Stereodefined tetraarylethylenes: Synthesis and applications

Luminescent materials with efficient aggregate‐state emissions are of growing interest due to their widespread applications in chemo‐/biosensing and optoelectronic devices. Aggregation‐induced emission (AIE) opens a new avenue for the applications of aggregate‐state luminescent materials. Among the AIE luminogens (AIEgens), tetraarylethylenes (TAEs) are typical AIEgens with a simple molecule scaffold and could be utilized as a framework for further elaboration, enabling structure‐property‐function relationship studies and multi‐functional applications. Since the existing approaches for the preparation of tetraarylethenes (TAEs) typically produce stereoisomeric mixtures, stereoselective synthesis of tetraarylethenes with desired geometry is a great challenge. In this review, we systematically compile the synthetic methodologies for the construction of TAEs in excellent regio‐ and stereoselectivities. The virtues and limitations of each methodology are discussed in detail as well. Meanwhile, the applications and the differences of properties between TAEs stereoisomers are introduced.


Aggregation-induced emission
Luminescent materials attract considerable attention, thanks to their scientific and technological significance. [1] In principle, luminescent materials are often utilized in aggregatestate rather than in solution-state. [2][3][4] A well-known example is organic light-emitting diodes (OLEDs), which require the luminogenic molecules to exhibit strong photoluminescence in aggregation state. [5][6][7] However, conventionally, numerous fluorescent materials displaying strong emission in dilute solutions suffer from aggregation-caused quenching (ACQ) in the solid state due to the intermolecular π-π stacking interactions between fluorogens. [8][9] Taking N,Ndicyclohexyl-1,7-dibromo-3,4,9,10 perylenetetracarbox-ylic diimide (DDPD) for example, [10] the strong luminescence is observed when it is dissolved in good solvent tetrahydrofuran (THF); however the emission weakened along with increasement of the fraction of poor solvent (H 2 O) ( Figure 1A(i)). Moreover, the ACQ effect seriously affects the practical application of these fluorophores in various aspects, such as poor circularly polarized luminescence performance in condensed phase. [3,11,12] Thus, massive research attempts including the physical, chemical, and supramolecu-This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2021 The Authors. Aggregate published by John Wiley & Sons Australia, Ltd on behalf of South China University of Technology and AIE Institute lar strategies have been dedicated to suppressing the detrimental effect caused by the ACQ. However, it is inherently difficult to circumvent the undesirable quenching pathway while maintaining the unique luminescent effect in aggregate-state. [13][14][15] Fortunately, an opposite and intriguing effect known as aggregation-induced emission (AIE) was disclosed by the group of Tang in 2001. [16] AIE describes a photophysical effect on the luminescence process exhibited by the luminescent materials which are nonemissive in molecular state, but display strong emission in the aggregate state. Specifically, as shown in Figure 1A(ii), when tetraphenylethene (TPE) is dissolved in good solvent (THF), no discernible emission can be observed, whereas the strong fluorescence intensity appeared in aggregate state. [10] Subsequently, intense research efforts toward AIEgens are motivated by the tremendous potential applications of this unique phenomenon, [17][18][19][20][21][22][23] and a series of luminogens displaying AIE effect with desired functions and applications have been reported over the past two decades. [4,18] Up to now, the restriction of intramolecular motion (RIM) which includes both the restricted intramolecular rotation (RIR) and restriction of intramolecular vibration becomes the generally acceptable mechanism for researchers in this fields. [24][25][26] Moreover, the mechanisms of quenching in solution-state and the key role of excited-state molecular transformations F I G U R E 1 (A) ACQ behavior of DDPD (i) and AIE behavior of TPE (ii). Reproduced with permission. [10] Copyright 2013, American Chemical Society. (B) The classification of tetraarylethylenes for AIE are demonstrated by several research groups. [27][28][29][30][31][32] Notably, the nonradiative decay paths of TAEs are related to the steric and electronic characteristics of the substituents on the TPE unit. [28] Furthermore, recent experimental and theoretical studies indicated photocyclization through a conical intersection was one of the major nonradiative decay paths of TAEs in solutions, and the kinetics of the photocyclization process may depend on the stereochemistry of TAEs. [27][28][31][32][33] In addition, J-aggregate formation, twisted intramolecular charge transfer, excited-state intramolecular proton transfer, restriction of access to dark state, and large separation of luminescence centers as well as E/Z isomerization are reported by different research groups in order to shed light on mechanistic pathways for luminescence of AIEgens. [25,33,34] Tetraarylethylenes As a prominent AIE luminogen, tetraarylethylenes (TAEs) are typical AIEgens with a simple molecule scaffold and distinguished AIE effect. In the early reports, the viscositydependent fluorescence quantum yields and fluorescence lifetime of TAEs were disclosed by Muszkat and Rentzepis, which implied its AIE feature. [35][36] Besides, the photophysics of tetraphenylethylene were pioneered by Stegemeyer and coworkers. [37][38] Additionally, the special photophysical behavior of TAEs demonstrated by previous reports significantly facilitates their applications in various functional materials. [36,[39][40][41][42][43][44][45] Compared with other AIEgens, ready functionalization makes TAEs versatile building blocks in the fabrication of optoelectronic devices. For example, blue, green, yellow, and red solid-state emitters with TAEsderived OLEDs are developed in past several decades. [7] Importantly, the facile modification and diversification of TAEs enable structure-property-function relationship studies and extensive applications. In addition, the simple molecular structure with brilliant AIE effect renders TAEs attractive in the construction of new AIE system. The efficient solidstate emissions of TAEs are demonstrated by their widespread applications in the construction of non-doped OLEDs, [46,47] and plenty of fluorophores based on TAEs exhibit a solidstate emission enhancement effect. [3,22] Of particular note, attaching TPE unit to the ACQ fluorophore could implement the turn of ACQ into AIE or AIE enhancement (AIEE). [7,[48][49][50][51] Furthermore, TAEs can be used as models for the studies of cis-trans isomerization of ethylenic double