Self-assembled orthoester cryptands: Orthoester scope, post-functionalization, kinetic locking and tunable degradation kinetics

Article abstract of DOI:10.1039/c8sc01750f

Dynamic adaptability and biodegradability are key features of functional, 21^st century host-guest systems. We have recently discovered a class of tripodal supramolecular hosts, in which two orthoesters act as constitutionally dynamic bridgeheads. Having previously demonstrated the adaptive nature of these hosts, we now report the synthesis and characterization-including eight solid state structures-of a diverse set of orthoester cages, which provides evidence for the broad scope of this new host class. With the same set of compounds, we demonstrated that the rates of orthoester exchange and hydrolysis can be tuned over a remarkably wide range, from rapid hydrolysis at pH 8 to nearly inert at pH 1, and that the Taft parameter of the orthoester substituent allows an adequate prediction of the reaction kinetics. Moreover, the synthesis of an alkyne-capped cryptand enabled the post-functionalization of orthoester cryptands by Sonogashira and CuAAC "click" reactions. The methylation of the resulting triazole furnished a cryptate that was kinetically inert towards orthoester exchange and hydrolysis at pH > 1, which is equivalent to the "turnoff" of constitutionally dynamic imines by means of reduction. These findings indicate that orthoester cages may be more broadly useful than anticipated, e.g. as drug delivery agents with precisely tunable biodegradability or, thanks to the kinetic locking strategy, as ion sensors.

Full text of DOI:10.1039/c8sc01750f

View Article Online
View Journal
Chemical
Science
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: H. Löw, E. Mena-
Osteritz and M. von Delius, Chem. Sci., 2018, DOI: 10.1039/C8SC01750F.
This is an Accepted Manuscript, which has been through the
Volume
7 Number 1 January 2016 Pages 1–812
Royal Society of Chemistry peer review process and has been
accepted for publication.
Chemical
Science
Accepted Manuscripts are published online shortly after
www.rsc.org/chemicalscience
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 2041-6539
EDGE ARTICLE
Francesco Ricci et al.
Electronic control of DNA-based nanoswitches and nanodevices
rsc.li/chemical-science

Please do not adjust margins
Chemical Science
Page 1 of 10
View Article Online
DOI: 10.1039/C8SC01750F
Chemical Science
EDGE ARTICLE
Self-Assembled Orthoester Cryptands: Orthoester Scope, Post-
Functionalization, Kinetic Locking and Tunable Degradation
Kinetics
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Henrik Löw, Elena Mena-Osteritz and Max von Delius*
Dynamic adaptability and biodegradability are key features of functional, 21st century host-guest systems. We have
recently discovered a class of tripodal supramolecular hosts, in which two orthoesters act as constitutionally dynamic
bridgeheads. Having previously demonstrated the adaptive nature of these hosts, we now report the synthesis and
characterization – including eight solid state structures – of a diverse set of orthoester cages, which provides evidence for
the broad scope of this new host class. With the same set of compounds, we demonstrated that the rates of orthoester
exchange and hydrolysis can be tuned over a remarkably wide range, from rapid hydrolysis at pH 8 to nearly inert at pH 1,
and that the Taft parameter of the orthoester substituent allows an adequate prediction of the reaction kinetics.
Moreover, the synthesis of an alkyne-capped cryptand enabled the post-functionalization of orthoester cryptands by
Sonogashira and CuAAC “click” reactions. The methylation of the resulting triazole furnished a cryptate that was kinetically
inert towards orthoester exchange and hydrolysis at pH>1, which is equivalent to the “turnoff” of constitutionally dynamic
imines by means of reduction. These findings indicate that orthoester cages may be more broadly useful than anticipated,
e.g. as drug delivery agents with precisely tunable biodegradability or, thanks to the kinetic locking strategy, as ion
sensors.
www.rsc.org/
Introduction
The development of new macro(bi)cyclic compounds has been
a key driving force of progress in supramolecular chemistry.1
The discovery of pillararenes,2 for instance, has opened up
new avenues in supramolecular polymer chemistry,3 and the
rational design of cyanostar4 and triazolophane macrocycles5
enabled remarkable binding affinities for hard-to-bind anions
-
such as PF6 , as well as unprecedented rotaxane syntheses4a,6
and fundamental insights on the nature of hydrogen bonding.7
In this article, we follow up on our discovery of a new class of
self-assembled macrobicyclic host8 and report comprehensive
data on the scope, structure and properties of these
compounds.
Dynamic combinatorial chemistry9 has been used
extensively for generating macrocycles and cages from smaller
subcomponents,9g,10 yet prior to our discovery of orthoester
cryptands,8 there were only few reports on the self-assembly
of purely organic dynamic covalent cages suitable to
encapsulate single11 cationic12 or anionic13 guests. Self-
assembled macrobicyclic hosts beyond dynamic covalent
Scheme 1 Overview on the scope of this study. (a) Template-directed self-assembly
of orthoester cryptates: scope of orthoesters (R1) investigated in this contribution;
(b) post-functionalization (R2) and kinetic locking (R3) of orthoester cryptates; (c)
tunability of the degradation kinetics. DEG: diethylene glycol. M+ in this work: Na+ or
Li+.
the feature that their host framework is no longer dynamic
and stimuli-responsive once the self-assembly process is
complete. This is different for orthoester cryptands, which
under anhydrous acidic conditions are adaptive to their
environment,16 which allowed us to demonstrate that a wide
range of metal ions selectively directs the self-assembly of
their thermodynamically preferred host.17
chemistry
have
been
reported,
most
notably
metallosupramolecular cryptates14 as well as clathrochelates.15
Another interesting feature of orthoester cryptands is that, in
contrast to conventional cryptands featuring nitrogen
bridgeheads, their synthesis requires only a single step whose
yield can be as high as 92%, as we demonstrate in this work
(Scheme 1a). Moreover, orthoester bridgeheads possess a
However, these compounds share with conventional cryptands
This journal is © The Royal Society of Chemistry 20xx
Chem. Sci., 2018, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 2 of 10
View Article Online
DOI: 10.1039/C8SC01750F
ARTICLE
Chemical Science
substituent (R1, Scheme 1) that should allow modulating the convenient handle for adding further functionality. However,
stability, solubility and lipophilicity of the cages and provide a prior to this work, only three such substituents (R1 = -CH3,
Scheme 2 Scope of self-assembled orthoester cryptands. Reaction conditions: 60 µmol sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (BArF) or LiBArF, 180 µmol
diethylene glycol, 120 µmol orthoester, 1.2 µmol TFA (R1 = -CH2Cl: 12 µmol TFA) in CHCl3, 7-13 days (for further details, see ESI†). Percent values indicate isolated yields. M+:
Na+; Li+. DEG: diethylene glycol. MS: 5 Å molecular sieves.
