哈佛大学：《高等有机化学》（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

D. A. Evans Carboxylic Acids(& Esters): Anomeric Effects Again? Chem 206 I Conformations: There are 2 planar conformations Hyperconjugation: Let us now focus on the oxygen lone pair in the hybrid orbital lying in the sigma framework of the C=O plane (2 Confor (2 Conformer (E)Conformer R C-O lone pair is aligned to overlap Formic H^o△G°=+2 carmol The(E)conformation of both acids and esters is less stable by 2-3 kcal/mol. If :(E) Conformer 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 co In the(E)cont considered. These effects will be introduced shortly lone pair is aligned to overlap o*C-R Rotational Barriers: There is hindered rotation about the =c-or bond These resonance structures suggest Since o*C-O is a better acceptor than GC-R hindered rotation about =c-or bond where R is a carbon substituent)it follows that This is indeed observed the(2)conformation is stabilized by this interaction R Esters versus Lactones: Questions to Ponder. o Rotational barriers are- 10 kcal/mol R G°-2-3 This is a measure of the strength of Esters strongly prefer to adopt the() conformation while CHaCH pi bond g lactones such as 2 are constrained to exist in the mation. From the preceding discussion explain the I Lone Pair Conjugation: The oxygen lone pairs conjugate 1)Lactone 2 is significantly more susceptible to nucleophilic attack at the carbonyl carbon than 1? Explain versus The filled oxygen p-orbital interacts with pi(and pi") 2) Lactone 2 is significantly more prone to enolization than 1? C=O to form a 3-centered 4-electron bonding system In fact the pKa of 2 is -25 while ester 1 is-30(DMSO). Explain 3)In 1985 Burgi, on carefully studying/Ow the X-ray structures of a number of SP2 Hybridization lactones, noted that the o-c-c (a)& o-C-o(B)bond angles were not equa a a Oxygen Hybridization: Note that the alkyl oxygen is Sp2. Rehybridizati i Explain the indicated trend in bond is driven by system to optimize pi-bonding angle changes a-B=123°a-B=6.9°a-=45

3) In 1985 Burgi, on carefully studying the X-ray structures of a number of lactones, noted that the O-C-C (a) & O-C-O (b) bond angles were not equal. Explain the indicated trend in bond angle changes. a-b = 12.3 ° a-b = 6.9 ° a-b = 4.5 ° a b a b a b 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. Since s* C–O is a better acceptor than s* 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 s* C–R. s* C–R s* C–O In the (Z) conformation this lone pair is aligned to overlap with s* 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. ■ 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 ■ Lone Pair Conjugation: The oxygen lone pairs conjugate with the C=O. Rotational barriers are ~ 10 kcal/mol This is a measure of the strength of the pi bond. barrier ~ 10 kcal/mol DG° ~ 2-3 kcal/mol Energy 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. The (E) conformation of both acids and esters is less stable by 2-3 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. DG° = +2 kcal/mol Specific Case: Formic Acid (Z) Conformer (E) Conformer ■ Conformations: There are 2 planar conformations. D. A. Evans Carboxylic Acids (& Esters): Anomeric Effects Again? Chem 206 O O R' R R O R' O O O H H O H H O R O R' O O – O R' R R O R O O O R R O C O R R C O O R R C R O R O R O R O R O C O R O R O O Et CH3CH2 O O O O O O O O O R •• •• •• ••

D. A. Evans Three-center Bonds Chem 206 Consider the linear combination of three atomic orbitals. The resulting molecular orbitals(MOs) usually consist of one bonding, one nonbonding Case 3: 2 p-Orbitals: 1 s-orbital and one antibonding MO antibonding Case 1: 3 p-Orbitals pI-onentation antibonding 2 nonbonding I Case 4: 2 s-Orbitals: 1 p-orbital Do this as bonding Note that the more nodes there are in the wave function, the higher its energy Examples of three-center bonds in organic chemistry H2C=CH-CH2 Allyl carbonium ion: both pi-electrons in bonding state A. H-bonds:(3-center, 4 electron) 0-H-0 The acetic acid dimer is H2c=CH—CH2Alyl 2 electrons in bonding obital plus 3 stabilized by ca 15 kcal/mol nonbonding MO B. H-B-H bonds:(3-center, 2 electron) Case 2: 3 p-Orbitals sigma-orientation antibonding i diborane stabilized by 35 kcal/mol nonbonding C. The SN2 Transition state: (3-center, 4 electron) The SN 2 transition state approximates a case 2 situation with a central carbon p-orbita The three orbitals in reactant molecules 1 nonbonding MO from Nucleophile (2 electr bonding 1 bonding Mo o C-Br(2 electrons) 1 antibonding MOσC-B

