Bringing a Molecular plus One: Synergistic Binding Creates Guest-Mediated Three-Component Complexes

Article abstract of DOI:10.1021/acs.joc.0c00220

C_ethyl-2-methylresorcinarene (A), pyridine (B), and a set of 10 carboxylic acids (Cn) associate to form A·B·Cn ternary assemblies with 1:1:1 stoichiometry, representing a useful class of ternary systems where the guest mediates complex formation between the host and a third component. Although individually weak in solution, the combined strength of the multiple noncovalent interactions organizes the complexes even in a highly hydrogen-bond competing methanol solution, as explored by both experimental and computational methods. The interactions between A·B and Cn are dependent on the pK_a values of carboxylic acids. The weak interactions between A and C further reinforce the interactions between A and B, demonstrating positive cooperativity. Our results reveal that the two-component system such as that formed by A and B can form the basis for the development of specific sensors for the molecular recognition of carboxylic acids.

Full text of DOI:10.1021/acs.joc.0c00220

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Article
Bringing a Molecular Plus One: Synergistic Binding
Creates Guest-Mediated Three Component Complexes
S. Maryamdokht Taimoory, Kwaku Twum, Mohadeseh Dashti, FangFang Pan, Manu
Lahtinen, Kari Rissanen, Rakesh Puttreddy, John F. Trant, and Ngong Kodiah Beyeh
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00220 • Publication Date (Web): 15 Mar 2020
Downloaded from pubs.acs.org on March 16, 2020
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The Journal of Organic Chemistry
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Bringing a Molecular Plus One: Synergistic Binding
Creates Guest- Mediated Three Component
Complexes
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S. Maryamdokht Taimoory†, Kwaku Twum‡, Mohadeseh Dashti†, Fangfang Pan§, Manu
Lahtinen‖, Kari Rissanen*‖, Rakesh Puttreddy*‖‡, John F. Trant*†, Ngong Kodiah Beyeh*‡
†University of Windsor, Department of Chemistry and Biochemistry, Windsor, ON, N9B 3P4, Canada
‡Oakland University, Department of Chemistry, 146 Library Drive, Rochester, MI 48309-4479, USA
§College of Chemistry, Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Central China
Normal University, Luoyu Road 152, Wuhan, Hubei Province, 430079, People’s Republic of China
‖University of Jyvaskyla, Department of Chemistry, P. O. Box 35, FI-40014, Jyväskylä, Finland
‡
Tampere University, Faculty of Engineering and Natural Sciences, P. O. Box 541, FI-33101, Tampere, Finland
ABSTRACT: CEthyl-2-Methylresorcinarene (A), pyridine (B), and a set of ten carboxylic acids (Cn) associate to form A·B·Cn
ternary assemblies with 1:1:1 stoichiometry, representing a useful class of ternary systems where the guest mediates
complex formation between the host and a third component. Although individually weak in solution, the combined
strength of the multiple non-covalent interactions organizes the complexes even in a highly hydrogen-bond competing
methanol solution as explored by both experimental and computational methods. The interactions between A·B and Cn
are dependent on the pKa values of carboxylic acids. The weak interactions between A and C further reinforce the
interactions between A and B, demonstrating positive cooperativity. Our results reveal that the two-component system
such as that formed by A and B can form the basis for the development of specific sensors for the molecular recognition
of carboxylic acids.
covalent interactions in solution, particularly in protic polar
solvents where hydrogen bonding is ubiquitous.23 Control is
rendered even more complicated as the co-operative binding
interactions involved, although derived from the nature of
the individual components, are true emergent properties of
the complex itself.
INTRODUCTION
Cooperativity1 among non-covalent interactions plays a
crucial role in supramolecular chemistry.2,3 When two
components associate, each with multiple functional groups,
the various non-covalent interactions will either reinforce or
partially negate each other.4 Advances in our understanding
of these cooperative interactions has had a significant impact
in diverse fields including pharmaceutical formulation,5–9
energy,10–14 and liquid crystalline materials.15,16 These
cooperative effects are further complicated in ternary
systems and can include hydrogen17 and halogen-bonded
networks.18,19 Complex multicomponent co-crystals have
been primarily characterized by X-ray diffraction analysis,20,21
however this provides less information about the solution-
phase behaviour of these materials which is often of greater
interest. Defined ternary complex formation is the result of
the interplay between a number of factors that determine the
overall thermodynamics, and structure: pKa value of acidic
protons, electronic effects, electrostatics, polarization,
resonance-assistance, and dipole-dipole interactions.22
Making ternary complexes requires control of the non-
Calixarenes, resorcinarenes, macrocyclic cavitands
extensively studied for host-guest applications,23–26 are well
known for their ability to bind molecular guests via non-
covalent interactions within their shallow and well-defined
bowl-shaped cavity.27 Two-component dimeric and
hexameric capsules are common28–30 but three-component
all-organic structures involving macrocycles remain rare, and
mostly involve either the host supported on a polymer or
surface or polymer-like backbone,31–34 or the host forming an
inclusion complex with two guests simultaneously.35–39 But
research into these systems has overlooked a potentially
useful topology.3,40–43 Resorcinarenes have been proposed as
useful point-of-care fluorescent diagnostics: for example,
guest encapsulation changes the emission spectrum and can
be used to measure binding.44 However, a major limitation of
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CH3
this application is that the choice of guest is restricted: small
O
O
H
H
N
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N
molecule heterocycles and salts are preferred. The utility of
the systems would be greatly expanded by taking advantage
of the emergent changes in the electronics of a bound guest
to bind a third component, an analyte. This type of synergistic
three-component interaction is typical for protein-ligand-
protein, and protein-ligand-ligand in biological systems,45
such as in the human leukocyte antigen system responsible
for initiating immune responses,46–48 but appears absent from
the synthetic supramolecular receptor literature. Can a
synthetic analogue of this system be envisioned? In a simple
multi-component system, for example, binding a pyridine in
the electron rich resorcinarene cavity should increase
electron density on the nitrogen, potentially making it more
basic; this could be exploited to bind a carboxylic acid,
creating a guest-mediated ternary complex. This binding
event would then further change the physical properties of
the complex which could be observed. To the best of our
H
O
O
O
O
H
H
H
H
O
Et
Et
Et
Et
B
H3C
CH3
O
O
H
H
A
A·(exo-B)
CH3
Ternary Component
O
O
O
O
O
R
R
H
O
R
O
N
A
C
H
+
R
O
H
9
H
N
N
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B
C
Or
N
A·(BH)+·(C)-
A·B·C
A·(endo-B)
Scheme 1. Schematic representation of the stepwise
assembly of ternary systems.
