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Nitrogen Heterocycles: Versatile Building Blocks Shaping Industries– MSE Supplies LLC

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Nitrogen Heterocycles: Versatile Building Blocks Shaping Industries

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In the previous blog, we provided an introduction to how heterocyclic chemistry is and the detailed general uses that heterocyclic compounds have. Today, we shift our focus to a specific subset of this fascinating discipline: N-containing heterocyclic small molecules. These compounds are defined by their nitrogen-containing ring structures and are widely known to be involved in a variety of scientific and industrial processes.
Starting from drugs and polymers through agrochemicals and dyes up to corrosion inhibitors and catalysts, nitrogen heterocycles can be applied effectively. In this blog post, let us explore these for various uses and suggest a unique purpose for each of them that will show how these small but powerful molecules are revolutionizing different fields.

Applications of N-Heterocyclic Small Molecules

Nitrogen Heterocycles as Drugs

Nitrogen-containing heterocycles are among the most prominent structural entities in pharmaceuticals. An analysis of U.S. FDA-approved drugs reveals that 59% of small-molecule drugs incorporate nitrogen heterocycles, underscoring their significance in drug design and development. These compounds include piperazine, morphinan, cepham, penam, and phenothiazine moieties, each contributing distinct biological activities.
A broad range of nitrogen heterocycles has been synthesized, showcasing diverse biological activities. These molecules are critical in drug design due to their structural variability, which allows for the fine-tuning of biological properties. For example, pyrido-benzothiazine derivatives exhibit potent antibacterial activity. Rufluoxacin, a fluoro-substituted derivative, demonstrates in vivo efficacy comparable to ofloxacin and ciprofloxacin, while methyl and pyrido-substituted variants achieve better absorption and stable plasma and urinary levels.
Similarly, structural modifications of thiazines, including N-methyl and N-acetyl piperazine derivatives, show significant antifungal activity against P. Marneffei and A. Niger. Substituting the 2,4-dichlorophenyl group in ketoconazole with a benzothiazine moiety results in improved antifungal activity, particularly in its trans analog. Moreover, benzothiazine derivatives with a (1-piperazinyl-4-phenyl) alkyl moiety at the 2-position exhibit strong antihypertensive activity, highlighting their potential as cardiovascular agents that interact with calcium channels.
Amino propyl derivatives of nitrogen heterocycles have emerged as a new class of anti-inflammatory agents. However, acetyl derivatives tend to be less effective than their precursors. Certain methyl and chloro-substituted benzothiazines linked with a pyrazine moiety have shown potential as neuroleptics. Novel methotrexate derivatives have been evaluated for anti-rheumatic activity, promising safer analogs without side effects.

Nitrogen Heterocycles as Polymers

Nitrogen heterocycles' ability to bond with metals, act as ligands, and engage in hydrogen bonding with proteins and drugs makes them valuable for creating multifunctional polymers with diverse applications. For instance, hydrogels derived from polymerized methylimidazolium-based ionic liquids self-assemble into structured lamellae with distinct swelling properties, offering promising bioactive applications.
Nitrogen heterocycles like imidazoles serve as precursors for various polymers. Vinyl-substituted imidazoles can bond with cobalt oxygen carriers, forming reversible oxygen-binding polymer membranes for oxygen transport. N-methyl pyrrole-containing heterocycles have been synthesized for sequence-specific DNA alkylation.
Symmetrical azine-based polymers have been evaluated for their photoelectrical, optical, and thermal properties, making nitrogen heterocycles a major class of electroactive polymers. Exposing these materials to specific electrolyte solutions results in ionic and electronic activity, suitable for applications like cosmetic hair conditioners, where low molecular weight piperazine-based film-forming cationic polymers are used.
Polypyrroles, biocompatible materials that cause minimal disturbance to their environment, have shown promise in forming miniature electrochemical immunosensors. These polymers are ideal for biosensors due to their compatibility and ease of immobilization. Polypyrrole-based stimulus-responsive biopolymers are used in chemical sensor technology as molecularly imprinted polymers, exhibiting molecular recognition properties with high-affinity constants comparable to naturally occurring recognition systems like antibodies.
In electrochemical detection, conducting polymers associated with bio-affinity reagents provides a desirable route for extending their use. Polyazines containing polypyrrole moieties are considered high-performance ambipolar semiconductors in organic thin-film transistors, used in logic circuits due to their environmental stability, architectural flexibility, solubility, and high optical absorption.
Polyazoles are used to synthesize polymer membranes and films with improved mechanical properties and retention above 100ºC. Acid-doped polymer membranes based on polyazoles find applications in fuel cells, battery systems, and capacitors. Polypyridine complexes, used in luminescent transition-metal complexes, have cellular and biological applications, serving as phototherapeutic agents and bioimaging reagents.
Organic photovoltaics benefit from azine-based π-conjugated polymers, promising semiconductors for electronics. A newly synthesized azine-based polymer, PDDBTA, acts as a donor in organic photovoltaics and a p-type semiconductor channel in organic thin-film transistors, highlighting the potential of azine-based polymers as cost-effective organic semiconductors.
N-based heterocycles are significant energetic materials, storing high energy derived from decomposition and forming gaseous by-products. High-nitrogen compounds like triazines, tetrazines, triazoles, and tetrazoles provide stable energetic backbones for propellants and payloads, with modifications enhancing their nitrogen content and heat of formation.

