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[Kentaro Tashiro](https://orcid.org/0000-0001-7424-0830)

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Chiral Symmetry Breaking in GelationChiral Symmetry Breaking in GelationKentaro TashiroResearch Center for Macromolecules & Biomaterials, National Institute for Materials Science (NIMS), Tsukuba, JapanCorrespondence: Kentaro Tashiro (TASHIRO.Kentaro@nims.go.jp)Received: 3 October 2025 | Revised: 26 December 2025 | Accepted: 26 January 2026Keywords: chirality | gelation | homochiral selective | secondary nucleation | symmetry breakingABSTRACTChiral symmetry breaking in gelation is a newly emerging research subject whose examples started to be reported after enteringinto this century. Although macroscopic chiral symmetry breaking that spontaneously affords an optically active gel from a race-mic or achiral gelator solution has been regarded as a rare phenomenon, recent studies indicate that it might not be true and thephenomenon has just been overlooked. This review aims to promote the updates of researcher’s understanding of chiral symmetrybreaking in gelation, which can take place with a certain level of probability by optimizing the nucleation conditions for gelation.1 | IntroductionResearches on chiral symmetry breaking phenomena in self-assembly have a relatively long history, where one of the famouspioneering works is the discovery of spontaneous resolution oftartrate salt enantiomers upon crystallization into their conglom-erate forms [1]. It is remarkable that this finding reported byLouis Pasteur in 1848 is even ahead of the establishment ofthe concept of molecular chirality [2, 3], rather helping chemiststo reach the correct understanding of the relationship betweenthe molecular structure and its chirality. At the same time,although chiral symmetry was broken within the individualhomochiral crystals of tartrate, it was still preserved amongthe overall crystals which were optically inactive as comparablenumbers of D- and L-conglomerates resulted from a singlemother solution of racemic tartrate through industrial processes.In contrast, similar crystallization with natural sources of tartratesuch as wines afforded crystals, the majority of which were dex-trorotatory L-conglomerates, as L-tartrate is naturally abundant.Such apparently mysterious observations in 19 C on the crystal-lization behavior of tartrate, dependent on its origin, graduallyevoked the interests in the chiral symmetry breaking phenomenathat can rationalize the origin of homochirality in nature [4]. Oneof the early proposed attractive scenarios to explain the currentchiral symmetry broken state in nature was based on the unidi-rectional crystallization of achiral organic molecules or inorganicsalts into one of the two possible conglomerate forms [5]. Later,examples of emerging chirality enriched in one of the enantiomor-phic forms were also observed in other self-assembling processessuch as J-aggregation [6, 7] or gelation, providing more optionsto figure out how nature could be homochiral from a chiralsymmetry-preserved starting state. Among various self-assemblingprocesses that could exhibit chiral symmetry breaking behavior[8–10], this review particularly focuses on gelation. Gels are lessstructurally ordered than crystals, whichmay be one of the reasonswhy chiral symmetry breaking phenomena in gelation have beenmuch less expected and explored than that in crystallization.However, after entering 21 C, several examples of this phenome-non have started to be reported within these two decades. Majorityof them were using achiral or chiral but fast-racemizing gelators,which have a clear advantage to achieve chiral symmetry breakingin their self-assembly by comparing with nonracemizing chiralones. Typical states at the end of gelation to obtain opticallyactive gels are also different between these two types of gelators(Scheme 1). Owing to their significant differences, the behaviorof these two types of gelators is separately described in the follow-ing two sections. Both sections are composed of two subsections,which are for chiral symmetry breaking in microscopic, that is,within individual nanofibers, and less abundant macroscopic, thatis, the entirety of the gel, levels, respectively. It would be importantto understand that the emergence of the latter needs to fulfill morerequisites than that for the occurrence of the former, where theThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, providedthe original work is properly cited.© 2026 The Author(s). Small Structures published by Wiley-VCH GmbH.Small Structures, 2026; 7:e202500712 1 of 13https://doi.org/10.1002/sstr.202500712Small Structureswww.small-structures.comREVIEWhttps://orcid.org/0000-0001-7424-0830mailto:TASHIRO.Kentaro@nims.go.jphttp://creativecommons.org/licenses/by/4.0/https://doi.org/10.1002/sstr.202500712http://www.small-structures.comhttps://doi.org/10.1002/sstr.202500712homochiral selective assembly is mandatory to occur at intra- aswell as interfiber levels for the macroscopic chiral symmetrybreaking in gelation. Examples in polymer physical gels were alsoincluded as the independent section, though this topic is one of theleast explored ones in the research field of chiral symmetry break-ing in gelation. The following section is served to highlight theunique aspects of chiral symmetry breaking in gelation throughthe comparisons with that in crystallization. Finally, this reviewis closed with an additional section for some applications.2 | Achiral or Fast Racemizing Chiral GelatorsAs mentioned in the introduction of this review, achiral or chiralbut fast-racemizing gelators, in comparison with nonracemizingchiral ones, have a clear advantage in achieving chiral symmetrybreaking