02-Lecture.206

Chem 206D. A. Evans Hyperconjugation, The Anomeric Effect, and More Kirby, A. J. (1982). The Anomeric Effect and Related Stereoelectronic Effects at Oxygen. New York, Springer Verlag. Box, V. G. S. (1990). “The role of lone pair interactions in the chemistry of the monosaccharides. The anomeric effect.” Heterocycles 31: 1157. Box, V. G. S. (1998). “The anomeric effect of monosaccharides and their derivatives. Insights from the new QVBMM molecular mechanics force field.” Heterocycles 48(11): 2389-2417. Graczyk, P. P. and M. Mikolajczyk (1994). “Anomeric effect: origin and consequences.” Top. Stereochem. 21: 159-349. Juaristi, E. and G. Cuevas (1992). “Recent studies on the anomeric effect.” Tetrahedron 48: 5019 (PDF) Useful LIterature Reviews Carey & Sundberg: Part A; Chapter 3 pp 151-156 R2 R1 oxone, CH3CN-H2O pH 10.5 R2 R2 R1 R2 O O O O O O Me Me Me Me O 2 1 equiv 2 (2) >90% ee Me Me O KO3SOOH CH3CN-H2O pH 10.5 Me Me O O (1) 1 Question 4. (15 points). The useful epoxidation reagent dimethyldioxirane (1) may be prepared from "oxone" (KO3SOOH) and acetone (eq 1). In an extension of this epoxidation concept, Shi has described a family of chiral fructose-derived ketones such as 2 that, in the presence of "oxone", mediate the asymmetric epoxidation of di- and tri-substituted olefins with excellent enantioselectivities (>90% ee) (JACS 1997, 119, 11224). Part A (8 points). Provide a mechanism for the epoxidation of ethylene with dimethyldioxirane (1). Use three-dimensional representations, where relevant, to illustrate the relative stereochemical aspects of the oxygen transfer step. Clearly identify the frontier orbitals involved in the epoxidation. Question: First hour Exam 2000 (Database Problem 34) Chemistry 206 Advanced Organic Chemistry Lecture Number 2 Stereoelectronic Effects-2 ! "Positive" and "Negative" Hyperconjugation ! Anomeric and Related Effects ! Peracid & Dioxirane Epoxidation (Stereoelectronics) D. A. Evans Wednesday, September 21, 2005 http://www.courses.fas.harvard.edu/~chem206/ Kirby, Stereoelectronic Effects Chapters 1-5 Carey & Sundberg: Part A; Chapter 1, Chapter 3 Fleming, Chapter 1 & 2 Fukui,Acc. Chem. Res. 1971, 4, 57. (pdf) Alabugin & Zeidan, JACS 2002, 124, 3175 (pdf) Chem 206D. A. Evans Hyperconjugation: Carbocation Stabilization The graphic illustrates the fact that the C-R bonding electrons can "delocalize" to stabilize the electron deficient carbocationic center. Note that the general rules of drawing resonance structures still hold: the positions of all atoms must not be changed. ! The interaction of a vicinal bonding orbital with a p-orbital is referred to as hyperconjugation. C C R H H H H C H H CH H R This is a traditional vehicle for using valence bond to denote charge delocalization. + Syn-planar orientation between interacting orbitals Stereoelectronic Requirement for Hyperconjugation: "The new occupied bonding orbital is lower in energy. When you stabilize the electrons is a system you stabilize the system itself." ! Take a linear combination of ! C–R and CSP2 p-orbital: ! C–R !" C–R ! C–R !" C–R The Molecular Orbital Description C H H C H H + + [F5Sb–F–SbF5]– The Adamantane Reference (MM-2) T. Laube, Angew. Chem. Int. Ed. 1986, 25, 349 First X-ray Structure of an Aliphatic Carbocation 110 ° 100.6 ° 1.530 Å 1.608 Å 1.528 Å 1.431 Å ■ Bonds participating in the hyperconjugative interaction, e.g. C–R, will be lengthened while the C(+)–C bond will be shortened. Physical Evidence for Hyperconjugation Me Me Me H Me Me Me C + + "Negative" HyperconjugationD. A. Evans Chem 206 ! Delocalization of nonbonding electron pairs into vicinal antibonding orbitals is also possible C X R H H H H X H H CH H R "" This decloalization is referred to as "Negative" hyperconjugation "" As the antibonding C–R orbital decreases in energy, the magnitude of this interaction will increase ! C–R !! !" C–R The Molecular Orbital Description X Since nonbonding electrons prefer hybrid orbitals rather that P orbitals, this orbital can adopt either a syn or anti relationship to the vicinal C–R bond. Nonbonding e– pair Note that ! C–R is slightly destabilized antibonding !" C–R ! Overlap between two orbitals is better in the anti orientation as stated in "Bonding Generalizations" handout. + – Anti Orientation filled hybrid orbital filled hybrid orbital antibonding !" C–R Syn Orientation – +C X H H C X H HCH CH H R X H R X C X H H C X H H R: R: "" "" "" "" R R NMR Spectroscopy! Greater e-density at R ! Less e-density at X NMR Spectroscopy ! Longer C–R bond X-ray crystallography Infrared Spectroscopy! Weaker C–R bond ! Stronger C–X bond Infrared Spectroscopy X-ray crystallography! Shorter C–X bond Spectroscopic ProbeChange in Structure The Expected Structural Perturbations Chem 206D. A. Evans Lone Pair Delocalization: N2F2 This molecule can exist as either cis or trans isomers The interaction of filled orbitals with adjacent antibonding orbitals can have an ordering effect on the structure which will stabilize a particular geometry. Here are several examples: Case 1: N2F2 There are two logical reasons why the trans isomer should be more stable than the cis isomer. ! The nonbonding lone pair orbitals in the cis isomer will be destabilizing due to electron-electron repulsion. ! The individual C–F dipoles are mutually repulsive (pointing in same direction) in the cis isomer. N N F F N F N F The cis Isomer ! Note that two such interactions occur in the molecule even though only one has been illustrated. ! Note that by taking a linear combination of the nonbonding and antibonding orbitals you generate a more stable bonding situation. !" N–F filled N-SP2 antibonding !" N–F filled N-SP2 In fact the cis isomer is favored by 3 kcal/ mol at 25 °C. Let's look at the interaction with the lone pairs with the adjacent C–F antibonding orbitals. (LUMO) N F N F (HOMO) The trans Isomer Now carry out the same analysis with the same 2 orbitals present in the trans isomer. filled N-SP2 antibonding !" N–F ! In this geometry the "small lobe" of the filled N-SP2 is required to overlap with the large lobe of the antibonding C–F orbital. Hence, when the new MO's are generated the new bonding orbital is not as stabilizing as for the cis isomer. filled N-SP2 (HOMO) !" N–F (LUMO)N N F F Conclusions ! Lone pair delocalization appears to override electron-electron and dipole-dipole repulsion in the stabilization of the cis isomer. ! This HOMO-LUMO delocalization is stronger in the cis isomer due to better orbital overlap. Important Take-home Lesson Orbital orientation is important for optimal orbital overlap. forms stronger pi-bond than forms stronger sigma-bond than This is a simple notion with very important consequences. It surfaces in the delocalized bonding which occurs in the competing anti (favored) syn (disfavored) E2 elimination reactions. Review this situation. A B A B A B BA Chem 206D. A. Evans The Anomeric Effect: Negative Hyperconjugation The Anomeric Effect It is not unexpected that the methoxyl substituent on a cyclohexane ring prefers to adopt the equatorial conformation. ! Gc° = +0.6 kcal/mol ! Gp° = –0.6 kcal/mol What is unexpected is that the closely related 2-methoxytetrahydropyran prefers the axial conformation: H OMe H OMe OMe H OMe H O O That effect which provides the stabilization of the axial OR conformer which overrides the inherent steric bias of the substituent is referred to as the anomeric effect. axial O lone pair!"