Thinking Outside the "blue Box": Induced Fit within a Unique Self-Assembled Polycationic Cyclophane

Article abstract of DOI:10.1021/jacs.8b12599

We present herein the development of a new polycationic molecular receptor, inspired by the ubiquitous cyclobis(paraquat-p-phenylene)cyclophane ("blue box"). Our analogue, the "white box", has been easily self-assembled on a preparative scale in water, using a template-assisted process by acyl hydrazone bonding of complementary bis(pyridinium)xylylene tweezers, followed by kinetic trapping of the empty receptor. The obtained macrocycle was found to display a marked pH responsiveness in water, because of an abnormal acidity of the amide protons within its structure. Consequently, and because of the concurrence of rotational isomerism under acidic conditions (fixed at higher pH values), the compound was found to display a dual behavior as a conformationally locked/flexible molecular host, being able to recognize appropriate aromatic substrates, in a lock and key or induced fit fashion, by a conjunction of π-π, C-H···π, and, crucially, the hydrophobic effect.

Full text of DOI:10.1021/jacs.8b12599

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Article
Thinking Outside the Blue Box: Induced Fit Within
a Unique Self-assembled Polycationic Cyclophane
Arturo Blanco-Gómez, Ángel Fernández-Blanco, Víctor
Blanco, Jaime Rodríguez, Carlos Peinador, and Marcos D. García
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b12599 • Publication Date (Web): 07 Feb 2019
Downloaded from http://pubs.acs.org on February 7, 2019
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Thinking Outside the Blue Box: Induced Fit Within a Unique Self-
assembled Polycationic Cyclophane †
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Arturo Blanco-Gómez,a Ángel Fernández-Blanco,a Víctor Blanco,b Jaime Rodríguez,a Carlos
Peinador,a,* Marcos D. Garcíaa,*
a Departamento de Química and Centro de Investigacións Científicas Avanzadas (CICA). Facultade de Ciencias,
Universidade da Coruña, 15071, A Coruña, Spain.
b Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Granada, Campus Fuentenueva S/N,
Granada, 18071, Spain.
Supporting Information Placeholder
of the molecular recognition, are mainly disrupted due to the
ABSTRACT: We present herein the development of a new
polycationic molecular receptor, inspired by the ubiquitous
cyclobis(paraquat-p-phenylene)cyclophane (blue box). Our
dominant effect of water on the association processes.19-
20Additionally, the most consistent approach for the self-
assembly of molecular receptors is still based on metal-
directed methodologies,21 where the precise geometry of the
different coordination modes of the metallic ions, as well as
their various degrees of kinetic/thermodynamic stability, offer
a reliable strategy for the prospective design of self-assembled
species with well-defined shapes and geometries. Conversely,
reports on the thermodynamically-controlled synthesis of
wholly organic and functional macrocyclic hosts are still quite
scarce.14
analogue, the white box, has been easily self-assembled on a
preparative scale in water, using a template-assisted process
by
acyl
hydrazone
bonding
of
complementary
bis(pyridinium)-xylylene tweezers, followed by kinetic
trapping of the empty receptor. The obtained macrocycle was
found to display a marked pH-responsiveness in water,
because of an abnormal acidity of the amide protons within its
structure. Consequently, and because of the concurrence of
rotational isomerism on acidic conditions (fixed at higher pH
values), the compound was found to display a dual behavior
as a conformationally locked/flexible molecular host, being
able to recognize appropriate aromatic substrates, on a lock-
and-key or induced fit fashion, by a conjunction of -, C-
H··· and, crucially, hydrophobic interactions.
