Neutral iodotriazole foldamers as tetradentate halogen bonding anion receptors

Article abstract of DOI:10.1039/c7cc00727b

Neutral tetradentate halogen bond donor foldamers were synthesised and exhibit enhanced anion affinities over their hydrogen bonding analogues, displaying iodide selectivity over lighter halide, carboxylate and dihydrogen phosphate anions. A foldamer with a chiral (S)-binaphthol motif was demonstrated to distinguish between enantiomers of chiral anions.

Full text of DOI:10.1039/c7cc00727b

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DOI: 10.1039/C7CC00727B.
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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
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Neutral iodotriazole foldamers as tetradentate halogen bonding
anion receptors
Arseni Borissova, Jason Y. C. Lima, Asha Browna, Kirsten E. Christensena, Amber L. Thompsona,
Martin D. Smitha and Paul D. Beera*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Neutral tetradentate halogen bond donor foldamers were which has only previously been observed in a bidentate
synthesised and exhibit enhanced anion affinities over their receptor.17
hydrogen bonding analogues, displaying iodide selectivity
O
O
over lighter halide, carboxylate and dihydrogen phosphate
anions. A foldamer with a chiral (S)-binaphthol motif was
demonstrated to distinguish between enantiomers of chiral
anions.
TEG
N
N
N
N
N
N
N
N
N
N
N
O
O
N
N
N
N
N
X
X
Halogen bonding (XB) is the attractive non-covalent
interaction between a terminal σ-hole on an electron deficient
X
X
X
X
halogen atom and
a
Lewis base.1
Its strength and
X
X
N
N
N
directionality have led to several applications in materials
3
R
R
N
N
N
N
science and, more recently, in supramolecular chemistry2,
1 3
ꢀ
N
and organocatalysis.4 In particular, XB donors have been
successfully used in anion receptors for molecular recognition
and sensing applications.5 Many of these have shown
enhanced binding properties over their hydrogen bonding (HB)
analogues.6, 7
The electron-deficient8 1,2,3-triazole motif has been
exploited for anion recognition as an effective C-H hydrogen
bond donor when integrated into multidentate macrocycles9
and acyclic foldamers.10-12 The related 5-iodotriazole unit has
been used as XB donor for anion binding, such XB anion hosts
are however rare in the literature.13 No tetradentate XB donor
foldamers have been described to date; the closest examples
are a tridentate halopyridinium14 and the use of triazole
foldamers as XB acceptor hosts for organohalogens.15
R
R
4
R =
1a (X = H), 1b (X = I)
OTEG
R =
4a
4b
(X = H),
(X = I)
R =
2a
3a
2b
3b
(X = H),
(X = H),
(X = I)
(X = I)
CO2TEG
TEG =
O
3
R =
Figure 1 Structures of the XB and HB anion receptors 1-4.
Importantly, the XB foldamers exhibited overall stronger
anion affinity than their HB analogs with the chiral XB host 4b
displaying chiral discrimination with bulky amino acid anions.
XB and HB foldamers 1-4 were synthesized via Cu(I)-
catalysed azide-(iodo)alkyne cycloaddition (CuAAC) reactions
(Scheme 1) using Cu(MeCN)4PF6 in the presence of
tris(benzyltriazolylmethyl) amine (TBTA) ligand. For the
Herein we sought to apply the potency of XB to enhance
the anion affinity of the known triazole-based HB foldamer
framework. Thus, XB foldamers with four 5-iodo-1,2,3-triazole
XB donors were synthesized (Figure 1) and their anion binding
properties probed in comparison with HB analogues. A few
preparation
of
1a
and
2a
an
alternative
benzyltriazolylmethylamine (BTA) ligand18 was used as these
compounds co-eluted with TBTA during chromatographic
purification. As seen in Scheme 1, a terminal azide synthon 5-7
was reacted statistically with an excess of bis-alkyne 8a or 8b
to afford an arm fragment 9-11. Two equivalents of 9-11 were
then coupled under CuAAC conditions with a bis-azide core
variants were prepared:
(TEG) chains for improved solubility, while in
anthrylmethyl termini have been introduced to provide a
fluorescent response.15, 16 System
also includes a chiral (S)-
1
and
2
contain triethylene glycol
3
and 9-
4
4
synthon 12 or 13 to give the anion receptors
1-4. The
binaphthol core in order to investigate XB chiral recognition,
cycloadditions proceeded in moderate to high yields of 64-88%
for 5H-triazole and 46-85% for 5I-triazole formation (see
Supplementary Information for full synthetic details).
