Chiral Triptycenes: Concepts, Progress and Prospects

Abstract Triptycenes have been established as unique scaffolds because of their backbone π‐structure with a propeller‐like shape and saddle‐like cavities. They are some of the key organic molecules that have been extensively studied in polymer chemistry, in supramolecular chemistry and in material science. Triptycenes become chiral molecules when substituents are unsymmetrically attached in at least two of their different aromatic rings. This Minireview highlights the chirality of triptycenes from basics to an advanced stage for the development of functional molecules.


Introduction
Triptycenei st he simplest member of the iptycenef amily with ab ridged bicyclooctatriene core structure (Figure 1). With its D 3h symmetry and 1208 angles between the three aromatic rings in ap addle-wheel rigid structure, the molecule provides al arge free volumea round the aromatic blades. [1] Because of these uniques tructural features, triptycenes have been incorporated as molecular scaffolds and extensively studied in various areas such as polymer chemistry,m aterial chemistry,m olecular machines, nanosized molecular cage, molecular balances,m edicinal chemistry,p eptide chemistry,m olecular assembly,h ost-guest chemistry and also catalysis. [2] 1,9-Disubstitutedt riptycenes have been valuablec ompounds for the investigation of p-interactions in aromatic systems. [3] The triptycene scaffold provides adequate reactive positions including sp 3 and sp 2 sites to install reactive handles and extensions of the p-scaffoldi nd esigning triptycened erivatives. Although the sp 3 positions in triptycenesa re difficult to functionalize compared to normal benzylic positions, [4] some strategies have been applied to make p-extended structures. [5] Al arge number of triptycene derivatives with functional groups at different positions has been synthesized, but regiospecific functionalizations of triptycenesa tt he ortho-positions next to the sp 3 carbons are limited. Mostly achiral triptycenes have been explored in areaso fs ynthesis and material applicationsa lthough the first synthesis of chiral triptycenes was reportedi n1 962. [6] Recent resultso fc hiral triptycenesh as awakened them from a three decades sleep to become an important playeri nm odern chemicals science. From synthesis to applications, achiral triptycenesa re well documented but chiral triptycenes have not been reviewed and only very recently as urvey has been published. [7] This Minireview coverst he concept and highlightst he development and applicationso fc hiral triptycenes. It also in-cludes clarifications of previously studied chiral triptycenes wherever available and shines alight on future prospects.

Chirality in Triptycenes
Chiralityi nt riptycenes have been studied in two different areas of stereoisomerism. Atropisomershaveb een investigated as well as triptycenes with stereocenters having defined configuration. In atropisomers the chiroptical properties are correlated with ap air of enantiomeric conformations. [8] For this, optically activea nd inactive rotational isomerso ft riptycene have been isolated andc haracterized.I ti sk nown that in many cases of organic compounds, it has been difficult to isolate optically active conformational isomerst os tudy their chiroptical properties at room temperature. Even if isolated,t hey rapidly interchange and racemizationo ccurs at room temperature. To understand the chemistry of atropisomers, triptycene derivatives of types 2 and 3 ( Figure 2) have been explored because substituents at the 9-position or at the peri position (ortho-position in aromatic ring closer to substituents at 9-position) can provideahigh barriert or otationa nd lead to stable conformational isomersa tr oom temperature. Triptycened erivatives of the general formula AB 2 C-CX 2 Yc an undergo ar otational circuit as showni nS cheme 1. Here, the ap-conformer has ap lane of symmetry and so it would be optically inactive. Because of the internal rotation, this compound may take the conformations as either + sc or Àsc form. The Àsc form and + sc form are mirrori mages and have C 1 symmetry.B oth isomers + sc and Àsc would be optically active if isolated.Acommon strategy used to isolate the optically active conformers are shown in Scheme2.R acemic AE sc was treated with ac hiral resolving agent andt hen each diastereomers were isolated.F inally,t he removal of the chiral resolvinga gent produces the optically active conformers + sc and Àsc,r espectively.
