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Abbreviation (ISO4): Prog Chem      Editor in chief: Jincai ZHAO

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Progress in Chemistry >

2023 , Vol. 35 >Issue 5: 721 - 734

DOI: https://doi.org/10.7536/PC221129

Review

Cascade RAFT Polymerization of Hetero Diels-Alder Cycloaddition Reaction

  • Ruyue Cao 1, 2, 3 ,
  • Jingjing Xiao 1, 2, 3 ,
  • Yixuan Wang 1, 2, 3 ,
  • Xiangyu Li 1, 2, 3 ,
  • Anchao Feng , 1, 2, 3, * ,
  • Liqun Zang 1, 2, 3
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  • 1 State Key Laboratory of organic and inorganic composites, Beijing University of Chemical Technology,Beijing 100029, China
  • 2 Beijing Key Laboratory of Preparation and Processing of New Polymer Materials, Beijing University of Chemical Technology,Beijing 100029, China
  • 3 School of Materials Science and Engineering, Center of Advanced Elastomer Materials, Beijing University of Chemical Technology,Beijing 100029, China
* Corresponding author e-mail:

Received date: 2022-12-01

  Revised date: 2023-02-15

  Online published: 2023-04-30

Supported by

National Natural Science Foundation of China(ZK20220198)

Foundation of State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology(oic-202103015)

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Abstract

Diels-Alder (DA) reaction is temperature-reversible, catalyst-free, efficient and fast with none harmful products, making it a favorable choice to build a self-healing and recyclable dynamic covalent elastomer network. However, classic DA reactions (such as the reaction between furan and maleimide) still have the problems of long reaction time, low efficiency and poor chemical modularity. Recent studies have shown that the efficient cascade of HDA reaction (Diels-Alder cycloaddition reaction containing heteroatom sulfur) and RAFT polymerization can be realized by highly reactive dienes reacting with specific RAFT agents, which can reduce the reaction temperature and time of DA. By virtue of the RAFT polymerization, it can control polymer molecular weight and its distribution at the same time. RAFT-HDA cascade reaction shows wide potential applications especially in the preparation of high molecular weight block or grafted polymer and surface modification. In this paper, the research and application of HDA-RAFT cascade reaction in the past 15 years are summarized, existing problems and solutions are discussed and the future development of this field is also prospected.

Contents

1 Introduction

2 RAFT-HDA reaction between cyclic conjugated diene and BPDF/BDEPDF

2.1 Preparation of high molecular weight copolymer by chain extension

2.2 Material surface finish

2.3 self healing and Self reporting materials

2.4 crosslinking networks with thermally reversible Crosslinking sites

3 RAFT-HDA reaction between linear conjugated diene and BPDF/BDEPDF

3.1 Preparation of high molecular weight copolymer by chain extension

3.2 Material surface finish

3.3 self healing and Self reporting materials

3.4 crosslinking networks with thermally reversible Crosslinking sites

4 Others

5 Conclusion and outlooks

Key words： hetero Diels-Alder cycloaddition reaction; RAFT polymerization; graft polymer; surface modification

Cite this article

Ruyue Cao , Jingjing Xiao , Yixuan Wang , Xiangyu Li , Anchao Feng , Liqun Zang . Cascade RAFT Polymerization of Hetero Diels-Alder Cycloaddition Reaction[J]. Progress in Chemistry, 2023 , 35(5) : 721 -734 . DOI: 10.7536/PC221129

1 Introduction

With the development of modern science and technology, there is an increasing need for purposeful design and precise preparation of polymer materials to meet various "high-demand" applications from biomedicine to nanoscience, which also leads to the development and progress of polymer materials research. Although controlled living polymerization methods such as living anionic polymerization, atom transfer radical polymerization (ATRP) and reversible addition-fragmentation chain transfer polymerization (RAFT) have been widely used in the synthesis of polymer materials with clear structure, diverse composition, controlled molecular weight and narrow molecular weight distribution, they are still difficult to meet the needs of special material properties in many cases[1,2][3,4]. The combination of controlled living polymerization (CRP) and click chemistry can realize macromolecular conjugation and further realize the precise control of the structure, molecular weight and functionalization of polymer materials[5].
Click reaction can regard functional polymers as building blocks, so as to achieve the construction of larger molecular structures and the enrichment of more material functions through click reaction. The widely studied click reactions include: (1) copper (Ⅰ) -catalyzed azide-alkyne cycloaddition (CuAAC); (2) thiol-X reactions, including radical-mediated thiol-ene and thiol-alkyne reactions. The CuAAC reaction can be completed in a few hours at room temperature and in benign solvents such as water, but the use of copper catalysts limits its biomedical and other applications. The outstanding advantage of the thiol-X reaction is that the reaction is fast, and it takes seconds to minutes to achieve complete conversion under ambient conditions. However, the possibility of thiols reacting with a variety of chemical substrates limits their orthogonality, resulting in side reactions, and the low stability and special taste of sulfhydryl compounds limit their application[6]. The Diels-Alder (DA) reaction is a reversible organic cycloaddition reaction, and its reaction mechanism is shown in Figure 1A: the 4π electron of the dienophile adds to the 2π electron of the dienophile to form a transition state structure, followed by the formation of a product molecule with a stable structure[7]. The DA reaction is temperature-reversible, catalyst-free, efficient and fast, and free of harmful products, making it a favorable choice for the construction of self-healing and recyclable dynamic covalent elastomer networks. The DA reaction meets some of the characteristics of the click reaction (easy availability and stability of raw materials, high efficiency and yield, mild conditions, no by-products and high selectivity), but the modularity of the DA reaction is not good.At the same time, the thermal reversibility of the reaction exists and the reaction temperature between different dienophiles and dienophile pairs needs to be adjusted. The DA reaction does not conform to the click reaction in the strict sense, so it is more reasonable to classify DA as a "click type" or "efficient conjugation reaction"[8]. However, it is undeniable that the DA reaction has played a prominent role in the construction of various polymers with special structures due to its reaction characteristics, and new DA reactions such as RAFT-HDA reaction and inverse electron demand Diels-Alder (iEDDA) reaction can achieve faster conversion under milder conditions[9][10].
图1 (a) DA反应机理;(b) RAFT-HDA反应机理