-CH2CH3, -H) have been explored.8
orthopropanoates (R1 = CH2CH3), and the self-assembly had
When considering applications in the emerging field of only been successful for the two latter starting materials.8,17
supramolecular medicinal chemistry,18 the most important We therefore chose five commercial and six non-commercial23
feature of orthoester cryptands is their inherent tendency to orthoesters with diverse functional groups ranging from
hydrolyze19 under general acid catalysis to ring-opened esters, electron-donating (e.g. R1 = -nC4H9) to aromatic (e.g.
which leads to the irreversible release of the encapsulated R1 = -C6H6) and strongly electron-withdrawing (e.g. R1 = -CF3).
guest. Although earlier studies have investigated the kinetics Furthermore, an alkynyl substituted orthoester was prepared
of orthoester hydrolysis and its pH dependency,20 a systematic in view of a possible post-functionalization of the self-
study on a wide range of orthoester substituents (R1, Scheme assembled host. As shown in Scheme 2, these eleven
1) is still elusive, and the kinetics of orthoester exchange as a orthoesters were subjected to standard reaction conditions for
new addition to the toolbox of dynamic covalent chemistry21 orthoester exchange. Specifically, these reaction conditions
remain unexplored.
entail the use of diethylene glycol (DEG; grey box in Scheme 2)
ligand for cation binding and substrate for
Herein, we report a comprehensive study on the scope and as
a
generality of self-assembled orthoester cryptands (Scheme 1a) orthoester/alcohol exchange, as well as trifluoroacetic acid
as well as their post-functionalization and post-synthetic (TFA) as catalyst. In addition, a suitable alkali metal template
stabilization against hydrolysis or exchange reactions (“kinetic (e.g. NaBArF) and molecular sieves (5 Å) are required to
locking”, Scheme 1b). Moreover, we explored the question to provide a driving force for cryptate self-assembly and to
which extent the kinetics of orthoester exchange and maintain anhydrous reaction conditions.
hydrolysis can be tuned as a function of different orthoester
By optimizing our procedures for preparing anhydrous
substituents and whether the observed trends can be starting materials (see ESI†), we were able to minimize the
rationalized on the basis of linear free energy relationships undesired hydrolysis of orthoesters to esters and to improve
(Scheme 1c).22
the isolated yield of previously reported orthoacetate cryptate
[Na+ o-(CH3)2-1.1.1]8 from 67% to 77%. Yields in the range of
50% to 92% were obtained for five new orthoester cryptates
(R1 = -nC4H9, -CH2C6H5, -C6H5, -C
C-Si(CH3)3 and -CH2Cl; Scheme
⊂
Results and discussion
≡
2), demonstrating that alkyl, benzyl and phenyl substituted
orthoester cryptates can be accessed in a straight-forward
manner. The reaction times were relatively long (7 to 13 days),
and we had previously speculated that this is mainly due to the
slow uptake of methanol by molecular sieves, which
Scope of orthoester cryptand self-assembly
The systematic exploration of the scope and generality of the
synthesis of orthoester cryptands was the first objective of this
study, because previous investigations had been limited to
orthoformates (R1
= = CH3) and
H), orthoacetates (R1
2 | Chem. Sci., 2018, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 3 of 10
View Article Online
DOI: 10.1039/C8SC01750F
Chemical Science
ARTICLE
presumably provides an additional entropic driving force for with anion exchange resin (Cl form; for further details, see
self-assembly.24
ESI†) to study the thermodynamics of lithium and sodium
binding. Therefore, we performed 1H NMR titrations with
NaBArF and LiBArF in acetonitrile at different concentrations
(1 to 10 mM) and fitted the resulting binding isotherms with a
1:1 stoichiometric model on the website supramolecular.org
(original data is available for download in the spirit of “open-
science”,26 see ESI†). The quality of the data was evaluated
based on triplicate titrations (95% confidence interval, Table 1)
and statistical analyses of the goodness of fit (see ESI†). The
resulting association constants show that lithium binds to o-
(H)2-1.1.1 about 200 times more strongly than sodium (see
Table 1). A comparison with data on methyl-substituted
cryptand o-(CH3)2-1.1.125 (Table 1, right column) reveals that
the substitution of methyl for hydrogen in o-(H)2-1.1.1 leads to
stronger binding of lithium and weaker binding of sodium.
These Ka values provide a compelling explanation for our
unexpected observation that cryptand o-(H)2-1.1.1 can be
obtained with a lithium template, but not with a sodium
template, even though titrations were performed in
acetonitrile and self-assembly reactions are carried out in
chloroform,§ where the relative magnitudes of ion-dipole
interactions are typically more pronounced than in
acetonitrile. It will be interesting to address the question why
cryptand o-(H)2-1.1.1 exhibits such outlier thermodynamic
behavior, but this will likely require high-level computational
studies that are beyond the scope of this contribution.
Table 1 Anomalous Li+/Na+ affinity of orthoformate cryptand o-(H)2-1.1.1 (Ka values).a
Entry
o-(H)2-1.1.1
13000 ± 1000 M-1
60 ± 20 M-1
o-(CH3)2-1.1.125
1700 M-1
1300 M-1
1
2
Li+
Na+
a
Titrations were performed using BArF salts in acetonitrile at different host
concentrations (1 to 10 mM). Association constants were determined by 1H NMR
titrations and fitting of isotherms on supramolecular.org. Estimates of
uncertainty reflect 95% confidence intervals (triplicate titrations). For further
details, see ESI†.
Our study on the kinetics of orthoester exchange supports this
hypothesis, by showing that the self-assembly reactions
require significantly more time than simpler exchange
reactions of the same orthoester substrates (vide infra).
Purification of the crude cryptates was possible by passing a
chloroform solution through a short plug of silica gel. The
highly efficient synthesis of a chloromethyl-substituted cage
shows that mildly electron-withdrawing substituents are
tolerated, even though their presence presumably destabilizes
the oxonium ion intermediate of the exchange reaction. In
fact, the observed isolated yield of 92% might well be a
consequence of this effect, because, for the same reason, this
cryptate is particularly stable against hydrolysis (vide infra),
which minimizes any losses during purification.
