Catalogo dei Corsi di studio

1.a. General expected learning outcomes
Organic chemistry is a chemistry discipline involving the scientific study of the structure, reactivity, properties and applications of compounds which are formed mainly by carbon atoms, forming covalent bonds, both from natural and artificial sources The general objective, is to provide students with the knowledge and competences necessary to understand the relationship between molecular structure and reactivity of the different functional groups, the mechanisms of organic reactions, the chemistry of heterocyclic compounds and biomolecules. For a CTF student, this learning is essential, because most drugs are organic compounds, and their biological activity depends on their interaction with biological targets, which are also organic compounds. This knowledge will allow the student to be able to understand the fundamental synthetic methodology for the construction heterocyclic compounds. Furthermore, stereochemical complements will be essential for improving the understanding of the drug-receptor interactions, a crucial topic in different next courses.

1.b. Specific expected learning outcomes
1. Knowledge and understanding
The specific objectives consist in acquiring the following knowledge and expertise:
1) to understand advanced stereochemistry and its importance on the reactivity of organic compounds;
2) to understand the relationship between structural distortion and reactivity for the different functional groups;
3) to acquire the specific knowledge to understand organic catalysis
4) to acquire the specific knowledge about the main chemical properties of heterocyclic compounds and the main routes to their synthesis;
5) to acquire the specific knowledge to understand the synthetic application of pericyclic reactions;
6) to acquire the specific knowledge to formulate reaction mechanism hypothesis;
7) to acquire the specific knowledge to understand the specific properties of biomolecules.

2. Applying knowledge and understanding
At the end of the course the student will be able to design the synthesis of heterocyclic derivatives through traditional organic and organometallic reactions; through the acquisition of stereochemical and molecular reactivity skills, student will be able to understand the mechanisms of drug-receptor interaction.

3. Making judgements
The Organic Chemistry 2 course is devoted to provide students with the adequate knowledge to be independent in solving problems about the main aspects of specific organic chemistry studies. This ability will be acquired by the means of frontal lesson submitting case studies of general interest.

4. Communication skills
In order to improve the exposure ability, students will be constantly encouraged to communicate their ideas to both specialists and non specialists audiences. The Erasmus programme will enable students to improve their communications skills, by exchanging informations, problems and solutions.

5. Learning skills
Teaching materials, available on line will support students during the lessons even thought studying the recommended text book is essential to acquire the skills and the competence that are necessary to perform the final exam.

Programme

Section 1. Structure and reactivity (12 hours)
Introduction to molecular mechanics. Conformational analysis of acyclic molecules: alkynes, aldehydes, ketones, conjugated dienes, alfa-beta-unsaturated carbonyl compounds. Conformational analysis of cyclic molecules: cyclohexane and its mono-, di- and polysubstituted derivatives. Anomeric effect. Heterocyclic systems: effect of the heteroatom on the conformation. Conformationally "blocked" and "conditioned" systems.
Effect of conformation on reactivity. Oxidation of cis- and trans-4-t-butyl-cyclohexanol. Acetylation of cis- and trans-4-t-butyl-cyclohexanol, saponification of cis- and trans-4-t-butyl-cyclohexanecarboxylic acid. Oxidation of piranosyl acetals with CrO3. Elimination of E2 type in cyclohexane systems. Competition between E2/SN2 in cyclohexane systems. Effect of steric tension on reactivity. Hydrolysis of esters with AAL1 type mechanism.
Effect of angular tension on reactivity. Carbonyl splitting in a basic environment. Reactions of solvolysis of alkyl bromides.
Cyclization Reaction: relationship between cycle size and cycling speed
Effect of torsional strein on reactivity: reduction of cyclic compounds
Effect of the steric tension on the acid-base properties. Trifenylmethane, proton sponges. Arylacetic acids derivatives. Electronic effects in nucleophilic substitution reaction.

Section 2. Complements of organic stereochemistry (4 hours)
Symmetry elements: axis of symmetry, plane of symmetry, axis of rotoriflexion, center of inversion. The stereogenic elements: tetrahedral center, chirality axis, chirality plan. Meso compounds. R/S nomenclature for compounds with chiral axis and plan.
Prostereisomery: definitions. Homotopic, enantiotopic, diastereotopic groups. Homotopic, enantiotopic, diastereotopic faces. Nomenclature for groups and enantiotopic faces.

Section 3. Study of the mechanisms of organic reactions (6 hours)
Use of thermodynamic data. Thermodynamic control and kinetic control in the distribution of reaction products: case of the formation of enolate anions. The postulate of Hammond. Energy graph of the electrophilic aromatic substitution reaction. Principle of Curtin-Hammet. Primary isotopic effect. Secondary isotopic effect. Linear relations of free energies. The Hammet equation. Interpretation of sigma and ro.
Catalysis. Brönsted acid-base catalysis: acidic (basic) specific catalysis: hydrolysis of acetals. Generalized (basic) acidic catalysis: hydrolysis of vinylethers, hydrolysis of orthoesters, enolization of ketones, elimination of E2. Brönsted's law. Correlation between pH and oxime formation rate. Catalysis mediated by Lewis acids. Intermolecular and intramolecular nucleophilic catalysis. Bifunctional catalysis.

