Adaptive Behavior of Dynamic Orthoester Cryptands

Article abstract of DOI:10.1002/anie.201609855

The integration of dynamic covalent bonds into macrocycles has been a tremendously successful strategy for investigating noncovalent interactions and identifying effective host–guest pairs. While numerous studies have focused on the dynamic responses of macrocycles and larger cages to various guests, the corresponding constitutionally dynamic chemistry of cryptands remains unexplored. Reported here is that cryptands based on orthoester bridgeheads offer an elegant entry to experiments in which a metal ion selects its preferred host from a dynamic mixture of competing subcomponents. In such dynamic mixtures, the alkali metal ions Li⁺, Na⁺, K⁺, Rb⁺, and Cs⁺exhibit pronounced preferences for the formation of cryptands of certain sizes and donor numbers, and the selection is rationalized by DFT calculations. Reported is also the first self-assembly of a chiral orthoester cryptate and a preliminary study on the use of stereoisomers as subcomponents.

Full text of DOI:10.1002/anie.201609855

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Communications
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International Edition: DOI: 10.1002/anie.201609855
German Edition: DOI: 10.1002/ange.201609855
Supramolecular Chemistry
Adaptive Behavior of Dynamic Orthoester Cryptands
Oleksandr Shyshov+, Renꢀ-Chris Brachvogel+, Tobias Bachmann, Rubitha Srikantharajah,
Doris Segets, Frank Hampel, Ralph Puchta, and Max von Delius*
Abstract: The integration of dynamic covalent bonds into
macrocycles has been a tremendously successful strategy for
investigating noncovalent interactions and identifying effective
host–guest pairs. While numerous studies have focused on the
dynamic responses of macrocycles and larger cages to various
guests, the corresponding constitutionally dynamic chemistry
of cryptands remains unexplored. Reported here is that
cryptands based on orthoester bridgeheads offer an elegant
entry to experiments in which a metal ion selects its preferred
host from a dynamic mixture of competing subcomponents. In
such dynamic mixtures, the alkali metal ions Li+, Na+, K+,
Rb+, and Cs+ exhibit pronounced preferences for the forma-
tion of cryptands of certain sizes and donor numbers, and the
selection is rationalized by DFT calculations. Reported is also
the first self-assembly of a chiral orthoester cryptate and
a preliminary study on the use of stereoisomers as subcompo-
nents.
metal-ligand cages, there have been numerous studies on
the adaptive behavior of dynamic combinatorial macrocycles
in response to guests.[1f,8] However, in most examples reported
to date, the selection occurs between oligomeric species, for
example, dimeric and trimeric species compete for guest
binding. Studies in which adaptive behavior is based on
subcomponent selection and subtle architectural differences
between competing organic hosts are rare.[2c,9]
As the smallest three-dimensional hosts, dynamic crypt-
ands represent an attractive, yet practically unexplored[10]
area of chemical (host–guest) space. We have recently
reported the first dynamic covalent self-assembly of a mono-
metallic cryptate[11] ([Na+ꢀo-Me2-1.1.1]), which was based on
the reversible, acid-catalyzed reaction of a simple orthoester
with diethylene glycol (Scheme 1a).[12] Herein, we report the
adaptive behavior of orthoester cryptands in response to
cationic guests (Scheme 1b).
