²H NMR Reveals Liquid State-Like Dynamics of Arene Guests Inside Hexameric Pyrogallol[4]arene Capsules in the Solid State.

Abstract

The dynamics of guests in molecular encapsulation complexes have been studied extensively in solution, but the corresponding behavior of those guests when the capsules are present in the solid state is not as well understood. Here we report on comparative solution ¹H and solid-state ²H NMR measurements of encapsulation complexes of fluorene(-d₂), fluoranthene(-d₁₀), and pyrene-(-d₁₀) in pyrogallol[4]arene hexamers assembled in the solid state by ball milling. In solution, the ¹H spectra show that these rigid guests tumble and exchange positions quickly within the capsules’ interiors, with the exception of pyrene, which has slower tumbling and positional exchange. Static solid-state ²H NMR using the deuterated guests shows that, when the capsules are in the solid state, their guests retain the liquid state-like dynamics observed for the capsules in solution. When the pyrogallol[4]arene hexamers’ pendant decyl groups were substituted with propyl groups, guest dynamics in the solid state were slowed. We propose that these pendant alkyl groups form an interdigitated and dynamic waxy domain surrounding the capsules in the solid state, and that the greater mobility of the decyl groups is translated across the walls of the host, resulting in more rapid guest dynamics in the capsules’ interiors

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Guest dynamics inside pyrogallol[4]arene hexamers in the solid state are sensitive to structure external to the host.

Introduction

Since the spontaneous formation of molecular encapsulation complexes was first reported, chemists have sought to understand how confinement within host molecules influences the motions, conformations, equilibria, and reactivity of guests.^1–6 Numerous examples have been studied using capsules stabilized by hydrogen bonding, metal–ligand interactions, or ion pairing, and these hosts’ interiors have been shown to stabilize reactive intermediates, offer unique forms of isomerism, accelerate reactivity, and change the outcomes of chemical reactions.^7–15 Guest exchange is regulated by a variety of mechanisms, including host conformational changes, temporary metal–ligand dissociation, and partial or complete capsule disassembly.^16,17 Despite the wealth of past research on host and guest dynamics in solution, comparatively little is known about the motions of guest molecules when those same capsules are present in the solid state. Guests are often disordered in the cavities of host molecules observed in crystal structures, and solid state NMR has been used in only a handful of studies on guest dynamics in discrete encapsulation complexes.^18–20 Given the extraordinary guest dynamics inside pyrogallol[4]arene hexamers in solution,^21–23 we wondered how the solid state would change guest dynamics inside these hexamers. To what extent would the solid state’s rigidity translate across the host’s walls?

Pyrogallol[4]arene hexamers 1₆ are self-assembled capsules that enclose approximately 1.3 nm³ in the form of a roughly spherical cavity (Figure 1).²⁴ After they were first characterized in the solid state by Atwood, a number of groups have studied their encapsulation complexes in solution, including applications in catalysis.^25–27 Our lab has shown that a variety of arenes can be encapsulated by cooling molten mixtures of pyrogallol[4]arene and guest.^21,22 The resulting encapsulation complexes can be dissolved and studied in solution, but most are not thermodynamically stable. Guest exchange for solvent occurs over time, but often with ΔG^‡ > 23 kcal/mol and an imperceptibly slow rate at ambient temperature.^22,28 Guests encapsulated in these hexamers are generally dynamic in the capsules’ interiors on the ¹H NMR timescale, although Cohen has shown evidence for distinct guest sites tied to attractive interactions between guests and the host’s alcohol groups.^19,23,29 Solid-state ¹³C NMR has been used by Cohen et al. to identify guest encapsulation in pyrogallol[4]arene hexamers in the solid state, and our lab has applied this method to the study of solid-state, mechanically induced hexamer assembly with guest inclusion by ball milling, extending the scope of molecular encapsulation.^19,20 Using this assembly method and static solid-state ²H NMR, we show here that liquid state-like guest dynamics in the capsules’ interiors are retained when those capsules are present in the solid state (Figure 1).

Figure 1.

Mechanical forces from ball milling induce the self-assembly of pyrogallol[4]arene hexamers 1a₆ and 1b₆ with guest inclusion. These assemblies, once formed in the solid state, can be dissolved in nonpolar organic solvents for study in solution or can be characterized by static solid-state NMR. * indicates signals for encapsulated guests. Decyl/propyl groups of 1a/b have been truncated from the molecular model for clarity.

Methods

Capsule Assembly and Guest Loading.