in gelation. When a racemic mixture of the latter typeof gelator exhibits a sign of chiral symmetry breaking by afford-ing a gel enriched in one of the enantiomers, for example, theD-enantiomer, at the beginning of gelation as a stochastic fluc-tuation, it inevitably causes the enrichment of the oppositeL-enantiomer in the remaining solution, from which another gelenriched in the L-enantiomer results preferentially (Scheme 2).Due to the presence of such a compensation mechanism to balancethe ratio of two enantiomers in the gel, its chiral symmetry break-ing tends to be suppressed or less significant than in the case of anachiral or chiral but fast-racemizing gelator whose solution isalways free from the enrichment of an enantiomer, and thereforeit is intrinsically irrelevant to the operation of the samemechanism.This difference is the main reason why chiral symmetry breakingin entire of the gel has been mostly observed for the achiral or chi-ral but fast-racemizing gelator.2.1 | Chiral Symmetry Breaking in the IndividualFibersOne of the early examples of chiral symmetry breaking on a sin-gle fiber of the gel was reported by Hong and coworkers in 2008in the gelation of achiral organogelator 1 (Figure 1) [11]. ThisSCHEME 1 | Schematic representations of the macroscopic chiralsymmetry breaking in gelation of achiral and racemic chiral gelatorsto spontaneously afford optically active gels.SCHEME 2 | Schematic representations of the compensation mechanism to balance the ratio of two enantiomers in the gel to suppress the progressof chiral symmetry breaking in gelation of a racemic mixture.FIGURE 1 | Molecular structures of gelators 1–3 and a SEM image ofthe xerogel of 1; Reproduced with permission [11]. Copyright 2008,Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.2 of 13 Small Structures, 2026 26884062, 2026, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/sstr.202500712 by Kentaro Tashiro - National Institute For , Wiley Online Library on [15/03/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons Licensegelator, a para-substituted aromatic compound bearing two alky-lamide moieties, formed gels in aromatic solvents such as tolueneand p-xylene. Its xerogel displayed helically twisted ribbon-likestructures having 4–5 μm in width and a few hundred μm inlength under scanning electron microscopy (SEM) observations.Both of the right- and left-handed helices were present in a singlegel to make the resultant gel circular dichroism (CD) inactive,demonstrating that chiral symmetry is preserved on the entireof the gel although it is broken in the individual twisted fiber.SEM and CD spectroscopy revealed that the handedness of thesehelices was able to be controlled by adding no more than 1% ofenantiomers of similar but chiral compounds (2, 3; Figure 1) attheir gelation, becoming an example of coassembly that followsthe “sergeants and soldiers” principle [12]. Another achiral gela-tor based on long alkylated N-9-fluorenylmethyloxycarbonyl(Fmoc) glycine (4, Figure 2) was found to show chiral symmetrybreaking behavior, not in its gel formation but in the thermalcollapse of the formed gel [13]. When an organogel preparedin ethyl acetate below –15°C, composed of entangled nanofiberswithout any chiral structural features, was heated up to roomtemperature, the gel collapsed to afford a heterogeneous mixtureof the precipitates and a solution. When this phase transition wastraced with SEM, the nanofibrous networks of the initial gel exhib-ited a structural transformation into dendritic twists with both left-and right-handed chirality (Figure 2). Molecular modeling byusing density functional theory (DFT), molecular mechanics(MM), and molecular dynamics (MD) simulations suggested thattwisting of the bilayer structure of the self-assembled 4 wasinduced upon elevation of the temperature.If the molecular structure of gelators becomes more complex, evenif they apparently look achiral, they can behave as chiral but fast-racemizing molecules due to the possible presence of conforma-tional chirality. Bent-shaped amphiphiles 5 having a carboxylicterminal (Figure 3) form an ion pair in aqueous media with smalldendritic polypropyleneimine 6 bearing four amino groups, whichwas found to gel in THF/water via its self-assembly into entanglednetworks of helical ribbons [14]. 5 was believed to adopt a chiralconformation by rotating the aromatic units around the estergroups, whose molecular chirality can be transferred into thesupramolecular chirality through self-assembly into helical rib-bons and tubes with lamellar nanostructures (Figure 3).When an achiral or chiral but fast-racemizing gelator shows chi-ral symmetry breaking in a single nanofiber level by affordingchiral morphologies such as twist or helix, chiral symmetry ofthe corresponding entire gel would be under the strong influenceof the preference of fiber–fiber interactions, where the domi-nance of homochiral selective entanglement of the fibrils pro-motes the entire gel to become homochiral or highly sensitiveto external chiral biases. Urea pentad 7 (Figure 4) containing aro-matic moieties in its backbone self-assembled to form helicalfibrils which undergo further hierarchical nano- or microstruc-ture construction such as braiding, branching, and networking toFIGURE 2 | Molecular structure of gelator 4 and SEM images of itsxerogels; Reproduced with permission [13]. Copyright 2012, AmericanChemical Society.FIGURE 3 | Molecular structures of 5 and 6 whose ion pair undergoes hierarchical assembly to afford a gel composed of helical ribbons and tubes;Reproduced with permission [14]. Copyright 2014, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.FIGURE 4 | Molecular structure of 7 whose gelation is highly responsive to an external chiral