Exploring the Scope of Macrocyclic “Shoe-last” Templates in the Mechanochemical Synthesis of RHO Topology Zeolitic Imidazolate Frameworks (ZIFs)

Abstract

The macrocyclic cavitand MeMeCH2 is used as a template for the mechanochemical synthesis of 0.2MeMeCH2@RHO-Zn16(Cl2Im)32 (0.2MeMeCH2@ZIF-71) and RHO-ZnBIm2 (ZIF-11) zeolitic imidazolate frameworks (ZIFs). It is shown that MeMeCH2 significantly accelerates the mechanochemical synthesis, providing high porosity products (BET surface areas of 1140 m2/g and 869 m2/g, respectively). Templation of RHO-topology ZIF frameworks constructed of linkers larger than benzimidazole (HBIm) was unsuccessful. It is also shown that cavitands other than MeMeCH2-namely MeHCH2, Me
i
BuCH2, HPhCH2, MePhCH2, BrPhCH2, BrC5CH2-can serve as effective templates for the synthesis of x(cavitand)@RHO-ZnIm2 products. The limitations on cavitand size and shape are explored in terms of their effectiveness as templates.

Full text

Molecules 2020, 25, 633; doi:10.3390/molecules25030633 www.mdpi.com/journal/molecules
Article
Exploring the Scope of Macrocyclic “Shoe-last”
Templates in the Mechanochemical Synthesis of
RHO Topology Zeolitic Imidazolate Frameworks
(ZIFs)
Ivana Brekalo 1, David E. Deliz 1, Christopher M. Kane 1, Tomislav Friščić 2,* and
K. Travis Holman 1,*
1 Department of Chemistry, Georgetown University, Washington, D.C. 20057, USA;
ib308@georgetown.edu (I.B.); ded46@georgetown.edu (D.E.D.); chris.kane@angstrom.uu.se (C.M.K.)
2 Department of Chemistry, McGill University, Montreal. QC, H3A 0B8, Canada
* Correspondence: kth7@georgetown.edu (K.T.H.), tomislav.friscic@mcgill.ca (T.F.)
Received: 16 December 2019; Accepted: 22 January 2020; Published: 1 February 2020
Abstract: The macrocyclic cavitand MeMeCH2 is used as a template for the mechanochemical
synthesis of 0.2MeMeCH2@RHO-Zn16(Cl2Im)32 (0.2MeMeCH2@ZIF-71) and RHO-ZnBIm2 (ZIF-11)
zeolitic imidazolate frameworks (ZIFs). It is shown that MeMeCH2 significantly accelerates the
mechanochemical synthesis, providing high porosity products (BET surface areas of 1140 m2/g and
869 m2/g, respectively). Templation of RHO-topology ZIF frameworks constructed of linkers larger
than benzimidazole (HBIm) was unsuccessful. It is also shown that cavitands other than
MeMeCH2—namely MeHCH2, MeiBuCH2, HPhCH2, MePhCH2, BrPhCH2, BrC5CH2—can serve as
effective templates for the synthesis of x(cavitand)@RHO-ZnIm2 products. The limitations on
cavitand size and shape are explored in terms of their effectiveness as templates.
Keywords: mechanochemical synthesis; zeolitic imidazolate frameworks; templation; microporous
materials
1. Introduction
Zeolitic imidazolate frameworks (ZIFs) [1,2], zeolitic metal organic frameworks (ZMOFs) [3,4],
tetrahedral imidazolate frameworks (TIFs) [5], or boron imidazolate frameworks (BIFs) [6] form a
class of metal organic frameworks (MOFs) that can be considered as expanded structural analogues
of zeolites. They are generally built from tetrahedral metal centers bridged with ditopic
ligands/linkers, where the metal-linker-metal bonding angles mimic those found in zeolites, resulting
in materials with extended 3D framework structures [7] analogous to zeolitic ones. Replacing the
zeolitic bridging oxide ligands, and the Si/Al centers with tetrahedral transition metals, not only
results in larger unit cell and pore sizes, but also has the added benefit of permitting easy
functionalization and access to a range of ligand and metal combinations. Ligand identity can also
affect framework flexibility and stability, as the ligand substituents can protect the metal from
nucleophilic attack, or steric interactions between ligand substituents can form a “secondary
network” that supports the framework architecture [8]. To date, over one hundred different metal-
ligand ZIF compositions have been realized, adopting over sixty different tetrahedral framework
structural (topological) variants [9].
The enormous structural diversity of ZIFs (and, more broadly, ZMOFs), however, inevitably
leads to issues of synthetic reproducibility and challenges with topological control. Indeed, syntheses

Molecules 2020, 25, 633 2 of 20
of ZIFs often yield a number of different topological forms (i.e., framework polymorphs, once
emptied) from the same set of starting materials and similar reaction conditions. Different ZIF
products often occur concomitantly within the same batch preparation. Moreover, under the reaction
conditions, the product distributions can often evolve over time, further complicating the synthesis
[10,11]. Consequently, potentially important ZIF materials have sometimes been observed only as
individual single crystals in a preparation, and their syntheses can sometimes be very difficult to
reproduce. For example, though the single crystal structure of the high porosity merlinoite (MER)
topological form of zinc imidazolate (ZnIm2), ZIF10 or MER-ZnIm2, was reported in 2006 [2], the
MER form of ZnIm2 was only prepared in phase-pure form, and fully characterized, ten years later
[10]. These synthetic issues are especially prevalent for the less dense, larger pore ZIF topologies
which are often not the most thermodynamically stable crystal form for a given metal-ligand
combination [12]. As high-porosity ZIFs tend to be the most potentially important ones, the issue of
framework topological control and reproducible synthesis is pressing.
Commonly, topological control in ZIF syntheses is achieved by developing successful synthetic
recipes. Choice of metal [13], exploitation of ligand sterics [14,15], use of solvents as putative
templates [16–19], choice of counterions (for charged ZMOFs) [3] and reaction conditions (e.g.,
reagents, base, temperature, time) [17], can all dramatically influence the topological outcome in ZIF
syntheses. Novel framework topologies for certain metal-ligand combinations have also been
achieved by post-synthetic linker or metal ion exchange [20,21]. Considering solvents, for example,
ZIFs with high porosity have been achieved by using large amide solvents, such as dipropyl and
dibutylformamide [19], which are included within the pores during synthesis. Several ligand-choice
strategies have also been employed, as some ligands or metal-ligand combinations are known to
favor certain topologies. For example, 2-nitroimidazole seems to bias mixed-ligand reactions toward
the gmelinite (GME) topology [15], and 4,5-disubstituted imidazoles often provide RHO topology
products [14]. Mixed ligand-steric index strategies have also been employed [22]. These approaches
generally seek to limit the possible framework topological outcomes via sterics. Controlling the
topological outcome within a family (where the ligand and metal are the same) of numerous possible
framework polymorphs, however, can be significantly more challenging. A particularly challenging
synthetic system is that of zinc imidazolate (ZnIm2), the simplest ZIF compositions. The
unsubstituted imidazolate ligand is capable of conforming to the greatest number of possible
framework topologies, as it is the least sterically demanding. Indeed, ZnIm2 has so far been prepared
in 15 different crystalline topological forms that are stable at ambient pressure and temperature [23],
as well as amorphous [24] and various temperature/pressure-dependent crystal forms [25]. Still, a
large number of other topological forms are theoretically possible.
To tackle the problem of framework topological control and synthetic reproducibility in ZIFs, it
seems reasonable to turn to templation, an approach often used in zeolite synthesis, and one that is
gaining traction in the MOF community [26]. Unfortunately, unlike the negatively charged zeolite
frameworks which can be templated by judicious choice of counter cations, most ZIFs are uncharged
frameworks and therefore do not include counterions. It has become clear, however, that the C-H
bonds of metal-coordinated imidazolate ligands are good hydrogen bond donors, akin to the C-H
bonds of N,N-disubstituted imidazolium cations [27], which exhibit pKa values as low as 20 [28]. For
example, the single crystal structures of many ZIF solvates reveal that the metal-coordinated
imidazolate ligands engage C-H···acceptor hydrogen bonds with the included solvent (e.g., BCT-
ZnIm2 (CSD reference codes VEJYIT, VEJYEP) [2,17] cag-ZnIm2 (VEJYUF) [2], CAN-ZnIm2 (PAJRUQ
[19]). Also, the Farha group has explored the deprotonation of the acidic imidazolate hydrogen
atom(s) in ZIFs such as SALEM-2 (SOD-Zn(Im)1.7(mIm)0.3, mIm = 2-methylimidazolate) [29]. Thus,
we hypothesized [10,23] that templation of specific topological motifs could be achieved by
introducing rigid molecules that can serve as hydrogen bond acceptors for the metal-imidazolate
hydrogen bond donors, and whose size and symmetry is compatible to that of the desired motif.

