Industrial pharmacy REPLICA LATINA

Section 1. Acids and bases (5 hours) Arrhenius, Lowry-Brönsted e, and Lewis acids and bases. Factors influencing the strength of Lowry-Brönsted acids and bases: hybridization, polarizability, electronegativity, inductive effect, field effect, resonance, hydrogen bond, solvent. Section 2. Hydrocarbons and 1,3-Dienes (18 hours) Alkanes and cycloalkanes Nomenclature, hybridization, structure, structural isomers, conformation (torsional strain, angle strain), hybridization and bond angle (cyclopropane). Newman projections. Haworth projections.Reactivity: radical halogenation [mechanism, selectivity (transition state and Hammond’s postulate)]. Radicals: structure, stability (hyperconjugation, resonance). Bicycles: nomenclature. Alkenes Nomenclature, hybridization, structure, stability, geometric isomerism, E-Z rules. Reactivity: addition of HX (X = halogens) [ionic (carbocations: structure, stability, carbocation rearrangement) and radical (HBr) mechanism], water (specific acid catalysis), halogens, synthesis of halohydrins, hydroboration-oxidation (regio- e stereochemistry), epoxidation (reaction with peracids), palladium-catalyzed hydrogenation and hydrogenation heats, Heck reaction, oxidation with OsO4 (oxidation numbers), addition of carbenes (carbenes from chloroform), Simmon-Smith reaction. Allylic halogenation: influence of the concentration of Br2 and temperature on the addition to double bond/allylic bromination ratio. Reaction with N-bromosuccinimide. Stability of the allylic radical. Regioselectivity 1,3-Dienes Structure. Stability. Reactions: 1,2 and 1,4 additions (kinetic and themodynamic control). Alkynes Nomenclature, hybridization, structure. Reactivity: palladium-catalyzed addition of hydrogen, addition of HX (X = halogen) (vinylic cations: hybridization, stability), addition of halogens, addition of water (catalyzed by sulfuric acid and Hg(II) salts), hydroboration-oxidation with internal and terminal (disiamylborane) alkynes, acidity of terminal alkynes (addition and nucleohilic substitution reactions of acetylides). Section 3. Stereochemistry (4 hours) Fundamentals of stereochemistry Stereoisomers. Chirality. Chiral and stereogenic center. Enantiomers and diastereoisomers. Symmetry elements: center, axis, plane. Enantiomers: nomenclature (Cahn, Ingold, and Prelog priority rules). Optical rotation. Racemates. Specific rotation. Enantiomeric excess. Compounds containing more than one chiral center (diastereoisomers and meso isomers). Fischer projections. Resolution of racemates. Stereoselectivity and stereospecificity. Section 4. Alkyl halides, alcohols, ethers and epoxides (14 hours) Alkyl halides Structure and IUPAC nomenclature. Nucleophilic substitution (SN), nucleophilicity and basicity. SN1: mechanism, stereochemistry, ion pairs, factors influencing the SN1 reaction (alkyl halide, leaving group, nucleophile, solvent (protic solvents, polar aprotic solvents, apolar aprotic solvents). SN2: mechanism, stereochemistry, factors influencing the SN2 reaction (alkyl halide, leaving group, nucleophile, solvent). SN1 vs SN2 (influence of the alkyl group, solvent, and nucleophile). beta-Elimination (E). E1: mechanism, regiochemistry (Saitseff’s rule). E2: mechanism, regiochemistry, stereochemistry. E2 in cyclic systems. E1 vs E2: influence of the alkyl halide, solvent, and base. SN1 vs E1 and SN2 vs E2. alfa-Elimination: formation of carbenes. Formation of organometallic compounds: alkyllithium compounds, alkylmagnesium compounds. Alcohols Nomenclature. Reactivity: acidity in the gas phase and in solution, synthesis of ethers (Williamson and acid-catalyzed dehydration), esters, and tosylates, addition to C-C double bonds (tetrahydropyranyl protecting group), oxidation (mechanism with chromic acid and pyridinium chlorochromate), reaction with PBr3, with SOCl2 in the absence (SNi) and in the presence of tertiary amines or pyridine, dehydration of alcohols and tosylates. Pinacol rearrangement. Ethers Nomenclature. Reactivity: reaction with con HX (X = halogens). Epoxides: nomenclature, ring opening (acid-catalyzed, with nucleophiles), reaction with Grignard reagents (synthesis of Grignard reagents and their reaction with water and carbon dioxide). Section 5. Aldehydes and ketones, carboxylic acids and their derivatives (12 hours) Aldehydes and ketones Nomenclature. Addition reactions: specific acid-catalyzed addition, reaction with boron and aluminum hydrides (reactivity of alkoxy derivatives of boron and aluminum hydrides), with terminal alkynes, Grignard reagents, HCN, water, alcohols (acetals as protecting groups). Addition-elimination reactions: Wittig reaction, reaction with primary and secondary amines. Bayer-Villiger reaction. Reduction to hydrocarbons: Clemmensen and Wolff-Kishner reactions. Carboxylic acids Nomenclature. Reactivity: acid-base reactions, reactions with LiAlH4, with alcohols, with SOCl2, with PBr3. Carboxylic acid derivatives Acyl halides, anhydrides, esters, lactones, amides, lactames, imides, nitriles - Nomenclature. Reactivity: reaction with water [acyl chlorides, anhydrides, esters, (esters from 1°, 2°, and 3° alcohols), amides, nitriles], with alcohols (acyl chlorides, anhydrides, esters), with carboxylic acid salts (acyl chlorides), with ammonia and amines [acyl chlorides, anhydrides, esters, with Grignard reagents (esters), with LiAlH4 (esters, amides, nitriles), Hoffmann’s degradation, Reformatsky’s reaction. Section 6. Enols, enolates and α,β-Unsaturated aldehydes and ketones (7 hours) Enols and enolates Keto-enol tautomerism (acid- and base-catalyzed), factors influencing the keto-enol equilibrium (hydrogen bond, resonance), thermodinamic and kinetic control in the formation of enolate anions in the presence of LDA. a-Bromination of ketones (under acid and basic conditions), Hell-Vohlard-Zelinski reaction. Aldol condensation, Aldol condensation-dehydration (under acid and basic conditions) intramolecular aldol condensation, crossed aldol condensation, Claisen and Dieckmann condensations, acetoacetic and malonic syntheses. α,β-Unsaturated aldehydes and ketones 1,4- and 1,2-Addition (reversible and irreversible). Reaction with Grignard reagents and anions from 1,3-dicarbonyl compounds. Robinson annulation. Section 7. Aromatic compounds, phenols and amines Aromatic compounds Aromaticity. Huckel rule. Aromatic, antiaromatic and non aromatic compounds. Aromatic ions. Heteroaromatics. Nomenclature. Electrophilic aromatic substitution: mechanism, substituent effects, halogenation, nitration, sulfonation, Friedel-Crafts alkylation and acylation. Nucleophilic aromatic substitution: addition-elimination, elimination-addition (evidences in favor of benzyne), via phenyl cation. Phenols Nomenclature. Reactivity: acidity, synthesis of esters and ethers, electrophilic aromatic substitution, Reimer-Tiemann reaction, synthesis of azo compounds. Amines Nomenclature. Chirality: tertiary amines and carbanions. Pyramidal inversion. Chirality of armonium salts. Eliminations of ammonium salts (Hofmann rule, variable transition state and steric strain). Reactivity: basicity (in gas phase and in solution), reaction with alkyl halides, with carbonyl compounds, reactions of aromatic amines with HNO2 (arenediazonium salts, coupling with anilines and phenols). Enamines - Alkylation, acylation, and conjugate addition. Section 8. Summary and exercises (8 hours)

