Chem 206D. A. Evans Matthew D. Shair Wednesday, October 30, 2002 http://www.courses.fas.harvard.edu/~chem206/ a73 Reading Assignment for this Week: Carey & Sundberg: Part A; Chapter 8Reactions 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 a73 Reactivity Trends a73 C=X Stereoelectronic Effects a73 Carbonyl Addition: Theoretical Models a73 The Felkin-Anh-Eisenstein Model for C=O Addition a73 Diastereoselective Ketone Reduction Carey & Sundberg: Part B; Chapter 2Reactions of Carbon Nucleophiles with Carbonyl Compounds Carey & Sundberg: Part B; Chapter 5Reduction of Carbonyl & Other Functional Groups a73 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. C ORR Nu CR R O CR R X C R R X R ~107 °δ – δ – 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 NH N R C R O R R C R N R R C=X Electrophiles: Carbonyls, Imines & Their Conjugate Acids A B Chem 206D. A. Evans Oxocarbeniumion IminiumionAldimineKetimine (Imine) AldehydeKetone 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. a73 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: δ + 0.51 δ + 0.61 (R = H)δ + 0.63 (R = Me)δ + 0.33 δ + 0.54 electrophilic reactivity a73 Proton Activation of C=X Functional groups δ + 0.51 δ + 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 formingbond σ Nu–C Stereoelectronic Considerations for C=O Addition pi C–O pi? C–O HOMO(Nu) LUMO LUMO is pi? C–O; HOMO Provided by Nu: pi? C–O Dunitz-Burgi trajectory a73 What was the basis for the Dunitz-Burgi analysis? a73 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 a73 The Set of Functional Groups: H3C CH3 Me2N O Me MeO O Me B C O N O Me RR Chem 206D. A. Evans The Dunitz-Burgi Trajectory for C=O Addition a73 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. a73 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. 2.56? In this structure (A), at 2.56? the C=O is starting to pyramidalize A (shown) 2.29? SekirkineBirnbaum 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. C NH H R R C OH 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 CH2OBnOBn OBn BnO H O CH2OBnOBn OBn BnO H O O H Me H Me Ph H Chem 206D. A. Evans Stereoelectronic Effects in the Addition to Iminium and Oxo-carbenium Ions a73 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, 536Kishi etal. , JACS 1982, 104, 4976-8 a73 The Proposal for Oxo-carbenium Ions (Eliel, Kishi) + Nu Nu kinetic productconformations 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 productconformations Path A Path B a73 The Proposal for Iminium Ions (Stevens) a73 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. a73 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 a73 Iminium Ions (Stevens) cited reference only one stereoisomer 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 OHBnO H C OH H Me C OH BnO H AlCl3 HgI2 OBnO H Allyl H Cl Cl N N H2C SiMe3 SiMe3 OSiR3 OSiR3 EtO2C O OSiR3 H H Cl N NCl HH O Allyl H H Me O Allyl H BnO H O Allyl H BnO H Chem 206D. A. Evans Stereoelectronic Effects in the Addition to Iminium and Oxo-carbenium Ions 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. H Me O H O H TIPSO H CH2R H O OHO H TIPSO H CH2R H O R TIPSO H 4 22 20 H Me 4 9 9 H Me O Me R HH MeN OMe H OTPS