Posts Tagged ‘Natural sciences’

An Ambimodal Trispericyclic Transition State: the effect of solvation?

Thursday, May 2nd, 2019

Ken Houk’s group has recently published this study of cycloaddition reactions, using a combination of classical transition state location followed by molecular dynamics trajectory calculations,[1] and to which Steve Bachrach’s blog alerted me. The reaction struck me as being quite polar (with cyano groups) and so I took a look at the article to see what both the original[2] experimental conditions were and how the new simulations compared. The reaction itself is shown below.


Turns out that chloroform was used as solvent (also benzene), whilst the transition state calculations and the subsequent molecular dynamics trajectories were modelled for the gas phase. The key observation is that if TS1 is used as the starting point for trajectory calculations, only 87% lead to the product predicted by classical transition state theory (3), as revealed by a classical intrinsic reaction coordinate (IRC) calculation. The remaining 13% lead to 4 and 5, the ambimodal effect. So here, I want to explore what effect including a continuum solvent on the computation of TS1 and its IRC might have on the classical (non-dynamic) model.

Firstly, the model for TS1 as reported[3], ωB97XD/6-31G(d) (FAIR data at DOI: 10.14469/hpc/5590). The basis set is modest by today’s standards, but is largely imposed by the need to use it for very large numbers of trajectory calculations. I was able to copy/paste the coordinates from the reported supporting information and then to replicate the IRC at this level (gas phase), also shown in the SI.

There is a feature in this IRC I want to expand upon (red arrow above). It occurs at an IRC value of ~-0.9 on the axis below.

It can be seen more clearly if the RMS gradient norm is plotted, the value of which drops to almost zero at IRC -0.9. Had it reached exactly 0.0, we would have had an intermediate formed. As it is we have what is called a hidden intermediate. The origins of this intermediate can be more readily inferred from this dipole moment plot along the IRC. At TS1, the dipole moment is > 10D. A rule of thumb I have often used is that if a TS has a DM > 10, then one cannot ignore solvation any more and a gas phase model must be augmented.

Here are the same plots, but now with an added solvent field for water, an extreme polarity.

The IRC now stops at -2, being a high energy true (ionic) intermediate (rather than a hidden one). The IRC stops because gradient norm has now reached 0.0 at IRC -2, again an indication of a true intermediate.

The dipole moment has been increased from 10 in the gas phase to around 15 at TS1 and it continues to increase until the ionic intermediate is reached. These differences from the gas phase plots are induced entirely by applying a continuum solvent model.

Next an intermediate solvent, chloroform, being one of the solvents used for the actual reaction. This time the gradient norm almost reaches a value of 0.0, avoiding it only by a whisker! A barely hidden intermediate.

The dipole moment totters around 13.5D, before finally collapsing as the ionic intermediate itself collapses to a neutral molecule again. Benzene as solvent (not shown here) reaches an intermediate dipole moment of about 12D. It too can stabilize an ionic intermediate noticeably even though it is not ionic itself.

I want to also briefly explore what effect if any the use of a relatively small basis set (6-31G(d)) has on the shape of the IRC. Below is a repeat of the gas phase IRC using the Def2-TZVPP basis, which is about twice the size of the smaller one (and hence is around 16 times slower to compute). The gradient norm shows that the “hidden intermediate” region around IRC -1 is a little more prominent (flatter).

So we see that both a solvent model (as a continuum field) and a larger basis set can increase the degree of “hidden intermediate” character in the classical reaction coordinate for this cycloaddition reaction, to the extent that if water is used as model solvent an actual discrete albeit shallow ionic intermediate forms. As Houk puts it, solvation induces a conversion from an entropic intermediate to an enthalpic one.[4] Molecular dynamics trajectories however have a propensity for not settling into quite shallow intermediates (those with escape barriers of < 3 kcal/mol, as would be the case here).

It will indeed be interesting to see the extent, if any, that either of the augmented models shown above affect the calculated distribution of molecular dynamics trajectories compared to those obtained using a gas phase model.