bias.Small Structures, 2026 3 of 13 26884062, 2026, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/sstr.202500712 by Kentaro Tashiro - National Institute For , Wiley Online Library on [15/03/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons Licenseafford organogels [15]. Helices of assembled 7 exhibited variousbraiding patters such as homochiral superhelix and heterochiralcrossings, where inversion of the helix sense to achieve homochi-ral interhelix interactions was visualized microscopically. Due tothe possible contribution of the flexibility of the helixes to inverttheir chirality into homochiral assemblies, the resultant gel pos-sesses a responsive nature to external chiral stimuli. While thegel had no CD activity when it was prepared without intentionalcontacts with any external chiral sources, it was found to bereproducibly enriched in right-handed fibrils and become CDactive if the hot precursor solution was filtered through cottonwool. The observed high sensitivity toward chiral biases suggeststhat the gelation process of 7 has a feature close to that of gelatorsexhibiting macroscopic chiral symmetry breaking in their gela-tion as described in the next subsection. Moreover, it wouldbe too early to deny the capability of 7 as well as 1, 4, and 5/6 to spontaneously afford CD active gels, since a change in gela-tion conditions, for example, by stirring a solution for gelation,was found to allow the emergence of macroscopic chiral symme-try breaking in the case of some other gelators described in thefollowing sections (2.2 and 3.2).2.2 | Chiral Symmetry Breaking at the Entire ofthe GelsAs described in 2.1, chiral symmetry breaking in individual fibersfor gelation is not sufficient to make the resultant gel CD active,for which spontaneous production of nonequal amounts of twoenantiomorphic forms of nanofibers is required. While there arestill rooms for the further arguments [16], homochiral selectiveor preferred secondary nucleation is currently believed to playthe critical role for macroscopic chiral symmetry breaking in self-assembly [17]. As the pioneering example, gelation behavior ofcoordination polymers composed of bent-shaped bis-imidazolylligand 8 (Figure 5) and Ag(I) ion was reported by You andcoworkers in 2008, where their 1:1 mixtures in MeOH/water mix-tures afforded tubular nanostructures with a helical feature asvisualized by transmission electron microscopy (TEM) andatomic force microscopy (AFM) [18]. These tubular fibersentangled each other to give a gel, which was found to be CDactive (Figure 5). The sign of the CD signal, located in UV region,showed a fluctuation dependent on the batch of the gel with theequal probability for positive and negative cases, excluding thedecisive effects from external chiral contaminants that shouldcause the unidirectional symmetry breaking behavior.Another example of macroscopic chiral symmetry breakingbehavior of an achiral gelator can be seen in the self-assemblyof cationic triaminoguanidinium derivative 9 (Figure 6), whosechloride salt afforded a gel in MeOH/water mixtures [19]. ASEM image of the xerogel displayed the coexistence of bundledfibers having M and P helical twists (Figure 6), whose origin wasascribed to the helical arrangement of 9 as observed in its crystalstructure. While the corresponding solutions were CD inactive,most of the drop-cast films, that is, 13 cases among 17 samplesfrom these solutions, became CD active with the comparablenumbers of 6 and 7 for positive and negative signs at 372 nm,respectively (Figure 6).Sonication has been recognized as one of the physical triggers tostart gelation [20]. It was also found to promote macroscopic chi-ral symmetry breaking in gelation of cycloalkane-based achiralbisamide gelators bearing long alkyl chains (10, 11; Figure 7)[21]. In their gelation with a series of less polar organic solvents,sonication of a solution not only accelerated the gelation but alsoinduced the production of optically active gel, as demonstratedthrough CD spectroscopy on the resultant powdered xerogelsmixed with KBr. In these cases, sonication was mandatory forthe chiral symmetry breaking, as gels prepared without sonica-tion showed no detectable CD signals.In order to check whether an obtained gel lacks chiral symmetrymacroscopically, CD spectroscopy on the wet or dried gel hasbeen mostly adopted, though it requires careful spectral dataevaluation to exclude the potential contaminations with otherphenomena such as linear dichroism (LD) [22]. Besides this,what CD spectroscopy provides is the averaged information onthe heterogeneous sample, which has been interpreted as the res-idue after the cancelation between the contributions from differ-ent domains having opposite chirality. Custom design of thespectrometer, equipped with a 2D CD scanner, allowed visuali-zation of the domain-dependent sign and intensity of the CD sig-nal from a hydrogel with a pixel size of 0.5 × 0.5 mm [23]. 