bonds, which is of great significance to AIE research. [52,53] Also, the TAEs are broadly utilized in the construction of metal-organic framework (MOF) and covalent organic frameworks (COF). [54,55] In the light of the aforementioned advantages and significance, substantial synthetic endeavor has been dedicated to designing and preparing manifold TAEs. Overall, classified by the kind of aryl groups, TAEs employed in chemistry and materials science can be divided into five groups, that is, Additionally, the TAEs with four different Ar groups have six structurally similar isomers. It should be noted that the structural diversity of TAEs indeed constructs a powerful platform for exploring their distinguished high-tech applications and providing huge opportunities for elucidating the differences in photophysical property of these stereoisomers. As illustrated by previous observation, [53,[56][57][58][59][60][61][62] stereoisomers may exhibit striking difference in their optical properties and practical applications because of the subtle configuration alteration. Hence, it is highly desirable to obtain pure TAEs stereoisomers. However, due to the indistinguishable aromatic substituents, the truly flexible and stereoselective synthesis of these TAEs still challenges synthetic chemists, and the stereo-control synthesis of [1+1+1+1]-TAEs engrossing up to six stereoisomers is a formidable task to the researchers in AIE domain. Accordingly, the urgent needs of the multifunctional TAEs systems encourage great efforts toward the enhancement of these existing synthetic routes and the development of innovative synthetic strategies. Benefited from the progress in synthetic methodologies, presently, a variety of synthetic methods are available to achieve the divergent and stereoselective construction of structurally complex TAEs molecules. Although there have been ample review articles about TAEs published to introduce their design strategies and applications, [4,18,19] the review focusing on the stereoselective synthesis of TAEs is rare. [63] In this review, we summarized the synthetic methodologies to TAEs with excellent regio-and stereoselectivity. Meanwhile, the virtue and limitation of each methodology were discussed in detail. Additionally, the applications of these synthetic strategies and the utility of the resulting TAEs were briefly introduced. Furthermore, the differences in properties and applications of TAEs stereoisomers were discussed with some typical examples. The synthetic protocols summarized here would be conducive to the straightforward preparation of TAEs with desired geometry and the development of novel AIE-active functional TAEs materials.

SYNTHETIC PROTOCOLS TOWARD STEREODEFINED TAEs
The general synthetic strategies for the TAEs synthesis include the McMurry coupling, Rathore's procedures, and Suzuki-Miyaura cross-coupling (SMCC) as well as transition-metal-catalyzed three-component coupling. Generally speaking, the often-encountered poor stereoselectivity renders the McMurry coupling and Rathore's procedures unsuitable for the straightforward preparation of stereodefined TAEs. The commonly used method to afford pure E-and Z-[2+2]-TAEs relies on HPLC separation of the E/Z-TAEs mixtures or the introduction of unique functional groups into the TAEs skeleton to enlarge their difference in the shape and polarity. For instance, pure E-isomer 1 reported by Liu group in 2016 was successfully separated by HPLC from the E/Z mixture ( Figure 2). [60] In addition, the incorporation of triazole groups into the TPE skeleton enlarges the difference of polarity between the stereoisomers, allowing the macroscopic separation of stereoisomers of 2 via silica-gel column chromatography. [53] Alternatively, SMCCs and transition-metal-catalyzed three-component couplings present significant approaches for the direct synthesis of stereodefined TAEs and have been extensively applied in the synthesis of TAEs-based AIEgens in materials science.

F I G U R E 2
The strategies for the synthesis of pure E-and Z-TAEs [53,60]

McMurry coupling
The McMurry coupling is the reductive coupling of two carbonyl compounds to deliver olefins in the presence of low-valent titanium generated from a titanium source and a reducing agent ( Figure 3A(i)), which was pioneered by McMurry in 1974. [64][65] Generally, this reaction works well for the aromatic carbonyl compounds, although high temperatures and prolonged time are usually required for the deoxygenation. Moreover, trans-olefins are generated in preference in the McMurry reaction. [66][67] Of note, the coupling of two unsymmetrical benzophenones may furnish six products, including two cross-coupling products and four selfcoupling products. If one of the carbonyl compounds was used in sacrificial excess, the cross coupling would be more favored. [66] The advantages of this transformation include the use of readily available starting materials, moderate to good yields, the operational simplicity, and scalable preparation. Lots of tetraarylethenes framework used in materials science are synthesized via the McMurry couplings. However, narrow scope of substrate and functional group incompatibility are often-encountered in the McMurry coupling because of the employment of strong Lewis acid (TiCl 4 ). [67] Besides, with regard to self-coupling, an E/Z mixture of TAEs would be obtained when the unsymmetrical diarylketones are utilized. In most cases, the ratio of the E/Z isomers is poor, but it is worth noting that a few stereodefined TAEs could be directly obtained from the E/Z mixtures generated from the McMurry reaction using appropriate separation methods. For example, the E-and Z-isomers of diyne-TPE can be separated by recrystallization, and the E-and Z-isomers of dialdehyde-TPE can be purified via silica gel column. [53,68,69] In addition, poor stereoselectivity is often-encountered in the cross-coupling, whether or not the diarylketones employed are symmetrical. [66] In the area of AIE research, although numerous AIEgens with TAE-based skeleton are prepared by the McMurry coupling reaction, further functionalization is usually required for the mixtures of generated stereoisomers to ensure the purity of desired stereoisomer. Taking the oxetane-substituted TAE-based AIEgens as a typical example, [59] a mixture of Z-and E-stereoisomers was synthesized from diarylketone 2 via the McMurry coupling, and the oxetane group was then incorporated through nucleophilic F I G U R E 3 (A) McMurry coupling reaction (i) [65] and application of McMurry coupling for TAEs-based AIEgens synthesis (ii). [59] (B) Rathore's procedures (i) [70] and application of Rathore's procedures for TAEs-based AIEgens synthesis (ii) [71] substitution ( Figure 3A(ii)). As a result, the pure Z-isomers 3 and E-isomers 4 could be readily separated by column chromatography.