References

  1. X. Xue, C.S. Jamieson, M. Garcia-Borràs, X. Dong, Z. Yang, and K.N. Houk, "Ambimodal Trispericyclic Transition State and Dynamic Control of Periselectivity", Journal of the American Chemical Society, vol. 141, pp. 1217-1221, 2019. https://doi.org/10.1021/jacs.8b12674
  2. C.Y. Liu, and S.T. Ding, "Cycloadditions of electron-deficient 8,8-disubstituted heptafulvenes to electron-rich 6,6-disubstituted fulvenes", The Journal of Organic Chemistry, vol. 57, pp. 4539-4544, 1992. https://doi.org/10.1021/jo00042a039
  3. https://doi.org/
  4. O.M. Gonzalez-James, E.E. Kwan, and D.A. Singleton, "Entropic Intermediates and Hidden Rate-Limiting Steps in Seemingly Concerted Cycloadditions. Observation, Prediction, and Origin of an Isotope Effect on Recrossing", Journal of the American Chemical Society, vol. 134, pp. 1914-1917, 2012. https://doi.org/10.1021/ja208779k

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Imaging normal vibrational modes of a single molecule of CoTPP: a mystery about the nature of the imaged species.

Thursday, April 25th, 2019

Previously, I explored (computationally) the normal vibrational modes of Co(II)-tetraphenylporphyrin (CoTPP) as a “flattened” species on copper or gold surfaces for comparison with those recently imaged[1]. The initial intent was to estimate the “flattening” energy. There are six electronic possibilities for this molecule on a metal surface. Respectively positively, or negatively charged and a neutral species, each in either a low or a high-spin electronic state. I reported five of these earlier, finding each had quite high barriers for “flattening” the molecule. For the final 6th possibility, the triplet anion, the SCF (self-consistent-field) had failed to converge, but for which I can now report converged results.†

charge

Spin

Multiplicity

 ΔG, Twisted Ph,
Hartree		 ΔG, “flattened”,
Hartree

ΔΔG,

kcal/mol
-1 Triplet -3294.68134 (C2) -3294.64735 (C2v) 21.3
-3294.60006 (Cs) 51.0
-3294.37012 (D2h) 195.3
Singlet -3294.67713 (S4) -3294.39418 (D4h) 175.6
-3294.39321 (D2h) 178.2
-3294.56652 (D2) 69.4
FAIR data at DOI: 10.14469/hpc/5486

I am exploring the so-called “flattened” mode, induced by the voltage applied at the tip of the STM (scanning-tunnelling microscope) probe and which causes the phenyl rings to rotate as per above. This rotation in turn causes the hydrogen atom-pair encircled above to approach each other very closely.‡ To avoid these repulsions, the molecule buckles into one of two modes. The first causes the phenyl rings to stack up/down/up/down. The second involves an all-up stacking, as shown below. Although these are in fact 4th-order saddle points as isolated molecules, the STM voltage can inject sufficient energy to convert these into apparently stable minima on the metal surface.

All syn mode, Triplet anion

The up/down/up/down “flattened” form (below) shows a much more modest planarisation energy than all the other charged/neutral states reported in the previous post, whereas the all-up isomer (which on the face of it looks a far easier proposition to come into close contact with a metal surface) is far higher in free energy.

The caption to Figure 3 in the original article[1] does not explicitly mention the nature of the metal surface on which the vibrations were recorded, but we do get “The intensity in the upper right corner of the 320-cm−1 map is from a neighbouring Cu–CO stretch” which suggests it is in fact a copper surface. Coupled with the other observation that 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),” the model below of a triplet-state anion on the Cu surface seems the most appropriate.

Syn/anti mode, Triplet anion with C2v symmetry

There is one final remark made in the article worth repeating here: “This suggests that the vibronic functions are complex-valued in this state, as expected for Jahn–Teller active degenerate orbitals of the planar porphyrin.26” Orbital degeneracy can only occur if the molecule has e.g. D4h point group symmetry, whereas the triplet anion stationary-point shown in the figure above has only C2v symmetry for which no orbital degeneracies (E) are expected. Enforcing D4h symmetry on Co(II) tetraphenylporphyrin results in eight pairs of H…H contacts of 1.34Å,‡ which is an impossibly short distance (the shortest known is ~1.5Å). Moreover this geometry has an equally impossible free energy 176 kcal/mol above the relaxed free molecule. Visually from Figure 3, the H…H contact distance looks even shorter (below, circled in red)! A D2h form (with no E-type orbitals) can also be located.

