Synthesis of an Adamantane-Based Tetralactam and Its Association with Dicarboxamides ^†

Abstract

Tetralactam macrocycles are suitable candidates to be employed as synthetic receptors for charged or neutral guests. In the sensing of neutral molecules, nonpolar solvents such as chloroform or dichloromethane are usually employed so the hydrogen-bonded interactions can be established. Thus, one of the main limitations of the studied macrocycles is their low solubility in those solvents. Herein, we describe the synthesis of an adamantane-based tetralactam macrocycle that is soluble in chlorinated solvents. For this purpose, by following a clipping methodology, we firstly synthesized a kinetically stable pseudorotaxane, constituted by a removable tetraalkylfumaramide thread and the desired macrocycle. A subsequent thermal dethreading straightforwardly yielded the adamantane-based macrocycle. Afterwards, the affinity of this receptor for a series of fumaramide and succinamide guests was studied, calculating the association constants when the corresponding [2]pseudorotaxanes are assembled.

1. Introduction

Mechanically interlocked compounds [1] consist of two or more entangled components between which there is no covalent linker. These components are connected by a so-called mechanical bond [2]. These systems are considered molecular compounds, and thus, a covalent bond must be broken in order to break apart their components [3,4].

[2]Rotaxanes [5,6,7] are the most important category of mechanically interlocked molecules, constituted by two components: A linear component, which has bulky groups at the ends, and a cyclic component, which surrounds the first. Although it has been more than four decades since the first [2]rotaxane was synthesized [8], the most important advances in the research of this type of compound have been produced in recent years [1,2,3,4,5,6,7].

In one of our research programs focused on the development of novel hydrogen-bonded rotaxanes [9,10,11,12,13,14,15,16], we described the preparation of kinetically stable pseudorotaxanes [12,15] bearing benzylic amide macrocycles and a dicarboxamide-based template such as fumaramides or succinamides. These studies settled the structural requirements of the interlocked systems to allow the dethreading reaction and their kinetic parameters under thermal and photochemical treatments.

Benzylic amide macrocycles have been employed as model compounds when investigating the effects of the mechanical bond in materials elaborated with hydrogen-bonded interlocked compounds [1,2,3,4,5,6,7,17]. These tetralactam rings are also able to bind to a variety of guests, such as squaraine [18,19] and acene [19,20,21] guests, through molecular recognition processes. In less extension, these macrocycles have been used for sensing carbon dioxide [22] and to detect glucose [23,24]. Recently, Smith et al. reported that square planar precious metal halogen complexes, such as AuCl₄⁻, AuBr₄⁻, and PtCl₄⁻, are excellent guests [25].

Herein, we describe the preparation of a benzylic amide macrocycle bearing two adamantane units by the dethreading of the corresponding hydrogen-bonded [2]rotaxane, which was prepared earlier via a five-component clipping reaction. The association studies with different dicarboxamides in a noncompetitive solvent are also reported.

2. Results and Discussion

For the synthesis of the desired adamante-based macrocycle 1, we followed a two-step protocol. Firstly, we assembled the corresponding [2]rotaxane 2 bearing a removable tetrapropyl fumaramide thread 3 (Scheme 1). For this, we carried out a five-component clipping reaction between p-xylylenediamine, 1,3-adamantanedicarbonyl dichloride, and the thread 3, providing the [2]rotaxane 2 in 5% yield. The advantage of the initial synthesis of the rotaxane 2 resides in its easy isolation from other reaction byproducts. The obtained yield was lower than the those reported for other tetraalkyl fumaramide analogs with an isophthaloyl-based macrocycle [15], a consequence of the lesser acidity of the hydrogens of the amides for the macrocycle and, thus, a lower stability of the different supramolecular intermediates.

The next step consisted of a thermal dethreading of rotaxane 2 to afford the free macrocycle 1 (Scheme 2) [12]. The reaction was conducted at 100 °C in two different solvents: Tetrachloroethane and DMSO. In both solvents, the reaction proceeded efficiently in short reaction times (84% yield for DMSO and 80% for C₂H₂Cl₄). When the more polar DMSO was employed, the dethreading was faster (less than 1 h). In contrast, traces of DMSO were observed when the macrocycle 1 was isolated, even after exhaustive washings with various solvents, which is undesirable when it is going to be tested as a hydrogen-bonding receptor. Importantly, the thread 3 could be completely recovered for future reutilizations. As expected, macrocycle 1 was soluble in CH₂Cl₂ or CHCl₃, preferred solvents for the NMR titration experiments.

