulate data using Fourier Transform methods over many hours. Few chemistry departments have such an instrument. So I will keep an eye out for when an effective chiral metalens operating in infra-red regions is announced! The prospect of routine VCD analyses is tantalising! 

 

References

  1. M. Khorasaninejad, W.T. Chen, A.Y. Zhu, J. Oh, R.C. Devlin, D. Rousso, and F. Capasso, "Multispectral Chiral Imaging with a Metalens", Nano Letters, vol. 16, pp. 4595-4600, 2016. https://doi.org/10.1021/acs.nanolett.6b01897
  2. K.K.(. Hii, H.S. Rzepa, and E.H. Smith, "Asymmetric Epoxidation: A Twinned Laboratory and Molecular Modeling Experiment for Upper-Level Organic Chemistry Students", Journal of Chemical Education, vol. 92, pp. 1385-1389, 2015. https://doi.org/10.1021/ed500398e
  3. W.T. Chen, A.Y. Zhu, V. Sanjeev, M. Khorasaninejad, Z. Shi, E. Lee, and F. Capasso, "A broadband achromatic metalens for focusing and imaging in the visible", Nature Nanotechnology, vol. 13, pp. 220-226, 2018. https://doi.org/10.1038/s41565-017-0034-6
  4. J.I. Murray, N.J. Flodén, A. Bauer, N.D. Fessner, D.L. Dunklemann, O. Bob‐Egbe, H.S. Rzepa, T. Bürgi, J. Richardson, and A.C. Spivey, "Kinetic Resolution of 2‐Substituted Indolines by <i>N</i>‐Sulfonylation using an Atropisomeric 4‐DMAP‐<i>N</i>‐oxide Organocatalyst", Angewandte Chemie International Edition, vol. 56, pp. 5760-5764, 2017. https://doi.org/10.1002/anie.201700977

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Conference report: OPEN SCIENCE AND THE CHEMISTRY LAB OF THE FUTURE

Tuesday, May 23rd, 2017

This is taking place in the idyllic surroundings of the Niederwald forest, Rüdesheim, Germany. Here I highlight only aspects of the first three talks.

Martin Hicks introduced the conference with concepts such as the global public good. In the area of open access, he reminded us of the terms Platinum/Diamond open access, which are journals with no article processing charges (which can reach £5000 per article for some other OA journals), but which go with the challenge of ensuring that more gatekeepers of this global public good are needed to avoid being overwhelmed. He ended by asking us all to consider what  the unit of knowledge is that needs to be shared.

The first talk was by Klaus Tochtermann who (amongst other topics) brought to our attention the Dutch GoFAIR initiative  in the European Open Science Cloud, sub-divided into Go-train (i.e. data experts, who will build e.g. metadata tools) and Go-build (eco-systems: Internet of FAIR data and FAIR services). I think the message is that all organisations with chemistry labs should consider this as being an essential part of their future infrastructures.

Jeremy Frey’s title was Reducing Uncertainty: The Raison d’Être for Open Science who defined the fundamental principles of open science as transparency, capability and obtainability and encouraged data publication at source (as opposed to e.g. PhD writing up period) to ensure fidelity in the capture of metadata.

The team of Leah McEwen, Ian Bruno, Stuart Chalk and Richard Kidd told us about Global Data Initiatives and Chemistry and the need for social and technical bridges to enable open data sharing. I learnt for example that the IUPAC Gold book of chemical terms and definitions now has DOIs for each of the terms. Thus chemical shift (DOI: 10.1351/goldbook.C01036[1]), spectroscopy (DOI: 10.1351/goldbook.S05848[2]) and electron density function (DOI: 10.1351/goldbook.ET07024[3]). I will now to associate such links with e.g. deposited NMR data to help increase the semantics of the data (see e.g. DOI: 10.14469/hpc/1975).

Finally, a photo from the region, taken from the gondola adjacent to the venue and riding down to the small town on the banks of the Rhine.

References

  1. "chemical shift", The IUPAC Compendium of Chemical Terminology, 2014. https://doi.org/10.1351/goldbook.c01036
  2. "spectroscopy", The IUPAC Compendium of Chemical Terminology, 2014. https://doi.org/10.1351/goldbook.s05848
  3. "electron density function", The IUPAC Compendium of Chemical Terminology, 2014. https://doi.org/10.1351/goldbook.et07024

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MOLinsight: A web portal for the processing of molecular structures by blind students.

Friday, March 31st, 2017

Occasionally one comes across a web site that manages to combine being unusual, interesting and also useful. Thus www.molinsight.net is I think a unique chemistry resource for blind and visually impaired students.

If you think perhaps that it might be a little too specialised to be useful for you, go visit it first. It does not overwhelm, but contains much valuable information about topics such as open source chemical structure editors, property calculators and stereochemical utilities. Some topics really stand out. For example, Sonification of IR spectra describes the technique for converting an infrared spectrum into non-speech sounds of varying tones. I wonder if they have plans for sonified NMR spectra?

Sonification of visual spectra

The project has been around for a little while and it’s really nice to see it well curated and up to date. In an era where $billions seems to be focused on augmented visual reality as the future means of delivering information, its nice to know that enabling chemistry via other senses is not forgotten.

