## Saturday, June 30, 2018

### Triplet-Tuning: A Novel Non-Empirical Construction Scheme of Exchange Functionals

Highlighted by Jan Jensen

The absolute error of the optical band gap computed with the CC-PVDZ basis set

The difference between the lowest triplet and singlet energy (ET) can be calculated both by UDFT and TDDFT but give different results because we don't know the exact density functional. So the authors suggest that functional can be improved by minimising this difference, i.e. without comparison to experimental data.

Indeed, such a triplet tuned (TT) functional "provide more accurate predictions for key observables in photochemical measurements, including but not limited to ET, optical band gaps (ES), singlet–triplet gaps (∆EST), and ionization potentials (I)" for a set of 100 organic molecules. Two parameters in the PBE exchange functional, the fraction of short-range HF exchange and the range-separation parameter, were adjusted.

One thing that is not clear to me is if the equivalence of UDFT and TDDFT is valid only for the exact density. If so, this would only be valid in the complete basis set limit. Either way, the results clearly improve using the CC-PVDZ basis set.

## Tuesday, June 26, 2018

### Intramolecular London Dispersion Interaction Effects on Gas-Phase and Solid-State Structures of Diamondoid Dimers

Fokin, A. A.; Zhuk, T. S.; Blomeyer, S.; Pérez, C.; Chernish, L. V.; Pashenko, A. E.; Antony, J.; Vishnevskiy, Y. V.; Berger, R. J. F.; Grimme, S.; Logemann, C.; Schnell, M.; Mitzel, N. W.; Schreiner, P. R., J. Am. Chem. Soc. 2017, 139, 16696-16707
Contributed by Steven Bacharach
Reposted from Computational Organic Chemistry with permission

Schreiner and Grimme have examined a few compounds (see these previous posts) with long C-C bonds that are found in congested systems where dispersion greatly aids in stabilizing the stretched bond. Their new paper1 continues this theme by examining 1 (again) and 2, using computations, and x-ray crystallography and gas-phase rotational spectroscopy and electron diffraction to establish the long C-C bond.

The distance of the long central bond in 1 is 1.647 Å (x-ray) and 1.630 Å (electron diffraction). Similarly, this distance in 2 is 1.642 Å (x-ray) and 1.632 Å (ED). These experiments discount any role for crystal packing forces in leading to the long bond.

A very nice result from the computations is that most functionals that include some dispersion correction predict the C-C distance in the optimized structures with an error of no more than 0.01 Å. (PW6B95-D3/DEF2-QZVP structures are shown in Figure 1.) Not surprisingly, HF and B3LYP without a dispersion correction predict a bond that is too long.) MP2 predicts a distance that is too short, but SCS-MP2 does a very good job.

 1 2
Figure 1. PW6B95-D3/DEF2-QZVP optimized structures of 1 and 2.

### References

1) Fokin, A. A.; Zhuk, T. S.; Blomeyer, S.; Pérez, C.; Chernish, L. V.; Pashenko, A. E.; Antony, J.; Vishnevskiy, Y. V.; Berger, R. J. F.; Grimme, S.; Logemann, C.; Schnell, M.; Mitzel, N. W.; Schreiner, P. R., "Intramolecular London Dispersion Interaction Effects on Gas-Phase and Solid-State Structures of Diamondoid Dimers." J. Am. Chem. Soc. 2017139, 16696-16707, DOI: 10.1021/jacs.7b07884.

### InChIs

1: InChI=1S/C28H38/c1-13-7-23-19-3-15-4-20(17(1)19)24(8-13)27(23,11-15)28-12-16-5-21-18-2-14(9-25(21)28)10-26(28)22(18)6-16/h13-26H,1-12H2
InChIKey=MMYAZLNWLGPULP-UHFFFAOYSA-N
2: InChI=1S/C26H34O2/c1-11-3-19-15-7-13-9-25(19,21(5-11)23(27-13)17(1)15)26-10-14-8-16-18-2-12(4-20(16)26)6-22(26)24(18)28-14/h11-24H,1-10H2
InChIKey=VPBJYHMTINJMAE-UHFFFAOYSA-N

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## Wednesday, May 30, 2018

### Reliable and Performant Identification of Low-Energy Conformers in the Gas Phase and Water

Anna Theresa Cavasin, Alexander Hillisch, Felix Uellendahl, Sebastian Schneckener, and Andreas H. Göller (2018)
Highlighted by Jan Jensen

In my opinion the most important conclusion from this article is that PBEh-3c/GFN-xTB is an excellent approximation to PBE0-D3(BJ)/def2-TZVP/GFN-xTB when finding low energy conformations in both the gas phase and water.