# C–H axial O lone pair!"# C–O Principal HOMO-LUMO interaction from each conformation is illustrated below: O H OMe O H OMe Let anomeric effect = A $ Gp° = $ Gc° + A A = $ Gp° – $ Gc° A = –0.6 kcal/mol – 0.6 kcal/mol = –1.2 kcal/mol !! !! ! Since the antibonding C–O orbital is a better acceptor orbital than the antibonding C–H bond, the axial OMe conformer is better stabilized by this interaction which is worth ca. 1.2 kcal/mol. Other electronegative substituents such as Cl, SR etc also participate in anomeric stabilization. This conformer preferred by 1.8 kcal/mol 1.819 Å 1.781 Å Why is axial C–Cl bond longer ? Cl HO O O H Cl H Cl Cl HO axial O lone pair!"# C–Cl O HOMO "# C–Cl " C–Cl "" "" The Exo-Anomeric Effect HO O R ! There is also a rotational bias that is imposed on the exocyclic C–OR bond where one of the oxygen lone pairs prevers to be anti to the ring sigma C–O bond O O R O OR favored A. J. Kirby, The Anomeric and Related Stereoelectronic Effects at Oxygen, Springer-Verlag, 1983 E. Jurasti, G. Cuevas, The Anomeric Effect, CRC Press, 1995 Chem 206D. A. Evans The Anomeric Effect: Carbonyl Groups Do the following valence bond resonance structures have meaning? C R O X C R O X !! Prediction: As X becomes more electronegative, the IR frequency should increase 1720 1750 1780!C=O (cm -1) Me CH3 O Me CBr3 O Me CF3 O Prediction: As the indicated pi-bonding increases, the X–C–O bond angle should decrease. This distortion improves overlap. C R O X !* C–X "O lone pair C R O X Evidence for this distortion has been obtained by X-ray crystallography Corey, Tetrahedron Lett. 1992, 33, 7103-7106 ! C–H = 3050 cm -1! C–H = 2730 cm -1 Aldehyde C–H Infrared Stretching Frequencies Prediction: The IR C–H stretching frequency for aldehydes is lower than the closely related olefin C–H stretching frequency. For years this observation has gone unexplained. C H C R O H C R R R Sigma conjugation of the lone pair anti to the H will weaken the bond. This will result in a low frequency shift. filled N-SP2 Infrared evidence for lone pair delocalization into vicinal antibonding orbitals. ! N–H = 2188 cm -1 ! N–H = 2317 cm -1 filled N-SP2 antibonding "# N–H .. antibonding "# N–H The N–H stretching frequency of cis-methyl diazene is 200 cm-1 lower than the trans isomer. N N Me H N H N Me N N Me N N Me ! The low-frequency shift of the cis isomer is a result of N–H bond weakening due to the anti lone pair on the adjacent (vicinal) nitrogen which is interacting with the N–H antibonding orbital. Note that the orbital overlap is not nearly as good from the trans isomer. N. C. Craig & co-workers JACS 1979, 101, 2480. H H Chem 206D. A. Evans The Anomeric Effect: Nitrogen-Based Systems N H H H H H Observation: C–H bonds anti-periplanar to nitrogen lone pairs are spectroscopically distinct from their equatorial C–H bond counterparts N HOMO !" C–H ! C–H Infrared Bohlmann Bands Bohlmann, Ber. 1958 91 2157 Characteristic bands in the IR between 2700 and 2800 cm-1 for C-H4, C-H6 , & C-H10 stretch Reviews: McKean, Chem Soc. Rev. 1978 7 399 L. J. Bellamy, D. W. Mayo, J. Phys. Chem. 1976 80 1271 Spectroscopic Evidence for Conjugation J. B. Lambert