knowledge this would be
a
new architecture for
1. Solution Studies
1.1. NMR Analysis
supramolecular constructs. However, resorcinarene-guest
constructs often dimerize to form stable self-inclusion
complexes: this needs to be less favourable than forming a
three-component system: is it possible to keep the guest
inside the host cavity, stabilized through multivalent
interactions, when a ternary-component is added while
preventing self-inclusion or capsule formation? Will binding
of the third component be synergistic, as it is essential
parameter for the co-crystal construction? Could this binding
event be detected and justified using a joint experimental-in
silico operation? These questions inspired the current study
on a simple model system.
Difluoroacetic acid exemplifies this analysis (C2, Figure 2).
Only one set of signals is present in NMR spectra of the
mixtures, indicating that the complexes are likely in fast
dynamic equilibrium with the individual components. Mixing
the acid (C2) and pyridine (B) together induces the expected
deshielding of the aromatic proton resonances due to a
decrease in aromatic electron density (Figure 2c vs 2b).
Similarly, the B resonances become increasingly shielded
when mixed with A, consistent with endo-complexation30
(Figure 2d vs 2b). The Hd difluoroacetic acid proton
experiences H-F coupling (Figure 2g). Mixing C2 with A
increases the splitting of the Hd signal but does not induce
any significant changes in the chemical shift. This suggests
that a weak hydrogen bond interaction induces asymmetry in
the fluorine atoms, but that the interaction with the phenol
does not result in a deprotonation (Figure 2f vs 2g).
RESULTS AND DISCUSSION
Combining Cethyl-2-methylresorcinarene (A) with pyridine (B)
makes a simple, and well-defined 1:1 dimeric endo-complex
(Scheme 1, Figure 1).49–52 This was then titrated with ten
different carboxylic acids (Cn; n = 1-10) which should initiate
a single strong B(N)⋯(H–O)Cn interaction between B and Cn.
Whether the ternary complex exists as hydrogen bonds
and/or ion pairs53-55 depends on the specific pKa values of Cn
(Figure 1). Alternatively, by first mixing the B and Cn, we can
make a strong hydrogen bond or ion-pair. The electron
deficient pyridine that would be a better guest for A. We
examined the monomeric, binary, and ternary components
and complexes using NMR and isothermal titration
calorimetry (ITC) to quantify the thermodynamics.
A
C
Component -
CH3
Component -
O
O
O
O
H
F
O
O
H
F
F
H
O
O
H
O
H
H
O
H
H
Cl
H
H
F
F
1
2
3
4
O
O
O
H
H
Et Et
pKa = 2.87
pKa = -0.25 pKa = 0.025
pKa = 3.75
H3C
CH3
Et
Et
O
O
H
H
O
O
O
H
H
O
H
O
H
O
H
O
H
O
O
H
H
H
CH3
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pKa = 5.50
pKa = 4.78
pKa = 4.75 pKa = 4.19
pKa = 4.80
B
Component -
O
O
N
O
O
H
H
9
10
pKb = 8.75
pKa = 4.80 pKa = 4.90
Figure 1. Components of the ternary complexes Cethyl-2-
methylresorcinarene (A), pyridine (B), and carboxylic acids
(Cn).
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The H NMR spectra of ternary complex A·B·C2 is clearly
different from any of the binary systems it is derived from. In
A·C2, the acid’s Hd shows additional splitting but no
significant shielding, suggesting that any interaction is exo.
However, the change in the Hd chemical shift in the A·B·C2
assembly is greater than that observed for B·C2, suggesting
a greater degree of hydrogen bonding is occurring in A·B·C2:
the nitrogen has become more basic. Similarly, the pyridine
resonances are shielded, indicating stronger endo-cavity
interaction with A than in the binary system alone.56 This is
significant as protonation of B in B·C2 deshields the
resonances; increased shielding in the ternary complex
(Figure 2e) over A·B, means that increasing the host-guest
absolute value must be carefully interpreted and mainly
provides for ready comparison with the computational
analysis (Table 3).
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interaction has
environment than the decrease in electron density arising
from pyridinium formation.
a stronger impact on the chemical
Figure 3. Expansions of the 1H NMR spectra (CD3OD, 20 mM,
298 K, 300 MHz) of (a) the titration of acid C2 into an
equimolar mixture of A and B; and (b) the ternary complexes.
Shift changes of the resonances, labels are in ppm.
To further support these observations, 19F NMR studies were
carried out on A·B·C2 as fluorine’s chemical shift is very
sensitive to the chemical environment. The -CF2H signal was
shielded by 0.24 ppm in the equimolar mixture of A and C2
indicating some interaction between the components (Figure
4b). A significant deshielding of -1.85 ppm was observed for
B·C2, indicating a strong B(N)⋯(H–O)C2 hydrogen bond
interaction (Figure 4c), while in A·B·C2, an even more
significant deshielding (–2.60 ppm) of the fluorine signal was
observed suggesting cooperativity (Figure 4d). A similar
phenomenon but with much smaller shift changes of the
fluorine signals was observed with the trifluoroacetic acid C1
in A·B·C1 (Figure S2).
Figure 2. Expansions of the 1H NMR (CD3OD, 20 mM, 298 K,
300 MHz) of the three-component A·B·C2 assembly of host
A, the pyridine guest B and difluoroacetic acid, C2 (pKa 0.025)
and their dimeric and ternary complexes.
