Ammonium Complexes of Orthoester Cryptands Are Inherently Dynamic and Adaptive

Article abstract of DOI:10.1021/jacs.9b01350

Fluxional chemical species such as bullvalene have been a valuable source of inspiration and fundamental insight into the nature of chemical bonds. A supramolecular analogue of bullvalene, i.e., a "fluxional host-guest system", in which the ensemble of a well-defined host and guest is engaged in continuous, degenerate constitutional rearrangements, is still elusive, however. Here, we report experimental and computational evidence for guest-induced dynamic covalent rearrangements in the ammonium complexes of self-assembled orthoester cryptands. This unique behavior is made possible by the ammonium guest playing a dual role: it is sufficiently acidic to initiate dynamic covalent exchange reactions at the orthoester bridgeheads, and as a hydrogen bond donor it acts as a supramolecular template, governing the outcome of a multitude of possible intra- and intermolecular rearrangement reactions. One particularly striking example of inherent dynamic behavior was observed in host-guest complex [NH₄⁺o-Me₂-2.1.1], which spontaneously rearranged into the larger and thermodynamically more stable complex [NH₄⁺o-Me₂-2.2.1], even though this process led to the formation of poor host o-Me₂-1.1.1 as a consequence of the excess of one subcomponent (diethylene glycol; "1" in our nomenclature). These inherently adaptive host-guest networks represent a unique platform for exploring the interrelationship between kinetic and thermodynamic stability. For instance, as a result of optimal NH₄⁺ binding, complex [NH₄⁺o-Me₂-2.2.1] was found to be thermodynamically stable (negligible intermolecular rearrangements over weeks), whereas computational studies indicate that the compound is far from kinetically stable (intramolecular rearrangements).

Full text of DOI:10.1021/jacs.9b01350

Article
pubs.acs.org/JACS
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Ammonium Complexes of Orthoester Cryptands Are Inherently
Dynamic and Adaptive
†
†
‡,§
,‡
̌
̌
̈
Xiang Wang, Oleksandr Shyshov, Marko Hanzevacki, Christof M. Jager,*
and Max von Delius*,†
†Institute of Organic Chemistry and Advanced Materials, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany
‡Department of Chemical and Environmental Engineering, University of Nottingham, University Park, Nottingham NG7 2RD,
United Kingdom
§Rudjer Boskovic Institute, Bijenicka 54, 10000 Zagreb, Croatia
S
* Supporting Information
ABSTRACT: Fluxional chemical species such as bullvalene
have been a valuable source of inspiration and fundamental
insight into the nature of chemical bonds. A supramolecular
analogue of bullvalene, i.e., a “fluxional host−guest system”, in
which the ensemble of a well-defined host and guest is
engaged in continuous, degenerate constitutional rearrange-
ments, is still elusive, however. Here, we report experimental
and computational evidence for guest-induced dynamic
covalent rearrangements in the ammonium complexes of
self-assembled orthoester cryptands. This unique behavior is
made possible by the ammonium guest playing a dual role: it
is sufficiently acidic to initiate dynamic covalent exchange
reactions at the orthoester bridgeheads, and as a hydrogen bond donor it acts as a supramolecular template, governing the
outcome of a multitude of possible intra- and intermolecular rearrangement reactions. One particularly striking example of
+
inherent dynamic behavior was observed in host−guest complex [NH4 ⊂o-Me2-2.1.1], which spontaneously rearranged into
+
the larger and thermodynamically more stable complex [NH4 ⊂o-Me2-2.2.1], even though this process led to the formation of
poor host o-Me2-1.1.1 as a consequence of the excess of one subcomponent (diethylene glycol; “1” in our nomenclature).
These inherently adaptive host−guest networks represent a unique platform for exploring the interrelationship between kinetic
+
and thermodynamic stability. For instance, as a result of optimal NH4+ binding, complex [NH4 ⊂o-Me2-2.2.1] was found to be
thermodynamically stable (negligible intermolecular rearrangements over weeks), whereas computational studies indicate that
the compound is far from kinetically stable (intramolecular rearrangements).
for components of complex food products such as carbohy-
drates, flavanols, and sialic acids.19,20
INTRODUCTION
■
Fluxional chemical species, defined as entities undergoing rapid
degenerate rearrangements (IUPAC),1 have inspired much
research and controversy over the past half-century.2−6
Bullvalene is perhaps the most widely known example of an
organic molecule that, above a certain temperature, exists as a
mixture of numerous, rapidly interconverting degenerate
constitutional isomers (Scheme 1a; left).7,8 Examples of
more recent work include the fascinating case of quasi-rotation
Dynamic combinatorial chemistry21−25 makes use of
reversible chemical bonds for generating complex mixtures
that are typically subject to global thermodynamic control.
