2. Third Year Organic Chemistry Course CHM3A2 Frontier Molecular Orbitals and Pericyclic Reactions Part 4: Advanced Cycloaddition Reactions Facial Selectivities Tandem Reaction Ionic Reactions 1,3-Dipolar Cycloadditions Secondary Orbital Interactions

3. – Learning Objectives Part 4 – Advanced Cycloaddition Reactions CHM3A2 – Frontier Molecular Orbitals and Pericyclic Reactions – After completing PART 4 of this course you should have an understanding of, and be able to demonstrate, the following terms, ideas and methods. (vi)Cycloaddition reactions can be regioselective. The regioselectivity cannot be predicted from the simple treatment given to frontier molecular orbitals in this course. However, generalisations can be made from looking at classes of substituents (C, Z, X) which are in conjugation with the  -systems, which allow us to predict the regioselectivity in an empirical manner (CHM2I3). (vii)Tandem cycloaddition reactions are useful synthetic reactions for the construction of fused cyclic systems, however, one has to consider the implications of kinetic and thermodynamic control, in many cases. (viii)1,3-Dipolar cycloadditions are an important class of cycloaddition reactions, as they are a versatile route to highly functionalised heterocycles. They involve the reaction of a 1,3-dipole with a dipolarophile. (viii)Cycloaddition reactions can be initiated by photoexcitation. This allows many reactions that are not thermally allowed to occur. However, it is not clear in some cases whether the mechanism is truly concerted in nature, or has some component of radical generation and a step-wise reaction.

4. Facial Selectivities

6. anti- and syn-Diels-Alder Adducts X% anti-Adduct % syn-Adduct H2080 SMe9010 S(O)Me>95<5 S(O) 2 ME>95<5 iPr>95<5 Et>95<5 CHO>95<5 CH 2 OH>95<5 OH<5>95 Sterically Favoured ? [  4s +  2s] ‡

7. Other Dienophiles and  -Facial Diastereoselectivity: [  4s +  2s] ‡

8. Tandem Diels-Alder Reactions

10. Tandem Diels-Alder Reactions Low T High T KINETIC PRODUCT THERMODYNAMIC PRODUCT LUMO of Dienophile Closest to Butadiene HOMO Z groups least sterically hindered [  4s +  2s] ‡ Retro [  4s +  2s] ‡

11. KINETIC PRODUCT THERMODYNAMIC PRODUCT Thermal [  4s +  2s] ‡

12. Ionic Cyclo-additions

14. Cationic Cycloadditions (Allyl Cation) Thermal [  2s +  4s] ‡

15. Anionic Cycloadditions (Allyl Anion) Thermal [  4s +  2s] ‡

16. 1,3-Dipolar Cyclo-additions

17. 1,3-Dipolar Cycloadditions REGIOISOMERS  4s +  2s  4s +  2s [  4s +  2s] ‡

18. Linear 1,3-Dipoles

19. Bent 1,3-Dipoles

20. K.N. Houk, J. Sims, R.E. Duke, R.W. Strozier, J.K. GeorgeJ. Am. Chem. Soc., 1973, 95, 7287 Desymmetrising Coefficients and Regiochemistry  2 HOMO

21. 1,3-Dipolar Cycloaddition Reaction Examples [  4s +  2s] ‡ Major Product Minor Product

22. Minor Product Major Product [  4s +  2s] ‡

24. Secondary Orbital Interactions

25. Secondary Orbital Interactions. 1 Thermal [  4s +  2s] ‡ Secondary Orbital Interaction Control

26. Note that all of the  -conjugated system of maleic anhdride needs to be considered, and not just the monoene unit, in order that the secondary orbital interactions can be taken into account The ENDO Transition State [  4s +  2s] ‡

27. The EXO Transition State This orientation of reactants in the transition state does not facilitate any secondary orbital interactions. Thermal [  4s +  2s] ‡

28. Energy Reaction Coordinate Endo Isomer: Kinetic Product  G 2 ‡<  G 1 ‡ G1°G1° G2‡G2‡ G1‡G1‡ G2°G2° Exo Isomer: Thermodynamic Product  G 1 ° >  G 2 ° Kinetic & Thermodynamic Product [  4s +  2s] ‡

30. Secondary Orbital Interactions. 2 Antibonding Secondary Orbital Interactions Thermal [  4s +  6s] ‡ Thermal 10 (4n+2, n=2) e D-A

