1. A! Aalto university School of Chemical Technology © Ari Koskinen KE-4.4120 Organic Synthesis 15. Chemistry of the Double Bond: Reactions at  -Center (Enolate Chemistry) Prof. Ari Koskinen Laboratory of Organic Chemistry C318

2. A! Aalto university School of Chemical Technology © Ari Koskinen Chemistry of the Double Bond 1. Reactions of the Carbonyl Group 1.1At Carbonyl 1.1.1Reduction (hydride addition) 1.1.2Alkylation 1.1.3Allylation/Propargylation 1.2At  -Center (Enolate Chemistry) 1.2.1Alkylation 1.2.2Aldol Reaction 1.3At  -Carbon of Enone 1.3.1Michael (1,4-) Addition 2.Reactions of Olefins 2.1Oxidation 2.1.1Epoxidation 2.1.2Dihydroxylation 2.1.3Aminohydroxylation 2.2Reduction

3. A! Aalto university School of Chemical Technology © Ari Koskinen Reactions of the Carbonyl Group Protons on the  -carbon are, in principle, acidic, and a non-nucleophilic base can deprotonate the carbon. A prerequisite for deprotonation is a correct conformation!

4. A! Aalto university School of Chemical Technology © Ari Koskinen Acidity of carbonyl compounds

5. A! Aalto university School of Chemical Technology © Ari Koskinen Acidity of keto and enol tautomers

6. A! Aalto university School of Chemical Technology © Ari Koskinen Simple carbonyls prefer keto form Bond strengths (kJ/mol )  bond  bond e Sum keto form(C-H) 440(C=O) 7201160 enol form(O-H) 500(C=C) 6201120 The enol form is usually less stable than the keto form. However, even small quantities of the enol form can be important!

7. A! Aalto university School of Chemical Technology © Ari Koskinen Carbonyl enolization in water

8. A! Aalto university School of Chemical Technology © Ari Koskinen Catalytic enolization in water: base

9. A! Aalto university School of Chemical Technology © Ari Koskinen Catalytic enolization in water: acid In both acid- and base-catalyzed enolizations, two things need to happen: 1) loss of proton from carbon and 2) protonation on oxygen. In the base-catalyzed enolization, these events take place in this order. In the acid-catalyzed enolization, the carbonyl is activated towards enolization by protonation at oxygen. A weak base (e.g. water) is then enough to pull off the proton.

10. A! Aalto university School of Chemical Technology © Ari Koskinen The enolate anion The enolate ion is quite nucleophilic and comparable to the allyl anion in its reactivity. The oxygen has more of the overall negative charge, but the carbon has more of the HOMO.

11. A! Aalto university School of Chemical Technology © Ari Koskinen Reactivity of the enolate anion

12. A! Aalto university School of Chemical Technology © Ari Koskinen Reactivity of the enolate ion In the enolate ion the oxygen atom has more of the overall negative charge the carbon atom has more of the HOMO Hard electrophiles (charged, polar electrophiles, RCOCl, R 3 SiCl, H + ) react preferably at the oxygen end Soft electrophiles (maximal orbital overlap; R-halides, I 2 ) react preferably at the carbon end

13. A! Aalto university School of Chemical Technology © Ari Koskinen Enolate Chemistry – The Beginning

14. A! Aalto university School of Chemical Technology © Ari Koskinen Enolate Chemistry – The Beginning

15. A! Aalto university School of Chemical Technology © Ari Koskinen Enolates The term enolate first appeared in 1907, when Hans Stobbe discussed the FeCl 3 color test for enols in terms of ‘das violette Eisenenolat’. The term was first applied to describe C=C-O - species in 1920, when Scheibler and Vo  described the preparation of several ester enolates. The first explicit formulation of a delocalized enolate was by Ingold, Shoppee and Thorpe in 1926, who represented base-catalyzed tautomerisms as shown below. The authors did not, however, use the term ‘enolate’, not even thirty years later! The ambident nucleophilic nature of enolates was established by 1937, when Hauser accurately described the base-promoted enolisation in the mechanism of acetoacetic ester condensation. In the early days, the enolates were generated in the presence of the electrophile. It was only in the ‘50’s that Hauser first reported the use of a preformed enolate to obtain cross-coupling products of esters and aldehydes.

16. A! Aalto university School of Chemical Technology © Ari Koskinen Enolates The first important base of reduced nucleophilicity was BMDA (bromomagnesium di-isopropylamide), which was first used by Hauser in 1949 as a catalyst for acetoacetic ester condensation. The first useful, nowadays perhaps the most popular base, was LDA (lithium di-isopropylamide), used originally by Levine for the same purpose in 1950  Hamell, M.; Levine, R. J. Org. Chem. 1950, 15, 162; Levine, R. Chem. Rev. 1954, 54, 467.  However, it took another decade until Wittig employed LDA for the deprotonation of aldimines in the ‘Wittig directed aldol condensation’.