Fig. 1 (a) Reaction mechanism of DA;(b) reaction mechanism of RAFT-HDA

At present, the DA reaction still has the following disadvantages: (1) the common diene and dienophile pair system is less; (2) the common DA reaction has a long reaction time (36 ~ 120 H) and a high reaction temperature (more than 110 ℃), which limits the formation of polymer conjugates from thermally unstable compounds through the DA reaction. Taking furan and maleimide as the most mature examples, the DA bond formed by their reaction is thermally reversible, but the forward reaction usually does not occur at a significant rate at room temperature and is not easy to complete when heated. In 2008, the Barner-Kowollik group proposed the concept of RAFT-HDA. Polymers prepared by RAFT polymerization in the presence of an electron-deficient dithioester are conjugated with a material bearing an appropriate diene via a hetero-Diels-Alder cycloaddition reaction, as shown in fig. 1b, resulting in polymers with thermally reversible reaction sites that can achieve on-demand thermally reversible bonding and exfoliation. Among them, the RAFT reagent acts as a chain transfer agent to mediate polymerization on the one hand, and provides a dienophile for DA reaction on the other hand. The DA reaction provides thermally reversible reaction sites for the polymer. The reaction is carried out at room temperature or 50 ° C and takes several minutes to several hours to achieve quantitative conversion. On the one hand, it expands the reaction system of DA reaction diene and dienophile, on the other hand, it achieves lower reaction temperature and shorter reaction time, and at the same time, some HDA reactions have better and more obvious modularization (Fig. 3), which is closer to click reaction.
RAFT polymerization and DA reaction are combined, and part of the characteristics of living polymerization and click reaction are integrated, so that not only can a polymer with a highly crosslinked structure be obtained to generate a very clear structure,Uch as large molecular weight star polymers, block polymers and graft polymers, and can also modify the surface of cellulose or divinylbenzene (DVB) microspheres and prepare networks with self-reporting and self-healing properties. Because the dithioester acts as a dienophile in the RAFT-HDA reaction, the RAFT chain transfer agent that can participate in the RAFT-HDA reaction generally has a strong electron-withdrawing group, which enhances its ability to participate in the HDA reaction while reducing the ability of the RAFT chain transfer agent to mediate monomer polymerization. We believe that the RAFT chain transfer agents that can participate in the RAFT-HDA reaction at present mainly have two structures of benzylpyridin-2-yl dithioformate (BPDF) and diethoxyphosphoryl dithioformate (BDEPDF) as shown in Figure 2.Two types of chain transfer agents, BPDF and BDEPDF, mediate the polymerization of styrene and isobornyl acrylate to obtain a dithioester-terminated polymer as a dienophile that undergoes HDA reaction with a cyclic or linear conjugated diene as shown in fig. 2. In the following, the related research of RAFT-HDA reaction in recent years will be discussed in detail and its future development will be prospected, hoping to provide help for the research and application of RAFT-HDA reaction.
图2 RAFT-HDA反应中可使用的RAFT试剂BPDF/BDEPDF的化学结构

Fig. 2 The structure of RAFT agent used in RAFT-HDA reaction

2 RAFT-HDA reaction of cyclic conjugated dienes with BPDF/BDEPDF

2.1 Preparation of high molecular weight copolymer by chain extension

The RAFT-HDA reaction was first proposed by Barner-Kowollik's group, and then a large number of related studies were carried out. In 2009, they reported the application of RAFT-HDA reaction for the preparation of high molecular weight block copolymers[11]. Cyclopentadienyl end-functionalized polystyrene (PS-Cp) was first prepared as a diene for DA reaction by atom transfer radical polymerization (ATRP) and reversible addition-fragmentation chain transfer polymerization (RAFT),HDA reaction with isobornyl polyacrylate (PiBOA) with dithioester end group obtained by RAFT polymerization, a block copolymer with well-defined structure and small polydispersity (PDI < 1.2) with molecular weight of 34 000~100 000 g·mol-1 was obtained (Figure 3A, B). The reaction proceeds in a very fast manner (less than 10 min in most cases) at ambient temperature and atmospheric conditions, and the reaction is fast and the conditions are mild. This study demonstrates for the first time that RAFT-HDA chemistry can provide high molecular weight block copolymers in a simple and straightforward manner. In 2011, Franck et al. Used nickelocene as the Cp unit source to functionalize polyethylene through ATRP reaction to obtain polyethylene with different molecular weights and capping rates of 94% and 91%, respectively, as the diene for HDA reaction[12]. At the same time, pyridyl dithioester (BPDF) was used as RAFT agent to realize the controlled polymerization of isobornyl acrylate and styrene. Dithioester with pyridine as electron-withdrawing group reacted with cyclopentadiene at 90 ~ 100 ℃ for 20 min to quantitatively form block copolymers of polyethylene with PiBOA and PS, respectively, and new polyethylene based materials with different molecular weights were obtained, which provided a new way for the preparation of block copolymers.
图3 (a) 通过RAFT-HDA反应制备结构明确的嵌段共聚物的一般合成策略 ;(b) HDA前后分子量对比[11]

Fig. 3 (a) General synthetic strategy for producing well-defined block copolymers via the RAFT-HDA click reaction; (b) comparison of molecular weight before and after HDA[11]

In 2014, Barner-Kowollik et al. Prepared a new class of amphiphilic diblock copolymers with temperature-switchable bonds through RAFT-HDA reaction[13]. As shown in fig. 4, styrene and isoprene were copolymerize by RAFT polymerization by preparing trithiocarbonate with bromine end group on tertiary carbon of R group (DMP-Br) as a chain transfer agent, and then that styrene-isoprene copolymer was cyclopentadiene-terminated with dicyclopentadiene nickel to obtain the hydrophobic segment as both the DA reactive diene and the amphiphilic block copolymer. BDEPDF was used as a chain transfer agent to mediate the polymerization of triglyme acrylate to prepare the dienophile for HDA reaction, which was also used as the hydrophilic segment of the amphiphilic block polymer. A temperature-responsive amphiphilic block copolymer, P(I-co-S)-b-PTEGA(16 000 g·mol-1≤Mn≤68 000 g·mol-1,1.15≤D-≤1.32), was prepared by the conjugation of carbon-sulfur double bonds with cyclopentadiene at room temperature using ZnCl2 as a catalyst. The temperature-controlled debonding test of amphiphilic polymers obtained by RAFT-HDA reaction showed that the concept of HDA reversible chain in block copolymers could be extended to amphiphilic systems. The obtained molecular chain is characterized by high controllable accuracy and repeated temperature cycling (> 4 cycles).
图4 制备具有可逆杂DA键的两亲性P(S-co-I)-b-PTEGA嵌段共聚物的合成策略[13]