In a first series of experiments, we tested whether the
orthoester cyptand o-Me2-1.1.1 would respond to the addition
of mismatched metal guests by either a dynamic covalent
shrinkage or expansion event (Scheme 2a). The combination
of one equivalent of LiTPFPB (lithium tetrakis(pentafluoro-
phenyl)borate), ethylene glycol, and acid catalyst, for
instance, should lead to the formation of the shrunken
cryptate [Li+ꢀo-Me2-1.1.0], if this host-guest pair repre-
T
he unique feature of dynamic covalent bonds, their stability
or dynamics depending on the reaction conditions, has led to
diverse applications in chemistry and adjacent disciplines.[1] In
supramolecular host–guest chemistry, the integration of
dynamic covalent bonds into macrocycles,[2] their combina-
tion with metal–ligand interactions,[3] and the structural
response of macrocyclic systems to (ionic) guests have
recently attracted considerable interest.[4]
The majority of constitutionally dynamic metal-ligand
cages are rigid and positively charged, a property which
makes them an ideal platform for the binding and recognition
of anions. The groups of Nitschke,[5] Clever,[6] and others[7]
have recently reported impressive examples of adaptive cage
transformations in response to different anions. Besides
[*] O. Shyshov,[+] R.-C. Brachvogel,[+] Prof. Dr. M. von Delius
Institute of Organic Chemistry and Advanced Materials
University of Ulm
Albert-Einstein-Allee 11, 89081 Ulm (Germany)
E-mail: max.vondelius@uni-ulm.de
R. Srikantharajah, Dr. D. Segets
Institute of Particle Technology (LFG) and
Interdisciplinary Center for Functional Particle Systems (FPS)
Friedrich-Alexander Universitꢀt Erlangen-Nꢁrnberg (FAU)
Cauerstrasse 4, 91058 Erlangen (Germany)
T. Bachmann, Dr. F. Hampel, Priv.-Doz. R. Puchta
Department of Chemistry and Pharmacy, Institute of Organic
Chemistry, and Computer Chemistry Center (CCC)
Friedrich-Alexander Universitꢀt Erlangen-Nꢁrnberg (FAU)
Henkestrasse 42, 91054 Erlangen (Germany)
Scheme 1. a) Sodium-templated self-assembly of the orthoester crypt-
ate [Na+ꢀo-Me2-1.1.1] and subsequent preparation of cryptand o-Me2-
1.1.1. b) Adaptive behavior of o-Me2-1.1.1 in the presence of triethylene
glycol (TEG), catalytic acid, and selected guest ions. DEG=diethylene
glycol.
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201609855.
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Scheme 2. a) Adaptive behavior of o-Me2-1.1.1 in the presence of different diols and metal ions. Reaction conditions: 5 mmol o-Me2-1.1.1, 5 mmol
metal salt, 5–10 mmol TEG, and 0.5 mmol TFA in CDCl3; equilibration time: 3–6 hours, yields (NMR) 20–83% (for further experiments see
Supporting Information). b) Direct self-assembly of the different orthoester cryptates. Method A: 5 mmol metal salt, 5–10 mmol TEG, 5–10 mmol
DEG, 1.5 mmol PFPA, 1,1,2,2-tetrachloroethane, 20 mbar, yield (isolated) 39–55%. Method B: 5 mmol metal salt, 0–5 mmol TEG, 10–15 mmol
DEG, 1.5 mmol TFA, 1.5 mL CDCl3, 5 ꢂ M.S. (ca. 0.5 g), yield (isolated) 27–49%. BArF=tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, DEG=di-
ethylene glycol, PFPA=perfluoropentanoic acid, TEG=triethylene glycol, TFA=trifluoroacetic acid.
sented the thermodynamic minimum. In the corresponding
experiment, we found that the dynamic system remained
mainly at the [Li+ꢀo-Me2-1.1.1] state, thus indicating that the
cryptand o-Me2-1.1.0 is either too small to accommodate Li+
or that binding to a host with one additional oxygen donor
atom outweighs a possible preference for the smaller host. It
is worth noting that [Li+ꢀo-Me2-1.1.1] does not only out-
compete the alternative host o-Me2-1.1.0, but also five-
membered ring products derived from an addition of both
alcohol functions in ethylene glycol to the orthoester.[12a]
When we studied larger alkali metal ions in combination
with longer diol triethylene glycol (TEG), we observed that
these metals exhibit pronounced preferences for the forma-
tion of certain orthoester hosts. The selectivity becomes
evident by the appearance of only one predominant signal in
the methyl region of the 1H NMR spectra of the crude
mixture in each of these experiments (Scheme 2a). For
example, potassium directs the dynamic system almost
exclusively towards the formation of the cryptand o-Me2-
2.1.1, whereas both rubidium and cesium direct towards o-
Me2-2.2.1. All these experiments were independently con-
ducted with zero, one, two, and three equivalents of TEG,
because the quantity of this subcomponent represents a bias
for the formation of certain species. Throughout these
experiments we found preferences for the same cryptates,
even in cases where the amount of TEG should favor other
reaction products (see the Supporting Information for all
experiments).
