Very contracted to extended co -conformations with or without oscillations in two- and three-station ['2]daisy chains

Article abstract of DOI:10.1021/jo101234u

The syntheses of various two- and three-station mannosyl [c2]daisy chains, based on a dibenzo-24-crown-8 macrocyclic moiety and an ammonium, a triazolium, and a mono- or disubstituted pyridinium amide station, are reported. The ability of these molecules to act as molecular machine based mimetics has been further studied by ¹H NMR studies. In all the protonated ammonium states, the interwoven rotaxane dimers adopt an extended co-conformation. However, carbamoylation of the ammonium station led to many different other [c2]daisy chain co-conformations, depending on the other molecular stations belonging to the axle. In the two-station [c2]daisy chains containing an ammonium and a mono- or disubstituted pyridinium amide station, two large-amplitude relative movements of the interwoven components were noticed and afforded either an extended and a contracted or very contracted state with, in the latter case, an impressive chairlike conformational flipping of the mannopyranose from ¹C₄ to ⁴C₁. In the case of the three-station-based [c2]daisy chains containing an ammonium, a triazolium, and disubstituted pyridinium amide, an extended and a half-contracted molecular state could be obtained because of the stronger affinity of the dibenzo-24-crown-8 part for, respectively, the ammonium, the triazolium, and the disubstituted pyridinium amide. Eventually, with axles comprising an ammonium, a triazolium, and a monosubstituted pyridinium amide, an extended conformation was noticed in the protonated state whereas a continuous oscillation between half-contracted and contracted states, in fast-exchange on the NMR time scale, was triggered by carbamoylation. Variations of the solvent or the temperature allow the modification of the population of each co-conformer. Thermodynamic data provided a small free Gibbs energy δG of 2.1 kJ·mol ^-1 between the two translational isomers at 298 K.

Full text of DOI:10.1021/jo101234u

pubs.acs.org/joc
Very Contracted to Extended co-Conformations with or without
Oscillations in Two- and Three-Station [c2]Daisy Chains
Camille Romuald, Eric Busseron, and Fr ꢀe d ꢀe ric Coutrot*
Institut des Biomol eꢀ cules Max Mousseron (IBMM), UMR 5247CNRS - Universit eꢀ s Montpellier 2 et 1,
B a^ timent de recherche Max Mousseron, Ecole Nationale Sup eꢀ rieure de Chimie de Montpellier,
8
rue de l’Ecole Normale, 34296 Montpellier Cedex 5, France
frederic.coutrot@univ-montp2.fr
Received June 30, 2010
The syntheses of various two- and three-station mannosyl [c2]daisy chains, based on a dibenzo-24-crown-
macrocyclic moiety and an ammonium, a triazolium, and a mono- or disubstituted pyridinium amide
station, are reported. The ability of these molecules to act as molecular machine based mimetics has been
8
1
further studied by H NMR studies. In all the protonated ammonium states, the interwoven rotaxane
dimers adopt an extended co-conformation. However, carbamoylation of the ammonium station led to
many different other [c2]daisy chain co-conformations, depending on the other molecular stations
belonging to the axle. In the two-station [c2]daisy chains containing an ammonium and a mono- or
disubstituted pyridinium amide station, two large-amplitude relative movements of the interwoven
components were noticed and afforded either an extended and a contracted or very contracted state with,
1
4
in the latter case, an impressive chairlike conformational flipping of the mannopyranose from C to C .
4
1
In the case of the three-station-based [c2]daisy chains containing an ammonium, a triazolium, and
disubstituted pyridinium amide, an extended and a half-contracted molecular state could be obtained
because of the stronger affinity of the dibenzo-24-crown-8 part for, respectively, the ammonium, the
triazolium, and the disubstituted pyridinium amide. Eventually, with axles comprising an ammonium, a
triazolium, and a monosubstituted pyridinium amide, an extended conformation was noticed in the
protonated state whereas a continuous oscillation between half-contracted and contracted states, in fast-
exchange on the NMR time scale, was triggered by carbamoylation. Variations of the solvent or the
temperature allow the modification of the population of each co-conformer. Thermodynamic data
-
1
provided a small free Gibbs energy ΔG of 2.1 kJ mol between the two translational isomers at 298 K.
3
Introduction
because the presence and the relative movements of the
macrocycle (translation and circumrotation) in the inter-
locked component have been shown to dramatically modify
the properties of the molecule. Many of these molecular
Molecular machines based on rotaxane architectures have
1
attracted much interest during the past decades, especially
(
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516 J. Org. Chem. 2010, 75, 6516–6531
Published on Web 09/03/2010
DOI: 10.1021/jo101234u
r 2010 American Chemical Society

