Controlling the Recognition and Reactivity of Alkyl Ammonium Guests Using an Anion Coordination-Based Tetrahedral Cage

Article abstract of DOI:10.1021/jacs.8b01488

Caged structures have found wide application in a variety of areas, including guest encapsulation and catalysis. Although metal-based cages have dominated the field, anion-coordination-based cages are emerging as a new type of supramolecular ensemble with

Full text of DOI:10.1021/jacs.8b01488

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Controlling the Recognition and Reactivity of Alkyl Ammonium
Guests using an Anion Coordination-based Tetrahedral Cage
Wenyao Zhang, Dong Yang, Jie Zhao, Lekai Hou, Jonathan L. Sessler, Xiao-Juan Yang, and Biao Wu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b01488 • Publication Date (Web): 27 Mar 2018
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Controlling the Recognition and Reactivity of Alkyl Ammonium
Guests using an Anion Coordination-based Tetrahedral Cage
Wenyao Zhang,†,# Dong Yang,†,# Jie Zhao,† Lekai Hou,† Jonathan L. Sessler,‡ Xiao-Juan Yang,†
Biao Wu†*
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† Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education, College of
Chemistry and Materials Science, Northwest University, Xi’an 710069, China, E-mail: wubiao@nwu.edu.cn
‡ Center for Supramolecular Chemistry and Catalysis, Shanghai University, Shanghai 200444, China
ABSTRACT: Caged structures have found wide application in a variety of areas, including guest encapsulation and cataly-
sis. Although metal-based cages have dominated the field, anion-coordination-based cages are emerging as a new type of
supramolecular ensemble with interesting host-guest properties. In the current work, we report a C3-symmetric tris-
bis(urea) ligand based on the 2,4,6-triphenyl-1,3,5-triazine spacer, which assembles with phosphate anions to form an
A4L4-type (A = anion, L = ligand) tetrahedral cage, 3, with unusually high packing coefficients (up to 99.5% for the best
substrate). Cage 3 is able to adjust its size and shape (from 136 to 216 Å3) by bending of the triphenyltriazine plane. This
allows it to accommodate relatively large guests. In the case of DABCO, inclusion within the cage allows the degree of
methylation to be controlled and the monomethylated product to be isolated cleanly under conditions where mixtures of
the mono- and dimethylated adduct are obtained in the absence of cage 3.
Introduction
Compared to metal-organic self-assembled cages, ani-
on-coordination-based supramolecular cages have only
emerged very recently.42-44 Recognizing that the phos-
phate anion (PO43−) can stabilize up to 12 hydrogen bonds
and thus achieve a kind of “coordination saturation”,42-49
our group has developed a strategy for constructing su-
pramolecular architectures wherein phosphate anions
serve as the binding nodes instead of the metal cations
found in more traditional cages.42-44,46,50,51 For instance, by
using C3-symmetric tris(bis-urea) subunits, we prepared
an A4L4-type face-based tetrahedral cage 1, where A de-
notes an anion and L is a linking anion receptor subunit.42
We also showed that the triphenylbenzene-spaced cage 2
(Scheme 1) is capable of encapsulating a wide range of
hazardous halocarbons,43 as well as highly reactive white
phosphorus and yellow arsenic.44
Self-assembled cages with well-defined cavities have at-
tracted considerable interest in recent years due to their
recognized utility in areas as diverse as guest recognition
and separation,1-5 luminescence,6,7 drug delivery,8-10 gas
storage,11-13 and catalysis,14-16 to name a few. Cage systems
have been constructed by exploiting metal coordination,17-
20
covalent bonds (organic cages),21-25 and noncovalent
interactions.26-29 To date, metal-organic M4L6- and M4L4-
type tetrahedral cages have been extensively studied be-
cause they are relatively easy to prepare and exhibit excel-
lent host-guest recognition features.30,31 Cages of this gen-
eral structure have been found to act as effective hosts for
biologically or environmentally important species. They
have been exploited to store hard-to-handle molecules
and have been used to stabilize both reactive species and
reaction intermediates.32-36 Metal coordination-based mo-
lecular containers also allow control over the microenvi-
ronment and have been used to lower the energy barrier
In an effort to explore further the applications of anion-
assembled tetrahedral cages, we designed a new tris(bis-
urea) ligand L (Scheme 1; see Supporting Information for
synthetic details), in which the central triphenylbenzene
backbone employed in the previously reported cage 2 was
replaced by a triphenyltriazine moiety. The incorporation
of an electron-deficient triphenyltriazine subunit was
expected to enhance further the binding interactions be-
tween the ligand L and the anionic phosphate nodes. Rel-
ative to the linker in cage 2, this N-fused aromatic system
is more rigid and more prone to retain planarity due to
the presence of intramolecular hydrogen bonding interac-
tions between the central triazine N atoms and the CH
protons on the phenyl rings. The resulting restricted rota-
tion of the phenyl rings was expected to stabilize for-
for certain chemical reactions.37 For example, Raymond et
12−
al. used
a
Ga4L6
tetrahedron (L
=
1,5-bis(2,3-
dihydroxybenzoylamino)-naphthalene) to promote acid-
catalyzed hydrolyses in strongly basic media,38 and to cat-
alyze alkyl-alkyl reductive eliminations.39 Mukherjee et al.