Capsules loaded with fluorene(-d₂), fluoranthene(-d₁₀), and pyrene(-d₁₀) were prepared in the solid state by ball milling stoichiometric mixtures of pyrogallol[4]arene 1a or 1b with each respective guest (for stoichiometry, see Table 1). A stoichiometric mixture of 1a or 1b and guest totalling approximately 550 mg was placed in a 5 mL steel chamber along with a 7 mm steel ball. Samples were milled using a Retsch MM400 ball mill running at 30 Hz for 2 minutes at room temperature (23 °C), removed from the chamber and mixed to prevent clumping, and returned to the chamber for 28 minutes of additional milling at 30 Hz. The resulting solids were heated in vials on a hot plate at 70 °C for 30 minutes and cooled prior to solution or solid-state NMR measurements. To confirm the success of milling-induced encapsulation, samples of 5–10 mg of each milled mixture were removed, dissolved in CDCl₃, and immediately measured by ¹H NMR to confirm percent guest encapsulation (Table 1).

Table 1.

Structures of guest molecules and capsule loading capacity.

Guest	vdW volume / A3	Max# encap.a	Packing coefficientb	Avg. loadingc
	180	4	0.55	83% (29%)
	202	3	0.47	56% (55%)
	198	3	0.46	70% (36%)

^aMaximum number of each guest that can be encapsulated inside a pyrogallol[4]arene hexamer.^20,22

^bThe ratio of the total van der Waals volume of the guests to the vdW volume of the cavity of the host.

^cThe experimentally determined (¹H NMR after dissolution) average number of guest molecules encapsulated in 1a₆ as a percent of the maximum, following solid-state capsule preparation as in the Methods. The percent of average guest loading in the 1b₆ hexamer is given in parentheses.

Solid-State Studies by Differential Scanning Calorimetry.

Following encapsulation complex preparation by ball milling, and with variable-temperature NMR measurements planned, we performed differential scanning calorimetry (DSC) studies on the milled powders of host and guest (these samples were not heated as described above) to assess any possible heat-induced changes in the solid state. Aluminum pans containing powdered samples after ball milling were hermetically sealed and subjected to five heat-cool cycles between 30 and 70 °C using a TA Instruments Q2000 differential scanning calorimeter (TA Instruments, New Castle, DE; Figure S12).

Static Solid-State ²H NMR Measurements.

Static ²H NMR experiments were performed on a 600 MHz Bruker Avance III HD NMR spectrometer equipped with a broad band 4mm probe. Samples were packed into plastic inserts with a sample mass between 25 and 27 mg. A quadrupolar echo sequence with composite pulses (90°_x 180°_−x 90°_x 135°_−x 45°_x - τ - 90°_y 180°_−y 90°_y 135°_−y 45°_y - τ/2 - acquisition) was applied to accumulate ²H NMR signals. 8192 scans were collected for each spectrum using a recycle delay of 0.25 s unless otherwise stated. The short recycle delay allows detection of only those deuteriums that relax faster than our recycle delay of 0.25 s, which are those that experience relatively fast tumbling dynamics, similar to what is observed in the liquid state. This T1-weighted filter was chosen to remove signals from less dynamics guests, including those that are not encapsulated.

Results and Discussion

Pyrogallol[4]arene hexamer synthesis and encapsulation complex formation.

Our past studies have shown that ball milling of pyrogallol[4]arene 1a or 1b with guest can lead to incomplete encapsulation, including the presence of semi-formed encapsulation complexes.²⁰ These milled mixtures will equilibrate, in the solid state, over time to increase the extent of guest encapsulation.³⁰ Gentle heating accelerates the equilibration. To better understand how the variable temperatures used in our solid-state NMR measurements would impact on encapsulation, we performed DSC measurements on mixtures of host and guest immediately after ball milling without prior heating. For all pairings of fluorene, fluoranthene, or pyrene with 1a or 1b, we recorded DSC data across a temperature range of 30–70 °C using freshly milled samples. In all cases, the first scan differed from subsequent scans, which were identical within experimental error (Figure S12). Consistent with past observations, milling was efficient but imperfect at assembling the host–guest encapsulation complexes in the solid state. A brief heating at 70 °C is sufficient to reach equilibrium, and solution NMR of dissolved samples shows an increase in the % guest encapsulation when the solid state has been equilibrated (final results are shown in Figure 2 and Table 1). Based on this result, we heated all milled samples at 70 °C for 30 minutes prior to performing the solution and solid-state ²H NMR measurements of guest dynamics, as discussed below.

Figure 2.

