哈佛大学：《高等有机化学》课程教材讲义（英文版）Lecture 2 Stereoelectronic Effects

D. A. Evans The Anomeric Effect: Negative Hyperconjugation Chem 206 Useful LIterature Reviews http://www.courses.fasharvardedu/-chem206/ Kirby, A J(1982). The Anomeric Effect and Related Stereoelectronic Effects at Chemistry 206 Box, VGS(1990). The role of lone pair interactions in the chemistry of the monosaccharides. The anomeric effect "Heterocycles 31 1157 Advanced organic Chemistry Box, V.G.S(1998). The derivatives Insights from the new QVBMM molecular mechanics force field. Heterocycles 48(11 ): 2389-2417. Lecture number 2 Graczyk, P. P and M. Mikolajczyk( 1994). "Anomeric effect: origin and consequences. "Top. Stereochem. 21: 159-349 Stereoelectronic Effects-1 Juaristi, E. and G. cuevas (1992 ) "Recent studies on the anomeric effect. Tetrahedron 48 5019 Plavec, J, C Thibaudeau, et al.(1996). "How do the Energetics of the Anomeric and related Effects Stereoelectronic gauche and Anomeric Effects modulate the Conformation of (t)ides? "Pure Appl. Chem. 68: 2137- a Electrophilic& Nucleophilic Substitution Reactions Thatcher, G R I, Ed. (1993). The Anomeric Effect and Associated i Stereoelectronic Effects. Washington DC, American Chemical Society u The Sn2 Reaction: Stereoelectronic Effects Olefin Epoxidation: Stereoelectronic Effects A Problem of the Day(First hr exam, 1999) u Baeyer-Villiger Reaction: Stereoelectronic Effects The three phosphites illustrated below exhibit a 750-fold span in reactivity with a test electrophile(eq 1)(Gorenstein, JACS 1984, 106, 7831) 十 Olefin Bromination Stereoelectronic Effects (RO)3P El(+)-(RO)3P-EI (1) Hard Soft Acid and Bases(not to be covered in class OMe HSAB Discussion: Fleming Chapter 3 OMe Matthew d. shair Friday Rank the phosphites from the least to the most nucleophilic and September 20, 2002 provide a concise explanation for your predicted reactivity order

D. A. Evans The Anomeric Effect: Negative Hyperconjugation Chem 206 Chemistry 206 Advanced Organic Chemistry Lecture Number 2 Stereoelectronic Effects-1 ■ Anomeric and Related Effects ■ Electrophilic & Nucleophilic Substitution Reactions ■ The SN2 Reaction: Stereoelectronic Effects ■ Olefin Epoxidation: Stereoelectronic Effects ■ Baeyer-Villiger Reaction: Stereoelectronic Effects ■ Olefin Bromination: Stereoelectronic Effects ■ Hard & Soft Acid and Bases (Not to be covered in class) Matthew D. Shair Friday, September 20, 2002 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. Plavec, J., C. Thibaudeau, et al. (1996). “How do the Energetics of the Stereoelectronic Gauche and Anomeric Effects Modulate the Conformation of Nucleos(t)ides?” Pure Appl. Chem. 68: 2137-44. Thatcher, G. R. J., Ed. (1993). The Anomeric Effect and Associated Stereoelectronic Effects. Washington DC, American Chemical Society. Useful LIterature Reviews ■ Problem of the Day (First hr exam, 1999) The three phosphites illustrated below exhibit a 750-fold span in reactivity with a test electrophile (eq 1) (Gorenstein, JACS 1984, 106, 7831). O P O OMe O P O OMe Rank the phosphites from the least to the most nucleophilic and provide a concise explanation for your predicted reactivity order. O P O O + El(+) (RO)3P–El (1) + A B C HSAB Discussion: Fleming Chapter 3 http://www.courses.fas.harvard.edu/~chem206/ (RO)3P

D. A. Evans The Anomeric Effect: Negative Hyperconjugation Chem 206 The Anomeric Effect I Since the antibonding C-o orbital is a better acceptor orbital than the antibonding C-H bond, the axial OMe conformer is better stabi It is not unexpected that the methoxyl substituent on a cyclohexane ring this interaction which is worth ca. 1.2 kcal/ mol prefers to adopt the equatorial conformation i Other electronegative substituents such as Cl, SR etc also participate in anomeric stabilization OMe 1781A △G。=+06 kcal/mol OMe What is unexpected is that the closely related 2-methoxytetrahydropyran prefers the axial conformation his conformer 1819A preferred by 1.8 kcal/mol Why is axial C-Cl bond longer? axial lone pair+)g* C-CI σ*CC △G°=-06 kcal/mol That effect which provides the stabilization of the axial OR H conformer which overrides the inherent steric bias of th substituent is referred to as the anomeric effect C HOMO Let anomeric effect=A aC-CI The Exo-Anomeric Effect A=△Gp°-△G A =-06 kcal/mol -0.6 kcal/mol =-1.2 kcal/mol a 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 Principal HOMO-LUMO interaction from each conformation is illustrated below 0 e A J. Kirby, Th axial o lone pair+o* C-H axial o lone paire o* C-O E. Jurasti G. cuevas. The Anomenc effect CRC Press. 15