reported the encapsulation of aromatic nitro-alkenes
(such as 1-(2-nitrovinyl)naphthalene) by an edge-directed
tetrahedron and promotion of Michael addition reactions
involving 1,3-dimethybarbituric acid.40 Nitschke’s group
used an M4L6 cage to prevent the Diels−Alder reaction of
maleimide with encapsulated furan.41
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mation of a tetrahedral cage with a larger central cavity the four C3-symmetric ligands occupy the triangular faces,
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than present in 2.
with contacts consistent with intramolecular hydrogen
bonds between the N atoms of the triazine and the H1
protons of the adjacent phenyl rings being seen (C···N
distances range from 2.768 to 2.853 Å, av. 2.810 Å and the
C−H···N angles range from 99 to 101°, av. 100°). The tri-
phenyltriazine moieties of L are almost planar. The dis-
tances separating the triazine planes from the triangular
faces of the tetrahedron (defined by the phosphorus at-
oms of the three phosphate ions) range from 0.61 to 0.81 Å
9
3−
(Figure 1). The PO43−···PO4
separation distances
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(16.6~17.0 Å, av. 16.7 Å, Figure S35) in 3 are similar to
those in cage 2⊃CH3CN (16.8~17.5 Å, av. 17.1 Å, Figure S34).
Presumably this correspondence reflects the fact that the
triphenyltriazine and triphenylbenzene moieties present
in 3 and 2 are roughly similar in size.
Scheme 1. Assembly of [A4L4]12−-type tetrahedral anion
cages.
In fact, treatment of ligand L with phosphate anion
leads to formation of a relatively large cage, 3 (Scheme 1).
This new cage was found to adjust its size and shape to
accommodate various guests as inferred from single crys-
tal structural studies and spectroscopic analyses. Cage 3
was found to bind several guests with unusually high
packing coefficients, which the latter term is defined in
terms of the ratio of the structurally defined volume of
the guest to that of the free cavity space after removing
mathematically the guest. Presumably as the result of the
tight spatial packing it provides, complex 3 was found to
function as a molecular catalyst capable of controlling the
outcome of certain N-methylation reactions. Here, we
report the synthesis of cage 3, its guest encapsulation
properties, and its use in promoting N-methylation reac-
tions.
Results and Discussion
Synthesis and characterization of the ‘empty’ cage 3
and its TEA+ complex 3⊃TEA+
Treatment of ligand L with an equimolar quantity of
(TBA)3PO4 in acetonitrile gave a clear solution. After sub-
jecting to slow diethyl ether vapor diffusion for about two
weeks,
diffraction
grade
single
crystals
of
(TBA)12[(PO4)4(L)4⊃CH3CN] were obtained, which proved
to be the cage adduct 3⊃CH3CN as inferred from an X-ray
diffraction analysis. Although cage 3 displays an overall
face-based A4L4 tetrahedral structure (Figure 1), slightly
different vertices are seen, presumably reflecting the
presence of the trapped solvent molecules. In the crystal
Figure 1. a) Crystal structure of (TBA)12[(PO4)4(L)4] (cage 3),
with the entrapped solvent molecules (one acetonitrile and
one water) omitted for clarity, b) longest and shortest dis-
tances between the triazine plane and the triangular face of
the tetrahedron defined by the phosphate phosphorous at-
oms.
3−
structure, four fully deprotonated PO4 ions are located
at the four vertices with the same ΔΔΔΔ or ΛΛΛΛ config-
uration. Each tetrahedron is thus homochiral, although
the system as a whole is racemic. As proved true for our
previously reported phosphate-based cage systems, each
The cavity volume of the “empty” cage 3 was estimated
using the VOIDOO52,53 program and 1.2 Å probe and
found to be 136 Å3 (Table S6). This is considerably larger
than the corresponding volume for 2 (87 Å3 based on the
crystal structure of the analogous solvent containing
complex, 2⊃CH3CN; cf. Table S6).54 The estimated interi-
or space within the putative solvent-free triazine-
3−
PO4 anion is coordinated by three bis(urea) arms
through twelve N−H···O hydrogen bonds (the N···O dis-
tances range from 2.707 to 3.020 Å, av. 2.822 Å, and the
N−H···O angles vary from 136 to 169°, av. 159°). Meanwhile,
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modified cage 3 led us to consider that it would be a suit-
able receptor for triethylammonium (TEA+) cation. We
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also postulated that cage 3 would bind the TEA+ cation in
preference over the smaller trimethylammonium (TMA+)
cation. Although detailed tests of specificity were not car-
ried out in the context of earlier work, this latter guest
was found to be accommodated well by cage 2.43 We were
thus keen to test whether the modification in cage struc-
ture, 3 vs. 2, would indeed translate into a selectivity for
larger alkylammonium guests.
