Deltamides and Croconamides: Expanding the Range of Dual H-bond Donors for Selective Anion Recognition

Article abstract of DOI:10.1002/chem.201704388

Dual H-bond donors are widely used as recognition motifs in anion receptors. We report the synthesis of a library of dual H-bond receptors, incorporating the deltic and croconic acid derivatives, termed deltamides and croconamides, respectively, and a comparison of their anion binding affinities (for monovalent species) and Br?nsted acidities to those of the well-established urea and squaramide dual H-bond donor motifs. For dual H-bonding cores with identical substituents, the trend in Br?nsted acidity is croconamides>squaramides>deltamides>ureas, with the croconamides found to be 10–15 pK_a units more acidic than the corresponding ureas. In contrast to the trends displayed by ureas, deltamides and squaramides, N,N′-dialkyl croconamides displayed higher binding affinity to chloride than the N,N′-diaryl derivatives, which was attributed to partial deprotonation of the N,N′-diaryl derivatives at neutral pH. A number of differences in anion binding selectivity were observed upon comparison of the dual H-bond cores. Whereas the squaramides display similar affinity for both chloride and acetate ions, the ureas have significantly higher affinity for acetate than chloride ions and the deltamides display higher affinity for dihydrogenphosphate ions than other oxoanions or halides. These inherent differences in binding affinity could be exploited in the design of anion receptors with improved ability to discriminate between monovalent anions.

Full text of DOI:10.1002/chem.201704388

A Journal of
Accepted Article
Title: Deltamides and croconamides: expanding the range of dual H-
bond donors for selective anion recognition
Authors: vincent zwicker, karen yuen, david smith, junming ho, lei qin,
peter turner, and Katrina Jolliffe
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201704388
Link to VoR: http://dx.doi.org/10.1002/chem.201704388
Supported by

10.1002/chem.201704388
Chemistry - A European Journal
FULL PAPER
Deltamides and croconamides: expanding the range of dual H-
bond donors for selective anion recognition
Vincent E. Zwicker,[a],‡ Karen K. Y. Yuen,[a],‡ David G. Smith,[a] Junming Ho,[b] Lei Qin,[a] Peter Turner[a]
and Katrina A. Jolliffe[a],*
Abstract: Dual H-bond donors are widely used as recognition motifs
in anion receptors. We report the synthesis of a library of dual H-bond
receptors, incorporating the deltic and croconic acid derivatives,
termed deltamides and croconamides, and a comparison of their
anion binding affinities (for monovalent species) and Brønsted
acidities to those of the well-established urea and squaramide dual H-
bond donor motifs. For dual H-bond cores with identical substituents,
the trend in Brønsted acidity is croconamides > squaramides
>deltamides > ureas, with the croconamides found to be 10-15 pKa
units more acidic than the corresponding ureas. In contrast to the
trends displayed by ureas, deltamides and squaramides, N,N’-dialkyl
croconamides displayed higher binding affinity to chloride than the
N,N’-diaryl derivatives, which was attributed to partial deprotonation
of the N,N’-diaryl derivatives at neutral pH. A number of differences in
anion binding selectivity were observed upon comparison of the dual
H-bond cores. Whereas the squaramides display similar affinity for
both chloride and acetate ions, the ureas have significantly higher
affinity for acetate than chloride ions and the deltamides display
higher affinity for dihydrogenphosphate ions than other oxoanions or
halides. These inherent differences in binding affinity could be
exploited in the design of anion receptors with improved ability to
discriminate between monovalent anions.
match for Y-shaped anions such as carboxylates.3 Dual hydrogen
bond donors have also been shown to have superior hydrogen
bond donicity to monodentate hydrogen bond donors of similar
acidity,4 providing improved anion binding capacity, together with
a decreased propensity for the receptor to be deprotonated by
basic anions. This latter property is of particular importance in the
development of new anion binding motifs, since if a hydrogen
bond donor is too acidic, it is no longer effective at binding to
anions at neutral pH.5 Finding dual hydrogen bonding motifs with
the right balance between hydrogen bond donicity and Brønsted
acidity should provide improved anion receptors and allow them
to be tailored towards specific anions.
Squaramides, which are derivatives of the cyclic oxocarbon
family,6 are widely recognized as having higher hydrogen bond
donicity than the analogous ureas (Figure 1), leading to higher
binding affinities for halide ions.7-9 This increase in affinity is
attributed to an increase in the aromaticity of the squaramide ring
upon anion binding10 and the ability to delocalize charge density
across both carbonyl groups.9 However, this also results in higher
Brønsted acidity, resulting in an increased propensity for
squaramide containing anion receptors to deprotonate in the
presence of basic anions such as acetate, leading to reduced
receptor selectivity.7
Introduction
The development of molecular receptors capable of the selective
recognition, sensing or transport of anionic species has numerous
potential applications, and this has led to an increasing interest in
anion receptor chemistry over the past two decades.1 While
several types of interactions including electrostatic interactions,
coordination bonds with metal ions and, more recently, halogen
bonds have been employed for anion recognition, hydrogen
bonds remain a key motif for binding to anions.1a,2 Dual hydrogen
bond donors such as (thio)ureas and squaramides (Figure 1) are
of particular interest in this regard, as they can form two hydrogen
bonds to an anionic guest and provide an excellent geometric
Figure 1. Structures of dual hydrogen bond donors for anion recognition.
The increased aromatic character of the squaramide ring upon
either hydrogen bonding or deprotonation is reflected in the high
Brønsted acidity of the parent squaric acid (pKa1 = 0.55).11 The
cyclic oxocarbon family also contains the three-carbon deltic acid
and five-carbon croconic acid, which have similar properties to
squaric acid but differ in their acidity (pKa1 = 2.57 and 0.68,
respectively).11 Whereas deltic acid (and the corresponding
dianion) are reported to be more strongly aromatic than squaric
acid, it has been suggested that croconic acid and its dianion are
not aromatic.12 We envisaged that these differences might impact
upon both the hydrogen bond donicity and Brønsted acidity of the
analogous amides: the deltamides and croconamides (Figure 1),
and impact their anion binding abilities. While anion recognition
by ureas and squaramides (including most of the compounds
UR1-6 and SQ1-6, Chart 1) has been extensively
investigated,3,7,9,13,14 there is only a single recent report of anion
[a]
Mr V. E. Zwicker, Dr K. K. Y. Yuen, Dr D. G. Smith, Mr L. Qin, Dr P.
Turner, Professor K. A. Jolliffe
School of Chemistry
The University of Sydney
NSW, 2006, Australia
E-mail: kate.jolliffe@sydney.edu.au
Dr J. Ho
[b]
School of Chemistry
University of New South Wales
NSW, 2052, Australia
‡ These authors contributed equally
Supporting information for this article is given via a link at the end of the
document.
This article is protected by copyright. All rights reserved.