Romuald et al.
JOCArticle
machines have been devoted to nanotechnology in the
2
domain of materials, whereas the potential interest of
been designed up to date to possess either a stretched co-
conformation or a continuous oscillating shuttling behavior
between a contracted and a half-contracted co-conformation
rotaxane-based molecules in the medicinal field has just
emerged in the past few years as a promising and exciting
7
as in a degenerate-like [2]rotaxane molecular machine. We
have recently described a very direct and efficient access
3
investigation field. As a part of rotaxane molecular ma-
4
5
8
chines, [c2]daisy chains acting as molecular muscles repre-
sent interesting targets, but few synthetic examples have been
reported so far. [c2]Daisy chains consist of a rotaxane dimer,
in which each interwoven hermaphrodite monomer contains
a macrocycle linked to a thread, which includes one or more
template moieties for the macrocycle. When two molecular
stations are located in the thread, such molecules can adopt
either a stable contracted or a stretched co-conformation,
depending on the relative affinity of the two sites of recogni-
tion for the macrocycle. The incorporation of [c2]daisy chain
moieties in polymeric chains has been recently realized by
Stoddart and Grubbs in order to modify the length of poly-
mers by controlling the pH, hence to change material
to bistable pH-sensitive mannosyl molecular machines
9
and molecular muscle containing a dibenzo-24-crown-8
(DB24C8) ring or a derivative and based on an ammonium
and either a pyridinium amide or a triazolium molecular
stations. Here, we report on the synthesis and the shuttling
behavior of different [c2]daisy chains, consisting of manno-
syl ends and DB24C8-like rings and based on two or three
molecular stations (ammonium, triazolium, pyridinium
amide stations) for the DB24C8 ring derivatives. In the case
of the three-station-containing [c2]daisy chains, each mole-
cular station was spaced out by a hexamethylenic alkyl chain,
allowing very well differentiated co-conformations of the
molecules (Figure 1). For all of the considered interwoven
[c2]daisy chain structures, the protonated ammonium state
1-2 allows for a stretched co-conformation in which the two
mannosyl ends are located far away from each other. Since
deprotonation of encircled ammonium required strong bases
for most of our interwoven molecules, and since the free
nucleophilic amine-containing molecular muscle was not
stable enough in time, it often led to side degradation. To
displace the protonation/deprotonation equilibrium, a mild
carbamoylation of the generated amine using a weak base
was used instead and afforded different desired unstretched
6
properties. To the best of our knowledge, no molecular
muscle, including more than two stations, and which could
then adopt more than two co-conformations has been en-
visaged until now. Moreover, no molecular muscles have
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JOCArticle
FIGURE 1. Cartoon representation of the different co-conformational states adopted by the mannosyl [c2]daisy chains 1-5 in (1) the
monosubstituted pyridinium amide station series a and (2) the disubstituted pyridinium amide series b.
compounds in a cleaner manner. When only two different
molecular stations are present on the axles (compounds 4a,b
containing an ammonium and either a mono- or a disubsti-
tuted pyridinium amide stations), large-amplitude molecular
shuttlings toward a contracted or a very contracted state can
be observed after the deprotonation and the further carba-
moylation of the amine, depending on the substitution of the
pyridinium amide. In the unique case of the very contracted
co-conformation, the displacement of the DB24C8 rings
around the pyridinium triggers a dramatic switch of the
chairlike conformation of the mannopyranose. If three sta-
tions are incorporated in the axle (compounds 5a,b including
ammonium, triazolium, and mono- or disubstituted pyridi-
nium amide stations), the shuttling of the system after depro-
tonation/carbamoylation is quite different and depends on
the different relative affinity of both the triazolium and the
mono- or disubstituted pyridinium amide for the DB24C8
moiety. Whereas in the presence of the disubstituted pyridi-
nium amide station the [c2]daisy chain 5b can only adopt a
half-contracted state, the machine acts very differently with
the monosubstituted pyridinium amide. Effectively, after
deprotonation/carbamoylation of the best ammonium sta-
tion, the two DB24C8 macrocycles shuttle toward both the
triazolium and the pyridinium amide moieties. Since these
two stations have almost similar affinity at room tempera-
ture for the DB24C8, a novel oscillating molecular muscle, in
which a contracted and a half-contracted co-conformation
are in fast equilibrium, is obtained. This oscillation of the
macrocycles can be stopped by decarbamoylation/proton-
ation or by decreasing the temperature. More interestingly,
the ratio at room temperature between the two translational
isomers (i.e., between the contracted and the half-contracted
co-conformation), which are in fast exchange on the NMR
time scale, strongly depends on both the temperature and the
nature of the solvent.
Results and Discussion
1. Synthesis of the Stretched Mannosyl [c2]Daisy Chains 1a,
b and 2a,b Containing Respectively Two and Three Molecular
Stations. The strategy used to obtain the interwoven mole-
cules 1 was based on an end-capping using the copper(I)-
1
0
catalyzed Huisgen alkyne-azide 1,3-dipolar cycloaddi-
1
1
tion, also called “the CuAAC click chemistry” (Scheme 1)
between the azido pyridinium mannosides 6a or 6b (1 equiv)
and the terminal alkyne pseudo[c2]daisy chain 7 (1 equiv) in the
presence of a catalytic amount of 2,6-lutidine (0.1 equiv) and
1
2
Cu(CH CN) PF (1 equiv). Interwoven mannosyl[c2]daisy
3
4
6
chains 1a and 1b were isolated in, respectively, 77% and 74%
yield after silica gel chromatographic column purification.
Interestingly, no other interlocked structure was isolated, which
demonstrates the much higher affinity of the DB24C8 cavity
for the ammonium template than for the mono- or disubstitut-
ed pyridinium amide one. The regioselective N-methylation of
the triazole 1a and 1b was further carried out using iodo-
methane as reactant and solvent at room temperature, and the
triazolium iodide, which was obtained after evaporation, was
6
518 J. Org. Chem. Vol. 75, No. 19, 2010

