Wednesday, February 29, 2012

Total Synthesis of Oxidized Welwitindolinones and (-)-N-Methylwelwitindolinone C Isonitrile

K. W. Quasdorf, A. D. Huters, M. W. Lodewyk, D. J. Tantillo, N. K. Garg, Journal of the American Chemical Society 2011, 134, 1396 (Paywall)
Contributed by Steven Bachrach.
Reposted from Computational Organic Chemistry with permission

A quick note here on the use of computed NMR to determine stereochemical structure. The Garg group synthesized two “oxidized welwitindolines”, compounds 1 and 2.1 The relative stereochemistry at the C3 position (the carbon with the hydroxy group) was unknown.

1                                               2

Low energy gas-phase conformers of both epimers of 1 and 2 were optimized at B3LYP/6-31+G(d,p). (These computations were done by the Tantillo group.) See Figure 1 for the optimized lowest energy conformers. Using these geometries the NMR chemical shifts were computed at mPW1PW91/6-311+G(d,p) with implicit solvent (chloroform). The chemical shifts were Boltzmann-weighted and scaled according to the prescription (see this post) of Jain, Bally and Rablen.2 The computed chemical shifts were then compared against the experimental NMR spectra. For both 3 and 4, the 13C NMR shifts could not readily distinguish the two epimers. However, the computed 1H chemical shifts for the S epimer of each compound was significantly in better agreement with the experimental values; the mean average deviation for the S epimer of 2 is 0.08 ppm but 0.36ppm for the R epimer. As a check of these results, DP4 analysis3 (see this post) of 2 indicated a 100% probability for the S epimer using only the proton chemical shifts or with the combination of proton and carbon data.

(1) Quasdorf, K. W.; Huters, A. D.; Lodewyk, M. W.; Tantillo, D. J.; Garg, N. K., "Total Synthesis of Oxidized Welwitindolinones and (-)-N-Methylwelwitindolinone C Isonitrile," J. Am. Chem. Soc. 2011, 134, 1396-1399, DOI: 10.1021/ja210837b

(2) Jain, R.; Bally, T.; Rablen, P. R., "Calculating Accurate Proton Chemical Shifts of Organic Molecules with Density Functional Methods and Modest Basis Sets," J. Org. Chem. 2009, 74, 4017-4023, DOI: 10.1021/jo900482q.

(3) Smith, S. G.; Goodman, J. M., "Assigning Stereochemistry to Single Diastereoisomers by GIAO NMR Calculation: The DP4 Probability," J. Am. Chem. Soc. 2010, 132, 12946-12959, DOI: 10.1021/ja105035r

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Tuesday, February 21, 2012

Roaming-mediated isomerization in the photodissociation of nitrobenzene

M. L. Hause, N. Herath, R. Zhu, M. C. Lin, A. G. Suits Nature Chemistry 2011, 3, 932 (Paywall)
Contributed by Steven Bachrach.
Reposted from Computational Organic Chemistry with permission

The roaming mechanism has gained some traction as a recognizable model.1,2 This mechanism involves typically the near complete dissociation of a molecule into two radical fragments. But before they can completely separate they form a loose complex on a flat potential energy surface. The two fragments can then wander about each other (the “roaming” part of the mechanism), eventually finding an alternative exit channel. The first example was the dissociation of formaldehyde which forms the complex H + CHO.3 The hydrogen atom roams over to the other side of the HCO fragment and then abstracts the second hydrogen atom to form H2 and CO – with the unusual signature of a hot H2 molecule and CO in low rotational/vibrational states.

The photodissociation of nitrobenzene is now suggested to also follow a roaming pathway.4 Bimodal distribution is found for the NO product channel. There is a slow component with low J and a fast component with high J. This suggests two different operating mechanisms for dissociation.

G2M(CC1)/UB3LYP/6-311+G(3df,2p) computations provide the two mechanisms. Near dissociation to phenyl radical and NO2 can lead to a roaming process that eventually leads to recombination to form phenyl nitrite, which can then dissociate to the slow NO product. The fast NO product is suggested to come from rearrangement of nitrobenzene to phenylnitrite on the triplet surface, again eventually leading to loss of NO, but with high rotational excitation.

(1) Herath, N.; Suits, A. G., "Roaming Radical Reactions," J. Phys. Chem. Lett. 2011, 2, 642-647, DOI: 10.1021/jz101731q

(2) Bowman, J. M.; Suits, A. G., "Roaming reactions: The third way," Phys. Today 2011, 64, 33-37, DOI: 10.1063/PT.3.1330

(3) Townsend, D.; Lahankar, S. A.; Lee, S. K.; Chambreau, S. D.; Suits, A. G.; Zhang, X.; Rheinecker, J.; Harding, L. B.; Bowman, J. M., "The Roaming Atom: Straying from the Reaction Path in Formaldehyde Decomposition," Science 2004, 306, 1158-1161, DOI: 10.1126/science.1104386.

