**3.6 Microwave-assisted click chemistry**

The use of microwave irradiation in cyclo-addition reactions for click chemistry has also been comprehensively deliberated. It allows efficient internal heat transfer and therefore decreases the reaction time as well as enhances the reaction rate with high yield [76, 77]. The increased temperature can be used over short periods thus avoiding decomposition or polymerization. Ashok and co-workers demonstrated the synthesis of 1,2,3-triazole analogs using microwave irradiations in 8–10 min and examined their antimicrobial activity [78] (**Figure 23 Method 1**). This method has also been applied in the preparation of 1,2,3-triazole analogs of nucleosides [79] (**Figure 23 Method 2)**. In general, those reactions which require prolonged conventional heating are accomplished in just 10–15 min using microwave irradiation. A chronological one pot Ru catalyzed cycloaddition was also designed from primary aryl or aliphatic bromides (**Figure 23 Method 3**) [80].

**Figure 23.** *Microwave assisted synthesis of triazole based scaffolds.*

Burykina *et al*. [67] synthesized different kinds of vinyl sulphides **(35)** in high yields with good selectivity using thiol-yne click reaction using visible light. The designed pathway is transition-metal-free and gave Markonvikov-type product

Recently, Wu *et al*. [68] synthesized triazole analogs **(36)** through photo-redox electron-transfer mechanism. The authors inspected the reaction of benzyl azide with phenylacetylene using diverse photo-catalysts under ambient reaction conditions like room temperature (RT), air, and visible light irradiation. The catalyst (piq)2Ir(acac) or TPPT-Cl catalyzed the formation of triazole derivatives. The designed pathway is high region-selective, high yielding, having a high atom econ-

Ultrasound assisted reactions are milder and faster. The mechanism of ultrasound is based on an acoustic cavitation phenomenon. This technology hastens the reaction in both heterogeneous and homogeneous media, due to amplified energy intake. It shortens the reaction time and augments the competence of the system by triggering the catalyst surface area and removing deposited impurities [69, 70]. A decades ago, Cintas *et al*. [71] depicted the synthesis of 1,4- disubstituted 1,2,3 triazole analogs using Cu under ultrasound irradiation exclusive of a ligand. Later on, a heterogeneous catalytic system, Cu(II) doped clay was used at RT with ultrasonic irradiations [72]. The use of heterogeneous catalyst evaded needless complexity due to copper (I) salt redox protocol that involved the presence of ligands and protecting agents. The reaction is eco-friendly, easy to prepare, and recoverable. One-pot synthesis of 1,4-disubstituted-1,2,3-triazoles was successfully achieved using a benzyl or alkyl halide, sodium azide, and a terminal alkyne under these conditions [73]. The formation of triazole starting from a TMS protected alkynylglycoside was also demonstrated under ultrasound conditions with *in situ*

through a radical photo-redox pathway (**Figure 21 Method 1**).

*Synthesis of ultrasound assisted 1-azido-3-chloropropan-2-ol azido chitin derivatives.*

omy, and using solar catalysis **(Figure 21 Method 2).**

**3.5 Ultrasound assisted click chemistry**

**Figure 21.**

**Figure 22.**

**76**

*Visible light assisted synthesis of vinyl sulphide.*

*Current Topics in Chirality - From Chemistry to Biology*

## **4. Click chemistry in polymer synthesis**

In the past two decades, various polymers have been introduced through ionene synthesis, click chemistry, and Michael addition *via* polycondensation and polyaddition process. Click chemistry reactions are known as reliable, powerful, high-yielding, and selective for the synthesis of novel and combinatorial compounds *via* Diels Alder cyclo-additions, copper-catalyzed azide-alkyne cycloadditions (CuAAC), and azide nitrile cycloadditions process [81, 82]. In 2013, Pasini reviewed the utility of click reaction for the efficient synthesis of macrocyclic structures like polymers, bio-conjugates, and dendrimers in different contexts [83]. Recently, Arslan and Tasdelen systematically reviewed the applications of click chemistry in polymer design and synthesis, and studies based on their architecture like block, cyclic, star, hyperbranched, and graftbrush comb polymers [84].

In 2018, Acik and co-authors demonstrated a simple copper (I)-catalyzed azidealkyne cyclo-addition "click" reaction for the synthesis of polypropylene-graft-poly (L-lactide) copolymers (PP-g-PLAs) using different feeding ratio of alkyne endfunctionalized poly(L-lactide) azide and side-chain functionalized polypropylene in the presence of CuBr/PMDETA and CuAAC [85]. This polymer exhibited special characteristics like good thermal property, wettability and biodegradability.

