Triptycene Synthesis and Derivatization: History
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Subjects: Chemistry, Organic
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Since the discovery of triptycenes, great progress has been made regarding their synthetic methodology and the understanding of inter- and intramolecular interactions that involve triptycenes. Several new synthetic approaches have been developed in the last few years, and progress has been made in the context of sterically congested triptycenes and regioselective synthesis of various derivatives.

  • triptycene
  • synthesis

1. Introduction

The parent triptycene (9,10-dihydro-9,10[1′,2′]-benzenoanthracene) is an eye-catching hydrocarbon with a paddlewheel or propeller-shaped molecule. The characteristic structure of triptycene is composed of three benzene rings joined by two sp3 carbon atoms in a D3h-symmetric structure with a barrelene core (Figure 1).
Figure 1. The chemical structure of the parent triptycene with a commonly used carbon atom numbering scheme based on the 9,10-dihydro-9,10[1′,2′]-benzenoanthracene nomenclature (CAS).
Triptycene was synthesized for the first time in 1942 by Bartlett et al., who also coined the name [1]. Fourteen years later, the rather laborious procedure became superseded by the more direct benzyne to anthracene cycloaddition route [2]. Since then, great progress has been made in the area of triptycenes synthesis, and recent developments are rich in examples of advanced structures, such as congested and structurally complex molecules [3,4,5,6,7].
Due to these inherent characteristics, triptycene has become an exemplar of a multipurpose molecular scaffold [9,10,11,12,13,14,15,16,17,18,19,20,21,22]. Triptycenes were used as building blocks for mechanically interlocked molecules [23,24,25,26,27,28,29,30,31,32,33] and for self-assembly and molecular recognition in the field of supramolecular chemistry [7,34,35,36,37,38,39,40,41,42]; as achiral or chiral ligands for catalysis [43,44,45,46,47,48,49,50]; anti-cancer agents [51,52,53,54]; models of hindered rotation [55,56,57,58,59]; as well as in broadly defined materials sciences [60,61,62]; as structural units in various functional polymers and porous materials [63,64,65,66,67,68,69], such as molecular cages [18,70,71,72,73,74]; and metal–organic frameworks [75,76,77,78,79,80]; as well as in chemical sensors [81,82,83,84,85,86] and liquid crystals [87,88,89,90,91,92].

2. Progress in Triptycene Synthesis and Derivatization

2.1. General Synthesis of the Triptycene Unit

The parent triptycene was obtained for the first time in 1942 by Bartlett et al., who used anthracene and 1,4-benzoquinone as starting materials (Scheme 1a) [1]. The rationale for this rather laborious, low-yielding, multi-step synthesis was laid in the study of radicals that can be generated on Csp3 bridgehead carbon atoms of triptycene (positions 9 and 10, Figure 1) [1,5].
Scheme 1. (a) The general synthetic pathways for the synthesis of triptycenes [1,2]. (b) Benzyne generation methods: Wittig [2], Stiles [95], Friedman and Logullo [96], Sharp [97], Kaur [98], Kitamura [99].
Although the procedure was later simplified by Craig both in terms of time and steps required [94], a true breakthrough came with the distinct discovery of a cycloaddition reaction between anthracene and a direct synthon of triptycene’s benzene ring—benzyne. In 1956, Wittig and Ludwig were the first to report such a reaction of benzyne (Scheme 1a), being a reactive intermediate generated in situ from 2-fluorophenylmagnesium bromide (Scheme 1b) [2]. A few years later, Stiles described the synthesis of triptycene using o-diazonium benzoate (Scheme 1b) [95].
In 1963, Friedman and Logullo found anthranilic acid to be a superior benzyne precursor (Scheme 1b) [96]. During the reaction, anthranilic acid undergoes seamless diazotization by amyl nitrite. The resulting benzenediazonium-2-carboxylate fragmentates giving N2, CO2, and benzyne, which in turn engages in Diels–Alder reaction with anthracene. The feasibility of the procedure manifests itself in the good yield (59%) and the availability of starting materials. To this day, various benzyne precursors have been presented (Scheme 1b), some of which allowed for the considerable improvement of the yield [97,98,99].