Section 4. Pericyclic reactions (4 hours)
Generality. Electrocyclic reactions: cyclization of dienic and trienic systems. Conrotatory and disrotatory mode for cyclization. Correlation diagrams, HOMO symmetry analysis, symmetry analysis of the transition state for predicting the cycling reaction mode. Dewar benzene. Opening reactions of cyclopropyl systems. Sigmatropic reactions: 1.3 shift of hydrogen, of alkyl, 1.5 shift of hydrogen, of alkyl. suprafacial and antarafacial way. 3.3 Claisen and Cope rearrangement. Correlation diagrams, HOMO symmetry analysis, symmetry analysis of the transition state for predicting the cycling reaction mode. Cycloaddition reactions: the Diels-Alder reaction. Orientation endo and exo. Correlation diagrams, HOMO symmetry analysis, symmetry analysis of the transition state for predicting the cycling reaction mode. Reactivity of various dienophiles and dienes in the Diels-Alder reaction. Regioselectivity in the Diels-Alder reaction. Dienophiles of synthetic interest. Dienes of synthetic interest: diene of Danishefsky, quinidinodimethane. Intramolecular reactions.

Section 5. Chemistry of heterocyclic compounds (26 hours)
Classification, structure, aromaticity, nomenclature of heterocycles: trivial and systematic names. Nomenclature rules according to Hantzsch-Widman for mono and polycyclic systems. Representative examples.
Three-term heterocycles.

a) Oxirane: structure, spectroscopic and physical properties.
Chemical properties: isomerization to carbonyl compounds, ring opening by nucleophiles, reduction to alcohol, deoxygenation to olefins.
Synthesis: alkene epoxidation, cyclodehydrohalogenation of beta-halogen alcohols, Sharpless oxidation, Darzens reaction, Corey synthesis.
Important derivatives, natural products, synthetic intermediates, biologically active compounds: oxirane, epichlorohydrin, epoxy resins.

b) Aziridine: structure, spectroscopic and physical properties. Stereoisomeric properties: stability to pyramidal inversion.
Chemical properties: acid-base reactions, reactions with electrophilic reagents, ring opening in the presence of nucleophiles.
Summary: cyclization of beta-substituted amines, (Mitsunobu reaction)

Four-term heterocycles.

a) Oxetane: structure, spectroscopic and physical properties.
Chemical properties: acid-catalyzed ring-opening, cycl oligomerization and polymerization reaction.
Synthesis: cyclization of gamma-substituted alcohols, Paterno-Büchi reaction.

b) Azetidine: structure, spectroscopic and physical properties.
Chemical properties: opening of the acid-catalyzed ring.
Synthesis: cyclization of beta-substituted amines, cyclisation of 1,3-dialogenoalkanes.
Important derivatives, natural products, synthetic intermediates, biologically active compounds: main synthetic routes for azetidin-2-one: cyclization of ethyl-beta-aminopropionates, chlorosulphonyl isocyanates and alkenes, imines and ketenes. Synthesis of stereocontrolled beta-amino carboxylic acids.

Five-term heterocycles with a heteroatom

a) Furane: structure, spectroscopic and physical properties. Aromaticity.
Chemical properties: aromatic electrophilic substitution, metallation, addition reactions, Diels Alder, ring opening reactions.
Retrosynthetic analysis.
Synthesis: Paal-Knorr synthesis of 2,5-disubstituted furans, Feist-Benary synthesis of 2,3,4-trisubstituted furans, transformation of oxazoles into furans.
Important derivatives, natural products, synthetic intermediates, biologically active compounds: furan, (deepening: reaction of Cannizzaro, Perkin, Knoevenagel), furfural (synthesis from the pentosans), use of furfural for the synthesis of 3,4-dihydropyran.

b) Benzofuran: structure, spectroscopic and physical properties. Aromaticity.
Chemical properties: aromatic electrophilic substitution, metallation reaction, cycloaddition reactions.
Synthesis: Perkin rearrangement, synthesis through phenols and alochetones, synthesis through catalyzed palladium cyclization of orto-hydroxyaryl acetylene, (Vielsmeir reaction).
c) Pyrrole: structure, spectroscopic and physical properties. Aromaticity.
Chemical properties: acid-base reactions, reactions with electrophilic reagents on the nitrogen atom, aromatic electrophilic substitution reaction, Houben-Hoesch acylation, reactions with diazonium salts, reactions with carbonyl compounds, addition reactions, cycloadditions [2+ 2], Paterno-Büchi reaction, opening of the catalyzed acid ring,
Retrosynthetic analysis.
Synthesis: Paal-Knorr synthesis of 2,5-disubstituted pyrroles, Hantzsch synthesis of 1,2,3,4-tetrasubstituted pyrroles, Knorr synthesis of 3-alkoxycarbonyl or 3-alkoxycrylic substituted pyrroles, Kenner synthesis of pyrroles 2 -carboxylcholine 3- substituted.
Important derivatives, natural products, synthetic intermediates, biologically active compounds: pyrrole.

