TO: FROM: Prospective Chemistry 5511 Students Peter Gaspar August 13, 2010 SUBJECT: Course Syllabus for Chemistry 5511 Fall 2010 Chemistry 5511 Mechanistic Organic Chemistry is the first semester of a two-semester sequence of physical organic chemistry courses, normally taught in the Fall semester. It is followed every other Spring by Chemistry 554. Chemistry 554 will next be offered in Spring 2011. In the view of the organic faculty, graduate students contemplating research in synthetic or mechanistic chemistry need, among their intellectual tools, a command of ideas about how reactions occur: that is, what are their mechanisms? And how does one elucidate a reaction mechanism? What relationships exist between the structure, geometric and electronic, of organic molecules and their reactivity? How does one predict structure and reactivity? Since an important goal of the graduate curriculum in organic chemistry is to make it possible for students to complete their course work during their first academic year of the PhD program, it is not practical to have a sequence longer than two courses in physical organic chemistry. It has therefore been decided to devote a semester each to: 1. An introduction to the ideas of physical organic chemistry. 2. Theoretical models and the prediction of molecular structures, properties, and reaction mechanisms by computational chemistry. Enrollments in Chemistry 554 have historically been lower than those for Chemistry 5511, so we recently and reluctantly decided to offer Chemistry 554 every other year. In previous years these subjects shared equal time with a third important topic: kinetic measurements as a tool for the elucidation of reaction mechanisms. But when two-thirds of a semester was devoted to each of these three topics, time was too short to do justice to any of them. Given the availability of several specialized kinetics courses in the preclinical curriculum of the Medical School, it has been decided to devote the Chemistry 5511 and 554 (formerly Chemistry 556) sequence to a full semester introduction to physical organic chemistry, including the major types of reaction mechanisms, and a full semester of molecular modeling and computational chemistry. The basic ideas underlying the use of kinetic measurements in mechanistic studies are briefly discussed in Chemistry 5511. Reading and homework assignments for Chemistry 5511 will be taken from Modern Physical Organic Chemistry by Eric V. Anslyn and Dennis A. Dougherty, University Science Books, Sausalito, CA, 2004. This modern text embraces bioorganic, organometallic, materials and supramolecular chemistry as well as the fundamental principles relating structure and reactivity in classical organic chemistry. It also has quite good homework problems. Occasional handouts will supplement the text. Anslyn and Dougherty has been written for a full-year course. I will largely follow the recommendations of the authors in selecting chapters for a single semester course. The chapters in Anslyn and Dougherty are self-standing, so the text is a fine reference work, and most of you will find occasion during your thesis research to read chapters not covered in this semester. This syllabus is printed on both sides of each page in the hard-copy version. -1-
Chemistry 5511 Fall 2010 This semester is devoted to the fundamental concepts of mechanistic organic chemistry, including the nature of the chemical bond and our views of it. Qualitative molecular orbital theory is introduced early because it offers a language and a conceptual framework for the understanding of the structures of organic molecules and of the changes that occur during reactions. Tools to determine reaction mechanisms include discussions of kinetics, linear free energy relationships, and thermochemistry, which introduce quantitative descriptions of structure and reactivity. Several weeks will be devoted to surveying types of reactions and their mechanisms to which you have already been introduced in undergraduate courses. The purpose will be to build on what you already have learned in order to provide a more powerful set of intellectual tools for the analysis and prediction of the reactions of organic chemistry. As the last topic of the semester, molecular orbital theory is applied to pericyclic reactions, so important in modern organic synthesis. Homework assignments will be turned in two weeks after the last lecture on a chapter in Anslyn and Dougherty, but that time includes your grading your own homework papers. There will be two evening examinations during the semester and a final examination. The three examinations and the average of the homework grades will each contribute 24% toward the final semester grade. The quality of your contribution to the discussion in class will contribute 4% to the final grade. Please read as much as you can of Chapter 1 in Anslyn and Dougherty before the first lecture, which will be held at 10 AM on Wednesday, September 1 in L561. I am looking forward to seeing you then! My office is L536, telephone (314) 935 6568, email gaspar@wustl.edu Week Topics 1 Introduction to Structure and Models of Bonding - Anslyn and Dougherty chapter 1 (lectures 1, 2, 3, 4, 5 and 6 September 1, 3, 8, 10, 13, 15) homework problems: 1, 2, 8, 9, 11, 12, 13, 14, 16, 18, 25, 30, 31, 34, 35. 2 C Review of basic bonding concepts - atomic and molecular structure C Molecular orbital theory C Orbital mixing to build larger units C Bonding and structures of reactive intermediates 3 C A peek at organometallic and inorganic bonding Strain and Stability - Anslyn and Dougherty chapter 2 (lectures 7, 8, 9, 10, 11 & 12, September 17, 20, 22, 24, 27, 29) homework problems: 1, 5, 6, 8, 9, 13, 14, 15, 20, 23, 24, 26, 30, 31, 34, 41, 47, 51. 4 C Thermochemistry of stable molecules - strain, energy, entropy, bond dissociation energies, heats of formation, the group increment method C Thermochemistry - stability vs persistence - radicals, carbocations, carbanions C Basic conformational analysis - relationships between structure and energetics 5 C Electronic effects - interactions involving B-systems: conjugation, aromaticity C Highly strained molecules C Molecular mechanics Acid-Base Chemistry - Anslyn and Dougherty chapter 5 (lectures 13, 14 &15, October 1, 4, 6) homework problems: 1, 2, 3, 7, 9, 11, 17, 19, 20, 21 6 C Brønsted acid-base chemistry C Aqueous solutions -2-
