Endohedral Hydrogen Bonding Templates the Formation of a Highly Strained Covalent Organic Cage Compound**

Article abstract of DOI:10.1002/chem.202005276

A highly strained covalent organic cage compound was synthesized from hexahydroxy tribenzotriquinacene (TBTQ) and a meta-terphenyl-based diboronic acid with an additional benzoic acid substituent in 2’-position. Usually, a 120° bite angle in the unsubstituted ditopic linker favors the formation of a [4+6] cage assembly. Here, the introduction of the benzoic acid group is shown to lead to a perfectly preorganized circular hydrogen-bonding array in the cavity of a trigonal-bipyramidal [2+3] cage, which energetically overcompensates the additional strain energy caused by the larger mismatch in bite angles for the smaller assembly. The strained cage compound was analyzed by mass spectrometry and ¹H, ¹³C and DOSY NMR spectroscopy. DFT calculations revealed the energetic contribution of the hydrogen-bonding template to the cage stability. Furthermore, molecular dynamics simulations on early intermediates indicate an additional kinetic effect, as hydrogen bonding also preorganizes and rigidifies small oligomers to facilitate the exclusive formation of smaller and more strained macrocycles and cages.

Full text of DOI:10.1002/chem.202005276

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&
Cage Compounds |Hot Paper|
Endohedral Hydrogen Bonding Templates the Formation of a
Highly Strained Covalent Organic Cage Compound**
[a, b]
[b]
[a, b]
[b]
[a, b]
Natalie Schäfer,
Michael Bühler, Lisa Heyer,
Merle I. S. Rçhr, and Florian Beuerle*
In memory of Carsten Schmuck
Abstract: A highly strained covalent organic cage com-
pound was synthesized from hexahydroxy tribenzotriquin-
acene (TBTQ) and a meta-terphenyl-based diboronic acid
with an additional benzoic acid substituent in 2’-position.
Usually, a 1208 bite angle in the unsubstituted ditopic linker
favors the formation of a [4+6] cage assembly. Here, the in-
troduction of the benzoic acid group is shown to lead to a
perfectly preorganized circular hydrogen-bonding array in
the cavity of a trigonal-bipyramidal [2+3] cage, which ener-
getically overcompensates the additional strain energy
caused by the larger mismatch in bite angles for the smaller
assembly. The strained cage compound was analyzed by
1
13
mass spectrometry and H, C and DOSY NMR spectroscopy.
DFT calculations revealed the energetic contribution of the
hydrogen-bonding template to the cage stability. Further-
more, molecular dynamics simulations on early intermedi-
ates indicate an additional kinetic effect, as hydrogen bond-
ing also preorganizes and rigidifies small oligomers to facili-
tate the exclusive formation of smaller and more strained
macrocycles and cages.
Introduction
synthesized. Potential applications for these porous molecular
[
10]
[11]
[12]
materials
gas storage
range from molecular recognition,
sensing,
[1]
[8i,13]
[14]
[15]
Subcomponent self-assembly is a powerful tool for the one-
pot-synthesis of complex nanoarchitectures directly from
simple precursors. Depending on the interactions that connect
and separation, to self-sorting, encapsula-
[
16]
[17]
tion
and reactivity control
of large aromatic guests. In
terms of complexity, rigid cages offer the tempting potential
to hierarchically organize multiple functionalities with high
spatial precision around the cage scaffold. Exohedral function-
[2]
the individual building blocks, supramolecular, metal–organ-
[3]
[4]
ic or dynamic covalent structures have been reported. For
design purposes, geometrical concepts such as the directional
[
18]
alization at the outer surface typically impacts the solubility
[
5]
[8f,19]
bonding approach allow control over geometry and topology
of the obtained scaffolds, as these properties are directly en-
or solid-state packing
of these modular porous units. Ulti-
mately, the implementation of cross-linkable functions in the
cage periphery can lead to covalently linked ‘cage-to-frame-
[
6]
coded in the molecular structure of the building blocks. In
[
7]
[20]
recent years, a large variety of covalent organic cages with
work’ materials. On the other hand, endohedral functionali-
[
8]
[9]
[21]
different size, shape and topology have been designed and
zation of cages is less explored. Besides chemical stabiliza-
[
22]
tion via post-synthetic modification, sixfold ether synthesis
[
23]
[
a] N. Schäfer, L. Heyer, Priv.-Doz. Dr. F. Beuerle
Institut für Organische Chemie, Julius-Maximilians-Universität Würzburg
Am Hubland, 97074 Würzburg (Germany)
within an imine cage and alkyne cages with inward-pointing
[24]
pyridines have been reported. Besides chemical modulation
of the pores, cavity-directing functional sites might be utilized
to template specific cage geometries or could interfere with
each other during the assembly process. To date, template-as-
E-mail: florian.beuerle@uni-wuerzburg.de
[
b] N. Schäfer, M. Bühler, L. Heyer, Dr. M. I. S. Rçhr, Priv.-Doz. Dr. F. Beuerle
Center for Nanosystems Chemistry (CNC)
[
25]
Julius-Maximilians-Universität Würzburg
Theodor-Boveri-Weg, 97074 Würzburg (Germany)
sisted synthesis
of covalent organic cage compounds has
been rarely addressed. With proper choice of functional precur-
sors however, switching between different cage geometries
might be realized.
[
**] A previous version of this manuscript has been deposited on a preprint
server (https://doi.org/10.26434/chemrxiv.13353257.v1).
