01-Lecture.206

Welcome to Chem 206 Fall Term, 2006, David A. Evans This course is designed to introduce upper-level undergraduates and beginning graduate students to advanced topics in organic chemistry. The course begins with a discussion of bonding phenomena, an introduction to FMO theory, and stereoelectronic effects. This section will be followed by lectures in conformational analysis in both cyclic and acyclic systems. Following this introduction, a discussion of the important classes of organic reactions will be presented. Topics include rearrangements, cycloadditions, carbonyl additions, and enolate-based transformations. Problems for this course may be accessed at the following website: http://daecr1.chem.harvard.edu/problems/ Pavel Nagornyy Undergraduate: Oregon State 6th-yr Graduate Student Lab No. Converse 316 Lab Phone: 617-496-8569 Expertise: Organic Synthesis nagornyy@fas.harvard.edu O MeMe OHOH MeMe OH HO Me Me OH OHOH OH OH Me OH Me OH OH OH Me O O O "The Asymmetric Synthesis of Oasamycin," Submitted, Angew. Chem Int Ed. 2006 Head Teaching Fellow Christian Markert Postdoctoral Fellow University of Basel, Switzerland Lab No. Converse 306A Lab Phone: 617-495-5248 Expertise: Catalysis & Synthesis markert@fas.harvard.edu OH Me Me Me O Me H Me N O Me O O Zoanthenol O Me Me Me O Me H Me N O Me O O Zoanthamine H Me C. Markert, A. Pfaltz: ‘Screening of Chiral Catalysts and Catalyst Mixtures by Mass Spectrometric Monitoring of Catalytic Intermediates’, Angew. Chem. Int. Ed. 2004, 43, 2498-2500. Hyun-Ji Song Undergraduate: KAIST, Korea 4th-yr Graduate Student Lab No. Converse 306B Lab Phone: 617-495-3245 Expertise: Asymmetric Catalysis hsong@fas.harvard.edu “Enantioselective Nitrone Cycloadditions of Unsaturated 2-Acyl Imidazoles Catalyzed by Bis(oxazolinyl)pyridine-Cerium(IV) Triflate Complexes” Evans, D.A.; Song, H.; Organic Lett., 8, 2006, 3351-3354 N N N O O Ph PhPh Ph Ce (OTf)4 O R1 N NMe N O R3 HR2 + 1 (5 mol %) N O R3 R1 R2 ON NMe X2O OX1 R1O NHX3R21 15 examples average ee: 91% average yield: 89% average dr: 68:1 Mathieu Lalonde Undergraduate: Univ of Ottawa, Ca 6th-year Graduate Student Lab No. Mallinckrodt 202F Lab Phone: 617-496-1836 Expertise: Asymmetric Catalysis Lalonde@fas.harvard.edu A Chiral Primary Amine Thiourea Catalyst for the Highly Enantioselective Direct Conjugate Addition of α,α Disubstituted Aldehydes to Nitroalkenes, Mathieu P. Lalonde, Yonggang Chen, and Eric N. Jacobsen*, Angew.Chemie, Int. Edit, 2006, ASAP For catalyst 3, dr >10:1, ee 99% Jason Hong Undergraduate: Yale University 2nd-yr Graduate Student Lab No. Mallinckrodt 202E Lab Phone: 617-496-1836 Expertise: Asymmetric Catalysis jhong@fas.harvard.edu Pattern-Based Detection of Different Proteins Using an Array of Fluorescent Protein Surface Receptors, Laura Baldini, Andrew J. Wilson, Jason Hong, and Andrew D. Hamilton, JACS 2004, 126, 5656 Pattern Recognition of Proteins Based on an Array of Functionalized Porphyrins, Huchen Zhou, Laura Baldini, Jason Hong, Andrew J. Wilson, and Andrew D. Hamilton, JACS 2006, 128, 2421 Mon, Sept 25: Study card day Mon, Oct 9: Columbus Day – Class will be held Fri, Oct 13: Exam 1 Friday, Nov 10: Veterans Day – Class will be held Mon, Nov 20: Exam 2 Wed, Nov 22: No Class in honor of Tom Turkey Mon, Dec 18: Exam 3 Wed, Dec 20 Winter recess begins Tuesday, Jan 2 Reading Period begins Friday, Jan 12 Reading Period ends Mon, Jan 22 Final Exam (Tentative) Significant Dates this Fall Textbooks Carey & Sundberg, Advanced Organic Chemistry, Parts A,B Kirby, A. J. Stereoelectronic Effects Web Problems 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 of your normalized hourly exam scores, the IHE score will replace those lower scores. The IHE score will also be used in the event that an hourly exam was missed. This plan provides you the opportunity to have the final exam count between 37% and 75% of your final grade. 300 pts 200 pts 300 pts Sections Sections will begin this week. Sign up prior to 5 PM this Wednesday Chem 206D. A. Evans 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 FIRST HOUR EXAM, 2005. The oxidation of acetals by electrophilic ozone is known to be sensitive to structure. Two striking examples of different reactivity are detailed in the questions below. Using clear three-dimensional drawings provide a rationale for the observation that rigid glycoside A readily undergoes oxidation but glycoside B does not. Be sure to indicate all relevant stereoelectronic interactions. O O H H O O H O O O H O OO _ + A O O H H O O H O O O H O OO _ + B Deslongchamps, Can. J. Chem. 1974, 3651-3664. D. A. Evans Monday, September 18, 2006 ! Reading Assignment for week: Kirby, Stereoelectronic Effects Carey & Sundberg: Part A; Chapter 1 Fukui,Acc. Chem. Res. 1971, 4, 57. (pdf) Alabugin & Zeidan, JACS 2002, 124, 3175 (pdf) Robertson, Org. Letters 2005, 7, 5007 (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 http://evans.harvard.edu/problems/ http://www.courses.fas.harvard.edu/colgsas/1063 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 DR = 95:5 HOMO NU CSP2 LUMO TRANSITION STATE HYPERCONJUGATION 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 Two: ! Rule Three: (C1) 2 + (C2) 2 = 1 The squares of the C-values are a measure of the electron population in neighborhood of atoms in question = 1antibonding(C*1) 2+bonding(C1) 2! Rule Four: In LCAO method, both wave functions must each contribute one net orbital 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 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 ! Bond strengths (Bond dissociation energies) are composed of a covalent contribution (! Ecov) and an ionic contribution (! Eionic). Useful generalizations on covalent bonding ! Overlap between orbitals of comparable energy is more effective than overlap between orbitals of differing energy. !" 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 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. 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 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. A C A CA C X XX Better than Case-2: Two anti sigma bonds ! C–Y HOMO !* C–X LUMO !* C–X LUMO ! C–Y HOMO C CC CA Y C X Y Y X X 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 poorest donor !-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 very close!! best acceptorIncreasing ! "-acceptor capacity !-anti-bonding States: (C–X) CH3–H CH3–CH3 CH3–NH2 CH3–OH CH3–F For the latest views, please read Alabugin & Zeidan, JACS 2002, 124, 3175 (pdf) 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. HCl: H2O: H3N: H2S: H3P: Radial Electron Density of S-States E le c tr o n P ro b a b il it y Distance from Nucleus 1S 2S 3S Radial Electron Density of S- & P-States E le c tr o n P ro b a b il it y Distance from Nucleus 2S 2P + + 2S-State View of Nucleus 2P-State 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 + +