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[Yasuyuki Nakamura](https://orcid.org/0000-0003-0078-6413), Yi-Shen Huang, [Chih-Feng Huang](https://orcid.org/0000-0002-8062-8708), [Sadaki Samitsu](https://orcid.org/0000-0002-4139-1656)

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[Passerini polymerization of α-lipoic acid for dynamically crosslinking 1,2-dithiolane-functionalized polymers](https://mdr.nims.go.jp/datasets/eebc6375-d8f7-429a-a531-cdd478a2de12)

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Passerini polymerization of α-lipoic acid for dynamically crosslinking 1,2-dithiolane-functionalized polymersThis journal is © The Royal Society of Chemistry 2024 Chem. Commun.Cite this: DOI: 10.1039/d4cc00751dPasserini polymerization of a-lipoic acid fordynamically crosslinking 1,2-dithiolane-functionalized polymers†‡Yasuyuki Nakamura, §*a Yi-Shen Huang,§b Chih-Feng Huang *b andSadaki Samitsu aPasserini polymerization using naturally occurring a-lipoic acid as araw material yields polyamides with 1,2-dithiolane functionalgroups in a one-step reaction. The polyamide exhibits character-istics of an adaptable dynamically crosslinked network throughreversible ring-opening reaction of 1,2-dithiolane, enabling self-healing, reusable strong adhesion, and regeneration throughdecrosslinking and re-crosslinking.1,2-Dithiolane is a five-membered ring structure with adjacentsulfur atoms. This chemical motif is inherent in naturallyoccurring a-lipoic acid (LA), also known as thioctic acid, whichexhibits biological activities such as robust antioxidant proper-ties (Fig. 1a).1,2 In addition, LA derivatives are recognized forvarious applications including the stabilization of quantumdots and metal nanoparticles.3–5 In recent years, considerableattention has been directed towards the utilization of 1,2-dithiolanes in polymer science as a pivotal motif for creating‘‘circular’’ plastics with recyclability,6,7 and adaptable networkswith functionalities like self-healing.8–11 These attributes arebased on the reversible ring-opening reaction of 1,2-dithiolaneand the resulting disulfide-containing chain which has thedynamic covalent bonding character (Fig. 1a). The developmentof methods for introducing the 1,2-dithiolane moiety into apolymer structure enables the creation of polymer materialswith controllable crosslinking and the resulting material prop-erties (Fig. 1b).Due to its natural occurrence and abundance, LA is highlyattractive as a source of the 1,2-dithiolane moiety, making it asustainable raw material for functional polymers. Recently,methods employing LA for polymer synthesis have been exten-sively studied, with most of them utilizing the ring-openingreaction of 1,2-dithiolane to form the S–S backbone ofpoly(disulfide)s.12–15 On the other hand, the 1,2-dithiolane-functionalized (pendant) polymers have high material potentialdue to the broad range of polymer chain structure. The synth-eses of such polymers were achieved through post-modificationof polymers using LA, such as amide condensation betweenthe CO2H group in LA and NH2 group in the polymerFig. 1 (a) The chemical structure of a-lipoic acid (LA), and the reversiblering-opening polymerization of 1,2-dithiolane. (b) Schematic illustration ofreversible polymer networks derived from 1,2-dithiolane functionalizedpolymers. (c) Synthetic routes for 1,2-dithiolane functionalized polymers:(i) grafting LA onto a functionalized precursor polymer, (ii) polymerizationof LA-derived monomer, and (iii) one-step Passerini polymerization of LA(this work).a Data-driven Polymer Design Group, Research Center for Macromolecules andBiomaterials, National Institute for Materials Science, 1-2-1 Sengen, Tsukuba,Ibaraki 305-0047, Japan. E-mail: NAKAMURA.Yasuyuki@nims.go.jpb Department of Chemical Engineering, i-Center for Advanced Science andTechnology (iCAST), National Chung Hsing University, 145 Xingda Road, SouthDistrict, Taichung 40227, Taiwan. E-mail: HuangCF@dragon.nchu.edu.tw† This paper is dedicated to Professor Atsuhiro Osuka on the occasion of his 70thbirthday‡ Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4cc00751d§ These authors contributed equally.Received 16th February 2024,Accepted 27th March 2024DOI: 10.1039/d4cc00751drsc.li/chemcommChemCommCOMMUNICATIONOpen Access Article. Published on 02 April 2024. Downloaded on 4/27/2024 1:00:25 AM.