Sarah Siska. C. A. Morales Models for Carbonyl Addition Chem 206 ■ Useful reviews http://www.courses.fasharvardedu/-chem206/ Mengel, A Reiser, O. Chem. Rev. 1999. 99, 1191-1223 Chemistry 206 Gung, B. W. Tetrahedron 1996, 52, 5263-5301 Advanced Organic Chemistry Reetz, M. T. Angew. Chem. Int. Ed. Engl. 1984, 23, 556-569 Lecture number 20 Morrison, J D; Mosher, H. S. Asymmetric Organic Reactions Prentice Hall Inc. 197 Wipf, P; Kim, Y.J. Am. Chem. Soc. 1994, 116, 11678-11688, ref. 1-5, 7 The Evolution of Models for Carbonyl Addition ■ A problem Construct a model for the addition process in eq 1 using the principles learned Ms O BF3. 0Et2 (1) 1.3-Anti Aldehydes 1& 2 contain 2 stereocenters, each of which may infiuence the course of the addition process. For 1, the reaction is Felkin selective for all Fischer Cornforth Anh/Eisenstein Tomoda enolsilanes; however, for 2, this is not the case. Explain. For the answer see Felkin Evans,JACS1996,118,4322.(pd) OPMB 1, 2-Asymmetric Induction Models 1,3-Asymmetric Induction Models Merged 1, 2-and 1, 3-Asymmetric Induction Felkin Me Unpredicted, highly selective carbonyl additions OTMS R=Me,tBu≥97:3 BF3. OEt2 a Reading Assignment for this Week Carey Sundberg: Part A; Chapter 8 OPMB Reactions of Carbonyl Compounds Monda Matthew d shair November 4.2002 R=t-Bu96:4 R=Me4:96
http://www.courses.fas.harvard.edu/~chem206/ R OTMS H Rb O OP BF3•OEt2 Me H iPr O OPMB Me iPr OH OPMB R O Me H iPr O OPMB Me iPr OH OPMB R O R OTMS BF3•OEt2 Rb OH OP R O iPr OH OPMB R O Me Sarah Siska, C. A. Morales Chem 206 Matthew D. Shair Monday, November 4, 2002 ■ Reading Assignment for this Week: Carey & Sundberg: Part A; Chapter 8 Reactions of Carbonyl Compounds Models for Carbonyl Addition Chemistry 206 Advanced Organic Chemistry Lecture Number 20 The Evolution of Models for Carbonyl Addition ■ Useful Reviews (1) 1,3-Anti Construct a model for the addition process in eq 1 using the principles learned thus far in the course. Felkin 96 : 4 4 : 96 R = t-Bu R = Me R = Me, t-Bu ³ 97 : 3 (2) (3) ■ A problem Aldehydes 1 & 2 contain 2 stereocenters, each of which may influence the course of the addition process. For 1, the reaction is Felkin selective for all enolsilanes; however, for 2, this is not the case. Explain. For the answer see: Evans, JACS 1996, 118, 4322. (pdf) 1 2 Fischer Cram Cornforth Felkin Anh/Eisenstein Cieplak Tomoda ■ 1,2-Asymmetric Induction Models ■ 1,3-Asymmetric Induction Models ■ Merged 1,2- and 1,3-Asymmetric Induction ■ Unpredicted, highly selective carbonyl additions Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191-1223 Gung, B. W. Tetrahedron 1996, 52, 5263-5301 Ager, D. J.; East, M. B. Tetrahedron 1992, 48, 2803-2894 Reetz, M. T. Angew. Chem. Int. Ed. Engl. 1984, 23, 556-569 Morrison, J. D.; Mosher, H. S. Asymmetric Organic Reactions; Prentice Hall Inc.: 1971 Wipf, P.; Kim, Y. J. Am. Chem. Soc. 1994, 116, 11678-11688, ref. 1-5, 7
