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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Am Chem Soc. Author manuscript; available in PMC 2010 May 20.
Published in final edited form as:
PMCID: PMC2744767

Thermodynamic Control of the Electrocyclic Ring Opening of Cyclobutenes: C=X Substituents at C-3 Mask the Kinetic Torquoselectivity


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The thermal ring-opening reactions of 4-phenyl-1,3,3-triethoxycarbonylcyclobutene and 4-methyl-1,3,3-triethoxycarbonylcyclobutene yield dienes that result from an unexpected selectivity for “inward” rotation of the phenyl and methyl groups. With 1-ethoxycarbonyl-4-phenylcyclobutene, “outward” rotation of the phenyl group occurs exclusively. Density functional theory was used to investigate the role of the 3,3-geminal diester groups and the origin of torquoselectivity in these electrocyclic reactions. The rules of torquoselectivity still hold, with a calculated 6–8 kcal/mol preference for outward rotation of the methyl and phenyl substituents. However, cyclization of the “out” dienes to pyran intermediates allows for isomerization and thermodynamic control of stereoselectivity.

Cyclobutenes undergo conrotatory ring-opening reactions under thermal conditions to yield dienes.1 Two conrotatory processes—clockwise or counter-clockwise rotation of all C-3 and C-4 substituents—are always possible, but one mode is preferred in asymmetric rings. This “torquoselectivity” is controlled by the electronic nature of the C-3 substituent: donors (X = CH3, OR, halides) rotate outward, while strong acceptors (CHO, NO, SiR3, B(OR)2) rotate inward.2 No violations of this fundamental stereochemical principle of electrocyclic reactions are known.

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However, one of our groups recently observed an unexpected inward rotation of donors in the ring-opening reactions of triester-substituted Cyclobutenes, 1a*–b* (Scheme 1).3 The 3-phenyl Cyclobutenes exhibit normal outward rotation of the phenyl group; no previous examples of inward rotation of phenyl groups were known.4 Because cyclobutene 1c* opens in the expected outward fashion to give 3c*, it became clear that the geminal esters play a role in determining the final diene ratio. We now report a computational study that provides an explanation for the unexpected torquoselectivities of Cyclobutenes la*–b*.5 All ethyl esters were modeled computationally by methyl esters; the experimental structures are designated by asterisks (“*”).

Scheme 1
1a*: R1 = CO2Et, R2 = Me (80 °C, 36h): 2a*/2a′*:3a*/3a′* = 4.5:1

In contrast to the experimental results in Scheme 1, all calculated activation enthalpies for inward (TS1) and outward (TS2) opening of Cyclobutenes 1a–c show a high selectivity for outward rotation of R2 (Table 1). Thus the rules of torquoselectivity are predicted to be preserved. TS1b and TS2b are shown in Figure 1.

Figure 1
Ring-opening transition structures of 1,3,3-trimethoxycarbonyl-4-phenyl-cyclobutene (1b)
Table 1
Calculated ring-opening activation enthalpies of 1a–ca

This disagreement between theory and experiment is reconcilable if there is thermodynamic control of the experimental results. We explored the possibility that the terminal ester groups (R1) may facilitate isomerization of “out” dienes 3*/3′* to the thermodynamically more stable “in” dienes 2*/2′* (Table 2). However, these isomerization barriers were calculated to be high (28–36 kcal/mol, entries 1–4). The lower barrier for 3b′ (entry 4) is presumably due to stabilizing C=O•••H interactions that are more pronounced compared to the other isomerization transition structures. (See Supporting Information). Diene 3c, which does not bear the geminal esters, isomerizes to the “in” diene with a similar barrier (entries 5–6). These calculations were also performed with UB3LYP6 and afforded the same results.

Table 2
Activation enthalpies for isomerization of 3/3′ to 2/2

During the investigation of the isomerization of 3a–b to 2a–b, we located a low-energy (2H)-pyran intermediate 4 (Scheme 2). A similar cyclization was previously observed in the electrocyclic ring opening of 3-formyl-3-carboxymethyl-cyclobutene;7 the resulting diene 5 cyclizes to (2H)-pyran 6, which was observable by 1H-NMR but could not be isolated in pure form. Its structure was verified by Diels-Alder cycloaddition with tetracyanoethylene (TCNE) to yield 7.

Scheme 2
Cyclization of dienes 3′ and 5 to (2H)-pyrans 4 and 6

The activation enthalpies for closing “out” diene 3′ to pyran 4 (TS4) was calculated to be only 12–13 kcal/mol (Table 3). The facile ring closure of 2,4-pentadienals has been attributed to the close proximity of the nucleophilic oxygen lone pairs with the C-5 terminus.8 Pyran 4 re-opens to “in” diene 2′ (TS5) with higher barriers of 14–17 kcal/mol. The preferential outward rotation of donor R2 (TS4 vs. TS5) is consistent with the torquoselectivities of previously investigated 6π electrocyclic reactions.9 The structures of TS4b, 4b, and TS5b are given in Figure 2.

Figure 2
Ring closure of 3b′ and ring opening of pyran 4b.
Table 3
Relative enthalpies for cyclization of 3

Based on these results, the overall free energy profile for the ring-opening reactions of 1a and 1b is shown in Figure 3. The normal rules of outward torquoselectivity are followed, but cyclization of dienyl esters 3a–b to pyrans leads to isomerization and thermodynamic control of stereoselectivity. 1H-NMR studies support this mechanism. When either cyclobutene 1a* or a 4.5:1 mixture of dienes 2a*:3a* is heated in d6-DMSO at 80 °C, a ratio of approximately 3:1 is established after 12 h.

Figure 3
Overall pathway (relative free energies).

Finally, because pyran 4 was not observed by 1H-NMR, we attempted to trap pyran intermediate 4a via a Diels-Alder cycloaddition with TCNE. The product was not observable even at 140 °C, which was not surprising considering the steric and electronic nature of 4. Calculations predict that the reaction of 4a with TCNE is highly unfavored, with ΔG = 23.0 kcal/mol (TS6) and ΔGrxn = 13.5 kcal/mol. In agreement with experimental results, the activation free energy for cycloaddition of simple pyran 6 with TCNE was calculated to be feasible, with ΔG = 20.9 kcal/mol (TS7) and ΔGrxn = −6.2 kcal/mol.

In conclusion, we have shown that electronic control of the kinetic torquoselectivity in thermal ring-opening reactions of cyclobutenes consistently holds, even in highly substituted cases, but extended conjugation at C-3 allows for isomerization of products and thermodynamic control of the diene in:out ratio.

Supplementary Material



We are grateful to the National Institute of General Medical Sciences, National Institutes of Health (GM 36700, K. N. H.) and University of Wisconsin (W. T.) for support of this work.


Supporting Information Available: Experimental procedures and spectral data for all new compounds. Cartesian coordinates and energies of all reported structures and full authorship of reference 5. This material is available free of charge via the Internet at


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