(4) Hause, M. L.; Herath, N.; Zhu, R.; Lin, M. C.; Suits, A. G., "Roaming-mediated isomerization in the photodissociation of nitrobenzene," Nat. Chem 2011, 3, 932-937, DOI: 10.1038/nchem.1194

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Saturday, February 18, 2012

Assessment of Popular DFT and Semiempirical Molecular Orbital Techniques for Calculating Relative Transition State Energies and Kinetic Product Distributions in Enantioselective Organocatalytic Reactions

S.Schenker, C. Schneider, S. B. Tsogoeva, T. Clark  Journal of Chemical Theory and Computation 2011, 7, 3586 (Paywall)

While the main focus of the article is on DFT methods, this is the first systematic study that I have come across that indicates that PM6 is significantly better at reproducing ab initio TS structures and barrier heights (or in this case barrier height differences).

For example, for the five aldol reactions considered in this paper both AM1 and PM3 predicted a completely different (multistep) reaction mechanism than PM6 and the ab initio methods.  The difference in barrier heights were predicted to within 2 kcal/mol of CC2/TZVP//M06-2X/TZVP results.

The performance of PM6 is a bit more disappointing for seven nitro-Michael reactions where the difference in barrier heights were underestimated by as much as 9 kcal/mol.  However, the authors note "Remarkably, the geometries optimized with PM6 are quite accurate in some cases. The RMSD of all interatomic distances relative to the MP2-optimized geometries is 0.42 Å for 4a and 0.61 Å for 4b, comparable to or better than most DFT optimizations for these systems."  Unfortunately, barrier-differences computed using ab initio single point calculations based on these geometries were not reported.

These findings are very interesting given the speed of PM6 which makes automatic high throughput searches for TSs feasible.

Acknowledgements: Thanks to Martin Hediger for alerting me to this paper.

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Friday, February 17, 2012

Regiochemical Substituent Switching of Spin States in Aryl(trifluoromethyl)carbenes

M.-G. Song and R.S. Sheridan Journal of the American Chemical Society 2011, 133, 19688 (Paywall)
Contributed by Steven Bachrach.
Reposted from Computational Organic Chemistry (where interactive models can be found) with permission

Can a remote substituent affect the singlet-triplet spin state of a carbene? Somewhat surprisingly, the answer is yes. Sheridan has synthesized and characterized the meta and para methoxy-substituted phenyltrifluoromethyl)carbenes 1 and 2. The UV-Vis spectrum of 1 is consistent with a triplet as its EPR and reactivity with oxygen. However, the para isomer 2 gave no EPR signal and failed to react with oxygen or hydrogen, suggestive of a singlet.

The conformations of 1 and 2 were optimized at B3LYP/6-31+G(d,p) and the lowest energy singlet and triplet conformers are shown in Figure 1. The experimental spectral features of 1 match up best with the computed features of the triplet, and the same is true for the singlet of 2.

The triplet of 1 is estimated to be about 4 kcal mol-1 below that of the singlet – larger than the general overestimation of the stability of triplets that beleaguer B3LYP. For 2, B3LYP predicts a singlet ground state.

The isodesmic reactions 1 and 2 help understand the strong substituent effect. For 1, the meta substituent destabilizes both the singlet and triplet by a small amount. For 2, the para methoxy group stabilizes the triplet slightly, but stabilizes the singlet by a large amount. This stabilization is likely the result of the contribution of a second resonance structure 2b. A large rotational barrier for both the methyl methyl and the trifluoromethyl groups supports the participation of 2b.

ΔEsinglet = -0.8 kcal mol-1
ΔEtriplet = -0.6 kcal mol-1

ΔEsinglet = -5.8 kcal mol-1
ΔEtriplet = -1.1 kcal mol-1

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Saturday, February 11, 2012

NMR Structure Determination for Larger Proteins Using Backbone-Only Data

S. Raman, O. F. Lange, P. Rossi, M. Tyka, X. Wang, J. Aramini, G. Liu, T. A. Ramelot, A. Eletsky, T. Szyperski, M. A. Kennedy, J. Prestegard, G. T. Montelioni, D. Baker Science 2010, 327, 1014 (Free access with registration)

Baker and co-wokers present show that inclusion of experimental NMR data for the backbone atoms (chemical shifts, RDC, and HN-HN NOEs) that can be measured relatively easily can help significantly in protein structure determination using ROSETTA.  This CS-RDC-NOE-ROSETTA protocol not only helps guide the conformational search, but also helps alleviate errors in the energy function.

The protocol was tested on 12 protein with up to 266 residues, which is quite large by NMR standards.  For the larger proteins "the computed structures are not completely converged and have large disordered regions.  Furthermore, the method was validated by a blind test on five proteins (with up to 122 residues) in which the CS-RDC-NOE-ROSETTA protocol found satisfactory structures in all cases. 

Another major step forward in protein structure determination from the Baker lab.  I could not find any mentioned of the required CPU time, but it is no doubt substantial.
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