Cycloaddition reactions [2+2]

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1. CYCLOADDITION REACTIONS [2+2 Cycloaddition Reactions] Dr. Harish Chopra Professor Department of Chemistry SLIET, LONGOWAL

2. INTRODUCTION Cycloaddition reactions are intermolecular pericyclic processes involving the formation of a ring from two independent conjugated systems through the formation of two new  -bonds at the termini of the  -systems. The reverse process is called cycloreversion or is referred to as a retro-reaction .

3. Types of Cycloaddition Cycloaddition reactions can be discussed under three important class of reactions [2+2] Cycloaddition [4+2] Cycloaddition [Diels-Alder reaction] [1,3]-Dipolar cycloaddition .

4. [2+2] Cycloaddition Thermally, [2 + 2] cycloaddition is geometrically forbidden , as the HOMO and LUMO of the participating olefins would not be able to achieve the orbital overlap required for σ-bond formation.

5. On the other hand, the photochemical [2 + 2] cycloaddition is allowed and leads to stereospecific cyclobutane formation .

6. If a closer look is taken about the thermal [2+2] cycloaddition, as it is geometrically forbidden, but not orbital symmetry forbidden . It can be explained on the basis of two new concepts, suprafaciality and antarafaciality , The consequence of suprafaciality and antarafaciality is that many processes that are Woodward-Hoffmann allowed can be forbidden to occur because of geometrical constraints on the system Suprafaciality - when, in a pericyclic reaction, the bond forming interaction occurs on the same face of a π-system , Antarafaciality - when, in a pericyclic reaction, the bond forming interactions occur on opposite faces of a π- system .

7. Removal of steric bulk (H-atoms) around the π-system (as in the ketene) allows antarafacial bond formation that is geometrically forbidden in the ethylene [2 + 2].

8. In the suprafacial-suprafacial cases, the cycloadditions are symmetry allowed and geometrically allowed . In the suprafacial-antarafacial cases, the cycloadditions are symmetry allowed and generally geometrically disallowed . Woodward Hofmann Rules for Cycloaddition Reactions

9. Photochemical[2+2] Cycloaddition Reaction is stereo-specific. Least hindered transition state is observed Reactions of Enones with Alkenes

10. Photochemical[2+2] Cycloaddition Reactions of Enones with Alkenes: The first step in Corey’s synthesis of caryophyllene involved addition of cyclohexenone to isobutene to give predominantly the trans- cyclobutane (head-to-tail) derivative Major Product Cycloaddition of an enone with a cyclic alkene (A) [ cyclobut-1-ene-1-carbonitrile] , can occur with good stereoselectivity in favour of the thermodynamically more stable exo diastereoisomer

11. Photochemical[2+2] Cycloaddition Reactions of Enones with Alkenes:

12. Photochemical[2+2] Cycloaddition Reactions of Enones with Alkenes

13. Photochemical[2+2] Cycloaddition Reactions of Enones with Alkenes Reactions of Enones with Allenes

14. Photochemical[2+2] Cycloaddition Reactions of Enones with Alkynes Reactions of Enols with Alkenes ( DeMayo Reaction)

15. Photochemical[2+2] Cycloaddition Addition of C=C and C=O [ Paterno-Buchi Reaction] If an aldehyde or ketone -system replaces one of the alkene units, then photochemical [2+2] cycloaddition is termed the Paterno–Buchi reaction and an oxetane product is produced. Typically a mixture of stereo- and regioisomers of the oxetane is formed in intermolecular cycloadditions of this type, although the use of small-ring alkenes favours the cis -fused ring products. Reactions are REGIOSELECTIVE

16. Photochemical[2+2] Cycloaddition Addition of C=C and C=O [ Paterno-Buchi Reaction] Synthesis of the antifungal agent (+)- preussin , cycloaddition of benzaldehyde with the dihydropyrrole led to the cis -fused products [A] and [B] . Hydrogenolysis of the benzylic C–O bond and reduction of the carbamate of the diastereomer [A] gave the target compound preussin . Preussin [A] [B]

17. Photochemical[2+2] Cycloaddition Addition of C=C and C=O [ Paterno-Buchi Reaction] Photocycloaddition of furan with nonanal gave the exo product [C] , which was converted to the antifungal metabolite avenaciolide . 3,4-Dimethylfuran and (3-Benzyloxy)- propanal undergoes Paterno-Buchi reaction to give oxetane derivative [D]. 3,4-Dimethylfuran (3-Benzyloxy)- propanal [D] Avenaciolide [A]

18. Photochemical[2+2] Cycloaddition Miscellaneous Reactions

19. Thermal [2+2] Cycloaddition HOMO/LUMO combination is anti-bonding at one end. However, if LUMO is rotated at an angle of 90° and HOMO & LUMO approaches perpendicular to each other than 2π s +2 π a interaction is possible which allows the thermal reaction to take place

20. Thermal [2+2] Cycloaddition Reactions Alkenes with Ketenes and Isocyanates

21. Thermal [2+2] Cycloaddition Reactions with Ketene Analogues and Equivalents

22. Thermal [2+2] Cycloaddition Reactions with Ketenes

23. Thermal [2+2] Cycloaddition Reactions of Ketenes with enamines Staudinger reaction (Synthesis of b - lactams )

24. Sources Used: 1. Modern Methods of Organic Synthesis, W. Carruthers ; Cambridge 2. Pericyclic Reactions, Ian Fleming, Oxford University Press, UK 3. NPTEL Lectures and Videos 4. Internet Sources are also Acknowledged

25. Thank You