Janus-like squaramide-based hosts: Dual mode of binding and conformational transitions driven by ion-pair recognition

Article abstract of DOI:10.1002/chem.201103345

New tripodal squaramide-based hosts have been synthesised and structurally characterised by spectroscopic methods. In 2.5 % (v/v) [D₆]DMSO in CDCl₃, compound 4 formed dimeric assemblies [log K _dim=3.68(8)] as demonstrated by ¹H NMR spectroscopy and UV dilution experiments. AFM and SEM analyses revealed the formation of a network of bundled fibres, which indicates a preferential mechanism for aggregation. These C₃-symmetric tripodal hosts exhibited two different and mutually exclusive modes of binding, each one easily accessible by simultaneous reorientation of the squaramide groups. In the first, a convergent disposition of the NH squaramide protons allowed the formation of an array of N-H...X^- hydrogen bonds with anions. In the second mode, reorientation of carbonyl squaramide groups allowed multiple C=O...H interactions with ammonium cations. The titration of 4 with different tetraalkylammonium iodides persistently showed the formation of 1:1 complexes, as well as 1:2 and 1:3 complexes. The corresponding stoichiometries and binding affinities of the complexes were evaluated by multi-regression analysis. The formation of high-order complexes, supported by ROESY, NOESY and mass spectrometry experiments, has been attributed to the insertion of NR ₄I ion pairs between the carbonyl and NH protons of the squaramide groups located in adjacent arms of 4. The observed effects reflect the induction of significant conformational changes in the hosts, mainly in relation to the relative orientation of the squaramide groups adapting their geometries to incoming ion-pair complementary substrates. The results presented herein identify and fully describe two different modes of ion-pair recognition aimed at directing conformational transitions in the host, therefore establishing a base for controlling more elaborate movements of molecular devices through ion-pair recognition. Copyright

Full text of DOI:10.1002/chem.201103345

FULL PAPER
DOI: 10.1002/chem.201103345
Janus-Like Squaramide-Based Hosts: Dual Mode of Binding and
Conformational Transitions Driven by Ion-Pair Recognition
Bartomeu Soberats, Luis Martꢀnez, Elena Sanna, Angel Sampedro, Carmen Rotger, and
Antoni Costa*[a]
Abstract: New tripodal squaramide-
based hosts have been synthesised and
structurally characterised by spectro-
scopic methods. In 2.5% (v/v)
hydrogen bonds with anions. In the
second mode, reorientation of carbonyl
squaramide groups allowed multiple
C=O···H interactions with ammonium
cations. The titration of 4 with different
tetraalkylammonium iodides persistent-
ly showed the formation of 1:1 com-
plexes, as well as 1:2 and 1:3 com-
plexes. The corresponding stoichiome-
tries and binding affinities of the com-
plexes were evaluated by multi-regres-
sion analysis. The formation of high-
try experiments, has been attributed to
the insertion of NR4I ion pairs between
the carbonyl and NH protons of the
squaramide groups located in adjacent
arms of 4. The observed effects reflect
the induction of significant conforma-
tional changes in the hosts, mainly in
relation to the relative orientation of
the squaramide groups adapting their
geometries to incoming ion-pair com-
plementary substrates. The results pre-
sented herein identify and fully de-
scribe two different modes of ion-pair
recognition aimed at directing confor-
mational transitions in the host, there-
fore establishing a base for controlling
more elaborate movements of molecu-
lar devices through ion-pair recogni-
tion.
[D6]DMSO in CDCl3, compound
4
formed dimeric assemblies [logKdim
=
3.68(8)] as demonstrated by 1H NMR
spectroscopy and UV dilution experi-
ments. AFM and SEM analyses re-
vealed the formation of a network of
bundled fibres, which indicates a prefer-
ential mechanism for aggregation.
These C3-symmetric tripodal hosts ex-
hibited two different and mutually ex-
clusive modes of binding, each one
easily accessible by simultaneous reor-
ientation of the squaramide groups. In
the first, a convergent disposition of
order
complexes,
supported
by
ROESY, NOESY and mass spectrome-
Keywords: conformation analysis ·
host–guest systems · ion pairs · mo-
lecular recognition · supramolecular
chemistry
the NH squaramide protons allowed
ꢀ
ꢀ
the formation of an array of N H···X
Introduction
ing both the cationic or anionic portions of ion-pair sub-
strates within a reversible binding pocket. This paper de-
scribes the synthesis of a series of tripodal hosts based on
the use of bis-secondary squaramides as binding units and
the characterisation of the different conformational transi-
tions that take place upon recognition of selected tetra-
The development of effective receptor systems for ion pairs
is an on-going challenge in supramolecular chemistry.[1] This
is not as a result of a natural evolution from cation- and
anion-alone host–guest chemistry, but according to the evi-
dence, from both ionic components of an ion pair being in-
volved in host–guest recognition events.[2] In particular, the
design of ion-pair receptors that induce changes in response
to discriminative stimulus is very engaging. Such systems are
interesting not only as switches,[3] but also in drug delivery[4]
and molecular sensing[5] or as templates for inducing the for-
mation of complex supramolecular structures.[6]
AHCTUNGTRENNUNG
squaramides are difunctional binding units. First, they are
effective hydrogen-bond donors for complexing anions.[7]
This effect is a result of the simultaneous participation of
two polarised NH bonds in a favourable disposition similar
to that in urea and other amide-type compounds but featur-
ing enhanced charge transfer from the anion guest to the
electron-deficient squaramide ring in the anion–squaramide
complex.[8] In a second role, squaramides are rare examples
of neutral groups capable of binding tetraalkylammonium
cations without using the most conventional means (i.e.,
electrostatic or cation–p interactions).[9,10] The two adjacent
carbonyl groups of the squaramide are well suited to binding
tetraalkylammonium groups through CH···O hydrogen
bonding with the diffuse positive charge located on the
methyl or methylenic protons closest to the quaternary ni-
trogen atom.[10a,11] Remarkably, theoretical calculations also
To gain insight into the possibilities of chemically regulat-
ed conformational transitions in artificial systems, we have
designed new neutral hosts aimed at alternatively recognis-
[a] Dr. B. Soberats, L. Martꢀnez, E. Sanna, A. Sampedro,
Prof. C. Rotger, Prof. A. Costa
Universitat de les Illes Balears, Ctra. Valldemossa, km 7.5
07122 Palma de Mallorca, Illes Balears (Spain)
Fax : (+34)971173426
E-mail: antoni.costa@uib.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103345.