The authors chose 93 drug-like molecules and generated up to 100 conformation low-energy (< 20 kcal/mol) structures for each and computed the relative PBE0 energy of the conformer ranked lowest according to, e.g. PBEh-3c/GFN-xTB for each molecule. As you can see from the box-plots above the lowest energy structure found by PBEh-3c/GFN-xTB is virtually always within 0.5 kcal/mol of that predicted by PBE0-D3(BJ)/def2-TZVP/GFN-xTB. This is remarkable given the fact that PBEh-3c is 100-1000 times faster than PBE0-D3(BJ)/def2-TZVP according to the authors.

## Saturday, May 26, 2018

### An Exceptionally Close, Non-Bonded Hydrogen–Hydrogen Contact with Strong Through-Space Spin–Spin Coupling

Xiao, Y.; Mague, J. T.; Pascal, R. A., Angew. Chem. Int. Ed. 2018, 57, 2244-2247
Contributed by Steven Bacharach
Reposted from Computational Organic Chemistry with permission

The competition for finding molecules with ever-closer non-bonding HH interactions is heating up. I have previously blogged about 1, a in,in-Bis(hydrosilane) designed by Pascal,1 with an HH distance of 1.57 Å, and also blogged about 2, the dimer of tri(di-t-butylphenyl)methane,2 where the distance between methine hydrogens on adjacent molecules is 1.566 Å.

Now Pascal reports on 3, which shows an even closer HH approach.3

The x-ray structure of 3 shows the in,in relationship of the two critical hydrogens, HA and HB. Though the positions of these hydrogens were refined, the C-H distance are artificially foreshortened. A variety of computed structures are reported, and these all support a very short HH non-bonding distance of about 1.52 Å. The B3PW91-D3/cc-pVTZ optimized structure is shown in Figure 1.

Figure 1. B3PW91-D3/cc-pVTZ optimized structure of 3.

The authors also note an unusual feature of the 1H NMR spectrum of 3: the HB signal appears as a double with JAB= 2.0 Hz. B3LYP/6–311++G(2df,2pd) NMR computations indicated a coupling of 3.1 Hz. This is the largest through-space coupling recorded.

### References

1. Zong, J.; Mague, J. T.; Pascal, R. A., "Exceptional Steric Congestion in an in,in-Bis(hydrosilane)." J. Am. Chem. Soc. 2013135, 13235-13237, DOI: 10.1021/ja407398w.
2. Rösel, S.; Quanz, H.; Logemann, C.; Becker, J.; Mossou, E.; Cañadillas-Delgado, L.; Caldeweyher, E.; Grimme, S.; Schreiner, P. R., "London Dispersion Enables the Shortest Intermolecular Hydrocarbon H···H Contact." J. Am. Chem. Soc. 2017139, 7428–7431, DOI: 10.1021/jacs.7b01879.
3. Xiao, Y.; Mague, J. T.; Pascal, R. A., "An Exceptionally Close, Non-Bonded Hydrogen–Hydrogen Contact with Strong Through-Space Spin–Spin Coupling." Angew. Chem. Int. Ed. 2018, 57, 2244-2247, DOI: 10.1002/anie.201712304.