et. al., JACS 1967 89 3761 H. P. Hamlow et. al., Tet. Lett. 1964 2553 NMR : Shielding of H antiperiplanar to N lone pair H10 (axial): shifted furthest upfield H6, H4: !" = " Haxial - " H equatorial = -0.93 ppm Protonation on nitrogen reduces !" to -0.5ppm A. R. Katritzky et. al., J. Chemm. Soc. B 1970 135 !G° = – 0.35kcal/mol N N N N N NCMe3 Me3C Me3C CMe3 Me3C Me3C Favored Solution Structure (NMR) J. E. Anderson, J. D. Roberts, JACS 1967 96 4186 N N N N Me Me Me Me MeN MeN NMe NMe 1.484 1.457 1.453 1.459 1.453 A. R. Katrizky et. al., J. C. S. Perkin II 1980 1733 N N N N Me Bn Me Bn B Favored Solid State Structure (X-ray crystallography) B N N N N BnBn Me Me A Rationalize why B might be more stable than A. D. A. Evans Chem 206Carboxylic Acids (& Esters): Anomeric Effects Again? The (E) conformation of both acids and esters is less stable by 3-5 kcal/mol. If this equilibrium were governed only by steric effects one would predict that the (E) conformation of formic acid would be more stable (H smaller than =O). Since this is not the case, there are electronic effects which must also be considered. These effects will be introduced shortly. !G° = +4.8 kcal/mol Specific Case: Methyl Formate (E) Conformer(Z) Conformer ! Conformations: There are 2 planar conformations. O O R' R R O R' O O O Me HH O Me O Rotational barriers are ~ 10-12 kcal/mol. This is a measure of the strength of the pi bond. barrier ~ 10-12 kcal/mol !G° ~ 2-3 kcal/mol E n e rg y These resonance structures suggest hindered rotation about =C–OR bond. This is indeed observed: ! Rotational Barriers: There is hindered rotation about the =C–OR bond. R O R' O O O R' R R O R O O O R R CO O R R ! Oxygen Hybridization: Note that the alkyl oxygen is Sp2. Rehybridization is driven by system to optimize pi-bonding. The filled oxygen p-orbital interacts with pi (and pi*) C=O to form a 3-centered 4-electron bonding system. SP2 Hybridization The oxygen lone pairs conjugate with the C=O.! Lone Pair Conjugation: C O O R R•• •• Since !* C–O is a better acceptor than !* C–R (where R is a carbon substituent) it follows that the (Z) conformation is stabilized by this interaction. (E) Conformer In the (E) conformation this lone pair is aligned to overlap with !* C–R. !* C–R !* C–O In the (Z) conformation this lone pair is aligned to overlap with !* C–O. (Z) Conformer ! Hyperconjugation: Let us now focus on the oxygen lone pair in the hybrid orbital lying in the sigma framework of the C=O plane. C R O R O R O R O R C O OR R O O R •• •• 3) In 1985 Burgi, on carefully studying the X-ray structures of a number of lactones, noted that the O-C-C (!) & O-C-O (") bond angles were not equal. Explain the indicated trend in bond angle changes. !#" = 4.5 °!#" = 6.9 °!#" = 12.3 ° " " "!!! Lactone 2 is significantly more prone to enolization than 1? In fact the pKa of 2 is ~25 while ester 1 is ~30 (DMSO). Explain. 2) 1) Lactone 2 is significantly more susceptible to nucleophilic attack at the carbonyl carbon than 1? Explain. Esters strongly prefer to adopt the (Z) conformation while small-ring lactones such as 2 are constrained to exist in the (Z) conformation. From the preceding discussion explain the following: 2 1 versus Esters versus Lactones: Questions to Ponder. O O Et CH3CH2 O O O O O OO O O Chem 206D. A. Evans Calculated Structure of ACG–TGC Duplex Adenine Thymine Cytosine Guanine Cytosine The Phospho-Diesters Excised from Crystal Structure Phosphate-1A Phosphate-1B Phosphate-2A Phosphate-2B The Anomeric Effect O P O O O R R Acceptor orbital hierarchy: !