The same NMR experiments were conducted for the other
A·B·Cn complexes. The degree of deshielding induced on B
by the formation of B·Cn was proportional to the pKa of Cn
(Figure 3). Clear deshielding of the pyridine resonances was
observed with strong acids trifluoroacetic acid C1,
difluoroacetic acid C2, chloroacetic acid C3, and formic acid
C4 (Figure S1-S4). Negligible changes were seen with the
weaker acids C5-C10 (Figures S5-S10). Similarly, the increase
in shielding of the B protons in A·B·Cn compared to A·B also
increased as a function of pKa for C1-C4. For the weaker acids
C5-C10, no significant increase in B shielding was observed
between A·B and A·B·Cn suggesting that the pyridine’s
position and interactions within the host cavity is not hugely
affected by binding to the weaker acids. For the reported
ternary systems, we made an approximation that A·B are in
equilibrium and treated as one entity. Cn were titrated into
an equimolar mixture of A and B. With this approximation,
when C is added, the equation for the binary process was
employed.57 Due to this approximation, the experimental
binding constants for the ternary system are relative, and the
Figure 4. Sections of the 19F NMR (CD3OD, 298 K, 300 MHz)
of the three-component ternary A·B·C2 assembly between
the host A, the pyridine guest B and difluoroacetic acid, C2
(pKa 0.025). Spectra are produced from (a) C2. Equimolar
mixture of: (b) Aand C2, (c) B and C2, (d) A, B, and C2. Dashed
lines highlight the observed shift changes of the resonances,
labels are in ppm.
1.2. DOSY NMR Analysis
DOSY further supports the presence of these ternary
complexes. The diffusion coefficient of a molecular species
depends on its molecular weight, solvodynamic radius, and
interactions with solvent.58–60 When comparing similar
species in the same solvent at the same concentration and
the same temperature,
a smaller diffusion coefficient
indicates a larger species. We studied a strong (C2) and a
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weak (C10) acid with monitorable protons (trifluoracetic acid
coefficients of host A, and B dropped to 0.59×10-9 m2s-1 and
1
2
3
4
5
6
7
8
C1 is not suitable due to the lack of a C−H bond). The
diffusion coefficient of A (20 mM) in CD3OD at 298 K was
0.63×10-9 m2s-1 (Table 1, Figure 5),61 consistent with other
previously reported resorcinarene-derived values confirming
that no dimeric or hexameric capsule is present.59,60 The
diffusion coefficients for the B and the acids (C2 and C10)
also reflect their different solvodynamic radii in methanol
(Table 1). When dimer and ternary structures are formed, the
diffusion coefficients decrease, indicating slower movement,
and likely a larger hydrodynamic radius. Taking the 1:1 host-
guest mixture of A and B as an example, the diffusion
1.91×10-9 m2s-1 respectively. In a capsular construct, the
diffusion coefficients would be the same. However, as an
open inclusion complex it is in dynamic equilibrium with the
monomeric species, and these different diffusion coefficients
are expected. In the 1:1 mixture of B and C2, the decrease in
the diffusion coefficients of both B and C2 show they both
participate in a larger assembly; however, in the C10 and B
complex, the diffusion coefficients resemble those of the free
species consistent with a much weaker interaction (Table 1,
Figure S30).
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Figure 5. 2D DOSY NMR spectra (in CD3OD at 298 K) of a 20 mM sample of: a) A, b) B, c) C2, and equimolar mixtures of d)
B+C2, e) A+B, f) A+B+C2 showing the chemical species present in the samples. The diffusion coefficient (×10-9 m2s-1) of each
species is shown in brackets.
Considering the host-acid dimers (A·C2 and A·C10), we see
that the interaction is weak: addition of the acid has little to
no effect on the diffusion coefficient of the host (Table 1,
Figure S31). Considering A·B·C2 the diffusion coefficients of
all components drop precipitously from all binary species: the
size difference would not be significant (as can be seen by
the minor change in A). This decrease in the values of B and
C are consistent with the equilibrium now lying more towards
the complex (Table 1, Figure 5, and Figure S31). In the case of
the C10 ternary complex, the changes are far more subtle.
The diffusion coefficients for C10 and B are lower than in their
dimeric pair, but the decrease is not as significant, again
the host clearly show strong through space interactions that
are only consistent with an endo-inclusion complex. The
fluorine resonances on the acid show exchange peak
behaviour with respect to the host phenolic protons. This
indicates either rapid changes in conformation, or rapid
exchange between bound and unbound forms. Together, all
of the NMR evidence supports the formation of the proposed
guest-mediated ternary system.
Table 1. Average diffusion coefficients Da (×10-9 m2s-1) of the
species in different combinations in CD3ODb at 298 K. The
mixtures are all equimolar.
1
A
0.63
–
B
C2
C10
–
CD3OD
2.61
2.39
2.47
2.23
2.36
2.35
2.41
consistent with the H NMR data. The shifts are moderated
as the process was measured in methanol, which competes
for hydrogen bonds, decreasing affinity. In previous
investigations of dynamic enclosed capsular resorcinarene-
based assemblies, methanol was routinely used as a
competing hydrogen bond solvent to actually break-up the
capsular assemblies.60 Seeing these effects in this solvent is
strong evidence of the high affinity these components have
for each other, especially in the presence of a competing
solvent.
A
B
–
–
–
2.16
–
–
C2
–
1.78
–
–
C10
A+B
B+C2
B+C10
–
–
1.40
–
0.59
–
1.91
1.82
2.14
–
1.60
–
–
–
1.44
All of these results are supported by the NOESY analysis
(Figures S32-33). In ternary complex A·B·C2, the pyridine and
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Table 2. Binding constants K [M-1] calculated for the A·B,
B·Cn system and A·B·Cn ternary system
A+C2
A+C10
0.58
0.59
0.57
0.59
–
1.80
–
–
2.38
2.33
2.32
2.32
1
2
3
4
5
6
7
8
9
–
1.12
–
ΔH
(kcal/mol)
TΔS
(kcal/mol)
ΔG
(kcal/mol)
K [M-1]
A+B+C2
A+B+C10
1.24
1.85
1.51
–
Entry
1.15
A·B
B·C2
301±80
533±46
70±1
-38.2±0.3
-16.9±0.7
-0.2±0.5
-7.7±0.8
-34.9
-13.2
2.4
-3.3
-3.7
-2.6
-3.9
aStandard deviation < 5%. bDiffusion coefficient of CD3OD is
~2.38×10-9 m2s-1.62
B·C10
1.3. ITC Analysis
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A·(B·C2)
A·(B·C10)
671±200
-3.8
1
DOSY and H NMR suggest the presence of a synergistic
[b]
[b]
[b]
[b]
–
–
–
–
binding mode, but the gold-standard approach for
measuring binding affinity is ITC, and for comparison the
measurements were conducted in methanol (Figures S34-35).