RO2C O Me OH H MeN OMe H OTPS H R H R Me Br HSi O HH O O N O Me HH H HO H CH2 Me O MeO OHH N O H H O O H HO H R 46 38 33 19 1 9 13 9 13 9 13 13 Et3SiH O H BnOCH2 H O O O H R Me H H RO H Me R Me OTMS O Me O H BnOCH2 H O O BF3?OEt2 C Et3SiH Me OTMS TMSOTf B O OAc H BnOCH2 H O OC C Et3SiH A B BF3?OEt2 Et3SiH A Chem 206D. A. Evans Diastereoselective Oxocarbenium Ion Additions in the Phorboxazole Synthesis >95:5 Diastereoselection ? Phorboxazole B Evans, Fitch, Smith, Cee, JACS 2000, 122, 10033 91% > 95:5 Diastereoselection 89% Diastereoselection89:11 A: The C-11 Reduction B: The C-22 Reduction C: The C-9 C–C Bond Construction Stereochemical analogies: Kishi et. al.: JACS 1982, 104, 4976-8 a73 4- vs 6-Membered Transition Structures for C=O Addition T1 OH CHH O H C OH H O H H OH H C O H H H O H C OH H O O H H H H O H OH H C O H H H T2 CHH OH OH B L L H BL L R R B L Me L C R' H O R2C=O R2C=O R2C=O Zn RR O Zn CHR R Zn I I R B LL CH2 C O H2C CH R R B LL CH2 C O H C R R R R B L CR R O Me L O Zn–R C RH R' Me C OBL 2RR CR R OBL2 H C OBL 2RR H2C R R ? The bimetallic transition state Observation: catalytic amounts of ZnI2 dramatically catalyze addition process. slow+ a73 Do these results relate to "real" reactions? Yes! Overall Process: Transiton structure T2 determined to be ~40 kcal/mol more stable than transition structure T 1. fast 2 ? a73 4– Versus 6–Center Transition States for Boron ? disfavored : rxn does not proceed!) favored 4-Centered 6–Centered 6–Centered favored Schowen J. Am. Chem. Soc. 105, 31, (1983). H2C=O + n HOH H2C(–OH)2 + (n-1) HOH +6.7 H2C=O + 2 HOHH2C=O + 1 HOH +42.2 + HOH Consider carbonyl hydration: D. A. Evans Carbonyl Addition Reactions: Transition State Geometry Chem 206 C O R R R2 Mg Br Al L Me L Al L CR R O Me L Me C OAlL 2RR Al L Me L O Al CRR Me Al LL Me L Me CR R OAlL2 Me Al L CRR Al Me O L Me L Me AlO Me L Me Al L C Me R R L AlO Me L Al Me L C Me L R R AlO Me L Al Me C L Me L R R O Al L CR R Al Me L Me L Me Mg S R2 Br SC R R O O Mg Br CR R R2 S Mg S Br C OR R R2 R2 Mg Br S MgR2 S Br C O R R C RR O R2 Mg Br S MgR2 Br Mg S Mg Br O Br R2 S R2CR R R2C=O R2C=O +S MgS Br C O R R R2 CRR O R2 MgBr Br MgMg O Br R2 S R2 C R R O MgBr C R2R R CRR O R2 MgR2 Chem 206Carbonyl Addition Reactions: Transition State GeometryD. A. Evans ? disfavored a73 4–Centered Carbonyl Addition: 4– Versus 6–Center Transition States for Aluminum a73 6–Centered ? favored 2 rel. Rate = 1 rel. Rate = 1,000 a73 Bimetallic Transition States 4-Centered 6-Centered Boat 6-Centered Chair Bicyclic TS Ashby JOC 1977, 42, 425 + solvent (S) The 6-membered geometry for transferring the R2 ligand from the metal to the C=O is far less strained. The molecularity and transition structure for this reaction have not been carefully elucidated. The fact that the Grignard reagent is not a single species in solution greatly complicates the kinetic analysis. + MgBr2 a73 Bimetallic (Binuclear) Mechanism: The more probable situation. ? slow + +fast+ slow fast ? + – solvent (S)+– + + + a73 Grignard Reagents: a73 Monometallic (Mononuclear) Mechanism: break bridge Observation: Increasingly bulky hydride reagents prefer to attack from theequatorial C=O face. Hindered