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.202005276.
Results and Discussion
ꢀ
2021 The Authors. Chemistry - A European Journal published by Wiley-
VCH GmbH. This is an open access article under the terms of the Creative
Commons Attribution Non-Commercial NoDerivs License, which permits
use and distribution in any medium, provided the original work is properly
cited, the use is non-commercial and no modifications or adaptations are
made.
Here, we report on the serendipitous formation of a highly
PhCOOH
strained [2+3] molecular cage A C
from hexahydroxy tri-
3
2
[18]
[
26]
benzotriquinacene (TBTQ) A and terphenyl diboronic acid
PhCOOH
derivative C
through the formation of six boronate esters
Part of a Special Collection on Noncovalent Interactions.
under water-removing conditions. DFT calculations suggest
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that the three endohedral PhCOOH groups in the trigonal-bi-
pyramidal cage are perfectly preorganized for intramolecular
hydrogen bonding, which overcompensates the additional
strain energy in relation to larger [4+6] assemblies (Figure 1).
In prior work, we reported on a series of shape-selective co-
valent organic cage compounds derived from orthogonal
dehyde (1) and carboxylic acid (4) starting materials. Here, we
PhCOOH
synthesized a novel linker C
possessing a PhCOOH sub-
stituent in 2’-position as an endohedral recognition site and a
tBuPh group in 5’-position to further enhance the solubility of
[
26,27]
the final assemblies. Diiodide 5
was synthesized in two lit-
erature-known steps and reacted to bispinacol ester 6 by two-
[18,15b]
TBTQ A and diboronic acids with varying bite angles.
2
For
’-methyl-[1,1’:3’,1’’-terphenyl]-4,4’’-diboronic acid (C ) pos-
sessing a 1208 bite angle at the central phenylene unit, tetra-
fold Miyaura borylation. Treatment of 6 with BBr followed by
3
Me
aqueous workup resulted in simultaneous cleavage of both pi-
nacol and methyl ester protecting groups to give diboronic
Me
6
PhCOOH
Me
PhCOOH
hedral A4C
cages were obtained as the only detectable self-
acid C
in 76% yield. As C and C
have very similar
Me
assembly product. Since the six bent C linkers are octahe-
drally distributed around the cage pore, all Me groups in 2’-po-
sition are located within the cage cavities, whereas any sub-
stituent in 5’-position would point to the outside of the cages.
Aiming for functionalized cavities, we envisioned the attach-
ment of supramolecular binding sites, for example, COOH
groups within the cage cavities. Based on a procedure intro-
bite angles between the two boronic acids, we initially expect-
ed a similar behavior in dynamic covalent reactions with cate-
chol-containing precursors such as A. However, subtle effects
caused by slight differences in solubility or rotational freedom
for the attached phenylene units cannot be ruled out entirely.
For initial investigations regarding cage formation, we ap-
[
15b]
plied our established protocol
and monitored the reaction
[27]
PhCOOH
duced by Hçger and co-workers, we applied a modular syn-
thetic approach (Scheme 1) that allows for easy modifications
of linkers C at both 2’- and 5’-position by proper choice of al-
of A and C
in THF in the presence of 4Š molecular sieves
1
Me
by H NMR spectroscopy (Figure S15). In contrast to A C 6, we
4
did not observe the quantitative formation of a closed boro-
nate ester assembly. Instead, rather broad signals and signifi-
cant amounts of free catechols were observed even after pro-
longed reaction times and further addition of molecular sieves.
MALDI-TOF mass spectrometry (MS) of the reaction mixture
showed the two most prominent signals at m/z=1883.24 and
2
382.70 (Figure S17), which correspond to smaller
PhCOOH
+
PhCOOH
+
[
A2C
2+Na] and [A2C
3+Na] assemblies containing
only two TBTQ units in a [2+3] cage or [2+2] macrocycle, re-
spectively. This somewhat unexpected finding contradicts the
[
5]
directional bonding approach, which predicts a tetrahedral
4+6] assembly for the combination of a tritopic 908 and a di-
[
Me [15b]
topic 1208 linker as it was realized for A4C 6.
As we did not
Me
observe notable precipitation in both reactions with C and
PhCOOH
C
, it is rather unlikely that the different outcome is
PhCOOH
caused by solubility issues. For C
instead, a closer look at
the structure of the molecular components and the MALDI-
Figure 1. Supramolecular templation of strained covalent organic cages.
TOF MS data for the reaction mixture suggests a strong preor-
PhCOOH
ganization of two or three C
molecules via hydrogen
bonding between the COOH groups, which favors the forma-
tion of the strained [2+2] macrocycles and [2+3] cage assem-
blies. In order to break these hydrogen bonds and to induce
the formation of larger assemblies, e.g., [4+6] cages, we also
attempted cage synthesis in the presence of up to two equiva-
PhCOOH
1
lents of AcOH, referred to C
. However, H NMR (Fig-
ure S16) and MALDI-TOF mass spectra looked identical as for
the reaction without AcOH (Figure S15), thus indicating the
strong driving force for supramolecular preorganization. How-
ever, no full conversion to the stoichiometric cage product was
achieved, as usually observed for binary mixtures in 2:3
[
18,15b]
ratio.
