Parth Vinod Joshi

English 21003- Writing for the Sciences

Professor Michael Grove

Improved Mechanisms for Synthesis of 1,2,3-Triazoles

 

Heterocycles are an important class of compounds that are prevalent in nature and in our everyday life. For example, they are part of carbohydrates, nucleic acids, some natural amino acids, as well as alkaloids. They have found a multitude of applications, such as in pharmaceutical and agrochemical chemistry, electronics, dyes and in polymer chemistry, to name a few.

1,2,3-Triazole is one of a pair of isomeric chemical compounds with molecular formula C2H3N3, called triazoles, which have a five-membered ring of two carbon atoms and three nitrogen atoms. 1,2,3-Triazole is a basic aromatic heterocycle.1

1,4 positions-substituted 1,2,3-triazoles is currently produced using the azide alkyne Huisgen cycloaddition process (AAHC) in which an azide and an alkyne undergo additions at the 1,3 positions. Though in this process, a lot of impurities like 1,3- and 1,4-disubstituted triazoles are formed.

It is a very stable structure compared to other organic compounds with three adjacent nitrogen atoms. However, flash vacuum pyrolysis at 500 °C leads to the loss of molecular nitrogen (N2) leaving a three-member C2H5N ring. 1,2,3-Triazole finds use in research in medicinal chemistry as a building block for more complex chemical compounds, including pharmaceutical drugs such as mubritinib and tazobactam.

The Huisgen ligation of azides and alkynes is an exceptionally atom-economical reaction leading to the formation of 1,2,3- triazoles. However, the thermal process is not region-selective, resulting in the formation of 1,4- and 1,5-disubstituted 1,2,3- triazoles.

The 1,2,3-triazole ring has been used as a heteroaryl ring in medicinal chemistry, and its well-known click chemistry (Huisgen reactions) has expanded the many pharmacological applications of N-1-substituted 1,2,3-triazoles. As synthesis reactants, broom- and iodo-1,2,3-triazoles are useful building blocks for metal-catalyzed coupling reactions, such as Suzuki-Miyaura coupling. There are few known synthetic routes to prepare Bromo- and iodo-1,2,3-triazoles. 4-Bromo-1,2,3-triazole, for example, is commercially available but expensive.

The classic click reaction is the copper-catalyzed reaction of an azide with an alkyne to form a 5-membered heteroatom ring. In chemical synthesis, “click” chemistry is a class of biocompatible small molecule reactions commonly used in bioconjugation, allowing the joining of substrates of choice with specific biomolecules. Click chemistry is not a single specific reaction but describes a way of generating products that follow examples in nature, which also generates substances by joining small modular units. In general, click reactions usually join a biomolecule and a reporter molecule. Click chemistry is not limited to biological conditions: the concept of a “click” reaction has been used in pharmacological and various biomimetic applications. However, they have been made notably useful in the detection, localization, and qualification of biomolecules

One of the methods that are used for the synthesis of such chemicals is using Copper-catalyzed azide-alkyne cycloaddition (CuAAC). In such a method, the production of the 1,3- and 1,4-disubstituted impurities are significantly reduced to ensure higher yield per mole of the reactants using deuterated carriers of hydrogen to proceed with the reaction. This gives a reduced chance of early protonation and subsequent formation of the impurities.2

However, in CuAAC, the reaction cannot reach equilibrium or completion in an aqueous medium as the deuterium atom reacts with the hydronium ions and for a protio-triazole without any radioactive ‘tags’ or a purer yield of the product, rendering it less useful for medicinal purposes.

While the reaction can be performed using commercial sources of copper(I) such as cuprous bromide or iodide, the reaction works much better using a mixture of copper(II) (e.g. copper(II) sulfate) and a reducing agent (e.g. sodium ascorbate) to produce Cu(I) in situ. As Cu(I) is unstable in aqueous solvents, stabilizing ligands are effective for improving the reaction outcome, especially if tris-(benzyltriazolylmethyl)amine (TBTA) is used. The reaction can be run in a variety of solvents, and mixtures of water and a variety of (partially) miscible organic solvents including alcohols, DMSO, DMF, trans-BuOH, and acetone. Owing to the powerful coordinating ability of nitriles towards Cu(I), it is best to avoid acetonitrile as the solvent. The starting reagents need not be completely soluble for the reaction to be successful. In many cases, the product can simply be filtered from the solution as the only purification step required.2

Souza et. Al. developed a mild and versatile one-pot three-component protocol for the synthesis of novel imine 1,2,3- triazole compounds involving a-thio aldehyde, propargylamine, and organoazides by the [3+2]-cycloaddition methodology. They performed other functionalizations on the products through different methodologies, which show the versatility of the molecule for the synthesis of more complex molecules.

The reaction to form the azide was successful and the product was obtained with a good yield after purification. The product was used to form bis-1,2,3-triazole, which did not show the same good performance as for the formation of the first triazole, but still retained an acceptable yield due be a complex molecule.

