Archive for August, 2011


As we have noted in many previous posts, Schreiner has observed tunneling in hydroxycarbenes that is either very rapid (1a-c) or not at all (1d-f).1-4 In a recent paper his group investigates whether cyclopropylhydroxycarbene 2 might have an intermediate lifetime due to the π-donating effect of the three-member ring.5

Schreiner makes this carbene in his usual manner: flash pyrolysis of the cyclopropylglyoxylic acid. Let’s now consider three possible rearrangements of carbene 2. The hydrogen can migrate (Scheme 1, path a) to give cyclopropylcarboxyaldehyde 3 similar to what was observed with the related hydroxycarbenes. Carbon can migrate (Scheme 1, path b), opening up the three-member ring to give the cyclobutenol 4. This ring could open to the diene 5 and tautomerize to the ketone 6. Lastly, a hydrogen migration from carbon (Scheme 1, path c) would lead to 7. The relative energies of these species computed at CCSD(T)//cc-pVTZ//M06-2x//6-311++G(d,p) are shown in Scheme 1.

Scheme 1. Relative energies in kcal mol-1.

The computed barriers for the initial step of each pathway is +30.4 kcal mol-1 for path a, +21.9 kcal mol-1 for path b and +35.8 kcal mol-1 for path c. Thus, one might expect to see only the reaction along path b at low temperature and mostly along b at high temperature with some small percent along path a. So what actually occurs?

After capturing the flash pyrolysis product in an Ar matrix, besides the unreacted cyclopropylglyoxylic acid, 6, 3, and 2 are observed in an approximate 8:5:1 ratio. 2 is identified on the basis of the nice agreement between the experimental and computed IR frequencies. Irradiation of 2 in the matrix leads to clean conversion to 4, also identified by comparison of the observed and computed IR frequencies. This is all consistent with the computed activation barriers. In the pyrolysis, at high T, 6 is the major product and 3 is the minor product. At very low T (11 K), irradiation of 2 produces 4 (crossing only the lowest barrier) and not continuing further along the rearrangement path to 6.

What is perhaps most exciting is that 2 disappears slowly in the dark at both 11 K and 20 K, converting at the same rate to 3. The half life is 17.7 h, much longer than for the alkyl and aryl substituted hydroxycarbenes 1a-c. This confirms the stabilization effect of the cyclopropyl group, as does its large singlet-triplet gap. The computed tunneling half-life using the WKB approach is 16.6 h, in excellent agreement with experiment. And as expected for a tunneling phenomenon, the dueterated analog has a much longer half-life, computed to be 105 years. Experimentally, 2-d persists with no conversion to 3-d observed.

As with methylhydroxycarbene, we see here an example of tunneling control vs kinetic control. At high T, the reaction crosses the lowest barrier (shown in Figure 1a), proceeding to 4 and subsequent rearrangement products. At low T, the reaction crosses a higher barrier (shown in Figure 1b), but this path involves tunneling of the very light hydrogen atom only, producing 3.

TS 2 → 3

TS 2 → 4

Figure 1. M06-2X/6-311++G(d,p) optimized geometry of the transition states connecting 2 to (a) 3 and (b) 4.


(1) Schreiner, P. R.; Reisenauer, H. P.; Pickard Iv, F. C.; Simmonett, A. C.; Allen, W. D.; Matyus, E.; Csaszar, A. G., "Capture of hydroxymethylene and its fast disappearance through tunnelling," Nature, 2008, 453, 906-909, DOI: 10.1038/nature07010.

(2) Schreiner, P. R.; Reisenauer, H. P., "Spectroscopic Identification of Dihydroxycarbene," Angew. Chem. Int. Ed., 2008, 47, 7071-7074, DOI: 10.1002/anie.200802105

(3) Gerbig, D.; Reisenauer, H. P.; Wu, C.-H.; Ley, D.; Allen, W. D.; Schreiner, P. R., "Phenylhydroxycarbene," J. Am. Chem. Soc., 2010, 132, 7273-7275, DOI: 10.1021/ja9107885

(4) Schreiner, P. R.; Reisenauer, H. P.; Ley, D.; Gerbig, D.; Wu, C.-H.; Allen, W. D., "Methylhydroxycarbene: Tunneling Control of a Chemical Reaction," Science, 2011, 332, 1300-1303, DOI: 10.1126/science.1203761.

(5) Ley, D.; Gerbig, D.; Wagner, J. P.; Reisenauer, H. P.; Schreiner, P. R., "Cyclopropylhydroxycarbene," J. Am. Chem. Soc., 2011, 133, 13614-13621, DOI: 10.1021/ja204507j

Schreiner &Tunneling Steven Bachrach 31 Aug 2011 4 Comments

[2+2] cycloaddition of tethered allene-ynes

Matt Seibert pointed out to me a paper of his related to a previous blog post that also deals with the allene-yne thermal [2+2] cyclization. (My apologies to Matt and Dean for overlooking this paper!) Tantillo and Brummond looked at the system with various saturated tethers between these functional groups.1 For example, UB3LYP/6-31+G(d,p) study of the cyclization of 1 indicates two possible paths, where the 5-member ring is formed first, or where the 7 member ring is formed first. The relative energies of the TSs and intermediates are shown in Figure 1. (Note that there are actually two intermediates on the first pathway, differing in the orientation terminal methyne hydrogen.) The closure to the smaller ring first is favored due to the allylic stabilization of the radical intermediate on this pathway.

Figure 1. Relative energies of TSs and critical point in the cyclization of 1.

Next, they examined the regioselectivity for the inner or outer double bond of the allene in 2. For the reaction with the outer double bond, the 6 member ring is formed first. For the reaction with the inner double bond, the 7-member ring is formed first, and this pathway has a higher barrier than the other. The preference for the reaction with the terminal double bond is consistent with experiments.

Figure 2. Relative energies of TSs and critical point in the cyclization of 2.

With potential diradical intermediates, they decided to append a cyclopropyl ring to as a trap. So, for example, the reaction of 3 can lead to the [2+2] product or to a diradical that might be trapped and identified. The computed energies along these two paths are shown in Figure 3. The activation barrier for the closure to the 2+2 product and for ring opening of the cyclopropyl group are nearly identical, so one might expect to observe both processes. Analogues of 3 were prepared and heated; some evidence of the ring opening of the cyclopropyl group was observed.

Figure 3. Relative energies of TSs and critical point in the cyclization of 3.


(1) Siebert, M. R.; Osbourn, J. M.; Brummond, K. M.; Tantillo, D. J., "Differentiating Mechanistic Possibilities for the Thermal, Intramolecular [2 + 2] Cycloaddition of Allene-Ynes," J. Am. Chem. Soc., 2010, 132, 11952-11966, DOI: 10.1021/ja102848z


1: InChI=1/C7H8/c1-3-5-7-6-4-2/h1,6H,2,5,7H2

1P: InChI=1/C7H8/c1-2-6-4-5-7(6)3-1/h2,5H,1,3-4H2

2: InChI=1/C8H10/c1-3-5-7-8-6-4-2/h1,6H,2,5,7-8H2

2Pa: InChI=1/C8H10/c1-2-4-8-6-5-7(8)3-1/h3,6H,1-2,4-5H2

2Pb: InChI=1/C8H10/c1-6-5-7-3-2-4-8(6)7/h5,8H,1-4H2

3: InChI=1/C11H14/c1-2-3-4-5-6-7-8-11-9-10-11/h3,11H,1,4-6,9-10H2

3P: InChI=1/C11H14/c1-2-4-10-9(3-1)7-11(10)8-5-6-8/h3,8H,1-2,4-7H2

electrocyclization Steven Bachrach 29 Aug 2011 1 Comment

cyclopenta[b]benzofuran – stereochemistry and mechanism of formation

Here is a nice example of an interesting synthesis, mechanistic explication using computation (with a bit of an unanswered question), and corroboration of the stereochemistry of the product using computed NMR shifts. Gil and Mischne1 reacted dimedone 1 with dienal 2 under Knoevenagel conditions to give, presumably, 3. But 3 is not recovered, rather the tricycle 4 is observed.

There are four stereoisomers that can be made (4a-d). Computed 13C chemical shifts at OPBE/pcS-1 (this is a basis set suggested for computing chemical shifts2) for these four isomers were then compared with the experimental values. The smallest root mean squared error is found for 4d. Better still, is that these authors utilized the DP4 method of Goodman3 (see this post), which finds that 4d agrees with the experiment with 100% probability!

Lastly, the mechanism for the conversion of 3 to 4 was examined at M06/6-31+G**. The optimized geometries of the starting material, transition state, and product are shown in Figure 1. The free energy barrier is a modest 14.5 kcal mol-1. The TS indicates a conrotatory 4πe electrocyclization. The formation of the C-O bond lags far behind in the TS. They could not identify a second transition state. It would probably be worth examining whether the product of this 4πe electrocyclization could be located, perhaps with an IRC starting from the transition state. Does this TS really connect 3 to 4?




Figure 1. M06/6-31+G** optimized geometries of 3 and 4 and the transition state connecting them.


