D. A. Evans Carbonyl and Azomethine Electrophiles-1 Chem 206 Additional Reading Material Provided http://ww.courses.fasharvardedu/-chem206/ Additions to 5-&6-Membered oxocarbenium ions Chemistry 206 Woerpel etaL. JACS 1999, 121, 12208 Woerpel etal. JACS 2000. 122, 168 Advanced Organic Chemistry "Theoretical Interpretation of 1, 2-Asymmetric Induction. The Importance of Antiperiplanarity", N. T. Anh, O Eisenstein Lecture number 18 Nouv j chem1977,1,61-70 Carbonyl and Azomethine Electrophiles-1 Relevant Dunitz Articles Geometrical Reaction Coordinates. Il. Nucleophilic Addition to Reactivity Trends a Carbonyl Group", JACS 1973, 95, 5065 C=X Stereoelectronic Effects Carbonyl Addition: Theoretical Models Stereochemistry of Reaction Paths at Carbonyl Centers Tetrahedron 1974. 30. 1563 The Felkin-Anh-Eisenstein model for c=o Addition Diastereoselective Ketone reduction From Crystal Statics to Chemical Dynamics", Accounts Chem Research1983,16,153 a Reading Assignment for this Week Stereochemistry of Reaction Paths as Determined from Crystal Carey& Sundberg: Part A; Chapter 8 Structure Data. A Relationship Between Structure and Energy Reactions of Carbonyl Compounds Burgi, H.-B. Angew Chem., Int Ed. Engl. 1975, 14, 460 Carey Sundberg: Part B; Chapter 2 Reactions of Carbon Nucleophiles with Carbonyl Compounds rey Sundberg: Part B; Chapter 5 Reduction of Carbonyl Other Functional Groups ednesday Matthew d shair October 30. 2002
D. A. Evans Chem 206 Matthew D. Shair Wednesday, October 30, 2002 http://www.courses.fas.harvard.edu/~chem206/ ■ Reading Assignment for this Week: Carey & Sundberg: Part A; Chapter 8 Reactions of Carbonyl Compounds Carbonyl and Azomethine Electrophiles-1 Additional Reading Material Provided Chemistry 206 Advanced Organic Chemistry Lecture Number 18 Carbonyl and Azomethine Electrophiles-1 R C R O R C R O R R C R N R R C R N R R ■ Reactivity Trends ■ C=X Stereoelectronic Effects ■ Carbonyl Addition: Theoretical Models ■ The Felkin-Anh-Eisenstein Model for C=O Addition ■ Diastereoselective Ketone Reduction Carey & Sundberg: Part B; Chapter 2 Reactions of Carbon Nucleophiles with Carbonyl Compounds Carey & Sundberg: Part B; Chapter 5 Reduction of Carbonyl & Other Functional Groups ■ Relevant Dunitz Articles "Geometrical Reaction Coordinates. II. Nucleophilic Addition to a Carbonyl Group", JACS 1973, 95, 5065. "Stereochemistry of Reaction Paths at Carbonyl Centers", Tetrahedron 1974, 30, 1563 "From Crystal Statics to Chemical Dynamics", Accounts Chem. Research 1983, 16, 153. "Stereochemistry of Reaction Paths as Determined from Crystal Structure Data. A Relationship Between Structure and Energy.", Burgi, H.-B. Angew. Chem., Int. Ed. Engl. 1975, 14, 460. Additions to 5- & 6-Membered oxocarbenium Ions: Woerpel etal. JACS 1999, 121, 12208. Woerpel etal. JACS 2000, 122, 168. "Theoretical Interpretation of 1,2-Asymmetric Induction. The Importance of Antiperiplanarity", N. T. Anh, O. Eisenstein Nouv. J. Chem. 1977, 1, 61-70
D. A. Evans C=X Electrophiles: Carbonyls, Imines Their Conjugate Acids Chem 206 The Set of Functional Groups Stereoelectronic Considerations for c=o Addition LUMO iS I*C-O: HOMO Provided by Nu: π*C-0 Aldimine minIum These functional groups are among the most versatile sources of electrophilic carbon 兀*C-0 in both synthesis and biosynthesis. The ensuing discussion is aimed at providing a more advanced discussion of this topic. ■C= X Polarization +0 HOMO Dunitz-Burgi trajectory Partial Charge: As the familiar polar resonance structure above indicates, the carbonyl carbon supports a partial positive charge due to the polarization of the sigma and pi system by the more electronegative heteroatom. The partial charges for this g NuC family of functional groups derived from molecular orbital calculations (ab