Harvard’s Advanced Organic Chemistry (Evans, Myers, Shair, et al.) PDF
Preview Harvard’s Advanced Organic Chemistry (Evans, Myers, Shair, et al.)
D. A. Evans An Introduction to Frontier Molecular Orbital Theory-1 Chem 206 ■ Problems of the Day http://www.courses.fas.harvard.edu/~chem206/ The molecule illustrated below can react through either Path A or Path B to form salt 1 or salt 2. In both instances the carbonyl oxygen functions as the http://evans.harvard.edu/problems/ nucleophile in an intramolecular alkylation. What is the preferred reaction path for the transformation in question? O Chemistry 206 O Path A 1 Br + N O – Br Br H Br Advanced Organic Chemistry N O H O Path B 2 + Br Lecture Number 1 N O – H Br This is a "thought" question posed to me by Prof. Duilo Arigoni at the ETH in Introduction to FMO Theory Zuerich some years ago ■ General Bonding Considerations ■ The H Molecule Revisited (Again!) 2 ■ Donor & Acceptor Properties of Bonding & Antibonding States (First hr exam, 1999) ■ Hyperconjugation and "Negative" Hyperconjugation The three phosphites illustrated below exhibit a 750–fold span in reactivity with a ■ Anomeric and Related Effects test electrophile (eq 1) (Gorenstein, JACS 1984, 106, 7831). ■ Reading Assignment for week: + (RO)3P + El(+) (RO)3P–El (1) Kirby, Stereoelectronic Effects OMe Carey & Sundberg: Part A; Chapter 1 O P O P O OMe Fleming, Chapter 1 & 2 P O O O O Fukui,Acc. Chem. Res. 1971, 4, 57. (pdf) A B C Curnow, J. Chem. Ed. 1998, 75, 910 (pdf) Rank the phosphites from the least to the most nucleophilic and Alabugin & Zeidan, JACS 2002, 124, 3175 (pdf) provide a concise explanation for your predicted reactivity order. Monday, D. A. Evans September 15, 2003 1-01-Cover Page 9/15/03 8:56 AM D. A. Evans An Introduction to Frontier Molecular Orbital Theory-1 Chem 206 Universal Effects Governing Chemical Reactions ■ Stereoelectronic Effects There are three: Geometrical constraints placed upon ground and transition states ■ Steric Effects by orbital overlap considerations. Nonbonding interactions (Van der Waals repulsion) between substituents within a molecule or between reacting molecules Fukui Postulate for reactions: Me Me "During the course of chemical reactions, the interaction of SN2 – Nu: C Br Nu C R Br: the highest filled (HOMO) and lowest unfilled (antibonding) R R R molecular orbital (LUMO) in reacting species is very important to the stabilization of the transition structure." RO RO H O O major H H ■ General Reaction Types Me Me2CuLi RO Me O Radical Reactions (~10%): A• + B• A B p. minor H H Polar Reactions (~90%): A(:) + B(+) A B ■ Electronic Effects (Inductive Effects): The effect of bond and through-space polarization by Lewis Acid heteroatom substituents on reaction rates and selectivities Lewis Base Inductive Effects: Through-bond polarization FMO concepts extend the donor-acceptor paradigm to Field Effects: Through-space polarization non-obvious families of reactions ■ Examples to consider Me + C Br SN1 R C Me + Br:– H2 + 2 Li(0) 2 LiH R R R CH3–I + Mg(0) CH3–MgBr rate decreases as R becomes more electronegative "Organic chemists are generally unaware of the impact of electronic effects on the stereochemical outcome of reactions." "The distinction between electronic and stereoelectronic effects is not clear-cut." 1-02-Introduction-1 9/12/03 4:44 PM D. A. Evans Steric Versus Electronic Effects; A time to be careful!! Chem 206 ■ Steric Versus electronic Effects: Some Case Studies O OSiR3 When steric and electronic (stereoelectronic) effects R3SiO lead to differing stereochemical consequences TiCl4 diastereoselection >94:6 EtO Woerpel etal. JACS 1999, 121, 12208. Nu R3Si OSiR3 OSiR3 O OAc SnBr 4 O O O O H Me Me Me AlCl3 diastereoselection 93:7 stereoselection 99:1 SiMe3 H stereoselection >95:5 OSiR3 OSiR3 O O O OAc SnBr4 Danishefsky et al JOC 1991, 56, 387 BnO BnO BnO pp.. O EtO2C (R)2CuLi diastereoselection O AcO H O 8:1 AcO EtO2C Bu N H Ph N OTBS N N O O O N only diastereomer OTBS Bu 3Al EtO2C only diastereomer N Ph O OAc O Bu H OAc R3 OTBS Ph N H OAc O Al O OAc H Yakura's EtO rationalization: O H O 60-94% N Ph R O TBS O Al Yakura et al R R Tetrahedron 2000, 56, 7715 Mehta et al, Acc Chem. Res. 2000, 33, 278-286 1-03-Introduction-1a 9/15/03 8:14 AM Energy Energy Energy D. A. Evans The H2 Molecular Orbitals & Antibonds Chem 206 The H Molecule (again!!) 