Week Topics C Nonaqueous solutions C Predicting acid strength in solution C Acids and bases of biological interest C Lewis acids and bases, electrophiles and nucleophiles Stereochemistry - Anslyn and Dougherty chapter 6 (lectures 16, 17, 18 & 19, October 8, 11, 13, 18) homework problems: 1, 2, 5, 8, 9, 10, 14, 16, 17, 22, 24, 30, 31, 38. 7 C Stereogenicity and stereoisomerism - basic concepts and terminology, stereochemical descriptors C Symmetry and stereochemistry C Topicity relationships C Reaction stereochemistry - stereoselectivity and stereospecificity C Symmetry and time scale C Topological and supramolecular stereochemistry C Stereochemical issues in chemical biology Energy Surfaces and Related Concepts- Anslyn and Dougherty chapter 7 (lectures 20, 21, 22, 23 & 24, October 20, 22, 25, 27, 29) homework problems: 1, 3, 4, 5, 9, 11, 13, 14, 15, 18, 19, 22, 23, 24. 8 C Energy surfaces and related concepts C Transition state theory and related topics C Postulates and principles related to kinetic analysis: the Hammond postulate, the Curtin-Hammett principle, microscopic reversibility, kinetic vs thermodynamic control C Kinetic experiments and kinetic analysis for simple mechanisms 9 C Deciphering mechanisms of complex reactions through kinetic analysis C Experimental methods for following kinetics C Calculating rate constants and Marcus theory C Considering multiple reaction coordinates, More O Ferrall-Jencks diagrams Experiments Related to Thermodynamics and Kinetics - Anslyn and Dougherty chapter 8 (lectures 25, 26, 27 & 28, November 1, 3, 5, 8 ) homework problems: 4, 5, 6, 7, 8, 10, 12, 14, 15, 16, 18, 19, 20, 22, 23, 25. 10 C Isotope effect experiments, primary and secondary kinetic isotope effects, equilibrium isotope effects, tunneling, solvent isotope effects, heavy atom isotope effects C Substituent effects C Hammett plots - a linear free energy relationship - a general method for examining changes in charges during a reaction C A brief look at other linear free energy relationships 11 C Acid-base related effects - Brønsted relationships C Why do linear free energy relationships work? Catalysis - Anslyn and Dougherty chapter 9 (Lectures 29, 30 & 31, November 10, 12, 15) homework problems: 2, 3, 5, 7, 8, 10, 11, 14, 15, 19. C General principles of catalysis C Forms of catalysis 12 C Brønsted acid-base catalysis - specific, general, the Brønsted catalysis law, the dynamics of proton transfers -3-
Week Topics C Enzymatic catalysis Organic Reaction Mechanism, Part 1; Reactions Involving Additions and/or Eliminations - Anslyn and Dougherty chapter 10 (lectures 32, 33, 34, 35 & 36, November 17, 19, 22, 29, December 1) homework problems: 1, 2, 4, 6, 9, 11, 12, 14, 17, 18, 20, 26, 29, 31, 39, 41, 42, 47, 50, 51. C Predicting organic reactivity from polarities, structures of reaction partners C Addition reactions: - hydration of carbonyl groups - hydration of alkenes and alkynes by electrophilic addition of water - electrophilic addition of hydrogen halides to alkenes and alkynes - electrophilic addition of halogens to alkenes - hydroboration - epoxidation - nucleophilic additions to carbonyl compounds - nucleophilic additions to olefins - radical additions to unsaturated systems - carbene additions and insertions 12 C Eliminations - eliminations to form carbonyls or carbonyl-like intermediates - eliminations of aliphatic systems forming alkenes - eliminations from radical intermediates 13 C Combining addition and elimination - substitution at sp 2 centers - addition of nitrogen nucleophiles to carbonyls, followed by elimination - addition of carbon nucleophiles followed by elimination - the Wittig reaction - acyl transfers 14 - electrophilic aromatic substitution - nucleophilic aromatic substitution - reactions involving benzyene 15 - the S RN 1 reaction on aromatic rings - radical aromatic substitutions Organic Reaction Mechanisms, Part 2: Substituions at Aliphatic Centers and Thermal Isomerizations/Rearrangements - Anslyn and Dougherty chapter 11 (lectures 37, 38, 39, December 3, 6, 8) homework problems: 2, 5, 7, 10, 13, 14, 17, 20, 23, 31, 34, 37, 40, 45, 47, 49, 54. C Substitution " to a carbonyl center: enol and enolate chemistry - tautomerization 16 - "-halogenation and alkylation - the aldol reaction C Substitutions at aliphatic centers - limiting S N 2 and S N 1 reactions and intermediate cases - carbocation rearrangements - radical aliphatic substitution C Isomerizations and rearrangements - migrations to electrophilic carbon and electrophilic heteroatoms - the Favorskii rearrangement and other carbanion rearrangements -4-
Week Topics - radicaland biradical rearrangements Thermal Pericyclic Reactions - Anslyn and Dougherty chapter 15 (lectures 40, December 10) homework problems: 1, 2, 6, 10, 11, 12, 15, 19, 20, 21, 23, 26, 28. C Detailed analysis of two model cycloadditions by two methods: orbital correlation diagrams and state correlation diagrams C Analysis of pericyclic reactions by frontier molecular orbital (FMO) theory C The aromatic transition state model C The generalized orbital symmetry rule for pericylcic reactions and comments about allowed and forbidden processes C A brief discussion of cycloadditions, electrocyclic reactions, sigmatropic rearrqngements, and chelotropic reactions End of the semester -5-