01-Lecture.206

Welcome to Chem 206 Fall Term, 2005, David A. Evans Chem 206 Teaching Fellows Regan Thomson Pavel Nagornyy Keith Fandrick Yimon Aye Meredeth McGowan These individuals are your mentors. They are here to help you through this course. Please take advantage of this opportunity. Dr. Regan Thomson PhD: Australian Nat. Univ Postdoctoral Fellow Evans Research Group Raised: New Zealand Lab No. Converse 308B Lab Phone: 617-495-3245 rthomson@fas.harvard.edu Pavel Nagornyy Undergrad: Oregon State 5th-yr Graduate Student Evans Research Group Lab No. Converse 316 Lab Phone: 617-496-8569 nagornyy@fas.harvard.edu Keith Fandrick Undergrad: UC San Diego 5rd-yr Graduate Student Evans Research Group Lab No. Converse 306B Lab Phone: 617-495-3245 fandrick@fas.harvard.edu Meredeth McGowen Undergrad: Dartmouth 2nd-yr Graduate Student Jacobsen Research Group Lab No. Mallinckrodt 202 Lab Phone: 617-496-1836 mcgowen@fas.harvard.edu Yimon Aye Undergrad: Oxford Univ. UK 2nd-yr Graduate Student Evans Research Group Lab No. Converse 316 Lab Phone: 617-496-8569 yimonaye@fas.harvard.edu Mon, Sept 24th: Study card day Mon, Oct 10th: Columbus Day – Class will be held Fri, Oct 14th: Exam 1 Mon, Nov 21th: Exam 2 Wed, Nov 24th: Class will not be held Thurs, Nov 24th: Thanksgiving recess begins Mon, Dec 19th: Exam 3 Wed, Dec 21st Winter recess begins Friday, January 23rd Scheduled Final Exam Significant Dates this Fall Textbooks Carey & Sundberg, Advanced Organic Chemistry, Parts A,B Kirby, A. J. Stereoelectronic Effects ( See DAE) Fleming, I. Frontier Orbitals and Organic Chemical Reactions. Web Problems (>500) http://daecr1.chem.harvard.edu/problems/ Course Grading 3 one-Hour Exams 10 Problem Sets Final Examination We will grade your best effort. We will take your final exam score and manufacture an imaginary hr exam score (IHE). If this score is better than any two of your normalized hourly exam scores, the IHE score will replace those low scores. The IHE score will also be used in the event that an hourly exam was missed. 300 pts 200 pts 300 pts Sections Sections will begin this week. Sign up prior to 5 PM this Wednesday First Reading Assignment ! Reading Assignment for week: Kirby, Stereoelectronic Effects Carey & Sundberg: Part A; Chapter 1 Fleming, Chapter 1 & 2 Fukui,Acc. Chem. Res. 1971, 4, 57. (pdf) Alabugin & Zeidan, JACS 2002, 124, 3175 (pdf) Chem 206D. A. Evans D. A. Evans Monday, September 19, 2005 http://www.courses.fas.harvard.edu/~chem206/ ! Reading Assignment for week: Kirby, Stereoelectronic Effects Carey & Sundberg: Part A; Chapter 1 Fleming, Chapter 1 & 2 Fukui,Acc. Chem. Res. 1971, 4, 57. (pdf) Alabugin & Zeidan, JACS 2002, 124, 3175 (pdf) Chemistry 206 Advanced Organic Chemistry Lecture Number 1 Introduction to FMO Theory ! General Bonding Considerations ! The H2 Molecule Revisited (Again!) ! Donor & Acceptor Properties of Bonding & Antibonding States ! Hyperconjugation and "Negative" Hyperconjugation ! Anomeric and Related Effects An Introduction to Frontier Molecular Orbital Theory-1 ! Problems of the Day 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 nucleophile in an intramolecular alkylation. What is the preferred reaction path for the transformation in question? + + Br – Br – 1 2 Path A Path B Br N H O Br O O Br ON H O ON H Br This is a "thought" question posed to me by Prof. Duilo Arigoni at the ETH in Zuerich some years ago http://evans.harvard.edu/problems/ O PO OMe O P O OMe O P O O A B C (RO)3P + (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). Rank the phosphites from the least to the most nucleophilic and provide a concise explanation for your predicted reactivity order. El(+) (RO)3P–El (1) + Chem 206D. A. Evans An Introduction to Frontier Molecular Orbital Theory-1 minor major Br: –Nu: Nonbonding interactions (Van der Waals repulsion) between substituents within a molecule or between reacting molecules ! Steric Effects Universal Effects Governing Chemical Reactions There are three: C Br Me R R C R R Me Nu RO