2 Linear Combination of Atomic Orbitals (LCAO): Orbital Coefficients Let's combine two hydrogen atoms to form the hydrogen molecule. ■ Rule Two: Mathematically, linear combinations of the 2 atomic 1s states create Each MO is constructed by taking a linear combination of the two new orbitals, one is bonding, and one antibonding: individual atomic orbitals (AO): Bonding MO σ = C1ψ1 + C2ψ2 ■ Rule one: A linear combination of n atomic states will create n MOs. σ∗ (antibonding) Antibonding MO σ∗ = C*1ψ1– C*2ψ2 The coefficients, C1 and C2, represent the contribution of each AO. ∆E 2 2 H 1s 1s H ■ Rule Three: (C1) + (C2) = 1 ψ1 ψ2 The squares of the C-values are a measure of the electron population in neighborhood of atoms in question p. ∆E 2 2 σ (bonding) ■ Rule Four: bonding(C1) + antibonding(C*1) = 1 In LCAO method, both wave functions must each contribute one net orbital Let's now add the two electrons to the new MO, one from each H atom: Consider the pi–bond of a C=O function: In the ground state pi-C–O σ∗ (antibonding) is polarized toward Oxygen. Note (Rule 4) that the antibonding MO is polarized in the opposite direction. ∆E1 C O π∗ (antibonding) H 1s 1s H ψ1 ψ2 ∆E2 σ (bonding) C O Note that ∆E1 is greater than ∆E2. Why? π (bonding) C O 1-04-Introduction-2 9/15/03 8:38 AM D. A. Evans Bonding Generalizations Chem 206 ■ Bond strengths (Bond dissociation energies) are composed of a ■ Orbital orientation strongly affects the strength of the resulting bond. covalent contribution (δ Ecov) and an ionic contribution (δ Eionic). For σ Bonds: Bond Energy (BDE) = δ Ecovalent + δ Eionic (Fleming, page 27) Better A B A B than When one compares bond strengths between C–C and C–X, where X is some other element such as O, N, F, Si, or S, keep in mind that covalent and ionic contributions vary independently. Hence, the mapping of trends is not a trivial exercise. For π Bonds: A B Better A B than Useful generalizations on covalent bonding This is a simple notion with very important consequences. It surfaces in ■ Overlap between orbitals of comparable energy is more effective the delocalized bonding which occurs in the competing anti (favored) than overlap between orbitals of differing energy. syn (disfavored) E2 elimination reactions. Review this situation. For example, consider elements in Group IV, Carbon and Silicon. We ■ An anti orientation of filled and unfilled orbitals leads to better overlap. p. -1 know that C-C bonds are considerably stronger by Ca. 20 kcal mol This is a corrollary to the preceding generalization. than C-Si bonds. There are two common situations. C C C C better than C Si C Si Case-1: Anti Nonbonding electron pair & C–X bond σ∗ C–C σ∗ C–Si X X X σ* C–X lone pair σ* C–X Si-SP3 LUMO HOMO LUMO A C Better A C A C C-SP3 C-SP3 C-SP 3 than lone pair σ C–Si •• HOMO σ C–C H3C–CH3 BDE = 88 kcal/mol H3C–SiH3 BDE ~ 70 kcal/mol Case-2: Two anti sigma bonds Bond length = 1.534 Å Bond length = 1.87 Å X Y X This trend is even more dramatic with pi-bonds: X σ* C–X Better σ C–Y σ* C–X LUMO than HOMO LUMO π C–C = 65 kcal/mol π C–Si = 36 kcal/mol π Si–Si = 23 kcal/mol A C C C C C ■ Weak bonds will have corresponding low-lying antibonds. σ C–Y HOMO Y Formation of a weak bond will lead to a corresponding low-lying antibonding Y orbital. Such structures are reactive as both nucleophiles & electrophiles 1-05-Introduction-3 9/12/03 4:36 PM D. A. Evans Donor-Acceptor Properties of Bonding and Antibonding States Chem 206 Donor Acceptor Properties of C-C & C-O Bonds Hierarchy of Donor & Acceptor States Consider the energy level diagrams for both bonding & antibonding Following trends are made on the basis of comparing the bonding and orbitals for C–C and C–O bonds. antibonding states for the molecule CH3–X where X = C, N, O, F, & H. σ* C-C σ-bonding States: (C–X) σ* C-O CH3–CH3 CH3–H 3 3 C-SP C-SP very close!! CH3–NH2 O-SP3 CH3–OH decreasing σ-donor capacity CH3–F σ C-C poorest donor σ C-O ■ The greater electronegativity of oxygen lowers both the bonding σ-anti-bonding States: (C–X) p. & antibonding C-O states. Hence: For the latest views, please read ■ σ C–C is a better donor orbital than σ C–O CH3–H Alabugin & Zeidan, JACS 2002, 124, 3175 (pdf) ■ σ∗C–O is a better acceptor orbital than σ∗C–C CH3–CH3 CH3–NH2 Donor Acceptor Properties of CSP3-CSP3 & CSP3-CSP2 Bonds CH3–OH σ* C–C CH3–F ∗ Increasing σ -acceptor capacity σ* C–C better acceptor best acceptor The following are trends for the energy levels of nonbonding states C-SP3 C-SP3 of several common molecules. Trend was established by photoelectron spectroscopy. 