The thermodynamic parameters of host-guest binding (K,
ΔH, ΔS, and ΔG) for the binary components were determined
by fitting the ITC data to a one-site binding model (Table 2,
See Table 3 for 1H NMR derived association constants).
Negative ΔG values reveal the binding to be spontaneous at
303 K. The negative ΔH and TΔS values for the B·Cn and
A·B·Cn systems indicate the complexation to be enthalpy
driven, but entropy compensated. The negative ΔH and
positive TΔS value for B·C10 indicates that the process is
favored by both enthalpy and entropy (desolvation) driven.
Resorcinarene A and pyridine B dimerize with a binding
constant of 301 M-1. The interaction between B and the
carboxylic acids reveal a binding constant of 533 M-1 for
strong acid C2 and 70 M-1 for the weak acid C10. This means
that at equilibrium, A and B essentially exist as the dimer,
while B and C2 also exist as the hydrogen-bonded ion pair,
while in B·C10 the interaction is far weaker. ITC is designed
to determine the thermodynamics of two-component
systems; there is no method to compute the thermodynamics
of a system consisting of three independent components
interacting simultaneously. However, in the case of B·C2 we
can assume that it behaves largely as a single component as
the binding is strong. Titrating host A into an equimolar
mixture of these compounds allowed the data to be fitted to
a one-site binding model with a binding constant of 671 M-
1. The fact that this value is larger than the observed binding
constant of A·B (301 M-1) means that the pyridinium cation is
a better guest than the neutral pyridine. Binding between B
and C10 was insufficient for the required assumption that the
mixture act like a single molecule: there is enough free B or
A·B to prevent the mathematical model from providing a fit.
This is not surprising; ITC is not designed to calculate three-
component interactions, the fact that B·C2 form a strong
enough dimer that it can be treated as a discrete single
species is exceptional—we could not find any examples in the
literature where it had been used for this previously.
However, the assumption is clearly fair for C2 as the B·C2
system acted as a single unit, a prerequisite for ITC parameter
calculation. The solution phase studies all strongly indicate
that proposed guest-mediated complexes are formed and
that formation is synergistic with respect to all possible binary
complexes.
b
aITC was done in CH3OH at 298 K. Data could not be fitted due to
sufficient deviation from a two-component system.
O
O
F
H
O
F
O
F
H
F
H
H
O
N
N
A
F
H
N
+
+
O
H
F
A·(BH)+·(C2)-
0.220
B+C2
A
B
C2
0.0038 0.0038
0.0114
0.030
Scheme 2. Representation of the approximate equilibrium
concentrations (M) of A, B, and C and their complexes at 0.25
M, illustrating the synergy of binding shown in Table 2.
2. X-Ray Crystallography
Crystallizing A·Cn binary complexes is highly challenging
and, we only obtained a crystal of A·C6 (Figure S46). Benzoic
acid dimers, typically observed in solid-state X-ray crystal
structures, do not generate a beneficial alignment for
resorcinarene endo-complexation processes. Therefore, in
the A·C6 binary complex, the host cavities are stabilized by
self-inclusion while the hydrogen bonded benzoic acid
dimers simply occupy 3-D crystal lattice. Our repeated
attempts to grow single crystals of B·Cn components from
various solvents provided only pyridinium trifluoroacetate,
B·C1, as a crystalline material (See Figure S45). To our
surprise, no SCXRD reports on pyridinium co-crystals of the
type, (BH)⁺·Cn⁻, except for co-crystal B·C1, could be found in
the Cambridge Structural Database (CSD).63 The X-ray crystal
structure of A·B contains a resorcinarene self-inclusion
complex where the pyridine (B) resides outside the host
cavity (Figure S44). None of these structures are auspicious
building blocks for the ternary complexes observed in
solution. Fortunately, the ternary complexes behave
differently: A reduces the molecular motion of B through C–
H⋯π and π-π interactions and combined with the strong
hydrogen bond/ion pair formed between the pyridine and Cn
provides sufficient lattice energy to yield single crystals for X-
ray diffraction analysis.
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aspects of this ternary assemblies applying ωB97X-D/6-
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7
8
a)
b)
311G** level of theory11, with the polarized continuum
solvation model (PCM) to consider the solvent effects. As
examples for discussion, the energies for the binary and
ternary components, A·C1, A·B, B·C1 and A·B·C1 are shown
in Figure 7 (see Supporting Information for all optimized
structures). The thermodynamic parameters for ternary
assemblies calculated in two different ways [1). ΔE = E A B C
–
･
･
EA – EB – EC, and 2). ΔE = E(A C – EA B – EC ] shows the same
･
･
･
B)
9
energetic trends and highlighted in Table 3. In A·C1, the A(O–
H)⋯(O–H)C1 hydrogen bonds are moderately strong64 (Figure
7a). In B·C1, the expected tight hydrogen bonded ion-pair
C1(O⁻)⋯(H–N⁺)B, similar to that observed in the X-ray crystal
structure (Figure S37), is formed. In A·B despite the symmetry
of the host, the endo-cavity pyridine ring does not face
straight up. Instead it is oriented at an angle, allowing it to
form B(C–H)⋯(π)A interactions with the host cavity using acid
C–H protons ortho- and para- to the N-atom, in addition to
the expected 휋B-휋A interactions (Figure 7c). The interactions
in each binary component, discussed above, combine
synergistically to define A·B·C1. The deprotonated C1 oxygen
further stabilizes this complex through C1(C=O)⋯(O–H)A
hydrogen bonds (Figure 7d).
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c)
d)
0
Figure 6. X-Ray crystal structure of ternary co-crystals a)
A·B·C5, b) A·B·C7, c) A·B·C9 and d) A·B·C10. Dashed black-
lines highlight the hydrogen bonding, orange capped-stick
model represents protonated B and disordered fragments
are omitted for clarity.