Romuald et al.
SCHEME 1. Synthesis of the Stretched [c2]Daisy Chains 1a,b and 2a,b Containing, Respectively, Two or Three Molecular Stations
JOCArticle
then submitted to an anion-exchange using ammonium hexa-
fluorophosphate. The mannosyl [c2]daisy chains 2a,b contain-
ing three molecular stations for the DB24C8 ring derivative
were obtained in, respectively, 81% and 83% yield (Scheme 1).
2. Molecular Machinery on Rotaxane Dimers 1a,b and 2a,b
Containing, Respectively, Two and Three Molecular Sta-
tions. 2.1. Preliminary Attempts of Deprotonation of Rotax-
ane Dimers 1-2. In a first instance, the deprotonation of the
two rotaxane dimers 1a and 1b was investigated in order to
study the possible pH-sensitive large-amplitude contraction/
stretching movements of the molecular muscles. Unfortu-
nately, clean deprotonation of 1a or 1b was not possible
(
10) (a) Huisgen, R. Pure. Appl. Chem. 1989, 61, 613–628. (b) Huisgen, R.
Angew. Chem. 1963, 75, 604-637; Angew. Chem., Int. Ed. Engl. 1963, 2,
5
2
65-598. (c) Huisgen, R.; Szeimies, G.; M o€ bius, L. Chem. Ber. 1967, 100,
494–2507. (d) Huisgen, R. Angew. Chem. 1963, 75, 742-754; Angew.
Chem., Int. Ed. Engl. 1963, 2, 633-645. For a recent review of the application
of copper(I)-catalyzed azide-alkyne 1,3-cycloaddition to catenane and
rotaxane synthesis, see: H €a nni, K. D.; Leigh, D. A. Chem. Soc. Rev. 2010,
whatever the bases (DIEA, NaOH, DBU, or P -phos-
1
phazene) or the solvent used (Scheme 2). On one hand, weak
bases were not found to be sufficiently basic to deprotonate
the ammonium because of the enhanced pK of the ammo-
3
9, 1240–1251. For recent syntheses of rotaxanes using a copper(I)-catalyzed
azide-alkyne 1,3-cycloaddition strategy, see: (e) Aucagne, V.; H €a nni, K. D.;
Leigh, D. A.; Lusby, P. J.; Walker, D. B. J. Am. Chem. Soc. 2006, 128, 2186–
a
nium/amine pair when the ammonium moiety is complexed
with the oxygens of the DB24C8. This was particularly
surprising as we reported in a recent paper the easy depro-
tonation of ammonium moieties of rotaxane dimer by
2
4
187. (f) Mobian, P.; Collin, J. -P.; Sauvage, J. -P. Tetrahedron Lett. 2006,
7, 4907–4909. (g) Braunschweig, A. B.; Dichtel, W. R.; Miljanic, O. S.;
Olson, M. A.; Spruell, J. M.; Khan, S. I.; Heath, J. R.; Stoddart, J. F. Chem.
Asian. J. 2007, 2, 634–647. (h) Aucagne, V.; Berna, J.; Crowley, J. D.;
Goldup, S. M.; H €a nni, K. D.; Leigh, D. A.; Lusby, P. J.; Ronaldson,
V. E.; Slawin, A. M. Z.; Viterisi, A.; Walker, D. B. J. Am. Chem. Soc.
9
washing with NaOH. Actually, an important difference
2
007, 129, 11950–11963. (i) Aprahamina, I.; Yasuda, T.; Ikeda, T.; Saha, S.;
Dichtel, W. R.; Isoda, K.; Kato, T.; Stoddart, J. F. Angew. Chem., Int. Ed.
007, 46, 4675–4679. (j) Aprahamian, I.; Miljanic, O.; Dichtel, W. R.; Isoda,
K.; Yasuda, T.; Kato, T.; Stoddart, J. F. Bull. Chem. Soc. Jpn. 2007, 80,
856–1859. (k) Aprahamian, I.; Dichtel, W. R.; Ikeda, T.; Heath, J. R.;
between our previous structure and the new ones resides in
the absence of a molecular station at a reasonable distance
from the ammonium, which, one can assume, helps the
deprotonation by assisting the move of the DB24C8. On
the other hand, the use of strong bases caused nonelucidated
side degradation of the rotaxane dimers. Nevertheless, in the
case of the [c2]daisy chain 2a, in which a triazolium station
resides at a reasonable distance from the ammonium site,
deprotonation of the ammonium occurred using NaOH and
led, at room temperature, to a continuous oscillation of the
DB24C8 derivative around both the triazolium and the
monosubstituted pyridinium amide (Scheme 2). It is inter-
esting to notice that even though deprotonation of 2a was
2
1
Stoddart, J. F. Org. Lett. 2007, 9, 1287–1290. (l) Miljanic, O. S.; Dichtel,
W. R.; Aprahamian, I.; Rohde, R. D.; Agnew, H. D.; Heath, J. R.; Stoddart,
J. F. QSAR Comb. Sci. 2007, 11-12, 1165–1174. (m) Spruell, J. M.; Dichtel,
W. R.; Heath, J. R.; Stoddart, J. F. Chem.;Eur. J. 2008, 14, 4168–4177. (n)
Zhang, W.; Dichtel, W. R.; Stieg, A. Z.; Benitez, D.; Gimzewski, J. K.;
Heath, J. R.; Stoddart, J. F. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 6514–
6
519. (o) Zheng, H.; Zhou, W.; Lv, J.; Yin, X.; Li, Y.; Liu, H.; Li, Y. Chem.;
Eur. J. 2009, 15, 13253–13262.
11) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
(
2
2
001, 40, 2004–2021. (b) Lutz, J. F. Angew. Chem., Int. Ed. 2008, 47, 2182–
184. (c) Meldal, M.; Tornoe, C. W. Chem. Rev. 2008, 108, 2952–3015.
(12) Compounds 6 and 7 were previously synthesized according to the
experimental procedures described in the Supporting Information.
J. Org. Chem. Vol. 75, No. 19, 2010 6519

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SCHEME 2. Molecular Machinery Using a pH Stimulus on (a) the Mannosyl [c2]Daisy Chains 1a,b and (b) 2a Containing, Respectively,
Two and Three Molecular Stations
possible, the oscillating molecular muscle 3a could only be
isolated for a short time as it underwent very quick self-
degradation.
96%. The same synthetic pathway could also be utilized from
4b to generate 5b in 91% yield.
The recovery of the starting stretched material 1a,b and 2a,
b was realized by standard removal of the Boc protection
using a solution of hydrochloric acid in diethyl ether, fol-
lowed by an exchange of the counteranion.
The chemical stimuli applied to our [c2]daisy chains gen-
erated various highly controllable co-conformations, from a
stretched to a very contracted state via half-contracted and
contracted states with different behaviors. Whereas one of
them, 5a, undergoes a continuous oscillating state at room
2
.2. Deprotonation-Carbamoylation of Rotaxane Dimers
1
-2. To remedy the problem of the tricky deprotonation,
which is either impossible in the case of the two station-
containing rotaxane dimers or accompanied by side-degradation
in the case of the three station-containing rotaxane dimers,
we decided to displace the deprotonation equilibrium, under
milder conditions, by consuming the in situ generated amine via
carbamoylation (Scheme 3).
In a typical procedure, the reaction was carried out in
acetonitrile using an excess of the diisopropylethylamine
temperature, in the case of 4b, an impressive conformational
1
flipping of the mannopyranosyl ring extremities from C to
C was noticed. All these different co-conformations, which
1
4
1
H u€ nig’s base (DIEA, 8 equiv) and di-tert-butyl dicarbo-
3
4
nate (Boc O, 16 equiv). Almost complete conversion took as
2
actually result from the different affinities of the molecular
stations for the DB24C8 derivative, were established by the
long as 2.5 to 16 days at room temperature to yield, after
Sephadex chromatographic purification, traces to 75% of
the desired compounds 4a,b and 5a,b, depending on the
presence of the triazolium moiety and on the substitution
of the pyridinium amide. As a comparison, the same condi-
tions of deprotonation/carbamoylation were applied to the
compound 7, which is not end-capped: in that case, the
reaction could be achieved in as fast as 2 h in a 93% yield
after purification. This highlights the very low reactivity of
the ammonium molecular station when interlocked in such a
stable assembled structure, compared to when it is only
incorporated in a pseudo [c2]daisy chain (i.e., without any
bulky stoppering ends). It is noteworthy that the formation
of 4b was very slow, probably because the disubstituted
pyridinium amide constitutes the weakest molecular station
for the DB24C8 part and, hence, does not help sufficiently
the deprotonation of the ammonium. For the preparation of
1
following H NMR studies.
a. Molecular Machinery of the Molecular Muscle Mimic
1
System 1a/4a. The comparison of H NMR spectra of
mannosyl [c2]daisy chains 1a and 4a with their uncomplexed
monomer analogues 1au and 4au reveals the interlocked
[c2]daisy chain architecture and the localization of the
DB24C8 along the threaded axle in 1a and 4a, thus demon-
strating the stretched and the contracted co-conformations
indicated in Scheme 3 (Figure 2a,b). Indeed, in the rotaxane
1
dimer 1a, the same H NMR observations as those recently
reported for the interwoven structure evidence of pseudor-
9
otaxane dimer 7 were noticed for the hydrogens of the
DB24C8 part. The methylenic hydrogens of the DB24C8
are split in the interwoven rotaxane dimer 1a, since they are
facing the two nonsymmetrical extremities of the molecule,
and the hydrogens of the aromatic rings of the DB24C8,
5
a, only traces of desired product were collected; however, 5a
could be very efficiently obtained from 4a by methylation
H2
, and H
, are all shielded, indicating a “sand-
41-44
9-32
wich”-like co-conformation. This co-conformation is con-
firmed by the absence of significant variations of the H2
and exchange of counteranion in an overall excellent yield of
0-24
which are next to the interaction site and which are not
undergoing any shielding effect by the aromatic ring of the
(
13) H u€ nig, S.; Kiessel, M. Chem. Ber. 1958, 91, 380–392.
6
520 J. Org. Chem. Vol. 75, No. 19, 2010