2 C-SP Nonbonding States σ C–C better donor σ C–C H3P: H2S: ■ The greater electronegativity of CSP2 lowers both the bonding & H 3N: antibonding C–C states. Hence: H 2O: HCl: ■ σ CSP3-CSP3 is a better donor orbital than σ CSP3-CSP2 ∗ ∗ decreasing donor capacity poorest donor ■ σ CSP3-CSP2 is a better acceptor orbital than σ CSP3-CSP3 1-06-donor/acceptor states 9/12/03 5:16 PM Radial Probability Radial Probability Pauling Electronegativity Pka of Carbon Acid D. A. Evans Hybridization vs Electronegativity Chem 206 Electrons in 2S states "see" a greater effective nuclear charge There is a linear relationship between %S character & than electrons in 2P states. Pauling electronegativity This becomes apparent when the radial probability functions for S 5 and P-states are examined: The radial probability functions for the N hydrogen atom S & P states are shown below. SP 4.5 100 % 100 % 4 1 S Orbital N SP2 N SP3 3.5 C SP 3 2 S Orbital 2 S Orbital C SP2 2.5 pp.. 2 P Orbital CSP3 2 Å Å 20 25 30 35 40 45 50 55 % S-Character 3 S Orbital 3 P Orbital There is a direct relationship between %S character & hydrocarbon acidity 6 0 CH (56) 4 5 5 S-states have greater radial penetration due to the nodal properties of the wave function. Electrons in S-states "see" a higher nuclear charge. 5 0 Above observation correctly implies that the stability of nonbonding electron 4 5 pairs is directly proportional to the % of S-character in the doubly occupied orbital C H (44) 6 6 4 0 Least stable Most stable 3 5 CSP3 CSP2 CSP PhCC-H (29) 3 0 The above trend indicates that the greater the % of S-character at a given atom, the greater the electronegativity of that atom. 2 5 2 0 2 5 3 0 3 5 4 0 4 5 5 0 5 5 % S-Character 1-07-electroneg/hybrization 9/12/03 4:49 PM D. A. Evans Hyperconjugation: Carbocation Stabilization Chem 206 ■ The interaction of a vicinal bonding orbital with a p-orbital is referred Physical Evidence for Hyperconjugation to as hyperconjugation. This is a traditional vehicle for using valence bond to denote charge ■ Bonds participating in the hyperconjugative interaction, e.g. C–R, delocalization. will be lengthened while the C(+)–C bond will be shortened. R R + + H H H C C H C C First X-ray Structure of an Aliphatic Carbocation H H H H The graphic illustrates the fact that the C-R bonding electrons can "delocalize" to stabilize the electron deficient carbocationic center. + 1.431 Å [F5Sb–F–SbF5]– Note that the general rules of drawing resonance structures still hold: the positions of all atoms must not be changed. + C pp.. Stereoelectronic Requirement for Hyperconjugation: 100.6 ° 1.608 Å Me Me Syn-planar orientation between interacting orbitals Me The Molecular Orbital Description σ∗ C–R σ∗ C–R T. Laube, Angew. Chem. Int. Ed. 1986, 25, 349 + + The Adamantane Reference H H C C (MM-2) 1.528 Å H H H 110 ° σ C–R σ C–R Me 1.530 Å Me Me ■ Take a linear combination of σ C–R and CSP2 p-orbital: "The new occupied bonding orbital is lower in energy. When you stabilize the electrons is a system you stabilize the system itself." 1-08-Hyperconj (+)-1 9/12/03 4:53 PM D. A. Evans "Negative" Hyperconjugation Chem 206 ●● antibonding σ∗ C–R ■ Delocalization of nonbonding electron pairs into vicinal antibonding Syn Orientation orbitals is also possible – R R ●● R: filled R ●● R ●● H C X H C X + H C X hybrid orbital H C X H H C X H H H H H H H H antibonding σ∗ C–R This decloalization is referred to as "Negative" hyperconjugation Anti Orientation R R: – R Since nonbonding electrons prefer hybrid orbitals rather that P filled orbitals, this orbital can adopt either a syn or anti relationship H C X H C X + H C X hybrid orbital ●● to the vicinal C–R bond. H H ●● H The Molecular Orbital Description ■ Overlap between two orbitals is better in the anti orientation as σ∗ C–R stated in "Bonding Generalizations" handout. The Expected Structural Perturbations – X Nonbonding e pair Change in Structure Spectroscopic Probe ●● ■ Shorter C–X bond X-ray crystallography ■ Longer C–R bond X-ray crystallography As the antibonding C–R orbital σ C–R decreases in energy, the magnitude ■ Stronger C–X bond Infrared Spectroscopy of this interaction will increase ■ Weaker C–R bond Infrared Spectroscopy Note that σ C–R is slightly destabilized ■ Greater e-density at R NMR Spectroscopy ■ Less e-density at X NMR Spectroscopy 1-09-Neg-Hyperconj 9/12/03 4:53 PM
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