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George Olah and the norbornyl cation.

Friday, March 10th, 2017

George Olah passed away on March 8th. He was part of the generation of scientists in the post-war 1950s who had access to chemical instrumentation that truly revolutionised chemistry. In particular he showed how the then newly available NMR spectroscopy illuminated structures of cations in solvents such “Magic acid“. The obituaries will probably mention his famous “feud” with H. C. Brown over the structure of the norbornyl cation (X=CH2+), implicated in the mechanism of many a solvolysis reaction that characterised the golden period of physical organic chemistry just before and after WWII. 

The dispute between Olah and Brown was not played on a pitch using quite the same goal posts. Olah did much of his work in magic acid and Brown did his in aqueous solutions. I was involved in a tiny way when the discussion about the precise character of the norbornyl cation was reaching its peak in the mid 1970s. At the time, I was working with Michael Dewar, who was himself not shy in joining in the fun and sometimes very acrimonious disputes at conferences. We contributed by calculating the so-called core-electron carbon ESCA spectrum.[1] History records that we came down on the wrong side,‡ by suggesting that this form of spectroscopy supported Brown rather than Winstein/Olah on the basis of a 6:1 spectral deconvolution (classical) rather than 5:2 (non-classical). More recently of course the crystal structure of the parent cation itself has been shown to be non-classical[2] (there are other crystal structures which differ in respect to having one or more additional methyl groups[3]). For a 3D model of norbornyl cation, see DOI: 10.5517/CCZ21LN. This still leaves the issue (very slightly) open for the structure of the solvated cation when formed in water! 

When I started to teach a course in molecular modelling, I touched briefly on how modelling could contribute and whilst updating the notes in the 1990s, wondered why the boron analogue had never been so studied (X=BH2). Unlike the crystallographically difficult norbornyl ion-pair, the iso-electronic boron species would be neutral and not need a counter-ion. Perhaps it might be a more manageable molecule? Checking the Cambridge structural database, such a species has never been reported!† So here as my homage to Olah, I report its calculated structure (b2plypd3/Def2-TZVPP, DOI: 10.14469/hpc/2236).

The norbornyl cation has symmetrical C-C bridging distances of ~1.80±0.02Å and a basal C-C distance of ~1.39±0.02Å. The calculated values for the boron equivalent are 2.16Å and 1.36Å respectively, with all positive force constants. B-C bonds are normally 1.66-1.72Å, significantly longer than C-C bonds, which makes the longer B-C lengths in this example unsurprising. More interestingly, the species has one vibrational normal mode (ν 203 cm-1) which corresponds to the [1,2] shift of the BH2 group across the basal C-C. For a classical species, this vibrational motion would correspond to a transition state (an imaginary vibration) but for a non-classical species it is of course real. In this sense it is analogous to the so-called real Kekulé mode in non-classical benzene, which “equilibrates” the two classical Kekulé structures. The corresponding calculated vibration for the norbornyl cation itself is ν 194 cm-1 (DOI: 10.14469/hpc/2238).

Of course, the entire controversy over the structure of this species is littered with comparisons between not quite similar systems, differing in a methyl group more or less. So morphing a C+ to a B might be seen as quite a large change. But perhaps if it had been crystallised in say the 1960s, would the subsequent debates have taken a different turn?

‡ We were also wrong about the symmetry of the Diels-Alder cyclisation, which is nowadays accepted to be synchronous rather than asynchronous for simple  Diels-Alder reactions. But that is another story.

†GAXLIA is perhaps the closest analogue.[4],

References

  1. M.J.S. Dewar, R.C. Haddon, A. Komornicki, and H. Rzepa, "Ground states of molecules. 34. MINDO/3 calculations for nonclassical ions", Journal of the American Chemical Society, vol. 99, pp. 377-385, 1977. https://doi.org/10.1021/ja00444a012
  2. F. Scholz, D. Himmel, F.W. Heinemann, P.V.R. Schleyer, K. Meyer, and I. Krossing, "Crystal Structure Determination of the Nonclassical 2-Norbornyl Cation", Science, vol. 341, pp. 62-64, 2013. http://dx.doi.org/10.1126/science.1238849
  3. T. Laube, "Redetermination of the Crystal Structure of the 1,2,4,7‐<i>anti</i>‐tetramethylbicyclo[2.2.1]heptan‐2‐yl cation at 110 K", Helvetica Chimica Acta, vol. 77, pp. 943-956, 1994. https://doi.org/10.1002/hlca.19940770407
  4. P.J. Fagan, E.G. Burns, and J.C. Calabrese, "Synthesis of boroles and their use in low-temperature Diels-Alder reactions with unactivated alkenes", Journal of the American Chemical Society, vol. 110, pp. 2979-2981, 1988. https://doi.org/10.1021/ja00217a053

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Braiding a molecular knot with eight crossings.

Friday, January 20th, 2017

This is one of those posts of a molecule whose very structure is interesting enough to merit a picture and a 3D model. The study[1] reports a molecular knot with the remarkable number of eight crossings.