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In an initial test of the above hypotheses, the TEA+ (tet-
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raethylammonium) cation was added to 3. The result was
formation
of
a
tetrahedral
cage
complex,
(TEA)11[(PO4)4(L)4⊃TEA] (3⊃TEA+), in which a single
TEA+ ion is encapsulated within the central cavity. In con-
trast to the less symmetric geometry observed for the
‘empty’ cage 3⊃CH3CN, this complex is characterized by a
slightly deflected T symmetry. It has four identical faces
that deviate slightly from a regular triangle (the lengths of
the three edges are 16.04, 16.14, and 16.34 Å, respectively).
The triphenyltriazine moiety within L is distorted; it devi-
ates from the face of the tetrahedron by 1.20 Å where the
distance in question is between the triazine plane and the
triangular face of the tetrahedron as defined by the three
phosphorous atoms (Figure 2). Similar distortions have
been observed in metal-organic frameworks containing
triphenyltriazine spacers.55 This distortion leads to short-
Figure 2. a) Crystal structure of 3⊃TEA+, b) vertical distance
between the triazine plane and the triangular face of the tet-
rahedron. Note: Peripheral cations and solvent molecules
have been omitted for clarity.
3−
er PO43−···PO4 separations (16.0~16.3 Å, av. 16.1 Å, Figure
S35) than those seen in the substrate-free cage 3⊃CH3CN
(16.6~17.0 Å, av. 16.7 Å, Figure S35). The bending of the C3
planes is ascribed to an ability of the cage to adopt so as
to encapsulate effectively the TEA+ cation. This cation is
situated at the center of cage 3 with each of the four ter-
minal methyl groups pointing to one peripheral phenyl
ring of the triphenyltriazine with the methylene units
oriented toward the PO43− ions (Figure 2).
Solution phase studies of cage 3 and its TEA+ complex
The formation of cage 3 in solution was supported by 1H
NMR spectroscopic studies carried out in DMSO-d6. This
solvent choice was dictated by the poor solubility of L in
less polar solvents. In DMSO-d6, the urea NH signals of L
in 3 resonate at lower field (Δδ = 2.42~3.63 ppm) com-
pared to the free ligand. Such shifts are typical of what is
Based on an analysis of the metric parameters, the TEA+
guest is held within cage 3 by a combination of weak in-
teractions. In addition to an electrostatic effect, the con-
tacts seen between the terminal TEA+ CH3 groups and the
aryl rings of ligand L (2.771~2.998 Å, av. 2.925 Å) provide
evidence for CH···π interactions.56 The protons of the
TEA+ CH2 units appear to form CH···N hydrogen bonds
(C···N distance is 3.88 Å) with the N atoms of the triazine
of ligand L (Figure S28). To provide for charge balance,
eleven additional TEA+ cations are located close to the
cage. These counter cations appear to interact with the
bridging subunits as inferred from the X-ray structural
analysis (Figure S29). Compared to these ‘peripheral’
TEA+ ions, the N-CCH2-CCH3 bond angle of the entrapped
TEA+ is larger (155° for trapped the TEA+ guest and
108~118°, av. 114° for the peripheral TEA+ cations). The
N−C and C−C bond lengths of the trapped TEA+ guest
(1.38 and 1.27 Å) are much shorter than those of the pe-
ripheral TEA+ guests (N−C: 1.38~1.53 Å, av. 1.48 Å and
C−C: 1.48~1.56 Å, av. 1.52 Å). This remarkable shortening
of the bond lengths leads us to conclude that significant
compression of the TEA+ cation takes place when trapped
in cage 3.
3−
seen for constructs where PO4 anions interact with
bis(urea) moieties through hydrogen bonding.42,43 The
proton signals of the aryl rings also differ from what is
seen for the free ligand (Figure S21). For example, the pro-
tons H8/7/4/5 resonate at higher field, presumably as the
result of a shielding effect, whereas the signals for H2/3/6
shift downfield because of an inferred decrease in the
electron density resulting from anion binding (see
Scheme 1 for proton numbering). The presence of only
1
one set of H NMR signals is consistent with the for-
mation of a single, highly symmetric species (i.e., cage 3).
The high-resolution ESI mass spectrum (HR ESI-MS spec-
trum) of cage 3 (with TBA+ or [K([18]crown-6)]+ used as
the counter cation) was characterized by the presence of
intense signals corresponding to [A4L4] species, including
those at m/z = 1950.9017 (x = 8), 1499.8827 (x = 7),
1199.3764 (x = 6) and m/z = 1828.9111 (x = 8), 1414.6742 (x =
7), 1138.5191 (x
[(PO4)4L4([18]crown-6)xKx]–(12–x)
[(PO4)4L4TBAx]–(12–x) (Figure S95), respectively.
