# Efficient Synthesis of Conformationally Constrained 5,5'-Bi-1,2,3-Triazole-Based Bis-Macrocycles

Teodor A Cucuiet, Cătălin C Anghel, Alexandra Pop, Mădălina Elena Moisă, Arnaud Gautier, Mounir Traïkia, Ion Grosu, Niculina D Hădade

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Teodor A Cucuiet, Cătălin C Anghel, Alexandra Pop, Mădălina Elena Moisă, Arnaud Gautier, et al.. Efficient Synthesis of Conformationally Constrained 5,5'-Bi-1,2,3-Triazole-Based Bis-Macrocycles. Synthesis: Journal of Synthetic Organic Chemistry, 2025, 57 (22), pp.3462-3468. 10.1055/a-2655-4863. hal-05375043

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# Efficient Synthesis of Conformationally Constrained 5,5'-Bi-1,2,3-Triazole-Based Bis-Macrocycles

Teodor A. Cucuiet<sup>a,b,1</sup>

Cătălin C. Anghel<sup>a,b</sup>

Alexandra Pop<sup>a,b</sup>

Mădălina Elena Moisă<sup>b</sup>

Arnaud Gautier<sup>c</sup>

Mounir Traikia<sup>c</sup>

Ion Grosu<sup>a,b</sup>

Niculina D. Hădade<sup>a,b,*</sup>

Dedicated to Academician Marius Andruh on the occasion of his 70th anniversary

<figure><img src="image_2.png" /></figure>

Received:

Accepted:

Published online:

DOI:

**Abstract** We report herein the synthesis and structural characterization of 5,5'-bi-1,2,3-triazole bis-macrocycles obtained via oxidative copper-catalyzed azide-alkyne cycloaddition (CuAAC) of acyclic precursors bearing azide and alkyne groups. Initially observed as by-products during the copper(I)-NHC-catalyzed CuAAC synthesis of a 1,2,3-triazole-based macrocycle, these compounds were selectively obtained after systematic optimization of the catalyst, ligand, reaction atmosphere, and precursor addition rate. The bis-macrocycles were characterized by NMR and HRMS, and in some cases, by single-crystal X-ray diffraction. Chiral HPLC experiments enabled enantiomer separation, confirming their configurational stability.

**Key words** 5,5'-bi-1,2,3-triazoles, bis-macrocycles, CuAAC, atropoisomer, N-heterocyclic carbenes

The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), independently reported by Meldal<sup>2</sup> and Sharpless<sup>3</sup> in 2002, is considered as the 'cream of the crop' of the 'click chemistry' toolbox due to its remarkable efficiency, regioselectivity, and compatibility with a wide range of functional groups and solvents.<sup>4-6</sup> The reaction typically affords 1,4-disubstituted 1,2,3-triazoles as major product under mild conditions and often with quantitative yields. These advantages have led to its widespread application across organic synthesis, bioconjugation, polymer chemistry, and materials science.<sup>7-9</sup>

Despite its high selectivity, the CuAAC reaction has been shown to afford side products under specific conditions, including diacetylenyles, 5-hydroxytriazoles, and 5,5'-bi-1,2,3-triazoles (bi-triazoles).<sup>3</sup> The selective formation of bi-triazoles over 1,2,3-triazoles was first reported by Burgess et al. using CuSO<sub>4</sub>/Cu(0) catalytic system under aerobic conditions, with potassium

carbonate as a base, which was shown to be essential for achieving high yields.<sup>10</sup> Since then, several studies have reported conditions favoring bi-triazole formation, including the use of excess of copper(I) halides in the presence of a base at low temperatures under air.<sup>11-14</sup>

The effect of the ligand has also been shown to be important. Namely secondary amine-functionalized polysiloxanes promoted the selective formation of bi-triazoles, whereas primary amines substituents led to the classical 1,2,3-triazole products.<sup>15</sup> Similarly, the use of Cu(OAc)<sub>2</sub> in alcoholic solvents, with tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) and/or NaNO<sub>2</sub> as additives under oxygen-rich conditions, resulted in high conversions and enhanced selectivity toward 5,5'-bistriazoles.<sup>16</sup> Additionally, the Fehling reagent/glucose system has also been shown to efficiently promote the synthesis of bi-triazoles.<sup>17</sup> The formation of 5,5'-bistriazoles is believed to proceed via oxidative coupling of copper-triazolide intermediates generated during the reaction.<sup>12,14,16</sup> Alternative synthetic strategies for bi-triazoles involve the use of prefunctionalized substrates such as 1,3-butadiynes or ethynyltriazoles, which undergo tandem cycloadditions with azides to afford the desired products.<sup>18</sup>