This implies that all members of a dynamic combinatorial
library (DCL) are connected through a network of, more or
less, rapid equilibria. As a consequence, even in a DCL that is
at equilibrium, exchange of subcomponents occurs continu-
ously and in a degenerate fashion. However, because this
exchange is generally not an intramolecular process (rearrange-
ment), it does not represent fluxionality according to the
IUPAC definition.1 Dynamic covalent bonds, e.g., imines,
disulfides, and hydrazones, also typically require the addition of
a chemical species (e.g., acid catalyst) for inducing the
transition from kinetically stable to dynamic, which is in
+
of a cyclic B3 fragment in the B13 cluster (Scheme 1a; right),
degenerate 1,2,6-hydride shifts in the nonclassical 2-norbornyl
cation (C7H11+),9 as well as (partially) degenerate positional
dynamics in cyclic10 and linear “walking” systems.10−15 While
fluxional systems are often considered scientific curiosities, of
no use beyond revealing fundamental insights, Bode has
recently demonstrated that the room-temperature fluxionality
of “shape-shifting”16−18 bullvalone derivatives provides a
unique approach for establishing analytic fingerprint readouts
Received: February 19, 2019
© XXXX American Chemical Society
A
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Scheme 1. (a) Prototypical Fluxional Systems. (b)
Schematic Illustration of Fluxional Behavior of Orthoester
+
+
Cryptate [NH4 ⊂o-Me2-2.2.1] via NH4 -Catalyzed Ring-
Opened Oxonium Intermediate
contrast to fluxional species that must be inherently dynamic,
at least above a certain temperature.
Herein, we report a dynamic covalent host−guest system
that is inherently dynamic at room temperature, i.e., shows
evidence for adaptive constitutional dynamic rearrangements
that do not require the addition of external agents.26 The
platform giving rise to this behavior is the dynamic covalent
reaction between orthoesters and diols,27 which we have
recently utilized to self-assemble monometallic cryptates.28−31
We have also demonstrated that such cryptands exhibit
adaptive behavior upon addition of acid catalysts and metal
ion templates.29 We now report that the ammonium cation is
sufficiently acidic to act both as a catalyst for orthoester
exchange and as a template that governs the outcome of
constitutional rearrangements (Scheme 1b). Experimental
studies are accompanied by computational simulations
designed to shed light on the transfer of H+ from guest to
host and to answer the question whether ammonium
complexes of orthoester cryptands can be considered “fluxional
host−guest complexes”.
Figure 1. (a) NH4BArF-catalyzed orthoester exchange (orthoester
concentration: 80 mM). (b) Schematic representation of a key
experiment on the inherent adaptive behavior of orthoester cryptate
+
[NH4 ⊂o-Me2-2.1.1]BArF− (cryptate concentration: 80 mM). (c)
1
+
Partial H NMR spectra of [NH4 ⊂o-Me2-2.1.1]BArF− over time,
+
showing the evolution from [NH4 ⊂o-Me2-2.1.1] to thermodynami-
cally favored [NH4 ⊂o-Me2-2.2.1].
+
assembly, we monitored ammonium complexes of orthoester
cryptands under careful exclusion of acid as well as light
(possible formation of HCl from chloroform) and under the
best-possible exclusion of water33 by means of 1H NMR
spectroscopy and ESI+ mass spectrometry (Supporting
Information). Symmetric cryptands o-Me2-1.1.1 and o-Me2-
2.2.2 based on either DEG (diethylene glycol) or TEG
(triethylene glycol) building blocks were investigated first. Five
hours after we added 1 equiv of NH4BArF to cryptands o-Me2-
1.1.1 or the larger cryptand o-Me2-2.2.2, which we had
prepared by means of metal-templated self-assembly (Support-
ing Information), we observed clear evidence for orthoester
exchange, i.e., formation of hydrolysis products (due to
residual water) and higher orthoester oligomers (e.g., crown
ethers) along with ca. 35% and 55% of the two respective
starting materials.
RESULTS AND DISCUSSION
■
Inherent Adaptive Behavior of Orthoester Cryptands.