10.1002/chem.201704388
Chemistry - A European Journal
FULL PAPER
Chart 1. Structures of the ureas, deltamides, squaramides and croconamides
binding by the croconamides15 and the analogous N,N’-
disubstituted deltamides have not previously been reported. In
order to compare the binding properties for monovalent anions of
ureas, deltamides, squaramides, and croconamides we
synthesized a systematic library of symmetrical croconamides
CR1-CR6 and deltamides DT1-DT6, bearing both alkyl and aryl
substituents (Chart 1). The aryl substituents were chosen to
include p-tert-butylphenyl derivatives for increased solubility in
organic solvents and p-nitrophenyl and p-trifluoromethylphenyl
groups, as these are commonly used to enhance anion binding
affinities for both urea and squaramide derivatives. The p-
nitrophenyl derivatives also allow the use of UV-visible
spectroscopy to monitor anion binding.9 For comparison, we also
synthesized and evaluated the known squaramide derivatives
SQ1,16 SQ217 and SQ4,18 for which little anion binding data has
been previously reported.
Results and Discussion
Synthesis.
Squaramides SQ1, SQ2, and SQ4 were synthesized via
condensation of diethyl squarate with two equivalents of
butylamine, benzylamine, and p-tert-butylaniline, respectively, as
reported previously.16-18 The aryl-substituted croconamides CR3-
CR6 were similarly prepared from dimethyl croconate,19 upon
condensation
with
aniline,
p-tert-butylaniline,
p-
trifluoromethylaniline,
and p-nitroaniline,
respectively.
Condensations with aniline and p-tert-butylaniline proceeded
within 24 hours and at room temperature whereas longer reaction
times (up to 48 hours) and elevated temperatures (up to 90oC)
were required for condensation of the electron deficient p-
trifluoromethylaniline and p-nitroaniline. In contrast, attempts to
synthesise the butyl-substituted croconamide CR1 from
dimethylcroconate and two equivalents of n-butylamine initially
gave a mixture of mono-, di-, and tri-functionalised derivatives of
croconic acid dimethyl ester (see ESI, Figure S2).20 This was
This article is protected by copyright. All rights reserved.

10.1002/chem.201704388
Chemistry - A European Journal
FULL PAPER
attributed to the increased nucleophilicity of the primary amine as
compared to aniline. Reduction of the reaction temperature to 5oC
and shortening of the reaction time to 30 minutes resulted in the
formation of the desired disubstituted croconamide CR1. The
synthesis of the benzyl substituted croconamide CR2 from
dimethylcroconate and two equivalents of benzylamine
proceeded within two hours and at room temperature. Crystals of
CR4 suitable for X-ray crystallography were obtained upon slow
evaporation of an acetonitrile solution. In the solid state, CR4
adopts a syn/syn conformation (see ESI Figure S89), similar to
excess sodium acetate and sodium carbonate, a low yield (5%) of
the corresponding cyclopropenone 12 could be isolated. Removal
of the DMB protecting groups with TFA proceeded smoothly to
give the bis(p-nitrophenyl)deltamide DT6.
With the exception of DT1, all of the prepared deltamides were
found to be stable when either stored under vacuum, at -20oC
under argon, or as DMSO solutions. DT1 was successfully
1
synthesized and characterized by H NMR, 13C NMR, and high
resolution mass spectrometry (HRMS) and its purity was
confirmed by liquid chromatography-mass spectrometry (LCMS).
However, DMSO and chloroform solutions of DT1 decompose
within few hours to give complex mixtures of ring-opened products
(Figure S1).22
that
recently
observed
for
the
N,N’-[3,5-
bis(trifluoromethyl)phenyl]-croconamide.15
Crystals of DT3 and DT4 suitable for single crystal X-Ray analysis
were obtained by slow evaporation of their respective dimethyl
sulfoxide (DMSO) solutions. (For full structure determination
details see the ESI.) In both cases, the deltamides adopt the
anti/anti-conformation required for dual H-bond donation to
anions. While the crystal structure of DT3 is solvent free (Figure
2, top), the DT4 structure incorporates a DMSO molecule.
Interestingly, the DMSO forms a hydrogen bond with only one of
the two available amide protons (N···O distance of 2.837(2) Å)
(Figure 2, bottom). This observation is in contrast to the solid-state
structures of a range of symmetrically substituted squaramides
such as SQ3, SQ5 or a 3,5-bis(tert-butyl) substituted squaramide,
all of which were found to bind to the DMSO oxygen in the solid
state through both amide hydrogen atoms.5,8
Scheme 1. Synthesis of deltamides DT1-DT6.
The deltamides were synthesised via an alternative approach,
using a modification of the method recently reported by Lambert
et al. for the synthesis of the deltic guanidinium macrostere.21
Deltamides DT1-DT6 were prepared starting from commercially
available tetrachlorocyclopropene 1 (Scheme 1). For DT1-DT5,
threefold nucleophilic substitution of 1 with the appropriate 2,4-
dimethoxybenzyl (DMB) protected anilines or aliphatic amines in
the presence of potassium carbonate afforded the corresponding
cyclopropenium chloride salts 2-6. Subsequent hydrolysis of the
trisubstituted species in the presence of excess sodium acetate
and sodium carbonate gave the corresponding cyclopropenones
7-11 which were then treated with trifluoroacetic acid (TFA) to
remove the DMB-protecting groups, affording deltamides DT1-
DT5 in moderate overall yields. Reaction of 1 with DMB-protected
p-nitroaniline under these conditions did not proceed even at
elevated temperatures. However, when the reaction was
performed at elevated temperatures and in the presence of
Figure 2. Single crystal X-ray diffraction determined depictions of DT3 (top) and
DT4∙DMSO (bottom) with displacement ellipsoids shown at the 50% probability
level. C=grey, O=red, N=blue, S=yellow, H=white, Hydrogen bonds=dashed
lines. The N···O distance is 2.837(2) Å..
Anion Binding Studies.
With the deltamides and croconamides in hand, we proceeded to
evaluate their anion binding abilities in d6-DMSO and d3-MeCN,
to allow comparison to previously reported data for the
squaramide and urea derivatives. Initial screening for anion
This article is protected by copyright. All rights reserved.