D. A. Evans The Anomeric Effect: Negative Hyperconjugation Chem 206 The Anomeric Effect It is not unexpected that the methoxyl substituent on a cyclohexane ring prefers to adopt the equatorial conformation. D Gc° = +0.6 kcal/mol D Gp ° = –0.6 kcal/mol What is unexpected is that the closely related 2-methoxytetrahydropyran prefers the axial conformation: 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: ■ 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 ? H OMe H OMe OMe H OMe H O O O H OMe O H OMe Cl O H O O H Cl H Cl Let anomeric effect = A D Gp ° = D Gc° + A A = D Gp ° – D Gc° A = –0.6 kcal/mol – 0.6 kcal/mol = –1.2 kcal/mol Cl H O axial O lone pair«s* C–Cl O HOMO s* C–Cl s C–Cl ●● ●● The Exo-Anomeric Effect H O 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 R O 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 ●● ●●

D. A. Evans The Anomeric Effect: Carbonyl Groups Chem 206 Do the following valence bond resonance structures have meaning? hyde 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 R Prediction: As X becomes more electronegative, the IR frequency should increase VC-H=2730 cm-1 vC-H= 3050 cm CH3 Me CBr3 MeCF Sigma conjugation of the lone pair anti to the H will weaken the bond UC=o(cm1)1720 1750 This will result in a low frequency shift 1780 Infrared evidence for lone pair delocalization into vicinal antibonding orbitals The N-H stretching frequency of cis-methyl diazene is 200 cm"lower Prediction: As the indicated pi-bonding increases, the X-C-0 than the trans isomer bond angle should decrease. This distortion improves overlap antibonding N-H=2188cm1 antibond d*CX→ o lone pair Evidence for this distortion has been obtained by X-ray crystallography , filled vN-H=2317 cm-1 Corey Tetrahedron Lett. 1992, 33, 7103-7106 a 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 Craig co-workers JACS 1979, 101, 2480

D. A. Evans The Anomeric Effect: Carbonyl Groups Chem 206 Do the following valence bond resonance structures have meaning? n C–H = 3050 cm -1 n 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 ●● ●● C R O X ●● ●● C R O X ●● ●● – + Prediction: As X becomes more electronegative, the IR frequency should increase uC=O (cm 1720 1750 1780 -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 ●● s* 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 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 N–H = 2188 cm -1 n N–H = 2317 cm -1 filled N-SP2 antibonding s* N–H .. antibonding s* 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

D. A. Evans The Anomeric Effect: Nitrogen-Based Systems Chem 206 Observation: C-H bonds anti-periplanar to nitrogen lone pairs are spectroscopically distinct from their equatorial C-H bond counterparts C-H A.R. Katritzky et aL., J. Chemm. Soc. B 1970 135 HOMO Favored Solution Structure(NMR) gC-H Men NMe NN Spectroscopic Evidence for Conjugation MeN、NMe Infrared Bohlmann Bands Characteristic bands in the ir between 2700 J E. Anderson. J.D. Roberts, JACS 1967 96 4186 and 2800 cm ' for C-H4, C-HG, &C-H10 stretch Bohlmann. Ber. 1958 91 2157 Favored Solid State Structure(X-ray crystallography) Reviews: McKean. Chem Soc. Rev. 19787399 L.J. Bellamy, D W. Mayo, J. Phy Chem.1976801271 1453 NMR: Shielding of H antiperiplanar to N lone pair H1o(axial): shifted furthest upfield H,H4.△6=6Ha×a-6 H equatorial=093ppm 1457 Protonation on nitrogen reduces△δt-0.5ppm H. P. Hamlow et al. Tet. Lett. 1964 2553 A.R. Katrizky et al., J. C.S. Perkin 1980 1733 J B. Lambert et al. JACS 1967 89 3761

D. A. Evans The Anomeric Effect: Nitrogen-Based Systems Chem 206 Infrared Bohlmann Bands 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: Dd = d Haxial - d H equatorial = -0.93 ppm Protonation on nitrogen reduces Dd to -0.5ppm 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 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 s* C–H s C–H Spectroscopic Evidence for Conjugation A. R. Katritzky et. al., J. Chemm. Soc. B 1970 135 DG° = – 0.35kcal/mol N N N N N CMe N 3 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 Favored Solid State Structure (X-ray crystallography)

D. A. Evans Anomeric Effects in DNa Phosphodiesters Chem 206 Calculated Structure of ACG-TGC Duplex The Phospho-Diesters Excised from Crystal Structure Guanine The anomeric Effect Acceptor orbital hierarchy: 8 P-OR*>8P-0- R R R Gauche-Gauche conformation R Phosphate-2A Phosphate-2B Oxygen lone pairs may establish a simultaneous hyperconjugative relationship with both acceptor orbitals only in the illustrated Anti-Anti conformation Plavec, et al. (1996). How do the Energetics of the Stereoelectronic Gauche& Gauche-Gauche conformation affords a better donor-acceptor relationship Anomeric Effects Modulate the Conformation of Nucleos(t)ides? Pure Appl. Chem. 68: 2137-44

O D. A. Evans Chem 206 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 1B 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