2,4,6-triaminopyrimidine 12 (Figure 8) and cyanuric acid modifiedwith a hexanoic acid tail 13 coassembled to form a C3-symmetricFIGURE 5 | Molecular structure of 8 whose coordination polymerswith Ag+ ion spontaneously afford CD active gels stochastically;Reproduced with permission [18]. Copyright 2008, The Royal Society ofChemistry.FIGURE 6 | Molecular structure of 9 whose chloride salt gels andexhibits macroscopic chiral symmetry breaking behavior in its film for-mation; Reproduced with permission [19]. Copyright 2016, AmericanChemical Society.4 of 13 Small Structures, 2026 26884062, 2026, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/sstr.202500712 by Kentaro Tashiro - National Institute For , Wiley Online Library on [15/03/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License3:3 rosette structure (Figure 8), which then stacked one anotherto end up with the formation of micron-length fibers that gel inaqueous media. The gel exhibited superhelical structures havingopposite handedness in different domains whose quantitativedistribution was successfully visualized by means of the 2DCD spectroscopy. These results demonstrated that the achiral“rosette” affords an optically active gel via the spontaneous emer-gence of homochiral domains of helical assemblies, opening away to evaluate the heterogeneity of the e.e. values of the mate-rials containing supramolecular chirality.One of the great challenges with a gelator that can spontaneouslyafford optically active gels could be the control of the direction ofmacroscopic chiral symmetry breaking bymeans of chiral physicalforces [24]. Gelation under a vortex flow has been an attractiveapproach by considering the successful examples in aggregatesand other assembling systems [25]. Benzene-1,3,5-tricarboxamideis another C3-symmetric structural motif whose achiral derivativeswere found to afford CD-active gels [26–29]. Liu and coworkersreported that 14 (Figure 9) forms chiral gels whose CD signs andthe major twist of the component fibers showed a clear correlation[26]. In the absence of any chiral sources, chiral symmetry break-ing in gelation of 14 occurred in a random manner. Moreover,the gelation conditions suitable for the emergence of chiral sym-metry breaking for 14 were found to be relatively limited, therebysmall modifications in the molecular structure to design 15(Figure 10) resulted in the loss of the ability to show chiral sym-metry breaking behavior [27]. However, by applying vortex mixingat the gelation, that ability was able to be recovered, where thedirection of chiral symmetry breaking was still uncontrollable(Figure 10). As already described, homochiral selective or pre-ferred secondary nucleation is regarded as the key mechanismto achieve macroscopic chiral symmetry breaking in self-assembly.Vortex mixing is thought to be effective for the promotion of sec-ondary nucleation of the gelator, which can amplify the nonrace-mic stochastic fluctuation at the beginning of the gelation processif homochiral selectivity is operative. In accordance with thisassumption, when the nonracemic assemblies obtained by apply-ing vortex mixing were fed into another gelator solution as thechiral seeds, they successfully controlled the direction of the sym-metry breaking in the following gelation (Figure 10). The vortex-triggering chiral symmetry breaking approach showed a drasticimprovement when the size of the vortex was down to submilli-meter scale [28]. Gelation of 14was conducted on a sophisticatedlydesigned microfluidic device, where multiple microchamberslocated between the inlets and outlets created laminar chiralmicrovortices (Figure 9). On-line monitoring of the CD of theproducts demonstrated the clear correlation between their CD signand the chirality of the applied microvortex. In contrast, gelationof 14 in a stirring cuvette, in which turbulent vortices with muchsmaller shear rate gradients were applied, resulted in the randomproduction of M- and P-chiral gels.FIGURE 7 | Molecular structures of 10 and 11 that exhibit sonication-triggered macroscopic chiral symmetry breaking behavior in their gelation;Reproduced with permission [21]. Copyright 2017, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.FIGURE 8 | Molecular structures of 12 and 13whose 3:3 complex affords gels with domain-dependent heterogeneous CD activity as visualized by 2DCD spectroscopy; Reproduced with permission [23]. Copyright 2019, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.Small Structures, 2026 5 of 13 26884062, 2026, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/sstr.202500712 by Kentaro Tashiro - National Institute For , Wiley Online Library on [15/03/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons LicenseIt is intriguing that a flat C3-symmetric molecular (9, 14, and 15)or supramolecular (12/13) structural feature appears as the rep-resentative for the achiral gelators that exhibit macroscopic chi-ral symmetry-breaking behavior. It is not surprising that thesestructural features are advantageous to afford chiral ID fibrilsthrough the stacking of gelator molecules with a staggeredgeometry. However, how these chiral fibers bundle or entangleeach other homochirally and selectively to give macroscopicallyoptically active gels has not yet been clarified, remaining as oneof the important future targets in this research area.3 | Nonracemizing Chiral GelatorsWhen the molecular structure of a gelator has chirality that canbe retained for a long period, chiral symmetry breaking in gelationhas two different meanings, that is, imbalance in chirality at themolecular and supramolecular levels. As described already, chiralsymmetry breaking of nonracemizing chiral gelators could be lesslikely to be observed than achiral or chiral but fast-racemizinggelators due to the presence of the intrinsic negative feedbackmechanism in the self-assembly of the former. Nevertheless, theirmacroscopic chiral symmetry breaking, if possible, has an attractiveaspect, that is, allowing them to provide a novel method for theresolution of enantiomers, which is absent in the case of the latter.This becomes an additional incentive to pursue the possibilityof chiral symmetry breaking of nonracemizing chiral gelators.Another thing particular to chiral molecules is the necessity forthe preparation of racemic mixtures for experiments. When a race-mic mixture is needed to be obtained by mixing equal quantities ofthe enantiomers, confirmation of the random preference on thedirection of chiral symmetry breaking is crucial to exclude thedecisive effects of