=
6) corresponding to complexes
(Figure S93) and
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Evidence for the formation of the encapsulated product
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(TEA)11[(PO4)4(L)4⊃TEA] (complex 3⊃TEA+) was also seen
in DMSO-d6 solution. For instance, the H1/H2 signals (see
Scheme 1 for proton numbering) of the phenyl rings in the
triphenyltriazine backbone of L are split into two broad
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Packing coefficients for cage 3
The volume of 3⊃TEA+ (215 Å3), evaluated using the
VOIDOO program, is considerably greater than that
found for 3⊃CH3CN using the same method (136 Å3; vide
supra). The volume of the entrapped TEA+ cation itself
was calculated to be about 181 Å3, which is somewhat
smaller than the value for the TEA+ cations found outside
the cage (193−195 Å3). Similar conclusions are drawn using
the DFT optimized structures (cf. Figure S116). Thus, the
occupancy ratio (also referred to as the packing coeffi-
cient) for 3⊃TEA+ is 181 Å3/215 Å3 × 100% = 84%.
1
peaks in the H NMR spectrum of 3⊃TEA+. This splitting
is attributed to the asymmetric environment of the tri-
phenyltriazine moiety, which reflects the fact that the
terminal CH3 groups of the encapsulated TEA+ guest do
not point to the center of triphenyltriazine (Figure 3).
Signals resonating at −0.01 ppm that are ascribed to the
TEA+ CH2 protons and shifted upfield by Δδ = −3.22 ppm,
as well as those observed at −1.73 ppm (Δδ = −2.88 ppm),
corresponding to the CH3 protons, are taken as evidence
for a strong shielding effect provided by the cage. Another
group of upfield shifted signals is seen for the peripheral
TEA+ guests (Δδ = −0.20 ppm for CH2 and Δδ = −0.14 ppm
for CH3) reflecting a modest shielding effect resulting
from association with 3.51,57 A key point is that is possible
in this way to distinguish the bound guest from other like
species.
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It has been reported that for optimal encapsulation, the
ratio of the guest volume to the host cavity volume should
fall within the 55% ± 9% range.58 Although packing coeffi-
cients exceeding this target range have been observed in
some cases, especially when there are strong interactions
and a good geometric match between the host and the
guest, as a general rule high encapsulation ratios are cor-
related with novel host-guest properties.59,60 To the best
of our knowledge, the packing coefficient for 3⊃TEA+
matches the highest value reported to date59 and could
reflect the conformational changes that accompany guest
binding (e.g., bending of the triphenyltriazine planes as
seen in the solid state structure discussed above). In other
words, the high occupancy ratio seen for 3⊃TEA+ may
benefit from a kind of “induced fit” binding phenome-
non.61,62
Host-guest chemistry of cage 3 with different types of
cations
To evaluate further the ability of cage 3 to undergo con-
formational changes to accommodate cationic guests,
four classes of ammonium salts with different sizes and
1
shapes were tested (Figure 5). The H NMR spectra of the
inclusion complexes 3⊃guest were recorded after 1.0 equiv
of the cation in question were added to 3⊃CH3CN in
CD3CN. In all cases, upfield shifts in the signals corre-
sponding to the entrapped guests were observed in the 1H
NMR spectra. Presumably, these shifts reflect the shield-
ing provided by the aromatic rings (Figures S36-S50). The
signals corresponding to H1 and H2 of the phenyl moie-
ties making up the triphenyltriazine core in L showed
differing degrees of upfield (−0.30 to −0.43 ppm) or down-
field (0.47 to 0.65 ppm) shifts, respectively; again, this is
ascribed to the strong CH···π interactions between the
hydrogen atoms of the trapped guest and the aryl rings
present in L. HR ESI-MS measurements also provide sup-
port for the formation of cages of general structure
3⊃guest (Figures S96-S103).
Figure 3. 1H NMR spectrum of (TEA)11[(PO4)4(L)4⊃TEA]
(complex 3⊃TEA+) (400 MHz, DMSO-d6, 296 K).
Further support for this conclusion came from 2D
NOESY spectral studies. Cross-peaks are observed be-
tween the urea NH protons and H8/H4,H5, H7/H4,H5,
H7/H3,H6 and H8/H3,H6. These cross-peaks are rational-
ized in terms of close contacts between the nitrophenyl
and o-phenylene rings in solution, a conclusion con-
sistent with the solid-state structure. The signals for pro-
tons Hα (CH2) and Hβ (CH3) of the trapped TEA+ show
strong through-space interactions with H1 and H2, con-
firming the proposed interactions between cage 3 and the
trapped TEA+ guest (Figures S53, S54). The HR ESI-MS
spectrum of 3⊃TEA+ also supports formation of a tetrahe-
dral cage. Specifically, intense peaks at m/z = 1026.1817 (x
= 6), 1257.4414 (x = 7), and 1604.5928 (x = 8) correspond-
ing to various [A4L4(TEA)] species, such as
[(PO4)4L4(TEA)x]–(12–x), are seen (cf. Figure 4).
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Figure 4. HR ESI-MS spectrum of (TEA)11[(PO4)4(L)4⊃TEA] (complex 3⊃TEA+).