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SCHEME 3. Molecular Machinery on the Mannosyl [c2]Daisy Chains 1a,b and 2a,b Containing, Respectively, Two and Three Molecular
Stations for the DB24C8 Derivative
DB24C8. Simultaneously, H25 and H27 are shifted downfield
in the [c2]daisy chain 1a (Δδ=þ0.44 and þ0.42 ppm, res-
pectively), whereas no other significant variations of chemi-
cal shifts are observed for the other hydrogens of the axles
experience the shielding effect of the aromatic pyridinium ring.
Eventually, hydrogens H1 are all more or less shifted
upfield in 4a because they are localized in the shielding cavity
of the aromatic ring of the DB24C8 parts. The same trend is
1
observed by comparing the H NMR spectra of the [c2]daisy
2-16
and more especially for H7 belonging to the pyridinium
-8
amide station, thus indicating the unique localization of the
DB24C8 parts around the best ammonium station, and
demonstrating a stretched co-conformation of 1a.
chain 4a and the monomer analogue 4au, thus corroborating
the contracted co-conformation of 4a (Figure 2c,d).
b. Molecular Machinery of the Molecular Muscle Mimic
System 1b/4b. In the protonated rotaxane dimer 1b, and
similarly to 1a, the DB24C8 parts only interact with the
ammonium station. It results a stretched co-conformation of
the interwoven architecture (Scheme 3, Figure 3a,b). Here, it
is noteworthy that a mixture of two isomers in the ratio 47/53
was observed, resulting from the cis/trans isomerization of
the disubstituted amide bond. Each conformer was unam-
After deprotonation-carbamoylation, the two macro-
cycles glide along the thread until the monosubstituted pyri-
dinium amide station, where they exclusively reside (Scheme 3,
Figure 2b,c). This is confirmed by the upfield shift of H25 and
H27 (Δδ=-0.31 and -0.19 ppm, respectively), due to the de-
protonation-carbamoylation of the ammonium moiety and
the shuttling of the DB24C8 ring, and more interestingly by the
dramatic downfield shift of the pyridinium amide hydrogens
H (Δδ=þ1.00 ppm) and to a lesser extent H (Δδ=þ0.29
1
biguously assigned thanks to a 2D-NOESY H NMR ex-
periment.
8
11
ppm). It is noteworthy that no significant variation of chemical
After deprotonation-carbamoylation, the macrocycles
shuttle toward the disubstituted pyridinium amide, where
they reside exclusively. This was demonstrated by the direct
shift is observed for H , indicating an accurate localization of
7
the macrocycle parts around the sole H and H11 belonging to
8
the monosubstituted pyridinium amide station. Another im-
portant observation is the downfield shift of the aromatic
1
comparison of H NMR spectra of rotaxane dimers 1b and
4b (Figure 3b,c). The hydrogens H25 and H , located next to
27
hydrogens H , H , H , and more specifically H32 of the
41-44
DB24C8 arising from the disappearance of the “sandwich”-like
stretched co-conformation. Concerning the NMR signals of
the ammonium moiety, are shifted upfield (Δδ=-0.30 and
-0.17 ppm, respectively) because of the deprotonation-
carbamoylation of the ammonium and the shuttling of the
macrocycles. In the meantime, and in contrast with the
previous molecular machine system 1a/4a, no variation of
29
33
the methylenic hydrogens H3
and H
belonging to the
DB24C8, they are shifted upfield, probably because they
6-37
48-49
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1
FIGURE 2. H NMR spectra (400 MHz, CD
3
CN, 298 K) of (a) the uncomplexed monomer 1au, (b) the protonated mannosyl [c2]daisy chain
1a, (c) the N-Boc mannosyl [c2]daisy chain 4a, and (d) the uncomplexed N-Boc monomer 4au. The numbering and coloring correspond to the
hydrogen assignments indicated in Scheme 3.
chemical shift is observed for H . Instead, H is dramatically
8
overlapping of the signals of H for the two cis/trans amide
1
7
shifted downfield in both the trans and the cis isomers (Δδ =
þ0.91 and þ0.96 ppm), revealing their strong implication in
hydrogen bonding with the DB24C8, and therefore, the new
localization of the macrocycle around the pyridinium unit,
but closer to the mannose moiety. Concerning the chemical
shifts of the hydrogens belonging to the DB24C8 part, they
also undergo important changes. First, the aromatic hydro-
bond containing-isomers) in the carbamoylated [c2]daisy
chain 4b. At the same time, the initial vicinal coupling
constants between, respectively, H
and H (1.6 Hz) importantly rise to 8.0 Hz.
In the cyclohexane ring, the theoretical values for vicinal
and H (3.5 Hz) and
3
4
H
4
5
coupling constants of hydrogens located both in axial posi-
tions are generally 8-10 Hz and usually become 2-4 Hz if at
least one of the two vicinal hydrogens is in an equatorial
gens H , H , H , and more specifically H32 of the
41-44
2
9
33
1
4
DB24C8 are deshielded in 4b because of the disappearance
of the “sandwich”-like stretched co-conformation. Second,
position. This variation of coupling constants observed
between 1b and 4b unambiguously indicates the conforma-
1
the H NMR signals of the methylenic hydrogens H3
1
tional change of the mannopyranose from the C
4
to the C
chair conformation observed for the
and
are shifted upfield, probably because they experience
4
1
6-37
1
conformation. The C
H4
the shielding effect of the aromatic pyridinium ring.
4
8-49
1
5
mannopyranose rings in the [c2]daisy chain 1b was already
reported in the literature with simpler mannosylpyridinium.
It is actually known that glycosyl pyridinium compounds
undergo the controversial reverse anomeric effect (RAE)
because a cationic charge, located at the anomeric position of
a glucide, forces the aglycon chain to sit in the energetically
preferred equatorial position, even though more protected
Very interestingly, the shuttling of the macrocycles from
the ammonium station to the pyridinium station brought
about an impressive and tremendous variation of the chair-
like conformation of the mannopyranosyl extremities. This
was evidenced by the important variations of both the
chemical shifts and the coupling constants of the mannopyr-
anosyl skeleton hydrogens H -H (Figure 4).
16
hydroxyl groups are in axial orientations on the pyranose.
1
6
Although no significant variation of chemical shift is
(14) Silverstein, R. M.; Webster, F. X.; Kiemle, D. J. Spectrophotometric
Identification of Organic Compounds, 7th ed.; Wiley: New York, 2005; p 172.
observed for H , the hydrogens H , H , and H are all shifted
1
3
5
6
1
4
observed in compounds 6a,b, 1a,b, 2a,b, 4a, and 5a,b.
upfield, whereas H and to a lesser extent H are shifted
4
(15) The C conformation of the chairlike mannopyranose was equally
2
downfield. More significantly, the measured vicinal coupling
constant between H and H (9.0 Hz) in the [c2]daisy chain
(16) (a) Perrin, C. L. Tetrahedron 1995, 51, 11901–11935. (b) Lemieux,
1
2
R. U.; Morgan, A. R. Can. J. Chem. 1965, 43, 2205–2213. (c) Lemieux, R. U.
Pure Appl. Chem. 1971, 43, 527–547.
1
b, dramatically falls to 0 Hz (broad singlet due to the
6
522 J. Org. Chem. Vol. 75, No. 19, 2010