Singlet, Calculated with D4h symmetry. Click for vibrations.

Singlet, Calculated with D2h symmetry. Click for vibrations.

Taken from Figure 3 (Ref 1).

These totally flat species are calculated to be at 13 or 12th-order saddle points, with the eight most negative force constants having vectors which correspond to up/down avoidance motions of the proximate hydrogen pairs encircled above and the remaining being buckling modes of the entire ring.

So to the mystery, being the nature of the “flattened” CoTPP on the copper metal surface, as represented in Figure 3 of the article.[1] Is it truly flat, as implied by the article? If so, the energy of such a species would be beyond the limits of what is normally considered feasible. Moreover, it would represent a species with truly mind-blowing short H…H contacts. Or could it be a saddle-shaped geometry, where the phenyl rings are not lying flat in contact with the metal but interacting via the phenyl para-hydrogens? That geometry has not only a much more reasonable energy above the unflattened free molecule, but also acceptable H…H contacts (~2.0.Å) However, would such a shape correspond to the visualised vibrational modes also shown in Figure 3? I have a feeling that there must be more to this story.

†These convergence problems were solved by improving the basis set via adding “diffuse” functions, as in (u)ωB97XD/6-311+G(d,p). ‡If the crystal structure for these species is flattened without geometry optimisation, the H-H distance is around 0.8Å

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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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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Smoke and mirrors. All is not what it seems with this Sn2 reaction!

Thursday, April 4th, 2019

Previously, I explored the Graham reaction to form a diazirine. The second phase of the reaction involved an Sn2′ displacement of N-Cl forming C-Cl. Here I ask how facile the simpler displacement of C-Cl by another chlorine might be and whether the mechanism is Sn2 or the alternative Sn1. The reason for posing this question is that as an Sn1 reaction, simply ionizing off the chlorine to form a diazacyclopropenium cation might be a very easy process. Why? Because the resulting cation is analogous to the cyclopropenium cation, famously proposed by Breslow as the first example of a 4n+2 aromatic ring for which the value of n is zero and not 1 as for benzene.[1] Another example of a famous “Sn1” reaction is the solvolysis of t-butyl chloride to form the very stable tertiary carbocation and chloride anion (except in fact that it is not an Sn1 reaction but an Sn2 one!)

Here is the located transition state for the above, using Na+.6H2O as the counter-ion to the chloride. The calculated free energy of this transition state is 3.2 kcal/mol lower than the previous Sn2′ version (FAIR data collection, 10.14469/hpc/5045), with an overall barrier to reaction of 26.5 kcal/mol. This compares to ~24.5 kcal/mol obtained by Breslow for solvolysis of the cyclopropenyl tosylate. Given the relatively simple solvation model I used in the calculation (only six waters to solvate all the ions, and a continuum solvent field for water), the agreement is not too bad.

The animation above is of a normal vibrational mode known as the transition mode (click on the image above to get a 3D rotatable animated model). The calculated vectors for this mode (its energy being an eigenvalue of the force constant matrix) are regularly used to “characterise” a transition state. I will digress with a quick bit of history here, starting in 1972 when another famous article appeared.[2] The key aspect of this study was the derivation of the first derivatives of the energy of a molecule with respect to the (3N) geometrical coordinates of the atoms, using a relatively simply quantum mechanical method (MINDO/2) to obtain that energy. Analytical first derivatives of the MINDO/2 Hamiltonian were then used to both locate the transition state for a simple reaction and then to evaluate the second derivatives (the force constant matrix) using a finite difference method. That force constant matrix, when diagonalized, reveals one negative root (eigenvalue) which is characteristic of a transition state. The vectors reveal how the atoms displace along the vibration, and should of course approximate to the path to either reactant or product.