The most salient property of 5,5'-bi-triazoles is their axial chirality and high racemization barriers. The chirality of these compounds arises from non-symmetric substitution of the triazole rings and restricted rotation around the C–C bond connecting the triazole units, representing a clear case of atropisomerism. Substitution with bulky groups confers significant rotational barriers about the triazole–triazole bond, rendering the molecules conformationally stable.<sup>19</sup> These

<footnote><sup>a</sup> Babes-Bolyai University, Faculty of Chemistry and Chemical Engineering, Department of Chemistry, 11 Arany Janos str., 400028, Cluj-Napoca, Romania.</footnote>

<footnote><sup>b</sup> Supramolecular Organic and Organometallic Chemistry Centre (SOOMCC), Cluj-Napoca, 11 Arany Janos str., 400028, Cluj-Napoca, Romania.</footnote>

<footnote><sup>c</sup> Université Clermont Auvergne, CNRS, Institut de Chimie de Clermont-Ferrand, F-63000 Clermont-Ferrand, France</footnote>

<footnote>e-mail: niculina.hadade@ubbcluj.ro</footnote>
axially chiral compounds have been successfully employed as ligands in scandium(III)-catalyzed nucleophilic additions.¹⁹ Their chirality has been investigated using chiral shift reagents such as Eu(hfc)₃,¹⁹ and their enantiomers have been resolved and structurally characterized.¹⁹,²⁰ Some derivatives were also found to exhibit interesting photophysical properties, making them potential candidates for fluorescence-based sensing applications.²¹

Diastereoselective syntheses of bi-triazoles have been achieved using sugar-derived azides, enabling access to single

atropisomer²²,²³ while the use of enantiopure ethynyl-decorated helicene derivatives allowed the first enantioselective synthesis of a bi-triazole compound.²⁴

While carrying out the macrocyclization of compound **1**²⁵,²⁶ (Scheme 1) via a CuAAC reaction catalyzed by copper(I)-NHC complex **Ia**,²⁷ we unexpectedly observed the formation of a second compound, in addition to the expected macrocycle **2** (44% yield). After purification, the side product was identified as bi-triazole bis-macrocycle **3** (12% yield), most probably arising from an oxidative CuAAC pathway.

<figure><img src="image_3.png" /><figcaption>Scheme 1 Formation of bi-triazole 3 as by-product in CuAAC macrocyclization of 1</figcaption></figure>

Considering the characteristics of bi-triazoles (vide supra) and the host-guest properties conferred by macrocyclic structures²⁸ - as well as the remarkable structural complexity achieved in a single step - we considered of great interest to optimize the reaction conditions in order to obtain suitable yield for the bis-macrocycle. This involved varying several parameters (e.g., catalyst, ligand, dilution conditions, reaction time, etc.) to reach acceptable yield of the bi-triazole product and to broaden the scope of the synthesis. To the best of our knowledge, these represent the first reported examples of macrocycles incorporating bi-triazole units.

## Results and discussion

With the aim of optimizing the reaction conditions for the formation of the bi-triazole derivative, we first designed and synthesized the acyclic precursor, **4**, bearing azide and alkyne functional groups (Scheme S1, Supporting Information). Because compound **1** could not be obtained in sufficient quantities, it was considered unsuitable for this purpose.

The CuAAC reaction performed in the presence of **Ia**, under the same conditions as used for compound **3**, afforded macrocycle **5** and bis-macrocycle **6** in a 7.6:1 molar ratio, as determined from the ¹H NMR spectrum of the crude reaction mixture (Figure S16). The singlet corresponding to the methylene protons at 4.72 ppm in the ¹H-NMR spectrum of **5** (Figure 1-bottom) and

the doublets at 4.44 ppm and 4.59 ppm in ¹H-NMR spectrum of compound **6** (Figure 1-top), assigned to the diastereotopic protons in the methylene groups adjacent to the triazole nitrogen, were used to calculate the macrocycle/bis-macrocycle ratio. Thankfully, compounds **5** and **6** could be separated by column chromatography and fully characterized as unique compounds (see Supporting Information).