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article OnlineView Journalhttps://orcid.org/0000-0003-0078-6413https://orcid.org/0000-0002-8062-8708https://orcid.org/0000-0002-4139-1656http://crossmark.crossref.org/dialog/?doi=10.1039/d4cc00751d&domain=pdf&date_stamp=2024-04-10https://doi.org/10.1039/d4cc00751dhttps://doi.org/10.1039/d4cc00751dhttps://rsc.li/chemcommhttp://creativecommons.org/licenses/by/3.0/http://creativecommons.org/licenses/by/3.0/https://doi.org/10.1039/d4cc00751dhttps://pubs.rsc.org/en/journals/journal/CCChem. Commun. This journal is © The Royal Society of Chemistry 2024(Fig. 1c).3,10,16,17 LA-derived monomers with the polymerizablefunctional groups have also been developed.9,11,18–20 However,there has been a lack of simple methods for directly utilizing LAas a raw material for polymers possessing the 1,2-dithiolanemoiety as a functional group.The Passerini reaction is a multicomponent reaction thataffords a three-component adduct from a carboxylic acid, analdehyde, and an isocyanide.21,22 Passerini polymerization,which extends the Passerini reaction to polymerization by usingdi-functional components, enables polymer synthesis with aversatile carboxylic acid when dialdehyde and diisocynanideare employed.23–26 1,2-Dithiolane has rich reactivity, under-going ring-opening reactions induced by temperature, light,and external radicals, nucleophiles, and electrophiles. Thesefeatures are the origin of 1,2-dithiolane’s chemistry and func-tions; however, they pose a challenge to polymerizing 1,2-dithiolane-containing monomers while retaining the 1,2-dithiolane moiety.27,28 To address this challenge, Passerinipolymerization provides an opportunity for the direct polymer-ization of LA, owing to the mild reaction conditions and thereaction mechanism without radicals, strong nucleophilic orelectrophilic species (Fig. 1c).In this study, we demonstrated the synthesis of 1,2-dithiolane-functionalized polymers directly using LA as a rawmaterial through Passerini polymerization, and the resultingpolymer exhibited characteristics of a dynamically crosslinkedpolymer network.First, we conducted the Passerini reaction using LA, butyr-aldehyde, and 1,6-diisocyanohexane to test the compatibility ofthe reaction condition for the 1,2-dithiolane moiety. The mix-ture of the three compounds afforded the adduct within 1 h at40 1C, and the 1H NMR analysis of the product confirmed theretention of 1,2-dithiolane moiety (Fig. S1 in ESI‡). Next, weconducted Passerini polymerization using LA, glutaraldehyde,and 1,6-diisocyanohexane (Fig. 2). The reaction in THF solventafforded the polyamide PA-LA with a 1,2-dithiolane pendantgroup derived from LA, whose structure was characterized by IRand NMR spectroscopies (Table 1 and ESI‡). ATR-IR measure-ment of the polyamide exhibited distinctive vibration signalsof nCQO,amide of the main chain amide moiety at 1658 cm�1. Inaddition, nCQO,ester at 1738 cm�1 indicated the presence of anester group, which corresponds to the a-acyloxy polyamidestructure (Fig. S2, ESI‡). These observations confirmed theincorporation of LA into the polymer main chain through theconversion of the CO2H group. The 1H NMR spectra of PA-LAconfirmed proton signals of CH of a-carbonyloxy amide (5.05ppm), amide NH (6.45 ppm), and those in LA-derived 1,2-dithiolane moiety, indicating the successful formation of poly-amide with 1,2-dithiolane pendant group (Fig. 2). The signalobserved at 9.76 ppm was assigned to the remaining CHO atthe polymer chain end, while no peaks assigned to the remain-ing isocyanide group in the polymer were observed. Thisindicated that the chain end structure of the polymer wouldbe CHO group derived from glutaraldehyde. GPC analysis of thePA-LA taken from the reaction mixture resulted in Mn = 6590and Ð = 1.95 (Fig. 3a). From this result, the number of 1,2-dithiolane groups was roughly determined to be 20 in one PA-LA chain on average according to calculations based on themolecular weight of the repeating unit.The study of the polymerization progress found that bothCHO and isocyanide groups were rapidly consumed in the earlystage of polymerization, following third-order reaction kinetics(Fig. 3b). The molecular weight increased with the conversionof functional groups, and nearly reached a plateau after around20–40 hours. The concentration of starting materials correlatedto the molecular weight of polymers, with higher concentra-tions yielded longer polymers (run 2–3). However, excessivelyhigh concentrations led to gelation during the reaction, makingthe analysis difficult. Such gelation was also observed whenCHCl3 was used as a solvent (run 4).After precipitating from a selective solvent (Et2O), the iso-lated PA-LA was crosslinked and insoluble in the solvent usedin the polymerization. Slow evaporation of sodium lipoateaqueous solution is reported to result in the concentration-induced formation of poly(disulfide) via ring-opening reactionof 1,2-dithiolane, which indicates that the reaction occurs evenat room temperature.13 Thus, the isolation of PA-LA causedFig. 