Amphoteric Homotropic Allosteric Association between a Hexakis-Urea Receptor and Dihydrogen Phosphate

Article abstract of DOI:10.1002/chem.201904241

Conformationally flexible hexakis-urea 1 was synthesized efficiently by condensing hexakis(aminomethyl)benzene with 4-nitrophenyl-(3,5-di-tert-butylphenyl)carbamate. The hexakis-urea 1 is unexpectedly soluble in organic solvents of low polarity due to int

Full text of DOI:10.1002/chem.201904241

A Journal of
Accepted Article
Title: Amphoteric Homotropic Allosteric Association between a
Hexakis-Urea Receptor and Dihydrogen Phosphate
Authors: Seiya Kondo, Junya Masuda, Tomoki Komiyama, Nobuhiro
Yasuda, Hikaru Takaya, and Masamichi Yamanaka
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.201904241
Link to VoR: http://dx.doi.org/10.1002/chem.201904241
Supported by

10.1002/chem.201904241
Chemistry - A European Journal
COMMUNICATION
Amphoteric Homotropic Allosteric Association between a
Hexakis-Urea Receptor and Dihydrogen Phosphate
Seiya Kondo+, Junya Masuda+, Tomoki Komiyama, Nobuhiro Yasuda, Hikaru Takaya,* Masamichi
Yamanaka*
Abstract: Conformationally flexible hexakis-urea 1 was synthesized
efficiently by condensing hexakis(aminomethyl)benzene with 4-
nitrophenyl-(3,5-di-tert-butylphenyl)carbamate. The hexakis-urea 1 is
unexpectedly soluble in organic solvents of low polarity due to
intramolecular hydrogen bonding. The hexakis-urea 1 recognizes
chloride, bromide, and acetate in a 1:2 host–guest ratio and in a
positive allosteric manner in CDCl3. The ability of 1 to recognize
dihydrogen phosphate is a unique outcome, and the structure of the
associated complex, which structure contains four dihydrogen
phosphate ions, was clarified by single-crystal X-ray structural
analysis. However, in solution, a complex with three dihydrogen
phosphate ions was identified. The dihydrogen phosphate association
in CDCl3 proceeds in an amphoteric allosteric manner; in a positive
allosteric manner (K1 < K2) in the first step and a negative allosteric
manner (K2 > K3) in the subsequent step.
these contradictory requirements of flexibility and rigidity remains
a challenging subject in supramolecular chemistry.
A hexa-substituted benzene bearing flexible methylene
linkers is a soft framework with changeable and conformational
flexibly; for example, the six substituents can be alternately
oriented above and below the plane of the benzene ring (the
ababab conformation), or they can all be oriented in the same
direction (the aaaaaa conformation) (Figure 1). In the absence of
interactions between substituents, the ababab conformation is the
thermodynamically most stable; this conformation has separate
cavities for guest recognition. By introducing appropriate
hydrogen–bonding substituents, the aaaaaa conformation can
become more favorable than the ababab conformation through
the formation of intramolecular hydrogen bonds.[8] The aaaaaa
conformation of a hexa-substituted benzene is a rigid and pre-
organized
conformation;
consequently,
hexa-substituted
benzenes with appropriate hydrogen–bonding functional groups
are expected to be adequate allosteric receptor structures.