Rathore's procedures
In 2004, Rathore and coworkers developed an elegant strategy for the rapid access to TAEs during the preparation of polychromophoric hexakis-(tetraphenylethylene) benzene. [72] Subsequently, the scope and the practical synthetic application in the synthesis of unsymmetrical TAEs were documented in 2007. [70] As depicted in Figure 3B(i), Rathore's procedure involves a two-step and one-pot synthetic operation toward TAEs, which can be applicable in the [4+0]-, [3+1]-, and gem-[2+2]-TAEs synthesis. [73] Specifically, the diarylmethyllithium prepared from diarylmethane and n-butyllithium acts as a nucleophile to attack diarylketone, leading to the corresponding tertiary alcohols, which could be easily dehydrated with acid treatment to furnish the target TAEs in excellent yields. For instance, archetypal luminogen tetraphenylethene 5 could be easily obtained by such a procedure. Additionally, substrates bearing two carbonyl groups could be exhaustively coupled with two diarylmethyllithium to yield the product 6 in excellent yield. Significantly, this approach would be of general utility due to the accommodation of bromo-containing starting materials (compound 7), [70] which could be diversified in subsequent reactions such as Bouveault aldehyde synthesis and palladium-catalyzed coupling reactions. Notably, thanks to the simplicity of the experimental operation, this transformation could be utilized in the preparation of large scale of symmetrical or unsymmetrical TAEs with remarkable ease using appropriately selected diarylketone and diarylmethane.
Overall, the Rathore's procedures are popularized in the synthesis of TAEs-based AIEgens. For example, Tang and Sun successfully prepared a pyridinyl-functionalized [3+1]-TAEs AIEgens 8 via sequential reactions of Rathore's procedures and Heck coupling ( Figure 3B(ii)). [71] Nevertheless, stereoselective synthesis of pure [2+1+1]-and E/Z-[2+2]-TAEs is a significant challenge for this synthetic route. In addition, it is significant to highlight that such synthetic strategy is often accompanied by the weak functional group tolerance because of the utilization of organolithium reagents and strong acid.

Suzuki-Miyaura Cross-Coupling
In 2010, Richard F. Heck, Ei-ichi Negishi, and Akira Suzuki received the Nobel Prize in chemistry for their splendid work on the palladium-catalyzed cross-coupling reactions. [74] Up to now, the Suzuki-Miyaura cross-coupling (SMCC) reaction is arguably the most important and practical method for the construction of carbon-carbon bonds, thanks to its wellprecedented functional group compatibility, wide substrate scope, and stereospecific transformation. [75][76][77] Not surprisingly, owing to its robust nature and practicality, the SMCC reaction has become one of the most useful reactions for the preparation of TAEs-based AIEgens. For example, Pdcatalyzed SMCC of 1,1-dibromoalkene with arylboronic acid is a practical and efficient route for preparing gem-TAEs (compound 9-10) ( Figure 4A(i)), [78,79] although it cannot be applied in the preparation of other kinds of TAEs. As displayed in Figure 4A(ii), (E)-1,2-dibromo-1,2-diarylethene generated from trans-dibromination of diarylethyne could be converted into E-[2+2]-TAEs 11 via the mild SMCC reaction. [80] Indeed, this synthetic protocol offered a new strategy for synthesizing E-[2+2]-TAEs isomers which are F I G U R E 4 (A) SMCC of 1,1-dibromoalkene with arylboronic acid (i). [78] Synthetic routes to E-TAEs (ii). [80] (B) Synthesis of tetraborylethylene (i).

Synthetic routes to [4+0]-, [3+1]-, [2+2]-, [2+1+1]-TAEs from vinylboronates (ii).
Stepwise SMCC for E-TAEs synthesis (iii). Compound 15 in THF-water mixtures (iv). Reproduced with permission. [81] Copyright 2020, Wiley VCH challenging to prepare before, thereby obviating difficulties of separating isomers. It is believed that such transformation would become popular in the synthesis of E-[2+2]-TAEs with the development of mild reaction conditions upon the transdibromination of diarylethyne. [82] Given the development of synthetic methodologies on vinylboronate synthesis [83][84][85] and the fact that there are much more aryl halides listed as commercially available than arylboronic acids, a more broadly applicable Suzuki-Miyaura cross-coupling approach to the structurally diverse TAEs from kinds of vinylboronates has recently been developed by the Zhao group. [81] Remarkably, a new tetraborylethylene (TBE) bearing four Bpin (pinacol boronic ester) 12 was synthesized from readily available trichloroethylene. Significantly, TBE is air-stable solid and could be amenable for gram-scale synthesis without chromatography purification ( Figure 4B(i)). Meanwhile, the application of TBE in the preparation of [4+0]-TAEs via four-fold coupling has been demonstrated. What is more, the stereoselective synthesis of -, and gem-TAEs were also developed, which displayed wide substrate scopes and broad functional group compatibility ( Figure 4B(ii)). Furthermore, reactive functional groups (13) and heteroaromatic rings (14,15) were tolerated for these coupling reactions. Notably, an array of pure E-[2+1+1]-and E-[2+2]-TAEs has been prepared by stepwise SMCC of triborylalkenes, representing a crucial supplement to the currently existing methods that suffer from separation issues. Of note, the absolute configuration of the E-isomer products was exemplified by a single crystal X-ray diffraction study of E-[2+2]-TAEs 16 ( Figure 4B(iii)). As illustrated in Figure 4B(iv), the dilute tetrahydrofuran solution of compound 15 was weakly emissive under UV irradiation. However, along with the increasing of water content, the luminescence enhancement of this system was appeared, displaying a splendid AIE effect.
