Pericyclic reactions remain a fruitful area of research despite the seminal publication of the Woodward-Hoffmann rules decades ago. Here are two related papers of pericyclic reactions that violate the Woodward-Hoffmann rules.

First, Solomek, Ravat, Mou, Kertesz, and Jurícek reported on the thermal and photochemical electrocyclization reaction of diphenylcetherene 1a.¹ Though they were not able to directly detect the intermediate 2, through careful examination of the photochemical reaction, they were able to infer that the thermal cyclization goes via the formally forbidden conrotatory pathway (see Scheme 1).

Scheme 2.

Kinetic studies estimate the activation barrier is 14.1 kcal mol^-1. They performed DFT computations of the parent 1b using a variety of functionals with both restricted and unrestricted wavefunctions. The allowed pathway to 2syn is predicted to be greater than 27 kcal mol^-1, while the formally forbidden pathway to 2anti is estimated to have a lower barrier of about 23 kcal mol^-1. The two transition states for these different pathways are shown in Figure 1, and the sterics that force a helical structure to 1 help make the forbidden pathway more favorable.

Figure 1. (U)B3LYP/6-31G optimized geometries of the transition states taking 1 into 2.

Nonetheless, all of the DFT computations significantly overestimate the activation barrier. The authors make the case that a low-lying singlet excited state results in an early conical intersection that reduces the symmetry from C₂ to C₁. In this lower symmetry pathway, all of the states can mix, leading to a lower barrier. However, since DFT is intrinsically a single Slater configuration, the mixing of the other states is not accounted for, leading to the overestimated barrier height.

In a follow up study, this group examined the thermal and photo cyclization of 13,14-dimethylcethrene 4.² The added methyl groups make the centhrene backbone more helical, and this precludes the formal allowed disrotatory process. The methyl groups also prohibit the oxidation that occurs with 1, driven by aromatization, allowing for the isolation of the direct product of the cyclization 5. This anti stereochemistry is confirmed by NMR and x-ray crystallography. The interconversion between 4 and 5 can be controlled by heat and light, making the system an interesting photoswitch.

Also of interest is the singlet-triplet gap of 1 and 4. The DFT computed ΔE_ST is about 10 kcal mol^-1 for 4, larger than the computed value of 6 kcal mol^-1 for 1b. The EPR of 1b does show a signal while that of 4 has no signal. To assess the role of the methyl group, they computed the singlet triplet gaps for 1b and 4 at two different geometries: where the distance between the carbons bearing the methyl groups is that in 1b (3.03 Å) and in 4 (3.37 Å). The lengthening of this distance by the methyl substituents is due to increased helical twist in 4 than in 1b. For 1b, the gap increases with twisting, from 7.1 to 8.3 kcal mol^-1, while for 4 the gap increases by 1.8 kcal mol^-1 with the increased twisting. This change is less than the effect of methyl substitution, which increases the gap by 2.2 kcal mol^-1 at the shorter distance and 2.8 kcal mol^-1 at the longer distance. Thus, the electronic (orbital) effect of methyl substitution affects the singlet-triplet gap more than the geometric twisting.

References

1) Šolomek, T.; Ravat, P.; Mou, Z.; Kertesz, M.; Juríček, M., "Cethrene: The Chameleon of Woodward–Hoffmann Rules." J. Org. Chem. 2018, 83, 4769-4774, DOI: 10.1021/acs.joc.8b00656.

2) Ravat, P.; Šolomek, T.; Häussinger, D.; Blacque, O.; Juríček, M., "Dimethylcethrene: A Chiroptical Diradicaloid Photoswitch." J. Am. Chem. Soc. 2018, 140, 10839-10847, DOI: 10.1021/jacs.8b05465.

