Chem 206D. A. Evans The Anomeric Effect: Negative Hyperconjugation Chemistry 206 Advanced Organic Chemistry Lecture Number 2 Stereoelectronic Effects-1 a73 Anomeric and Related Effects a73 Electrophilic & Nucleophilic Substitution Reactions a73 The SN2 Reaction: Stereoelectronic Effects a73 Olefin Epoxidation: Stereoelectronic Effects a73 Baeyer-Villiger Reaction: Stereoelectronic Effects a73 Olefin Bromination: Stereoelectronic Effects a73 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 a73 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). OPO OMe OPO OMe Rank the phosphites from the least to the most nucleophilic andprovide 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 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-methoxytetrahydropyranprefers 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: a73 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 ? 1.781 ? Why is axial C–Cl bond longer ? H OMe HOMe OMe HOMeH OO O H OMe O H OMe Cl HO O OHCl H Cl Let anomeric effect = A ? Gp° = ? Gc° + AA = ? G p° – ? Gc°A = –0.6 kcal/mol – 0.6 kcal/mol = –1.2 kcal/mol Cl HO axial O lone pair?σ? C–Cl OHOMO σ? C–Cl σ C–Cl a71a71 a71a71 The Exo-Anomeric Effect HO O R a73 There is also a rotational bias that is imposed on the exocyclicC–OR bond where one of the oxygen lone pairs prevers to be anti to the ring sigma C–O bond OO R OORfavored A. J. Kirby, The Anomeric and Related Stereoelectronic Effects at Oxygen, Springer-Verlag, 1983 E. Jurasti, G. Cuevas, The Anomeric Effect, CRC Press, 1995 a71a71 a71a71 Chem 206D. A. Evans The Anomeric Effect: Carbonyl Groups Do the following valence bond resonance structures have meaning? ν C–H = 3050 cm -1ν 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. CHCR OH CR RR a71a71 a71a71 CR OX a71a71a71a71 C R O X a71a71a71a71– + Prediction: As X becomes more electronegative, the IR frequency should increase 1720 1750 1780υC=O (cm-1) Me CH3 O Me CBr3 O Me CF3 O Prediction: As the indicated pi-bonding increases, the X–C–Obond angle should decrease. This distortion improves overlap. CR O X a71a71 σ* C–X →O lone pair CR O X a71a71 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. ν N–H = 2188 cm -1 ν N–H = 2317 cm -1 filled N-SP2 antibonding σ? N–H .. antibonding σ? N–H The N–H stretching frequency of cis-methyl diazene is 200 cm-1 lower than the trans isomer. N NMe H N HNMe N NMe N N Me a71a71a71a71 a71a71 a71a71 a73 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 Infrared Bohlmann Bands J. B. Lambert et. al., JACS 1967 89 3761H. P. Hamlow et. al., Tet. Lett. 1964 2553 NMR : Shielding of H antiperiplanar to N lone pair H10 (axial): shifted furthest upfield H6, H4: ?δ = δ Haxial - δ H equatorial = -0.93 ppm Protonation on nitrogen reduces ?δ to -0.5ppm Bohlmann, Ber. 1958 91 2157 Characteristic bands in the IR between 2700 and 2800 cm-1 for C-H 4, 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 HH H HH Observation: C–H bonds anti-periplanar to nitrogen lone pairs are spectroscopically distinct from their equatorial C–H bond counterparts NHOMO σ? C–H σ C–H Spectroscopic Evidence for Conjugation A. R. Katritzky et. al., J. Chemm. Soc. B 1970 135?G° = – 0.35kcal/mol NN N NN NCMe3 Me3C Me3C CMe3 Me3C Me3C Favored Solution Structure (NMR) J. E. Anderson, J. D. Roberts, JACS 1967 96 4186 NN N NMe Me Me MeMeN MeN NMeNMe 1.484 1.457 1.453 1.459 1.453 A. R. Katrizky et. al., J. C. S. Perkin II 1980 1733 NN N N Me Bn Me Bn Favored Solid State Structure (X-ray crystallography) O Chem 206D. A. EvansCalculated 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 OP OO 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 OO O R R – – OP OO O R R– – OP OO 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 3) In 1985 Burgi, on carefully studying the X-ray structures of a number of lactones, noted that the O-C-C (α) & O-C-O (β) bond angles were not equal. Explain the indicated trend in bond angle changes. α?