Of the ten potential ternary systems, we obtained SCXRD
data for five A·B·Cn ternary complexes (n = 1, 5, 7, 9, and 10;
Figures 6 and S47). All adopt the same core geometry: B
resides, protonated, inside A’s cavity and interacting with the
carboxylate through the (N–H)⁺⋯(⁻O)Cn hydrogen bond. In
B
A·B·C5, B sits deeper inside the host cavity at a position 2.51
Å from the centroid of the lower rim carbon atoms, compared
to A·B·C1 [3.04 Å], A·B·C7 [2.74 Å], A·B·C9 [2.94 Å], and
A·B·C10 [2.95 Å]. The shortest B(C–H)⋯(π)A contact was
observed between pyridine H-atom and the endo-cavity host
carbon in A·B·C1 [2.41 Å]. The contact distances in the other
systems vary: A·B·C5 [2.50 Å], A·B·C7 [2.67 Å], A·B·C9 [2.52
Å], and A·B·C10 [2.55 Å].
Figure 7. The computed thermodynamic parameters for
binary components of A·C1, (ΔG = GA C1 – GA – GC1), A·B, (ΔG
･
= GA B – GA – GB), B·C1, (ΔG = GB C1 – GB – GC1), and ternary
･
･
3. Computational Studies
component A·B·C1 (ΔG = GA.B.C1 – GA – GBC1).
We performed computational modelling on these multi-
component assemblies to probe the structural and energetic
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a)
b)
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50.0
40.0
30.0
20.0
10.0
0.0
-2
-4
R² = 0.9399
-6
-8
-10
-12
-14
-16
9
-10.0
-20.0
-30.0
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11
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-4.5
-4
-3.5
-3
-2.5
-2
C1 C2 C3 C4 C5 C6 C7 C8 C9 C10
ΔGexp (kcal/mol)
Figure 8. (a) The calculated binding free energy (ΔG times negative sign, (–) * (ΔG) blue), enthalpy (ΔH times negative sign, (–) *
ΔH, yellow), and entropy (+TΔS, times negative sign, (–) * TΔS green) of (a) A·B·Cn in MeOH (PCM); (b) Linear correlation of the
experimental free energy of binding ΔGexp of the A·B·Cn ternary complexes with predicted binding free energies (ΔGcalc).
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Table 3. The calculated thermodynamic parameters and key atomic distances of the ternary complexes A·B·C (ΔG = GA B C – GA
･
･
– GB – GC1); (ΔH = HA B C – HA – HB – HC); T(ΔS = SA B C – SA – SB – SC). The values in the brackets are the calculated thermodynamic
･
･
･ ･
parameters for the association of Cn with the binary complex A·B (defined as ΔG = G(A B) C – GA B – GC; ΔH = H(A B) C – HA B – HC;
･
･
･
･
･
･
T(ΔS = S(A B) C – SA B – SC) which is comparable to the values obtained from the NMR data (ΔGExp).
･
･
･
TΔScalc
b
Entry
B(N)⋯(H–O)Cn
Cn(O–H)⋯(O–H)A
ΔHcalc (kcal/mol)a
ΔGcalc (kcal/mol)a
KaExp
ΔGExp (kcal/mol)a
(kcal/mol)a
A·B·C1
A·B·C2
A·B·C3
A·B·C4
A·B·C5
A·B·C6
A·B·C7
A·B·C8
A·B·C9
A·B·C10
1.05
1.06
1.06
1.07
1.07
1.58
1.08
1.08
1.07
1.07
1.72
1.71
1.69
1.64
1.60
1.77
1.61
1.61
1.59
1.59
-47.1 (-28.2)
–45.2 (–26.4)
–44.9 (–26.0)
–38.8 (–19.9)
–38.0 (–19.1)
–39.0 (–20.2)
–37.0 (–17.9)
–38.8 (–20.0)
–39.0 (–20.2)
–38.5(–19.6)
–27.7 (–13.7)
–27.5 (–13.5);
–28.1 (–14.1)
–26.9 (–12.8)
–28.5 (–14.5)
–29.6 (–15.5)
–27.2 (–13.2)
–28.7 (–14.6)
–29.0 (–14.7)
–29.6 (–15.1)
–19.4 (–14.5)
–17.7 (–12.8)
–16.8 (–11.9)
–12.0 (–7.1)
–9.5 (–4.6)
–9.5 (–4.6)
–9.6 (–4.7)
–9.5 (–4.6)
–10.3 (–5.4)
–9.4 (–4.5)
1173 ± 40
1073 ± 38
509 ± 6
357 ± 2
116 ± 2
110 ± 1
100 ± 2
101 ± 2
124 ± 3
79 ± 4
–4.2 ± 0.2
–4.1 ± 0.2
–3.7 ± 0.1
–3.5 ± 0.1
–2.8 ± 0.1
–2.8 ± 0.1
–2.7 ± 0.1
–2.7 ± 0.1
–2.8 ± 0.1
–2.6 ± 0.1
aThe calculated thermodynamics of ternary complexes estimated in three different mechanistic ways defined as a) A·B·C (ΔG = GA･B･C11– GA – GB – GC); (ΔH = HA･B･C
– HA – HB – HC); T(ΔS = SA･B･C – SA – SB – SC); b) The calculated thermodynamic parameters for the association of Cn with the binary complex A·B defined as ΔG =
G(A･B)･C – GA･B – GC; ΔH = H(A･B)･C – HA･B – HC; T(ΔS = S(A･B)･C – SA･B – SC)reported in order. bThe experimental data was acquired from the NMR titrations (Figure 1).
The titrations provide an estimate of the binding constant, and the Gibbs’ free energy can be calculated from this parameter. The experimental data treats a 1:1
equimolar solution of A and B as dimeric complex AB as a single unit introducing error into the measurement. For all proposed mechanistic scenarios see table S2.
Since Cn is the only component that differs between any two
ternary systems, it would be unsurprising if the stability of the
complexes is highly dependent on the pKa of the acid. This
would be expected to be especially true if one is simply
analyzing the interaction between the pyridine and the acid
as a binary system. However, this is not the case. Due to the
steric demands of the different acids, the pKa values of the
carboxylic acids alone do not correlate or predict with the
binding free energies of B·Cn dimers (R2 = 0.5, Figure 9).
Interestingly, a far better free energy correlation with the Cn
acidic strength is obtained in A·B·Cn complexes with R2 =
0.86 (Figure 9) compared with the predicted binding free
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energies of B·Cn dimers. This result supports co-operativity:
0
-5
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pKa is more important in the ternary system than in a simple
binary acid-base system because the acidity and basicity
behavior are enhanced. The presence of the resorcinarene, by
increasing electron density on the pyridine and decreasing it
on the acid, increases the affinity of the acid for the base.
