Click Chemistry in Building Hierarchical Structures

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Adel Badria	--	1630	2022-11-30 19:29:17	\|
2	Reference format revised.	Lindsay Dong	-18 word(s)	1612	2022-12-01 10:31:35	\|

This entry is adapted from the peer-reviewed paper 10.3390/polym14194077

Hierarchical structures are an essential part of numerous types of architecture in nature. They are defined as the presence of different structural elements with different length scales in a single body. This different length scale gives each hierarchical structure its “order, n” and characteristic properties. The higher the (n) the more sophisticated hierarchical structures; where n = 0 refers to continuum materials with only a single length scale. Noteworthy, several composites are considered low-ordered hierarchical structures. The idea of building blocks for hierarchical structures intersects perfectly with the modularity concept in click chemistry. Click chemistry is a powerful tool for constructing nano, micro and macro structures through two different approaches: (A) the first approach: through direct crosslinking of (pico-building blocks) monomers give a final micro/macro structure such as hydrogels; (B) the second approach: through nano-building blocks formation using click chemistry (e.g., dendrimers and dendrons) followed by connecting and crosslinking those formed nano-building blocks again using click chemistry to form bigger structures

click chemistry hierarchial structures 0D/nano/micro building blocks

1. Click Chemistry

The dawn of modern chemistry dates to the onset of the 18th Century. Since then, chemistry passed through different major stations. One of them was a new synthesis paradigm called click chemistry, or “CC”. This paradigm was proposed by American chemist Karl Sharpless and coworkers, for building a wide range of new chemical compounds using a simple approach.

In general, organic compounds are formed of a backbone of carbon atoms (representing building blocks), linked together to form bigger molecules. In practice, this process of adding carbon atoms to each other is not flawless. Instead, time consumption, expensive costs, low yield, low selectivity of the different reactions used, the complicated purification process required to separate the desired product, the aggressiveness of the used solvents and reactants, the low stability of the final products and the different stereoisomers formed for different reactions are all common drawbacks for the traditional synthesis approaches.

In contrast to the traditional synthesis approaches, click chemistry exploits certain reactions, which are as simple as the clicking of interlocking fasteners hence the name was coined, for forming endless numbers of linkage chemical bonds ^[1]. Usually, those reactions are selected based on fulfilling certain criteria as shown in Table 1.

Table 1. Criteria for defining a certain reaction as a click reaction.

Advantage	Explanation
High Selectivity	-
High yield	-
Mild conditions	Usage of mild solvents and reactants
Fast reaction	The exothermicity of both thermodynamic and kinetics of the reaction allowed fast and stable final products
Minimum byproducts	-
Easy purification	No need for complicated chromatography or other purification techniques
Modularity	The ability of forming diverse library of chemical structures from simple chemical modules
Regiospecific	Minimum stereoisomers are being formed

Historically, the first reaction to being identified as click chemistry is the copper-catalyzed azide-alkyne reaction to form a 5-membered ring. Nowadays, the click chemistry approach is being handled as a toolbox that different groups worldwide are adding to and modifying with different new reactions. So far, four categories have been identified to represent the different click chemistry reactions.

2. Hierarchical Structures and Click Chemistry

For any hierarchical structures in nature there have been repeated smaller building blocks which have been arranged in a certain manner to provide the required functionality for this hierarchical construction.

Moreover, click chemistry acts through different pathways for building higher structures either alone or in combination with different assisting chemistries, techniques, and tools. While in the first approach mentioned above, the role of click chemistry involves connecting the different building blocks, using the spatial hindrance and the chemical natures of the involved compounds to give the final topological and internal structures of the final product. In the second approach, click chemistry is used as an assisting tool for the fabrication techniques, such as STAMP-Lithography, SLA 3D printing, phase separation, self-assembly, etc.

Noteworthy, the following considerations have been taken: 0D is the xyz < 100 nm, 1D xy < 100nm and 2D x or y < 100 nm ^[2]. Additionally, there has been no differentiation between micro and higher dimensions. Moreover, as molecules, atoms and monomers do not fall into any of those categories, a general term to describe them was used: “Pico building blocks”.

2.1. The First Approach

All the micro/macro structures to be constructed must pass first through the nanoscale level. However, what is meant in this category is the whole continuous process (click orthogonal), i.e., from the pico/0D nano to the micro/macro without the involvement of intermediate processing and modifications.

In 2020, Hassan et al. published an excellent review discussing the construction of hierarchical structures from MOF (Metal/covalent Organic frame) using click chemistry (Figure 1) ^[3]. The significant potential of clickable MOF for building high precision hierarchical structures, porosity control, the transformation of internal and external structures and post-synthesis modifications (PSM) opened a new horizon in the field of bio/material science.

/media/item_content/202212/63886da6188b3polymers-14-04077-g005.png

Figure 1. Hierarchical structures from MOF (Metal/covalent Organic frame) using click chemistry. A good example of the first approach. The illustration is based on the work conducted by ^[3].

