Thursday, August 16, 2018

Readily Accessible Ambiphilic Cyclopentadienes for Bioorthogonal Labeling

Levandowski, B. J.; Gamache, R. F.; Murphy, J. M.; Houk, K. N., J. Am. Chem. Soc. 2018, 140, 6426-6431
Contributed by Steven Bacharach
Reposted from Computational Organic Chemistry with permission

I recently posted on a paper proposing 1,2-benzoquinone and related compounds as the diene component for bioorthogonal labeling. Levandowski, Gamache, Murphy, and Houk report on tetrachlorocyclopentadiene ketal 1 as an active ambiphilic diene component.1
1 is sterically congested to diminish self-dimerization and will react with both electron-rich and electron-poor dienes. To test it as an active diene in bioorthogonal labeling applications, they optimized the structures of the transition states at CPCM(water)/M06-2X/6-311+G(d,p)//CPCM(water)/M06-2X/6-31G(d) for the Diels-Alder reaction of 1 with a variety of dienophiles including trans-cyclooctene 2 and endo-bicyclononyne 3. These transition states are shown in Figure 1. The activation free energy is quite low for each: 18.1 kcal mol-1 with 2 and 18.9 kcal mol-1 with 3.

TS(1+2)

TS(1+3)
Figure 1. CPCM(water)/M06-2X/6-31G(d) optimized geometries for the TSs of the reaction of 1 with 2and 3.

Experiments were successfully run using 1 as a label on a neuropeptide.

References

1) Levandowski, B. J.; Gamache, R. F.; Murphy, J. M.; Houk, K. N., "Readily Accessible Ambiphilic Cyclopentadienes for Bioorthogonal Labeling." J. Am. Chem. Soc. 2018140, 6426-6431, DOI: 10.1021/jacs.8b02978.

InChIs

1:InChI=1S/C7H4Cl4O2/c8-3-4(9)6(11)7(5(3)10)12-1-2-13-7/h1-2H2
InChIkey=DXQQKKGWMVTLOJ-UHFFFAOYSA-N



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Sunday, July 29, 2018

Error-Controlled Exploration of Chemical Reaction Networks with Gaussian Processes

Gregor N. Simm and Markus Reiher (2018)
Highlighted by Jan Jensen



See if you recognise this scenario: you benchmark a cheap method against an accurate, but expensive, method for a set of molecules and get a mean error that you can use to correct the results obtained with the cheap method. But sooner or later you  start using the cheap method on molecules that look increasingly different from your benchmark set. At what point should you do another benchmark calculation against your expensive method? Simm and Reiher use Gaussian Processes (GP) to provide a quantitative answer.

GP is a way to fit a numerical function to a set of data points with uncertainties of the fit for every point in the fit. Simm and Reiher's basic idea is to arrange the benchmark points on the x-axis by computing a distance between pairs of molecular structures and performing a GP fit. Now compute the x-coordinate of the molecule you're uncertain about: if the uncertainty in the GP fit for that point is larger than the standard deviation of the mean error of your cheap method computed for the benchmark set, then you need to benchmark your cheap method against the more expensive method for that molecule.

Wednesday, July 25, 2018

Spectroscopic Evidence for Aminomethylene (H−C̈−NH2)—The Simplest Amino Carbene

Eckhardt, A. K.; Schreiner, P. R., Angew. Chem. Int. Ed. 2018, 57, 5248-5252
Contributed by Steven Bacharach
Reposted from Computational Organic Chemistry with permission

Eckhardt and Schreiner have spectroscopically characterized the aminomethylene carbene 1.1 Their characterization rests on IR spectra, with comparison to the computed AE-CCSD(T)/cc-pCVQZ anharmonic vibrational frequencies, and the UV-Vis spectra, with comparison to the computed B3LYP/6–311++G(2d,2p) transitions.


1 can be converted to 2 by photolysis. Interestingly, 1 does not convert to 2 after 5 days on the matrix in the dark. This is in distinct contrast to hydroxycarbene and related other carbene which undergo quantum mechanical tunneling (see this post and this post). Examination of the potential energy surface for the reaction of 1 to 2 at AE-CCSD(T)/cc-pCVQZ (see Figure 1) identifies that the lowest barrier is 45.8 kcal mol-1, about 15 kcal mol-1 larger than the barrier for the hydroxycarbene rearrangement. Additionally, the barrier width for 1 → 2 is 25% larger than for the hydroxycarbenes. Both of these suggest substantially reduced tunneling, and WKB analysis predicts a tunneling half-life of more than a billion years. The stability of 1 is attributed to the strong π-donor ability of nitrogen to the electron-poor carbene. This is reflected in a very short C-N bond (1.27 Å).