The valuable alkynyl-substituted cryptate [Na+
⊂o-(C≡CH)2-
1.1.1] could be obtained in 46% yield over two steps after
deprotection of the corresponding TMS-alkynyl-substituted
cryptate. We were unable to self-assemble this compound
Solid state structures
To gain structural insights into the prepared macrobicyclic
compounds, we attempted to crystallize all new orthoester
cryptates by slow diffusion of hexane into chloroform
solutions. To our delight, we were able to obtain single crystals
suitable for X-Ray crystallography of eight new orthoester
cryptates (see Chart 1). All sodium-based architectures,
directly from the corresponding orthoester (R1 = C
≡CH), which
is likely a result of the stronger electron-withdrawing effect of
the free alkyne, in comparison to the silyl-protected
analogue.‡ In line with this reasoning, we did not observe any
evidence for cryptand formation starting from even more
electron-deficient orthoesters (R1 = -CCl3, -CF3, -CN). It should
be noted that, in model experiments (vide infra), we were able
to induce orthoester exchange in two of these substrates, but
including previously reported [Na+ o-(CH3)2-1.1.1] 8
⊂ , feature
the encapsulation of the alkali metal ion at the centre of the
cavity, held in place by nine Na–O bonds. The only exception
to this mode of binding is [Na+
⊂o-(C6H5)2-1.1.1], in which only
the
required
strong
acid
catalysts
(e.g.,
eight Na−O bonds are observed. One orthoester oxygen is
more distant (3.53 Å) and two are closer to the metal ion
(2.32, 2.40 Å) than in all other sodium-containing structures
(2.43-2.92 Å). Due to this slight distortion, caused most likely
by packing effects, the three chain oxygen atoms are closer to
the metal ion (2.37-2.46 Å) than in the other seven sodium
cryptates (2.48-2.67 Å; see Chart 1i for a statistical analysis of
bond lengths). Most of the orthoester cryptates crystallize in a
triclinic crystal system (space group P-1), but monoclinic (P21/n
or P21/c) and orthorhombic (Pbca) systems were also
observed.
trifluoromethanesulfonic acid) appear to be too harsh to allow
for template-directed cryptate self-assembly.
Arguably the most intriguing case in this scope study is the
reaction of trimethyl orthoformate (R1 = H) with diethylene
glycol. In our initial communication on cryptate [Na+
⊂o-(CH3)2-
1.1.1] we had reported that trimethyl orthoformate (H-
C(OCH3)3) under standard conditions gives rise to the self-
assembly of crown ether complexes [Na+
⊂o-(H)2-(OCH3)2-16-
crown-6], but not to the corresponding cryptands. This was a
surprising finding, because the cryptate self-assembly would
simply require the addition of one additional DEG bridge to the
crown ether complex. We have now discovered that an
orthoformate cryptate [Li+
⊂o-(H)2-1.1.1] can in fact be
obtained, but only if a lithium, instead of a sodium template is
We were also able to obtain X-Ray crystallographic data on
a cryptate encapsulating a lithium ion for the first time.
Numerous previous attempts at crystallizing [Li+
⊂o-(CH3)2-
1.1.1] had been met with failure, presumably due to the
relatively low binding constant (Table 1) and (degenerate)
binding dynamics in this host.25 In stark contrast to the
sodium-based structures, cryptate [Li+
⊂o-(H)2-1.1.1] features
used.
To better understand this unexpected result, we isolated
empty cryptand o-(H)2-1.1.1 by treatment of [Li+
⊂o-(H)2-1.1.1]
This journal is © The Royal Society of Chemistry 20xx
Chem. Sci., 2018, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 4 of 10
View Article Online
DOI: 10.1039/C8SC01750F
ARTICLE
Chemical Science
only five Li−O bonds. This binding mode leads to rather short that are involved in Li−O bonds (1.96 Å). Hence, the remaining
Li−O bonds of the three chain oxygen atoms (2.16-2.23 Å) and four orthoester
Chart 1 Solid-state structures of eight orthoester cryptands. Single crystals were obtained by the layering method (hexane/ chloroform). Hydrogen atoms, anions, solvent and
disorder (where applicable) are omitted for clarity. Metal ions are displayed at 100% of effective ionic radius.27 a) Crystal system: triclinic. Na–O distance (orthoester oxygen):
2.45-2.92 Å. Na–O distance (chain oxygen): 2.48-2.53 Å. b) Crystal system: monoclinic. Na–O distance (orthoester oxygen): 2.47-2.76 Å. Na–O distance (chain oxygen): 2.51-2.57
Å. c) Crystal system: orthorhombic. Na–O distance (orthoester oxygen): 2.32-3.53 Å. Na–O distance (chain oxygen): 2.37-2.46 Å. d) Crystal system: triclinic. Na–O distance
(orthoester oxygen): 2.48-2.59 Å. Na–O distance (chain oxygen): 2.54-2.67 Å. e) Crystal system: monoclinic. Na–O distance (orthoester oxygen): 2.47-2.89 Å. Na–O distance
(chain oxygen): 2.48-2.57 Å. f) Crystal system: triclinic. Na–O distance (orthoester oxygen): 2.43-2.69 Å. Na–O distance (chain oxygen): 2.56-2.61 Å. g) Crystal system: triclinic.
Na–O distance (orthoester oxygen): 2.46-2.66 Å. Na–O distance (chain oxygen): 2.53-2.67 Å. h) Crystal system: orthorhombic. Li–O distance (orthoester oxygen): 1.96-3.67 Å. Li–
O distance (chain oxygen): 2.16-2.23 Å. i) Comparison of average Na–O distance of all sodium-based solid-state structures with average Li–O distance in [Li+⊂o-(H)2-1.1.1],
including standard deviation. For further details, see ESI†.
even shorter contacts for the two orthoester oxygen atoms
oxygen atoms are significantly more distant (2.94-3.67 Å) than of ethanol (B) and acid catalyst under standardized conditions
in the sodium-containing solid state structures (see Chart 1i). and the reaction progress was monitored for up to 16 hours by
The crystal system observed for [Li+
⊂
o-(H)2-1.1.1] is 1H NMR spectroscopy. To account for the vast differences in
reactivity between the orthoesters, both the amount of acid,
as well as the type of acid had to be varied. For example, the
CCl3- and CF3-substituted orthoesters were found to be so
orthorhombic (P212121).
