Aromatic Heterocycles

Heterocycles Overview

• Heterocycles are cyclic compounds containing at least two different atom types in the ring structure.

• Key themes: synthesis, reactivity, and applications in drug development.

Definition of Heterocycles

• Isocyclic Compounds: Cyclic compounds composed of one type of atom.

• Heterocycles: Composed of at least two different atom types.

• Approximately 100 million registered chemical compounds; about 50% are heterocycles (Chemical Abstract Service - CAS, 2015).

Important Heterocycles

• Pyrrole, Furan, Thiophene, Imidazole, 1,2,3-triazole, Tetrazole, Pyridine, Pyrimidine, Indole, quinoline and Isoquinoline.

Known Compounds

• Lawsson's Reagenz: 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide.

• Various organic heterocycles like Pyridine, Oxazole, Epoxide, etc.

Heterocycles in Nature

• Carbohydrates:

  • β-D-Glucopyranose and β-D-2-Deoxyribofuranose are examples.

• Nucleotides and Nucleic Acids:

  • Components of DNA and RNA: Cytosine, Purine, Pyrimidine, etc.

• Amino Acids:

  • Examples include L-Histidine (Imidazole) and L-Tryptophan (Indole).

• Vitamins:

  • Vitamin B1, B6, B7, B9, B12 have heterocyclic structures that are crucial in biochemical reactions.

Heterocycles as Drugs

• Esomeprazole (Nexium®): Proton pump inhibitor used for ulcers.

• Atorvastatin (Lipitor®): Inhibitor for cholesterol regulation.

• Duloxetine (Cymbalta®): Antidepressant affecting serotonin and norepinephrine uptake.

• Oxicodon (Oxycontin®): Opioid pain reliever.

• Amoxicillin (Amoxypen®): β-lactam antibiotic.

• Cocaine: Tropane alkaloid functioning as a serotonin-norepinephrine reuptake inhibitor.

Heterocycles - Top 200 Drugs (2023)

• Leading drugs for various conditions like HIV, blood clots, and hormonal therapies identified.

• Anticoagulants: Reduce stroke risk in atrial fibrillation.

• Integrase Inhibitors: Block HIV replication.

Heterocycles in Industry and Research

• Key applications include dyes (indigo), semiconductors, and OLED technology.

• Indigo: Derived from plants (e.g., Indigofera tinctoria).

• Polythiophen and Polypyrrol: Important in fluorescent dyes.

Classification of Heterocycles

• Classification on basis of the type and number of heteroatoms

  • e.g. nitrogen-, oxygen- and sulfur-containing heterocycles.

• Classification on basis of the ring size

• Classification on basis of saturation

  • saturated, unsaturated and aromatic

Ring Strain in Heterocycles

• Ring strain varies with the size and composition of rings.

• 3- and 4-membered rings have similar strain values.

Epoxidation of Olefins

• Various methods for creating epoxides from olefins such as Sharpless and Jacobsen epoxidation.

• Catalysts play a crucial role in the efficiency and selectivity of these reactions.

Aflatoxins

When aflatoxin B1 (AFB1) reaches the liver, it undergoes two processes:

1. Activation (Toxic Pathway)

• Cytochrome P450 enzymes convert AFB1 into aflatoxin B1-8,9-epoxide, a highly toxic and carcinogenic compound.

• This epoxide:

  • Binds to DNA, causing mutations (e.g., in the p53 gene), which increase the risk of liver cancer.

  • Binds to proteins, disrupting liver function

  2. Detoxification (Protective Pathway)

• Glutathione S-transferase (GST) detoxifies the epoxide by binding it to glutathione, forming a water-soluble product excreted in bile/urine.

• AFB1 is also hydroxylated into less toxic forms like aflatoxin M1 (AFM1), excreted in urine or milk.

Oxetanes

• Oxetanes are four-membered cyclic ethers, consisting of three carbon atoms and one oxygen atom in a ring structure.

• The ring is highly strained due to its small size, making it reactive in various chemical transformations.

• Paclitaxel is a natural anti-cancer drug derived from the bark of the Pacific yew tree (Taxus brevifolia).

  • Targets microtubules, which are essential for cell division.

  • Uses: e.g. breast cancer

DNA Damage by UV Radiation

• UV radiation damages DNA primarily by inducing covalent bonds between adjacent pyrimidine bases (cytosine or thymine) on the same DNA strand.

  • Cyclobutane Pyrimidine Dimers (CPDs):

  • 6-4 Photoproducts (6-4 PPs):

• This leads to the formation of dipyrimidine photoproducts, which interfere with DNA replication and transcription.