Fig. 4 Synthetic strategy for the preparation of amphiphilic P(S-co-I)-b-PTEGA block copolymers with a reversible hetero Diels-Alder linkage[13]

Nitrile rubber (NBR) is an important commercial product with a wide range of applications. In 2012, Christoph et al. Connected NBR with styrene-acrylonitrile copolymer (SAN) through RAFT-HDA reaction to construct block copolymers and micro-arm star polymers with excellent elastic elastomers and thermoplastic materials[14]. Through the Hetero-Diels-Alder (HDA) mechanism, the cyclopentadiene-terminated NBR was conjugated with the styrene-acrylonitrile copolymer (SAN) with the dithioester with an electron-withdrawing group as the terminal group, which was synthesized by RAFT polymerization (Figure 5A), to obtain copolymers with molecular weights ranging from 1000~11000 g·mol-1. According to the scheme shown in Figure 5B, 1,4-diazodibutane-2,3 diol is used as a core to obtain the corresponding double-ended RAFT reagent through the copper-catalyzed reaction of azide and alkyne and the subsequent substitution reaction, which mediates the copolymerization of acrylonitrile and butadiene, and then the double-armed styrene-butadiene rubber with dicyclopentadiene functional group is obtained through the substitution reaction of cyclopentadiene nickel and bromine atom. The application of that method in the preparation of the miktoarm star polymer is realize by obtaining the miktoarm star polymer simultaneously have two-arm NBR and two-arm SAN through the reaction of cyclopentadiene and HDA with electron-withdrawing group dithioester, and the star polymer with the molecular weight up to 11 000 g·mol-1 can be obtained. Through RAFT polymerization, the polymerization reaction is effectively controlled, and combined with Diels-Alder reaction, the metal toxicity catalyzed by copper azide is avoided, which further confirms the effectiveness of RAFT-HDA method to construct complex macromolecular structures.
图5 (a) 通过RAFT-HDA反应制备NBR和SAN嵌段共聚物;(b) 通过RAFT-HDA反应制备微臂星形聚合物[14]

Fig. 5 (a) Preparation of NBR and SAN block copolymers by RAFT-HAD reaction;(b) Preparation of micro-armed star-shaped polymers by RAFT-HDA reaction[14]

By combining controlled/living polymerization with orthogonal conjugation, a large number of new materials with diverse functions and structures can be obtained. RAFT-HDA has become one of the representative tools because of its mild and rapid reaction conditions. However, most of the reported RAFT-HDA reactions are carried out in organic solvents, and there are few reports on water as a solvent. In 2012, Glassner's team successfully realized the RAFT-HDA reaction with water as the solvent for the first time[15]. Phosphoryl dithioester and pyridyl dithioester were selected as RAFT reagents to prepare poly (2-hydroxyethyl acrylate) and poly (glucopyranosyl acrylate), respectively, which were used as dienophiles to react with cyclopentadiene-terminated polyethylene glycol in water at ambient temperature without catalyst. A series of tests confirmed the success of the HDA reaction. Water is used as a green solvent, and the RAFT-HDA reaction is carried out in water, and the corresponding product has potential application value in biomedicine, so the RAFT-HDA can be used as a protein functionalization tool.

2.2 Surface modification of materials

Surface modification of materials is an important tool to change the surface properties of materials and thus change the interaction between materials and the environment. For example, modifying the surface of microspheres to obtain shell-functionalized microspheres, so as to realize their application in biomedicine, has become a hot research topic in recent years[16⇓~18]. Surface grafting techniques can be roughly divided into two categories: "grafting to" and "grafting from". For the grafting to technique, the polymer (with appropriate functional groups) reacts with the surface of the material to form covalently linked chains. For the grafting from technique, the polymerization initiator is initially fixed to the surface and then used to initiate polymerization of the monomer from the surface. Both methods can be combined with various living/controlled radical polymerization techniques such as: nitroxide-mediated polymerization (NMP), atom transfer radical polymerization (ATRP) and reversible addition fragmentation chain transfer polymerization (RAFT)[19,20][21⇓~23][24,25]. RAFT polymerization, due to its ability to generate complex macromolecular structures with well-defined end groups and narrow polydispersity, combined with HDA reaction, can be applied to surface modification of materials to achieve high grafting density and efficient surface modification.
In 2010, Leena Nebhani's group modified the surface of DVB microspheres by two different HDA reactions, and used them as samples to quantitatively analyze the surface grafting density of microspheres[26]. Firstly, the microspheres with residual vinyl groups on the surface were capped with cyclopentadiene by substitution reaction between cyclopentadienyl sodium and bromine, and benzyl (diethoxyphosphinyl) dithiocarbamate (BDEPDF) was selected as RAFT reagent.The thiocarbonylthio end-functionalized polymer chain was obtained as the dienophile component, and the HDA reaction occurred between the two to graft the polymer on the surface of the microsphere (Fig. 6). The second method is to directly use the residual vinyl group on the surface of the microsphere as the diene to carry out HDA reaction with the polymer mediated by dithioester with phosphoryl as the Z group. The microspheres were characterized by ATR-IR spectroscopy, confocal microscopy and elemental analysis at different modification stages, which confirmed that the RAFT functionalized polymer was successfully grafted onto the surface of the microspheres.
图6 通过RAFT-HDA反应对微球表面进行改性 [26]

Fig. 6 Surface modification of microspheres by RAFT-HDA reaction[26]