In consideration of the fact that six structurally diverse stereoisomers exist for [1+1+1+1]-TAEs, the stereoselective synthesis of tetraarylethenes with four different F I G U R E 5 (A) Three-fold functionalization of enolphosphate dibromide for the [1+1+1+1]-TEAs synthesis. [86] (B) Sequential chemoselective SMCC for the [1+1+1+1]-TEAs synthesis. [87] (C) Iterative SMCC reactions for [1+1+1+1]-TEAs synthesis [88] aromatic rings is inherently challenging. Indeed, among the various synthetic protocols to TAEs, practical routes for the preparation of [1+1+1+1] conformer are relatively rare. In 2015, Tobrman and coworkers uncovered a general and highly stereoselective pathway toward the [1+1+1+1]-TAEs synthesis. [86] As exemplified in Figure 5A, the single isomer of [1+1+1+1]-TAEs could be generated from the enolphosphate dibromide templates and appropriate aryl nucleophiles via the Pd-catalyzed coupling reactions. Of note, the presence of the activated C−O bond enabled the discrimination of geminal bromine atoms for the subsequent stepwise coupling reactions. Ultimately, the activated C−O bond could serve as a latent leaving group, leading to the desired stereospecific [1+1+1+1]-TAEs via coupling reaction with Grignard or organoaluminum reagents. For example, the stereoisomers 17 and 18 could be prepared by this transformation with acceptable yield. However, the multiple operations and limited functional group compatibility due to the use of organometallic reagents strongly limit their practical application. Alternatively, the sequential chemoselective Suzuki-Miyaura reactions gradually become a powerful gateway to assemble tetraarylethenes with four different aromatic substituents in an excellent level of stereoselectivity. The first example of this synthetic route involving silylborylation and stepwise SMCC reaction is presented in Figure 5B. [87] A highly stereo-and regioselective silylborylation of alkynylboronates was achieved under the Pd-catalyst system. Notably, the C-B bond positioned trans with respect to the Ar 1 groups was proved to be more reactive with an electrophilic Pd(II) intermediate, which may arise from a stronger nucleophilicity by electron flow from the Ar 1 group. Finally, the desired sin-gle isomer of TAE was afforded via the transformation of the silyl group into bromide followed by the Suzuki-Miyaura coupling. As evident from the resulting compound 19, this synthetic route offers significant alternative to [1+1+1+1]-TAEs, although the multistep operations narrow its practical application in TAEs synthesis.
Very recently, Tsuchimoto and coworkers reported that triborylalkenes with one B(dan) (1,8-diaminonaphthyl boronamide) and two B(pin) groups could be employed for the extended π-conjugated molecules synthesis. [88] The application of this methodology to synthesize [1+1+1+1]-TEAs and AIE-active light-emitting molecules has also been demonstrated. As displayed in Figure 5C, the key triborylalkene was generated by the Pt-catalyzed diboration of alkynyl-B(dan)s with B 2 (pin) 2 . Owing to the inertness of C-B(dan) bond, the remained two Bpin groups could engage into the SMCC reactions in preference to the B(dan) group. Of importance to note is that the two B(pin) groups could undergo the cross-coupling reactions in stepwise manner with excellent chemoselectivity, yielding the alkenyl-B(dan)s with three different aryl groups. Ultimately, the acid-induced transformation of the B(dan) group to the B(pin) moiety followed by the SMCC reaction with corresponding aryl halides provided tetraarylalkene with four different aryl groups in excellent yields and stereoselectivity. Remarkably, the unmasking step could be avoided by utilizing the SMCC reaction condition developed by Saito group. [89] Interestingly, stereoisomers 20, 21, and 22 were synthesized from the different alkynyl-B(dan)s via sequential introduction of appropriate aryl rings in a selective order of the three-step SMCC reactions. Conceivably, when the TAEs with desired geometry are needed, F I G U R E 6 (A) Three-component coupling reactions (i). Mechanisms of Palladium-catalyzed three-component coupling reactions (ii). [90] (B) Threecomponent couplings utilizing organotin reagents (i). [91] Three-component coupling reactions utilizing organoboron reagents (ii). [90] Nickel-catalyzed threecomponent coupling reactions (iii). [92] Three-component couplings utilizing Grignard reagents (iv) [93] this protocol would provide a practical and reliable choice allowing chemists to synthesize TAEs-based AIEgens at will.
However, SMCC reactions also suffer from some limitations stemmed from the disadvantages of these transformation. For example, transition-metal complexes and ligands are involved in these synthetic routes, which is costly for large-scale preparation. Besides, quantitative additives in these transformations are crucial to ensure the high efficiency, which fails to meet the requirement of sustainable chemistry.

Transition-metal-catalyzed three-component coupling
In recent decades, three-component coupling reactions catalyzed by transition metal have been developed into robust synthetic strategies for regio-and stereoselective synthesis of highly substituted alkenes. [94] With regard to the construction of TAEs-based AIEgens, compared with the methods described above, three-component reactions stand out in terms of atom and step economy ( Figure 6A(i)). Moreover, the three-component reactions for the synthesis of TAEs enable rapid generation of TAEs complexity from readily available starting materials. Mechanistically, aryl palladium complex generated from the oxidative addition reacts with the alkyne to give the alkenylpalladium species, which then undergoes transmetalation with organometallic reagents and reductive elimination to generate the target compounds (Figure 6A(ii)). During the migratory insertion process, the aryl group from aryl halides is usually incorporated into the less hindered or more electron-rich site of the alkyne, and the aryl group from the organometallic reagents is added to the other end. However, the initial arylpalladium intermediate could undergo transmetalation with organometallic reagents, resulting in the biaryl side product. Of note, the side reactions could be suppressed by the careful screening of reaction conditions. Nonetheless, although the stereoselectivity derived from cisarylpalladation is excellent, the regioselectivity is generally poor when unsymmetrical diarylalkynes are utilized.
The synthetic route to tetraphenylethene 7 utilizing organotin reagents was demonstrated by Kosugi in 1996 (Figure 6B(i)). [91] In addition, an impressive contribution came from the Larock group disclosed a rapid access to TAEs through a three-component coupling of internal alkynes, aryl iodides with arylboronic acids (Figure 6B(ii)). [90,95] As evident from the products 23, 24, and 25, this method provides a convenient and direct gateway to the [4+0]-, [3+1]-TAEs, although the inaccessibility to other types of TAEs is an obvious limitation of this protocol. Remarkably, Hayashi and coworkers disclosed that three-component reaction of Grignard reagents, alkynes, and aryl halides catalyzed by a simple Ni salt was also a reliable and operationally simple F I G U R E 7 (A) trans-selective carbofunctionalization of internal alkynes for E-TAEs synthesis. [96] (B) Hyperconjugation between the electrons of C−Pd σ bond and the p-orbital of boron (i). Palladium-catalysed three-component coupling (ii). Reproduced with permission. [97] Copyright 2019, Springer Nature method for synthesizing [2+1+1]-TAEs with high stereoselectivity ( Figure 6B(iii)). [92] As shown, the [2+1+1]-TAEs 26 and [3+1]-TAEs 27 and 28 could be readily accessed by this approach with moderate yields. Apart from the control of stereochemistry, this process is also incompatible with sensitive functional groups due to the participation of the Grignard reagents. Interestingly, TAEs with sterically hindered aromatic rings such as 29 and 30 could be accessed via the cross-coupling of corresponding Grignard reagents with the alkynes. [93] Most recently, a palladium-catalyzed stereoselective synthesis of trans-TAEs from internal alkynes has been reported by Cheng and coworkers ( Figure 7A). [96] This method proceeded through an unusual anti-carbopalladation of internal alkynes, affording trans-alkenyl palladium species which then underwent transmetalation with aryl boronic acids to give E-[2+2]-TEAs with good stereoselectivity. Significantly, the unusual anti-carbopalladation of internal alkynes resulting from the steric bulk of both the aryl iodides and the ligand was supported by relevant mechanistic studies and DFT calculations. Notably, the representative trans-[2+1+1]-TAEs 31, 32, and 33 were obtained in excellent stereoselectivity and acceptable yields by the synthetic protocol. However, the aryl iodides employed in this transformation must be preinstalled with a group at ortho-position to ensure the high stereoselectivity, resulting in a limited substrate scope. Notably, although all these methods in Figures 6 and 7A are useful in TAEs synthesis, they are unsuitable to prepare unsymmetrical diarylalkynes substrates due to their poor regioselectivity.
Indeed, due to the inherent difficulty to distinguish the two aryl groups in unsymmetrical diaryl alkynes, the control of regioselectivity in the three-component couplings is highly challenging when unsymmetrical diaryl alkynes are involved. In theory, the poor regioselectivity originated from the migratory insertion step could be improved when an alkyne substrate prefunctionalized by a suitable directing group. The directing group is expected to remain intact during the process of three-component coupling, and to be easily transformed to aryl group. To this end, Wang group disclosed a regioselective migratory insertion of internal alkynes that was achieved by using sp 3 -hybridized MIDA (N-methyliminodiacetyl) boron as a directing group. [97] Remarkably, the unique regioselectivity can be explained by the stabilization of TS-1 resulting from the hyperconjugation between the electrons of C−Pd σ bond and the porbital of boron. It is worth noting that the special stabilization arising from such hyperconjugation was verified by DFT analysis. As shown in Figure 7B, this three-component coupling reaction offered a facile approach for the synthesis of triarylalkenyl boronates with good regio-and stereoselectivity. The structure of the triarylalkenyl boron product 34 was exemplified by X-ray diffraction. The resulting triarylalkenyl boronate then underwent stereospecific SMCC reaction with aryl iodide, allowing for an effective and programmable synthesis of TAEs. As exampled by representative compound 35-37, this transformation enabled rapid access to [1+1+1+1]-TEAs with high regioselectivity. Compared with the methods mentioned above, this strategy produces [1+1+1+1]-TAEs via two-step and one-pot synthesis, which is more atom-and step-economic.
