Synthesis, Physicochemical Characteristics, Self‐Assembly and Encapsulation Ability of per‐Ethylene‐Glycol‐Functionalized Resorcin[4]Arenes and Their Molecular Capsules: On the Road to Liquid Capsules

Gangadhara Angajala; Inbar Horin; Tamar Evan‐Salem; Yoram Cohen

doi:10.1002/chem.71489

. 2026 Jul 30;32(40):e71489. doi: 10.1002/chem.71489

Synthesis, Physicochemical Characteristics, Self‐Assembly and Encapsulation Ability of per‐Ethylene‐Glycol‐Functionalized Resorcin[4]Arenes and Their Molecular Capsules: On the Road to Liquid Capsules

Gangadhara Angajala ¹, Inbar Horin ¹, Tamar Evan‐Salem ¹, Yoram Cohen ^1,^✉

PMCID: PMC13716021 PMID: 42530424

ABSTRACT

Self‐assembled molecular cages and capsules attracted considerable attention, owing to their unique structures and ability to function as nano‐reactors and catalysts. In recent years, porous liquids have emerged into an intriguing class of functional materials. Herein, we prepared a series of per‐ethylene‐glycol (EG)‐functionalized resorcin[4]arene hosts, bearing side chains with three, four, or five EG units (compounds 1d, 1e, and 1f, respectively). We studied their melting points, solubility, self‐assembly, and encapsulation abilities. Interestingly, 1e and 1f were found to be viscous liquids at RT and compound 1d melts at 104°C–105°C, while alkyl‐substituted resorcin[4]arenes (1a and 1c) melt at ∼300°C. We found in contrast to expectations, that the number of EG groups on the side chains affects the self‐assembly, the stability of the formed aggregates, and the encapsulation power of those systems in organic solvents. System 1d behaved, in CDCl₃, much like alkyl‐substituted resorcin[4]arenes, forming self‐assembled hexameric capsules of comparable stability and size capable of encapsulating even tetra‐hexyl ammonium salts. Compounds 1e and 1f, however, form, in CDCl₃, hexameric capsules, which are more dynamic than the capsules of 1c or even 1d that encapsulate smaller ammonium salts and appear to be promising candidates for the preparation of liquid capsules and capsular liquids.

Keywords: capsules, diffusion NMR, macrocycles, per‐ethylene‐glycol, resorcin[4]arenes

Per‐ethylene‐glycol (EG)‐functionalized resorcin[4]arenes containing 12, 16, and 20 EG groups namely compounds 1d, 1e, and 1f, respectively, were prepared and found to self‐assemble, in organic solvents, into hexameric capsules. These capsules are more dynamic than the ones prepared based on alkyl substituted resorcin[4]arenes. Macrocycles 1e and 1f are liquids at RT providing new avenues for the preparation of liquid capsules and capsular liquids.

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1. Introduction

Supramolecular chemistry uses, among others, self‐assembly to create new molecular systems that have myriad applications in different fields [1, 2]. Macrocycles are essential building blocks for the preparation of host–guest and many self‐assembled supramolecular systems [3, 4, 5]. Macrocyclic arenes [6, 7, 8] have played a pivotal role in the preparation of self‐assembled molecular cages and capsules [9, 10, 11, 12, 13, 14]. Cram and co‐workers prepared the first covalent molecular cage based on a macrocyclic arene already in the mid‐1980s [15, 16]. However, cages and capsules based on non‐covalent interactions have attracted much more attention than the covalent cages, partially since they can be self‐assembled in a modular way from relatively simple building blocks [9, 10, 11, 12, 13, 14, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27]. Such self‐assembled molecular containers and capsules have been studied quite extensively not only for aesthetic reasons but mainly since these molecular species provide a means to separate molecular species from the bulk in a reversible manner, thus enabling chemistry to be conducted in confined spaces [9, 10, 11, 12, 13, 14, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27]. As such, molecular containers and capsules can be regarded as nano‐reactors or nano‐flasks where new phenomena, new chemistry and catalysis may occur. Indeed, in the last two decades, cages stabilized by metal‐ligand interactions, hydrogen bonds, and hydrophobic effects have been reported [11, 12, 13, 14, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27]. The water‐soluble deep cavitands, which self‐assemble through hydrophobic effects, have also been used as nano‐reactors and drug delivery systems [24, 25, 26, 27]. Noncovalent cages and capsules were shown to affect the outcome of different reactions and, in some cases, yield products that differ from the ones obtained in the bulk [17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27].

