Benzotriazole

Benzotriazole is a heterocyclic compound containing a fused benzene ring and a triazole ring. It is used in various applications such as corrosion inhibition, UV stabilization in plastics, and as a precursor for the synthesis of other compounds like pharmaceuticals.

  1. History

Benzotriazole has a long and interesting history since its first synthesis in 1876. Over the past century and a half, it has become an important compound used in a wide variety of applications due to its unique chemical properties.

Discovery and Early Uses

Benzotriazole was first prepared by the German chemist August Ladenburg in 1876[1]. In the early 20th century, it began to find use as a corrosion inhibitor for copper and copper alloys. It forms a complex with copper that protects the metal surface from oxidation and other corrosive reactions. This made benzotriazole useful for applications like preventing tarnishing of copper cookware and architectural elements[2].

Expanding Applications in the Mid-20th Century

As the understanding of benzotriazole’s chemistry grew, so did its range of uses. In the 1940s, benzotriazole derivatives began to be used as ultraviolet light absorbers in plastics, photographic film, and other polymeric materials[2]. Benzotriazole also proved to be a versatile reagent and synthetic intermediate in organic chemistry.

Current and Emerging Applications

Today, benzotriazole continues to find new applications in diverse fields like pharmaceuticals, electronics, and materials science. 

  1. Properties
  • Physical Properties

Benzotriazole is a white to light yellow crystalline solid at room temperature. It has a melting point of 98.5°C and a relatively high boiling point of 350°C, reflecting its stability[3]. The compound is slightly soluble in water (solubility of 1.9 g/100 mL at 23°C) but readily soluble in many organic solvents such as ethanol, acetone, and chloroform[3, 4].

In the solid state, benzotriazole molecules are planar and form stable hydrogen-bonded dimers. The crystal structure shows π-π stacking interactions between the aromatic rings of adjacent molecules[3].

  • Chemical Properties

Benzotriazole is an amphoteric compound, meaning it can act as both an acid and a base. The triazole ring can be protonated on the nitrogen atoms, giving benzotriazole a pKa of 8.2[3]. This allows it to act as a weak acid. At the same time, the nitrogen atoms can also accept protons, allowing benzotriazole to form stable complexes with metal ions[3].

The benzotriazole molecule is electron-rich due to the presence of the three nitrogen atoms and the aromatic ring. This makes it a good electron donor and allows it to form coordination complexes with various metal ions, especially transition metals like copper, zinc, and silver[5]. These complexes are the basis for benzotriazole’s use as a corrosion inhibitor.

Benzotriazole is also a fairly stable compound. The aromatic ring and the triazole ring are both resistant to oxidation and reduction under normal conditions. However, benzotriazole can be oxidized by strong oxidizing agents to form benzotriazole N-oxides[6].

  • Spectroscopic Properties

The UV-Vis absorption spectrum of benzotriazole shows a strong absorption band around 260 nm, corresponding to the π-π* transition of the aromatic system. The exact position and shape of this band can be influenced by substitution on the benzotriazole ring and by the solvent environment[3, 7].

Benzotriazole is also fluorescent, with an emission maximum around 350 nm when excited at 260 nm. The fluorescence is sensitive to the protonation state of the triazole ring and to complexation with metal ions, making benzotriazole a useful probe molecule[3].

The IR spectrum of benzotriazole shows characteristic bands for the N-H stretch (around 3400 cm-1), the C=C and C=N stretches of the aromatic and triazole rings (1600-1400 cm^-1), and the C-H bending modes (below 1000 cm-1)[8].

  1. Synthesis

Several synthetic routes have been developed for the preparation of benzotriazole, with the choice of method depending on the desired yield, purity, and availability of starting materials. In this section, we will explore the most common synthetic methods for benzotriazole, including their reaction mechanisms and equations.

  1. Diazotization of o-phenylenediamine followed by cyclization

The most common industrial method for the synthesis of benzotriazole involves the diazotization of o-phenylenediamine followed by cyclization[9, 10]. The reaction mechanism consists of two main steps:

Diazotization of o-phenylenediamine:

In this step, o-phenylenediamine is treated with sodium nitrite (NaNO2) in the presence of an acid, typically hydrochloric acid (HCl), at low temperatures (0-5°C). The reaction leads to the formation of a diazonium salt intermediate.