reagents react through more highly developed transition states than unhindered reagentsAssumption: H Me3C O R L O R M H [H] C O RR L H R M H R L Nu R M OHR C R O R L H Me3C H OH R M R OH R M NuR L M+ H CR O H B CH Me CH2Me R L H Me3C OH H R M H H CH O C OR R L R L C O R R Nu R M R M H H C RO R L CO H R L R M R M HOMO Burgi, Dunitz, Acc. Chem. Res. 1983, 16, 153-161 attack angle greater than 90 °; estimates place it in the 100-110 ° range Nu: The Dunitz-Bürgi Angle ~107 ° Stereoelectronic Effect: The HOMO-LUMO interaction dictates the following reaction geometry: δ – pi C–O δ – pi? C–O LUMO wrong prediction a19 destabilizinginteractionpredicted to be favored TS Nu: destabilizinginteraction predicted to be favored TS Nu:Nu: The flaw in the Felkin model: A problem with aldehydes!! Nu: Carbonyl Addition: Evolution of Acyclic Models Nu: favored disfavored KarabatsosJACS 1967, 89, 1367 Nu: Nu: CramJACS 1952, 74, 5828 Nu: FelkinTL. 1968, 2199-2208 % Axial Diastereomer 0 10 20 30 40 50 60 70 80 90 100 LiAlH4 93:7 LiAlH(Ot-Bu)3 92:8 NaBH4 79:21 K-Selectride 3:97 L-Selectride 8:92DIBAL-H 72:28 3 – a73 Product Development & Steric Approach Control: Dauben, JACS 1956, 78, 2579 a73 The principal steric interactions are between Nu & R. a73 Torsional strain considerations are dominant.Staggered TS conformations preferred a73 Transition states are all reactant-like rather than product-like. D. A. Evans Evolution of a Model for C=O Addition Chem 206 Assumptions in Felkin Model: H H C H C H C C HH C HO H Nu C Nu OHH R L R L R M R M R L O R M H H C OH R L R M H H CH O C HO R L R L R M R M H C HO R L R M Y C C C C X H Following this argument one might conclude that: a73 The staggered conformer has a better orbital match between bonding and antibonding states. a73 The staggered conformer can form more delocalized molecular orbitals. σ C–H σ? C–H In the eclipsed conformation there are 3 syn-periplanar C–H Bonds σ* C–H LUMOσ C–HHOMO σ? C–H σ C–HH In the staggered conformation there are 3 anti-periplanar C–H Bonds σ C–H HOMO σ* C–H LUMO ? G =+3 kcal mol -1 Lets begin with ground state effects: Ethane Rotational Barrier Chem 206The Felkin-Anh Eisenstein ModelD. A. Evans wrong prediction destabilizinginteraction predicted to be favored TS Nu:Nu: The flaw in the Felkin model: A problem with aldehydes!! Anh & Eisenstein Noveau J. Chim. 1977, 1, 61-70 Anh Topics in Current Chemistry. 1980, No 88, 146-162 anti-Felkin Nu: Nu: Nu: Felkin ? ? Nu: favored disfavored a73 The antiperiplanar effect: Hyperconjugative interactions between C-RL which will lower pi*C=O will stablize the transition state. a73 Dunitz-Bürgi C=O–Nu orientation applied to Felkin model. New Additions to Felkin Model: Theoretical Support for Staggered Transition states Houk, JACS 1982, 104, 7162-6 Houk, Science 1986, 231, 1108-17 "The tendency for the staggering of partially formed vicinal bonds is greater than for fully formed bonds" One explanation for the rotational barrier in ethane is that better overlap is achieved in the staggered conformation than in the eclipsed conformation. Houk: Nu OH H Me H H MeMe H H Me H O H Cram R L H R M O H Me OR O Me H R OLi OLi OMeMe Me H H CH O C HO R L R L R M R M R OOH Me R Me OH O OMe Me Me OH R M NuR L R L Nu R M OH H Me O R1 O Me H BF3-Et2O R2 OSiMe2tBu R Me OH R2 OOH Me R1 ClMg C CEt Li >90 : 10(R–MgX gives Ca 3:1 ratios) R–Ti (OiProp)3 R = n-Bu R-Titanium Ratio >90 : 10R = Me M. Reetz & Co-workers, Angew Chemie Int. Ed.. 1982, 21, 135. C. Djerassi & Co-workers, J. Org, Chem. 1979, 44, 3374. 