Consider the linear combination of three atomic orbitals. The resulting molecular orbitals (MOs) usually consist of one bonding, one nonbonding and one antibonding MO. Case 1: 3 p-Orbitals 3 Energy bonding nonbonding antibonding Note that the more nodes there are in the wave function, the higher its energy. + Allyl carbonium ion: both pi-electrons in bonding state ● Allyl Radical: 2 electrons in bonding obital plus one in nonbonding MO. – Allyl Carbanion: 2 electrons in bonding obital plus 2 in nonbonding MO. antibonding nonbonding bonding Energy 3 Case 2: 3 p-Orbitals pi-orientation sigma-orientation 2 + Case 3: 2 p-Orbitals; 1 s-orbital Examples of three-center bonds in organic chemistry A. H-bonds: (3-center, 4 electron) The acetic acid dimer is stabilized by ca 15 kcal/mol B. H-B-H bonds: (3-center, 2 electron) diborane stabilized by 35 kcal/mol C. The SN2 Transition state: (3-center, 4 electron) The SN 2 transition state approximates a case 2 situation with a central carbon p-orbital The three orbitals in reactant molecules used are: 1 nonbonding MO from Nucleophile (2 electrons) 1 bonding MO s C–Br (2 electrons) 1 antibonding MO s* C–Br D. A. Evans Three-center Bonds Chem 206 H2C CH CH2 H2C CH CH2 H2C CH CH2 O H H O O O CH3 CH3 B H B H H H H H B H B H H H H H C H H H Nu Br bonding nonbonding antibonding Case 4: 2 s-Orbitals; 1 p-orbital Do this as an exercise

D. A. Evans Substitution Reactions: General Considerations Chem 206 Why do sn2 Reactions proceed with backside displacement? Electrophilic substitution at saturated carbon may occur with either inversion of retention R Inversion x—-|№u-2-x Ra Given the fact that the LUMo on the electrophile is the C-X antibonding orbital, Nucleophilic attack could occur with either inversion or retention Retention Inversion Retention M E(+) 白 HOMO LUMO Constructive overlap between Overlap from this geometry results Ra nu &o*C-x in no net bonding interaction M○ HOMO Expanded view of o*C-X Retention LUMO Examples HOMO 人2,丈2人 Nu Fleming page 75-76 predominant inversion predominant retention Stereochemistry frequently determined by electrophile structure

D. A. Evans Substitution Reactions: General Considerations Chem 206 Why do SN2 Reactions proceed with backside displacement? d– d– ‡ Nu: – X: C – H H R Nu X C H H R Nu Given the fact that the LUMO on the electrophile is the C–X antibonding orblital, Nucleophilic attack could occur with either inversion or retention. Nu Inversion C X R H H C X R H H Constructive overlap between Nu & s*C–X C X R H H Retention Nu Overlap from this geometry results in no net bonding interaction Expanded view of *C–X C X Nu HOMO LUMO LUMO antibonding bonding ●● ●● ●● HOMO Electrophilic substitution at saturated carbon may occur with either inversion of retention d+ d+ ‡ El(+) C R H b Ra Nu M C H Rb Ra C M Nu Ra Rb H C M Ra Rb H LUMO El(+) Retention C M Ra Rb H El(+) Inversion HOMO ●● ●● Inversion Retention ‡ El(+) C M Ra Rb H C Ra M Rb H El d+ d+ C El Ra Rb H Fleming, page 75-76 Li H Br2 H Br predominant inversion CO2 CO2Li H predominant retention Examples Stereochemistry frequently determined by electrophile structure M+ M+

D. A. Evans SN2 Reaction: Stereoelectronic Effects Chem 206 The reaction under discussion: The use of isotope labels to probe mechanism. i 1 and 2 containing deuterium labels either on the aromatic ring or on the methyl group were prepared. A 1: 1-mixture of 1 and 2 were allowed to react a If the rxn was exclusively intramolecular, the products would only contain only three deuterium atoms a The Nu-C-x bonding interaction is that of a 3-center, 4-electron bond. The frontier orbitals which are involved are the nonbonding orbital from ell as CD3-Ar-Nu- gC-X and o+C-X H3C a If the reaction was exclusively intermolecular, products would only contain I Experiments have been designed to probe inherent requirement for achieving possilbilier'3e №-C--X RCHrx differing amounts of D-label depending on which two partners underwent reaction. The deuterium content might be analyzed by mass spectrometry. Here are the a 180Nu-C-X bond angle: Here both Nu and leaving group are constrained to D3-product 2 CD3-Ar-NL-CH3 be part of the same ring 2+2 D'3-product 2 CH3-Ar-NU--CD 1+2 Do-product 1 CD3-Ar-NU-CD3 №u- Hence, for the strictly intermolecular situation one should see the following ratios Do:D3:D3:D6=1:2:2:1 tethered reactants constrained transition state The product isotope distribution in the Eschenmoser expt was found to b exclusively that derived from the intermolecular pathway The Eschenmoser Experiment(1970): He/v Chim Acta 1970, 53, 2059 Other Cases a The reaction illustrated below proceeds exclusively through bimolecular pathway exclusive rcH~80→(a~s0 in contrast to the apparent availability of the intramolecular path 16‰ intramolecular SO3CH3 84% intermolecular Hence, the Nul-C-x 180 transition state bond angle must be rigidly maintained for the reaction to take place

