Benzene and aromaticity; Hückel's MO Theory. Aromatic substitution. Synthesis and reactivity of aromatic compounds. Aromatic heterocycles. Reactions catalyzed by Pd. Enolates and enamines. Aldol, Claisen and Diekmann reactions. Acetoacetic and malonic syntheses. Michael and Robinson reactions. Diels-Alder Cycloaddition. Lipids. Amino acids. Peptides. Carbohydrates. Nucleic acids.
Laboratory: Separation and characterization of two unknown aromatic compounds. Mass spectrometry and NMR.
Lessons mainly (but not exclusively) follow the topics covered in "Organic Chemistry" W.H. Brown, B.L. Iverson, E.V. Anslyn, C.S. Foote. Generally speaking, all the topics covered in the course are present in all the texts of Organic Chemistry for the Degree courses in Chemistry. The same text covers both the courses of Organic Chemistry I and II. It is advisable to refer to the handouts to get the track of the topics that must be studied in a suitable textbook.
Learning Objectives
The course is the continuation of the course of Organic Chemistry I and aims to furnish the student with a picture on structure and reactivity of organic compounds, including classes of natural products such as lipids, amino acids, carbohydrates and nucleic acids.
Basic knowledge of mass spectrometry (EI) and 13C NMR is also provided. The practical experience concerns the separation and structural characterization of two unknown compounds.
Prerequisites
Required courses: Organic Chemistry I and Laboratory of Organic Chemistry I
This course is the continuation of the O.C. I course and Lab. of C.O. I and all the contents are closely related.
Teaching Methods
Lectures: 32 hours
Training exercises (in class): 12 hours
Laboratory practice: 12 hours
Further information
lesson slides are available on the Moodle platform.
Compulsory attendance of the introductory lessons to the laboratory activity (first part of the course)
Type of Assessment
Students must deliver a report at the end of the preparatory laboratory experience for the oral exam.
The final test consists of an oral exam carried out on the blackboard in which, through exercises and questions on three topics chosen by the teacher, the following occurs:
- knowledge of the structure, properties and reactivity of benzene derivatives and aromatic heterocycles.
- knowledge of the structure, properties and reactivity of oenols and their analogues.
- knowledge of reactions catalyzed by palladium and of Diels-Alder cycloadditions.
- knowledge of the structure, properties and reactivity of sugars, amino acids, peptides and proteins, lipids and nucleic acids.
- knowledge of the mechanisms of the reactions analyzed during the lessons and of the relative aspects of selectivity.
- the ability to design the retrosynthetic analysis of the compounds analyzed in class and of analogous compounds.
- the ability to know how to apply the studied synthetic processes to short multistage syntheses.
The ability to correctly explain the concepts learned during the course and to know how to apply them through reasoning to the resolution of the proposed exercises will be assessed.
Course program
DETAILED PROGRAM
Part I:
Benzene: structure and properties. Molecular Orbitals (OM) model. Resonance Model. Resonance energy: definition, calculation of resonance energy. Concept of aromaticity: Huckel's criteria for aromaticity and anti-aromaticity. Frost's circumference method. Aromatic, anti-aromatic and non-aromatic annulenes: structure and reactivity. Theoretical and experimental methods for determining aromaticity. NMR: chemical shift of protons in annulenes.
6- and 5-term aromatic heterocycles (pyridine, pyrimidine, furan, thiophene, pyrrole, imidazole, indole, purine): structure, relative resonance energy, acid-base properties. Aromatic and antiaromatic hydrocarbon ions: structure, stability, and acid-base properties (pKa value of cyclopentadiene compared with pKa of alkanes and other classes of compounds). Application of Frost's circumference method. Generation of the tropylium ion and its fragments in the mass spectrometer.
Rules for nomenclature of mono- and polysubstituted benzene derivatives. Systematic and common names: toluene, phenol, aniline, benzaldehyde, benzoic acid. Phenyl and benzyl groups. Phenol and its derivatives: structure and acid-base properties (pKa value of phenol, carboxylic acids and alcohols, influence of substituents on pKa of substituted phenols). Aniline and its derivatives: structure and acid-base properties (pKa value of aniline and amines, influence of substituents on pKa of substituted anilines).