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predict a positive cooperative effect when the same squara-
mide unit binds simultaneously to anion and cation guests
through its NH and C=O groups. In this case, the calcula-
tions predict a net gain in energy in the cation–squaramide–
anion system due to the enhanced aromatic character of the
squaramide ring in the ternary complex.[12]
cording to a previously reported “on water” procedure to
give tris(aminoalkynyl)benzene derivative 1 in a yield of
80% (Scheme 1).[17] Condensation of 1 with a slight excess
of diethyl squarate in EtOH gave the mixed squaramide
Like a molecular Janus,[13] these two-faced squaramides
are unique among related amide-type binding units. In this
work, taking advantage of this feature, we synthesised and
studied a host capable of changing its hydrogen-bonding
pattern from an all-donor to an all-acceptor. In our design,
three bis-disecondary squaramide units were covalently at-
tached to a tris-aminopropargylbenzene spacer. The result-
ing hosts have a semi-rigid framework to avoid intramolecu-
lar collapse due to intramolecular hydrogen bonding of the
squaramide units. However, they are flexible enough to
allow unrestricted rotation of the squaramide units due to
the presence of a methylenic bridge in each arm. A prelimi-
nary structure optimisation of a basic host complexed to
a tetramethylammonium cation or a trimesoate anion by
DFT calculations at the B3LYP/6-31G* level of theory sup-
ported the design.[14] The resulting structures showed that
the C3-symmetric host can simultaneously interact through
the hydrogen bonding of six squaramide carbonyls with at
least nine protons of the tetramethylammonium cation.
After reorientation, the same host can interact simultane-
ously with three carboxylate groups of a trimesoate anion
(Figure 1). In both cases, the calculated parameters are well
within the limits of typical CH···O[15] and NH···O[16] hydro-
gen bonds.
Scheme 1. Synthesis of tripodal squaramides. The labelling of key hydro-
gen atoms (Ha, Hb and Hc) indicated in the scheme is used throughout
the text.
ester 2 in a yield of 50% without having to use high-dilution
conditions. Subsequent condensation with N,N-dimethylpro-
pane-1,3-diamine or tert-butyl 3-{2-[2-(2-aminoethoxy)ethox-
y]ethoxy}propanoate gave tripodal squaramides 3 and 4 in
yields of 82 and 54%, respectively. Mono- and bis-amino-
propargyl squaramides 5 and 6, analogues of 4 with only
one and two arms, respectively, were also prepared for com-
parison purposes and to provide information on aggrega-
tion.
Figure 1. Representative axial and side views (B3LYP/6-31G*) of C3 com-
plexes of a squaramide-based tripodal receptor with +NMe4 (a,c) and
a trimesoate anion (b,d), respectively. Non-acidic hydrogen atoms have
been omitted for clarity.
Studies of aggregation: Model compounds 5 and 6 are solu-
ble in neat CDCl3, however, tripodal host 4, which also con-
tains poly-oxyethylene chains, was only slowly solubilised up
to 1ꢂ10ꢀ3 m, giving a gel-like viscous solution. In this sol-
vent, tripodal squaramide host 3 is totally insoluble. The
1H NMR spectra of 5 and 6 show two exchangeable NH-
Results and Discussion
Synthesis: A convenient tripodal spacer was prepared by
triple Sonogashira cross-coupling of 1,3,5-triiodobenzene
with commercially available 1-ethynylcyclohexylamine ac-
ACTHGNUTERNUN(NG Hb,Hc) signals at around 6.4–6.5 ppm in CDCl3 and CD2Cl2.
These values, typical of non-hydrogen-bonded secondary
squaramides, were taken as references and, at the same
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Janus-Like Squaramide-Based Hosts
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time, showed the absence of significant intramolecular hy-
drogen bonding in model compound 6, which has two poten-
tially interacting squaramide rings. By analogy, we also infer-
red that intramolecular hydrogen bonding could be neglect-
ed in tripodal receptor 4. Although in neat CDCl3 the NH
protons of 4 were undetectable, the propensity of 4 to aggre-
gate was readily deduced from the broad signals in the rest
of the spectrum, even at dilute concentration (5ꢂ10ꢀ4 m).
All these compounds are soluble in dimethyl sulfoxide. The
1H NMR spectra of compounds 3–6 in neat [D6]DMSO at
298 K exhibit only sharp resonances. The two distinct NH-
thinner distinguishable fibre bundles were 20–22 nm, where-
as the thicker fibres consisted of bundles of thinner fibres,
which split or fused to create a more or less regular net-
work. Although the mechanism of formation is uncertain,[19]
molecular modelling (MMFF) suggests the formation of cy-
lindrical elemental fibres (4–5 nm diameter) of 4 packed
through a combination of multiple hydrogen-bonding and p-
stacking interactions. These results are relevant to this study
as they highlight the hydrogen-bonding donor–acceptor du-
ality of squaramides. The addition of a small percentage of
[D6]DMSO to a solution of 4 in CDCl3 transforms the initial
gel-like solution into a clear mobile solution. Therefore, to
minimise the self-aggregation of hosts and guests and to en-
hance the solubility of 4, all subsequent experiments were
carried out in CDCl3 incorporating 2.5% (v/v) [D6]DMSO.
