Synthesis of a linearly linked triscalixarene consisting of calix[4]arene units with combined axial chirality and inherent chirality

Abstract

A linearly linked triscalix[4]arene, in which each calix[4]arene unit possesses both axial chirality and inherent chirality, was synthesized by repeated use of two stereoselective Williamson etherification on calix[4]arene. In the crystal lattice of the biscalix[4]arene intermediate, there are interesting alternate layers of biscalixarene molecules and solvent molecules in the ab plane.

Introduction

Multicalixarenes are oligomers of defined molecular weight and architecture, formed by the covalent bonding of multiple calixarene units. According to the linkage pattern, multicalixarenes can be classified as linear multicalixarenes [1] and hyperbranched multicalixarenes such as calixarene dendrimers [2]. As an aggregate of multiple calixarene units linked via covalent bonds, multicalixarenes are not only of synthetic interest, but also capable of realizing specific function such as ion-binding [3,4,5,6], DNA binding [7], and gene transfection [7]. The controlled synthesis of multicalixarenes usually relies on definite and highly efficient reactions such as etherification, esterification, amidation, Friedel–Crafts alkylation, Glaser coupling, Sonogashira coupling, ring-closing metathesis (RCM), click reaction, etc [1]. To date, though a third-generation calixarene dendrimers consisting of calixarene units up to 21 has been synthesized [8], linear multicalixarenes with ≥4 calixarene units are rarely seen [9,10,11,12].

Meanwhile, Most of the linear multicalixarenes are comprised of achiral calixarenes and achiral linkers. Representative exceptions include the multicalixarene series containing peptidic linkers [13,14,15] and the biscalixarenes containing one inherently chiral calixarene unit [16,17,18]. Linear multicalixarenes with each calixarene units being inherently chiral have not been reported previously.

The assembly of multiple chiral calixarene units in a linear manner by covalent bonds to form a well organized architecture has the potential to demonstrate novel properties which are otherwise unattainable for individual calixarene components, due to the synergistic effects of the neighboring calixarene units [19] or by generating higher-ordered structural features [13, 14]. Meanwhile, as a transition specie between chiral calixarene monomer and chiral calixarene-based polymers [20,21,22,23,24,25,26], the study of such chiral calixarene oligomers with definite architecture is helpful to the understanding of chiral polymers made up of numerous chiral calixarene units.

Recently, we have developed a highly efficient method to generate inherent chirality [27] in calix [4] arene starting from a 1,2-substituted calix[4]crown containing an axially chiral BINOL moiety (reaction 1, Diagram 1) [28]. This reaction enjoys several merits, including mild condition (1 equiv of Cs₂CO₃, 1 equiv of electrophile, DMF, 60–80 °C), desirable yield (ca. 80%), easy separation of the resultant diastereomers on a gram scale by column chromatography on silica gel due to their significant difference in polarity, and high diastereoselectivity (up to 72% based on isolated products). The presence of (S)-BINOL moiety favors the formation of cS-form in terms of inherent chirality and that of (R)-BINOL cR-form. The reaction is feasible for numerous electrophiles R¹X, including ⁿPrI, BnBr, BrCH₂CO₂Et, ClCH₂CONEt₂ etc and proceeds quite fast. The tri-substituted cone products of reaction 1 can be further alkylated with an electrophile R²X to produce the fully substituted calix[4]arenes via reaction 2 (excess Cs₂CO₃, excess electrophile, DMF, 60–80 °C), which highly stereoselectively furnishes the partial cone (paco) products (reaction 2, Diagram 1).

Diagram 1

The use of two stereoselective reactions to synthesize calix[4]arenes with combined axial chirality and inherent chirality

The high generality of this two reactions tempted us to try the repeated use of them to produce linear multicalix [4] arenes consisting of optically pure calix[4]arene units with combined axial chirality and inherent chirality. We envisaged that reaction 1 is crucial to the covalent bonding of individual calix[4]arene units when R¹X is a (multi)calixarene-based electrophile, while reaction 2 is crucial to the formation of appropriate (multi)calixarene-based electrophiles for the purpose of linkage.

Herein we report the synthesis of a linearly linked triscalix[4]arene by sequential use of two stereoselective Williamson etherifications on calix[4]arene, in which each calix[4]arene units is optically pure and possesses both axial chirality and inherent chirality. The structures of were studied with NMR technology, X-ray crystallography, and circular dichroism spectra.

Results and discussion

As depicted in Scheme 1, (R)-BINOL-containing calix[4]crown 1 underwent reaction 1 with BrCH₂CH₂CH₂CO₂Et to produce the tri-substituted cone conformer 2 in 68% yield. The diastereoselectivity was determined to be 57%, based on the integration of the OH signals in ¹H NMR spectrum of the crude reaction mixture (major/minor diastereomer = 3.66:1). Calix[4]arene 2 then underwent reaction 2 with ⁿPrI for the purpose of protecting the free phenolic hydroxyl group in 2, thus furnishing the fully substituted partial cone conformer 3. Ester 3 was transformed into corresponding tosylate 5 by two additional steps. Upon treatment of Calix[4]crown 1 with calix[4]arene electrophile 5 under the condition of reaction 1, biscalix[4]arene 6 with two chiral calix[4]arene units was successfully produced as a partial cone–cone conformer in 47% yield, with a diastereoselectivity of 59% (major/minor diastereomer = 3.88:1). Biscalix[4]arene 6 was subsequently transformed into a partial cone-partial cone electrophile 9 by reaction 2 (with BrCH₂CH₂CH₂CO₂Et) and two additional reactions. A second round of reaction 1 of calix[4]arene 1 with biscalix[4]arene electrophile 9 smoothly afforded triscalix[4]arene 10 as a partial cone-partial cone–cone conformer in 35% yield. The diastereoselectivity decreased to 47% (major/minor diastereomer = 2.79:1).