Following investigations on the adaptive behavior of orthoester
cryptands in the presence of trifluoroacetic acid and alkali
cations,29 we envisaged that the ammonium cation (NH4 )
+
could also be a suitable template for the self-assembly of
orthoester cryptates. Under typical conditions for self-
assembly,28 we indeed observed H NMR spectroscopic and
1
ESI mass spectrometric evidence for ammonium cryptate
formation. However, despite numerous attempts, we were not
able to isolate the corresponding products, which we thought
+
could be due to the acidity of the NH4 guest that would
render the cryptate complexes constitutionally dynamic and
exceptionally fragile to hydrolysis during workup procedures.31
To verify this hypothesis, we tested NH4BArF (ammonium
tetrakis[3,5-bis(trifluoromethyl)phenyl]borate)32 as a catalyst
for orthoester exchange between trimethyl orthoacetate and
ethanol. The experiment revealed that the addition of 4 mol %
of NH4BArF was sufficient to reach equilibrium in this
exchange reaction within only 10 min (Figure 1a and Figure
S6).
We next turned our attention to the more interesting
unsymmetric cryptands o-Me2-2.1.1 and o-Me2-2.2.1, whose
+
NH4 -catalyzed constitutional dynamics can give rise to the
formation of all four possible cryptates (of type 1.1.1, 2.1.1,
2.2.1, and 2.2.2) along with oligomers. As shown in Figure 1c,
+
[NH4 ⊂o-Me2-2.1.1] slowly converted over 48 h to a mixture
+
+
Having established that NH4 indeed catalyzes orthoester
containing larger cryptate [NH4 ⊂o-Me2-2.2.1] as main
+
exchange under conditions typically used for cryptate self-
product, suggesting that [NH4 ⊂o-Me2-2.2.1] is thermody-
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+
1
namically more stable than [NH4 ⊂o-Me2-2.1.1]. H NMR
integration shows that the ratio between these two compounds
at equilibrium is ca. 2.5:1, which would indicate a free energy
difference of ca. 0.5 kcal mol−1 if mass balance effects34,35 were
not taken into account. Even though the observation of some
hydrolysis complicates the picture even further (Figure S13), it
stands to reason that the mass balance in fact provides a bias
+
toward smaller cryptate [NH4 ⊂o-Me2-2.1.1] in this experi-
ment because, simply speaking, there is not enough TEG
+
available to form [NH4 ⊂o-Me2-2.2.1] exclusively, which
forces the reaction in the opposite direction. As such, the
+
thermodynamic preference for [NH4 ⊂o-Me2-2.2.1] may well
be larger than 0.5 kcal mol−1. Interestingly, the dynamic
network seems to respond to the deficiency in TEG by forming
+
the smallest cryptate [NH4 ·o-Me2-1.1.1] as a major side
product (ESI+-MS).
+
If [NH4 ⊂o-Me2-2.2.1] is the thermodynamically most
stable within the four possible cryptates, it is an intriguing
question if and how this host−guest complex rearranges over
1
time. A H NMR monitoring study over 50 days showed that
+
[NH4 ⊂o-Me2-2.2.1] remains the dominant library member
over the entire period (Figure S18). It should be noted that we
can be rather certain that the library is in fact dynamic because
we observe a slow increase of hydrolysis products DEG
(diethylene glycol), TEG (triethylene glycol), and esters that
require the formation of the same oxonium intermediates that
are involved in orthoester exchange. The observation of esters
can thus be considered as “trapping” of oxonium ions (see the
Supporting Information, Scheme S1 and Figure S19, for further
trapping experiments). A noteworthy NMR spectroscopic
phenomenon in the unsymmetric cryptates is that hetero-
1
+
nuclear spin−spin coupling between H and 14N in NH4 was
Figure 2. (a) Schematic representation and (b) partial 1H NMR
+
observed. We suggest that this phenomenon is due to slow
spectra corresponding to the adaptive behavior of [NH4 ⊂o-Me2-
+
+
exchange kinetics of the acidic NH4 protons, which only
2.1.1] and [NH4 ⊂o-Me2-2.2.2] in the presence of 1 equiv of TEG or
DEG, respectively (cryptate concentrations: 80 mM).
seems to be the case in the two more strongly binding
+
+
cryptates [NH4 ⊂o-Me2-2.1.1] and [NH4 ⊂o-Me2-2.2.1]
(Figure 2b).