However, dilution experiments performed in this solvent
mixture revealed that some degree of aggregation still re-
mained. Upon dilution, the two protons of 4 experienced
considerable downfield shifts (Figure 3). In comparison, par-
ACHTUNGTRENNUNG(Hb,Hc) squaramide resonances appear shifted around 1.2–
1.4 ppm downfield in [D6]DMSO compared with in apolar
solvents due to hydrogen bonding between the NH groups
and the solvent dimethyl sulfoxide. In addition, the
1H NMR spectra of 3 and 4 in [D6]DMSO are independent
of concentration, thereby indicating their monomeric
nature. Accordingly, the chemical shifts of the squaramide
NH moieties are temperature-dependent within the range
295–343 K. Upon heating, the two NH groups experience
upfield shifts of ꢀ0.2 and ꢀ0.3 ppm, respectively, due to par-
tial breakage of the hydrogen bonds between polar dimethyl
sulfoxide molecules and the squaramide NH groups.[18]
The macroscopic gel-like morphology of 4 in CDCl3 was
also supported by atomic force microscopy (AFM) and scan-
ning electron microscopy (SEM; Figure 2). Analysis of the
AFM images obtained from a solution of 4 in chloroform
after evaporation on a mica surface showed the formation
of non-radial fibrous networks (Figure 2a). In addition,
a SEM image of a dried gel-like material obtained by drop-
casting 4 into chloroform on carbon-coated grids revealed
an entangled network of cylindrical fibres. The widths of
Figure 3. Concentration dependence of the 1H NMR chemical shifts of 4
in 2.5% [D6]DMSO/CDCl3 (v/v) at ambient temperature (298 K) for
a range of concentrations from 1.0ꢂ10ꢀ4 to 2.0ꢂ10ꢀ3 m. The symbols are
experimental data points. The curves were calculated by simultaneous
non-linear regression of experimental data assuming a monomer/dimer
model. The inset shows the distribution of monomer and dimer species.
allel dilution experiments performed on model compounds 5
and 6 revealed only very minor changes in the chemical
shifts in the same concentration range. These observations
reflect a distinctive behaviour of 4 in comparison with 5 and
6. The enhanced aggregation of tripodal compound 4 can be
accounted for by the simultaneous participation of the three
arms of the tripodal host in an n-mer of 4 obtained by the
displacement of solvating dimethyl sulfoxide molecules to
give oligomeric head-to-tail aggregated structures (Fig-
ure 2c,d); this is likely to occur in a low polarity solvent as
the concentration of 4 increases. The observed shifts were
successfully fitted to a simple monomer/dimer model by
using the HypNMR[20] program to obtain a dimerisation
constant [Kdim =4770mꢀ1, logKdim =3.68(8)]. The distribution
diagram shows that up to 50% of the dimer is present at
a concentration of around 5ꢂ10ꢀ4 m (Figure 3, inset). This
dimerisation constant was incorporated into all subsequent
calculations involving 1H NMR titrations of the tripodal
host 4.
Figure 2. a,b) AFM and SEM images of aggregate structures of 4 ob-
tained by the evaporation of 4 (5.0ꢂ10ꢀ4 m) in chloroform. c,d) Perspec-
tive and top partial views of an energy-minimised (MMFF) head-to-tail
trimer of 4. The average distance between two consecutive aryl ring cent-
roids is 4.5 ꢃ. The calculated O···N hydrogen-bond distances are within
the range 2.4–3.3 ꢃ and the NHO angles are in the range 161–1658. In
these views, all non-participating substituents as well as non-acidic hydro-
gen atoms have been omitted for clarity.
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Additional evidence for dimerisation was obtained by
UV/Vis spectroscopy (see the Supporting Information). The
UV/Vis absorption spectra of the mono-, bis- and tris-squar-
amide compounds 4–6 display a band with a maximum at
293 nm, which indicates the presence of a common chromo-
phore assigned to the squaramide group.[21] Although com-
pounds 5 and 6, which feature one and two squaramides
arms, respectively, gave a linear response, the intensity of
the absorption observed with 4 clearly deviated from lineari-
ty. In addition, 4 also shows a characteristic concentration-
dependent shoulder at around 316 nm, compatible with p-
stacking interactions of the aromatic chromophores.[22]
A
dimer of 4 was also detected by mass spectrometry: a weak
peak with m/z=3036.325 Da corresponding to [42 +Na]+
was observed by positive MALDI-TOF mass spectrometry.
At this point, the structure of the dimer remains uncer-
tain. In particular, we considered the formation of capsular
dimeric assemblies as described for related amide-type and
urea compounds.[23] Unfortunately, so far we have been
unable to find any evidence supporting the formation of di-
meric capsules of 4. Thus, without neglecting other possibili-
ties, we turned our attention to variants that involve the
preferential head-to-tail dimerisation of tripodal receptor 4
by the simultaneous NH···O=C hydrogen bonding of three
pairs of NH and carbonyl groups of the squaramides.[24]
Figure 4. Plots of simultaneous changes in the chemical shifts of signifi-
cant 1H NMR (300 MHz) signals of
4
(5.9ꢂ10ꢀ4 m) with increasing
amounts of TBAT in titration experiments performed in 2.5%
[D6]DMSO/CDCl3 (v/v) at 298 K. The symbols are experimental data
points. The solid lines are best fit curves obtained by simultaneous non-
linear regression of the shifting resonances of NHb, NHc and ArHa in the
receptor and ArHT in the substrate.