To improve in some extent some of the above-mentioned
drawbacks, and following our continuous interest on the
development of self-assembled receptors in aqueous media,22-
27 we have turned our attention to the use of hydrazone-based
dynamic covalent chemistry for the task.28 This methodology
has very recently erupted in the literature, allowing the
thermodynamically-controlled preparation in aqueous media
of entirely organic molecular receptors and mechanically
interlocked molecules.29-34 Even though the strategy has been
proven quite successful, in most of the cases the amphiphilic
character of the building blocks results rather into
hydrophobically-driven self-catenation or knotting,29-33 than
into fully functional and empty kinetically stable hosts.34
Introduction
Currently commercially available macrocycles such as
cyclodextrins,1 crown ethers,2 calixarenes3 or cucurbiturils,4
are prominent examples of the myriad of molecular receptors
developed over the years since the seminal works of
Pedersen,5-6 Lehn7-8 and Cram.9
Nevertheless, such fully static hosts have many weaknesses
that constrain the adjustment of their properties,10 as well as
the exploration of new biomimetic concepts that could
potentially evolve the field of host-guest chemistry in
particular, and supramolecular chemistry in general.11-13
Firstly, the synthesis of those macrocycles, and therefore of
fine-tuned analogues, is hampered by cyclization steps being
carried out typically under kinetic control and, therefore,
resulting on low yields on the desired target.14,15 Likewise, rigid
receptors are usually preferred over conformationally flexible
analogues,16 prevailing therefore in their host-guest chemistry
Fischer’s lock and key17 over Koshland’s induced fit.18
The above-discussed limitations are even more pronounced
in two scenarios. Firstly, in aqueous media, where most of the
weak intermolecular forces, commonly used as driving force
Scheme 1. Depiction of the planned self-assembly of the
white box W4+, and its potential conformational isomerism.
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expected inclusion complex W4+2,7-DHN (Figure 1).
Essentially, compared with the free guest, signals of the
substrate appear consistently shielded, being H3 particularly
affected due to the typical occurrence of [C-H···π] interactions
with the phenylene moieties of W4+(H3 = -1.2 ppm, Ha =
0.27 ppm and Hj = 0.3 ppm).42 Furthermore, the resonances
observed for Hf (Hf = 7.35 ppm) and Cf (Cf = 143.9 ppm), are
completely congruent with the formation of the expected
imine bonds. Finally, DOSY NMR also allowed us to support
the formation of the inclusion complex, with all its resonances
on the aggregate diffusing as a whole on the corresponding
spectrum (Figure 1d)
In this scenario, we propose herein the development of the
white box (W4+), a new self-assembled cyclophane analogue to
the well-known blue box (cyclobis(paraquat-p-
phenylene)cyclophane) developed by Stoddart and
coworkers.15, 16 In essence, to avoid the kinetically-controlled
synthesis of the receptor, we projected its self-assembly of W4+
in water by acyl hydrazone bonding (Scheme 1), using
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complementary
hydrophilic
bis(pyridinium)-xylylene
tweezers 12+ and 22+, building blocks prepared in excellent
yield as the corresponding dibromides starting from 1,4-
bis(bromomethyl)benzene.35 The -deficient and hydrophilic
character of the components, was designed not only to
minimize the propensity to self-thread observed in similar
systems,29-33 but to promote host-guest interactions in a blue
box-like fashion (i.e. by maximization of host-guest -, C-
H··· and hydrophobic interactions with four parallel
pyridinium rings).15, 16, 36
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The synthesis of W·4Br2,7-DHN could be achieved on a
preparative scale (0.4 mmol), allowing for the expulsion of the
template from the cavity of the receptor and the isolation of
virtually pure W·4PF6 on a 83% yield, simply by addition of
excess KPF6 to the aqueous reaction media, filtration and
washing of the obtained solid with AcOEt. 1D/2D NMR
experiments in CD3CN showed a sole main species, in good
agreement with the expected cyclophane W4+. The identity of
the macrocycle was corroborated as well by ESI-MS, showing
Results and discussion
In a first effort to produce cyclophane W4+, we attempted
typical reaction conditions for thermodynamic control on the
hydrazone bonding,30 monitoring by 1H-NMR the TFA-
catalyzed reaction at 80 °C of an equimolar 1.5 mM mixture of
1·2Br and 2·2Br in D2O. After 24 hours, the results were quite
misleading, with the starting materials being transformed into
a complex mixture of presumably, oligomeric and isomeric
imine-containing species.36 In order to simplify the analysis of
the outcome of the self-assembly, we decided to use the very
same reaction conditions, but with an excess of 2,7-
-
both the typical loss of PF6 counterions on the macrocyclic
structure, as well as HPF6 fragments as a result of acid-base
reactions occurring on the gas phase (Figure 2),43 a fact that
could be later correlated with an increased acidity of the
amide protons of the structure (vide infra).
