A Long-Lived Halogen-Bonding Anion Triple Helicate Accommodates Rapid Guest Exchange

Article abstract of DOI:10.1002/anie.201810415

Anion-templated helical structures are emerging as a dynamic and tractable class of supramolecules that exhibit anion-switchable self-assembly. We present the first kinetic studies of an anion helicate by utilizing halogen-bonding m-arylene-ethynylene oligomers. These ligands formed high-fidelity triple helicates in solution with surprisingly long lifetimes on the order of seconds even at elevated temperatures. We propose an associative ligand-exchange mechanism that proceeded slowly on the same timescale. In contrast, intrachannel anion exchange occurred rapidly within milliseconds or faster as determined by stopped-flow visible spectroscopy. Additionally, the helicate accommodated bromide in solution and the solid state, while the thermodynamic stability of the triplex favored larger halide ions (bromide≈iodide?chloride). Taken together, we elucidate a new class of kinetically stable helicates. These anion-switchable triplexes maintain their architectures while accommodating fast intrachannel guest exchange.

Full text of DOI:10.1002/anie.201810415

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Accepted Article
Title: A Long-Lived Halogen-Bonding Anion Triple Helicate
Accommodates Rapid Guest Exchange
Authors: Casey John Massena, Daniel Adam Decato, and Orion Boyd
Berryman
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201810415
Angew. Chem. 10.1002/ange.201810415
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10.1002/anie.201810415
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A Long-Lived Halogen-Bonding Anion Triple Helicate
Accommodates Rapid Guest Exchange
Casey J. Massena, Daniel A. Decato, and Orion B. Berryman*
Abstract: Anion-templated helical structures are emerging as a
dynamic and tractable class of supramolecules that exhibit anion-
switchable self-assembly. We present the first kinetic studies of an
anion helicate by utilizing halogen-bonding m-arylene-ethynylene
oligomers. These ligands formed high-fidelity triple helicates in
solution with surprisingly long lifetimes on the order of seconds even
at elevated temperatures. We propose an associative ligand-
exchange mechanism that proceeded slowly on the same timescale.
In contrast, intrachannel anion exchange occurred rapidly within
milliseconds or faster as determined by stopped-flow visible
spectroscopy. Additionally, the helicate accommodated bromide in
solution and the solid state, while the thermodynamic stability of the
triplex favored larger halide ions (bromide ≈ iodide >> chloride). Taken
together, we elucidate a new class of kinetically stable helicates.
These anion-switchable triplexes maintain their architectures while
accommodating fast intrachannel guest exchange.
guest dynamics of our triple-helicate system to better understand
this nascent class of supramolecules. 1H 2D EXSY NMR
spectroscopy revealed surprisingly long ligand lifetimes—on the
order of seconds even at elevated temperatures. Variable-
temperature EXSY NMR and other kinetic studies suggest an
associative ligand-exchange mechanism that proceeded slowly
on the same timescale. In contrast, stopped-flow visible
spectroscopy established millisecond-or-faster anion exchange,
demonstrating that the helicate holds its shape while bromide and
iodide flit in and out of its helical cavity. Furthermore, we
characterize the first bromide triple helicate in solution and the
solid state. Through judicious use of the halogen bond, we offer a
strategy to form bromide- and iodide-switchable triple helicates
that, once assembled, accommodate seconds-long ligand
transfers and rapid intrachannel guest exchange.
Increasingly, chemists and biologists seek the underlying rules
governing the structure and dynamics of organized matter,[1]
a
task shared by physical scientists from diverse fields.[2] To this
end, supramolecular chemists have constructed and studied
libraries of helical foldamers[3] and metal-templated helicates[4]—
imitating and complementing one of the most pervasive structural
elements of biomolecules. In contrast, helicates that self-
assemble around anions are underdeveloped,[5] and there are
only three other examples of kinetically stable higher-order anion
helicates. De Mendoza’s bicyclic guanidinium sulfate duplexes[6]
and Wu’s bis(biurea) triplexes[7] chelated di- and trivalent
oxoanions, respectively, while Maeda’s pyrrole-based double
helicates[8] encapsulated chloride and bromide. Elegant examples
of the closely related mononuclear foldamers include Flood’s aryl-
triazole chloride duplex.[9] Thus, it has been established that
anions instigate and maintain helical secondary structure, but how
labile are the ligands, and are the anions dynamic? Here, we
present the first kinetic studies of an anion helicate to promote
these supramolecular structures as useful and moving
nanocomponents.
Scheme 1. m-Arylene-ethynylene ligands and synthesis of triple helicate 4.