Kinetics of orthoester exchange and hydrolysis
To shed light on the differences in reactivity and stability of inert that even large quantitites of trifluoracetic acid did not
orthoesters and their corresponding cryptands, we decided to lead to discernible exchange products. Hence, whenever an
investigate the kinetics of the exchange reactions of a diverse orthoester was found to be too inert to react within 16 h
set of orthoesters with ethanol (see Table 2). To this end, 13 under mild reaction conditions, the next harsher set of
trimethyl orthoesters (A3) were treated with three equivalents reaction conditions was investigated (and so on). Besides this
4 | Chem. Sci., 2018, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 5 of 10
View Article Online
DOI: 10.1039/C8SC01750F
Chemical Science
ARTICLE
step-wise enhancement of acid catalysis, the second crucial and variations thereof are a poor fit, which is not too
parameter in Table 2 is the equilibration time t, which we surprising given that the Hammet reference reaction is rather
defined as the first data point at which ≥99% conversion to the unlike orthoester exchange. As can be deduced from Table 2,
equilibrium distribution was reached based on 1H NMR the Taft parameter for the R1 group does, however, correlate
integration. The kinetic data allowed us to order the 13 studied very well with the observed reactivity trend with the only
orthoesters from most reactive to most inert (top to bottom in exception (CCl3 vs. CF3, see Table 2, entries 10 and 12) being
Table 2) with horizontal lines indicating steps where harsher based on a very narrow margin and not relevant to templated
reaction conditions were necessary.
cryptate self-assembly. From a mechanistic perspective, this
finding makes good sense, because the Taft LFER is based on
the acid-catalysed hydrolysis of aliphatic esters, which
proceeds via the same oxonium intermediates as orthoester
exchange.28 Because many orthoester derivatives are
commercially available, this correlation with the Taft LFER will
be very valuable for designing and optimizing future self-
assemblies based on orthoester exchange.
tb
Product ratio
(A3:A2B:AB2:B3)
n.d.
Entry
Acid
R1
Taft22
[min]
10
1
2
-nC4H9
-0.13
0.00
0.01%
TFA
-CH3
280
26:44:24:6
0.1%
TFA
3
-CH2C6H5
650
23:41:29:6
0.22
4
5
6
7
8
-H
-C6H5
40
50
19:43:31:7
23:42:27:7
22:41:29:7
n.d.
0.49
0.60
-
In respect to the scope of self-assembled orthoester
crpytates (vide supra), these results imply that there is a
threshold where self-assembly is no longer possible, because
the R1 substituent is too strongly electron-withdrawing and
that this threshold lies between -CH2Cl (Taft 1.05, see Table 2,
1%
-C≡C-Si(CH3)3
-triazolec
-CH2Cl
90
TFA
130
640
-
16:42:32:10
1.05
10%
TFA
9
-C≡CH
300
32:35:26:6
2.18
entry 8) and -C≡CH (Taft 2.18, see Table 2, entry 9).
10
11
12
13
50%
-CCl3
-triazoliumd
-CF3
330
490
n.d.
16:39:33:11
n.d.
2.65
-
Nevertheless, we would like to emphasize that cryptands
equipped with functional groups with Taft values >1 are
TfOH
100%
TfOH
accessible via post-functionalization methods (e.g. R1 = -C
≡CH
>1000
2.61
3.30
-CN
decomposition
by deprotection or –triazolium by methylation, vide infra:
Scheme 3).
Table 2 Kinetics and scope of orthoester exchange.a
When considering the thermodynamic, rather than kinetic
implications of these results, it is evident from Table 2 that the
observed equilibrium compositions (A3:A2B:AB2:B3) are mostly
unaffected by the R1 substituent and the acid catalyst. Yet to
our surprise, when plotting the evolution of individual species
over time, we found that the thermodynamically least
favoured product (B3) generally reaches its plateau level first.
This finding can be rationalized by conflicting steric and
electronic effects: the sterically more demanding ethyl group
makes B3 the thermodynamically least stable product, yet the
oxonium ion that leads to the formation of B3 is the most
stable intermediate, which means that the conversion of A2B
into AB2 is slower than the conversion of AB2 into B3. See ESI†
for further details and kinetic simulations of this interesting
“bottleneck” in the evolution of the chemical network over
time,29 including the exchange reaction with 2-chloroethanol,
which confirms the above reasoning.
A comparison of the equilibration times reveals that electron-
rich orthoesters are vastly more reactive than electron-
deficient orthoesters and that the reactivity of orthoesters can
be fine-tuned over a remarkably wide range. For instance,
trimethyl orthovalerate (R1 = -nC4H9, see Table 2, entry 1)
equilibrates with ethanol in only 13 min with 0.01% TFA,
whereas the reaction of 1,1,1-trifluoro-2,2,2-trimethoxyethane
(R1 = -CF3, see Table 2, entry 12) did not reach equilibrium
after 16 h, even with 100 mol% trifluoromethanesulfonic acid
(TfOH).
In view of possible applications of orthoester cryptates in
drug delivery,19,30 we turned our attention towards the
hydrolytic degradation of orthoesters and the corresponding
self-assembled cryptands (Table 3). Six representative
orthoesters were dissolved in phosphate buffer solutions of
varying pH. The reactions were monitored by 1H NMR
spectroscopy to determine the half-life t1/2 and the kinetic rate
kobs of the hydrolysis reaction under pseudo first order
conditions. As expected, the kinetics of orthoester hydrolysis
follow the same trend that was observed for orthoester
exchange. While electron-rich orthoesters (e.g., R1 = -CH3, see
Table 3, entry 1) hydrolyze readily even at neutral pH, more
electron-deficient orthoesters (e.g., R1 = -triazolium, -CCl3, see
Table 3, entries 5 and 6) are remarkably stable: even at pH 1
Because the results summarized in Table 2 represent the
first account of a reactivity sequence for orthoester exchange,
we attempted to identify a linear free energy relationship
(LFER) that would correlate with the observed trend. We
quickly noticed that the Hammet substituent parameter (σ)
a
Reaction conditions: orthoester (A3, 37.5 µmol, 1.0 equiv.), alcohol (B, 112.5 µmol,
3.0 equiv.), internal standard (9.41 µmol) and acid catalyst (0.01 to 100 mol%) were
added to the reaction vessel from stock solutions. CDCl3 was added to obtain a total
volume of 750 µL. The reaction was monitored by 1H NMR spectroscopy. t:
b
equilibration time, defined as data point when 99% conversion to plateau-level of
methanol A was exceeded for the first time; n.d.: not determined due to peak overlap
c
in NMR spectrum.
d 1-benzyl-3-methyl-4-(trimethoxymethyl)-1H-1,2,3-triazol-3-ium.