Elemental analysis provides a way to quantify the grafting density in terms of chains per gram as well as chains per square nanometer. The results show that different chemical medium strategies lead to different surface grafting densities. Since the reactivity of cyclopentadiene as a diene is higher than that of vinyl groups, the grafting density obtained in the method using cyclopentadiene-functionalized microspheres is significantly higher than that of styrene-functionalized microsphere systems. On the one hand, from the synthetic point of view, the current work is to effectively functionalize microspheres under ambient conditions, in a short time, without using any catalyst. On the other hand, it can realize the quantitative research and analysis of grafting density. It has a certain application prospect in the design of functional microspheres for chromatographic packaging materials and diagnostic kits.
Cellulose is the most productive renewable biomaterial and has abundant functional groups that can be modified, making it a versatile template for the preparation of biocompatible materials. Therefore, the modification of cellulose is also the focus of research in the field of biomaterials. In 2012, the Barner-Kowollik group utilized the RAFT-HDA reaction as an efficient modular conjugation method for grafting thioamide-terminated functional oligopeptides onto solid cyclopentadienyl (Cp) functional cellulose matrix to generate cellulose-peptide hybrid materials[27]. Functionalization of the peptide with an electron-deficient thiocarbonyl sulfide species with HDA capability generated a novel thioamide functional oligopeptide, which was subsequently reacted with cyclopentadiene-surface-modified cellulose to give a cellulose-peptide hybrid material (Figure 7).
图7 纤维素-肽杂化材料的制备方案[27]

Fig. 7 Preparation scheme of cellulose peptide hybrid materials[27]

Dienophilic functional peptides readily undergo HDA reactions under mild conditions, in solution with synthetic polymers, and on solid (biological) substrates. The dienophilic functional peptide was reacted with cyclopentadiene-functionalized poly (methacrylate) and cellulose, respectively, to produce the corresponding graft polymers. The addition of trifluoroacetic acid (TFA) improved the solubility of the thioamide-functionalized peptide and accelerated the reaction. The authors characterized the cellulose-peptide hybrid materials using high-resolution FT-IR microscopy, XPS, and elemental analysis. The successful "grafting" of the model oligopeptide onto the cyclopentadienyl functionalized cellulose was realized, and the cellulose-peptide hybrid material with antibacterial properties was obtained. The successful grafting of bioactive peptides onto biological surfaces provides a new approach in the fields of tissue engineering, biohybrid materials, and modular surface modification.
Carbon nanotubes (CNTs) are nanomaterials that have been widely studied and industrialized in recent years. As a filler, CNTs can enhance the mechanical strength of the existing polymer matrix and induce the conduction of the polymer[28]. However, in order to achieve efficient and uniform distribution of carbon nanotubes in a given polymer material, proper functionalization of carbon nanotubes is required. In general, when CNTs are mixed with polymeric materials, phase separation and bundling are often observed, resulting in the presence of CNTs in the polymeric compound producing little or no desired effect. Therefore, covalent modification of carbon nanotubes using suitable polymer chains for good intercalation of carbon nanotubes into polymer matrices requires effective and facile strategies.
In 2011, Barner-Kowollik et al. Reacted single-walled carbon nanotubes (SWCNTs) in a dienophile form in a one-step Diels-Alder cycloaddition reaction with diene-terminated polymer chains without premodification[29]. Cyclopentadienyl-terminated poly (methyl methacrylate) (PMMA) was grafted onto SWCNTs at room temperature and without any catalyst at 80 ℃ to complete the surface functionalization of SWCNTs while ensuring the structural integrity of carbon nanotubes. Subsequently, in 2013, they studied the application of RAFT-HDA reaction in the modification of SWCNTs[30]. The HDA reaction of cyclopentadienyl-terminated polymers was carried out on prefunctionalized SWCNTs modified with electron-deficient pyridyl dithioesters. SWCNTs were first oxidized by nitric acid to express carboxyl groups on their surface, and then esterified with hydroxylated pyridyl RAFT reagent to obtain SWCNTs with disulfide ester on their surface. Finally, SWCNTs were modified with cyclopentadiene modified polymethyl methacrylate by HDA reaction, and PMMA was grafted on SWCNTs to complete the modification. The samples were characterized by infrared spectroscopy and thermogravimetric analysis, which qualitatively proved that the surface of SWCNTs was successfully grafted with polymer chains. Compared with the previous case of SWCNTs as direct dienophiles for DA reaction with cyclopentadiene-modified PMMA to obtain surface polymer-grafted SWCNTs, the pre-functionalization of SWCNTs was able to increase the grafting density of polymer chains of selected molecular weight (PMMA,Mn=2700g·mol-1), improving the grafting efficiency by a factor of 2. However, this method is also destructive to SWCNTs, so the final method will depend on the higher grafting density or the more complete structure of SWCNTs.
In 2012, Kaupp's team first realized the grafting of sugar polymers onto cyclopentadiene-functionalized microspheres through RAFT-HDA reaction[31]. Poly (glycidyl methacrylate) microspheres (PGMA) were synthesized by suspension polymerization using azobisisobutyronitrile (AIBN) as initiator. The epoxy group on the surface of PGMA rapidly undergoes a nucleophilic addition reaction with sodium cyclopentadienate, thereby carrying out cyclopentadiene functionalization on the surface of the microsphere, and then serving as a diene for the HDA reaction. At the same time, benzyl pyridine-2-yl dithioformate was used as RAFT reagent, and 3-oxo-acryloyl-1,2: 5,6-di-oxo-isopropylidene-α-D-glucofuranoside was used as monomer to obtain dithioester-terminated sugar polymer by RAFT polymerization. Then the functionalized microspheres were prepared by the conjugation reaction of diene and dienophile in chloroform with TFA as catalyst. The microsphere sugar polymer is endowed with special properties such as high water solubility, polarity, biocompatibility, and specific binding interaction with biomolecules (such as lectins). Opens the way for a range of new aqueous microsphere applications such as (water) chromatography or drug delivery methods.