Romuald et al.
JOCArticle
1
FIGURE 3. H NMR spectra (400 MHz, CD
3
CN, 298 K) of (a) the uncomplexed monomer 1bu, (b) the protonated mannosyl [c2]daisy chain
1b, (c) the N-Boc mannosyl [c2]daisy chain 4b, and (d) the uncomplexed N-Boc monomer 4bu. The numbering and coloring correspond to the
hydrogen assignments indicated in Scheme 3.
1
FIGURE 4. H NMR partial expanded spectra (400 MHz, CD
N-Boc mannosyl [c2]daisy chain 4b. The numbering and coloring correspond to the hydrogen assignments indicated in Scheme 3.
3
CN, 298 K) of (a) the protonated mannosyl [c2]daisy chain 1b and (b) the
In our case, one can assume that the reverse anomeric effect
observed in 1b is switched off in 4b due to the masking of the
cationic charge of the pyridinium and the implication of H7
in hydrogen bonding with the DB24C8. Eventually, the
the flipping of the mannopyranose chairlike conformation to
4
the C conformation in 4b (Figure 3c,d).
1
To summary, the molecular [c2]daisy chain shuttling
system 1b/4b exist in either the stretched and the very
contracted co-conformations. A domino effect from one
extremity to the other was also observed. Indeed, the depro-
tonation-carbamoylation sequence applied to the ammo-
nium station at one extremity of the molecule imposes the
1
direct comparison between H NMR spectra of [c2]daisy
chain 4b and monomer 4bu confirmed, on one hand, the
localization of the DB24C8 rings around the hydrogens H7
belonging to the pyridinium station and, on the other hand,
J. Org. Chem. Vol. 75, No. 19, 2010 6523

Romuald et al.
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1
FIGURE 5. H NMR spectra (400 MHz, CD
3
CN, 298 K) of (a) the uncomplexed monomer 2bu, (b) the protonated mannosyl [c2]daisy chain
2b, (c) the N-Boc mannosyl [c2]daisy chain 5b, and (d) the uncomplexed N-Boc monomer 5bu. The numbering and coloring correspond to the
hydrogen assignments indicated in Scheme 3.
impressive conformational change of the mannopyranosyl at
the other extremity, thanks to the shuttling of the macro-
cycles.
H25 and H , which are shifted downfield in 2b (Δδ = þ0.54
27
and þ0.48 ppm, respectively), due to their hydrogen-bond-
ing interaction with the oxygens of the DB24C8, no other
variations of chemical shift are observed for the hydrogens
belonging to the two other molecular stations. Concerning
the hydrogens of the DB24C8 parts in the [c2]daisy chain 2b,
the same trend of variations is observed than in 1a and 1b: the
aromatic hydrogens of the DB24C8 are shielded because of a
“sandwich”-like assembling structure, and the methylenic
hydrogens of the crown ether are split due to the interlocked
structure. After deprotonation-carbamoylation, and simi-
larly to the already described molecular machines, H25 and
H , which are located next to the ammonium station, are
c. Molecular Machinery of the Molecular Muscle Mimic
System 2b/5b. In the three stations;including [c2]daisy
chains 2b/5b, the DB24C8 parts are initially localized around
the best ammonium stations and force the molecule to adopt
a stretched co-conformation (Scheme 3). However, upon de-
protonation-carbamoylation, the movement of the DB24C8
along the thread appears to be quite different compared to the
large amplitude two stations [c2]daisy chain molecular ma-
chines 1/4, and the shuttling of the macrocycle directly depends
here on the relative affinity of the DB24C8 for the disubstituted
pyridinium amide and the triazolium stations. When the
2
7
shifted upfield (Δδ = -0.36 and -0.29 ppm, respectively),
due to the deprotonation of the ammonium group and the
shuttling of the DB24C8 parts (Figure 5b,c). Interestingly,
and contrary to the previously studied [c2]daisy chain mo-
lecular machines 1a/4a and 1b/4b, no variations of chemical
shifts for hydrogens H and H belonging to the pyridinium
[c2]daisy chain 2b was deprotonated and carbamoylated to
give 5b, the DB24C8 shuttled from the ammonium to the
triazolium interaction site, as a result of the better affinity of
the DB24C8 for this molecular station than for the disubsti-
tuted pyridinium amide. It implicated a half-contracted co-
conformation of the rotaxane dimer 5b. This observation was
7
8
amide unit are observed in 5b, whereas the hydrogens H ,
17
1
evidenced by the comparison of the H NMR spectra of the
H18 of the triazolium unit are shifted downfield (Δδ = þ0.47
and þ0.61 ppm, respectively) as a result of their hydrogen-
bonding implication with the oxygens of the crown ether. At
the same time, the methylic triazolium hydrogens H52 are
dramatically shifted upfield in 5b (Δδ = -0.41 ppm) because
of their localization in the shielding cavity of the aromatic
ring of the crown ether parts. Concerning the aromatic
uncomplexed monomer 2bu, the protonated rotaxane dimer 2b,
the carbamoylated rotaxane dimer 5b, and the carbamoylated
monomer 5bu (Figure 5).
1
By comparing the H NMR spectra of 2bu and 2b, it is
possible to accurately localize the DB24C8 parts around the
best ammonium station. Indeed, apart from the hydrogens
6
524 J. Org. Chem. Vol. 75, No. 19, 2010