Since that time, it has been a more or less mandatory requirement for any study reporting transition state models to characterise them using the vectors of the negative eigenvalue. The eigenvalue invariably expressed as a wavenumber. Because this comes from the square root of the mass-weighted negative force constant, it is often called the imaginary mode. Thus in this example, 115i cm-1, the i indicating it is an imaginary number. The vectors are derived from quadratic force constants, which is a parabolic potential surface for the molecule. Since most potential surfaces are not quadratic, it is recognized as an approximation, but nonetheless good enough to serve to characterise the transition state as the one connecting the assumed reactant and product. Thousands of published studies in the literature have used this approach.

So now to the animation above. If you look closely you will see that it is a nitrogen and not a carbon that is oscillating between two chlorines (here it is the lighter atoms that move most). The vectors confirm that, with a large one at N and only a small one at C. So it is Sn2 displacement at nitrogen that we have located? 

Not so fast. This is a reminder that we have to explore a larger region of the potential energy surface, beyond the quadratic region of the transition state from which the vectors above are derived. This is done using an IRC (intrinsic reaction coordinate). Here it is, and you see something remarkable.

The Cl…N…Cl motions seen above in the transition state mode change very strongly in regions away from the transition state. On one side of the transition state, it forms a Cl…C bond, on the other side a Cl…N.

It is also reasonable to ask why the paths either side of the transition state are not the same? That may be because with only six explicit water molecules, three of which solvate the sodium ion, there are not enough to solvate equally the chloride anions either side of the transition state. As a result one chlorine does not behave in quite the same way as the other. The addition of an extra water molecule or two may well change the resulting reaction coordinate significantly.

The overall message is that there are two ways to characterise a computed reaction path. One involves looking at the motions of all the atoms just in the narrow region of the transition state. Most reported literature studies do only this. When the full path is explored with an IRC, a different picture can emerge, as here. The Cl…N…Cl Sn2 mode is replaced by a Cl…C/N…Cl mode. This example however is probably rare, with most reactions the transition state vibration and the IRC do actually agree!

References

  1. R. Breslow, "SYNTHESIS OF THE s-TRIPHENYLCYCLOPROPENYL CATION", Journal of the American Chemical Society, vol. 79, pp. 5318-5318, 1957. https://doi.org/10.1021/ja01576a067
  2. J.W. McIver, and A. Komornicki, "Structure of transition states in organic reactions. General theory and an application to the cyclobutene-butadiene isomerization using a semiempirical molecular orbital method", Journal of the American Chemical Society, vol. 94, pp. 2625-2633, 1972. https://doi.org/10.1021/ja00763a011

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Impossible molecules.

Monday, April 1st, 2019

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

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

17 18 19

 
328[3] 348 713

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

The procedure is as follows

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

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

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

References

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

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The 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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The Graham reaction: Deciding upon a reasonable mechanism and curly arrow representation.

Monday, February 18th, 2019

Students learning organic chemistry are often asked in examinations and tutorials to devise the mechanisms (as represented by curly arrows) for the core corpus of important reactions, with the purpose of learning skills that allow them to go on to improvise mechanisms for new reactions. A common question asked by students is how should such mechanisms be presented in an exam in order to gain full credit? Alternatively, is there a single correct mechanism for any given reaction? To which the lecturer or tutor will often respond that any reasonable mechanism will receive such credit. The implication is that a mechanism is “reasonable” if it “follows the rules”. The rules are rarely declared fully, but seem to be part of the absorbed but often mysterious skill acquired in learning the subject. These rules also include those governing how the curly arrows should be drawn.† Here I explore this topic using the Graham reaction.[1]‡

I start by noting the year in which the Graham procedure was published, 1965. Although the routine representation of mechanism using curly arrows had been established for about 5-10 years by then, the quality of such representations in many articles was patchy. Thus, this one (the publisher will need payment for me to reproduce the diagram here, so I leave you to get it yourself) needs some modern tidying up. In the scheme below, I have also made a small change, using water itself as a base to remove a NH proton, rather than hydroxide anion as used in the article (I will return to the anion later). The immediate reason is that water is a much simpler molecule to use at the start of our investigation than solvated sodium hydroxide. You might want to start with comparing the mechanism above with the literature version[1] to discover any differences. 

