Posts Tagged ‘Fluorine’

The shortest known CF…HO hydrogen bond.

Sunday, March 24th, 2019

There is a predilection amongst chemists for collecting records; one common theme is the length of particular bonds, either the shortest or the longest. A particularly baffling type of bond is that between the very electronegative F atom and an acid hydrogen atom such as that in OH. Thus short C-N…HO hydrogen bonds are extremely common, as are C-O…HO.‡ But F atoms in C-F bonds are largely thought to be inert to hydrogen bonding, as indicated by the use of fluorine in many pharmaceuticals as inert isosteres.[1] Here I do an up-to-date search of the CSD crystal structure database, which is now on the verge of accumulating 1 million entries, to see if any strong C-F…HO hydrogen bonding may have been recently discovered.

The search query uses the CF…HO distance as one variable, and the C-F-H angle as the second. The first diagram shows just intermolecular interactions, up to a distance of 2.7Å which is the sum of the van der Waals radii of the two elements. The hot spot occurs at this value, and an angle of ~95°.

The intra-molecular plot shows a similar value for the most common F…H distance, with the interesting variation that the angle subtended at F is about 80°. The outlier at the short end of the spectrum (arrow) was observed in 2014[2] with the structure shown below. It is indeed the current record holder by some margin! This length by the way is however a great deal longer than the shortest O…HO hydrogen bonds, which can be in the region of 1.2Å (with the proton sometimes symmetrically disposed between the two oxygen atoms). The value is also very similar to the record holder for the shortest C-H…H-C interaction.

It is always useful to check up on crystallographic hydrogen atom positions using a quantum calculation, so here is one at the ωB97XD/Def2-TZVPP level (Data DOI: 10.14469/hpc/5131) which replicates the values nicely.

ωB97XD/Def2-TZVPP Calculation

A QTAIM analysis of the critical points shows that the F…H BCP has a high value of ρ(r) (most hydrogen bonds only reach about 0.03 au).

NBO analysis indicates the  E(2) perturbation energy for donation from an F lone pair into the H-O σ* orbital is 21.2 kcal/mol, which indicates a strong  H-bond (typical C-O…HO values are 18-22 kcal/mol). The F…H bond order is 0.05.

This molecule has another interesting property, also noted in the original article;[2] the shift in wavenumber of the O-H stretching vibration. Most hydrogen bonds are characterised by the shift (mostly red and recently discovered blue shifts) that occurs in the OH group when it hydrogen bonds. These shifts are typically 100-200 cm-1 but in this molecule there is no shift, which is described as “exceptional”.

The 1H NMR shift of the OH proton is observed at δ 4.8 ppm, with the value calculated here (ωB97XD/Def2-TZVPP) being 4.75 ppm. A very large H-F coupling was observed of 68 Hz, again a very high value for a “through space” hydrogen bond.

So another record for the molecule makers to try to break!

‡Respectively 7142 and 31428 intermolecular (3859 and 10602 intra) examples using the same search parameters as above, with the shortest values being ~1.28 and ~1.2Å.

References

  1. S. Purser, P.R. Moore, S. Swallow, and V. Gouverneur, "Fluorine in medicinal chemistry", Chem. Soc. Rev., vol. 37, pp. 320-330, 2008. https://doi.org/10.1039/b610213c
  2. M.D. Struble, C. Kelly, M.A. Siegler, and T. Lectka, "Search for a Strong, Virtually “No‐Shift” Hydrogen Bond: A Cage Molecule with an Exceptional OH⋅⋅⋅F Interaction", Angewandte Chemie International Edition, vol. 53, pp. 8924-8928, 2014. https://doi.org/10.1002/anie.201403599

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Concerted Nucleophilic Aromatic Substitution Mediated by the PhenoFluor Reagent.

Thursday, September 20th, 2018

Recently, the 100th anniversary of the birth of the famous chemist Derek Barton was celebrated with a symposium. One of the many wonderful talks presented was by Tobias Ritter and entitled “Late-stage fluorination for PET imaging” and this resonated for me. The challenge is how to produce C-F bonds under mild conditions quickly so that 18F-labelled substrates can be injected for the PET imaging. Ritter has several recent articles on this theme which you should read.[1],[2]. 