Both [2+2] macrocycles and [2+3] cages were si-
multaneously obtained as the two main products, accompa-
nied by significant amounts of open oligomers. Presumably,
additional strain is induced when closing the macrocyclic
PhCOOH
[
2+2] intermediate with a third linker C
, thus shifting the
PhCOOH
Scheme 1. Modular synthesis of diboronic acid C
2
3 2
: i) BF ·OEt , 1008C,
[28]
equilibrium towards the macrocyclic fragment, which still pos-
[27]
[29]
h, 38%; ii) 4 /NaOH, MeOH, 30 min, then Ac
iii) B pin /KOAc/Pd(dppf)Cl , DMF, reflux, 2.5 h, 71%; iv) BBr
.75 h, 76%.
2
O, 1608C, 2 h, 55%;
sesses two unreacted catechol units. In order to facilitate full
2
2
2
3
, CH Cl
2
2
, 08C!rt,
PhCOOH
3
conversion and isolation of A2C
3, we screened for opti-
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PhCOOH
mized reaction conditions. Finally, reaction of A and C
in
MeCN/THF 10:1 under reflux for 24 hours (Scheme 2) resulted
in precipitation of a crude product. Resolvation of the isolated
material in [D ]MeOH induced complete disassembly into the
4
1
monomeric building blocks. Based on H NMR integration, the
PhCOOH
measured ratio of A/C
=2:3 indicates the predominant
formation of a closed-shell [2+3] or [4+6] assembly rather
than open [2+2] macrocycles or other oligomeric side prod-
ucts. MALDI-TOF MS for the isolated product (Figure 2c) re-
PhCOOH
vealed only one set of signals at m/z=2323.29 [A C
3-
2
+
PhCOOH
+
C H +Na] ,
2340.29
] , 2364.27
[A2C
[A2C
-C H +K] ,
2357.32
4
9
3
4
9
+
PhCOOH
+
PhCOOH
[
[
A2C
A2C
+Li]
3
and 2381.31
3
3
PhCOOH
+
PhCOOH
+Na] that were all assigned to A2C
and vari-
3
ous monocationic adducts. Remarkably, the very high tendency
for adduct formation with alkali metal ions indicates that the
endohedral array of COOH groups might serve as an efficient
binding station for metal ions.
In contrast to the reaction in THF under equilibrating condi-
tions (Figure S17), the absence of signals for other assemblies
PhCOOH
confirms the isolation of pure A2C
cages from reaction
3
in MeCN. Presumably, closed-shell cages in MeCN are signifi-
cantly less soluble than the more polar open intermediates,
thus driving the dynamic formation of boronate esters towards
PhCOOH
completion. Finally, A2C
cages are kinetically trapped by
3
precipitation. After filtration and subsequent washing with
MeCN and n-hexane, the raw product was further purified by
suspending it in dry acetone for four hours at 608C to obtain
PhCOOH
cage A2C
in pure form. After work-up, the isolated cage
3
1
was soluble in CHCl3 and the H NMR spectrum (Figure 2a)
shows only one single peak at 4.55 ppm for the TBTQ bridge-
head proton, thus further confirming the formation of one
single cage species. Integration of protons corresponding to
PhCOOH
either TBTQ A or linker C
A/C
confirmed the expected ratio of
PhCOOH
=2:3, whereas the occurrence of one single set of
peaks for all chemically distinguishable protons argues for a
1
PhCOOH
Figure 2. a) Aromatic region of H NMR spectrum (400 MHz, rt) for A
2
C
3
highly symmetrical assembly.
PhCOOH
(CDCl
3
), C
([D
8
]THF) and 6 (CDCl
3
), b) DOSY NMR (600 MHz, CDCl
3
, rt;
PhCOOH
In comparison to precursors 6 (in CDCl ) and C
(in
3
inset shows PM6-minimized space-filling model with the solvodynamic di-
[
D ]THF), there is a striking upfield shift of roughly 0.5 ppm for
ameter indicated as a semi-transparent gray sphere) and c) MALDI-TOF MS
8
PhCOOH
for A
2
C
3
.
the aromatic protons of the PhCOOH substituents that are lo-
cated in the cage cavity. We attribute this effect to additional
shielding by the p-surface of the cage interior and, primarily,
efficient hydrogen bonding between the closely arranged
PhCOOH groups. For the acidic protons, a broad and barely
detectable signal at 10.9 ppm was observed. To estimate the
cage size and ultimately differentiate between a [2+3] or
[
4+6] assembly, the solvodynamic diameter was determined
via DOSY NMR measurements (Figure 2b). In CDCl , a diffusion
3
À10
2
À1
constant of 3.43”10 m s was obtained for the monodis-
perse cage species. According to the Stokes-Einstein equation,
this value correlates to a solvodynamic diameter of 2.3 nm,
[
30]
which is in very good agreement with a PM6 -minimized
space filling model (depicted as a semi-transparent sphere in
PhCOOH
Figure 2b). Cage A2C
shows a considerably smaller diam-
3
Me
eter than the previously reported tetrahedral cage A C
(d=
6
4
PhCOOH
[15b]
Scheme 2. Synthesis of A
2
C
3
: i) THF/MeCN 10:1, reflux, 24 h, 64%.
3.0 nm),
even though the protruding tBuPh substituents in
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PhCOOH
5
’-position at the bent linkers C
are expected to result in
tent field method using the integral equation formalism model
[
33]
[34]
even larger values for the tetrahedral [4+6] assemblies, thus
ultimately proving the formation of the smaller [2+3] cage.
