PRINCIPLES OF ORGANIC SYNTESIS
- Overview
- Assessment methods
- Learning objectives
- Contents
- Full programme
- Bibliography
- Teaching methods
- Contacts/Info
Prerequisite of the course are simply the knowledge of the fundamentals aspects of the organic chemistry, acquired during the main theoretical and laboratory courses attended during the three-year degree. Some of the main rules observed in the basic courses will be reviewed, but the course content will be set exclusively to the application to the synthesis.
The final exam is based on a written test with open questions, exercises and problems on the topics covered in the course and carried out during the lessons. The duration of the written test is 2.5-3 hours after which the student achieves a final evaluation.
For open questions, the following are positively evaluated:
-depth analysis of the answer
- the ability to organize knowledge discursively;
- rigor and argumentative originality;
-the ability of critical reasoning on the study carried out;
- the quality of the exhibition, the competence in the use of specialist vocabulary, the effectiveness and linearity of the topics and methods exposed
Honors are reserved for students who show a thorough knowledge of the topics covered and a remarkable ability to rework them by applying the theories learned to individual problems.
The aim of the course is to introduce some techniques and principles of organic synthesis even with a more applicative nature after having absorbed the fundamental concepts transmitted in the courses of basic organic chemistry. In this course we plan to tackle some topics that lead to broadening the knowledge through some themes that concern aspects of particular innovation in the field of organic synthesis and that are the subject of recent publications in the scientific literature. New transformations of functional groups and the transmission of a certain elasticity to the problem solving in organic synthesis are the main aims of the course. Aim of the course is the introduction of concepts and principles that are used in the reasoning modality of a synthetic organic chemist: retrosynthetic approach, protection of functional groups, ecc.
EXPECTED LEARNING RESULTS
At the end of the course, the student will be able to:
1. apply the concepts learned also in previous organic chemistry courses in the context of organic synthesis
2. prepare derivatives with high added value.
3. understand innovative synthesis techniques which are of particular importance also in current scientific literature such as the use of multicomponent reactions, combinatorial chemistry, asymmetric syntheses, unconventional methods (microwave, ultrasound, etc.) and flow chemistry.
4. discuss particularly current cases concerning ethical aspects in the context of scientific publications.
5. analyze some examples of ethically incorrect conduct, plagiarism and more
6. determine the best conditions through which it is possible to adopt the use of protective groups by evaluating the best conditions of orthogonality for their removal
7. consider the different concepts of selectivity in the context of organic synthesis
8. reason in detail about possible retrosynthetic approaches using some key concepts in the logic of organic synthesis.
9. evaluate the reactivity of particularly important chemical species such as radicals, carbenes and carbenoids
10. define some aspects related to stereoelectronic characteristics
Introduction to the Organic Synthesis (2h). Retrosynthesis (concepts, principles, examples and applications (8h). Chemoselectivity (2h). Protecting Groups (protection and deprotection of functional groups in organic synthesis, peptide synthesis) (8h). Rearrangement reactions and Fragmentation processes (8h). Asymmetric Synthesis (chiral auxiliares, chiral catalysts, chiral pool e organocatalysis) (6h). Concepts of Green Chemistry (12 Principles by Anastas and Warner) (4h). Process Chemistry and Intensification in Organic Synthesis (Combinatorial Chemistry, Flow Chemistry) (2h). Multicomponent Reactions (2h). Outline of radical and carbenoid reactivity (2h). Brief introduction to stereoelectronic effects (2h). Special topics (scientific literatures, plagiarism, ethical conduct and misconduct, mistakes and experimental errors) (2h).
What is Organic Synthesis? Organic Synthesis Classifications. A short History of Organic Synthesis. Total Synthesis. Facets of Organic Synthesis. Organic synthesis as a central science. Plan of a synthesis. New chemical reactions. Concepts in organic synthesis: selectivity (chemoselectivity, regioselectivity, stereoselectivity), Atom economy.
Retrosynthetic analysis. Organic Chemistry as a creative science. Backward process: disconnections. Syntons as idealized reagents. Choice of a disconnection. Multi-step synthesis and chemoselectivity. Functional groups interconversions. Two groups disconnection and one group disconnection. Carbon-carbon bond disconnections. Donor syntons and acceptor syntons. Disconnections of two carbon-carbon groups. 1,3- and 1,5-Groups disconnections. Natural reactivity and umpolung. 1,2 and 1,4-Bifunctional compounds.