This journal is © The Royal Society of Chemistry 20xx
Chem. Sci., 2018, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 6 of 10
View Article Online
DOI: 10.1039/C8SC01750F
ARTICLE
Chemical Science
their half-lives are beyond 16 h. In the context of drug delivery, 3, entry 7). As anticipated,8 the observed hydrolysis rate for
we believe that orthoformates (R1 = -H; t1/2 70 min at pH 6, see cryptand o-(CH3)2-1.1.1 is somewhat lower than that for the
Table 3, entry 2) and chloromethyl-substituted orthoesters simple orthoester but in the same range, indicating that our
(R1 = -CH2Cl; t1/2 121 min at pH 5 and 34 min at pH 4, see Table
3, entry 3) offer the most appealing hydrolysis profiles.§§
Finally, we monitored the hydrolysis of cryptand o-(CH3)2-
1.1.1 under comparable reaction conditions (Table 3, see Table
O
Table
3
O
O
O
H3C
O
O
OH
OMe
O
O
O
H2O
H2O
R1
OMe
OMe
O
R1
OMe
H3C
CH3
O
O
O
O
pH 7
pH 1-8
3] = 50 mM
O
O
O
H3C
-(CH ) -1.1.1
] = 25 mM
O
O
CH3
1A
[o
[
MeOH
3
2
1A3
Hydrolysis of orthoesters and a representative orthoester cryptand.a
o-(CH3)2-1.1.1
HO
OH
Entry
1
R1
pH 8
60
1.8 × 10-4
>1000
pH 7
10
1.3 × 10-3
510
2.5 × 10-5
>1000
pH 6
2
6.1 × 10-3
70
1.6 × 10-4
660
1.7 × 10-5
pH 5
<1
pH 4
pH 3
pH 1
-CH3
t1/2 [min]
kobs [s-1]
t1/2 [min]
kobs [s-1]
t1/2 [min]
kobs [s-1]
t1/2 [min]
2
3
-H
20
7
<1
<1
8.8 × 10-4
120
2.0 × 10-3
30
-CH2Cl
8.6 × 10-5
2.9 × 10-4
4
5
-triazoleb
-triazoliumd
<1c
t1/2 [min]
kobs [s-1]
inert
>10000
1.6 × 10-6
6
7
-CCl3
t1/2 [min]
>1000c
o-(CH3)2-1.1.1
t1/2 [min]
30
3.5 × 10-4
k
obs [s-1]
a
Reaction conditions: orthoester (A3, 37.5 µmol) or cryptand (o-(CH3)2-1.1.1, 18.75 µmol) and internal standard (12.3 µmol) were added to the reaction
vessel. Buffer solution was added to obtain a total volume of 750 µL. The reaction was monitored by 1H NMR spectroscopy. t1/2: half-life of starting
b
material, defined as point when 50% of starting material were consumed. Estimated error: ±4%. 1-benzyl-4-(trimethoxymethyl)-1H-1,2,3-triazole.
c
400 µL DMSO added to increase solubility of starting material. Comparison of measurements in pure buffer and with addition of DMSO revealed that kobs is
.
d 1-benzyl-3-methyl-4-(trimethoxymethyl)-1H-1,2,3-
decreased by ca. one order of magnitude upon addition of the co-solvent (for further details, see ESI†)
triazol-3-ium.
6 | Chem. Sci., 2018, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 7 of 10
View Article Online
DOI: 10.1039/C8SC01750F
Chemical Science
kinetic findings are transferable from orthoesters to orthoester
cryptands.
Post-functionalization and kinetic locking of orthoester cryptands
Having established the broad scope and the kinetic limitations
of the self-assembly reaction, we turned our attention towards
further diversifying orthoester cryptates by post-
functionalization (see Scheme 3a).31 Cryptate [Na+
1.1.1] containing two functional alkyne handles, was
subjected to a Sonogashira reaction with iodobenzene to
furnish cryptand in 94% yield. The basicity of the reaction
⊂o-(C≡CH)2-
,
1
conditions had the advantageous effect that no orthoester
hydrolysis was observed, but also led to decomplexation, thus
requiring a trivial second step to reintroduce the sodium guest,
thus furnishing cryptate [Na+
⊂1]. We believe that this type of
reaction will be particularly useful for the preparation of
intriguing degradable 1D polymers and for applications in ion
sensing, because the aromatic substituents are in conjugation
with the orthoester bridgeheads. The introduction of
conjugated chromophores or fluorophores should result in
pronounced differences in optical output depending on the
nature of guest ions, and could also provide a theranostic
readout32 for cage degradation and concomitant guest release.
An alternative method for post-functionalization was
Scheme 3 Post-functionalization of orthoester cryptands. a) Reaction conditions: (i)
[Na+⊂o-(C≡CH)2-1.1.1] (11.8 µmol, 1.0 equiv.), iodobenzene (23.6 µmol, 2.0 equiv.),
NEt3 (35.4 µmol, 3.0 equiv.), CuI (0.12 µmol, 0.01 equiv.), Pd(PPh3)4 (0.12 µmol,
0.01 equiv.), THF, 40 °C, 4 d, 94%. ii) 1 (9.28 µmol, 1.0 equiv.), NaBArF (9.28 µmol,
1.0 equiv.), CH3CN, r.t., 5 min, quant. (iii) [Na+⊂o-(C≡CH)2-1.1.1] (11.0 µmol,
1.0 equiv.), benzyl azide (22.0 µmol, 2.0 equiv.), Cu(MeCN)4PF6 (0.11 µmol,
0.01 equiv.), TBTA (0.11 µmol, 0.01 equiv.), MeOH, 70 °C, 24 h, 92%. (iv) [Na+⊂2]
(3.9 µmol, 1.0 equiv.), MeI (excess), MeCN, 70 °C, 3 d, 83%. b) Partial 1H NMR
stacked plot (500 MHz, 298 K, CD3CN).