Separation by chemically active extraction
Basic concepts of mass spectrometry (MS).
Reactions of benzene and its derivatives. Aromatic electrophilic substitutions (halogenation, nitration, sulfonation, alkylation, acylation): reactants, mechanism, effect of substituents. Indirect substitution processes (synthesis of anilines, alkylbenzenes and benzoic acids). Disubstitution and polysubstitution. Hammond's postulate. Theory of orienting, activating and deactivating effects and corresponding energy diagrams. Multistage synthesis.
Kinetic product. Thermodynamic product. Reaction under kinetic control. Reaction under thermodynamic control.
Aromatic nucleophilic substitutions of aryl halides: via aryl intermediate and by an addition-elimination mechanism.
Alkylbenzenes. Resonance hybrid of benzyl cation, anion and radical. Benzyl position reactions: oxidation, radical halogenation (mechanism and selectivity), synthesis and hydrogenolysis of benzyl ethers and their use as protecting groups. Fragmentation of benzyl derivatives in the MS.
Synthesis and reactivity of phenols and phenoxide ions (bidentate nucleophiles): structure and acid-base reactions, Williamson reaction for the preparation of alkyl-aryl ethers, Kolbe carboxylation reaction for the synthesis of salicylic acid, oxidation to quinones, reduction of quinones, synthesis of phenols from anilines via diazonium salts, deprotection of O-benzyl-phenols via hydrogenolysis.
Synthesis and reactivity of aromatic amines: structure and acid-base reactions. Reaction with nitrous acid of primary secondary and tertiary amines. Comparison of aliphatic and aromatic amines. Synthesis and reactivity of aromatic diazonium salts.
Retrosynthetic analysis: definition, disconnections, FGI. Symbol.
Saturated and aromatic heterocyclic compounds: definition. Names and structure of some common heterocycles (pyridine, pyrimidine, furan, thiophene, pyrrole, imidazole, oxazole, thiazole, benzofuran, indole, benzothiophene, purine, tetrahydrofuran, pyrrolidine). Electronrich aromatic heterocyclic compounds: pyrrole, furan, thiophene, indole, benzofuran, benzothiophene, imidazole, oxazole, and thiazole. Pyrrole, furan, thiophene: structure, resonance energy, acid-base properties, and reactivity. Polymerization of pyrrole in acid environment, furan ring opening in acid environment, aromatic electrophilic substitution. Furan: Diels-Alder cycloaddition reaction. Benzofuran, indole, benzothiophene: structure, regioselectivity of aromatic electrophilic substitution reactions. Imidazole, oxazole, thiazole: structure, aromaticity, acid-base properties, reactivity and regioselectivity in aromatic electrophilic substitution reactions.
Pyridine: structure, resonance energy, acid-base properties and nucleophilicity. Electrophilic additions to nitrogen: alkylation, acylation, reaction with Lewis acids. Aromatic electrophilic substitution: reactivity with respect to benzene, regioselectivity, orientation in polysubstitution, temporary activation by N-oxide formation, comparison with phenoxide. Pyridine N-oxide: synthesis, reactivity in aromatic electrophilic substitutions, reduction to pyridine. Pyridine aromatic nucleophilic substitution reactions: reactivity and regioselectivity. Chichibabin reaction and its use for indirect introduction of various substituents on the pyridine ring. Pyridones:
Alkylpyridines: structure, acid-base properties and reactivity.
Part II:
Organometallic compounds: synthesis and reactivity of Grignard reagents, alkyllithium reagents and cuprates.
Transition metal complexes: oxidative addition and reductive elimination. Heck reaction: reactants, reaction conditions, mechanism and catalytic cycle, aspects of regioselectivity, stereoselectivity and stereospecificity, reactions with alkene isomerization.
Palladium-catalyzed coupling reactions: general mechanism and catalytic cycle. Aspects of stereoselectivity and stereospecificity. Suzuki coupling. Stille coupling. Sonogashira coupling.