Sarah Siska. C. A. Morales Models for Carbonyl Addition Introduction Chem 206 ■ Definition of terms Fischer, and the Dawn of Asymmetric Induction Felkin product commonly COOH COOH accepted term for the major Nu carbonyl addition product predicted 1)HCN the felkin-Anh model also predicted by Cram and Karabatsos R M for steric cases. Cornforth for CH2OH a-heteroatom(non-chelating)cases M arabinose L-gluconic acid RuX not isolated initially. but later found in mother liquor Felkin-Anh model "To my knowledge these observations furnish the first definitive evidence that further synthesis with asymmetric Felkin products anti-Felkin products/ systems proceeds in an asymmetric manner Emil Fischer. 1894 Fischer. E. Ber. 1890. 23 2611 NUM Fischer. E. Ber. 1894. 27. 3189 R RS Assimilation in nature: propagation of asymmetry from one chiral molecule to another CO. HcO glucose also Cram-chelate produc Fischer. E. Ber. 1894. 27. 3189 Freudenberg, K Adv in Carbohydrate Chem. 1966, 21, 1
Sarah Siska, C. A. Morales Models for Carbonyl Addition Introduction Chem 206 R RS RM RL O H RL RM O H RM/L O X R RS RM RL HO Nu Nu RL OH RM Nu RM/L OH X Nu RL OH RM Nu RM/L OH X R RS RM RL Nu OH RL/X RS RM R O M Felkin product = commonly accepted term for the major carbonyl addition product predicted by the Felkin-Anh model; also predicted by Cram and Karabatsos for steric cases, Cornforth for a-heteroatom (non-chelating) cases Nu: Felkin-Anh model Felkin products anti-Felkin products ■ Examples: also Cram-chelate product Nu–M Nu–M Nu–M + + + ■ Definition of Terms glucose* CHO H OH HO H HO H CH2OH CO2, H2CO H OH H OH HO H HO H CH2OH COOH H OH HO H HO H CH2OH HO H COOH chlorophyll* Fischer, E. Ber. 1894, 27, 3189 Freudenberg, K. Adv. in Carbohydrate Chem. 1966, 21, 1 chlorophyll* Fischer, and the Dawn of Asymmetric Induction Fischer, E. Ber. 1890, 23, 2611 Fischer, E. Ber. 1894, 27, 3189 Assimilation in nature: propagation of asymmetry from one chiral molecule to another "To my knowledge these observations furnish the first definitive evidence that further synthesis with asymmetric systems proceeds in an asymmetric manner." L-arabinose 1) HCN 2) hydrolysis L-mannonic acid L-gluconic acid + ~3 : 1 not isolated initially, but later found in mother liquor -Emil Fischer, 1894
Sarah siska. C. A. Morales Crams rule Chem 206 Don cram: 1952 Among the 27 cited reactions whose stereoselection Cram's rule: "In reactions of the is predicted by Crams acyclic rule following type, that diastereomer will predominate which would be Rs formed by the approach of the hindered side of the double bond NH3CI then the rotational conformation mInol of the c-c bond is such that the Felkin (Felkin) double bond is flanked by the two Cram acyclic model least bulky groups attached to the Curtin, D.Y., Pollak, P 1. J. Am. Chem. Soc. 1951, 73, 992 adjacent asymmetric center. Ranking of steric bulk of a-substituents is somewhat arbitrary. Cram, D. J. Elhafez, F.A. A.J. Am. Chem. Soc. 1952, 74, 5828 Me NH3Cl due to the amino group's formation of a non-rigid"more adaptable"ion pair Basis for model Nu-M=RMgX, LAH one proposed transition state in the end, a suggestion of a chelate Nu-M RR=Ph RM= Me, Et RS RS RM Rs=H R=H. Ph Me Et edicted -MaB -Ma Br (Felkin product) selectivities ranging from 2: 1 to >4: 1, favoring Felkin product Features and Liabilities activated carbonyl considered Nu: to be largest group ■ Possib| e Pitfalls Low or unreported yields may result in misleading selectivitie Model based on qualitative assessment of steric bulk ■Bot steric repulsion Crams acyclic model is a convenient mnemonic that predicts Felkin between Rl and torsional effect products in a-alkyl or aryl aldehydes or ketones R not discussed not considered Cram. D. J. Elhafez F A.A. J. Am. chem. Soc. 1952. 74 5828