Molecules 2020, 25, 633 3 of 20
Figure 1. (a) Schematic representation of the “shoe-last” templating approach. (b) Cavitand naming
scheme illustrating the rccc forms of RR’Y-n (where omitted, n = 4). (c) Top-down and side views of
the general MeMeCH2@d8r motif. MeMeCH2 is bound via eight C-H···O hydrogen bonds (green
dashes). (d) Crystal structure of MeMeCH2@RHO-Zn16(Im)32∙solvent, illustrating the fused empty and
occupied d8rs with the empty d8r shown from the top and filled from the side (left) and vice-versa
(right). Relevant θ angles of different 8r imidazoles are pointed out. (e) The crystal structure of
MeMeCH2@RHO-ZnIm2⋅x(solvent) as a ball-and-stick representation. Half of the d8rs are occupied
by a (disordered) MeMeCH2 cavitand, shown in spacefill. The disorder is represented by green and
black color on one of the cavitand molecules.

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Along these lines, we and others [30,31] have begun to explore the confinement of useful solute
molecules within ZIFs, and it was reasoned that Cram’s ubiquitous and persistently bowl-shaped
cavitands (RR′Y, Figure 1) [32] would be interesting candidates. Conveniently, cavitands can be
easily modified at the upper (R) rims, lower (R′) rims, and bridging moieties (Y) of the bowl. They
are available in various stereoisomeric forms related to the relative cis/trans stereochemistry of lower
rim R’ substituents (rccc form depicted in Figure 1). They are also available in different ring sizes (e.g.,
n = 4, 5, 6, etc.), and many forms can be prepared in multigram quantities. Moreover, these stable
molecules can typically withstand the conditions of ZIF syntheses. In exploring the possible
encapsulation of cavitands by ZIFs, it was quickly discovered that one such cavitand, rccc-MeMeCH2
(R = Me, R’ = Me, Y = CH2; with all methyl groups directed parallel to the C4-axis; hereafter,
MeMeCH2), introduced into a solvothermal synthesis of zinc imidazolate, served to template the
elusive MER topology of zinc imidazolate, as MeMeCH2@MER-ZnIm2, allowing, for the first time,
synthesis of phase-pure material and characterization of its porosity [10]. Single crystal X-ray
structural analysis of MeMeCH2@MER-ZnIm2⋅x(solvent) revealed the MeMeCH2 template to be
encapsulated within the double-8-ring (d8r) motifs of the MER framework. The eight short C-H···O
hydrogen bonds (C···O = 3.135(6) Å , Figure 1) between the C-H groups at the 2-position of the
imidazolate ligands of the ZnIm2 framework and the ether oxygen atoms of the encapsulated
MeMeCH2 cavitand clearly illustrate the role of the MeMeCH2 as an eight-fold hydrogen bond
acceptor template for the d8r motif. Moreover, the MeMeCH2 template was found to be bound tightly
within MeMeCH2@MER-ZnIm2, and was not susceptible to removal via solvent washing or thermal
activation for sorption analysis. We therefore hypothesized that MeMeCH2 acts as a “shoe-last”
template around which the d8r motif (the “shoe”) is assembled.
This proof of concept result prompted us to explore the scope of the templation approach.
Specifically, we wondered if we can induce the formation of other framework topologies, such as the
RHO, TSC, PAU, and/or SBE zeolitic topologies, that exhibit the same d8r structural motif.
Furthermore, we wanted to improve the templated synthesis, increasing yields, decreasing reaction
times, and minimizing waste and energy consumption. To achieve these goals, we explored for the
first time the mechanochemical templation of ZIF syntheses using a non-ionic solid (NIS) as template.
Mechanochemical synthesis of metal-organic frameworks in general has recently gained
considerable attention [33–35]. For example, UiO-66 can be easily synthesized from simple zirconium
benzoate or methacrylate precursors [36], and MOF-74 (or CPO-27), one of the quintessential MOFs,
can be made from zinc oxide without bulk liquid [37]. Additionally, mechanochemical syntheses use
almost no liquid, require little energy input (no heat), and often give quantitative yields in shorter
times than solution based synthetic methods, making mechanochemistry a promising technique in
the synthesis of MOFs [38]. Importantly, mechanochemistry has been applied to the synthesis of ZIFs,
revealing that the direct reaction of metal oxides (ZnO/CoO) [39–43] and carbonates
([Zn(OH)2]3[ZnCO3]2) [44] with simple imidazoles can provide different ZIF materials under various
mechanochemical conditions, including neat grinding (NG, milling without addition of liquid),
liquid-assisted grinding (LAG, milling with the addition of catalytic amounts of liquid), ion-and-
liquid-assisted grinding (ILAG, milling with the addition of catalytic amounts of liquid and simple
inorganic salts), or accelerated aging (short milling followed by aging in liquid vapors, often warm
water vapor).
Our recent combination of the “shoe-last” templation approach with mechanochemical
synthesis resulted in the first synthesis of the highly porous RHO topological form of zinc imidazolate
[23]. We demonstrated that short (2 min) milling of nanoparticulate zinc oxide, imidazole (HIm), and
the MeMeCH2 cavitand template with diethylformamide (DEF) in a molar ratio of 1:2:0.5:4, followed
by aging of the resulting paste at ambient conditions in a capped vial (the LAG-aging procedure)
results in essentially quantitative preparation of 0.9MeMeCH2@RHO-Zn16Im32. Single crystal X-ray
structural analysis of a fortuitous crystal of MeMeCH2@RHO-Zn16Im32⋅x(solvent) grown via a
solution-based synthesis showed that, as with the aforementioned MeMeCH2@MER-
Zn16Im32⋅x(solvent) structure, the MeMeCH2 template molecules occupy the d8r motifs (now inside
the RHO framework, Figure 1d), and are engaged in eight short C-H···O contacts (C···O = 3.24(1) Å ,