InChIs

1b: InChI=1S/C28H16/c1-5-17-7-3-11-23-25(17)19(9-1)15-21-13-14-22-16-20-10-2-6-18-8-4-12-24(26(18)20)28(22)27(21)23/h1-16H
InChIKey=GBMHAGKZRAVBDO-UHFFFAOYSA-N

4: InChI=1S/C30H20/c1-17-9-11-19-5-3-7-21-15-23-13-14-24-16-22-8-4-6-20-12-10-18(2)26(28(20)22)30(24)29(23)25(17)27(19)21/h3-16H,1-2H3
InChIKey=MXTVFWTUCPRNIW-UHFFFAOYSA-N

5: nChI=1S/C30H20/c1-29-13-11-17-5-3-7-19-15-21-9-10-22-16-20-8-4-6-18-12-14-30(29,2)28(24(18)20)26(22)25(21)27(29)23(17)19/h3-16H,1-2H3/t29-,30-/m0/s1
InChIKey=SUMMGEBJORQMAI-KYJUHHDHSA-N

Aromaticity and orbital symmetry rules, though seemingly of ancient origin, remain areas of active interest. This paper by Fukazawa, et al combine both issues.¹ The multiple-step electrocyclization of 1 gives 2 in a reaction that takes 9 days at 80 °C. What would be the effect of diminishing the aromatic character of the fused rings of 1? Would the reaction be faster or slower?

Before discussing the experimental results, let’s examine the B3LYP/6-31G(d) results for the reaction of 1’, 3 and 5. (Note that a slightly smaller pendant substituent is used in the computations than in the experiment.) The optimized geometries of the critical points along the reaction pathway for the cyclization of 3 are shown in Figure 1.

3 (0.0)	3-TS1 (17.9)
3-INT (10.4)	3-TS2 (13.3)
4 (-60.7)

Figure 1. B3LYP/6-31G(d) optimized geometries and relative energies (kcal mol^-1) for the critical points along the reaction 3 → 4.
Remember that all structures on my blog can be viewed interactively by clicking on the image of the molecule.

For 1’, the first barrier (for the 8π cyclization) has a barrier of about 23 kcal mol^-1, but the second step (the 4π cyclization) has an even larger barrier of 28 kcal mol^-1. However, reducing the aromaticity of one of the fused rings (compound 3) leads to lower barriers of 18 and 13 kcal mol^-1. For the cyclization of 5, only a single transition state was found – no intermediate and no second TS – with a barrier of 12 kcal mol^-1. Thus, removing these external aromatic rings reduces the barrier of the reaction, and that is exactly what is found experimentally!

References

(1) Fukazawa, A.; Oshima, H.; Shimizu, S.; Kobayashi, N.; Yamaguchi, S. "Dearomatization-Induced Transannular Cyclization: Synthesis of Electron-Accepting Thiophene-S,S-Dioxide-Fused Biphenylene," J. Am. Chem. Soc. 2014, 136, 8738-8745, DOI: 10.1021/ja503499n.

InChIs:

1: InChI=1S/C44H64S4Si4/c1-41(2,3)49(13,14)37-25-29-30-26-38(50(15,16)42(4,5)6)46-34(30)23-24-36-32(28-40(48-36)52(19,20)44(10,11)12)31-27-39(51(17,18)43(7,8)9)47-35(31)22-21-33(29)45-37/h25-28H,1-20H3/b30-29-,32-31-
InChIKey=OCNQBMWQONUVNH-IOYDOZLVSA-N

1’:InChI=1S/C32H40S4Si4/c1-37(2,3)29-17-21-22-18-30(38(4,5)6)34-26(22)15-16-28-24(20-32(36-28)40(10,11)12)23-19-31(39(7,8)9)35-27(23)14-13-25(21)33-29/h17-20H,1-12H3/b22-21-,24-23-
InChIKey=GTFPBRMBCLREPG-ICHHBZPXSA-N

2: InChI=1S/C44H64S4Si4/c1-41(2,3)49(13,14)29-21-25-26-22-30(50(15,16)42(4,5)6)46-38(26)34-33(37(25)45-29)35-36(34)40-28(24-32(48-40)52(19,20)44(10,11)12)27-23-31(47-39(27)35)51(17,18)43(7,8)9/h21-24H,1-20H3
InChIKey=OTDXAOVIIQYYNV-UHFFFAOYSA-N