10.1002/chem.201704388
Chemistry - A European Journal
FULL PAPER
binding was performed by adding ten equivalents of the
tetrabutylammonium salts of a range of halide (Cl-, Br-, I-) and
substituents bearing electron withdrawing groups increases
affinity for a range of anions.3,8
monovalent oxoanions (HSO4 , H2PO4 , NO3 , ReO4 , ClO4 , TsO-,
BzO-, AcO-) to d6-DMSO solutions of receptors CR1-CR5 and
DT2-DT5, respectively. For CR1-CR5, only the addition of
chloride gave rise to significant downfield shifts of the
croconamide NH protons indicating the formation of hydrogen
-
-
-
-
-
Table 1. Apparent Association Constants (Ka, M-1) of Deltamides and
Croconamides for Anions in d6-DMSOa
-
bonds between the receptors and chloride. Addition of H2PO4 ,
-
Cl-
H2PO4
AcO-
BzO-
BzO-, and AcO- led to the disappearance of the NH signals and a
distinct color change from yellow to red, suggesting that these
anions deprotonate CR1-CR5. This was confirmed by UV-visible
spectroscopy, where upon addition of 10 equiv. of H2PO4- to CR5
the absorbance at 420 nm increased, together with the
disappearance of the two absorption bands at 383 and 470 nm.
Almost identical spectra were obtained upon addition of 10 equiv.
of hydroxide, confirming the deprotonation event (Figure 3).
For CR6, binding to anions was not observed in either d6-DMSO
or d3-MeCN. Signals attributable to the croconamide NH protons
were not observed in the NMR spectra in either solvent, and the
UV-vis spectra indicated that this compound exists in its
deprotonated form in both DMSO and MeCN solution (Figure S5).
Similar behavior has previously been observed for the analogous
p-nitrophenyl squaramide SQ6.18
c
c
c
CR1
CR2
CR3
CR4
CR5
CR6
DT2
DT3
DT4
DT5
DT6b
230
110
42
–
–
–
c
c
c
–
–
–
c
c
c
–
–
–
c
c
c
20
–
–
–
c
c
c
19
–
–
–
c
c
c
c
–
–
–
–
<5
9
110
11
6
>104
8700
>104
2300
1200
6500
730
500
4300
6
12
<100d
c
c
c
–
–
–
a
Determined by 1H NMR spectroscopy in DMSO-d6 (0.5% water) at 300 K
unless otherwise noted. Anions were added as their tetrabutylammonium
(TBA) salts. Values rounded to a maximum of two significant figures.
b
Estimated errors in Ka <15%.
Binding studies performed by UV-vis
spectroscopy in DMSO (0.5% water) at 298 K. c Addition of the anion caused
the receptor to deprotonate. d Changes in spectra too small to fit to a binding
model.
Given the propensity for the croconamides to deprotonate upon
addition of basic anions in DMSO, we also evaluated their binding
behavior in MeCN, since deprotonation of hydrogen bond donors
by anions is less likely in this solvent.25 In d3-MeCN, downfield
shifts of the signals attributable to the NH protons were observed
-
upon addition of all halide anions (Cl-, Br-, and I-) as well as NO3 ,
TsO-, and HSO4 and the titration data were fitted to 1:1 binding
-
Figure 3. Representative UV-Vis spectra recorded over the course of a titration
of CR5 (20 µM) with TBAOH (0 to 10 equiv.) in MeCN/water (9:1, v/v) at 298 K.
[OH-]=0, 4, 8, 12, 16, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140,
150, 160, 180, 200 µM.
models (as above) to provide association constants for these
-
anions (Table 2). However, the addition of H2PO4 , BzO-, and
AcO- again led to the deprotonation of receptors CR1-CR5 (as
observed for these anions in DMSO). In d3-MeCN, CR1-CR5 were
observed to bind halides with complex stability decreasing across
the series Cl- > Br- > I-, reflecting a correlation between binding
affinity and higher charge density of the anion. For the oxoanions,
Subsequent titrations of CR1-CR5 with TBACl were performed
and the data analyzed using bindfit (v0.5)23 and HypNMR.24 In all
cases, the best fit with the highest reproducibility was to a 1:1
binding model (Figure S29-S33) to give the association constants
in Table 1. Unexpectedly, alkyl derivatives CR1 and CR2 were
found to have higher affinities for chloride than the aryl derivatives
CR3-CR5, and for the aryl derivatives, the addition of the electron
withdrawing p-CF3 group to CR5 resulted in a decrease in affinity
in comparison to that observed for phenyl derivative CR3. This
trend is opposite that normally observed for urea and squaramide
derivatives, where it is well-established that addition of aryl
-
complex stability decreases along the series TsO- > HSO4- > NO3 ,
reflecting the intrinsic basicity of these oxoanions. For both
halides and oxoanions these trends parallel those previously
observed for both ureas and squaramides.9 However, in contrast
to both ureas and squaramides, the alkyl croconamides have
higher binding affinities for a given anion than the aryl derivatives,
as was observed in d6-DMSO.
This article is protected by copyright. All rights reserved.

10.1002/chem.201704388
Chemistry - A European Journal
FULL PAPER
Table 2. Apparent Association Constants (Ka, M-1) of Deltamides and Croconamides for Anions in MeCNa
Receptor
Association Constant Ka (M-1)
-
-
-
Cl-
Br-
I-
H2PO4
>104
BzO-
AcO-
NO3
48
TsO-
900
HSO4
590
5.0×104
390
680
60
Deltamides
Croconamides
DT4
DT6b
CR1
CR2
CR3
CR4
CR5
CR6b
630
120
970
5300
5700
550
140
280
27
>104
6500
c
2100
>104
>104
>104
1400
2100
280
230
2.8×107
2.4×105
2.5×106
—
3900
1500
1900
d
d
d
—
—
—
300
560
e
d
d
d
—
—
—
—
e
d
d
d
e
e
—
—
—
—
—
—
d
d
d
6
—
—
—
13
31
32
21
d
d
d
22
—
—
—
110
43
f
f
f
f
f
f
f
f
f
—
—
—
—
—
—
—
—
—
a Apparent association constants (Ka/M-1) determined by 1H NMR spectroscopy in MeCN-d3 (0.5% water) at 300 K unless otherwise noted. Anions were added as
their tetrabutylammonium (TBA) salts. Values rounded to a maximum of two significant figures. Estimated errors in Ka <15%. b Binding studies performed by UV-vis
c
spectroscopy in MeCN (0.5% water) at 298 K. Changes in UV-vis absorbance too small to obtain the association constant. d Addition of the anion resulted in
f
deprotonation of the receptor. e Ka could not be determined due to broadening of the NH proton signal. Receptor exists in its deprotonated form at neutral pH in
MeCN.
For the deltamides DT2-DT5, an anion screen in d6-DMSO (as
described above) showed negligible shifts of the signals
-
-
attributable to the NH protons upon addition of Br-, I-, HSO4 , NO3 ,
-
-
ReO4 , or ClO4 , with very small downfield shifts observed upon
addition of Cl-, and significant downfield shifts observed upon the
-
addition of H2PO4 , BzO-, and AcO-, indicating the formation of
hydrogen bonds to these anions. Subsequent titrations with Cl-,
-
H2PO4 , BzO-, and AcO- were performed and in all cases the
binding data was best fit to a 1:1 binding model (Table 1 and
Figure 4).26,27 For DT2-DT5, binding to Cl- was found to be very
weak (Ka < 12 M-1 in all cases), but stronger binding was observed
to the oxoanions with binding affinities decreasing across the
-
series H2PO4 > AcO- > BzO-. This trend does not correlate with
the basicity of the anions, in direct contrast to previous
observations for the urea and squaramide compound series,9,28
nor does it correlate with the recently reported hydrogen bond
acceptor parameter series, in which carboxylates are shown to be
stronger hydrogen bond acceptors than –O2P(OR)2.29
In general, the series DT2-DT5 follows the expected trend of aryl
substituents on the deltamide nitrogen atoms resulting in
increased binding affinity for all anions in comparison to alkyl
substituents and the introduction of electron withdrawing groups
onto the deltamide substituents results in increased anion affinity,
as has been previously observed for ureas and squaramides.8
The low solubility of the deltamides in MeCN prevented a detailed
evaluation of the binding affinities of DT2, DT3 or DT5 in this
solvent, but DT4 was sufficiently soluble to allow NMR titrations
to be performed in d3-MeCN with a wide range of anions, with
subsequent determination of association constants by fitting to a
1:1 binding model (Table 2). In this solvent, the binding trend for
the halide ions shows complex stability decreasing across the
series Cl- > Br- > I-, while for the oxoanions, complex stability
Figure 4. 1H NMR spectroscopic binding studies of DT3. (Top) Representative
stack plot of the 1H NMR spectrum of receptor DT3 (2.5 mM) upon titration with
TBA benzoate in DMSO-d6 (0.5% water) at 300 K. (Bottom) Fitting curves for
the titration data of DT3 with chloride, benzoate, and acetate. The titration data
was fitted to a 1:1 binding model.
-
decreases along the series H2PO4 > AcO- ≈ BzO- > TsO- ≈
-
-
HSO4- >> NO3 , with Cl- having a similar affinity to HSO4 . For DT6,
anion binding affinity was determined in more dilute solution using
This article is protected by copyright. All rights reserved.