Reaction equation:

C6H4(NH2)2 + 2 NaNO2 + 4 HCl → C6H4(N2+Cl–)2 + 2 NaCl + 4 H2O

Mechanism:

  1. The nitrosonium ion (NO+) is formed by the reaction of sodium nitrite with hydrochloric acid.
  2. The nitrosonium ion reacts with one of the amino groups of o-phenylenediamine to form a nitrosamine.
  • The nitrosamine undergoes a tautomeric shift to form a diazohydroxide.
  1. The diazohydroxide is protonated by hydrochloric acid to form a diazonium salt.

Cyclization:

The diazonium salt intermediate undergoes intramolecular cyclization under acidic conditions, resulting in the formation of benzotriazole.

Reaction equation:

C6H4(N2+Cl–)2 → C6H4N3H + 2 HCl

Mechanism:

  1. The lone pair of electrons on the second amino group attacks the diazonium group, forming a five-membered ring.
  2. The cyclized intermediate undergoes a proton transfer, leading to the elimination of nitrogen gas and the formation of benzotriazole.

Overall reaction:

C6H4(NH2)2 + 2 NaNO2 + 2 HCl → C6H4N3H + 2 NaCl + 3 H2O

  1. Reaction of o-aminoazocompounds with nitrous acid

Another method for synthesizing benzotriazole involves the reaction of o-aminoazocompounds with nitrous acid[11]. In this process, an o-aminoazocompound, such as 2-[(2-bromo-4,6-dinitrophenyl)azo]-4-methoxy-5-[bis(2-methoxyethyl)amino]acetoanilide (AZO DYE-1), is treated with a reducing agent, like sodium hydrosulfite (Na2S2O4), to form the corresponding 2-phenylbenzotriazole derivative. Subsequent chlorination of this derivative leads to the formation of benzotriazole.

Reaction equation:

AZO DYE-1 + Na2S2O4 → deClPBTA-1

deClPBTA-1 + NaOCl → PBTA-1 (benzotriazole derivative)

  1. Cyclization of N-phenylbenzamidines

Benzotriazole can also be synthesized through the cyclization of N-phenylbenzamidines[12]. In this method, N-phenylbenzamidine is subjected to diazotization conditions using sodium nitrite and an acid, leading to the formation of benzotriazole.

Reaction equation:

C6H5C(=NH)NHC6H5 + NaNO2 + HCl → C6H4N3H + NaCl + H2O

  1. Other Synthetic Methods
  2. Photochemical synthesis: The text refers to transnitrosation reactions involving N-nitrosodiphenylamine and benzene-1,2-diamine derivatives under photochemical conditions, as described in[13].
  3. Oxidative cyclization: The oxidative cyclization of certain o-phenylenediamine derivatives to form benzotriazole derivatives is mentioned, which is supported by[14], reporting on oxidative cyclization reactions catalyzed by transition-metal complexes for the synthesis of various heterocyclic compounds, including benzotriazoles.
  • Transition metal-catalyzed cyclizations: The text mentions transition metal-catalyzed cyclization reactions for the synthesis of benzotriazole derivatives, which is corroborated by[15], a review covering denitrogenative cyclization of triazoles and benzotriazoles, often involving transition metal catalysis.

In conclusion, benzotriazole can be synthesized through various methods, each involving specific reaction mechanisms and equations. The most common industrial method is the diazotization of o-phenylenediamine followed by cyclization, while other methods include the reaction of o-aminoazocompounds with nitrous acid and the cyclization of N-phenylbenzamidines.

  1. Applications

Benzotriazole and its derivatives have found numerous applications in various fields due to their unique properties. Here are some of the major uses and applications of benzotriazole:

  • Corrosion Inhibition

One of the most widespread applications of benzotriazole is as a corrosion inhibitor for copper and copper alloys. Benzotriazole forms a protective film on the metal surface, preventing oxidation and corrosion[16]. It is commonly used in cooling systems, automotive antifreeze formulations, and metal cleaning solutions.

  • Photovoltaic Applications

Benzotriazole-based polymers have been extensively studied for their potential use in organic photovoltaic (OPV) devices and organic solar cells[17]. These polymers exhibit desirable properties such as broad absorption spectra, high charge carrier mobility, and suitable energy levels for efficient charge transfer. The incorporation of benzotriazole units into polymer backbones has been shown to improve the performance of OPV devices[17].