dihydroxynaphthalene (2,7-DHN, 1.5 eq.), acting as
a
template. The aromatic substrate would, a priori, not only
decrease the energetic penalties of the process, but, we argued
that in order to maximize host-guest interactions, the
macrocycle would prefer to adopt
a
blue box-like
conformation, that is Waa4+, the only conformer able to
potentially align the -deficient pyridinium moieties of each
side of the rectangle.36 In that manner, the observation of
conformers on the NMR would be conveniently precluded.
FIGURE 2. LR ESI-MS spectrogram for W·4PF6 showing the
loss of PF6- and HPF6 fragments. Insets, HR ESI-MS for some
of the most relevant peaks.
The convenient ease on the synthesis of the cyclophane by
anion exchange is not surprising. Due to the suppression of
the hydrophobic effect, W4+ can be anticipated as a quite
22-23
deficient molecular host in organic solvents.15-16,
To
corroborate that hypothesis, we unfruitfully attempted in
CD3CN the synthesis of the corresponding inclusion
complexes of W·4PF6 and variety of electron rich aromatics,
1
FIGURE 1. H NMR (D20, t.a., 500 MHz) of: a) 1.5 mM DHN;
1
with the corresponding H NMR showing the absence of
b) equimolar 1.5 mM mixture of 1·2Br, 2·2Br and 2,7-DHN at
r.t. and t = 0; c) the same mixture after 24 hour heating at 80
°C; d) DOSY NMR for mixture c). Proton numbering on
Scheme 1
appreciable host-guest interactions.35
Turning our attention to the study of W4+ in aqueous
media, W·4Cl could be easily obtained in an excellent yield of
89% by ion metathesis of the hexafluorophosphate salt
In this case, after 24 hours, the results obtained for the
acid-catalyzed reaction were in good agreement with the
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dissolved in CH3CN.35 In this case, the H NMR of the empty
receptor in D2O at r.t., matched with the existence of various
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imine-containing isomeric species. As it can be seen on the
spectrum shown in Figure 3, two sets of sharp resonances
As shown on Figure 4, the appearance of the conjugated
base W2+ on increasing the pH, clearly results on a substantial
decrease of the originally observed main absorption for W4+
(max = 325 nm, associated to -* transitions), and the
concomitant appearance of a new band clearly indicating an
intramolecular charge-transfer (max = 400 nm), associated
with the delocalization of negative charge over the pyridinium
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appear on the spectrum accompanied by another, quite
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complex, set of signals in a minor proportion. VT H NMR
experiments, competition reaction with excess of 4-
(dihydroxymethyl)-1-methylpyridin-1-ium iodide, and the
non-alteration of the observed signals over time, account for
the kinetic stability of the products detected on these
conditions.35 Based on these experimental observations, the
extended bibliography on the occurrence of rotational
isomerism of acylhydrazones,29-34,37-41 as well as the different
1D/2D NMR experiments recorded for W·4Cl in D2O, we
established the hypothesis of the macrocycle appearing as a
mixture of the three potentially stable rotamers that were
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rings upon deprotonation. In addition, the H-NMR for a
buffered aqueous solution of the macrocycle at pH = 7.2
(Figure 3c), clearly simplifies the initially observed complex
spectra for W4+ to a sole set of resonances for the cyclophane,
a compelling evidence for the compound appearing as the
conformationally rigid species W2+ at a sufficiently basic pH.