Sarah Siska, C. A. Morales Cram's Rule Chem 206 R O M R O M O R RS RM RL RL RM RS RL RM RS R RS RM RL HO Nu R RS RM RL Nu OH RL RM RS R OH Nu Don Cram: 1952 Nu: Nu-M Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc. 1952, 74, 5828 predicted (Felkin product) (anti-Felkin product) Cram acyclic model torsional effects not considered Nu: activated carbonyl considered to be largest group steric repulsion between RL and R not discussed Features and Liabilities Cram's Rule: "In reactions of the following type, that diastereomer will predominate which would be formed by the approach of the entering group from the least hindered side of the double bond when the rotational conformation of the C–C bond is such that the double bond is flanked by the two least bulky groups attached to the adjacent asymmetric center." + 90° trajectory of nucleophile Nu-M = RMgX, LAH RL = Ph RM = Me, Et RS = H R = H, Ph, Me, Et Basis for Model selectivities ranging from 2:1 to >4:1, favoring Felkin product H N H Me Ph O MgBr NH H MgBr Ph O MgBr O Ph Me NH3Cl Me Me Ph p-tolyl OH NH3Cl Me Ph HO p-tolyl NH3Cl Nu: ■ Bottom Line Cram's acyclic model is a convenient mnemonic that predicts Felkin products in a-alkyl or aryl aldehydes or ketones. p-CH3C6H4MgBr Nu: Among the 27 cited reactions whose stereoselection is "predicted" by Cram's acyclic rule: Ranking of steric bulk of a-substituents is somewhat arbitrary: Me > NH3Cl due to the amino group's formation of a non-rigid "more adaptable" ion pair major (anti-Felkin) minor (Felkin) yield not reported Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc. 1952, 74, 5828 one proposed transition state: in the end, a suggestion of a chelate . . . Curtin, D. Y.; Pollak, P. I. J. Am. Chem. Soc. 1951, 73, 992 • Low or unreported yields may result in misleading selectivities • Model based on qualitative assessment of steric bulk + ■ Possible Pitfalls
Sarah Siska. C. A. Morales Cornforth-1 Chem 206 Don Cram :1959 t Cornforth: 1959 ater effective bulk than oh argument based on importance of of Winstein, who compares the Rs polarization in transition state, and evidence relative tendency of groups to occupy the equator of selectivity in a-chlorocyclohexanone position on a cyclohexane ring O-M additions CH3>OSo2CgH4CH3-P>OCOCH3>OH where the dipoles are antiparallel, the polarization of the carbonyl group would be thec yclic model would predict the opposite product Cram acyclic model easiest, thereby lowering transition state e case of an a-heteroatom - a new model is Cornforth model instein. S. Holmes, N. J.J. Am. chem. so a modification of cram s rule for 1955,77,5562 a-substituents x Additions to a-Chloro Carbonyls ucleophile approaches from the back face M ROH 1)R-M RSR Et2O.70℃ 2) ACOH Cram chelate model predicted (anti-Felkin) (Felkin) Features 1)R-M activated carbonyl considered Nu: to be largest group 2)H3O 90° trajectory R-M A: B yield of A (%) CH3Mgl OH 11.5 CHaLi OMe m电可e expects groups OH, OR, OAc, NR2, NHAc to chelate as in Cram acyclic model torsional effects not considered The open-chain model s to systems which conti oups attached to asymmetric carbon of the starting material which re incapable of complexing with organometallic reagents Comforth. J W. Comfort R H. Mathew. KK J. Chem. Soc. 1959. 112 Cram, D J; Kopecky, K.R. J. Am. Chem. Soc. 1959, 81, 2748