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Table 1 Association constantsa Ka [M-1] for
1
-
4
with halides and oxyanions.a
-
Cl-
Br-
I-
H2PO4
AcO-
L-tartrate
1a 232 (3) 356 (10) 427 (9) 1244 (83) 69 (1)
---b
331 (3)
1b 433 (44) 600 (46) 1202 (87)
320 (57) 281 (27)
672 (9)
2a 466 (18) 740 (29) 960 (46) 2751 (92) 174 (4)
2b 592 (59) 902 (76) 2131 (142)
3a 20 (2) 15 (1) 24 (1)
---b
504 (88) 549 (41)
---d
87 (11)c
64 (1)
3b 742 (65) 1235 (79) 2712 (187) 493 (80)e 753 (116) 585 (43)
---d ---d ---d ---d ---d
4a
37 (3)
4b 335 (14) 384 (28) 511 (94) 207 (4)
165 (9) 445 (16)
a1:1 binding stoichiometry. All anions introduced as TBA salts;
in CDCl3; in 1:1 CDCl3/acetone-d6 (500 MHz, 298 K); [receptor] = 1.5 mM.
Unless stated otherwise, Ka for 1a 4a were derived from HA; for 4b from HC;
for 1b 3b from HA of the reference compound 2a using the competition
1-3 studied
4
-
-
b
method. Uncertainties are given in parentheses. Could not be determined
-
as HB foldamers are too strong H2PO4 binders to be used as reference
compounds. cDerived from HE dToo weak to be quantified. eDerived from HC
using the standard 1H NMR titration method.
Scheme 1 Synthesis of the anion receptors 1-4. Reaction conditions: i) 0.05 eq
Cu(MeCN)4PF6, 0.05 eq TBTA or BTA, 0.1 eq DIPEA, DCM, rt; ii) 0.1 eq
Cu(MeCN)4PF6, 0.1 eq TBTA, THF, rt, darkness.
In the case of XB foldamers 1b-4b only small downfield
perturbations Δδ of 0.03-0.2 ppm were observed for the ortho
phenylene protons HC and HE. This is most likely due to the
large size of the receptors’ iodine atoms binding the guest
anion at a significant distance from these protons (vide infra).
Upfield shifts of similar magnitude were also observed for the
aromatic and methylene protons in the terminal groups. Due
1
were studied by H
The anion binding properties of
1
-4
NMR titrations by adding increasing amounts of different
anions as tetrabutylammonium (TBA) salts and monitoring
1
changes in H NMR spectra. For the HB receptors 1a
-4a large
downfield shifts (Δδ) of up to 2 ppm were observed for the
triazole protons HA and HB; while smaller Δδ of 0.4-0.5 ppm
occurred for the phenylene protons HC and HE (Figure 2). This
is consistent with the known binding mode of tetradentate
triazole HB receptors10 wherein the triazole protons and the
phenylene ortho protons all contribute to guest complexation.
Binding isotherms were obtained by monitoring HA signals and
1:1 stoichiometric association constants calculated using
WinEQNMR2 software.19
to very small Δδ values reliable association constants could not
1
3b using the standard H NMR titration
be obtained for 1b
-
protocol. Therefore, 1b
-
3b were instead analysed using a host-
host competition binding method similar to approaches
previously employed to study alkali metal complexation with
crown ethers.20 In a typical experiment a small amount (5
mol%) of HB receptor 2a was added to the solution of a XB
compound 1b-3b as a reference. Changes of the reference
compound HA signals upon anion addition were then
monitored (Figure 2), which enabled reliable association
constant data to be determined for 1b-3b (see Supporting
Information for full details). While 4b could not be analysed by
this technique due to the lack of a suitable reference
compound, it exhibited sufficient magnitude of downfield
shifts in its HC protons to provide good quality data using a
standard 1H NMR titration protocol.
As shown by the anion association constants for
in Table 1, the XB foldamers 1b 4b were found to be stronger
halide and oxoanion receptors than their HB analogs. This
difference is especially prominent in systems and . This is
1-4 given
-
3
4
because the XB receptors rely predominantly on the
iodotriazole XB donors for anion affinity, whereas their HB
analogues benefit in part from secondary HB donors at the
Figure 2 Top: Labeling of protons monitored in 1H NMR anion binding studies
11
(consistent across 1-4
). Bottom left: Partial 1H NMR spectra of 2a titrated with
phenylene rings next to the triazoles.10, Deletion of these
TBABr. Bottom right: partial 1H NMR spectra of a competition experiment where
binding elements as in 3a and 4a leads to fewer convergent HB
interactions and consequently a large loss of anion affinity. The
XB receptors, on the other hand, are tolerant to these
2b with 5 mol% of 2a as reference is titrated with TBABr (500 MHz, CDCl3, 298 K).