investigated by the CuAAC “click” reaction between [Na+
(C CH)2-1.1.1] and benzyl azide. This reaction proceeded in
protocol, the product cryptate [Na+
2] was obtained in
⊂o-
≡
⊂
excellent yield (92%), and in contrast to the Sonogashira
orthoester is below one minute, which accounts for an
increase in stability of at least four orders of magnitude (Table
3, entries 4 and 5). As such, this post-stabilization method is
akin to the kinetic locking of imines by means of reduction to
the corresponding amines, which has found widespread use in
the synthesis of mechanically interlocked molecules, organic
cages, porous materials and other applications of dynamic
covalent chemistry.37
reaction without decomplexation of the metal guest. Although
electronic communication between substituents and cage is
likely weak in such bis-triazoles,33 we believe that this type of
functionalization will prove valuable for installing functional
moieties, for example for modulating lipophilicity, targeting
biological binding motifs34 or stimuli-responsive triggering of
cage decomposition.35
Encouraged by the efficient post-functionalization
reactions and the observed differences in hydrolysis rates
(Table 3), we wondered whether we could drastically stabilize
⊂
compound [Na+ 2] by methylation of the triazoles.36 At least
Conclusions
In this work, we have demonstrated that orthoester cryptands
equipped with a broad range of substituents are accessible in
one step via efficient, metal-templated self-assembly
reactions. Cryptands substituted with strongly electron-
withdrawing groups could not be obtained, but this limitation
was circumvented by highly efficient post-functionalization
methodologies based on a Sonogashira or CuAAC reaction of
in principle, the electron-withdrawing effect of the resulting
triazolium on the orthoester bridgehead could lead to
significantly reduced orthoester reactivity and pave the way
towards applications of orthoester cryptands that require
stability in water. As shown in Scheme 3a, treatment of
[Na+
corresponding bis-triazolium cryptate [Na+
⊂
2] with an excess of iodomethane furnished the
3] in 83% yield
⊂
the the bis-alkynyl cryptate. Methylation of
a triazole-
(Scheme 3a, bottom). In proof-of-principle experiments, the
corresponding triazolium-substituted orthoester indeed
proved to be inert towards hydrolysis at pH 3 (Table 3, entry 5)
and underwent orthoester exchange only with 50% triflic acid
(Table 2, entry 10). At pH 1 the half-life for hydrolysis was
beyond 16 h, whereas all other orthoesters suitable to prepare
cryptates hydrolyzed rapidly under these conditions. The
extrapolated half-life of the triazolium-orthoester in fact
exceeded 10000 min, whereas the half-life of the triazole-
substituted cryptate furnished a supramolecular host that can
be considered kinetically locked in respect to orthoester
exchange and hydrolysis, but still binds effectively to cationic
guests. In future studies, it could be beneficial to reverse this
“locking” by site-selective N-dealkylation, which appears to be
possible under relatively mild basic conditions.38 We also
carried out detailed, comparative kinetic studies on orthoester
exchange and hydrolysis, firmly establishing that the tunability
of orthoester degradation makes these architectures
This journal is © The Royal Society of Chemistry 20xx
Chem. Sci., 2018, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 8 of 10
View Article Online
DOI: 10.1039/C8SC01750F
ARTICLE
Chemical Science
interesting candidates for the (topical) delivery of ionic drugs,
which strictly requires the biodegradability of otherwise toxic
supramolecular hosts.39 Further studies on (an)ion
encapsulation, sensing, transport and release are underway in
our laboratory.
4
5
(a) S. Lee, C. H. Chen and A. H. Flood, Nat. Chem., 2013,
710; (b) E. M. Fatila, M. Pink, E. B. Twum, J. A. Karty and A. H.
Flood, Chem. Sci., 2018, , 2853–3070.
(a) Y. Li and A. H. Flood, Angew. Chem., Int. Ed., 2008, 47, 2649–
5, 704–
9
2652; (b) Y. Li and A. H. Flood, J. Am. Chem. Soc., 2008, 130
,
12111–12122.
6
7
8
9
B. Qiao, Y. Liu, S. Lee, M. Pink and A. H. Flood, Chem. Commun.,
2016, 52, 13675–13678.
Conflicts of interest
Y. Liu, A. Sengupta, K. Raghavachari and A. H. Flood, Chem,
There are no conflicts to declare.
2017,
R.-C. Brachvogel, F. Hampel and M. von Delius, Nat. Commun.,
2015, , 7129.
3, 411–427.
6
Acknowledgements
(a) P. T. Corbett, J. Leclaire, L. Vial, K. R. West, J.-L. Wietor, J. K.
M. Sanders and S. Otto, Chem. Rev., 2006, 106, 3652–3711; (b)
J. Li, P. Nowak and S. Otto, J. Am. Chem. Soc., 2013, 135, 9222–
9239; (c) Y. Jin, C. Yu, R. J. Denman and W. Zhang, Chem. Soc.
Rev., 2013, 42, 6634; (d) S. Otto, R. L. E. Furlan and J. K. M.
This
work
was
supported
by
the
Deutsche
Forschungsgemeinschaft (Emmy-Noether grant DE1830/2-1).
We would like to thank Tobias Bachmann for experimental
work carried out during his master thesis. Bernhard Müller is
acknowledged for assistance with X-ray crystallography.
Sanders, Curr. Opin. Chem. Biol., 2002,
6, 321–327; (e) R.-C.
Brachvogel and M. von Delius, Eur. J. Org. Chem., 2016, 2016
,
3662–3670; (f) Q. Ji, R. C. Lirag, and O. Š. Miljanić, Chem. Soc.
Rev., 2014, 43, 1873–1884; (g) A. Herrmann, Chem. Soc. Rev.,
2014, 43, 1899–1933.
Notes and references
‡
In principle, oxonium ions of alkynyl-substituted orthoesters
could undergo 1,4-addition with alcohol nucleophiles, thus
generating tetrasubstituted allene derivatives. However, our
results suggest that such side reactions do not occur. For
instance, the orthoester with R1 = -C≡CH undergoes clean
exchange in the presence of 10% TFA (Table 2).
10 (a) N. Ponnuswamy, F. B. L. Cougnon, J. M. Clough, G. D. Pantoş
and J. K. M. Sanders, Science, 2012, 338, 783–785; (b) A.
González-Álvarez, I. Alfonso, F. López-Ortiz, Á. Aguirre, S.