Romuald et al.
JOCArticle
1
FIGURE 6. H NMR spectra (400 MHz, CD
3
CN, 298 K) of (a) the uncomplexed monomer 2au, (b) the protonated mannosyl [c2]daisy chain
2a, (c) the N-Boc mannosyl [c2]daisy chain 5a, and (d) the uncomplexed N-Boc monomer 5au. The numbering and coloring correspond to the
hydrogen assignments indicated in Scheme 3.
hydrogens of the DB24C8, they are again deshielded in 5b as
a result of the disappearance of the “sandwich”-like co-
conformation. However, it is important to notice that the
signals of the methylenic hydrogens belonging to the
DB24C8 parts are less shielded in 5b than in the previously
discussed [c2]daisy chain 4a and 4b because they are ob-
viously not experiencing the shielding effect of the pyridi-
both with the triazolium and the monosubstituted pyridi-
nium amide stations as a result of a similar affinity of the
DB24C8 for the two stations. This was demonstrated by the
1
comparison of the H NMR spectra of the uncomplexed
monomer 2au, the protonated rotaxane dimer 2a, the depro-
tonated-carbamoylated rotaxane dimer 5a, and the depro-
tonated-carbamoylated monomer 5au (Figure 6). In the
protonated ammonium state 2a, and as observed for the
[c2]daisy chain 2b, the rotaxane dimer adopts a stretched
“sandwich”-like co-conformation, resulting from the higher
affinity of the DB24C8 parts for the ammonium station than
for the triazolium and the monopyridinium amide stations.
Indeed, in comparison with the monomer 2au, the hydrogens
H25 and H27 of 2a are deshielded (Δδ = þ0.47 and þ0.45
ppm, respectively) because of their implication in hydrogen
bonds and the aromatic hydrogens of the DB24C8 are
shielded due to their localization in the shielding cavity of
the aromatic ring of the DB24C8 (Figure 6a,b, Scheme 3).
After deprotonation-carbamoylation of the ammonium
station, the new localization of the DB24C8 around both the
triazolium and the monosubstituted pyridinium amide sta-
1
nium aromatic ring. The direct comparison of the H NMR
spectra of 5b and 5bu corroborates the interaction sites
implicating the triazoliums and the macrocycles (Figure 5c,
d). In summary, all these NMR observations unambiguously
demonstrate that 5b adopts an half-contracted [c2]daisy
chain co-conformation, where the DB24C8 macrocycle parts
exclusively interact with the triazolium molecular station:
they highlight as well the higher affinity of the DB24C8 for
the triazolium molecular station than for the disubstituted
pyridinium amide one.
d. Molecular Machinery of the Molecular Muscle Mimic
System 2a/5a Using Chemical Stimulus at Room Temperature
and Influence of either Solvent or Temperature Stimuli on 5a.
In the monosubstituted pyridinium amide series, the molec-
ular machine behaves very differently. Indeed, the already
discussed stretched co-conformation observed in 2a chan-
ged, after deprotonation-carbamoylation, to a continuous
oscillating molecular muscle 5a adopting at room tempera-
ture an alterning co-conformation between a half-contracted
to a contracted co-conformation, where the DB24C8 interact
1
tions can be deduced from the comparison between the H
NMR spectra of rotaxane dimers 5a and 2a (Figure 6b,c). In
the rotaxane dimer 5a, the disappearance of the ammonium
hydrogens and the appearance of the hydrogen signal of the
carbamoylated group H26 are accompanied by the usual
upfield shift of the hydrogens H25 and H27 which are initially
J. Org. Chem. Vol. 75, No. 19, 2010 6525

Romuald et al.
JOCArticle
2 2 1 2
FIGURE 7. Effect of the solvent polarity (at 298 K) and the temperature (in CD Cl ) on the proportions of the translational isomers 5a and 5a .
1 2
SCHEME 4. Translational Isomers 5a /5a Which Are in Fast Exchange at Room Temperature and Comparison with a Simpler
[
2]Rotaxane A
located next to the ammonium moiety. In 5a, the same
downfield shift of H32 is observed than the one noticed in
all the previously described carbamoylated [c2]daisy chain
any hydrogen bonding interactions (i.e., in monomers
2au and 5au) and when they are totally engaged in hydro-
gen bonding with the DB24C8 (i.e., in rotaxane dimer 4a
for H8 and rotaxane dimer 5b for H18) (Scheme 4,
Figure 7).
4
H3 and H are shielded (more than in 5b, but a little
a, 4b, and 5b, whereas the DB24C8 methylenic hydrogens
6-37
48-49
less than in 4a and 4b) since they partially experience the
shielding effect of the aromatic pyridinium moiety. Even
more interestingly, all of the hydrogens belonging to the two
triazolium and monopyridinium amide molecular stations
H , H , H , H , and H are shifted downfield in 5a (Δδ =
Surprisingly, an average ratio of 68:32 in favor of the half
contracted co-conformation 5a was determined at room
temperature in CD CN, although it was found in parallel in a
3
1
recent study with a simpler [2]rotaxane analogue A that the
pyridinium amide was a slightly better station for the
1
7
18
20
8
11
17
þ0.26, þ0.41, þ0.44, þ0.32, and þ0.09 ppm, respectively),
indicating their hydrogen-bonding interactions with the
oxygens of the DB24C8. It is noteworthy that even though
the DB24C8 parts interact with the two molecular stations,
DB24C8 than the triazolium one at room temperature.
One could have thus assumed similar affinities of the two
stations for the DB24C8 parts in our rotaxane dimers 5a than
in our [2]rotaxane monomer analogue A. Nevertheless, the
possible repulsion between the two triazolium cationic charges
1
only one set of H NMR signals is present on the NMR time
scale for 5a. Moreover, the hydrogens, which are implicated
in hydrogen-bonding interactions with the DB24C8, are all
broadened in 5a, assuming a continuous fast oscillation of
the macrocycles on the NMR time scale at room temperature
between the triazolium and the monosubstituted pyridinium
amide stations, resulting in a molecular muscle continuously
changing its co-conformation from a half-contracted to a
contracted one. This result is confirmed by the direct com-
in the contracted molecular muscle 5a , which directly results
2
from the nature of the constrained interwoven dimer structure,
should not be energetically favorable and should therefore
increase the population of the half-contracted molecular muscle
translational isomer 5a . The population of each translational
1
isomer 5a and 5a in the oscillating state was further studied in
2
1
different more or less dissociating solvents and at different
temperature: the shuttle oscillation of the DB24C8 around the
1
18
two molecular stations was found to be solvent and tempera-
parison between the H NMR spectra of 5a and the monomer
5au (Figure 6c,d).
ture dependent (Figure 7).
Solvent Effect at Room Temperature on Molecular Muscle
5a. Unsurprisingly, with the exception of the DMSO, the
The proportion at room temperature of the two transla-
tional isomers 5a /5a of the carbamoylated molecular mus-
1
2
cle 5a, which are in fast exchange on the NMR time scale, was
evaluated thanks to the known chemical shift of hydrogens
(
3 1 2
17) In CD CN, a ratio A :A of 38:62 in favor of the isomer containing
the DB24C8 around the monosubstituted pyridinium amide station was
found in a [2]rotaxane containing the two same stations. Busseron, E.;
Romuald, C.; Coutrot, F. Chem.;Eur. J. 2010, 16, 10062-10073.
H and H (which are directly relevant to the two transla-
8
18
tional isomers 5a and 5a ) when they are not engaged in
1
2
6
526 J. Org. Chem. Vol. 75, No. 19, 2010