2 | J. Name., 2017, 00, 1-3
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modifications. Thus, the anthryl-terminated 3b displayed
affinity for Br- and I- that was two orders of magnitude
stronger than of 3a. Likewise, XB receptor 4b exhibited notable
Ka values of up to 500 M-1 in 1:1 CDCl3/acetone-d6, while 4a
displayed almost no binding (too weak to be quantified).
Comparing the XB foldamers, the anion binding strength is
in the order 3b
> 2b > 1b > 4b. This indicates that the wider
spacing of the bis-iodotriazole arms in 4b leads to less effective
alignment of its XB donors with halides and carboxylates. As
expected, 2b exhibited 1.5-2 times higher Ka values than 1b
due to its more electron-withdrawing termini, which is also
observed in the HB analogues 1b and 2b
.
The XB receptors displayed the order of selectivity I- > Br- >
-
Cl- ≈ AcO- ≈ H2PO4 , which suggests better host-guest size
complementarity with larger halides. Additionally, neutral XB
donors 1-4 do not display charge assistance that might favour
binding of small, hard anions in cationic hosts. Interestingly,
tartrate2- > AcO- selectivity was observed in HB receptors 1a
and XB receptor 4b but not in 1b 3b. This may indicate that
with 1b 3b, the anion binding cavity is too small to
-3a
-
-
simultaneously bind both anionic groups in a dicarboxylate due
to the large size of the four convergent iodine atoms.
Increased spacing between the bis(iodotriazole) arms in 4b
allows both carboxylate groups to be bound and induces
dicarboxylate selectivity. This is also seen in HB analogues
which have a less crowded anion binding site.
Figure 4 Emission spectra of 3b (top) and 4b (bottom) titrated with TBABr. Host
concentration: 1 µM in CHCl3 (3b) or 1:1 CHCl3/acetone (4b), λex = 350 nm.
The XB receptors 3b and 4b displayed an intense
fluorescence in 375-525 nm region arising from the emission
of anthracene termini (Figure 4). In 3b a large increase in
emission intensity, without changes in wavelength, occurred
upon addition of TBABr. A small increase was also observed for
4b; the most significant change occurred in the emission peak
at 420 nm for both receptors. The overall increase in
fluorescence intensity upon anion binding is most probably
due to conformational rigidification of the receptor which
suppresses non-radiative decay pathways. Thus, the larger
fluorescence enhancement in 3b is likely due to 3b being less
disordered in its bound state than 4b. As seen in the solid state
Figure 3 X-ray crystal structure of 3b∙NaI showing the face-on (left) and side-on
(right) view, visualising the folding of the receptor in a capped configuration.
Single crystals of 3b∙NaI suitable for X-ray structural structure of 3b∙NaI, the anthracene termini are too far from
analysis were obtained by combining 3b and excess NaI in 6:4 each other for effective intramolecular π-stacking which
CHCl3/acetone.§ The structure (Figure 3) shows the XB host accounts for the absence of excimer emission.23
encapsulating I- via four linear halogen bonds [C
–
–
I···I-
I···I- of Boc-Ala, Boc-Leu, Boc-Trp, Glu and tartrate as TBA salts. The
Chiral XB 4b receptor was titrated with both enantiomers
21
distances: 3.484(1)–3.574(2) Å (88–90% of ΣrvdW
)
C
angles: 165.7(3)–178.3(3)°]. Due to the large size of the four association constant values shown in Table 2 reveal varying
iodine XB donor atoms the wrapping of the foldamer around degrees of chiral discrimination was observed with different
the guest anion is less tight than in the analogous HB anions. The greatest difference in affinity was observed for
systems.22 The iodotriazoles are tilted by 29-54° relative to the tryptophan (KD/KL = 1.69), followed by leucine and alanine,
neighbouring phenylene rings and the I- guest is situated which correlates with the steric bulk of the amino acid residue.
3.01 Å above the mean plane of the foldamer backbone. The In the case of the dicarboxylate guests, a modest degree of
Na+ countercation is complexed by the triethylene glycol chain, discrimination was seen for tartrate while no difference was
with an acetone solvate molecule and a triazole N3 atom from observed for glutamate. This is once again consistent with the
an adjacent molecule competing its coordination sphere.
steric factors of guest anions.