Remarkably, the simple exchange from Me to PhCOOH as
endohedral substituent completely switched the cage size
from a [4+6] to a [2+3] assembly and the geometrical arrange-
ment of the linkers C from octahedral to trigonal planar, re-
spectively. To evaluate if these selectivities are driven by differ-
ent thermodynamic stabilities, we performed geometry optimi-
(IEFPCM)
as implemented in the Gaussian 16
quantum
chemical software package. Again, an energy difference of
À1
+62 kJmol was calculated, indicating that the equilibrium
between the two cages is hardly affected by solvation but
rather a consequence of the inherent stability of the individual
cage geometries. In accordance with the directional bonding
approach, this selectivity is matched in the synthetic experi-
ment and is most presumably related to the inherent strain
energy induced by the larger mismatch in the bite angles and
[
31]
zations employing DFT calculations with the wB97XD func-
[32]
Me
tional and the def2-SVP basis set for cages in tetrahedral
a significant bending in the three struts for C (see Figure 3a).
Me
PhCOOH
[
4+6] and trigonal-bipyramidal [2+3] geometry for both C
For C
however, DFT optimization in the gas phase re-
PhCOOH
and C
. In order to decrease the computational demand,
vealed a completely reversed thermodynamic driving force, as
PhCOOH
À1
the apical nBu substituents in A were replaced by Me groups
and the exohedral tBuPh groups in 5’-position for C
the theoretical results indicate A2C
to be À207 kJmol
3
PhCOOH
were
more stable in electronic energy than the larger [4+6] assem-
replaced by H atoms, as these groups are located on the outer
cage surface and should not influence the inherent cage stabil-
bly (Figure 3a). For calculations with the MeCN continuum
À1
model, this energy difference is reduced to À150 kJmol , indi-
Me
ity or preference for a specific topology. For C , a formal
cating the pronounced stabilization of polar COOH groups in
polar aprotic solvents such as MeCN. The geometry-optimized
structures for both A C cages show a very good overlap for
Me
Me
transformation of one A4C into two A2C
cages revealed a
6
3
À1
difference in electronic energies of +60 kJmol in the gas
phase, indicating a significantly higher thermodynamic stability
for the larger cage (Figure 3a). To adjust for any solvation ef-
fects, we simulated MeCN as solvent by applying a self-consis-
4
6
the cage backbone (Figure S21a). As a response to the pore
filling with the internal hydrogen bonding array of the
PhCOOH groups, a slight deviation was observed for the A2C3
cages (Figure S21b). Therefore, we conclude that the inherent
strain induced by the rigid scaffold of a specific cage stoichi-
ometry does not depend on the inner substituents. However,
attractive supramolecular interactions between the endohedral
PhCOOH groups in the cage pores overcompensate the higher
PhCOOH
strain energy for the A2C
cage.
3
To further probe this stabilizing contribution, we performed
relaxed scans for the endohedral substituents in both geome-
tries (Figure 3b). For this purpose, we constructed model sys-
tems containing six and three benzoic acid molecules in the
respective octahedral (A C ) or trigonal-planar (A C ) arrange-
4
6
2 3
ment. To artificially adjust for varying cage sizes, we systemati-
cally scanned the distance of all COOH groups from the center
of mass for both model systems. During these constrained op-
timizations, all benzoic acid molecules were kept fixed at the
CÀH unit in 4-position (indicated as orange boxes in Figure 3b)
to simulate the rigid character of the cage pores, while the
molecules itself were allowed to structurally relax. The ob-
tained potential energy profiles presented in Figure 3b show
that the actual arrangement of the three PhCOOH groups in
PhCOOH
A2C
is very close to the energetically most favorable dis-
3
PhCOOH
tance, while the separation in the larger A4C
is very far
6
from the potential minimum. Essentially, there is no attractive
interaction between the COOH groups at a distance of 7.49 Š
PhCOOH
from the focal point in A4C
, whereas the A C scaffold
2 3
6
preorganizes the COOH groups almost perfectly for a circular
threefold hydrogen-bonding motif (see inset in Figure 3a). To
quantify this stabilizing interaction, we reoptimized the three-
fold array with DFT and the MeCN continuum model at both
the distance realized in the cage and the most distant arrange-
ment as reference. From the electronic energies, a binding
Figure 3. a) Equilibria between tetrahedral A
4 6
C and trigonal-bipyramidal
2 3
A C
cages with endohedral Me (top) and PhCOOH (bottom) functionaliza-
tion (electronic energies and geometry-optimized models derived from DFT
calculations, H atoms are omitted for clarity); b) potential energy plots for
À1
energy of À104 kJmol was calculated. Assuming that the in-
PhCOOH
the assembly of six or three PhCOOH moieties as realized in A
4
C
6
and
PhCOOH
Me
PhCOOH
herent strain in A C
is the same as for the empty A C 3,
2
A C
3
, respectively (the actual distance in the DFT-optimized cages is in-
2
3
2
À1
dicated in red).
a stabilizing contribution of À106 kJmol per cage was esti-
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mated from the reaction equations in Figure 3a. The very
good agreement between these two values further corrobo-
rates the subtle balance between the geometrical strain dis-
tributed in the cage backbone and any stabilizing interactions
within the cage cavities.
with one of the PhCOOH units forming a hydrogen bond to
the opposite boronate ester (Figure S24). However, as this
À1
structure is approximately 18 kJmol higher in energy than
the U-shaped arrangement, this metastable conformer is pre-
sumably only populated in neglectable amounts. For a more
Besides the hydrogen-bond mediated thermodynamic driv-
ing force for the formation of the more strained [2+3] cages,
kinetic effects might also play a role, as hydrogen bonding
could already fixate early intermediates during cage formation,
thus directing any further reactions towards more strained
specific analysis, we used one representative starting configu-
PhCOOH
ration for AC
to calculate an ensemble of ten trajectories
2
with randomly generated initial velocities based on a Maxwell–
Boltzmann distribution at room temperature (Figure S23).