2 Reaction scheme and 1H NMR spectrum of PA-LA (sample ofTable 1, run 3).Table 1 Synthesis of PA-LA and PA-LA/HAaRun Carboxylic acidb Solvent Conversion: CHO, NCc (%) Mnd Ðd1 LA THF 97, 100 6590 1.952 LA THFf 88, 100 2980 2.293 LA THFg 98, 100 8740 2.014 LA CHCl3 —e — —5 LA/HA (1/1) THF 99, 100 8860 1.986 LA/HA (1/2) THF 98, 100 8750 2.027 LA/HA (1/4) THF 98, 100 8920 2.00a [Carboxylic acid] : [glutaraldehyde] : [1,6-diisocyanohexane] = 2.2 : 1 : 1.[Carboxylic acid] = 2.0 M. For the detailed conditions, see ESI. b Molarratio is given for lipoic acid (LA) and hexanoic acid (HA) mixture.c Conversions of aldehyde and isocyanide groups calculated by the1H NMR signal intensity of CHO in the starting dialdehyde. d Calcu-lated against PMMA standards. e The reaction mixture became a gelduring the reaction. f [Carboxylic acid] = 1.0 M. g [Carboxylic acid] =2.5 M.Communication ChemCommOpen Access Article. Published on 02 April 2024. Downloaded on 4/27/2024 1:00:25 AM.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article Onlinehttp://creativecommons.org/licenses/by/3.0/http://creativecommons.org/licenses/by/3.0/https://doi.org/10.1039/d4cc00751dThis journal is © The Royal Society of Chemistry 2024 Chem. Commun.such concentration-induced crosslinking. However, the cross-linked PA-LA could be applied for hot-press molding at 150 1C(Fig. 4a). This experiment indicated that the dynamic covalentbond nature of 1,2-dithiolane-derived disulfide bonds in cross-linked PA-LA (Fig. 4b).To study the effect of the number of crosslinking 1,2-dithiolane groups in the polymer chain, copolymerizationusing another carboxylic acid was examined. We conductedPasserini polymerization using LA and hexanoic acid (HA) in1 : 1 ratio, and glutaraldehyde and 1,6-diisocyanohexane(Table 1, run 5). The polymerization successfully afforded PA-LA/HA with high monomer conversion. Polymerization mon-itoring by 1H NMR measurements indicated a random incor-poration of LA and HA units into the polymer chain. Thestructure of PA-LA/HA was further identified, as well as PA-LA(Fig. S3, ESI‡). The Mn = 8860 of PA-LA/HA corresponded totwelve 1,2-dithiolane groups, which is half of the dithiolanedensity compared to PA-LA. Similarly, PA-LA/HA from differentfeeding ratios of LA and HA were synthesized in the samemanner (Table 1, runs 6 and 7).PA-LA and PA-LA/HA (LA/HA = 1/1) exhibited a swellingproperty with a swelling ratio of 120% for PA-LA and 308%for PA-LA/HA using CHCl3 (Fig. 4a). The higher swelling ratio forPA-LA/HA is attributed to the lower crosslink density in the net-work. These swelling behaviours without dissolution indicates thepresence of covalent crosslinks in the material. Thermal gravimetryanalysis (TGA) of these polymers exhibited the 5% thermal decom-position temperatures (Tdeg,5%) above 278 1C, showing their ther-mal robustness (Fig. S4, ESI‡). Differential scanning calorimetry(DSC) measurements revealed the glass transition temperature (Tg)at 29 1C and 24 1C for crosslinked PA-LA and PA-LA/HA, respectively(Fig. S5, ESI‡). The lower Tg of PA-LA/HA is likely due to theincorporation of a less sterically bulky C5-alkyl chain instead of atetramethylene 1,2-dithiolane chain.The viscoelastic properties of the crosslinked PA-LA and PA-LA/HA (LA/HA = 1/1) were characterized by rheology measure-ments. These materials exhibited typical curves of crosslinkedpolymers in temperature ramp measurements, with a notablemodulus at low temperature and a rubbery plateau at hightemperature (Fig. S6 and S7, ESI‡). While both materialsshowed almost identical moduli (approximately 100 MPa) atthe temperature below their respective Tg, PA-LA/HA exhibitedan order of magnitude lower modulus (0.3 MPa) compared tothat of PA-LA (2.3 MPa) at the temperature above their respec-tive Tg. These experiments suggest the potential for tuningviscoelastic properties of these materials using additionalcarboxylic acid. The mechanical property of the material wasfurther examined by a uniaxial tensile test, and PA-LA/HA (1/1)exhibited a stretch ratio of over 500% (Fig. S10, ESI‡).The dynamic covalent bonding nature of S–S bonds in PA-LA(/HA) imparted the characteristics of healable elastomers(Fig. S11, ESI‡) and recyclable adhesives. These polymers hadalmost no tackiness and lacked adhesive strength when theywere simply sandwiched between stainless steel plates underpressure. On the other hand, when these specimens wereheated at 180 1C under pressure for 10–20 min, they displayedsignificant adhesive properties with a shear strength of 10.8MPa for PA-LA/HA (LA/HA = 1/1, Fig. 5). After the break of thespecimen, the polymer was collected and used for a newFig. 