Heterocyclic Chemistry Course

• 3A-CHI552 is the course code.
• The course is titled Heterocyclic Chemistry.
• Organisation of the course contains 4 lessons in advanced heterocyclic chemistry by Dr. Samir Messaoudi, and 5 lessons in advanced organometallic chemistry by Dr. Sophie Carenco.

Course Objectives for Heterocyclic Chemistry

• Develop knowledge on important heterocyclic families and their preparation and reactivity.
• Learn to name heterocycles.
• Understand reactivity trends in aromatic heterocycles.
• Focus on synthetic approaches.
• Study medicinal and agrochemical applications.

Course Organization

• There are 4 lessons, each 2 hours long.
• There are 4 exercice sessions, each of 2 hours.
• Evaluation takes place at the end of the course.
• Basic organic chemistry (CHI421) knowledge is assumed.

Recommended Reading

• Heterocyclic Chemistry by J. A. Joule, K. Mills, and G. F. Smith
• Heterocyclic Chemistry (Oxford Primer Series) by T. Gilchrist
• Aromatic Heterocyclic Chemistry by D. T. Davies

Course summary

• Introduction: including Why are heterocycles so important? Definition of terms and classification of heterocycles (monocyclic and fused heterocycles, aromatics and non-aromatics, saturated and unsaturated...etc)
• Pyridines and derivatives
• Pyrroles, furans and thiophenes
• Indoles (and azaindoles)
• Access course documents (oral and slides) and PC (exercises and corrections)

Classification and Naming

• Covered in the course for: Aromatic Five-Membered, Aromatic Six-Membered, and Fused heterocycles

Introduction: why are heterocycles important?

• Medicine and Crop Protection: Many pharmaceuticals and agrochemicals contain at least one heterocyclic unit.
• Relatively stable compounds compatible with the gastrointestinal tract due to acid and enzymatic hydrolysis resistance.
• Pharmacokinetic optimization using acido-basic couples (AH+/A).
• Interaction with receptors via H bonds.
• Structures are similar to products in natural biological pathways such as indoles and pyrimidine.
• Easy to prepare and low cost.
• Key building bloks for materials with electronic properties
• Nucleic acids contain pyrimidines (T, U, C) and purines (A,G) which are heterocycles: these are in living systems, DNA and RNA
• Nucleic acids: RNA Vaccine
• The strategy for active RNA vaccine is Uridine to pseudouridine
• Tryptophan and histidine are in proteins

Top Drugs by Retail Sales in 2022 Containing Heterocycles

• Venclexta (Venetoclax): for Oncology
• Tagrisso (Osimertinib): for Oncology
• Tasigna (Nilotinib): for Hematology
• Farxiga (Dapagliflozin): for Diabetes
• Januvia (Sitagliptin): for Diabetes.
• Sandostatin (Octreotide): for Oncology.
• Lenvima (Lenvatinib): for Oncology.
• Juvederm (Hyaluronic Acid): for Dermatology.
• Xarelto (Rivaroxaban): for Cardiology/Vascular Diseases.
• Rexulti (Brexpiprazole): for Neurology

Naming Heterocycles

• Hantzsch-Widman system is used for monocyclic structures but in the right priority order
• Naming conventions proposed by Hantzsch (1887) and Widman (1888), extended in 1940 by Patterson and Campbell, adopted by IUPAC (1957) for Nitrogen cycles with 5 or 6 atoms
• Consists of a prefix (nature of heteroatom) and a suffix (size of the ring).
• Prefixes should be used to number the position of heteroatoms in the cycle
• Priority of heteroatoms: Oxygen, Sulphur, Selenium, Nitrogen, Phosphorus, Silicium, Bore
• Suppress the final "a" when the prefix is followed by a vowel

Suffixing Conventions

• Suffix depends on cycle length and saturation degree.
• "Ane" replaces certain suffixes directly after "ox," "thi," "selen" or "tellur."
• For aza + iridine = aziridine
• Partially saturated heterocycles are named using dihydro or tetrahydro prefixes.
• Numbering is used to differentiate structural isomers.
• When an aromatic ring tethers heterocycles, the prefix benzo is used before the heterocycle's name, indicating bond relationships with a letter, e.g., [x].
• When numbering, write the horizontal structure and number from the atom closest to the benzene ring.

