66214 - Organic Sythesis

Learning outcomes

After completing this course, students are able to plan a few hypotheses of total synthesis of an organic molecule by mainly adopting the retrosynthetic logic, and are able to compare them on the basis of a feasibility, economy and sustainability assessment. Students also aquire practice on a few modern experimental procedures in the field of multistep organic synthesis

Course contents

Prerequisites: to attend this course, student needs a good background in fundamental organic chemistry, including structural and mechanistic features, and structure-reactivity correlations. Moreover student must known the basics of natural organic compounds and master fundamental organic chemistry laboratory techniques such as to perform simple reactions, work-ups, and purifications

Program: as part of the broader theme of process innovation, acquiring the ability to design and carry out new, more efficient and sustainable syntheses of organic compounds is a priority in the training of a modern chemist. The course is divided into two teaching units: 1) a theoretical unit; 2) a laboratory unit

Contents, concepts and theory.

1. Introduction. Nobel Recipients and Masters in synthetic organic chemistry.

a) Synthetic glossary: linear vs convergent syntheses, total yield, economic, safety and environmental factors in the assessment of a chemical process.

b) Carbon-cabon bond forming reactions, intermolecular reactions, cyclization and annulation reactions, and rearrangements.

c) Functionl group interconversions: functionality level, review of the most common refunctionalization techniques.

d) Extrasteps: separations and purifications, introduction of temporary control elements, protective groups, mobile activating groups, chiral auxiliaries.

2. Retrosynthetic analysis: glossary, three levels of retrosynthetic analysis, strategic bonds disconnection, synthons.

a) Symmetry elements as a guideline to the identification of strategic disconnections.

b) Repeated structural units as a guideline to the identification of strategic disconnections.

c) Substructure search of possible available starting materials as a guideline to the identification of strategic disconnections.

d) Strategic bond analysis in alkanes and monofunctional target molecules: functional group (FG)-strategic bond correlation tables for alkanes, alkenes, alkynes, alcohols and their derivatives, carbonyl compounds and their derivatives, carboxylic acids and their derivatives.

3. Retrosynthetic analysis of polyfunctional molecules. Span between functional groups (functionality span, FS), and FS-strategic bond disconnection correlation tables.

a) Oxygen or nitrogen containing FGs. Two functional groups with FS = 2, 3, 4 or 5.

b) Dienes, diynes and enynes. Two functional groups with FS = 2, 3, 4 or 5.

c) Compounds with an oxygen-containing group and a C=C multiple bond with FS = 2, 3, 4 or 5.

d) How to use two groups FS-strategic bond correlation tables in the case of a polyfunctional target.

4. Retrosynthetic analysis of a chiral target molecule.

a) In-depth survey of stereochemical features of complex chiral molecules.

b) Resolution techniques of enantiomers, kinetic and dynamic kinetic resolution.

c) How to exploit the "wrong" enantiomer.

d) Defensive strategies in the synthesis design of chiral target molecules by using starting materials deriving from the chiral pool of natural products.

e) Chiral auxiliary strategy.

f) Offensive strategies in the synthesis design of chiral target molecules: asymmetric induction, chiral reagents, asymmetric catalysis.

5. Retrosynthetic analysis of a cyclic target molecule.

a) Cyclization reactions leading to homo- and heterocyclic molecules.

b) Main annulation classes [1+2], [2+2], [3+2] and [4+2].

6. Practicing retrosynthetic analysis of complex organic molecules

Lab contents:

1. In-class discussion of the mechanism and application examples of cross-coupling reactions. Laboratory execution of a Sonogashira reaction.

2. In-class discussion of the mechanism and application examples of organocatalyzed reactions. Laboratory execution of a stereoselective Michael reaction.

3. In-class discussion of the mechanism and application examples of olefin metathesis. Laboratory execution of the total synthesis of a drug via a multi-step process that includes a ring-closing metathesis.

As part of the practical activities, students will acquire basic skills for carrying out organic reactions and will apply techniques such as synthesis under inert gas, enzymatic synthesis, and various chromatographic and spectroscopic methods for the isolation and characterization of organic molecules.

Readings/Bibliography

The slides presented during lectures, along with procedures and reference literature for the laboratory activities, are available for download on Virtuale.

