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.
The methods developed in class will be applied to the resolution of problems of synthesis of complex organic molecules, mainly drugs or biologically active compounds. It is strongly recommended that you follow the lessons and exercises.

Characterization module.

Important!

In consideration of the type of activity and teaching methods adopted, the attendance of this training activity requires the prior participation of all students in the training modules 1 and 2 on safety in the study places, [https: //elearning-sicurezza.unibo .it /] in e-learning mode

Characterization Module Program:

1. Classroom Lectures: - Summary of the basic concepts of one-dimensional 1H and 13C NMR spectroscopy. - Most commonly used two-dimensional NMR techniques (COSY, HSQC, HMBC, NOESY): theoretical overview, execution, and interpretation. - Application of these techniques to a practical example. - More up-to-date NMR techniques (TOCSY, DOSY, gradient techniques).

2. Computer lab exercises (4 mornings, each student has a PC available for individual work): - Each day, a different complete set of NMR spectra will be processed and shared with the class using Spinwork software (free download). - Determination of the structure and conformation of molecules of increasing complexity.

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 written and consists of two separate parts, which students can take at their discretion and convenience. The number of exam sessions and the lack of courses in the fourth semester favor this approach. The exam for the characterization module aims to assess knowledge of the interpretation of NMR analyses of complex substances, using advanced techniques that can help assign the structure of an unknown compound. The second module, on methodologies, requires knowledge of the synthetic methods developed in class, through examples and discussion. The written exam also requires the application of the methods discussed in class to two exercises selected from the literature on organic synthesis applied to fine chemicals and large-scale production, and close to industrial practice. The following marks are assigned for the exam evaluation for the methodologies component.

5 questions (5 x 4 points). 2 exercises (1 non-heterocyclic part, 1 heterocyclic part) x 5 points. Starting score: 4 points. Grades for honors: 32 points.

The grade is composed of the scores for the two parts in equal proportions. Honors is awarded if the student achieves a grade of 30 cum laude in at least one of the two exams. The written exam for both parts covers the syllabus and assesses the skills and abilities acquired. During the Methodologies course, numerous exercises are discussed and solved by the instructor, encouraging participation and selecting examples from modern industrial molecular synthesis practices.

If the assignment is rated as insufficient, this is due to gaps in the course content; serious gaps in basic chemical knowledge; insufficient development of the proposed synthesis problems; lack of orientation within the topics covered in the course; incorrect interpretation of NMR analyses. If the assignment is rated as sufficient: The assignment has received a sufficient score, but there are still gaps in knowledge or topics that have not been covered. For the characterization module, the assignment only reports the signal assignment without any further study. If the assignment is rated as good, the student has achieved a good understanding of the course content and a good rote knowledge of the subject matter; the student has also successfully addressed and solved the proposed problems, with minor errors. For the characterization module, the assignment reports the signal assignment and the discussion is complete.

An Excellent student, in addition to their skills, is able to present solutions to the proposed problems that are similar or similar to those published by industry researchers. The student has acquired a clear and comprehensive understanding of the topics, a high level of skill in using the various organic synthesis techniques, and broad expertise. For the characterization module, the assignment includes signal assignment, the discussion is comprehensive, and the techniques explored are discussed, demonstrating a strong ability to combine the information provided. N.B. Basic knowledge of organic chemistry is required to properly understand the topics. The time required for the written exam is 1 hour and 30 minutes for both modules. 

Students with learning disabilities (LD) or temporary or permanent disabilities: please contact the relevant University office promptly (https://site.unibo.it/studenti-con-disabilita-e-dsa/it). They will be responsible for suggesting any accommodations to the students concerned. However, these accommodations must be submitted to the instructor for approval 15 days in advance, who will evaluate their suitability also in relation to the educational objectives of the course.

 

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