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4+
tentatively assigned as Waa4+, Wss and Was4+ (Scheme 1),36
being the three in slow exchange on the NMR timescale on a
0.40:0.35:0.25 proportion, respectively (Kaaas = 0.82, Kasss
=
1.40, Kaass = 1.15).44 An EXSY NMR experiment recorded for
the product, was specially in good agreement with the
hypothesis of the conformers, with signals for the three
potential species showing appropriate cross peaks on the
diagonal of the corresponding 2D spectrum.35 Furthermore,
addition of an equimolar amount of 2,7-DHN to a D2O
solution of the conformationally flexible receptor,
spontaneously recovered the very same NMR data obtained
for W4+2,7-DHN. Going back to the analysis of the VT
1HNMR experiment, we clearly detected an increase on the
exchange velocity for the signals assigned to different isomers,
allowing for the rough assessment of coalescence
temperatures for some of those, and the estimation of a G# ~
17.3 Kcal/mol for the interconversion processes,35 a value
clearly matching that frequently observed for the rotational
barrier of amide bonds within acylhydrazones.40-41
Figure 4. A) Schematic depiction of the acid-base equilibrium
for W4+ in water. B) UV-Vis spectra for the titration of 30 μM
W·Cl with solutions of citric acid/Na2HPO4 buffer of
increasing pH. Insets on B): Absorption for the compound at
 = 400 nm plotted against the pH.
Attracted by the pH-dependent nature of our macrocycle,
we proceeded to study its ability as molecular receptor in
water. Consequently, 2,7-DHN was used as archetypical
aromatic guest, and its association with the host studied by 1H
NMR titrations in buffered solutions. Firstly, we conducted
the experiments at pH = 7.8, assuring that our receptor would
be mainly deprotonated. The obtained data showed the host-
guest complexation to be fast on the NMR timescale, allowing
for its convenient fitting to a 1:1 association model using the
software Dynafit.45 The obtained value of Ka = 4960 ± 330 M-1
for W2+2,7-DHN, is in good agreement to the reported values
for similar systems.15, 21-27
1
FIGURE 3. H NMR (D20, t.a., 500 MHz) of: a) equimolar 1.5
mM mixture of 1·2Br, 2·2Br at r.t.; b) product obtained after
ion metathesis of W·4PF6 with TBACl (pH = 4); c) same as b)
in a buffered solution at pH = 7.2. Legend: Waa4+, diamonds;
Wss4+ circles; Was4+, stars. Proton numbering on Scheme 1.
The same experiments at pH = 4, guaranteeing the
protonation of the compound, yielded really interesting
results. As shown on Figure 5, it can be clearly observed that
upon addition of substrate, only one out of the three sets of
signals assigned to the rotamers on slow exchange, that
tentatively assigned to Waa4+ (Figure 3), shows a shifting on
its resonances accounting for a host-guest complex on rapid
equilibrium with this rotamer on the NMR timescale.
Conversely, the signals attributed to the other two isomers,
In order to further validate our hypothesis of the obtained
macrocycle W4+ being observed as a mixture of isomers on
NMR on aqueous media, we argued that deprotonation of the
amide protons at a sufficiently basic pH would eliminate the
proposed rotational isomerism, as
a
result of the
delocalization of the negative charges over two of the
pyridinium rings (Figure 4). As a corollary of this prediction,
a decreased acidity should be observed for the macrocycle, a
fact that was conveniently verified by an UV-Vis titration
yielding a pKa = 6.5 for an acid-base process where two
protons are released to the aqueous media.35.
4+
Wss and Was4+, are practically unaltered, on their chemical
shifts, during the titration. Fitting of the obtained data to the
4+
4+
global process [Waa ⇆ Was ⇆ Wss4+] ⇆ Waa4+2,7-DHN
(Figure 5), using the software Dynafit,45 allowed for the
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estimation of a Ka = 2630 ± 200 M-1 for the induced fit
cyclophane, supporting the longitudinal insertion mode of the
guest and the coplanar conformation of Waa4+, being the
distance between the mean plane of 2,7-DHN and each of the
long sides of the guest around 3.3-3.4 Å, optimal for the
process,47 a value that accounts as well for the hydrophobic
effect, and not the total charge of the macrocycle, being
mainly responsible for the observed aggregation
proccesses.14,22-27
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establishment of -interactions as in similar systems. 15, 24-26,
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FIGURE 6. DFT optimized structure (M06/6-31G(d,p)) of
Waa4+ (top) and Waa4+2,7-DHN (bottom).