Reagents and conditions: a) TBA bromide, 1:3 v/v DMF-CH3CN, RT. 4 is shown
as its X-ray crystal structure (extrachannel bromides and intrachannel positional
disorder not shown for clarity; for crystallographic data and structural refinement
details, see Section 4.1 of the SI).
Optimizing a previous route, we synthesized m-arylene
ethynylene ligand 3 (Scheme 1) in higher yield (see Sections S2–
3 in the Supporting Information, SI).[14] tert-Butyl and methoxy
methyl groups were appended to the oligomeric backbone to
enhance solubility and serve as spectroscopic handles for 1H
NMR experiments. Yellow plates of bromide helicate 4 suitable for
single crystal X-ray diffraction were grown by slow vapor diffusion
of diethyl ether into a 1:1:2 v/v/v DMF-CH3NO2-CH3CN solution of
2 with excess tetra-n-butylammonium (TBA) bromide at 4 °C.[15]
As was the case with 2, each triplex is composed of three
intertwined tricationic ligands offset along a common screw axis
as defined by the two intrachannel bromides (Scheme 1, Figures
S5–6). Each bromide is bound by four strong and linear halogen
bonds within the helical channel. The height and width of 4 are
equivalent to that of 2 (13 and 19 Å, respectively). However, on
average, 4 adopts shorter intrachannel I⋅⋅⋅Br– contacts and more
linear C–I⋅⋅⋅Br– angles (3.3 Å, 84 % vdW radii, and 173 °,
Due to its stringent linearity, halogen bonding is a promising
noncovalent interaction that has been successfully applied to
many fields,[10] including foldameric,[11] capsular,[12] and
mechanical-bond-based[13]
self-assembly.
Recently,
we
assembled iodide-binding triple helicates in solution utilizing
halogen bonds.[14] In the present study, we explore the ligand and
[*]
C. J. Massena, D. A. Decato, Prof. Dr. O. B. Berryman
Department of Chemistry and Biochemistry
University of Montana
32 Campus Drive, Missoula, MT 59812 (MT)
E-mail: orion.berryman@umontana.edu
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201810415
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respectively) as compared to the C–I⋅⋅⋅I– contacts and angles of 2
(Figure S5).[14]
Quantification of ligands in the triple-helical vs. lower-order
conformations was possible due to slow-exchanging and resolved
sets of methoxy-methyl resonances (Figures S21–26). At room
temperature, 65(1) % of the ligands formed triple helicates (1.0
mM ligand with six ligand equiv of iodide). We investigated the
thermodynamic impact of adding TBA bromide to 2 (1.0 mM
ligand with three ligand equiv each of iodide and bromide) due to
the formation of fine precipitates during the preparation of 4. The
resulting hybrid helicate that dynamically housed both halide ions
(vide infra) was slightly more stable: 68(2) % of the ligands were
triple helical (Table S6).[17] In contrast, chloride failed to induce
high-fidelity self-assembly (Figure 1c). The trend in
thermodynamic stability—Br– ≈ I– >> Cl–—is unsurprising given
the similar solid-state structures of 4 and 2. Moreover, we have
seen size selectivity for large halide ions in our previous work with
iodopyridinium-ethynylene receptors.[18]
Like its iodide counterpart, the bromide triple helicate self-
assembled with high fidelity in solution. Adding excess TBA
1
bromide to 3 produced a H NMR spectrum consistent with the
molecular C2 symmetry of 4 and 2 (Figures 1a–b and S10–13).[14]
Addition of excess silver hexafluorophosphate resulted in
complete recovery of
3 (Figure S14), demonstrating the
switchability of the halogen-bond-induced self-assembly. A 1D
selective transient nOe experiment (DPFGSE)[16] corroborated the
proximity of the pyridinium-methyl and tert-butyl extrachannel
functionalities of 4 (Figure S13). These NOE data are consistent
with the solid-state structure of 4 but impossible for a single strand
(over 7 Å apart, Figure S13g). Finally, 2D DOSY experiments
were used to compare the hydrodynamic radii (rH) of both
helicates in solution. Unremarkably, the rH ratio was 1.0(1),
confirming the comparable size of 4 relative to 2 (Figures S15–16
and Tables S2–5).
