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