Sarah Siska, C. A. Morales Cornforth-1 Chem 206 Don Cram: 1959 R O M X RS RM/L R O M O Ph Ph X Me O Ph OR M Me Ph CH3MgI CH3Li A major Ph Ph X Me R' OH X OH OMe RL RM RS Ph Ph X Me HO R' B minor Nu: Methyl has greater effective bulk than OH; Cram cites "A-values" of Winstein, who compares the relative tendency of groups to occupy the equatorial position on a cyclohexane ring. CH3 > OSO2C6H4CH3 -p > OCOCH3 > OH The acyclic model would predict the opposite product in the case of an a-heteroatom -- a new model is needed! Cram acyclic model Cram chelate model Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81, 2748 "The open-chain model applies to systems which contain only groups attached to asymmetric carbon of the starting material which are incapable of complexing with organometallic reagents." Nu: + • expects groups OH, OR, OAc, NR2, NHAc to chelate 1) R'-M 2) H3O + R'-M A : B Winstein, S.; Holmes, N. J. J. Am. Chem. Soc. 1955, 77, 5562 nucleophile approaches from the back face Nu: 11.5 : 1 9 : 1 yield of A (%) 20 50 R O M R O M X O R Cl RS RL RL RS X RL RS R Cl RS RL HO R' R Cl RS RL R' OH X RL RS R OH Nu Cornforth: 1959 Nu: Cornforth model Cornforth, J. W.; Cornforth, R. H.; Mathew, K. K. J. Chem. Soc. 1959, 112 1) R'-M Et2O, -70 °C 2) AcOH • argument based on importance of polarization in transition state, and evidence of selectivity in a-chlorocyclohexanone additions • ". . . where the dipoles are antiparallel, the polarization of the carbonyl group would be easiest," thereby lowering transition state energy • a modification of Cram's rule for electronegative, non-chelating a-substituents X + predicted (Felkin) as in Cram acyclic model, torsional effects not considered Nu: activated carbonyl considered to be largest group Features 90° trajectory of nucleophile net dipole of molecule minimized (anti-Felkin) Additions to -Chloro Carbonyls
Sarah Siska. C. A. Morales Cornforth-2 Chem 206 Comforth: Rationalization and Evidence Karabatsos: 1967 Support and Contradict Given Crams acyclic model, Karabatsos is surprised by the followit for Dipole Minimizati selectivities Rs Nu-M M RL Corey, E.J. J. Am. Chem. Soc. 1953, 75, 2301 Corey, E.J. Burke, H J. ibid. 1955, 77, 5418 Cornforth model R it appears that i-Pr is effectively smaller than Me, if Ph=RL 2-4:1 Karabatsos explanation Cram transition states are incorrect Nu Bellamy, L J; Thomas, L C. Williams Prelog, V. Bull. Soc. Chim. Fr. Ph R L J. Chem. Soc. 1956. 3704 1956,987 Bellamy, L J; Williams, R L.ibid. 1957 (note: methylpyruvate does Chlorohydrin Synthesis Karabatsos model Compared Interaction △△H° 1)n-BuMgBr Me +0-Ph+*0 0.6 kcal/mol Pr +0-ph++0 0.2 kcal/mol ratios depend not on№u→Hand№RM but instead on RM +0 vS RL+ 7(Felkin) 3(anti-Felkin ag. NaoH aq. NaOH M These were known products minor 2nd-best conformer Cornforth, J. W: Comfort. R H Mathew, K.K. J. Chem. Soc. 1959. 11 Karabatsos. G.J. J Am. chem. soc. 1967. 89. 1367