Again, all simulations were quickly trapped in the two fixed ge-
ometries and the distance of the free boronic acids stayed con-
stant for the remaining simulation. The average BÀB distance
smaller assemblies. As a key intermediate, we identified bisbo-
PhCOOH
ronate ester AC
2, since hydrogen bonding between the
PhCOOH moieties might severely restrict rotational motions in
this molecule. To test this hypothesis, we performed molecular
for the prearranged U-shaped conformer of intermediate
PhCOOH
AC
is very close to the value of 9.6 Š calculated for the
2
Me
PhCOOH
dynamics (MD) simulations for both AC
and AC
with
2
DFT-optimized structures of the two isomers of the macrocycle
2
[30]
[35]
PhCOOH
the semi-empirical PM6 method along with the D3H4 cor-
rection for an adequate description of hydrogen bonding and
A2C
2, which is assumed to act as the next intermediate
within the mechanism of cage formation.
[
36]
dispersion as implemented in the MOPAC2016
program
Therefore, we postulate an additional kinetic effect that
favors the preorganization of the building blocks towards the
facile synthesis of the strained [2+2] macrocycle. Hereby, the
formation of larger macrocycles, for example, [3+3] or [4+4] is
prevented, which are essential on-pathway intermediates in
the synthesis of the larger tetrahedral [4+6] cages. Interesting-
ly, DFT calculations showed that the trans-isomer is
suite. As a measure for preorganization, we plotted the B-B dis-
tance of the two remaining unfunctionalized boronic acid moi-
eties. For both structures, ten MD trajectories at 298 K with
randomly generated starting configurations were calculated for
1
ns (see Figure 4 for one selected example for each structure
PhCOOH
Me
and Figure S22 for all trajectories for AC
2). For AC 2, the
À1
structure appeared to be rather flexible and a wriggling
À17 kJmol more stable than the cis-isomer (Figure 4b). Since
motion with a large variation of the B-B distance for the boron-
the [2+3] cage can only be formed via the less preferred cis-
isomer, the trans-macrocycle serves as a resting state, thus pre-
venting further ring closure to the even more strained [2+3]
cage assemblies. These subtle energy differences might be the
explanation for the pronounced occurrence of the [2+2] mac-
rocycles while performing the reactions under equilibrium con-
PhCOOH
ic acids ranging from 14 to 35 Š was observed. For AC
2
however, after a short time period of 100 ps, most trajectories
were trapped in a U-shaped structure with a fixed B-B distance
of around 13 Š (Figure 4a). Few simulations resulted in the
population of an even more compact structure (d =5.3 Š),
BÀB
ditions in THF (see Figures S15 and S16). Dynamic covalent re-
PhCOOH
action of A/C
in a 1:1 ratio in THF further confirmed the
inherent stability of the macrocyclic intermediates. MALDI-TOF
MS of the reaction mixture predominantly showed signals at
m/z=1843.37 and 3745.94, which can be assigned to [2+2] as-
PhCOOH
+
PhCOOH
+
semblies [A2C
-H O+H] and [2·A2C
+Na] , re-
2
2
2
PhCOOH
spectively (Figure S18). In particular, no evidence for A2C
3
or other larger assemblies was found.
Me
Me
6
For the A/C reaction mixture, A4C is the only observable
product despite a significant mismatch between optimal (1418)
Me
and actual (1208) bite angle for the linker C . Therefore, strain
energy is released in a social self-sorting experiment for a A/
Me
n
C /D mixture (D=2,5-di- butyl-1,4-diboronic acid) by forming
Me
[15a,b]
the mixed A4C D cage as the predominant product.
To
4
2
probe the effect of the endohedral PhCOOH groups on the for-
mation of mixed cages, we performed a similar self-sorting ex-
PhCOOH
periment for A/C
/D by dissolving the building blocks in
[
D ]THF in a 4:4:2 ratio, followed by the addition of 4Š molecu-
8
lar sieves as water removing agent. Progress of the reaction
1
was monitored by H NMR spectroscopy and MALDI-TOF MS.
Me
Me
PhCOOH
In contrast to A/C /D, no formation of mixed cages was ob-
Figure 4. a) Molecular dynamics calculations of AC
2
(black) and AC
2
Me
(
8
green) for 1 ns at 298 K (1–3 display structures for AC
2
at 250, 500 and
at 1 ns; yellow dashed lines indi-
cate the B-B distance for the free boronic acids, the yellow line in the graph
served but rather narcissistic self-sorting into binary assemblies
PhCOOH
00 ps, 4 displays structure for AC
2
(
Figure 5). MALDI-TOF MS of the reaction mixture confirms the
[18]
concurrent formation of the cubic cage A D
(m/z=5953.83
(m/z=1882.95 for
2
PhCOOH
8
12
indicates the B-B distance in macrocyclic A
2
C
2
); b) equilibrium between
(structures and electronic energies derived from
DFT calculations, H atoms are omitted for clarity).