Scheme 1

Synthesis of triscalix[4]arene 10 by sequential linking chiral calix[4]arene units

In order to enhance the efficiency of covalently linking calix[4]arene units, we tested the use of calix[4]arene-based bifunctional electrophile 11 (see supporting information) to react with calix[4]arene 1 for the purpose of constructing the triscalix[4]arene 12 in one step. However, an inseparable mixture was produced, indicating the reaction was complicated by the formation of several possible configurational isomers (Scheme 2). Therefore, though the protocol of linking individual chiral calix[4]arene units one by one by repeated use of reaction 1 and reaction 2 seems a bit tedious, it is reliable after all.

Scheme 2

Attempted synthesis of triscalix[4]arenes using a bifunctional electrophile

¹H NMR spectra

In the ¹H NMR spectrum of biscalix[4]arene 6, the eight signals (1.35, 1.33, 1.24, 1.12, 1.08, 1.02, 0.83, and 0.81 ppm) attributable to the eight tert-butyl groups confirmed the existence of two chiral calix[4]arene units in the molecule. Likewise, the ten signals (1.31, 1.252, 1.248, 1.19, 1.13, 1.08, 1.05, 1.00, 0.79, 0.77 ppm, slightly overlapped) attributable to the 12 tert-butyl groups confirmed the existence of three chiral calix[4]arene units in the molecule of triscalix[4]arene 10 (Fig. 1 ). In addition, ESI–MS data confirmed the molecular weights of all the intermediates and products, including that of the biscalix[4]arene 6 (m/z 2093.1 [M+Na]⁺), and triscalix[4]arene 10 (m/z 3134.8 [M+Na]⁺).

X-ray crystallographic study

We cultivated single crystals of monocalix[4]arene partial cone conformers 3, 4, and biscalix[4]arene cone-partial cone conformer 6, which are suitable for crystallographic study. Using the (R)-BINOL moiety as an internal reference, the absolute configuration concerning inherent chirality was assigned as cR in all cases (Fig. 2).

Fig. 1

The ¹H NMR spectra: a  biscalix[4]arene 6 and b triscalix[4]arene 10

Fig. 2

The crystal structure of calix[4]arene 3: a side view, and b top view

Partial cone conformers 3 (Fig. 2) and 4 (Fig. 3) crystallize in P2(1)2(1)2(1) space group. In the solid state, the tilt angles measured between individual phenolic rings (from ring A to ring D) and the mean plane defined by the four bridging methylene carbons are 108.27°, 139.20°, 108.11°, and 82.65° for 3, and 98.37°, 138.27°, 96.55°, and 82.51° for 4. The dihedral angles of the BINOL moiety are 93.39° and 100.45° for 3 and 4, respectively. In the crystal structure of 3, the n-propyl group attached to the inverted ring D tilts inward and bisects the calix[4]arene cavity. Such a self-inclusion phenomenon also exists in its CDCl₃ solution, as was evidenced by the pertinent terminal methyl signal appearing at remarkably high field (δ = 0.42 ppm) in its ¹H NMR spectrum. In the crystal structure of 4, the n-propyl group attached to the inverted ring D tilts away from the calix cavity. By contrast, in its CDCl₃ solution, the n-propyl group points toward the calix cavity, as was confirmed by its terminal methyl signal appearing at 0.38 ppm.

Fig. 3

The crystal structure of calix[4]arene 4: a side view, and b top view

Biscalix[4]arene cone-partial cone conformer six crystallizes in P1 space group (Fig. 4). In the asymmetric unit, there are one biscalix[4]arene molecule and four solvent molecules including three CHCl₃ and one CH₃OH, which are positioned at one side of the partial cone calix[4]arene unit. In the partial cone calix[4]arene unit, the tilt angles measured between individual phenolic rings (from ring A to ring D) and the mean plane defined by the four bridging methylene carbons are 107.34°, 125.84°, 108.99°, and 72.95°, the dihedral angle of the attached BINOL moiety being 93.54°. The n-propyl group attached to the inverted ring D tilts inward the calix cavity in the solid state, as well as in the CDCl₃ solution (δ = 0.36 ppm for the terminal methyl signal). In the cone calix[4]arene unit, the tilt angles measured between individual phenolic rings (from ring A’ to ring D’) and the mean plane defined by the four bridging methylene carbons are 98.29°, 138.51°, 79.52°, 138.39°, suggesting a slightly distorted pinched cone conformation. The dihedral angle of the BINOL moiety is 65.91°, distinctly smaller than that attached to the partial cone calix[4]arene unit. There are one intramolecular hydrogen bond (O⋯O, 2.922 Å) between the phenolic hydroxyl group (ring D’) and the proximal phenolic oxygen (ring A’), and one intermolecular hydrogen bond (O⋯O, 2.852 Å) between the phenolic oxygen on ring D and CH₃OH. In biscalix[4]arene 6, the two calix[4]arene units are connected by a butylene spacer at the lower rims in such a manner that the two mean planes defined by the bridging methylene carbons of individual calix[4]arene units adopt a dihedral angle of 17.84°. In the top view the two calix[4]arene skeletons are neither staggered nor overlapped much.

Fig. 4

The crystal structure of biscalix[4]arene 6: a side view, b top view, and c packing

The packing plot revealed the existence of a large number of intermolecular short contacts between CHCl₃ molecules, CHCl₃ and CH₃OH, CHCl₃ and BINOL moiety, CHCl₃ and calixarene phenolic ring, BINOL moiety and calixarene phenolic ring, BINOL moiety and bridging methylene, BINOL moiety and the glycolic chain, t-butyl groups, t-butyl group and bridging methylene, etc. As a result, in the crystal lattice, there are alternate layers of biscalixarene molecules and solvent molecules in the ab plane, which is rarely seen in calixarene single crystals.