Among the most intriguing examples of self‐assembled molecular cages and capsules are the hexameric capsules of resorcin[4]arenes and pyrogallol[4]arenes (Scheme 1) [28, 29, 30, 31, 32, 33, 34]. These giant capsules can be obtained from simple macrocycles quite easily. The solid‐state structures of these hexameric capsules were reported first [28, 29]. Subsequently, the Rebek and Cohen groups at the beginning of this millennium probed their existence in solution [30, 31, 32, 33, 34]. We showed, using diffusion NMR, that hexameric capsules are indeed the resting state of lipophilic resorcin[4]arenes and pyrogallol[4]arenes in chlorinated and aromatic solvents [31, 32, 33, 34]. However, it was only in the last decade that these hexamers were shown to catalyze important chemical reactions [35, 36, 37, 38, 39, 40, 41, 42]. This work originated from contributions by Scarso and co‐workers [35, 36] and gained momentum, first, due to research by the Tiefenbacher group [37, 38, 39, 40] and then by the Neri group [41, 42]. In recent years, both groups have described additional applications of hexameric capsules of the resorcin[4]arenes in catalysis [43, 44, 45, 46, 47, 48, 49]. Tiefenbacher and his co‐workers also demonstrated that water molecules that are part of the hexameric capsules of the lipophilic resorcin[4]arene [32] (1c in Scheme 1) play a crucial role in the ability of such hexamers to affect the course of important chemical reactions in organic solvents [45].

SCHEME 1 — The molecular structures of compounds 1a‐c, 2a, b, and the new compounds 1d‐f, prepared in this study along with a cartoon representation of their monomers and hexamers.

Even though these molecular capsules have been known for more than 25 years, in recent studies, many new features of these systems have been reported [50, 51, 52, 53, 54, 55, 56, 57]. For example, it was recently claimed that the more reactive species in resorcin[4]arene catalysis is the hexamer with 14 water molecules, and Szumna et al., showed that anions can also assemble such hexameric arene capsules [50, 51]. In addition, based on our finding that the hexameric capsules of 2b (Scheme 1) can encapsulate ammonium salts in benzene, [52] it was found in contrast to previous claims, [40] that the hexameric capsules of 2b can indeed catalyse some 1,3 dipolar cycloaddition reactions [53]. The Sakurai group claimed, using small‐angle neutron and x‐ray scattering, that in toluene,1c forms non‐capsular octameric aggregates in contrast to the hexameric capsules found in chloroform and other chlorinated solvents [54, 55]. A recent diffusion NMR study showed, however, that 1c forms, in aromatic solvents, hexameric capsules and another minor product which appears to be of octameric nature [56]. Very recently, simple fluorination of the resorcin[4]arenes allowed expansion in the reactivity of such capsules [57] and fluorinated guests were used, for the first time, to study exchange in the hexameric capsules of 2b [58]. These recent studies demonstrate that even subtle changes in the structure and experimental conditions may affect the endpoint of these simple, yet intriguing and important self‐assembled systems.

Porous liquids (PLs) are a new type of porous material that are liquids at low temperature and possess permanent, intrinsic porosity in contrast to conventional solvents [59, 60, 61, 62, 63, 64, 65]. These materials combine the characteristics of porous solids with the fluidity and fast mass and heat transfer of liquids. The James group introduced the concept of PLs in 2007 and classified them into three major types [59]. Type I PLs are neat molecular liquids containing permanent internal cavities, whereas type II and type III PLs are made of porous molecules or porous particles, respectively, dissolved or suspended in a cavity excluded solvent. Preparing these PLs proved challenging, and the very first examples were described only about a decade ago [60, 61, 62]. Even now, nearly two decades after the concept paper by James [59], there are not too many PL systems [66, 67, 68, 69, 70]. Type I porous liquids are perhaps the scarcest despite being intriguing systems with huge potential. This may partially be because Type I PLs are more difficult to prepare compared to other types of PLs mainly due to the self‐filling of the cavities in such systems by their own side chains used to reduce the melting point of the formed system. In addition, applications of many PLs are limited due to their relatively small intrinsic cavities [66, 67, 68, 69, 70]. Inspired by these materials, and in the framework of our long‐term goals to explore the possibility of preparing liquid capsules and capsular liquids, which are reminiscent of PLs, we synthesized a series of the per‐ethylene‐glycol‐functionalized resorcin[4]arenes 1d‐f (Scheme 1) and studied their solubility, melting point, self‐assembly, and encapsulation ability.

2. Results and Discussion

The rationale of using resorcin[4]arenes over pyrogallol[4]arenes even though their capsules are more complex systems [28, 29, 30, 31, 32, 33, 34], is that their synthesis is somewhat easier and, more importantly, that resorcin[4]arene capsules can encapsulate a much larger repertoire of compounds [71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81], and are much better catalyst in organic solvents [35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49]. As stated, the main challenge in preparing type I PLs is, generally, the self‐filling or self‐penetration of their own side chains used to reduce the melting point of the system into their own cavity. This self‐penetration reduces the hosting ability of the system quite significantly. However, in molecular capsules, this effect may be less detrimental. Therefore, we decided to concentrate, first, on the attempt to prepare low melting point resorcin[4]arenes and study their characteristics, self‐assembly, and encapsulation power in organic solvents. Note that studying such systems in the neat requires an efficient multi‐gram synthesis, which is yet to be developed.