+
PhCOOH
PhCOOH
for [A D +Na] ), macrocycle A C
8 2
cis- and trans-A
2
C
2
12
PhCOOH
+
PhCOOH
[A2C
+Na] ) and closed-shell cage A C
(m/z=
3
2
2
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PhCOOH
PhCOOH
Figure 5. a) Narcissistic self-sorting for A/C
/D reaction mixture; b) MALDI-TOF MS for reaction of A, C
and D in 4:4:2 ratio in THF at room tempera-
ture and in the presence of 4Š molecular sieves.
PhCOOH
+
PhCOOH
2
382.35 for [A2C
+Na] ) with no evidence for any mixed
with 1208 diboronic acid C
in 2:3 molar ratio in MeCN. As
3
assemblies. Apparently, molecular recognition of the COOH
we have shown in previous work, the bite angle of 1208 for
PhCOOH
groups via the pronounced stabilization of C
-containing
the ditopic linker C would usually trigger the assembly of tetra-
PhCOOH
assemblies by intramolecular hydrogen bonding enforces nar-
hedral [4+6] cages. For C
however, pre-organization in
PhCOOH
cissistic self-sorting of the linkers C
and D into separated
dimers or trimers via intermolecular hydrogen-bonding be-
tween the COOH groups induces the formation of strained
boronate ester bonds in smaller macrocycles and cages.
hydrogen-bonded structures and cubic cages, respectively. For-
1
mation of A D was also observed in the H NMR spectrum of
8
12
PhCOOH
1
13
the reaction mixture (Figure S19). Alongside, linker C
was
cage and open olig-
3
MALDI-TOF MS and H, C and DOSY NMR confirmed the for-
mation of a highly symmetrical closed-shell assembly with the
PhCOOH
distributed between the closed A C
2
PhCOOH
omers such as A C
in a similar manner as for the A/
2
hydrodynamic radius being in good agreement with a PM6-
2
PhCOOH
PhCOOH
C
mixture, thus indicating that the self-sorted system is
minimized model for A2C
3. DFT calculations with a MeCN
under thermodynamic equilibrium.
continuum model revealed that there is indeed a stabilizing
À1
Based on both experimental and computational results, we
contribution of À106 kJmol for the circular threefold hydro-
PhCOOH
PhCOOH
rationalize the observed formation of the strained A2C
cage as follows. For reactions in THF, we assume reversible
gen bonding motif in the cavity of A C
, which overcom-
3
2
3
À1
pensates the implemented strain energy of +62 kJmol when
formally transforming one [4+6] into two [2+3] cages. This
model system illustrates the limitations of the directional
bonding approach for the prediction of cage geometry and
topology through geometrical considerations for the molecular
precursors. Supramolecular interactions between attached
functional units and with solvent molecules can strongly influ-
ence the stability and formation pathways for complex dynam-
ic covalent assemblies, thus giving access to structures that are
normally not preferred. MD simulations on small oligomeric in-
termediates showed that there is also a kinetic contribution to
boronate ester formation, at least for the initial steps. For
PhCOOH
C
, smaller assemblies, e.g., [2+3] cage, [2+2] macrocycles
or [1+2] open fragments, are significantly stabilized compared
to larger [4+6] cages due to intramolecular hydrogen bonding.
However, the subtle balance between hydrogen bonding and
inherent strain energy results in a rather complex equilibrium
mixture and no clear preference for one specific product. From
PhCOOH
reactions in MeCN, A2C
is isolated in pure form as the
3
only kinetic product due to significant lower solubility of the
closed cage compared to other fragments with unreacted
polar catechol or boronic acid groups. Just recently, a detailed
the observed selectivity, since intramolecular hydrogen bond-
[37]
PhCOOH
mechanistic study on [2+3] imine cages revealed the influ-
ence of different solvents on the exchange dynamics between
isostructural cages indicating that kinetic trapping of the final
assemblies might play a much bigger role as initially assumed
in dynamic covalent cage formation.
ing in AC
already facilitates the formation of strained
2
[2+2] macrocycles via fixation of preferential conformers. The
PhCOOH
PhCOOH
pronounced tendency of A2C
and A2C
to form ad-
3
2
ducts with monocations in MALDI-TOF MS experiments show-
cases the potential of these cages as ionic receptors. In future
work, the implementation of switchable recognition sites
within the cage pores could be utilized for a stimuli-responsive
assembly of cages with different shapes and geometries.
Conclusions
A highly strained [2+3] trigonal-bipyramidal boronate ester
cage has been synthesized by reacting hexahydroxy TBTQ A
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13
C NMR (101 MHz, CDCl , rt): d=167.23, 150.91, 144.54, 144.51,
Experimental Section
3
1
42.30, 140.73, 137.43, 136.74, 134.35, 131.82, 129.40, 128.85,
Chemicals and solvents were purchased from commercial suppliers
Alfa Aesar, Merck, Acros, Abcr, Fischer and Sigma–Aldrich and were
used without further purification. Solvents were distilled prior to
use. CH Cl and DMF were dried with the solvent purification
128.56, 127.78, 126.98, 126.01, 83.91, 52.07, 34.73, 31.49,
25.02 ppm; FTIR (ATR): n˜ =660 (s), 829 (m), 1087 (m), 1143 (m),
À1
1276 (m), 1359 (s), 1608 (m), 1719 (m), 2977 (w) cm ; MS (MALDI-
+
+
2
2
TOF, DCTB in CHCl , pos): m/z=748.41 [M] , 771.40 [M+Na] ; ele-
3
system “PureSolv MD 7” from Inert Technology. TLC sheets ALU-
GRAM Xtra SIL G/UV254 were purchased from Macherey–Nagel.