Solution ¹H NMR spectra of guest encapsulation complexes of fluorene, fluoranthene, and pyrene in 1a₆ as prepared by ball milling, heating, and subsequent dissolution in CDCl₃ (500 MHz, 298 K). ○, □, and ▽ denote the signals for the encapsulated guests; the pyrene spectrum shows a mixture of two forms of the capsule that differ in the arrangement of the hydrogen bonds.²² See Figure S13 for the full spectra.

Solution ¹H NMR analysis of guest dynamics.

Guest dynamics inside pyrogallol[4]arene hexamers can be studied in solution by observing the ¹H NMR spectra of encapsulation complexes. When four molecules of fluorene or three molecules of fluoranthene are encapsulated in 1a₆ or 1b₆, the NMR spectra of the guests are slightly broadened and shifted upfield (Figure 2; spectra of encapsulation complexes of 1b₆ are very similar and can be seen in the Figure S14; full spectra, with resonances for free guests between 7.2 and 8.2 ppm except for the fluorene methylene at 3.9 ppm, are shown in Figures S13 and S15). The hexamers are chiral but racemic, owing to the clockwise or counterclockwise arrangement of their hydrogen bonds, as evidenced by the fact that there are three alcohol resonances in the ¹H spectra and six distinct aryl C resonances in the ¹³C NMR (for ¹H NMR, see Figure S13). This observation is true when the capsules are filled with fluorene, fluoranthene, CDCl₃, or other solvents.²² In our opinion, the most striking feature of these NMR spectra is that all encapsulated guest molecules give rise to the same set of NMR signals. Molecular modelling shows that three fluoranthene molecules that can fit within the hexamer in a stacked or a slipped arrangement (Figures 1 and S2). In both cases, the three fluoranthenes are clearly not in the same environment. Nonetheless, the fact that they all exhibit the same ¹H NMR resonances at 298 K indicates that these guests tumble rapidly within the capsule and the central fluoranthene exchanges places with those on the top and bottom. Clearly, these guest dynamics require significant distortion of the capsule, likely with temporary rupture of at least some of its hydrogen bonds. Perhaps most striking is the fact that fluoranthene encapsulation is not thermodynamically stable in CDCl₃; if the capsule opens sufficiently, then the fluoranthene guests will be exchanged completely for guest solvent. The capsule exhibits a remarkable degree of plasticity in allowing these guest dynamics, but without opening sufficiently to allow guest exchange.

Pyrene is a structural isomer of fluoranthene with a shape that is comparatively wider in the middle and more tapered at the ends. As can be seen in molecular modelling (Figure 1 and S1–S3), its shape is a better match than fluoranthene to the interior of the pyrogallol[4]arene hexamer. The rate of guest exchange of pyrene for solvent is slower than that of fluoranthene, and the ¹H NMR spectrum shows reduced symmetry, indicative of slow tumbling of a stack of three pyrene molecules in the capsules’ interiors on the NMR timescale.

Fluorene is likely arranged in the capsule with three molecules stacked and a fourth beside the stack and oriented roughly perpendicularly to the others (Figure S1). We observe dynamics similar to those of fluoranthene—slightly faster, as indicated by the sharper ¹H NMR resonances—with all guests experiencing on average the same environment on the NMR timescale. Although this encapsulation complex has the highest packing coefficient, it is likely that the smaller size of this guest and the impossibility of arranging four in a neat stack to complement the capsule’s shape (c.f. pyrene) contribute to these fastest guest dynamics.

Static solid-state ²H NMR analysis of guest dynamics.

Solid-state ²H NMR is an established method for studying guest and ligand dynamics in metal–organic frameworks and related systems.^31–37 Here, we applied it to discrete molecular encapsulation complexes in the solid state.^18,38 Using the same procedures for encapsulation complex synthesis by ball milling as discussed above for protio-guests, we prepared encapsulation complexes using fluorene-d₂, fluoranthene-d₁₀, and pyrene-d₁₀ and recorded their static solid-state ²H NMR spectra at temperatures from 273–333 K. Control static solid-state ²H spectra recorded for the pure deuterated fluorene-d₂ and fluoranthene-d₁₀ guest molecules showed very weak Pake pattern signals (Figure S10), characteristic of little rotational motion of these molecules, as expected of arenes in the solid state. For pyrene-d₁₀ however, we were able to observe a narrow Pake pattern and large isotropic component, indicating that pyrene retains high levels of motion as a powder—likely a spinning motion—even with a fast recycle delay meant to record motions occuring on the liquid-like timescale. After the milling with 1a₆ and 1b₆, the trend of its dynamics follows those of fluorene-d₂ and fluoranthene-d₁₀, as discussed below.