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1
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2601.
Table
carboxylates.a
2
Association constants Ka [M-1
]
for 4b with enantiomers of chiral
b
Ka
KD/KL
2
3
P. Metrangolo, F. Meyer, T. Pilati, G. Resnati and G. Terraneo,
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B. Schulze and U. S. Schubert, Chemical Society Reviews, 2014,
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L-Boc-Ala
D-Boc-Ala
L-Boc-Leu
D-Boc-Leu
L-Boc-Trp
D-Boc-Trp
L-tartrate
D-tartrate
336 (23)
265 (52)
287 (38)
436 (21)
200 (14)
337 (4)
0.79 (0.17)
1.52 (0.21)
1.69 (0.12)
1.29 (0.04)
0.92 (0.15)
4
5
6
725 (6)
932 (28)
1483 (220)
1363 (99)
7
L-glutamate
D-glutamate
8
9
aAll anions were introduced as TBA salts. All titrations were undertaken in
1:1 CDCl3/acetone-d6 (500 MHz, 298 K). Uncertainties are given in
parentheses. bDetermined from titration data monitoring HD.
Y. L. Li and A. H. Flood, Journal of the American Chemical
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Communications, 2016, 52, 4505-4508.
In summary a series of novel neutral tetrakis(5-iodo-1,2,3-
triazole) foldamers 1b
halogen bonding anion receptors. Importantly, compared to
their HB analogues 1a 4a, the XB foldamers showed enhanced
-4b was prepared and evaluated as
-
anion affinities, with a general preference for binding heavier
halides over oxoanions. The advantage of XB for anion binding
is especially evident in 3b and 4b where the HB analogues 3a
and 4a displayed very weak affinities due to the deletion of
secondary HB donors, while the XB foldamers 3b and 4b
remained effective as anion receptors. The incorporation of
anthracene and chiral BINOL groups into the XB foldamer
structure design demonstrated fluorescent anion sensing and
chiral discrimination capabilities which are currently under
further investigation.
13 A. Brown and P. D. Beer, Chemical Communications, 2016, 52,
8645-8658.
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We thank the EPSRC centre for Doctoral Training in Synthesis
for Biology and Medicine, the Agency for Science, Technology
and Research (A*STAR), Singapore, and the European Research
Council (FP7/2007–2014, ERC Advanced Grant Agreement No.
267426) for financial support, Diamond Light Source for an
award of beamtime on I19 (MT13639) and the beamline
scientists for technical support.
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Notes and references
§ Single crystal diffraction data were collected at 100(2) K using a customꢀ
built Crystal Logic diffractometer and synchrotron radiation (λ = 0.6889 Å)
at Diamond Light Source, beamline I19.24 Unit cell parameter
determination and data reduction were carried out using CrysAlisPro. The 24 H. Nowell, S. A. Barnett, K. E. Christensen, S. J. Teat and D. R.
structures were solved by chargeꢀflipping with SUPERFLIP25 and refined
Allan, Journal of Synchrotron Radiation, 2012, 19, 435-441.
25 L. Palatinus and G. Chapuis, J. Appl. Crystallogr., 2007, 40, 786-
by full matrix least squares on F2 using CRYSTALS.26ꢀ28 Full refinement
details
C64H48I5N12NaO5Zn—4(C3H6O),
a = 14.3220(4) Å, b = 17.7665(5) Å, c = 17.7815(5) Å,
= 100.303(2)°,
= 93.903(2)°, V = 4038.8(2) Å3; data, restraints,
parameters: 11420/955/928; Rint = 0.195, final R1 = 0.100, wR2 = 0.281 (F2;
[I>2σ(I)]); ꢀρmin max
= −3.28, +2.38 eÅꢀ3. Crystallographic data have been
are
given
in
the
ESI.
Single
crystal
data:
790.
Mr = 1954.99;
triclinic,
P‾1;
26 P. W. Betteridge, J. R. Carruthers, R. I. Cooper, K. Prout and D. J.
Watkin, J. Appl. Crystallogr., 2003, 36, 1487-1487.
27 P. Parois, R. I. Cooper and A. L. Thompson, Chemistry Central
Journal, 2015, 9.
28 R. I. Cooper, A. L. Thompson and D. J. Watkin, Journal of Applied
Crystallography, 2010, 43, 1100-1107.
α
= 113.335(2)°,
β
γ
,
deposited with the Cambridge Crystallographic Data Centre (CCDC
1529410).
4 | J. Name., 2017, 00, 1-3
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