Öztürk and companions introduced efficient click chemistry inspired synthesis of an amphiphilic copolymer **(41)** from the reaction of propargyl-PEG and terminally azidepoly(ε-caprolactone) in CHCl3 at ambient temperature **(Figure 24)** [86]. This method displayed a synergistic arrangement of hydrophilic PEG and crystalline PCL to furnish novel materials with good applicability.

Yang *et al*. synthesized poly(3-hexylthiophene)-multiwalled carbon nanotube (P3HT-MWCNT) hybrid materials from in-situ click chemistry using Cu(I) / DBU catalytic system [87]. This novel hybrid also termed as organic–inorganic donoracceptor material displayed special characteristics such as better thermal stability, higher melting point of 243.2 °C, good solubility, and optical properties.

Wang *et al*. reported a novel and efficient method for the synthesis of amphiphilic star-like rod-coil block copolymer poly(acrylic acid)-*block*poly(3-hexylthiophene) through the combined effect of atom transfer radical polymerization, quasi-living Grignard metathesis method, and thiol–ene click reaction to furnish narrow molecular weight distribution and well-defined molecular structures [88].

Agrihari *et al.* introduced CuAAC catalyzed synthesis of *p-tert-*butylcalix[4] arene linked benzotriazolyl dendrimers using CuSO4.5H2O and NaN3 to prepare N-1, N-2 type 6 fold compounds in good yields [89]. The synthesized compounds were evaluated for *in vitro* and *in vivo* anti-bacterial studies against a range of microbes and demonstrated good biological potential. Chen and his companions devised superhydrophobic cotton fabric from mercaptan and vinyl trimethoxysilane using ultraviolet irradiation *via* thiol-ene click chemistry [90]. This fabric possesses special characteristics like economic, highly resistant towards acids, acetone, UV light, water, and other liquids.

Henning *et al*. utilized copper-catalyzed azide/alkyne cycloaddition reaction for the efficient synthesis of triazole-based photo-initiators **(42)** for the two-photon polymerization process **(Figure 25)** [91]. Here Me-Mono and Ph-Mono initiators

,N″,N″-

displayed higher tolerability and sensitivity in microfabrication areas.

demonstrated by Luo *et al*. **(Figure 26)** [92].

**Figure 25.**

**Figure 26.**

**Figure 27.**

**79**

*Functionalized poly(1-butene) synthesis.*

*Synthesis of triazole-based photo-initiators.*

*Role of Click Chemistry in Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.96146*

*3-and 4-arm star-shaped poly(2-methyl-N-aziridine)s.*

A novel, facile and efficient synthesis of 3- and 4-arm star-shaped poly (2-methyl-N-aziridine)s **(43, 44)** from ring opening reaction of N-sulfonyl aziridines in the presence of trimethylsilylazide and PMDETA (N,N,N<sup>0</sup>

pentamethyldiethylenetriamine) through click reaction with CuBr and alkyne was

Cai *et al.* presented a one-step click chemistry process for the synthesis of high performance graphene oxide/ styrene-butadiene rubber (GO/SBR) composites using pentaerythritoltetra(3-mercapto propionate) [93]. Experiments and molecular

$$\begin{array}{ll} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2} \cline{2-2$$

**Figure 24.** *Poly(CL-co-EG)star-type amphiphilic coploymer.* *Role of Click Chemistry in Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.96146*

**Figure 25.** *Synthesis of triazole-based photo-initiators.*

**4. Click chemistry in polymer synthesis**

*Current Topics in Chirality - From Chemistry to Biology*

In the past two decades, various polymers have been introduced through ionene

In 2018, Acik and co-authors demonstrated a simple copper (I)-catalyzed azidealkyne cyclo-addition "click" reaction for the synthesis of polypropylene-graft-poly (L-lactide) copolymers (PP-g-PLAs) using different feeding ratio of alkyne endfunctionalized poly(L-lactide) azide and side-chain functionalized polypropylene in the presence of CuBr/PMDETA and CuAAC [85]. This polymer exhibited special characteristics like good thermal property, wettability and biodegradability.

Öztürk and companions introduced efficient click chemistry inspired synthesis of an amphiphilic copolymer **(41)** from the reaction of propargyl-PEG and terminally azidepoly(ε-caprolactone) in CHCl3 at ambient temperature **(Figure 24)** [86]. This method displayed a synergistic arrangement of hydrophilic PEG and crystal-

Yang *et al*. synthesized poly(3-hexylthiophene)-multiwalled carbon nanotube (P3HT-MWCNT) hybrid materials from in-situ click chemistry using Cu(I) / DBU catalytic system [87]. This novel hybrid also termed as organic–inorganic donoracceptor material displayed special characteristics such as better thermal stability,