Romuald et al.
JOCArticle
variation of the polarity of the solvent (from CDCl to
3
upfield at lower temperature until it reaches the chemical
shift value of H18 in the uncomplexed N-Boc monomer 2au
(Figure 8a-c). The displacement of the translational iso-
CD CN via CD Cl and MeOD) caused negligible varia-
3
2
2
tions of chemical shifts for the hydrogens H (Δδ less than
8
0
(
5
.07 ppm) in the contracted [c2]daisy chain 4a and for H18
Δδ less than 0.07 ppm) in the half-contracted [c2]daisy chain
b, corroborating that they are strongly interacting by
meric equilibrium occurred in the same way in CD CN,
3
however, in a lesser extent, probably because upon decreas-
ing the temperature, the energetic gain, resulting from the
translation of the DB24C8 around the monosubstituted
pyridinium amide station, is compensated by an energetic
unfavorable repulsion of the triazolium stations.
hydrogen bonding with the DB24C8 macrocycle. On the
contrary, the chemical shifts of H in the monomer 5au and
8
H18 in the monomer 2au (up to Δδ = 0.17 and 0.30 ppm,
respectively) and in the oscillating molecular muscle 5a
Thermodynamic parameters corresponding to the fast
exchange on the NMR time scale between 5a and 5a were
(respectively up to Δδ = 0.43 and 0.27 ppm) obviously
1
2
1
extracted from a Van’t Hoff plot (Figure 9) thanks to the
9
proved to be more sensitive to the nature of the solvent. This
is consistent with the better accessibility of the solvent due to
the absence of any intramolecular strong hydrogen-bonding
interaction in 2au and 5au and to the oscillation of the
macrocycle in the molecular muscle 5a. Much more interest-
ingly, contrary to the translational isomeric [2]rotaxanes A1
2
thermodynamic constants K determined at different tem-
0
peratures. The plot appeared linear over the examined range
of temperature (with a linear regression coefficient R =
0.999) and provided the translational isomeric exchange
2
-
1
enthalpy from 5a to 5a ΔH = 12.4 kJ mol and entropy
2
1
1
-1
3
-
and A which are not sensitive at all to the solvent polarity,
2
ΔS = 34.4 J K mol . A free Gibbs energy ΔG (298K) of
1
2.1 kJ mol was calculated, indicating the more energeti-
cally favorable translational isomer 5a due to the slightly
3
3
-
an unexpected and impressive inversion of the ratio 5a :5a
1
2
3
was observed by changing the solvent from the less dissociat-
ing CDCl to the more dissociating DMSO via the inter-
2
better affinity of the DB24C8 for the monosubstituted
pyridinium amide unit. It is interesting to note that this
energy is twice the value found for the exchange between
translational isomers of the simpler monomeric [2]rotaxane
analogues A.
3
mediate CD Cl , MeOD, and CD CN (Figure 7). At room
2
2
3
temperature in DMSO and CD CN, a molecular muscles
3
ratio 5a :5a of, respectively, 97.5:02.5 and 68:32, in favor of
2
1
the half-contracted co-conformation, was evaluated. How-
ever, in CDCl , an inverted molecular muscle’s average ratio
DB24C8 Macrocycle as a Molecular Brake for the Rotation
of the C -C Bond. Eventually, in CD Cl , hydrogens H
3
5
a :5a of 11.5:88.5 in favor of the contracted molecular
1 2
9
10
2
2
8
muscle co-conformation was evaluated, suggesting that the
energetically unfavorable repulsion of the two triazolium
units in the contracted state is a dominant factor in dissociat-
belonging to the oscillating rotaxane 5a appear as single
NMR frequency above 213 K, whereas they coalesce at a
temperature of 213 K and are split at lower temperature
(Figure 8). This is attributed to the decrease of the rotation
rate of the bond C -C between the pyridinium and the
ing solvents like DMSO and to a lesser extent CD CN,
3
whereas in less dissociating solvent like CD Cl and CDCl ,
3
2
2
9
10
the repulsion between the more diluted positively charged
triazolium units constitutes a weaker factor and the higher
affinity of the pyridinium amide station for the DB24C8
imposes the localization of the macrocycle derivatives. In the
amide carbonyl when lowering temperature, due to the
anchoring of the macrocycles at the two H-bonding sites
surrounding the C -C linkage. Above 213 K, the rotation
9
10
of the link C -C is fast on the NMR time scale, whereas it
9
10
intermediary CD OD solvent, a quasi-equimolar ratio for
3
becomes slow below 213 K. Remarkably, no coalescence of
H is observed either for the monomeric noninterlocked
5
a :5a of 51.5:48.5 was detected.
1 2
8
Temperature Effect on Molecular Muscle 5a and Extracted
1
Thermodynamic Parameters. A low variable-temperature H
analogues 2au and 5au and the half-contracted [c2]daisy
chain 5b, where the DB24C8 moieties sit around the triazo-
lium stations, highlighting the role of molecular brake of the
DB24C8 in the rotation of the covalent bond C -C when
NMR experimental study was conducted both in a dissociat-
ing solvent like CD CN and in a less dissociating solvent like
3
9
10
CD Cl with the aim of freezing the system (Scheme 4,
2
the macrocycles are located around both the pyridinium and
2
Figure 7). Upon decreasing the temperature, the fast-ex-
change equilibrium between 5a and 5a clearly shifts toward
the monosubstituted amide hydrogens. At 213 K, a rate
-
1
constant for the rotational isomeric exchange of 290 s was
1
2
√
2
1
5
progressive increase of the population of the translational
a . In CD Cl , decreasing the temperature results in the
provided by the equation krot=πδν/ 2, where δν (130.6
Hz) corresponds to the line width at half-height of the
2
2
2
isomer 5a until the macrocycle froze exclusively around the
2
coalesced NMR signal for H . This kinetic rate gave access
8
pyridinium amide station (Figure 8). This was demonstrated
1
by the progressive downfield shift of the H NMR signal
to the free energy of activation between the rotamers
q
-1 22
ΔG
= 41.5 kJ mol .
rot 213
3
1
observed for H , until it reached the H NMR chemical shift
8
Conclusions
of H belonging to the contracted N-Boc mannosyl [c2]daisy
8
chain 4a at the same temperature (Figure 8a,b). Parallel to
1
this observation, the H NMR signal for H18 is shifted
Four new [c2]daisy chain molecular machines based on a
DB24C8 macrocycle and containing two or three stations,
(
18) For other solvent-dependent molecular switches, see: (a) Lane, S. A.;
(19) Pastor, A.; Martinez-Viviente, E. Coord. Chem. Rev. 2008, 252,
Leigh, D. A.; Murphy, A. J. J. Am. Chem. Soc. 1997, 119, 11092–11093. (b)
Tzu-Chiun, L.; Chien-Chen, L.; Sheng-Hsien, C. Org. Lett. 2009, 11, 613–
2314–2345.
(20) Thermodynamic constants K were calculated from the mean propor-
and
1
which were determined from both H NMR signals H
6
16. (c) Ambrosi, G.; Dapporto, P.; Formica, M.; Fusi, V.; Giorgi, L.;
Guerri, A.; Micheloni, M.; Paoli, P.; Pontellini, R.; Rossi, P. Chem.;Eur. J.
003, 9, 800–810. (d) Chiang, P.-T.; Cheng, P.-N.; Lin, C.-F.; Liu, Y.-H.; Lai,
tions of 5a
1
/5a
2
8
18
H .
2
(21) Dynamic NMR Spectroscopy; Sandstrom, J., Ed.; Academic Press:
New York, 1982.
(22) The free enthalpy of activation was calculated using the Eyring
equation: ΔG
C.-C.; Peng, S.-M.; Chiu, S.-H. Chem.;Eur. J. 2006, 12, 865–876. (e)
Hannam, J. S.; Kidd, T. J.; Leigh, D. A.; Wilson, A. J. Org. Lett. 2003, 5,
q
T
1
907–1910.
b
= -RT ln(kh/k T).
J. Org. Chem. Vol. 75, No. 19, 2010 6527