Allosteric cooperativity is important for realizing complex
biological processes.[1] For example, the positive homotropic
allosteric association between four oxygen molecules and
hemoglobin enables the efficient binding and release of molecular
oxygen at appropriate organs.[2] Protein structural dynamics is the
key to realizing allosteric association in nature.[3] Inspired by
nature, much attention has been paid to creating artificial
allosteric systems, especially for allosteric receptors.[4,5] The
flexible conformational alteration of a receptor is the key to
achieving allosteric recognition of guest molecules.[5,6] On the
other hand, pre-organization[7] is a typical strategy used to design
artificial receptors with high affinities and selectivities. Accordingly,
the development of an artificial allosteric receptor that satisfies
Ideal positive allosteric cooperativity accompanying guest
recognition occurs through the dynamic conformational
transformation of the aaaaaa conformation into the ababab
conformation. With this in mind, we selected ureido as a
hydrogen–bonding functional group for incorporation onto the
hexa-substituted benzene framework. The ureido group has been
used as an anion receptor,[9] in organocatalysis,[10] as
components of supramolecular polymers,[11] and in capsular
assembly.[12] Some allosteric receptors have been developed for
anions by appropriately arranging multiple ureido groups.[13] In
this paper, we report a highly symmetrical and conformationally
flexible hexakis-urea 1 as an allosteric receptor for anions; 1
recognizes typical anions in 1:2 host–guest ratios in a positive
homotropic allosteric manner. Furthermore,
1 recognizes
[*]
S. Kondo,[+] J. Masuda,[+] T. Komiyama, Prof. Dr. M. Yamanaka
Department of Chemistry, Faculty of Science, Shizuoka University
836 Ohya, Suruga-ku, Shizuoka 422-8529 (Japan)
E-mail: yamanaka.masamichi@shizuoka.ac.jp
Dr. N. Yasuda
Research and Utilization Division, Japan Synchrotron Radiation
Research Institute, Sayo 679-5198 (Japan)
Prof. Dr. H. Takaya
dihydrogen phosphate in a 1:3 host–guest ratio with a unique
amphoteric homotropic allosteric manner; i.e., a positive allosteric
manner (K1 < K2) in the first step and negative allosteric manner
(K2 > K3) in the subsequent step. Single crystal X-ray analyses
revealed the flexible conformations of hexakis-urea 1 and the
structures of its guest-associated complexes.
Institute for Chemical Research, Kyoto University
Gokasho, Uji, Kyoto 611-0011 (Japan)
E-mail: takaya@scl.kyoto-u.ac.jp
Prof. Dr. M. Yamanaka
Research Institute of Green Science and Technology
Shizuoka University
836 Ohya, Suruga-ku, Shizuoka 422-8529 (Japan)
These authors contributed equally to this work.
[+]
Supporting information and the ORCIDidentification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.
Figure 1. Schematic representation of the flexible conformation conversion of a
hexa-substituted benzene: the ababab conformation (left) and the aaaaaa
conformation (right).
This article is protected by copyright. All rights reserved.

10.1002/chem.201904241
Chemistry - A European Journal
COMMUNICATION
Hexakis-urea 1, which bears six ureido groups bonded to the
core benzene ring through methylene linkers, was designed as a
receptor molecule for anions. The methylene groups of 1 play
important roles in term of realizing flexible conformational
conversion (Figure 1). The ureido groups in 1 are all oriented in
the same direction in a non-polar organic solvent, which is due to
intramolecular hydrogen bonding.[8] Hexakis-urea 1 is efficiently
are positioned outwards. Solvation between the tert-butyl groups
and organic solvents of low polarity results in the high solubility of
hexakis-urea 1 in these solvents. Variable-concentration 1H NMR
spectra in CDCl3 indicated that 1 exists in a discrete monomeric
form through intramolecular hydrogen bonding (Figure S2).
synthesized
from
hexakis(aminomethyl)benzene
which was in-situ converted into
hexahydrochloride 2[14]
,
hexakis(aminomethyl)benzene, the free-base form, by the
reaction of appropriate amount of sodium hydroxide, followed by
condensation
with
4-nitrophenyl-(3,5-di-tert-
butylphenyl)carbamate (3) to afford 1 (Scheme 1). To our delight,
the desired hexakis-urea 1 was isolated in 80% yield, and no
partially reacted by-products (pentakis-urea, tetrakis-urea, etc.)
were detected. The structure of 1 was confirmed by NMR
spectroscopy and mass spectrometry (MS) (Supporting
Information).
Figure 2. 1H NMR spectra of 1 in a) CDCl3, b) DMSO-d6.