Molecules 2020, 25, 633 5 of 20
Figure 1) with the framework imidazolates. The role of MeMeCH2 as a hydrogen bond acceptor
template was confirmed by the observation that the RHO topology product is not formed if the
template is not used in mechanochemical synthesis, and removing the C-H hydrogen bond donor by
using 2-methylimidazole instead of imidazole results in no RHO product. The formed
0.9MeMeCH2@RHO-Zn16Im32 is thermally stable up to >350 °C, highly porous (BETN2,77K = 1650 m2/g),
and can be synthesized in multigram quantities from inexpensive starting materials, using a
solventless procedure with little energy input.
We herein probe the limits of the RHO-topology ZIF templation effect by exploring different
cavitand templates within the ZnO/HIm mechanochemical synthetic system. Conversely, we also
explore the use of the MeMeCH2 template for the templation of RHO-topological forms of ZIFs with
different imidazolate ligands (RIm), as depicted in Figure 2. We proposed that structure-direction
depends on the template fitting into the ZnRIm2 d8r motif (or at least a portion of it) and forming
hydrogen bonds with the imidazolate moieties that make up the d8r. Therefore, the size/functionality
of the imidazolate ligands and the size/shape of the putative cavitand templates were expected to
have a substantial effect on the templation. In fact, adding/changing substituents on the imidazolate
ligand is generally expected to limit the available topological landscape for a given ZIF synthesis. In
this work we demonstrate the successful mechanochemical templation of RHO topological forms of
zinc 4,5-dichloroimidazolate, RHO-Zn(Cl2Im)2 (ZIF-71 [14]), and the elusive zinc benzimidazolate,
RHO-ZnBIm2 (ZIF-11 [2]), by the MeMeCH2 cavitand, and the use of several different cavitands to
prepare RHO-ZnIm2.
Figure 2. Exploration of the scope of the templation of the RHO topological form of zinc imidazolates,
using different cavitands (see Table 1) and ligands.
2. Results and Discussion
2.1. Accelerated Synthesis of RHO-Zn16(Cl2Im)32 and RHO-ZnBIm2 Using the MeMeCH2 Template
We previously demonstrated that the MeMeCH2 template is unable to template RHO-topology
ZIFs constructed with 2-substituted imidazolates (e.g., 2-Mem), as the ligand cannot hydrogen bond
with the template within a putative d8r system. Furthermore, to make any ZIF, both nitrogen atoms
of the imidazole used must be non-substituted, as the nitrogen atoms bind to the zinc metal ions.

Molecules 2020, 25, 633 6 of 20
Therefore, only ZIFs constructed with 5- and/or 4-substituted imidazolate ligands could be
susceptible to RHO-templation by the MeMeCH2 template.
The first modification explored was the use of 4,5-dichloroimidazole, HCl2Im. Two crystal forms
of Zn(Cl2Im)2 are known to form via reaction of HCl2Im with zinc salts (with no other ligands) in
solution: RHO-Zn(Cl2Im)2 (ZIF-71), and lcs-Zn(Cl2Im)2 (ZIF-72) [14]. The RHO topology product
(ZIF-71) is reportedly formed under higher dilution and higher temperature conditions, over a
shorter period of time, and has since been used extensively as a sorbent [45,46]. It was therefore
deemed interesting to determine whether RHO-Zn(Cl2Im)2 is amenable to our templation approach
in mechanochemical synthesis. A liquid-assisted grinding (LAG)-aging synthesis was performed
using nanoparticulate ZnO, HCl2Im, and MeMeCH2 as the templating agent, with DEF as the liquid
additive. The reaction reached completion within approximately 4 days, and, after washing with
chloroform to remove excess MeMeCH2, yielded essentially phase-pure 0.2MeMeCH2@RHO-
Zn16(Cl2Im)32. The reaction conversion was nearly quantitative, based on powder X-ray diffraction
(PXRD). NMR analysis suggests that only a tenth of the d8r-motifs (a fifth of accessible d8r motifs) in
the RHO framework are filled with cavitand, a factor of about four less than the previously reported
imidazolate-based material, 0.9MeMeCH2@RHO-Zn16Im32 [10]. The result suggests that increasing
the ligand size may interfere with cavitand incorporation into the ZIF, likely due to steric effects. In
the cavitand-free RHO ZIFs, the imidazolate ligands forming both 8-rings (8r) of the d8r motif
alternate between being near parallel to the plane of the 8r (θ ≤ 0, Figure 1c, 3c, 4c), and being near
perpendicular to it (θ ≈ 90°, Figures 1c, 3c, 4c). For the cavitand template to fit into the d8r,
imidazolates of the bottom 8r must swing open so that they are all near parallel to the d8r axis (θ3 ≈
θ4 ≈ 90°, Figure 1c), while imidazolates of the top 8r still alternate between being parallel and
perpendicular (θ1 ≈ 0, θ2 ≈ 90°, Figure 1c). It is easy to predict that the all-perpendicular orientation
will be harder to assume for ligands with increasing steric bulk.
Low temperature and pressure nitrogen sorption analysis of activated 0.2MeMeCH2@RHO-
Zn16(Cl2Im)32 (Figure 3a) reveals a Type I isotherm and a surface area of 1140 m2/g. The material
maintains crystallinity and its RHO topology after sorption, as evidenced by the post-sorption PXRD
pattern. Interestingly, the surface area of 0.2MeMeCH2@RHO-Zn16(Cl2Im)32 is higher than the values
previously reported for activated RHO-Zn16(Cl2Im)32 (ZIF-71: 652 m2/g [14] and 1050 m2/g [45]). The
results suggest that the MeMeCH2 cavitand may exhibit a stabilizing effect on the RHO-Zn16(Cl2Im)32
framework, potentially limiting framework flexibility with respect to contraction upon
activation/emptying.
In a control reaction, the LAG-aging procedure was performed with the same metal source and
ligand, nanoparticulate ZnO and HCl2Im, but without the addition of the MeMeCH2 template.
Similar to the templated reaction, the non-templated control reaction also provides RHO-Zn(Cl2Im)2
(ZIF-71). However, monitoring the templated and non-templated reaction mixtures by PXRD over
time revealed that the MeMeCH2-templated reaction is significantly faster. In fact, after only 1 day,
the templated reaction shows approximately the same conversion (based on relative amount of ZnO)
as the non-templated reaction does after 35 days. And though the non-templated reaction shows a
large amount of residual ZnO after 3 days, the templated reaction undergoes full conversion in that
time, both on a small (220 mg) and large (≈ 1.7 g) scale (Figure 3e). The results demonstrate that,
despite the low level of incorporation of MeMeCH2 into the RHO-Zn(Cl2Im)2 framework, not only
does MeMeCH2 help direct the topological outcome of a mechanochemical synthesis, it also allows
the reaction to proceed significantly faster, and provides material of excellent porosity. Interestingly,
this reaction is also significantly faster than the synthesis of 0.9MeMeCH2@RHO-Zn16Im32. We
hypothesize that the increased acidity of HCl2Im as compared to HIm is responsible for the increased
reactivity and also stronger hydrogen-bonding interactions between the zinc-coordinated Cl2Im-
ligands and the MeMeCH2 template.

Molecules 2020, 25, 633 7 of 20
Figure 3. Synthesis and characterization of 0.2MeMeCH2@RHO-Zn16(Cl2Im)32 (0.2MeMeCH2@ZIF-
71). (a) The 77 K low pressure N2 isotherm. (b) The crystal structure of RHO-Zn(Cl2Im)2 (CSD code
GITVIP) as viewed down the [001] axis (the d8r motif is shaded blue). (c, d) Side and top views of the
d8r motif of RHO-Zn(Cl2Im)2 (shaded blue). (e) Powder X-Ray diffraction (PXRD) patterns of the non-
templated liquid-assisted grinding (LAG)-aging reaction of ZnO and HCl2Im after i) 3 days and ii) 12
days; the MeMeCH2 templated LAG-aging reaction of ZnO and HCl2Im after iii) 1 day and iv) 3 days;
the templated large scale (≈ 1.7 g) LAG-aging reaction of ZnO and HCl2Im v) after 3 days, and vi) the
washed 0.2MeMeCH2@RHO-Zn16(Cl2Im)32 final product after 4 days, and vii) the same material after
activation and 77 K low pressure N2 sorption analysis. viii) Simulated PXRD pattern of
MeMeCH2⋅2DEF ix) PXRD pattern of nanoparticulate ZnO. Tick marks denote predicted peak
positions of the RHO-Zn(Cl2Im)2 (ZIF-71, GITVIP).