10.1002/chem.201704388
Chemistry - A European Journal
FULL PAPER
UV-vis spectroscopic titrations.30 Addition of anions resulted in a
red-shift of the absorbance band at 385 nm, with a clear isosbestic
point indicating the presence of only two species in solution,
consistent with the formation of 1:1 complexes (Figure 5, top). A
similar trend in anion binding affinities was observed for DT6
under these conditions to that observed above for DT4 by NMR
titration (Table 2). Notably, no deprotonation of this receptor was
Crystals of the DT4 and DT5 complexes with benzoate suitable
for single crystal X-Ray analysis were obtained by slow
evaporation of DMSO solutions of DT4 and DT5, respectively in
the presence of tetrabutylammonium benzoate (TBABzO). As
shown in Figure 6, in the DT5-benzoate structure a DT5 molecule
forms a 1:1 complex with a benzoate anion through two hydrogen
bonds. The asymmetric interaction between the two at least in
part reflects the difference between the 2.238(3) Å carboxylate
oxygen-oxygen separation and the 3.582(2) Å amine nitrogen-
nitrogen separation. In contrast, as Fig. 7 indicates, in the DT4-
benzoate crystal structure the benzoate bridges two (of three; see
ESI material) crystallographically independent deltamide
-
observed in MeCN. However, in DMSO, addition of H2PO4 ,
AcO- and BzO- led to deprotonation of this receptor, as evidenced
by a decrease in the absorbance band at 406 nm and concomitant
increase in absorbance at 538 nm (Figure 5, bottom), which was
accompanied by a colour change of the receptor solution from
yellow to red. The addition of OH- led to similar changes in the
spectra, confirming that these were a result of deprotonation
(Figure S70). This is comparable to the behavior of the
corresponding p-nitrophenyl urea derivative, previously reported
by Fabbrizzi and coworkers.31
molecules, with one carboxylate oxygen participating in
a
hydrogen bond interaction with the amide proton of one deltamide
and the other carboxylate oxygen likewise linked to the amide of
the second deltamide. A water molecule provides a second
hydrogen bond bridge between the two deltamides.
Figure 6. Single crystal X-ray diffraction determined depictions of the
DT5∙benzoate complex, with displacement ellipsoids shown at the 50%
probability level. The tetrabutylammonium counterion and rotational disorder of
the p-CF3 groups (see the ESI material) are omitted for clarity. C=grey, O=red,
N=blue, F=bright green, H=white, Hydrogen bonds=dashed lines. The N···O
distances are 2.715(2) and 2.736(2) Å.
The structures of the DT4 and DT5 complexes demonstrate
binding mode flexibility that reflects both packing interactions and
the difference in separation between the carboxylate oxygens and
amine nitrogens. The DFT-optimized structures of DT5 and the
-
1:1 DT5 complexes with OAc- and H2PO4 indicate that the
-
H2PO4 ion is a better geometric match for the deltamide unit
(Figure 8), requiring less alteration of the free DT5 structure upon
binding. This provides a possible explanation for the unusual
binding trends observed for the deltamides with respect to these
oxoanions, since any change to the structure required for binding
to an anion would incur a ‘reorganisation’ energy penalty.
Figure 5. UV-Vis Spectroscopic Binding Studies of DT6. (Top) Representative
UV-Vis spectra recorded over the course of a titration of DT6 (20 µM) with TBA
acetate in MeCN (0.5% water) at 298 K. [AcO-] = 0, 2, 4, 6, 8, 10, 12, 14, 16, 18,
20, 22, 24, 26, 30, 34, 40, 50, 60, 70, 80, 100 µM. Inset: Fitting curve for the
titration data at 414 nm to a 1:1 binding model. (Bottom) Representative UV-Vis
spectra recorded over the course of a titration of DT6 (20 µM) with TBA acetate
in DMSO (0.5% water) at 298 K. [AcO-] = 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24,
30, 40, 50, 60, 80, 100 µM.
This article is protected by copyright. All rights reserved.

10.1002/chem.201704388
Chemistry - A European Journal
FULL PAPER
pKa<14.7 This is consistent with the pKa values of DT1-DT5
obtained computationally, which range from 13.9 to 22.4. In
contrast, the pKa for DT6 was established experimentally as 12.0,
indicating the increased acidity of the deltamide protons when the
strongly electron withdrawing p-nitrophenyl substituent is
appended to the nitrogen atom.
a
b
Figure 7. Single crystal X-ray diffraction determined depiction of the solid state
DT4∙benzoate complex, with displacement ellipsoids at the 50% probability level.
Two crystallographically independent DT4 molecules are bridged by hydrogen
bond interactions with a benzoate anion and a water molecule. A hydrogen
bond interaction between the bridging water molecule and the benzoate anion
is expected, however the water hydrogen sites were not located. A third
crystallographically independent DT4 molecule which does not participate in a
hydrogen bonding interaction with the benzoate anion (see ESI material) and
the tetrabutylammonium counterion are omitted for clarity. Disorder of the
benzoate anion and the water molecule is also not shown (see ESI material).
C=grey, O=red, N=blue, H=white, Hydrogen bonds=dashed lines.
c
pKa determination. To gain further insight into the anion binding
behavior of the croconamides and deltamides and place this in
context with regards to that of the ureas and squaramides, we
evaluated the Brønsted acidity of all four compound classes,
either through direct measurement of experimental pKa values or
via computation (Table 3). Where possible, experimental pKa
values were determined by pH-spectrophotometric titrations in a
mixture of acetonitrile-water (9/1, v/v) and in the presence of
TBAPF6 (0.1 M) as described previously for squaramide (SQ3
and SQ5, among others), thiosquaramide, urea (UR5), and
sulfonamide based anion receptors.5,7 Additionally, and in cases
where experimental values could not be obtained, theoretical pKa
values in MeCN were calculated using density functional theory
(DFT) at the G3(MP2,CC)-(+)32 level in conjunction with the SMD
implicit solvation model33 (see ESI for full details).34 In general,
the experimentally and computationally determined pKa values
are in reasonable agreement (within 1.3 pKa units) and allow for
a comparison of the acidity of the four different receptor classes
as well as for a comparison within one class.
Figure 8. M06-2X/6-31+G(d) optimized molecular structure of DT5,
DT5∙benzoate, and DT5∙dihydrogenphosphate complex in DMSO. H-H and O-
O bond distances (Å) and C-C-N bond angles (o) are indicated. C=cyan, O=red,
N=blue, F=pink, P=bronze, H=white.
For deltamides DT1-DT5, no deprotonation was observed in the
pH-spectrophotometric titrations. This behavior is similar to that
reported previously for UR57 indicating that the pKa values of
deltamide based receptors DT1-DT5 as well as the value for UR5
lie outside the range covered by the described pH-
spectrophotometric method, which is limited to compounds with
Deprotonation of the croconamides was more readily observed
experimentally. In the course of the pH-spectrophotometric
titrations, CR1 and CR2 were found to undergo a single
deprotonation event characterized by a decrease in absorbance
at ~397 nm with an increase at approx. 430 nm (Figure 9). An
absorbance peak at approx. 360 nm did not change significantly
This article is protected by copyright. All rights reserved.