### InChI

3: InChI=1S/C27H24S3/c1-4-17-13-28-10-16-11-29-14-18-5-2-8-21-24(18)27-23(17)20(7-1)26(21)22-9-3-6-19(25(22)27)15-30-12-16/h1-9,16,26-27H,10-15H2
InChIKey=NJBHGDPNFALCTL-UHFFFAOYSA-N

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## Friday, May 11, 2018

### MD studies of simple pericyclic reactions

Mackey, J. L.; Yang, Z.; Houk, K. N., "Dynamically concerted and stepwise trajectories of the Cope rearrangement of 1,5-hexadiene." Chem. Phys. Lett. 2017, 683, 253-257
Yang, Z.; Zou, L.; Yu, Y.; Liu, F.; Dong, X.; Houk, K. N., "Molecular dynamics of the two-stage mechanism of cyclopentadiene dimerization: concerted or stepwise?" Chem. Phys. 2018, in press
Yang, Z.; Dong, X.; Yu, Y.; Yu, P.; Li, Y.; Jamieson, C.; Houk, K. N., "Relationships between Product Ratios in Ambimodal Pericyclic Reactions and Bond Lengths in Transition Structures." J. Am. Chem. Soc. 2018, 140, 3061-3067
Contributed by Steven Bacharach
Reposted from Computational Organic Chemistry with permission

At the recent ACS meeting in New Orleans, Ken Houk spoke at the Dreyfus award session in honor of Michele Parrinello. Ken’s talk included discussion of some recent molecular dynamics studies of pericyclic reactions. Because of their similarities in approaches and observations, I will discuss three recent papers from his group (which Ken discussed in New Orleans) in this post.

The Cope rearrangement, a fundamental organic reaction, has been studied extensively by computational means (see Chapter 4.2 of my book). Mackey, Yang, and Houk examine the degenerate Cope rearrangement of 1,5-hexadiene with molecular dynamics at the (U)B3LYP/6-31G(d) level.1 They examined 230 trajectories, and find that of the 95% of them that are reactive, 94% are trajectories that directly cross through the transition zone. By this, Houk means that the time gap between the breaking and forming C-C bonds is less than 60 fs, the time for one C-C bond vibration. The average time in the transition zone is 35 fs. This can be thought of as “dynamically concerted”. For the other few trajectories, a transient diradical with lifetime of about 100 fs is found.

The dimerization of cyclopentadiene finds the two [4+2] pathways merging into a single bispericylic transition state. 2 Only a small minority (13%) of the trajectories sample the region about the Cope rearrangement that interconverts the two mirror image dimers. These trajectories average about 60 fs in this space, which comes from the time separation between the formation of the two new C-C bonds. The majority of the trajectories quickly pass through the dimerization transition zone in about 18 fs, and avoid the Cope TS region entirely. These paths can be thought of as “dynamically concerted”, while the other set of trajectories are “dynamically stepwise”. It should be noted however that the value of S2 in the Cope transition zone are zero and so no radicals are being formed.

Finally, Yang, Dong, Yu, Yu, Li, Jamieson, and Houk examined 15 different reactions that involve ambimodal (i.e. bispericyclic) transition states.3 They find a strong correlation between the differences in the bond lengths of the two possible new bond vs. their product distribution. So for example, in the reaction shown in Scheme 1, bond a is the one farthest along to forming. Bond b is slightly shorter than bond c. Which of these two is formed next is dependent on the dynamics, and it turns out the Pab is formed from 73% of the trajectories while Pac is formed only 23% of the time. This trend is seen across the 15 reaction, namely the shorter of bond b or c in the transition state leads to the larger product formation. When competing reactions involve bonds with differing elements, then a correlation can be found with bond order instead of with bond length.

Scheme 1

### References

1) Mackey, J. L.; Yang, Z.; Houk, K. N., "Dynamically concerted and stepwise trajectories of the Cope rearrangement of 1,5-hexadiene." Chem. Phys. Lett. 2017, 683, 253-257, DOI: 10.1016/j.cplett.2017.03.011.
2) Yang, Z.; Zou, L.; Yu, Y.; Liu, F.; Dong, X.; Houk, K. N., "Molecular dynamics of the two-stage mechanism of cyclopentadiene dimerization: concerted or stepwise?" Chem. Phys. 2018, in press, DOI: 10.1016/j.chemphys.2018.02.020.
3) Yang, Z.; Dong, X.; Yu, Y.; Yu, P.; Li, Y.; Jamieson, C.; Houk, K. N., "Relationships between Product Ratios in Ambimodal Pericyclic Reactions and Bond Lengths in Transition Structures." J. Am. Chem. Soc. 2018,140, 3061-3067, DOI: 10.1021/jacs.7b13562.