CD spectra

CD spectra of calix[4]arenes 1, 2, 3, biscalix[4]arenes 6, 7, and triscalix[4]arene 10 were measured in CH₂Cl₂. All the CD spectra resemble that of (R)-BINOL (Fig. 5) [29], with the strong negative cotton band characteristic of the ¹B transition of the naphthol chromophore centering at ca. 238 nm, and the two weak positive cotton bands centering at 286 nm (¹L_a transition), and 326 nm (¹L_b transition). The CD spectra differ only slightly in intensity at the absorption extrema. Therefore, the axially chiral BINOL moieties in these calix[4]arenes and multicalix[4]arenes determine the shape of the cotton curves and the contribution of inherent chirality is overshadowed. Meanwhile, no clue to high-ordered structures of these chiral calix[4]arenes were observable in CH₂Cl₂ based on the CD spectra.

Fig. 5

The CD spectra of calix[4]arenes 1–3, biscalix[4]arenes 6, 7, and triscalix[4]arene 10 (CH₂Cl₂, 25 °C)

Conclusion

This work demonstrated the power of jointly using two stereoselective calix[4]arene-related Williamson etherification to produce multicalix[4]arenes with both axial chirality and inherent chirality. It is highly probable that by varying the R¹ and R² groups according to the need of molecular design, in conjunction with other highly efficient coupling/RCM/click reaction/condensation, the customized partial cone axially chiral/inherently chiral calix[4]arenes could be used in the construction of diverse novel chiral calixarene-based oligomeric/dendritic/polymeric architectures.

Experimental

Calix[4]arene 1

To a suspension of p-tert-butylcalix[4]arene (5.0 g, 7.7 mmol) in DMF (500 mL) was added NaH (60% in mineral oil, 2.16 g, 54.0 mmol) under N₂ atmosphere. The reaction mixture was stirred at room temperature for 1.5 h, followed by the addition of (R)- 2,2′-bis(2-tosyloxy-1-ethyloxy)-1,1′-binaphthalene (6.31 g, 9.24 mmol). The reaction mixture was stirred at 60 °C for 1 day and the reaction was quenched by slow addition of methanol. After evaporation of the solvent under reduced pressure, ethyl acetate (EtOAc) was used to dissolve the residue. The insoluble p-tert-butylcalix[4]arene was removed by filtration. After evaporation of EtOAc, the residue was recrystallized with CH₂Cl₂/petroleum ether. The crude product was subjected to column chromatography on silica gel (petroleum ether/EtOAc 30:1) to give (R)-1 as a white solid. Yield 43% (3.27 g). Mp 202–204 °C. [α]²⁵ _D = +133° (c 0.30, CHCl₃). ¹H NMR (400 MHz, CDCl₃, 25 °C): δ 8.99 (s, 1H), 8.53 (s, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.39–7.32 (m, 2H), 7.24–7.19 (m, 2H), 7.13 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 2.0 Hz, 1H), 6.99 (s, 2H), 6.96 (d, J = 2.4 Hz, 2H), 6.94 (d, J = 2.8 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 4.94–4.88 (m, 1H), 4.75–4.70 (m, 1H), 4.60–4.55 (m, 1H), 4.48 (d, J = 12.4 Hz, 1H), 4.47–4.41 (m, 1H), 4.25 (d, J = 13.6 Hz, 1H), 4.19 (d, J = 12.8 Hz, 1H), 4.17 (d, J = 13.2 Hz, 1H), 4.08–4.03 (m, 3H), 3.96–3.92 (m, 1H), 3.36 (d, J = 13.2 Hz, 1H), 3.34 (d, J = 13.6 Hz, 1H), 3.28 (d, J = 12.8 Hz, 2H), 1.19 (s, 9H), 1.18 (s, 9H), 1.15 (s, 9H), 1.08 (s, 9H). ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ 155.3, 154.1, 151.7, 150.7, 149.6, 148.8, 147.5, 146.6, 143.1, 142.5, 134.7, 134.6, 134.2, 133.6, 133.1, 132.9, 130.23, 130.15, 129.8, 129.6, 129.31, 128.88, 128.7, 128.3, 128.1, 127.9, 126.9, 126.7, 126.57, 126.55, 126.2, 125.9, 125.84, 125.78, 125.7, 125.6, 125.5, 124.2, 124.1, 121.31, 121.25, 118.1, 116.1, 74.7, 73.9, 69.3, 67.9, 34.3, 34.2, 34.1, 34.1, 33.1, 32.9, 32.7, 31.8, 31.7, 31.5, 31.4, 30.9. ESI-HRMS m/z calcd. for C₆₈H₇₄O₆Na⁺ 1009.5378 [M+Na]⁺, found 1009.5354.

General procedure for the synthesis of 2, 6, and 10

To a solution of (R)-1 and Cs₂CO₃ in DMF was added an electrophile. The reaction mixture was stirred at 60 °C for a period of time. After evaporation of the solvent under reduced pressure, the residue was partitioned between CH₂Cl₂ and 3.6% aqueous HCl. The organic layer was dried with anhydrous MgSO₄. Column chromatography on silica gel afforded 2, 6, or 10 as a white solid.