<figure><img src="image_4.png" /><figcaption>Figure 1 ¹H NMR spectra (fragments) of macrocycle 5 (bottom) and bis-macrocycle 6 (CDCl₃, 400 MHz).</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>Scheme 2 Model reaction employed to optimize the conditions for the selective synthesis of bi-triazole 6.</figcaption></figure>
First, we focused on the identification of the best catalytic system leading to a favorable 6/5 ratio (Table 1). Catalyst **Ia** (Scheme 1), **Ib** (Scheme 2) with various ligands, and catalytic systems previously reported in literature¹⁶ were employed in this step, while the reaction atmosphere was varied from reactions performed under air to highly inert conditions. The reactions were carried out by adding a 32 mM methanol solution of **4**, over a period of 8 hours to a solution of catalyst (10 mol%), ligand and in some cases additives, dissolved in 50 mL of methanol.

The best results were obtained when copper(I)-NHC catalyst **Ib** and imidazole ligand, under argon atmosphere with air traces was used (Table 1, entry 6). Similarly, it has been previously reported that use of (N-methyl-imidazole) NMI affords a highly active catalyst but prompt to degradation in presence of oxygen.²⁹ Furthermore, it is worth mentioning that using highly inert conditions drastically decreases the amount of bis-triazole formed, highlighting the crucial role of oxygen and supporting the previously proposed oxidative CuAAC mechanism.¹²,¹⁴,¹⁶ However, the use of an open-air atmosphere resulted, in most cases, in catalyst degradation, as evidenced by the low conversion of the starting material into macrocycle 5 and/or bis-macrocycle 6.

<table><caption>Table 1 Optimization of macrocycle 5: bis-macrocycle 6 molar ratio</caption><thead><tr><th>Entry</th><th>Catalyst</th><th>Reaction conditions</th><th>5:6:4 molar ratio</th></tr></thead><tbody><tr><td>1</td><td>Ia</td><td>Ar (air traces)<sup>a</sup></td><td>7.5:1:0</td></tr><tr><td>2</td><td>Ia</td><td>air</td><td>6.6:3.5:1</td></tr><tr><td>3</td><td>Ia</td><td>Ar (highly inert)*</td><td>33.3:1:1.8</td></tr><tr><td>4</td><td>Ib/pyridine</td><td>Ar (air traces)</td><td>0:1:2.3</td></tr><tr><td>5</td><td>Ib/2,2'-bipyridine</td><td>Ar (air traces)</td><td>9.92:1:1.5</td></tr><tr><td>6</td><td>Ib/imidazole</td><td>Ar (air traces)</td><td>1:5.1:1.8</td></tr><tr><td>7</td><td>Ib/imidazole</td><td>air</td><td>0:0:1<sup>a</sup></td></tr><tr><td>8</td><td>Cu(OAc)<sub>2</sub>·H<sub>2</sub>O / K<sub>2</sub>CO<sub>3</sub><sup>15</sup></td><td>air</td><td>0:0:0<sup>a</sup></td></tr><tr><td>9</td><td>Cu(OAc)<sub>2</sub>·H<sub>2</sub>O / K<sub>2</sub>CO<sub>3</sub> / TBT<sub>A</sub><sup>15</sup></td><td>air</td><td>0:0:0<sup>a</sup></td></tr><tr><td>10</td><td>Ib / 0.02 eq. Cu(OAc)<sub>2</sub>·H<sub>2</sub>O<sup>a</sup></td><td>air</td><td>10:6.6:1</td></tr></tbody></table>

a-formation of 5 or 6 was not observed.

# - The reaction flask was purged with argon and an inert atmosphere was maintained throughout the reaction using argon-filled balloons.

**. The solvent was degassed using the freeze-pump-thaw technique and an inert atmosphere was maintained throughout the reaction using argon-filled balloons.

Next, the reaction conditions that resulted in the best selectivity for bis-macrocycle 6 (entry 6, Table 1) were used in a second optimization phase, which aimed to improve the isolated yield of bis-triazole bis-macrocycle 6 by adjusting the catalyst loading and applying high-dilution conditions to favor macrocycle formation over linear oligomers.