Conclusions
In summary, we have reported herein the successful
template-assisted self-assembly of a new pH-dependent and
conformationally modulable molecular receptor, the white
box, an acyl hydrazone-extended analogue of Stoddart’s blue
box, able to recognize a variety of aromatic substrates in
aqueous media by a combination of -, C-H··· and,
decisively, hydrophobic interactions. The host-guest
chemistry of the receptor could be studied in detail, being a
nice example of key-and-lock recognition in neutral/basic
conditions, and induced fit on more acidic media. The
reported results open the door not only for the easy design and
synthesis of new fine-tuned analogues of the white box (for
instance by replacing the aldehyde groups on 12+ by
structurally-diverse ketones), but also for the exploration of
refreshing concepts in dynamic supramolecular chemistry, as
exemplified by the induced-fit mechanism reported herein.
.
FIGURE 5. A) Proposed equilibria involved on the induced fit
process. B) Selected spectra form the titration of W·4Cl (1.8
mM in D2O, pH= 4), with increasing amounts of 2,7-DHN,
1
showing a selected region of the H NMR spectra (D2O, t.a.,
500 MHz). C) Fitting of the observed variation on the chemical
shifts of protons Hd and Hg plotted against the total
concentration of added guest.
The assignment of the rotamer Waa4+ as the one involved
on the induced fit process, is argued on the basis of different
evidences. First, the slow interconversion rate between
rotamers, and the fast exchange regime for the complexation
of the guest, producing only one set of 12 sharp resonances,
directly confirms both the induced fit mechanism and
ASSOCIATED CONTENT
Supporting Information
4+
exonerates isomer Was as being the one selected on the
process (Figure 5B).44 In order to clarify whether Waa or
4+
Complete experimental procedures, 1D/2D NMR experiments
and ESI MS data for new compounds, extra figures and
computational details. This material is available free of charge
via the Internet at http://pubs.acs.org.
4+
Wss
is the symmetric conformation chosen on the
series of NMR
recognition process, we performed
a
experiments to evaluate the association at pH = 4 of W4+ with
appropriate guests of increasing sizes (1,5-DHN < carbazole <
phenanthrene < pyrene). The obtained results are very similar
to those discussed for W4+2,7-DHN, with the aggregates
showing not only the expected deshielding for the nuclei on
the guest because of - interactions, but as well diagnostic
protons on the longitudinal axis of the guests clearly involved
in C-H··· interactions, a fact that fits extremely well with fixed
longitudinal insertion modes for all the substrates within the
AUTHOR INFORMATION
Corresponding Author
Carlos Peinador: carlos.peinador@udc.es; Marcos D. García:
marcos.garcia1@udc.es.
Notes
4+
The authors declare no competing financial interests.
Waa conformer, as is also typically shown in similar
†
systems.15, 24-26, 35
By analogy to Stoddart’s blue box, we have named the host
developed herein as the white box, obviously based not in its
shade, but in honor to the common surname of three of the
authors of the present work.
4+
Finally, to shed some light on the structures of both Waa
and its inclusion complex Waa4+2,7-DHN, those were
minimized using DFT methods at the M06/6-31G(d,p) level in
water. The obtained results (Figure 6), show minor
differences between the conformation of free and complexed
ACKNOWLEDGMENT
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on N-Monoalkyl-4,4′-Bipyridinium Derivatives. In Molecular Self-
Assembly: Advances and Applications; Li, A. D. Q., Ed.; Pan Stanford
Publishing: Singapore, 2012; p 351.
(23) García, M. D.; Alvariño, C.; López-Vidal, E.; Rama, T.; Peinador,
C.; Quintela, J. M. Complexation of Aromatic Compounds with Self-
Assembled PdII and PtII Metallacycles. Inorg. Chim. Acta 2014, 417, 27.
(24) Peinador, C.; Pía, E.; Blanco, V.; García, M. D.; Quintela, J. M.
Complexation of Pyrene in Aqueous Solution with a Self-Assembled
Palladium Metallocycle. Org. Lett. 2010, 12, 1380.
This research was supported by the Ministerio de Economía y
Competitividad (MINECO FEDER, Grant CTQ2016-75629-P).