Aromaticity in Five-Membered Rings

• Key Concepts:

  • Aromatic compounds include five-membered rings featuring atoms like oxygen (O), nitrogen (N), and sulfur (S).

  • Electronegativity leads to variances in aromaticity; for example, furan (least aromatic) is more reluctant to release electrons compared to pyrrole and thiophene.

  • Reactivity:

    • Pyrrole, furan, thiophene can react with electrophiles due to their electron density:

      • Pyrrole has a heat of formation of 88 kJ/mole, furan 67 kJ/mole, thiophene 122 kJ/mole.

5.1 Synthesis of Five-Membered Heterocycles

• Reagents and Processes:

  • Synthesis by using 1,4-dicarbonyl compounds together with one of the following reagents:

    • Ammonia (NH3)

    • Acid

    • Lawesson’s reagent

Achmatowicz Rearrangement from Furyl Alcohols

• Classical Mechanism:

  • Steps include:

    1. Use of Bromine (Br2) and Methanol (MeOH) to initiate the rearrangement.

    2. Followed by hydrochloric acid (H2SO4) in aqueous solution.

  • Modern Variants:

    • Use of mCPBA for oxidations leading to variants with carbamate protecting groups.

Pyrroles in Nature

• Biological Importance:

  • Pyrroles are integral to various biological molecules:

    • Cyanocobalamine: A form of Vitamin B12, essential for blood formation and brain health.

    • Bilirubin, Urobilin, Heme B: Critical in metabolism and physiological processes.

Pyrroles in Nature

• Medicinal Applications:

  • Netropsin serves as an antibiotic through binding to DNA minor grooves.

  • Pseudoalteromonas spp. produce hybrid antibiotics that hinder translation and transcription processes.

Pyrrole-Forming Reactions

• Synthesis Methods:

  • Knorr’s Pyrrole Synthesis

  • Hantzsch Reaction: Two-step synthesis involving various reactants leading to pyrrole formation.

Five-membered heterocycles

• Good nucleophiles

• Preferred reacting with electrophile at postion besides the nitrogen atom.

Pyrrole reactions

• Very reactive in electrophilic substitution reactions

• Reagents used:

  • Ac2O, Et3N

  • 1. DMF, POCl3

    2. Na2Co3, H2O

  • Me2NH, CH2O, HOAc

Indoles in Nature

• Key Compounds and Effects:

  • Psilocybin: A psychedelic compound from certain mushrooms.

  • Serotonin: A neurotransmitter involved in multiple physiological functions, derived from Tryptophan.

  • Bufotenin: A naturally occurring compound from the secretion of certain toads, associated with hallucinogenic properties.

Ehrlich‘s reagent for indole detection

• Ehrlich's reagent is a chemical test used to detect the presence of indoles.

• Composition: Ehrlich's reagent is typically made by dissolving p-dimethylaminobenzaldehyde (DMAB) in:

  • An acidic solution and Alcohol

• Mechanism: Indoles react with DMAB in the presence of acid to form a colored compound, usually red, purple, or blue.

• The reaction involves the condensation of the indole with DMAB to form a Schiff base.

Mechanisms in Indole Synthesis

• Bartoli Indole Synthesis:

  • Involves a vinyl Grignard reagent and then a acid work-up process to yield substituted indoles.

• Nenitzescu Indole Synthesis:

  • Highlights transformations involving substituted nitrogen groups and elaborate reagents causing indole formation.

Heterocyclic Carbenes

• Reactivity and Applications:

  • Typically act as nucleophiles; involved in various biochemical pathways like the Stetter Reagent reactions.

  • Importance in biochemistry exemplified by Thiamin diphosphate and its cofactor roles.

Triazoles as a Click Chemistry Approach

• Copper (I)-Catalyzed Cycloaddition

• Ruthenium(II) catalyzed cycloaddition

• Bioorthogonal Chemistry

Pyridines in Nature

• Notable Compounds:

  • Nicotine: Found in tobacco, exhibits paralyzing effects and insecticidal properties.

  • Pyridoxalphosphate (Vitamin B6): Vital cofactor for amino acid metabolism.

Pyridine Reactivity

• Unique Characteristics:

  • Reactivity inclined towards nucleophiles rather than electrophiles due to electron deficiency in pyridine

  • Pyridine is less reactive toward electrophiles due to the electron-withdrawing nature of nitrogen, which makes the aromatic ring electron-deficient. However, the nitrogen lone pair and electron-deficient carbons make it susceptible to reactions with nucleophiles.