  • Nonlinear Optical (NLO) Materials

Benzotriazole-containing crystals and compounds have been investigated for their nonlinear optical properties, making them potential candidates for applications in optoelectronics, photonics, and optical data storage[18]. The non-centrosymmetric structure of some benzotriazole derivatives contributes to their third-order nonlinear optical susceptibility, which is essential for NLO applications[18].

  • UV Stabilizers

Benzotriazole derivatives, known as benzotriazole UV stabilizers (BUVs), are widely used as UV absorbers and light stabilizers in various materials, including plastics, coatings, and personal care products[19]. They protect materials from degradation caused by UV radiation by absorbing harmful UV light and dissipating the energy as heat.

  • Fluorescent Probes and Sensors

The fluorescent properties of some benzotriazole compounds have been exploited in the development of fluorescent probes and sensors for detecting and monitoring various analytes, such as metal ions, pH, and reactive oxygen species[16]. The benzotriazole moiety can act as a fluorophore or a recognition unit, enabling selective and sensitive detection.

  • Pharmaceutical Applications

Benzotriazole and its derivatives have shown potential in pharmaceutical applications due to their diverse biological activities. Some benzotriazole compounds have been investigated for their antimicrobial, antiviral, anticancer, and anti-inflammatory properties, among others[19]. However, further research is needed to fully explore their therapeutic potential.

  1. Safety
  • Toxicity
  1. Aquatic Toxicity: Some benzotriazole UV stabilizers (BUVSs) like UV-P, UV-9, and UV-090 have been shown to activate the aryl hydrocarbon receptor (AhR) in fish, leading to adverse effects such as embryo lethality[20]. The rank order of potency for AhR activation was UV-P > UV-9 > UV-090.
  2. Metabolite Toxicity: The photocatalytic degradation of BTA can produce metabolites like triazole, tolyltriazole, and aniline, which show toxic effects, although generally less toxic than BTA itself[21].
  • Oxidative Stress: A study on oncology nurses found that occupational exposure to antineoplastic drugs, including BTA-based compounds, can lead to increased oxidative stress, as indicated by elevated levels of 8-hydroxy-2′-deoxyguanosine (a biomarker of oxidative DNA damage)[22].
  • Safe Handling
  1. Handling Precautions: Guidelines and training programs emphasize the importance of safe handling precautions for healthcare workers dealing with hazardous drugs like antineoplastic agents and BTA-based compounds[22]. These precautions include the use of personal protective equipment (PPE), closed system transfer devices, and proper disposal of contaminated materials.
  2. Occupational Exposure: Studies highlight the need for enhanced knowledge and skills among healthcare workers, particularly nurses, regarding the safe handling, administration, and waste management of chemotherapeutic drugs and BTA-based compounds to reduce occupational exposure and potential health risks[22].
  • Waste Management: Proper disposal and management of cytotoxic waste containing BTA and its derivatives are crucial to minimize environmental contamination and potential health risks.
  1. Training and Guidelines: Implementing strict guidelines, training programs, and standard operating procedures (SOPs) can improve the safe handling practices and reduce occupational exposure to BTA and other hazardous substances in healthcare and laboratory settings[22].

In summary, while benzotriazole and its derivatives have various industrial and pharmaceutical applications, their potential toxicity, particularly to aquatic organisms and through occupational exposure, necessitates strict adherence to safe handling practices, proper waste management, and comprehensive training programs for workers handling these substances