Professor Jose Luis Barriada is greatly acknowledge for their
helpful discussions on the acid-base behavior of the acyl
hydrazone derivatives. We acknowledge the “Centro de
Servicios de Informática y Redes de Comunicaciones” (CSIRC)
from University of Granada for supercomputing facilities
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5
6
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8
9
(25) Blanco, V.; García, M. D.; Terenzi, A.; Pía, E.; Fernández-Mato,
A.; Peinador, C.; Quintela, J. M. Complexation and Extraction of PAHs
to the Aqueous Phase with a Dinuclear PtII Diazapyrenium-Based
Metallacycle. Chem. Eur. J. 2010, 16, 12373.
(26) Alvariño, C.; Pía, E.; García, M. D.; Blanco,V.; Fernández, A.;
Peinador, C.; Quintela, J. M. Dimensional Matching of Polycyclic
Aromatics with Rectangular Metallacycles: Insertion Modes
Determined by [C-H⋅⋅⋅π] Interactions. Chem. Eur. J. 2013, 19, 15329.
(27) Rama, T.; López-Vidal, E. M.; García, M. D.; Peinador, C.;
Quintela, J. M. Complexation and Catenation in Aqueous Media Using
a Self-Assembled PdII Metallacyclic Receptor. Chem. Eur. J. 2015, 21,
9482.
(28) Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders, J. K. M.;
Stoddart, J. F. Dynamic Covalent Chemistry. Angew. Chem. Int. Ed.
2002, 41, 898.
(29) Li, H.; Zhang, H.; Lammer, A. D.; Wang, M.; Li, X.; Lynch, V.
M.; Sessler, J. L. Quantitative Self-Assembly of a Purely Organic Three-
Dimensional Catenane in Water. Nat. Chem. 2015, 7, 1003.
(30) Zheng, X.; Zhang, Y.; Wu, G.; Liu, J.-R.; Cao, N.; Wang, L.;
Wang, Y.; Li, X.; Hong, X.; Yang C.; Li, H. Temperature-Dependent
Self-Assembly of a Purely Organic Cage in Water. Chem. Commun.
2018, 54, 3138.
(31) Wu, G.; Wang, C.-Y.; Jiao, T.; Zhu, H.; Huang, F.; Li, H.
Controllable Self-Assembly of Macrocycles in Water for Isolating
Aromatic Hydrocarbon Isomers. J. Am. Chem. Soc. 2018, 140 , 5955.
(32) Wang, C.-Y.; Wu, G.; Jiao, T.; Shen, L.; Ma, G.; Pana; Y.; Li, H.
Precursor Control over the Self-Assembly of [2]Catenanes via
Hydrazone Condensation in Water. Chem. Commun. 2018, 54, 5106.
(33) Cougnon, F. B. L.; Caprice, K.; Pupier, M.; Bauza, A.; Frontera
A. A Strategy to Synthesize Molecular Knots and Links Using the
Hydrophobic Effect. J. Am. Chem. Soc. 2018, 140, 12442.
(34) Zhang, Y.; Zheng, X.; Cao, N.; Yang, C.; Li, H. A Kinetically
Stable Macrocycle Self-Assembled in Water. Org. Lett. 2018, 20, 2356.
(35) See ESI for further details.
(36) The presence of two acyl hydrazone moieties potentially confer
our designed receptor both configurational (E-/Z-) and
conformational (syn-/anti-) isomerism. Considering the well-known
REFERENCES
(1) See, for instance: Crini, G. Review: A History of Cyclodextrins.
Chem. Rev. 2014, 114, 10940.
(2) See, for instance: Crown Ethers and Analogous Compounds;
Hiraoka, M., Ed.; Elsevier: Amsterdam, 2013.
(3) See, for instance: Gutsche, C. D. Calixarenes: An Introduction;
Royal Society of Chemistry: Cambridge, U.K., 2008.
(4) See, for instance: Barrow, S. J.; Kasera, S.; Rowland, M. J.; del
Barrio, J.; Scherman, O A. Cucurbituril-Based Molecular Recognition.
Chem. Rev., 2015, 115, 12320.