Wang *et al*. reported a novel and efficient method for the synthesis of amphiphilic star-like rod-coil block copolymer poly(acrylic acid)-*block*poly(3-hexylthiophene) through the combined effect of atom transfer radical polymerization, quasi-living Grignard metathesis method, and thiol–ene click reaction to furnish narrow molecu-

Agrihari *et al.* introduced CuAAC catalyzed synthesis of *p-tert-*butylcalix[4] arene linked benzotriazolyl dendrimers using CuSO4.5H2O and NaN3 to prepare N-1, N-2 type 6 fold compounds in good yields [89]. The synthesized compounds were evaluated for *in vitro* and *in vivo* anti-bacterial studies against a range of microbes and demonstrated good biological potential. Chen and his companions devised superhydrophobic cotton fabric from mercaptan and vinyl trimethoxysilane using ultraviolet irradiation *via* thiol-ene click chemistry [90]. This fabric possesses special characteristics like economic, highly resistant towards acids, acetone, UV light,

higher melting point of 243.2 °C, good solubility, and optical properties.

lar weight distribution and well-defined molecular structures [88].

water, and other liquids.

*Poly(CL-co-EG)star-type amphiphilic coploymer.*

**Figure 24.**

**78**

line PCL to furnish novel materials with good applicability.

synthesis, click chemistry, and Michael addition *via* polycondensation and polyaddition process. Click chemistry reactions are known as reliable, powerful, high-yielding, and selective for the synthesis of novel and combinatorial compounds *via* Diels Alder cyclo-additions, copper-catalyzed azide-alkyne cycloadditions (CuAAC), and azide nitrile cycloadditions process [81, 82]. In 2013, Pasini reviewed the utility of click reaction for the efficient synthesis of macrocyclic structures like polymers, bio-conjugates, and dendrimers in different contexts [83]. Recently, Arslan and Tasdelen systematically reviewed the applications of click chemistry in polymer design and synthesis, and studies based on their architecture like block, cyclic, star, hyperbranched, and graftbrush comb polymers [84].

**Figure 26.** *3-and 4-arm star-shaped poly(2-methyl-N-aziridine)s.*

**Figure 27.** *Functionalized poly(1-butene) synthesis.*

Henning *et al*. utilized copper-catalyzed azide/alkyne cycloaddition reaction for the efficient synthesis of triazole-based photo-initiators **(42)** for the two-photon polymerization process **(Figure 25)** [91]. Here Me-Mono and Ph-Mono initiators displayed higher tolerability and sensitivity in microfabrication areas.

A novel, facile and efficient synthesis of 3- and 4-arm star-shaped poly (2-methyl-N-aziridine)s **(43, 44)** from ring opening reaction of N-sulfonyl aziridines in the presence of trimethylsilylazide and PMDETA (N,N,N<sup>0</sup> ,N″,N″ pentamethyldiethylenetriamine) through click reaction with CuBr and alkyne was demonstrated by Luo *et al*. **(Figure 26)** [92].

Cai *et al.* presented a one-step click chemistry process for the synthesis of high performance graphene oxide/ styrene-butadiene rubber (GO/SBR) composites using pentaerythritoltetra(3-mercapto propionate) [93]. Experiments and molecular

simulation results concluded that these composites displayed upgraded gas permeability, thermal conductivity, dynamic, and static mechanical performances.

Tian and companions demonstrated the synthesis of the functionalized poly(1 butene)**(45)** *via* sequential thiol-ene click reaction and ring-opening polymerization using poly(1,3-butadiene) as a substrate **(Figure 27)** [94]. Here C═C bond was further functionalized from thiol-ene reaction using hydroxyl-containing thiol compounds.

Zhang *et al*. devised synthesis of thiol-maleimide 'click' chemistry based β-cyclodextrin polymers in an aqueous medium without generating by-products [95]. The structure of products was affected by temperature range *i.e.* higher temperature gave higher molecular weighted and compact structures. The obtained polymers showed better dissolution performance and drug complex-forming capacity as compared to the parental structure.

Gao *et al*. reported thiol-ene click reactions in polysulfide oligomers and acrylate monomers to prepare processable and self-healable thermosets and elastomers **(46)** *via* different pathways like photo-initiator, redox-initiator system and base mediated catalytic approaches **(Figure 28)** [96]. Reprocessable and self-healable properties depend upon polymer structure and their synthetic methodology, therefore, DBU based catalytic synthesis displayed better activity as compared to other processes, due to their catalytic efficiency for disulfide bond exchanges.