Nitrogen Heterocycles as Agrochemicals

Nitrogen heterocycles play a pivotal role in modern agrochemicals, constituting the backbone of many crop protection agents. Over 70% of introduced agrochemicals feature heterocyclic structures containing nitrogen atoms. These compounds are integral to the synthesis of advanced fungicides, herbicides, and insecticides, enhancing crop protection significantly.

Key Agrochemicals:

  • Fungicides:
    • Boscalid: Utilized for its broad-spectrum activity against various fungal pathogens.
    • Fludioxonil: Known for its efficacy in controlling fungal diseases in crops.
    • Benomyl: A systemic fungicide effective against a range of fungal diseases.
  • Herbicides:
    • Pinoxaden: Effective in reducing grass weed growth in cereals.
    • Bixafen: Exhibits significant activity against cereal diseases.
  • Insecticides:
    • Indoxacarb: Targets Lepidoptera in fruits, vegetables, and cotton.

Structural Design and Optimization:

  • Structure-based design: This approach has become essential in crop protection research, leveraging virtual screening methods to find better analogs.
  • Template usage: For example, flupropacil and imadapyracil templates have led to the discovery of novel fungicidal and herbicidal agents, such as triazoylpyridines and phenylpyridadinones.
  • Structural modifications: Adjusting the core heterocyclic structure, such as replacing a 1,3,5-triazine nucleus with a pyrimidine nucleus, has yielded promising results in enhancing fungicidal and herbicidal activities.
Innovations and Advancements:
  • N-butylated pyridines: These have emerged as leads in synthesizing potent fungicides.
  • 1,2,4-triazole ring derivatives: Notable for their enhanced fungicidal activity.
  • Trifluoromethoxy group incorporation: This addition to various heterocycles, such as pyrimidines and quinolines, significantly boosts their biological activity.
  • Novel compounds: Heteroaryl azoles and their N-oxides, 2-amino-5-trifluoromethoxy benzothiazole, and thiazolo-5-carboxylic acid are noteworthy for their fungicidal properties.
  • Nano-sizing: Enhancing the fungicidal activity of compounds like 1,3,4-thiadiazole derivatives through nano-sizing has proven highly effective.
Insecticidal Compounds:
  • General formula: Insecticidal nitrogen-bearing compounds often feature a 6/5 membered heteroaryl group containing nitrogen, oxygen, or sulfur.
  • Sulfanyl derivatives: Thiadiazoles synthesized for their phytopathogenic fungi activity, when nanosized, show significantly higher efficacy.

Nitrogen Heterocycles as Dyes

Nitrogen-containing heterocycles are crucial in dye chemistry, utilized in traditional dyes and advanced applications like fluorescent probes, solar cells, and optoelectronics. They are significant in various industries, including textiles, pharmaceuticals, cosmetics, and food coloring.

  • Textile and Industrial Dyes:
    • Pyrroloids (Basic Yellow): Used extensively in paper dyeing, inkjet printing, and textile dyeing.
    • Benzoindolium derivatives: Known for their fluorescent properties and commercial usage.
  • Solar Cells and Optoelectronics:
    • Indolenes: Used in dye-sensitized solar cells with a power conversion efficiency of about 3.0%.
    • Carbazoles: Evaluated for use in solar cells and other innovative applications.
  • Fluorescent Probes:
    • Hemicyanine-coumarin hybrids: Useful for bioanalytical applications due to their fluorescence.
    • Squarylium dyes: Noted for water solubility and photostability.
  • Specialized Dyes:
    • Imidazole derivatives: Used in UV absorbers and fluorescent probes for cyanide detection.
    • Pyridine and Pyrazine rings: Utilized in various chromogenically interesting architectures and organic light-emitting diodes.
  • Environmental and Analytical Chemistry:
    • Phenolic dipyrrole: Acts as a chromogenic probe for water determination in organic solvents.
    • Quinoxaline derivatives: Employed in polymerization sensitizers and as fluorophores for organic electronics.

Nitrogen Heterocycles as Corrosion Inhibitors

Iron and its alloys are widely used in various industries, making corrosion inhibition crucial. Nitrogen heterocycles, particularly those with electronegative functional groups and conjugated π electrons, have shown promise as corrosion inhibitors. These compounds often interact with metal surfaces through functional groups containing nitrogen, oxygen, or sulfur, which enhances their inhibitive properties.