(5) Pedersen, C. J. Cyclic Polyethers and their Complexes with
Metal Salts. J. Am. Chem. Soc. 1967, 89, 2495.
(6) Pedersen, C. J. Cyclic Polyethers and their Complexes with
Metal Salts. J. Am. Chem. Soc. 1967, 89, 7017.
(7) Dietrich, B.; Lehn, J.-M.; Sauvage, J.-P. Diaza-Polyoxa-
Macrocycles et Macrobicycles. Tetrahedron Lett. 1969, 10, 2885.
(8) Dietrich, B.; Lehn, J.-M.; Sauvage, J.-P. Les Cryptates.
Tetrahedron Lett. 1969, 10, 2889.
(9) Kyba, E. P.; Helgeson, R. C.; Madan, K.; Gokel, G. W.;
Tarnowski, T. L.; Moore, S. S.; Cram, D. J. Host-Guest Complexation.
1. Concept and Illustration. J. Am. Chem. Soc. 1977, 99, 2564.
(10) Cram, D. J.; Cram, J. M. Container Molecules and Their Guests;
Royal Society of Chemistry: Cambridge, U.K., 1997.
(11) Lehn, J.-M. Toward Self-Organization and Complex Matter.
Science, 2002, 295, 2400.
(12) Lehn, J.-M. Perspectives in Chemistry-Steps towards Complex
Matter. Angew. Chem., Int. Ed., 2013, 52, 2836.
(13) Lutz, J.-F.; Lehn, J.-M.; Meijer, E. W.; Matyjaszewski, K. From
Precision Polymers to Complex Materials and Systems. Nat. Rev. Mats.
2016, 1, 16024.
(14) Martí-Centelles, V.; Pandey, M. D.; Burguete, M. I.; Luis, S. V.
Macrocyclization Reactions: The Importance of Conformational,
Configurational, and Template-Induced Preorganization. Chem. Rev.
2015, 115, 8736.
(15) The development of the blue box, and by extension the whole
family of related molecular receptors ExnBoxm4+, is a classic example
of the benefits of molecular self-assembly. The initially-reported
kinetically-controlled synthesis, leading to low yields even in the
presence of adequate templates, was immensely improved by using
thermodynamically-controlled conditions on the key SN2
macrocyclation step: Dale, E. J.; Vermeulen, N. A.; Juríček, M.; Barnes,
J. C.; Young, R. M.; Wasielewski, M. R.; Stoddart, J. F. Supramolecular
Explorations: Exhibiting the Extent of Extended Cationic
Cyclophanes. Acc. Chem. Res. 2016 49, 262.
(16) Liu, Z.; Nalluri, S. K. M.; Stoddart, J. F. Surveying Macrocyclic
Chemistry: from Flexible Crown Ethers to Rigid Cyclophanes. Chem.
Soc. Rev. 2017, 46, 2459.
(17) Behr, J.-P., Eds. The Lock and Key Principle. The State of the
Art−100 Years On; Wiley: New York, 1994.
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12
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prevalence of the less sterically-hindered E- form on the imine bond
37-40
on most aryl acyl hydrazones,33-34,
the isomerism would be, in
principle, restricted to the appearance of the syn-/anti-conformers of
the amide bonds. In consequence, the two acyl hydrazone moieties on
our envisaged receptor would result in three potential conformers for
W4+ (labeled as Wss4+, Wsa4+ and Waa4+, Scheme 1).
(37) Syakaeva, V. V.; Podyacheva, S. N.; Buzykina, B. I.; Latypova, S.
K.; Habicherb, W. D.; Konovalova, A. I. NMR Study of Conformation
and Isomerization of Aryl- and Heteroarylaldehyde 4-tert-
Butylphenoxyacetylhydrazones. J. Mol. Struct. 2006, 788, 55.
(38) Chaur, M. N.; Collado, D.; Lehn, J.-M. Configurational and
Constitutional Information Storage: Multiple Dynamics in Systems
Based on Pyridyl and Acyl Hydrazones. Chem. Eur. J. 2011, 17, 248.
(39) Palla, G.; Predieri, G.; Domiano, P.; Vignali, C.; Turner, W.