Optically active chiral triptycenes have also been prepared by attaching enantiomerically pure molecule to the triptycene unit. [9] The chiral auxiliary (S)-3,7-dimethyloctyl bromide has been connected to at riptycene moiety to obtain ac hiralp olymer. [10a] Similarly,( R)-(+ +)-1,1'-bi-2-naphthol has been used in the synthesis of chiral triptycene-basedr eceptors [10b] and (1S,2S)-1,2-diphenyl-1,2-diaminoethane for generatingc hiral triptycene-based N-heterocycliccarbene ligands. [10c] Progress Chiralt riptycenes:E arly 90s development The first synthesis of chiral triptycenes was reportedb yN akagawa and co-workers in 1962 with the compound 5,8-diacetoxy-9,10-dihydro-9,10-[1,2]benzenoanthracene-1-carboxylic acid as at risubstitutedt riptycene. [6] Nakagawa and his group wanted to study the relationship between the optical activity and differently substituted functional groups in am olecule, for which they selected the chiral triptycene molecule. The reason for their choice of chiral triptycenes wast he rigid and fixed geometry of these derivatives. Therefore, triptycene can exclude the influence of the complicatede ffects that generally arise in flexible molecule while studying the optical activity in relation to substituted functional groups.I nitially, compound 6 ( Figure 5) [6] was prepared in as tepwise mannerb ut the resolution of rac-6 using naturallyo ccurring chiral bases wasu nsuc-Md. Nasim Khan has workedi np harma industries for five years as ar esearch associate in processR &D department. After qualifying GATE and CSIR-JRF fellowship examsh e moved for aP hD degree. He completed his PhD in 2016 at Indian Institute of Technology Patna under the supervisiono fD r. Lokman H. Choudhury.H is doctoral studies were on the synthesis of "'N'' & ''O''-heterocycles using multicomponent reaction strategy.A fter working as an assistantp rofessor in chemistry department at the RK University,h em ovedt o Cardiff Universityi n2 019 to join the group of Prof. Thomas Wirth as aM arie-Curie postdoctoralf ellow,w here he is currently doing research in the chemistry of hypervalent iodine reagents.
Thomas Wirth is professor of organic chemistry at Cardiff University.A fter receiving his PhD from TU Berlin, he stayed at Kyoto University as aJ SPS fellow. Thenh ew orkedi ndependentlya tt he Universityo fB asel before taking up his current position atC ardiff University in 2000. He was awarded the Werner-Prize from the New Swiss Chemical Society, the Wolfson Research Merit Award from the RoyalS ociety and the Bader-Award from the RoyalS ocietyo fC hemistry.I n2 016h ew as elected as af ellow of The Learned Society of Wales. His main interests of researchc oncern stereoselective electrophilic reactions, oxidative transformations with hypervalent iodine reagents and flow chemistry performed in microreactors.
Scheme2.Flow diagram for the isolation of atropisomers + sc and Àsc.  cessful. They prepared 7 insteada nd resolved the enantiomers using brucinet etrahydrate. Pleasingly,w ith this strategy several optically active triptycenes based on the structure 7 were synthesized ( Figure 5). [11] It was expectedt hat all these derivatives should have the same configuration as that of the parent triptycene 7a,b ecause the rigidity of the triptycene avoidsa ny racemizationorW alden inversion during the course of transformation. From the study of the rotatoryd ispersion (RD) curves it was observed that the sign of plain curveso f7g and 7i were positive whereas 7h and 7j showedn egative plain curve despite having the same configurations as 7g and 7i.F rom the analysis it was concludedt hat the determining factor for the change in the sign of the RD-curvew as guided by the direction of the electronic polarization.
Further CD analysis( Figure 6) [12] of the diastereomericc ompounds 7g and 7h shows the sign of the longest wavelength Cotton effect is reversed as suggested by the ORD data. [11] This indicates that the center of the transition dipole of the 1 B 2u state in the hydroquinone ring is displaced in the opposite direction according to the inversion of the positiono fe lectron attractive substituent. However,t he CD spectralp attern at shorterw avelength region suggests that the effect is restricted to the 1 B 2u state.
In the process of their studies Nakagawa et al. synthesized a series of functionalized optically active 8 ( Figure 5) [13] from 7a following different functional group transformation steps and determined the absolutec onfiguration( 1 R,6S)f or the derivative 8d using X-ray crystallographic analysis. It revealed that all the synthesized compounds in this series have the same absolute configuration and shows dextro opticalr otation regardless of the substituent in the 1-position.