2’: InChI=1S/C32H40S4Si4/c1-37(2,3)21-13-17-18-14-22(38(4,5)6)34-30(18)26-25(29(17)33-21)27-28(26)32-20(16-24(36-32)40(10,11)12)19-15-23(35-31(19)27)39(7,8)9/h13-16H,1-12H3
InChIKey=IYZNCPPDTHWWCO-UHFFFAOYSA-N

3: InChI=1S/C32H40O2S4Si4/c1-39(2,3)29-17-21-22-18-30(40(4,5)6)37-27(22)15-16-28-24(20-32(38(28,33)34)42(10,11)12)23-19-31(41(7,8)9)36-26(23)14-13-25(21)35-29/h17-20H,1-12H3/b22-21-,24-23-
InChIKey=ZJBDGDJVLGNVOD-ICHHBZPXSA-N

4: InChI=1S/C32H40O2S4Si4/c1-39(2,3)21-13-17-18-14-22(40(4,5)6)36-30(18)26-25(29(17)35-21)27-28(26)32-20(16-24(38(32,33)34)42(10,11)12)19-15-23(37-31(19)27)41(7,8)9/h13-16H,1-12H3
InChIKey=QUSJUOMZBJUGON-UHFFFAOYSA-N

5: InChI=1S/C32H40O8S4Si4/c1-45(2,3)29-17-21-22-18-30(46(4,5)6)42(35,36)26(22)15-16-28-24(20-32(44(28,39)40)48(10,11)12)23-19-31(47(7,8)9)43(37,38)27(23)14-13-25(21)41(29,33)34/h17-20H,1-12H3/b22-21-,24-23-
InChIKey=NNZTUSIYEPMHMP-ICHHBZPXSA-N

6: InChI=1S/C32H40O8S4Si4/c1-45(2,3)21-13-17-18-14-22(46(4,5)6)42(35,36)30(18)26-25(29(17)41(21,33)34)27-28(26)32-20(16-24(44(32,39)40)48(10,11)12)19-15-23(47(7,8)9)43(37,38)31(19)27/h13-16H,1-12H3
InChIKey=JZHQQYXUIQXWLQ-UHFFFAOYSA-N

Hoffmann¹ reports on a number of new benzene dimer structures, notably 5-8, whose RIJCOSX-MP2/cc-pVTZ² structures are shown in Figure 1. A few of these new dimers are only somewhat higher in energy than the known dimers 1-4. The energies of these dimers, relative to two isolated benzene molecules, are listed in Table 1.

1	2
3	4
5	6
7	8

Figure 1. RIJCOSX-MP2/cc-pVTZ optimized geometries of 1-8.

Table 1. Energy (kcal mol^-1) of the dimers relative to two benzene molecules and activation energy for reversion to two benzene molecules.

The energy for reversion of the isomers 5-8 to two isolated benzene molecules is calculated to be fairly large, and so they should be stable relative to that decomposition mode. They also examined a series of other decomposition modes, including [1,5]-hydrogen migration, all of which had barriers of 21 kcal mol^-1 or greater, retrocyclization ([2+2]), for which they could not locate transition states, electrocyclic ring opening (Cope), with barriers of at least 17 kcal mol^-1 and dimerization – some of which had relatively small enthalpic barriers of 4-5 kcal mol^-1. However, the dimerizations all have very unfavorable entropic activation barriers.

So, the conclusion is that all of the novel dimers (4–8) can be reasonable expected to hang around for some time and therefore are potential synthetic targets.

