Azide N3: A key building block in modern chemistry
Azides (N3) are a high energy functional group of growing interest in organic synthesis. N3 azides can be easily introduced into organic molecules by SN2 substitution to form alkyl azides. The source of N3 is usually NaN3 or a organic N3 azide such as trimethylsilyl azide (TMS-azide). There are various procedures to produce non alkyl azides such as the Sandmayer reaction for the production of aromatic azides. Azides are so interesting for organic synthesis because, despite their high energy levels, they only react with a few other functional groups under physiological conditions such as alkynes or P[III] compounds. The quantitative and biorthogonal reaction of azides with alkynes enables the specific and efficient labelling of biomolecules in aqueous environments and was therefore the first reaction to be classified as click chemistry. Azides N3 can react with alkynes under Cu[I] catalysis CuAAC or with strain promoted alkynes (SPAAC) such as dibenzocyclooctine (DBCO). The importance of the development of the click reaction can be seen from the fact that it was granted with the 2022 Nobel Prize in chemistry. The possibility of forming heterocycles from organic azides via Husigen addition is also of great interest for classical chemical synthesis. Therefore, baseclick offers a variety of different azides to label your biomolecules in an efficient and enviromentally friendly way.
What is Azide N3?
Organic N3 azides consist of 3 nitrogen atoms which are linked together in an almost linear form. The two most important resonance structures for organic azides R-N=N=N and R-N-N≡N explain the chemical and physical behaviour of azide N3. They explain why there are different binding lengths between the nitrogen atoms in azide N3 structures and why N3 azides are able to serve as 1,3 dipoles for Huisgen cyclo additions. The resonance structures of azides N3 also explain why they can easily react to nitrenes and nitrogen N2 or the possibility to reduce them to amines via the Staudinger reaction. This reaction enables the use as N3 azides as a protective group for an amine in organic synthesis. The high energetic nature of azides can also be seen in their use as primary explosives in combination with heavy metals such as lead in lead azide.
Key applications of Azide N3 in science & industry
Azide N3 in organic synthesis
Due to their specific reactivity N3 azides are important precursors in organic synthesis. Despite their high reactivity N3 azides are stable to most reactants and reaction conditions, such as acidic or basic reaction environments. The ability to reduce azides N3 to amines in high yields makes them ideal for introduction as protected amines in early stages of chemical synthesis and allows for high yield deprotection with Staudinger ligation. As the byproducts of Staudinger ligation are nitrogen N2 and a P(V) compound, easy purification is also an advantage. The other main use of N3 azide is as precursor for cycloaddition to form a variety of aromatic heterocycles such as tetrazole with cyanide. The most common cycloaddition for azide N3 is the reaction with an alkyne to form triazoles. As cycloadditions are atom economical reactions and the azide alkyne cycloaddition can be performed in an aqueous environment, azides are important precursors for green chemistry synthesis.
Azide N3 in pharmaceutical & medicinal applications
The role of N3 azide in pharmaceutical and medical applications can be as a functional group to be introduced to form azide modified biomolecules similar to natural ones but due to the fact that azides N3 are not used in natural processes by metabolism. Thus, the main use of azides is as a modification of biomolecules to enable an easy and highly efficient chemical linkages of different building blocks to form new therapeutic approaches such as antibody-drug-conjugates (ADCs). N3 azide have great advantages in ADC development due to the highly stable triazole bond formed when clicked with an alkyne. As well as the high reaction yields and easy handling of azide N3 modifications due to their bioorthogonality in combination with alkynes.
Azide N3 in material science & advanced polymers
Azides are of great value for the production of functionalized surfaces as azides (N3) can be used for controlled photo-crosslinking and subsequent click modifications. The amount of azides consumed for photo-crosslinking can be controlled by irradiation time and live monitored via FT-IR spectroscopy. Due to the molecular structure of azides this technique is also ideal to modify the structures of nanobodies. In nanotechnology also the great reaction properties of azides in CuAAC are of great importance to prepare completely modified structures under mild conditions.
Azides can also be used to produce new high energy polymeres. These azide modified polymeres have the advantage of improved thermal stability and a decrease of partical size instead of the standard used nitrocellulose as high energy polymere. The introduction of N3 groups into polymeric structures enables the possibility to cross link them by azides to form highly ractive nitrenes by heat or irradiation.
The future of Azide N3 research & applications
Sustainable innovations in Azide N3 chemistry
Azides make a major contribution to green chemistry since their use as 1,3-dipols in cycloadditions is atom economical and therefore produces no side products as waste. In addition, the most important of N3 azides cycloadditions the reaction with alkynes can be carried out in an aqueous environment instead of using organic solvents. Organic solvents are typically high energy carbon based molecules that are energy intensive to produce an produce large amounts of carbon dioxide when disposed of. There are new processes for alkyne azide cycloaddition which can be performed solvent free, again reducing the amount of waste. The other main reaction of azides N3 is the Staudinger ligation which is not atom economical, but per reaction only one molecule of dinitrogen (N2) is produced which gases out of the reaction. Therefore, no purification of the products is necessary. In combination with the high yields, mild reaction conditions and easy purification also the Staudinger ligation is a great way to link molecules in an environmentally friendly way.
Expanding Azide N3’s role in drug discovery
Azides N3 allow through bio-orthogonal click chemistry the efficient and environmentally friendly conjugation of various biomolecules to carriers, such as liposomes or micelles, or to antibodies to form new ADCs creating new specific drug delivery systems. This reaction of azides can also be used to conjugate a variety of tags as fluorescent dyes to biomolecules to allow to create better imaging of labelled biomolecules. The usage of 15N3 labelled biomolecules is of great importance in magnetic resonance imaging (MRI) due to the long-live hyperpolarization of 15N azide.