Carbonyl compounds: general reactivity. Keto-enolic tautomeria: mechanism. Acidity constants of amines, alcohols, water, ketones, esters, -diketones, -ketoesters, malonic esters. Formation and reactions of enolate anions: nucleophilic substitution and nucleophilic addition. O-alkylation and C-alkylation (kinetic product and thermodynamic product). Bromination of aldehydes and ketones.
Characteristics of enols and enolate ions compared. Aldol reaction: aldol addition reaction and aldol condensation reaction (reaction conditions and mechanisms: acid catalysis, basic catalysis, dehydration of -hydroxyaldehydes and -hydroxyketones catalyzed by bases and acids). Inter- and intramolecular cross aldolic reaction. Cross aldolic reaction using preformed enamines. Retrosynthetic analysis of -hydroxycarbonyl and carbonyl compounds ,-isaturated carbonyls.
Claisen and Dieckmann condensation reactions. Claisen cross-condensation reaction. Retrosynthetic analysis of -ketoesters. Hydrolysis of -ketoesters and decarboxylation of -keto acids. Retrosynthetic analysis of ketones by intermediate formation of -ketoesters.
Structure of hemiaminals and enamines. Synthesis and hydrolysis of enamines. Reactivity of enamines: alkylation reaction, acylation reaction, hydrolysis of products. Retrosynthetic analysis of carbonyl, -dicarbonyl, 1,4-diketone and 4-ketoester compounds.
Acetoacetic synthesis. Retrosynthetic analysis of alkylated derivatives of -ketoesters and carbonyl compounds substituted on C with alkyl groups. Malonic synthesis. Retrosynthetic analysis of alkylated derivatives of malonic acid diester and carboxylic acids substituted on C with alkyl groups.
Conjugate additions. Michael's addition of stabilized enolate anions and enamines. Nucleophiles and acceptors that can be used in the Michael addition reaction. Addition 1,4 vs addition 1,2 on carbonyl compounds ,-unsaturated. Retrosynthetic analysis of 1,5-dicarbonyl compounds, 1,5-ketonitriles, 1,4-nitroketones, derivatives of 1,3-dicarbonyls, ketones, carboxylic acids and -ketonitriles.
Robinson's anellation reaction. Retrosynthetic analysis of cyclohexenones.
Synthesis of lithium diorganocuprates. Conjugate addition of lithium diorganocuprates. Retrosynthetic analysis of carbonyl derivatives.
LDA. Synthesis and structure of LDA. pKa of diisopropylamine, butane, ketones and simple esters. Aldol and Claisen cross reactions using LDA-generated enolates. Reactions of lithium enolates. Regioselectivity of the enolization reaction of non-symmetric ketones with LDA, kinetic control and thermodynamic control.
Cycloaddition and cyclization reactions: definition. Diels-Alder cycloaddition reaction: reactants, products, mechanism and its rationalization by frontier molecular orbital analysis, aspects of stereospecificity and endo/eso diastereoselectivity. Retrosynthetic analysis of cyclohexene derivatives.
Part III:
Carbohydrates: structure, biosynthesis, classification, and nomenclature. Stereochemistry.
Structure representation of linear monosaccharides: three-dimensional structure with the "zig-zag" chain, Fischer projection. Relative and absolute configuration. D and L configuration. R/S descriptors. Stereoisomers: enantiomers, diastereoisomers, epimers. Structure of D-series aldoses. Ketoses and amino sugars. Hemiacetals and acetals: structure, mechanism of formation and hydrolysis. Cyclic forms of monosaccharides: mechanism of formation. Three-dimensional structure representations: chair conformation. Haworth projection. Anomers and anomeric carbon. Mutarotation. Anomeric effect.
