THE CLICK CHEMISTRY

 

Synthesis is the oldest &  main theme in chemistry. Twenty years ago,M. G. Finn,  Hartmuth C. Kolb &  K. Barry Sharpless tried  to define one style of synthesis by focusing on its reasons of existence : achieved a new molecular behaviour (function) rather than appearance (structure). They named it  “click chemistry”,meant to easily connect two objects.  After long term experiments in two sectors, polymer chemistry and biochemistry , concluded that,  that reliable connectivity enables molecules of complex function to be easily assembled. 

Click chemistry links proteins, lipids, nucleic acids, and carbohydrates to partner molecules with high efficiency, under physiological conditions, and without toxic catalysts or byproducts. These partner molecules include reporters & imaging agents, allowing the in vivo visualization and tracking of biomolecules and cells.  Polymers, providing scaffolds for tissue engineering; nanoparticles, facilitating advances in drug delivery; and nanomaterials, enabling the design of electrochemical biosensors.

Barry Sharpless ,a  Nobel Prize winner for year 2022 in Chemistry, coined the concept of click chemistry around the year 2000. It is a form of simple & reliable chemistry, where reactions occur quickly & unwanted by-products are avoided. 

Morten Meldal & Barry Sharpless ,independent of each other, presented the copper catalyzed azide-alkyne cycloaddition, which is now a jewel in the crown of click chemistry.  

Among many other uses, it is utilized in the development of pharmaceuticals, for mapping DNA & creating materials that are more fit for purpose. 

The first such synthesis was the in situ azide–alkyne reactivity and later in more versatile form with SuFEx reagents. Both transformations are not possible without the presence of catalysts which provides  resistant to interference from other chemicals & reaction. 

Nevertheless, their inherent linkage reactivities are always present, and the formation of triazoles & diaryl sulfates can be vastly accelerated when held in the right environment, such as that of a ‘live’ protein as the reaction vessel.

Thus, azides, alkynes & S–F bonds are ‘sleeping beauties’ in different depths of slumber, waiting to be awakened by the kiss of the desired partner. Indeed, it is believed that click chemistry reactivity holds the key to the routine discovery of synthetic molecular agents with affinities and selective matching or exceeding those of antibodies. Synthesis of such  substance was done by joining small units together with heteroatom links (C−X−C). The goal was to develop an expanding set of powerful, selective, and modular “blocks” that work reliably in applications. The reaction must be modular, wide in scope, give very high yields, generate only inoffensive byproducts that can be removed by non -chromatographic methods, and be stereospecific .  The required process characteristics include simple reaction conditions. The process should be insensitive to oxygen & water. It should have readily available starting materials & reagents, the use of no solvent or a solvent that is benign or easily removed, and simple product isolation. 

Purification , if required, must be by non-chromatographic methods, such as crystallization or distillation, and the product must be stable under physiological conditions. Click reactions achieve their required characteristics by having a high thermodynamic driving force, usually greater than 20 kcal/mol . Such processes proceed rapidly to completion and also tend to be highly selective for a single product .

Carbon–heteroatom bond forming reactions comprise the most common examples, including the following classes of chemical transformations: Cycloadditions of unsaturated species, especially 1,3-dipolar cycloaddition reactions, but also the Diels–Alder family of transformations; Nucleophilic substitution chemistry, particularly ring-opening reactions of strained heterocyclic electrophiles such as epoxides, aziridines, aziridinium ions, and episulfonium ions; Carbonyl chemistry of the “non-aldol” type, such as formation of ureas, thioureas, aromatic heterocycles, oxime ethers, hydrazones, and amides; & Additions to carbon–carbon multiple bonds, especially oxidative cases such as epoxidation, dihydroxylation, aziridination, and sulfenyl halide addition, but also Michael additions of Nu−H reactants.

Engineers were the first to pick up click chemistry in its earliest days, unsurprising because they are driven by a need to solve functional challenges. Indeed, click chemistry is always regarded as profoundly democratic, allowing many, to discover & produce successful molecular products.

Barry Sharpless  argued for a new & minimalistic approach in chemistry. He recommends the chemists to stop imitating natural molecules. This resulted in molecular constructions that were very difficult to master, which is an obstacle to the development of new pharmaceuticals.  If a potential pharmaceutical is found in nature, small volumes of the substance can often be manufactured for in vitro testing and clinical trials. However, if industrial production is required at a later stage, a much higher level of production efficiency is necessary. Sharpless used a powerful antibiotic, meropenem, as an example. According to Barry Sharpless, all biomolecules have a framework of linked carbon atoms. It is biologically synthesized, but it has proven difficult for chemists. The carbon atoms from different molecules often lack a chemical drive to form bonds with each other, so they need to be artificially activated. This activation often leads to numerous unwanted side reactions and a costly loss of material. 

Instead of trying to deal with reluctant carbon atoms into reacting with each other, Barry encouraged to start with smaller molecules that already had a complete carbon frame. 