To probe the equilibrium dynamics of the m-arylene-
ethynylene ligands, we subjected 2 to a series of variable-
1
temperature H 2D EXSY NMR experiments.[19] An overall two-
state equilibrium was evidenced by the two sets of methoxy-
methyl resonances—corresponding to free ligand and/or lower-
order speciation (Figure 2a, mA; see Tables S4–5 for 2D DOSY
data) and the triple helicate (Figure 2a, mB). The mB singlets of 2
were shifted upfield as a result of ring shielding effects from the
20]
-stacked m-arylene-ethynylene ligands.[14,
Slow chemical
1
exchange (confirmed by H 2D ROESY NMR, Figures S27–29)
allowed for the integration of cross peaks mA–mB and mB–mA
Figure 1. Partial 1H NMR spectra of triple helicates and low-fidelity chloride
species. (a) Bromide triple helicate 4; (b) iodide triple helicate 2; (c) low-fidelity
chloride species. (a–b) 500 MHz; (c) 400 MHz; (a–c) 1:3 v/v DMF-d7-CD3CN.
Figure 2. (a–b) Partial 1H 2D NOESY NMR spectra of 2 (500 MHz, 333 K, 1:3 v/v DMF-d7-CD3CN, 300 ms mixing time); (c) proposed ligand-queuing exchange
mechanism; (d) iodononameric m-arylene-ethynylene ligand with pyridinium (p) and methoxy-methyl (m) protons demarcated; (e) model of triple helicate with labeled
central pyridiniums on the middle (pA) and terminal (pB) strands (anions and some functional groups not shown for clarity).
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10.1002/anie.201810415
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along with their same-phase diagonal peaks (Figure 2a). From
these data, nuclear spin state lifetimes were calculated using
EXSYCalc 1.0 (Mestrelab Research).[21] At room temperature, the
helical-state lifetime was extremely long and outside the ideal
range of 2D EXSY NMR (Table S7).[22] Repeating the experiment
at 40 °C failed to shorten the lifetime sufficiently (Table S8).
Finally, at 60 °C, the lifetime of the ligands was still protracted and
on the order of seconds (Table S10).
At elevated temperatures, examination of the pyridinium
EXSY cross peaks of 2 (Figure 2b) resulted in comparable
lifetimes. Moreover, 1H NOEs between pyridinium and pyridinium-
methyl signals enabled the assignment of the single central
iodopyridinium resonance (Figure 2d) of the middle strand
(Figures 2b,e, pA and S40). The two central iodopyridinium
resonances arising from the terminal strands were deduced from
EXSY cross peaks (Figure 2b,e, pB). As evidenced by the
magnetization transfer between protons pA and pB, dynamic
ligand positional exchange (middle-to-terminal and vice versa)
was deduced.[23] Flanking pyridinium resonances on the middle
and terminal strands could not be assigned but their EXSY cross
peaks validated the same mechanism along with terminal-to-
terminal exchange (Table S16 and Figure S41). At 60 °C, the
average lifetime of a given ligand position was 1.7(3) s.[24] Due to
their commensurate timescale, these helical movements were
likely coupled with the mA–mB equilibrium (see Section S6.3 in the
SI). In support of a unified bimolecular process, all exchange rates
were markedly accelerated upon increasing the concentration of
free ligand 3 (see Section S6.4 in the SI). Finally, and without
exception, activation energies (G‡) of all exchanges intensified
with increasing temperature, indicating a negative entropy of
activation (S‡, Table S17). Together, these data imply the
formation of an activated complex that consists of a triplex and a
queuing ligand (Figure 2c, black).[25] We hypothesize that this
incoming ligand competitively displaces a distal terminal strand
(Figure 2c, green) in an SN2-like fashion.
Bromide-for-iodide exchange at room temperature was
monitored by visible absorption upon adding three ligand equiv of
TBA bromide to 2 at steady state (1.0 mM ligand). The absorption
at 460 nm dropped by 38 %, concomitant with a lightening of the
orange-yellow solution (Figure S47). This bromide-induced
spectral change may have stemmed from C–I•••I–/Br– charge
transfer effects.[26] Under the same conditions, intrachannel guest
exchange was monitored with stopped-flow visible spectroscopy
at 460 nm. First, 2 was rapidly mixed with plain solvent, and the
kinetic profile was monitored over the course of five seconds
(Figure 3a, purple). A slight decay in absorption (0.003 AU)
between 2–100 ms was noted—feasibly as a result of dilution-
induced population shifts between 2 and lower-order species
(Figure S48)—followed by a flat kinetic profile. However, rapidly
mixing 2 with three ligand equiv of TBA bromide produced a 35 %
drop in absorption during the two-millisecond dead time (Figure
3a, orange). In contrast to the control trace, a more precipitous
absorption decay between 2–4 ms was also evident,
corresponding perhaps to the tail end of guest exchange (Figure
3b). Overall, the commensurate absorption decrease monitored
at steady state (38 %) and within the stopped-flow dead time upon
perturbation (35 %) supports millisecond-or-faster intrachannel
guest exchange.