2.3 Self-healing and self-reporting materials

With the progress and development of scientific research and the increasing demand for technology, there is a demand for more complex, innovative and durable materials. More and more "smart" polymer materials have been developed, such as self-healing and self-reporting materials. Self-healing materials have the ability to change properties triggered by one or more stimuli, such as mechanical force, temperature, pH, light, ultrasound, magnetic fields, or chemicals[32]. The mechanism of the self-healing process is highly dependent on the initial design strategy. On the one hand, the mechanism can be autonomous, meaning that the injury itself triggers the healing process by releasing healing agents (e.g., microcapsules, hollow (glass) fibers, or vasculature) embedded in the injured area. Nonautonomous systems, on the other hand, require external triggers, such as heat, light, or chemical activation, to induce (reversible) cross-linking or polymerization reactions to repair damage[33⇓⇓~36].
However, most self-healing processes are irreversible. Once the healing agent is released or polymerization proceeds, it cannot be used again to heal further damage. Therefore, it is crucial to first report the presence and exact location of the lesion before the actual healing process occurs. As a result, self-reporting materials have emerged, smart materials that can instantly and visibly indicate changes or damage by changing color, fluorescence, or chemiluminescence. In recent years, a lot of research has been done on the preparation of self-reporting materials by RAFT-HDA reaction.
Polymers based on stepwise polymerization can be designed to contain responsive moieties in each repeating unit, potentially degrading the polymer into small molecules, thereby drastically changing the mechanical and physical properties of the polymer. In 2017, Barner-Kowollik et al. Reported a polycarbonate network with self-reporting thermal reversible adhesion/peel on demand characteristics[37]. Reversible connections within the network are based on HDA moieties, which are capable of cleavage and reassociation within minutes depending on temperature. The material carries reversible linkages in each repeating unit, allowing degradation to the level of small molecules, resulting in drastic changes in the physical properties of the network. Phosphoryl dithioester with cyclopentadiene was selected as the HDA reaction pair, which showed binding/stripping behavior within a few minutes between 30 and 140 ° C, resulting in rapid changes in material properties under relatively mild conditions.

2.4 Cross-linked network containing thermally reversible cross-linking sites.

The Diels-Alder reaction is used in polymer synthesis as a method to produce highly cross-linked structures due to the generality of its mechanism and its temperature reversibility. In 2013, Barner-Kowollik's group used P-Di-linker (1,4-phenylenebis (methylene) bis ( (diethoxyphosphoryl) methane dithioformate) as a dienophile with two different bifunctional dienes (one based on IPDI-salicylic acid,Another dicyclopentadiene-terminated poly (isobornyl acrylate-n-butyl acrylate) was subjected to DA reaction to obtain a crosslinked structure, and they explored the factors affecting the decrosslinking of the crosslinked structure[38]. It is proved that the debonding temperature of polymer can also be adjusted by changing the chain length of polymer building blocks, thus changing the entropy released during debonding. There is a direct relationship between the size of the bifunctional dienophile and the debonding temperature. In each case, the inverse Diels-Alder temperature of the bifunctional dienophile decreased significantly (up to 60 ° C) as its chain length increased. It has been shown that for any given pair of reversibly bonded functional groups, the debonding point, i.e., the decrosslinking temperature, can be adjusted simply by changing the chain length of one or both building blocks associated with the functional group, which is also a prominent feature of the RAFT-HDA reaction as a means of macromolecular conjugation.
Adhesives are essential in life, and adhesives obtained by free radical polymerization generally contain irreversible curing networks, resulting in permanent irreversible adhesion. In 2016, Schenzel et al. Used the HDA reaction between cyclopentadiene and phosphoryl dithioester to introduce the corresponding part of thermal reversible stimulation into the adhesive system with low toxic methacrylate polymer as the matrix. An adhesive that can be degraded rapidly (less than 3 min) at a low temperature (≈ 80 ℃) and can be quantitatively analyzed was prepared[39]. The novel adhesive is based on a polymer network formed by free radical polymerization of dimethacrylate, and the crosslinking agent comprises two thermosensitive HDA groups. HDA groups bound in the cross-linked network can undergo cleavage by the reverse reaction that occurs upon heating. Cleavage results in network degradation and degumming with the concomitant formation of highly colored (red) dithioester species. At the same time, the system uses a double-ended cyclopentadiene capped polymer to introduce twice the HDA group, which improves the cracking efficiency in the network. When the adhesive is applied to oral gingiva, the adhesive shows good adhesion ability and rapid and effective peeling ability on demand, and has good application potential in biomedicine.

3 RAFT-HDA reaction of linear conjugated dienes with BPDF/BDEPDF

The HDA reaction between a cyclic conjugated diene and a dithioester is generally a reaction between a cyclopentadiene-terminated polymer and a dithioester-terminated polymer. Due to the high activity of cyclopentadiene as a diene, the conjugation of Cp functional polymers and polymers prepared by RAFT polymerization can be simply carried out in a few minutes under ambient conditions of atmosphere and temperature, but at the same time, the preparation of Cp terminated polymers also has certain difficulties and complexities. By exploring linear conjugated dienes, on the one hand, the preparation of Cp-terminated polymers has been avoided, on the other hand, the application potential and prospects of RAFT-HDA reaction in many aspects have been expanded.

3.1 Preparation of high molecular weight copolymer by chain extension

In 2008, Barner-Kowollik's group successfully used the combination of RAFT and HDA cycloaddition reactions to synthesize PS star polymers with up to four arms[40]. They used diethoxyphosphoryl dithioformate (BDEPDF) and benzylpyridin-2-yl dithioformate (BPDF), two RAFT reagents in which the Z group is a strong electron-withdrawing group,Styrene was used as a monomer to obtain a dithioester-terminated polymer by RAFT polymerization, which was used as a dienophile to conjugate with multifunctional linear conjugated dienes in the presence of zinc chloride as a catalyst. Depending on the number of diene functional groups, the number of polystyrene arms is different, resulting in 2-arm, 3-arm, and 4-arm star polymers, respectively (Figure 8). In addition, star polymers with different molecular weights can be obtained by adjusting the molecular weight of polystyrene. In this protocol, 92% conversion was achieved in 24 H for the phosphoryl diethoxy dithiocarbamate capped polymer and 96% conversion was achieved in 10 H for the pyridine-2-yl dithiocarbamate capped polymer. Quantitative cleavage of the star polymer arm can also be achieved due to the thermal reversibility of the DA reaction. This work verifies the ability of RAFT-HDA reaction in the synthesis of macromolecules with predetermined complex structures.
图8 通过HDA反应制备星形聚合物[40]

Fig. 8 Star polymers via the hetero-Diels-Alder cycloadditiona[40]