Aromaticity and Huckel's Rule

• The course goes on to describe aromatic heterocycles following huckel's rule
• 6 π electrons, adhering to the formula 4n+2 =6, satisfy Hückel's rule for aromaticity

Aromatic Heterocycles

• Includes: Benzene, Pyrrole, Furan, Thiophene, Cyclopropenyl ion, Pyridine, Imidazole, Oxazole, Pyrimidine and Napthalene

Reactivity and Regiochemistry

• Mesomeric forms are often necessary to understand the reactivity
• Pyrrole, 2-pyridone and 4(γ)-pyrone are aromatic, the remainder of unsaturated heterocycles (i.e. 1,2-oxazol-5-one) are non aromatic

Pyrrole Molecular Orbitals

• Electron-rich heterocycle (reactivity close to dimethoxybenzenes)

Pyridine Molecular Orbitals

• Electron poor heterocycle (reactivity close to nitrobenzene)

Electron Pairs on N

• Pyridine: The electron pair is not shared with the π system.
• Pyrrole: The electron pair is conjugated and poorly available.

Basicity and Dipolar Strength

• Basicity/Dipolar Strengths (pKa, Debyes): Pyrrole (0.4, 1.8D), Pyridine (5.25, 2.2D), Pyrrolidine (11.27, 1.6D)
• Nitrogen's electron pair in pyridine interacts with electrophiles as well as nucleophiles

General Trends in Heterocycles

• Electron rich systems (σ attractors, π donnors)
• Electron poor systems (σ attractors, π attractors)
• The presence of more than one heteroatom

Heterocycle Aromaticity

• Determined by Dewar Resonance Energy (DRE).
• Positive DRE indicates aromaticity; zero DRE indicates non-aromaticity; negative DRE suggests anti-aromaticity.

General trends for heterocycles

• Pyridine: electron poor but highly stabilized: ex no reaction with NaBH4 (Cf pyridinium)
• Thiophene, pyrrole and most of all furan limited stability, easy electrophiles additions, Easy loss of aromaticity in furan reations.
• Stability of benzothiophene, indole and benzofuran linked to the benzo cycle, Nucleophilic behavior close to enamines, enols, thioethers...
• Pyrazoles, imidazoles...very stable.

General Strategies for Heterocycle Synthesis

• 5- and 6-membered rings are the easiest to form by cyclisation.
• Carbon-heteroatom bond formation requires heteroatom nucleophiles to react with carbon electrophiles.
• Unsaturation is achieved by elimination reactions such as dehydration or dehydrohalogenation.

Common strategies

• "4+1" Strategy: The strategy can be adapted to incorporate more than one heteroatom.
• "5+1" Strategy: Unsa1,5-Dicarbonyl compounds can be prepared by Michael addition of enones.
• "3+2” Strategy + "3+3" Strategy

Metalation

• Usefull and more difficult to control, Addition onto the heterocycle/deprotonation, LDA/nBuLi, Low temperatures to avoid homocoupling

Use of superbases (nBuLi+ROLI):

• The metalization of of electron poor heterocycles

Palladium Couplings (Heck, Suzuki, Stille, Sonogashira...)

• This is a very useful for useful access to functionalised heterocycles
• There are two traditional approaches: 1) Direct metallation with RLi followed by transmetallation. 2) Use of iodo, bromo heterocycles (by metallationor or else) followed by transmetallation.

More Recent Approaches:

• CH activation processes: a Pd(II) activation of a CH bond followed by Heck type addition or Arylation ( a Cooxydant necessary)

Palladium Cross-Coupling Reactions

• Limitation: organometallics R-M in a stoichiometric amount

Introduction to Pyridines and Quinolins

• Many FDA approved drugs used in pharma et agro

FDA Approved Drugs

• Isoniazide: An agent to treat tuberculosis
• Paraquat: One of the oldest herbicides (toxic and non-selective)

Natural Compounds

• Nicotine is pharmacologically active, a constituent of tobacco-toxic and addictive.
• Discusses nicotinamide adenine dinucleotide (NAD+/NADH)
• Describes Redox type Coenzymes (ternary complex formation)

Heterocyclic Synthesis

• Most important reactions of heterocycles are pyridines
• Hantzsch synthesis (“5+1 synthesis)
• From Enamines or Enamine Equivalents is the Guareschi synthesis ("3+3")

Reaction Topics

• N insertion + C deletion strategy
• Pyrdine and Pyridine Derivatives
• Electronwithdrawing and Donating Properties
• Isomer Properties

Pyridines Reactivity to Electrophiles

• Beta positions are most stable, resonance is favored
• Nitrogen is electron sink
• Aromaticisty is regained during a reaction through the loss of a hydride

Alkyl-Pyridies Reactivity

• This can be tuned with a Strong Base

PYRIDINES: Reactivity (N-Oxide)

• Nitrogen oxides differ considerably from the same reaction without the oxides
• It can used to be a temporarly switch to activate at a specific nucleophilic or electrophilic position

Questions about the core focus, assumed knowledge, and classification of heterocycles. Also covers applications and reaction mechanisms in heterocyclic chemistry.