Shuttling through anion recognition

Article abstract of DOI:10.1002/anie.200353248

A negative response: Anion formation induces translocation of the macrocycle in a molecular shuttle (see picture). Shuttling only occurs in polar solvents and is unaffected by the nature of the countercation or the presence of other anions.

Full text of DOI:10.1002/anie.200353248

Communications
Molecular Shuttles
Shuttling through Anion Recognition**
Claire M. Keaveney and David A Leigh*
The reversible hydrogen bonding of anions is a key feature of
many biological processes, including the remarkable trigger of
molecular (and, ultimately, macroscopic) motion in photo-
active yellow proteins (PYPs).[1,2] The photoisomerization-
induced protonation of a hydrogen-bonded cinnamate anion
in PYPs coincides with a large conformational change in the
protein, which acts as the signal for E. halophilia and other
bacteria to swim away from harmful blue light. Despite
considerable advances[3–5] in the understanding of noncova-
lent anion binding in recent years, its application in synthetic
systems beyond sensors[4] and templating[5] is still rare. Here
we describe the use of anion hydrogen bonding to induce
translocation of a macrocycle in a bistable molecular shuttle.[6]
À
The polarity of the N H bond, combined with its
relatively high pKa value, makes secondary amides excellent
hydrogen-bond donors for neutral[7] functional groups (par-
ticularly amides, sulfoxides, nitrones, and phosphane oxides)
and anions[8] which are insufficiently basic to deprotonate the
amide. Isophthalamide groups, in particular, bind strongly to
halides[9] and oxyanions[10] in a variety of solvents and such
observations have been exploited to template the synthesis of
rotaxanes through isophthalamide-anion hydrogen bonding
where the anion is either consumed (phenolate as the
template[10]) or retained (chloride as the template[11]) during
the synthesis. Although there is limited data or theory with
which to reliably compare the hydrogen-bonding ability of
anions with neutral functional groups,[12] it seemed plausible
that such strong anion binding might be able to translocate an
isophthalamide-based macrocycle from a neutral hydrogen-
bonding station in a molecular shuttle.
Rotaxane 1H contains a thread which features two
potential hydrogen-bonding stations for a benzylic amide
macrocycle. The succinamide group (Scheme 1, green) has
previously been shown[13] to be an excellent geometrical and
electronic fit for benzylic amide macrocycles. The second
station is related to the cinnamate group found in PYPs and is
weakly hydrogen bonding as either a donor or acceptor in the
phenol form (red) but a powerful hydrogen-bond acceptor as
the phenolate anion (purple).
Scheme 1. Synthesis of the bistable molecular shuttle 1H/1À (SEM=
Me3SiCH2CH2OCH2-): a) Diisopropylazodicarboxylate (DIAD), PPh3,
70%; b) 3, NaH, THF, 85%; c) isophthaloyl dichloride, p-xylylene di-
amine, Et3N, CHCl3, 19%; d) tetrabutylammonium fluoride (TBAF),
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 4Š
molecular sieves, 75%; e) various bases, DMF; f) CF3CO2H (1 equiv),
DMF; g) TBAF, DMPU, 4Š molecular sieves, 61%. Full experimental
procedures can be found in the Supporting Information.
rotaxane from the unconsumed thread. Deprotonation of the
rotaxane and thread phenol groups to form 1À and 2À,
respectively, could be accomplished with a variety of bases
(for example, HOÀ, tBuOÀ, DBU, and Schwesinger's P1
base[14]). Since the xylylene units of the macrocycle shield
the encapsulated regions of the thread, the position of the ring
in rotaxanes 1H and 1À could be readily determined from the
chemical-shift differences of the protons in the corresponding
threads, 2H and 2À (Figure 1). In the neutral form, the succinic
methylene protons are shielded by > 1.2 ppm in the rotaxane
in
a range of solvents (CDCl3, CD2Cl2, [D3]MeCN,
[D7]DMF),[15] which indicates that the macrocycle resides
preferentially on the succinamide station. Remarkably, this is
true even in DMF (> 95% succinamide-bound translational
isomer, 298 K, [D7]DMF, Figure 1a and b) where the solvent
is comparable, and probably slightly superior, in terms of
hydrogen-bond basicity to the succinamide amide groups.[16]
1H NMR confirms that deprotonation of the phenol
provides an excellent alternative hydrogen-bonding station
for the macrocycle. The shielding of the protons of 1À
(Figure 1d) and 2À (Figure 1c) in [D7]DMF (298 K, P1H+
counterion) show the ring is now located overwhelmingly
over the phenolate anion (Hp shifted by d = À0.6 ppm in the
rotaxane anion compared to the thread anion) and the
adjacent parts of the alkyl chain (relative shifts of Hm d =
The shuttle was prepared according to Scheme 1. The
rotaxane-forming reaction was unusually low yielding (19%)
as a result of a difficult chromatographic separation of the
[*] Dr. C. M. Keaveney, Prof. D. A. Leigh
School of Chemistry, University of Edinburgh, The King's Buildings,
West Mains Road, Edinburgh EH9 3JJ (UK)
Fax: (+44)131-667-9085
E-mail: David.Leigh@ed.ac.uk
[**] This work was supported by the European Union Future and
Emerging Technology Program MechMol and the EPSRC.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200353248
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Angewandte
Chemie
Figure 1. 400 MHz 1H NMR spectra ([D7]DMF, 298 K) of a) thread 2H; b) rotaxane 1H; c) thread 2À with the P1H+ counterion; d) rotaxane 1À
with the P1H+ counterion. The color coding and assignments correspond to those indicated in Scheme 1. The resonances of P1H+ ions are shown
in orange and those of the residual solvent and H2O in grey (8).
À1.7 ppm, Hl d = À1.3 ppm, Hk d = À0.8 ppm, Hj d =
À0.7 ppm, Hi d = À0.4 ppm). Note also the virtually