D. A. Evans SN2 Reaction: Stereoelectronic Effects Chem 206 d– d– ‡ Nu: – X: – The reaction under discussion: ■ The Nu–C–X bonding interaction is that of a 3-center, 4-electron bond. The frontier orbitals which are involved are the nonbonding orbital from Nu as well as sC–X and s*C–X: s *C–X sC–X Nu: – d– d– energy ■ Experiments have been designed to probe inherent requirement for achieving a 180 ° Nu–C–X bond angle: Here both Nu and leaving group are constrained to be part of the same ring. d– d– "tethered reactants" "constrained transition state" Nu: – – – ■ The reaction illustrated below proceeds exclusively through bimolecular pathway in contrast to the apparent availability of the intramolecular path. 1 2 1 and 2 containing deuterium labels either on the aromatic ring or on the methyl group were prepared. A 1:1-mixture of 1 and 2 were allowed to react. ■ If the rxn was exclusively intramolecular, the products would only contain only three deuterium atoms: exclusively intramolecular exclusively intramolecular The use of isotope labels to probe mechanism. ■ If the reaction was exclusively intermolecular, products would only contain differing amounts of D-label depending on which two partners underwent reaction. The deuterium content might be analyzed by mass spectrometry. Here are the possibilities: 1 + 1 D3 -product D'3 2 + 2 -product D6 -product 1 + 2 D0 -product 2 CD3–Ar–Nu–CH3 2 CH3–Ar–Nu–CD3 (CD3–Ar–Nu–CH3 ) (CH3–Ar–Nu– CD3 ) 1 CD3–Ar–Nu–CD3 1 CH3–Ar–Nu–CH3 Hence, for the strictly intermolecular situation one should see the following ratios D0 : D3 : D'3 : D6 = 1 : 2 : 2 : 1. The product isotope distribution in the Eschenmoser expt was found to be exclusively that derived from the intermolecular pathway! + – exclusively intermolecular + – 16% intramolecular 84% intermolecular – – – – Other Cases: The Eschenmoser Experiment (1970): Helv. Chim Acta 1970, 53, 2059 C X R H H C H H R Nu X C H H R Nu Nu C X Nu C X R H H C X R H H Nu: S O CH3 O O Nu CH3 SO3 Nu: S O CH3 O O Nu CH3 SO3 Nu SO3 CD3 S O O O CD3 Nu: (CH3 )2N SO3CH3 SO3 (CH3 )3N SO3CH3 N(CH3 )2 N(CH3 )3 SO3 D3C H3C H3C D3C Hence, the Nu–C–X 180 ° transition state bond angle must be rigidly maintained for the reaction to take place. RCH2–X

D. A. Evans Intramolecular methyl transfer: Speculation on the transition structures Chem 206 (CH3)N 16% intramolecular: 84% intermolecular exclusively intermolecular 9-membered cyclic transition state 8-membered cyclic transition state est C-o bond est c-o bond length 2.1 A length 2.1 A est C-n bond length 2.1 A est c-n bond length 2.1 A Approximate representation of the transition states of the intramolecular alkylation reactions. Transition state C-O and C-N bond lengths were estimated to be 1.5x(C-X)bond length of 1.4 A

16% intramolecular; 84% intermolecular – + exclusively intermolecular + – D. A. Evans Intramolecular methyl transfer: Speculation on the transition structures Chem 206 est C–N bond length 2.1 Å est C–O bond length 2.1 Å 174° est C–O bond length 2.1 Å est C–N bond length 2.1 Å 174° Approximate representation of the transition states of the intramolecular alkylation reactions. Transition state C–O and C–N bond lengths were estimated to be 1.5x(C–X) bond length of 1.4 Å (CH3 )2N SO3CH3 SO3 (CH3 )3N SO3CH3 N(CH3 )2 N(CH3 )3 SO3 9- membered cyclic transition state 8- membered cyclic transition state