The next stage is to compute all of this using quantum mechanics, which will tell us about the energy of the system as it evolves and also identify the free energy of the transition states for the reaction. I am not going to go into any detail of how these energies are obtained, suffice to say that all the calculations can be found at the following DOI: 10.14469/hpc/5045 The results of this exercise are represented by the following alternative mechanism.♥

How was this new scheme obtained? The key step is locating a transition state in the energy surface, a point where the first derivatives of the energy with respect to all the 3N-6 coordinates defining the geometry (the derivative vector) are zero and where the second derivative matrix has just one negative eigenvalue (check up on your Maths for what these terms mean). Each located transition state (which is an energy maximum in just one of the 3N-6 coordinates) can be followed downhill in energy to two energy minima, one of which is declared the reactant of the reaction and the other the product, using a process known as an IRC (intrinsic reaction coordinate). The coordinates of these minima are then inspected so they can be mapped to the conventional representations shown above. New bonds in the formalism above are shown with dashed lines and have an arrow-head ending at their mid-point; breaking bonds (more generally, bonds reducing their bond order) have an arrow starting from their mid-point. The change in geometry along the IRC for TS1 can then be shown as an animation of the reaction coordinate, which you can see below.

Don’t worry too much about when bonds appear to connect or disconnect, the animation program simply uses a simple bond length rule to do this. The major difference with the original mechanism is that it is the chlorine on the nitrogen also bearing a proton that gets removed. Also, the N-N bond is formed as part of the same concerted process, rather than as a separate step.

Shown above is the computed energy along the reaction path. Here a “reality check” can be carried out. The activation free energy (the difference between the transition state and the reactant) emerges as a rather unsavoury ΔG‡=40.8 kcal/mol. Why is this unsavoury? Well, according to transition state theory, the rate of a (unimolecular) reaction is given by the expression: Ln(k/T) = 23.76 – ΔG‡/RT where T is temperature (~323K in this example), R = is the gas constant and k is the unimolecular rate constant. When you solve it for ΔG‡=40.8, it turns out to be a very slow reaction indeed. More typically, a reaction that occurs in a few minutes at this sort of temperature has ΔG‡= ~15 kcal/mol. So this turns out to be an “unreasonable” mechanism, but based on the quantum mechanically predicted rate and not on the nature of the “curly arrows”. And no, one cannot do this sort of thing in an examination (not even on a mobile phone; there is no app for it, yet!) I must also mention that the “curly arrows” used in the above representation are, like the bonds, based on simple rules of connecting a breaking with a forming bond with such an arrow. There IS a method of computing both their number and their coordinates “realistically”, but I will defer this to a future post. So be patient!

The next thing to note is that the energy plot shows this stage of the reaction as being endothermic. Time to locate TS2, which it turns out corresponds to the N to C migration of the chlorine to complete the Graham reaction. As it happens, TS2 is computed to be 10.6 kcal/mol lower than TS1 in free energy, so it is not “rate limiting”.

To provide insight into the properties of this reaction path, a plot of the calculated dipole moment along the reaction path is shown. At the transition state (IRC value = 0), the dipole moment is a maximum, which suggests it is trying to form an ion-pair, part of which is the diazacylopropenium cation shown in the first scheme above. The ion-pair is however not fully formed, probably because it is not solvated properly.

We can add the two reaction paths together to get the overall reaction energy, which is no longer endothermic but approximately thermoneutral. Things are still not quite “reasonable” because the actual reaction is exothermic.

Time then to move on to hydroxide anion as the catalytic base, in the form of sodium hydroxide. To do this, we need to include lots of water molecules (here six), primarily to solvate the Na+ (shown in purple below) but also any liberated Cl–. You can see the water molecules moving around a lot as the reaction proceeds, via again TS1 to end at a similar point as before.

The energy plot is now rather different. The activation energy is now lower than the 15 kcal/mol requirement for a fast reaction; in fact ΔG‡= 9.5 kcal/mol and overall it is already showing exothermicity. What a difference replacing a proton (from water) by a sodium cation makes!

