Industrial pharmacy

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.

B. Botta. Chimica Organica II edizione. Edi-Ermes 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 (or remotely, depending on the evolution of the pandemic)) 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, 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 exams 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 of a written exam preparatory to the oral exam. The characteristics of the written test will be conditioned by the evolution of the pandemic situation: therefore, the following methods are envisaged: 1. Written test with closed stimulus and open answer, lasting 20 minutes, to be carried out in person, consisting in the administration of three questions randomly selected from all those prepared by the commission and assigned to the students so that each one has a personalized task. The test is passed if 2 (two) of the 3 (three) quizzes proposed are correctly solved; 2. Written test with closed stimulus and closed response, in electronic mode lasting 20 minutes, using the Moodle platform, consisting in the administration of a multiple-choice test. The test is passed if the student achieves a score equal to or greater than 18 / 30- In any case, the Commission reserves the right to admit to the oral exam students whose task, although not meeting the above requirements, is overall sufficient. The oral exam, of the closed stimulus and open response type, ends with an evaluation out of thirty whose numerical formulation includes the following elements: 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. The minimum to pass the examination is (18/30). Students exhibiting detailed knowledge will pass with first-class honors ( 30/30 cum laude). The exam may be performed in every programmed session.

The didactic activity takes place face to face and via videoconference in combined mode. The typical lesson takes place with the teaching aid consisting of the course slides, which have been prepared in original form by the teacher and are subject to annual revision. The lesson is supplemented by in-depth studies proposed to students using the electronic whiteboard in the classroom.

Section 1. Acids and bases (4 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 (16 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 (12 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 (10 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 (6 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 (8 hours) 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 armonium 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 (integrative lesson, 4 hours)

Essential: To understand the lessons of Organic Chemistry I, it is essential that the student possesses the following knowledge: hybridization, resonance, aromaticity, basic elements of thermodynamics (enthalpy, free energy, entropy), chemical equilibrium, basic elements of chemical kinetics, reaction rate theory, and transition state theory.

B. Botta. Chimica Organica II edizione. Edi-Ermes Exercises books 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, 2016

The course (9 CFU) is provided through traditional lessons integrated with exercises. The lessons are held in classrooms (or remotely depending on the pandemic situation) 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, is not mandatory.

The course is delivered through lectures integrated with practical exercises. Lectures are held in the classroom. Attendance is not mandatory.

The acquisition of the CFU of the course is contingent upon passing the final exam, which will take place at the end of the course, during the exam periods established by the degree program board. The instructor will also be available to examine students in small groups during the exam session, allowing them to organize their study effectively. No midterm exams will be provided during the course. The purpose of the final exam is to certify the student's knowledge of the topics covered during the course. The final exam consists of a written test, which is preparatory to the oral exam. The final exam consists of a written exam preparatory to the oral exam. The written exam will be conducted according to the following modalities: 1. The written test consists of closed-prompt, open-answer questions, lasting 20 minutes and is to be taken in person. It includes three questions randomly selected from a pool prepared by the examination board and assigned to students in such a way that each receives a personalized set. The exam is considered passed if the student correctly answers at least two (2) out of the three (3) proposed questions; 2. The written exam consists of closed-prompt, multiple-choice questions, administered online via the Moodle platform, with a duration of 20 minutes. The exam is considered passed if the student achieves a score equal to or greater than 18 out of 30. In any case, the Commission reserves the right to admit to the oral exam students whose written exam, although not meeting the criteria outlined above, is deemed overall sufficient. The oral exam, consisting of closed-ended and open-ended questions, ends with a grade out of thirty, determined by the following factors: 1) evaluation of written exam; 2) evaluation of general and specific knowledge about all the subject of the class; 3) clarity of expression; 4) ability to make connections and synthesize between different topics. The minimum to pass the examination is (18/30). Students exhibiting detailed knowledge will pass with first-class honors (30/30 cum laude). The exam may be performed in every programmed session.

The course (8 CFU) is provided through traditional lessons integrated with exercises. The lectures take place in classrooms equipped with devices suitable for projecting course slides, which are also available to registered students on the Sapienza E-learning platform. The exercises, provided throughout the course, cover all the topics addressed in the theoretical lectures and prepare students for the written exam. Several review sessions are scheduled, during which various exercises representative of those given in the exams are presented. Students also have access to self-assessment tests related to all the chapters covered during the theoretical course. Attendance to lectures and exercises, although highly beneficial for achieving the course learning objectives, is not mandatory.