2.1. Synthesis of Macrocycles 1d‐f

The per‐ethylene‐glycol‐functionalized resorcin[4]arenes 1d‐f were prepared according to Scheme 2 by modifying the Rebek procedure to obtain compound 1e [82, 83]. Note that the Rebek group prepared compound 1e as an intermediate in their synthetic pathway for obtaining some other deep cavitands [82, 83].

Briefly, we first prepared compounds 4 by condensation of resorcinol with compound 3 in an acidic environment in methanol. The phenolic groups of 4 were first protected with benzyl bromides to give compound 5 and then its aliphatic hydroxyls were reacted and activated with mesyl chloride to form compound 6. Compound 6 was first reacted with the respective ethylene glycols (EGs) in THF under basic conditions to form compounds 7a‐7c that were then de‐protected to afford macrocycles 1d‐1f, respectively, as shown in Scheme 2. The per EG‐functionalized resorcin[4]arenes were obtained in five synthetic steps and the total yields of 1d, 1e, and 1f were 11%, 7%, and 12%, respectively. The detailed synthesis and the spectroscopic characterization of compounds 4, 5, 6, 7a‐c, and 1d‐1f are presented in the experimental section and in the supporting information section (SI, see also Figures S1–S9).

2.2. Melting Points, Solubility, and Spectroscopic Characteristics of 1d‐1f

One of the most important physical parameters in the context of the present study is the melting points of these macrocycles. We found that, as expected, the larger the number of EG groups in the macrocycle, the lower its melting point. We found that compounds 1f and 1e are both viscous liquids at RT (25°C) having melting points of about −6°C and 11–12°C, respectively, while 1d has a melting point of 104°C–105°C. These melting points, which were recorded immediately after drying the materials in high‐vacuum at 50°C for more than 48 h, are indeed dramatically lower than that of C₁ ‐ and C₁₁ ‐alkyl‐resorcin[4]arenes (1a and 1c, respectively) which are more than 320°C for 1a and about 295°C for 1c. Based on the melting points and solubility characteristics, compound 1f appears to be the most promising and relevant one in the context of liquid capsules.

Compound 1f was found to be soluble in water and in organic solvents, whereas 1d and 1e showed significant solubility only in organic solvents. Figure 1 shows the ¹H‐NMR spectra of macrocycle 1f in different deuterated solvents. These ¹H‐NMR spectra indicate that compound 1f, which self‐assembles using hydrogen bonds and is expected to prevail as a monomer in CD₃OD, exhibits narrow linewidths in CD₃OD, while in other organic solvents such as CDCl₃ and C₆D₆ clear line broadening is observed. For 1f the line broadening observed in D₂O may originate from significant solvation of the compound or from some self‐aggregation driven by hydrophobic effects. The ¹H‐NMR spectra of compounds 1d and 1e in different solvents are presented in Figures S10 and S11, respectively. As anticipated, compounds 1d and 1e exhibit sharp line in their ¹H‐NMR spectra in CD₃OD. In CDCl₃, however, 1d and 1e show, like 1f, broadened signals in their ¹H‐NMR spectra (see Figures S10 and S11). These signals become sharper in water‐saturated CDCl₃ solutions. Upon addition of approximately 10% of CD₃OD to these CDCl₃ solutions, further sharpening is observed. In DMSO_d6 solutions, the ¹H NMR signals of 1d and 1e are, as expected, narrow. Taken together, these findings suggest the formation of higher aggregates in the water‐saturated CDCl₃ solutions, which are disassembled upon addition of CD₃OD to the solution. In CD₃OD and DMSO_d6 solutions the ¹H‐NMR signals of 1d‐1f are sharp as expected for monomers. However, line‐shapes alone are only indicative and are not conclusive evidence for aggregation; therefore, we turned to diffusion NMR for further support [84, 85].

¹H‐NMR (500 MHz, 298K) of 10 mM solutions of compound 1f in different deuterated solvents; (a) CDCl₃, (b) C₆D₆, (c) CD₃OD, and (d) D₂O.