Take a look also at this dipole moment plot as the reaction proceeds! TS1 is almost entirely non-ionic!

To complete the reaction, the chlorines have to rearrange. This time a rather different mode is adopted, as shown below, termed an Sn2′ reaction. The energy of TS2′ is again lower than TS1, by 9.2 kcal/mol. Again no explicit diazacylopropenium cation-anion pair (an aromatic 4n+2, n=0 Hückel system) is formed.



Combing both stages of the reaction as before. The discontinuity in the centre is due to further solvent reorganisation not picked up at the ends of the two individual IRCs which were joined to make this plot. Note also that the reaction is now appropriately exothermic overall.

So what have we learnt?

  1. That a “reasonable” mechanism as shown in a journal article, and perhaps reproduced in a text-book, lecture or tutorial notes or even an examination, can be subjected in a non-arbitrary manner to a reality check using modern quantum mechanical calculations.
  2. For the Graham reaction, this results in a somewhat different pathway for the reaction compared to the original suggestion.
    1. In particular, the removal of chlorine occurs from the same nitrogen as the initial deprotonation
    2. This process does not result in an intermediate nitrene being formed, rather the chlorine removal is concerted with N-N bond formation.
    3. The resulting 1-chloro-1H-diazirine does not directly ionize to form a diazacyclopropenium cation-chloride anion ion pair, but instead can undertake an Sn2′ reaction to form the final 3-chloro-3-methyl-3H-diazirine.
  3. A simple change in the conditions, such as replacing water as a catalytic agent with Na+OH–(5H2O) can have a large impact on the energetics and indeed pathways involved. In this case, the reaction is conducted in NaOCl or NaOBr solutions, for which the pH is ~13.5,♣ indicating [OH–] is ~0.3M.
  4. The curly arrows here are “reasonable” for the computed pathway, but are determined by some simple formalisms which I have adopted (such as terminating an arrow-head at the mid-point of a newly forming bond). As I hinted above, these curly arrows can also be subjected to quantum mechanical scrutiny and I hope to illustrate this process in a future post.

But do not think I am suggesting here that this is the “correct” mechanism, it is merely one mechanism for which the relative energies of the various postulated species involved have been calculated relatively accurately. It does not preclude that other, perhaps different, routes could be identified in the future where the energetics of the process are even lower. 

†This blog is inspired by the two students who recently asked such questions. ‡In fact, you also have to acquire this completely unrelated article[2] for reasons I leave you to discover yourself. ♥You might want to consider the merits or demerits of an alternative way of showing the curly arrows. Is this representation “more reasonable”? ♣I thank Ed Smith for measuring this value for NaOBr and for suggesting the Graham reaction in the first place as an interesting one to model.

References

  1. W.H. Graham, "The Halogenation of Amidines. I. Synthesis of 3-Halo- and Other Negatively Substituted Diazirines<sup>1</sup>", Journal of the American Chemical Society, vol. 87, pp. 4396-4397, 1965. https://doi.org/10.1021/ja00947a040
  2. E.W. Abel, B.C. Crosse, and D.B. Brady, "Trimeric Alkylthiotricarbonyls of Manganese and Rhenium", Journal of the American Chemical Society, vol. 87, pp. 4397-4398, 1965. https://doi.org/10.1021/ja00947a041

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Free energy relationships and their linearity: a test example.

Sunday, January 13th, 2019

Linear free energy relationships (LFER) are associated with the dawn of physical organic chemistry in the late 1930s and its objectives in understanding chemical reactivity as measured by reaction rates and equilibria.

The Hammett equation is the best known of the LFERs, albeit derived “intuitively”. It is normally applied to the kinetics of aromatic electrophilic substitution reactions and is expressed as;

log KR/K0 = σRρ (for equilibria) and extended to log kR/k0 = σRρ for rates.