Binding studies with tetraalkylammonium tricarboxylate
salts: Neutral and charged squaramide-derived hosts are
known to form complexes with a variety of monoanions, for
ꢀ
2ꢀ
2ꢀ
example, Fꢀ, Clꢀ, Brꢀ, NO3 , SO4
,
HPO4
and
AcOꢀ,[7c,d,e,18,25] and also with di- and tricarboxylate anions,
such as oxalate, citrate, glutarate[7a,f] and trimesoate
anions.[7b] Based on this experience, we expected that tripo-
dal squaramide receptors 3 and 4 would also form host–
guest complexes with anions (Figure 1).
which the observed shifts were shifted downfield by around
2 ppm (Figure 4). These apparently contradictory CIS
changes clearly indicate the existence of at least two differ-
ent host–guest equilibria. Here, the overall movement of
To gain information about this mode of binding, the com-
plexation-induced shifts (CIS) of tripodal hosts 3 and 4 were
examined by 1H NMR spectroscopy on complexation with
the tetraalkylammonium salts of tricarboxylic acids in 2.5%
(v/v) [D6]DMSO/CDCl3. In this rather apolar medium, the
carboxylate salts are found as associated ion pairs capable
of interacting with neutral hydrogen-bond donors.[26] Initial
experiments with the tetrabutylammonium (TBA) salts of
tricarboxylic acids, such as nitrilotriacetic, cis-1,3,5-cyclohex-
anetricarboxylic, and Kempꢄs triacid, resulted in the forma-
tion of host–guest complexes by interaction between the car-
boxylate groups of the guests and both NH groups on the
squaramide moieties. Unfortunately, with these guests, the
experimental data could only be partially characterised by
manual fitting using the downfield shifts of both NH reso-
nances of the squaramides. In all these cases, the data avail-
able suggested the formation of 1:1 and 2:1 host–guest com-
plexes. Further work was carried out with the TBA salts of
the trimesoate anion (TBAT) because this salt offers a well-
separated aromatic hydrogen useful as a 1H NMR probe.
Upon titration of 4 with TBAT, the NH protons shifted
around ꢀ1 ppm upfield to reach an inflexion point, beyond
both NH groups is accounted for by the strong hydrogen-
ꢀ
ꢀ
bonding interactions N H···O formed with the carboxylate
groups of the trimesoate replacing the solvating dimethyl
sulfoxide molecules and disturbing the monomer/dimer
equilibrium of 4. In addition, the aromatic signals ArHa on
the receptor and ArHT on the substrate guest shifted upfield,
which suggests their close proximity within the limits of
mutual diamagnetic shielding by aromatic stacking.
After investigating several plausible models, all available
shift changes were simultaneously fitted by taking into ac-
count the formation of 1:1 as well as 2:1 host–guest com-
plexes and by including the dimerisation constant of 4 al-
ready calculated [Equations (1)–(3)]. This model is based on
the assumption that TBAT is present as associated ion
pairs,[27] therefore [L]ꢁ[TBAT]. Several attempts to include
the ion-pair dissociation equilibrium of TBAT and the com-
plexation of the individual ions did not produce any im-
provement in fitting.[28] The calculated values for the step-
wise association constants have the same order of magnitude
for both the 1:1 and the 2:1 host–guest complexes TBATꢂ4
[K11 =1.59ꢂ104 mꢀ1, logK11 =4.20(9)] and TBATꢂ42 [K21 =
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1.12ꢂ104 mꢀ1, logK21 =4.05(9)]. Remarkably, the fitting of
data failed completely when the dimerisation constant of 4
was removed from the overall equilibria. In this regard, it is
worth mentioning the work by Roelens et al. on the partici-
pation of dimers of a related tripodal ureido host in the
binding of tetraalkylammonium compounds in a three-re-
agent model.[28]
groups of the trimesoate even in the presence of a strong
competing agent such as dimethyl sulfoxide. Moreover, the
upfield shifts of the aromatic hydrogen atoms are consistent
with the mutual shielding effect of the aromatic stack
formed upon binding. In this regard, the moderate magni-
tude can be explained on the basis of the calculated average
distance of 4.0–4.2 ꢃ between the two aromatic rings in the
complex formed between a tripodal squaramidic host and
the trimesoate anion, which is larger than the typical aryl–
aryl stacking distance of 3.6–3.7 ꢃ observed in crystal struc-
tures.[29]
½RLꢃ
ð1Þ
ð2Þ
ð3Þ
R þ L Ð RLK11
¼
½Rꢃ½Lꢃ
½R2Lꢃ
The binding affinities in these systems were calculated
R2 þ L Ð R2LK21
¼
1
½RLꢃ½Lꢃ
from the corresponding H NMR titration data by simulta-
neously fitting the changes in the chemical shifts of the Ha–
Hc protons of receptors 3 and 4 and HT of the trimesoate
½R2ꢃ
2R Ð R2Kdim
¼
2
½Rꢃ
anion to
a 1:1 two-reagent model. As expected, in
[D6]DMSO, both tripodal receptors afforded only 1:1 com-
plexes, giving TMATꢂ3 [K1 =7440mꢀ1, logK1 =3.87(3)] and
TMATꢂ4 [K1 =4600mꢀ1, logKas =3.66(3)], respectively.