Conformational Behaviour and E/Z Isomerization of N-Acyl and N-
Aroylhydrazones. Tetrahedron 1986, 42, 3649.
(40) Oliveira, P.F.M.; Guidetti, B.; Chamayou, A.; André-Barrès, C.;
Madacki, J.; Korduláková, J.; Mori, G.; Orena, B.S.; Chiarelli, L.R.;
Pasca, M.R.; Lherbet, C.; Carayon, C.; Massou, S.; Baron, M.; Baltas, M.
Mechanochemical Synthesis and Biological Evaluation of Novel
Isoniazid Derivatives with Potent Antitubercular Activity. Molecules
2017, 22, 1457.
(18) Koshland, D. E., Jr. The Key–Lock Theory and the Induced Fit
Theory. Angew. Chem. Int. Ed. Engl. 1994, 33, 2375.
(19) Oshovsky, G.; Reinhoudt, D.; Verboom, W. Supramolecular
Chemistry in Water. Angew. Chem. Int. Ed. 2007, 46, 2366.
(20) Taylor, L.; Riddell, I.; Maarten M.; Smulders J. Application
Driven Self-Assembly of Discrete, Three-Dimensional Architectures
in Water. Angew. Chem. Int. Ed. DOI: 10.1002/anie.201806297.
(21) See, for instance: Chakrabarty, R.; Mukherjee, P. S.; Stang, P. J.
Supramolecular Coordination: Self-Assembly of Finite Two- and
Three-Dimensional Ensembles. Chem. Rev. 2011, 111, 6810.
(22) Peinador, C.; Blanco, V.; García, M. D.; Quintela, J. M. PdII and
PtII Metal-Directed Self-Assembly of Supramolecular Structures Based
(41) Lopes, A.B.; Miguez, E.; Kümmerle, A.E.; Rumjanek, V.M.;
Fraga, C.A.M.; Barreiro, E.J. Characterization of Amide Bond
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(46) For instance, on the 1H NMR for W4+2,7-DHN, strong C-H···
interactions are solely observed for equivalent protons H2,7 on the
longitudinal axis of the PAH ( = -3.1 ppm), with the other equivalent
protons H1,3,6,8 and H4,5,9,10 being far less deshielded and pointing out a
fixed longitudinal insertion mode for the PAH. Any other
conformation of the host within the aggregate different than that of
Waa4+, would clearly result on a quite different pattern of deshielding.
For an extensive discussion on the assessment of insertion modes on
bipyridinium-based metallacycles of similar dimension, see reference
26.
(47) The quite large residuals observed on the fitting shown on
Figure 5C, most likely account for the ‘non-correct’ conformers, Was
and Wss, being able to weakly complex 2,7-DHN in a much lesser
extent than Waa. Due to the limitations of the NMR technique, no
signs of those other potential inclusion complexes were observed on
the recorded spectra, so the consequent equilibria could not be
included on a more complex binding model.
Conformers for a Novel Heterocyclic Template of N-acylhydrazone
Derivatives. Molecules 2013, 18, 11683.
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(42) As observed in Figure 1b, the signals for 2,7-DHN are already
shielded on the initial mixture of components at r.t. and t = 0,
accounting for a weak interaction with both tweezers in those
conditions, probably illustrating the ability of the substrate to
preorganize the reacting building blocks en route to the macrocycle.
(43) Schalley, C. A. mass spectrometry and gas-phase chemistry of
non-covalent complexes, Wiley, Hoboken/NJ, 2009.
(44) Because of the symmetry of the potentially-occurring
rotamers, and on a situation of slow interconversion on the NMR
4+
timescale, both Waa4+and Wss (C2h), should appear as two sets of 9
9
1
different resonances on the corresponding H-NMR. Conversely, the
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4+
decreased symmetry of Was (C1), would result on a more complex
situation, with the two different large sides of the molecular rectangle
yielding 14 different signals, and the phenylene rings on the short sides
appearing as 4 extra doublets.
(45) Kuzmic, P. Program DYNAFIT for the Analysis of Enzyme
Kinetic Data: Application to HIV Proteinase. Anal. Biochem. 1996, 237,
260.
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