β = 4.5 °α?β = 6.9 °α?β = 12.3 ° β β βααα 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 nucleophilicattack 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 thefollowing: 2 1 versus Esters versus Lactones: Questions to Ponder. Since σ* C–O is a better acceptor than σ* 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 σ* C–R. σ* C–R σ* C–OIn the (Z) conformation this lone pair is aligned to overlap with σ* C–O. (Z) Conformer a73 Hyperconjugation: Let us now focus on the oxygen lone pair in the hybrid orbital lying in the sigma framework of the C=O plane. a73 Oxygen Hybridization: Note that the alkyl oxygen is Sp2. Rehybridizationis 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.a73 Lone Pair Conjugation: Rotational barriers are ~ 10 kcal/molThis is a measure of the strength of the pi bond. barrier ~ 10 kcal/mol ?G° ~ 2-3 kcal/molEne rgy These resonance structures suggest hindered rotation about =C–OR bond. This is indeed observed: + a73 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. Ifthis 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° = +2 kcal/molSpecific Case:Formic Acid (E) Conformer(Z) Conformer a73 Conformations: There are 2 planar conformations. D. A. Evans Chem 206Carboxylic Acids (& Esters): Anomeric Effects Again? O O R'R R OR' O O OHHH O H O R O R' O O – O R'R R O R O O ORR CO O R R C OO R R CRO R O R O R O R O C OOR R O O EtCH3CH2 O O O O O OO O O R ???? ?? ?? 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 Ener gy 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 a71 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 Ener gy 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 σ C–Br (2 electrons)1 antibonding MO σ* C–Br D. A. Evans Chem 206Three-center Bonds H2C CH CH2 CH CH2H2C CH CH2H2C O H OH O OCH 3 CH3 B H BHH HH H B HBH HH H H C H H H Nu Br bonding nonbonding antibonding Case 4: 2 s-Orbitals; 1 p-orbital Do this as an exercise Chem 206D. A. Evans Substitution Reactions: General Considerations Why do SN2 Reactions proceed with backside displacement? δ– δ– ? Nu: – X: –C HH R XNu C HHRNu 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 XRHH C X R HH Constructive overlap between Nu & σ*C–X C X R HH Retention NuOverlap from this geometry results in no net bonding interaction Expanded view of *C–X C X Nu HOMO LUMO LUMO bondingantibonding a71a71 a71a71 a71a71HOMO Electrophilic substitution at saturated carbon may occur with either inversion of retention δ+ δ+ ? El(+) C HRb Ra MNu C HR b RaNuC MRa RbH C M Ra RbH LUMO El(+) Retention C M Ra RbH El(+) Inversion HOMO a71a71 a71a71 Inversion Retention ? El(+) C MRaR b H C MRa RbH El δ+ δ+ C El Ra RbH Fleming, page 75-76 Li H Br2H Brpredominant inversion CO2 CO 2LiH predominant retention Examples Stereochemistry frequently determined by electrophile structure M+ M+ D. A. Evans Chem 206SN2 Reaction: Stereoelectronic Effects δ– δ– ? Nu: – X: – The reaction under discussion: a73 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 σC–X and σ?C–X: σ ?C–X σC–X Nu: – δ–δ– ener gy a73 Experiments have been designed to probe inherent requirement for achievinga 180 ° Nu–C–X bond angle: Here both Nu and leaving group are constrained to be part of the same ring. δ–δ– "tethered reactants" "constrained transition state" Nu: – – – a73 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. a73 If the rxn was exclusively intramolecular, the products would only contain only three deuterium atoms: exclusivelyintramolecular exclusivelyintramolecular The use of isotope labels to probe mechanism. a73 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 