Spectral examination greatly contributed to the elucidation
of the precise structures of the complexes. The structures of
3 and 4 complexed with the trimesoate anion were deter-
mined by ROESY and NOESY experiments. In particular,
the ROESY spectrum of a 1:1 mixture of 3 and TMAT in
[D6]DMSO shows key intermolecular cross-peaks between
the two aromatic protons Ha and HT and between HT and
the two squaramide NHb and NHc hydrogen atoms, thus
confirming that the trimesoate anion is located in a cavity
created by the tripodal receptor in a C3-symmetric confor-
mation. Moreover, the TMA cations must remain in close
proximity to the complex, probably as solvent-separated ion
pairs, because they show intermolecular contacts with the ar-
omatic protons of both the trimesoate (HT) and 3 (Ha).
Plausible structures of these complexes, which account for
all the observed NOE effects, are proposed in Figure 6a.
To avoid interference due to aggregation phenomena, the
binding of the trimesoate anion was also investigated by
using tetramethylammonium trimesoate (TMAT) in neat
[D6]DMSO. In contrast to the previous titrations, in this
media the two non-equivalent squaramide NH protons ex-
perienced large downfield shifts (Figure 5). In turn, the aro-
matic hydrogen atoms of the host (Ha) and guest (HT) expe-
rienced moderate upfield shifts, whereas the rest of the spec-
tra remained essentially unchanged. Qualitatively, these ob-
servations indicate that the two squaramide NH groups are
involved in strong hydrogen bonding with the carboxylate
Binding studies with tetraalkylammonium iodides: A dis-
tinctive feature of squaramides compared with urea or other
amide-type groups is the hydrogen-bond accepting abilities
of the two adjacent carbonyl oxygen atoms of squaramides.
We previously demonstrated the potential of the binding of
the carbonyl groups of squaramides through the design of
Figure 5. Representative plots of the changes in the chemical shifts of sig-
nificant 1H NMR (300 MHz) signals of 3 (3.2ꢂ10ꢀ3 m) with increasing
amounts of TMAT in titration experiments performed in [D6]DMSO at
298 K. The symbols are experimental data points. The lines are best fit
curves obtained by simultaneous non-linear regression of the four shifting
resonances of NHb, NHc, ArHa and ArHT to a 1:1 model of complexa-
tion.
Figure 6. MMFF optimised structures and schematic representations pro-
posed for the complexes a) TMATꢂ4 and b) TEAIꢂ4.
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A. Costa et al.
a fluorescent molecular sensor based on this exclusive abili-
ty in choline-containing phospholipids.[9c] In addition, the in-
teraction energy between a single plain squaramide and
a TMA cation (ꢀ22.00 kcalmolꢀ1) is clearly favourable com-
pared with that of urea with TMA (ꢀ16.53 kcalmolꢀ1).[11] In
this regard, host 4 was initially expected to provide optimal
size and shape complementarity to tetraalkylammonium cat-
ions through multiple NCH···O=C hydrogen bonding (Fig-
ure 2a,c) without too much competition from the weakly
basic iodide counterions.
Complexation-induced changes in the chemical shifts (Dd)
1
of both the host and guest were examined by H NMR spec-
troscopy for the complexation of 4 with selected tetraalky-
lammonium iodides. Thus, upon addition of a 24-fold molar
excess of tetraethylammonium iodide (TEAI), the squara-
mide NH protons underwent parallel limiting upfield shifts
of ꢀ1.04 and ꢀ0.87 ppm for NHc and NHb, respectively
(Figure 7), which indicates a similar participation in hydro-
gen bonding. Remarkably, the observed shift changes con-
trast the usual observations of downfield shifts for protons
involved in hydrogen bonding. Here, the observed upfield
shifts of the NHs are due to the displacement of the dimer/
monomer equilibrium of 4 and subsequent hydrogen bond-
ing of the NH groups to iodide anions. In turn, the NCHa
protons of TEAI are shifted downfield by +0.05 ppm, which
suggests a deshielding effect is operating in the complex.[30]
This is in contrast to the absence of any significant shifts of
the alkylammonium protons of TBA and TMA observed
with the trimesoate salts. A downfield shift is what one
might expect of a proton involved in hydrogen bonding with
the squaramide carbonyl. In addition, the downfield shift of
the NCHa protons suggests that TEA cations are outside of
the cavity away from the diamagnetic influence of the aro-
matic ring of 4.[9a,10c] In all the cases studied, only one set of
Figure 7. Representative plots of changes in the chemical shifts of signifi-
cant 1H NMR (300 MHz) signals of
4
(5.2ꢂ10ꢀ4 m) with increasing
amounts of TEAI in titration experiments performed in 2.5%
[D6]DMSO/CDCl3 (v/v) at 298 K. The symbols are experimental data
points. The solid lines are best fit curves obtained by simultaneous non-
linear regression of the four shifting resonances of NHb, NHc, ArHa and
NCHa to a model of multiple complexation that includes the dimerisation
of the receptor (see Table 1).
the media. Other CH protons, although less affected by ex-
ternal factors, were also important for improving the good-
ness of fit.[31] After several attempts using different equilibri-
um models of increasing complexity, we realised that the
distances between the carbonyl groups of one squaramide
unit and the NHs of the adjacent squaramide in 4 were suit-
able for accommodating up to three NR4X ion-pair guests
between two consecutive arms. This fact was incorporated
into a model of multiple equilibria that included the forma-
tion of 1:1 to 1:3 host–guest complexes. These equilibria
were characterised by three microscopic association con-
stants, K1, K2 and K3, as well as the dimerisation constant of
the host Kdim. Analysis of the titration data with this model
gave a consistent fit, as shown in Figure 7 for TEAI. Table 1
summarises the association constants calculated for the
binding of the tripodal receptor 4 to several NR4I com-
pounds. Overall, these data reveal that receptor 4 not only
binds to NR4I compounds to give complexes with 1:1 stoi-
signals was observed, which indicates
a fast-exchange
regime at room temperature on the NMR timescale.