d) Indole: structure, spectroscopic and physical properties. Aromaticity.
Chemical properties: acid-base reactions, reactions with electrophilic reagents on the nitrogen atom, aromatic electrophilic substitution reaction (Mannich reaction), oxidation reactions.
Retrosynthetic analysis.
Synthesis: Reissert synthesis, Gassmann synthesis, Batcho-Leingruber synthesis, Bishler synthesis, synthesis through Sonogashira reaction, Fisher synthesis, Japp-Klingemann modification of Fisher synthesis, Buchwald modification of Fisher synthesis, synthesis of Nenitzescu.
Important derivatives, natural products, synthetic intermediates, biologically active compounds: indole, indole -3 (2H) -one, oxindole, isatin, melanins.

e) Thiophene: structure, spectroscopic and physical properties. Aromaticity.
Chemical properties: aromatic electrophilic substitution reaction, metallation reaction, Diels Alder reaction, ring opening.
Retrosynthetic analysis.
Synthesis: Paal synthesis, Fiesselmann synthesis, Gewald synthesis.

Five-term heterocycles with two heteroatoms

a) Oxazole: structure, spectroscopic and physical properties. Aromaticity.
Chemical properties: formation of salts, metallation reaction, reactions with electrophilic reagents, reactions with nucleophiles, cycloaddition reactions.
Retrosynthetic analysis.
Synthesis: Paal synthesis, Robinson-Gabriel synthesis and variants (in-depth analysis: Dakin-West reaction), van Leusen synthesis (in-depth study: chemical properties of tosylmethylisocyanate), Schöllkopf synthesis.
Important derivatives, natural products, synthetic intermediates, biologically active compounds: oxazole, aryloxazole, vitamin B6 synthesis.

b) Thiazole: structure, spectroscopic and physical properties. Aromaticity.
Chemical properties: salts formation, metallation reaction, reactions with electrophilic reagents, reactions with nucleophiles, reactions of 2-alkyl thiazoles.
Retrosynthetic analysis.
Summary: synthesis of Hantzsch and its variants.
Important derivatives, natural products, synthetic intermediates, biologically active compounds: thiazole, 2-aminothiazole, thiamine (thiamine role in decarboxylases).
c) Imidazole: structure, spectroscopic and physical properties. Aromaticity.
Chemical properties: acid-base reactions, annular tautomerism, complexes formation metallation reaction, carbenes formation , reactions with electrophilic reagents, electrophilic aromatic substitution reactions, reactions with nucleophiles.
Retrosynthetic analysis.
Synthesis: synthesis of alfa-dicarbonyl compounds, Bredereck synthesis, Marckwald synthesis, van Leusen synthesis
Important derivatives, natural products, synthetic intermediates, biologically active compounds: imidazole, histidine, histamine, (use of imidazole as acylating agent)
d) Pyrazole: structure, spectroscopic and physical properties. Aromaticity.
Chemical properties: acid-base reactions, annular tautomerism, metallation reaction, reactions with electrophilic reagents, electrophilic aromatic substitution reactions.
Retrosynthetic analysis.
Synthesis: synthesis of hydrazine derivatives,
Important derivatives, natural products, synthetic intermediates, biologically active compounds: pyrazole.

Six-term heterocycles with a heteroatom

a) Pyridine: structure, spectroscopic and physical properties. Aromaticity.
Chemical properties: pyridine derivatives basicity, electrophilic reactions on the nitrogen atom, N-adducts with Lewis acids formation, aromatic electrophilic substitution reactions: nitration, sulfonation (kinetic and thermodynamic control), aromatic nucleophilic substitution reaction: mechanism of addition / elimination and elimination / addition (Chichibacin reaction, Ziegler reaction), metallation reaction, side-alkyl chain reactivity, pyridinine N-oxide derivatives and their chemical properties, oxidation and reduction.
Retrosynthetic analysis.
Synthesis: a )by cyclocondensation reactions; b) by Hantzsch synthesis and variants; d) by cycloaddition reactions; e) from furan.
Important derivatives, natural products, synthetic intermediates, biologically active compounds: pyridine, nicotinic acid, natural alkaloids, B vitamins, NAD+/NADH, 2-chloro-1-methylpyridinium iodide as esterifying agent, N-benzylpyridinium salts as oxidizing agents.