Molecules 2020, 25, 633 8 of 20
Encouraged by the successful templation of the RHO-Zn(Cl2Im)2 by the “shoe-last” template
MeMeCH2, we turned to bulkier ligands. Benzimidazole was chosen as the next target ligand, seeking
synthesis of RHO-Zn(BIm)2 (ZIF-11). The bulky ligands of ZIF-11 give rise to an unusual MOF
structure; ZIF-11 possesses very large (~14.6 Å diameter) LTA (Linde Type A) cages, but very small
apertures (< 3 Å ), making it of interest for the sieving of commodity gases, such as ethylene/ethane,
CO2/H2, etc. [47]. Traditional solvothermal synthetic procedures have found that reaction of HBIm
with tetrahedral metal ions gives only three ZIF topological outcomes in the absence of other co-
ligands: the RHO topology RHO-ZnBIm2 (ZIF-11), RHO-CoBIm2 (ZIF-12) [2], the SOD topology
SOD-ZnBIm2 (ZIF-7) [2], SOD-CoBIm2 (ZIF-9) [2], SOD-CdBIm2 (CdIF-13) [48] or the layered, close-
packed sql-ZnBIm2 [49]. sql-ZnBIm2 [42] and sql-CoBIm2 [50] have also been prepared by
mechanochemical synthesis, by aging of a ZnO/HBIm mixture with addition of (NH4)2SO4 in H2O
vapors, and LAG of a Co(NO3)2⋅6H2O/HBIm mixture with ethanol, respectively. Of the zinc-based
materials, the SOD-ZnBIm2 and RHO-ZnBIm2 products are obtained under similar conditions, by the
reaction of zinc nitrate tetrahydrate and benzimidazole via solvothermal methods. The SOD-ZnBIm2
(ZIF-7) product was obtained from DMF after heating at 130 °C for 2 days, and the RHO-ZnBIm2
(ZIF-11) product was obtained from DEF, under less concentrated conditions, and after 4 days of
heating at 100 °C. A “toluene-assisted” synthesis of RHO-ZnBIm2 (ZIF-11) was later reported by He
et al. using zinc acetate as the metal source, and ammonium hydroxide in ethanol as the solvent/base
system [51]. Since this report (cited 50 times to date), the number of studies concerning the properties
of RHO-ZnBIm2 (ZIF-11) have risen. In our hands, however, both the original and toluene-assisted
procedures fail to give RHO-ZnBIm2 (see Figure S11). We note that others have synthesized RHO-
ZnBIm2 (ZIF-11), citing He et al., but using a different solvent (e.g., MeOH[47]). It was hypothesized
that our LAG-aging templation procedure might give a simple and reproducible way to synthesize
this elusive member of the RHO family of zinc imidazolates.
A LAG-aging synthesis of RHO-ZnBIm2 (ZIF-11) was performed using nanoparticulate ZnO,
HBIm, and MeMeCH2 as the “shoe-last” template. The reaction proceeded significantly slower than
the analogous HCl2Im reaction; even after 12 days, a small amount of unreacted ZnO remained
(based on PXRD analysis). The reaction, however, reached complete conversion within 45 days, and,
after washing with chloroform to remove excess MeMeCH2, yielded phase-pure RHO-ZnBIm2 (ZIF-
11, Figure 4e). 1H-NMR analysis of the digested RHO-ZnBIm2 product showed that, unlike
0.9MeMeCH2@RHO-Zn16(Im)32 and 0.2MeMeCH2@RHO-Zn16(Cl2Im)32, it contained no MeMeCH2
residual template.
To confirm that, even though it is not incorporated into the product, MeMeCH2 actually has a
templation effect on the mechanochemical reaction, a control LAG-aging reaction was performed
without MeMeCH2. The MeMeCH2-free control reaction provides very small amounts of RHO-
ZnBIm2, after a much longer period of time than the MeMeCH2-templated reaction, as evidenced by
PXRD (Figure 4e). Specifically, the MeMeCH2-free reaction shows no sign of RHO-ZnBIm2 product
after 3 days, and only a very small amount after 12 days, with a very large amount of residual ZnO.
The templated reaction, however, shows more conversion after 3 days than the MeMeCH2-free
reaction after 12 days, and is nearly quantitative after 12 days (Figure 4e). The difference in reaction
rate demonstrates that there is a templation effect: addition of MeMeCH2 significantly accelerates the
synthesis of the RHO-ZnBIm2 product. As mentioned, benzimidazole has so far been reported as a
reagent in the mechanochemical synthesis of ZIFs only twice, using cobalt(II) nitrate or ZnO to
synthesize the layered sql-topology CoBIm2 [50] or ZnBIm2 [42], respectively. This scarcity of reports
is likely due to the very slow kinetics of the template-free reaction [42].
The question then remains: why is there no incorporation of the MeMeCH2 template into the
RHO-ZnBIm2 framework, if templation is happening? Earlier crystal structural analysis of
MeMeCH2@RHO-Zn16(Im)32⋅x(solvent) (Figure 1) revealed that, due to the conformation of the
imidazolates that must be assumed to allow C-H···O hydrogen bonding with the template in the
MeMeCH2@d8r motif, all face-shared d8r neighbors must remain MeMeCH2-free, and a maximum
of half of the d8rs (there are two d8rs per RHO-Zn16RIm32 formula unit) can be occupied by
MeMeCH2.

Molecules 2020, 25, 633 9 of 20
Figure 4. Synthesis and characterization of RHO-ZnBIm2 (ZIF-11). (a) The 77 K low pressure N2
isotherm. (b) The crystal structure of RHO-ZnBIm2 (CSD code VEJZOA) as viewed down the [001]
axis (the d8r motif is shaded blue). (c, d) Side and top views of the d8r motif of RHO-ZnBIm2 (shaded
blue). (e) PXRD patterns of the non-templated LAG-aging reaction of ZnO and HBIm after i) 3 days,
and ii) 12 days; the MeMeCH2 templated LAG-aging reaction of ZnO and HBIm after iii) 3 days, iv)
12 days, v) the washed RHO-ZnBIm2 (ZIF-11) final product after 45 days, and vi) the same material
after activation and 77 K low pressure N2 sorption analysis. vii) Simulated PXRD pattern of
MeMeCH2⋅2DEF. viii) PXRD pattern of nanoparticulate ZnO. Tick marks denote predicted peak
positions of RHO-ZnBIm2 (ZIF-11, VEJZOA).