These simple molecules could then be linked together using bridges of nitrogen atoms or oxygen atoms, which are easier to control. If chemists choose simple reactions , where there is a strong intrinsic drive for the molecules to bond together , they avoid many of the side reactions, with a minimal loss of material. Barry Sharpless called this robust method for building molecules click chemistry, saying that even if click chemistry cannot provide exact copies of natural molecules, it will be possible to find molecules that fulfil the same functions. Combining simple chemical building blocks makes it possible to create an almost endless variety of molecules, so he was convinced that click chemistry could generate pharmaceuticals that were as fit for purpose as those found in nature, and which could be produced on an industrial scale. 

MELDAL’S REACTION VESSEL

Morten Meldal constructed enormous molecular libraries. He conducted a reaction, to react an alkyne with an acyl halide. The reaction usually goes smoothly, as long as chemists add some copper ions and perhaps a pinch of palladium as catalysts. 

 It turned out that the alkyne had reacted with the wrong end of the acyl halide molecule. At the opposite end was a chemical group called an azide. Together with the alkyne, the azide created a ring-shaped structure, a triazole. 

Triazoles are stable & are found in some pharmaceuticals, dyes & agricultural chemicals, among other things. Because triazoles are desirable chemical building blocks, researchers had previously tried to create them from alkynes and azides, but this led to unwanted by-products.

Morten Meldal realised that the copper ions had controlled the reaction so that, only one substance formed. Even the acyl halide did not form any bond with Alkynes. This made the reaction between the azide & alkyne , something exceptional. If chemists want to link two different molecules they can now, introduce an azide in one molecule and an alkyne in the other. They then snap the molecules together with the help of some copper ions.  

USES OF “CLICK CHEMISTRY”

Among other things, click reactions facilitate the production of new materials that are fit for purpose. If a manufacturer adds a clickable azide to a plastic or fibre, changing the material at a later stage is straightforward; it is possible to click in substances that conduct electricity, capture sunlight, are antibacterial, protect from ultraviolet radiation or have other desirable properties. 

Softeners can also be clicked into plastics, so they do not leak out later. 

In pharmaceutical research, click chemistry is used to produce and optimize substances that can potentially become pharmaceuticals.

ELUSIVE CARBOHYDRATES

This thread begins in the 1990s, when biochemistry & molecular biology were undergoing explosive progress. Using new methods in molecular biology, researchers around the world were mapping genes & proteins in their attempts to understand how cells work. 

 One group of molecules received hardly any attention: glycans. These are complex carbohydrates that are built from various types of sugar and often sit on the surface of proteins and cells. They play an important role in many biological processes, such as when viruses infect cells or when the immune system is activated. 

In the early 1990s, Carolyn Bertozzi began mapping a glycan that attracts immune cells to lymph nodes. It took four years to get a grip on how the glycan functioned. She developed in vivo click reactions ,to map the biomolecules on the surface of cells called as ‘glycans’. Her bioorthogonal reactions take place without disrupting the normal chemistry of the cell. 

If the cells could incorporate the modified sialic acid in different glycans, she would be able to use the chemical handle to map them.  For example, she could  attach a fluorescent molecule to the handle. The emitted light would then reveal where the glycans were hidden in the cell. 

The handle must not react with any other substance in the cell. It had to be insensitive to absolutely everything apart from the molecules she was going to link to the handle. 

She coined a term for this ,the reaction between the handle and the fluorescent molecule had to be bioorthogonal. Bertozzi modified the Staudinger reaction & used it to connect a fluorescent molecule to the azide she introduced to the cells’ glycans. Because the azide does not affect the cells, it can even be introduced into living creatures.  Carolyn Bertozzi knew that, the azide can rapidly click onto an alkyne as long as there are available copper ions. But copper is toxic to living things. But azides & alkynes can react in an almost explosive manner, without the help of copper, if the alkyne is forced into a ring-shaped chemical structure. 

The strain creates so much energy that the reaction runs smoothly. In 2004, she published the copper-free click reaction, called the strain-promoted alkyne-azide cycloaddition and then demonstrated that it can be used to track glycans. 

Bertozzi focused on, glycans on the surface of tumour cells. She revealed that, some glycans appear to protect tumours from the body’s immune system, as they make the immune cells shut down. 

Bertozzi joined a glycan-specific antibody to enzymes that break down the glycans on the surface of the tumour cells, which blocked this protective mechanism. This pharmaceutical is now being tested in clinical trials on people with advanced cancer.

Many researchers have also started to develop clickable antibodies that target a range of tumours. Once the antibodies attach to the tumour, a second molecule that clicks to the antibody is injected. 

A trio of chemists, Carolyn Bertozzi, Morten Meldal and Barry Sharpless, are this year’s Nobel laureates for Chemistry. They won it for pioneering ‘click chemistry’, which underpins green chemistry.