B·Cn (R² = 0.4991)
-10
-15
-20
-25
A·B·Cn (R² = 0.8486)
Ternary assemblies involving the stronger acids C1-C4
feature stronger intermolecular hydrogen bonding and/or
hydrogen bond ion-pair interactions (as judged based on the
distance contacts between N-atom of the endo-pyridine and
carboxylic acid functional group) compared to their simple
B·Cn binary complexes. The stronger acids either form
stronger Cn(O–H)⋯(N)B or Cn(O⁻)⋯(H–N⁺)B hydrogen bond
interactions improving the dispersion corrected binding
energies (Ebinding) calculated as A) the binding energy
between host, A, and the B·C binary assembly in their ternary
complex geometry E(B C) A – EB C – EA are larger ranging from
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-1.0
0.0
1.0
2.0
3.0
4.0
5.0
pKa
Figure 9. The calculated Gibbs free energy of ternary
hydrogen-bonded complexes and binary complexes in
MeOH (PCM) solvation model vs pKa values of carboxylic acid
molecules.
･
･
･
The Williamson cooperativity model,66,67 a thermodynamic
data cyclic process that quantifies the cooperativity in
multicomponent systems by using four equilibrium constants
(Kn, n = 1-4) and their corresponding free energies (ΔGn , n =
1-4), was applied to these A·B·Cn ternary systems. This
proposed model provides further insights into the binding
interactions between the A, B, and Cn components. As an
example, the model for A·B·C2 is shown in Figure 10 (for
more examples, see Figure S54). According to this model, in
the A·B·C2 system, guest B binds to either C2 or A, to give
the respective binary components B·C2 and A·B. The
corresponding free energies are ΔG1 = –2.6 kcal/mol (K1,
clockwise) and ΔG2 = –4.9 kcal/mol (K2, anti-clockwise),
respectively.
Addition of A to B·C2, and C2 to A·B generates free
energies of ΔG4 = –15.1 kcal/mol (K3, clockwise) and ΔG3 = –
12.8 kcal/mol (K4, anti-clockwise), respectively. In both the
clockwise or anticlockwise route, the coupling free energy,
ΔΔG = ΔG1−ΔG4 = ΔG2−ΔG3, is defined as the free energy
upon addition and removal of the same third component. In
other words, G is the free energy generated by the formation
or breaking of new binding interactions during addition or
removal of the same third component, at two different
reaction stages, within an A·B·Cn system. The coupling free
energies of 10.1 kcal/mol and 10.2 kcal/mol for A·B·C2
suggests that both routes are cooperative and
thermodynamically favourable. In both routes the stronger
interaction forms second in line reflecting the Williamson
model suggesting the ternary complex formation is a
synergistic process.
–28.4 kcal/mol to –36.6 kcal/mol for A·B·C1-4 complexes
than A·B·C5-10 ranging from –25.6 kcal/mol to –26.0
kcal/mol. In addition, to be consistent with NMR titration
study of A·B treated as one entity and in equilibrium with C,
the calculated binding energy of E(A B) C – EA B – EC are ranging
･
･
･
from –31.1 to –40.4 kcal/mol for A·B·C1-4 complexes and are
ranging from –22.6 to –30.8 kcal/mol A·B·C5-10.
On the other hand, the Cn(O–H)⋯(O–H)A interactions between
carboxylic acids and host hydroxyl group in A·B·C1-4 are
weaker compared to those in A·B·C5-10 (Table 3). In A·B·C5-
10, the hydrophobic aggregation between carboxylic acid
bulky backbones and the host methyl groups also influences
binding energies in calculated structures. In those structures,
a balanced combination of steric interactions, weak hydrogen
bonds, and electrostatic factors contributes to their
decreased free energy and binding enthalpy (Figure S53;
Table 3). When compared to the experimentally-determined
binding
energies,
the
computational
calculations
systematically overestimate the binding. This might partially
arise from the assumptions around the solvation model of
these systems, but could also arise from limitations to the
experimentally-derived
measurements
which
were
determined using the 1H NMR shifts. This systematic
discrepancy is not atypical for these types of comparisons,
and what is notable is that the trends observed
experimentally are mirrored in the computational analyses
(Figure 8b).
Evidence of cooperativity effects in the ternary
assembly
The cooperativity derived differences in the thermodynamics
of A·B·C1-10 versus A·B, B·C1-10, and A·C1-10 can be
evaluated. The hydrogen bond interactions between B and C
in A·B·Cn systems improves the A·B host-guest interactions
within the cavity (positive cooperativity).65–67 In addition to
the obvious B and Cn interactions, the interactions between
A and Cn also modulate the formation of the A·B·Cn
complex, reinforcing the strength of the non-covalent
interactions within the assembly binding B and A as well as B
and Cn together.
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complexation is enthalpy driven and compensated by
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entropy. This was supported by in silico ternary experiments
showing complexation is driven by favourable enthalpy that
overcomes the entropic barrier. Furthermore, the DFT
calculations support the positive cooperativity between three
components according to
a
Williamson model. By
broadening the pool of analytes for supramolecular
diagnostic tools from those that fit in a macrocycle’s cavity,
to include those that interact with the guests in the cavity,
these guest-mediated ternary complexes could prove very
useful as the basis for next-generation sensors in
biomedicine and environmental science applications.
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EXPERIMENTAL SECTION
General information: Pyridine (B), carboxylic acids (C1-
C10), and solvents used for syntheses, NMR and ITC
experiments, and crystallizations were purchased from Sigma
Aldrich or Oakwood Chemicals (Estill SC, USA). The Cethyl-2-
methylresorcinarene (A) was synthesized according to
1
reported procedures.68 The H, 19F -NMR, DOSY and NOESY
NMR experiments were carried out in CD3OD at 298 K on a
either Bruker Avance 300, 400 or 500 MHz spectrometers. ITC
measurements were performed using VP-ITC instrument
made by MicroCal.
