66288 - Methods of Synthesis and Characterization

Learning outcomes

At the end of the course, the student is able to choose the method best suited for the formation of carbon-carbon bonds using organometallic compounds (prepared in advance or generated in situ), with maximum control of regioselectivity, chemoselectivity and stereoselectivity. The students will be also mastering fundamental heterocyclic chemistry and will be able to design synthesis of biological active molecules containing heterocyclic compounds. The student is also able to analyze mono- NMR spectra and two-dimensional for the elucidation of molecules of complex structures.

Course contents

Chapter 1. Organic lithium. Use and reactivity. Safety and preparation procedures. Synthesis methodologies. Titrations. Use of activating groups and directing groups. Additives. Magnesium derivatives functionalized. Preparation. Knochel procedures. TurboGrignard. Use of LiCl.

Exercises: synthesis and use of organic lithium in pharmaceutical compounds, heterocycles and total syntheses.

Chapter 2. Zinc derivatives. Zinc derivative reactions and preparation. Dialkyl zinc derivatives. Synthesis and properties. Allilzinco. Insertion of zinc derivatives and preparation of intermediates. Knochel procedures.

Use of zinc derivatives in synthesis of natural products. Allyl zinc reactions and stereochemical control. Listing on heterocycles. Examples of synthesis drugs, intermediates and natural compounds.

Chapter 3. Preparation and properties of organotitanium. Structures and use of reagents. Ate complexes. Titanium homogenates. Diastereoselective reactions. Cram Rules, Chelated Cram, Felkin. Use of titanium complexes in diastereoselective synthesis. MacMurry type olefination and coupling reagents. Catalytic redox reactions. Examples with titanium. Stereoselective pinacolinic coupling reaction. Titanium enolates. Stereoselection rules. Evans type auxiliaries. Aldolo Evans and Non Evans. Applications. Organozirconio. Hydrozirconation reaction. Use in summary. Various organozirconium reactions. Polymerization reactions.

Examples of applications of titanium and zirconium reagents in synthesis of natural substances. Control of diastereo and enantioselectivity.

Chapter 4 Organorames and cuprates. Synthesis and preparation. Copper salts. Cuprate reactions. Mixed cuprates. Cyan cuprates with low and high order. Conjugated reactions. Transmetallation reactions. Tin and silica reagents. Use of Grignard. Use of catalytic quantities of copper salts. Zinc cuprati. Examples of other organometallic reagents. Catalysis with copper.

Use of cuprates in the synthesis, particularly in the synthesis of heterocyclic compounds.

Chapter 5. Catalytic addition of organozinc. Binders. Catalytic system. Use of amino alcohols. Titanium isopropoxide present. Organotitanio. Additions of double bonds. Addition of aryl derivatives. Alkinilzinco derivatives. Additions to ketone and imine. Michael's reactions with organometallic compounds. Copper hydride compounds. Selective reductions of imines, carbonyls, and Michael-like reactions.

Chapter 6. Other organometallic reagents. Introduction to the chemistry of Organocromo, Organomanganese, Organoindio and organosamario.

Chapter 7. The Mukaiyama reaction and acid catalyzed reactions. Mechanism and structure of transition states. Diastereoselective reactions. Check of anti selectivity. Diastereoselective reaction. Transitional states. Chelated and non-chelated. Examples in complex synthesis applications.

Chapter 8. heterocycles.

Synthesis and properties of main heterocyclic systems (pyrrole, thiophene, furan, pyridine, indole). Main reactions and behavior of heterocyclic systems. Applications of heterocyclic reactions to the synthesis of drugs containing heterocyclic systems. Retrosynthetic approaches and applications.

Characterization module.

Program

Program / content:

Classroom lessons: 1. Summary of basic concepts of 1H and 13C one-dimensional NMR spectroscopy. 2. Two-dimensional NMR techniques most commonly used (COZY, HSQC, HMBC, NOESY): theoretical outline, execution and interpretation. 3. Most commonly used two-dimensional NMR techniques (COZY, HSQC, HMBC, NOESY): theoretical outline, execution and interpretation.3. Application of these techniques to a practical example. 4. Outline of the most up-to-date NMR techniques (TOCSY, DOSY, gradient techniques. 5. Exercises in the computer lab (each student has a PC available to work individually):
Processing of a complete set of NMR spectra via Spinwork software (free download)
Determination of the structure and conformation of a medium complexity molecule

Readings/Bibliography

course PDF (teacher's notes) uploaded to the teaching materials and available.

Characterization Part: Classroom lessons (8 hours in November): Exercises in the computer lab (5 afternoons in December), compulsory attendance at the exercises with signature collection

Teaching methods

Part of Synthesis Methodologies: Powerpoint presentations of lessons with slides available to students

Characterization Part:

-Powerpoint presentations of classroom lessons provided the day before the lesson

-NR specters studied in the laboratory supplied as files at the end of the exercises

Assessment methods

The exam is divided into two parts: part of methodologies and part of characterization.
The final mark is the average of the marks obtained in the two single exams.

Part of Synthesis Methodologies: Written exam lasting 90 minutes.

4 Questions chosen by the teacher (4 x 3 points) = 12 points. 2 exercises (1 non-heterocyclic part, 1 heterocyclic part) x 6 points = 12 points. Starting score 10 points. Marks for praise: 32 points.


Characterization Part:

Written exam lasting two hours. The set of NMR spectra of a molecule with a known structure is provided and a complete interpretation of all analyzes is required.

Teaching tools

Course slides and contents provided by the teacher. Exercises and examples carried out in the classroom. Recommended texts for the characterization course: 1) R.M. Silverstein; F.X. Webster; D. J. Kiemle; D.L. Bryce "Spectrometric identification of organic compounds", Ambrosiana Publishing House 2) A. Randazzo "Practical Guide to the Interpretation of NMR Spectra", Publisher Loghia

Office hours

See the website of Pier Giorgio Cozzi

See the website of Alessandra Tolomelli