2a, top). It is also worth noting that particularly low extents of
hydrolysis were observed in these fast reactions, e.g., only 6%,
suggesting that higher extents of hydrolysis in experiments that
required significantly longer equilibration times were likely due
to water influx.
+
The extent of hydrolysis in the rearrangement of [NH4 ⊂o-
Me2-2.1.1] to [NH4 ⊂o-Me2-2.2.1] gave us a valuable clue
+
regarding the mechanism of such cage-to-cage transformations
because we noticed that the rearrangement proceeds
significantly faster in experiments where more than the
typically observed 10−20% of hydrolysis had occurred due
to inadequately dried reagents.33 The mechanistic implication
of this finding is that free diols generated by hydrolysis are
most likely the species that do attack oxonium ions and thus
lead to the rearrangement of one cryptate into another.26,36 An
alternative, less likely mechanistic scenario would involve diol
scrambling via compounds, in which a diol forms a bridge
between two cages (Scheme S2).
Thermodynamics of Ammonium Binding and Solid-
State Structure of [NH4 ⊂o-Me2-2.2.1]BArF−. In order to
+
better understand the thermodynamic origins of the observed
adaptive behavior that is inherent to these host−guest systems,
we determined the binding constants between all four
+
1
cryptands and NH4 in anhydrous MeCN-d3 by H NMR
spectroscopy (Figure 3 and Table 1). To minimize hydrolysis
and competing intermolecular dynamic exchange processes,
NMR spectra were recorded as fast as possible in J-Young
tubes and the experiments were carried out at lower
concentrations compared to the experiments on adaptive
behavior. As shown in Figure 3b, after addition of NH4BArF to
To provide further support for our hypothesis that
+
[NH4 ⊂o-Me2-2.2.1] is the thermodynamically most stable
complex within the series of ammonium cryptates, we carried
1
out experiments in which TEG or DEG was added to freshly
cryptand o-Me2-2.2.1 in MeCN-d3, the H NMR signal of the
+
+
prepared cryptates [NH4 ·o-Me2-1.1.1], [NH4 ⊂o-Me2-2.1.1],
methyl bridgehead shifted to low field, indicating the formation
+
+
and [NH4 ⊂o-Me2-2.2.2] (Figure 2). In all three experiments,
relatively fast orthoester exchange kinetics were observed, e.g.,
equilibration in 4 h instead of 48 h, further supporting our
of cryptate [NH4 ⊂o-Me2-2.2.1], as well as fast exchange
kinetics in this solvent. Interestingly, with more than 1 equiv of
NH4BArF, the triplet of the NH4+ protons converge to a broad
peak, further confirming that the observation of 1H/14N spin−
spin coupling is somewhat correlated with guest inclusion.
Data fitting using supramolecular.org according to 1:1
stoichiometry gave a binding constant (Ka) of ca. 6000 M−1
for this host−guest complex.
+
mechanistic hypothesis. More importantly, [NH4 ⊂o-Me2-
2.2.1] was found to be the major product at equilibrium in
these experiments (Figure 2b), which we conducted in such a
way that there is no mass balance bias between pairs of
cryptates (e.g., between o-Me2-2.1.1 and o-Me2-2.2.1 in Figure
C
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Figure 3. (a) Schematic representation of titration of o-Me2-2.2.1
1
with NH4BArF. (b) Partial H NMR (400 MHz, 298 K, CD3CN)
stack plot for titration of o-Me2-2.2.1 (1.0 mM) with NH4BArF. (c)
Binding isotherm for titration of o-Me2-2.2.1 with NH4BArF. Blue
spheres: experimental points. Black line: fit according to 1:1 model.
+
Figure 4. (a) Solid-state structure of [NH4 ⊂o-Me2-2.2.1]BArF−. (b)
+
Table 1. Binding Constants (Ka) for Three Representative
Side view and (c) top view of cryptate complex [NH4 ⊂o-Me2-2.2.1].
a
Hydrogen atoms, solvent, and disorder (where applicable) are
omitted for clarity. Carbon: gray. Nitrogen: purple. Oxygen: red.
Fluorine: lime. Boron: green.