D 3-productD' 3-product2+2 D 6-product2+1 D 0-product 2 CD3–Ar–Nu–CH32 CH 3–Ar–Nu–CD3 (CD3–Ar–Nu–CH3) (CH3–Ar–Nu–CD3) 1 CD3–Ar–Nu–CD31 CH 3–Ar–Nu–CH3Hence, 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% intramolecular84% intermolecular – – – – Other Cases:The Eschenmoser Experiment (1970): Helv. Chim Acta 1970, 53, 2059 C XR HH C HH R XNu C H H RNu CNu X CNu X R H H C XR HH Nu: S O CH3O O Nu CH3 SO3 Nu: S O CH3O O Nu CH3 SO3 Nu SO3 CD3 S OO O CD3 Nu: (CH3)2N SO3CH3 SO3(CH3)3N SO3CH3 N(CH3)2 N(CH3)3SO3 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 16% intramolecular; 84% intermolecular –+ exclusively intermolecular –+ Intramolecular methyl transfer: Speculation on the transition structures Chem 206D. A. Evans est C–N bond length 2.1 ? est C–O bond length 2.1 ? 174° est C–O bond length 2.1 ? est C–N bond length 2.1 ? 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 ? (CH3)2N SO3CH3 SO3(CH3)3NSO3CH3N(CH 3)2 N(CH3)3 SO3 9- membered cyclic transition state 8- membered cyclic transition state R O OH O + a71 R R R R +a71 a71 a71R R R R O OHR OH OAc OH H MeMe Me Me O O H Me Me O H O Me MeMe Me Me O-O bond energy: ~35 kcal/mol View from below olefin a73 The transition state: 0.40.050.61.0 a73 The indicated olefin in each of the diolefinic substrates may be oxidized selectively. a73 Reaction rates are governed by olefin nucleophilicity. The rates of epoxidation of the indicated olefin relative to cyclohexene are provided below: HOMO piC–C Per-arachidonic acid Epoxidation E. J. Corey, JACS 101, 1586 (1979) a73 The General Reaction: Chem 206D. A. Evans Olefin Epoxidation via Peracids: An Introduction LUMO σ*O–O note labeled oxygen is transferfed For theoretical studies of TS see R. D. Bach, JACS 1991, 113, 2338R. D. Bach, J. Org. Chem 2000, 65, 6715 For a more detailed study see P. Beak, JACS 113, 6281 (1991) a73 The General Reaction: Chem 206D. A. Evans Olefin Epoxidation with Dioxiranes O-O bond energy: ~35 kcal/molHOMOpiC–C ++ LUMOσ*O–O a71 note labeled oxygen is transferfedR R R R OR R R R RRO OR R a71 a73 Synthesis of the Dioxirane Oxidant O RR O S O O H O–OK+ (Oxone) O OR R SO 3 H O OR R a71 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 Curci, JOC, 1980, 4758 & 1988, 3890; JACS 1991, 7654. Transition State for the Dioxirane Mediated Olefin Epoxidation O O RRplanar O O RR rotate 90° spiro Houk, JACS, 1997, 12982. stabilizing Olp → pi* C=Ccis olefins react ~10 times faster than trans R2 R1 oxone, CH3CN-H2OpH 10.5R2 R2 R1 R2 O O OO O O MeMe Me Me O 2 1 equiv 2 (2) >90% ee Me Me O KO3SOOH CH3CN-H2OpH 10.5 Me Me O O (1)1 Question 4. (15 points). The useful epoxidation reagent dimethyldioxirane (1) may beprepared 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 thepresence 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 proposedabove and rationalize the sense of asymmetric induction of the epoxidation of trisubstituted olefins (eq 2). Use three-dimensional representations, where relevant, to illustrate theabsolute stereochemical aspects of the oxygen transfer step. Question: First hour Exam 2000 Asymmetric Epoxidation with Chiral Ketones Review: Frohn & Shi, Syn Lett 2000, 1979-2000 O OO O O MeMe Me Me O chiral catalyst oxone, CH3CN-H2OpH 7-8 R2 R1 R2 OR2 R1 R2 Ph Ph>95% ee Ph Me84% ee Ph Ph92% ee Me RL C RS O C O MeR OR C Me O O MeR C O C O RSORL CH3(CH2)2 R CH3CH2 (CH3)3C PhCH2 RL C O O OHRS R O O ORL RSC O CMe3Me H H O H O OO R Me3C Me Me3C Me Me CMe3 O HO R O O O O O O R H Me O CMe3 O H O R O O OMe CMe3 Me O CMe3 O Migrating group Migrating group Steric effects destabilize Conformer B relative to Conformer A; hence, the reaction is thought to proceed via a transition state similar to A. Conformer B Conformer A Disfavored Favored The important stereoelectronic components to this rearrangement: 1. The RL–C–O–O dihedral angle must be180° due to the HOMO LUMO interaction σ-RL–C?