The resonance was that back in 1999 I had been collaborating with colleagues to study the mechanism of rapid fluoridation using R2IF reagents.[3]. This article, by the way, contains a very early example of the use of FAIR data (see here).‡ A further resonance is that Ritter computes that the displacement of an aryl-O bond by a nucleophilic fluorine is a concerted process, unlike the stepwise Meisenheimer like complexes normally occurring in nucleophilic aromatic substitutions. A few years back I explored the possibility of concerted nucleophilic substitutions, finding that F in particular was very prone to such behaviour. So it is nice to see Ritter’s real-world example of such a mechanism and indeed that his reagents (PhenoFluor) represent a significant improvement on the R2IF ones we had been exploring.

To celebrate this new chemistry, I include some results of my own which augment Ritter’s. Firstly I should start with the structure of the reagent, which contains a carbon surrounded by four heteroatoms. There are few such motifs known.♥ Thus a carbon attached to two N, one F and one O has no reported crystal structures. Relaxing the criterion to two N, one F and one other offers 71 examples, of which the most interesting are the outliers with C-F distances > 1.4Å. 

The one with the value 1.5Å (DOI: 10.5517/ccdc.csd.cc1njjg5) is probably an error, as is the one at 1.45Å[4]. So it was a surprise to find that the calculated structure of PhenoFluor (R=2,6-di-isopropyl, B3LYP+D3BJ/Def2-TZVPPD/SCRF=toluene) had a C-F distance of 1.456Å which is surely a candidate for the longest known C(sp3)-F bond.† The computed Wiberg C-F bond order is 0.687, which is well reduced from a single bond order. This is probably due to strong anomeric effects from both nitrogens and the one oxygen, which “gang up” on the fluorine to weaken its bond and expel it as a nascent fluoride anion. Thus the E(2) NBO interaction energy is 25.1 kcal/mol for the N(Lp)-CFσ* interaction, which is unusually large, whereas the N(Lp)-COσ* interaction is only 9.2 kcal/mol.

The fluoridation is indeed computed as a concerted process, the IRC animation being shown below. Note that the trajectory of the F is initially away from the carbon but not towards the aryl group. Here it is simply forming a “hidden” fluoride anion intermediate. The trajectory then changes direction to attack the ipso-carbon. So it is a concerted but two-stage reaction path.

The IRC energy profile corresponds to a free energy barrier of 23 kcal/mol, as reported by Ritter. 

Here is a less well used property along the reaction path, the dipole moment response. This shows a very abrupt charge separation in the region of the transition state and its collapse shortly after which suggests that the reaction barrier might be sensitive to the polarity of the solvent.

The issue then arises as to how much aromatic resonance is lost at the transition state. A NICS(1) aromaticity probe placed 1Å above the centroid of the aryl ring has the value -9.3 ppm, close to the value of ~ -10ppm for benzene itself. So this relatively facile reaction is in part due to significant preservation of the aryl stabilisations by aromatic resonance.

To close, the Phenofluor reagent is commercially available as a 0.1M solution in toluene, which makes one wonder if it is possible to obtain crystals. It might be of course that when the solution is concentrated, it reverts to the iminium fluoride ion pair shown above. But if crystals are possible, then it would be interesting to verify that the C-F bond in this species is indeed unusually long, perhaps even a record holder?

‡The data represent an early use of the Chime plugin to present a visual 3D model. I really should re-work that page to allow use of eg JSmol, enabled here on this blog.

♥Excepting CF3X motifs.