The intramolecularly hydrogen-bonded monomeric structure
of hexakis-urea 1 was finally confirmed by single crystal X-ray
analysis of a crystal prepared by the slow diffusion of cyclohexane
to a CHCl3 solution of 1 (1-CHCl3) (Table S2). As shown in Figures
3a and S3, all of the ureido groups are locked by intramolecular
hydrogen bonding and are aligned in the same direction to form
the aaaaaa conformation and a bowl-shaped structure with
appreciable interior space for cyclohexane encapsulation (Figure
S4). The hydrogen bonds in this assembly show different lengths
at the bottom of the core benzene–ring (Hb) and the mouth of the
bowl (Hc), with average distances of 1.90 and 2.32 Å, respectively;
the latter is substantially longer than the common value of an
inter-ureido hydrogen bond (~2.00 Å). The molecular packing
structure of 1-CHCl3 shows no intermolecular hydrogen bonds
(Figure S4e) and all ureido groups participate in the
intramolecular hydrogen-bonded assembly. These results are in
Scheme 1. Synthesis of hexakis-urea 1.
1
good agreement with the H NMR spectrum of 1 in CDCl3. Note
that a chiral ureido-group conformation is formed in the crystalline
phase, in which all ureido groups are directed in a left-handed
manner as viewed from the bowl mouth; the C2 crystal space
group of 1 is in agreement with the observed chiral separation
(Figure S4f). Such spontaneous chiral crystallization of achiral
molecule has been well known phenomenon where the achiral
organic molecules are assembled in an enantioselective manner
through hydrogen bonding, -, or C-H- interactions, giving a
mixture of chiral crystal.[16] Unfortunately, we could not succeeded
X-ray crystallographic analysis of the crystal of 1 possessing an
opposite right-handed chirality.
Ureidos are generally poorly soluble in organic solvents,
especially organic solvents of low polarity, such as chloroform and
benzene, if the hydrogen bond donors and acceptors cannot be
saturated intramolecularly as in the receptor described here.[15]
Their poor solubilities are obstacles that prevent their applications
as supramolecular receptors. However, somewhat unexpectedly,
1 was found to be extremely soluble in organic solvents (Table
S1); it was highly soluble in halogenated solvents, with its
saturation concentrations in dichloromethane, chloroform, and
1,1,2,2-tetrachloroethane determined to be 11 mM, 19 mM and
60 mM, respectively. The saturation concentrations of 1 in non-
polar toluene and benzene are 4 mM and 7 mM, respectively,
while the solubility of 1 in polar DMSO, in which higher solubility
1
was expected, is low, at 2.5 mM. The H-NMR spectra of 1 in
DMSO-d6 and CDCl3 are significantly different (Figures 2 and S1).
The NH proton (Hb) signal of the ureido moieties in CDCl3 appear
down field (9.36 ppm) compared to the shift in DMSO-d6 (6.49
ppm). The methylene protons (Ha) are split into two signals in
CDCl3, while they appear as a broad singlet in DMSO-d6. These
spectral differences are ascribable to conformational differences
in the two solvents. The ureido moieties of 1 can freely change
their orientations in DMSO-d6, while their orientations are more
rigid in CDCl3 as a result of intramolecular hydrogen bonding
between ureido groups. In the latter conformation, the polar ureido
groups are positioned inwards and the less polar tert-butyl groups
Figure 3. X-ray crystal structures of a) 1-CHCl3 (the aaaaaa conformation from
CHCl3 and cyclohexane), b) 1-DMSO (the ababab conformation from DMSO).
All the solvated molecules are omitted for clarify.
This article is protected by copyright. All rights reserved.

10.1002/chem.201904241
Chemistry - A European Journal
COMMUNICATION
In marked contrast, the single crystals of 1 formed from the
DMSO solution are significantly different (Figures 3b and S5,
Table S3). The ababab conformation of 1-DMSO reveals six
ureido groups that are alternately positioned on opposite side of
the plane of the benzene ring. In the crystalline phase, two pairs
of ureido groups are intermolecularly hydrogen bonded to afford
a ladder-like conformation; the remaining ureido pairs are
intramolecularly hydrogen bonded to tightly maintain the ababab
conformation (Figure S6). No molecule is encapsulated in the
ababab conformer of 1-DMSO in the crystal phase, despite the
presence of cavity spaces of sufficient size.
complex and free 1 (Figure 4a), which means that the association
and dissociation of dihydrogen phosphate with 1 are sufficiently
slower than the NMR timescale.