These template-based desymmetrization reactions are
also remarkable from a synthetic perspective, because
conventional unsymmetric cryptands require multistep syn-
theses.[13] However, having to synthesize a symmetric crypt-
and en route to an unsymmetric one, does not meet the
requirements of any modern metric of synthesis efficiency.[14]
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As a result, we focused our efforts on the direct self-assembly
of unsymmetric orthoester cryptates. To achieve this, we
needed to identify reaction conditions under which methanol
could be slowly removed from equilibrium, while no source of
sodium ions [e.g. 4 ꢀ molecular sieves (M.S.)] is present,
because the latter would lead to the formation of the
symmetric cryptate [Na+ꢀo-Me2-1.1.1].[11] As shown in Sche-
me 2b, two such methods, based on either reduced pressure or
5 ꢀ M.S. (containing Ca2+ ions) could be identified, thus
leading to the preparation of the desired unsymmetric
cryptates in yields of 27–55%.
In light of possible applications it is worth noting that all
cryptands can conveniently be prepared in quantitative yield
from the corresponding cryptates by treatment with ion-
exchange resin (see the Supporting Information). We were
also able to prepare the symmetric cryptate [Cs+ꢀo-Me2-
2.2.2], which interestingly, was not observed in previous
experiments, where this compound would have been a possi-
ble product. The preference of Cs+ for the cryptand o-Me2-
2.2.1 was confirmed by a shrinkage experiment, in which
[Cs+ꢀo-Me2-2.2.2], under reaction conditions for orthoester
exchange was treated with DEG, and [Cs+ꢀo-Me2-2.2.1] was
observed as predominant product (see the Supporting Infor-
mation).[16]
Adaptive behavior at a higher level of complexity was
observed in the multi-metal/multi-cryptand exchange experi-
ment illustrated in Scheme 2c. The symmetric cryptands o-
Me2-1.1.1 and o-Me2-2.2.2 were combined with mismatched[17]
metal ions K+ and Cs+, and orthoester exchange was initiated
by addition of acid. The NMR spectrum of the crude mixtures
after equilibration and the ESI+ mass spectrum after work-up
(see the Supporting Information) clearly demonstrate that
a 1:1 mixture of the unsymmetric cryptates [K+ꢀo-Me2-2.1.1]
and [Cs+ꢀo-Me2-2.2.1] was formed. Even though we cannot
deduce from our data which one of the two host–guest pairs
provides the main thermodynamic driving force, this cryptate
metathesis is nevertheless a remarkable case of adaptive
behavior.
To shed further light on the underlying noncovalent
interactions, we grew single crystals from all cryptates which
represented preferred species in self-assembly experiments.
The resulting X-ray structures are depicted in Figure 1a,
along with the structure of previously reported [Na+ꢀo-Me2-
1.1.1]. Relatively symmetric coordination geometries are
adopted in the cryptates [K+ꢀo-Me2-2.1.1], [Rb+ꢀo-Me2-
2.2.1], and [Cs+ꢀo-Me2-2.2.1], while the unique combination
of orthoester bridgeheads with glycol side chains results in the
formation of up to eleven metal–oxygen bonds. An apparent
limit for binding is reached with the cryptand o-Me2-2.2.2,
Figure 1. a) Solid-state structures of five orthoester cryptates.[21] The
structure of [Na+ꢀo-Me2-1.1.1] was reported previously[11] and is
shown for comparison. Single crystals of [K+ꢀo-Me2-2.1.1] were
obtained by the vapor diffusion method (cyclopentane/ chloroform).
Single crystals of [Rb+ꢀo-Me2-2.2.1], [Cs+ꢀo-Me2-2.2.1], and
[Cs+ꢀo-Me2-2.2.2] were obtained by the layering method (n-heptane/
chloroform). Hydrogen atoms, anions, solvent, and disorder (where
applicable) are omitted for clarity. Metal ions are displayed at 100% of
effective ionic radius.[15] Selected bond length ranges: Na O: 2.5–
ꢁ
ꢁ
ꢁ
ꢁ
2.6 ꢂ; K O: 2.8–3.0 ꢂ; Rb O: 3.0–3.3 ꢂ; Cs O: 3.2–3.3 ꢂ in
+
ꢁ
[Cs ꢀo-Me2-2.2.1]; Cs O: 3.1–3.7 ꢂ (binding) and 4.4 ꢂ (nonbinding)
in [Cs+ꢀo-Me2-2.2.2].