Various dilution conditions were tested, including modifications to the initial solvent volume (from 10 mL to 100 mL MeOH) and the duration over which precursor **4** (2 mL, 135 mM solution in methanol) was added to the reaction mixture (ranging from one-pot addition to slow addition over 8 hours). Additionally, different amounts of catalyst **Ib** (10 mol% to 45 mol%) were evaluated. Yields were determined after isolation of compound **6** as a pure product.

As previously mentioned, we noted that under the tested reaction conditions, the **Ib**/imidazole catalytic system decomposed rapidly, resulting in favorable 5:6 molar ratios

(approximately 1:5), but low overall yields (7-10%). To address this limitation, catalyst **Ib** was added in portions throughout the reaction.

Finally, the optimized conditions involved the addition of compound **4** over a period of 2 hours to a solution containing 45 mol% imidazole and 10 mol% catalyst **Ib** in 20 mL of methanol. Additionally, seven subsequent portions of 5 mol% catalyst were added every 30 minutes, starting from the beginning of the reaction. Under these conditions, compound **6** was obtained in 50 % yield. Gratefully, an improved selectivity, 1:26 (5:6) molar ratio was observed.

Next, we sought to expand the scope of the reaction by synthesizing new bis-macrocycles. Under the optimized conditions, the yield of compound **3** (Scheme 1) was improved from 12% to 30%. Furthermore, two additional bis-triazole precursors, **7** and **9** (Scheme 3), bearing azide and ethynyl functional groups, were synthesized (see Supporting Information for details on the synthesis of **7** and **9**) and subsequently employed in the synthesis of the corresponding bis-triazole bis-macrocycles **8** and **10**, obtained in 30% and 17% yield, respectively.

The structures of the bis-macrocycles were fully characterized by NMR and high-resolution mass spectrometry (HRMS). In addition to confirm the structures, the ¹H NMR spectra also provided initial insights into their chirality. Specifically, for chiral derivatives (i.e. the rotation around the triazole-triazole single bond is hindered) the protons of methylene groups adjacent to the triazole unit become diastereotopic, thus appearing as distinct signals.

<figure><img src="image_6.png" /><figcaption>Scheme 3 Synthesis of bis-triazoles 8 and 10 performed under the optimized reaction conditions.</figcaption></figure>

Analysis of the ¹H NMR spectra indicated the presence of atropisomeric structures for **3**, **6** and **10** (Figures S10, S7 and S9, respectively). Regarding, the smallest bis-macrocycles **8**, its ¹H-NMR spectrum recorded at room temperature, in CDCl₃, showed signals at coalescence (Figure S6). This behavior could be attributed either to a less hindered rotation around the triazole-triazole bond leading to exchange between the enantiomers, or, more likely, to a more hindered flipping of the bridges from one side of the triazole ring to the other (Figure 1), compared to the larger analogs. We attributed this spectral behavior to the flipping motion of the two bridges as the enantiomers of **8** were found to be stable at room temperature and could be separated by chiral HPLC (vide infra and Supporting Information S.5). As illustrated for the *aS* enantiomer in Figure 2, this flipping process gives rise to four

Commenté [AG1]: Une ou deux étoiles? Une seule dans la table.
conformations, three of which (I, II, and IV) are diastereomeric, while conformations I and III are identical.

<figure><img src="image_7.png" /><figcaption>Figure 2 Representation of the equilibrium between different conformations of the *a*S enantiomer of compound 8, resulting from the flipping of the bridges from one side of the triazole ring to the other.</figcaption></figure>

Variable-temperature ¹H NMR experiments (Figure S17), recorded in CD₃CN, indicated that free flipping of the bridges in bis-macrocycle **8** does not occur up to 65 °C, as the signals corresponding to various protons remain at coalescence. However, lowering the temperature to 5 °C froze the conformational equilibria. The ¹H NMR spectrum recorded at this temperature displays a complex pattern of signals, indicating the presence of several diastereoisomeric structures. Assignment of the signals to individual diastereoisomers was not possible due to significant signal overlapping.

We also investigated the separation of enantiomers of compounds **6**, **8**, and **10** by chiral HPLC. After screening various chiral stationary phases and elution systems, separation of the enantiomers was successfully achieved under normal-phase conditions using a Chiralpak IA column (0.46 cm × 25 cm). Chromatograms recorded at room temperature showed two well-resolved peaks, with retention time (RT) differences of 9.3 minutes for **6**, 10 minutes for **8**, and 1.7 minutes for **10** (see Supporting Information).