Qualitatively, the CIS changes observed for TEAI are
similar to those of several of the tetraalkylammoniums al-
ready tested. Quantitative evaluation of the binding affini-
ties of 4 towards TEAI, benzyltrimethylammonium iodide
(BTAI) and tetrabutylammonium iodide (TBAI) was carried
out by titration of 4 with increasing amounts of the NR4I. In
all cases, the protons available for fitting were the two ex-
changeable squaramide NHs and ArHa of 4 and NCHa of
the ammonium compound. Upon titration, both NH protons
shifted upfield due to their sensitive response to changes in
Table 1. Macroscopic (logKi’) and microscopic binding constants (logKi) for the 1:1, 2:1 and 3:1 complexes formed between 4 and tetraalkylammonium
iodide compounds.[a,b]
R+LQRL
logK1
RL+LQRL2
RL2 +LQRL3
[c]
[d]
[c]
[c]
NR4I
logK1’
K1
660
8200
1740
a1
logK2’
logK2
K2
2750
13500
5500
a2
logK3’
logK3
K3
TEAI
TBAI
BTAI
3.30(5)
4.39(9)
3.72(4)
2.82
3.91
3.24
4.16
1.65
3.16
3.44(1)
4.13(18)
3.74(4)
3.44
4.13
3.74
1.78
0.18
0.19
3.22(1)
2.90(15)
2.53(2)
3.70
3.38
3.01
5000
2400
1020
[a] Measured for 0.5ꢂ10ꢀ3 m of 4 in 2.5% [D6]DMSO/CDCl3 (v/v) at 298 K. The dimerisation constant for 4 was fixed at logKdim =3.68(8). [b] Standard
deviations are given in parentheses. [c] Statistical corrections applied: K1 =K1’/3, K2 =K2’ and K3 =3K3’. [d] Molecular interaction parameters: a1 =K2/K1
and a2 =K3/K2.
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Janus-Like Squaramide-Based Hosts
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chiometry, but it provides three non-independent binding
sites capable of accommodating up to three NR4I ion pairs.
At the molecular level, the cooperativity of the systems is
described by the corresponding interaction parameters a1
and a2.[32] In the three cases studied so far, the system exhib-
ited an initial positive cooperativity, a1 =K2/K1 >1, which fa-
vours a second complexation of the NR4I pair. However,
complexation of a third ion pair of TBAI and BTAI showed
negative cooperativity, a2 =K3/K2 <1, probably due to steric
crowding arising from the relatively large volume of these
cations hindering the formation of higher-order complexes.
Although the origin of the observed cooperativity is un-
certain, it can be presumed that large entropic effects arising
from the solvation effects of the host and guests could be
neglected in the apolar solvent mixture used in this work.[33]
In our case, the observation of the initial positive coopera-
tivity can be explained on the basis of the existence of three
identical, non-independent binding sites in 4. In such sys-
tems, the first complexation restricts the conformational
motion of two arms of the host, thus increasing its pre-or-
ganisation and facilitating a second complexation event. In
this scenario, given the tripodal structure of 4, the binding
of a third guest molecule would be disfavoured unless the
ion pair exactly matched the optimal distances of binding,
a condition that apparently is only satisfied by TEAI
(a1,a2 >1).
The interplay between TEA cations and host 4 was deter-
mined by NOESY and ROESY experiments (see the Sup-
porting Information). The ROESY spectra revealed strong
intramolecular contacts between NHb and at least two dif-
ferent hydrogen atoms on the cyclohexylidene ring, which
indicates the close spatial proximity of the squaramide NHb
and the cyclohexylidene substituent. Remarkably, any com-
parable cross-peak between NHb and the cyclohexylidene
protons in the TBATꢂ4 and TMATꢂ4 complexes already
described was lacking. Furthermore, ROESY experiments
revealed strong intermolecular contacts between the aro-
matic proton of 4 (ArHa) and the ethyl chains of TEA. As
these contacts are dependent on distance, this strongly sug-
gests a close spatial proximity between NHb, ArHa and the
cyclohexylidene ring of the host 4 on the one hand, and be-
tween these protons and TEA on the other. Figure 6b shows
an energy-minimised molecular structure that encompasses
all the NOE effects observed. In these complexes the angle
between the alkynyl and the squaramide moieties is 55–608,
as defined in Figure 8B.
Additional evidence for the existence of NR4Iꢂ4 com-
plexes was obtained by MALDI-TOF mass spectrometry
(see the Supporting Information). The mass spectra of solu-
tions of host 4 containing TEAI or the better BTAI exhibit
peaks corresponding to the loss of one or other component
of the ion pair. These results support the remarkable affinity
1
Figure 8. Left: Partial stacked H NMR (300 MHz) spectra of 4 (5.0ꢂ10ꢀ4 m) with increasing amounts of first TBAI and then TBAT at the concentrations
(mm) indicated, recorded in 2.5% [D6]DMSO/CDCl3 (v/v) at 298 K. *The last spectrum in this series reflects the equilibrium after 24 h. The inset be-
tween 8.3 and 9.3 ppm, shows the shift and shape of the NHa,b protons at the equilibrium. Right: Schematic representation of the conformational transi-
tion of 4 driven by the binding of TBAT.