Molecules 2020, 25, 633 10 of 20
It must be noted that, in the synthesis of bulk 0.9MeMeCH2@RHO-Zn16(Im)32, slightly less than
half of the d8r motifs of the RHO frameworks are occupied by the MeMeCH2 template. Regarding
RHO-ZnBIm2, we hypothesize that, in the early stages of framework assembly the MeMeCH2 may,
via hydrogen bonding, transiently direct metal-coordinated imidazolate species into an orientation
amenable to d8r and RHO formation — via a partially formed MeMeCH2@d8r motif — yet dissociate
from those assemblies before formation of the MeMeCH2@d8r motif is complete. Indeed,
incorporation of MeMeCH2 into the d8r motif requires significant conformational reorientation of the
imidazolate ligands within the 8-rings relative to the native empty d8r structure (see Figure 1; Figure
2). Thus, we hypothesize that the greater steric bulk of the BIm- inhibits the necessary reorientation
of the 8-ring ligands and thereby prevents formation of the completed, MeMeCH2-encapsulated
MeMeCH2@d8r motifs. The template is thereby rejected from the material during later stages of
d8r/RHO-framework formation, allowing it to be easily washed away in the chloroform rinsing step,
leaving pure RHO-ZnBIm2. This hypothesis is also consistent with the observation that the degree of
template incorporation in 0.2MeMeCH2@RHO-Zn16(Cl2Im)32 (derived from the moderately bulky
Cl2Im- ligand) lies between that of 0.9MeMeCH2@RHO-Zn16(Im)32 (non-bulky ligand) and
MeMeCH2-templated RHO-ZnBIm2 (very bulky ligand).
Nitrogen sorption analysis of our sample of RHO-ZnBIm2 (ZIF-11, Figure 4a) gave surprising
results. Whereas other samples of RHO-ZnBIm2 (ZIF-11) have, in multiple instances [2,52], been
reported to be more or less “closed” to sorption of dinitrogen at 77 K—presumptively due to the
small aperture sizes—our sample of RHO-ZnBIm2 exhibits a Type I isotherm with slight hysteresis
in the mesoporous region, indicative of an open pore structure. The BET surface area measures 869
m2/g, and our RHO-ZnBIm2 material maintains crystallinity and the RHO topology after activation
and sorption analysis, as evidenced by the post-sorption PXRD pattern (Figure 4e-vi). Interestingly,
though others’ samples of RHO-ZnBIm2 (ZIF-11) do not appear to be porous to dinitrogen at 77 K,
the isostructural cobalt analog, RHO-CoBIm2 (ZIF-12), has been reported to readily absorb dinitrogen
at 77 K [2,52]. The difference in behavior had previously been attributed to the slightly larger pore
apertures in the cobalt-based material. We suggest that the unusual behavior of ZIF-11 may instead
be due to flexibility of the RHO-ZnBIm2 framework. While traditional solvothermal synthesis
provides ZIF-11 material with ligand conformations which block the pore opening (the 8r motif,
Figure 4c), it is possible that the association-dissociation of MeMeCH2 during the early stages of
RHO-ZnBIm2 framework assembly gives rise to a product with a more open conformation of the of
BIm- ligands in the 8-rings, as per the steric requirements of the cavitand described above. It is also
possible that our RHO-ZnBIm2 is more defect-laden, providing avenues through which N2 can
diffuse. Additionally, mechanochemical synthesis inherently provides materials with relatively small
particle sizes,[53] which increases the percentage of cages whose apertures are on the particle surface,
where ring structures are inherently more flexible. This could potentially allow transient pore
aperture widening and giving rise to a kinetic effect that allows observation of more rapid pore filling.
Finally, we attempted to synthesize RHO-ZnRIm2 frameworks with even bulkier ligands, in
order to determine the limits of the templating procedure. We chose three benzimidazole derivatives
with increasing numbers of substituents: 5-nitrobenzimidazole (HNO2BIm, one substituent), 5,6-
dimethylbenzimidazole (HMe2BIm, two substituents), and theophylline (HTheo, four substituents).
Of these, only one has been found to form a ZIF product without the addition of other ligands, namely
zea-Zn(Me2BIm)2. Synthesis of zea-Zn(Me2BIm)2 has been achieved via solvothermal reaction of zinc
acetate and HMe2BIm in 2-aminobut-1-ol and benzene at 150 °C [54]. It would therefore be very
interesting if RHO topology ZIFs could be synthesized using these ligands by our approach. LAG-
aging experiments were conducted by milling nanoparticulate ZnO, the MeMeCH2 template and
each of the ligands with DEF. Unfortunately, none of the three reactions gave any sign of an RHO
topology product by PXRD, and only the HTheo reaction showed significant conversion to any
product, giving the known discrete zinc theophylline dihydrate after about one year of aging (Figure
S21).
We have therefore demonstrated that MeMeCH2 templation of RHO-topology zinc imidazolate
ZIFs in a mechanochemical reaction can be expanded to ligands smaller or equal in size to

Molecules 2020, 25, 633 11 of 20
benzimidazole, with the amount of cavitand incorporation into the final RHO-ZnRIm2 product
frameworks being inversely proportional to the size of the ligand.
2.2. Exploring Different Cavitand Templates in the Synthesis of (Template)x@RHO-ZnIm2 Materials
Having explored the ligand scope of the MeMeCH2-templated mechanochemical synthesis of
RHO-ZnRIm2 ZIFs, we endeavored to explore the effect of template molecular structure on the
topological outcome of the LAG-aging procedure using the simplest and least sterically demanding
ligand, imidazole. The resulting (template)x@RHO-ZnIm2 materials are anticipated to have different
properties—e.g., effective pore volume/diameter, framework flexibility, chemical and thermal
stability—according to the level of incorporation and location of incorporation of the template and
the size/shape or chemical functionality of the template. Moreover, RHO-ZnIm2 (with no template
incorporation) remains unknown, and it would be of interest to compare the stability and properties
of (template)x@RHO-ZnIm2 materials with native RHO-ZnIm2. Also, going forward, it would be of
great interest to use the template@d8r encapsulation mechanism as a means to systematically
introduce useful chemical functionalities (e.g., specific binding sites, catalytically active moieties, etc.)
into the LTA cages of high porosity RHO-ZnIm2 ZIFs, for various applications. This could be done
by chemically installing such moieties at the R’ “feet” of the encapsulated cavitand templates, which
protrude into the large diameter (~1.5 nm) LTA cages of the ZIF. Thus, it was deemed useful to
explore the steric limits of putative templates that can be encapsulated within (template)x@RHO-
ZnIm2 materials.
It was originally hypothesized that the ideal template for a certain topological motif (here: the
d8r) must match the motif in symmetry (4-fold or 8-fold for the d8r), shape (near cylindrical) and size,
as well as have properly positioned hydrogen bond acceptors. To test this hypothesis we chose a
larger cavitand of the “wrong” symmetry and total size (MeHCH2-6, n = 6, with 6 repeating resorcinol
units, Figure 1), a cavitand of the “wrong” shape (MeHSiMe2, with an upper rim wider than the
bottom rim and too wide for the d8r), and several cavitands with top (R = H, Me, Br) and bottom (R’
= H, Me, Br, iso-butyl (i-Bu), Ph, 4-methylphenyl (4-MePh), and n-pentyl (C5H11)) rim substituents
of varying sizes and lengths. Varying the R’ substituents was intended to explore the size/length
limitations of substituents that can protrude into the LTA cages of the RHO-ZnIm2 frameworks. In
addition to these cavitands, all of which conform to the rccc stereochemistry, a sample of MePhCH2
cavitand containing 87% of the rctt stereoisomer—with two adjacent phenyl rings pointing
orthogonal to the C4-axis of the cavitand bowl—was also explored. The rctt-MePhCH2 stereoisomer
is mismatched to the d8rs in both size/shape (far too “wide” for the d8r) and overall symmetry.
A series of LAG-aging experiments using nanoparticulate zinc oxide, imidazole, and the
putative template in the presence of DEF (molar ratio of 1:2:0.5:4) were performed. The reactions were
monitored over time by PXRD and the products were worked up for analysis (chloroform washing)
after near-complete consumption of ZnO. The PXRD patterns of the resulting final, chloroform-
washed products are shown in Figure 5. The control reaction (see ref. [23]), using no added template,
gave mainly coi-ZnIm2 (EQOCOC). It is worth noting that, for all mechanochemical ZIF syntheses,
care must be taken to thoroughly clean the milling jars and equipment before every experiment. Due
to the diverse topological landscape (framework polymorphism) of zinc imidazolate, it was found
that residual seeds of ZnIm2 materials with various framework topologies can provide a competing
templation effect, and sometimes results in the formation of mixtures. We are currently exploring
intentional framework seeding as a possible means of controlling ZnIm2 framework polymorphism
and/or achieving novel ZnIm2 framework polymorphs.
The framework topologies of the discernable ZIF products associated with each putative
template are summarized in Table 1. In identifying the products of mechanochemical reactions, the
region of the PXRD pattern below 10° 2θ (Cu K<>) was particularly useful for establishing the
presence of RHO-topology ZIFs, as there are up to nine observable (hkl) reflections that are
characteristic of the RHO-ZnIm2 framework in this region. Many of the more dense ZnIm2 ZIF
framework polymorphs exhibit much smaller units cells and therefore no (or few) low-angle peaks
(e.g., cag-ZnIm2 (VEJYUF), coi-ZnIm2 (EQOCOC), zni-ZnIm2 (IMIDZB06), Zn4(HIm)Im8