b) Quinoline: structure, spectroscopic and physical properties. Aromaticity.
Chemical properties: aromatic electrophilic substitution reactions: (study of the relative reactivity of the various carbon atoms by D/H exchange), nitration reaction, halogenation, sulfonation. Reaction of aromatic nucleophilic substitution, Reissert reaction, N-oxide quinoline reactivity, side-alkyl chain reactivity, oxidation and reduction reactions.
Retrosynthetic analysis.
Synthesis: nitroderivative synthesis, example of palladium-catalyzed synthesis, Friedländer synthesis, Ptizinger synthesis, Combes synthesis (deepening: regioselectivity in cyclization), Knorr synthesis, Skraup and Doebner-Miller synthesis, (deepening: synthesis of acrolein from glycerol), synthesis of Meth-Cohn, (synthesis of 2-quinolones alochinolines).
Important derivatives, natural products, synthetic intermediates, biologically active compounds: quinoline, 8-hydroxyquinoline, natural alkaloids.

Section 6. Carbohydrate chemistry (4 hours)
Classification, D / L convention, correlations, cyclic hemiacetal structure, mutarotation. Pseudo-asymmetric centers. Reactions of monosaccharides: reduction to alditol, oxidation to aldaric and aldonic acids. Reducing and non-reducing sugars: test of Tollens, Benedict and Feeling. Glucoside formation of N-glycosides. Disaccharides: lactose, sucrose, maltose. Polysaccharides: starch, cellulose.

Section 7. Peptide chemistry (4 hors)
Amino acids. Classification, stereisomeric properties, acid-base properties, isoelectric point, peptide bond. Determination of the amino acid sequence of a polypeptide: cyanogen bromide method, Edman degradation. Synthesis of chemical polypeptides: retrosynthetic strategy, use of the protecting groups, activation of the carboxylic function via mixed anhydride formation and with DCC. Solid phase synthesis: synthesis and use of Merrifield resin.

Section 8. Lipid Chemistry.
Classification. Group A. a) Triglycerides: structure, chemical-physical properties, reduction, saponification, formation of micelles; b) Phospholipids: structure, chemical-physical properties; c) Prostaglandins: structure, biosynthesis; d) fat-soluble vitamins: Vitamin A, D, E and K: structure, activity. Group B. a) Cholesterol: chemical structure and chemical-physical properties, cholesterol biosynthesis; b) steroid hormones: chemical structure and chemical-physical properties; c) bile acids: chemical structure and chemical-physical properties.

Section 9. Summary and exercises (8 hours)
Nomenclature rules of heterocyclic compounds. Acid-base properties of organic molecules.

Adopted texts

Chapter 1, 3, 4: “Advanced Organic Chemistry”; F. A. Carey, R. J. Sundberg, Plenum
Publishing Corporation, ISBN 0-306-43457-1.
Chapter 2: “Stereochemistry of Organic Compounds”; E. L. Eliel, S. H. Wilen, Wiley
Int. ISBN 0-471-05446-1.
Chapter 5: “The Chemistry of Heterocycles”; T. Eicher, S. Hauptmann, Wiley-VCH,
ISBN 3-527-30720-6 and "Chimica dei composti eterociclici"; G. Broggini, G. Zecchi, Zanichelli, ISBN 978-88-08-42087-9
Chapter 6-8: a textbook of Organic Chemistry.

Prerequisites

Essential: students are expected to posses the following essential knowledge : acido-basic properties of organic compounds, fundamentals of stereochemistry, reactivity of functional groups.

Frequency modes

Attendance to lectures, although very useful for achieving the course's educational objectives, is not mandatory.

Exam modes

In order to acquire the CFU of the course, by the end of the class students have to pass the final exam that will take place during the examination sessions designed by CCS . Midterm exam are not provided.
In order to facilitate the student in their study planning, the date of the exam may be designated during the whole session.
The oral examination result is expressed in thirtieths and depends on:
2) evaluation of general and specific knowledge about all the subject of the class;
3) clarity in exposure ;
4) ability to create links between the studied topics.
Minumum to pass examination is (18/30) .Students exhibiting a detailed knowledge will pass with first-class honours( 30/30 cum laude).
The exam may be performed in every programmed session.

Exam reservation date start	Exam reservation date end	Exam date
19/10/2021	10/01/2022	18/01/2022
19/10/2021	14/02/2022	15/02/2022
19/10/2021	05/04/2022	12/04/2022
27/04/2022	28/04/2022	29/04/2022
19/10/2021	05/06/2022	14/06/2022
19/10/2021	05/07/2022	12/07/2022
19/10/2021	01/09/2022	06/09/2022
19/10/2021	15/11/2022	22/11/2022
19/10/2021	10/01/2023	24/01/2023