García-Granda and V. Gotor, Eur. J. Org. Chem., 2004, 2004
,
1117–1127; (c) B. Fuchs, A. Nelson, A. Star, J. F. Stoddart and S.
Vidal, Angew. Chem., Int. Ed., 2003, 42, 4220–4224; (d) G. R. L.
Cousins, R. L. E. Furlan, Y.-F. Ng, J. E. Redman and J. K. M.
Sanders, Angew. Chem., Int. Ed., 2001, 40, 423–428; (e) G.
Zhang and M. Mastalerz, Chem. Soc. Rev., 2014, 43, 1934–1947;
(f) A. J. McConnell, C. S. Wood, P. P. Neelakandan and J. R.
Nitschke, Chem. Rev., 2015, 115, 7729–7793.
§
NMR titrations had to be carried out in acetonitrile to guarantee
fast exchange on the NMR timescale, as well as sufficient
solubility of all starting materials.
§§ The toxicity profile of all possible hydrolysis products will need
to be considered for applications in drug delivery. For instance,
DEG will likely have to be replaced with a less toxic derivative
(proof-of-principle reported in ref. 17) and R1 = CH2Cl might
pose a major liability due to the potential formation of toxic
chloroacetic acid.
11 (a) O. W. Howarth, G. G. Morgan, V. McKee and J. Nelson, J.
Chem. Soc. Dalt. Trans., 1999, 2097–2102; (b) Q. Lu, J.-M.
Latour, C. J. Harding, N. Martin, D. J. Marrs, V. McKee and J.
Nelson, J. Chem. Soc. Dalt. Trans., 1994, 1471–1478; (c) D.
MacDowell and J. Nelson, Tetrahedron Lett., 1988, 29, 385–386;
(d) J. Jazwinski, J.-M. Lehn, D. Lilienbaum, R. Ziessel, J. Guilhem
and C. Pascard, J. Chem. Soc. Chem. Commun., 1987, 1691–
1694.
1
(a) Z. Liu, S. K. M. Nalluri and J.F. Stoddart, Chem. Soc. Rev.,
2017, 46 2459–2478; (b) P. A. Gale and J. W. Steed,
,
Supramolecular chemistry: from molecules to nanomaterials,
Wiley, 2012.
2
3
T. Ogoshi, S. Kanai, S. Fujinami and T. Yamagishi, J. Am. Chem.
Soc., 2008, 5022–5023.
12 (a) S. Otto, R. L. E. Furlan and J. K. M. Sanders, Science, 2002,
297, 590–593; (b) H. Y. Au-Yeung, F. B. L. Cougnon, S. Otto, G. D.
(a) Z. Zhang, Y. Luo, J. Chen, S. Dong, Y. Yu, Z. Ma and F. Huang,
Angew. Chem., Int. Ed., 2011, 50, 1397–1401; (b) T. Ogoshi, T.A.
Yamagishi and Y. Nakamoto, Chem. Rev., 2016, 116, 7937–8002;
(c) N. L. Strutt, H. Zhang, M. A. Giesener, J. Lei and J. F. Stoddart,
Chem. Commun., 2012, 48, 1647–1649; (d) B. Shi, D. Xia and Y.
Yao, Chem. Commun., 2014, 50, 13932–13935; (e) W. Xia, M. Ni,
C. Yao, X. Wang, D. Chen, C. Lin, X. Y. Hu and L. Wang,
Macromolecules, 2015, 48, 4403–4409; (f) T. Ogoshi, H. Kayama,
Pantoş and J. K. M. Sanders, Chem. Sci., 2010,
Berrocal, R. Cacciapaglia and S. Di Stefano, Org. Biomol. Chem.,
2011, , 8190; (d) Y. Zhang, Y. M. Legrand, A. Van Der Lee and
1, 567; (c) J. A.
9
M. Barboiu, Eur. J. Org. Chem., 2016, 2016, 1825–1828.
13 (a) Z. Rodriguez-Docampo, E. Eugenieva-Ilieva, C. Reyheller, A.
M. Belenguer, S. Kubik and S. Otto, Chem. Commun., 2011, 47
,
9798; (b) E. A. Katayev, G. D. Pantos, A. D. Reshetova, V. N.
Khrustalev, V. M. Lynch, Y. A. Ustynyuk and J. L. Sessler, Angew.
Chem., Int. Ed., 2005, 44, 7386–7390.
D. Yamafuji, T. Aoki and T. Yamagishi, Chem. Sci., 2012,
3226; (g) S. Sun, X.-Y. Hu, D. Chen, J. Shi, Y. Dong, C. Lin, Y. Pan
and L. Wang, Polym. Chem., 2013, , 2224–2229; (h) B. Xia, B.
Zheng, C. Han, S. Dong, M. Zhang, B. Hu, Y. Yu and F. Huang,
Polym. Chem., 2013, , 2019–2024; (i) X. Wang, K. Han, J. Li, X.
Jia and C. Li, Polym. Chem., 2013, , 3998–4003.
3, 3221–
14 (a) R. W. Saalfrank, A. Dresel, V. Seitz, S. Trummer, F. Hampel,
M. Teichert, D. Stalke, C. Stadler, J. Daub, V. Schunemann and A.
4
X. Trautwein, Chem. - Eur. J., 1997, 3, 2058–2062; (b) R. W.
4
Saalfrank, H. Maid and A. Scheurer, Angew. Chem., Int. Ed.,
2008, 47, 8795–8824.
4
8 | Chem. Sci., 2018, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 9 of 10
View Article Online
DOI: 10.1039/C8SC01750F
Chemical Science
ARTICLE
15 (a) Y. Z. Voloshin, O. A. Varzatskii, A. I. Stash, V. K. Belsky, Y. N. 32 S. S. Kelkar and T. M. Reineke, Bioconjug. Chem., 2011, 22
Bubnov, I. I. Vorontsov, K. A. Potekhin, M. Y. Antipin and E. V. 1879–1903.
Polshin, Polyhedron, 2001, 20, 2721–2733; (b) M. D. Wise, J. J. 33 S. Potratz, A. Mishra and P. Bäuerle, Beilstein J. Org. Chem.,
Holstein, P. Pattison, C. Besnard, E. Solari, R. Scopelliti, G. 2012, , 683–692.