2.3. Self‐assembly of 1d‐f in Organic Solvents

To determine whether compounds 1d‐f self‐assemble into higher aggregates, we used diffusion NMR and DOSY, which are instrumental in the characterization of different types of aggregates and other supramolecular systems including molecular cages and capsules [31, 32, 33, 34, 71, 72, 73, 84, 85, 86]. First, we explored 1f, which, as said, is a liquid at room temperature and has better solubility and more informative ¹H‐NMR spectra than 1e and 1d in different organic solvents. The results of the diffusion NMR measurements, that is, the diffusion coefficient of 1f in 10 mM solutions in the different solvents, and the Stokes radii (r _s) extracted thereof, are presented in Table 1. The detailed r _s calculations can be found in the Supporting Information. The smallest r _s value (1.19 nm) was observed in methanol, consistent with the expected presence of monomeric species. In contrast, the largest r _s value (3.06 nm) was found in water, suggesting the formation of larger aggregates, likely due to solvation effects in water and/or self‐association of 1f, most likely driven by some hydrophobic interactions. As it is plausible to assume that compounds 1d‐1f cannot form hydrogen bond‐based capsules in water per se, this will not be addressed further in the present study. The r _s values found for 1f in chloroform and benzene solutions (1.75 and 2.58 nm, respectively) suggest the presence of aggregates that are formed by self‐aggregation due to hydrogen bonds between the different phenol groups of the system. We found that the diffusion coefficient of compound 1f in CDCl₃ is 0.23 ± 0.01 × 10⁻⁵ cm²s⁻¹. This value is as low as the one we found for 1c known to form a [1c ₆(H₂O)₈] type hexameric capsule in CDCl₃ solutions [31, 32]. These results are somewhat surprising because of the higher molecular weights (MWs) of 1f compared to 1c and may suggest that these compounds self‐assemble somewhat differently. Based on the MWs of compounds 1f and 1c that are ∼1658 and ∼1106 g mol⁻¹, respectively, we anticipate a ∼1.14–1.22 reduction in the diffusion coefficient of 1f compared to that of 1c [84]. However, no such reduction was observed in CDCl₃.

TABLE 1.

Diffusion coefficient (D) at 298K of 10 mM solutions of 1f in different solvents. The reported D values are means ± standard deviations of three measurements.

Solvent of the sample	δ [ppm], attribution	D value, [× 10⁻⁵ cm²s⁻¹]	r _s [nm]
CDCl₃	4.2, 1f	0.23 ± 0.01	1.75
CDCl₃	7.2, solvent	2.32 ± 0.01	0.17
C₆D₆	4.6, 1f	0.14 ± 0.01	2.58
C₆D₆	7.1, solvent	1.99 ± 0.01	0.18
D₂O	4.2, 1f	0.08 ± 0.01	3.06
D₂O	4.6, solvent	1.86 ± 0.01	0.13
CD₃OD	4.3, 1f	0.33 ± 0.01	1.19
CD₃OD	4.8, water in CD3OD ^a	2.10 ± 0.04	0.19
CDCl₃+ 2.5% CD₃OD	4.2, 1f	0.25 ± 0.01	—
CDCl₃+ 2.5% CD₃OD	7.2, solvent	2.31 ± 0.01	—
CDCl₃+ 11% CD₃OD	4.2, 1f	0.33 ± 0.01	—
CDCl₃+ 11% CD₃OD	7.2, solvent	2.30 ± 0.01	—

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The CD₃OD signal at 3.3 ppm overlaps with a signal of 1f and therefore cannot be analyzed.

There are, in principle, several plausible explanations to the above observations. One such explanation may suggest that, at least in CDCl₃, the aggregates of 1f are hexameric in nature like in the case of 1c but with a smaller effective radius. Another less plausible explanation is that lower aggregates are formed in the case of 1f as compared to 1c in CDCl₃. A third and more plausible explanation is that, in the CDCl₃ solutions, the aggregates formed by 1f are less stable and more dynamic than those of 1c, exchanging faster with a larger population of their monomers. If there is such an exchange and the equilibrium between the aggregates of 1f and their monomers is shifted more toward their monomeric species as compared to the situation with 1c for example, the measured diffusion coefficient which, under fast exchange on the NMR time scale, represents a weighted average of the diffusion coefficients of all the species that prevail in the solution, should be higher than that expected based on MWs alone. If the above explanation is correct both the use of less polar solvent and increasing the concentration of the macrocycles, which shift the equilibrium toward the self‐assembled aggregates, should result in lower diffusion coefficients for 1f. Indeed, increasing the concentration of 1f in D₂O‐saturated CDCl₃ solution from 10 to 30 mM resulted in an approximately 30% decrease in the diffusion coefficient of 1f. The measured diffusion coefficient of 1f in this concentration is 0.16‐0.17 ± 0.01 × 10⁻⁵ cm²s⁻¹, which is significantly lower than that of 1c (0.21 ± 0.01 × 10⁻⁵ cm²s⁻¹) at the same concentration. This shows that, at the concentration of 30 mM, we do observe the expected 1.2 ratio between the diffusion coefficients of 1c and 1f, consistent with the higher MW of 1f compared to 1c. Note that similar results were observed when the diffusion coefficients of 1c and 1d‐1f were measured at 50 and 100 mM D₂O‐saturated CDCl₃ solutions. In C₆D₆ solutions, however, even at a concentration of 10 mM we do observe the expected 1.20 ratio between the diffusion coefficients of 1f and 1c which were found to be 0.14 ± 0.01 × 10⁻⁵ cm²s⁻¹ and 0.17 ± 0.01 × 10⁻⁵ cm²s⁻¹, respectively. The significantly lower diffusion coefficients of 1f compared to 1c in C₆D₆ suggests that in the less polar solvent benzene, 1f forms hexameric capsules with minimal contributions of their monomers in contrast to the situation in the more polar water‐saturated chloroform solvent. Overall, these results are consistent with the formation of similar but more dynamic aggregates of 1f compared to 1c in CDCl₃ solutions.