10.1002/chem.201704388
Chemistry - A European Journal
FULL PAPER
decomposition of the croconamide core under these conditions.35
The experimentally obtained pKa values of CR1-CR5
corresponding to the first deprotonation event range from 7.3 to
10.2 and are summarized in Table 3. These values are in good
agreement with the calculated values also shown in Table 3. In
the case of CR6, the pKa could not be determined experimentally,
as the receptor was unstable in acidic conditions (pH < 5.5) as
determined by changes in both the UV-vis spectrum and NMR
spectra (Figure S88).
Table 3. Experimental and Calculated pKa Values for Ureas UR1-UR6,
Deltamides DT1-DT6, Squaramides SQ1-SQ6, and Croconamides CR1-CR6.
pKa
pKa
Exp.a
Calc.b
Exp.a
Calc.b
h
UR1
UR2
n.d.c
n.d.c
26.3
24.3
SQ1
SQ2
—
16.7
14.6
n.d. c
k
18.7d,
19.5e
n.d.c
18.3
SQ3
—
11.7i,
12.5j
UR3
1.6
UR4
UR5
18.7
15.3
SQ4
SQ5
n.d. c
9.8i
12.9
10.4
1.4
1.1
f
—
UR6
DT1
DT2
DT3
DT4
DT5
DT6
n.d. c
14.8
22.4
20.8
15.8
16.3
13.9
12.9
SQ6
CR1
CR2
CR3
CR4
CR5
CR6
n.d. c
10.2
9.3
10.0
11.2
10.4
7.1
1.2
0.8
Data
g
—
Fit
0.5
0.2
h
—
0.8
0.4
0.0
h
—
8.4
2
5
7
10 12
h
pH
—
8.6
7.8
h
—
7.3
6.8
l
12.0
—
5.9
aExperimental values determined using the pH-spectrophotometric method
described above in MeCN/water mixture (9/1, v/v; in the presence of 0.1 M
TBAPF6 unless otherwise stated. Errors estimated as ±0.5 pKa units.
bCalculated values determined in pure MeCN. Errors in calculated pKa values
[±1 pKa unit].34 cThe pKa value has not been determined or reported in the
literature. dData from reference 37. Measured in dry DMSO at 25oC using the
Bordwell overlapping indicator method;36 error ±0.1 pKa units. eData taken from
reference 38. Measured in DMSO at 25oC using the Bordwell overlapping
indicator method;36 error not reported. fNo deprotonation observed using the pH-
spectrophotometric method described above as reported in reference 7.
gReceptor not stable (see above). hPresent work. No deprotonation observed
250
350
450
550
650
750
Wavelength (nm)
Figure 9. Absorption spectra taken over the course of a pH-spectrophotometric
titration of CR1 in acetonitrile/water solvent mixture (9:1, v/v; in the presence of
0.1 M TBAPF6). (Inset): Four parameter sigmoid curve fit with the point of
inflexion corresponding to the pKa value of CR1.
i
using the pH-spectrophotometric method described above. Data taken from
reference 5. jData taken from reference 39. Measured in DMSO at 25oC using
the Bordwell overlapping indicator method;36 error ±0.1 pKa units. kReference
pKa for pKa calculations performed in this work. lNot determined due to instability
of receptor under acidic conditions.
While a direct comparison is not possible as a result of the
different solvent systems used, both the experimental and
computational pKa1 values determined for CR5 (7.3 and 6.8) in
this work are inconsistent with the previously reported pKa for this
compound in DMSO (10.8).15 Our titration data, which shows two
clear transitions between pH 4 and 12, suggests that the
previously reported value is in fact that of the second
deprotonation event (pKa2) for this molecule. Our lower pKa1 value
is more consistent with the observation that CR5 is readily
throughout the titrations. However, for the aryl-substituted
croconamides CR3, CR4 and CR5, a more complex titration
profile was observed. This is most obvious for the p-
trifluoromethylphenyl derivative CR5, although all compounds
follow the same trend. At low pH, CR5 has a broad absorbance
band (lmax 416 nm) with a shoulder evident at approx. 374 nm. An
absorbance of much lower intensity is also evident at 500 nm. As
the pH is increased, the shoulder at 374 nm grows in intensity and
an absorbance band grows at 454 nm, with a concomitant
decrease in absorbance at 416 nm. As the pH is increased further
(pH >9) the absorbance at 374 nm decreases in intensity while
the absorbance band at 454 nm is blue-shifted to 422 nm.
However, for this second transition, clear isosbestic points were
not obtained, suggesting the presence of multiple species in
solution. We postulate that the second transition may be the
second deprotonation event for the aryl-substituted croconamides
(CR3-CR5), which appear to be highly acidic, as indicated by their
-
deprotonated upon addition of the relative weak base, H2PO4 .
The ease with which the croconamides are deprotonated is further
demonstrated by the isolation of the tetrabutylammonium salt of
the bis(o-chlorophenyl) croconamide CR7 upon slow evaporation
of a MeCN solution of CR7 in the presence of five equivalents of
tetrabutylammonium sulfate (TBA2SO4). This resulted in the
formation of single crystals suitable for X-ray diffraction analysis.
The so obtained X-ray crystal structure shows
a singly
deprotonated CR7 anion with a tetrabutylammonium counterion
(TBA[CR7-H+]) (see Fig. 10 and the ESI material); the structure
does not contain sulfate. The C-N bond length between the five-
membered ring carbon and the deprotonated nitrogen atom is
1.285(2) Å, while that of the opposite C-N bond is 1.349(2) Å. The
C-O bond on the opposite side of the deprotonated nitrogen is
slightly but significantly elongated with respect to the adjacent and
the central C-O bond in the five-membered ring (1.239(2) Å c.f.
1.2262(19) Å and 1.2294(19) Å respectively). These observations
-
ready deprotonation by weakly basic anions such as H2PO4 . This
is consistent with the highly acidic nature of the parent croconic
acid, for which the reported values of pKa1 and pKa2 are 0.80 and
2.24, respectively.11 However, this could also reflect hydration or
This article is protected by copyright. All rights reserved.

10.1002/chem.201704388
Chemistry - A European Journal
FULL PAPER
are in agreement with the two resonance structures of [CR7-H+]-
(Fig. 10). The deprotonated croconamide crystal structure affirms
the conclusions drawn from the 1H NMR binding studies and pH
titrations. Croconamides appear to be prone to deprotonation
even in the presence of only slightly basic anions such as sulfate.
the low observed binding affinities for chloride ions and their
deprotonation by acetate. A similar trend in both binding affinity
and proton acidity has previously been observed for the
thiosquaramides.5 However, the pKas of the alkyl-substituted
croconamides CR1 and CR2, are similar to that of N,N’-
diphenylsquaramide SQ3 and this is reflected in the similar (and
relatively high) binding affinities observed for chloride ions by CR1
(Ka = 230 M-1) and SQ3 (Ka =260 M-1) in d6-DMSO. Both the alkyl
croconamides (CR1, CR2) and the arylsquaramides (SQ3-SQ6)
are deprotonated in DMSO solution upon addition of acetate.
One additional factor that may contribute to the different trend
observed for the croconamide series in comparison to the ureas
and squaramides is the energy penalty required for the molecules
to adopt the conformation required for anion binding. In DMSO
solution, the anti/anti- conformation required for anion binding is
favoured as a result of hydrogen bonding to DMSO solvent
molecules. In this conformation there is a tendency towards
planarization for all compounds upon chloride binding, increasing
the sp2 character on the nitrogen atom and providing more
favourable electrostatic interactions with the anion.34 The cost of
this ‘reorganisation’ energy penalty is higher for aryl
croconamides than for alkyl croconamides (Table S2) as a result
of increased steric interaction between the phenyl rings and the
carbonyl groups and this may contribute to the lower binding
affinities observed for the aryl croconamides.
In contrast, both urea and deltamide series of compounds bind
chloride only weakly (Ka <75 M-1) in d6-DMSO and binding
affinities follow the trend aryl > alkyl with the introduction of
electron withdrawing groups onto the aromatic substituents
providing a significant boost in binding affinity for the urea series,
but not for the deltamides. Since the deltamides are more acidic
than the corresponding ureas, this difference can not be explained
by differences in pKa and is more likely a result of geometric
factors, with the dual H-bond donors in the deltamides spaced
further apart than they are in the corresponding ureas. Indeed,
computational calculations suggest that complexation to chloride
incurs a significantly higher energy penalty in deltamides.34
Similarly, binding affinities for acetate are similar for both UR3 and
DT3, but DT3 is approx. 2.5 pKa units more acidic than UR3, so
would be expected to bind acetate more strongly if acidity of the
NH donor was the primary consideration.
Figure 10. (Top) Single crystal X-ray diffraction determined depiction of [CR7-
H+]- and it’s with TBA counterion. Displacement ellipsoids are shown at the 50%
probability level; disorder found for 2-chlorophenyl residue has been omitted
for clarity. C=grey, O=red, N=blue, Cl=purple, H=white. (Bottom) Mesomeric
structures of [CR7-H+]-.
Comparison of dual H-bond motifs. Table 4 summarizes the
apparent association constants Ka obtained as part of this work
for deltamides DT1-DT6, squaramides SQ1, SQ2, and SQ4, and
croconamides CR1-CR6, with chloride and acetate in DMSO
(0.5% water, unless otherwise noted). Where possible, literature
values are also given for ureas UR1-UR6 and squaramides SQ3,
SQ5, and SQ6. A number of differences are apparent between
these dual H-bond motifs, with regards to anion binding affinities
and selectivity. Some of these are partly explained by the
differences in pKa between the compound classes. For
compounds bearing the same substituents, the trend for pKa
values is ureas > deltamides > squaramides > croconamides with
the croconamides being 10 – 15 pKa units more acidic than the
corresponding ureas. Within each compound class the diaryl
derivatives are 4 – 8 pKa units more acidic than the dialkyl
derivatives, with the addition of p-nitro or p-trifluoromethyl groups
leading to decreased pKa values compared to the unsubstituted
phenyl derivatives.
The binding affinities for the p-nitrophenyl derivatives UR6, DT6,
and SQ6 in MeCN are provided in Table 5. No binding was
observed for CR6 under these conditions, as the receptor exists
predominantly in its deprotonated form. However, the differences
in binding affinities between the other dual H-bond donors are
readily observed in this less polar solvent. While all three
receptors display similar binding affinities for acetate (log Ka = 6.4-
6.6), chloride binding affinities vary by three orders of magnitude,
with SQ6 > UR6 > DT6. DT6 is therefore better able to
discriminate acetate from chloride than either SQ6 or UR6. DT6
-
also displays significantly higher affinity for H2PO4 than either
SQ6 or UR6, binding to this anion with a higher affinity than it
-
displays for acetate (DT6: log Ka 7.45 for H2PO4 , log Ka 6.40 for
AcO-); this trend is opposite to that displayed by either UR6 or
SQ6 and does not correlate with anion basicity. Thus, both
deltamides and ureas favor binding to oxoanions whereas the
Strikingly, the pKa of the aryl croconamides is 6-8, indicating that
they are partially deprotonated at neutral pH and explaining both
This article is protected by copyright. All rights reserved.