Nitrogen-Based Cations
Ka (M−1
)
NH4
CH3NH3
C(NH2)3
+
+
+
o-Me2-1.1.1
o-Me2-2.1.1
o-Me2-2.2.1
o-Me2-2.2.2
540 40
1100 100
6000 1000
400 30
290 10
750 30
1700 20
120 10
nd
nd
nd
70 10
+
structure unambiguously confirms the inclusion of NH4 into
the cavity of cryptand o-Me2-2.2.1. The nitrogen atom is
located at the center of the cavity, as becomes evident from
N−O distances in the relatively narrow range of 2.69−3.55 Å.
The cryptand framework is somewhat less symmetric
compared to previously reported crystal structures of alkali
metal complexes of orthoester cryptands,28,29,31 which is also
observed in simulations (vide infra) but could in principle also
be due to packing effects. X-ray crystallography does
unfortunately not provide information on the location of the
ammonium hydrogen atoms, which is one of the reasons why
we decided to investigate the structural and dynamic behavior
of the cryptates in more detail by computational methods.
Computational Studies of Ammonium Binding. The
intrinsic flexibility and reactivity of the described ammonium
orthoester cryptates results in a complex dynamic picture of
their behavior. Hence, we chose classical molecular-dynamics
(MD), hybrid quantum mechanics / molecular mechanics
(QM/MM) simulations, (QM/MM) simulations, and static
DFT calculations to investigate the structure.
a
1H NMR titrations carried out in separate J-Young tubes (solvent:
MeCN-d3; counteranions: tetrakis[3,5-bis(trifluoromethyl)phenyl]-
borate). In the spirit of open science,37 the raw data is available on
supramolecular.org (see Supporting Information for hyperlinks).
Errors reflect goodness of fit.
The binding constants of o-Me2-1.1.1, o-Me2-2.1.1, and o-
Me2-2.2.2 with NH4BArF were determined in the same
manner (Supporting Information), and the results are
summarized in Table 1. Even though experiments on adaptive
behavior were carried out in less polar solvent chloroform,
these results in acetonitrile corroborate that o-Me2-2.2.1
+
possesses the highest affinity toward NH4 . We also
investigated the complexation of methylammonium, which
binds significantly weaker to all four cryptands, while
unsymmetric cryptands o-Me2-2.2.1, and o-Me2-2.1.1 are
also the preferred hosts for this larger cation. Finally, we
tested whether the larger, D3h-symmetric and less acidic
guanidinium ion would potentially be an ideal guest for the o-
Me2-2.2.2 cryptand. Based on the observed binding constant
of ca. 70 M−1, we suggest that this complex does either not fit
the cavity of this cryptand or that there is simply no strain-free
conformation available that would allow effective hydrogen
bonding between host oxygen atoms and the six guanidinium
hydrogen atoms.
From classical atomistic MD simulations of the cryptates in
chloroform (detailed methods described in section 5.1 of the
Supporting Information), we were able to retrieve a dynamic
picture of the cryptates’ structural flexibility and their hydrogen
+
bonding with NH4 . Not surprisingly, the flexibility of the
systems increases with increasing size of the cryptand
framework from o-Me2-1.1.1 over o-Me2-2.1.1 to o-Me2-
2.2.2, as demonstrated by higher atomic root-mean-square
fluctuation (rmsf) values extracted from 200 ns simulations
(Figure 5a,b and Table S11). The differences in flexibility seem
to be driven by how well the ion fits into and forms favorable
interactions within the cavity. When compared with flexibility
patterns of monometallic cryptates (Figure S43 and Table S11,
Supporting Information), the ammonium cryptates resemble
most closely the Rb+ cryptates, which also preferentially self-
assembles into the [Rb+⊂o-Me2-2.2.1] cage.29
+
The high thermodynamic stability of cryptand [NH4 ⊂o-
Me2-2.2.1]BArF− and thus relatively low propensity of this
compound to undergo intermolecular rearrangements allowed
us to obtain crystallographic data on this host−guest
architecture. Suitable single crystals were obtained by slow
vapor diffusion of anhydrous n-pentane into a solution of
+
[NH4 ⊂o-Me2-2.2.1]BArF− in CDCl3 in a well-sealed vial
devoid of moisture. As shown in Figure 4, the solid-state
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+
binding is observable for [NH4 ·o-Me2-1.1.1]. Regarding the
two unsymmetric cryptates, the simulations suggest that within
the series of cryptands the exo association is most favorable for
[NH4 ⊂o-Me2-2.2.1] by 3.8 kcal mol−1 over [NH4 ·o-Me2-
+
+
1.1.1] and 4.5 kcal mol−1 over [NH4 ⊂o-Me2-2.1.1], while
endo binding is significantly more stable than exo binding in
+
+
both unsymmetric cryptands (e.g., [NH4 ⊂o-Me2-2.1.1]
favored by 2.5 kcal mol−1). Thus, the simulations are in
good qualitative agreement with the experimental association
constants (Table 1), while the subtle difference in affinity
between o-Me2-2.1.1 and o-Me2-2.2.1 is beyond the
limitations of this computational method. Additional density
functional theory (DFT) calculations starting from selected
snapshots of these simulations (Supporting Information,
section 5.8) and carried out with implicit solvation additionally
+
indicate that [NH4 ⊂o-Me2-2.2.1] is thermodynamically the
most stable cryptate. Calculating the reaction energies (zero
point corrected free energies) of the cryptate formation also
shows that the Gibbs free energies in chloroform is always
+
exergonic with the formation of [NH4 ⊂o-Me2-2.2.1] being
the most favorable.