Molecules 2020, 25, 633 12 of 20
(KUMXEW)). Other (non-RHO) low density framework polymorphs may exhibit low angle (hkl)
reflections, but they are at discernably different 2θ positions from RHO-ZnIm2 (e.g., 10mr-ZnIm2
(GOQSIQ), MER-ZnIm2 (VEJZIU, EWENUR)). Peaks above ≈ 10–15 °2θ (Cu K<>) in the PXRD
pattern are less conclusive when it comes to identifying the topological products, as a number of ZIF
framework polymorphs can give rise to (hkl) reflections at those 2θ angles, and RHO-ZnIm2 itself has
many peaks in that region. It can therefore be difficult to establish whether the samples containing
an RHO-ZnIm2 framework product also contain other more dense ZIF framework polymorphs as
impurities. To assist in making that decision, an expanded comparison of each of the product PXRD
patterns, alongside the predicted peaks positions for RHO-ZnIm2, is provided in the Supporting
Information.
Another complication arises from the relative intensities of the PXRD peaks. It is important to
recognize that the ZnIm2 framework topology can be assigned on the basis of the 2θ positions of the
collective (hkl) reflections, where the relative peak intensities can vary widely depending upon how
the electron density—associated with solvent (e.g., solvent identity and/or atomic scattering factors,
position, order/disorder, or absence) or included cavitand template—is distributed within the pores
of the ZIF framework. It has been reported, for instance, that the relative intensities of the two lowest
angle peaks—the (100) and (110) peaks at 3.04° and 4.32° 2θ, respectively—of RHO-ZnBIm2 (ZIF-11)
are dramatically affected by the occupancy of the pores by solvent.[51] Among other relative intensity
differences, filling the ZnBIm2 (ZIF-11) pores (i.e., the LTA cages) with toluene was shown to
dramatically increase the relative intensity of the (100) peak, while concomitantly lowering the
relative intensity of the (110) peak.
Table 1. Summary of cavitand putative templates explored in the LAG-aging reactions between zinc
oxide, imidazole, DEF, and RR’Y-n cavitand (Figure 1), as well as the framework topological products
of the reactions.
R
R’
Y
n
Stereochemistry
Topological Result
H
Ph
CH2
4
rccc
RHO
H
4-MePh
CH2
4
rccc
cag
Me
H
CH2
4
rccc
RHO
Me
H
CH2
6
rccc
RHO
Me
H
SiMe2
4
rccc
cag
Me
i-Bu
CH2
4
rccc
RHO
Me
Ph
CH2
4
87% rctt: 13% rccc
nog + RHO
Br
n-C5H11
CH2
4
rccc
RHO
Br
Ph
CH2
4
rccc
RHO
The first modified template that was evaluated was MeHCH2 (R = Me, R’ = H, Y = CH2). MeHCH2
differs from the original MeMeCH2 template only in the fact that it has a smaller lower rim
substituent (H instead of CH3). It was hypothesized that the smaller H atoms should be less
demanding with respect to the requisite conformational reorganization of the imidazolate ligands
within the eight-rings of the template@d8r motifs (θ3-4, Figure 1). Thus, it was anticipated that
MeHCH2 would function similarly to MeMeCH2 as a template for RHO-ZnIm2. Indeed, the LAG-
aging procedure, after 16 days, resulted in near-quantitative conversion into the RHO topology
product, isolated as 1.6MeHCH2@RHO-Zn16Im32 (Figure 5i). The relatively high degree of MeHCH2
incorporation indicates that all accessible d8rs (half of the overall number are deemed accessible
based on crystallographic analysis[23] of MeMeCH2@RHO-Zn16Im32) are occupied and that there is
an excess of MeHCH2 remaining in the structure, even after extensive washing. It seems likely that
the excess MeHCH2 is contained in the LTA cages, though it is also possible that the smaller size of
MeHCH2 compared to MeMeCH2 may enable some of the d8rs that are deemed inaccessible to be
filled with the smaller cavitand.

Molecules 2020, 25, 633 13 of 20
Figure 5. Experimental PXRD patterns of LAG-aging syntheses using nanoparticulate ZnO,
imidazole, DEF, and selected cavitands, washed after t days. i) cavitand = MeHCH2, t = 16 d, ii)
cavitand = MeiBuCH2, t = 16 d, iii) cavitand = BrPhCH2, t = 7 d, iv) cavitand = BrC5CH2, t = 5 d, v)
HPhCH2, t = 12 d, vi) cavitand = MePhCH2 (rctt:rccc = 87:13), t = 5 d, vii) cavitand = MeHCH2-6, t = 5
d, viii) MeHSiMe2, t = 11 d, ix) H(4MePh)CH2, t = 11 d, and xii) nanoparticulate ZnO. Simulated PXRD
patterns of x) cag-ZnIm2 (VEJYUF) and xi) nog-ZnIm2 (HIFWAV). Tick marks denote predicted peak
positions of 0.90MeMeCH2@RHO-Zn16Im32. Stars denote small amounts of impurities that are not
defined in Table 1.
Next, the MeHCH2-6 cavitand (R = Me, R’ = H, Y = CH2, n = 6), containing six 2-methylresorcinol
units, was used. The upper and lower rim substitution in MeHCH2-6 is identical to that of MeHCH2,
but the addition of two more resorcinol units makes the overall cavitand significantly larger and
incompatible with the 4/8-fold symmetry of the d8rs. Clearly, also, MeHCH2-6 cannot fit within a
completely formed ZnIm2 d8r motif. However, MeHCH2-6 exhibits a “double-bowl” type C2v
symmetric conformation in the solid state and in solution.[55] The conformation (Figure 6) is such
that two narrow ends of the elongated, pinched double-bowl structure, mimic, almost perfectly, three

Molecules 2020, 25, 633 14 of 20
of the four rings of the four-fold symmetric MeHCH2-4 cavitand. Thus, it was of interest to determine
whether MeHCH2-6 can give rise to the RHO-ZnIm2 framework by templating only partial formation
of d8r motif. PXRD analysis of the product of the LAG-aging synthesis using MeHCH2-6 as a putative
template (washed after 5 days) revealed that the main product was in fact an RHO-ZnIm2 framework
ZIF, isolated as 5.8MeHCH2-6@RHO-Zn16Im32 (Figure 5.vii). Notably, a significant portion of the
MeHCH2-6 template is retained of the MOF after washing. Yet the large MeHCH2-6 macrocycle
simply cannot fit within a d8r of the RHO-ZnIm2 structure. We conclude that the residual MeHCH2-
6 must be retained within the large LTA cage. This conclusion is also consistent with the relative
intensities of the 5.8MeHCH2-6@RHO-Zn16Im32 PXRD pattern, which are quite different from the
aforementioned 0.9MeMeCH2@RHO-Zn16Im32 and 1.6MeHCH2@RHO-Zn16Im32 (Figure 5.i)
materials. The most notable differences correspond to the two lowest angle peaks. The (100) peak is
intense in 5.8MeHCH2-6@RHO-Zn16Im32 but it almost absent in 1.6MeHCH2@RHO-Zn16Im32.
Conversely, the (110) peak is almost missing (and appears to be shifted to somewhat higher angle) in
5.8MeHCH2-6@RHO-Zn16Im32, but is the most intense peak in 1.6MeHCH2@RHO-Zn16Im32. These
results suggest that only a portion of the requisite structural motif—in this case, the d8r—needs to be
formed to have an influence on the topological outcome of the final framework. Thus, even though a
template may not be able to fit entirely within a given desired motif (e.g., the d8r), it may still be
capable of templating the desired structure by biasing the assembly process. Moreover, the ultimate
location of the template in the final structure may not be a reflection of portion of the structure for
which it exerts a structural influence.
Figure 6. Comparison of the crystal structures of MeHCH2 (left; CSD code VUWMIL [56]) and
MeHCH2-6 (right; CSD code QUCWOA [55], chloroform solvate, solvent molecules omitted for
clarity), illustrating the similarities of a portion of their molecular structures. (a) top view, (b) side
view.
Next, we explored MeHSiMe2 (R = Me, R’ = H, Y = SiMe2). as a possible template. MeHSiMe2
differs from the effective MeHCH2 template in that the “Y” groups (Y = -SiMe2-) that connect the
resorcinol units around the upper rim of the bowl are much larger, and make the rim of the bowl
much wider. The dimethylsilyl moieties were expected to inhibit approach of the metal-coordinated
imidazolate ligands to the eight ether oxygen atoms that function as hydrogen bond acceptors in the
original template. Moreover, structural models suggest that the outwardly directed methylsilyl
moieties cannot be sterically accommodated by the imidazolates of the eight-rings of the d8rs. Not
surprisingly, MeHSiMe2 proved not to be a functional template for the RHO-ZnIm2 framework. The