Among the various synthetic protocols to TAEs, the methods for the synthesis of TAEs with heteroaromatic rings are still limited. Nevertheless, the rapid and concise synthesis of heteroaromatic TAEs is highly desired given their unique electronic and structural properties, and their broad applications. [20] In 2017, the You group reported an elegant method to afford the tetra(hetero)arylethylenes with two trans-azoles from internal alkynes enabled by F I G U R E 8 (A) trans-selective 1,2-diheteroarylation of internal alkynes (i). Photoluminescence (PL) spectra of 38 in THF/water mixtures (ii). Plots of the emission intensity of 38 in THF/water mixtures (iii). AIE phenomenon of 38 (iv). Reproduced with permission. [98] Copyright 2017, American Chemical Society. (B) Synthesis of TAEs bearing two cis-furan rings (i). Variations of fluorescence quantum yield of 39 with different water fraction (ii). Head to tail packing of 39 (iii). Reproduced with permission. [99] Copyright 2015, Royal Society of Chemistry. (C) Synthesis of TAEs from triazenes. [100] (D) Platform synthesis of TAEs via sequential assembly strategy [101] rhodium/copper co-catalysis, featuring excellent atom and step economy ( Figure 8A). [98] It is significant to underline that this work demonstrated transition metal-catalyzed C-H activation strategies can be employed in the preparation of stereodefined tetrasubstituted alkenes. An array of heteroatom-doped TAE molecules have been synthesized via this trans-selective 1,2-diheteroarylation in a regio-and stereoselective manner. As shown, the PL spectra of representative product 38 in THF-water mixtures exhibited the pronounced AIE effect. Non or negligible change in emission intensity was observed when water faction was less than 60%, and an emission peak at 475 nm emerged when the water content reached 62%. The PL intensity rose to an approximately maximum value with the water faction reaching 75%. Intrigu-ingly, the fluorescent intensity weakened when the water content was more than 75%, probably resulted from the precipitation of 38 from the system due to its poor solubility in water.
A remarkable and particularly interesting protocol for the preparation of TAEs containing two cis-furan rings was developed by the group of Xu in 2015 ( Figure 8B). [99] Under the established reaction conditions, an array of cistetrasubstituted TAEs was obtained in moderate to good yields. What is more, some tetraarylethenes bearing two cisfuran rings possessed distinct AIE features. For instance, higher fluorescence quantum yields (Φ F ) were observed in solid state than in solution for the representative product 39 ( Figure 8B(ii)). However, the phenyl substituted product 40 exhibited very weak emission in both solution and aggregate-state. By analyzing the crystal structures and packing modes of compound 39 and 40, the differences of their photophysical property could be explained by the intramolecular π-π interactions and intermolecular CH⋯O interactions. Specifically, the branched butyl group in the compound 39 can be regarded as a hand to distort the molecular plane, hence circumventing close packing between molecules. Moreover, the intermolecular CH⋯O interaction rendered the whole molecular pack into a relative rigid structure ( Figure 8B(iii)). Conversely, the compound 40 showed a distinct intramolecular π-π stacking, which may be the reason for their quenching in the aggregate state.

Other synthetic strategies
Beyond the reactions discussed above, the synthesis of TAEs promoted by acid has been established recently by coupling aromatic and heteroaromatic compounds with triphenylethenyl triazene reagents. [100] Obviously, this transformation avoids the use of transition-metals and circumvents the limitations in transition-metal catalyzed reactions such as the use of oxygen-sensitive and/or moisture-sensitive catalysts or reagents, providing a convenient entry into a wide range of asymmetric tetraarylethenes. For example, this methodology allowed the direct graft of triarylethenyl groups into bioactive molecules (41), commercial polymers (42), and supramolecular hosts (43) (Figure 8C), highlighting its synthetic utility in the synthesis of TAEs derivatives. However, the safety issue arising from the utilization of triazene reagent should be taken into consideration when using this approach. In addition, this transformation was mainly limited to prepare [4+0]-and [3+1]-TAEs.
The rational design of prefunctionalized starting materials and target-oriented synthesis have been the main stream in the construction of TAEs. Nevertheless, the diversity-oriented synthesis disclosed by Yoshida and coworkers offered a complementary approach to the existing methods, allowing access to TEAs with molecular diversity in a programmable format. [101] As illustrated in Figure 8D, [1+1+1+1]-TAEs can be formed by utilizing vinyl 2-pyrimidyl sulfide as a platform. Firstly, one-pot double Pd-catalyzed Mizoroki-Heck reaction of vinyl 2-pyrimidyl sulfide produced β,βdiarylvinyl sulfides in excellent regio-and stereoselectivity. Secondly, the incorporation of the third component could be realized through a α-lithiation/cross-coupling sequence. Finally, the target TAE molecule was generated through Pdcatalyzed cross-coupling of α,β,β-triarylated vinyl sulfides with Grignard reagents. The desired TAEs can be synthesized by this method in acceptable overall yields and high regio-and stereoselectivities. However, the functional group incompatibility resulted from the employment of strong base (t-BuLi and Grignard reagents) and multi-step synthetic operation severely diminish the practical applications of this transformation in TAEs synthesis.

APPLICATIONS OF STEREODEFINED TAES
Geometric (Z)-and (E)-TAE stereoisomers with identical molecular formulas but different configurations show marked difference in molecular properties and applications. [102][103][104] Notably, different molecular packing modes of TAEs stereoisomers and unique cavity formed by the Z-isomer were proposed for their differences in photophysical and mechanochromic behaviors. [53,61] Undoubtedly, the discovery and explanation of the differences in characteristic properties and functions of TAEs stereoisomers are not only helpful for fundamental research but also provide guidance on designing novel TAEs-based AIEgens and exploring their practical applications. Herein, the differences between TAEs stereoisomers in terms of their properties and applications are discussed.