fabricated membrane exhibited excellent separation (99%) of various oil–water

Synthetic organic chemistry includes the synthesis of biologically active molecules and designing of potent scaffolds. Click chemistry is one of the toolboxes for chemistry, biology, nano, and material sciences. It has vivid applications in the synthesis of organic molecules, polymers, nanoparticles, biosensors, and many more. The concept of click chemistry fulfills the green aspects of a reaction. In this chapter, we have deliberated an incredible flurry of activities in the field of click chemistry inspired synthesis. This study highlights the current advancements in the synthesis of heterocyclic and other cyclic structures using click reactions. The insertion of a triazole ring with the help of click reaction increases the biological activity of the synthesized compounds. Different pathways with metal or metal-free conditions using conventional or non-conventional reaction methods have also been

The authors are grateful to the Department of Chemistry, Mohan Lal Sukhadia University, Udaipur (Raj.), India for providing necessary library facilities for car-

rying out the work. A. Sethiya is thankful to UGC-MANF (201819MANF-2018-2019-RAJ-91971) for providing Senior Research Fellowship to carry out this work. N. Sahiba is very much grateful to CSIR-Delhi (file no. 09/172(0088) 2018-EMR-I), New Delhi for providing Senior Research Fellowship as a financial

emulsion and fouling-resistant ability.

*Role of Click Chemistry in Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.96146*

demonstrated in this chapter.

**Acknowledgements**

**Conflict of interest**

The authors declare no conflict of interest.

support.

**81**

**5. Conclusion**

**Figure 30.**

*PEGylated PAN membranes.*

Zhu *et al*. introduced facile click chemistry assisted poly(2,2,6,6-tetramethylpiperidin-1-oxyl-4-yl methacrylate) graphene oxide composite (PTMA-GO) **(47)** assisted reaction in ambient conditions and utilized them as cathode materials **(Figure 29)** [97]. After completing 300 charge–discharge cycles,the specific capacity was found to be 2.3 times higher for this composite as compared to the PTMA electrode.

Shen *et al.* devised synthesis of superhydrophilic and superoleophobic PEGylated PAN membrane **(48)** from poly (ethylene glycol) methyl ether methacrylate (PEGMA) monomers *via* thiol-ene click chemistry **(Figure 30)** [98]. After this fabrication, pore size of the membrane was reduced and displayed low flux. The

**Figure 28.** *Process able and self-healable polymer synthesis.*

**Figure 29.** *PTMA-GO polymer synthesis.*

*Role of Click Chemistry in Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.96146*

**Figure 30.** *PEGylated PAN membranes.*

simulation results concluded that these composites displayed upgraded gas permeabil-

Tian and companions demonstrated the synthesis of the functionalized poly(1 butene)**(45)** *via* sequential thiol-ene click reaction and ring-opening polymerization using poly(1,3-butadiene) as a substrate **(Figure 27)** [94]. Here C═C bond was further functionalized from thiol-ene reaction using hydroxyl-containing thiol

Gao *et al*. reported thiol-ene click reactions in polysulfide oligomers and acrylate monomers to prepare processable and self-healable thermosets and elastomers **(46)** *via* different pathways like photo-initiator, redox-initiator system and base mediated catalytic approaches **(Figure 28)** [96]. Reprocessable and self-healable properties depend upon polymer structure and their synthetic methodology, therefore, DBU based catalytic synthesis displayed better activity as compared to other pro-

Zhang *et al*. devised synthesis of thiol-maleimide 'click' chemistry based β-cyclodextrin polymers in an aqueous medium without generating by-products [95]. The structure of products was affected by temperature range *i.e.* higher temperature gave higher molecular weighted and compact structures. The obtained polymers showed better dissolution performance and drug complex-forming

ity, thermal conductivity, dynamic, and static mechanical performances.

cesses, due to their catalytic efficiency for disulfide bond exchanges.

Zhu *et al*. introduced facile click chemistry assisted poly(2,2,6,6-tetramethylpiperidin-1-oxyl-4-yl methacrylate) graphene oxide composite (PTMA-GO) **(47)** assisted reaction in ambient conditions and utilized them as cathode materials **(Figure 29)** [97]. After completing 300 charge–discharge cycles,the specific capacity was found to be 2.3 times higher for this composite as compared to the PTMA electrode. Shen *et al.* devised synthesis of superhydrophilic and superoleophobic PEGylated PAN membrane **(48)** from poly (ethylene glycol) methyl ether methacrylate (PEGMA) monomers *via* thiol-ene click chemistry **(Figure 30)** [98]. After this fabrication, pore size of the membrane was reduced and displayed low flux. The

capacity as compared to the parental structure.

*Current Topics in Chirality - From Chemistry to Biology*

compounds.

**Figure 28.**

**Figure 29.**

**80**

*PTMA-GO polymer synthesis.*

*Process able and self-healable polymer synthesis.*

fabricated membrane exhibited excellent separation (99%) of various oil–water emulsion and fouling-resistant ability.