RL O Ph O O RS RM O R Cl RS RL Cl O R O M RL RS R(M) H Ph H O M R(M) H H O M Ph Nu: Nu: O Cl O R Cl RL RS O H Et Cl n-Bu Et O n-Bu Et Cl OH X n-Bu Et Cl OH n-Bu Et O Ph R O H R Me i-Pr Ph Nu R OH A Ph Nu R OH Ph Nu R OH Ph Nu R OH B Karabatsos: 1967 Karabatsos, G. J. J. Am. Chem. Soc. 1967, 89, 1367 Nu-M Karabatsos model Given Cram's acyclic model, Karabatsos is surprised by the following selectivities: + • it appears that i-Pr is effectively smaller than Me, if Ph = RL Karabatsos' explanation: Cram transition states are incorrect • ratios depend not on Nu ↔ H and Nu ↔ RM, but instead on RM ↔ O vs. RL ↔ O major minor H° Me ↔ O – Ph ↔ O i-Pr ↔ O – Ph ↔ O Compared Interaction 0.6 kcal/mol 0.2 kcal/mol A : B 2–4 : 1 1–2 : 1 2nd-best conformer Cornforth, J. W.; Cornforth, R. H.; Mathew, K. K. J. Chem. Soc. 1959, 112 Prelog, V. Bull. Soc. Chim. Fr. 1956, 987 Bellamy, L. J.; Thomas, L. C.; Williams, R. L. J. Chem. Soc. 1956, 3704 Bellamy, L. J.; Williams, R. L. ibid. 1957, 4294 Nu: Cornforth model Sarah Siska, C. A. Morales Cornforth-2 Chem 206 7 (Felkin) 3 (anti-Felkin) aq. NaOH 1) n-BuMgBr 2) AcOH + aq. NaOH (±) (±) (±) : 68% Cornforth: Rationalization and Evidence Corey, E. J. J. Am. Chem. Soc. 1953, 75, 2301 Corey, E. J.; Burke, H. J. ibid. 1955, 77, 5418 Support and Contradiction for Dipole Minimization Chlorohydrin Synthesis (note: methylpyruvate does not adopt this conformation) These were known products
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
Sarah Siska. C. A. Morales Ciekplak Model Chem 206 Anh's Calculated Transition State Energies Cieplak Model for Carbonyl Addition The model on-perpendicular attack similar to Anh-Eisenstein modification of the 15A6=90°.100110 Felkin model: stabilization of nucleophile via h2 Me a quadratic curve) Rn-105° assumes an electron-poor transition state L aligns best donor C-Xp anti to incoming nucleophile to stabilize o*of forming bond 163A a model generated rotate C-C bond by for optimum overlap Cieplak model STo-3G ab initio method (low level) Houk, Paddon-Row) disputed relkin. Anh importance of torsional effects Lowest energy transition states 0=107° σ*CNu Felkin Anh 、oCNu C 2-methylbutanal 2-chloropropanal C—X oC- (Felkin-Anh model (Felkin-Anh polar model Rs Structures are stabilized by stabilizing one of the fundamendal assumptions in frontier molecular orbital theory >2.7 kcal/mol Cieplak hypothesis is nonsense," ne Just because a hypothesis correlates a most stable Oc-Xd f'0 C-Nu set of observations doesn t make that ground state EFelkin model - EG1 Karabatsos conformed better donor DAE Anh. N. T. Eisenstein O. Tetrahedron Lett. 1976. 155 C-H>C-C>C-N>C-0 Cieplak, A S.J. Am. Chem 03.4540 Anh. N. T: Eisenstein. O. Nouv. J. Chim. 1977. 1. 61 (Houk disputes the Cieplak, A S; Tait, B D ; Je 111.8447 Anh, N. T. Top. Curr. Chem. 1980, 88, 14 ordering of C-H, C-C)