32. – Summary Sheet Part 4 – Apied Cycloaddition Reactions CHM3A2 –Frontier Molecular Orbitals and Pericyclic Reactions – Attack of a monoene on appropriately substituted dienes can take place in a suprafacial/suprafacial process on either face of the diene, leading two diastereoisomers. It is often found that there is some p-facial diastereoselectivity, which can usually be explained by considering the ease of accessibility of the monoene to the two different faces. In many cycloaddition reactions with the correct substitution on the two partners, the two components are able to react to afford regioisomers. In practice it is found that one regioisomer is formed in preference to the other. The reason for this is attributed to the matching of the coefficients of the HOMO and LUMO in the transition state. Calculation predicts that the smallest coefficient of one partner (HOMO) will interact with the smallest coefficient of the second partner (LUMO), and vice versa for the large coefficients, because this results in the smallest energy gap and the lowest energy transition state. In many, instances the use of a Bronsted (H+) or a Lewis acid, increases the propensity for one regioisomer. The reason for this is that the coefficients at the termini of p-system are made increasingly larger and smaller, respectively, and as a result, the overlap with the second reacting partner becomes even more efficient. Cycloaddition reactions can also be utilised to construct multiple ring systems, via what are referred to as tandem cycloaddition reactions. These are important reactions in synthetic chemistry as complex fused ring systems with high degrees of stereo and regio control can be formed in one-pot reactions. The nature of tandem cycloaddition reactions generally means that the second cycloaddition has two choices, one of which is controlled by thermodynamics (the product stability) and the other by kinetics (the ease of attainment of the transition state). Thus, it is important to bear this in mind in experimental design: should the reaction be carried out a low temperatures (favouring the kinetic product) or high temperatures (favouring the thermodynamic product), for example. Another extremely important class of cycloaddition reactions are the 1,3-dipolar cycloadditions. This class of reactions allows the construction of heterocycles with high degrees of stereo and regioselectivity, and is thus very valuable in organic synthesis. The reactions involve a 1,3-dipole (X — Y + =Z, a 4 p-electron system) and a dipolarophile (generally an alkene, a 2 p -electron system), reacting in a concerted fashion via an ss transition state. Cycloaddition reactions which were not permitted by thermal routes because the phase overlap of the FMOs was not appropriate, can be accomplished under photochemical conditions. For example, monoenes can be photodimerised. However, the product outcomes sometimes suggest that the reaction is not concerted (a stepwise radical mechanism may be involved). Furthermore, the issue is complicated by the fact that photoexcited singlet and triplet states can be formed, which results in different product outcomes. In appropriate cases, the Diels-Alder reaction proceeds kinetically with endo selectivity. The so-called endo rule can be rationalised in terms of favourable secondary orbital interactions. Additionally, these so-called secondary orbital interaction can also explain the formation of only one diastereoisomer, by observing antibonding secondary orbital interactions (a point we shall return to when examining sigmatropic rearrangements).

33. Remember the following very wise phrase: The man who says he can and The man who says he can’t Are both right! Ali G!! Good Luck with your exams… …but remember they are nothing more than a stepping stone in life.

35. J.D. Walker Tandem Diels-Alder Cycloadditions in Organic Synthesis Chem. Rev., 1996, 96, 167. W. Adams, M. Prein  -Facial Diastereoselectivity in the [4+2] Cycloaddition of Singlet Oxygen as a Mechanistic Probe Acc. Chem. Res., 1996, 29, 275. P.J. Parsons, C.S. Penkett, A.J. Shell Tandem Reactions in Organic Synthesis: Novel Strategies for Natural Product Elaboration and the Development of New Synthetic Methodology Chem. Rev., 1996, 96, 195. Further Reading on Cycloaddition Reactions

36. Exercise 1: 4n+2  Cycloadditions Identify the starting materials and propose arrow pushing mechanisms for the formation of the following products 64% 23% 45%

37. Answer 1: 4n+2  Cycloadditions Identify the starting materials and propose arrow pushing mechanisms for the formation of the following products 45% 23% 64%

38. Exercise 2: 4n+2  Cycloadditions Identify the starting materials and propose arrow pushing mechanisms for the formation of the following products

39. Answer 2: 4n+2  Cycloadditions Identify the starting materials and propose arrow pushing mechanisms for the formation of the following products

40. Exercise 3: 4n+2  Cycloadditions and a bit more! Rationalise the following reaction scheme utilising frontier molecular orbitals and identify reagent A.

41. Answer 3: 4n+2  Cycloadditions and a bit more! Rationalise the following reaction scheme utilising frontier molecular orbitals and identify reagent A. Attacking from least hindered side  4s +  2s

42. Exercise 4: 4n+2  Cycloadditions Rationalise the following reaction scheme utilising secondary orbital interactions.

43. Answer 4: 4n+2  Cycloadditions Rationalise the following reaction scheme utilising secondary orbital interactions. Thermodynamic Product Kinetic Product  2 HOMO  3 LUMO Primary Orbital Interactions Secondary Orbital Interactions