To obtain further evidence for the existence of hydrogen bond‐based aggregates of 1d‐1f, we added small amounts of CD₃OD to the CDCl₃ solution of 1d‐1f and the results are presented in Tables 1, S1, and S2. After the addition of ∼10% of CD₃OD to the chloroform solutions of 1d‐1f we observed, as expected, an increase in the diffusion coefficients of the macrocycles that reached the values observed for the same macrocycles in methanol. The results are in line with the formation of hydrogen bond‐based aggregates in the chloroform solution, which disintegrate upon addition of methanol. However, diffusion measurements per se can only probe the existence of aggregates and inform on the degree of aggregation, but do not provide detailed information concerning the nature and the structure of the formed aggregates. To obtain more information about that, we need to evaluate the hosting and the encapsulation power, if any, of the formed aggregates as we describe in the next section.

2.4. Encapsulation Ability of 1d‐1f in Organic Solvents

Here again, we started by exploring the hosting and the encapsulation ability of the aggregates of 1f in chloroform. Guest compounds in arene‐based molecular capsules are generally in slow exchange, on the NMR time scale, with their free population in the bulk. This results in distinct signals for the encapsulated guest and relatively large ¹H‐NMR chemical shift changes (ΔδH) upon encapsulation [86]. So first, we attempted the addition of adamantine carboxylic acid (3), glutaric acid (4), and tetraethylammonium bromide (TEABr, 5), three known guests of the hexameric capsules of 1c, to the CDCl₃ solutions of 1f as shown in Figure S12. In the ¹H‐NMR spectra of these CDCl₃ solutions of 1f, we observed only high‐field broad signals that may be attributed to encapsulated TEABr. Knowing that ammonium salts have high affinity toward the cavity of the hexameric capsules of 1c [71, 72, 73, 74], we added TEABr (5), tetrabutylammonium bromide (TBABr, 6), and tetrahexylammonium bromide (THABr, 7) to the D₂O‐saturated CDCl₃ solutions of 1f.

The ¹H‐NMR spectra of those solutions at 25°C and −50°C are presented in Figure 2. In this Figure we see evidence only for the encapsulation of TEABr into the capsule formed by 1f. The larger ammonium salts appear not to be encapsulated in the capsules of 1f. Figure S13 shows the same data as in Figure 2 but for compound 1e. From the spectra presented in that Figure, we see evidence for the encapsulation of TEABr in 1e and residual encapsulation of the TBABr salt and perhaps some encapsulation of THABr. Figure 3 shows the ¹H‐NMR spectra of D₂O‐saturated CDCl₃ solutions of 1d in the presence of 5, 6, and 7 at RT. These spectra clearly show that 1d, much like 1c, can encapsulate all the three ammonium salts tested.

¹H‐NMR spectra (400 MHz, D₂O saturated CDCl₃) of (a) 1f:TEABr (5) 10:5 mM at 25°C, (b) the solution of a at −50°C, (c) 1f:TBABr (6) 10:20 mM at 25°C, (d) the solution of c at −50°C, (e) 1f:THABr (7) 10:20 mM at 25°C, and (f) the solution of e at −50°C.

¹H‐NMR spectra (500 MHz, at 25°C, D₂O saturated CDCl₃) of (a) TEABr (5) 5 mM, (b) 1d:TEABr 10:20 mM, (c) TBABr (6) 5 mM, (d) 1d:TBABr (6) 7.5:20 mM, (e) THABr (7) 5 mM, and (f) 1d: THABr (7) 7.5:20 mM.