Calix[4]arene 2: (R)-1 (4.75 g, 4.81 mmol), Cs₂CO₃ (1.88 g, 5.77 mmol), DMF (150 mL), and ethyl 4-bromobutyrate (826 µL, 5.77 mol), 60 °C, 4 h. Column chromatography: petroleum ether/ethyl acetate = 25:1. Yield 68% (3.58 g). Mp 165–167 °C. [α]²⁵ _D = +102° (c 0.30, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 8.02 (d, J = 9.2 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 9.2 Hz, 1H), 7.42 (d, J = 9.2 Hz, 1H), 7.36–7.28 (m, 2H), 7.22–7.17 (m, 3H), 7.12 (s, 2H), 7.10–7.08 (m, 2H), 7.04 (d, J = 2.4 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 6.48 (s, 2H), 5.48 (s, 1H), 5.08–5.02 (m, 1H), 4.95–4.89 (m, 1H), 4.52–4.51 (m, 1H), 4.51 (d, J = 12.8 Hz, 1H), 4.36 (d, J = 12.8 Hz, 1H), 4.35–4.32 (m, 1H), 4.25 (d, J = 12.8 Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H), 4.10 (d, J = 12.8 Hz, 1H), 4.06–3.98 (m, 3H), 3.91–3.87 (m, 2H), 3.77–3.73 (m, 1H), 3.30 (d, J = 13.2 Hz, 1H), 3.22 (d, J = 12.8 Hz, 1H), 3.18 (d, J = 13.6 Hz, 1H), 3.16 (d, J = 12.8 Hz, 1H), 2.71 (t, J = 7.6 Hz, 2H), 2.46–2.32 (m, 2H), 1.33 (s, 18H), 1.22 (t, J = 7.2 Hz, 3H), 0.81 (s, 9H), 0.80 (s, 9H). ¹³C NMR (100 MHz, CDCl₃): δ 173.2, 156.5, 154.02, 153.36, 153.0, 151.4, 150.9, 146.3, 145.70, 145.66, 141.8, 136.11, 136.05, 134.6, 134.1, 132.3, 131.91, 131.88, 131.6, 130.1, 130.0, 129.4, 129.31, 129.25, 128.3, 128.1, 126.6, 126.2, 126.0, 125.9, 125.8, 125.5, 125.3, 125.2, 125.0, 124.7, 123.8, 123.6, 121.0, 119.8, 118.8, 114.2, 75.5, 75.0, 71.4, 70.3, 68.4, 60.8, 34.4, 34.1, 33.9, 32.0, 31.9, 31.7, 31.6, 31.5, 31.2, 31.0, 26.0, 14.5. ESI-HRMS m/z calcd. for C₇₄H₈₄O₈Na⁺ 1123.6058 [M+Na]⁺, found 1123.6044.

Biscalix[4]arene 6: (R)-1 (1.58 g, 1.60 mmol), Cs₂CO₃ (2.09 g, 6.40 mmol), DMF (100 mL), and calix[4]arene tosylate 5 (2.03 g, 1.60 mmol), 60 °C, 8 h. Column chromatography: petroleum ether/acetone = 50:1. Yield 47% (1.56 g). Mp 240–242 °C. [α]²⁵ _D = +76° (c 0.31, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 8.02 (d, 1H, J = 9.2 Hz), 7.94 (d, 1H, J = 8.8 Hz), 7.91 (d, 1H, J = 9.2 Hz), 7.90 (d, 1H, J = 7.6 Hz), 7.84–7.79 (m, 4H), 7.72 (d, 1H, J = 9.2 Hz), 7.43 (d, 1H, J = 8.8 Hz), 7.37 (d, 1H, J = 9.2 Hz), 7.34–7.31 (m, 3H), 7.28–7.05 (m, 13H), 7.03 (d, 1H, J = 2.0 Hz), 6.97–6.95 (m, 3H), 6.92 (d, 1H, J = 8.4 Hz), 6.89 (d, 1H, J = 2.4 Hz), 6.83 (d, 1H, J = 2.4 Hz), 6.74 (d, 1H, J = 2.0 Hz), 6.66 (d, 1H, J = 2.4 Hz), 6.57 (d, 1H, J = 2.4 Hz), 6.54 (d, 1H, J = 2.4 Hz), 6.50 (s, 2H), 5.69 (s, 1H), 5.16–5.10 (m, 1H), 5.00-4.94 (m, 1H), 4.56–4.49 (m, 3H), 4.44 (d, 1H, J = 12.8 Hz), 4.39–4.35 (m, 1H), 4.31 (d, 1H, J = 12.4 Hz), 4.20–3.96 (m, 12H), 3.90–3.56 (m, 9H), 3.53–3.47 (m, 1H), 3.42 (d, 1H, J = 13.6 Hz), 3.23 (d, 1H, J = 12.8 Hz), 3.20 (d, 1H, J = 12.4 Hz), 3.19 (d, 1H, J = 13.6 Hz), 3.03 (d, 1H, J = 12.4 Hz), 2.96 (d, 1H, J = 12.8 Hz), 2.67–2.57 (m, 2H), 2.35–2.28 (m, 2H), 2.23–2.13 (m, 2H), 1.35 (s, 9H), 1.33 (s, 9H), 1.26–1.21 (m, 2H), 1.24 (s, 9H), 1.12 (s, 9H), 1.08 (s, 9H), 1.02 (s, 9H), 0.83 (s, 9H), 0.81 (s, 9H), 0.36 (t, 3H, J = 7.2 Hz). ¹³C NMR (100 MHz, CDCl₃): δ 156.5, 155.7, 155.0, 154.0, 153.9, 153.8, 153.7, 153.4, 153.2, 152.7, 151.4, 150.9, 146.3, 145.8, 145.54, 145.52, 144.5, 144.1, 143.4, 141.7, 136.1, 135.4, 134.6, 134.5, 134.1, 133.4, 133.13, 133.08, 132.8, 132.7, 132.5, 132.0, 131.9, 131.7, 130.5, 130.1, 130.0, 129.7, 129.52, 129.49, 129.4, 129.3, 129.03, 128.97, 128.4, 128.10, 128.05, 128.0, 127.8, 127.6, 126.8, 126.7, 126.4, 126.3, 126.1, 126.0, 125.9, 125.8, 125.62, 125.55, 125.40, 125.35, 125.3, 125.1, 124.7, 124.0, 123.8, 123.54, 123.50, 122.8, 121.1, 120.5, 120.0, 119.4, 118.6, 114.1, 113.1, 76.4, 74.8, 73.74, 73.70, 72.7, 71.4, 71.2, 70.3, 69.9, 68.4, 67.2, 38.9, 38.6, 34.4, 34.2, 34.1, 34.00, 33.99, 33.93, 33.92, 33.85, 32.0, 31.9, 31.8, 31.5, 31.23, 31.21, 31.1, 27.2, 23.6, 10.2. ESI–MS m/z 2093.1 [M+Na]⁺. Anal. Calcd. for C₁₄₃H₁₆₀O₁₂:C 82.94, H 7.79; found C 82.56, H 7.82.