17. A! Aalto university School of Chemical Technology © Ari Koskinen Methods for Enolate Generation

18. A! Aalto university School of Chemical Technology © Ari Koskinen Catalytic Cycloreductions, Cycloadditions and Cycloisomerizations: Enones as Latent Enolates in Catalysis Michael J. Krische, Univeristy of Texas at Austin Deprotonation-Derivatization of Unmodified Carbonyl Compounds Hauser (1951): First Use of Preformed Enolates (LiNH 2 /NH 3 ). Wittig (1963): First Use of LDA for Preformation of Aldimine Anion. Rathke (1970): First Use of LHMDS for Ester Enolate Preformation. Posner (1972): First Use of LDA for Ester Enolate Preformation. Metallo-Enolates and Related Enol Derivatives Stoichiometric Enolate Preformation Enolates from Carbonyls

19. A! Aalto university School of Chemical Technology © Ari Koskinen Regioselective enolisation of ketones Thermodynamic enolates: more substituted more stable favored by excess ketone, high temperature, long reaction time less than stoichiometric amount of base weak, sterically non-hindered base protic solvents Kinetic enolates: less substituted less stable favored by strong, hindered bases, low temperature, short reaction time at least stoichiometric amount of base strong, bulky base polar aprotic solvents House J. Org. Chem. 1971, 36, 2361. Stork J. Org. Chem. 1974, 39, 3459.

20. A! Aalto university School of Chemical Technology © Ari Koskinen Regioselective enolization

21. A! Aalto university School of Chemical Technology © Ari Koskinen Kinetic and thermodynamic control A tetrasubstituted alkene A is more stable If A and B can equilibrate, and [A] > [B] –A is the thermodynamic enolate If equilibration is not possible (e.g. large, strong base, which only ‘sees’ the methyl group), a kinetically controlled product mixture is formed; –B is the kinetic enolate

22. A! Aalto university School of Chemical Technology © Ari Koskinen Kinetic and thermodynamic control Kinetic vs. thermodynamic control

23. A! Aalto university School of Chemical Technology © Ari Koskinen Regioselective Enolate Formation THERMODYNAMIC ENOLATE FORMATION THERMODYNAMIC ENOLATE FORMATION: less than stoichiometric amount of base weak, sterically non-hindered base protic solvents KINETIC ENOLATE FORMATION KINETIC ENOLATE FORMATION: at least stoichiometric amount of base strong, bulky base polar aprotic solvents House J. Org. Chem. 1971, 36, 2361. Stork J. Org. Chem. 1974, 39, 3459.

24. A! Aalto university School of Chemical Technology © Ari Koskinen Kinetic and thermodynamic control

25. A! Aalto university School of Chemical Technology © Ari Koskinen Enolates Hydrophobic strong bases (triphenylmethylsodium, -potassium, and -lithium) were developed in the ‘50’s and ‘60’s as reagents soluble in most common organic solvents and basic enough to deprotonate ketones and esters. Furthermore, they are highly colored, and can thus serve as indicators - this is their principal use nowadays. Early examples of stoichiometric enolisation from normal ketones originated from the laboratories of Herbert O. House.

26. A! Aalto university School of Chemical Technology © Ari Koskinen Kinetic and thermodynamic control House, H.O.; Sayer, T.S.B.; Yau, C.-C. J. Org. Chem. 1978, 3, 2153.

27. A! Aalto university School of Chemical Technology © Ari Koskinen Kinetic and thermodynamic control House, H. J. Org. Chem. 1979, 44, 2400.

28. A! Aalto university School of Chemical Technology © Ari Koskinen Enolates, enol equivalents and metalloenamines

29. A! Aalto university School of Chemical Technology © Ari Koskinen Reactivity scale for neutral enol equivalents

30. A! Aalto university School of Chemical Technology © Ari Koskinen Regioselective Enolate Formation 1. Use of Activating Groups Baisted, J. Chem. Soc. 1965, 2340. Johnson, J. Am. Chem. Soc. 1960, 82, 614. Coates, Tetrahedron Lett. 1974, 1955.

31. A! Aalto university School of Chemical Technology © Ari Koskinen Regioselective Enolate Formation 2. Use of Blocking Groups Woodward J. Chem. Soc. 1957, 1131.

32. A! Aalto university School of Chemical Technology © Ari Koskinen Regioselective Enolate Formation 3. Use of Enamines Augustine Org. Synth Coll Vol V 1973, 869. E rel = 1.6 kcal/mol E rel = 0

33. A! Aalto university School of Chemical Technology © Ari Koskinen Regioselective Enolate Formation 4. Use of Enamines - Robinson type Augustine Org. Synth Coll Vol V 1973, 869.