For further study, the following readings are recommended:

• K. C. Nicolaou, E. J. Jorgensen, "Classics in Total Synthesis", VCH
• K. C. Nicolaou, S. A. Snyder, "Classics in Total Synthesis II", Wiley-VCH
• M. B. Smith, "Organic Synthesis", McGraw Hills-Chemistry Book
• S. Warren, "Organic Synthesis: The Disconnection Approach", Wiley
• P. Wyatt, S. Warren, "Organic Synthesis: Strategy and Control", Wiley
• C. Willis, M. Wills, "Organic Synthesis", Oxford Chemistry Primers N. 31
• G.D. Meakins, "Functional Groups: Characteristics and Interconversions", Oxford Chemistry Primers N. 35

Teaching methods

The course is divided into two teaching units:

1) theoretical unit, taught by Prof. Marco Lombardo through in-person classroom lectures, accompanied by exercises on the application of the concepts presented and on retrosynthetic logic, with the goal of training students in the design of multi-step organic syntheses.

2) Laboratory unit. To ensure the effective delivery of the laboratory unit, students will be divided into two groups, which will carry out the activities separately:

GROUP 1 (Prof. A. Tolomelli): classroom lectures (8 hours in November) + laboratory activities (24 hours in December).

GROUP 2 (Prof. A. Quintavalla): classroom lectures (8 hours in December) + laboratory activities (24 hours in January).

The laboratory unit aims to experimentally explore some of the most modern synthetic methodologies.

Given the nature of the activities and the teaching methods adopted, participation in this course requires all students to complete Modules 1 and 2 in e-learning mode and attend Module 3, which provides specific training on health and safety in learning environments. Information on dates and attendance procedures for Module 3 can be found in the dedicated section of the degree program website.

Assessment methods

Assessment Methods

Learning is assessed solely through a final exam, which verifies the acquisition of the expected knowledge and skills in the synthesis of organic molecules. The exam consists of a written test, lasting 1.5 hours, without the aid of notes, textbooks, or electronic devices, followed by an oral exam. Both parts focus on the retrosynthetic analysis of an organic molecule. In order to be admitted to the oral exam, the student must achieve a minimum score of 18 points on the written test. The final grade is calculated as the arithmetic average of the grades obtained in the written and oral parts. 

Exam Evaluation Criteria and Grade Breakdown

Given an organic molecule of medium structural complexity, the written test includes the following exercises:

• Identification of functional groups and assessment of their level of functionality (5 points)

• Determination of the configuration of stereochemical elements (5 points)

• Evaluation of the spatial distance between functional groups (5 points)

• Retrosynthetic analysis and identification of selected synthetic steps (15 points)

The oral exam, lasting approximately 20–30 minutes, focuses on the retrosynthetic analysis of a medium-complexity organic molecule and includes a question related to the topics covered in the laboratory teaching unit.

Grading Scale

• Grade 18–24:
  The student demonstrates knowledge of a limited number of topics covered in the course, with only a partial understanding of retrosynthetic principles and an analytical ability that emerges only with the instructor’s guidance. The approach to evaluating synthetic strategies is underdeveloped or contains conceptual errors. The use of subject-specific terminology is generally correct, but not always precise.

• Grade 25–29:
  The student demonstrates a good command of a broad range of topics, and is able to independently apply retrosynthetic principles, critically evaluating synthetic strategies in terms of feasibility, practicality, cost-effectiveness, and sustainability. The use of chemical terminology is appropriate and consistent. The student has acquired solid knowledge of key modern experimental techniques and can relate them to relevant applications.

• Grade 30–30 cum laude:
  The student demonstrates comprehensive and in-depth knowledge of all course topics, with full mastery of retrosynthetic planning and methodologies for designing a total synthesis. They are able to make independent, well-reasoned, and critical decisions, thoughtfully evaluating all relevant parameters (practicality, sustainability, cost, feasibility). The use of scientific terminology is precise and sophisticated, and the student shows strong argumentation skills, personal insight, and critical integration of experimental techniques.

Students with Specific Learning Disorders (SLD) or Disabilities

Please, contact the office responsible (https://site.unibo.it/studenti-con-disabilita-e-dsa/en/for-students) as soon as possible so that they can propose acceptable adjustments. The request for adaptation must be submitted in advance (15 days before the exam date) to the lecturer, who will assess the appropriateness of the adjustments, taking into account the teaching objectives.

Teaching tools

Lectures are delivered in the classroom with multimedia support. The slides used during lectures are available to students on Virtuale. For the laboratory activities, students make use of reference scientific literature and procedures available on Virtuale. Experimental data collected by students during the laboratory sessions are uploaded and made available on Virtuale so that students can analyze and compare them.

Office hours:

See the website of Marco Lombardo
See the website of Alessandra Tolomelli
See the website of Arianna Quintavalla

Office hours

See the website of Marco Lombardo

See the website of Alessandra Tolomelli

See the website of Arianna Quintavalla