(1) Riveira, M. J.; Gayathri, C.; Navarro-Vazquez, A.; Tsarevsky, N. V.; Gil, R. R.; Mischne, M. P., "Unprecedented stereoselective synthesis of cyclopenta[b]benzofuran derivatives and their characterisation assisted by aligned media NMR and 13C chemical shift ab initio predictions," Org. Biomol. Chem., 2011, 9, 3170-3175, DOI: 10.1039/C1OB05109A

(2) Jensen, F., "Basis Set Convergence of Nuclear Magnetic Shielding Constants Calculated by Density Functional Methods," J. Chem. Theory Comput., 2008, 4, 719-727, DOI: 10.1021/ct800013z

(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/C8H12O2/c1-8(2)4-6(9)3-7(10)5-8/h3-5H2,1-2H3

2: InChI=1/C12H12O/c1-11(10-13)6-5-9-12-7-3-2-4-8-12/h2-10H,1H3/b9-5+,11-6+

3: InChI=1/C20H22O2/c1-15(8-7-11-16-9-5-4-6-10-16)12-17-18(21)13-20(2,3)14-19(17)22/h4-12H,13-14H2,1-3H3/b11-7+,15-8+

4d: InChI=1/C20H22O2/c1-19(2)11-15(21)17-16(12-19)22-20(3)10-9-14(18(17)20)13-7-5-4-6-8-13/h4-10,14,18H,11-12H2,1-3H3/t14-,18+,20+/m1/s1

electrocyclization &NMR Steven Bachrach 23 Aug 2011 3 Comments

Stepwise cyclization of allene-ynes

Continuing their studies of ene-yne cyclizations, the Schmittel group examined the apparent [2+2] cyclization of the allene-yne 1.1 They proposed that it first closed the diradical 2 and then in a second step the four-member ring is formed, giving 3.

a: R1=Ph, R2=R3=H
b: R1=Ph, R2=H,
c: R1=Ph, R2=POPh2,

Evidence supporting the intermediate diradical is that heating 1a in the presence of 1,4-cyclohexadiene gives 11% of the trapped species 4a. Interestingly, heating 1b gives 26% of 3b, while the reaction of 1c gives 72% of the ring closed product 3c.

Schmittel suggests the intermediate diradical 2b is planar, while 2c is not, and the radical centers are nicely position in the latter compound for quick closure to product.

UBLYP/6-31G(d) computations support the mechanism. The transition state taking 1b to 2b (TS1, shown in Figure 1) lies 20.2 kcal mol-1 above reactant. The intermediate diradical 2b is 7.9 kcal mol-1 above reactant 1b. The second transition state (TS2) for closing the four-member ring lies 27.8 kcal mol-1 above reactant, making it the rate determining step. The overall reaction is exothermic by -12.4 kcal mol-1. The transition state for a single step reaction, taking 1b directly into 3b (TS3) is very high, 49.0 kcal mol-1 above 1b, and is therefore non-competitive with the stepwise pathway. These computations suggest a reversible formation of the intermediate, followed by a rate limiting step to making the four-member ring, completely consistent with the experiments.





Figure 2. UBLYP/6-31G(d) optimized structures of 2b, TS1, TS2, and TS3.


1) Cinar, M. E.; Vavilala, C.; Fan, J.; Schmittel, M., "The thermal C2-C6/[2 + 2] cyclisation of enyne-allenes: Reversible diradical formation," Org. Biomol. Chem. 2011, 9, 3776-3779, DOI: 10.1039/C0OB01275K


1b: InChI=1/C21H20/c1-21(2,3)17-9-14-19-12-7-8-13-20(19)16-15-18-10-5-4-6-11-18/h4-8,10-14,17H,1-3H3/t9-/m0/s1

3b: InChI=1/C21H20/c1-21(2,3)20-17-13-15-11-7-8-12-16(15)19(17)18(20)14-9-5-4-6-10-14/h4-13,20H,1-3H3

diradicals &electrocyclization Steven Bachrach 16 Aug 2011 1 Comment

Topics for a new edition of Computational Organic Chemistry

I am very much contemplating a second edition of my book Computational Organic Chemistry, which is the basis of this blog. I have been in touch with Wiley and they are enthusiastic about a second edition.

Here is a list of some of the things I am contemplating as new topics for the second edition

  1. Discussion of the failures of many of the standard functionals (like B3LYP) to treat simple organics
  2. Predicting NMR, IR and ORD spectra
  3. Möbius compounds, especially aromatics
  4. π-π-stacking
  5. tunneling in carbenes (Schreiner and Allen’s great work)
  6. acidity of amino acids and remote protons
  7. bifurcating potential energy surfaces and the resultant need for dynamic considerations
  8. even more examples of dynamics – especially the roundabout SN2

So, I would like to ask my readers for suggestions of other ideas for new topics to add to the book. These can be extensions of the topics already covered, or brand new areas!

Additionally, I am planning on interviewing a few more people for the book, similar in spirit to the 6 interviews in the first addition. Again, I welcome any suggestions for computational chemists to interview!

Uncategorized Steven Bachrach 09 Aug 2011 6 Comments