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## Friday, April 27, 2018

### Hunting for organic molecules with artificial intelligence: Molecules optimized for desired excitation energies

Highlighted by Jan Jensen

Figure 1 from the paper. Reproduced under the CC-BY-NC-ND license

Sumita and co-workers combine Monte Carlo tree search (MCTS) and a recurrent neural network (RNN) to discover molecules with specific excitation levels.  The general approach is very similar to the one used by Segler, Waller, and co-workers to predict retrosynthetic pathways, that I highlighted last month

At the core of the method (called ChemTS) is a RNN trained to generate SMILES string representations of molecules - another approach pioneered by Segler and Waller. Trained on thousands of valid SMILES strings, the RNN predicts that, for example, a likely next character in the SMILES string "c1ccccc" is "1" (to form benzene), just like an RNN trained on thousands of English words would predict that a likely next character in "chemistr" is "y".

Since there is more than one probable choice for each new character the number of possible SMILES strings quickly become unmanageable: even five possible characters for each position in a 20-character SMILES string results in $10^{14}$ possibilities. This is where MCTS is helpful (paraphrased from my previous highlight):

A MCTS starts by evaluating a number of possible SMILES strings randomly and then assigning likelihood scores to the early parts of the string depending on whether the encoded molecule has a desired property or not. The process is then repeated except that the early parts of the SMILES string is chosen based on likelihood scores, which are continuously updated and added to unscored characters. The changing likelihood scores means that the search for new SMILES strings is directed towards the more promising areas of the tree. I have given a short illustration of the process here. The process is repeated for a given number of steps and the SMILES strings with properties closest to the target are selected.

The desired property is a certain value of the molecules lowest excitation level (200, 300, 400, 500, or 600 nm), which is predicted using TDFT at the B3LYP/3-21G* level of theory.  For example, given two days of CPU time on 12 cores, ChemTS generated 646 possible molecules of which 34 has a predicted excitation energy within 20 nm of 200 nm. Two of these molecules where tested experimentally and one molecule did indeed have an excitation energy in the desired range.

## Thursday, April 26, 2018

### The Molecular Structure of gauche-1,3-Butadiene: Experimental Establishment of Non-planarity

Baraban, J. H.; Martin-Drumel, M.-A.; Changala, P. B.; Eibenberger, S.; Nava, M.; Patterson, D.; Stanton, J. F.; Ellison, G. B.; McCarthy, M. C., Angew. Chem. Int. Ed. 2018, 57, 1821-1825
Contributed by Steven Bacharach
Reposted from Computational Organic Chemistry with permission

Sometimes you run across a paper that is surprising for a strange reason: hasn’t this work been done years before? That was my response to seeing this paper on the structure of gauche-1,3-butadiene.1Surely, a molecule as simple as this has been examined to death. But, in fact there has been some controversy over whether the cis or gauche form is the second lowest energy conformation. Computations have indicated that the cis form is a transition state for interconverting the two gauche isomers, but experimental confirmation was probably so late in coming due to the small amount of the gauche form present and its small dipole moment.

This paper describes Fourier-transform microwave (FTMW) spectroscopy using two variants: cavity-enhanced FTMW combined with a supersonic expansion and chirped-pulse FTMW in a cryogenic buffer gas cell. In addition, computations were done at CCSD(T) using cc-pCVTZ through cc-pCV5Z basis sets and corrections for perturbative quadruples. The computed structure is shown in Figure 1. In addition to confirming this non-planar structure, with a C-C-C-C dihedral angle of 33.8°, they demonstrate the tunneling between the two mirror image gauche conformations, through the cis transition state.

Figure 1. Computed geometry of gauche-1,3-butadiene.

### References

1. Baraban, J. H.; Martin-Drumel, M.-A.; Changala, P. B.; Eibenberger, S.; Nava, M.; Patterson, D.; Stanton, J. F.; Ellison, G. B.; McCarthy, M. C., "The Molecular Structure of gauche-1,3-Butadiene: Experimental Establishment of Non-planarity." Angew. Chem. Int. Ed. 2018, 57, 1821-1825, DOI: 10.1002/anie.201709966.