References

(1) Rogachev, A. Yu.; Wen, X.-D.; Hoffmann, R. "Jailbreaking Benzene Dimers," J.
Am. Chem. Soc., 2012, 134, 8062-8065, DOI:10.1021/ja302597r

(2) Kossmann, S.; Neese, F. "Efficient Structure Optimization with Second-Order Many-Body Perturbation Theory: The RIJCOSX-MP2 Method," J. Chem. Theory Comput., 2010, 6, 2325-2338, DOI: 10.1021/ct100199k

InChIs

1: InChI=1S/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H/t9-,10+,11-,12+
InChIKey=WMPWOGVJEXSFLI-UHFFFAOYSA-N

2: InChI=1S/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H/t9-,10+,11+,12-
InChIKey=WMPWOGVJEXSFLI-IWDIQUIJSA-N

3: InChI=1S/C12H12/c1-2-4-12-10-7-5-9(6-8-10)11(12)3-1/h1-12H/t9?,10?,11-,12+
InChIKey=ONVDJSCNMCYFTI-CAODYFQJSA-N

4: InChI=1S/C12H12/c1-2-10-4-3-9(1)11-5-7-12(10)8-6-11/h1-12H
InChIKey=BCBHEUOKKNYIAT-UHFFFAOYSA-N

5: InChI=1S/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H/t9-,10-,11+,12+/m1/s1
InChIKey=WMPWOGVJEXSFLI-WYUUTHIRSA-N

6: InChI=1S/C12H12/c1-2-4-12-10-7-5-9(6-8-10)11(12)3-1/h1-12H/t9?,10?,11-,12-/m0/s1
InChIKey=ONVDJSCNMCYFTI-QQFIATSDSA-N

7: InChI=1S/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H/t9-,10-,11-,12+/m1/s1
InChIKey=WMPWOGVJEXSFLI-KKOKHZNYSA-N

8: InChI=1S/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H/t9-,10-,11-,12-
InChIKey=WMPWOGVJEXSFLI-NQYKUJLISA-N

Bendikov and co-workers have examined the dimerization of linear acenes at M06-2x/6-31G(d).¹ They have looked at the formal forbidden [4+4] reaction that takes, for example, 2 molecules of benzene into three possible dimer products 1P_anti1-2, 1P_syn1-2, and 1P_syn1-4. The relative energies of these products increases in that order, and all three are much higher in energy than reactants; the lowest energy dimer is 1P_anti1-2, lying 47.4 kcal mol^-1 above two benzene molecules. Similarly, the dimerization of naphthalene is also endothermic, but the formation of the symmetric dimer of anthracene 3P-2,2’ is exothermic by 5.4 kcal mol^-1. This gibes nicely with the best estimate of -9 ± 3 kcal mol^-1.² Dimerization of the higher acenes are increasingly exothermic.

The transition state for the dimerization of benzene is concerted, though very asymmetric, as seen in Figure 1. Its energy is quite high (77.79 kcal mol^-1) and so this reaction can be completely discounted. The TS for the dimerization of naphthalene is also concerted and asymmetric, but the reaction pathway for the dimerization is stepwise, with a diradical intermediate. Furthermore, the highest barrier for this stepwise reaction is 33.3 kcal mol^-1. The activation energy of the back reaction (anthracene dimer to two anthrecene molecules) was measured 36.3 kcal mol^-1,³ and the computed barrier of 38.7 kcal mol^-1 is in nice agreement. The computed barriers for the dimerization of the higher acenes are predicted to be even lower than that of anthracene, consistent with the observation of dimers of these molecules.

1Panti1-2	1TSanti1-2
1P-42	1TS-42

Figure 1. M06-2x /6-31G(d) optimized structures.

I was curious that the authors did not consider the formally allowed [4+2] dimerization, leading for example to 1P-42. So, I optimized this product and the concerted transition state leading to it. These are shown in Figure 1. The barrier through this transition state is still very large (54.1 kcal mol^-1) but it is 23 kcal mol^-1 lower in energy than the barrier of the [4+4] reaction! The Product of the [4+2] is also lower in energy (by 9 kcal mol^-1) than 1P_anti1-2. It seems to me that this type of dimerization is worth examining too – though I must say I have not as yet looked to see if anyone has explored this already.