The E/Z isomerization (EZI) in the TAEs-based AIEgens was once regarded as an important part in the interpretation of AIE mechanism. The mechanism of E/Z isomerization argues that the excited states of TAEs are non-radiatively due to the EZI process in the solution state, and the luminescence efficiency is increased as the EZI process is suppressed in the solid state. [25] To figure out what role the EZI process plays in the AIE phenomenon, 1,2-diphenyl-1,2di(p-tolyl)ethene (DPDTE) was prepared in a high E/Z ratio (E:Z = 7:93) via palladium-catalyzed three-component coupling (Figure 9A), and its photophysical behavior was investigated by Tang and coworkers. [52] In contrast to E-and Zstilbene featuring ACQ effect resulted from the EZI process, DPDTE was AIE active as demonstrated by the PL spectra of DPDTE in THF/water mixtures. Surprisingly, the power of the UV light source exerted huge influence on the conformation change. As shown, the NMR spectrum of DPDTE remained intact under the low-power UV irradiation. However, the isomerization took place after irradiation by a UV lamp with much stronger power (E/Z = 50 : 50). Hence, this result revealed that the EZI process was likely unrelated to the AIE phenomenon under the normal photoluminescence spectral measurement conditions. Although this work provided a profound interpretation on the role of EZI in luminescence mechanism of TAEs-based AIEgens, the result was imperfect as the DPDTE employed was Z-rich but not 100% pure. Accordingly, to draw a clear mechanistic picture, pure stereoisomers 47 and 48 were designed and synthesized via the incorporation of triazole groups into the TPE unit through the click reaction, and they can be separable by column chromatography due to the difference of polarity ( Figure 9B). [53] Notably, the stereochemistry of stereoisomers 47 and 48 was verified by various spectroscopic methods and the comparison of their NMR data with the target products prepared from the pure isomers of starting materials. In line with the previous study, thermal treatment or irradiation with a highpower UV lamp of the E isomer readily yielded the Z isomer. As shown in Figure 9B(i), starting from pure E isomer, the Z fraction was increased with the extension of the heating time or irradiation time. Since AIE phenomenon of TAEs is observed under the PL spectral measurement conditions, Tang and co-workers argued that the E/Z isomerization was not involved in the AIE phenomenon. However, in 2018, Sada and coworkers disclosed that the isomerization of TAEs stereoisomers can occur under typical fluorescence measurement conditions with prolonged light irradiation time, which indicates the crucial role of EZI process for the quenching of TAEs in solution. [68] Consolidating the information derived from these studies mentioned above, it is worth pointing out that the E/Z isomerization of TAEs must be taken into account even if the isomerization is not observed under the PL spectral measurement conditions in a specific F I G U R E 9 (A) PL spectra of DPDTE (left) and E-and Z-stilbenes (right) in THF/water mixtures (i). 1 H NMR spectra of Z-rich DPDTE in CDCl 3 before and after irradiation by the UV lamp with low power and high power (ii). Reproduced with permission. [52] Copyright 2012, Royal Society of Chemistry. (B) Variation of the Z fraction during the irradiation of the E conformer (left) or heating of the solid powder of the E conformer (right) (i). Mechano-and thermochromic processes of 47 and 48 (G = grinding; H = heating) and PL spectra of (left) E-and (right) Z-BPHTATPE before and after grinding (ii). Reproduced with permission. [53] Copyright 2012, American Chemical Society case. Additionally, the configuration of E and Z conformers has a strong impact on their molecular packing, leading to different chromic responses to external perturbation as given in Figure 9B(ii). Interestingly, the off-white solid E-isomer 48 with a blue emission changed into a pale-yellow powder with a bluish-green emission after grinding. The inverse phenomenon was appeared with the thermal treatment. However, mechanical grinding of the solid Z-isomer 47 caused little change in its physical appearance or emission color.
Inspired by the elusive yet intriguing differences between geometric cis and trans isomers, Liu group synthesized the pure isomer 49 and 50 to investigate the differences in optical properties of pure isomers ( Figure 10A). [60] It should be noted that the stereochemistry of two stereoisomers was confirmed by both COSY and NOESY NMR spectra. As illustrated in Figure 10A(i), both E-and Z-stereoisomers demonstrated distinct AIE effect and showed roughly identical spectroscopic properties. The same red fluorescence was observed when two isomers were stored for at -20 • C for 12 min in DMSO. Interestingly, with the storage time increasing, the fluorescence color of cis-isomer 49 in the solidified DMSO solution changed from red to yellow, whereas no such phenomenon appeared for trans-isomer 50, and only stronger red fluorescence was observed, indicating that the conformation of 49 changed with increased storage time.
In 2017, Tang and coworkers demonstrated an interesting and impressive fabrication of TPE-based geometric cis-and trans-isomers ( Figure 10B). [61] The two TAE isomers were synthesized by incorporating ureidopyrimidinone (UPy) into TPE unit. The introduction of UPy markedly enlarged the differences between the two stereoisomers in polarity, enabling their successful separation via routine silica gel chromatography. Importantly, the stereochemistry of stereoisomers 51 and 52 was verified by both COSY and NOESY NMR spectra. The unique heteroatom-containing cavity formed by the UPy groups in Z-isomer 51 made it suitable for the specific detection of Hg 2+ (Figure 10B(i)). Of interest, the Eisomer 52 showed high viscosity due to the high degree of . Reproduced with permission. [61] Copyright 2017, American Chemical Society polymerization in CHCl 3 , which facilitated fiber fabrication. As shown, this rod-like fiber generated from E-isomer 52 showed bright blue fluorescence, thanks to the AIE character of the TPE moiety. Additionally, 2D and 3D photopatterns were generated from E-isomer 52, due to its splendid supramolecular polymerizability ( Figure 10B(ii)).