Column chromatography was carried out with individually packed
glass-columns of different sizes (silica, grain-size 40–63 mm, Ma-
cherey–Nagel). NMR spectra were recorded on a Bruker Avance III
mental analysis calcd (%) for C H B O : C 77.02, H 7.27; found: C
76.52, H 7.43.
48
54
2
6
PhCOOH
Diboronic acid C
: Under nitrogen atmosphere, bispinacol
4
00 or 600 spectrometer. Chemical shifts are indicated in ppm
ester 6 (800 mg, 1.07 mmol, 1.0 equiv) was dissolved in dry CH Cl
2 2
using the residual protonated solvent signal as internal standard
(88 mL) and cooled to 08C. BBr3 (910 mL, 2.41 g, 9.62 mmol,
9.0 equiv, d=2.65 gmL ) was added dropwise and the solution
1
13
À1
(
H NMR: 7.26 ppm for CDCl and 1.72 ppm for [D ]THF; C NMR:
3
8
7
7.16 ppm for CDCl and 67.21 ppm for [D ]THF). Signal multiplici-
was stirred for one hour at 08C, then two hours and 45 minutes at
room temperature. Water (100 mL) was added to quench the reac-
tion and the mixture was stirred overnight at room temperature.
The mixture was extracted with EtOAc (3”50 mL) and the com-
bined organic phases were washed with water (100 mL) and brine
and dried over Na SO . The solvent was removed under reduced
3
8
ties are denoted as s (singlet), d (doublet), t (triplet), m (multiplet)
and br (broad). Processing of the raw data was performed with the
[36]
program Topspin 3.0. MALDI-TOF mass spectra were recorded on
a ultrafleXtreme Bruker Daltonics (matrix: trans-2-(3-(4-tertButyl-
phenyl)-2-methyl-2-propenylidene)-malononitrile, DCTB). ESI mass
spectra were recorded on a micrOTOF focus spectrometer from
Bruker Daltonics GmbH. Infrared spectra were taken on a Jasco FT/
IR-430. Elemental analyses were performed on an Elementar CHNS
2
4
pressure and the remaining solid was suspended in CH Cl
2
2
(150 mL) and treated in an ultrasonic bath, before it was filtrated
and washed with CH Cl (40 mL) and n-hexane (40 mL) to obtain
2
2
PhCOOH
9
32 analyzer.
C
as a beige solid (465 mg, 815 mmol, 76%). m.p. 222.18C
1
(
decomposition); H NMR (400 MHz, [D ]THF, rt): d=11.19 (b, 1H,
8
All geometry-optimizations for the cages, macrocycles and inter-
mediates were performed with density functional theory (DFT),
using the wB97XD functional and the def2-SVP basis set. Addi-
tionally, a self-consistent reaction field method using the integral
equation formalism model (IEFPCM) was used to simulate the sol-
4’/6’
3
COOH), 7.68 (s, 2H, H ), 7.66 (d, JHH =8.6 Hz, 2H, HOOCPh-H),
7.62 (d, JHH =8.6 Hz, 2H, tBuPh-H), 7.58 (d, JHH =8.2 Hz, 4H,
H
3
3
[31]
[32]
3
/5/3’’/5’’
3
2/6/2’’/6’’
), 7.49 (d, J =8.6 Hz, 2H, tBuPh-H), 7.08 (m, 8H, H
/
HH
3
B(OH) ), 6.95 (d, J =8.6 Hz, 2H, HOOCPh-H), 1.35 (s, 9H, C(CH3)3);
2
HH
13
[33]
[34]
C NMR (101 MHz, [D ]THF, rt): d=167.48, 151.24, 145.56, 144.22,
8
vent MeCN
as implemented in the Gaussian 16
quantum
1
1
43.50, 141.48, 138.50, 137.81, 134.28, 132.61, 129.77, 129.44,
29.25, 128.89, 127.59, 126.51, 35.18, 31.68 ppm; FTIR (ATR): n˜ =
chemical software package. Relaxed scans and molecular dynamics
simulations were performed in the framework of the semi-empiri-
cal PM6 method along with the D3H4 correction for an ade-
quate description of hydrogen bonds and dispersion by using the
MOPAC2016 program suite. In order to decrease the computa-
tional demand, the tBuPh substituents in C were replaced by H
atoms and the nBu chains in TBTQ A were replaced by Me groups
in all DFT and molecular dynamics calculations.
[30]
[35]
555 (m), 657 (m), 704 (m), 826 (m), 1017 (m), 1335 (s), 1607 (m),
À1
1
694 (m), 2960 (w), 3393 (br) cm ; MS (ESI-TOF, MeOH/MeCN,
À
[36]
neg): m/z=569.22 [MÀH] ; elemental analysis calcd (%) for
C H B O ·0.5 H CCOOCH CH : C 72.34, H 5.91; found: C 72.16, H
35
32
2
6
3
2
3
5
.93.
[
27]
[29] [28]
[18]
Compounds 3, 4,
5
and A have been synthesized accord-
PhCOOH
Cage A2C
ronic acid C
3: TBTQ A (20.0 mg, 46.3 mmol, 1.0 equiv) and dibo-
ing to previously published procedures.
