http://www.courses.fas.harvard.edu/~chem206/ J. I. Seeman, J. Chem. Ed. 1986, 63, 42-48 The Curtin-Hammett Principle (Handout) O OMe Me Me CO2Me N Ph O H LiNR2 Me-I N Ph O O H O OMe Me Me CO2MeMe Chem 206D. A. Evans Matthew D. Shair Wednesday, October 2, 2002 a73 Reading Assignment for week A. Carey & Sundberg: Part A; Chapter 4"Study & Descrption of Reaction Mechanisms" Conformational Analysis: Part–4 Chemistry 206 Advanced Organic Chemistry Lecture Number 7 Conformational Analysis-4 a73 Problems of the Day: (To be discussed) K. Houk, Science. 1986, 231, 1108-1117Theory & Modeling of Stereoselective Organic Reactions (Handout) a73 Conformational Analysis of C6 → C8 Rings continued a73 Transition State Torsional Effects a73 Curtin–Hammett Principle Leading References: The Curtin-Hammett Principle J. I. Seeman, J. Chem. Ed. 1986, 63, 42-48. J. I. Seeman, Chem Rev. 1983, 83, 83-134. Eliel, pp. 647-655 Carey & Sundberg,Part A, CH 4, pp 187-250 a73 Other Reading Material mCPBA Martinelli, et.al. Tett. Lett. 1989, 30, 3935 Predict the stereochemical outcome of this reaction. The diastereoselection is 99:1 Rationalizethe stereochemical outcome of this reaction. Ladner, et.al. Angew. Chemie, Int. Ed 1982, 21, 449-450 Eliel & Wilen, Stereochemistry of Carbon Compounds" Chapter 11 (on reserve in CCB library) diastereoselection is 8:1. Torsional Angle: also known as dihedral angle H H H H H HO Me HX H C HC H H H C HC H H H H H C HC H H C HC H H H H HO H H H H H HX H H Me H H AB B C HH H CH2 CH2 H A B A H CH HH D. A. Evans Chem 206Ground State Torsional Effects Torsional Strain: the resistance to rotation about a bond Torsional energy: the energy required to obtain rotation about a bond Torsional steering: Stereoselectivity originating from transition state torsional energy considerations ?G = +3 kcal mol-1 Torsional Strain (Pitzer Strain): Ethane staggered eclipsed Relevant Orbital Interactions: Dorigo, A. E.; Pratt, D. W.; Houk, K. N. JACS 1987, 109, 6591-6600. Wiberg K. B.; Martin, E. J. Amer. Chem. Soc. 1985, 107, 5035-5041. σ C–H's properly aligned for pi? overlap hence better delocalizationσ C–H & pi electrons are destabilizing Conformational Preferences: Acetaldehyde The eclipsed conformation (conformation A) is preferred.Polarization of the carbonyl decreases the 4 electron destabilizing Rotational barrier: 1.14 kcal/mol Houk, JACS 1983, 105, 5980-5988. Conformational Preferences1-Butene (X = CH 2); Propanal (X = O) Conformation A is preferred. There is little steric repulsion between the methyl and the X-group in conformation A. Torsional Effects eclipsed conformation staggered conformation +2.0 kcal/mol See Lecture 5 for previous discussion D. A. Evans Chem 206Transition State Torsional Effects According to Houk CH2C H* CH2C H* CH2C H* 60° 90° 0° 120° 30° 60° 90° 120° 2 Kcalmol-1 +4.7 0 0 H 0 HH +1.6 HHH 0° H 30° HH +5.3 +2.4 no H* Transition states Houk, JACS 1981, 103, 2438 Houk: "Torsional effects in transition states are more important than in ground states" C Nu C RL H-radical and H-anion: antiperiplanar σ?C–R orbital stabilized the TS illustrated for Nu addition Houk, Science 1981, 231, 1108-1117"The Theory and Modeling of Stereoselective Organic Reactions" Same trends are observed for H+ addition σC-Nu σ?C-RL σC-Nu homo σ?C-RL lumo Forming bond Forming bond Houk, JACS 1982, 104, 7162 H H H C HCHH RL H H Nu σC-Nu σ?C-RLTransition state C HR RL H HNu σC-Nu σ?C-RLGround state H- H? H+ Steric effects Least nuclear motion Orbital distortion Nitrogen protecting group does not affect selectivities H H N Ph O OH OH H OsO4 N Ph O H A B A N Ph O O H B D. A. Evans Chem 206Transition State Torsional Effects: Olefin Additions a73 Olefin Addition Reactions: Case one How do we account for the high exo selectivities in addition reactions to norbornene? exo endo Highly exo selective for electrophilic, nucleophilic and cycloaddition reactions The Controversy over origin of high exoselectivities Schleyer: torsional steering Rate enhancement due to strain Schleyer, P. R. J. Amer. Chem. Soc. 1967, 89, 701. Addition from exo face avoids eclipsing A & B hydrogens (better hyperconjugative stabilization of transition state) 98 : 2 diastereoselectivity 99 : 1 diastereoselectivity Martinelli, et.al. Tett. Lett. 1989, 30, 3935 mCPBA a73 Olefin Addition Reactions: Case two Favored Addition from indicated olefin face avoids eclipsing A & B H's (better hyperconjugative stabilization of transition state) How do we account for the high selectilvities in the oxidation of the indicated olefin? Martinelli has carried out further studies on related structures........... 63° 62° 74° 40° major Me O H Me O O H D. A. Evans Chem 206Transition State Torsional Effects: Olefin Additions Martinelli: Torsional steering important in selectivity 99 : 1 diastereoselectivity 50 : 50 diastereoselectivity 99 : 1 diastereoselectivity Martinelli & Houk, J. Org. Chem. 1994, 59, 2204. mCPBA mCPBA mCPBA 89° major Authors propose that diastereoselection controlled by TS torsional effects Nu: Nu: H Me3C O [H] H Me3C H OH M+ H B CH Me CH2Me H Me3C OH H HA H Me3C O H Me3C H OH H Me3C OH H H NHR Me3C H NHR H Me3C HNPh Me3C H LiBH(s-Bu)3 (R) [H] KBH(s-Bu)3 LiBH(s-Bu)3 [H] HA private communication Hutchins, JOC 1983, 48, 3412 R = Ph 01 :99 03 :97R = Bn Al/Hg/MeOH Ganem, Tet. Let 1981, 22, 3447 Cyclohexanone Addition Reactions: Hydride ReductionD. A. Evans Chem 206 – 3 DIBAL-H 72:28 L-Selectride 8:92 K-Selectride 3:97NaBH4 79:21 LiAlH(Ot-Bu)3 92:8 LiAlH4 93:7 1009080706050403020100 % Axial Diastereomer Increasingly bulky hydride reagents prefer to attack from the equatorial C=O face. Observation: Stereoselective Reductions: Cyclic Systems The most stereoselective Reductions Reagent Ratio 03 :97 99 :01Li in NH3 ~90 :10 RatioReagent The steric hindrance encountered by Nu-attack from the axial C=O face by the axial ring substituents (hydrogens in this case) at the 3-positions is more severe than the steric hinderance encountered from Nu-attack from the equatorial C=O face. Attack Trajectories for Cyclohexanone(Torsional Argument) HE This approach favored stericallyHE O–C–C–He dihedral: +63.0 ° Axial Attack Equatorial Attack O–C–C–He dihedral: +4.0 ° O–C–C–He dihedral: –56.0 ° H: – H: – Attack across equatorial C=O face sterically more favorable. However, attack across the axial face of the C=O group avoids development of eclipsing interactions in the transition state. (Note the dihedral angle sign changes between reactants & products shown above). These "torsional effects" favor axial attack. Steric Effects: Torsional Effects: For "small" hydride reagents such as LiAlH4, torsional effects are felt to be dominant and this explains the predisposition for axial attack. Prediction Prediction For "large" hydride reagents such as H–BR4, steric effects now are dominant and this explains the predisposition for equatorial attack. The Issues Associated with the Reduction Process 3 J. I. Seeman, Chem Rev. 1983, 83, 83-134. J. I. Seeman, J. Chem. Ed. 1986, 63, 42-48. NMeN Me PA [PA] [PB] [B]o [A]o A B PB (1)k B kA k2k1 PA ON Me Me H A Me–Br N O Me Me Me H B Me O NMe H N O Me Me H Me PB Me–Br Conformational Analysis and Reactivity: Curtin-Hammett PrincipleK. A. Beaver, D. A. Evans Chem 206 Leading References: How does the conformation of a molecule effect its reactivity? Consider the following example: Do the two different conformers react at the same rate, or different rates? What factors determine the product distribution? minormajor Consider two interconverting conformers, A and B, each of which can undergo a reaction resulting in two different products, PA and PB. The situation: See also Eliel, pp. 647-655 13 Me–I13 Me–I ?G° ?GAB? ?G1? ?G2? Rxn. Coord. En erg y k1, k2 >> kA, kB: If the rates of reaction are faster than the rate of interconversion, A and B cannot equilibrate during the course of the reaction, and the product distribution (P