artifacts at the mixing of enantiomers, as it isexperimentally inevitable for the “racemic” sample to have a tinydeviation from the exact 1:1 ratio of enantiomers.FIGURE 9 | Molecular structure of 14 and its gelation direction controllable by means of microvortices produced in a microfluidic device;Reproduced with permission [28]. Copyright 2018, Springer Nature.FIGURE 10 | Molecular structure of 15 that exhibits stirring-triggered macroscopic chiral symmetry breaking in its gelation via the promotion ofhomochiral selective secondary nucleation; Reproduced with permission [27]. Copyright 2019, The Royal Society of Chemistry.6 of 13 Small Structures, 2026 26884062, 2026, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/sstr.202500712 by Kentaro Tashiro - National Institute For , Wiley Online Library on [15/03/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License3.1 | Chiral Symmetry Breaking in the IndividualFibersAs like the case of achiral or chiral but fast-racemizing gelators,chiral symmetry breaking in the smallest supramolecular sub-structures for gels, that is, individual nanofibers, would be thefirst requisite to be fulfilled for nonracemizing chiral gelatorsto achieve macroscopic chiral symmetry breaking in gelationfrom a racemic solution of them. It means that the homochiral-selective assembly of the enantiomers needs to be superior to theheterochiral-selective one at this structural level in the assemblyprocess. In 2003, Žinić and coworkers reported the comparisonsof the gelation behavior of enantiopure and racemic bis(aminoalcohol)oxalamide 16 having two chiral centers (Figure 11)[30]. In contrast to the majority of the chiral gelators [31], 16as the form of its racemic mixture (rac-16), showed a better gela-tion capability than one of its enantiopure forms ((S,S)-16) intoluene, indicating the operation of heterochiral-selective inter-actions in the gelation of rac-16. Structural analyses on theirxerogels as well as the corresponding crystals allowed to concludethat rac-16 undergoes homochiral-selective assembly to affordhomochiral layers, which exhibit heterochiral-selective inter-layer hydrogen-bonding interactions to form meso bilayers(Figure 11). Therefore, the resultant gel has no way to be opticallyactive despite the formation of homochiral monolayers. Similarstepwise assemblies composed of 1) spontaneous resolution ofthe enantiomers into homochiral primary nanostructures followedby 2) their heterochiral-selective aggregation were proposed forthe gelation of the racemic forms of phenylglycine-based gelators(17-mn; Figure 12) [32] and lysine-based chiral dendron 18-1,2,3/achiral amine 19-n two-component systems (Figure 12) [33], astheir racemic mixtures also exhibited superior gelation ability thanthe corresponding the enantiopure forms. Operation of heterochi-ral-selective interactions is not always mandatory to suppressmacroscopic chiral symmetry breaking in gelation. In the caseof gelation of N-trifluoroacetylated aminoalcohol 20 (Figure 13)[34], its racemic solution in CCl4 was found to afford an opticallyinactive gel composed of comparable numbers of two types ofenantiomorphic homochiral strings that gave the same X-raydiffraction pattern as that of enantiopure one. While the stereose-lectivity of 20 with no detectable operation of the heterochiral–selective interaction in its gelation seems to be advantageous thanthat of 16, 17, and 18/19 to achieve macroscopic chiral symmetrybreaking, no enrichment of either of the two enantiomers tookplace even in the case of gelation of 20. The aforementioned“intrinsic negative feedback mechanism in the self-assembly froma racemic mixture” (Scheme 2) would be the responsible for thesuppression of macroscopic chiral symmetry breaking in the gela-tion of 20.3.2 | Chiral Symmetry Breaking at the Entire ofthe GelsAlthough macroscopic chiral symmetry breaking in gelation ofnonracemizing chiral gelators has been regarded as a hardly observ-able phenomenon for these decades, its example found in the gela-tion of an Fmoc-protected glutamate derivative (21; Figure 14) wasreported in 2022 by Tashiro and coworkers [35]. The enantiopureFIGURE 11 | Molecular structure of 16 whose racemic mixture shows a better gelation capability than its one of the enantiopure forms due to theheterochiral-selective inter-layer hydrogen-bonding interactions; Reproduced with permission [30]. Copyright 2003, Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim.FIGURE 12 | Molecular structures of 17-mn and acid/base pair 18-1,2,3/19-n that exhibit a feature of the operation of heterochiral-selective inter-actions in their gelation.FIGURE 13 | Molecular structure of 20 that affords an optically inac-tive gel composed of comparable numbers of two types of enantiomorphichomochiral strings.Small Structures, 2026 7 of 13 26884062, 2026, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/sstr.202500712 by Kentaro Tashiro - National Institute For , Wiley Online Library on [15/03/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons Licenseform of 21, as is the case of analogous molecule 22 (Figure 14)[36–38], gels in a wide range of organic solvents. In contrast,rac-21 was found to afford less stable gels or crystals dependenton the solvent, where the gel prepared in acetonitrile was enrichedin either of the enantiomers in a stochastic fashion by leaving asupernatant enriched in the opposite enantiomer. Detailed struc-tural and spectroscopic analyses on the assemblies of 21 as well as22 revealed that rac-21 undergoes homochiral columnar assemblyformation as the result of intermolecular π–π stacking and hydro-gen-bonding interactions. Following surveys newly revealed thatnonracemic gels were also obtained from racemic solutions ofcommercially