Figure 10. Williamson cooperativity model for A·B·C2
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Solid-state X-ray crystallography: Data for B·C1 was
measured on a Bruker-Nonius Kappa CCD diffractometer
equipped with an APEX-II CCD detector using graphite-
monochromated Mo-Kα (λ = 0.71073 Å) radiation.69 The data
for A·B·C5 were collected using a Rigaku SuperNova single-
source Oxford diffractometer with an Atlas EoS CCD detector
using mirror-monochromated Mo-Kα (λ = 0.71073 Å)
radiation. Single-crystal X-ray data for A·B, A·C6, A·B·C1,
A·B·C7, A·B·C9, and A·B·C10·was measured using a Rigaku
SuperNova dual-source Oxford diffractometer equipped with
an Atlas detector using mirror-monochromated Cu-Kα (λ =
1.54184 Å) radiation.70
showing the calculated energies of the binding interactions
and that the two possible overall pathways both proceed
through a first favourable binding interaction followed by a
strongly favourable binding of the third component. The
difference between ternary formation and binary formation
can be taken as the calculated co-operative energy of the
process.
Powder X-ray diffraction: The bulk crystallizations were
examined by powder X-ray diffraction using a PANalytical
X’Pert PRO diffractometer with Cu Kα1 radiation (1.5406 Å; 45
kV, 40 mA).
CONCLUSIONS
The reported pyridine-mediation of
a resorcinarene-
carboxylic acid interaction represents a clear example of this
ternary supramolecular archetype. The formation of these
1:1:1 stoichiometric systems are investigated both in solution
and as solid-state co-crystals, and their strongly positive co-
operative association is supported by in silico analysis. The
presence of the carboxylic acid, located outside the cavity,
stabilizes the pyridine-resorcinarene inclusion complex. The
electron-rich resorcinarene cavity makes the pyridine N-atom
more basic via the host-guest C–H⋯π interactions. In the
ternary systems, the strength of the O–H⋯N hydrogen bond
between exo-carboxylic acid and endo-pyridine varies from
−104.0 kcal/mol to −121.0 kcal/mol for carboxylic acids with
pKa values ranging between −0.25 and 3.75; and −37.0
kcal/mol to −102.0 kcal/mol for acids with pKas between 4.19
and 4.90. The ITC derived thermodynamic parameters,
negative ΔH and positive TΔS values, for carboxylic acid-
pyridine (binary) and ternary systems indicate that
Computational studies: All binary and ternary
complexes were optimized using the Gaussian 09 suite of
programs71 at the ωB97X-D/6-311G** level of theory72, with
the polarized continuum solvation model (PCM) to account
for solvent effects and the default solvent parameters for
methanol. All minima were further confirmed by the presence
of only real vibrational frequencies and thermochemical
quantities were calculated at 298 K. Further structure analysis
and visualizations was performed using GaussView v5.0.8.4 as
well as Maestro 10.1.73 The binding energies for all binary and
ternary host‒guest assemblies were calculated at B3LYP-
D3/6–311G**//ωB97X-D/6-311G** level of theory in a MeOH
(PCM) solvation model to account for dispersion interactions.
We used Grimme’s dispersion corrected functional B3LYP-
D374 together with long-range corrected (LRC) exchange-
correlation functional with inclusion of dispersion correction,
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ωB97X-D, to accurately predict the binding energy in those
Synthesis of A·B. To host A (21.0 mg, 0.032 mmol)
dissolved in methanol (1.0 mL), added pyridine B (2.53 mg
0.032 mmol) at room temperature.
Synthesis of B·C1. To host B (25.0 mg, 0.32 mmol) in
methanol (1.0 mL), added trifluoroacetic acid C1 (36.1 mg
0.032 mmol) at room temperature.
Synthesis of A·C6. To host A (16.0 mg, 0.024 mmol) in
methanol (1.0 mL), added benzoic acid C6 (2.97 mg 0.024
mmol) at room temperature.
Synthesis of A·B·C1. To Cethyl-2-methylresorcinarene (A)
(17.0 mg 0.026 mmol) dissolved in methanol (1.0 mL)
sequentially added pyridine B (2.10 mg 0.026 mmol) and
trifluoroacetic acid C1 (2.96 mg 0.026 mmol).
Synthesis of A·B·C5. To Cethyl-2-methylresorcinarene (A)
(21.0 mg 0.032 mmol) dissolved in methanol (1.0 mL)
sequentially added pyridine B (2.53 mg 0.032 mmol) and
acetic acid C5 (1.92 mg 0.032 mmol).
Synthesis of A·B·C7. To Cethyl-2-methylresorcinarene (A)
(21.5 mg 0.033 mmol) dissolved in methanol (1.0 mL)
sequentially added pyridine B (2.59 mg 0.033 mmol) and
cyclopropane carboxylic acid C7 (2.84 mg 0.33 mmol).
Synthesis of A·B·C9. To Cethyl-2-methylresorcinarene (A)
(20.0 mg 0.031 mmol) dissolved in methanol (1.0 mL)
sequentially added pyridine B (2.41 mg 0.031 mmol) and
cyclopentane carboxylic acid C9 (3.53 mg 0.032 mmol).
Synthesis of A·B·C10. To Cethyl-2-methylresorcinarene (A)
(19.0 mg 0.029 mmol) dissolved in methanol (1.0 mL)
sequentially added pyridine B (2.29 mg 0.029 mmol) and
cyclohexane carboxylic acid C10 (3.72 mg 0.029 mmol).
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multicomponent supramolecular skeletons which depends
on the intermolecular and intramolecular distance. We
selected this system based on both its virtues for
supramolecular modelling, and because it outperformed
other competitor models in a preliminary validation scan. This
dual dispersion-corrected functional considers dispersion
and range separated corrections and competently describes
non-covalent interactions originating from dispersion
interactions such as multipole−induced multipole,
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dipole−dipole,
dipole−quadrupole,
and
polarization
permanent multipole-induced multipole, that are all involved
in stabilizing the ternary complex. The binding energy (ΔEb)
of A·B·C systems (originated from different intermolecular
binning forces) was calculated according to either equation 1
or 2:
ΔEb = EA·B·C – (EB·C + EA)
ΔEb = EA·B·C – (EA·B + EC)
(1)
(2)
where E(A·B·C), E(A·B), E(B·C), E(A) and E(A) are the energies of the
ternary complex, the binary B·C, and A·B complexes, as well
as A and C fragments, respectively.