initio, -Nu 3-21(G) HF)are illustrated below R C=0 6+0.33 6+0.51 8+0.54 6+0.61{R=H a What about C=X VS C=X-R(+)? a Proton Activation of C=X Functional groups 6+0.61 The electrophilic potential of the C=o FG may be greatly increased by either Lewis acid coordination of by protonation. The magnitide of this increase in reactivity is-10*6 Among the weakest Bronsted acids that may be used for C=O activation(ketalization) The LUMo coefficient on carbon for B will be considerably larger than for A.Does is pyridinium ion(pKa=5). Hence, the Keq below, while quite low, is still functional this mean that there is a lower constraint on the approach angle for the attacking H nucleophile? There is no experimental proof for this question; however, it is wort Keq -10 pka=5 a What was the basis for the Dunitz-Burgi analysis
C O R R Nu C R R O C R R X C R R X R ~107 ° d – d – R C R O R C R N R R C R O R C R O R R C R O R C R N R R R C R N R R + C R O – R C R O R C R O H H–A A – R C R O R C R O H N H N R C R O R R C R N R R C=X Electrophiles: Carbonyls, Imines & Their Conjugate Acids A B D. A. Evans Chem 206 Oxocarbenium ion Iminium ion Aldimine Ketimine (Imine) Aldehyde Ketone These functional groups are among the most versatile sources of electrophilic carbon in both synthesis and biosynthesis. The ensuing discussion is aimed at providing a more advanced discussion of this topic. ■ C=X Polarization Partial Charge: As the familiar polar resonance structure above indicates, the carbonyl carbon supports a partial positive charge due to the polarization of the sigma and pi system by the more electronegative heteroatom. The partial charges for this family of functional groups derived from molecular orbital calclulations (ab initio, 3-21(G)*, HF) are illustrated below: d + 0.51 d + 0.61 (R = H) d + 0.63 (R = Me) d + 0.33 d + 0.54 electrophilic reactivity ■ Proton Activation of C=X Functional groups d + 0.51 d + 0.61 + The electrophilic potential of the C=O FG may be greatly increased by either Lewis acid coordination of by protonation. The magnitide of this increase in reactivity is ~ 10+6 . Among the weakest Bronsted acids that may be used for C=O actilvation (ketalization) is pyridinium ion (pKa = 5). Hence, the Keq below, while quite low, is still functional. + pka = 5 pka = -6 Keq ~ 10-11 The forming bond s Nu–C Stereoelectronic Considerations for C=O Addition p C–O p* C–O HOMO (Nu) LUMO LUMO is p* C–O; HOMO Provided by Nu: p* C–O Dunitz-Burgi trajectory ■ What was the basis for the Dunitz-Burgi analysis? ■ What about C=X vs C=X-R(+)? The LUMO coefficient on carbon for B will be considerably larger than for A. Does this mean that there is a lower constraint on the approach angle for the attacking nucleophile? There is no experimental proof for this question; however, it is worthy of consideration ■ The Set of Functional Groups:
D A. Evans The Dunitz-Burgi Trajectory for C=O Addition Chem 206 Relevant Dunitz Articles Geometrical Reaction Coordinates. Il. Nucleophilic Addition to a Carbonyl Group", JACS 1973, 95, 5065. Stereochemistry of Reaction Paths at Carbonyl Centers", Tetrahedron 1974, 30, 1563 From Crystal Statics to Chemical Dynamics", Accounts Chem. Research 1983, Stereochemistry of Reaction Paths as Determined from Crystal Structure Data. A Relationship Between Structure and Energy Burgi, H.B. Angew. Chem., Int Ed EngL1975.14,460 a Dunitz Method of Analysis A series of organic structures containing both C=O and Nu FGs disposed in a eometry for mutual interaction were designed. These structures positioned the In this structure(A), at 2.56A the C=0 is starting to pyramidalize interacting FGs an increasingly closer distances. The X-ray structures of these structures were determined to ascertain the direction of c=o distortion the two families of structures that were evaluated are shown below Cyclic amine es. Medium-ring ketones of various ring sizes were analyzed for the interaction of amine an C=O FGs. One example is shown below Nu------ c-o Dunitz. Helv. Chem. Acta 1978. 61. 2783 229A Analysis of distortion of C=o in this basis of value should be taken as A(shown) Birmbaum JACS 1974. 966165