Next, the conditions to prepare bromo- and iodo-1,2,3-triazoles had to be explored. Because the halogenation of 1,2,3-triazole using one equivalent of bromine or NIS generated dihalo-1,2,3-triazole as a major product, the direct preparation of monohalo-1,2,3- triazoles from 1,2,3-triazole was believed to be difficult.3 Therefore, the team investigated the removal of one halogen atom from the dihalo-1,2,3-triazoles. 4,5-Dibromo-1,2,3-triazole was treated with sodium sulfite in water at 110 C, and the reaction interestingly gave 4-bromo-1,2,3-triazole without notable over-reaction. In addition, basic and acidic conditions were examined. In the presence of K3PO4, no desired product was observed. The addition of acetic acid did not affect the reaction. To minimize the risk of thermal decomposition of the desired product, the hot plate was set to 100 C, at which temperature the reaction took 3 days, which is unreliable for research purposes. For the reduction of 4,5-diiodo-1,2,3-triazole, mild conditions (80 C for 2.5 h) produced the desired product in good yield.

The conditions of the di-iodination and reduction reactions used only common reagents and solvents. Using these facile synthetic methods, halo-1,2,3-triazoles become easily accessible, expanding the synthetic strategies to produce 1,2,3-triazole derivatives. Since a lot of publications have been developed on the click reaction by Huisgen, many papers have appeared to construct those compounds.

The modified method, introduced by Melda and Sharpless, uses a metal catalyst to address the Regio isomer problem by giving 1,4-disubstituted 1,2,3-triazole as the only Regio isomer. It is also of advantage because it produces high yields and can be performed under mild reaction conditions.

In a different experiment, various 4-trifluoroacetyl1,2,3-triazoles were attempted to synthesize, as it makes synthesizing tazobactam sodium simpler. The scope of azide substrates was first examined. All benzyl azide compounds were reacted smoothly under mild conditions to give the corresponding triazoles, where electron donating groups or electron withdrawing groups in the para position include methyl, F, Cl substituted benzyl azide provides excellent yield and high regioselectivity.3

To further improve on this mechanism, another modification done to this procedure was the addition of CaC2 gar in situ in an aqueous medium. In such conditions, the stability of D2O is increased and thus does not cleave the D—O bond so the proton is not released early in the reaction.

Recently, the discovery of a general Ag(I)-catalyzed azide-alkyne cycloaddition reaction (Ag-AAC) leading to 1,4-triazoles is reported. Mechanistic features are like the generally accepted mechanism of the copper(I)-catalyzed process. Silver(I)-salts alone are not enough to promote the cycloaddition. However, ligated Ag(I) sources have proven to be exceptional for AgAAC reaction. Curiously, pre-formed silver acetylides do not react with azides; however, silver acetylides do react with azides under catalysis with copper(I).

Though the use of isocyanides has been prevalent in the production of triazoles, primarily the synthesis of 1,2,4-triazoles take place. Though irrelevant to the current discussion of beta-lactams like the 1,2,3-triazoles, its importance is significant in the process of drug-manufacturing.

As discussed by the authors of the articles indicating the mentioned methods to accurately synthesize triazoles with further influence on the yield and the purity of the final product, the click chemistry process is still used to commercially generate the chemicals.

 

Professor Grove’s evaluation:

Parth –

 

There are two major issues that I think you’d want to address in a revision of this paper.  While you’ve clearly got a focus, the importance of that focus to an audience isn’t entirely clear: you present a great deal of information to your readers, but that information seems to be aimed solely at giving us an overview of different processes for synthesizing triazoles effectively and efficiently.  But without a practical sense of the value of these different processes in comparison with one another, I’m left puzzled. Why are scientists pursuing these different approaches to synthesis? What kind of benefits do these different processes yield, and how does it impact the lives of a larger audience? Being able to make points like this is key because if you present information like this in isolation, readers won’t understand why you’re presenting it in the first place.  Part of your role as a writer is curating the information you present to your readers so that the importance of the topic you’re sharing with them, either to you or to a larger group, is readily apparent.

The second major concern I have is your paragraph structure in this essay.  Right now you vary your paragraphs a bit, sometimes presenting a series of single sentence paragraphs, sometimes presenting paragraphs that seem to be related to surrounding material which is, in the end, not fully connected to that material.  Slowing down during your review process and reading your work aloud may help you with organizational concerns like this, but conceptualizing the goals of your paper, and mapping paragraphs to those goals could also help. Paragraphs are effectively a unit of thought: each paragraph should explain a concept or idea to your readers, and without an effective paragraph structure, it becomes difficult to differentiate ideas from one another, or clearly comprehend the relationship between concepts you’re attempting to share.

Finally, my last concern is a minor one: while you do show us footnotes, there are no Works Cited page for this paper, and some of your footnotes have inconsistencies (like omitted page ranges, volume numbers, and issue numbers).  I’d like to see you collect that information, and include it on a separate page in your revision. Also, if you feel unsure of how to proceed with this project, feel free to drop by and talk things through. I’m here to help, and while I can’t engage in the kind of deliberative discussion that occurs in Writing Centers, I can try to talk you through any points you’re confused by.

 

0/10 – Missing Works Cited Page

 

– Professor Grove