For instance, 4-chloro-1H-pyrazolo[3,4-d]pyrimidine in 1M HCl demonstrates good anti-corrosion activity for mild steel, with inhibition efficiency increasing with concentration and decreasing with rising temperatures. This compound acts as a mixed-type inhibitor, predominantly affecting the anodic reaction. Various methods, including galvanostatic polarization, hydrogen evolution, potentiodynamic anodic polarization, and electrochemical impedance, have revealed that compounds like 2,6-bis-[1-(2-phenylhydrazono)ethyl]pyridine exhibit significant corrosion inhibition for zinc electrodes in 1.0M HCl.

Nitrogen heterocycles, especially pyrazine and quinoxaline derivatives, are commonly used due to the presence of two or more nitrogen atoms, facilitating electrophilic attack. Quinoxaline derivatives, in particular, are being explored for their corrosion inhibition properties against copper and steel in acidic media. Pyrazines, known for their low-lying unoccupied π-molecular orbitals, have been investigated for their inhibitory actions in different acidic environments.


 

 

Nitrogen Heterocycles as Catalysts

Nitrogen-heterocyclic carbene (NHC) ligands have been extensively studied in catalytic research, particularly for their role in various transition metal complexes used in olefin polymerization and C-C coupling reactions. NHCs are neutral, two-electron-giving ligands with a heterocyclic moiety, including pyrazole, triazole, tetrazole, benzimidazole, and imidazole, capable of chelating both hard and soft acids.

  1. Ru-NHC Complexes
    Ruthenium-catalyzed olefin metathesis, particularly with NHC-stabilized ruthenium complexes (second-generation catalysts), is a significant area of study. These complexes have facilitated various difficult reactions, with efforts focused on fine-tuning the steric and electronic characteristics of the NHC ligand to impact catalytic behavior. Unsymmetrical NHCs (uNHCs) have notably influenced the reactivity and selectivity of these catalysts. For example, highly Z-selective ruthenium catalysts with bidentate uNHC ligands have been developed, showcasing significant advancements in this field.
  2. Cu-NHC Complexes
    Copper chemistry has been revitalized with the introduction of NHC ligands. NHC-copper complexes are used in various catalytic applications, including the 1,4-reduction of enones and enoates, conjugate additions, carboxylation of alkenes, and semi-hydrogenation of alkynes. For instance, Buchwald and Sadighi reported the conjugate reduction of α,β-unsaturated carbonyls using a Cu-NHC system, while Tsuji demonstrated the semi-hydrogenation of terminal alkynes to (Z)-alkenes using a Cu-NHC approach.
  3. Pd-NHC Complexes
    Pd-NHC complexes have become desirable catalysts for Suzuki and Heck reactions and other C-C coupling reactions. These complexes, particularly those derived from imidazole, triazole, and other nitrogen heterocycles, have been explored extensively. Single-site Pd-NHC complexes, such as hexa or tetra-coordinated derivatives, are used to enhance catalytic applications and extend supramolecular chemistry into biomedical fields. Imidazole-based Pd-NHC complexes are particularly noted for their catalytic efficiency in various reactions, with stereochemistry playing a critical role in their catalytic behavior. Triazole-based Pd-NHC complexes have also shown promise in organic synthesis, further broadening the scope of nitrogen heterocycles in catalysis.


N-heterocyclic Small Molecules prove their versatility in the field of organic chemistry, continuing to be the building blocks across various industries. From drug design for defeating diseases in the pharmaceutical industry to catalyzing the reactions in material sciences these versatile compounds prove the best for organic chemistry exploration.

Due to their structural flexibility as well as practical duality, they are essential when it comes to synthesizing dozens of valuable industrial chemicals. Whether it is in the improvement of pharmaceutical activity, the increase in plant defense, or in the promotion of intricate reactions, nitrogen heterocycles continue to shape the landscape of modern chemistry.

Given the ongoing trends of expanding chemical research and development, MSE Supplies emerges as a key facilitator in accessing a wide range of chemicals beyond nitrogen heterocycles. Allowing our clients to discover, select, and purchase from an extensive range of MSE PRO N-heterocyclic Small Molecules and tailor-made solutions, MSE Supplies assists researchers and industries in expanding horizons, enhancing improvements, and advancing faster.

Ready to harness the power of chemistry for your next breakthrough? Contact MSE Supplies today to access a comprehensive range of chemicals and tailor-made solutions for your research and industrial needs.


References:

  1. A Review on The Medicinal And Industrial Applications of N-Containing Heterocycles. (n.d.). Openmedicinalchemistryjournal.com. Retrieved June 27, 2024, from https://openmedicinalchemistryjournal.com/VOLUME/16/ELOCATOR/e187410452209010/
  2. Jampilek, J. (2019). Heterocycles in Medicinal Chemistry. Molecules, 24(21), 3839. https://doi.org/10.3390/molecules24213839

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