Computational Studies of Proton Transfer and Cage
Opening. The formation of oxonium ions as key inter-
mediates for orthoester exchange reactions, as shown in
Scheme 1, was investigated by means of combined quantum
mechanical and molecular mechanics (QM/MM) simulations.
Here, the cryptand and the ammonium ion were treated by the
density functional based tight binding method (DFTB),38
while the solvent was treated by classical molecular mechanics
(Supporting Information, sections 5.4−5.6). On the basis of
these simulations, the cryptand opening was first simulated
using umbrella sampling. To investigate if the mechanism is
stepwise or concerted we carried out two-dimensional
umbrella sampling scans investigating the energy profile for
the C−Oo bond breakage and the H−Oo bond formation
simultaneously (Figure 6). The ring-opening transition state
indeed represents a concerted mechanism with simultaneous
proton transfer and C−O bond dissociation. The barrier of
16.2 kcal mol−1 and the strongly endergonic character remain
Figure 5. (a) Flexibility of cryptands illustrated by superimposed and
smoothed snapshots from 200 ns MD simulations color coded by
simulation time, (b) RMSF fluctuations (in Å), and (c) hydrogen-
bonding occupancy derived from 200 ns MD simulations mapped on
averaged cryptate structures. Oxygen and nitrogen atoms shown as
spheres; hydrogen atoms omitted for clarity.
+
comparable with the 1D scan for [NH4 ⊂o-Me2-2.2.1].
The trends in flexibility are also reflected in the hydrogen-
bonding features of the encapsulated ammonium ions (Figure
5b, Table S12) with average hydrogen bonding numbers of 1.3,
1.1, 1.7, and 3.3 following decreasing cryptand size. More
importantly, hydrogen bonds between NH4+ and ether oxygens
(Oe) are preferred over orthoester oxygens (Oo), and
hydrogen bonds to DEG oxygens are preferred over TEG
oxygens. The average occupancy of hydrogen bonds to Oo
Therefore, these results confirm that the formation of the
oxonium ion is very slow due to a high barrier and that the
concentration of free oxonium ions must be very small.
Another observation was that in all simulations the formed
NH3 tends to leave the open cryptand cage after oxonium ion
formation, which is in agreement with the results of trapping
experiments (Figure S19).
+
In summary, our simulations show that oxonium ion
formation by proton transfer from an encapsulated ammonium
ion is plausible but subject to a significant kinetic barrier,
drops from 0.25 for [NH4 •o-Me2-1.1.1] to the minimum of
+
0.04 for [NH4 ⊂o-Me2-2.2.1] with the latter additionally
having the highest Oe:Oo hydrogen bond ratio (3.6:1) in the
series. In other words, hydrogen bonding to orthoester oxygens
is very limited in this cryptate, which might influence its
thermodynamic and kinetic stability (tendency to form an
oxonium ion intermediate).
+
+
which is very similar for [NH4 ⊂o-Me2-2.2.1] and [NH4 ⊂o-
Me2-2.1.1]. One of the reasons for the high barrier for ring-
opening seems to lie in the fact that the strong hydrogen-
bonding network of the ammonium ion decreases its reactivity
(acidity) significantly, which is a well-established effect often
referred to as “complexation-induced pKa shift”.39−41 DFT
calculations based on the QM/MM simulations (Supporting
Information, section 5.9) show that the protonation and ring
opening barriers are predominately influenced by the number
of hydrogen bonds formed with the cage.