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The second class of guests (Type-II in Figure 5) consists
of asymmetric tetraalkylammonium ions with sizes in-
termediate between those of TMA+ and TPA+; it includes
N1112+, an ammonium cation that contains three N-methyl
groups and one N-ethyl substituent on the central N at-
+
om, N2333 with one ethyl and three propyl groups, as well
as other putative guests of varying size (the subscripted
numbers represent the number of carbon atoms on each
of the four alkyl groups of R4N+).64 All of these cations can
be encapsulated by cage 3, as inferred from the large up-
1
field shifts observed in the corresponding H NMR spec-
tra: Δδ = −2.72~−3.26 ppm for N1112+, Δδ = −2.77~−3.17 ppm
for N1122+, Δδ = −3.10~−3.61 ppm for N1113+, Δδ = −2.82~−3.12
ppm for N1222+, Δδ = −2.76~−3.50 ppm for N2223+, Δδ =
+
−2.83~−3.14 ppm for N2233 and Δδ = −2.42~−3.38 ppm for
N2333+. However, for the largest member of this class, the
ethyltripropylammonium cation, N2333+, with a calculated
V = 287 Å3, only 10% of the available cages were occupied
+
by the guest when 2 equiv of N2333 were added to a
1
CD3CN solution of cage 3 (1 mM) as deduced from H
Figure 5. The four types of cationic guests considered in this
study.
NMR spectroscopic integrations. For the same initial con-
centration of 3, the occupancy increased to 27% upon the
+
addition of a large excess (30 equiv) of N2333 (cf. Figure
S44). In comparison, the second largest diethyldiprop-
ylammonium, N2233+, with a calculated V = 257 Å3 dis-
played a much higher level of 3⊃ N2233+ complex formation
(ca. 95% for a 1 mM solution of 3 in the presence of 2.0
equivalents of the guest, Figure S43). Under otherwise
identical solution phase conditions, essentially complete
encapsulation was seen for the smaller Type-II cations,
even in the presence of only 1.0 equivalent of the guest in
question.
The first type of guest cation includes TMA+, TEA+,
TPA+ and TBA+ (Type-I in Figure 5). These are regular
symmetric tetrahedra and encompass the tetramethyl-
and tetraethylammonium substrates analyzed in the solid
state in the case of 243,44 and 3, respectively. In the case of
3, both smaller guests (i.e., TMA+ and TEA+) are readily
encapsulated into the cage in CD3CN as evidenced by the
large upfield shifts of the signals corresponding to the
trapped TMA+ (Δδ = −2.84 ppm) and TEA+ (Δδ = −3.17
ppm for CH2; −2.86 ppm for CH3) guests in the relevant
1H NMR spectra.63 The peaks ascribed to H1 and H2 also
undergo broadening when 3 is treated with either TMA+
or TEA+. Such a finding is consistent with the cage inter-
acting with these entrapped guests. In contrast, no evi-
dence of encapsulation by 3 was seen in the case of TPA+
and TBA+ cations. Presumably, these cations are not
bound appreciably in deuterated acetonitrile under the
conditions of the 1H NMR spectral analysis.
The above results, wherein the TPA+ cation with four
propyl groups is not appreciably bound but the slightly
+
smaller N2333 (one ethyl and three propyl groups) conge-
ner is weakly bound by cage 3, lead us to consider that the
maximum number of C and N atoms that can be accom-
modated within cage 3 might be 12. However, in addition
to this presumed size limitation, there could be further
constraints imposed by the shape of the guest. To explore
this latter possibility, a third type of quaternary ammoni-
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um guest (Type-III in Figure 5) was studied. Here, three of
of binding was found in the case of the corresponding
dimethylated species, MeDMe2+. On the other hand, ASN+
1
2
3
4
5
6
7
8
the substituents were fixed as methyl groups while the
fourth was allowed to vary considerably. This class of pos-
sible guests thus includes the butyltrimethylammonium
(N1114+), trimethyl(2-methoxyethyl)ammonium (N111.1O2+),
and isobutyltrimethylammonium (N111.I4+) cations. Based
on spectroscopic studies analogous to those noted above,
it was concluded that none of these three guests could be
encapsulated within cage 3. This proved true even though
is encapsulated within cage 3 (Δδ = −2.67 ~ −3.19 ppm;
+
+
Figures S48-S50). Except for the larger N2233 and N2333
cationic guests, the proposed encapsulation was further
supported by HR ESI-MS studies.