The equilibrium constants are normally derived from the ionisation of substituted benzoic acids, with K0 being that for benzoic acid itself and KR that of a substituted benzoic acid, with σR being known as the substituent constant and ρ the reaction constant. The concept involved obtaining the substituent constants by measuring the ionisation equilibria. The value of σR is then assumed to be transferable to the rates of reaction, where the values can be used to obtain reaction constants for a given reaction. The latter would then be assumed to give insight into the electronic nature of the transition state for that reaction.

The term log kR/k0 (the ratio of rates of reaction) can be related to ΔΔG = -RT ln kR/k0 and this latter quantity can be readily obtained from quantum calculations, where ΔΔG is the difference in computed reaction activation free energies for two substituents (of which one might be R=H). The most interesting such Hammett plots are the ones where a discontinuity becomes apparent. The plot comprises two separate linear relationships, but with different slopes. This is normally taken to indicate a change of mechanism, on the assumption that the two mechanisms will have different responses to substituents. 

A test of this is available via the calculated activations energies for acid catalyzed cyclocondensation to give furanochromanes[1] which is a two-step reaction involving two transition states TS1 and TS2, either of which could be rate determining. A change from one to the other would constitute a change in mechanism. In this example, TS1 involves creation of a carbocationic centre which can be stabilized by the substituent on the Ar group; TS2 involves the quenching of the carbocation by a nucleophilic oxygen and hence might be expected to respond differently to the substituents on Ar. As it happens, the reaction coordinate for TS2 is not entirely trivial, since it also includes an accompanying proton transfer which might perturb the mechanism.

Fortunately for this reaction we have available full FAIR data (DOI: 10.14469/hpc/3943), which includes not only the computed free energies for both sets of transition states but also the entropy-free enthalpies for comparison. This allows the table below to be generated. For each substituent, the highest energy point is in bold, indicating the rate limiting step. The span of substituents corresponds to a range of rate constants of almost 1010, which in fact is rarely if ever achievable experimentally.

Highest free energy overall route for HCl catalysed mechanism,

trans stereochemistry
Sub ΔH‡/ΔG‡ Reactant ΔH‡/ΔG‡, TS1 ΔH‡/ΔG‡, TS2 RDS
p-NH2 0.2/6.36 0.0/0.0 0.15/4.0 0.2/6.4 TS2/TS2
p-OMe 2.7/8.48 0.0/0.0 2.7/8.45 2.1/8.48 TS1/TS2
p-Me 5.5/10.00 0.0/0.0 5.5/9.9 3.9/10.00 TS1/TS2
p-Cl 7.7/12.28 0.0/0.0 7.7/12.28 5.9/11.84 TS1/TS1
p-H 7.6/13.01 0.0/0.0 7.6/13.01 5.5/11.51 TS1/TS1
p-CN 10.6/18.02 0.0/0.0 10.6 /17.61 10.5/18.02 TS1/TS2
p-NO2 12.4/19.85 0.0/0.0 12.4/18.24 12.0/19.85 TS1/TS2

For the free energies, you can see that TS2 is the rate limiting step for the first two electron donating substituents, and the last two electron withdrawing ones, whilst TS1 represents the rate limiting step for the middle substituents. This represents two changes of rate limiting step over the entire range of substituents. A different picture emerges if only the enthalpies are used. Now TS1 is rate limiting for essentially all the substituents. The difference of course arises because of significant changes to the entropy of the transition states. The Hammett equation, and its use of  σR constants to try to infer the electronic response of a reaction mechanism, does not really factor in entropic responses. Nor is it often if at all applied using a really wide range of substituents. So any linearity or indeed non-linearity in Hammett plots may correspond only very loosely to the underlying mechanisms involved.

Starting in the 1940s and lasting perhaps 40-50 years, thousands of different reaction mechanisms were subjected to the Hammett treatment during the golden era of physical organic chemistry, but very few have been followed up by exploring the computed free energies, as set out above. One wonders how many of the original interpretations will fully withstand such new scrutiny and in general how influential the role of entropy is.

References

  1. C.D. Nielsen, W.J. Mooij, D. Sale, H.S. Rzepa, J. Burés, and A.C. Spivey, "Reversibility and reactivity in an acid catalyzed cyclocondensation to give furanochromanes – a reaction at the ‘oxonium-Prins’ <i>vs.</i> ‘<i>ortho</i>-quinone methide cycloaddition’ mechanistic nexus", Chemical Science, vol. 10, pp. 406-412, 2019. https://doi.org/10.1039/c8sc04302g

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Epoxidation of ethene: a new substituent twist.