PhCOOH
(39.6 mg, 69.4 mmol, 1.5 equiv) were dissolved in
Bispinacol ester (6): Under nitrogen atmosphere, B pin2 (1.19 g,
THF (0.5 mL). MeCN (5 mL) was added and a violet precipitate
formed. The suspension was stirred for 24 hours at 908C. After
cooling down to room temperature, the solid was filtrated and
washed with MeCN (5 mL) and n-hexane (10 mL). Then, the raw
2
4
.68 mmol, 2.5 equiv), Pd(dppf)Cl (205 mg, 281 mmol, 0.15 equiv),
2
KOAc (1.10 g, 11.2 mmol, 6.0 equiv) and diiodide
5 (1.40 g,
1
.87 mmol, 1.0 equiv) were dissolved in dry DMF (120 mL) and
stirred at 908C for two hours and 30 minutes. Afterwards, DMF was
removed under reduced pressure. The remaining solid was sus-
pended in water (170 mL), treated in an ultrasonic bath for 40 mi-
nutes, filtrated and washed with water (150 mL) to remove the re-
maining DMF. Then, the solid was dissolved in EtOAc and filtrated
over celite to remove the catalyst. The solvent was again removed
under reduced pressure before the remaining solid was dissolved
product was stirred in dry acetone (9 mL) for 4 hours at 608C and
PhCOOH
the remaining solid was filtrated to obtain cage A2C
as a
3
light pink solid (34.8 mg, 14.7 mmol, 64%). m.p. >2308C (decom-
1
position); H NMR (400 MHz, CDCl , rt): d=10.92 (s br, 3H, COOH),
3
4’/6’
3
3
7.80 (s, 6H, H ), 7.71 (d, J =8.5 Hz, 6H, tBuPh-H), 7.65 (d, J
8.3 Hz, 12H, H
18H, HOOCPh-H/TBTQ-Ar-H), 7.13 (d, JHH =8.3 Hz, 12H, H
=
HH
HH
3/5/3’’/5’’
3
), 7.53 (d, J =8.5 Hz, 6H, tBuPh-H), 7.20 (m,
HH
3
2/6/2’’/6’’
),
3
in a minimum amount of CHCl and impurities were precipitated
6.53 (d, J =8.5 Hz, 6H, HOOCPh-H), 4.56 (s, 6H, TBTQ-CH), 2.01
3
HH
by addition of n-hexane. The precipitate was filtered over a mem-
brane filter and the solvent of the mother liquor was removed
under reduced pressure. The remaining solid was dissolved in a
minimum amount of EtOAc and the product was precipitated with
n-hexane, filtrated, and carefully washed by dropwise addition of
(m, 4H, CH CH CH CH ), 1.38 (m, 35H, C(CH ) /CH CH CH ), 0.90 (t,
2
2
2
3
3 3
2
2
3
3
13
JHH =7.1 Hz, 6H, CH CH ppm; C NMR (151 MHz, CDCl , rt): d=
2
3)
3
169.30, 151.01, 148.42, 145.16, 145.07, 142.25, 140.26, 140.02,
139.73, 137.56, 134.04, 130.77, 129.92, 128.22, 127.09, 126.10,
125.71, 125.53, 124.20, 107.87, 67.21, 60.51, 40.06, 34.78, 31.52,
26.55, 23.55, 14.27 ppm; FTIR (ATR): n˜ =553 (s), 662 (s), 831 (m),
cold EtOAc (3 mL) to obtain bispinacol ester 6 as a beige solid
1
(
1.00 g, 1.34 mmol, 71%). m.p. 193.58C; H NMR (400 MHz, CDCl ,
1017 (m), 1067 (m), 1328 (s), 1607 (m), 1689 (m), 2964 (w), 3384
3
4
’/6’
À1
rt):
tBuPh-H/H
8
3
d
=
3
7.67 (m, 4H, MeOOCPh-H/H ), 7.62 (m, 6H,
(br) cm ; MS (MALDI-TOF, DCTB in CHCl , pos): m/z=2323.29426
3
/5/3’’/5’’
3
3
+
+
+
), 7.49 (d, J =8.6 Hz, 2H, tBuPh-H), 7.11 (d, J
), 6.95 (d, J =8.6 Hz, 2H, MeOOCPh-H), 3.87 (s,
H, COOCH ), 1.37 (s, 9H, C(CH ) ), 1.34 (s, 24H, BOC(CH ) ) ppm;
=
[M-C H +Na] , 2340.28800 [M-C H +K] , 2357.31661 [M] ,
4 9 4 9
2381.47 [M+Na] ; elemental analysis calcd (%) for
HH
HH
2
/6/2’’/6’’
3
+
.2 Hz, 4H, H
HH
C157H120B6O ·8H O: C 75.32, H 5.48; found: C 75.24, H 5.45.
3
3 3
3 2
18
2
Chem. Eur. J. 2021, 27, 6077 – 6085
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Chemistry—A European Journal
doi.org/10.1002/chem.202005276
[
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Keywords: boronate esters · cage compounds · density
functional calculations
hydrogen bonding
·
dynamic covalent chemistry
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Manuscript received: December 9, 2020
Revised manuscript received: January 31, 2021
Accepted manuscript online: February 2, 2021
Version of record online: March 3, 2021
Chem. Eur. J. 2021, 27, 6077 – 6085
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6085 ꢀ 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH