Halogen bonding rotaxanes for nitrate recognition in aqueous media

Article abstract of DOI:10.1039/C6OB02339H

Targeting the biologically and environmentally important nitrate anion, halogen bonding (XB) has been incorporated into three novel [2]rotaxane structural frameworks via an axle component containing covalently linked 3,5-bis-iodotriazole pyridine-pyridinium motifs. This has enabled the recognition of nitrate in aqueous media containing up to 90% water with equivalent binding affinity to chloride, illustrating the potency of XB for anion recognition in highly competitive aqueous solvent mixtures.

Full text of DOI:10.1039/C6OB02339H

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DOI: 10.1039/C6OB02339H
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Halogen bonding rotaxanes for nitrate recognition in aqueous
media
Sean W. Robinsona and Paul D. Beera*
Received 00th January 20xx,
Accepted 00th January 20xx
Targeting the biologically and environmentally important nitrate anion, halogen bonding (XB) has been incorporated into
three novel [2]rotaxane structural frameworks via an axle component containing covalently linked 3,5-bis-iodotriazole
pyridine -pyridinium motifs. This has enabled the recognition of nitrate in aqueous media containing up to 90% water with
equivalent binding affinity to chloride, illustrating the potency of XB for anion recognition in highly competitive aqueous
solvent mixtures.
DOI: 10.1039/x0xx00000x
www.rsc.org/
[2]rotaxanes and a [2]catenane host containing respectively, a
bis-triazolium acridine axle component, and covalently linked
isophthalamide-3,5-bis-amide pyridinium axle and macrocycle
Introduction
Stimulated by the crucial roles that anions play in chemical,
biological and environmental processes, the field of anion
recognition has grown dramatically over the last couple of
decades with reports of a vast array of synthetic hosts capable
of binding anions in organic and aqueous media.1-5 Recently,
halogen bonding (XB),6 has been introduced into anion host
systems as an alternative to the prevalent hydrogen bond
(HB), typically resulting in a dramatic enhancement in anion
binding strength as well as noteworthy changes in selectivity.7
Advantageously, XB is comparable in strength to HB, demands
strict directionality of interaction, and its pH-independence
and solvent resistance provide significant benefits for the
motifs are the only examples, binding nitrate in aqueous
45:45:10 CDCl3:CD3OD:D2O solution.28-30
In an effort to exploit the stringent directionality of XB as a
means of elevating the strength and selectivity of nitrate anion
recognition in higher percentage water containing solvent
media and taking into account our previous nitrate selective
interlocked HB host design, herein we report the synthesis of
three XB [2]rotaxane anion receptors which incorporate two
XB 3,5-bis-iodotriazole pyridine or pyridinium donor sites into
the axle component, one of which is demonstrated to bind
nitrate in 90% water (9:1 D2O: CD3COCD3).
binding of anions in aqueous media.8, Nonetheless, while
9
anion receptors exploiting XB interactions are relatively rare,10-
Results and discussion
Synthesis
The synthesis of the crucial XB axle component of the target
[2]rotaxane required the incorporation of two XB 3,5-bis-
iodotriazole pyridine or pyridinium donor sites while the
macrocycle component was prepared via standard
procedures.31 Initially, attempts were made to prepare
unsymmetrically functionalised axle precursors via various
14
integrating XB motifs into mechanically interlocked anion
host systems has facilitated anion recognition in organic–
aqueous media and pure water.15-21
Of particular biological and environmental importance is the
nitrate anion, which has been implicated in blue baby
syndrome (methemoglobinemia) and its anthropogenic
overuse in arable farming has led to eutrophication of dams
and lakes. Various acyclic tripodal systems,22,
macrocyclic
23
receptors24 and trigonal cages25, 26 have been demonstrated to
accommodate the oxoanion’s trigonal planar geometry,
employing spatially-oriented HB amide motifs to complex each
of the three nitrate oxygen atoms; however, all these host
systems only function in organic solvents.27 Indeed, receptors
capable of nitrate recognition in aqueous media are
exceptionally scarce. To the best of our knowledge, two
alkyne functional group protection methods. Sonogashira
33
reaction32,
between commercially available 3,5-dibromo-
pyridine and 2-methylbut-3-yn-2-ol afforded
Subsequent Sonogashira reaction32, 33 with TBDMS-acetylene
gave the unsymmetrically protected 3,5-diethynyl pyridine in
87% yield. However, selective deprotection of with 2-
