Learning objectives
At the end of the course the student is able:
- to know the IUPAC nomenclature of aromatic heterocyclic compounds and to apply the IUPAC rules to unknown compounds;
- to know the structural features of the main aromatic heterocycles;
- to know the synthesis of the aromatic heterocycles handled in the course;
- to know the reactivity of the heterocycles handled during the course and, for each class of compounds, to understand the regioselectivity issue of the different reactions;
- to be able to analyze the chemical behavior of the heterocycles in the presence of given reactants;
- to know the acid-base behavior and the tautomeric equilibria (when present) of the heterocycles handled during the course, and to be able to order different heterocycles based on scales of reactivity and basicity/acidity;
- to be able to apply the acquired knowledge in solving simple exercizes of synthesis and retrosynthesis of heterocycles.
Prerequisites
It is necessary to have knowledge of organic chemistry. To access the final examination, the student must have passed the Organic Chemistry I exam (for CFT students) or Organic Chemistry Basics/Organic Chemistry (for Pharmacy students).
Course unit content
The course mainly describes aromatic heterocycles, in particular five- and six-membered monocyclic and bicyclic systems, focusing on the following aspects: nomenclature, structure, physical-chemical properties, tautomerism, main syntheses and reactivity.
Particular attention will be paid to bioactive compounds and heterocyclic drugs.
Full programme
Definition and classification of heterocyclic compounds. Aromaticity. IUPAC rules for the nomenclature of mono- and polycyclic heteroaromatic compounds.
Pyrrole, pyrrole-containing natural compounds and drugs. Structure of pyrrole and pyridine: comparison; pyrrole-like and pyridine-like nitrogen atoms in nitrogen-containing aromatic heterocycles and their implications in the structure-reactivity relashionship.
Pyrrole syntheses: Paal-Knorr, Knorr, Hantzsch. Acidity. Reactivity: nitration, sulfonation, formylation, Mannich reaction, metalation.
Indoles. Natural compounds and drugs. Syntheses (Fischer, Reissert). Reactivity. Electrophilic substitutions, alkylations, reactions with alpha,beta-unsaturated compounds.
Furans and thiophenes. Syntheses (Paal-Knorr, Feist-Benary, Hinsberg,). Reactivity: nitration, bromination, metalation, acylation, Mannich reaction, Diels-Alder cycloaddition.
Pyrilium ions, pyrons, coumarins, chromones, anthocyanins. Natural compounds and drugs. Reactions with nucleophiles. Synthesis of coumarines.
Pyridine. Natural compounds and drugs. Properties, basicity. Reactivity with electrophiles and nucleophiles. Metal-halogen exchange. Metalation. Pyridones. Pyridine-N-oxides. Synthesis of pyridines: (Hantzsch, Robinson, Guareschi-Thorpe).
Quinolines and isoquinolines: natural compounds and drugs containing these heterocycles. Main syntheses (Combes, Conrad-Limpach, Skraup, Friedlander; Pomeranz-Fritsch, Bischler-Napieralski, Pictet-Spengler). Reactions with electrophiles and nucleophiles. Halogen exchange.
Imidazoles, oxazoles and thiazoles. Natural compounds and drugs. Acid/base properties. Tautomerism. Reactivity: nitration, sulfonation, bromination, alkylation, acylation, reactions with bases, metalation, SNAr. Some mentions to synthesis methods.
Pyrazoles, isoxazoles, isothiazoles. Natural compounds and drugs. Main syntheses. Acidity. Reactivity, SEAr, metalation. Five-membered heterocycles containing 3-to-5 heteroatoms. Syntheses. Properties, mentions to bioisosterism.
Diazines (pyrazines, pyrimidines, pyridazines). Introduction on main syntheses. Reactivity. Pyrimidines and purines: structure and tautomerism. RNA- and DNA-based nitrogen-containing bases: structure and tautomerism.
Bibliography
Textbook and Reference Books:
1) F. BROGGINI, G. ZECCHI, Chimica dei composti eterociclici, Ed. Zanichelli, 2017
2) J. CLAYDEN, N. GREEVES, S. WARREN, “Chimica Organica”,
PICCIN Ed., Italian Edition based on the Second Edition in English, 2023, Chapters 29 and 30 (or directly the English version "Organic Chemistry" by the same authors, same Chapters).
3) D. SICA, F. ZOLLO, Chimica dei composti eterociclici farmacologicamente attivi, Ed. Piccin. 2008.
4) J.A. JOULE, K. MILLS, Heterocylic Chemistry, 5th Edition, Wiley-Blackwell Edition.
5) T. GILCHRIST, Heterocyclic Chemistry, Ed. Longman, 1997.
6) D. T. DAVIES, Aromatic Heterocyclic Chemistry, OUP Ed., Oxford Chemistry Primers, 1992.
Additional teaching material for students (loaded on Elly platform):
-slides of the lessons (PDF files);
-exercises for each subject matter and their solutions (PDF files).
Teaching methods
The present course is carried out via frontal lessons with in-presence modality. In particular, the teacher gives lessons in the classroom with the help of PC (Powerpoint slides) and graphic table connected to the PC.
The content of the slides of each lesson are loaded in the Elly platform of the course.
The teacher also performs exercises in the classroom with the help of students to enhance the ability of students to apply knowledge on the synthesis and reactivity of heterocyclic compounds.
At the end of each topic, the teacher loads exercises (on Elly) which are solved by students by themselves to evaluate their knowledge. Thereafter, the teacher furnishes solutions to the problems to give the students an instrument of self-evaluation.
Assessment methods and criteria
Learning outcomes are checked by a written examination. The written examination aims at verifying whether the student has acquired the knowledge and developed skills in applying this knowledge in the analysis and resolution of exercises. The examination usually takes 90 minutes and consists of the resolution of 9 or 10 exercises (open questions) concerning the nomenclature, properties, reactivity and synthesis of heterocycles. Each exercise corresponds to a numeric value, which is reported. The student is qualified (idoneo) when the exam is judged equal or superior to 18/30.
No texts, notes, or references are permitted during the examination (a part from some maps previously agreed with the teacher during th course).
Possible compensatory material will be allowed to students with DSA or BES, which will be agreed upon with the teacher at least one week before the examination, by following the rules of the Centre CAI of this University.
Other information
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2030 agenda goals for sustainable development
The topic of this course deals with the structure, properties and synthesis of heterocyclic compounds, which are ubiquitous motifs in small-molecule drugs currently used worldwide. In this sense, the knowledge and competence obtained in this course may be linked to the Objective 3- Health and Wellness.