10.1002/chem.201704388
Chemistry - A European Journal
FULL PAPER
squaramides display similar affinities to both carboxylates and
chloride. In addition, the deltamides have a subtly different
selectivity profile to the ureas as a result of the greater distance
between the hydrogen bond donor atoms.
Table 5. Apparent Association Constants (logKa) for p-nitrophenyl Derivatives
in MeCN at 25 oC, Determined by UV-vis Titration.
Anion
UR6a
DT6
SQ6 a
CR6
Cl-
Br-
I-
4.55
3.22
<2
3.32
2.99
2.44
<2
6.05
4.70
3.51
3.68
4.02
n.d.
Deprot.
Deprot.
Deprot.
Deprot.
Deprot.
Deprot.
Deprot.
Table 4. Apparent Association Constants for Ureas UR1-UR6, Deltamides DT1-
DT6, Squaramides SQ1-SQ6, and Croconamides CR1-CR6 with chloride and
acetate in DMSOa
-
NO3
3.65
4.26
n.d.
5.37
-
HSO4
TsO-
4.70
3.59
7.45
Ka (M-1)
Cl-
Ka (M-1)
-
H2PO4
5.42
AcO-
Cl-
AcO-
AcO-
BzO-
6.61
6.40
5.38
6.5
Deprot.
Deprot.
c
UR1
UR2
< 10b
—
SQ1
SQ2
56
57
2200
c
c
—
—
2000k
a Values from reference 9.
c
UR3
UR4
UR5
UR6
DT1
DT2
DT3
DT4
31d
2100e
SQ3
SQ4
SQ5
SQ6
CR1
CR2
CR3
CR4
260d
—
c
c
j
—
—
300
—
c
c
75d
—
460d
—
Conclusions
g
m,i
l
120f
>104
—
—
A library of compounds incorporating dual H-bond motifs in the
form of croconamides and the hitherto unreported deltamides has
been prepared and their anion binding behavior and Brønsted
acidity has been evaluated and compared to that of the known
dual H-bond motifs, the ureas and squaramides. The
croconamides were found to be considerably more acidic than the
corresponding squaramides, and displayed an unusual trend in
chloride binding affinities, with the N,N’-dialkylcroconamides
having higher affinities than the N,N’-diaryl derivatives. This was
attributed to a combination of the N,N’-diaryl derivatives existing
partially in deprotonated form at neutral pH, therefore reducing
their ability to bind to anions, and the higher ‘reorganisation
energy’ penalty for aryl- vs alkyl-croconamides . In contrast, the
deltamides are less acidic than the squaramides, but more acidic
than the ureas. Within the deltamide series, the anion affinity trend
is analogous to that observed previously for both ureas and
squaramides, with the N,N’-diaryl derivatives displaying higher
affinity than the N,N’-dialkyl derivatives, and the introduction of
electron withdrawing groups to the aryl substituents resulting in
increased anion affinity. Hence binding affinity within a series
reflects the inherent acidity of the amide protons.
h
h
j
—
—
230
110
42
—
j
< 5
9
11
—
j
2300
6500
—
j
6
20
—
j
DT5
DT6
12
1200
CR5
CR6
19, 10m
—
j
l
l
<100i
—
—
—
aApparent association constants (Ka/M-1) determined by 1H NMR spectroscopy
in DMSO-d6 (0.5% water) at 300 K unless otherwise noted. Anions were added
as their tetrabutylammonium (TBA) salts unless otherwise noted. Values
rounded to a maximum of two significant figures. Estimated errors in Ka <15%
unless otherwise noted. bValue reported in reference 40 for the UR1 analogue
1-butyl-3-isopentylurea as determined by 1H NMR spectroscopy in DMSO-d6
(0.5% water) at 298 K (estimated error <15%). cKa not reported in the literature.
dValue from reference 8. Ka in DMSO-d6 (0.5% water) at 298 K (estimated error
in Ka <15%). eValue from reference 41. Ka in DMSO-d6 (0.5% water) at 298 K
(error in Ka ±18%). f Value from reference 42. Ka in DMSO-d6 (0.5% water) at
298 K (error in Ka ±2%). gValue from reference 42. Ka in DMSO-d6 (0.5% water)
at 298 K. Acetate was added as its tetramethylammonium salt. hReceptor not
stable. iThe absorbance changes observed during UV-vis spectroscopic
titrations of DT6 with chloride in DMSO-d6 (0.5% water) at 298 K were too small
to obtain an accurate value for Ka. jAddition of the anion caused the receptor to
deprotonate. kValue from reference 17. Ka in DMSO-d6 at 295 K (error in Ka
<5%). Acetate was added as its tetramethylammonium salt. lThe receptor exists
in its deprotonated form in DMSO. mValue from reference 15. Ka in dry DMSO-
d6 at 295 K (error in Ka <1%).
Some interesting differences in anion binding selectivities emerge
when different dual H-bond cores with the same substituents are
compared. The deltamides display lower anion binding affinities
for chloride than the corresponding ureas and squaramides,
whereas the affinity of all three dual H-bond cores for acetate ions
is similar. In contrast to the ureas and squaramides, where anion
binding affinity correlates with anion basicity, the deltamides also
-
display higher affinity for H2PO4 than for carboxylates and other
oxoanions. This can be attributed to the differences in structure
between these three cores, which position the amide protons at
different distances and different angles with respect to one
another. Hence the geometric match between the receptor and
anion appears to be a significant factor in determining anion
selectivity.
This article is protected by copyright. All rights reserved.