On the other hand, one of the good examples in the literature manifesting this concept of combining click chemistry with 3D printing for building hierarchical structures is the 3D printing of clickable microsphere ^[4]. Xin et al. clicked norbornene—PEG with excess Dithiol-PEG to give gel microspheres, and the formed microsphere building blocks were extruded using a 3D printer under UV to form a hierarchical structure through S-S bonds between excess added dithiol-PEG (Figure 2).

/media/item_content/202212/63886dbd6f031polymers-14-04077-g006.png

Figure 2. Clickable PEG hydrogel microspheres as building blocks for 3D bioprinting. The illustration is based on the work conducted by ^[4].

Among the enormous publications in this area, three examples are demonstrated for the direct formation of micro/macro structures from pico-building blocks: gels, crystals, and controlled porous structures.

2.2. The Second Approach

2.2.1. Picometer ➔ 0D-Nanometer

For such small dimensions of controlled fabrication, a significant number of articles and review articles have already been published covering the usage of click chemistry to synthesize 0D structures: dendrimers, dendrons, hyperbranched polymer ^[5], single chain nanoparticles ^[6] and sequence-controlled polymers ^[7].

Other reactions which do not include a construction frame behind it, e.g., conjugation for labelling or targeting purposes have also been shown in literature such as nanoparticles ^[8], buckyballs ^[9], micelles ^[10] and microparticles ^[11].

2.2.2. 0D/1D-Nanometer ➔ 2D-Nanometer

The idea of creating a unified theory covering the use of 0D-nanobuilding blocks for building higher structures was a detailed cornerstone theoretical work of Tomalia et al. 2009 ^[12]. In his published works, Tomalia suggested a similar system to the periodic atomic table system for higher structures (0D) ^[13]. The dendrimers were used as the explanatory model for his idea. The 0D nanoscale building blocks were categorized into two main classes, hard and soft nanostructures, and under each category six subcategories were proposed based on compositional/architectural considerations as shown in the following (Figure 3).

/media/item_content/202212/63886dd73ca6bpolymers-14-04077-g006.png

Figure 3. Proposed nano system by Donald Tomalia. The figure has been reproduced from another article ^[12] under a CC−BY license.

Soft/Soft Nano Building Blocks

Clicking bisMPA based dendrimers/dendrimers, Vestberg et al. 2007, showed a significant control over the hierarchical architecture building up. Using CuCCA click chemistry, the film thickness could be accurately controlled by manipulating the dendrimers size (generation) and layer thickness ^[14]. The exploitation of dendrimers from different materials whether alone or in combination, core sizes and branch lengths would open endless possibilities for the control of different layers thickness.

Hard/Hard Nano Building Blocks

For electro/photocatalytic applications, alkyne-azide click chemistry showed a very efficient potential to form mono/multilayers, hetero/homo structure on different substrates using metallic, semiconductor and dielectric nanoparticles. Upadhyay et al. showed even further control over the packing ratio and crystal unit by controlling the number of click groups on the substrates, substrate surface roughness and the solvent used ^[15]. Williams and Teplyakov showed another metal/metal assembly, in which azide-terminated Si nanoparticles and alkyne-terminated Si nanoparticles were added alternatively to a gold substrate using click chemistry to form nearly 100% coverage of the substrate ^[16]. For self-healing polymers applications, Le Neindre and Nicolaÿ, used a thiolated copolymer with silver nanoparticles as crosslinkers ^[17]. The self-healing potential was attributed to the reversible thiolates exchange that takes place over the Ag nanoparticles.

Soft/Hard Nano Building Blocks

Fullerene and dendrimers represent different types of hard and soft building blocks, respectively. The clicking between those two types both dendrimers in the core and fullerene in the shells or the opposites has been published in the literature ^[18]^[19]. While Hahn et al. 2012 used fullerene as a peripheral decoration of the polypropylene simine (PPI) dendrimers, Nierengarten 2017, showed different dendrimers using fullerene hexa-adduct core building blocks bearing twelve equivalent clickable groups (Figure 4). Their post-modification allows for the introduction of twelve equivalent peripheral subunits.

/media/item_content/202212/63886dff77148polymers-14-04077-g010.png

Figure 4. The use of soft/hard nanobuiling blocks to fabricate hierarchical structures using click chemistry. (A) Fullerene is used as the core for the formation of this dendrimer, (B) the polymeric nanoparticles and DNA are coupled using an azide/alkyne click reaction followed by DNA hybridization to form the final hierarchical structure. These figures have been reproduced from other articles ^[20]^[21] under a CC−BY license.

2.2.3. 2D-Nanometer ➔ 3D

In contrast to the other shown categories, the 2D ➔ 3D fabrication using click chemistry is not significantly mentioned in the literature. Moreover, several comprehensive reviews such as ^[22]^[23]^[24]^[25] in the field did not mention click chemistry at all as a possible method for such a purpose.

The first example is the use of molybdenum disulfide MoS₂ nanoflakes in the formation of a hydrogel composite using N,N′-methylenebis(acrylamide) ^[26]. The formed composite has the potential to self-heal at 70 °C which allows it to be an efficient building block for bigger structures. Similarly, exfoliated MoS₂ nanosheets reacted with chitosan-treated polystyrene spheres to form a hierarchical core/shell structure to improve thermal stability and fire safety ^[27].

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