To compare the relative binding affinities of these cati-
onic species, competitive experiments were carried out by
adding concurrently two different guests (1 equiv of each)
to cage 3 and then comparing the signals of the entrapped
guests. On the basis of these competition experiments
(specific permutations tested are listed in Table S1), the
+
the N1114 cation (containing a combination of 8 C+N at-
9
oms) is smaller than the TEA+ cation (containing a total
of 9 C+N atoms). Replacing the n-butyl group in N1114+ by a
presumably more flexible methoxyethyl substituent (giv-
ing N111.1O2+) did not provide a guest that was appreciably
bound by cage 3. A similar absence of binding was seen
when the n-butyl chain was replaced by an isobutyl group
(giving guest N111.I4+). On the basis of these findings we
conclude that both total volume and shape play a role in
dictating the encapsulation process. The underlying selec-
tivity permits construction of a logic gate truth table; it is
shown in Table 1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
following approximate order of binding affinities was de-
+
duced (strongest to weakest binding): TEA+ > N1222
>
>
MeD+ > N1122 > N2223 > N1112 > TMA+ > N1113 > N2233
+
+
+
+
+
ASN+ > N2333+. Figure 6 shows the underlying data in his-
togram fashion and is designed to illustrate a binding
trend that first increases as the cation increases in size
from TMA+ to TEA+ but then becomes weaker as the guest
becomes larger. The effect of shape were also inferred
from these studies.60 For instance, TEA+ and MeD+ pos-
sess the same number of atoms. However, the tetrahedral
TEA+ cation is bound more strongly; presumably, this
reflects a better shape complementarity with cage 3.
Table 1. Logic gate truth table reflecting the inclusion
selectivity of cage 3 towards quaternary ammonium
cations (A, B, C, D represent the number of non-
hydrogen atoms on the four branches of the central
nitrogen atom). The abbreviations "I" and "O" refer
to "iso-" and "oxygen", respectively.
INPUT
OUTPUT
A
1
B
C
1
D
1
TMA+
1
1
1
1
+
+
N1112
1
1
2
2
2
2
3
3
3
3
3
4
4
4
+
N1122
1
1
2
2
2
2
3
3
3
1
1
+
N1222
1
2
2
2
2
3
3
1
1
TEA+
2
2
2
2
3
1
1
+
N2223
1
+
Figure 6. Histogram designed to illustrate the relative bind-
ing affinities cage 3 displays towards various cations (TMA+,
N1112+, N1122+, MeD+, N1222+, TEA+, N2223+, N1113+, N2233+, ASN+,
N2333+) as inferred from 1:1 competition studies carried out in
CD3CN.
N2233
1
+
N2333
1
TPA+
0
1
+
N1113
+
Isothermal titration calorimetry (ITC) was used to ob-
tain quantitative binding data for several test cations in
CH3CN. Good fits were seen to a 1:1 binding profile in the
case of N2233+, TMA+ and TEA+. This allowed Ka values of
4.87 × 104 M−1, 1.10 × 106 M−1, and 1.61 × 108 M−1 to be calcu-
lated for these three guests, respectively (cf. Supporting
Information, Figures S90-S92). These values are fully con-
sistent with the qualitative inferences of relative affinities
N111.1O2
1
1
1
0
0
0
+
N1114
1
1
1
+
N111.I4
1
1
1
Three bicyclic cations with a similar number of non-
hydrogen atoms as present in TEA+ were also tested (cf.
the species designated as Type-IV in Figure 5). Two of
1
these
putative
guests
are
methylated
1,4-
deduced on the basis of the H NMR spectroscopic ex-
diazabicyclo[2.2.2]octane (DABCO, abbreviated as ‘D’)
derivatives, namely 1-methyl-DABCO (abbreviated as
MeD+) and 1,4-dimethyl-DABCO (MeDMe2+), while the
third member of the class is azoniaspiro[4.4]nonane
(ASN+). While MeD+ could readily be included within
cage 3 (as inferred from the large upfield shifts seen in the
1H NMR spectrum: Δδ = −2.88 ~ −3.09 ppm), no evidence
change studies discussed above.
+
Crystal structure of the inclusion complex 3⊃N2223
A salient feature of cage 3 is that it appears able to cap-
+
ture guests, such as N2333 whose calculated volume (287
Å3), exceeds that of the cation-free cage (215 Å3). This abil-
ACS Paragon Plus Environment

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Journal of the American Chemical Society
−2.68 ppm for CH3) in the 1H NMR spectrum. Competitive
ity is thought to reflect the self-adjusting nature of the
1H NMR spectroscopic studies were then carried out using
cages 2 and 3 and the TMA+ and TEA+ cations, respective-
ly. On the basis of the induced shifts observed, it was
concluded that cage 3 encapsulates better the TEA+ cation
(Δδ = −3.17 for CH2 and Δδ = −2.86 ppm for CH3), while
cage 2 shows a preference for the TMA+ cation (Δδ = −2.87
ppm). The corresponding relative equilibrium constants,
Krel,66 are 0.05 for 2⊃TEA+/2⊃TMA+, and 31.1 for
3⊃TEA+/3⊃TMA+ (cf. Figures S78 and S58 in the Support-
ing Information for details of the underlying calcula-
tions). This is true even though the gross structure, if not
the cavity sizes, of the two cages are ostensibly similar (cf.
Figures S34 and S35).