σ??O–O. 2. The C–O–O–C' dihedral angle will be ca. 60° due to the gauche effect (O-lone pairs?σ??C–O). This gauche geometry is probably reinforced by intramolecular hydrogen bonding as illustrated on the opposite page: The Intermediate >2000 830 150 72 kR / KMekR kMe + CF3CO3H major minor The major product is that wherein oxygen has been inserted into theR L–Carbonyl bond. + minormajor – RCO2H + RCO3H Let RL and RS be Sterically large and small substituents. The Baeyer-Villiger Reaction: Stereoelectronic Effects Chem 206D. A. Evans - MeCO2H+ RCO3H The destabilizing gauche interaction For relevant papers see: Crudden, Angew. Chem. Int. Ed 2000, 39, 2852-2855 (pdf) Kishi, JACS 1998, 120, 9392 (pdf) FMO-Theory/HSAB Principle 1B. Breit Chem 206 Hard and Soft Acids and Bases (HSAB-Principle) Pearson, JACS 1963, 85, 3533. Hard Acids prefer to interact with hard basesSoft acids prefer to interact with soft bases. Softness: Polarizability; soft nucleophiles have electron clouds, which can be polarized (deformed) easily. Hardness: Charged species with small ion radii, high charge density. Qualitative scaling possible: FMO-Theory and Klopman-Salem equation provide an understanding of this empirical principle: Hard Acids have usually a positive charge, small ion radii (high charge density), energy rich (high lying) LUMO. Soft Acids are usually uncharged and large (low charge density), they have an energy poor (low lying ) LUMO (usually with large MO coefficient). Hard Bases usually have a negative charge, small ion radii (high charge density), energy poor (low lying) HOMO. Soft Bases are usually uncharged and large (low charge density), energy rich (high lying) HOMO (usually with large MO coefficient). Molecular Orbital Energies of an idealized Hard Speciesidealized Soft Species EE large HOMO/LUMO gapsmallHOMO/LUMO gap E E Soft-Soft Hard-Hard FMO-Theory for interaction: Acid Base Acid Base Significant Energy gain through HOMO/LUMO interaction Only neglectable energy gain through orbital interaction. Reading Assignment: Fleming, Chapter 3, p33-46 FMO-Theory/HSAB Principle 2B. Breit Chem 206 QNQE Q: Charge densityε: Dielectricity constant R: distance (N-E)c: coefficient of MO β: Resonance IntegralE: Energy of MO ?E = 2(cNcEβ)2EHOMO(N) - ELUMO(E)εRNE Coulomb Term Frontier Orbital Term Klopman-Salem Equation for the interaction of a Nucleophile N (Lewis-Base) and an Electrophile E (Lewis-Acid). Soft-Soft Interactions: Coulomb term small (low chargedensity). Dominant interaction is the frontier orbital interaction because of a small ?E(HOMON/LUMOE).? formation of covalent bonds Hard-Hard Interactions: Frontier orbital term small because of large ?E(HOMON/LUMOE). Dominant interaction is described by the Coulomb term (Q is large for hard species), i.e.electrostatic interaction. ? formation of ionic bonds Hard-Soft Interactions: Neither energy term providessignificant energy gain through interaction. Hence, Hard-Soft interactions are unfavorable. FMO-Theory/HSAB Principle 3B. Breit Chem 206 HSAB principle - Application to Chemoselectivity Issues (a) Enolate Alkylation C C O hard soft MeI TMSCl O Me OTMS C-Alkylation O-Alkylation (b) 1,2- vs. 1,4-addition to α,β-unsaturated carbonyl compounds O H+ 0.01 + 0.29 Charge density O H LUMO-coefficients+ 0.62 - 0.48 softMe 2CuLi hardMeLihard soft 1,2-Addition Conjugate Addition O OH Me OMe (c) SN2 vs E2 H Br soft CO2RCO2R S N2 E2hardOC 2H5 soft hard (d) Ambident Nucleophiles S C N soft hard MeIAg Na S C NH3C S C N O Rhard soft O N soft hard MeIAg Nahard soft O t-BuCl H3C NO2 ONO S-Alkylation N-Acylation N-Alkylation O-Alkylation HC(COOR)2 RCOX