References

(1) Zade, S. S.; Zamoshchik, N.; Reddy, A. R.; Fridman-Marueli, G.; Sheberla, D.; Bendikov,
M., "Products and Mechanism of Acene Dimerization. A Computational Study," J. Am. Chem. Soc., 2011, 133, 10803-10816, DOI: 10.1021/ja106594v

(2) Grimme, S.; Diedrich, C.; Korth, M., "The Importance of Inter- and Intramolecular van der Waals Interactions in Organic Reactions: the Dimerization of Anthracene Revisited," Angew. Chem. Int. Ed., 2006, 45, 625-629, DOI: 10.1002/anie.200502440

(3) Greene, F. D., "Problems of stereochemistry in photochemical reactions in the anthracene area," Bull. Soc. Chim. Fr., 1960, 1356-1360

InChIs

Benzene: InChI=1/C6H6/c1-2-4-6-5-3-1/h1-6H
InChIKey=UHOVQNZJYSORNB-UHFFFAOYAH

1P_anti1-2: InChI=1/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H
InChIKey=WMPWOGVJEXSFLI-UHFFFAOYAP

1P_syn1-2: InChI=1/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H
InChIKey=WMPWOGVJEXSFLI-UHFFFAOYAP

1P_syn1-4: InChI=1/C12H12/c1-2-10-4-3-9(1)11-5-7-12(10)8-6-11/h1-12H
InChIKey=BCBHEUOKKNYIAT-UHFFFAOYAI

1P-42: InChI=1/C12H12/c1-2-4-12-10-7-5-9(6-8-10)11(12)3-1/h1-12H
InChIKey=ONVDJSCNMCYFTI-UHFFFAOYAY

Anthracene: InChI=1/C14H10/c1-2-6-12-10-14-8-4-3-7-13(14)9-11(12)5-1/h1-10H
InChIKey=MWPLVEDNUUSJAV-UHFFFAOYAK

3P-2,2’: InChI=1/C28H20/c1-2-10-18-17(9-1)25-19-11-3-4-12-20(19)26(18)28-23-15-7-5-13-21(23)27(25)22-14-6-8-16-24(22)28/h1-16,25-28H
InChIKey=JUTIJVADGQDBGY-UHFFFAOYAY

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.

References

(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

InChIs

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

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

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

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

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

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

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

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?

3	TS
4

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

References

(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

InChIs

1: InChI=1/C8H12O2/c1-8(2)4-6(9)3-7(10)5-8/h3-5H2,1-2H3
InChIKey=BADXJIPKFRBFOT-UHFFFAOYAX

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+
InChIKey=VFBDYWDOVMUDEB-MPEOSAONBY

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+
InChIKey=IBEGRISKTNRVOU-YQQAFNMCBC

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
InChIKey=VEGSTZFBNRXEAX-WNYOCNMUBZ

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.

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.

2b
TS1	TS2
TS3

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

References

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

InChIs

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
InChIKey=HRQIWBDQUVQGEK-VIFPVBQEBW>

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
InChIKey=GKHJKEWSMNKHEN-UHFFFAOYAW

Mosey has a nice follow-up study on the origin of Woodward-Hoffman forbidden ring opening of cyclobutene under mechanical stress.¹ (See this blog post discussing the earlier work of Martinez.²) Pulling on cis substituents of a cyclobutene causes the ring to open in a disrotatory fashion. Normally, the WH forbidden pathway is accessed by photolysis which creates a new electronic state. Mosey asks if this same mechanism is occurring during mechanical stress.

On the face of things, this seems unlikely; how can a mechanical force lead to a new electronic state? CASSCF computations with either no applied external force or with varying sized external forces and IRC computations help answer this question. Without an external force, a diradical (or at least a species with high diradical character – and this could be the transition state) is found along the disrotatory pathway. This same diradical is found regardless of the size of the externally applied mechanical force. What does change is the position of the TS along the pathway: as the force increases, the TS becomes earlier, and the reaction barrier diminishes. No change in the electronic state is affected by the applied mechanical stress.