In asimilar way Nakagawae tal. synthesized other chiral triptycenes,determined their absolute configurationbycorrelation methodsa nd studied their UV and CD properties. [14] The absolute configuration of chiral compounds can also be determined by using electronic circulard ichroism exciton chirality method in an on-empiricalw ay without using any known reference compound with absolute configuration. [15] In this direction Harada et al. studied and determined the absolute configuration of benzo-extendedc hiral triptycene derivatives. [16] This wast he first report of an unambiguous and nonempirical way to determine the absolutec onfiguration of chiral triptycenes applying the CD excitonc hirality methodi ns upport with quantum mechanical calculations.
11 was first oxidized with hydrogen peroxide to make the corresponding phosphine oxidesw hich were then isolated chromatographically and finally reduced together with the sulfoxides using HSiCl 3 to obtain 12 and ent-12 as chiral ligands.
Chiral triptycenes as catalysts in asymmetric synthesis were exploredf or the first time by Leung et al. in 2017. Chiral monophosphine ligand 22 was synthesized in as tepwise manner startingf rom 1,8-dihydroxytriptycene via compound 21 (Scheme7,t op). [21] Optical resolution of 22 was unsuccessful, therefore the enantiomerso fi ts precursor 21 were separated using chiral HPLC and were subjected to UV and circular dichroism (CD) studies. The isolated isomerso f21 were reduced to 22 using HSiCl 3 .T he monophosphine ligand 22 was used in Pd-catalyzed Suzuki-Miyaura cross-couplingsw here no asymmetrici nduction was observed, buti nt he asymmetrich ydrosilylation the reduced product 23 was obtained with 58 % ee (Scheme7,b ottom).
The recent advancement of chemicals cience to create high quality materials for various applications has also involved the search forn ew and useful structures. Triptycenes possess such features due to their special arrangement andh ave therefore been studied in polymer science, supramolecular chemistry and materials chemistry,b ut only as achiral compounds. Materials with chiroptical properties have been investigated for applications in advanced technologiess uch as three-dimensional displays,q uantum computing and teleportation as they show electronic circular dichroism (ECD) and circularly-polarized lu-minescence (CPL). [22] Molecules have to be designed that they should either have an helical molecular geometry or possess chiral supramolecular assemblies. [23] Chiral triptycenes provide such building blocks suitable for the synthesis of chiroptical materials. Interesting resultso btained from the work based on chiral triptycenes have attracted attention,b ut the examples are scant. Based on the chiral triptycene buildingb lock 2,6-dihydroxytriptycene and its derivatives chiral macrocyclic arenes have been synthesized. Chen et al. reportedt he synthesis of a chiral 2,6-helix [6]arene 26 [24] where chirality is generated by using 2,6-dimethoxy-3-hydroxymethyltriptycene 24 as shown in Scheme8. Rac-26 was obtained after the cleavage of the methoxy groups andr esolved into the two enantiomers P-26 and M-26 using (+ +)-camphorsulfonyl chloride. Thed etermination of the absoluteconfigurations was performed by X-ray diffraction andC Da nalysis. This methodology was extended further to the synthesis of al ibrary of macrocycles that have been used in the studies forp otential applications in chiral recognition, stimuli-responsiveh ost-guestc omplexation and molecular machines. [2j,25] Cycloparaphenylenea re referred to as 'carbon nanohoops' and are strained carbon nanotube structures that show interesting size-dependent optoelectronic and host-guest properties. Xu et al. have reported an ew type of chiral dual nanohoop molecule 27 ( Figure 7) and studied their chiroptical properties by CD and CPL spectroscopy. [26] The key step involved in the synthesis was ar ing expansion through dianthracenec ycloreversion followed by at ransannular [4+ +2] cycloaddition in a6 4-membered macrocycle. The enantiomers of 27 were resolved by chiral HPLC.
