Chemistry 206 Advanced organic chemistry Handout-03A Steric. electronic Conformational Effects in Epoxide- Nucleophile Reactions Mick dart Evans group seminar, december, 1993 Matthew d shair Mond September 23, 2002
Chemistry 206 Advanced Organic Chemistry Handout–03A Steric, Electronic, & Conformational Effects in Epoxide–Nucleophile Reactions Matthew D. Shair Monday September 23, 2002 Mick Dart Evans Group Seminar, December, 1993
D. A. Evans. M. Dart Epoxides as electrophiles Chem 206 STERIC ELECTRON/C AND CONFORMATIONAL EFFECTS IN EPOXIDE/NUCLEOPHILE REACTIONS REGIOSELECTIVITY OF EPOXIDE RING OPENING NEUTRAL OR BASIC CONDIT/ONS: SN2 arkerRE. Isaacs, N. c. Chem. rev. 1959. 59. 737-799. Rosowsky, A. In The Chemistry of Heterocyclic Compounds Weissberger, A, Ed; Interscience: New York, 1964: Vol 19, Part 1, p 1. H SN2 Transition-State Buchanon, J. G: Sable, H. Z. In Selective Organic Transformations: Thyagarajan, B S Ed. Wiley: New York, 1972: VoL. 2, p 1 Berti, G. In Topics in Stereochemistry, Allinger, N. L. Eliel, E L, Eds. Interscience Publishers: New York, 973: Vol. 7, p93 rnha R=various alkyl, aryl, or vinyl substituents Rao,A.S:Paknikar,SK;Kirtane,JG.Tetrahedron1983,39,2323 R2NH Sharpless, B K, Behrens, C. H. Katsuki, T Lee, A. W. M; Martin, V.S.; Takatani, M Viti, S. M: Walker, F. J; Woodward, S.S. Pure Appl. Chem. 1983, 55, 589-604 Behrens, C H;, Sharpless, B. K. Aldrichimica Acta 1983, 16, 67-80 Due to ring strain, bond breaking is more advanced than bond making in the transition-state relative to a normal SN2 reaction. In addition, the carbon atom Gorzynski Smith, J. Synthesis 1984, 629-656 at which displacement takes place will bear a partial positive charge in the ewars,E.G. In Comprehensive Heterocyclic Chemistry, Katritzky, A.R., Ed; transition-state Normal" SN2 behavior is observed under neutral or basic conditions to provide Rossiter, B E. In Assymetric Synthesis; Morison, J D, Ed. Academic: New York, Ris alkyl or a group having no marked inductive or conjugative effects 1985: Vol 5, Chapter 7. Hanson, R. M. Chem Rev. 1991, 91, 437-475 Exceptions: Hydrogenation in the presence of Raney-nickel proceeds with Also see: Larock, R. C. Comprehensive Organic Transformations, p 505-526 opposite regioselection Parker,RE:Isaacs,NC.Chem.Rev.1959,59,737-799
O R' H Nu H H O R' R' Nu OH D. A. Evans, M. Dart Epoxides as Electrophiles Chem 206 Parker, R. E.; Isaacs, N. C. Chem. Rev. 1959, 59, 737-799. Rosowsky, A. In The Chemistry of Heterocyclic Compounds; Weissberger, A., Ed.; Interscience: New York,1964: Vol 19, Part 1, p 1. Buchanon, J. G.; Sable, H. Z. In Selective Organic Transformations; Thyagarajan, B. S., Ed.; Wiley: New York,1972: Vol. 2, p 1. Berti, G. In Topics in Stereochemistry; Allinger, N. L. ; Eliel, E. L., Eds.; Interscience Publishers: New York, 973: Vol. 7, p 93. Rao, A. S.; Paknikar, S. K.; Kirtane, J. G. Tetrahedron 1983, 39, 2323. Sharpless, B. K.; Behrens, C. H.; Katsuki, T.; Lee, A. W. M.; Martin, V. S.; Takatani, M.; Viti, S. M.; Walker, F. J.; Woodward, S. S. Pure Appl. Chem. 1983, 55, 589-604. Behrens, C. H.; Sharpless, B. K. Aldrichimica Acta 1983, 16, 67-80. Gorzynski Smith, J.; Synthesis 1984, 629-656. Lewars, E. G. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Ed.; Pergamon Press: New York,1984: Vol. 7, p 100. Weissberger, A.; Taylor, E.C. In The Chemistry of Heterocyclic Compounds; Hassner A., Ed.; Wiley: New York, 1985: Vol. 42, Part 3, p 1. Rossiter, B. E. In Assymetric Synthesis; Morrison, J. D., Ed.; Academic: New York, 1985; Vol. 5, Chapter 7. Hanson, R. M. Chem Rev. 1991, 91, 437-475. Also see: Larock, R. C. Comprehensive Organic Transformations, p 505-526. STERIC, ELECTRONIC, AND CONFORMATIONAL EFFECTS IN EPOXIDE / NUCLEOPHILE REACTIONS Reviews Parker, R. E.; Isaacs, N. C. Chem. Rev. 1959, 59, 737-799. R = various alkyl, aryl, or vinyl substituents SN2 Transition-State Due to ring strain, bond breaking is more advanced than bond making in the transition-state relative to a normal SN2 reaction. In addition, the carbon atom at which displacement takes place will bear a partial positive charge in the transition-state. "Normal" SN2 behavior is observed under neutral or basic conditions to provide nucleophilic attack at the least substituted carbon with inversion. R' is alkyl or a group having no marked inductive or conjugative effects. Exceptions: Hydrogenation in the presence of Raney-nickel proceeds with opposite regioselection. d - d - d + H - N3 - RORSRNH2 R2NH NH3 R - Nu = Nu REGIOSELECTIVITY OF EPOXIDE RING OPENING NEUTRAL OR BASIC CONDITIONS: SN2 ‡
D. A Evans. M. Dart Epoxides as Electrophiles Chem 206 GJOSELECTIVITY OF EPOXIDE RING OPENING ACIDIC CONDITIONS: BORDERLINE SN2 TO SN1 REGIOSELECTIVITY OF EPOXIDE RING OPENING ACIDIC CONDITIONS: BORDERLINE SN2 TO SN1 №u 70-85℃Me Normal prod Abnormal prod 56 HC,Et2O,△74 Disfavored sterically More"abnormal" is formed in H2o than in Et2o which is expected since the "Normal Product reaction proceeds through a polar transition state Major product usually Favored sterically The electron donating inductive effect of an extra methyl substituent slightly a In the borderline SN2 mechanisms overrides the additional steric effect thereby enhancing C-a attack HI, whose anion is most nucleophilic in the series of acids, provides the highest Nucleophilic attack occurs on the conjugate acid of the epoxide proportion of normal product as expected The transiton state is more polar and c-o bond cleavage is more advanced than in SN2 reactions Buchanon, J G: Sable, H. Z. In"Selective Organic Transformations Thyagarajan, B. S, Ed. Wiley: New York, 1972: VoL. 2, p 1 Epoxides which exhibit normal SN2 behavior under basic or neutral conditions give mixtures under acidic conditions Stewart, C A: VanderWerf, C. A. J Am. Chem. Soc. 1954, 76, 1259 Swain. C. G: Scott. C. B. J. Am. Chem. Soc. 1953. 75. 141 Steric factors are important although less so than observed in SN2 reactions The positive charge build up is stabilized by electron releasing groups