The dynamics of all three guest molecules are much different when they are present in the interiors of the pyrogallol[4]arene hexamers in the solid state. The static solid-state ²H spectra for each guest, encapsulated in either 1a₆ or 1b₆, show intense signals centered near 0 kHz, indicative of guest isotropicity, or rapid tumbling (Figure 3). Greater signal intensity and a narrower line width are both indicative of faster guest motion within the interior of the host. Two relationships between host and guest structure are immediately apparent. First, the rapidity of guest motions in the capsules’ interiors decreases from fluorene to fluoranthene to pyrene, mirroring the trend in relative dynamics of these guests when the capsules are in CDCl₃ solution. Second, guest dynamics are faster in decyl pyrogallol[4]arene 1a₆ in the solid state as compared with propyl pyrogallol[4]arene 1b₆. To explain this observation, we propose a model that treats pyrogallol[4]arene capsules in the solid state as relatively rigid and ordered, but surrounded by a relatively flexible, mobile, and likely disordered domain made up of the interdigitated alkyl groups of neighboring capsules. Alkyl chains in waxy solids are mobile, and one would expect that alkyl domain mobility is greater in the solid state for decyl pyrogallol[4]arene than for propyl.^§ We propose that the enhanced guest mobility observed in the decyl pyrogallol[4]arene hexamers in the solid state as compared with the propyl is the result of greater alkyl domain dynamics, translated across the walls of the host, and manifest in the greater dynamic motions of guests in the capsules’ interiors. Guest motion in the inner space of pyrogallol[4]arene hexamers in the solid state is similar to that observed in solution, but slower, and regulated by the relative rigidity of the solid state exterior to the capsules.

Figure 3.

Comparative static solid-state ²H NMR spectra of the encapsulation complexes of fluorene-d₂, fluoranthene-d₁₀, and pyrene-d₁₀ in propyl pyrogallol[4]arene hexamer (PPG) 1b₆ and decyl pyrogallol[4]arene hexamer (DPG) 1a₆. Spectra are normalized using the same number of scans (8192) and the same vertical display.

To further support this interpretation, we measured the static solid-state ²H NMR spectrum of all of these encapsulation complexes across a temperature range from 0 to 60 °C (data for fluorene-d₂ is shown in Figure 4; data for the other two guests are in the SI). As expected, the spectra show sharper signals and more intense signals at higher temperatures. It is possible to freeze out the motions of the guests, as indicated by the disappearance of the isotropic guest signal near 0 kHz, especially in the propyl pyrogallol[4]arene hexamer 1b₆. The motions of fluoranthene-d₁₀, and pyrene-d₁₀ inside 1b₆ become slow at temperatures below 30 °C (Figure S9).

Figure 4.

Comparative static solid-state ²H NMR spectra of fluorene-d₂ encapsulated in propyl pyrogallol[4]arene 1b₆, and fluorene-d₂ encapsulated in decyl pyrogallol[4]arene 1a₆. Spectra are normalized using the same number of scans (8192) and the same vertical display.

Conclusions

Ball milling and gentle heating of mixtures of decyl pyrogallol[4]arene 1a or propyl pyrogallol[4]arene 1b with fluorene(-d₂), fluoranthene(-d₁₀), or pyrene(-d₁₀) results in the formation of pyrogallol[4]arene hexamers in the solid state with guest encapsulation. When these mixtures are dissolved in CDCl₃ and studied using solution ¹H NMR, the guests are observed to tumble and exchange position rapidly within each host, although pyrene’s dynamics are somewhat slower. When the same solid-state, mechanical synthesis is performed using deuterated analogues of the guests and static solid-state ²H NMR is used to measure dynamics, we observe the same trend of guest mobility: fluorene > fluoranthene > pyrene. In all cases, static ²H NMR indicates a substantial degree of guest isotropicity that derives from tumbling and positional exchange in the capsules; the pure guests alone are much less dynamic in the solid state. The environment inside the pyrogallol[4]arene hexamers is remarkably similar in the solid state and solution, with the guests retaining their liquid state-like dynamic motions. By increasing the overall rigidity of the solid state—swapping the hosts’ external decyl groups for propyl groups—the dynamics of the guests are slowed. These results show that molecular encapsulation can offer nanoscale, homogeneously structured, liquid state-like molecular environments regularly interspersed throughout the solid state. The relative rigidity of the solid state translates across the walls of the hosts, influencing the dynamics of the guests.