Posts Tagged ‘Ken Houk’

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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WATOC 2017 report.

Tuesday, August 29th, 2017

The triennial conference is this year located in Munich. With 1500 participants and six parallel sessions, this report can give only a flavour of proceedings.

  1. Edward Valeev talked about the scaling problem in coupled cluster theories, the so-called gold standard for computing the energy and properties of small molecules. The problem is that the number of basis functions N describing the atomic basis set for the atoms scales from between N6 to N10 in terms of computer time, with similar behaviour for the memory required for the calculation. He described methods based on natural pair orbitals and localisation schemes which can achieve linear scaling, ie N1 for the energy, quite a break through! Using reasonable basis sets, CCSD(T)-like energies for molecules with 100s of atoms were reported. During the Q&A time afterwards (the tight schedules associated with so many speakers means questions are often limited to 1-2, with very short answers) a question was posed about the prospects for first and second derivatives for the method. This means that e.g. reaction mechanisms can then be probed with unprecedented energetic accuracy. The answer was non-committal, but if these derivatives do arrive, it will revolutionise our ability to understand mechanisms.
  2. Which brings me nicely to Jeremy Harvey, who talked about calculating accurate overall rate constants for complex mechanistic cycles. The rate equations are solved for the steady state condition and include concentrations of all species and the energies are obtained using CCSD(T)-F12 theory (a modification which allows better basis set scaling without increased computation time) as single point geometries. He described an example where the barrier associated with a postulated mechanism was about 6 kcal/mol higher than derived from the observed rate. This was sufficient to induce them to explore alternative mechanisms, which were indeed located with an appropriately lower barrier. I have used the value of ~10 kcal/mol as my mechanistic test on this blog, and it’s really nice to see this value being reduced further.
  3. Yet again this theme emerged with Yitzhak Apeloig, who asked about the mechanism for C=Si bond rotations in substituted systems recently made in his group. The energy of this rotation is low enough to be observed in NMR spectra. But when the energy of C=Si bond rotation is computed it comes out about 10 kcal/mol too high. Again alternative mechanisms were explored and it turns out that a 1,2 migration from R2C=SiR2 to form a carbylidene species, R-C-SiR3, rotation and then 1,2 again to reformulate the R2C=SiR2 system came up with the goods.
  4. Peter Scheiner talked about how attractions between molecules can be induced by dispersion. He described how Ph3C-CPh3 is an unknown molecule (dissociating into Ph3P• radicals) but when 4,6-di-tert-butyl groups are placed on all the phenyl rings, the dispersion attractions between them can account for ~60 kcal/mol (!), more than enough to stabilise the system. I have already described some of this work in a post here. The prospects are very exciting for more dispersion-stabilised molecules to emerge. During Q&A, a question was posed about what other atom pairs other than H…H might be brought into ultra-short contact by these attractive dispersion forces; we may expect further examples to emerge in the near future.
  5. Ken Houk gave a fascinating glimpse into the post-transition state world of reaction dynamics, as applied to Diels Alder cycloadditions and Cope rearrangements. The reactions are characterised by the residency times of the dynamic trajectories in the region of the transition state as short (~4 fs), medium (20-40fs) and long (80+fs), these times mapping on to what we used to call “synchronous”, “asynchronous” and “stepwise”. A good example is the so-called bis-pericyclic reaction of cyclopentadiene where the trajectories pass through a transition state but then bifurcate into two (in this case) equivalent pathways. He discussed other examples where the trajectories follow either a 2+4 cycloaddition pathway or a 4+6 alternative pathway and how the number of trajectories for each can be influenced by either solvent (water) or an enzyme. Ken described several 20-40fs trajectories as corresponding to “dynamic stepwise” reactions, which during Q&A was suggested are equivalent to the term “hidden intermediate” pathways coined by Dieter Cremer and as revealed in many posts here from the intrinsic reaction coordinates or IRCs. This is a clear growth area and expect many more examples of reaction dynamics to be applied to many exciting systems in the future.
  6. Leo Radom talked about very simple molecules, H3CX and the effects on the bond dissociation energy (BDE) of the C-H bonds if the group X is either strongly or weakly protonated (the latter via a hydrogen bond), or deprotonated (again strongly or weakly via a hydrogen bond from hydroxide anion). This is important in several enzymic pathways, where the CH bond might be activated in a similar manner by the enzyme. He also talked about similar effects on the ionisation potential. I noticed a connection between this theme and what might be called the electron affinity of H3CX. If you want to see what the connection is, go visit the Aachen bond Slam, about which I have previously blogged! 

I will stop with an observation that all the notes above were taken in real-time during the talks, which all emerged as Powerpoint slides, having an average residency time on the screen of perhaps 1-2 minutes each. References were invariably given as full journal citations (authors, journal, year, volume, pages) rather than as DOIs, and given the time constraints I did not try to capture them. Hence the lack of citations above to the presenters’ work. The slide displays are traditionally not made available to audiences‡ and photography of the screen or recording is considered very bad form. Conferences are not really about FAIR data, which I have described often on this blog.

I hope these six examples give one flavour of what is happening at WATOC 2017. If another interesting collection emerges, I may describe it here.

‡But see e.g. doi: b9r9 for an Aachen talk.

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