H H Nu H R H O R O H + R OH + OH R Nu R O H O H H R H Nu R O OH Nu R Nu R OH Me O OH X Me X Me OH O Me Me Me Cl OH Me Me OH Me Cl HI HBr HCl HX B A More "abnormal" is formed in H2O than in Et2O which is expected since the reaction proceeds through a polar transirtion state. The electron donating inductive effect of an extra methyl substituent slightly overrides the additional steric effect thereby enhancing C_a attack. HI, whose anion is most nucleophilic in the series of acids, provides the highest proportion of normal product as expected. HCl, Et2O, D 74 26 82 18 71 29 56 44 REGIOSELECTIVITY OF EPOXIDE RING OPENING ACIDIC CONDITIONS: BORDERLINE SN2 TO SN1 Normal Prod Abnormal Prod HX, H2O 70-85 °C HCl, H2O 45 55 a b a b Buchanon, J. G.; Sable, H. Z. In "Selective Organic Transformations"; Thyagarajan, B. S., Ed.; Wiley: New York, 1972: Vol. 2, p 1. Stewart, C. A.; VanderWerf, C. A. J. Am. Chem. Soc. 1954, 76, 1259. Swain, C. G.; Scott, C. B. J. Am. Chem. Soc. 1953, 75, 141. REGIOSELECTIVITY OF EPOXIDE RING OPENING Nucleophilic attack occurs on the conjugate acid of the epoxide. The transiton state is more polar and C_O bond cleavage is more advanced than in SN2 reactions. Epoxides which exhibit normal SN2 behavior under basic or neutral conditions give mixtures under acidic conditions. Steric factors are important although less so than observed in SN2 reactions. The positive charge build up is stabilized by electron releasing groups. ■ In the borderline SN2 mechanisms: "Normal Product" "Abnormal Product" "BORDERLINE" SN2 b a d + d - ++ ++ d - d + d + d + ACIDIC CONDITIONS: BORDERLINE SN2 TO SN1 b a SN1 SN1 Favored electronically Disfavored sterically Disfavored electronically Favored sterically R = alkyl Major product usually D. A. Evans, M. Dart Epoxides as Electrophiles Chem 206
D. A Evans. M. Dart Epoxides as Electrophiles Chem 206 EFFECT OF ELECTRONEGAT/VE NONCONJUGATING SUBSTITUENTS REGIOSELECTIVITY OF EPOXIDE RING OPENINGS Me EPOXIDES ADJACENT TO CARBONYLS (NH2) oMe Conformational effects are guiding the regioselectivity o Steric effects do ations(Furst-Plattner rule portant. However and substituent EWG=Electron Withdrawing Group Other nucleophiles such as amines, various hydrides, and malonate anions show Attack at C-a is discouraged due to destabilization the same regioselectivity of the transition state by juxtaposition of positive charge IPrNH2 R=Hor Bn NHR aq PINH2 The opposite selectivity observed in this case is due to stabilization of the developing positive charge at C-2 by the carboxylate anion. The reaction proceeds with inversion of stereochemistry at this center Liwschitz. Y: Rabinsohn. Y: Perera. d. J chem. soc. 1962. 1116 Parker, R. E, Isaacs, N. C. Chem. Rev. 1959, 59, 737-799 配uKm159152
Me OH O O HO O NHR Me OH O O Me OEt Me F3C OEt O O OEt O O O O NH2 O NH2 HO F OEt 3C Me OEt NH2 OH O Me H2N OH O OEt NH2 O H2N OH O R' R' H Nu EWG OH OMe NH2 O Me OAr Me OAr O O OMe OMe O OMe OH OMe OMe OH OMe O Me NHiPr Me OAr OH NHiPr Me OAr OH F3C Me O OH OEt Me F3C NaOMe NaOMe NH3 (NH2 ) RNH2 NH3 Parker, R. E.; Isaacs, N. C. Chem. Rev. 1959, 59, 737-799. Lemieux, R. U.; Kullnig, R. K.; Moir, R. Y. J. Am. Chem. Soc. 1958, 80, 2237. Steric effects dominate regioselectivity, especially in acyclic systems in which conformational considerations (Fürst-Plattner rule) may not be as important. However, in many systems sterics on each side of the epoxide may be similar and substituent electronic effects emerge as the important factors in determining regioselection. EtOH, H2SO4 aq iPrNH2 aq iPrNH2 or NH3 d + d - d - EWG = Electron Withdrawing Group Attack at C- is discouraged due to destabilization of the transition state by juxtaposition of positive charge. a b EFFECT OF ELECTRONEGATIVE, NONCONJUGATING SUBSTITUENTS Conformational effects are guiding the regioselectivity of reaction 3. 