Chem 106: Advanced Organic Chemistry Instructor Dr. Eugene Kwan (Converse 204A, 617-496-4299, ekwan@fas.harvard.

edu) Office Hours: Wednesdays (11 am 12 pm) or by appointment. Dr. Fillipo Sladojevich (sladojevich@fas.harvard.edu) Mondays, Wednesdays, and Fridays (10 11 am, Pfizer Lecture Hall) One hour per week. Valency and Bonding: A Natural Bond Orbital Donor-Acceptor Perspective Weinhold, F.; Landis, C. 2005, Cambridge University Press. (not required) Roughly bi-weekly. You are encouraged to discuss your work with others, but the final solutions you submit should be your own work. Grading will be conducted using the following scheme: problem sets, 25% writing assignment, 25% midterm exam, 25% final exam, 25% Acknowledgments This course is based on the classic Chem 206 course that was taught by Professor David A. Evans from the late 1990s until 2006. I am grateful to him for providing me with a substantial amount of material. Many others have helped; please see the slides. All mistakes are my own. This is a graduate course about the structure and reactivity of organic molecules from a physical-organic perspective. It is a continuation of the Chem 20/30 sequence for advanced undergraduates and is a gateway to more advanced courses in organic synthesis (Chem 115), physical organic chemistry (Chem 205), organometallic chemistry (Chem 153), and chemical biology (Chem 101 or Chem 170). Any can be taken concurrently. Students who performed well in Chem 27 are welcome. Students from MIT are welcome. http://isites.harvard.edu/k90501

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Detailed Course Outline # 1 Date: Sep. 5 (W) Topics: Bonding and Hybridization: the hydrogen atom; multielectron atoms; variational theorem; linear combination of atomic orbitals; natural atomic orbitals; virial theorem and the hydrogen molecule; s-p hybridization; shape of lone pairs Donor-Acceptor Interactions: Koopmans Theorem; non-Lewis corrections to Lewis structures; amide resonance; anomeric effect; spectroscopic evidence; trends in donor/acceptor ability; gauche effect; rotational barrier in ethane; steric exchange energy; Coulsons Theorem; Bents Rule Hypervalency and Hypovalency: Pimentel-Rundel model; hypervalency in the main block; bimolecular nucleophilic and electrophilic displacements; hypovalency in the main block; protonated alkanes; diborane; analysis of the hydroboration TS Energy and Reactivity: the Mayr nucleophilicity and electrophilicity scale; reactivityselectivity; entropy and spontaneity; Curtin-Hammett kinetics; transition state theory; effective molarity; enthalpic vs. entropic effects in rates of ring closure No Class Stereoelectronic Effects on Reactivity: endocyclic restriction test; Baldwins Rules; fragmentation reactions; elimination reactions; epoxidation with dioxiranes and peracids; the Burgi-Dunitz trajectory; the Cram chelate model; the Felkin-Anh model

Sept. 7 (F)

Sept. 10 (M)

Sept. 12 (W)

Sept. 14 (F) 5 Sept. 17 (M)

Sept. 19 (W)

-Bonding: -* hyperconjugation; aromaticity and antiaromaticity; Hckel

approximation; Mbius vs. Hckel topology Pericyclic Reactions 1: the Dewar-Zimmerman approach; electrocyclizations; torquoselectivity; Nazarov reaction; the Diels-Alder reaction; the frontier orbital approach; regiocontrol; endo selectivity and secondary orbital overlap; synthesis of the endiandric acids Pericylic Reactions 2: [2+2] cycloadditions, Cope rearrangement; Doering-Roth experiments; nature of the Cope transition state; oxy-Cope reaction; the Claisen and its variants; Bergman cyclization; enediyne antibiotics Pericylic Reactions 3: [2+3] dipolar cycloadditions; [2,3], [1,5], and [1,7] sigmatropic shifts; cheletropic reactions; the ene reaction; solving cascade problems Pericyclic Reactions, continued Acyclic Conformational Analysis: simple alkanes; the gauche and syn-pentane interactions; simple olefins; 1,2- and 1,3-allylic strain; models for the Thorpe-Ingold effect Small Ring Conformational Analysis: types of strain in cyclic systems; cyclopropane and role of geminal hyperconjugations; Walsh vs. Coulson-Moffitt models; cyclobutanes; cyclopentanes; cyclohexanes; A values; cyclohexenes and the Frst-Plattner rule; fused ring systems; stereoselective reactions of substituted oxocarbenium ions

Sept. 21 (F)

Sept. 24 (M)

Sept. 26 (W)

Sept. 28 (F) 10 Oct. 1 (M)