Further confirmation of the molecular structures of compounds **6** and **8** was obtained by single-crystal X-ray diffraction. Crystals suitable for analysis were obtained either by slow evaporation of a solution of **6** in a 1:3 (v/v) mixture of dichloromethane and hexane, or by slow diffusion of diethyl ether vapors into a dichloromethane solution of **8**. Both compounds crystallized as

racemates. Analysis of the molecular structures (Figure 3) revealed that, in both cases, the macrocycles points on the same side of the molecule. The torsion angles of the triazole rings in **6** and **8** were found to be 69° and 70°, respectively. In the lattice of **6**, molecules with the same chirality are organized into chains. Adjacent chains consist of molecules of opposite chirality. Within different chains, the molecules alternate between head-to-head and tail-to-tail orientations (Figure 4). The molecules displaying a head-to-head arrangement display two C-H···O short contacts with H···O distances of 2.484 Å and a C,H,O angle of 147°, two C-H···N short contacts (H···N distance of 2.582 Å, C,H,N angle of 163°), and an additional C-H···N short contact with an H···N distance of 2.599 Å and C,H,N angle of 159°.

The molecules displaying tail-to-tail orientation exhibit two C-H···O short contacts with H···O distances of 2.574 Å (C,H,O angle of 122°), and two additional C-H···O short contacts with distances of 2.604 Å and C,H,O angles of 130°.

These interactions result in the formation of 2D layers composed of alternating chains of enantiomers (Figure 3). Molecules from adjacent layers (Figure 4, inert) adopt a head-to-tail orientation, exhibit opposite chirality, and display a C-H···N (H···N distance of 2.579 Å, C,H,N angle of 140°), two C-H···O (2.587 Å, C,H,O angle of 156°) short contacts, and another C-H···O interaction (2.576 Å, C,H,O angle of 151°).

<figure><img src="image_8.png" /><figcaption>Figure 3 Molecular structures of compounds 6 (a) and 8 (b), showing the *a*R enantiomers.</figcaption></figure>

<figure><img src="image_9.png" /><figcaption>Figure 4. Crystal packing of 6, viewed along *b* crystallographic axis.</figcaption></figure>
Crystal packing of compound **8** also revealed several interesting features. Chains of bis-macrocycles with the same chirality (Figure 5; *aR* on the left, *aS* on the right) show two C–H···O short contacts, with H···O distances of 2.515 Å and 2.258 Å, and C,H,O angles of 137° and 174°, respectively. The molecules are arranged along a crystallographic axis, forming channels. Within each channel, the molecules share the same chirality display two C–H···N short contacts, with H···N distances of 2.618 Å and 2.634 Å, and C,H,N angles of 131° and 138°, respectively (Figure 5, inset).

<figure><img src="image_10.png" /><figcaption>Figure 5. Crystal packing of 8, viewed along *a* crystallographic axis.</figcaption></figure>

## Conclusions

In summary, we report a new catalytic system for the efficient one-step synthesis of bis-macrocycles containing the 5,5'-bi-triazole unit, starting from simple bifunctional acyclic precursors via oxidative CuAAC. Noteworthy, access to this class of compounds was made possible following the serendipitous observation of their formation as by-products during the synthesis of a 1,2,3-triazole-based macrocycle, followed by careful optimization of the reaction conditions to enhance both selectivity and yield.

The scope of the reaction was explored, leading to the isolation of four new bis-macrocycles. Their structures were characterized by ¹H and ¹³C NMR spectroscopy and HRMS, and in two cases by single-crystal X-ray diffraction. Variable-temperature NMR studies provided insights into conformational dynamics, indicating hindered flipping of the macrocyclic bridges in the case of the bis-macrocycles with the smallest cavity. Additionally, the chirality of the reported bis-triazoles was confirmed by successful resolution of enantiomers using chiral HPLC. Altogether, these findings open new avenues for the application of bis-triazole macrocycles in host–guest chemistry, sensing, catalysis, and the design of new chiral materials.

The experimental section has no title; please leave this line here.