Because some of our experiments represent a stoichio-
metrically unbiased[18] competition between two dynamic
cryptands for a metal ion, we wanted to test, whether the
observed trends could be rationalized by theory. In a first set
of DFT-based (B3LYP/LANL2DZp) model equations (see
the Supporting Information for details), we determined
complexation energies for the combination of the cryptands
o-Me2-1.1.0, o-Me2-1.1.1, o-Me2-2.1.1, o-Me2-2.2.1, and o-
Me2-2.2.2 with five alkali metal ions.[19] We also carried out
NMR titrations for all 20 host-guest combinations, as well as
one representative isothermal titration calorimetry (ITC)
study, which revealed that sodium binding to o-Me2-1.1.1 is
driven both enthalpically and entropically (see the Supporting
Information).
With the exception of two outliers ([Li+ꢀo-Me2-1.1.1] and
[Rb+·o-Me2-1.1.1]), we observed good agreement between
the trends in experiment (Figure 2a) and theory (Figure 2b).
More importantly, the relative binding energies do indeed
allow rationalizing our findings on adaptive behavior. For
instance, K+ represents a clear minimum for o-Me2-2.1.1
(Figure 2a and 2b), thus explaining the predominant forma-
tion of [K+ꢀo-Me2-2.1.1] in the experiment shown in
Scheme 2a. It is also evident from the data that binding of
Rb+ and Cs+ only becomes favorable for the larger cryptands
o-Me2-2.2.1 and o-Me2-2.2.2. The flat line observed in the
computational binding energies for o-Me2-1.1.0 (Figure 2b)
suggests that no alkali-metal ion fits into this host, and would
explain why not even the small Li+ template led to its
formation.
ꢁ
which only forms eleven out of twelve possible Cs O bonds.
This observation might explain why [Cs+ꢀo-Me2-2.2.1] is the
preferred species in experiments where o-Me2-2.2.1 and o-
Me2-2.2.2 compete for Cs+. An unusual type of anisotropic
long-range order was observed in the crystal structure of
+
ꢁ
[Cs ꢀo-Me2-2.2.1]: the presence of Cs F bonds between
counteranion and cryptates results in the formation of
a helical coordination polymer (see the Supporting Informa-
tion for the packing diagram).
A second set of model equations was designed to more
adequately mimic the competition of two cryptands for cation
binding. For each metal ion, these calculations revealed
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Figure 2. a) Experimental binding energies determined by 1H NMR titrations and data fitting ([D3]acetonitrile, 298 K). b) Computational binding
enthalpies (B3LYP/LANL2DZp; gas phase) based on a model equation that mimics the transfer of a metal ion from sixfold water coordination to
the orthoester cryptand. c) Computational binding enthalpies (B3LYP/LANL2DZp; gas phase) based on a model equation that mimics the transfer
of a metal ion from one orthoester cryptand to another. *: metal was expelled from cage as a result of DFT calculation. See the Supporting
Information for experimental/computational details and a discussion of the limitations of the DFT calculations.
energy differences between five host-guest species (Fig-
ure 2c). Although these calculations fail to correctly predict
all experimental outcomes (for example, o-Me2-2.1.1 should
represent the minimum in the case of K+), they do reveal
relatively large energy cutoffs above which a metal ion
seemingly is too large to fit into the cavity of the host
(highlighted by dashed lines).
Finally, we turned our attention to more complex
subcomponents, from which stereochemical insights could
be gained.[20] When enantiopure diol SS-1 was subjected to
standard self-assembly conditions, the corresponding homo-
chiral cryptate [Na+ꢀo-Me2-SS,SS,SS] formed as the pre-
dominant product (Scheme 3a). Interestingly, the corre-
sponding meso diastereomer RS-1 failed to produce detect-
able quantities of the corresponding cryptate under identical
reaction conditions (Scheme 3b). A complex mixture of
species formed instead (see the Supporting Information),
thus indicating that the self-assembly is highly sensitive to
conformational differences between diastereomers.