Sarah Siska, C. A. Morales Ciekplak Model Chem 206 Et H Me H O Li H – Cl H Me H O Li H – RS RL RS RL R O RM R O M RM q = 107° Nu: X H Me H O Li H – O R R M Anh's Calculated Transition State Energies Anh, N. T.; Eisenstein, O. Tetrahedron Lett. 1976, 155 Anh, N. T.; Eisenstein, O. Nouv. J. Chim. 1977, 1, 61 Anh, N. T. Top. Curr. Chem. 1980, 88, 146 1.5 Å q q = 90°, 100°, 110° rotate C–C bond by 30° increments 1.63 Å 2-methylbutanal (Felkin-Anh model) 2-chloropropanal (Felkin-Anh polar model) The model: Lowest energy transition states: STO-3G ab initio method (low level) (interpolated using a quadratic curve) Karabatsos model Nu: 95 – 105° Non-perpendicular attack most stable ground state conformer a range of angles for optimum overlap >2.7 kcal/mol EFelkin model EG1 G1 C Nu s* C Nu H XD H RM/L O M Nu C XD C XD C XA C XA XD RS RM/L R O M s (Houk disputes the ordering of C–H, C–C) Cieplak Felkin Anh s s* s* s Cieplak, A. S. J. Am. Chem. Soc. 1981,103, 4540; Cieplak, A. S.; Tait, B. D.; Johnson, C. R. J. Am. Chem. Soc. 1989, 111, 8447 Cieplak Model for Carbonyl Addition - DAE Cieplak model Nu: • similar to Anh-Eisenstein modification of the Felkin model: stabilization of nucleophile via antiperiplanar C–XD bond • assumes an electron-poor transition state: aligns best donor C–XD anti to incoming nucleophile to stabilize s* of forming bond • a model generated to explain unexpected selectivities • importance of torsional effects (Felkin, Anh, Houk, Paddon-Row) disputed sC–Xd ↔ s*C---Nu C–H > C–C > C–N > C–O better donor "Structures are stabilized by stabilizing their highest energy filled states. This is one of the fundamendal assumptions in frontier molecular orbital theory. The Cieplak hypothesis is nonsense." "Just because a hypothesis correlates a set of observations doesn't make that hypothesis correct
Sarah siska. C. A. Morales Correlating Theory with Experiment-Peter Wipf-1 Chem 206 4,4-Disubstituted Cyclohexadienones: Experimental Data Wipf Seeking an Explanation A Stereoelectronic effect? MeMaB OR、THF Neither vinylogous Felkin nor vinylogous Cieplak sufficiently explains or predicts selectivity 78°CMe HO R Vinylogous Felkin-Anh") KEY:a:βed) vinylogous Anh-Eisenstein"model" vinylogous Cieplak"model LUMO of enone has phase inversion due to double bond stabilizing a of the incipient bond between carbonyl and donorlacceptor orbital correlation between ratio of isomers 79:1(26%) 48:1(81%) 86:1(32%) stabilizing homo of nucleophile predicts B attack-wrong product ng of the b face is OTMS ce 1.4-addition, when Electrostatic effect? Substrate with inverted dipole exhibits good B selectivity! 55:1(53%) 77:1(93%) 82:1(85% OMe CF2 CF3 1 CF2CF3 solvent OMe Wipf, P. Kim, Y.J. Am. Chem. Soc. 1994, 116,11678 32:1(79 11:1(29%) Wipf, P. Jung, J-K. Chem. Rev. 1999, 99, 1469
Sarah Siska, C. A. Morales Correlating Theory with Experiment-Peter Wipf-1 Chem 206 Me OMe O O O Me OTMS O Me OBz O O O O O O O O O Me OH O ' (58%) ' (39%) ' (42%) R' OR O R' HO OR Me R' Me OR HO MeMgBr THF -78 °C + 4,4-Disubstituted Cyclohexadienones: Experimental Data 7.9 : 1 (26%) 4.8 : 1 (81%) 8.6 : 1 (32%) 5.5 : 1 (53%) 17.7 : 1 (93%) KEY: : (yield) 8.2 : 1 (85%) 32 : 1 (79%) 11 : 1 (29%) ~4 Å ("vinylogous Felkin-Anh") CF2CF3 OMe O R' OR O M O Me OMe O Me OMe Nu b a b a Nu CF2CF3 HO OMe Me CF2CF3 Me OMe HO Nu-M solvent + 1 5 : Wipf Seeking an Explanation "vinylogous Anh-Eisenstein" model "vinylogous Cieplak" model • stabilizing s* of the incipient bond • predicts a attack, but no qualitative correlation between ratio of isomers and s energy of donor C–C bonds LUMO of enone has