Triscalix[4]arene 10: (R)-1 (108 mg, 0.11 mmol), Cs₂CO₃ (36 mg, 0.11 mmol), DMF (10 mL), and biscalix[4]arene tosylate 9 (210 mg, 0.09 mmol), 60 °C, 8 h. Column chromatography: petroleum ether/ethyl acetate = 25:1. Yield 35% (100 mg). Mp 249–251 °C. [α]²⁵ _D = +55° (c 0.26, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.94–7.77 (m, 12H), 7.62 (d, J = 8.8 Hz, 1H), 7.41–7.28 (m, 8H), 7.22–6.87 (m, 30H), 6.83 (d, J = 2.0 Hz, 1H), 6.75 (d, J = 1.6 Hz, 1H), 6.71 (d, J = 2.0 Hz, 1H), 6.61–6.60 (m, 2H), 6.500 (s, 1H), 6.495 (s, 1H), 6.46 (s, 1H), 6.45 (s, 1H), 5.63 (s, 1H), 5.10–5.04 (m, 1H), 4.93–4.88 (m, 1H), 4.56–4.45 (m, 3H), 4.35–3.49 (m, 46H), 3.31 (d, J = 13.2 Hz, 1H), 3.20 (d, J = 13.2 Hz, 1H), 3.14 (d, J = 13.2 Hz, 2H), 3.09 (d, J = 13.2 Hz, 1H), 3.06 (d, J = 12.8 Hz, 1H), 2.99 (d, J = 12.4 Hz, 1H), 2.89 (d, J = 12.4 Hz, 1H), 2.69–2.58 (m, 2H), 2.21–2.13 (m, 4H), 1.87–1.82 (m, 2H), 1.42–1.36 (m, 2H), 1.31 (s, 18H), 1.252 (s, 9H), 1.248 (s, 9H), 1.19 (s, 9H), 1.13 (s, 9H), 1.08 (s, 9H), 1.05 (s, 9H), 1.00 (s, 18H), 0.79 (s, 9H), 0.77 (s, 9H), 0.35 (t, J = 7.2 Hz, 3H). ¹³C NMR (150 MHz, CDCl₃): δ 156.4, 155.70, 155.67, 154.9, 154.0, 153.9, 153.6, 153.44, 153.40, 153.35, 153.2, 152.79, 152.75, 151.1, 150.9, 146.3, 145.8, 145.7, 145.4, 144.5, 144.24, 144.18, 144.0, 143.4, 141.6, 136.1, 136.0, 135.6, 135.5, 135.4, 135.3, 134.54, 134.51, 134.47, 134.4, 134.0, 133.5, 133.2, 133.0, 132.94, 132.88, 132.8, 132.7, 132.49, 132.45, 132.4, 132.2, 131.9, 131.7, 131.63, 130.58, 130.5, 130.0, 129.9, 129.7, 129.6, 129.5, 129.42, 129.37, 129.2, 129.0, 128.7, 128.3, 128.1, 128.04, 128.00, 127.95, 127.6, 126.9, 126.72, 126.67, 126.5, 126.3, 126.2, 126.1, 126.0, 125.90, 125.86, 125.74, 125.69, 125.65, 125.62, 125.57, 125.5, 125.42, 125.37, 125.34, 125.25, 125.2, 125.0, 124.6, 124.5, 124.10, 124.06, 123.8, 123.5, 123.2, 123.0, 120.92, 120.87, 120.7, 119.5, 119.3, 119.2, 118.6, 114.0, 112.9, 112.8, 76.4, 74.7, 74.1, 73.9, 73.8, 72.8, 72.5, 71.8, 71.3, 71.11, 71.09, 70.3, 70.2, 69.9, 68.4, 67.3, 67.1, 38.9, 38.8, 38.6, 38.4, 34.4, 34.3, 34.2, 34.1, 34.02, 33.99, 33.94, 33.88, 33.8, 32.1, 32.04, 31.98, 31.9, 31.8, 31.71, 31.65, 31.59, 31.56, 31.5, 31.20, 31.17, 30.4, 30.3, 29.9, 27.4, 27.3, 27.2, 23.5, 22.9, 14.4, 10.1. ESI–MS m/z 3134.8 [M+Na]⁺. Anal. Calcd. for C₂₁₅H₂₄₀O₁₈: C 82.97, H 7.77; found C 82.58, H 7.88.

General procedure for the synthesis of 3, and 7

To a suspension of 2, or 6, Cs₂CO₃ in DMF was added 20 equiv. of an electrophile. The reaction mixture was stirred at 60 °C for 1 day. After evaporation of the solvent under reduced pressure, the residue was partitioned between CH₂Cl₂ and 3.6% aqueous HCl. The organic layer was dried with anhydrous MgSO₄. Column chromatography on silica gel afforded 3, or 7 as a white solid.