H SN2 O Me2CuLi RO H O H Me RO H O Me H ! Electronic Effects (Inductive Effects): Inductive Effects: Through-bond polarization Field Effects: Through-space polarization The effect of bond and through-space polarization by heteroatom substituents on reaction rates and selectivities + Br:– + SN1 rate decreases as R becomes more electronegative C R R Me Br C Me R R "During the course of chemical reactions, the interaction of the highest filled (HOMO) and lowest unfilled (antibonding) molecular orbital (LUMO) in reacting species is very important to the stabilization of the transition structure." Geometrical constraints placed upon ground and transition states by orbital overlap considerations. ! Stereoelectronic Effects Fukui Postulate for reactions: ! General Reaction Types Radical Reactions (~10%): A• B•+ A B Polar Reactions (~90%): A(:) B(+)+ A B Lewis Base Lewis Acid FMO concepts extend the donor-acceptor paradigm to non-obvious families of reactions "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." ! Examples to consider H2 2 Li(0)+ CH3–I Mg(0)+ CH3–MgBr 2 LiH Chem 206D. A. Evans Steric Versus Electronic Effects; A time to be careful!! ! Steric Versus electronic Effects: Some Case Studies Woerpel etal. JACS 1999, 121, 12208. O OAc Me SnBr4 O Me O Me stereoselection 99:1 O OAc BnO SiMe3 SnBr4 O BnO O BnO stereoselection >95:5 When steric and electronic (stereoelectronic) effects lead to differing stereochemical consequences O OTBS EtO2C O OTBS EtO2C Bu diastereoselection 8:1 Bu3Al O OTBS EtO2C Bu only diastereomer Yakura et al Tetrahedron 2000, 56, 7715 Yakura's rationalization: O O EtO O Al R3 TBSAl R R R (R)2CuLi Danishefsky et al JOC 1991, 56, 387 O OSiR3 OSiR3 OSiR3 Nu R3SiO EtO diastereoselection >94:6 O OSiR3 H H OSiR3 O diastereoselection 93:7 TiCl4 R3Si AlCl3 only diastereomer 60-94% OAc OAc N N N O O Ph N N AcO AcO N O O Ph H H N O O Ph OAc OAc N O O Ph H H H H Mehta et al, Acc Chem. Res. 2000, 33, 278-286 Chem 206D. A. Evans The H2 Molecular Orbitals & Antibonds The H2 Molecule (again!!) Let's combine two hydrogen atoms to form the hydrogen molecule. Mathematically, linear combinations of the 2 atomic 1s states create two new orbitals, one is bonding, and one antibonding: E n e rg y 1s 1s !" (antibonding) ! Rule one: A linear combination of n atomic states will create n MOs. #E #E Let's now add the two electrons to the new MO, one from each H atom: Note that #E1 is greater than #E2. Why? ! (bonding) ! (bonding) #E2 #E1 !" (antibonding) 1s1s $2 $2 $1 $1 E n e rg y H H HH +C1!1" = C2!2 Linear Combination of Atomic Orbitals (LCAO): Orbital Coefficients Each MO is constructed by taking a linear combination of the individual atomic orbitals (AO): Bonding MO Antibonding MO C*2!2"# = C*1!1 – The coefficients, C1 and C2, represent the contribution of each AO. ! Rule Three: (C1) 2 + (C2) 2 = 1 = 1antibonding(C*1) 2+bonding(C1) 2! Rule Four: E n e rg y $# (antibonding) $ (bonding) Consider the pi–bond of a C=O function: In the ground state pi-C–O is polarized toward Oxygen. Note (Rule 4) that the antibonding MO is polarized in the opposite direction. C C O C O The squares of the C-values are a measure of the electron population in neighborhood of atoms in question In LCAO method, both wave functions must each contribute one net orbital ! Rule Two: O Chem 206D. A. Evans Bonding Generalizations 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. Bond Energy (BDE) = ! Ecovalent + ! Eionic (Fleming, page 27) ! Bond strengths (Bond dissociation energies) are composed of a covalent contribution (! Ecov) and an ionic contribution (! Eionic). !" C–Si !" C–C ! C–Si ! C–C Bond length = 1.87 ÅBond length = 1.534 Å H3C–SiH3 BDE ~ 70 kcal/molH3C–CH3 BDE = 88 kcal/mol Useful generalizations on covalent bonding For example, consider elements in Group IV, Carbon and Silicon. We know that C-C bonds are considerably stronger by Ca. 20 kcal mol-1 than C-Si bonds. ! Overlap between orbitals of comparable energy is more effective than overlap between