Since resorcin[4]arenes such as 1a‐c form hexameric capsules with the aid of eight water molecules [28, 31, 32, 34], we decided to explore the effect of the amount of water in the chloroform solution on the formation of capsules of 1d‐1f. We decided to perform these experiments on the TEABr CDCl₃ solutions of 1d‐1f since they each encapsulate TEABr to some extent. Figure 4 presents the spectra of the reference compound 1c and of 1d‐1f both before and after addition of D₂O to the CDCl₃ solutions, and the results clearly show that water is indeed needed to observe the encapsulation of TEABr. We also found that more water is needed for seeing the encapsulation in cases of 1d‐1f compared to 1c. This may well be due to the fact that some of the water molecules added to the CDCl₃ solutions are also used to solvate the ethylene glycol moieties of hosts 1d‐1f. The spectra presented in Figure 4 also imply that for the 1d‐1f series, the encapsulation of TEABr is the highest for 1d and lowest for 1f.

Partial ¹H‐NMR spectra (500 MHz, 298K, CDCl₃) of (a) TEABr 5 mM, (b) 1c:TEABr 10:20 mM before and (c) after addition of D₂O, (d) 1d:TEABr 10:20 mM before and (e) after addition of D₂O, (f) 1e:TEABr 10:20 mM before and (g) after addition of D₂O, and (h) 1f:TEABr 10:20 mM before and (i) after addition of D₂O.

Next, as we observed that the encapsulation and probably the capsule formation and stability are sensitive to, among others, the amount of water in the organic solvents, we prepared samples of hosts’ 1c‐1f each mixed with the same water‐saturated CDCl₃ stock solution containing one of three ammonium guests: TEABr, TBABr or THABr. We then measured the diffusion coefficients of all species in each sample using diffusion NMR. Selected diffusion coefficients for representative signals of the different species, namely hosts and both free and bound ammonium salts, in these samples are presented in Table 2. The same diffusion coefficients, within experimental errors, were measured for the encapsulated guest TEABr and hosts 1c‐1f, indicating that these molecular species move as a single entity. Surprisingly, we found however, that the diffusion coefficients of both 1f and encapsulated TEABr in that solution were higher than those found for the same species in the CDCl₃ solutions of 1c‐1e, in contrast to expectation based on their MWs. Similarly, the same diffusion coefficient was measured for guests TBABr and THABr with host 1c, also confirming that they move as a single entity. However, the diffusion coefficients measured for the encapsulated guests TBABr and THABr with host 1d were found to be slightly higher than that of the 1d. This suggest that the hexameric capsules of 1d are more labile than those of 1c.

TABLE 2.

Diffusion coefficients (D) (500 MHz, 298K) of D₂O‐saturated CDCl₃ solutions of hosts 1c‐1f with TEABr, TBABr, and THABr.

Sample	1c:guest (10:20 mM)	1d:guest (7.5:20 mM)	1e:guest (10:20 mM)	1f:guest (10:20 mM)
δ [ppm], attribution	D value [X 10⁻⁵ cm²s⁻¹] ^a
Guest molecule = TEABr
−0.2 to ‐0.01, encapsulated TEABr	0.24 ± 0.01	0.20 ± 0.01	0.24 ± 0.01	0.24 ± 0.01
∼4.3, host in the presence of TEABr	0.24 ± 0.01	0.20 ± 0.01	0.23 ± 0.01	0.23 ± 0.01
Guest molecule = TBABr
∼−0.2, encapsulated TBABr	0.24 ± 0.01	0.32 ± 0.01	NA	NA
0.9, free TBABr	0.64 ± 0.01	0.60 ± 0.01	0.62 ± 0.01	0.64 ± 0.01
∼4.3, host in the presence of TBABr	0.23 ± 0.01	0.22 ± 0.01	0.23 ± 0.01	0.24 ± 0.01
Guest molecule = THABr
∼−0.4, encapsulated THABr	0.23 ± 0.01	0.28 ± 0.01	NA	NA
1.6, free THABr	0.61 ± 0.01	0.58 ± 0.01	0.60 ± 0.01	0.61 ± 0.01
∼4.3, host in the presence of THABr	0.23 ± 0.01	0.22 ± 0.01	0.22 ± 0.01	0.23 ± 0.01

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The reported D values are means ± standard deviations of three measurements.

These findings further support the assumption that the equilibrium of 1d differs to some extent from that of 1c. For 1e and 1f, we could not measure the diffusion coefficients of the encapsulated guests in the cases of TBABr and THABr, probably due to exchange. The diffusion NMR results presented in Table 2 indicate that, at least with TEABr, 1d behaves similarly to 1c. For the TBABr and THABr cases, however, we observe that the diffusion coefficients of the encapsulated guests are slightly higher than that of the host 1d indicating that these capsules are indeed more labile. In the case of 1e and 1f, the capsules formed are significantly more labile and for 1f this is manifested by the fact that the diffusion coefficient of these capsules, which have higher molecular weight compared to the capsules of other macrocycles, are the same or slightly higher.