In 2008, Sinnwell et al. Realized the combination of RAFT polymerized PS and diene-terminated polycaprolactone (PCL) to form a well-defined PS-b-PCL block copolymer through HDA cycloaddition[41]. The ring-opening polymerization (ROP) of ε-caprolactone was carried out by using PS chains with appropriate dithioester end groups obtained by RAFT polymerization and trans-2,4-hexadien-1-ol as initiator, and PCL with linear conjugated diene end groups was obtained by RAFT-HDA reaction using benzyl diethoxyphosphoryl dithioformate and benzyl pyridine-2-yl dithioformate as chain transfer agents. The research results confirm for the first time that these structures as end groups of polymer systems have similar behavior and can be used for the formation of polymer conjugates. The tendency of electron-poor dithioesters to undergo HDA cycloaddition can be successfully exploited to generate polymer conjugates, helping to expand the field of efficient coupling of polymers.
In 2008, Barner-Kowollik et al. Proposed the first combination of RAFT-HDA reaction and copper-catalyzed azide-alkyne cycloaddition (CuAAC)[42]. Using α-diene-ω-alkyne functionalized polycaprolactone as linear conjugated diene and RAFT polymerized polystyrene with dithioester functional group (Z group is pyridyl), the PS-b-PCL arm was formed by HDA cycloaddition, and then the three-arm star polymer with arm as block polymer was obtained by CuAAC reaction with triazide coupling agent in "arm-first" and "core-first" ways. In both ways, HDA cycloaddition achieved a click efficiency of 94% in the arm-first method and 81% in the core-first method. RAFT living polymerization is combined with DA reaction and click reaction to achieve the purpose of efficiently and controllably preparing well-defined and multifunctional polymers.
With the development of CPR (living controlled polymerization) technology, the synthesis of macromolecules with complex structures has made great progress. The simultaneous CRP method, combined with efficient, orthogonal post-polymerization coupling reactions, broadens the possibility of studying complex macromolecular structures from a single building block. Sinnwell et al. Combined RAFT, ATRP and Diels-Alder reaction to prepare block copolymers of styrene and isobornyl acrylate. Conversion of the bromine groups of multifunctional arm star poly (isobornyl acrylate) polymerized by ATRP to linear conjugated diene end groups followed by HDA reaction via HDA cycloaddition with phosphoryl dithioester end groups of RAFT polymerized polystyrene gave a 12-star graft polymer with a graft density of 77%[43]. The results show that on the one hand, RAFT-HDA reaction has potential in the preparation of complex macromolecules, on the other hand, the introduction of ATRP reaction will expand its preparation and application to more complex macromolecules.
In 2010, Stenzel's team efficiently prepared comb polymers in a "grafting to" manner by combining RAFT polymerization and Diels-Alder reaction[44]. HDA reactive monomer trans-2,4-dienyl acrylate (ttHA) was copolymerized with styrene by RAFT polymerization. Cross-linking was minimized by lowering the monomer concentration (while keeping the conversion of monomer to polymer low), resulting in a living backbone with an average of 10 styrene units with one living side chain diene group. The copolymer poly (n-butyl acrylate) with a dithioester group was then obtained by RAFT polymerization using pyridyldithioformate as a RAFT reagent, and the HDA conjugate cycloaddition reaction between the diene group on the active backbone and the dithioester group on poly (n-butyl acrylate) resulted in a comb polymer with a thermally reversible site (Figure 9). The coupling reaction was completed at 50 ℃ within 24 H, and the grafting rate varied from 75% to 100% with the molecular weight of the two moieties, which further indicated that the chain length of the diene and dienophile had a certain effect on the HDA reaction.
图9 通过RAFT-HDA反应制备梳型聚合物[44]

Fig. 9 Synthetic strategy for the generation of comb polymers via the RAFT-HDA concept[44]

Polymer mechanochemistry is a chemical method that uses polymers as actuators to induce chemical transformation of polymers under the action of mechanical force. In 2014, Jia's group synthesized a new mechanical carrier DAPy-2Br by HDA reaction from dithioester derivatives and open-chain dienes[45]. DAPy-2Br was used as an initiator to initiate the polymerization of methyl acrylate (MA) by single electron transfer living radical polymerization (SET-LRP), and DAPy-2Br was embedded into the polymer chain. The degradation rate constant of PMA homopolymer chain and the cleavage rate constant of polymer chain with mechanophore, the appearance of dithioester detected by UV-Vis and NMR spectra, and the color change of the system were observed, which proved that the cleavage of polymer chain was indeed caused by the mechanically promoted anti-RAFT-HDA cycloaddition reaction. A series of polymers with different molecular weight were synthesized by controlling the feed ratio of MA and DAPy-2Br. The dissociation process was monitored by ultrasonic detection at different time, which proved that the initial molecular weight was an important factor affecting the fragmentation of polymers. The reported mechanophores may broaden the family of polymer mechanochemistry and provide new insights into the development of polymerization methods and new materials.

3.2 Surface modification

In 2008, Barner-Kowollik's group proposed the application of RAFT-HDA in the surface modification of microspheres[46]. They successfully prepared functional core-shell microspheres using a combination of RAFT polymerization and Hetero-Diels-Alder (HDA) chemistry. DVB microspheres with RAFT end groups were synthesized using 1-phenylethyldithiobenzoate as the RAFT reagent during precipitation polymerization. Subsequently, the surface of DVB microspheres was modified by HDA cycloaddition with diene-functionalized PCL under mild reaction conditions (50 ° C, 24 H) (Fig. 10). The dithioester function of the RAFT reagent in the RAFT-HDA reaction serves two purposes: first, the dithioester moiety functions as a RAFT reagent in the synthesis of surface-expressed DVB microspheres, and second, it is used as a reactive dienophile for the HDA reaction with functionalized dienes, performing conjugation on the surface of the microspheres. The functionalized microspheres are obtained by modifying the microspheres in a simple and quantitative manner. The chemical composition and surface functionalization of the microspheres were characterized by optical examination (color changed from purple to white), X-ray photoelectron spectroscopy (XPS) and attenuated total reflection spectroscopy (ATR). The success of surface grafting modification of microspheres was confirmed. The RAFT-HDA grafting technique can conveniently obtain a large number of functional grafted microspheres for application in diagnostic kits or drug delivery.
图10 通过RAFT-HDA反应对二乙烯基苯微球进行表面接枝[46]