11 Oct. 3 (W)

12 Oct. 5 (F)

Computational Chemistry I: the potential energy surface; optimization algorithms; molecular mechanics; wavefunction and DFT methods; basis sets and orbitals; single point energy calculations; accuracy for ground and transition state properties Columbus Day (no class) Large Ring Conformational Analysis (J. Wzorek): cyclooctanes; cyclodecanes; unsaturated analogs; the peripheral attack model; macrocyclic stereocontrol Midterm Exam (two hours) Nitrogen/Carbenes (F. Sladojevich) structure, stability, generation, and reactivity; C-H insertions, cyclopropanations, aziridinations, Wolff rearrangement; Ardt-Eistert homologation; Hoffmann degradation; Bamford-Stevens and related reactions; vinylidenes: Corey-Fuchs, Bestmann reagent Computational Chemistry II: kinetic isotope effects and the Bigeleisen-Mayer equation; transition state geometries: dihydroxylation; solvent effects on the Diels-Alder reaction Dynamic Effects: reactions as trajectories; quasi-classical dynamics; hydroboration; ozonolysis; SN2 reaction; vinylcyclopropane; cyclopentadiene dimerization; aryldiazonium sovolysis Acidity: review of aqueous acidity concepts; measuring pKa; pKa in DMSO; gas vs. solution phase pKa; hybridization effects; induction vs. resonance effects; solvation entropy effects; ion-pairing; kinetic vs. thermodynamic acidity Organolithium Aggregates: aggregates of LiHMDS and LDA; enthalpy and entropy of aggregation vs. solvation; aggregation and reactivity; role of HMPA and TMEDA; method of continuous variation and DOSY spectra; solution kinetics and order in reagents; ortholithiations and Fries rearrangement; variables for optimizing reactions Heteroatom-Stabilized Carbanions: configurationally stable organolithium reagents; sparteine-mediated enantioselective deprotonations; the Wittig reaction; oxaphosphetanes vs. betaine intermediates; pseudorotation; stereochemical equilibration; isotope effects; puckered vs. planar models for stereoselectivity Enolates: diastereoselective imide and amide alkylation; enolate tautomerism and the Michael reaction; dicarbonyl enolates; Claisen/Dieckmann condensation; the Mander reagent; decarboxylation; soft enolization: titanium, boron, and magnesium enolates Aldol Reaction (J. Beiger): Zimmerman-Traxler transition states; E vs. Z enolates in aldol reactions; carbonyl -facial selectivity; Cornforth model; double diastereodifferentiating reactions; transformations of imide aldol products; polyketide synthesis First Order Kinetics: first-order kinetics; rate of approach to equilibrium; McKay equation; equilibrium and steady-state approximations; 1+rate laws; Chang-Prussoff corrections; rate-determining steps

Oct. 8 (M) 13 Oct. 10 (W)

Oct. 12 (F) 14 Oct. 15 (M)

15 Oct. 17 (W)

16 Oct. 19 (F)

17 Oct. 22 (M)

18 Oct. 24 (W)

19 Oct. 26 (F)

20 Oct. 29 (M)

21 Oct. 31 (W)

22 Nov. 2 (F)

23 Nov. 5 (M)

Application of Kinetics: Halpern-Landis work on asymmetric hydrogenation; methods for measuring rates; initial rates vs. reaction progress kinetics (Blackmond); same excess experiments; catalyst deactivation vs. product inhibition; the Heck reaction Tetrahedral Intermediates: ester and acetal hydrolysis; direct observation of tetrahedral intermediates; stereoelectronic requirements for cleavage; Weinreb amides; mixed aggregation effects Intermolecular Forces and Hydrogen Bonding: classical vs. non-classical forces; donoracceptor vs. electrostatic views of hydrogen bonding; prototypical hydrogen bonds; optimal geometry; charge- and resonance-assisted hydrogen bonds; cooperative effects; hydrogen bonding as interrupted proton transfer; formyl hydrogen bonding and catalysis Halogen Bonding Hydrogen Bonding Catalysis (F. Sladojevich) Lewis Acid Catalysis (F. Sladojevich): oxazaborolidines: CBS reductions, cycloadditions; Cu-box catalysts: carbonyl additions, cycloadditions; Zn: aldol, acetylide additions, autocatalysis; Ti (Sharpless epoxidation, TADDOL); Mn, Cr: Jacobsen reactions; Au: enyne rearrangements Thanksgiving no class Thanksgiving no class Thanksgiving no class

24 Nov. 7 (W)

25 Nov. 9 (F)

26 Nov. 12 (M) 27 Nov. 14 (W) 28 Nov. 16 (F)

Nov. 19 (M) Nov. 21 (W) Nov. 23 (F) 29 Nov. 26 (M)

- Stacking and Cation- Interactions: optimal geometries; role of electrostatic and

dispersion effects; double mutant cycles; crystal structures of packed benzenes; importance in catalysis and synthesis; summary of noncovalent interactions in crystals

30 Nov. 28 (W)

Nucleophilic Catalysis: 4-dimethylaminopyridines; Baylis-Hillman reaction; Nheterocyclic carbenes; benzoin condensation; Stetter reaction; acylation agents Special Lecture Professor Corey Stephenson (4-5 pm) Amine Organocatalysis: iminium ion catalysis; enamine catalysis; merged cycles; SOMO catalysis Final Exam (covering all lectures)

31 Nov. 30 (F) 32 Dec. 3 (M)

TBA