2.2. Synthesis of Ortho-Functionalized Triptycenes

Electrophilic aromatic substitution (SEAr) reactions are disfavored at the ortho (α) positions respective to the bridgeheads. For example, nitration of the parent triptycene (HNO3/AcOH in Ac2O, 27–29 °C) yields products with the α to β substitution ratio of 1 to 40 [100]. This feature is a manifestation of the so-called “fused ortho effect” [101], according to which the reactivity toward electrophiles is largely diminished at the positions of the aryl ring that are ortho in respect to a fused strained ring [102]. In other words, a strained ring, such as triptycene’s bicyclo [2.2.2]octatriene, acts as a deactivating, meta/para directing group when fused with an arene.
Since nitrotriptycenes provide access to the corresponding amines and other derivatives, such as alcohols and halogenated compounds, some optimized synthetic procedures for nitration were developed with regioselectivity in mind. Even though there are six β positions in the parent triptycene, mononitration to 2-nitrotriptycene was achieved with as high yield as 58–64% [80,103]. Optimized dinitration protocols yield 2,6-dinitrotriptycene (39%) [104], or a mixture of 2,6-/2,7-dinitrotriptycenes (56%) [105], and trinitration gives 2,7,14- and 2,6,14-trinitrotriptycene (21% and 64%, respectively) [106]. The potentially explosive product of an exhaustive nitration, 2,3,6,7,14,15-hexanitrotriptycene, was obtained in 42% yield [105]. Other SEAr reactions, such as acetylation [107,108] and formylation [108], also occur at β positions.
Because of the fused ortho effect, α-functionalized triptycenes are usually prepared from appropriate prefunctionalized substrates. 1,8,13-Functionalized triptycenes epitomize an example of such an α-substitution pattern. The significance of this family originates from the structure–property relationship. The symmetry and rigidity of the triptycene itself, combined with the advantage of the substituents being located on the same face of the scaffold (pointing in one direction), facilitate the juxtaposition of functional groups in proximity.
As tripodal molecules, 1,8,13-functionalized triptycenes recently found advanced application in surface modification—in 2015, Seiki et al. utilized the triptycene with three C12 side chains to self-assembly a remarkable organic thin film that was free of domain boundaries and structurally ordered up to the centimeter length scale [109]. The order and precise alignment of the molecular units of choice, which 1,8,13-functionalized triptycene allows for, are advantageous features for the promising field of high-performance organic thin-film materials [62,110,111,112]. The same 1,8,13 substitution pattern was used in models of molecular-level magnetic anisotropy [113], close nonbonded H–H contacts [114], and through-space Me–Ar interactions [115].
In 2010, the Mitzel group investigated the steric influence of the additional substituent at C-10 on the syn/anti ratio of 1,8,13/16-trichlorotriptycenes [117] and found that anti-isomer is generally favored. Unexpectedly, this was true for large substituents too, so the Mitzel group changed their focus from steric to electronic effects. Recently, they have investigated the cycloaddition of 3-chlorobenzyne to three 1,8-dichloroanthracenes equipped with CMe3, SiMe3, or GeMe3 group in position 10 [119]. It was observed that the electronic properties of the substituent influence regioselectivity—with electropositive SiMe3 and GeMe3, the syn triptycene formed predominantly, whereas for CMe3 only an anti-isomer was observed (Scheme 2a). Quantum chemistry calculations of the reaction pathway revealed that dispersion forces are one of the factors responsible for the observed effects.
Scheme 2. Studies on the regioselectivity of the synthesis of ortho-substituted triptycenes by the Mitzel group: (a) the electronic character of a substituent on C10 influences the syn/anti ratio of the product [119,120]; (b) triptycenes functionalized with triflate or (trimethylsilyl)ethynyl groups [120].
Another approach aimed at regioselective synthesis of triptycene derivatives was presented by the group in 2018—Shwartzen et al. used cycloaddition of 1,4-benzoquinone to substituted anthracenes for the preparation of triptycenes functionalized with triflate or C≡C-SiMe3 groups (Scheme 2b)[120].
For the intermediate with two sterically demanding SiMe3 groups, a distortion of the molecular framework was observed. For that reason, attempts to obtain the 1,8,13-trisubstituted derivative by introduction of the third C≡C-SiMe3 were unsuccessful.
On the other hand, since the regioisomeric course of the Diels–Alder reaction depends on the nature of substituents in prefunctionalized substrates, approaches departing from chloroderivatives are also being explored. In their work reporting the synthesis of a porous molecular cube, Elbert at al. presented a path towards 1,8,13-trihydroxytriptycene [118], starting with the Diels–Alder reaction of 1,8-dimethoxyanthracene and 3-methoxybenzyne. The latter was generated in situ by a mild, fluoride-induced 1,2-elimination [121] of the corresponding trimethylsilyl triflate precursor [122]. A poorly soluble 2:1 mixture of syn- and anti-trimethoxytriptycenes was collected, and the target 1,8,13-trihydroxytriptycene was obtained after ether cleavage, esterification with capronyl chloride, crystallization of the desirable regioisomer, and hydrolysis of the pure 1,8,13-triester. The same method was used in the above-mentioned work of Seiki [109], who reported that syn-trihydroxytriptycene can be separated from the anti-isomer by recrystallization from DMF at −35 °C.
The challenge of sterically crowded triptycene synthesis was also taken by Szupiluk, who presented a route towards 9-nitro- and 9-aminotriptycenes (Scheme 3) [123]. The procedure comes down to cycloaddition of benzynes to 9-nitroanthracenes, followed by reduction of the nitro group. The reaction of electron-deficient anthracenes was not regioselective and accompanied by the formation of considerable amounts of side products. For example, 1,2,3,4-tetrabromo-9-nitrotriptycene was obtained in 7% yield; two other products were identified. On the other hand, it was demonstrated that the final reduction of nitro group on C9 in triptycenes proceeds smoothly and in a good yield, giving products equipped with the synthetically useful ammonium group.
Scheme 3. Synthesis of new ortho-functionalized triptycenes from deactivated, electron-deficient nitroanthracenes [123].
Recently, Yoshinaga et al. published a follow-up article reporting some new developments in ynolate/benzyne chemistry [129]. The group presented the synthesis of 1,8,13-trisilylated triptycenes obtained from 3-silylbenzynes via the above-described triple cycloaddition route (Scheme 6).
Scheme 6. Trisilyltriptycene (obtained according to Scheme 5 for R = Me and X = SiMe3) as a starting material for heterosubstituted triptycenes. An exemplary 1-bromo-8-chloro-13-iodo product was obtained with 55% overall yield in a chromatography-free procedure involving selective halogenations with (i) NCS (1.2 eq. in DMF, 60 °C, 2.5 h); (ii) NBS (2.0 eq. in DMF, 60 °C, 24 h); (iii) ICI (2.0 eq. in DCM, rt, 1 h) [129].