Bricogne and K. Severin, Chem. Sci., 2015, , 1004–1010; (c) S. 34 M. Srinivasarao and P. S. Low, Chem. Rev., 2017, 117, 12133–
M. Jansze, G. Cecot, M. D. Wise, K. O. Zhurov, T. K. Ronson, A. 12164.
M. Castilla, A. Finelli, P. Pattison, E. Solari, R. Scopelliti, G. E. 35 T. Nakashima, K. Tsuchie, R. Kanazawa, R. Li, S. Iijima, O.
,
8
6
Zelinskii, A. V. Vologzhanina, Y. Z. Voloshin, J. R. Nitschke and K.
Galangau, H. Nakagawa, K. Mutoh, Y. Kobayashi, J. Abe and T.
Severin, J. Am. Chem. Soc., 2016, 138, 2046–2054; (d) E.
Kawai, J. Am. Chem. Soc., 2015, 137, 7023–7026.
Anxolabéhère-Mallart, C. Costentin, M. Fournier, S. Nowak, M. 36 M. M. Obadia, B. P. Mudraboyina, A. Serghei, T. N. T. Phan, D.
Robert and J.-M. Savéant, J. Am. Chem. Soc., 2012, 134, 6104–
6107; (e) M. D. Wise, A. Ruggi, M. Pascu, R. Scopelliti and K.
Gigmes and E. Drockenmuller, ACS Macro Lett., 2014, 3, 658–
662.
Severin, Chem. Sci., 2013,
4
, 1658.
37 (a) C. D. Meyer, C. S. Joiner and J. F. Stoddart, Chem. Soc. Rev.,
2007, 36, 1705; (b) M. E. Belowich and J. F. Stoddart, Chem. Soc.
Rev., 2012, 41, 2003; (c) J. L. Segura, M. J. Mancheño and F.
Zamora, Chem. Soc. Rev., 2016, 45, 5635–5671; (d) Y. W. Wu, S.
Te Tung, C. C. Lai, Y. H. Liu, S. M. Peng and S. H. Chiu, Angew.
Chem., Int. Ed., 2015, 54, 11745–11749; (e) F. R. Bowler, J. J.
Diaz-Mochon, M. D. Swift and M. Bradley, M., Angew. Chem.,
Int. Ed., 2010, 49, 1809–1812.
16 (a) J.-M. Lehn, Angew. Chem., Int. Ed., 2015, 54, 3276–3289; (b)
C. W. Hsu and O. Š. Miljanić, in Dynamic Covalent Chemistry
Reactions, Principles, and Applications, eds. W. Zhang and Y. Jin,
John Wiley & Sons Ltd., First Edit., 2017, pp. 253–286.
17 O. Shyshov, R.-C. Brachvogel, T. Bachmann, R. Srikantharajah, D.
Segets, F. Hampel, R. Puchta and M. von Delius, Angew. Chem.,
Int. Ed., 2017, 56, 776–781.
18 (a) P. A. Gale, J. T. Davis and R. Quesada, Chem. Soc. Rev., 2017, 38 Z. Monasterio, A. Irastorza, J. I. Miranda and J. M. Aizpura, Org.
46, 2497–2519; (b) J. Zhou, G. Yu and F. Huang, Chem. Soc. Rev.,
2017, 46, 7021–7053.
Lett. 2016, 18, 2511–2514.
39 M. von Delius and R.-C. Brachvogel, Novel Crown ether
complexes and methods for producing the same, EP14186189.8,
2014.
19 S. Binauld and M. H. Stenzel, Chem. Commun., 2013, 49, 2082–
2102.
20 (a) J. N. Brönsted and W. F. K. Wynne-Jones, Trans. Faraday
Soc., 1929, 25, 59–76; (b) E. H. Cordes and H. G. Bull, Chem.Rev.,
1974, 74, 581–603; (c) Y. Chiang, A. J. Kresge, M. O. Lahti and D.
P. Weeks, J. Am. Chem. Soc., 1983, 105, 6852–6855; (d) P.
Deslongchamps, Y. L. Dory and S. Li, Tetrahedron, 2000, 56
,
3533–3537; (e) S. L. Repetto, J. F. Costello, C. P. Butts, J. K. W.
Lam and N. M. Ratcliffe, Beilstein J. Org. Chem., 2016, 12, 1467–
1475.
21 R.-C. Brachvogel and M. von Delius, Chem. Sci., 2015, 6, 1399–
1403.
22 J. A. Dean and N. A. Lange, Lange’s Handbook of Chemistry,
McGraw-Hill, New York, 15th edn., 1999.
23 (a) R. H. DeWolfe, Synthesis, 1974,
Kirchmeyer, A. Mertens, M. Arvanaghi and G. A. Olah, Synthesis,
1983, , 498–500; (c) K. Yamamoto, S. Abrecht and R. Scheffold,
Chimia, 1991, 45 86–88; (d) R. L. Talbott, Fluorocarbon
3, 152–172; (b) S.
6
,
Orthoesters, US3415847A, 1968.
24 M. von Delius, Synlett, 2015, 27, 177–180.
25 R.-C. Brachvogel, H. Maid and M. von Delius, Int. J. Mol. Sci.,
2015, 16, 20641–20656.
26 D. Brynn Hibbert and P. Thordarson, Chem. Commun., 2016, 52
12792–12805.
,
27 R. D. Shannon, Acta Cryst., 1976, A32, 751–767.
28 (a) R. W. Taft, J. Am. Chem. Soc., 1952, 74, 2729–2732; (b) R. W.
Taft, Steric Effects in Organic Chemistry, Wiley, New York, 1956.
29 A. G. Orrillo, A. La-Venia, A. M. Escalante and R. L. E. Furlan,
Chem. - Eur. J., 2018, 24, 3141–3146.
30 (a) S. Ulrich and P. Dumy, Chem. Commun., 2014, 50, 5810–
5825; (b) E. Bartolami, Y. Bessin, V. Gervais, P. Dumy and S.
Ulrich, Angew. Chem., Int. Ed., 2015, 54, 10183–10187.
31 D. A. Roberts, B. S. Pilgrim and J. R. Nitschke, Chem. Soc. Rev.,
2018, 47, 626–644.
This journal is © The Royal Society of Chemistry 20xx
Chem. Sci., 2018, 00, 1-3 | 9
Please do not adjust margins

Chemical Science
Page 10 of 10
View Article Online
DOI: 10.1039/C8SC01750F
Self-assembled orthoester cryptands offer appealing properties for applications in ion sensing and
transport, such as convenient post-functionalization and tunable biodegradation.