Sarah Siska. C. A. Morales Felkin-1 Chem 206 Fe/kin 1968 energy difference(44H)between interactions of RM+0 and Rl +o determines product reactant-like"transition state reactant-like transition state assumption of torsional strain in partially formed or broken bonds first fully staggered acyclic model based on most stable ground-state contormauon substituents minimized around R: leads to Karabatsos model energy differences between major and minor inconsistency in aldehyde substrates conformations are <1 kcal/mol see DAE Chem 206 Lecture Notes(2000) 18-08 Felkin model olar effect: maximize separation between Nu-M LRL ∠RL incoming anionic nucleophile and electronegative substituent(Rs, RM, or RL Reduction of a-Methyl Ketones R RI= RL Me 16 anti-Felkin t-Bu 1.6 Rationalizations Features Rs 时→Nm=m most stable a)AH(imine N+R)AH(carbonyl 0+R) ground state b)imine geometry =complexed C=0 geometry substituents minimized around conformer (complexed C=OOFR) RL RL ketone R accounted for: leads to Karabatsos. G.J. J. Am. Chem. Soc. 1967. 89. 1367 Cherest, M. Felkin, H. Prudent, N. Tetrahedron Lett. 1968, 18, 2199
R O M RS RL R O M RM RS RM O H M RM RL RS RS RL R O N H Z RM RL RS » O H RL RM RM RL Nu RM OH RL Nu RM OH RL O R RL Me RL RS RM R O M LiAlH4 RL RS RM R O M R RL Me OH R RL Me OH A B R Me Et i-Pr t-Bu RL RS RM Nu R OH Felkin: 1968 Chérest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 18, 2199 Felkin model • "reactant-like" transition state • assumption of torsional strain in partially formed or broken bonds: first fully staggered acyclic model • substituents minimized around R; leads to inconsistency in aldehyde substrates ➞ see DAE Chem 206 Lecture Notes (2000), 18-08 • polar effect: maximize separation between incoming anionic nucleophile and electronegative a-substituent (RS, RM, or RL) Nu: larger RL » better selectivity substituents minimized around ketone R 90° trajectory of nucleophile RL = Cy RL = Ph A / B 1.6 2.0 4.1 1.6 2.8 3.2 5.0 49 torsional strain accounted for; leads to fully staggered product + Features larger nucleophile » better selectivity Reduction of -Methyl Ketones Sarah Siska, C. A. Morales Felkin-1 Chem 206 Karabatsos model Nu: Nu: Karabatsos, G. J. J. Am. Chem. Soc. 1967, 89, 1367 • energy difference (DDH°) between interactions of RM ↔ O and RL ↔ O determines product ratio • reactant-like transition state • model based on most stable ground-state conformation • energy differences between major and minor conformations are <1 kcal/mol Nu-M + major (Felkin) minor (anti-Felkin) Rationalizations most stable ground state conformer a) DH°(imine N ↔ R) » DH°(carbonyl O ↔ R) b) imine geometry » complexed C=O geometry DH°(imine N ↔ R) » DH°(complexed C=O O ↔ R) Z = alkyl, OR, NR2 Nu:
Sarah Siska. C. A. Morales Felkin-2 Chem 206 Felkin: Accounting for Less Selective Reactions Weaknesses in Felkins Argument 1)The t-butyl ketone case 1)Polar effect with a-branching, in any staggered conformation, syn-pentane is impossible to avoid main repulsion to minimize between Nu and electronegative group X le xre no justification given Rs 2)Breakdown for aldehydes 2) Transition states for minor products(does not consider conformers without ketone R, important steric interaction removed with Rl next to R) would predict RM to be next to H rather than carbonyl Rs possible for wrong prediction when RM is+Ry small sma Anh's Solutions RL 1)Antiperiplanar effect 3)2-methylcyclohexanone best acceptor o* orbital aligned parallel to t and*c=0+0c-x cannot adopt Felkin-type conformation; still considered as a reactant-like orbitals of carbonyl n地ucx transition state stabilization of incoming selectivity based on competition between torsional strain and steric 2)Non-perpendicular attack ation of the bur Anh. N. T: Eisenstein. O Nouv. J. Chim. 1977. 1. 61 Burgi, H.B∴Dunt,J.D (CH steric strain (small Nur 1973,955065 igi, H. B; Dunitz, J. D Tetrahedron 1974. 30. 1563 Cherest, M. Felkin, H. Prudent, N. Tetrahedron Lett. 1968. 18, 2199: 2205 favored disfavored
RL RS RM M O R RM RL RS M O R (CH2)4 (CH2)4 O Me H Nu: Nu: O Cy t-Bu Me O Me LAH LiAlH4 Me t-Bu Cy OH 1.6 Me OH t-Bu Cy Me OH 1 Me OH H O Me RL RS RM Me Me Me O Felkin: Accounting for Less Selective Reactions 1) The t-butyl ketone case • cannot adopt Felkin-type conformation; still considered as a reactant-like transition state • selectivity based on competition between torsional strain and steric strain possible when RM is relatively small torsional strain (large Nu:) steric strain (small Nu:) + : Sarah Siska, C. A. Morales Felkin-2 Chem 206 major Nu: • with a-branching, in any staggered conformation, syn-pentane is impossible to avoid 2) Transition states for minor products (does not consider conformers with RL next to R) 3) 2-methylcyclohexanone possible for small nucleophiles + Chérest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 18, 2199; 2205 RL RS RM M O H RL RS RM M O H RL RS RM H O M Nu: Nu: Nu: X RS RM/L R O M O X RM/L RS H M Anh, N. T.; Eisenstein, O. Nouv. J. Chim. 1977, 1, 61 Bürgi, H. B.; Dunitz, J. D.; Shefter, E. J. Am. Chem. Soc. 1973, 95, 5065 Bürgi, H. B.; Dunitz, J. D.; Lehn, J. M.; Wipff, G. Tetrahedron 1974, 30, 1563 Weaknesses in Felkin's Argument Nu: • main repulsion to minimize between Nu and electronegative group X -- no justification given 1) Polar effect 2) Breakdown for aldehydes wrong prediction Anh's Solutions 1) Antiperiplanar effect • best acceptor s* orbital aligned parallel to p and p* orbitals of carbonyl; stabilization of incoming anion pC=O ↔ s*C-X nNu ↔ s*C-X • without ketone R, important steric interaction removed: would predict RM to be next to H rather than carbonyl 2) Non-perpendicular attack • incorporation of the Bürgi-Dunitz trajectory favored disfavored Nu