Common monosaccharides: representations of both open and cyclic, three-dimensional structures with the "zig,zag" chain, chair conformation, Fisher projection and Haworth projection: D- and L-glyceraldehyde, ribose, 2-deoxyribose, arabinose, glucose, mannose, galactose, fructose, glucosamine, mannosamine, galactosamine, N-acetyl-glucosamine
Carbohydrate reactions: esterification, heterification, glycosides, N-glycosides and disaccharides, reduction of aldoses to alditols with NaBH4, oxidation to aldonic acids (Tollens' reagent; Br2/CaCO3/H2O), oxidation to uronic acids, oxidative cleavage with periodic acid. Reducing sugars and nonreducing sugars. Glycosides, glycosidic bonding, aglycone, N-glycosides. Hydrolysis of glycosides. Disaccharides and polysaccharides: maltose, cellobiose, lactose, sucrose, starch (amylose and amylopectin), glycogen, cellulose.
Lipids: definition and classification. Saturated and unsaturated fatty acids. Triglycerides: fats and oils. Saponification reaction. Name and structure of some common fatty acids: palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and arachidonic acid. Omega-3 and omega-6 essential fatty acids. Hardening process of oils. Waxes. Soaps and detergents (natural and synthetic, anionic, cationic, neutral). Phospholipids. Glycerophospholipids, phosphatidic acid, phosphatidylethanolamine, phosphatidylserine. Phospholipids and cell membranes. Prostaglandins. Prostanoic acid. Biotransformation of arachidonic acid into prostaglandins (CENNI). Steroids: structure. Cholesterol. Major classes of steroid hormones. Bile acids: structure. Cholic acid. Fat-soluble vitamins. Vitamin A. Cycle of vision.-Carotene, vitamin A (retinol), retinal.
Amino acids. Proteinogenic amino acids. Acid-base properties: zwitterion and physical properties. Chirality and absolute configuration. Three-dimensional writing and Fischer projection. Classification according to side chain and acid-base properties. Name, three-letter code, and structure of the 20 proteinogenic -amino acids. Determination of pKa values by titration. Isoelectric point. Prevalent forms at acidic, neutral, basic pH, at isoelectric point and at pH=pKa). Electrophoresis. Ninhydrin as an amino acid detector.
Proteins: classification (simple, conjugated, fibrous, globular). Peptides and proteins: primary structure. Peptide binding. 'Zig-zag' chain writing of dipeptides, tripeptides etc. Composition analysis of a polypeptide: acid hydrolysis, ion exchange chromatographic analysis and ninhydrin detection. Analysis of the amino acid sequence of a polypeptide: cyanogen bromide (BrCN, cleavage of the peptide bond formed by the CO2H of methionine, NO MECHANISM); Edman degradation: selective cleavage of the N-terminal amino acid (NO MECHANISM); enzymatic hydrolysis (NO DETAILS).
Formation of amides with dicyclohexylcarbodiimide (DCC). Peptide synthesis: strategies. Amine group protecting groups, carbamates: Cbz (or Z) and BOC, properties, synthesis, and removal methods. Carboxyl group protecting groups (methyl and benzyl esters, synthesis, hydrolysis or hydrogenolysis). Peptide bond formation with DCC. Merrifield resin. Synthesis on solid phase of Merrifield.
Three-dimensional structure of peptides and proteins: peptide bond geometry. Relative geometry of adjacent peptide bonds. Peptides and proteins: primary structure, secondary structure, tertiary structure, and quaternary structure. Bonds and forces that stabilize protein structure: disulfide bond, hydrogen bridge bond, salt bridges, hydrophilic and hydrophobic interactions. Denaturation of proteins.
Nucleic acids DNA and RNA. Nitrogenous bases, nucleosides, and nucleotides (mono-, di- and tri-phosphate nucleosides): structure and names. D-ribose, 2-deoxy-D-ribose, purine, adenine, adenosine, AMP, dAMP, ADP and ATP, guanine, guanosine, GMP and dGMP, pyrimidine, uracil, uridine, UMP, cytosine, cytidine, CMP and dCMP, thymine, thymidine, TMP. DNA: primary structure (dinucleotide, trinucleotide, etc, and strand section), secondary structure (double helix model) and tertiary structure (supercoiling). DNA replication. RNA: structure, classification (ribosomal RNA, transfer RNA and messenger RNA) and their functions. Transcription. Genetic code and Translation (codon and anticodon). Protein biosynthesis.