unchanged chemical-shift values of the succinic methylene
protons Hd,e in 1À and 2À. The shuttling is reversible and
protonation of 1À with CF3CO2H smoothly regenerates 1H,
which returns the macrocycle to the original succinamide
station.
The proton-mediated translocation of the macrocycle in
1H/1À was investigated in the presence of other ions.[18] First,
shuttling was found to be independent of the base used. The
1
same H NMR chemical shifts were observed using various
bases capable of deprotonating the phenol (LiOH, NaOH,
KOH, CsOH, Bu4NOH, tBuOK, DBU, phosphazine P1) but
not bases that do not generate the rotaxane anion (Et3N,
pyridine). Although the strength of anion hydrogen bonding
can be strongly influenced by the nature of the accompanying
cation,[19] the co-conformation adopted by rotaxane anion 1À
is unaffected by the counterion.
Second, not only is the macrocycle observed to switch with
excellent positional integrity between the different stations in
1H and 1À in the presence of strong alternative neutral
hydrogen-bond acceptors (e.g. [D7]DMF), the shuttling also
proved unaffected by competition from anionic hydrogen-
bond acceptors. The addition of up to 10 equivalents of
Bu4NX (X = FÀ, ClÀ, BrÀ, IÀ, HOÀ, NO3À, AcOÀ) had no
effect on the degree of translational isomerism exhibited by
either rotaxane.[18] The shuttling in 1À can therefore be
considered to result from a precise recognition event rather
than an unselective anion interaction with the amide groups in
the macrocycle or thread.
The anion-induced shuttling is highly solvent dependent.
Normally hydrogen-bonded molecular shuttles work best in
nonpolar solvents where the designed intercomponent hydro-
gen bonding is strongest.[13] For 1À, however, the opposite is
true. The degree of discrimination of the macrocycle for the
phenolate station over succinamide is excellent in [D7]DMF,
[D3]MeCN, and [D4]MeOH but not in CDCl3 or CD2Cl2,
where the 1H NMR spectra shows that intramolecular folding
occurs but the macrocycle remains located over the succina-
mide station.[17] This is presumably because the phenolate
anion only provides a hydrogen-bonding site for one of the
two isophthalamide units of the macrocycle. Good hydrogen-
bond-accepting solvents are able to adequately solvate the
second isophthalamide site (and, equally important, the
succinamide groups of the thread) and induce shuttling, but
CDCl3 and CD2Cl2 cannot. It is indicative of the strength of
the anion hydrogen bonding in 1À that the isophthalamide–
phenolate interaction can displace the macrocycle from the
succinamide binding site in [D3]MeCN, a solvent of modest
hydrogen-bond basicity (bH2 = 0.45[12b]) compared to an amide
(bH2 ~ 0.66[12b]).
In conclusion, we have demonstrated the reversible
control of translation motion in a rotaxane through hydrogen
bonding to an anion. The shuttle has several remarkable
features, including that translocation of the macrocycle only
occurs in solvent systems where the designed hydrogen-
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ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
1993, 22, 73 – 83). However, the large effects of solvation and ion
pairing make it far harder to assess the inherent hydrogen-bond
accepting ability of anions beyond their pKa value or position in
a Hofmeister series.
bonding interactions are relatively weak (and competing
hydrogen-bonding interactions weaker still), and that under
these conditions shuttling is unaffected by the nature of the
countercation or the presence of alternative anionic hydro-
gen-bond acceptors. This adds to the range of methods
already developed for switching the position of macrocycles
in bistable molecular shuttles and provides a new type of
model system for probing anion hydrogen-bonding interac-
tions.
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[15] The chemical shift difference for the succinic methylene protons
of 1H/2H is 0.5 ppm in [D6]DMSO and 0.4 ppm in [D4]MeOH,
which indicates a lower occupancy of the succinamide station in
these solvents.
Received: November 4, 2003 [Z53248]
Keywords: anions · hydrogen bonds · molecular recognition ·
.
molecular shuttles · rotaxanes
[16] J. Y. Le Questel, C. Laurence, A. Lachkar, M. Helbert, M.
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[17] The chemical shifts of Hd,e are virtually unchanged between
rotaxanes 1H and 1À in CDCl3 or CD2Cl2 (see Supporting
Information), which shows that the macrocycle of 1À is
preferentially located over the succinamide station in these
solvents. Similarly, with the exception of Hm, the alkyl chain
protons are shielded by < 0.2 ppm in 1À compared with 2À,
which confirms that the alkyl chain near the phenolate unit is not
encapsulated by the macrocycle. However, there are significant
shifts in the amide protons of the macrocycle (ꢀ 1.2 ppm, which
indicates their involvement in stronger hydrogen bonding in the
deprotonated rotaxane), Hc, Hm, and some of the phenolate
resonances in 1À compared to 1H, all consistent with a folded,
hydrogen-bonded structure for 1À where the macrocycle is
situated over the succinamide station while simultaneously
hydrogen bonding to the phenolate anion.
[18] The standard experimental set up for all our experiments, from
which one variable was changed or another component added,
was: rotaxane or thread (0.009 mmol), P1 base (0.010 mmol), and
[D7]DMF (0.6 mL) as solvent at 298 K. The base-induced
shuttling in the rotaxane is rapid on the NMR timescale (the
spectrum shown in Figure 1d is immediately apparent and not
time dependent). Shuttling away from a succinamide binding site
in a similar rotaxane has been shown to occur on the micro-
second timescale.[13a,b]
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