Friday, December 21st, 2018

Five years back, I speculated about the mechanism of the epoxidation of ethene by a peracid, concluding that kinetic isotope effects provided interesting evidence that this mechanism is highly asynchronous and involves a so-called “hidden intermediate”. Here I revisit this reaction in which a small change is applied to the atoms involved.

Below are two representations of the mechanism. The synchronous mechanism involves five “curly arrows”, two of which are involved in forming a bond between oxygen and carbon, and three of which transfer a proton to the group X (X=O). The second variation asynchronously stops at the half way stage to form a pseudo ion-pair (the “hidden intermediate”) and the proton transfer only occurs in the second stage. If the ethene is substituted with deuterium, experimentally an inverse kinetic isotope effect is observed, which provides strong evidence that at the transition state, no proton transfer is occurring

Before I go on, I should say that you will not find the mechanism as shown in either variation above in very many text books, which tend to practice “curly arrow economy” by employing only four arrows. I will not pursue this aspect here, except to note that as drawn above, the synchronous mechanism resembles that of a pericyclic reaction in a variation known as coarctate, as I noted in the original post (DOI: 10.14469/hpc/4807).

Now I introduce a veritable variation into this reaction, known as Payne epoxidation[1],† which replaces the peracid with a reagent generated by adding hydrogen peroxide to a nitrile to generate a transient species which can be represented by X=NH above. How does this change things? The model below also uses propene rather than ethene (M062X/Def2-TZVPPD/SCRF=dichloromethane).‡ This transition state (ΔG298 31.3 kcal/mol) shows two C-O bond formations, and as before the proton is clearly not yet transferred to the nitrogen (X=NH). Because of this asynchrony, the reaction could also be called a coarctate pseudo-pericyclic reaction.

Asynchronous concerted mechanism. Click for 3D

However, the proton transfer is nonetheless part of a concerted mechanism, as shown by the IRC profile.

The gradient norm most clearly shows the “hidden ion-pair intermediate” at IRC = -1, and the proton transfer only occurs after this point is passed.

This is even more spectacularly illustrated with a plot of dipole moment along the IRC;

In truth, no real differences are yet revealed between the Payne reagent and the peracid. In fact, this is a real surprise, since the NH of the Payne reagent should be very much more basic than the carbonyl oxygen of the peracid. But more exploration of the potential energy surface reveals another transition state!

Stepwise mechanism. Click for 3D

This is seen forming the two C-O bonds AFTER the proton transfer from oxygen to nitrogen. It is 4.2 kcal/mol lower than the first transition state, which corresponds to the scheme below.

The new ion-pair shown above is 7.1 kcal/mol higher than the previous reactant, but is so much more basic than before that the overall activation energy is indeed lowered. Two distinctly separate IRCs can be constructed for this alternative, the first a pure proton transfer (not shown) and the second a pure C-O bond forming process (below). This second step is both concerted and almost purely synchronous.

So now we see how a small change to the reactant molecules (X=O to X=NH) can induce a reaction for which two quite different mechanisms can operate, an asynchronous one albeit with a hidden intermediate and a fully stepwise one in which a quite different, but this time real, intermediate is involved. Nevertheless for both the peracid mechanism and the peroxyimine variation shown here, the proton transfer is NOT involved in the rate limiting step. So for this variation too, inverse kinetic isotope effects would be expected.

‡FAIR data for the calculations at DOI: 10.14469/hpc/4909 †Thanks Ed for pointing this out.

References

  1. G.B. PAYNE, P.H. DEMING, and P.H. WILLIAMS, "Reactions of Hydrogen Peroxide. VII. Alkali-Catalyzed Epoxidation and Oxidation Using a Nitrile as Co-reactant", The Journal of Organic Chemistry, vol. 26, pp. 659-663, 1961. https://doi.org/10.1021/jo01062a004

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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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