phase inversion due to double bond between carbonyl and donor/acceptor orbital Stereoelectronic effect? Chelate shielding of the b face is not likely, since 1,4-addition, when it does occur, is b-selective. Electrostatic effect? Substrate with inverted dipole exhibits good b selectivity! Neither vinylogous Felkin nor vinylogous Cieplak sufficiently explains or predicts selectivity. • stabilizing HOMO of nucleophile • predicts b attack -- wrong product! Wipf, P.; Kim, Y. J. Am. Chem. Soc. 1994, 116, 11678 Wipf, P.; Jung, J-K. Chem. Rev. 1999, 99, 1469
Sarah Siska, C A Morales Correlating Theory with Experiment-Peter Wipf-2 Chem 206 Quantitative Correlation Between Facial Selectivity An Electrostatic Take on Some Controversial Cases and Dipole Moment (Felkin-Anh) Qualitative Assessment H p-PhNO 2 NaBH CO Me OMe 43:57 A Cheung, et al. J. Am. Chem. Soc. 1986, 108, 1598 86:1(32% 4.8:1(81%) [P"(42%) create too electrostatic much Dipole Moment Calculations interaction EWG Adcock, W; Cotton, J. Trout, N A. J. Org. Chem. 1994, 59, 1867 M (Felkin-Anh) Nu、OH Nu-M CO2 Me CO2 Me CO2 Me CF2CF3 c NaBH4 calculated dipole moments of five representative dienones using SPARTAN 6 linear correlation between pe ular vector of dipole moment and natural favorable log of facial selectivity electrostatic Mehta, G. Khan, FA J Am. Chem. S, 1990, interaction 112,6140 Paddon-Row, M N; Wu, Y-D: Houk, K N.J. ralidity of ground-state dipole moment: complexed carbonyl should affect dipoles of all dienone substrates in same manner Am.chem.Soc.1992,114,10638 Mehta, G.J. Org. Chem. 1993, 58, 1734 approach of nucleophile toward positive end of dipole favored
-3 -2 -1 0 1 2 3 4 -3 -2 -1 0 1 2 3 4 calc. dipole moment [Debye] ln Sarah Siska, C. A. Morales Correlating Theory with Experiment-Peter Wipf-2 Chem 206 O O O O O Me OMe O CF2CF3 OMe O O O Me OMe O O [ ' (42%)] 32 : 1 (79%) 8.6 : 1 (32%) 4.8 : 1 (81%) Quantitative Correlation Between Facial Selectivity and Dipole Moment Qualitative Assessment • calculated dipole moments of five representative dienones using SPARTAN • linear correlation between perpendicular vector of dipole moment and natural log of facial selectivity • validity of ground-state dipole moment: complexed carbonyl should affect dipoles of all dienone substrates in same manner • approach of nucleophile toward positive end of dipole favored Dipole Moment Calculations CO2Me O CO2Me O EWG O OH CO2Me CO2Me HO Nu O O O R R CO2Me CO2Me Nu OH anti d + Nu: d – syn anti d + Nu: d – d – syn Nu d – d + d – d – d + d + d + anti syn O X NaBH4 Nu-M NaBH4 MeLi A X HO H C D X H OH B p-PhNO2 F CO2Me CF3 SiMe3 OH X An Electrostatic Take on Some Controversial Cases anti syn Cheung, et al. J. Am. Chem. Soc. 1986, 108, 1598 A : B + 66 : 34 62 : 38 61 : 39 59 : 41 45 : 55 43 : 57 favorable electrostatic interaction hydroxyl may create too much lone-pair repulsion (Felkin-Anh) Adcock, W.; Cotton, J.; Trout, N. A. J. Org. Chem. 1994, 59, 1867 (Felkin-Anh) + Nu-M 70 >90 30 10 : : : favorable electrostatic interaction Mehta, G.; Khan, F. A. J. Am. Chem. S, 1990, 112, 6140 Paddon-Row, M. N.; Wu, Y-D.; Houk, K. N. J. Am. Chem. Soc. 1992, 114, 10638 Ganguly, B.; Chandrasekhar, J.; Khan, F. A.; Mehta, G. J. Org. Chem. 1993, 58, 1734