10.1002/chem.201704388
Chemistry - A European Journal
FULL PAPER
[13] For recent reviews on anion recognition by ureas see: V. Blazek Bregovic,
N. Basaric, K. Mlinaric-Majerski, Coord. Chem. Rev. 2015, 295, 80-124;
A.-F. Li, J.-H. Wang, F. Wang, Y.-B. Jiang, Chem. Soc. Rev. 2010, 39,
3729-3745.
These differences in binding selectivity for the different dual H-
bond donor cores could be exploited through their incorporation
into more complex molecular scaffolds containing multiple dual
hydrogen bond donors, where, in addition to matching anion
geometry through scaffold design, the inherent selectivity of the
dual H-bond donor motifs can now be tuned to match the anion of
interest, while the strength of the interaction for a given core can
be tuned through appropriate substitution of the amide nitrogen
atoms. This will assist in the design of future anion receptors that
bind to their targets using hydrogen-bonding.
[14] For reviews on squaramides see J. Aleman, A. Parra, H. Jiang, K. A.
Jorgensen, Chem. Eur. J. 2011, 17, 6890-6899; R. I. Storer, C. Aciro, L.
H. Jones, Chem. Soc. Rev. 2011, 40, 2330-2346.
[15] A. Jeppesen, B. E. Nielsen, D. Larsen, O. M. Akselsen, T. I. Solling, T.
Brock-Nannestad, M. Pittelkow, Org. Biomol. Chem. 2017, 15, 2784-2790.
[16] S. P. Kumar, P. M. C. Gloria, L. M. Goncalves, J. Gut, P. J. Rosenthal, R.
Moreira, M. M. M. Santos, Medchemcomm 2012, 3, 489-493.
[17] R.; Prohens, S. Tomas, J. Morey, P. M. Deya, P. Ballester, A. Costa,
Tetrahedron Lett. 1998, 39, 1063-1066.
[18] A. Rostami, A. Colin, X. Y. Li, M. G. Chudzinski, A. J. Lough, M. S. Taylor,
J. Org. Chem. 2010, 75, 3983-3992.
Acknowledgements
[19] R. Malachowsky, S. Prebendowsky, Ber. Deutsch. Chem. Ges. 1938, 71,
2241-2247.
We thank the Australian Research Council for financial support
(DP170100118 and DP140100227). We thank the University of
Sydney for an International Postgraduate Research Scholarship
(V.E.Z.) and the School of Chemistry (USyd) for John A.
Lamberton Scholarships (V.E.Z. and L.Q.). Data collection
assistance from the EPSRC funded UK National Crystallography
Service at the University of Southampton is gratefully
acknowledged.
[20] R. Breslow, C. Werner, Tetrahedron Lett. 1999, 40, 2447.
[21] K. Mishiro, F. H. Hu, D. W. Paley, W. Min, T. H. Lambert, Eur. J. Org.
Chem. 2016, 1655-1659.
[22] K. J. Walst, R. Yunis, P. M. Bayley, D. R. Macfarlane, C. J. Ward, R. Wang,
O. J. Curnow, RSC Adv. 2015, 5, 39565-39579; M. J. Taylor, P. W. J.
Surman, G. R. Clark, J. Chem. Soc., Chem. Commun. 1994, 2517.
[23] http://supramolecular.org (accessed 12th of April, 2017)
[24] P. Gans, A. Sabatini, A. Vacca, Talanta 1996, 43, 1739-1753.
[25] D. Esteban-Gómez, L. Fabbrizzi, M. Licchelli, J. Org. Chem. 2005, 70,
5717-5720.
Keywords: anion recognition • hydrogen bonding • deltamide •
[26] A 1:1 binding model was used as it gave the most consistent and
reproducible association constants with the best fits, but analysis of the
residuals43 suggests that at higher anion concentrations, the 1:1 model is
no longer valid for these compounds. However, attempts to fit the binding
data to alternative models (e.g. 2:1) using both bindfit (v0.5) and HypNMR
gave highly variable results.
[27] For titration of DT5 with H2PO4- the changes in chemical shift of the signals
for the NH protons could not be followed due to peak broadening. In this
case, the association constant was determined by monitoring the changes
in chemical shift of the aromatic proton signals.
croconamide • squaramide
[1] (a) P. A. Gale, E. N. W Howe, X. Wu, Chem 2016, 1, 351-422; (b) T. S.
Snowden, E. V. Anslyn, Curr. Opin. Chem. Biol. 1999, 3, 740-746; (c) T.
Gunnlaugsson, M. Glynn, G. M. Tocci, P. E. Kruger, F. M. Pfeffer, Coord.
Chem. Rev. 2006, 250, 3094-3117; (d) E. A. Katayev, Y. A. Ustynyuk, J.
L. Sessler, Coord. Chem. Rev. 2006, 250, 3004-3037; (e) E. J. O'Neil, B.
D. Smith, Coord. Chem. Rev. 2006, 250, 3068-3080; (f) S. Kubik, Chem.
Soc. Rev. 2010, 39, 3648-3663; (g) A. Caballero, F. Zapata, P. D. Beer,
Coord. Chem. Rev. 2013, 257, 2434-2455; (h) R. B. P. Elmes, K. A. Jolliffe,
Chem. Commun. 2015, 51, 4951-4968; (i) M. J. Langton, C. J. Serpell, P.
D. Beer, Angew. Chem. Int. Ed. 2016, 55, 1974-1987.
[28] I. L. Kirby, M. Brightwell, M. B. Pitak, C. Wilson, S. J. Coles, P. A. Gale,
Phys. Chem. Chem. Phys. 2014, 16, 10943-10958.
[29] S. J. Pike, J. J. Hutchinson, C. A. Hunter, J. Am. Chem. Soc., 2017, 139,
6700-6706.
[2] For a recent review see N. Busschaert, C. Caltagirone, W. Van Rossom,
P. A. Gale, Chem. Rev. 2015, 115, 8038-8155.
[30] Sufficient quantities of DT6 to perform NMR titrations were not readily
available.
[3] V. Amendola, L. Fabbrizzi, L. Mosca, Chem. Soc. Rev. 2010, 39, 3889-
3915.
[31] M. Boiocchi, L. Del Boca, D. Esteban-Gómez, L. Fabbrizzi, M. Licchelli, E.
Monzani, J. Am. Chem. Soc., 2004, 126, 16507-16514.
[32] D. J. Henry, M. B. Sullivan, L. Radom, J. Chem. Phys. 2003, 118, 4849-
4860.
[4] S. Tshepelvitsch, A. Trummal, K. Haav, K. Martin, I. Leito, J. Phys. Chem.
A 2017, 121, 357-369.
[5] N. Busschaert, R. B. P. Elmes, D. D. Czech, X. Wu, I. L. Kirby, E. M. Peck,
K. D. Hendzel, S. K. Shaw, B. Chan, B. D. Smith, K. A. Jolliffe, P. A. Gale,
Chem. Sci. 2014, 3617-3626.
[33] A. V. Marenich, C. J. Cramer, D. G. Truhlar, J. Phys. Chem. B 2009, 113,
6378-6396.
[34] J. Ho, V. E. Zwicker, K. K. Y. Yuen, K. A. Jolliffe, J. Org. Chem., 2017, 82,
10732-10736.
[6] R. West, Aldrichimica Acta 1968, 1, 3-6.
[7] V. Amendola, L. Fabbrizzi and L. Mosca, F. P. Schmidtchen, Chem. Eur.
J. 2011, 17, 5972-5981.
[35] W. Städeli, R. Hollenstein, W. von Philipsborn, Helv. Chim. Acta., 1977,
60, 948-958.
[8] N. Busschaert, I. L. Kirby, S. Young, S. J. Coles, P. N. Horton, M. E. Light,
P. A. Gale, Angew. Chem. Int. Ed. 2012, 51, 4426-4430.
[9] V. Almendola, G. Bergamachi, M. Boiocchi, L. Fabbrizzi, M. Milani, Chem.
Eur. J. 2010, 16, 4368-4380.
[36] W. S. Matthews, J. E. Bares, J. E. Bartmess, F. G. Bordwell, F. J.
Cornforth, G. E. Drucker, Z. Margolin, R. J. Mccallum, G. J. Mccollum, N.
R. Vanier, J. Am. Chem. Soc. 1975, 97, 7006-7014.
[37] G. Jakab, C. Tancon, Z. G. Zhang, K. M. Lippert, P. R. Schreiner, Org.
Lett. 2012, 14, 1724-1727.
[10] D. Quiñonero, C. Garau, A. Frontera, P. Ballester, A. Costa, P. M. Deyà,
Chem. Eur. J. 2002, 8, 433.
[38] F. G. Bordwell, D. J. Algrim, J. A. Harrelson, J. Am. Chem. Soc. 1988, 110,
5903-5904.
[11] L. M. Schwartz, R. I. Gelb, D. A. Laufer, Physical Chemistry of
Oxocarbons, Chapter 3 in Oxocarbons, Ed. R. West, Academic Press,
New York, 1980, pp43-58.
[39] X. Ni, X. Li, Z. Wang, J. P. Cheng, Org. Lett. 2014, 16, 1786-1789.
[40] N. J. Andrews, C. J. E. Haynes, M. E. Light, S. J. Moore, C. C. Tong, J. T.
Davis, W. A. Harrell, P. A. Gale, Chem. Sci. 2011, 2, 256-260.
[12] D. Quiñonero, A. Frontera, P. Ballester, P. M. Deyà, Tetrahedron Lett.,
2000, 41, 2001-2005.
This article is protected by copyright. All rights reserved.

10.1002/chem.201704388
Chemistry - A European Journal
FULL PAPER
[41] S. A. Kadam, K. Martin, K. Haav, L. Toom, C. Mayeux, A. Pung, P. A.
Gale, J. R. Hiscock, S. J. Brooks, I. L. Kirby, N. Busschaert, I. Leito, Chem.
Eur. J. 2015, 21, 5145-5160.
[42] L. Kirby, M. B. Pitak, M. Wenzel, C. Wilson, H. A. Sparkes, S. J. Coles, P.
A. Gale, CrystEngComm 2013, 15, 9003-9010.
[43] P. Thordarson, Chem. Soc. Rev. 2011, 40, 1305-1323.
This article is protected by copyright. All rights reserved.

10.1002/chem.201704388
Chemistry - A European Journal
FULL PAPER
Layout 1:
FULL PAPER
Vincent E. Zwicker Karen K. Y. Yuen‡
David G. Smith, Junming Ho, Lei Qin,
Peter Turner and Katrina A. Jolliffe*
Bite-angle and Brønsted acidity
control anion binding affinity and
selectivity by amides from the oxo-
carbon family.
Page No. – Page No.
Deltamides and croconamides:
expanding the range of dual H-bond
donors for selective anion
recognition
hic here: max. width: 5.5 cm; max.
This article is protected by copyright. All rights reserved.