H3C CH3 Me2N O Me MeO O Me B C O N O Me R R D. A. Evans The Dunitz-Burgi Trajectory for C=O Addition Chem 206 ■ Relevant Dunitz Articles "Geometrical Reaction Coordinates. II. Nucleophilic Addition to a Carbonyl Group", JACS 1973, 95, 5065. "Stereochemistry of Reaction Paths at Carbonyl Centers", Tetrahedron 1974, 30, 1563 "From Crystal Statics to Chemical Dynamics", Accounts Chem. Research 1983, 16, 153. "Stereochemistry of Reaction Paths as Determined from Crystal Structure Data. A Relationship Between Structure and Energy.", Burgi, H.-B. Angew. Chem., Int. Ed. Engl. 1975, 14, 460. ■ Dunitz Method of Analysis A series of organic structures containing both C=O and Nu FG's disposed in a geometry for mutual interaction were designed. These structures positioned the interacting FGs an increasingly closer distances. The X-ray structures of these structures were determined to ascertain the direction of C=O distortion. The two families of structures that were evaluated are shown below. Nu 1,8-Disubstituted Naphthalenes. Substituents located at these positions are strongly interacting as illustrated by the MM2 minimized di-methyl-naphthalene structure shown below. 2.56Å In this structure (A), at 2.56Å the C=O is starting to pyramidalize A (shown) 2.29Å Sekirkine Birnbaum JACS 1974, 96 6165 Dunitz, Helv. Chem. Acta 1978, 61, 2783 Analysis of distortion of C=O in this and related structures formed the basis of the 107° attack angle. This value should be taken as approximate. Cyclic aminoketones. Medium-ring ketones of various ring sizes were analyzed for the interaction of amine an C=O FGs. One example is shown below
D. A. Evans Stereoelectronic Effects in the Addition to iminium and oxo-carbenium ions Chem 206 ■ Pivotal articles R.V. Stevens in L An early example from Eliel; JACS 1969, 91, 536 ategies and tactics in Organic synthesis", vol. 1 Salts:a Powerful Heuristic Principle for the Stereorationale Design of Alkaloid Synthesis OMe PhMgBr H Eliel etal. JACS 1969. 91 Kishi etal. JACS 1982. 104. 4976-8 dioxolenium ion ans:cs95:5(95% a The Proposal for Oxo-carbenium lons(Eliel, Kishi) Eliel was the first to attibute stereoelectronic factors to the addition of nucleophiles to yclic oXo-carbenium ions Path A I Kishi Examples: JACS 1982, 104, 4976-8 conformations Me3 Bno BF, oEt PMBOO stereoselection 10: 1 a The Proposal for Iminium lons(Stevens OBn Et3Si-H BF3°Et2 O CH2OBn Path a Chair-aixal attack on oxo-carbenium ion occurs for both carbon and hydride nucleophiles d Iminium lons( Stevens)cited reference It was proposed that chair-axial addition would be preferred as a consequence of the only one stereoisomer tervention of a transition state anomeric effect(Path A). Attack through Path B would necessitate the generation of the twist-boat kinetic product conformation thus PrMgl destabilizing attack from the equatorial diastereoface. While Stevens espoused this concept for iminium ions in the late 70s, his untimely death at the age of 42 significantly CAH