The anion recognition properties of 1 in CDCl3 were examined
1
by acquiring and analyzing the H NMR spectra of mixtures of 1
and tetrabutylammonium (TBA+) salts. The chemical shifts of the
protons in 1 changed upon addition of the chloride (Cl−), bromide
(Br−), and acetate (CH3COO−) salts of TBA (Figure S7), while the
−
addition of the corresponding hexafluorophosphate (PF6 ),
−
perchlorate (ClO4 ), and iodide (I−) did not result in any changes
in these chemical shifts (Figure S8). A Job plot constructed by the
1H NMR titration of 1 and TBACl revealed a 1:2 (1:Cl−) complex
stoichiometry (Figures S9 and S10). Electrospray ionization
Fourier-transform ion cyclotron resonance MS (ESI FT-ICR
MS)[17] of a mixture of 1 and TBACl revealed a peak at m/z =
855.5481 that corresponds to the [1·2Cl]2− (Figure S11).
Association constants in CDCl3 were determined by nonlinear
least-squares regression from the 1H NMR-titrated concentrations
of 1 and the chloride-bound complexes. The association
constants obtained in this manner are K1 = 21 M−1 for the 1:1
complex and K2 = 230 M−1 for the 1:2 complex (from the 1:1
complex), with a cooperativity factor[18] (12 = 4K2/K1) of 44 (Table
1, and Figures S12 and S13). Positive allosteric associations with
1 were also found for the bromide (K1 = 42 M−1; K2 = 390 M−1; 12
= 37) and acetate (K1 = 490 M−1; K2 = 5800 M−1; 12 = 47) (Table
1 and Figures S14–S17).
Figure 4. 1H NMR spectra of 1 and TBAH2PO4 in CDCl3 a) 1 (1.0 mM) +
TBAH2PO4 (2.0 equiv.), b) 1 (3.0 mM) + TBAH2PO4 (3.8 equiv.), c) 1 (10.0 mM)
+ TBAH2PO4 (2.9 equiv.), d) 1 (10.0 mM) + TBAH2PO4 (31.2 equiv.). The typical
signals of the free 1, 1:2 complex (1·2H2PO4−), and 1:1 complex (1·H2PO4−) are
marked with ○, ▲, and ■, respectively. e) X-ray crystal structures of 1 +
dihydrogen phosphate (1·4H2PO4−). The tert-butyl groups are omitted for clarify.
f) ESI FT-ICR MS of 1:3 complex (1·3H2PO4−).
Table 1. Association constants of 1 with anions in CDCl3
and DMSO-d6, and their cooperativity factors.[a]
[b]
[c]
anion
solvent
K1
(M−1
K2
(M−1
12
K3
23
)
)
(M−1
)
Cl−
CDCl3
21
42
230
390
44
37
47
63
-
-
-
-
-
Br−
CDCl3
ESI FT-ICR MS of a mixture of 1 and TBAH2PO4 indicated the
AcO−
H2PO4
Cl−
CDCl3
490
83
5800
1300
150
-
−
formation of a 1:2 complex (1:H2PO4 ), and a molecular ion peak
corresponding to [1·2H2PO4]2− was detected at m/z = 917.0532
−
CDCl3
6
-
0.005
(calcd. 917.0603) (Figure S18). The association constant (K12
=
K1 × K2) was calculated to be 1.07×105 M−2 by integrating the ratio
DMSO-d6
DMSO-d6
140
2100
4.3
3.6
-
-
−
1
of the complex (1·2H2PO4 ) to free 1 (Figure 4a). The H NMR
spectrum of a mixture of 1 (3.0 mM) and TBAH2PO4 (11.4 mM)
shows two sets of signals (Figure 4b); one set is readily assigned
−
H2PO4
1900
-
[a] Association constants measured by 1H NMR titration. Uncertainties are
less than 15%. All anions were used as TBA salts. [b] 12 = 4K2/K1. [c] 23
K3/K2.
−
to the 1:2 complex of 1 and dihydrogen phosphate (1·2H2PO4 ).