3 (a) GPC profiles in the synthesis of PA-LA, (b) the kinetic curve, and(c) Mn evolution against the conversion of CHO group (Table 1, run 1).Fig. 4 (a) Cycle of crosslinked PA-LA: molding, swelling, decrosslinking,and recovery. (b) A plausible mechanism of bond exchanging.Fig. 5 Adhesion cyclic test of PA-LA/HA (1/1) (a) and a demonstratingloading test (b). The standard errors are shown on the bars.ChemComm CommunicationOpen Access Article. Published on 02 April 2024. Downloaded on 4/27/2024 1:00:25 AM.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article Onlinehttp://creativecommons.org/licenses/by/3.0/http://creativecommons.org/licenses/by/3.0/https://doi.org/10.1039/d4cc00751dChem. Commun. This journal is © The Royal Society of Chemistry 2024specimen under the same preparation procedure. The speci-men exhibited adhesion strength again, and this recyclingprocess could be repeated (Fig. 5). This strong adhesion canbe attributed to the polar and flexible main chain of polyamidethat enhances the interaction at the interface, the flexible alkylside chain derived from LA and HA, and dynamic and robustdisulfide crosslinks that reconstruct the network structureenabling a large and optimal contact area.Finally, we studied the solubilization and recovery of thesecrosslinked polymers via catalytic decrosslinking of disulfidebonding. The crosslinked PA-LA was immersed in CHCl3 andadded a catalytic amount of benzyl sulfide (BnSH) and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU).17 The crosslinked poly-mer underwent dissolution in CHCl3, yielding a homogeneoussolution. GPC analysis of the resulting polymer solutionrevealed a profile consistent with that of the precursor PA-LAbefore crosslinking, showing successful decrosslinking (Fig. 6).The recovered PA-LA were crosslinked again by concentratingthe solution or precipitating the polymer using Et2O. Similarly,the decrosslinking of crosslinked PA-LA/HA was achieved in thesame manner (Fig. S12, ESI‡). These experiments suggest thatthe 1,2-dithiolane pendant group allowed facile manipulationof the crosslinked and non-crosslinked structure of the poly-mers, highlighting the recyclability of these polymers.In conclusion, we have developed a synthesis of 1,2-dithiolane-functionalized polymer directly using naturallyabundant LA as a raw material by Passerini polymerization.The resulting dynamically crosslinked polymer exhibited char-acteristics of adaptable elastomers, such as re-processabilityand recyclable adhesion. This work provides easy access to avariety of polymers with 1,2-dithiolane functionalities, whichencompass not only dynamic crosslinking presented in thisstudy but also inherent features of 1,2-dithiolane, such asantioxidant activity and applications in nanomaterials.Y. N., Y.-S. H. and C.-F. H. designed and conceivedthe experiments; Y. N., Y.-S. H., and S. S. conducted theexperiments.This work was partially supported by the Japan Society forthe Promotion of Science KAKENHI Grand No. 23K04845 (Y.N.). Y.-S. H. acknowledges the NIMS Internship Program forsupporting his research at NIMS. The authors thank N. Yama-moto for the experimental support.Conflicts of interestThere are no conflicts to declare.References1 G. P. Biewenga, G. R. Haenen and A. Bast, Gen. Pharmacol., 1997, 29,315–331.2 L. Packer, E. H. Witt and H. J. Tritschler, Free Radicals Biol. Med.,1995, 19, 227–250.3 W. Wang, A. Kapur, X. Ji, M. Safi, G. Palui, V. Palomo, P. E. Dawsonand H. Mattoussi, J. Am. Chem. Soc., 2015, 137, 5438–5451.4 B. C. Mei, K. Susumu, I. L. Medintz, J. B. Delehanty, T. J. Mountziarisand H. Mattoussi, J. Mater. Chem., 2008, 18, 4949–4958.5 H. T. Uyeda, I. L. Medintz, J. K. Jaiswal, S. M. Simon andH. Mattoussi, J. Am. Chem. Soc., 2005, 127, 3870–3878.6 Q. Zhang, Y. Deng, C.-Y. Shi, B. L. Feringa, H. Tian and D.-H. Qu,Matter, 2021, 4, 1352–1364.7 C.-Y. 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