Chemoselectivity. Reducing agents. Reduction of carbonyl groups. Catalytic hydrogenation. Getting rid of functional groups. Reduction with metals in solution. Kinetic reactivity and thermodynamic reactivity. Reactivity of the less reactive group. Chemoselectivity with dianions. Use of protective groups. Oxidizing agents.
Examples of organic synthesis: benzocaine, saccharin, salbutamol, tyroxine, muscalure, grandisol. Peptide synthesis. Protecting groups in peptide synthesis. Synthesis of dofetilide. Solid phase synthesis.
Protection of functional groups. Deprotection: concept of orthogonality. Basic solvolysis. Acid conditions. Heavy metals. Fluoride ions. Reductive elimination. betha-elimination. Hydrogenolysis. Oxidation. Reduction with metals in solution. Nucleophilic substitution. Catalysis with transition metals. Photochemistry. Enzymatic reactions
Rearrangements and fragmentations. Anchimeric assistance. Stereochemical aspects. Payne rearrangement. Rearrangement with alkyl groups. Rearrangements with carbocations. Wagner-Meerwin rearrangement. Bredt's rule. Ring expansion. Pinacol Rearrangement. Rearrangement of epoxides. Semipinacol rearrangement. Rearrangement with diazonium salts. Dienone phenol rearrangement. Benzilic acid rearrangement. Favorskii rearrangement. The reaction of Baeyer-Villiger. Beckmann rearrangement. Which groups tend to migrate the most. C-C bond polarization and fragmentation. Fragmentations and stereochemistry. Eschenmoser fragmentation. Synthesis of longifolene and of nootkatone. Cycloadditions and rearrangements.
Concepts and principles of organic synthesis: convergent synthesis, linear synthesis, divergent synthesis. Diversity oriented Synthesis. Combinatorial chemistry. Techniques and applications. Libraries of products. Multicomponent reactions. Examples of typical multi-component reactions. Green chemistry and process intensification. Alternative techniques and methodologies: microwaves, ultrasounds, ionic liquids, planetary ball-milling. Flow chemistry.
Asymmetric synthesis. Natural asymmetric molecules. Resolution for the separation of enantiomers. The chiral pool. Chiral auxiliaries. Chiral reagents and catalysts. Asymmetric formation of carbon-carbon bonds. asymmetric conjugate addition. Organocatalysis. Asymmetric aldol reactions. Enzymatic catalysis. Hints of reactivity of particular species such as radicals, carbenes and carbenoids. Typology of radical and carbenic species. Stereoelectronic effects (anomeric effect, Thorpe-Ingold effect) and Baldwin's rules for the formation and breaking of cyclic derivatives.
A glance at the literature (plagiarism, ethics, frauds, experimental errors,..)
The reference material used during the course will be provided. Literature articles in organic synthesis will also constitute study material and analysis in the classroom. Each individual topic may also have a different reference text. A basic text of certain interest for the development of some topics is:
Clayden, Warren, Wothers, Greeves
Organic Chemistry
1st Edition - Oxford University Press
or
Clayden, Warren, Greeves
Organic Chemistry
2nd Edition - Oxford University Press
Some of the following titles are examples of possible reference texts:
S. Warren, P. Wyatt - Organic Synthesis: the Disconnection Approach
S. Warren, P. Wyatt - Organic Synthesis: Strategy and Control
E. J. Corey, Xue-Min Cheng - The Logic of Chemical Synthesis
P. G. M. Wuts - Greene’s Protecting Groups in Organic Synthesis
P. J. Kocienski - Protecting Groups
P. J. Walsh, M. C. Kozlowski - Fundamentals of Asymmetric Catalysis
M.B. Smith - Organic Synthesis
S. Caron – Practical Synthetic Organic Chemistry
G. F. Zweifel, M. H. Nantz – Modern Organic Synthesis
W. Carruthers, I. Coldham – Modern Methods of Organic Synthesis
J. Leonard, B. Lygo, G. Procter – Advanced Practical Organic Chemistry
The course will be articulated through a series of lectures on the different topics covered in the program and with a series of powerpoint file presentations. Particular emphasis may be devoted to the illustration, study, analysis and discussion of some scientific publications.
The classroom debate allows the student to make a self-assessment of their own learning and, at the same time, allows the teacher to check the progress of the students' knowledge.
A part of the teaching is dedicated to solving problems and exercises in the classroom. Generally at the end of each topic some short sessions of exercises are carried out. These sessions take about 4-6 hours, but can obviously be implemented at the request of the students.
The lecturer is available to more details and clarifications on any requests made by the students receiving at his office by previous contact via email: andrea.penoni@uninsubria.it or by phone (031-2386440).