1
2
3
4
5
6
7
8
cage, which undergoes conformational changes to ac-
commodate guests of different sizes and shapes. Support
for the protean nature of cage 3 came from single crystal
X-ray diffraction studies of 3⊃N2223+, in which the guest
+
N2223 contains one more carbon atom than TEA+. The
resulting structure (Figure 7a) is similar to that of the
TEA+ complex (3⊃TEA+). Comparable N−H···O hydrogen
bond parameters involving the phosphate anions and
urea groups of the ligand L are seen. For instance, the
N···O distances are in the range of 2.721−3.056 Å, av. 2.817
Å, whereas the N−H···O angles range from 143º to 169º, av.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
159º. However, the cage in complex 3⊃N2223 is character-
ized by a lower symmetry (C3) than in 3⊃TEA+. The en-
+
capsulated N2223 cation is also located close to one of the
triangular faces of the tetrahedron rather than in the cen-
ter of cavity as it is in 3⊃TEA+ (the deviation of N2223+ from
the center of the cage is 0.80 Å). The ‘basal’ plane closest
+
to the N2223 cation is curved (by 1.49 Å, representing the
distance between the triazine and the plane formed by
three phosphate phosphorus atoms; cf. Figure 7) com-
pared to the other three much flatter faces (bent by 0.91
Å, Figure S33). The extent of basal plane bending is larger
than what is seen in the TEA+ analogue (1.20 Å; cf. Figure
3−
S32). In 3⊃N2223+, the PO43−···PO4 separations (16.6−16.8
Å, av. 16.7 Å) are slightly longer than those in the 3⊃TEA+
(16.0~16.3 Å, av. 16.1 Å). On this basis, we conclude that
cage 3 adjusts its size and shape to accommodate the
asymmetric N2223+ guest.
The cavity volume of cage 3 in the inclusion complex
+
3⊃N2223 (216 Å, calculated from the crystal structure data
+
by removing mathematically the guest N2223 from the
cage) was estimated by the VOIDOO program using a 1.2
Å probe.53 This is a slightly higher value than that (215 Å3)
calculated from the crystal structure of 3⊃TEA+. The vol-
ume of the entrapped N2223 cation is about 215 Å3 based
+
on the structural data.65 On the basis of these experi-
mental values, the occupancy ratio is >99% (215 Å3/216 Å3
× 100% = 99.5%). When a smaller probe (1.0 Å) was used,58
the cavity volume estimated for cage 3 (235 Å3) increases
slightly. Nevertheless, even taking this into account, the
occupancy ratio remains high (215 Å3/235 Å3 × 100% =
91.4%). We thus conclude that cage 3 is able to accom-
modate the N2223+ cation with very high packing efficiency.
+
Figure 7. a) Crystal structure of 3⊃N2223 and b) separation
between the triazine plane and the triangular face of the tet-
rahedron (the indicated values correspond to the longest and
shortest vertical distances).
Comparison of the guest inclusion properties of cag-
es 2 and 3
The recognition features of the analogous tri-
phenylbenzene-derived cage 2 were tested with repre-
sentative quaternary ammonium cations so as to permit
comparisons with cage 3. First, we sought first to test if
cage 2, which was found to form a complex with the
TMA+ cation, would also encapsulate the larger congener-
ic tetraalkylammonium cation, TEA+. This is not some-
thing that had been tested in the context of the original
studies. It was found that addition of 1 equiv of TEA+ ions
to the “empty” cage 2 (i.e., 2⊃CH3CN) in CD3CN led to
large upfield shifts (i.e., Δδ = −3.25 ppm for CH2 and Δδ =
Further support for this inferred preference came from
an experiment wherein cage 2, cage 3, TMA+, and TEA+
were mixed together in a 1:1:1:1 molar ratio in CD3CN in
1
the same NMR tube. The H NMR spectrum of this mix-
ture exhibited two groups of upfield-shifted signals, in
which the signals at −0.06 and −1.65 ppm were very simi-
lar to those observed for cage 3⊃TEA+ and the other sig-
nal (at 0.28 ppm) was the same as that found for cage
2⊃TMA+. In contrast, signals corresponding to cage
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2⊃TEA+ (at −0.02 and −1.47 ppm) and to cage 3⊃TMA+ (at
0.31 ppm) were not visible in this H NMR spectrum. On
1
1
Table 2. Results of competitive guest encapsulation
studies involving cages 2 and 3.
2
3
4
5
6
7
8
9
this basis, we conclude that under the conditions of this
NMR spectroscopic study, cages 2 and 3 selectively encap-
sulate TMA+ and TEA+, respectively (Figure 8). These re-
sults were also supported by HR ESI-MS analyses (cf. Fig-
ures S104-S106).
Guest
TMA+
Cage 2 (%)a
67.6
44.3
33.9
27.7
15.5
Cage 3 (%)a
32.4
+
N1112
55.7
The relative binding affinities of cages 2 and 3 were de-
termined by challenging the receptors with the same
guest. For these experiments, both cages 2 and 3 were
dissolved in CD3CN and treated with the test guest in an
overall 1:1:1 ratio within the same NMR tube. The encapsu-
lation ratio of the guest cations in the two different cages
was then calculated from the integrals of the signals cor-
responding to the entrapped guests. On this basis, it was
concluded that cage 2 encapsulates the TMA+ cation in
preference to other guests, while larger guests were en-
capsulated preferentially by cage 3 (Table 2). The ASN+,
+
N1113
66.1
+
N1122
72.3
+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N1222
84.5
TEA+
MeD+
13.4
13.3
86.6
86.7
88.3
+
N2223
11.7
+
N2233
0b
50.3
ASN+
0b
0b
26.4
2.9
+
N2333
+
+
N2233 and N2333 cations are not appreciably encapsulated
a
Note: Ratios involving each guest in question were de-
within cage 2; however, these guests are trapped by cage
3.