orbitals of differing energy. C-SP3 Si-SP3 C-SP3C-SP3 better thanC C C C C Si SiC ! Weak bonds will have corresponding low-lying antibonds. ! Si–Si = 23 kcal/mol! C–Si = 36 kcal/mol! C–C = 65 kcal/mol This trend is even more dramatic with pi-bonds: Formation of a weak bond will lead to a corresponding low-lying antibonding orbital. Such structures are reactive as both nucleophiles & electrophiles Better than For ! Bonds: For " Bonds: ! Orbital orientation strongly affects the strength of the resulting bond. Better 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 BABA •• Better than Better than Case-2: Two anti sigma bonds ! C–Y HOMO !* C–X LUMO !* C–X LUMO lone pair HOMO !* C–X LUMO !* C–X LUMO lone pair HOMO Case-1: Anti Nonbonding electron pair & C–X bond ! Anti orientation of filled and unfilled orbitals leads to better overlap. This is a corrollary to the preceding generalization. There are two common situations. ! C–Y HOMO A C A C C CC C A C X A Y C X Y Y X X XX Haihua 高亮 Haihua 高亮 Chem 206D. A. Evans Donor-Acceptor Properties of Bonding and Antibonding States C-SP3 ! !"C–O is a better acceptor orbital than !"C–C ! ! C–C is a better donor orbital than ! C–O ! The greater electronegativity of oxygen lowers both the bonding & antibonding C-O states. Hence: Consider the energy level diagrams for both bonding & antibonding orbitals for C–C and C–O bonds. Donor Acceptor Properties of C-C & C-O Bonds O-SP3 !* C-O ! C-O C-SP3 ! C-C !* C-C ! !"CSP3-CSP2 is a better acceptor orbital than ! "CSP3-CSP3 C-SP3 !* C–C ! C–C C-SP3 ! C–C !* C–C C-SP2 Donor Acceptor Properties of CSP3-CSP3 & CSP3-CSP2 Bonds ! The greater electronegativity of CSP2 lowers both the bonding & antibonding C–C states. Hence: ! ! CSP3-CSP3 is a better donor orbital than ! CSP3-CSP2 better donor better acceptor decreasing donor capacity Nonbonding States poorest donor The following are trends for the energy levels of nonbonding states of several common molecules. Trend was established by photoelectron spectroscopy. best acceptor poorest donor Increasing !"-acceptor capacity !-anti-bonding States: (C–X) !-bonding States: (C–X) decreasing !-donor capacity Following trends are made on the basis of comparing the bonding and antibonding states for the molecule CH3–X where X = C, N, O, F, & H. Hierarchy of Donor & Acceptor States CH3–CH3 CH3–H CH3–NH2 CH3–OH CH3–F CH3–H CH3–CH3 CH3–NH2 CH3–OH CH3–F For the latest views, please read Alabugin & Zeidan, JACS 2002, 124, 3175 (pdf) very close!! HCl: H2O: H3N: H2S: H3P: Chem 206D. A. Evans Hybridization vs Electronegativity 3 P Orbital This becomes apparent when the radial probability functions for S and P-states are examined: The radial probability functions for the hydrogen atom S & P states are shown below. 3 S Orbital Electrons in 2S states "see" a greater effective nuclear charge than electrons in 2P states. Above observation correctly implies that the stability of nonbonding electron pairs is directly proportional to the % of S-character in the doubly occupied orbital Least stable Most stable The above trend indicates that the greater the % of S-character at a given atom, the greater the electronegativity of that atom. Å R ad ia l P ro ba bi lit y 100 % 2 P Orbital 2 S Orbital2 S Orbital 1 S Orbital 100 % R ad ia l P ro ba bi lit y Å S-states have greater radial penetration due to the nodal properties of the wave function. Electrons in S-states "see" a higher nuclear charge. CSP3 CSP2 CSP 2 2.5 3 3.5 4 4.5 5 P a u lin g E le c tr o n e g a ti v it y 20 25 30 35 40 45 50 55 % S-Character C SP3 C SP2 C SP N SP3 N SP2 N SP 25 30 35 40 45 50 55 60 P k a o f C a rb o n A c id 20 25 30 35 40 45 50 55 % S-Character CH 4 (56) C 6 H 6 (44) PhCC-H (29) There is a direct relationship between %S character & hydrocarbon acidity There is a linear relationship between %S character & Pauling electronegativity 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 + + Haihua 高亮 "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 Haihua 高亮