**General experimental data:** Reactions were monitored by thin-layer chromatography (TLC) on silica gel 60 F254-coated aluminum plates, and compounds were visualized under UV light and/or using a basic KMnO₄ solution as a staining agent. Column chromatography was carried out using silica gel (40–63 µm) as the stationary phase. ¹H and ¹³C NMR spectra were recorded at room temperature on Bruker Avance 400 or Bruker Avance 600 spectrometers. Variable-temperature NMR experiments were performed on a Bruker Avance 500 spectrometer. Chemical shifts are reported in parts per million (ppm), with signal multiplicities designated as follows: *s* = singlet, *d* = doublet, *t* = triplet, *q* = quartet, *m* = multiplet. High-resolution mass spectra (HRMS) were acquired on a Thermo Scientific LTQ ORBITRAP XL mass spectrometer using electrospray ionization in positive mode (ESI*').* The crystals of 6 and 8 were mounted on MiTeGen microMounts cryoloops and data were collected on a Bruker DB VENTURE diffractometer using Mo-Kα radiation (λ = 0.71073 Å) for 6 and Cu-Kα radiation (λ = 1.54178 Å) for 8, respectively from a IµS 3.0 microfocus source with multilayer optics, at 100(2) K. The structures were refined with anisotropic thermal parameters for non-H atoms. Hydrogen atoms were placed in fixed, idealized positions and refined with a riding model and a mutual isotropic thermal parameter. For structure solving and refinement the Bruker APEX3 Software Package was used.³⁰ The drawings were created using the Diamond program.³¹ Details about the crystal structure determination and refinement data are given in Tables S1. The CCDC reference numbers are 2455035 (6) and 2455034 (8) and contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif.

Chiral HPLC separations were performed on an Agilent 1200 Series system using a Chiralpak IA column (0.46 × 25 cm), with a flow rate of 1 mL/min at 25 °C, and UV–Vis detection at 240 nm.

## General procedure for the synthesis of bis-macrocycles 3, 6, 8 and 10

A solution of linear precursor **4**, **7** or **9** (0.270 mmol, 1 eq.) in methanol (2 mL) was added dropwise with a push syringe, over 2 hours, to a solution of catalyst I (10.96 mg, 0.027 mmol, 0.1 eq.) and imidazole (7.33 mg, 0.108 mmol, 0.4 eq.) in methanol (20 mL), under argon atmosphere (ppm air level). Additional 7 portions of Ib (5.48 mg, 0.0135 mmol, 0.05 eq. each portion) were added to the reaction mixture at intervals of 30 minutes. An hour after the last portion of Ib was added, the solvent was removed under reduced pressure, a saturated HEDTA solution (5 mL) was added and the mixture was extracted with CH₂Cl₂ (5x 5 mL). The combined organic layers were dried over anhydrous MgSO₄ and the solvent was removed under reduced pressure. Purification was carried out by column chromatography (silica gel, ethyl acetate: methanol 4:1, v:v or dichloromethane : methanol 9:1 v:v).

**Note:** Bismacrocycle **8** was obtained using 0.174 mmol of **7**, using the same reaction conditions as in the general procedure.

41,41'-bi[2(10,13,16,21,24,27,30,33-nonaoxa-5,6,7-triazatetetracyclo [32.2.2.2]17,20,14'7]hentetracontane]-1(36),1'(36'),4(41),4'(41'),5,5',17,17',19,19',34,34',37,37',39,39'-hexadecane 3

Obtained as a colourless solid in 30% yield (30 mg).

¹H NMR (400 MHz, CDCl₃), δ₉ (ppm): 6.78-6.52 (overlapped signals, 16H, CH₃ₚ), 4.88 (d, $^{2}$J=11.6 Hz, 2H, CHH), 4.75 (d, $^{2}$J=11.6 Hz, 2H, CHH), 4.39-4.32 (m, 2H, CH), 4.30-4.21 (m, 2H, CH), 4.01 (t, $^{3}$J=4.7 Hz, 4H, CH₂), 3.96-3.64 (overlapped signals, 36H, CH₂), 3.52-3.29 (overlapped signals, 12H, CH₂).

¹³C APT NMR (100 MHz, CDCl₃), δc (ppm): 153.5, 153.2, 153.0, 152.4, 144.6, 123.7, 115.6 (2C), 115.5, 115.2, 71.2, 71.0, 70.7 (2C), 70.2, 70.0, 69.8, 69.5, 69.4, 68.3, 68.1, 67.8 (2C), 61.7, 49.3.