Molecules 2020, 25, 633 15 of 20
LAG-aging synthesis using MeHSiMe2 gave, after 11 days, a mixture of products, the majority
component being cag-ZnIm2 (presumably originally occupied by DEF, Figure 5.viii)). We can
conclude that broadening the top rim of the cavitand, and/or sterically preventing the ether oxygen
atoms from hydrogen bonding with the imidazolate ligands, results in failure of the template.
Finally, we greatly broadened the lower rim of the cavitand bowl by using an rctt stereoisomer
of MePhCH2 (R = Me, R’ = Ph, Y = CH2). As mentioned, all other cavitand templates employed herein
are in their stereopure rccc-forms (or have no stereoisomers: R’ = H), where all R’ groups point
“down” from the bowls (axial with respect to the macrocylic ring), parallel to the C4 axis. In the rctt
form of MePhCH2, however, two adjacent phenyl rings are directed approximately orthogonal
(equatorial to the macrocylic ring) to the cavitand bowl. As two of the bottom rim substituents are
protruding horizontally outward, the effective diameter of the lower rim substituents of any rctt
cavitand is much larger than its rccc stereoisomer. Clearly, like MeHCH2-6, rctt-MePhCH2 cannot fit
within a fully formed d8r ZnIm2 motif, but assembly of up to half of the d8r may be possible. When
MePhCH2 cavitand, enriched in the rctt stereoisomer (rctt:rccc = 87:13), was used as a template in a
LAG-aging synthesis, the washed product after 5 days proved to be a mixture of nog-ZnIm2 and
xMePhCH2@RHO-Zn16Im32 (Figure 5.vi)). Remarkably, the product was found by 1H NMR
spectroscopy to have incorporated both the rccc and the rctt forms of MePhCH2, in approximately
the same ratio as the starting cavitand mixture (Figure S24). As nog-ZnIm2 is not sufficiently porous
to accommodate either cavitand, we conclude they are embedded within the RHO-ZnIm2 portion of
the product. We hypothesize that, similar to the templation of RHO-ZnBIm2 by MeMeCH2, and
RHO-ZnIm2 by MeHCH2-6, both the rctt cavitand and the rccc cavitand can initiate templation of the
RHO framework through at least partial formation of d8r motifs. Though it may be possible for rccc-
MePhCH2 to be encapsulated by the d8rs, rctt-MePhCH2 clearly cannot be, and therefore must reside
within the LTA cages. Clearly, though, and not surprisingly, rctt-MePhCH2 is not a very effective
template for formation of the RHO-ZnIm2 framework, as a similar amount of nog-ZnIm2 is formed
in this reaction.
It appeared that changes to the upper rim of the cavitand affected the templation of d8rs and
RHO-ZnIm2 more than changes to the bottom rim. Since templation is based on hydrogen bonding
interactions, and the only hydrogen bond donors in the cavitand molecule are the oxygen atoms
nearer the upper rim, this observation is not particularly surprising. The question then remained:
keeping the basic backbone of the cavitand the same (four-membered macrocyclic ring, rccc
stereochemistry, Y = CH2 bridging substituents), are there limitations on the size of substituents on
the upper, R, and lower, R’, rims of the cavitand?
To test this, we first increased the bulk of the lower rim substituents, exploring MeiBuCH2 (R =
Me, R’ = i-Bu, Y = CH2) as a template. The LAG-aging synthesis resulted in mainly
0.3MeiBuCH2@RHO-Zn16Im32 after 16 days of aging, as confirmed by PXRD and NMR analysis
(Figure 5.ii). Similar to 0.2MeMeCH2@RHO-Zn16(Cl2Im)32, only one tenth of the d8rs (or one fifth of
the ‘accessible’ d8r motifs) are occupied by cavitand. This is likely due to the steric bulk of MeiBuCH2,
limiting the amount of cavitand that is ultimately incorporated.
If a phenyl-footed cavitand, namely HPhCH2 (R = H, R’ = Ph, Y = CH2), is used, the LAG-aging
experiment results in 0.8HPhCH2@Zn16Im32 after 12 days of aging, as confirmed by NMR analysis.
The PXRD pattern of this material PXRD is unusual (Figure 5.v) in that the peaks are broad, but the
peak positions are nonetheless almost entirely consistent with the RHO-ZnIm2 framework topology.
The relative intensities of the peaks are unusual as compared to the other RHO-ZnIm2 materials.
Namely, the (100) peak (at 3.06° 2θ), which is very small in PXRD patterns of 1.6MeHCH2@RHO-
Zn16Im32 and 0.9MeMeCH2@RHO-Zn16Im32, is very intense, whereas the (110) peak, which is the
dominant peak in 1.6MeHCH2@RHO-Zn16Im32 and 0.9MeMeCH2@RHO-Zn16Im32, is much broader
and of lower maximum intensity. The pattern more resembles that of 5.8MeHCH2-6@RHO-Zn16Im32,
but is more broad. We hypothesize that these effects could be due to the large quantity of the
relatively bulky HPhCH2 cavitand trapped inside the d8rs of the material. The level of incorporation
of the HPhCH2 is four times that of MeiBuCH2. Though this might seem counterintuitive due to the
fact that a phenyl group contains 6 carbon atoms, and an isobutyl group only 4, the effective total