NMR solution experiments: 1H and 19F NMR spectra
were recorded on a Bruker Avance 300 MHz (for 1H) and 500
MHz (for 19F) spectrometers. All signals are given as δ values
in ppm relative to TMS using residual solvent signals as the
internal standard. For sample preparation, stock solutions of
the receptor A (60 mM), the pyridine, B (60 mM), and all the
carboxylic acids Cn (n = 1-10; 60 mM) were prepared in
CD3OD. For the pure A, 200 µL of the stock solution was
transferred to an NMR tube and diluted with 400 µL of pure
CD3OD providing a 20 mM sample concentration. For the
pure B, 200 µL of the stock solution was measured into an
NMR tube and diluted with 400 µL of pure CD3OD to give a
20 mM sample concentration. For each of pure carboxylic
acids Cn (n = 1-10), 200 µL of the stock solution was
transferred into an NMR tube and diluted with 400 µL of pure
CD3OD to give a 20 mM sample concentration.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: xxxx.
Experimental details, copies of the 1H, 19F NMR, DOSY and
NOESY data, ITC data, and computational data (PDF).
X-ray crystallographic data for A·B, A·C6, B·C1, A·B·C1,
A·B·C5, A·B·C7, A·B·C9, and A·B·C10 can be obtained free
of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif. CCDC
1938866-1938873 (CIF).
For a 1:1 (A·B) mixture, 200 µL of A, 200 µL of B and 200 µL
of pure CD3OD provided a 20 mM sample concentration of
the each component in the mixture.
For a 1:1 (A·Cn) mixture, 200 µL of A, 200 µL of each Cn (n =
1-10) and 200 µL of pure CD3OD provided a 20 mM sample
concentration of each component in the mixture.
For a 1:1 (B·Cn) mixture, 200 µL of Py, 200 µL of each Cn (n
= 1-10) and 200 µL of pure CD3OD provided a 20 mM sample
concentration of each component in the mixture.
For a 1:1:1 (A·B·Cn) mixture, 200 µL of A, 200 µL of B and 200
µL of each Cn (n = 1-10) were mixed to give a 20 mM sample
concentration of each component in the mixture.
Synthesis of co-crystals: In general, single crystals of
binary and ternary complexes were grown by slow
evaporation of the respective methanol solutions at room
temperature. The prescription of quantities is given below.
AUTHOR INFORMATION
Corresponding Authors
*Email: kari.t.rissanen@jyu.fi
*Email: rakesh.t.puttreddy@jyu.fi
*Email: j.trant@uwindsor.ca
*Email: beyeh@oakland.edu
ORCID
S. Maryamdokht Taimoory: 0000-0002-5350-227X
Kwaku Twum: 0000-0001-5390-0609
Mohadeseh Dashti: 0000-0001-8200-1602
Fangfang Pan: 0000-0002-3091-6795
Manu Lahtinen: 0000-0001-5561-3259
Kari Rissanen: 0000-0002-7282-8419
ACS Paragon Plus Environment

Page 11 of 14
The Journal of Organic Chemistry
Rakesh Puttreddy: 0000-0002-2221-526X
John F. Trant: 0000-0002-4780-4968
Ngong Kodiah Beyeh: 0000-0003-3935-1812
Pharmaceutical Cocrystals: A Decade of Fast-Moving New
Science and Patents. Pharm. Pat. Anal. 2012, 1, 313–327.
https://doi.org/10.4155/ppa.12.29.
1
2
3
4
5
6
7
8
(10) Landenberger, K. B.; Matzger, A. J. Cocrystals of 1,3,5,7-
Tetranitro-1,3,5,7-Tetrazacyclooctane (HMX). Cryst. Growth
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(11) Landenberger, K. B.; Matzger, A. J. Cocrystal Engineering of a
Prototype Energetic Material: Supramolecular Chemistry of
2,4,6-Trinitrotoluene. Cryst. Growth Des. 2010, 10, 5341–5347.
https://doi.org/10.1021/cg101300n.
Author Contributions
The manuscript was written and edited through the
contributions of all authors. All authors have given approval
to the final version of the manuscript. Rakesh Puttreddy:
original concept and SCXRD analyses. S. Maryamdokht
Taimoory: Computational and NMR analyses. Kwaku Twum:
NMR and ITC analyses. Mohadeseh Dashti: NMR analysis.
Fangfang Pan: SCXRD analysis, Manu Lahtinen: PXRD
analysis. Kari Rissanen: supervised the work in Finland. John
F. Trant: supervised the work in Canada. Ngong Kodiah
Beyeh: supervised the work in the USA.
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(12) Bolton, O.; Matzger, A. J. Improved Stability and Smart-
Material Functionality Realized in an Energetic Cocrystal.
Angew.
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(13) Bolton, O.; Simke, L. R.; Pagoria, P. F.; Matzger, A. J. High Power
Explosive with Good Sensitivity: A 2:1 Cocrystal of CL-20:HMX.
Notes
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4311–4314.
https://doi.org/10.1021/cg3010882.
The authors declare no competing financial interest.
(14) Guo, D.; An, Q.; Zybin, S. V; Goddard III, W. A.; Huang, F.; Tang,
B. The Co-Crystal of TNT/CL-20 Leads to Decreased Sensitivity
toward Thermal Decomposition from First Principles Based
Reactive Molecular Dynamics. J. Mater. Chem. A 2015, 3, 5409–
5419. https://doi.org/10.1039/C4TA06858K.
ACKNOWLEDGMENTS
The authors gratefully acknowledge financial support from
the Academy of Finland (RP: grant# 298817), the University
of Jyväskylä, Natural Sciences and Engineering Research
Council of Canada (JFT: grant # 2018-06338), National
Natural Science Foundation of China (FP: grant# 21602071)
and Oakland University, MI, USA. This work was made
possible by the facilities of the Shared Hierarchical Academic
(15) Park, L. Y.; Hamilton, D. G.; McGehee, E. A.; McMenimen, K. A.
Complementary
C3-Symmetric
Donor−Acceptor
Components:ꢀ Cocrystal Structure and Control of Mesophase
Stability. J. Am. Chem. Soc. 2003, 125, 10586–10590.
https://doi.org/10.1021/ja036540o.
Research
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www.sharcnet.ca) and Compute/Calcul Canada.
Malthête, J. Columnar Mesophase from
Mesogen Based on a 3,5-Dicyano-2,4,6-Tristyrylpyridine Core.
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a New Disclike
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