available Fmoc amino acids such as Fmoc-protectedphenylalanine and tryptophan (23 and 24, respectively; Figure 14)[39], whose gelation behavior had been already well-explored[40–42]. These results suggest that macroscopic chiral symmetrybreaking in gelation of nonracemizing chiral molecules mightnot be an exceptional but rather an overlooked ordinary event,which could be observed for various chiral compounds under opti-mized conditions if their racemic mixtures are able to form gel.Seeding of an optically active gel of 21 or 23 into a racemic solutionof the same gelator was found to determine the enantiomerenriched in the newly formed gel homochiral-selectively, support-ing that homochiral-selective secondary nucleation plays the rolefor achieving chiral symmetry breaking over the entire of the gel.In fact, some approaches in self-assembly, which are known toenlarge the relative contribution of secondary nucleation withrespect to that of primary nucleation, were also effective to obtaina nonracemic gel. One of these approaches is to start the gelationwith the least sufficient concentration to retard the stereochemi-cally random primary nucleation for gelation as much as possible.Another approach is to stir the solution for the self-assembly, asreported in the crystallization of NaClO3 [43] or ortho-phenyleneoligomers [44] into their conglomerates as well as the gelation ofachiral 15. Applications of these two approaches together allowedto afford optically active gels of 23 or 24 from the correspondingracemic mixtures under the solvent conditions otherwise unsuit-able (Figure 15).4 | Covalent Polymer GelatorsA physical gel obtained from covalent polymers can be regarded asan important reference for that made of a low molecular weightgelator, where the former and the latter are composed of covalentand supramolecular polymers, respectively. One of the differencesof the covalent polymer gelators with respect to low molecularweight gelators is the presence of molecular weight distributionin polymers. This feature makes the preparation of an exact race-mic polymer sample difficult, becoming an obstacle for the experi-mental verification of macroscopic chiral symmetry breaking in thegelation of nonracemizing chiral polymers. Meanwhile, achiral pol-ymers that lack asymmetric centers in their structures can adoptchiral conformations such as helix to produce chirality in theirgels, which has a similarity to the assembly of achiral low molecu-lar weight gelators into chiral supramolecular nanostructures.Therefore, this behavior of the covalent polymers can be usedfor seeking the possibility of chiral symmetry breaking in gelationof polymers, as similar to the gelation of achiral small moleculesthat afford twisted supramolecular fibrils as observed for 1 and 4.4.1 | Chiral Symmetry Breaking in the IndividualFibers or DomainsPolymers with controlled tacticity prefer to adopt particularconformations because of the steric requirements. SyndiotacticFIGURE 14 | Molecular structures of 21–24, among which all the attempted gelators (21, 23, and 24) afford gels enriched in one of their enantiomersfrom their racemic mixtures.FIGURE 15 | Enantiomeric excess values of gels obtained from (A) rac-23 in phosphate buffer (PB) and (B) rac-24 in PB/DMSO (9/1, in vol.). Greenand purple-colored values were obtained with and without stirring the solutions for gelation, respectively; Reproduced with permission [39]. Copyright2024, The Royal Society of Chemistry.8 of 13 Small Structures, 2026 26884062, 2026, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/sstr.202500712 by Kentaro Tashiro - National Institute For , Wiley Online Library on [15/03/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons Licensepoly(methylmethacrylate) 25 (Figure 16) is a representativeexample that has been known to form a helical conforma-tion in its physical gel in the presence of solvents [46] and/orπ-electronic compounds such as fullerenes [45] suitable for theirinclusion into the pore of the helix. Therefore, left- or right-handedchirality based on the helicity exists in the individual polymerchain to afford chiral symmetry broken states, while the entire gelsprepared in achiral as well as racemic solvents showed no clearsign of macroscopic chiral symmetry breaking [45].Physical crosslinking of polymers to afford gels can proceedthrough the crystalline domain formation of the polymers.Syndiotactic polystyrene 26 (Figure 17) prefers to adopt thetrans–trans–gauche–gauche (T2G2) helical conformation in itscrystalline domain by including the solvent molecules in the latticespace [48]. One of the typical cocrystalline forms called δ-clathrateof 26 with solvent molecules was found to exhibit alternatingmonolayers of right- and left-handed helices of 26 (Figure 17)[47]. Due to this structural feature of δ-clathrate of 26, the entireof the single crystalline domain as well as the entire of the multiplecrystalline domains in a gel become racemic, although chiral sym-metry was broken within the individual homochiral monolayers.In contrast, another helix-forming achiral polymer, poly(2,6-dimethyl-1,4-phenylene)oxide 27 (Figure 18) gels through thecocrystal domain formation with an enantiomer of chiral solvent,α-pinene, where the structure of the individual single crystaldomain was modeled as the assembly of homochiral helicesof 27 based on the X-ray diffraction data of the cocrystals [49].Cocrystals of 27 obtained from racemic α-pinene also showed verysimilar diffraction pattern, allowing to assume the presence ofhomochiral single crystalline domains. These results might bethe indications of the intriguing potential of 27 to afford unprece-dented macroscopically chiral symmetry broken polymer gels.FIGURE 16 | Molecular structure of 25 