=
The other set of signals are assigned to the 1:1 complex of 1 and
−
dihydrogen phosphate (1·H2PO4 ) because the signals appear to
The association dynamics of chloride, bromide, and acetate
with 1 were fast in the chemical shift time scale; hence the H
NMR spectra of these mixtures are averaged. In contrast, the 1H
be of lower symmetry than those of the 1:2 complex; the ureido
1
−
moieties of the 1:1 complex (1·H2PO4 ) are magnetically non-
−
equivalent. The existence of the 1:1 complex (1·H2PO4 ) was also
NMR spectrum of a mixture of 1 and dihydrogen phosphate
confirmed by an ESI FT-ICR MS peak at m/z = 1737.1428 that
corresponds to the [1·H2PO4]− molecular ion in addition to the
−
(H2PO4 ) showed two sets of signals assigned to the association
This article is protected by copyright. All rights reserved.

10.1002/chem.201904241
Chemistry - A European Journal
COMMUNICATION
molecular ion peak of the 1:2 complex (Figure S19). The
association constant K2 was calculated to be 1300 M−1 from the
integration ratio of the 1:1 to the 1:2 complex (Table 1). Finally,
the association constant K1 and the cooperativity factor 12 were
calculated to be 83 M−1 and 63, respectively (Table 1).
encapsulated 1-CHCl3. No intramolecular hydrogen bonds are
formed between the ureido groups, and all ureido C=O groups are
directed outside.
−
We conclude that the H2PO4 at the fourth vertex only binds
−
in the crystal phase because this H2PO4 is bound only to the
−
We proposed the following mechanism to account for the
observed positive allosteric recognition (Figure 5). In organic
solvents of low polarity, such as CDCl3, 1 is present in the aaaaaa
conformation with all ureido groups directed in the same manner
through intramolecular hydrogen bonding. The conformation of
hexakis-urea 1 changes from the aaaaaa conformation to the
alternating ababab conformation in the presence of a strongly-
associative anion, capable of disrupting the intramolecular
hydrogen bonding in 1. Two independent anion recognition sites
are formed in the ababab conformation, which results in strong
positive allosteric cooperativity.
three basal H2PO4 units through three hydrogen bonds without
interacting with any ureido group (Figure S25a and S25f). The 1:4
association in the crystal phase, and the 1:3 association in the
gas and solution phases, as confirmed by MS and NMR
experiments, can be rationalized by considering the substantial
stabilization associated with TBA crystal packing, where three
TBA molecules cap the aperture of the urea cage to the hold
−
H2PO4 assembly (Figure S25c–e). ESI FT-ICR MS of a mixture
of 1 and excess TBAH2PO4 indicates the formation of a 1:3
−
complex (1:H2PO4 ), with a molecular ion peak corresponding to
[1·3H2PO4·Bu4N]2− detected at m/z
= 1086.6878 (calcd.
1086.6871) (Figure 4f). The addition of excess TBAH2PO4 to a 1.0
mM CDCl3 solution of 1 showed identical 1H NMR signals to that
of the 1:2 host-guest complex described above. When a highly
concentrated solution of 1 in CDCl3 (10 mM) was titrated with
TBAH2PO4, changes in the signals suggestive of the formation of
a 1:3 complex were observed (Figure 4c,d). The association
constant K3 obtained for this complex by nonlinear least-squares
regression was found to be 6 M−1 (from the 1:2 complex) (Table 1
and Figures S26 and S27). The cooperativity factor (23 = K3/K2)
of 0.019 is indicative of a negative allosteric association in going
from the 1:2 complex to the 1:3 complex. Thus, the association of
hexakis-urea 1 with dihydrogen phosphate in CDCl3 occurs in an
amphoteric allosteric manner; the formation of the 1:2 complex
from the 1:1 complex progresses in a positive allosteric manner,
while the formation of the 1:3 complex from the 1:2 complex
proceeds in a negative allosteric manner. To the best of our
knowledge, this is the first example of an amphoteric homotropic
allosteric association of guest molecule.
Figure 5. Schematic representation of guest recognition in hexakis-urea 1
accompanied by a conformational change.
Intramolecular hydrogen bonding in hexakis-urea 1 must play
an important role in the expression of allosteric cooperativity.
