Chapter 39 — Exercises

Forty problems on pericyclic reactions and Woodward-Hoffmann rules. Drawing required wherever a structure or mechanism is asked for. ∗ marks problems with full worked solutions in Appendix Answers to Selected Exercises.

Section A — Classification

39.1∗ (routine) Classify each as cycloaddition, electrocyclic, or sigmatropic: (a) Diels-Alder (4π + 2π) (b) Cope rearrangement (1,5-hexadiene → 1,5-hexadiene) (c) Claisen rearrangement (allyl vinyl ether → γ,δ-unsaturated aldehyde) (d) 1,3,5-hexatriene → 1,3-cyclohexadiene (e) Two ethenes + UV → cyclobutane (f) Carbonyl ene reaction (g) [1,5]-hydrogen shift in 1,3-pentadiene

39.2 (routine) Why are pericyclic reactions concerted? What does "concerted" mean mechanistically?

39.3 (moderate) Compare a Diels-Alder ([4+2]) with a [2+2] cycloaddition. Why is one thermally allowed and the other not?

Section B — Cycloadditions

39.4∗ (routine) Apply Woodward-Hoffmann: is each cycloaddition thermal or photo allowed? (a) [4+2] (Diels-Alder) (b) [2+2] (c) [6+4] (d) [4+4] (e) [3+2] (1,3-dipolar)

39.5 (routine) Why is the Diels-Alder [4+2] cycloaddition thermal allowed? Show the FMO analysis (HOMO of diene + LUMO of dienophile).

39.6 (moderate) Predict the stereochemistry of the Diels-Alder product of: (E,E)-2,4-hexadienoate + dimethyl maleate.

39.7 (moderate) A [2+2] photochemical cycloaddition of two ethenes gives cyclobutane. Why does this work under UV but not thermally?

39.8 (challenge) A 1,3-dipolar cycloaddition of azide + alkyne (the click reaction) gives a 1,2,3-triazole. Verify it is thermally allowed by counting electrons.

Section C — Electrocyclic reactions

39.9∗ (routine) Electrocyclic closure of 1,3-butadiene (4 π electrons): is it thermal allowed? Conrotatory or disrotatory? Predict product stereochemistry from (E,E)-2,4-hexadiene → 3,4-dimethylcyclobutene.

39.10 (routine) Electrocyclic closure of 1,3,5-hexatriene (6 π electrons): is it thermal allowed? Conrotatory or disrotatory?

39.11 (moderate) Predict the stereochemistry of the electrocyclic closure of (E,Z,E)-2,4,6-octatriene → 5,6-dimethylcyclohexa-1,3-diene under thermal conditions.

39.12 (moderate) The same substrate as 39.11, but under photochemical conditions. Compare.

39.13 (challenge) Sketch the orbital symmetry argument for the conrotatory thermal closure of butadiene → cyclobutene. Show the HOMO of butadiene.

Section D — Sigmatropic rearrangements

39.14∗ (routine) Draw the Cope rearrangement of 1,5-hexadiene. Identify the [3,3] sigmatropic shift. What happens (degenerate rearrangement)?

39.15 (routine) Draw the Claisen rearrangement of allyl vinyl ether. Identify the [3,3] sigmatropic shift.

39.16 (moderate) Draw the Ireland-Claisen rearrangement of an ester enolate. Predict the product.

39.17 (moderate) Predict the product of [1,5]-H shift in 1,3-pentadiene-d₃ (with H replaced by D at one carbon).

39.18 (challenge) Why is [1,3]-H shift thermal forbidden but [1,5]-H shift thermal allowed? Connect to electron count and supra/antarafacial argument.

Section E — Stereochemistry of pericyclic reactions

39.19∗ (routine) A Claisen rearrangement uses a chair-like TS. Predict the stereochemistry of: (E)-allyl vinyl ether + heat → ?

39.20 (moderate) A Cope rearrangement of (E,E)-1,5-hexadiene-2,3-diol gives a syn or anti diol product? Hint: chair TS.

39.21 (challenge) A Diels-Alder of an enantiopure diene + dienophile gives one diastereomer. How does the chair-like TS of the [4+2] determine this?

39.22 (challenge) Enantioselective Diels-Alder uses a chiral Lewis acid catalyst. Sketch the principle.

Section F — Vitamin D photobiology

39.23∗ (routine) Sketch the conversion of 7-dehydrocholesterol to vitamin D₃ via: (a) photochemical electrocyclic ring opening (B-ring of steroid). (b) thermal [1,7]-sigmatropic H shift to give vitamin D₃.

39.24 (moderate) Why does the photochemical step require UVB light specifically (280-315 nm)? Connect to the energy gap of the steroid's π system.

39.25 (challenge) Why are people at high latitudes (UK, Canada, etc.) at higher risk of vitamin D deficiency? Connect to the Woodward-Hoffmann pericyclic step.

Section G — Diels-Alder applications

39.26∗ (routine) Predict the product of the Diels-Alder of 1,3-butadiene + maleic anhydride.

39.27 (routine) Why is maleic anhydride a particularly good dienophile? Connect to its LUMO energy.

39.28 (moderate) Predict the product of an intramolecular Diels-Alder (IMDA) of a diene + dienophile in the same molecule. Tethered substrates close to give a polycyclic product.

39.29 (challenge) Design a Diels-Alder reaction to make a complex 6-membered ring with 4 stereocenters in one step.

Section H — Modern pericyclic reactions

39.30 (routine) What is the Nazarov cyclization? Why is it pericyclic-like (4π electrocyclic) but Lewis acid-catalyzed?

39.31 (moderate) What is the carbonyl ene reaction? Compare to Diels-Alder.

39.32 (challenge) What is hetero-Diels-Alder? Give an example with a C=N or C=O dienophile.

39.33 (challenge) Modern catalytic Diels-Alder uses chiral Lewis acid. Sketch the principle.

Section I — Drawing TSs

39.34∗ (moderate) Draw the chair-like TS for a Diels-Alder. Identify suprafacial-suprafacial.

39.35 (moderate) Draw the chair-like TS for a [3,3] sigmatropic Cope rearrangement.

39.36 (challenge) Compare the chair-like and boat-like TS for a Cope rearrangement. Why is chair preferred?

Section J — Synthesis applications

39.37 (routine) Use a Claisen rearrangement to install a stereocenter in a terpene synthesis. Sketch the substrate and product.

39.38 (moderate) Use a Diels-Alder to make a 6-membered ring with two new stereocenters. Plan the substrate.

39.39 (challenge) Combine Diels-Alder + Claisen rearrangement in a synthesis. Show the sequence.

39.40 (challenge) A natural product has a key 6-membered ring with two contiguous stereocenters. Propose a Diels-Alder retrosynthesis.

Notes for instructors: Common stumbling blocks for Chapter 39: (1) Mismatching thermal vs photochemical with allowed/forbidden. (2) Confusing disrotatory vs conrotatory. (3) Forgetting that the Cope/Claisen are [3,3]. (4) Missing the chair-like TS preference for [3,3]. Computational exercises: visualize HOMO and LUMO of dienes and dienophiles using molecular orbital software.