Diffusion measurements were also performed during the study of methanol titrations into the four host samples namely 1c and 1d‐1f, each mixed with the same D₂O‐saturated CDCl₃ stock solution of TEABr. Methanol titration is expected to gradually disrupt the hydrogen bonds that form the aggregate. Methanol is added incrementally until a plateau in the diffusion coefficient is reached, indicating the presence of only monomeric species in the solution. As anticipated, we observed an increase in the diffusion coefficient values after each methanol addition, suggesting that a de‐aggregation process occurs in all the samples, as shown in Figure 5. Note, however, that the diffusion coefficient of the macrocycle remained the same after the first addition of CD₃OD only in the case of 1c, implying that its capsules are more stable than the capsules of 1d‐1f.

Effect of methanol‐d₄ titrations on the diffusion coefficients (D) of 10 mM of 1c‐1f in wet‐CDCl₃ solutions in the presence of 20 mM of TEABr. Note that in the case of 1d, the concentration of TEABr was 7.5 mM. The points represent means ± standard deviations of three independent diffusion measurements. The solid lines are just to connect data points. Note that in most cases the measured error bars are smaller than the symbols of the graphs.

Table 3 presents the diffusion coefficients of samples of 10 mM of 1c‐1f and 20 mM TEABr in D₂O‐saturated CDCl₃ solution, before the first methanol addition, along with their molecular weights. Taking only the molecular weights into account, we should anticipate a 1.14–1.22 reduction in the diffusion coefficients by passing from 1c to 1f. Similarly, for compounds 1d (∼1305 g mol⁻¹) and 1e (∼1482 g mol⁻¹) compared to 1c (∼1106 g mol⁻¹), we should anticipate a 1.06–1.09 and 1.10–1.16 reduction, respectively. As shown in Table 3, the observed results for 1d compared to 1c fall within the expected range (1.09). The diffusion coefficients ratio for 1e and 1c is only 1.02, which a significant deviation from expectation. The reduction observed for the 1f:1c pair which is also ∼1.02 deviates even further from the expectation. These findings suggest again that 1c and 1d behave similarly in terms of aggregation, whereas 1f forms significantly more labile capsules compared to 1c. Host 1e appears to behave as an intermediate between 1d and 1f, but with characteristics that appear more like those of 1f. Note also that when the concentration of the hosts was increased from 10 to 30 mM no significant changes in the encapsulation power toward the tested ammonium salts could be detected.

TABLE 3.

Diffusion coefficients (D) (500 MHz, 298K) along with molecular weights of the monomers of hosts 1c, 1d, 1e, and 1f. ^a ^.

Sample	1c	1d	1e	1f
Molecular weight [g/mol]	1105.70	1305.53	1481.74	1657.95
δ [ppm], attribution	D value [X 10⁻⁵ cm²s⁻¹] ^b
∼−0.1, encapsulated TEABr	0.24 ± 0.01	0.20 ± 0.01	0.24 ± 0.01	0.24 ± 0.01
∼4.3, host	0.24 ± 0.01	0.20 ± 0.01	0.23 ± 0.01	0.23 ± 0.01
7.2, solvent	2.31 ± 0.01	2.32 ± 0.02	2.30 ± 0.01	2.25 ± 0.01

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^{^[a]}

D₂O saturated CDCl₃ solutions of 10:20 mM of Host:TEABr (6 µL of CHCl₃ were added to each sample to increase the accuracy of the D values of the solvent).

^{^[b]}

The reported D values are means ± standard deviations of three measurements.

The inter‐sample uncertainties of diffusion measurements are higher than within‐sample measurements, assuming no interaction between the measured compounds. Therefore, we decided to concentrate on the diffusion coefficient of 1d‐f relative to a relevant control reference compound. For this purpose, we selected 2b as a reference, since previous studies have shown that only homo‐hexamers are formed from mixtures of resorcin[4]arenes (1) and pyrogallol[4]arenes (2) [34]. We prepared samples containing 1d, 1e or 1f with 2b in D₂O‐saturated CDCl₃ solutions and measured the diffusion coefficient of each species. The results of these diffusion NMR experiments that were performed on 10 mM of water saturated chloroform solutions of 1d‐1f with 10 mM of 2b are presented in Figures S14–S16. The results presented in Figures S14 and S15 are consistent with expectations, and significantly, lower diffusion coefficients are observed for 1d and 1e compared to 1c. The situation is different regarding 1f (Figure S16). Given the difference in MWs between 2b (∼1170 g mol⁻¹) and 1f (∼1658 g mol⁻¹), we should expect about a 12% to 19% reduction in the diffusion coefficient when moving from 2b to 1f, but we observed no such reduction. Again, these results show that in chloroform in the case of 1f, a concentration of 10 mM is not enough to push the equilibrium all the way to the hexameric capsule.