1 in 79% yield.
2
2
hydroxy propane and TBDMS protecting groups was
problematic. Whilst the 2-hydroxy propyl protecting group
could easily be selectively cleaved in the presence of TBDMS
a.Chemistry Research Laboratory, Department of Chemistry, University of Oxford,
12 Mansfield Road, Oxford, OX1 3TA, United Kingdom.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
by refluxing
remove TBDMS either resulted in the unexpected removal of
the 2-hydroxy propyl protecting group instead ( to ) or the
2 with NaOH in toluene, the use of TBAF to
2
3
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decomposition of the iodotriazole group, for example, in
prototriazole in later steps in the synthesis (Scheme 1).
5
to a THF afforded the mono-substituted precursor 13 Viinew3A1rt%icleyOienllidne.
Reaction of azido-propyl-mesylate 14 wDitOhI:1103.1u03si9n/Cg6tOhBe02s3a3m9He
CuAAC conditions gave the intermediate 15 in 86% yield.
Substitution of the mesylate to produce azide 16 was achieved
with NaN3 in 87% yield and methylation with [Me3O][BF4] gave
the pyridinium tetrafluoroborate salt 17·BF4 in 46% yield.
Scheme 1: Stepwise alkyne protection and deprotection steps using TBDMS and 2-
hydroxy propyl protecting groups.
Since the TMS protecting group offered a more labile
alternative to TBDMS, and could be selectively deprotected in
the presence of the 2-hydroxy propyl protecting group, the
TMS analogue of
reaction32, 34 between 3,5-dibromopyridine and TMS-acetylene
to afford
in 79% yield. Thereafter, Sonogashira reaction32
with 2-methylbut-3-yn-2-ol gave in 91% yield. The TMS
protecting group was selectively deprotected using KOH in
MeOH, quantitatively giving , which was reacted with various
stopper azides (terphenyl-propyl , terphenyl-aryl 10 and
2 was prepared using an initial Sonogashira
6
7
Scheme 2: Selective alkyne protection and deprotection steps using TMS and 2-hydroxy
propyl protecting groups.
8
9
permethylated β-cyclodextrin 11) using a one-pot iodo-CuAAC
click reaction.35 Unfortunately, the click reactions to stopper
the mono-deprotected alkyne were unsuccessful (Scheme 2)
with the recovery of only starting materials after purification.
Since stepwise alkyne protection/deprotection synthetic
techniques could not be used to prepare the axle component,
the synthesis of target XB [2]rotaxanes 19·PF6 and 20·(PF6)2
was reliant upon an initial statistical stoppering step shown in
Scheme 3. Employing a modification of the copper(I)-catalysed
azide-iodoalkyne cycloaddition (CuAAC) click reaction,36, 37 an
equimolar mixture of 3,5-diiodoethynyl pyridine 12 and
The synthesis of rotaxanes 19·PF6 and 20·(PF6)2 is shown in
Scheme 4. The synthesis of [2]rotaxane 19·PF6 was achieved in
32% yield using a chloride anion-templated mono-stoppering
CuAAC click methodology: equimolar amounts of 13 and
17·BF4 were mixed with 10 equivalents of isophthalamide
macrocycle 18 in the presence of Cu(I), TBTA and one
equivalent of TBA·Cl. Methylation of [2]rotaxane 19·PF6 with
CH3I afforded the dicationic [2]rotaxane 20·(PF6)2 in 37% yield
after
anion
exchange
to
the
non-coordinating
hexafluorophosphate anion.
terphenyl stopper azide
9 in the presence of Cu(I) and TBTA in
Scheme 3: Synthesis of axle component precursors 13 and 17·BF4.
2 | J. Name., 2012, 00, 1-3
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Scheme 4: Synthesis of [2]rotaxanes 19·PF6 and 20·(PF6)2.
Whilst terphenyl stopper units are suitable for organic and (Scheme 5). Mono-substitution of 12 with azido-propyl-
organic–aqueous solvent media, permethylated β-cyclodextrin mesylate 14 was achieved using the same statistical modified
stopper units are required in order to solubilise a [2]rotaxane CuAAC conditions for the preparation of 13, producing 21 in
analogue in pure water, or solvent mixtures containing a high 27% yield. The CuAAC reaction of 21 with azide functionalised
percentage of water, since permethylation improves the permethylated β-cyclodextrin 1140-42 gave 22 in 20% yield.‡
aqueous solubility of β-cyclodextrin.38, 39 In a similar manner to Conversion of mesylate 22 to the azide 24 was achieved
rotaxanes 19·PF6 and 20·(PF6)2, β-CD-stoppered rotaxane quantitatively using NaN3 in DMF. The pyridinium azide axle
27·(OTf)3 was synthesised according to the stepwise procedure precursor 25·Cl was obtained in 69% yield after methylation
shown in Scheme 6 using permethylated β-cyclodextrin using CH3I and subsequent anion exchange to the chloride salt
functionalised axle component precursors 23 and 25.Cl using a chloride-loaded Amberlite® column (Scheme 5).
Scheme 5: Synthesis of axle component precursors 23 and 25·Cl.
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