* P–OR * > !* P–O– Oxygen lone pairs may establish a simultaneous hyperconjugative relationship with both acceptor orbitals only in the illustrated conformation. !– !– P O O O R R !– !– O P O O O R R!– !– O P O O O R R!– !– Gauche-Gauche conformation Anti-Anti conformation Gauche-Gauche conformation affords a better donor-acceptor relationship Anomeric Effects in DNA Phosphodiesters Plavec, et al. (1996). “How do the Energetics of the Stereoelectronic Gauche & Anomeric Effects Modulate the Conformation of Nucleos(t)ides? ” Pure Appl. Chem. 68: 2137-44. 1A 1B 2B Chem 206D. A. Evans Olefin Epoxidation via Peracids: An Introduction OH O-O bond energy: ~35 kcal/mol HOMO !C–C ++ ! The General Reaction: LUMO "*O–O " note labeled oxygen is transferfed R O R R R O R O R R R R OHR " HOMO !C–C LUMO "*O–O LUMO !#C–C HOMO O lone pair Since 2 C–O bonds are formed in the epoxidation reaction, there are two HOMO–LUMO pairs that should be considered. They are illustrated below. HOMO–LUMO Interactions for Peracid Epoxidation View from below olefin ■ The transition state: R R R R 0.40.050.61.0 ! The indicated olefin in each of the diolefinic substrates may be oxidized selectively. ! Reaction rates are governed by olefin nucleophilicity. The rates of epoxidation of the indicated olefin relative to cyclohexene are provided below: OH OAc OH Me Me Me Me Me H MeMe Me Me Chem 206D. A. Evans Olefin Epoxidation with Dioxiranes O-O bond energy: ~35 kcal/mol HOMO1 !C–C LUMO2 !"C–C ++ LUMO1 #*O–O HOMO2 O lone pr note labeled oxygen is transferfed R R R R O R R R R RR O OR R ! ! Transition State for the Dioxirane Mediated Olefin Epoxidation O O R Rplanar O O R R rotate 90° spiro Houk, JACS, 1997, 12982. stabilizing Olp ! "* C=C cis olefins react ~10 times faster than trans ! Synthesis of the Dioxirane Oxidant O RR O S O O H O –OK+ (Oxone) O OR R SO3 H O OR R " Synthetically Useful Dioxirane Synthesis oxoneO Me Me Me OO Me co-distill to give ~0.1 M soln of dioxirane in acetone oxoneO F3C CF3 F3C OO CF3 co-distill to give ~0.6 M soln of dioxirane in hexafluoroacetone Asymmetric Epoxidation with Chiral Ketones Review: Frohn & Shi, Syn Lett 2000, 1979-2000 (PDF) O O O O O Me Me Me Me O chiral catalyst oxone, CH3CN-H2O pH 7-8 R2 R1 R2 OR2 R1 R2 Ph Ph >95% ee Ph Me 84% ee Ph Ph 92% ee Me R2 R1 oxone, CH3CN-H2O pH 10.5 R2 R2 R1 R2 O O O O O O Me Me Me Me O 2 1 equiv 2 (2) >90% ee Me Me O KO3SOOH CH3CN-H2O pH 10.5 Me Me O O (1) 1 Question 4. (15 points). The useful epoxidation reagent dimethyldioxirane (1) may be prepared from "oxone" (KO3SOOH) and acetone (eq 1). In an extension of this epoxidation concept, Shi has described a family of chiral fructose-derived ketones such as 2 that, in the presence of "oxone", mediate the asymmetric epoxidation of di- and tri-substituted olefins with excellent enantioselectivities (>90% ee) (JACS 1997, 119, 11224). Part A (8 points). Provide a mechanism for the epoxidation of ethylene with dimethyldioxirane (1). Use three-dimensional representations, where relevant, to illustrate the relative stereochemical aspects of the oxygen transfer step. Clearly identify the frontier orbitals involved in the epoxidation. Part B (7 points). Now superimpose chiral ketone 2 on to your mechanism proposed above and rationalize the sense of asymmetric induction of the epoxidation of trisubstituted olefins (eq 2). Use three-dimensional representations, where relevant, to illustrate the absolute stereochemical aspects of the oxygen transfer step. Question: First hour Exam 2000 (Database Problem 34)