To study a racemic mixture of diols, we prepared the
deuterated compound d4-RR-1, which was subsequently
mixed (1:1) with SS-1 to form a pseudo-racemate (Sche-
me 3c). Because orthoester cryptands comprise an uneven
number of diol building blocks, we wondered whether only
the homochiral cryptates would form or if opposite enantio-
mers could be incorporated into the bicyclic structure.
Analysis of the reaction outcome by NMR spectroscopy and
mass spectrometry revealed that the latter is the case: all four
possible cryptate species were formed in roughly statistical
mixture.
In conclusion, we have demonstrated that dynamic
orthoester cryptands can shrink or expand by subcomponent
exchange in response to the addition of alkali-metal ions. We
found that certain host-guest pairs represent pronounced
thermodynamic minima, which allowed us to use spherical
metal templates for the desymmetrization of symmetric
cryptands and to carry out an unprecedented cryptate meta-
thesis reaction. We now plan to extend this concept to the
combination of transition metals with diols featuring hetero-
atoms other than oxygen, where added selectivity based on
Scheme 3. a) Self-assembly of a chiral cryptate based on diol SS-1.
Solid-state structure of [Na+ꢀo-Me2-SS,SS,SS].[21] Single crystals were
obtained by the vapor diffusion method (CDCl3/ cyclopentane). Hydro-
ꢁ
gen atoms, anions, and solvent are omitted for clarity. Na O bond
length range: 2.4–2.8 ꢂ. b) Attempted self-assembly based on the meso
diol RS-1 (no cryptate formation observed by either NMR spectroscopy
or ESI+-MS). c) Self-assembly based on pseudo-racemate: 1:1 mixture
of SS-1 and deuterated enantiomer d4-RR-1. Formation of a statistical
mixture of all four cryptate stereoisomers, as indicated by ESI+-HRMS
(bottom). Reaction conditions: trimethyl orthoacetate (0.12 mmol,
2.0 equiv), diol (0.18 mmol, 3.0 equiv), NaBArF (0.06 mmol, 1.0 equiv),
TFA (trifluoroacetic acid, 1.2 mmol, 2 mol%) in 6 mL CDCl3 with 5 ꢂ
M.S. Yields: 15–53%.
the HSAB principle and applications in sensing and delivery
might become viable.
Acknowledgments
This work was supported by the Fonds der Chemischen
Industrie (FCI doctoral fellowship for R.-C.B.) and the
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DE1830/2-1). We would like to thank Margarete Dzialach,
Wolfgang Donaubauer, Dr. Harald Maid, and Dr. Svetlana
Begel for assistance with mass spectrometry, X-ray crystal-
lography, NMR spectroscopy and the analysis of DFT
calculations, respectively. Prof. Wolfgang Peukert is acknowl-
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Deutsche Forschungsgemeinschaft (DFG) through the Clus-
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(EAM). R.P. thanks Prof. Tim Clark for hosting this work at
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Conflict of interest
The authors declare no conflict of interest.
Keywords: cryptands · dynamic combinatorial chemistry · host–
guest chemistry · NMR spectroscopy · supramolecular chemistry
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template. Preliminary results indicate that ammonium cryptates
+
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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Angewandte
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Chemie
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2.2.1]), 1505905 ([Cs+ꢀo-Me2-2.2.1]), 1505904 ([Cs+ꢀo-Me2-
2.2.2]), and 1505903 ([Na+ꢀo-Me2-SS,SS,SS]) contain the sup-
plementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge
Crystallographic Data Centre.
´
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Manuscript received: October 8, 2016
Revised: November 22, 2016
Final Article published: && &&, &&&&
6
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Communications
Chemie
Communications
Supramolecular Chemistry
A lid for every pot: Cryptands based on
orthoester bridgeheads offer an elegant
entry to experiments in which a metal ion
selects its preferred host from a dynamic
mixture of competing subcomponents. In
such dynamic mixtures the alkali metal
ions Li+, Na+, K+, Rb+, and Cs+ exhibit
pronounced preferences for the forma-
tion of cryptands of certain sizes and
donor numbers.
O. Shyshov, R.-C. Brachvogel,
T. Bachmann, R. Srikantharajah,
D. Segets, F. Hampel, R. Puchta,
M. von Delius*
&&&& — &&&&
Adaptive Behavior of Dynamic Orthoester
Cryptands
Angew. Chem. Int. Ed. 2016, 55, 1 – 7
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!