In parallel with the development of chiral macrocycles and ligands, chiral triptycene scaffolds have also been explored in the synthesis of chiral functional materials. The scarce examples show that chiral triptycenes have the potential to provide ap latform for making advanced functionalm aterials.S wager and co-workers have reported the synthesis and potential of chiral triptycenes as luminescence material in 2017. As supramolecular chirality is induced in hydrogen-bonded aggregates, the synthesized chiral molecules emitted left-or right-handed circularly polarizedl ight (CPL) after irradiation with UV light. A limiting factor is that these small molecules can show CPL only when they are in an aggregated state. This special feature limits them in making practical applications of materials, as the material should be free from any influence of external effects such as temperature, solvent and concentration.T he synthesized triptycene-pyrene hybrid system is shown in Scheme 9. [27] The first step in this synthetic route involves the amide formation of rac-2,6-diaminotriptycene and 4-ethynylbenzoic acid. The obtained compound rac-28 was subjected to preparative chiral HPLC. The enantiomers(R,R)-28 (and (S,S)-28)were isolated and the absolute configurations determined by single crystal X-ray analysis. The subsequent Sonogashira-Hagihara crosscoupling reactionw ith pyrenyl compound R-I led to optically pure (R,R)-29 [and( S,S)-29]. It was observed that the fluorescence emissiona nd the chiroptical properties of 29 were dependento nt he solvent andi ts concentration. Compound 29 in the solvent mixture of THF and hexane showedared shift of emission from 470 nm (blue emission) to 520 nm (green emission) when the volumeo fh exane wasi ncreased ( Figure 8). The addition of hexane resulted in aggregation induced excimer formation between the pyrenyl units. CD and absorption spectra for (R,R)-29 and (S,S)-29 are shown in Figure 9. When the solventc ombination was changed from THF to THF/hexane, av ariation in the CD spectra was observed with ah ypsochromic effect (absorption spectrum). The CD signals were weak in THF but increased fivefold in THF/hexane. The chiral hydrogen bonded aggregates hadapreferred handedt wist of stacked pyrene units;( R,R)-29 stacked in a clockwise orientation (Figure 9, Ba nd C). The average size of the aggregates was determinedw ith dynamic light scattering (DLS) and found to be > 200 nm in THF/hexane (1/99 v/v %). In the same solvent the aggregates showed ac ircularly polarized luminescence (CPL) signal reaching dissymmetry factors as high as 1.5 10 À3 .
The CPL emission waso bserved only in the aggregate form so there are limited practical applications. From ap ractical point of view Swager and co-workers realized that it was necessary to make new types of materials that can show CPL activities independently without being affected by other environmental factors. [28] In the search for such chiral materials where aggregation could avoided, chiral triptycene building blocks were explored andaseries of triptycene-based optically active polymers 30 was synthesized ( Figure 10). [29] Comparing CD spectra of the polymers with the monomer and the computationally designed model compounds revealed that the chiral triptycene unit wasr epeated in the polymer backbone but the polymer structure wasn ot helical. Therefore, the CPL emission properties werei ndependent and not affected by other environmental factors. The glum value (dissymmetry factor)o f these polymers, obtained from CPL studies, was almost constant and independento ft he included chromophore. It means that the wavelength of the fluorescencec an be modified by changing the achiral co-monomer withoute ffecting CPL properties.
Expanding the synthetic scope, optically actives inglehandedhelical ladder polymers employing intramolecular cyclisation of rigid chiral framework of triptycenes were synthesized. [30] It is noteworthy to mention that the aromatic electrophilic substitution proceeded in ah ighly regioselective manner at positions 3a nd 7i nt he triptycene moiety (Scheme 10) in quantitative yield. The perfect regioselectivity wasa ttainedb ecause of the steric repulsion between the bridgehead proton   and the 4-alkoxyphenyl substituent. The first step reaction involves the Suzuki-Miyaura coupling copolymerization of enantiomerically pure 2,6-diiodotriptycene 31 with diboronic acid bis(pinacol) ester containing two 4-alkoxyphenylethynyl substituents. Polymer 32 with ar andom coil structure formed 33 on treatment with TFA, ao ne-handed helical structure. The number-average molecular mass, M n (SEC) value was estimated 1.05 10 4 gmol À1 for 32 and 0.80 10 4 gmol À1 for 33,r espectively.I twas assumed that cyclization loweredt he radius of gyration in 32 and so lowered the M n (SEC) value with ar estricted structuralf reedom in 33.W hen the backbonec onformation with ar andom coil in 32 was changed to ar igid ladder structure in 33,achange in the photoluminescence (PL) was observed with a3 8nmred shift due to the higherdegree of electronic delocalization. Ab luish white emission in 33 was observed because of ab road PL band in the region of 470-600 nm. The UV spectrum of 33 were independent of temperature because of the rigid helical ladders tructure and showed an intense CD signal compared to 32.P olymer 33 was used as ac hiral stationary phase for high-performance liquid chromatography (HPLC)w ith resolution ability.