Additionally, it becomes apparent from these simulations
that o-Me2-1.1.1 is essentially too small to accommodate the
NH4+ ion, resulting in an exo mode of binding, whereas o-Me2-
2.2.2 is too large and leads to a highly dynamic endo mode of
binding.
More detailed umbrella sampling simulations to pull the
ammonium ion out of the cavity into the solvent (Supporting
Information, section 5.3, and Figure S46) support these
observations, in which a distinct barrier between exo and endo
Based on these considerations, ammonium ions approaching
from the outside of the cage should demonstrate higher acidity
and reactivity. However, this attack competes with the high
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ring-opening attack. Moreover, the free energy difference
associated with NH4+ dissociation is more endergonic than the
+
kinetic barrier for ring opening (in case of NH4 ⊂o-Me2-2.2.1
+
and NH4 ⊂o-Me2-2.1.1). We therefore consider it highly
unlikely that adaptive behavior would be based on the
dissociation of the ammonium ion.
Are These Host−guest Complexes Fluxional? Finally,
we attempted to answer the question whether the ammonium
cryptates are undergoing intramolecular rearrangements in a
manner that would meet the definition of fluxionality
according to IUPAC.1
As shown in Figure 7a, the first step for such a
rearrangement would be oxonium ion formation (vide
supra), leading to release of NH3 into the solvent. Oxonium
ion I is essentially a lariate crown ether42−44 whose alcohol
group can attack the electrophilic carbon atom from the
opposite side from where it left and therefore invert the
absolute configuration at this bridgehead (Figure 7a,b). The
possible formation of this (out,in) intermediate structure was
confirmed for o-Me2-2.2.1 by umbrella sampling simulations.
Unsurprisingly, the (out,in) cage is not able to accommodate
an ammonium ion within its cavity (Supporting Information,
sections 5.7−5.8). Thus, the reactivity of this species will not
be decreased by strong hydrogen-bonding networks and attack
by external ammonium ions should be fast, which is confirmed
by DFT calculations presented in section 5.9 of the Supporting
Information. Also, the fact that (out,in) cryptands cannot
accommodate the NH4+ ion helps to explain why such species
are not observed in significant quantities during our experi-
ments (thermodynamic control provides a strong driving force
for effective hosts).
Figure 6. (a) Free energy representation of a two-dimensional QM/
MM umbrella sampling trajectory of oxonium ion formation of
+
[NH4 ⊂o-Me2-2.2.1]. Bond formation between the orthoester
+
oxygen and the hydrogen from NH4 ion and the carbon oxygen
bond breakage have been used as sampling coordinates. Energies
given in kcal mol−1; contour lines shown represent steps of 2.5 kcal
mol−1 between 2.5 and 20.0 kcal mol−1. (b) Representative structures
at characteristic points from this simulation. All cryptand hydrogens
omitted for clarity. Hydrogen involved in reaction shown in orange.
driving force to enter the cavity, and all QM/MM umbrella
sampling approaches for this reaction step with o-Me2-2.2.1
resulted in the highly stable encapsulated configuration and no
Figure 7. (a) Reaction sequence of a “fluxional” intramolecular rearrangement leading to exchange of the two triethylene glycol chains via several
ring-opening and -closing reactions. (b) Snapshots extracted from QM/MM umbrella sampling simulations for the backside attack of the oxonium
ion to form the inverted o-Me2-2.2.1 (out,in) intermediate. All CH2 hydrogens omitted for clarity. Orthoester atoms of different side chains
highlighted in different colors in analogy to part a of this figure. (c) DFT-optimized transition-state structures for the ring-opening of the o-Me2-
2.2.1 (out,in) intermediate. Selected interatomic distances given in Å.
F
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Journal of the American Chemical Society
Article
DFT transition-state calculations (Figure 7c and section 5.9
of the Supporting Information) at the PBE0/def2TZVP(D3)
level of theory provided barriers for ring-opening by proton
transfer between 1.3 and 26.3 kcal mol−1 for either side of the
o-Me2-2.2.1 (out,in) intermediate. As indicated in the previous
section, the large difference between the activation barriers is
related to the nature of noncovalent interactions of NH4+ with
the host in the optimized precursor structures. For cases where
case the modulation of reactivity occurs from the guest to the
host,51−54 and not in the other direction.