To probe the different biological functions of isomeric probes, a dual-labeled probe based on a TPE fluorogen was designed to in vitro monitor caspase-3 activity, and synthesized from a caspasespecific Asp-Glu-Val-Asp (DEVD) peptide and TPE unit. [56] The two stereoisomers were furnished via incorporating triazole groups and HPLC separation. Notably, the stereochemistry of two stereoisomers was characterized by NMR and comparing the retention time in HPLC. As shown in Figure 11A, owing to the good water solubility, no fluorescence was observed for both 53 and 54 in a mixture of DMSO-PIPES buffer, whereas distinct fluorescence signals appeared for both probes after treatment with caspase-3. Furthermore, the PL intensities of the probe solutions were significantly suppressed in the presence of caspase-3 inhibitor. The changes of fluorescence for both 53 and 54 incubated with recombinant caspase-3 were shown in Figure 11A(i). The different rates of reaching equilibrium in fluorescence intensity indicated that the enzyme interacted with E-isomer 54 more efficiently than the Z conformer. After treatment of normal and apoptotic MCF-7 cells with Z-isomer 53 and E-isomer 54, respectively, as shown in Figure 11A(ii), quite a low fluorescence signal was detected, indicating little caspase-3 activity (image A and E). After treating with an apoptosis inducer staurosporine, obvious fluorescence sig-nals were detected (image C and G), suggesting the potential of the probe for specific imaging of cell apoptosis. It is worth mentioning that the fluorescence signal of Z-isomer 53 was evidently higher than the signal of E-isomer 54.
In addition, Wu and Liu developed oxetane-substituted TPE (TPE-OXE) and got pure stereoisomers via column chromatographic separation. [59] It should be noted that the stereochemistry of two stereoisomers was exemplified by both COSY and NOESY NMR spectra. Interestingly, stereoisomer 3 exhibited bathochromic emission with a quantum yield five times higher than that of E-isomer 4. It is worth noting that the differences were ascribed to the locally excited state emission of E-isomer 4 and charge transfer (CT) state emission of Z-isomer 3. As illustrated in Figure 11B, the isomer 3 and 4 exhibited blue emission at the pristine state. However, the emission wavelength of both isomers was redshifted after grinding. What is more, the red-shifted emission quickly turned back to the initial emission when the sample was fumed by DCM.
The geometry of supramolecular coordination complexes containing TAEs is closely related to the configuration of double bond in TAEs. [105][106][107] For example, the rhomboid platinum(II) metallacycles 55-57 were designed and prepared by Stang and Zhao ( Figure 11C). [81] Interestingly, a broad absorption at 365 nm was observed for the three rhomboids. The emission maximum of the three rhomboids 55-57 is at 540 nm, 540 nm, and 590 nm, respectively. Importantly, the special donor-π-acceptor structure of rhomboids 57 gave rise to a red shift in emission spectra ( Figure 11C(iii)). On the basis of the results mentioned above, the metallacycles with F I G U R E 1 1 (A) PL spectra of 53 and 54 before and after incubation with caspase-3 (left) and time-dependent PL spectra of 53 and 54 upon addition of caspase-3 (right) (i). Images of normal MCF-7 cells treated with 54 (A and B) and 53 (E and F), apoptotic MCF-7 cells treated with 54 (C and D) and 53 (G and H) (ii). Reproduced with permission. [56] Copyright 2014, Royal Society of Chemistry. (B) Image of two isomers in column chromatography and fluorescent pictures of two isomers solid (i). Fluorescent spectra of 3 (left) and 4 (right): pristine, ground, and fumed by dichloromethane (DCM) (ii). Reproduced with permission. [59] Copyright 2016, American Chemical Society. (C) Synthesis of rhomboid platinum(II) metallacycles 55-57 via self-assembly (i). Absorption and fluorescence emission spectra of 55-57 (ii-iii). Reproduced with permission. [81] Copyright 2020, Wiley VCH near-infrared (NIR) emission wavelength might be formed with appropriately selected the donor and acceptor units.

SUMMARY AND PERSPECTIVE
Over the past two decades, considerable effort has been devoted to the development of AIE-active functional materials. The TAEs are attractive in the construction of new AIE systems due to their simple molecular structure and brilliant AIE effect. Undoubtedly, the rapid and facile synthesis of TAEs is a precondition for their multi-functional applications. In this review, we have systematically compiled the synthetic methodologies for the synthesis of TAEs, and focused on the protocols with excellent regio-and stereoselectivity. A variety of practically synthetic protocols for the preparation of stereodefined TAEs were presented, such as the McMurry coupling, Rathore's procedures, Suzuki-Miyaura cross-coupling, and transition-metalcatalyzed three-component coupling. Meanwhile, the virtues and limitations of each methodology were discussed in detail. Additionally, the applications of these synthetic strategies and the functions of the corresponding TAEs are introduced. Furthermore, differences in properties and applications of TAEs stereoisomers were discussed. Despite these impressive advances in stereodefined TAEs synthesis, several challenges still exist in the acquisition of desired structure. For example, it is challenging to confirm the stereochemistry of cis/trans-TAEs. Although X-ray diffraction is a reliable tool to confirm the geometry of stereoisomer, this strategy is tedious and only suitable for those isomers that can readily grow as single crystals. Besides, transition metals are often involved in the synthesis of stereoselective TAEs. In this regard, sustainable synthetic methods toward stereoselective synthesis of TAEs, such as photochemical reaction and electrochemical reaction are highly desirable. We believe that the booming development of practical synthetic protocols would greatly accelerate the advancement of TAEs in innovative high-tech applications.
In summary, we sincerely hope this review would offer guidelines for the synthesis of TAEs-based AIEgens with desired geometry in high efficiency and inspire more synthetic endeavors toward the AIE field, leading to the significant progress of TAEs-based AIEgens in materials science.

A C K N O W L E D G M E N T S
We are grateful for the support from the National Natural Science Foundation of China (grant numbers: 21971059 and 21702056), the National Program for Thousand Young Talents of China, and the Fundamental Research Funds.

C O N F L I C T O F I N T E R E S T
The authors declare no competing financial interest.