Calix[4]arene 3: calix[4]arene 2 (3.00 g, 2.73 mmol), Cs₂CO₃ (17.79 g, 54.60 mmol), DMF (10 mL), and ⁿPrI (5.3 mL, 54.60 mmol). Column chromatography: petroleum ether/ethyl acetate = 25:1. Yield 90% (2.80 g). Mp 277–279 °C. [α]²⁵ _D = +27° (c 0.28, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.94 (d, J = 9.2 Hz, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.38 (d, J = 9.2 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.24–7.10 (m, 4H), 7.04 (d, J = 2.4 Hz, 1H), 7.00-6.92 (m, 4H), 6.89 (d, J = 2.4 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H), 4.53–4.49 (m, 1H), 4.24 (q, J = 7.2 Hz, 2H), 4.22–4.16 (m, 2H), 4.13–4.03 (m, 2H), 4.05 (d, J = 12.0 Hz, 1H), 4.02 (d, J = 12.0 Hz, 1H), 3.92–3.84 (m, 3H), 3.74–3.48 (m, 6H), 3.06 (d, J = 12.4 Hz, 1H), 2.98 (d, J = 12.4 Hz, 1H), 2.80–2.68 (m, 2H), 2.64–2.50 (m, 2H), 2.33–2.25 (m, 2H), 1.38–1.29 (m, 2H), 1.33 (t, J = 7.2 Hz, 3H), 1.26 (s, 9H), 1.13 (s, 9H), 1.08 (s, 9H), 1.04 (s, 9H), 0.42 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 173.3, 155.8, 155.0, 153.8, 153.7, 152.7, 145.6, 144.5, 144.2, 143.5, 135.4, 135.3, 134.6, 134.5, 133.3, 133.1, 133.0, 132.8, 132.7, 130.6, 129.7, 129.5, 129.1, 128.04, 127.99, 127.9, 127.5, 126.8, 126.6, 126.4, 126.1, 125.9, 125.7, 125.64, 125.56, 125.5, 125.4, 124.0, 123.5, 122.9, 120.69, 120.68, 119.4, 113.1, 73.8, 73.5, 72.7, 71.3, 69.8, 67.2, 60.8, 38.9, 38.5, 34.2, 34.01, 33.99, 33.96, 32.0, 31.8, 31.54, 31.49, 31.12, 31.05, 26.2, 23.6, 14.6, 10.2. ESI-HRMS m/z calcd. for C₇₇H₉₀O₈Na⁺ 1165.6528 [M+Na]⁺, found 1165.6543.

Biscalix[4]arene 7: biscalix[4]arene 6 (495 mg, 0.24 mmol), Cs₂CO₃ (1.57 g, 4.80 mmol), DMF (5 mL), and ethyl 4-bromobutyrate (687 µL, 4.80 mmol). Column chromatography: petroleum ether/ethyl acetate = 25:1. Yield 64% (335 mg). Mp 213–215 °C. [α]²⁵ _D = +62° (c 0.29, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.92 (d, J = 8.8 Hz, 2H), 7.90–7.85 (m, 4H), 7.79 (d, J = 8.4 Hz, 2H), 7.40–7.28 (m, 8H), 7.22–6.90 (m, 20H), 6.75 (d, J = 1.6 Hz, 1H), 6.73 (d, J = 1.6 Hz, 1H), 6.71 (d, J = 2.0 Hz, 1H), 6.70 (d, J = 1.6 Hz, 1H), 4.57–4.47 (m, 2H), 4.28–3.47 (m, 32H), 3.09 (d, J = 12.0 Hz, 2H), 3.02–2.89 (m, 4H), 2.72–2.61 (m, 2H), 2.18 (s, 4H), 2.03–1.95 (m, 2H), 1.92 (t, J = 7.6 Hz, 2H), 1.77–1.70 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H), 1.261 (s, 9H), 1.256 (s, 9H), 1.19 (s, 9H), 1.18 (s, 9H), 1.08 (s, 18H), 1.05 (s, 9H), 1.04 (s, 9H), 0.37 (t, J = 7.6 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 173.1, 172.9, 155.72, 155.65, 155.3, 155.0, 154.8, 153.93, 153.86, 153.81, 153.67, 153.66, 152.8, 152.7, 145.68, 145.65, 144.6, 144.5, 144.4, 144.2, 143.6, 143.4, 135.41, 135.36, 134.6, 134.5, 133.4, 133.3, 133.2, 133.1, 133.0, 132.93, 132.88, 132.8, 132.7, 130.6, 130.5, 129.7, 129.5, 129.04, 129.00, 128.1, 127.98, 127.95, 127.6, 127.5, 126.9, 126.7, 126.5, 126.4, 126.2, 125.9, 125.7, 125.6, 125.43, 125.39, 125.3, 124.10, 124.08, 123.5, 123.2, 123.0, 120.9, 120.6, 119.33, 119.29, 113.1, 112.8, 74.0, 73.9, 73.8, 72.8, 72.7, 71.2, 71.1, 70.2, 70.0, 67.3, 67.2, 66.9, 64.1, 60.7, 60.4, 38.9, 38.8, 38.7, 38.6, 34.2, 34.04, 34.00, 33.96, 32.10, 32.05, 31.79, 31.77, 31.5, 31.2, 30.8, 30.7, 27.3, 25.8, 24.3, 23.4, 14.5, 14.4, 10.1. ESI–MS m/z 2207.2 [M+Na]⁺. Anal. Calcd. for C₁₄₉H₁₇₀O₁₄: C 81.91, H 7.84; found C 81.60, H 8.20.

General procedure for the synthesis of 4, and 8

To an ice cold solution of 3, or 7 in THF was added LiAlH₄ in small portions. The reaction mixture was stirred under reflux for 4 h. After cooling to 0 °C, H₂O (1 mL), 15% aqueous NaOH (1 mL), and H₂O (3 mL) was sequentially added with an interval of 10 min between each addition. After filtration, the solvent was removed under reduced pressure. Column chromatography on silica gel afforded 4, or 8 as a white solid.

Calix[4]arene 4: calix[4]arene 3 (2.80 g, 2.45 mmol), LiAlH₄ (558 mg, 14.70 mmol), THF (10 mL). Column chromatography: petroleum ether/ethyl acetate = 5:1. Yield 97% (2.64 g). Mp > 300 °C. [α]²⁵ _D = +44° (c 0.30, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.95 (d, 1 H, J = 9.2 Hz), 7.92 (d, 1 H, J = 9.6 Hz), 7.91 (d, 1 H, J = 8.0 Hz), 7.80 (d, 1 H, J = 8.0 Hz), 7.43 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 9.2 Hz, 1H), 7.41–7.34 (m, 1H), 7.25–7.21 (m, 1H), 7.19–7.15 (m, 2H), 7.14–7.10 (m, 1H), 7.04 (d, J = 2.4 Hz, 1H), 7.01–6.96 (m, 3H), 6.92 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 6.69 (d, J = 2.4 Hz, 1H), 4.56–4.52 (m, 1H), 4.25–4.17 (m, 2H), 4.15–4.03 (m, 2H), 4.08 (d, J = 12.4 Hz, 1H), 4.00 (d, J = 12.4 Hz, 1H), 3.94–3.82 (m, 5H), 3.75–3.56 (m, 5H), 3.45–3.42 (m, 1H), 3.05 (d, J = 12.4 Hz, 1H), 3.00 (d, J = 12.8 Hz, 1H), 2.73–2.61 (m, 2H), 2.11–1.96 (m, 2H), 1.86–1.75 (m, 2H), 1.41–1.27 (m, 2H), 1.26 (s, 9H), 1.13 (s, 9H), 1.08 (s, 9H), 1.05 (s, 9H), 0.38 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 155.7, 155.0, 154.0, 153.9, 153.7, 152.8, 145.6, 144.5, 144.1, 143.5, 135.4, 135.3, 134.60, 134.55, 133.4, 133.1, 133.0, 132.84, 132.78, 132.7, 130.7, 129.7, 129.6, 129.1, 128.1, 128.0, 127.8, 127.5, 126.9, 126.7, 126.4, 126.2, 125.8, 125.7, 125.64, 125.60, 125.43, 125.35, 124.2, 123.6, 123.2, 121.0, 119.4, 113.0, 74.1, 73.7, 72.8, 71.2, 70.2, 67.2, 63.1, 38.9, 38.6, 34.2, 34.01, 34.00, 33.96, 32.0, 31.8, 31.6, 31.5, 31.2, 31.1, 29.8, 27.3, 23.6, 10.2. ESI-HRMS m/z calcd. for C₇₅H₈₈O₇Na⁺ 1123.6422 [M+Na]⁺, found 1123.6429.

Biscalix[4]arene 8: biscalix[4]arene 7 (335 mg, 0.15 mmol), LiAlH₄ (58 mg, 1.53 mmol), THF (5 mL). Column chromatography: petroleum ether/ethyl acetate = 5:1. Yield 88% (287 mg). Mp 225–227 °C. [α]²⁵ D = +72° (c 0.24, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.94–7.78 (m, 8H), 7.71–6.90 (28 H, m), 6.76 (d, J = 1.6 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.72 (d, J = 2.0 Hz, 1H), 6.70 (d, J = 2.0 Hz, 1H), 4.58–4.53 (m, 1H), 4.41–4.37 (m, 1H), 4.29–3.50 (m, 32H), 3.37–3.23 (m, 2H), 3.12 (d, J = 12.4 Hz, 1H), 3.10 (d, J = 12.4 Hz, 1H), 3.01 (d, J = 12.4 Hz, 1H), 2.89 (d, J = 12.4 Hz, 1H), 2.75–2.63 (m, 2H), 2.15 (s, 4H), 1.53–1.36 (m, 6H), 1.27 (s, 9H), 1.24 (s, 9H), 1.20 (s, 9H), 1.18 (s, 9H), 1.09 (s, 18H), 1.07 (s, 9H), 1.05 (s, 9H), 0.39 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 155.7, 155.5, 155.0, 153.93, 153.90, 153.8, 153.7, 153.6, 153.5, 152.81, 152.76, 145.7, 145.4, 144.5, 144.4, 144.2, 143.5, 143.4, 135.4, 135.24, 135.19, 134.6, 134.5, 133.5, 133.4, 133.2, 133.1, 132.99, 132.97, 132.94, 132.88, 132.7, 132.6, 132.4, 130.6, 130.4, 129.7, 129.6, 129.5, 129.2, 129.0, 128.1, 128.0, 127.5, 126.9, 126.72, 126.65, 126.5, 126.4, 126.22, 126.17, 126.0, 125.9, 125.8, 125.7, 125.54, 125.49, 125.34, 125.31, 124.1, 124.0, 123.6, 123.5, 123.3, 122.7, 120.9, 119.9, 119.5, 119.3, 113.9, 112.8, 74.99, 73.95, 73.8, 72.8, 72.6, 72.0, 71.5, 71.1, 70.2, 69.8, 67.7, 67.2, 62.9, 38.9, 38.8, 38.7, 38.5, 34.2, 34.03, 34.00, 32.1, 32.0, 31.8, 31.6, 31.5, 31.2, 29.6, 27.3, 27.2, 23.6, 10.1. ESI–MS m/z 2165.3 [M+Na]⁺. Anal. Calcd. for C₁₄₇H₁₆₈O₁₃: C 82.39, H 7.90; found C 82.25, H 8.01.

General procedure for the synthesis of 5, and 9

To a solution of 4, or 8 in CH₂Cl₂ was added TsCl, NEt₃, and DMAP. The reaction mixture was stirred at room temperature for 12 h, followed by removal of the solvent under reduced pressure. Column chromatography on silica gel afforded 5, or 9 as a white solid.