The DOI for the 3D model is 10.5517/CCDC.CSD.CC1M85Y0 (or click on the image above). Such topology intersects with work we did a few years back on high-order crossings in fully conjugated π-systems[2], which were then illustrated[3] with hypothetical charged higher order annulenes exhibiting linking numbers Lk of up to 6π. A fully π-conjugated system, also with a linking number in the π-framework of 6π but in the form of a trefoil braid was even suggested on this blog, with a common feature of a central templating atom (a cation rather than an anion). Another example of a previously reported pentadecanuclear manganese metallacycle[4] was also assigned a linking number of 6π.

The molecule above is not completely π-conjugated around the braid and so special properties related to aromaticity and associated ring currents resulting from the topology of the cyclic conjugation[5] are not expected to accrue in the eight-crossing molecular braid[1]. We might also look forward to examples of the characterisation of braids with an odd-number of crossings such as trefoils, pentafoils, heptafoils, etc, as associated with the name Möbius.

References

  1. J.J. Danon, A. Krüger, D.A. Leigh, J. Lemonnier, A.J. Stephens, I.J. Vitorica-Yrezabal, and S.L. Woltering, "Braiding a molecular knot with eight crossings", Science, vol. 355, pp. 159-162, 2017. https://doi.org/10.1126/science.aal1619
  2. S.M. Rappaport, and H.S. Rzepa, "Intrinsically Chiral Aromaticity. Rules Incorporating Linking Number, Twist, and Writhe for Higher-Twist Möbius Annulenes", Journal of the American Chemical Society, vol. 130, pp. 7613-7619, 2008. https://doi.org/10.1021/ja710438j
  3. C.S. Wannere, H.S. Rzepa, B.C. Rinderspacher, A. Paul, C.S.M. Allan, H.F. Schaefer, and P.V.R. Schleyer, "The Geometry and Electronic Topology of Higher-Order Charged Möbius Annulenes", The Journal of Physical Chemistry A, vol. 113, pp. 11619-11629, 2009. https://doi.org/10.1021/jp902176a
  4. H.S. Rzepa, "Linking Number Analysis of a Pentadecanuclear Metallamacrocycle: A Möbius-Craig System Revealed", Inorganic Chemistry, vol. 47, pp. 8932-8934, 2008. https://doi.org/10.1021/ic800987f
  5. P.L. Ayers, R.J. Boyd, P. Bultinck, M. Caffarel, R. Carbó-Dorca, M. Causá, J. Cioslowski, J. Contreras-Garcia, D.L. Cooper, P. Coppens, C. Gatti, S. Grabowsky, P. Lazzeretti, P. Macchi, . Martín Pendás, P.L. Popelier, K. Ruedenberg, H. Rzepa, A. Savin, A. Sax, W.E. Schwarz, S. Shahbazian, B. Silvi, M. Solà, and V. Tsirelson, "Six questions on topology in theoretical chemistry", Computational and Theoretical Chemistry, vol. 1053, pp. 2-16, 2015. https://doi.org/10.1016/j.comptc.2014.09.028

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Hydrogen bonding to chloroform.

Monday, November 14th, 2016

Chloroform, often in the deuterated form CDCl3, is a very common solvent for NMR and other types of spectroscopy. Quantum mechanics is increasingly used to calculate such spectra to aid assignment and the solvent is here normally simulated as a continuum rather than by explicit inclusion of one or more chloroform molecules. But what are the features of the hydrogen bonds that form from chloroform to other acceptors? Here I do a quick search for the common characteristics of such interactions.

  1. This first search (R < 0.05, no errors, no disorder) is for interactions from the CH… O, and is a plot of that distance against the angle subtended at the oxygen.

    clcho-rt

    Note that there are not that many crystalline examples. The “hotspot” is at a distance of ~2.3Å, but real examples down to 1.9Å exist. The angle subtended at the oxygen is close to 120° (the angle subtended at the hydrogen is always close to 180°). The plot below constrains the search to data collected below 140K to reduce the thermal noise in the measurements, with the hotspot shortening slightly to 2.2Å. clcho-140

  2. The next search is for interactions to N rather than O (T < 140K). There are rather fewer hits, but again with similar features.clchn-140
  3. Finally, an attempt to see if there is a correlation between the C-H length and the H…O length. ch-vs-co

    This has odd characteristics, which suggests that in most cases the C-H distance is not measured from the diffraction data but simply “idealised” (and which therefore renders this plot meaningless). Unless its been added recently, it is not possible to specify in the search how the hydrogen positions have been refined, if at all and hence to restrict the search only to those structures where the C-H distance is meaningful.

In the last ten years or so, great progress has been made in assigning experimental spectra with the help of quantum calculations. This is true of chemical shifts in NMR, but especially so for chiroptical measurements such as ORP, ECD and VCD. Given that explicit hydrogen bonds can introduce anisotropy into the otherwise isotropic solvent continuum, it might be worth including perhaps one chloroform molecule into these calculations, especially if the  CH…O distance is <2Å (which suggests it is fairly strong). If nothing else, chloroform is rather big and might exert effects based on dispersion attractions or steric repulsions as well as the H-bonding.

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