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A. Costa et al.
of 4 for both the anionic and cationic components of the
basicity of trimesoate anions compared with iodide and the
NR4I ion pairs.
optimal C3-symmetric pre-organisation of the host.
Conformational transitions driven by the ion pair: The dif-
ferent behaviour of the tripodal squaramide host 4 in the
presence of the tetraalkylammonium iodide or trimesoate
compounds prompted us to use two ammonium compounds
to drive the precise conformational transitions in 4. Thus, in
a preliminary experiment, we initially added increasing
amounts of TBAI to induce a transition from the dimer/mo-
nomer 4 to a TBAIꢂ4 complex and then added TBAT to
induce a second conformational transition. Note that TBA
was used as the cation in each ion pair to avoid interference.
Therefore the observed shift changes had to be attributed
mainly to the effect of the counterions, namely iodide and
trimesoate (Figure 8).
Conclusion
We have shown that effective ion-pair recognition can be
obtained with squaramides. The squaramide-based tripodal
hosts described herein exhibit dual behaviour as cascade-
type ligands in the presence of alkylammonium trimesoate
salts. This host–guest relationship is driven by the high ba-
sicity of the carboxylate groups of the trimesoate anion ide-
ally disposed for hydrogen-bond formation. In sharp con-
trast, these tripodal hosts are tris-heteroditopic ligands able
to form 1:3 complexes with NR4I ion pairs. These host–guest
interactions, which are based on hydrogen bonding, over-
come the observed tendency for the tripodal squaramides to
dimerise. Note, the formation of well-defined complexes
with trimesoate and other tricarboxylate anions triggered
a drastic reorientation response of the host. Given its modu-
lar structure and neutral character, this approach should be
well suited to ion sensing and the development of movable
molecular devices.
Initially, upon addition of increasing amounts of TBAI to
4 (0.5ꢂ10ꢀ3 m), the resonances of the NHs became sharper
and their shifts moved upfield, as described above, as the
complex represented in Figure 8B was formed. Subsequent
addition of TBAT caused a significant reorientation of the
system, as evidenced by pronounced effects on several key
resonances. Among them, the signal of the aromatic proton
of 4 (Ha) broadened and moved upfield due to the influence
of the shielding of the phenyl ring of the trimesoate. Before
completion, some splitting of this signal was observed, evi-
dencing the existence of several species in a relatively slow
exchange regime. The aromatic proton of trimesoate (HT),
initially a sharp singlet at 8.80 ppm, evolved to a broad
signal upfield at 8.60 ppm, also due to the influence of
shielding of the tris-alkynylbenzene portion of 4. Further-
more, the signal of the two NH protons broadened and shift-
ed to around 9.0 ppm due to strong hydrogen bonding with
the trimesoate anion. Comparative NOESY and ROESY ex-
periments (see the Supporting Information) revealed intra-
molecular contacts between NHb and three different protons
of the cyclohexylidene ring, which indicates the spatial prox-
imity of NHb to the cyclohexylidene residue of 4. Moreover,
the ROESY spectrum reveals intermolecular contacts be-
tween the butyl residues of TBAI and Ha due to the spatial
proximity between the aromatic portion of 4 and the TBA
cations typical of associated ion pairs.[26e] In contrast, the
ROESY spectrum of a solution containing 4 and TBAT
shows intermolecular contacts not only between the butyl
chains of TBA and Ha but also with HT and, significantly, be-
tween the two aromatic protons ArHa and ArHT. All togeth-
er, these observations are accommodated by assuming an in-
itial transition of 4 from the initial monomer/dimer state to
a complexed state dictated by intramolecular head-to-tail
binding of TBAI. The addition of TBAT triggered a drastic
conformational transition by rotation of the squaramide
units. The resulting outward movement of the squaramides
created an array of three pairs of NH hydrogen-bond
donors that converged on the trimesoate anion guest located
in the centre of the tripodal cavity created by 4 (Figure 8C).
This conformational transition supposes a competitive dis-
placement of iodide anions by trimesoate due to the high
Experimental Section
General: All temperatures quoted are uncorrected. Tetraalkylammonium
iodides were purchased from Aldrich and stored under vacuum over
P2O5 for several days prior to use. The tris-tetrabutylammonium salts of
the tricarboxylic acids were prepared according to the literature.[34] NMR
spectra were recorded with Bruker Avance 300 and Avance III 600 MHz
spectrometers equipped with a cryoprobe (2D-NOESY and ROESY).
Chemical shifts are given in parts per million referenced to the residual
peak of CDCl3 or [D6]DMSO. In the NMR titrations, typically, solutions
of 4 (ca. 0.5 mm) were prepared in CDCl3 containing 2.5% (v/v) of
[D6]DMSO. The tetraalkylammonium compound (ca. 1–2 mm) was dis-
solved in the above solvent just prior to use. Titrations were carried out
by adding small volumes of the solution of the tetraalkylammonium com-
pound to the solution of the host (0.5 mL) in a NMR tube. After each ad-
dition the solution was shaken well and left to stand for 4 min before re-
cording the spectra. The chemical shifts of all the NH and CH protons
that undergo changes upon titration were taken into consideration in the
fitting. Stability constants were calculated by non-linear least-square re-
gression with HypNMR2008.[20] Mass spectra were recorded with Micro-
mass Autospec 3000 (HRMS-ESI) and Bruker Autoflex (MALDI-TOF)
spectrometers with trans-2-[3-(4-tert-butylphenyl)-2-methyl-2-propenyli-
dene]malononitrile (DCTB) as matrix.