†FAIR data for the results reported here can be found at DOI: 10.14469/hpc/4713

References

  1. P. Tang, W. Wang, and T. Ritter, "Deoxyfluorination of Phenols", Journal of the American Chemical Society, vol. 133, pp. 11482-11484, 2011. https://doi.org/10.1021/ja2048072
  2. C.N. Neumann, and T. Ritter, "Facile C–F Bond Formation through a Concerted Nucleophilic Aromatic Substitution Mediated by the PhenoFluor Reagent", Accounts of Chemical Research, vol. 50, pp. 2822-2833, 2017. https://doi.org/10.1021/acs.accounts.7b00413
  3. M.A. Carroll, S. Martín-Santamaría, V.W. Pike, H.S. Rzepa, and D.A. Widdowson, "An ab initio and MNDO-d SCF-MO computational study of stereoelectronic control in extrusion reactions of R2I–F iodine(III) intermediates†", Journal of the Chemical Society, Perkin Transactions 2, pp. 2707-2714, 1999. https://doi.org/10.1039/a906212b
  4. T.N. Bhat, and H.L. Ammon, "Structure of N,N,N'N'-tetrakis(2-fluoro-2,2-dinitroethyl)oxamide by the consistent electron density approach", Acta Crystallographica Section C Crystal Structure Communications, vol. 46, pp. 112-116, 1990. https://doi.org/10.1107/s0108270189005044

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Quintuple bonds: part 2

Saturday, February 20th, 2010

In the previous post, I ruminated about how chemists set themselves targets. Thus, having settled on describing regions between two (and sometimes three) atoms as bonds, they added a property of that bond called its order. The race was then on to find molecules which exhibit the highest order between any particular pair of atoms. The record is thus far five (six has been mooted but its a little less certain) for the molecule below

A molecule with a Quintuple-bond

There are many ways of describing the electronic behaviour in that region called a bond, one being the ELF (Electron localization function) technique, which certainly sounds as if it is describing a bond! The ELF function for the molecule above however was distinctly odd, and this was attributed to the Cr-Cr bond being not so much a covalent bond, but another (much less recognized type) known as a charge-shift bond. In particular, two of the ELF basin centroids did not occupy the central region between the two atoms, but had in effect fled that region, and in the process had also each split into two. Other ELF basins did not much look like bonds, but retained much of their core-electron (i.e. non bonding) character. The issue now becomes whether the ELF method is sensible, or simply an artefact. In other words, it needs calibrating against other (homonuclear) molecules which might exhibit charge-shift behaviour.

Three such molecules are in fact the halogens, F2, Cl2, Br2 as discussed by Shaik, Hiberty and co (DOI: 10.1002/chem.200500265). So lets take a look at what an ELF analysis shows for these, and how it compares with the chromium quintuple bond.

ELF analysis for F2

ELF analysis for Cl2

ELF analysis for Br2

At the B3LYP/6-311G(d) level, the ELF function shows the (valence) electrons located in two regions. Firstly, what we might call the lone pairs are located in a torus surrounding each halogen atom (i.e. the molecule must be axially symmetric). The remaining electrons are in basins with centroids along the axis of each bond. The Br2 centroid is a single conventional disynaptic basin, with an integration of 0.77 electrons. With Cl2 however, something odd happens (and the effect was described in DOI: 10.1002/chem.200500265 ); the disynaptic basin splits into a close pair, each integrating to 0.33 electrons, and looking as if the two parts want to run away from one another. This was interpreted as indicating that the purely covalent description of the halogen bond is in fact repulsive and not attractive! The effect is enhanced for F2, with two very much split basins, each integrating to 0.08 electrons. This serves to remind us of how odd a bond the F-F one truly is (and how easily it is homolyzed)!

Now that we have our calibration, does it match to the Cr-Cr quintuple bond? Very much so! Again, the valence basins show very low integrations (compared to the nominal bond order), and again they appear to have split and run away from each other. Most of the valence electrons in that species prefer instead to masquerade as core-electrons. So we can conclude that by the ELF criterion, the Cr-Cr bond is not quintuple, and not covalent but charge shifted. Of course, this does seem at odds with the Cr-Cr internuclear distance, which is indeed very short! This shortening probably arises from electrostatic attractions in the charge-shifted valence bond forms. It simply goes to show that what the nuclei get up to and what the electrons do may not be one and the same thing!

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