Comprehensive computational studies confirmed that the
crucial step for constitutional cryptate rearrangement, i.e., the
formation of oxonium ion intermediates is significantly
hindered by the ammonium ion’s ability to strongly bind to
the cryptands through multiple hydrogen bonds and the
associated complexation-induced pKa shift. This finding also
explains the rather slow kinetics of the intermolecular
rearrangement processes and the failure to trap oxonium ion
intermediates experimentally. QM/MM simulations and DFT
calculations further indicated that the host-guest system
+
NH4 is engaged in strong hydrogen bonding, the barrier is
high, whereas the barrier is minimal, if the cation is only
associated with one orthoester oxygen atom. In general, the
+
reactivity of NH4 decreases with effective encapsulation, and
+
+
[NH4 ⊂o-Me2-2.2.1] is indeed fluxional, i.e., that the
NH4 should be most reactive in conjunction with hosts o-
experimentally proven intermolecular rearrangements are
accompanied by intramolecular degenerate rearrangements.
Me2-1.1.1 and (out,in)-o-Me2-2.2.1 and least reactive for o-
Me2-2.2.1 and o-Me2-2.1.1.
To complete the fluxional rearrangement sequence, the
second orthoester oxygen of the diethylene glycol chain (green
in Figure 7) needs to be involved in a second ring-opening
step, so that the cryptand can subsequently undergo inversion
of the second bridgehead (via backside attack) to form an
inverted (out,out) configuration with encapsulated ammonium
ion (Figure 7a). From the structures displayed on the left-hand
side of Figure 7, it is evident that the two triethylene glycol
chains (red and blue) have now changed position and that
their stereochemical relationship is enantiotopic (mirror plane
in Figure 7).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b01350.
■
S
Experimental procedures, characterization and spectral
data. Detailed description of the simulations (MD and
QM/MM) and DFT setups, Cartesian coordinates,
details into the 2D umbrella sampling strategies, and
more detailed DFT results and analysis and force field
parameters used (PDF)
The described inversion pathway based on the formation of
an (in,out) cryptand and reactive oxonium ions I and II is
plausible for three reasons. First, the formed NH3 dissociates
after ring opening, which allows the flexible side chains to
adopt conformations suitable for back-side attack and ring
closure as a key process leading to stereochemical inversion.
Second, the (out,in) cryptand as a key intermediate has a
calculated ground-state energy that is 7.2 kcal mol−1 more
stable than the corresponding empty o-Me2-2.1.1 cryptand
(5.2 kcal mol−1 in case of o-Me2-2.2.1), which suggests that its
formation is possible, even though it cannot encapsulate the
X-ray data for compound [NH4 ⊂o-Me2-2.2.1]BArF−
(CIF)
+
AUTHOR INFORMATION
Corresponding Authors
*max.vondelius@uni-ulm.de
*christof.jaeger@nottingham.ac.uk
ORCID
■
̈
Christof M. Jager: 0000-0002-1802-1892
+
Max von Delius: 0000-0003-1852-2969
NH4 ion. Third, for that same reason, the formed reactive
(out,in) cryptand is equally prone to NH4+ attack on both sides
of the molecule (if no additional hydrogen bonds are formed)
leading to a stochastic chance for ring opening on both sides
including the described pathway. We therefore conclude that
there is a plausible pathway for “fluxional” intramolecular
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Deutsche Forschungsgemein-
schaft (Emmy-Noether grant DE1830/2-1), an Experiment!
grant of the VolkswagenStiftung, and the DAAD (PhD
fellowship to O.S.). We thank Dr. Elena Mena-Osteritz for
crystal structure refinement, Mrs. Margit Lang for ICP-AES
+
degenerate rearrangements in the [NH4 ⊂o-Me2-2.2.1] host−
guest complex with each elementary step of the corresponding
reaction sequence supported by computational evidence
(DFT, QM/MM, and MD simulations).
́
analyses, and Dr. Rene-Chris Brachvogel for laying early
foundations of this study. C.M.J. gratefully acknowledges
access to the University of Nottingham’s Augusta HPC service.
The Croatian Science Foundation (Project No. IP11-2013-
8238) and the British Scholarship Trust are acknowledged for
the additional financial support.
CONCLUSION
■
In this study, we demonstrated experimentally that the
ammonium complexes of orthoester cryptands are highly
unusual chemical species. The ammonium guest is sufficiently
acidic to initiate orthoester exchange and thus imparts
constitutional dynamics onto the covalent framework of the
host. The inherently dynamic nature of these host−guest
complexes became evident in experiments, in which the
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