Accordingly, the ability of 1 to recognize anions in DMSO solution,
in which intramolecular hydrogen bonds are difficult to form, was
examined. DMSO-d6 solutions of 1 were titrated using TBACl and
TBAH2PO4. In both cases, the equilibrium dynamics were faster
than the NMR timescale; therefore, the 1H NMR spectra of these
mixtures were averaged. The association constants were
determined by nonlinear least-squares regression by calculating
the concentrations of 1 and the anion-bound complexes. In
DMSO-d6, 1 and the anions also associated in 1:2 host–guest
ratios, with moderate association constants for chloride (K1 = 140
M−1; K2 = 150 M−1; 12 = 4.3) and dihydrogen phosphate (K1 =
2100 M−1; K2 = 1900 M−1; 12 = 3.6) (Table 1 and Figures S20–
S23). The total association constants (K1×K2) were greater in
DMSO-d6 than in CDCl3 for both chloride and dihydrogen
phosphate, probably because energy is required to break the
intramolecular hydrogen bonds and associate the anion in CDCl3.
In conclusion, we synthesized hexakis-urea 1 in satisfactory
yield. Despite having six polar ureido groups, 1 is extremely
soluble in organic solvents of low polarity. Solid-state structures
were determined by single crystal X-ray analyses. Hexakis-urea
1 is an anion receptor and typically two anionic molecules
associated with 1; these associations in CDCl3 proceed in a
positive allosteric manner due to a dynamic alteration in
conformation. Furthermore, 1 associates dihydrogen phosphate
in a 1:3 host-guest ratio, and this associations proceeds in an
unprecedented amphoteric allosteric manner (K1 < K2, K2 > K3)
(Figure 5).
In order to determine the structures of 1 associated with guest
anions, single crystals of 1 in the presence of a large excess of
TBAH2PO4 were prepared; X-ray diffractometry showed that the
host-guest complex has an unexpected 1:4 structural ratio
(Figures 4e and S24, Table S4).[19] The X-ray structure of 1-
4H2PO4 clearly reveals that guest H2PO4− molecules are bound to
1 through intermolecular hydrogen bonds between the ureido N-
Acknowledgements
This work was supported by Grant-in-aid for the Scientific
Research (No. 15H03826 and 17H06374 for MY and No.
17H03056 for HT) the Japan Society for the Promotion of Science
(JSPS) or the Ministry of Education, Culture, Sports, Science and
Technology (MEXT). The synchrotron single-crystal X-ray
analysis was performed at SPring-8 beam lines of BL02B1 and
BL40XU with the approval of JASRI (BL02B1: 2018B1206;
BL40XU:2019A0948, 2018B0948, and 2018A1173). We thank
−
−
H and the oxygen atoms of H2PO4 (Figure S25). Four H2PO4
molecules are encapsulated in 1 in the crystal phase, in which a
−
pyramidal assembly of H2PO4 is formed and the three basal
−
H2PO4 molecules are clipped by ureido groups through
intermolecular N-H···O=P/O(H)-P hydrogen bonding (Figure
S25a,b). It is noteworthy that the ureido-group orientations in 1-
4H2PO4 clearly different from those of the cyclohexane-
This article is protected by copyright. All rights reserved.

10.1002/chem.201904241
Chemistry - A European Journal
COMMUNICATION
Int. Ed. 2011, 50, 486–490; f) N. Busschaert, M. Wenzel, M. E. Light, P.
Iglesias-Hernández, R. Pérez-Tomás, P. A. Gale, J. Am. Chem. Soc.
2011, 133, 14136–14148; g) J. V. Gavette, N. S. Mills, L. N. Zakharov,
C. A. Johnson, II., D. W. Johnson, M. M. Haley, Angew. Chem. 2013,
125, 10460–10464; Angew. Chem. Int. Ed. 2013, 52, 10270–10274; h)
V. B. Bregović, N. Basarić, K. Milnarić-Majerski, Coord. Chem. Rev. 2015,
295, 80–124; i) V. Diemer, L. Fischer, B. Kauffmann, G. Guichard, Chem.
Eur. J. 2016, 22, 15684–15892.
Prof. Shigehisa Akine, Kanazawa University, for TitrationFit
(program for analyses of host-guest complexation). We are
grateful to Mr. Daisuke Higashi, Shizuoka University, for his
preliminary investigations of this research project.
Keywords: allosteric cooperativity • anion recognition • host-
guest system • hydrogen bonding • receptors
[10] a) S. J. Connon, Synlett 2009, 354–376; (b) Z. Zhang, P. R. Schreiner,
Chem. Soc. Rev. 2009, 38, 1187–1198; (c) G. Pupo, F. Ibba, D. M. H.