Synthesis of Pyridine Derivatives

• Hantzsch Pyridine Synthesis:

  • Reaction involving diethylacetylene, ammonia, and other reagents yielding various pyridine derivatives.

  • Example: Synthesis of felodipine, highlighting a two-step reaction.

Pyridine Reactions

• Pyridine is utilized in reactions involving nitrogen:

  • Protonation: in acidic conditions

  • Methylation: with MeI

  • N-oxide: In H2O2 and HOAc

  • Chichibabin's Reaction: with NaNH2, 135 °C

  • Reduction: H2, Pt, H+

  • Phenyl addition: with PhLi, 35 °C

Pyridine-N-oxides

• Pyridine-N-oxides are reactive with electrophiles and nucleophiles

  • Reduction Agents: SmI2, SnCl2, Pd/NH4 + HCOO-, Ph3P, PCl3, P(OMe)3 for pyridine oxides.

Halogen Dance Mechanism

• The Halogen Dance Mechanism refers to a reaction where a halogen atom (e.g., Cl, Br, or I) on an aromatic or heteroaromatic ring migrates to a different position on the same ring. This reaction typically occurs under basic conditions and is often seen in polyhalogenated aromatic compounds.

Synthesis Using Halogen Dancing

• Deprotonation:

  • A strong base (e.g., LDA) removes a hydrogen atom from the aromatic ring at a position adjacent to a halogen, generating a carbanion (or a resonance-stabilized intermediate).

• Halogen Migration:

  • The carbanion undergoes a rearrangement where the halogen shifts from its original position to a more favorable one, typically influenced by electronic or steric factors.

• Reprotonation:

  • The intermediate is protonated, restoring aromaticity and forming the halogenated product with the halogen in a new position.

Halogen Dancing in a Thiazole

• Reactions carried out with LDA and Br2 yielding significant product formation.

  • Importance of lithiation at critical positions during the halogenation process.

Indocyanine Green (ICG)

• Use as a fluorescence dye approved for intravenous applications in:

  • Ophthalmology and Hepatology.

Synthesis of Cyanine Dyes

• Chemical structure and synthesis pathway illustrated for in-vivo fluorescence dyes.

  • Overview of various synthetic methods including the importance of NaO3S and AcOH.

Properties of Cyanine Dyes

• Emission and absorbance spectra detailed for non-sulfonated cyanine dyes:

  • Wavelength ranges: from 450 nm to 850 nm indicating key peaks in absorbance and emission.

In-vivo Imaging with Cyanine Fluorescent Dyes

• Reference to studies demonstrating utilizaing cyanine dyes for imaging (Ning et al., 2011).

NADP+/NADPH and NAD+/NADH Equivalents

• Discussion of coenzymes in biological systems outlining:

  • NAD+: cellular oxidation reagent.

  • NADPH: cellular reduction reagent.

Quinolines and Isoquinolines

• Natural substances from the Chinese tree Quinine shows an effectiveness against plasmodia (antimalaria medium).

• Quinidine is an antiarrythmic

• Cinchonidine acts from vegetative nervous system.

• Tubocurarine nerve poison, use as an arrow poison for hunting in indigenous of South America

Pyrimidines and Their Derivatives

• Pyrimidine nucleic acid bases (nucleotides):

  • Cytosine: A pyrimidine base found in DNA and RNA, pairing with guanine.

  • Thymine: A pyrimidine base exclusive to DNA, pairing with adenine.

  • Uracil: A pyrimidine base found in RNA, also pairing with adenine.

• Pyrimidine nucleic acid bases (nucleosides):

  • Cytidine

  • Thymidine

  • Uridine

• A nucleotide is a nucleoside carring a phosphare on the 5’ (or 3’) OH.

• RNA contains ribonucleotides, while DNA contains deoxyribosides.

DNA Base Pairing

• Explanation of complementary base pairing (A-T, G-C) and structural arrangement of nucleotides.

Synthesis of Theophylline and Caffeine

• Theophylline inhibits phosphodiesterase and blocks adenosine receptors.

• Theophylline treats chronic obstructive pulmonary disease (COPD) and asthma

• Coffeine is synthesised from Theophylline.

Rosetta Mission

The Rosetta Mission was a groundbreaking space mission by the European Space Agency (ESA) to study comet 67P/Churyumov-Gerasimenko. It provided valuable insights into the composition and behavior of comets, shedding light on the early solar system.

Prebiotic Formation Pathway

• Highlighting a study on regioselective formation pathways for purine nucleosides (Becker et al., 2016).

  • Emphasizes the importance in understanding the origin of life.