Calix[4]arene 5: calix[4]arene 4 (3.21 g, 2.83 mmol), TsCl (3.24 g, 17.00 mmol), NEt₃ (2.39 mL, 17.00 mmol), DMAP (346 mg, 2.83 mmol), CH₂Cl₂ (20 mL). Column chromatography: petroleum ether/ethyl acetate = 15:1. Yield 94% (3.39 g). Mp 151–153 °C. [α]²⁵ _D = +36° (c 0.29, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.96 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 9.6 Hz, 1H), 7.92 (d, J = 6.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 9.2 Hz, 1H), 7.36 (d, J = 6.0 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.28–7.11 (m, 6H), 7.03 (d, J = 2.4 Hz, 1H), 6.99 (s, 2H), 6.97 (d, J = 9.2 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.65 (d, J = 2.4 Hz, 1H), 4.55–4.51 (m, 1H), 4.21 (t, J = 6.4 Hz, 2H), 4.18–4.07 (m, 3H), 4.05–4.02 (m, 1H), 3.98 (d, J = 12.4 Hz, 1H), 3.95 (d, J = 12.0 Hz, 1H), 3.89–3.65 (m, 6H), 3.58–3.52 (m, 2H), 3.42–3.36 (m, 1H), 3.00 (d, J = 12.4 Hz, 1H), 2.99 (d, J = 12.4 Hz, 1H), 3.79–2.66 (m, 2H), 2.35 (s, 3H), 2.05–1.97 (m, 2H), 1.93–1.86 (m, 2H), 1.42–1.31 (m, 2H), 1.26 (s, 9H), 1.11 (s, 9H), 1.07 (s, 9H), 1.04 (s, 9H), 0.41 (t, J = 7.6 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 155.7, 155.0, 153.9, 153.8, 153.7, 152.8, 145.7, 145.0, 144.5, 144.2, 143.5, 135.4, 135.3, 134.6, 134.5, 133.4, 133.2, 133.0, 132.9, 132.8, 132.6, 132.5, 130.7, 130.2, 129.8, 129.6, 129.1, 128.1, 128.0, 127.8, 127.4, 126.9, 126.7, 126.4, 126.2, 125.9, 125.7, 125.59, 125.57, 125.5, 125.4, 124.1, 123.6, 123.1, 120.9, 119.4, 113.0, 73.8, 73.4, 72.7, 71.2, 70.4, 70.1, 67.1, 38.8, 38.6, 34.2, 34.00, 33.96, 33.9, 32.0, 31.8, 31.5, 31.13, 31.05, 26.9, 26.1, 23.6, 21.8, 10.2. ESI-HRMS m/z calcd. for C₈₂H₉₄O₉SNa⁺ 1277.6511 [M+Na]⁺, found 1277.6517.

Biscalix[4]arene 9: calix[4]arene 8 (347 mg, 0.16 mmol), TsCl (186 mg, 0.98 mmol), NEt₃ (137 µL, 0.98 mmol), DMAP (20 mg, 0.16 mmol), CH₂Cl₂ (10 mL). Column chromatography: petroleum ether/ethyl acetate = 8:1. Yield 77% (286 mg). Mp 204–206 °C. [α]²⁵ _D = +71° (c 0.24, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.91 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.79–7.75 (m, 4H), 7.39 (d, J = 1.6 Hz, 1H), 7.37–7.30 (m, 7H), 7.26 (d, J = 2.4 Hz, 1H), 7.22–7.14 (m, 4H), 7.10–7.05 (m, 4H), 7.01 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 6.97–6.91 (m, 8H), 6.88 (d, J = 2.0 Hz, 1H), 6.79 (d, J = 2.4 Hz, 1H), 6.78 (d, J = 2.4 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 6.71 (d, J = 2.0 Hz, 1H), 6.66 (d, J = 2.0 Hz, 1H), 6.64 (d, J = 2.4 Hz, 1H), 4.57–4.52 (m, 1H), 4.44–4.40 (m, 1H), 4.27–3.85 (m, 22H), 3.83–3.70 (m, 7H), 3.64–3.48 (m, 7H), 3.26–3.16 (m, 2H), 3.09 (d, J = 12.0 Hz, 1H), 3.01 (d, J = 12.0 Hz, 1H), 3.00 (d, J = 12.8 Hz, 1H), 2.88 (d, J = 12.0 Hz, 1H), 2.70–2.59 (m, 2H), 2.41 (s, 3H), 2.19–2.11 (m, 4H), 1.40–1.33 (m, 2H), 1.25 (s, 9H), 1.23 (s, 9H), 1.18 (s, 9H), 1.15 (s, 9H), 1.07 (s, 9H), 1.05 (s, 9H), 1.03 (s, 9H), 0.98 (s, 9H), 0.36 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 155.7, 155.6, 155.0, 154.9, 153.93, 153.87, 153.71, 153.67, 153.6, 153.5, 152.8, 152.7, 145.7, 145.5, 144.9, 144.5, 144.4, 144.3, 144.2, 143.6, 143.4, 135.41, 135.38, 135.34, 135.28, 134.6, 134.51, 134.50, 133.4, 133.32, 133.31, 133.1, 133.03, 132.99, 132.96, 132.9, 132.7, 132.5, 132.4, 132.3, 130.6, 130.5, 130.0, 129.7, 129.6, 129.5, 129.1, 129.0, 128.1, 128.0, 127.5, 126.9, 126.71, 126.68, 126.5, 126.2, 126.0, 125.9, 125.8, 125.7, 125.64, 125.56, 125.51, 125.46, 125.32, 125.28, 124.13, 124.05, 123.6, 123.5, 123.3, 122.8, 120.9, 120.2, 119.4, 119.3, 113.4, 112.8, 74.0, 73.9, 73.8, 72.8, 72.6, 71.4, 71.3, 71.1, 70.3, 70.2, 69.8, 67.5, 67.2, 38.9, 38.8, 38.6, 38.4, 34.24, 34.21, 34.04, 34.01, 33.99, 33.94, 33.90, 32.1, 32.0, 31.8, 31.6, 31.5, 31.2, 27.29, 27.27, 26.8, 25.8, 23.6, 21.8, 10.1. ESI–MS m/z 2319.2 [M+Na]⁺. Anal. Calcd. for C₁₅₄H₁₇₄O₁₅S: C 80.52, H 7.63; found C 80.26, H 7.68.