C N H H R R C O H H R N Nu H R R N Nu H H R R O Nu H R O Nu H H R N H Nu H R R O H Nu H R O O H Me H Me OMe H O CH2OBn OBn OBn BnO OH C4H9 N Me O CH2OBn OBn OBn BnO PMBO PhMgBr NaCNBH3 BF3•OEt2 Et3Si–H BF3 •OEt2 SiMe3 O O H Me H Me H C4H9 N n-PrMgBr C4H9 N n-Pr C4H9 N Me O CH2OBn OBn OBn BnO H O CH2OBn OBn OBn BnO H O O H Me H Me Ph H D. A. Evans Stereoelectronic Effects in the Addition to Iminium and Oxo-carbenium Ions Chem 206 ■ Pivotal Articles R. V. Stevens in "Strategies and Tactics in Organic Synthesis", Vol. 1. On the Stereochemistry of Nucleophilic Additions to Tetrahydropyridinium Salts: a Powerful Heuristic Principle for the Stereorationale Design of Alkaloid Synthesis.; Lindberg, T., Ed.; Academic Press, 1984; Eliel etal. , JACS 1969, 91, 536 Kishi etal. , JACS 1982, 104, 4976-8 ■ The Proposal for Oxo-carbenium Ions (Eliel, Kishi) + Nu Nu kinetic product conformations It was proposed that chair-axial addition would be preferred as a consequence of the intervention of a transition state anomeric effect (Path A). Attack through Path B would necessitate the generation of the twist-boat kinetic product conformation thus destabilizing attack from the equatorial diastereoface. While Stevens espoused this concept for iminium ions in the late 70's, his untimely death at the age of 42 significantly delayed his cited publication. Path A Path B + Nu Nu kinetic product conformations Path A Path B ■ The Proposal for Iminium Ions (Stevens) ■ An early example from Eliel; JACS 1969, 91, 536 trans : cis 95:5 (95%) dioxolenium ion Eliel was the first to attibute stereoelectronic factors to the addition of nucleophiles to cyclic oxo-carbenium ions. ■ Kishi Examples; JACS 1982, 104, 4976-8 stereoselection 10:1 (55%) stereoselection 10:1 (55%) Chair-aixal attack on oxo-carbenium ion occurs for both carbon and hydride nucleophiles ■ Iminium Ions (Stevens) cited reference only one stereoisomer
D. A. Evans Stereoelectronic Effects in the Addition to Iminium and oxo-carbenium lons Chem 206 5-Membered oxocarbenium lons: Woerpel etal. JACS 1999, 121, 12208 BF3.OEt2 Me0 SiMe3 trans: c is 99: 1(69%) 一 SiMe cis trans 89: 11(75%) BFr. oEt Bno These cases provide dramatic evidence for the importance of electrostatic effects in C=( controlling face selectivity 6-Membered oxocarbenium lons: Woerpel etaL. JACS 2000, 122, 168 cis trans 83: 17(84%) Controling ta ce selectdcaty atc evidence for the importance of ectrostatcefect in BF3OEt Are the preceding addition reactions somehow related to the apparently OSiR SiMe cis: trans 94: 6(74%) R3SIO Eto2C oc1991,56,387 trans cis 99:1(75%) C↓ This analysis presumes that only pseudo-chai transition states need be considere Allyl OSiR3 OSiR 3 oerpel's model states that axial attack from the most stable chair former predicts the major product. exclusive adduct Tet. Lett.1988,29,6593
O BnO OAc O Me OAc O OAc BnO O OAc Me BF3•OEt2 BF3•OEt2 SnBr4 SnBr4 O BnO O C OBn H H O C H Me H O Me SiMe3 SiMe3 O BnO O Me O H Me Allyl H O OBn H Allyl H O BnO OAc O Me OAc O OAc OBn R3SiO EtO BF3 •OEt2 BF3 •OEt2 BF3•OEt2 OSiR3 O O OSiR3 C O H BnO H C O H H Me C O H BnO H AlCl3 HgI2 BnO O H Allyl H Cl Cl N N H2C SiMe3 SiMe3 OSiR3 OSiR3 EtO2C O OSiR3 H H Cl N Cl N H H O Allyl H H Me O Allyl H BnO H O Allyl H BnO H D. A. Evans Stereoelectronic Effects in the Addition to Iminium and Oxo-carbenium Ions Chem 206 5-Membered oxocarbenium Ions: Woerpel etal. JACS 1999, 121, 12208. stereoselection 99:1 stereoselection >95:5 These cases provide dramatic evidence for the importance of electrostatic effects in controlling face selecticity. 6-Membered oxocarbenium Ions: Woerpel etal. JACS 2000, 122, 168. cis:trans 94:6 (74%) trans:cis 99:1 (75%) Are the preceding addition reactions somehow related to the apparently contrasteric reactions shown below?? trans:cis 99:1 (69%) cis:trans 89:11(75%) cis:trans 83:17(84%) These cases provide dramatic evidence for the importance of electrostatic effects in controlling face selecticity. Tet. Lett. 1988, 29, 6593 JOC 1991, 56, 387 >94 : 6 93 : 7 exclusive adduct Woerpel's model states that axial attack from the most stable chair conformer predicts the major product. This analysis presumes that only pseudo-chair transition states need be considered