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.