Figure 3. (a) Stopped-flow kinetic traces of 2 (purple) and 2 with three ligand
equiv of TBA bromide (orange); (b) same kinetic traces from 0–30 ms; (a–b)
298 K, 1:3 v/v DMF-CH3CN, 1.0 mM ligand post-mixing, 2 ms deadtime (red
diamonds), monitored at 460 nm, 2 mm pathlength; each kinetic trace is the
mean of five independent experiments (average standard deviation: 0.001 AU).
To provide further evidence of fast exchange,[27] we probed
the structural features of 4, 2, 4 with addition of TBA iodide, and
2 with addition of TBA bromide using 1H NMR spectroscopy.
Considerable anion-induced differences in chemical shifts
between the 1H NMR spectra of 4 and 2 were witnessed (Figure
S50a,b). However, 2.3 ligand equiv each of TBA iodide and
bromide added to 4 and 2, respectively, abolished these
1
discrepancies (Figure S50c,d). As expected, nearly identical H
NMR traces corresponding to a hybrid triple helicate engaged in
dynamic exchange of both guests were observed (see Section
S7.4 in the SI). Collectively, these data support millisecond-or-
faster intrachannel guest exchange.
In conclusion, we have elucidated the ligand and guest
dynamics for a new class of halogen-bonding triple helicates. The
triplex encapsulated both iodide, bromide, and mixtures of both
halide ions. Employing 1H 2D EXSY NMR, we discovered the
remarkably long lifetimes of the triplex ligands and found that they
exchanged through an associative process. In contrast, stopped-
flow visible spectroscopy evidenced millisecond-or-faster
1
intrachannel anion exchange. With H qNMR spectroscopy, we
established that helicate stability favored larger halide ion (Br– ≈
I– >> Cl–). The biological and environmental relevance of anions
and the lack of kinetic data on anion helicates underscores the
importance of halogen bonding as a powerful strategy to create
long-lived helical containers that facilitate rapid anion movement.
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Acknowledgements
This work was funded by the National Science Foundation (NSF)
CAREER CHE-1555324, the Center for Biomolecular Structure
and Dynamics CoBRE (NIH NIGMS grant P20GM103546),
Montana University System MREDI 51030-MUSRI2015-02, and
the University of Montana (UM). The X-ray crystallographic data
were collected using a Bruker D8 Venture principally supported
by NSF MRI CHE-1337908. We thank Earle Adams for his tireless
assistance with 1H NMR spectroscopy and Ed Rosenberg for
valuable EXSY NMR advice. We wholeheartedly thank Bruce
Bowler, Moses Leavens, and Haotian Lei for their help with
stopped-flow experiments.
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Conflict of interest
The authors declare no conflict of interest.
Keywords: halogen bonding • helical structures • host-guest
systems • supramolecular chemistry • kinetics
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1703.46, monoclinic, space group C2/c (no. 15), a = 54.427(4) Å, b =
36.427(3) Å, c = 35.844(3) Å,  = 128.989(2) °, V = 55236(7) Å3, Z = 24,
T = 100 K, (Cu) = 9.728 mm-1, 2max = 73.238 °, 96618 reflections
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2(I)), wR2 = 0.2298 (all data). See Section S4 in the SI for all
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crystallographic data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
https://www.ccdc.cam.ac.uk/structures/.
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[16] Slow SNAr halide exchange (bromide for iodide) limited experiment times
to several hours (see Section S4.4 in the SI).
[17] The P value from a two-tailed paired t-test was 0.024 (Table S6).
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[18] A. M. S. Riel, D. A. Decato, J. Sun, C. J. Massena, M. J. Jessop, O. B.
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[27] Additionally, we combined 2 with three ligand equiv of TBA bromide and
monitored the reaction at 460 nm for five minutes. Virtually no spectral
changes were detected (Figure S49).
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Entry for the Table of Contents
COMMUNICATION
Anion helicates are an emerging
class of secondary structure that
possess both anion-switchable and
dynamic properties. The first kinetic
studies of an anion helicate reveal
that its ligands can hold their shape
for seconds while anionic guests
hop in and out on the order of
milliseconds or faster.
Casey J. Massena, Daniel A. Decato,
and Orion B. Berryman*
Page No. – Page No.
A Long-Lived Halogen-Bonding
Anion Triple Helicate
Accommodates Rapid Guest
Exchange
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