Molecular Models for Problem Set 4, 2001.

Model energies are given in kcal/mol and are obtained using the AM1 Hamiltonian and the Chem3D modelling program.

Question 1.

Formulae establish that the missing component from A is phenylethene (styrene), produced by a retro-1, 3-dipolar cycloaddition reaction (suprafacial Huckel 4n+2 transition state). A then undergoes an intramolecular dipolar cycloaddition reaction to give a key intermediate in the synthesis of Histrionicotoxin. The suprafacial addition across the alkene ensures the stereochemistry of the cyano group as shown. The indicated regiochemistry of the cyanoalkene addition to the 1,3 dipole is indicated as perplexing by the authors (G. M. Williams, S. D. Roughley, J. E. Davies, A. B. Holmes and J. P. Adams, J. Am. Chem. Soc., 1999, 121, 4900) since normally the oxygen atom of such a dipole adds to the carbon of the alkene directly bearing the electron withdrawing group.

C (formed) C (not formed)
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Question 2

  1. The p2s + p2s cycloaddition is a 4n electron photochemical allowed process proceeding with suprafacial addition across both alkene components (M. L. Randall, P. C. K. Lo, P. J. Bonitatebus and M. L. Snapper, J. Am. Chem. Soc., 1999, 121, 4534).
  2. The alternate regioisomer is not formed when R=Me (or larger) due to steric hindrance between the two methyl groups (see molecular models).
  3. Three other so-called endo/exo stereoisomers are all consistent with the p2s + p2s cycloaddition. Molecular modelling can be used to establish the relative energies of all four isomers. The one actually formed is found to be at least 20 kJ/mol lower in energy then the other three, largely a result of minimisation of the steric repulsions between the R group and other atoms. Other stereoisomers could result from p2s + p2a addition across the two alkenes to give a trans ring geometry, but such stereochemistry would not be consistent with the rules for a 4n electron photochemically mediated cycloaddtion.

  4. Thermolysis requires a p2s + p2a retro- cycloaddition (4n electrons, Mobius transition state with an antarafacial component). The antarafacial component can be located on either of the forming two alkene bonds. For isomer X, this produces the cis alkene shown, twisting the original trans relationship of the two hydrogens on these two carbons by 180 degrees.

  5. Locating the antarafacial component on the other possible forming alkene results in the following isomer of X:
  6. Compound X has the characteristic 3-single/two-double bond pattern associated with the [3,3] sigmatropic Cope rearrangement. This is actually possible in two directions, but we concentrate on the one that creates an sp2 centre at C-8, the atom at which inversion of configuration is observed to occur. This produces a flexible 9-membered ring, which can flip the trans alkene bond by rotation about the adjacent single bonds, to produce a conformer with the C-8 hydrogen pointing up. Reverting the [3,3] sigmatropic reaction using this conformation will now reform the 5-8-5 ring system but with the correct stereochemistry at C-8.
  7. Repeating the sequence of events on the isomer of X produces the following compounds, i.e. bond rotation about the trans alkene and [3,3] Cope reclosure now inverts the configuration at the C-7 carbon. Molecular modelling indicates this pathway is only about 20 kJ/mol higher than the observed one, suggesting this might be a minor (unobserved) product of this reaction.

W (formed, -38.3) W (regio isomer,-35.6)
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W (stereoisomer, -28.2) W (stereoisomer,-34.1) W (stereoisomer,-32.1)
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X ( -48.8) Y (-40.9) Y (rotamer,-44.7) Z (-63.2)
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Isomeric X ( -51.1) Isomeric Y (-37.2) Isomeric Y (rotamer,-38.3) Isomeric ZZ (-64.6)
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