Fig. 10 Surface grafting of divinylbenzene microspheres by RAFT-HDA reaction[46]

In 2009, Nebhani et al. Modified the silicon surface by HDA conjugation[47]. Styrene functionalized silicon surface was obtained by pretreatment of silicon surface with 3- (n-styrylmethyl-2-aminoethylamine) -propyltrimethoxysilane (SM-TMS). PiBA-PSDTF was prepared by polymerization of isobornyl acrylate (PiBA) with pyridyl dithioester (PSDTF) as dienophile. A well-defined polymer is grafted onto the silicon surface in a "grafting to" manner. In this work, the stimulated reaction polymer was used for grafting, and the success of grafting well-defined polymer on silicon surface by RAFT-HDA reaction was confirmed by the characterization of groups by infrared spectroscopy, the change of silicon surface roughness by atomic force microscopy, and the change of hydrophilic and hydrophobic properties of silicon surface after PiBA hydrolysis.
Proteins are essential compounds in modern medicine and biotechnology, but their physicochemical properties, especially in terms of solubility and stability, seriously limit their application. One of the most important approaches to these problems relies on the attachment of synthetic polymer chains to produce so-called protein polymer conjugates (PPCs)[48⇓⇓~51].
The most widely used polymer for PPCs today is polyethylene glycol (PEG). In 2020, Beloqui et al. Obtained PPCs based on RAFT-HDA reaction by reacting one end of the synthesized polymer with one or several residues on the protein surface, which expanded the range of available polymers for the preparation of PPCs and avoided the shortcomings of PEG immunogenicity[52]. A reaction protein is obtained by chemical modification as a linear diene,A series of water-soluble acrylic polymers based on ethylene glycol side chain, homopolymer of triethylene glycol methyl ether acrylate (PmTEGA) and copolymer of diethylene glycol ethyl ether acrylate and poly (ethylene glycol methyl ether acrylate) (P (eDEGA-co-mOEGA)), were synthesized by using 2-cyanopropyl dioxyphosphorodithioformate (CPDPDT) as RAFT agent. Protein-polymer conjugates are obtained by modification of the protein by a DA reaction between a conjugated diene and a dithioester. On the one hand, the reaction is carried out at ambient temperature and does not require the addition of a catalyst to fit the ideal conditions for protein functionalization. On the other hand, PmTEGA-based PPCs can improve protein solubility, and P (eDEGA-co-mOEGA) has a lower critical solution temperature (LCST), resulting in thermoresponsive PPCs at a certain temperature. It has research prospects in controlling the activity of biomolecules, triggering reversible self-assembly and biohybrid nanostructures.

3.3 Cross-linked network containing thermally reversible cross-linking sites.

In 2012, Zhou et al. Studied the DA-based reversible reaction of bifunctional isophorone bis (sorbityl carbamate) and bifunctional dithioester 1,4-benzenebis (methylene) bis (diethoxyphosphoryl) methane dithioformate, and used the polymer to carry out a series of reverse DA reactions at different reaction temperatures and times to study its debonding process[53]. It was found that the degumming rate reached the maximum of 59% at 219 ℃ after 30 min. The cross-linking system with reversible cross-linking sites was successfully prepared by RAFT-HDA reaction.
In 2022, Simon et al. Used phosphodithiocarbonylmethylbenzoic acid (PDTMBA) as a dienophile and conjugated C-18 fatty acids as linear conjugated dienes to form HDA adducts[54]. With the epoxy hardener, the HDA adduct was introduced into the epoxy resin as a thermally reversible crosslinking site through the reaction between the amine and the epoxy group (fig. 11A). NMR analysis confirm that that HDA adduct has good thermal reversibility in solution, and the HDA-based epoxy amine coating exhibit excellent scratch healing performance when heated at 95 ℃ compared with the inert control coat (fig. 11B), which is of great significance for the preparation of thermally triggered healing epoxy coatings.
图11 (a) 由蓖麻油、蓖麻酸甲酯和PDTMBA合成HDA硬化剂,(b) 加热前后划痕的OM图像[54]

Fig. 11 (a) Synthesis the HDA hardener from castor oil, methyl ricinoleate and PDTMBA, (b) OM image of scratch before and after heating [54]

4 Study on Novel Dithioester/Diene

RAFT-HDA reaction is widely used in the preparation and research of macromolecules with complex structures. It not only combines the advantages of mild reaction conditions, quantitative conversion and selectivity, but also takes advantage of the good control of chemical structure and microstructure of polymers by RAFT polymerization. However, the biggest limitation of RAFT-HDA reaction is that the RAFT reagent Z group of RAFT-HDA reaction is a strong electron-withdrawing group, which tends to reduce its ability to regulate and control polymerization. Therefore, the selectivity of the polymerizable monomer is limited, and the wide application of RAFT-HDA is restricted. In order to overcome this limitation, new dithioesters and more active dienes have been explored to expand the application of RAFT-HDA reaction, so as to obtain new polymers suitable for biomedical and other fields.

4.1 Research on New RAFT Reagents

In 2009, Barner-Kowollik et al. Synthesized a class of reversible addition-fragmentation chain transfer agents with methylsulfonyl and phenylsulfonyl as Z groups, benzyl methylsulfonyldithiocarbonate (MSDTF) and benzyl phenylsulfonyldithiocarbonate (PSDTF)[55]. Isobornyl acrylate (PiBA) was used as monomer and the above two reagents were used as chain transfer agents for RAFT polymerization. Sulfonyl RAFT reagents can efficiently mediate the polymerization of PiBA, which can be used as a dienophile to react with different dienes, and can carry out effective DA reactions. Compared with the first generation of RAFT-HDA reagents (benzyl benzylphosphoryl dithiocarbamate and benzyl pyridine-2-dithiocarbamate), the reaction mediated by these RAFT-HDA reagents does not require a catalyst and has a similar coupling rate, which is a new type of RAFT-HD a reagent with application potential.