1
termined by H NMR spectral integrations. Experiments
were carried out in at least duplicate. Further details are
b
provided in the Supporting Information. No evidence of
guest encapsulation was seen
Catalytic methylation reactions regulated by cage 3
Given the unique alkyl ammonium guest inclusion
properties of cage 3, we set out to explore whether it
could be used to regulate reactions involving such species
or leading to their preparation. We were particularly keen
to explore N-methylation reactions. N-methylation reac-
tions, including those involving DNA, RNA and histone,
play a key role in biology.67-69 The degree and site of
methylation conveys biological information, such as sig-
naling transcriptional activation or repression, and ab-
normal methylation can serve as a cancer trigger.70 As
noted above, cage 3 acts as a receptor for monomethyl-
substituted DABCO (MeD+) cation but not the corre-
sponding dimethylated species, MeDMe2+. We thus con-
sidered it likely that cage 3 could be used as a "supramo-
lecular protecting group" to control the nature of the al-
kylation products when DABCO is allowed to react with
iodomethane. In the absence of cage 3, treatment with
CH3I gives rise to both MeD+ and MeDMe2+. Cage 3, capa-
ble of encapsulating MeD+, was expected to preclude fur-
ther reaction with iodomethane thus preventing for-
mation of doubly substituted product, MeDMe2+.
Figure 8. a) Schematic illustration of the proposed selective
encapsulation of TMA+ and TEA+ ions by cages 2 and 3, re-
spectively; b) 1H NMR spectra of cage 2⊃TEA+; cage 2⊃TMA+;
2:3:TMA+:TEA+ = 1:1:1:1; cage 3⊃TEA+; cage 3⊃TMA+ (from top
to bottom; 400 MHz, CD3CN, 296 K).
Support for the above hypothesis came first from a
room temperature experiment wherein 1.0 molar equiv of
iodomethane was added to a solution of DABCO in the
presence of cage 3 (1 equiv). Under these conditions, only
the singly methylated MeD+ species is formed. This prod-
uct is encapsulated within the cage, as inferred from NMR
spectroscopic analyses. Upon further addition of 9.0 equiv
of CH3I to this mixture, the MeD+ product remained un-
changed within the cage. In contrast, in the absence of
cage 3, the initial mono-methylated product MeD+ con-
tinues to react. It gives the dimethyl-substituted adduct,
MeDMe2+ upon the further addition of CH3I resulting in a
The above findings are rationalized in terms of the size
of the cages in question. As noted above, the relatively
planar nature of the triphenyltriazine spacer leads to a
significantly larger internal space when used to prepare
cage 3 (136 Å3) than does the corresponding triphenylben-
zene-based analogue used to prepare 2 (87 Å3). However,
the fact that cage 3 can undergo guest-induced expansion
may also contribute to its ability to capture larger guests.
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Journal of the American Chemical Society
ASSOCIATED CONTENT
mixture of mono- and dialkylated species the exact com-
1
2
3
4
5
6
7
8
position of which depends on the reaction conditions
(Figures S107, S108). Similar results were obtained at ele-
vated temperatures. For instance, when an excess (10
equiv) of iodomethane was added to DABCO at 50 °C in
the presence of cage 3, only one group of upfield-shifted
signals corresponding to trapped MeD+ was seen in the 1H
NMR spectrum (Figure 9b). Conversely, two sets of sig-
nals corresponding to MeD+ and MeDMe2+, respectively,
Supporting Information.
Experimental details including synthesis of the guest-
inclusion complexes, figures showing the crystal structures,
NMR and ESI-MS studies, and crystal data in the CIF format.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
1
were observed in the H NMR spectrum in the absence of
9
Corresponding Author
cage 3 (Figure 9a). We thus infer, that selective
monomethylation can be achieved in the presence of cage
3 over a range of reaction conditions.71,72 Finally, it was
found that the encapsulated MeD+ could be readily re-
leased from the cage upon the addition of 2.0 equiv of
TEA+ (Figure S109). Thus, the protection provided by cage
3 allows for the clean production of MeD+. This monoal-
kylated product can then be isolated readily by exploiting
the preferential recognition features of cage 3.
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60
* wubiao@nwu.edu.cn
Author Contributions
# W.Z. and D.Y. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the National Natural Science
Foundation of China (21602173, 21325102, 21772154 and
21271149) and the Natural Science Foundation of Shaanxi
Province (16JS111). Support from Shanghai University for the
Center for Supramolecular Chemistry and Catalysis is also
acknowledged.
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