Archive for February, 2012

Welwitindolinones structure

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.



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 1 and 2, 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.



Figure 1. B3LYP/6-31+G(d,p) optimized geometries of the
lowest energy conformations of 1 and 2.


(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


1: InChI=1/C22H21ClN2O3S/c1-6-20(4)15(23)10-13-17(26)21(20,24-11-29)12-8-7-9-14-16(12)22(28,19(13,2)3)18(27)25(14)5/h6-10,13,28H,1H2,2-5H3/t13-,20+,21+,22-/m0/s1

2: InChI=1/C22H21ClN2O3/c1-7-20(4)15(23)11-13-17(26)21(20,24-5)12-9-8-10-14-16(12)22(28,19(13,2)3)18(27)25(14)6/h7-11,13,28H,1H2,2-4,6H3/t13-,20+,21+,22-/m0/s1

NMR Steven Bachrach 28 Feb 2012 1 Comment

Roaming mechanism in photodissociation of nitrobenzene

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


Nitrobenzene: InChI=1/C6H5NO2/c8-7(9)6-4-2-1-3-5-6/h1-5H

Dynamics Steven Bachrach 21 Feb 2012 No Comments

Singlet-triplet carbene gap and remote subtituents

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 2.1 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.





Figure 1. B3LYP/6-31+G(d,p) optimized geometries of 1 and 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

Rxn 1

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

Rxn 2


(1) Song, M.-G.; Sheridan, R. S., "Regiochemical Substituent Switching of Spin States in
Aryl(trifluoromethyl)carbenes," J. Am. Chem. Soc. 2011, 133, 19688-19690, DOI: 10.1021/ja209613u


1: InChI=1/C9H7F3O/c1-13-8-4-2-3-7(5-8)6-9(10,11)12/h2-5H,1H3

2: InChI=1/C9H7F3O/c1-13-8-4-2-7(3-5-8)6-9(10,11)12/h2-5H,1H3

carbenes Steven Bachrach 14 Feb 2012 4 Comments

Synthetic application of the Bergman cyclization

Synthetic application of the Bergman cyclization is rare. Basak reports a real interesting use of this reaction to create polycyclic aromatics.1 So, for example, heating up 1 in DMSO leads to the 4helicene 2. The proposed mechanism is shown in Figure 1. The Bergman cyclization leads to the biradical 3, which adds to the pendant phenyl group to give 4. Hydrogen abstraction then gives 5, which abstracts hydrogens from the solvent to produce 6. (Use of DMSO-d 6 provides deuterium incorporated products consistent with the diradical shown in 4.) Oxidation then gives the final product 2.

Figure 1. Proposed mechanism for the conversion of 1 to 2.

B3LYP computations were performed to examine the relative rates with substituents on the phenyl ring. The structure of 1’ (with a methyl group replacing the Ns group – 4-nitrobenzenesulfonyl) and the transition state for the Bergman cyclization are shown in Figure 2. Unfortunately, computations were not used to analyze the complete proposed mechanism – a project that awaits the eager student perhaps?



Figure 2. B3LYP/def2-TZVP//BP86/def2-TZVP optimized structures of 1’ and transition state for the Bergman cyclization of 1’.


(1) Roy, S.; Anoop, A.; Biradha, K.; Basak, A., "Synthesis of Angularly Fused Aromatic Compounds from Alkenyl Enediynes by a Tandem Radical Cyclization Process," Angew. Chem. Int. Ed., 2011, 50, 8316-8319, DOI: 10.1002/anie.201103318


1’: InChI=1/C21H17N/c1-22-15-7-12-20-10-5-6-11-21(20)14-13-19(17-22)16-18-8-3-2-4-9-18/h2-6,8-11,16H,15,17H2,1H3/b19-16+

2’: InChI=1/C21H17N/c1-22-12-16-10-14-6-2-4-8-18(14)21-19-9-5-3-7-15(19)11-17(13-22)20(16)21/h2-11H,12-13H2,1H3

Bergman cyclization Steven Bachrach 07 Feb 2012 No Comments

Computed NMR of a large organometallic

Bergman and Raymond have prepared a Ga4L612- host that can encapsulate small monocations and neutral species.1,2 Figure 1 shows the host with an encapsulated tetraethylammonium ion NEt4+. (Note that the hydrogens have been suppressed for easier viewing. And be sure to click on the structure in order to interact with the 3-D model.)

Figure 1. Structure of the Ga4L612- host encapsulating NEt4+.

Of interest for readers of this blog is that they have now computed the NMR spectra of the encapsulated species.3 The geometry of the host is fixed to that found in the crystal structure where Cp*Co is the guest and the geometry of the guest (NEt4+, PEt4+ and others) is optimized with molecular mechanics. The complex is then computed at B3LYP with the 3-21G basis set for the host and the G-311(g,p) basis set for the guest. The computed 1H chemical shifts are actually within 0.1 ppm of experiment, and show the swapping of the relative position of the chemical shifts of the methyl vs methylene proton for the two guests.

This demonstrates the computed NMR shifts can be applied to some very large molecules including organometallics.


(1) Caulder, D. L.; Powers, R. E.; Parac, T. N.; Raymond, K. N., "The Self-Assembly of a Predesigned Tetrahedral M4L6 Supramolecular Cluster," Angew. Chem. Int. Ed. 1998, 37, 1840-1843, DOI: 10.1002/(SICI)1521-3773(19980803)37:13/14<1840::AID-ANIE1840>3.0.CO;2-D

(2) Biros, S. M.; Bergman, R. G.; Raymond, K. N., "The Hydrophobic Effect Drives the Recognition of Hydrocarbons by an Anionic Metal-Ligand Cluster," J. Am. Chem. Soc. 2007, 129, 12094-12095, DOI: 10.1021/ja075236i

(3) Mugridge, J. S.; Bergman, R. G.; Raymond, K. N., "1H NMR Chemical Shift Calculations as a Probe of Supramolecular Host-Guest Geometry," J. Am. Chem. Soc. 2011, 133, 11205-11212, DOI:

NMR Steven Bachrach 02 Feb 2012 No Comments