Figure 1 displays the stacked ¹H NMR spectra of the thread 3, its corresponding rotaxane 2, and the free-targeted macrocycle 1, isolated after the dethreading protocol. The presence of the macrocycle over the fumaramide station in rotaxane 2 triggers shifting to a high field of its corresponding signals (ΔδH_a: 1.4 ppm). After the dethreading reaction, the signals referred to the methylene protons H_E in macrocycle 1, which appeared as two signals due to the diastereotopic nature of these protons in rotaxane 2, resonating as only one signal at 4.43 ppm, due to the loss of the common chair-like conformation of this type of polyamide macrocycle in entwined structures. Moreover, the amide protons NH_D experienced an important movement to lower chemical shifts when the rethreading took place, revealing the disruption of the hydrogen-bonded interactions of thread–macrocycle.

Next, we tested the behavior of the macrocycle 1 as a hydrogen-bonding receptor for the dicarboxamides N,N,N’,N’-tetramethylfumaramide (4) and N,N,N’,N’-tetramethylsuccinamide (5), which were obtained using the reported synthetic protocols (

Table 1. Calculated association constants between macrocycle 1 and guests 4 and 5.

Guest	kassoc (M−1) a
4	28.3
5	24.9

^a Calculated using the software HypNMR 2008.

) [26,27]. The dynamic slipping process of guests 4 and 5 with macrocycle 1 was studied by carrying out titration experiments, followed by ¹H NMR spectroscopy. For this goal, a 40 mM solution of guest (G) was sequentially added to a 1 mM solution of macrocycle 1 in CDCl₃, and the corresponding association constants were calculated. The displacement of the ¹H NMR signal of the amide NH_D was monitored during the successive addition of the guests. The addition of increasing amounts of guest triggered the displacement of this signal to a lower field due to the establishment of hydrogen-bonded interactions towards the dynamic formation of the pseudorotaxanes. The obtained constants for the formation of the 1:1 complex G·1 were low when compared with the constants of other polyamide macrocycles with similar guests [28]. Probably, the low acidity of the hydrogen of the macrocyclic amides diminished the ability of this ring as a receptor. The structural similarity of the employed dicarboxamides, having linkers between the hydrogen bond acceptors in 4 and 5, −CH=CH−, and −CH₂−CH₂−, afforded comparable association constants for these guests (Table 1). Note that the interaction was slightly stronger when the more rigid fumaramide 4 was used as guest.

3. Conclusions

In summary, we described the assembly of an adamantane-based polyamide macrocycle, which was shown to be soluble in chlorinated solvents. This system was studied as a receptor for succinamide and fumaramide guests. By carrying out titration experiments, the association constants were calculated, revealing a limited capacity of this adamantane-based macrocycle for the establishment of hydrogen-bonded interaction with the selected threads. Currently, we are looking for other suitable candidates to enhance the interaction with this receptor.

4. Materials and Methods

4.1. Preparation of [2]Rotaxane 2

The thread 2 (1.00 g, 3.50 mmol) and Et₃N (6 mL, 42 mmol) in CHCl₃ (250 mL) were stirred whilst solutions of p-xylylenediamine (3.85 g, 28.32 mmol) in CHCl₃ (20 mL) and 1,3-adamantanedicarbonyl dichloride (7.40 g, 28.32 mmol) in CHCl₃ (20 mL) were simultaneously added over a period of 4 h using a motor-driven syringe pump. Afterwards, the resulting suspension was filtered through a Celite^® pad, and the filtrate was washed with water (2 × 100 mL), NaHCO₃ (2 × 100 mL), HCl 1M (2 × 100 mL), and brine (2 × 100 mL). The organic phase was dried over anhydrous MgSO₄, filtered, and removed under reduced pressure. The resulting solid was subjected to column chromatography (silica gel) to yield unconsumed thread and [2]rotaxane 2 (141 mg, 5%). Rotaxane 2 showed identical spectroscopic data to those reported in [15].

4.2. Preparation of Macrocycle 1

A solution of rotaxane 2 (104 mg, 0.111 mmol) in tetrachloroethane (3 mL) was stirred at 100 °C for 2 days. After this time, Et₂O (1 mL) and pentane (3 mL) were added, precipitating a white solid. The solid residue was filtered and washed with pentane, giving the title product as a white solid (58 mg, 80 %). Macrocycle 1 showed identical spectroscopic data to those reported in [15].

4.3. Titration Experiments of Macrocycle 1 with Dicarboxamides 4 and 5

¹H NMR titration spectra were recorded on a Bruker Avance 400 MHz spectrometer, in CDCl₃ at 298 K.

General method for the titration experiments: A solution of guest (40 mM, and 1 mM in macrocycle 1) was added to a solution of macrocycle 1 (0.5 mL, 1 mM). The chemical shift of a specific host proton was monitored for 14 titration points (for 0.0–34.0 equivalents of added guest). The signal referring to the amide proton NHD was used to determine the corresponding association constant k_assoc by using the software HypNMR 2008.