Molecules 2020, 25, 633 16 of 20
“width” of an isobutyl group is surely larger than that of a phenyl group due to the conformational
degrees of freedom. Whereas the isobutyl group is branched at the C2 position, however, the phenyl
group is branched at C1. Thus, the local steric ramifications (near the eight-rings of the framework)
associated with accommodating the bulky tetraphenyl-substituted end of the cavitand within the d8rs
could cause local twisting and/or ‘breathing’-like structural perturbations of the affected 8-rings of
the framework. Such local structural perturbations may be responsible for broadening of the peaks.
Lastly, the relatively high intensity of the (100) peak may be due to protrusion of the phenyl feet into
the LTA cage.
Finally, we explored H(4MePh)CH2 (R = H, R’ = 4-MePh, Y = CH2) as a putative template.
Compared to HPhCH2, H(4MePh)CH2 is simply rigidly extended at the phenyl feet (R’) by one
methyl group. Remarkably, after 11 days, the LAG-aging reaction products proved to be a mixture
of zinc imidazolates, but mainly cag-ZnIm2 (presumably originally occupied by DEF, Figure 5.ix),
containing no traces of an RHO-ZnIm2 framework product. We therefore conclude that cavitands
with 4-methylphenyl (or longer) feet are too long to successfully template RHO-ZnIm2. The result is
somewhat surprising considering that H(4MePh)CH2 possesses the same core molecular architecture
as HPhCH2, which appears to template formation of an RHO-ZnIm2 product, and the observation
that the ability to be encapsulated by the framework does not seem not to be a prerequisite for a
successful cavitand RHO template.
Having explored the effects of changing the size of substituents on the lower rim ‘feet’ of the
cavitand, we turned toward increasing the size of the upper rim substituents. We employed two
different cavitands in the LAG-aging procedure, namely BrPhCH2 (R = Br, R’ = Ph, Y = CH2) and
BrC5CH2 (R = Br, R’ = n-C5H11, Y = CH2), each possessing bromine atoms at the upper rim. Structural
models suggest that the upper rim bromine atoms may interact favorably with the imidazolate
ligands of the d8r eight-rings. At the lower rim are phenyl groups or n-pentyl substituents. BrPhCH2
has analogous feet to the successful HPhCH2 template, and BrC5CH2 possesses feet with the same
approximate total length of the unsuccessful H(4MePh)CH2 template (five-carbon atoms), but its feet
are flexible. Based on PXRD (Figures 5.iii) and 5.iv) and 1H-NMR analysis, both cavitands successfully
yielded high quality RHO-ZnIm2 framework products, as 0.2BrC5CH2@RHO-Zn16Im32 (after 5 days),
and 0.6BrPhCH2@RHO-Zn16Im32 (after 7 days), respectively. Higher incorporation of the phenyl-
footed cavitand, compared to the pentyl cavitand, follows the trend set by MeiBuCH2 and HPhCH2,
where the flat arene feet seem to allow for greater cavitand incorporation than the nominally smaller
but conformationally flexible, and thus potentially bulkier, aliphatic feet.
3. Materials and Methods
Full details of all experimental procedures and characterizations can be found as Supplementary
Information. In a typical LAG-aging experiment, nanoparticulate zinc oxide, imidazole ligand, the
cavitand template, and DEF were mixed in a 1:2:0.5:4 molar ratio, and milled in a poly(methyl
methacrylate) jar (Form-Tech Scientific, Montreal, QC, Canada) for 2 min at 30 Hz. The MeMeCH2[32]
cavitand was used to template reactions employing 4,5-dichloroimidazole (HCl2Im), benzimidazole
(HBIm), 5-nitrobenzimidazole (HNO2BIm), 5,6-dimethylbenzimidazole (HMe2BIm), and
theophylline (Theo). Nine cavitands were explored as possible templates in reaction with the simple
imidazole (HIm) ligand: HPhCH2 [57], H(4-MePh)CH2 [57], MeHCH2 [55], MeHCH2-6 [55],
MeHSiMe2 [58], MeiBuCH2 [56], MePhCH2 [59], BrC5CH2 [60] and BrPhCH2 [57]. All cavitands were
prepared according to literature procedures[32] and were used in unsolvated form, after drying in a
vacuum oven (Precision Scientific, Chicago, IL, USA) at 120 °C for 24h. The resulting dense paste was
transferred to a 5 mL glass vial and left to age. Reaction progress was monitored by PXRD. When the
reaction had reached completion, as evidenced by the disappearance of ZnO peaks from the PXRD
pattern, the sample was washed extensively with chloroform according to a procedure previously
shown to remove all excess template, and the product was analyzed by PXRD and NMR to confirm
product topology and determine the cavitand incorporation ratio, respectively. Control experiments
were performed for syntheses using HCl2Im and HBIm by conducting the LAG-aging procedure
without the addition of the MeMeCH2 template. Low temperature and pressure (T = 77 K, p < 1 bar)

Molecules 2020, 25, 633 17 of 20
nitrogen adsorption measurements for the synthesized RHO topology zinc 4,5-dichloroimidazolate
and zinc benzimidazolate were performed using a Quantachrome Autosorb 1 (Quantachrome
Instruments, Boynton Beach, Florida, USA; now Anton Paar QuantaTec Inc.) volumetric analyzer.
4. Conclusions
In conclusion, it has been shown that MeMeCH2, a macrocylic cavitand that acts as a ‘shoe-last’
template for framework d8rs in the mechanochemical synthesis of xMeMeCH2@RHO-Zn16Im32 (the
first example of an RHO-ZnIm2 framework ZIF), can be used to accelerate the synthesis of other RHO-
ZnRIm2 frameworks. Employing a LAG-aging templation approach with MeMeCH2 allowed
preparation of 0.2MeMeCH2@RHO-Zn16(Cl2Im)32 (xMeMeCH2@ZIF-71) and RHO-ZnBIm2 (ZIF-11),
the latter framework being prepared by mechanochemical methods for the first time. The
mechanochemically prepared sample of RHO-ZnBIm2 (ZIF-11), which had long been thought to be
nonporous to N2 at 77 K, appears to be open to dinitrogen sorption under these conditions, revealing
it to have a high surface area. It has further been shown that several other related macrocyclic
cavitands—MeHCH2, MeHCH2-6, HPhCH2, MeiBuCH2, BrC5CH2, and BrPhCH2—can serve as
templates for the mechanochemical synthesis of x(cavitand)@RHO-ZnIm2 ZIFs, each being
encapsulated to varying degrees by the framework. Notably, even cavitands that cannot be fully
encapsulated by the d8r motifs in the final products can serve as templates for at least partial assembly
of these motifs and the overall RHO framework topology, and must thereby reside in defect sites or,
more likely, in the LTA cages of the framework. Footed cavitands with rctt stereochemistry, not
surprisingly, act as poor templates for the RHO-ZnIm2 framework, but may still be encapsulated.
Cavitands with bulky—e.g., dimethylsilyl—moieties bridging the resorcinol units appear to inhibit
the C-H···O hydrogen bonding interaction responsible for the templation effect, preventing successful
formation the RHO-ZnIm2 framework. Similarly, bottom rim substituents should be smaller/shorter
than rigid 4-methylphenyl groups. The wide variety of cavitands that can be used for templation of
RHO topology zinc imidazolates with no change in synthetic protocol indicates that cavitand
functionalization might be a good way to introduce desired elements, such as useful functional
groups or catalytically active moieties, into the pores of high porosity RHO-framework ZIFs. More
broadly, the results suggest that a wide array of small molecules may be chosen or designed to direct
the topological outcome in the synthesis of ZIFs susceptible to framework polymorphism. Besides
representing a step forward towards topologically-controlled synthesis of zeolitic metal-organic
frameworks, the presented work is also a notable contribution to mechanochemical and
mechanically-activated synthesis of complex structures, as it represents a still rare example of using
templates to direct the outcome of solvent-less synthetic procedures [61].
Supplementary Materials: Full details of all experimental procedures, assigned 1H-NMR spectra, detailed PXRD
patterns for all prepared materials, and sorption analysis details for 0.2MeMeCH2@RHO-Zn16(Cl2Im)32 and
RHO-ZnBIm2 are available online.
Author Contributions: Conceptualization, I.B. and K.T.H.; methodology, I.B.; formal analysis, I.B.; investigation,
I.B., D.E.D., and C.M.K.; data curation, I.B.; writing—original draft preparation, I.B.; writing—review and
editing, I.B., K.T.H. and T.F.; visualization, I.B.; supervision, K.T.H. and T.F.; project administration, I.B.; funding
acquisition, K.T.H. All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by the NSF (DMR-1610882). IB thanks Georgetown University (Kunin
Fellowship, GSAS Dissertation Research Grant), and the ICDD (Ludo Frevel Scholarship).
Acknowledgments: We thank Dr. Krunoslav Užarević and Dr. Ivan Halasz of InSolido Technologies, Zagreb,
Croatia, EU, as well as Form-Tech Scientific, Montreal, QC, Canada for providing us with milling jars.
Conflicts of Interest: The authors declare no conflict of interest.
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