ESI(+)-HRMS (*m/z*): Calculated for C₅₀H₇₆N₆O₁₈: 1145.5289, found 1145.5254 [M+H]⁺.

8,8',11,11',14,14',17,17',20,20' -decaoxa-1,1',23,23',24,24'-hexaaza[25,25'-bi(bicyclo[20.2.1]pentacosane)]-22(25),22',23,23'-tetraene-7,7'dione 6

Obtained as a colourless solid in 50% yield (50 mg). ¹H NMR (400 MHz, CDCl₃), δ₉ (ppm): 4.60 (d, $^{3}$J = 12.5, 2H, CHH), 4.44 (d, $^{3}$J = 12.5, 2H, CHH),
4.38-4.28 (m, 2H, CH), 4.26-4.09 (overlapped signals, 6H, CH₂ and CH), 3.75-3.48 (overlapped signals, 2H, CH₂), 2.29 (t, ³J = 6.7Hz, 4H, CH₂), 2.03-1.90 (m, 2H, CH), 1.84-1.70 (m, 2H, CH), 1.68-1.54 (m, 4H, CH₂), 1.29-1.16 (m, 4H, CH₂).¹³C NMR (100 MHz, CDCl₃), δc (ppm): 173.4, 145.4, 123.0, 71.0, 70.8 (2C), 70.7, 69.7, 69.2, 63.8, 63.1, 49.5, 33.9, 28.4, 25.4, 24.3. ESI(+)-HRMS (m/z): Calculated for C₃₈H₅₆N₆O₁₂: 741.4029, found 741.3974 [M+H]⁺.

4,4',7,7',10,10',13,13'-octaoxa-1,1',16,16',17,17'-hexaaza-18,18'-bi(bicyclo[13.2.1]octadecane-15(18), 15',16',16'-tetraene) 8

Obtained as a colourless solid in 30% yield (21 mg). Signals in NMR spectrum are at coalescence at room temperature and cannot be assigned. ESI(+)-HRMS (m/z): Calculated for C₂₂H₃₆N₆O₆: 513.2667, found 513.2663 [M+H]⁺.

27,27'-bi[(8,11,14,17,20-pentaoxa-3,4,5-triazatricyclo[20.2.2.1³⁶]heptacosane)-1(24),1'(24'),4,4',6(27), 6'(27)22,22',25,25'-decaene-21,21'-dione 10

Obtained as a colourless solid in 17% yield (18.4 mg).

¹H NMR (400 MHz, CDCl₃), δₘ (ppm): 7.63 (d, ³J = 8.1, 4H, CH₄), 6.48 (d, ³J = 8.1, 4H, CH₄), 5.82 (d, ²J = 16.8, 2H, CH/CH), 5.65 (d, ³J = 16.8, 2H, CH), 4.58-4.45 (overlapped signals, 4H, CH), 4.37 (d, ²J = 13.1, 2H, CH), 4.29-4.19 (m, 2H, CH), 3.95 (t, ³J = 9.2Hz, 2H, CH), 3.89-3.81 (m, 2H, CH), 3.81-3.57 (overlapped signals, 16H, CH₂), 3.57-3.40 (overlapped signals, 8H, CH₂).

¹³C NMR (100 MHz, CDCl₃), δc (ppm): 165.5, 146.0, 140.8, 130.2, 129.7, 125.3, 123.8, 71.4, 70.9, 70.6, 70.4, 70.3, 68.9 (2C), 64.6, 62.6, 52.1. ESI(+)-HRMS (m/z): Calculated for C₃₈H₄₈N₆O₁₂: 803.3222, found 803.3185 [M+Na]⁺.

## Funding Information

This work was supported by the project "EVOLUTION" funded by European Union - NextGenerationEU and the Romanian Government, under National Recovery and Resilience Plan for Romania, contract no 760033/23.05.2023, cod PNRR-C9-IB-CF16/2022, through the Romanian Ministry of Research, Innovation and Digitalization, within Component 9, Investment 18

## Acknowledgment

Teodor Cucuiet thanks to Babeş-Bolyai University for a one year scholarship.

## Supporting Information

YES

## Primary Data

NO.

## Conflict of Interest

The authors declare no conflict of interest.

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