Figure 1. Structures and energies of 1 and 2 and the transition states that connect them. The relative energies (kcal mol-1) are computed at AE-CCSD(T)/cc-pCVQZ.


References

1) Eckhardt, A. K.; Schreiner, P. R., "Spectroscopic Evidence for Aminomethylene (H−C̈−NH2)—The
Simplest Amino Carbene." Angew. Chem. Int. Ed. 201857, 5248-5252, DOI: 10.1002/anie.201800679.


InChIs

1: InChI=1S/CH3N/c1-2/h1H,2H2
InChIKey=KASBEVXLSPWGFS-UHFFFAOYSA-N
2: InChI=1S/CH3N/c1-2/h2H,1H2
InChIKey=WDWDWGRYHDPSDS-UHFFFAOYSA-N

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This work is licensed under a Creative Commons Attribution-NoDerivs 3.0 Unported License.

Wednesday, July 18, 2018

Longest C–C Single Bond among Neutral Hydrocarbons with a Bond Length beyond 1.8 Å

Ishigaki, Y.; Shimajiri, T.; Takeda, T.; Katoono, R.; Suzuki, T., Chem 2018, 4, 795-806
Contributed by Steven Bacharach
Reposted from Computational Organic Chemistry with permission

This is a third post in a series dealing with very short or very long distances between atoms. Ishigaki, Shimajiri, Takeda, Katoono, and Suzuki have prepared three related analogues of hexaphenylethane that all have long C-C bonds.1 The idea is to create a core by fusing two adjacent phenyls into a naphylene, and then protect the long C-C bond through a shell made up of large aryl groups, 1. Fusing another 5-member ring opposite to the stretched C-C bond (2) creates a scissor effect that should stretch that bond further, even more so in the unsaturated version 3.

Their M062-x/6-31G* computations predict an increasing longer C-C bond (highlighted in blue in the above drawing): 1.730 Å in 1, 1.767 Å in 2, and 1.771 Å in 3. The structure of 3 is shown in Figure 3.

Figure 1. M06-2x/6-31G(d) optimized structure of 3.

These three compounds were synthesized, and characterized by IR and Raman spectroscopy. Their x-ray crystal structures at 200 K and 400K were also determined. The C-C distances are 1.742 Å (1), 1.773 Å (2) and 1.798 Å (3) with distances slightly longer at 400 K. These rank as the longest C-C bonds recorded.


References

1) Ishigaki, Y.; Shimajiri, T.; Takeda, T.; Katoono, R.; Suzuki, T., "Longest C–C Single Bond among Neutral Hydrocarbons with a Bond Length beyond 1.8 Å." Chem 20184, 795-806, DOI: 10.1016/j.chempr.2018.01.011.


InChIs

1: InChI=1S/C40H26/c1-5-17-32-27(11-1)23-24-28-12-2-6-18-33(28)39(32)36-21-9-15-31-16-10-22-37(38(31)36)40(39)34-19-7-3-13-29(34)25-26-30-14-4-8-20-35(30)40/h1-26H
InChIKey=IFIFQLGAOZULMX-UHFFFAOYSA-N
2: InChI=1S/C42H28/c1-5-13-33-27(9-1)17-18-28-10-2-6-14-34(28)41(33)37-25-23-31-21-22-32-24-26-38(40(37)39(31)32)42(41)35-15-7-3-11-29(35)19-20-30-12-4-8-16-36(30)42/h1-20,23-26H,21-22H2
InChIKey=HSJDZFLRPWJAGF-UHFFFAOYSA-N
3: InChI=1S/C42H26/c1-5-13-33-27(9-1)17-18-28-10-2-6-14-34(28)41(33)37-25-23-31-21-22-32-24-26-38(40(37)39(31)32)42(41)35-15-7-3-11-29(35)19-20-30-12-4-8-16-36(30)42/h1-26H
InChIKey=QQYNKBIOZSXWGD-UHFFFAOYSA-N

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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.


This work is licensed under a Creative Commons Attribution 4.0 International License.

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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This work is licensed under a Creative Commons Attribution-NoDerivs 3.0 Unported License.

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

Copyright 2018 American Chemical Society

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.