Ascough, A. C. Vicini, P. Ricci, K. E. Christensen, L. Pfeifer, J. R. Morphy,
J. M. Brown, R. S. Paton, V. Gouverneur, Science 2018, 360, 638–642.
[11] a) J. J. van Gorp, J. A. J. M. Vekemans, E. W. Meijer, J. Am. Chem. Soc.
2002, 124, 14759–14769; b) V. Simic, L. Bouteiller, M. Jalabert, J. Am.
Chem. Soc. 2003, 125, 13148–13154; c) T. Kishida, N. Fujita, K. Sada,
S. Shinkai, J. Am. Chem. Soc. 2005, 127, 7298–7299; d) E. Obert, M.
Bellot, L. Bouteiller, F. Andrioletti, C. Lehen-Ferrenbach, F. Boué, J. Am.
Chem. Soc. 2007, 129, 15601–15605; e) M. Yamanaka, J. Inclusion
Phenom. Macrocyclic Chem. 2013, 77, 33–48; f) K. Fukushima, S. Liu,
H. Wu, A. C. Engler, D. J. Coady, H. Maune, J. Pitera, A. Nelson, N.
Wiradharma, S. Venkataraman, Y. Huang, W. Fan, J. Y. Ying, Y. Y. Yang,
J. L. Hedrick, Nat. Commun. 2013, 4, 2861.
[1]
a) M. F. Perutz, Q. Rev. Biophys. 1989, 22, 139–236; b) J.-P, Changeux,
S. J. Edelstein, Science 2005, 308, 1424–1428.
[2]
[3]
T. Yonetani, M. Laberge, Biochim. Biophys. Acta 2008, 1784, 1146–1158.
S. P. Meisburger, W. C. Thomas, M. B. Watkins, N. Ando, Chem. Rev.
2017, 117, 7615–7672.
[4]
[5]
a) C. A. Hunter, H. L. Anderson, Angew. Chem. 2009, 121, 7624–7636;
Angew. Chem. Int. Ed. 2009, 48, 7488–7499; b) G. Ercolani, L. Schiaffino,
Angew. Chem. 2011, 123, 1800–1809; Angew. Chem. Int. Ed. 2011, 50,
1762–1768; c) L. K. S. von Krbek, C. A. Schalley, P. Thordarson, Chem.
Soc. Rev. 2017, 46, 2622–2637.
a) J. Rebek, Jr., Acc. Chem. Res. 1990, 23, 399–404; b) S. Shinkai, M.
Ikeda, A. Sugasaki, M. Takeuchi, Acc. Chem. Res. 2001, 34, 494–503;
c) T. Nabeshima, Bull. Chem. Soc. Jpn. 2010, 83, 969–991; d) C. Kremer,
A. Lützen, Chem. Eur. J. 2013, 19, 6162–6196; e) A. M. Lifschitz, M. S.
Rosen, C. M. McGuirk, C. A. Mirkin, J. Am. Chem. Soc. 2015, 137, 7252–
7261; f) J. S. Park, J. L. Sessler, Acc. Chem. Res. 2018, 51, 2400–2410
and references therein.
[12] a) J. Rebek, Jr., Chem. Commun. 2000, 637–647; b) M. Alajarín, A.
Pastor, R.-Á. Orenes, J. W. Steed, J. Org. Chem. 2002, 67, 7091–7095;
c) A. Bogdan, Y. Rudzevich, M. O. Vysotsky, V. Böhmer, Chem.
Commun. 2006, 2941–2951; d) P. Ballester G. Gil-Ramírez, Proc. Natl.
Acad. Sci., U.S.A. 2009, 106, 10455–10459; e) A. Basu, G. Das, J. Org.
Chem. 2014, 79, 2647–2656; f) K. Pandurangan, J. A. Kitchen, S. Blasco,
E. M. Boyle, B. Fitzpatrick, M. Feeney, P. E. Kruger, T. Gunnlaugsson,
Angew. Chem. 2015, 127, 4649–4653; Angew. Chem. Int. Ed. 2015, 54,
4566–4570.