that forms a racemic gel composed of right- and left-handed helixes upon inclusion of fullerenes; Reproducedwith permission [45]. Copyright 2007, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.FIGURE 17 | Molecular structure of 26 that forms δ-clathrates with (A) toluene, (B) p-nitroaniline, (C) 1,4-dinitrobenzene, and (D) norbornadienecomposed of alternating monolayers of right- and left-handed helices; Reproduced with permission [47]. Copyright 2013, Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim.FIGURE 18 | Molecular structure of 27 that forms homochiral assembly of left-handed helices upon cocrystallization with (1S)-(–)-α-pinene;Reproduced with permission [49]. Copyright 2012, The Royal Society of Chemistry.Small Structures, 2026 9 of 13 26884062, 2026, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/sstr.202500712 by Kentaro Tashiro - National Institute For , Wiley Online Library on [15/03/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License5 | Similarities and Differences in ChiralSymmetry Breaking in Gelation and Crystallizationof Small MoleculesThe researches on chiral symmetry breaking in self-assembly havebeen developed mainly through studies on that phenomenon incrystallization, which can be used as the most well-explored refer-ences for understanding chiral symmetry breaking in other self-assembling processes. Here the similarities and differences ofchiral symmetry breaking in gelation and crystallization of smallmolecules are discussed to highlight the unique aspects of theformer.5.1 | SimilaritiesWhile the degree of structural similarity of gels and crystalsobtained from the same molecule sometimes becomes a matterof discussion [50], it is still a popular choice to adopt the latterstructure as the first approximation for the former. This is alsopartly because the structural analyses on a crystal can provideample information on the molecular packing, which is not easilyachieved by directly solving the corresponding gel structure.Another similarity can be seen in a way of understanding themechanism of chiral symmetry breaking in gelation and crystal-lization. Recent studies on chiral symmetry breaking in gelationrevealed that some protocols provide the same effects on the fol-lowing self-assembly as is the case of crystallization. Stirring asolution for gelation [27, 39] as well as crystallization [43, 44]was found to enhance the degree of chiral symmetry breakingin both of these two self-assembling processes, suggesting theoperation of a commonmechanism, i.e. homochiral-selective sec-ondary nucleation in gelation and crystallization.5.2 | DifferencesOne of the clear differences in gelation and crystallization as self-assembling processes would be the number of steps in theseprocesses. Gelation of small molecules has at least two distinctsteps composed of supramolecular polymerization to afford nano-fibrils and their entanglement to form entire gel, where chiral sym-metry breaking in individual nanofibers and entire gel alwaysneeds to be considered. In contrast, crystallization involves onlya single step if nucleation and growing processes are not separatelytreated. Therefore, when chiral symmetry breaking is discussed incrystallization, it is usually regarded as a phenomenon within indi-vidual crystals, that is, whether the crystal is conglomerate or race-mate, while comparison of the numbers of two enantiomorphicconglomerates obtained from a solution is less attempted [51].It has also been recognized that a gel structure is sometimes akinetically preferred metastable one, which is then convertedinto a thermodynamically more stable crystalline form in a lon-ger timescale [50]. Such a difference might be originating fromthe different structural requisites for gels and crystals, where 1Dand 3D-ordered molecular packings are mandatory for the for-mer and the latter, respectively. These structural features of gelsand crystals can produce different stereoselective behavior whena mixture of enantiomers is subjected to these self-assemblingprocesses. When a chiral molecule forms 1D supramolecularpolymers, especially via π-stacking and hydrogen-bonding inter-actions, homochiral-selective assembly is assumed to be the pre-ferred choice (Scheme 3) [52]. In accordance with this preference,gelation of 21, 23, and 24 undergo homochiral selectively, as evi-denced by the enrichment of their major enantiomers in the gela-tion of their scalemic mixtures. Crystallization from a mixture ofenantiomers, on the other hand, mostly results the racemate for-mation (Scheme 3) [53], as observed for 21. These contrastingstereochemical preferences indicate the potential advantage ofgelation to achieve chiral symmetry breaking than crystalliza-tion. It is also noteworthy that mixing of enantiomers tends todestabilize gels [31], while racemic crystals are thermodynami-cally more favorable than conglomerates. Because of such mutualinhibitory effects of enantiomers in their gelation, a racemicmixture of a gelator is not always able to afford a gel due tothe suppression of the fibrillation. Although further surveys toincrease the examples of chiral symmetry breaking in gelationSCHEME 3 | Schematic representation of the possible contrast in stereochemical preferences of a racemic mixture of enantiomers in their assem-blies. Their preference toward heterochiral-selective assembly in crystallization has been confirmed experimentally, while that toward homochiralselective assembly in its nanofibrillation for gelation has been proposed recently; Reproduced with permission [39]. Copyright 2024, The RoyalSociety of Chemistry.10 of 13 Small Structures, 2026 26884062, 2026, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/sstr.202500712 by Kentaro Tashiro - National Institute