B/PA) will reflect the initial composition. = In this case, the product distribution depends solely on the initial ratio of the two conformers. major product minor product less stable more stable Padwa, JACS 1997 4565 ?G = -3.0 kcal/mol(ab initio calculations) Case 1: "Kinetic Quench" We'll consider two limiting cases: (1) The rate of reaction is faster than the rate of conformational interconversion (2) The rate of reaction is slower than the rate of conformational interconversion -78°C While enolate conformers can be equilibrated at higher temperatures, the products of alkylation at -78° C always reflect the initial ratio of enloate isomers. If the rates of conformationall interconversion and reaction are comparable, the reactants are not in equilibrium during the course of the reaction and complex mathmatical solutions are necessary. See Seeman, Chem. Rev. 1983, 83 - 144 for analytical solutions. steric hindrance PB (2) (3) Using the rate equations (4)=[PB][P A]BA k2[B] [B] [A] [PB] [PA] [PB] [PA] PA k B kA k2k1 d[PA] d[PB] = k1[A] d[PA]d[PB] k1[A]= k2[B]or Since A and B are in equilibrium, we can substitute Keq = k1= k2 K eq e -?G2/RT e-?G1/RT (e-?G°/RT) e-?G2/RTe-?G°/RTe?G1/RT= e-(?G2 + ?G°-?G1)/RT= or e-??G/RT= A B PB [PB] [PA] PA K. A. Beaver, D. A. Evans Chem 206Curtin - Hammett: Limiting Cases k1, k2 << kA, kB: If the rates of reaction are much slower than the rate of interconversion, (?GAB? is small relative to ?G1? and ?G2?), then the ratio of A to B is constant throughout the course of the reaction. ?G° ??G? ?G1? ?G2? Rxn. Coord. En erg y minormajor d[PA] dt = k1[A] and d[PB] dt = k2[B] we can write: d[PA]d[PB] k 1 = k2 Keq k 1 = k2 KeqIntegrating, we get To relate this quantity to ?G values, recall that ?Go = -RT ln Keq or Keq = e-?G°/RT, k1 = e-?G1?/RT, and k2 = e-?G2?/RT. Substituting this into the above equation: Where ??G? = ?G2?+?G°-?G1? The Derivation: Curtin - Hammett Principle: The product composition is not solely dependent on relative proportions of the conformational isomers in the substrate; it is controlled by the difference in standard Gibbs energies of the respective transition states. When A and B are in rapid equilibrium, we must consider the rates of reaction of the conformers as well as the equilibrium constant when analyzing the product ratio. (1) Case 2: Curtin-Hammett Conditons Within these limits, we can envision three scenarios: ? If the major conformer is also the faster reacting conformer, the product from the major conformer should prevail, and will not reflect the equilibrium distribution. ? If both conformers react at the same rate, the product distribution will be the same as the ratio of conformers at equilibrium. ? If the minor conformer is the faster reacting conformer, the product ratio will depend on all three variables in eq (2), and the observed product distribution will not reflect the equilibrium distribution. This derivation implies that you could potentially isolate a product which is derived from a conformer that you can't even observe in the ground state! Combining terms: ?GAB? slow slow fast N Me H Me3C O – Me3C H MeNN Me H Me3C NMeN Me NMe 13Me N Me 13Me + ++ i-Pr2N O Me H i-Pr2N O Me Li?sparteine s-BuLi Me3C H Me N O – i-Pr2N O Me Cl H2O2 i-Pr2N O Me Li i-Pr2N O Me i-Pr2N O Me Li?sparteine N N Some Curtin-Hammett ExamplesK. A. Beaver, D. A. Evans Chem 206 k1 k2 Keq = 10.5 Ratio: 5 : 95 + more stableless stable fasterslower minor product major product Oxidation of piperidines: major product minor product 13 Me–I13 Me–I slowerfaster less stable more stable Tropane alkylation is a well-known example. When the equilibrium constant is known, the Curtin-Hammett derivation can be used to calculate the relative rates of reaction of the two conformers. Substituting the above data into [PB]/[PA] = k2K/k1, the ratio k2/k1 ~ 2. Note that in this case, the more stable conformer is also the faster reacting conformer! The less stable conformer