[6]
For example: a) S. Freye, J. Hey, A. Torras-Galán, D. Stalke, R. Herbst-
Irmer, M. John, G. H. Clever, Angew. Chem. 2012, 124, 2233–2237;
Angew. Chem. Int. Ed. 2012, 51, 2191–2194; b) Q. Gan, T. K. Ronson,
D. A. Vosburg, J. D. Thoburn, J. R. Nitschke, J. Am. Chem. Soc. 2015,
137, 1770–1773; c) I. Saha, J. H. Lee, H. Hwang, T. S. Kim, C.-H. Lee,
Chem. Commun. 2015, 51, 5679–5682; d) L. Moreira, J. Calbo, J. Aragó,
B. M. Illescas, I. Nierengarten, B. Delavaux-Nicot, E. Ortí, N. Martín, J.-
F. Nierengarten, J. Am. Chem. Soc. 2016, 138, 15359–15367.
D. J. Cram, Angew. Chem. 1986, 98, 1041–1060; Angew. Chem. Int. Ed.
Engl. 1986, 25, 1039–1057.
[13] a) A. Basu, G. Das, J. Org. Chem. 2014, 79, 2647–2656; b) D. M. Gillen,
C. S. Hawes, T. Gunnlaugsson, J. Org. Chem. 2018, 83, 10398–10408.
[14] J. Masuda, S. Kondo, Y. Matsumoto, M. Yamanaka, ChemistrySelect,
2018, 3, 6112–6115.
[7]
[8]
[15] a) F. Lortie, S. Boileau, L. Bouteiller, Chem. Eur. J. 2003, 9, 3008–3014;
b) S. Kondo, H. Sonoda, T. Katsu, M. Unno, Sens. Actuators, B. 2011,
160, 684–690.
a) J. V. Gavette, A. L. Sargent, W. E. Allen, J. Org. Chem. 2008, 73,
3582–3584; b) M. Arunachalem, P. Ghosh, Chem. Commun. 2011, 47,
6269–6271; c) S. Chakraborty, R. Dutta, B. M. Wong, P. Ghosh, RSC
Adv. 2014, 4, 62689–62693.
[16] T. Matsuura, H. Koshima, J. Photochem. Photobiol., C, 2005, 6, 7–24.
[17] A. G. Marshall, Int. J. Mass Spectrom. 2000, 200, 331–356.
[18] K. A. Connors, D. D. Pendergast, J. Am. Chem. Soc. 1984, 106, 7607–
7614.
[9]
a) B. Alonso, C. M. Casado, I. Cuadrado, M. Morán, A. E. Kaifer, Chem.
Commun. 2002, 1778–1779; b) A. J. Evans, S. E. Matthews, A. R.
Cowley, P. D. Beer, Dalton Trans. 2003, 4644–4650; d) D. R. Turner, M.
J. Paterson, J. W. Steed, J. Org. Chem. 2006, 71, 1598–1608; e) M.
Hamon, M. Ménand, S. Le Gac, M. Luhmer, V. Dalla, I. Jabin, J. Org.
Chem. 2008, 73, 7067–7071; e) C. Jia, B. Wu, S. Li, X. Huang, Q. Zhao,
Q.-S. Li, X.-J. Yang, Angew. Chem. 2011, 123, 506–510; Angew. Chem.
[19] Examples of unique aggregated structures of dihydrogen phosphate ions
in solid phase host-guest complex: Q. He, P. Tu, J. L. Sessler, Chem
2018, 4, 46–93 and references therein.
This article is protected by copyright. All rights reserved.

10.1002/chem.201904241
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
S. Kondo, J. Masuda, T. Komiyama, N.
Yasuda, H. Takaya*, M. Yamanaka*
Page No. – Page No.
Amphoteric Homotropic Allosteric
Association between a Hexakis-Urea
Receptor and Dihydrogen Phosphate
Conformationally flexible hexakis-urea 1 is an allosteric receptor for anions; it
recognizes chloride, bromide, and acetate in a 1:2 host-guest ratio in a positive
allosteric manner. On the other hand, dihydrogen phosphate is recognized by 1 in a
1:3 host-guest ratio in a unique amphoteric allosteric manner.
This article is protected by copyright. All rights reserved.