For , Wiley Online Library on [15/03/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons Licenseare necessary to experimentally check the validity of such hypo-thetical idea, it sounds a stimulating prediction that successfulgelation of a racemic mixture can be regarded as a suggestionfor the occurrence of homochiral preferred assembly, where spon-taneous formation of a nonracemic gel is probable by optimizingthe conditions.6 | Contributions to Materials EngineeringAlthough the research history of chiral symmetry breaking ingelation is not long, there have already been examples of engi-neering soft materials by taking advantage of this phenomenon.Since chiral symmetry breaking in gelation of achiral moleculesallows to create chiral and optically active soft materials withoutany chiral sources, it opens a way to use achiral chemicals thatwere directly not applicable so far for the fabrication of func-tional materials such as asymmetric catalysts [54] and circularlypolarized light emitters [55, 56]. The chirality of these gels van-ishes upon gel-to-sol transition or chiral-to-achiral structuralreorganization, suggesting another their potential for the materi-als with on–off functions linked with the assembly–dissociationprocesses [57]. Moreover, the chiral symmetry breaking processesgenerally possess a mechanism to amplify the initially producednondetectable amount of chirality up to the recognizable level[58], gels exhibiting macroscopic chiral symmetry breakingbehavior are potential candidate materials for the ultrasensitivesensing of chirality. The same dynamic feature of these gels, par-ticularly hydrogels, is also attractive for the design of bioadaptivematerials [59] whose chirality, optical purity, and mechanicalproperties can be determined by the mutual effects and responsesof the gels and cultivated cells on them. While these exemplifiedapplications have a certain level of reality, one of the most ambi-tious ideas to make use of the chiral symmetry broken gels wouldbe originating from their unique intrinsic nature, that is, “no onecan predict the direction of symmetry breaking” and “the resultsof the individual symmetry breaking are not reproducible,” as itis a randomly emerging output. Although these properties as amaterial apparently look fatal from the conventional applicationpoint of view, they could be attractive for newly appearing par-ticular demands related with security or artificial intelligencewhere “randomness” or “fluctuation” plays an important role.7 | Future PerspectivesSince chiral symmetry breaking in gelation is a relatively newresearch subject, there are still plenty of rooms for the future tri-als to advance the related research frontiers. As mentioned in 4.1,macroscopic chiral symmetry breaking in covalent polymer gelsis still a missing piece of chiral symmetry breaking phenomenafor their better understanding. It is also fundamentally crucial tounveil the molecular structural features that allow the emergenceof macroscopic chiral symmetry breaking in gelation. Anotherambitious research direction would be the usage of hydrody-namic flows such as Tayler vortex flow for controlling the pro-cesses of chiral symmetry breaking [60] or clarifying the mysteryabout the possible chiral symmetry breaking at the primarynucleation step [16]. Since research on chiral symmetry breakingin gelation can provide valuable insights into what is ongoing atthe nucleation steps by using chirality as a probe, it will alsocontribute to a deeper understanding of the nucleation eventsin several self-assembling processes [61, 62]. As a longer-termtrial, surveys on the effects of gravity on this phenomenon willbe valuable to seek the possibility of chiral symmetry breaking inspace. One of the proposed hypotheses to explain the origin ofhomochirality in nature is the production of chiral symmetrybroken states in space, which was later transferred to earthvia the migration of meteorites such as MurchisonMeteorite con-taining nonracemic isovaline, an amino acid that is rare to befound in nature [63]. Since carbonaceous chondrite, a typicaltype of meteorite found to contain various organic compounds,exhibits the trace of the presence of water in the past [64], itwould be a stimulating idea that a chiral compound such asan amino acid on a meteorite afforded a chiral symmetry-brokenhydrogel, which became the origin of the homochirality on earth.AcknowledgementsThe author acknowledges KAKENHI (JP23K04844) for funding.FundingPart of the works in this review was supported by JSPS KAKENHIJP23K04844.Conflicts of InterestThe author declares no conflicts of interest.Data Availability StatementThe data related to this review can be obtained from the correspondingreferences or their authors.References1. L. Pasteur, “On the Relationships Between the Crystalline Form,Chemical Composition and the Direction of Optical Rotation,”Annales de Chimie Physique 24 (1848): 442.2. L. Bel and J. 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See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons Licensehttps://doi.org/10.1038/s41586-025-09483-0 Chiral Symmetry Breaking in Gelation 1. Introduction 2. Achiral or Fast Racemizing Chiral Gelators 2.1. Chiral Symmetry Breaking in the Individual Fibers 2.2. Chiral Symmetry Breaking at the Entire of the Gels 3. Nonracemizing Chiral Gelators 3.1. Chiral Symmetry Breaking in the Individual Fibers 3.2. Chiral Symmetry Breaking at the Entire of the Gels 4. Covalent Polymer Gelators 4.1. Chiral Symmetry Breaking in the Individual Fibers or Domains 5. Similarities and Differences in Chiral Symmetry Breaking in Gelation and Crystallization of Small Molecules 5.1. Similarities 5.2. Differences 6. Contributions to Materials Engineering 7. Future Perspectives