  1. References
  2. Giraudo, M., et al., Transcriptional and cellular effects of benzotriazole UV stabilizers UV-234 and UV-328 in the freshwater invertebrates Chlamydomonas reinhardtii and Daphnia magna.Environ Toxicol Chem, 2017. 36(12): p. 3333-3342.
  3. Cantwell, M.G., J.C. Sullivan, and R.M. Burgess, Benzotriazoles: History, Environmental Distribution, and Potential Ecological Effects.Comprehensive Analytical Chemistry, 2015. 67: p. 513-545.
  4. Naumov, S., B. Herzog, and B. Abel, Spectra and Photorelaxation of Hydroxyphenyl-benzotriazole-Type UV Absorbers: From Monomers to Nanoparticles.J Phys Chem A, 2020. 124(4): p. 625-632.
  5. Cai, L., A 1H-Benzotriazole Derivative Nucleated Poly(L-lactic acid): Thermal Behavior and Physical Properties.Journal of the Chemical Society of Pakistan, 2020. 42: p. 383.
  6. Brusic, V., M. Angelopoulos, and T.O. Graham, Use of Polyaniline and Its Derivatives in Corrosion Protection of Copper and Silver.Journal of The Electrochemical Society, 1997. 144: p. 436-442.
  7. Qu, Y., et al., Synthesis and Properties for Benzotriazole Nitrogen Oxides (BTzO) and Tris[1,2,4]triazolo[1,3,5]triazine Derivatives.International Journal of Materials Science and Applications, 2018. 7: p. 49.
  8. Mai, C.K., et al. Title Optical Properties of Benzotriazole-Based Conjugated Polyelectrolytes Permalink. 2016.
  9. Boto, A. and J. Escalante. 1‐(Trimethylsilyl)‐1H‐benzotriazole. 2010.
  10. Zou, R., J.C. Drach, and L.B. Townsend, Design, synthesis, and antiviral evaluation of 2-substituted 4,5-dichloro- and 4,6-dichloro-1-beta-D-ribofuranosylbenzimidazoles as potential agents for human cytomegalovirus infections.J Med Chem, 1997. 40(5): p. 802-10.
  11. Zhilitskaya, L.V., B.A. Shainyan, and N.O. Yarosh, Modern Approaches to the Synthesis and Transformations of Practically Valuable Benzothiazole Derivatives.Molecules, 2021. 26(8).
  12. Datta, A., et al., Review on synthetic study of benzotriazole.GSC Biological and Pharmaceutical Sciences, 2020. 11: p. 215-225.
  13. Preusser, S., et al., Mechanistic investigations on C–H activated dealkylating cyclo-amination reactions of substituted triazenes, formamidines and amidines.Zeitschrift für Naturforschung B, 2020. 75: p. 651 – 664.
  14. Farkas, R., et al., Synthesis of new 2-(2´-hydroxyaryl)benzotriazoles and evaluation of their photochemical behavior as potential UV-filters.Molecules, 2010. 15(9): p. 6205-16.
  15. Singh, A., et al., Oxidative Cyclization Reactions Catalyzed by Designed Transition-Metal Complexes: A New Strategy for the Synthesis of Flavone, Quinolone, and Benzofuran Derivatives.Synthesis, 2023. 55: p. 4191 – 4203.
  16. Li, W. and J. Zhang, Synthesis of Heterocycles through Denitrogenative Cyclization of Triazoles and Benzotriazoles.Chemistry, 2020. 26(52): p. 11931-11945.
  17. Zulkefli, N.I.H., M.S.A. Khiar, and S.A. Ghani, Sensing the Presence of Benzotriazole Passivator in Thermally Aged Corrosive Transformer Insulating Oil Using UV-Vis Spectroscopy.2023 19th IEEE International Colloquium on Signal Processing & Its Applications (CSPA), 2023: p. 140-143.
  18. Gedefaw, D., et al., Synthesis and characterization of benzodithiophene and benzotriazole-based polymers for photovoltaic applications.Beilstein J Org Chem, 2016. 12: p. 1629-37.
  19. Sahaya Infant Lasalle, B., et al., Theoretical and Experimental Investigation on 1,2,3‐Benzotriazole 4‐Hydroxybenzoic Acid (BTHBA) Single Crystals for Third‐Order Nonlinear Optical (NLO) Applications.Crystal Research and Technology, 2022. 58.
  20. Khare, A., et al., Benzotriazole UV stabilizers (BUVs) as an emerging contaminant of concern: a review.Environ Sci Pollut Res Int, 2023. 30(58): p. 121370-121392.
  21. Johnson, H.M., et al., Assessing the Toxicity of Benzotriazole Ultraviolet Stabilizers to Fishes: Insights into Aryl Hydrocarbon Receptor-Mediated Effects.Environ Sci Technol, 2024. 58(1): p. 110-120.
  22. Moslemi, S., H. Nassehinia, and A. Rahmani, Photocatalytic degradation of benzotriazole (BTA): by-products, bio-toxicity and kinetic study.DESALINATION AND WATER TREATMENT, 2022.
  23. Topçu, S., et al., Implementation and Evaluation of Safe Handling Precautions Training for Oncology Nurses: An Experimental Design.Nursing and Health Sciences Journal (NHSJ), 2022.
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