1 : 1 Reagent Ratio 5 : 1 3 : 1 4 : 1 Ratio Li enolate R = Ph 24 : 1 C. Heathcock & L. Flippin J. Am. Chem. Soc. 1983, 105, 1667. Ketone (R1) Ratio 10 : 1R = Ph R = Me Enolate (R2) R = t-Bu -78 °C R = OMe 15 : 1R = Ph R = Ph 36 : 1R = Ot-Bu R = Ot-Bu 16 : 1R = c-C6H11 a73 This trend carries over to organometallic reagents as well Lewis acid catalyzed rxns are more diastereoselectiveTrend-2: Trend-1: For Li enolates, increased steric hindrance at enolate carbon results in enhanced selectivity L. Flippin & Co-workers, Tetrahedron Lett.. 1985, 26, 973. R = Ph + Anti-Felkin Isomer >200 : 1 RatioKetone (R)L. Flippin & Co-workers, Tetrahedron Lett.. 1985, 26, 973. 9 : 1R = c-C6H11 R = OtBu 4 : 1 Enolate (R) Ratio 3 : 1 + Anti-Felkin Isomer R = Me Addition of Enolate & Enol Nucleophiles anti-Felkin Nu: Nu: Nu: Felkin ? ? Nu: (Felkin) favored disfavored D. A. Evans The Felkin-Anh Eisenstein Model: Verification Chem 206 + Anti-Felkin Isomer + Anti-Felkin Isomer + Anti-Felkin Isomer HMe H H MeHO H R L C OR BH R R R M CramR L R R M O H2C (CH2)2Ph O Me R O Me Me M–H M–H H H CR O C RO R L R L R M R M Me Me OH R Me OH (CH2)2PhH2C OH Me Me OH R M RR L R L R R M OH O R M RR L H O Me H H Me R2B–H R2B–H [H] H CO R HB R R R L R M LiAlH4 NaBH4 R L R R M OH OH R M RR L Exercise: Draw the analogous bis(R2BH)2 transition structures Nonspherical nucleophiles are unreliable in the Felkin Analysis Transition States for C=O-Borane Reductions anti-Felkin Felkin ? ? (Felkin) disavored favored Note: Borane reducing agents do not follow the normal trend M. M. Midland & Co-workers, J. Am. Chem. Soc. 1983, 105, 3725. TS ? Anti-Felkin Felkin H–B(Sia)2 1 : 4 22 : 1Li+H–B–(sec-Bu)3 RatioReagent Reagent Ratio Li+H–B–(sec-Bu)3 96 : 4 Ketone (R) R = H - 78 °C R = H 47 : 53DIBAL DIBAL 88 : 12R = Me R = Me >99 : 1Li+H–B–(sec-Bu)3 G. Tsuchihashi & Co-workers, Tetrahedron Lett. 1984, 25, 2479. TS ? Anti-FelkinH–B(Sia)2 1 : 10 54 : 1Li+H–B–(sec-Bu)3 RatioReagent 5 : 1 3 : 1 M. M. Midland & Co-workers, J. Am. Chem. Soc. 1983, 105, 3725. Hydride Chem 206The Felkin-Anh Eisenstein Model: Ketone ReductionD. A. Evans disfavored (Felkin) favoredNu: ? ? Felkin Nu: Hydride anti-Felkin Addition of Hydride Nucleophiles + Anti-Felkin Isomer + Anti-Felkin Isomer Felkin Felkin Felkin O Me H H Me O OLi OMeMe Me R Me OH O OMe Me Me Me Me O SMe Ph Ph SMe O Me Me M–H LiBH(s-Bu)3 C OH Nu MeMe OMe OOH Me R Ph H R M C Cyclohexyl C Cyclohexyl C Nu H O R MH Cyclohexyl C Ph C Ph Ph SMe O Me Me Ph SMe O Me Me LiBH(s-Bu)3 LiBH(s-Bu)3 Me2HC H CPh O CO Ph SMe Me Me OH SMe Ph Me Me OH SMe Ph CHMe2 H SMe Ph SMe OH Me Me Ph SMe OH Me Me Me Me OH SMe Ph Ph SMe OH Me Me If this analysis is correct, the electronic contributions to transition state stabilization dominate nonbonding destabilization diastereoselection 4 : 96 a73 Dominant Electronic Effects: SMe provides better acceptor antibonding orbital favoredelectronic modelNu: ? ? Nu: favoredsteric model a73 Dominant Steric Effects: CHMe2 larger than SMe A Second Case Study: Shimagaki Tetrahedron Lett. 1984, 25, 4775 σ? σ σ σ? σ? CSP3–CSP2 is lower in energy than σ? CSP3–CSP3 bond. "Best acceptor σ* orbital is oriented anti periplanar to forming bond." Anh-Eisenstein Explanation based on HOMO-LUMO Analysis: The molecular volume occupied by cyclohexyl acknowledged to be largerthan that for phenyl. Because of shape phenyl "can get out of the way." Ratio > 200 : 1 Ratio 9 : 1 L. Flippin & Co-workers, Tetrahedron Lett.. 1985, 26, 973. Several cases have already been presented which may be relevant Are there electronic effects in the reaction? D. A. Evans The Felkin-Anh Eisenstein Model: Electronic Effects Chem 206 + Anti-Felkin Isomer + Anti-Felkin Isomer Is this another case where we are ignoring electrostatic effects? Felkin-Anh analysis predicts the wrong product! H O CO2MeCO 2Me C OH Nu Ph R M C Ph C Ph H C Nu H O Me CO2MeCO2Me HO R M Cyclohexyl C Cyclohexyl C Cyclohexyl Me OH CO2MeCO 2Me R R O CO2MeCO 2Me O Me-Li NaBH4 CO2MeCO2Me O Nu M O Et Et Me-Li BA NaBH4 Me–Li NaBH4 A EtEt HHO HO RR Me HO CO2Me CO2Me H CH=CH2 C O OMe CH2OMe CH2–CH3 H Et Et OH B R R OHMe CO2Me CO2Me OHH σ? σ σ σ? σ? CSP3–CSP2 is lower in energy than σ? CSP3–CSP3 bond. "Best acceptor σ* orbital is oriented anti periplanar to forming bond." Anh-Eisenstein: Chem 206The Felkin-Anh Eisenstein Model: A BreakdownD. A. Evans Felkin-Anh analysis predicts B for R = electronegative substituent. (R) Substituent A/B Ratio 17:83 27:73 34:66 >90:10G. Mehta, JACS 1990, 112, 6140 Are there cases not handled by the Anh-Eisenstein Model? Felkin-Anh analysis predicts B Case I: Electronegative -CO2Me substituentwill stabilize both C–C bonding & antibonding states (Felkin-Anh Prediction) 70: 30 39: 61 34: 66 G. Mehta, Chem. Commun. 1992, 1711-2: "These results can be reconciled in terms of the Cieplak model." H N OH Me NMe HHO C Nu C Nu C Nu σ? σ? NMe O NaBH4 O R NaBH4 R OHH R O (R) NaBH4 C X H R OH C X (R) X H C X C OR Nu R C X C X σ "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." Point D: Point C: Point B: Point A: C–X Electron donating ability follows the order: C–H > C–C > C–N > C–O Importance of torsional effects (Felkin, Anh, Houk, Padden-Row) disputed. (Houk disputes the ordering of C–H, C–C) CieplakFelkin Anh σ σ? σ? σ Cieplak, JACS 1981,103, 4540; Cieplak/Johnson, JACS 1989, 111, 8447 TS is stabilized by antiperiplanar allylic bond, but.... Cieplak Model for C=O Addition Nature of the stabilizing secondary orbital interactions differ: σ Le Noble, J. Org. Chem. 1989, 54, 3836 43:57 Anti:Syn Ratio 45:55R = SiMe3 R = CO2Me 61:39 62:38R = F R = OH i-PrOH, 25 °C + Syn Isomer Pyramidally distorted C=O ruled out from inspection of X-ray structures. Felkin-AnhPrediction Ratio, ≥ 95:5 i-PrOH, 25 °C Case II: The Le Noble Examples Le Noble, JACS 1992, 114, 1916 D. A. Evans The Felkin-Anh Eisenstein Model: A Breakdown Chem 206 MeOH, 0 °C R = NH2 Halterman, JACS 1990, 112, 6690 R = NO2 79:21 63:37R = Cl R = OMe 43:57 Anti:Syn Ratio 36:64 + Syn Isomer The management