2.3. Functionalization of the Bridgehead Positions of the Triptycene Unit

In the chemistry of triptycene, the desired substitution pattern dictates the synthetic strategy. Low reactivity of triptycene’s aromatic ortho positions contrasts with the well-known activated character of the analogous position in simple alkyl-substituted arenes. In the same vein, while a benzylic position is generally reactive, the bridgehead C-H groups in triptycene are relatively inert to many reactions. Therefore, both ortho and 9,10-functionalized triptycenes are usually obtained from already functionalized precursors.
However, Oi et al. recently disclosed a Pd-catalyzed cross-coupling protocol that offers efficient functionalization of the bridgehead carbon atom in 9-bromotriptycene through C9-C bond formation (Scheme 7a) [131]. Various iodo- and bromoaromatic compounds were successfully tested as coupling partners, leading to a library of C9-Csp2 coupled products, which were obtained in good yields despite inherent steric hindrances. Illustrative C9-Csp coupling with (iodoethynyl)benzene and C9-Csp3 coupling with methyl bromoacetate were also successful. The procedure constitutes a highly attractive way of triptycene extension—its scope seems wide, the conditions are mild, and isolated yields were usually between 60% and 90%. Moreover, the required reagents—Pd(OAc)2 and tris(o-methoxyphenyl)phosphine (SPhos ligand)—are commercially available. 9-Triptycenylcopper, an active participant in the coupling reaction, forms in situ from 9-bromotriptycene treated with n-butyllithium followed by copper(I) halide (Scheme 7b). Additionally, the authors performed screening of other 9-metalated triptycene derivatives and found that 9-triptycenylboronate ester and 9-triptycenylzinc were not reactive under the tested conditions. In addition to triptycene, the scope of the work included C-C bond formation with other hindered structures—namely, adamantyl and mesityl.

This entry is adapted from the peer-reviewed paper 10.3390/molecules27010250

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