reacts much faster than the more stable conformer, resulting in an unexpected major product! JOC 1974 319 Tet. 1972 573Tet. 1977 915 (-)-Sparteine slowerfaster 82 - 87% ee This is a case of Dynamic Kinetic Resolution: Two enantiomeric alkyl lithium complexes are equilibrating during the course of a reaction with an electrophile. Beak, Acc. Chem. Res, 1996, 552 Enantioselective Lithiation: (-)-Sparteine Enantioselectivities are the same, regardless of whether or not the starting material is chiral, even at low temperatures. Further, reaction in the absence of (-)-sparteine results in racemic product. Note that the two alkyllithium complexes MUST be in equilibrium, as the enantioselectivity is the same over the course of the reaction. If they were not equilibrating, the enantioselectivity should be higher at lower conversions. Because sparteine is chiral, these two complexes are diastereomeric and have different properties. Rh O P H P H Ph HN Me CO2Me Rh O H P P H Ph NH Me MeO2C Rh O P P Ph NH Me MeO2C Rh S H P P O Me NH CO2Me CH2Ph Rh O P P Ph HN Me CO2Me S R S Rh O P P Ph NH Me MeO2C S Rh O P P Ph HN Me CO2Me Ph NHAcMeO2C R Ph NHAcMeO2C Ph NHAcMeO2C R Rh S H P P O Me HN MeO2C PhH2C Ph NHAcMeO2C > 95% ee 2 Ph NHAcMeO2C H2 H2 Ph NHAcMeO2C S,S Rh S SP P Ph NHAcMeO2C Mechanism of Asymmetric HydrogenationK. A. Beaver, D. A. Evans Chem 206 The asymmetric hydrogenation of prochiral olefins catalyzed by Rhodium is an important catalytic process. [L2Rh]+ > 95% ee Enantioselectivities are generally very high when the ligand is a chelating diphosphine. (ee's are given for S,S-CHIRAPHOS) coordinationcoordination hydrogen addition hydrogen addition migration reductive eliminationreductive elimination migration -L2RhS2-L2RhS2 Observations: ? Complex 2 is the only diasteromer observed for the catalyst-substrate complex (1HNMR, X-Ray crystallography) in the absence of hydrogen ? The enantioselectivity is strongly dependant on the pressure of H2, and degrades rapidly at higher hydrogen pressures ? The observed enantiomer is exclusively derived from the minor complex 2 These observations may be explained using the Curtin - Hammett Principle Halpern, Science, 217, 1982, 401 When a chiral ligand is used, there are two diastereomeric complexes which may be formed: observed product major complex1 * * faster slower (NMR, X-Ray) + S + S minor complex majorminor fast slow PBBAPA k B kA k2k1 Cl O O2NO SnBu2 OPh Cl O O2N O OPh OSnBu2Cl Ar OCOAr OSnBu2ClPh TMS-Cl OCOAr OTMSPh OSnBu2Cl OCOArPh TMS-Cl OTMS OCOArPh Reactions Involving Interconverting IsomersK. A. Beaver, D. A. Evans Chem 206 Ar= p-NO2C6H4 Ratio 2:1 Product Ratio 22:1 more stable less stable Stannylene ketals provide an efficient way to acylate the more hindered site of 1,2-diols. The Curtin-Hammett treatment can be extended to ANY case where different products are formed from two rapidly intereconverting starting materials, whether they are conformers, tautomers or isomers. minormajor The two stannyl esters are in equilibrium at room temperature, and the more stable isomer is initially formed more slowly. The stannyl esters are allowed to equilibrate before quenching with TMS-Cl, which reacts more rapidly with the less hindered primary alkoxystannane. THE TAKE-HOME LESSON: Never assume that the most stable conformation of a compound is the most reactive. It may be, but then again, it may not. Curtin - Hammett Principle: The product composition is not solely dependent on relative proportions of the conformational isomers in the substrate; it is controlled by the difference in standard Gibbs energies of the respective transition states. "It was pointed out by Professor L. P. Hammett in 1950 (private communication) that ..." David Y. Curtin, 1954 " Because Curtin is very generous in attributing credit, this is sometimes referrred to as the Curtin-Hammett principle rather than the Curtin principle." Louis Plack Hammett, 1970 JOC 1996, 5257 faster slower