To further verify the resemblance between the behaviour of compounds 1d and 1c, we prepared samples from the same CDCl₃ stock solutions. Two solutions contained 1d, while the other two contained the control compound 1c. We obtained the ¹H‐NMR spectra of these solutions, as shown in Figure 6. The signals of the bridge protons at about 4 ppm suggest that under the tested conditions (298K, CDCl₃, guest molar excess), only about 50% of the aggregates of 1d encapsulate THABr. In contrast, for the reference sample, that is, the hexamers of compound 1c, 100% encapsulation was observed. This notable difference in the hosting capabilities strengthens the idea that EG‐functionalized resorcin[4]arenes form capsules that have lower affinity toward larger ammonium salts such as THABr, when compared to 1c for example.

¹H‐NMR spectra (298K, D₂O‐saturated CDCl₃) of solutions of (a) 1c 30 mM (500 MHz), (b) 1c:THABr 10:10 mM (400 MHz), (c) 1d 30 mM (500 MHz), and (d) 1d:THABr 10:10 mM (400 MHz). The red rectangle encloses the signals of the protons on the bridges of the macrocycles.

3. Conclusion

We successfully prepared three low melting point per‐EGs‐functionalized resorcin[4]arenes, namely 1d, 1e, and 1f, having 12, 16, and 20 ethylene glycol groups, respectively, and studied their physicochemical characteristics, self‐assembly and encapsulation power in organic solvents. We found that both 1f and 1e are viscous liquids at room temperature while 1d has a melting point of 105°C–107°C. These values are much lower than those of other alkyl‐substituted resorcin[4]arenes whose melting points are around 300°C or higher. We also found, surprisingly, that in contrast to the length of the alkyl substituents of resorcin[4]arenes, the number of EG‐groups on the side chains of the resorcin[4]arene skeleton, affects the self‐assembly, the relative stability, and the encapsulation power of the formed capsules. In CDCl₃, compound 1d behaves not very differently from the reference lipophilic resorcin[4]arene 1c known to form 1c ₆[H₂O]₈‐type capsules. Resorcin[4]arene 1d forms, as 1c, hexameric capsules, probably 1d ₆[H₂O]₈‐type capsules, capable of encapsulating ammonium salts such as TEABr, TBABr, and THABr, albeit with lower affinity when compared to 1c. Compound 1e and, even more so host 1f, form in CDCl₃, more fragile and dynamic capsules capable of efficiently hosting only smaller ammonium salts such as TEABr and with a lower affinity compared to 1c or even 1d. However, in the less polar organic solvent C₆D ₆ , 1f appears to form hexameric capsules similarly to 1c. Since the capsules of 1f are more dynamic, higher concentrations are needed to obtain the expected diffusion characteristics. In all cases, water was found to be crucial for the formation of these capsules both in the absence and presence of ammonium salts. These findings show that at least 1e and 1f are promising candidates for the preparation of liquid capsules or capsular liquids. However, studying liquid capsules in the neat will require the development of an efficient multi‐gram synthesis of macrocycles 1d‐1f. Such efforts are currently underway.

Conflicts of Interest

The authors declare no conflict of interest.

Supporting information

The Supporting Information includes experimental procedures, analytical data, NMR, and mass spectra of the prepared molecules (Figures S1–S9), diffusion NMR data (Figures S10–S16; Tables S1 and S2) and extraction of molecule diameter and more. The authors have cited additional references within the Supporting Information.^[87‐89]

Supporting File 1: chem71489‐sup‐0001‐SuppMat.docx

CHEM-32-e71489-s001.docx^{(6.1MB, docx)}

Acknowledgments

Financial support from the Israel Science Foundation (ISF), Jerusalem, Israel (1006/19 and 1559/24) is acknowledged.

Data Availability Statement

The data that supports the findings of this study are available in the Supporting Information of this article.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supporting File 1: chem71489‐sup‐0001‐SuppMat.docx

CHEM-32-e71489-s001.docx^{(6.1MB, docx)}

Data Availability Statement

The data that supports the findings of this study are available in the Supporting Information of this article.

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PERMALINK

Synthesis, Physicochemical Characteristics, Self‐Assembly and Encapsulation Ability of per‐Ethylene‐Glycol‐Functionalized Resorcin[4]Arenes and Their Molecular Capsules: On the Road to Liquid Capsules

Gangadhara Angajala

Inbar Horin

Tamar Evan‐Salem

Yoram Cohen

ABSTRACT

1. Introduction

SCHEME 1.