Synthesis of squaramide ester 2: A solution of 1[17] (0.33 g, 0.76 mmol) in
diethyl ether (15 mL) was added dropwise to a solution of diethyl squa-
rate (0.7 g, 5.4 mmol) in ethanol (10 mL) and the resulting solution was
stirred at 358C for 3 d. After removal of the solvents by rotary evapora-
tion, the residue was purified by silica gel column chromatography with
ethyl acetate/dichloromethane (30:70, v/v) as eluent (Rf =0.27) to afford
3 in 48% yield. 1H NMR (300 MHz, CDCl3): d=1.25 (m, 3H), 1.41 (t,
J=7.2 Hz, 9H), 1.64–1.82 (m, 21H), 2.23 (m, 6H), 4.79 (q, J=7.2 Hz,
6H), 6.55 (brs, 3H), 7.37 ppm (s, 3H); 13C NMR (75.4 MHz, CDCl3): d=
184.3, 177.0, 134.1, 123.9, 91.5, 83.6, 69.6, 55.0, 38.1, 24.6, 23.2, 16.1 ppm;
HMRS (ESI): m/z: calcd for C48H51N3NaO9: 836.3523 [M+Na]+; found:
836.3349.
Synthesis of host 3:
A solution of 3-dimethylamino-1-propylamine
(100 mg, 98 mmol) in ethanol (10 mL) was added dropwise to a solution
of 2 (200 mg, 0.24 mmol) in ethanol (20 mL) under stirring. Then the
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Janus-Like Squaramide-Based Hosts
FULL PAPER
temperature of the reaction mixture was warmed to 308C and maintained
at that temperature for 4 d. The resulting precipitate was collected by
centrifugation and purified by digesting twice with chloroform (10 mL).
The insoluble material was dried in vacuo to afford 3 as an amorphous
white solid in 82% yield. 1H NMR (300 MHz, [D6]DMSO): d=1.20 (m,
6H), 1.63 (m, 12H), 1.87 (t, J=9.3 Hz, 6H), 2.08 (s, 18H), 2.20 (m,
12H), 3.50 (m, 6H), 7.37 (s, 3H), 7.45 (brs, 3H), 7.88 ppm (brs, 3H);
13C NMR (75.4 MHz, [D6]DMSO): d=183.9, 181.0, 169.2, 167.7, 134.2,
123.7, 93.9, 82.5, 79.6, 56.5, 54.0, 45.5, 42.2, 38.4, 29.1, 24.7, 23.0 ppm;
HMRS (ESI): m/z: calcd for C57H75N9NaO6: 1004.5738 [M+Na]+; found:
1004.5757.
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Synthesis of host 4: Compound 4 was produced by following the above
procedure, starting from 2 (100 mg, 0.12 mmol) and tert-butyl 12-amino-
4,7,10-trioxadodecanoate (200 mg, 0.72 mmol). The initial precipitate was
crystallised in chloroform/ethanol 8:2 v/v to afford 4 as a waxy off-white
solid in 54% yield. 1H NMR (600 MHz, [D6]DMSO): d=1.30 (m, 3H),
1.38 (s, 27H), 1.55–1.71 (m, 15H), 1.89 (t, J=10.0 Hz, 6H), 2.19 (d, J=
10.0 Hz, 6H), 2.40 (t, J=6.0 Hz, 6H), 3.45–3.71 (m, 42H), 7.37 (s, 3H),
7.59 (brs, 3H), 7.98 ppm (brs, 3H); 13C NMR (75.4 MHz, [D6]DMSO):
d=183.9, 181.0, 170.8, 169.1, 167.7, 134.2, 123.7, 93.9, 82.5, 80.1, 75.0,
70.2, 70.1, 66.7, 65.4, 54.0, 43.8, 38.4, 36.3, 28.2, 24.7, 23.0, 15.6 ppm;
HMRS (ESI): m/z: calcd for C81H114N6NaO21: 1529.7935 [M+Na]+;
found: 1529.7954; elemental analysis calcd (%) for C81H114N6O21:
64.52, H 7.62, N 5.57; found: C 64.01, H 7.37, N 5.70.
C
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Acknowledgements
We thank the Direcciꢅn General de Investigaciꢅn Cientꢀfica y Tꢆcnica of
Spain (DGICYT; projects CTQ2008-00841BQU and CTQ201127512/
BQU), theComisiꢅn Interministerial de Ciencia y Tecnologꢀa (CICYT;
Consolider Ingenio Grant CSD2010-00065) and the Direcciꢅ General de
Recerca i Innovaciꢅ (CAIB; project 23/2011) for financial support. B.S.
and E.S. thank the CAIB for predoctoral fellowships and L.M. thanks
the Ministerio de Ciencia e Innovaciꢅn (MICINN) of Spain also for a pre-
doctoral fellowship.
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Received: October 24, 2011
Revised: February 9, 2012
Published online: && &&, 0000
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www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Janus-Like Squaramide-Based Hosts
FULL PAPER
Two-faced hosts! Tripodal squaramide-
based hosts form host–guest complexes
with NR4I compounds with stoichi-
Molecular Janus Host
B. Soberats, L. Martꢀnez, E. Sanna,
A. Sampedro, C. Rotger,
ACHTUNGTRENNUNGometries of 1:1 to 1:3 (see scheme).
However, in the presence of ammoni-
um trimesoate compounds, the same
host drastically changes its conforma-
tion to form a distinct 1:1 complex
with the trimesoate anion. This prop-
erty has been used to drive a controlled
conformational transition of the host.
A. Costa* ...................... &&&& — &&&&
Janus-Like Squaramide-Based Hosts:
Dual Mode of Binding and Conforma-
tional Transitions Driven by Ion-Pair
Recognition
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
11
&
ÞÞ
These are not the final page numbers!