References

(1) Kochhar, G. S.; Bailey, A.; Mosey, N. J., "Competition between Orbitals and Stress in Mechanochemistry," Angew. Chem. Int. Ed., 2010, 49, 7452-7455, DOI: 10.1002/anie.201003978

(2) Ong, M. T.; Leiding, J.; Tao, H.; Virshup, A. M.; Martinez, T. J., "First Principles Dynamics and Minimum Energy Pathways for Mechanochemical Ring Opening of Cyclobutene," J. Am. Chem. Soc., 2009, 131, 6377-6379, DOI: 10.1021/ja8095834

Torquoselectivity rules (discussed in Chapter 3.5 of my book) indicate that 3-phenylcyclobutene will ring-open to give the outward rotated product (Reaction 1). Houk and Tang report a seeming contradiction, namely the ring opening of 1 gives only the inward product 3 (Reaction 2).¹

B3LYP/6-31G* computations on the ring-opening of 4 indicate that the activation barrier for the outward path (leading to 5) is nearly 8 kcal mol^-1 lower than the barrier for the inward path (leading to 6, see Reaction 3). This is consistent with torquoselectivity rules, but what is going on in the experiment?

In the investigation of the isomerization of the outward to inward pathway, they discovered a low-energy pyran intermediate 7. This led to the proposal of the mechanism shown in Reaction 3. The highest barrier is for the electrocyclization that leads to the outward product 5. The subsequent barriers – the closing to the pyran 7 and then the torquoselective ring opening to 6 –  are about than 13 kcal mol^-1 lower in energy than for the first step. The observed product is the thermodynamic sink. And the nice thing about this mechanism is that torquoselection is preserved.

References

(1) Um, J. M.; Xu, H.; Houk, K. N.; Tang, W., "Thermodynamic Control of the Electrocyclic
Ring Opening of Cyclobutenes: C=X Substituents at C-3 Mask the Kinetic Torquoselectivity," J. Am. Chem. Soc. 2009, 131, 6664-6665, DOI: 10.1021/ja9016446.

InChIs

4: InChI=1/C16H16O6/c1-20-13(17)11-9-16(14(18)21-2,15(19)22-3)12(11)10-7-5-4-6-8-10/h4-9,12H,1-3H3
InChIKey=VBOGEHVOAGDMNG-UHFFFAOYAR

5: InChI=1/C16H16O6/c1-20-14(17)12(9-11-7-5-4-6-8-11)10-13(15(18)21-2)16(19)22-3/h4-10H,1-3H3/b12-9-
InChIKey=PZRWKBUUAFMPBC-XFXZXTDPBF

6: InChI=1/C16H16O6/c1-20-14(17)12(9-11-7-5-4-6-8-11)10-13(15(18)21-2)16(19)22-3/h4-10H,1-3H3/b12-9+
InChIKey=PZRWKBUUAFMPBC-FMIVXFBMBS

7: InChI=1/C16H16O6/c1-19-14(17)11-9-12(15(18)20-2)16(21-3)22-13(11)10-7-5-4-6-8-10/h4-9,13H,1-3H3/t13-/m0/s1
InChIKey=QSJZITDSTPMCEM-ZDUSSCGKBG

Can one steer the course of a reaction by selectively applying a force to a molecule? Atomic force microscopy opens up this avenue. Martinez¹ has just published a computational study on the ring opening of cyclobutene with applied forces. Cyclobutene should ring-open in a conrotatory fashion according to the Woodward-Hoffman rules. But Martinez shows that by pulling on cyclobutene in a cis fashion, the disrotatory pathway can become the more favored route. Thus, it appears that mechanochemistry might be an alternative way to create selectivity in chemical reactions!

References

(1) Ong, M. T.; Leiding, J.; Tao, H.; Virshup, A. M.; Martinez, T. J., “First Principles Dynamics and Minimum Energy Pathways for Mechanochemical Ring Opening of Cyclobutene,” J. Am. Chem. Soc., 2009, 131, 6377-6379, DOI: 10.1021/ja8095834.

InChIs

cyclobutene: InChI=1/C4H6/c1-2-4-3-1/h1-2H,3-4H2
InChIKey: CFBGXYDUODCMNS-UHFFFAOYAN