In the development of chiral stationary phases for HPLC, Swagera nd co-workers had already explored the use of chiral triptycene synthon. The distorted cyclic structure 34 (Scheme1 1) was synthesized from rac-2,6-diaminotriptycene. [31] Both enantiomers were separated using preparative HPLC on a chiral column. Absolute configurations of 34 were assigned by comparing CD spectra with optically active2 ,6-diaminotriptycene. After silyl group removal,t he subsequent Huisgen 1,3-dipolar cycloaddition with an azide functionalized silica gel formed ac hiral stationary phase 35 (CSP) which was utilized efficiently for the resolution of axially chiral biphenyl compounds.
An achiral three dimensional (3D) nanographenew ithh exaperi-hexabenzocoronenei ncorporating at riptycene unit has been explored as af luorescent agent for in vitro and in vivo fluorescencei maging. [32] Wada et al. reported am ethod for the synthesis and isolationo f36 as an asymmetric 3D nanographene framework ( Figure 11). [33] In search for aC PL-active material, Ikai andh is group have made this new asymmetric 3D nanographene bearing triptycene scaffolds with am aximum j g lum j value of 1.0 10 À3 matching those reported for conjugated chiral organic materials. [34] In addition, ac onglomerate crystallization was observed during crystallization of a racemic mixture of 36.T he conglomerate allowed to generate the right-and left-handed circularp olarized light without using any speciali nstruments. This interesting property could provideaconvenienta pproach for the synthesis of chiroptical materials without enantiomeric resolution.
Scheme10. Synthesis of optically active single-handed helical ladder polymers 33. [30] Scheme11. Synthesis of triptycene based chiral stationary HPLC phases. [31] Figure 11. Optically active triptycene 36 with hexa-peri-hexabenzocoronene units. [33] Prospective Triptycenes possessi mportants tructural features such as a psystemsa nd saddle-like cavities. Due to these properties, they have been extensively explored in many areas of chemistry with useful applications. Similarp ossibilities remainw ith chiral triptycenes. The outcomem ay be amazing for chiral triptycenes if used in the same way as achiral triptycenes have been explored.R ecently,s ome developments based on chiral triptycenes showed interesting properties such as stimuli-responsive host-guestc omplexation, chiroptical properties and as ac hiral stationary phases in HPLC. These resultsshow that chiral triptycenes have high potentiali nf uture developments. 1,9-Disubstitutedt riptycenes are valuable tools in studying p-interactions in aromatic systems. [3] Non-covalent p-interactionsh ave opportunities in catalyst design. [35] Depending on non-covalent interactions, different approaches for substrates are possible towardsatriptycene moiety in as ide-on (37)o ra nd end-on approach( 38) ( Figure 12). The feature of different interactions with at riptycene molecule has potentialf or selectiveo rganic transformationsa nd with chiral triptycenes it may advance stereoselectiver eactions. Until today two chiral triptycene based ligandso ft ype 39 have been synthesized with one of them being used in stereoselective reactions. There seem to be many opportunitiesr emaining with chiral triptycene as ligands or catalysts in organic synthesis including pincer compounds of type 40 ( Figure 12).

Conclusions
Early research on chiral triptycenes was focusedt og enerate varioust riptycene derivatives using different synthetic routes, to study their absolute configurations and opticalp roperties by correlationm ethods. As hift from synthetic methodologies to advanced materiala pplicationsh as been observed.C hiral triptycenes have been successfully incorporated into helical polymers, solid supported materials,m acrocyclic hosts and as catalysts for stereoselective reactions. Interesting results were obtainedw hen investigating chiral triptycene in polymers, advancedmaterials and catalysis showing their future potential.