1. 2. 3. d - d + ‡ D. A. Evans, M. Dart Epoxides as Electrophiles Chem 206 EPOXIDES ADJACENT TO CARBONYLS Other nucleophiles such as amines,various hydrides, and malonate anions show the same regioselectivity. REGIOSELECTIVITY OF EPOXIDE RING OPENINGS Liwschitz, Y.; Rabinsohn, Y.; Perera, D. J. Chem. Soc. 1962, 1116. R = H or Bn The opposite selectivity observed in this case is due to stabilization of the developing positive charge at C-2 by the carboxylate anion. The reaction proceeds with inversion of stereochemistry at this center. Parker, R. E.; Isaacs, N. C. Chem. Rev. 1959, 59, 737-799. 2 3
D.A. Evans, M. Dart Epoxides as Electrophiles Chem 206 REGIOSELECTIVITY OF EPOXIDE RING OPENINGS REGIOSELECTIVITY OF EPOXIDE RING OPENINGS EFFECT OF CONJUGATING SUBSTITUENTS EFFECT OF CONJUGATING SUBSTITUENTS ubstituent(X) Rati 100:00 36:64 70:30 7624 MeOH, H2SO4 10:90 -OMe NaoMe -H 30:70 Nadph 24:76 Good I donors(OMe)can stabilize the incipient carbocation to offset steric HOPh, TSOH 06: 94 effects Methoxide, which is more nucleophilic than phenoxide, has increased The reaction of styrene oxide with nucleophiles is a balance between sensitivity to sterics and exibits more SN2 behavior with attack at C-B being somewhat favored relative to phenoxide Resonance stabilization favors attack at the a-carbon Steric effects direct attack to the B-carbon Lewars, E.G.: In"Comprehensive Heterocyclic Chemistry": Katritzky, A.R. Ed Under acidic conditions attack at the a-carbon becomes more favorable Olefinic and acetylenic substituents behave similarly Parker.RE. Isaacs. N c. Chem. Rev. 1959. 59. 737-799
O OH Nu Nu OH O X Nu OH X OH Nu X NaOMe -H NaOPh -OMe -H -NO2 NaOPh HOPh NaN3 MeONa PhLi LiBH4 LiAlH4 30:70 Nu 100:0 76:24 36:64 substituent (X) Ratio Lewars, E. G.; In "Comprehensive Heterocyclic Chemistry"; Katritzky, A. R., Ed.; Good p donors (OMe) can stabilize the incipient carbocation to offset steric effects. Methoxide, which is more nucleophilic than phenoxide, has increased sensitivity to sterics and exibits more SN2 behavior with attack at C-b being somewhat favored relative to phenoxide. REGIOSELECTIVITY OF EPOXIDE RING OPENINGS EFFECT OF CONJUGATING SUBSTITUENTS Nua b 24:76 12:88 HOPh, TsOH 06:94 00:100 MeOH, H2SO4 10:90 100: 00 70:30 74:26 Nucleophile Ratio 100: 00 Parker, R. E.; Isaacs, N. C. Chem. Rev. 1959, 59, 737-799. REGIOSELECTIVITY OF EPOXIDE RING OPENINGS EFFECT OF CONJUGATING SUBSTITUENTS NuThe reaction of styrene oxide with nucleophiles is a balance between resonance and steric effects: Resonance stabilization favors attack at the -carbon. Steric effects direct attack to the -carbon. Olefinic and acetylenic substituents behave similarly. Under acidic conditions attack at the a-carbon becomes more favorable. a b D. A. Evans, M. Dart Epoxides as Electrophiles Chem 206