The purpose of this course is to furnish to chemistry students, interested in deepening organic synthesis, methods and tools for organizing and rationalizing all their organic chemistry knowledge, acquired in previous organic chemistry courses. In particular, the course will focus on the following aspects: concepts, methods and reagents useful for the design of organic systems, taking into account, in particular, methods to achieve reaction selectivity and commercially availability of starting reagents.
Expected learning outcomes
At the end of the course students will be able to manage simple reactions from the chemical engineering point of view, evaluating the chemical kinetics and sizing the ideal reactor to carry out the chemical reaction to the study.
Lesson period: First semester
(In case of multiple editions, please check the period, as it may vary)
The course illustrates the retrosynthetic approach to the elaboration of strategies for preparing organic compounds, considering regio- and stereoselectivity aspects. Following the thread of the different types of disconnection, a number of synthetic methodologies are discussed, most of which are not included in the topics studied in the basic organic chemistry courses. Synthetic methods are discussed in terms of applicability, simplicity and selectivity. The main topics are the following: 1) The retrosynthesis approach and the concept of synthon 2) Donor synthons: i) Metal-halogen exchange; ii) alkylating and d1 synthons; iii) d1 synthons stabilized by heteroatoms; iv) d2 synthons: enolates and enolate equivalents; dn synthons (n > 3) 3) Umpolung: reversal of polarity 4) Acceptor synthons 5) One-group C-C disconnections: i) alkylation (use of organocuprates; use of boranes; use of 1,3-dithianes; alkylation of anions in α to COOR and derivatives; alkylation of anions in α to COR; alkylation of enamines; alkylation of hydrazones; alkylation of aldols; alkylation of terminal alkynes); ii) olefination (Wittig reaction; Horner-Wadsworth-Emmons reaction; Horner-Wittig reaction; Peterson reaction; Julia olefination; McMurry reaction; Barton-Kellogg reaction); iii) alkynylation (Corey-Fuchs reaction; Seyferth-Gilbert reaction; Bestmann-Ohira reaction); iv) coupling reactions (free radical coupling; coupling involving boranes; Heck reaction; Suzuki-Miyaura reaction; Stille reaction; Negishi reaction; Sonogashira reaction); v) synthesis of alcohols by addition of organometal reagents to C=O bonds (diastereoselective additions; Cram and Cram-Felkin-Anh stereoselection model); vi) synthesis of carbonyl compounds (by addition of organometal reagents to carboxylic acid derivatives; from borane-CO complexes; with the Collman reagent). 6) Two-group C-C disconnections: i) synthesis 1,2-difunctional compounds (oxidation of carbon-carbon multiple bonds; α-functionalization of carbonyl compounds; opening of epoxides with d0 synthons; use of acyl anion equivalents; use of α-methylsulfinyl ketones; reductive coupling); ii) synthesis 1,3-difunctional compounds (aldol reaction under thermodynamic control; aldol reaction under kinetic control with lithium and boron enolates; Mukaiyama aldol reaction; control of facial relative and absolute stereochemistry in aldol reactions; Claisen condensation; Dieckman condensation; Stobbe reaction; Knoevenagel reaction; Reformatsky reaction; Mannich reaction); iii) synthesis of 1,4-difunctional compounds (from enolate-type compounds and α-bromo carbonyl compounds; from enolate-type compounds and epoxides; from alkynes and epoxides; from nitroalkanes and α,β-unsaturated compounds; from cyanides and α,β-unsaturated compounds; allylation of carbonyl compounds; from allylboron compounds; from allylsilanes; from allyl trialkylstannanes; opening of carbonyl or 1-hydroxyalkyl substituted cyclopropanes; reductive coupling; oxidative coupling); synthesis of 1,5-difunctional compounds (Michael addition under thermodynamic control; Michael addition under kinetic control; Mukaiyama-Michael addition; Robinson annulation); synthesis of 1,6-difunctional compounds (the reconnection approach: ozonolysis of cyclohexenes; epoxidation followed by periodate cleavage). 7) Oxidation/reduction: oxidation of alcohols to aldehydes, ketones and carboxylic acids; addition of oxygen at carbon-carbon double bond; oxidative cleavage of carbon-carbon double bond; oxidation of ketones and aldehydes. Emphasis on methods that could be applied on large-scale. Critical analysis of synthetic procedure, with particular attention to large-scale preparation, reported in the literature. 8) Protection/deprotection (OH, NH2, CO, COOH): principal protective groups, revision of the mechanisms involved in the principal reactions for the introduction and removal of protective groups. 9) Exercises at the blackboard.
Prerequisites for admission
Courses of Organic Chemistry I and II passed - Basic concepts of organic chemistry.
Traditional teaching with PPT slides, and written exercises at the blackboard.
a) Copies of the lecture slides uploaded on https://ariel.unimi.it/ b) F. A. Carey, R. J. Sundberg, Advanced Organic Chemistry, Part B: Reactions and Synthesis, V Edition, 2007 Springer Science. c) J.-H. Fuhrhop, G. Li, Organic Synthesis - Concepts and Methods, 3rd Edition, Wiley-VCH, 2003. d) J. Clayden, N. Greeves, S. Warren - Organic Chemistry, II Edition, 2012 Oxford. e) S. Warren, P. Wyatt - Organic Synthesis: The Disconnection approach. 2008 Wiley. f) S. Warren, P. Wyatt - Workbook for Organic Synthesis: The Disconnection approach. II Edition, 2008 Wiley.
Assessement methods and criteria
Written examination: the exam usually consists of 6 exercises on retrosynthesis or on the application of reactions and concepts presented in the course.