Students are expected to know the following fundamentals of chemistry: hybridization, resonance, aromaticity, fundamentals of thermodynamics (enthalpy, Gibbs energy, entropy), chemical equilibria, fundamentals of chemical kinetics, reaction rate, transition state.

A cura di B. Botta. Autori vari. CHIMICA ORGANICA, II edizione. Edi-Ermes. ISBN: 9788870513271 For exercises session: 1) S. Cacchi, F. Nicotra “ESERCIZI DI CHIMICA ORGANICA ” Casa Ed. Ambrosiana, 1999 2) N. E. Schore, K. P. Vollhartdt “ESERCIZI RISOLTI DI CHIMICA ORGANICA ” Zanichelli

The course (9 CFU) is provided through traditional lessons integrated with exercises. The lessons are held in classrooms where there are devices suitable for projecting the slides of the course, available to CTF students on the Sapienza E-learning platform. The exercises, provided throughout the course, cover all the topics covered during the theoretical lessons and prepare students for the written test. There are several summarizing sessions in which different quiz that are representative of those given to the exam, are shown. Students have at their disposal self-assessment tests related to all the chapters dealt with during the theoretical course.

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

In order to acquire the CFU of the course, by the end of the class students have to pass the final exam that is planned every month ( other than in August). 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 final exam consists in a written examination (essay test) and in an oral examination; its purpose is to certify the acquired knowledge about organic chemistry. In order to be eligible for the oral examination students must pass the written examination. This latter has the duration of 20 minutes and consist in three random-selected exercises which are prepared by the examination board. Each student will have his own test. In order to get a positive results, students must correctly solve at least two of the three proposed exercise. Alternatively the commission may decide to assign to students a multiple choice test, always personalized, using Moodle; in this case the test is passed if the student answers 60% of the questions correctly. The examination board reserves the right to consider eligible for the oral examination those students whose written test is considered adequate even if not completely responding to the previous requests. The oral examination result is expressed in thirtieths and depends on: 1) evaluation of written exam; 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.

The course consists of taught classes and numerical exercises on the blackboard that are intended to prepare students for the written test. During the lessons, the teacher stimulates the students with questions related to what it has just been presented, with the aim of making them participate and stimulate the study at home, lesson by lesson. Students are invited to read the various textbooks recommended at the beginning of the course and to find, on them, the discussion of the various topics proposed in class.