4.2 Research on New High Activity Diene

In 2013, Oehlenschlaeger et al. selected 2-cyanopropyl dithiobenzoate (CPDB), which has the ability to control the polymerization of most common vinyl monomers, as a RAFT reagent to mediate polymerization and act as a dienophile for HDA reaction[56]. 2-Methoxy-6-methylbenzaldehyde as a dienomer precursor under UV irradiation gives highly reactive dienes that undergo HDA reaction with non-reactive (i.e., electron-rich) RAFT reagents. The polymer obtained by RAFT polymerization was placed in acetonitrile solution together with the photoelectric enol, and irradiated by 320 nm ultraviolet light for 3 H. The photoelectric enol was activated into a conjugated diene, which reacted with the dithioester at room temperature to form a quantitative coupling in a short time (Fig. 12). It can be applied to traditional RAFT reagents to increase the selectivity of polymerization monomers and has certain application advantages.
图12 二硫代苯甲酸酯封端的聚甲基丙烯酸甲酯与2-甲氧基-6-甲基苯甲醛的光共轭[56]

Fig. 12 Photo-conjugation of the dithiobenzoate end-capped poly(methyl methacrylate) with 2-methoxy-6-methylbenzaldehyde[56]

Peptides have enhanced stability against protease degradation, small size, and pharmaceutical potential, and have been extensively studied and chemically synthesized to mimic natural cyclic peptides. In 2019, Barner-Kowollik et al. Promoted the chain collapse of synthetic precursor polymers by forming single-chain nanoparticles (SCNPs) through intra-chain crosslinking at high dilution, and realized the simulation of compact, hierarchical (multi-ring) structures in naturally occurring naphthenes with synthetic polymers (Fig. 13)[57]. Firstly, ( (4-cyano-4- ( (phenylcarbonylthio) valeryl) oxy) ethyl) 4- ( (2-formyl-3-methylphenoxy) methyl) benzoate CEFB is prepared as a difunctional chain transfer agent, one end is a dithioester group as a dienophile, and the other end is a photoelectric enol part as a high-activity diene. Copolymers of styrene and chloromethylstyrene were obtained by RAFT polymerization. Monocyclic nanoparticles (SRNPs) were prepared by intramolecular HDA reaction of dithioester with α-methylbenzaldehyde in the terminal group of copolymer (1) under UV irradiation. Subsequent replacement of the chloro group of the CMS moiety by sodium azide via copper (I) -catalyzed azide-alkyne cycloaddition (CuAAC) with the addition of 2,2 '-oxybis (N- (prop-2yn-1-yl) acetamide) (BPAM) as an exo-bifunctional cross-linker. Intramolecular cross-linked SCNPs were obtained. The stepwise folding-activation-folding method introduced in this study opens up a new way to prepare a variety of artificial ring compounds by taking advantage of the versatility of synthetic polymers and the feasibility of orthogonal folding chemistry.
图13 通过逐步折叠活化-折叠过程将单环纳米颗粒(SRNP)作为环肽模拟物的合成路线示意图[57]

Fig. 13 Schematic illustration of the synthetic route toward single-ring nanoparticles (SRNPs) as cyclotide mimetics by a stepwise folding-activation-collapse process[57]

At present, except for the RAFT reagents with phosphoryl and pyridyl groups, there are few related RAFT reagents, only the sulfonyl RAFT reagent, which has a faster HDA reaction rate than the previous RAFT reagents, but has not contributed to the expansion of monomer types suitable for RAFT-HDA reaction. The related research on dienes focuses on the preparation of more active dienes such as photoactivated photoelectric enols. Improving the activity of dienes can break the restriction that the dithioester part of RAFT reagents must be an electron-withdrawing group.The use of common RAFT reagents can mediate the polymerization of more kinds of monomers and participate in the RAFT-HDA reaction at the same time, but the current research is limited to the contribution of photoelectric enols to the further development of RAFT-HDA reaction.

5 Conclusion and prospect

To sum up, the click reaction can produce functional groups for controlled polymerization, thus realizing an efficient cascade of click reaction and controlled living polymerization. In this paper, based on the types of RAFT reagents that can participate in the HDA reaction and the structures of dienes that can participate in the HDA reaction, the common RAFT reagents and dienes for the RAFT-HDA reaction, as well as the preparation and application of modular macromolecules through the HDA reactions between them are summarized.
At present, the commonly used RAFT reagents that can participate in the RAFT-HDA reaction include BPDF/BDEPDF chain transfer agents with strong electron-withdrawing Z groups, and the corresponding dienes mainly include cyclic diene-cyclopentadiene and linear conjugated dienes. BPDF/BDEPDF-mediated polymerization of styrene with isobornyl acrylate gave dienophile building blocks with dithioester end groups. The preparation of cyclic dienes, which are the building blocks of dienes, requires relatively complex steps and is of high difficulty, but at the same time has high reactivity. For linear conjugated dienes, the scope of RAFT-HDA reaction and the potential of its application in different fields are further expanded. Dienophile and dienophile building blocks are combined through HDA reaction to construct larger conjugated molecules, which are applied to the preparation of macromolecular grafting and block copolymers, and further extended to the surface modification of materials. At the same time, combined with the thermal reversibility of DA reaction, the application of RAFT-HDA reaction is extended to the preparation of self-healing, self-reporting materials and thermally reversible crosslinking networks.
However, the RAFT-HDA reaction is limited by the type of RAFT reagents and the electron-deficient nature of RAFT reagents, and the reduction of their ability to mediate monomer polymerization limits the choice of polymerizable monomers, resulting in a corresponding reduction in their reactivity and application range. In order to solve this problem, it is generally from the perspective of the diene and the dienophile. On the one hand, we should find or design RAFT reagents that can react with RAFT-HDA, and increase the types of polymerizable monomers while increasing the types of reactive RAFT reagents, so as to enrich the forms of dienophile building blocks. On the one hand, the preparation and design of higher activity dienes which can react with non-electron-withdrawing dienophiles (dithioesters) can expand the possibility of RAFT-HDA reaction to a greater extent, and produce more forms of macromolecular conjugated building blocks, thus expanding the application scope and potential of RAFT-HDA reaction. In conclusion, RAFT-HDA reaction has become a powerful means for the preparation of modular macromolecules, but its development and application are still facing greater challenges, and it has great potential for development and exploration.

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