34. A! Aalto university School of Chemical Technology © Ari Koskinen Use of enol equivalents: enamines The overall process achieves an alkylation of a ketone but strong bases are avoided altogether so there is no danger of uncontrolled addition reactions.

35. A! Aalto university School of Chemical Technology © Ari Koskinen Alkylation of enamines Enamines can be used only with the most reactive alkylating agents: allylic and benzylic halides  -halo carbonyl compounds methyl iodide

36. A! Aalto university School of Chemical Technology © Ari Koskinen Alkylation of aldehydes via enamines

37. A! Aalto university School of Chemical Technology © Ari Koskinen Regioselective Enolate Formation 5. Enones as Enolate Precursors

38. A! Aalto university School of Chemical Technology © Ari Koskinen Enones as Latent Enolates in Catalysis

39. A! Aalto university School of Chemical Technology © Ari Koskinen Regioselective Enolate Formation 6. Enol Derivatives a) Enol acetates House J. Org. Chem. 1965, 30, 1341, 2502. E rel = 2.3 kcal/mol E rel = 0

40. A! Aalto university School of Chemical Technology © Ari Koskinen Regioselective Enolate Formation 6. Enol Derivatives b) Silyl enolates Stork, G. J. Am. Chem. Soc. 1968, 90, 4462. House, H.O. J. Org. Chem. 1969, 34, 2324. Stork, G. J. Am. Chem. Soc. 1974, 96, 7114.

41. A! Aalto university School of Chemical Technology © Ari Koskinen Regioselective Enolate Formation

42. A! Aalto university School of Chemical Technology © Ari Koskinen LOBA: Bulky base Corey, S.J.; Gross, A.E. Tetrahedron Lett. 1984, 25, 495. Corey, S.J.; Gross, A.E. Org. Synth. 1987, 65, 166.

43. A! Aalto university School of Chemical Technology © Ari Koskinen Regioselective Enolization Denniff, P.; Whiting, D.A. J. Chem. Soc., Chem. Commun. 1976, 712. Denniff, P.;Macleod, I.; Whiting, D.A. J. Chem. Soc. Perkin I 1981, 82.

44. A! Aalto university School of Chemical Technology © Ari Koskinen Regioselective Enolization Lee, R.A.; McAndrews, C.; Patel, K.M.; Reusch, W. Tetrahedron Lett 1973, 965. Ringold, J.; Malhotra, S.K. Tetrahedron Lett 1972, 669.

45. A! Aalto university School of Chemical Technology © Ari Koskinen Regioselective Enolization Vetiver oil (originally cous-cous, from Indian perennial grass of Poaceae family) contains vetivones and khusimone, used in nearly 90% of western fragrances. Annual production of Lavania ca 250 tonnes.

46. A! Aalto university School of Chemical Technology © Ari Koskinen Regioselective Enolization Stork, G.; d’Angelo, J. J. Am. Chem. Soc. 1974, 06, 7114.

47. A! Aalto university School of Chemical Technology © Ari Koskinen Regioselective Enolization Gelin, S.; Gelin, R. Bull. Chim. Soc. Fr. 1970, 340-341.

48. A! Aalto university School of Chemical Technology © Ari Koskinen Synthesis of PGE 2 Intermediate Suzuki, M.; Yanagisawa, A.; Noyori, R. J. Am. Chem. Soc. 1985, 107, 3348.

49. A! Aalto university School of Chemical Technology © Ari Koskinen Enolates: Regioselectivity Krafft, M.E.; Holton, R.A. J. Org. Chem. 1984, 49, 3669. Kharasch reagent: Krafft, M.E.; Holton, R.A. J. Am. Chem. Soc. 1984, 106, 7619.

50. A! Aalto university School of Chemical Technology © Ari Koskinen The ene reaction Frontier orbital explanation: Normally we simply treat the  orbital of an alkene as an independent unit, without considering combinations with other orbitals. Here we need to do this to form the molecular HOMO. Review: Conia J.M. Synthesis 1975, 1–19.

51. A! Aalto university School of Chemical Technology © Ari Koskinen The ene reaction: examples The ene reaction usually requires a very reactive enophile (e.g. maleic anhydride) or a rather reactive alkene. Lewis acid catalysis can activate enophiles towards ene reactions, and intramolecular ene reactions are easier:

52. A! Aalto university School of Chemical Technology © Ari Koskinen Commercial synthesis of menthol

53. A! Aalto university School of Chemical Technology © Ari Koskinen Pd catalyzed alkylation Hegedus, L. J. Am. Chem. Soc. 1977, 99, 7093–7094. J. Am. Chem. Soc. 1980, 102, 4973–4979.

54. A! Aalto university School of Chemical Technology © Ari Koskinen Greener alkylation? Mo, F.; Dong, G. Science 2014, 345, 68–72.

55. A! Aalto university School of Chemical Technology © Ari Koskinen Explanation Mo, F.; Dong, G. Science 2014, 345, 68–72.