Romuald et al.
JOCArticle
FIGURE 9. Thermodynamic Van’t Hoff plot for the translational
isomeric exchange between 5a and 5a in CD Cl (253-298 K).
1 2 2 2
was reached. However, in the presence of the disubstituted
pyridinium amide station, the macrocycles shuttled toward a
slightly different very contracted state and triggered an im-
pressive flipping of the chairlike mannopyranose extremity by
turning off the reverse anomeric effect. Incorporation of a
third station (i.e., triazolium) allowed us to reach two new
molecular machines. A half-contracted co-conformation was
possible with the disubstituted pyridinium amide station,
whereas in the monosubstituted pyridinium amide station
series, an interesting oscillating molecular muscle occurred.
The continuous oscillation of the DB24C8 between the triazo-
lium and the monosubstituted pyridinium amide stations could
be highly controlled by the variation of the solvent polarity or
by the temperature. In a dissociating solvent like DMSO, the
higher repulsion between triazolium moieties favors the half-
contracted translational isomer, even though the pyridinium
amide station has a slightly better affinity for the DB24C8
than the triazolium. On the contrary, the nondissociating
solvents like CDCl favor the contracted translational isomer
3
because the stabilization by hydrogen bonding between the
DB24C8 and the best pyridinium amide station is not com-
pensated by the repulsion of the triazolium, which is actually
much lower due to a more diluted cationic charge. In CD Cl ,
2
2
when no such triazolium repulsion occurred, the decrease of the
temperature highly displaced the translational exchange equi-
librium from the half-contracted to the unique energetically
favorable contracted state, until no more oscillation persists.
Thermodynamic parameters could then be extracted from the
variable-temperature NMR study and provided the free Gibbs
energy of the translational equilibrium, which exactly matches
to twice the free Gibbs energy calculated for a simpler analo-
gous monomeric [2]rotaxane. Finally, it was demonstrated the
molecular brake role of the DB24C8 when it is located around
the monosubstituted pyridinium amide moiety: it caused a
tremendous decrease of the rotation of the surrounded bond
C -C . Improving the knowledge of the behaviors of molec-
1
2 2
FIGURE 8. Partial H NMR spectra (400 MHz, CD Cl ) of (a) the
oscillating N-Boc mannosyl [c2]daisy chain 5a at different tempera-
tures; (b) the contracted N-Boc mannosyl [c2]daisy chain 4a at
03 K; and (c) the uncomplexed monomer 2au at 203 K. The
numbering and coloring correspond to the hydrogen assignments
indicated in Scheme 3.
2
9
10
among an ammonium, a triazolium, and a mono- or a dis-
ubstituted pyridinium amide stations, have been prepared
and studied. They gave rise to molecular machines which are
triggered by deprotonation-carbamoylation, solvent polarity,
and temperature. Two large-amplitude molecular muscles,
from stretched to contracted or very contracted co-confor-
mations, could be obtained using two molecular stations for
the DB24C8. They both behave differently depending on the
substitution of the pyridinium amide. In the presence of the
monosubstituted pyridinium amide station, a contracted state
ular muscles, depending on the nature and the number of
stations, may prove useful for the development of new molec-
ular switches.
Experimental Section
All reactions were carried out under an atmosphere of argon
unless otherwise indicated. The reagents were used as received
without further purification. Dichloromethane was distilled
over P O and was degassed by bubbling Ar for 20 min.
2
5
Analytical thin-layer chromatography (TLC) was performed
6
528 J. Org. Chem. Vol. 75, No. 19, 2010

Romuald et al.
JOCArticle
= 9.0 Hz, H1),
3
), 5.26 (dd, 2H,
3
3
= 8.4 Hz, H ), 6.37 (d, 2H, J
on silica gel 60 F254 plates. Compounds were visualized by
dipping the plates in an ethanolic solution of 10% sulfuric acid,
ninhydrin, or an aqueous solution of KMNO , followed by
J
H32-H33
32
3
H1-H2
3
5.57 (t, 2H, JH3-H2 = JH3-H4 = 3.5 Hz, H
3
J
3
4
H2-H1 = 9.0 Hz, JH2-H3 = 3.5 Hz, H
2
), 5.13-5.10 (m, 2H, H
4
),
1
13
3
4.80 (dd, 2H, J
2
=9.0 Hz, J
heating. H NMR and C NMR spectra were obtained at
4
0
=12.6 Hz, H ), 4.59-4.54
H6-H5
H6-H6
6
1
00.13 and 100.62 MHz, respectively. Chemical shifts of H
(m, 2H, H
5
), 4.59-4.41 (m, 4H, H27), 4.35-4.19 (m, 6H, H
O), 3.48-3.38 (m, 4H, H25), 3.08 (t, 4H,
H12-H13 = 7.4 Hz, H12), 3.03 (s, 6H, H11), 2.63-2.55 (m, 4H,
H ), 2.20 and 2.14 and 2.01 and 1.90 (4*s, 24H, CH CO),
6
0
H17),
13
NMR and C NMR are given by using CHCl
MeOH, or CH CN as references (7.27, 5.32, 2.50, 3.31, or 1.94
ppm, respectively, for the H spectrum, and 77 and 118.26 ppm,
3
CH
2
Cl
2
, DMSO,
4.35-3.54 (m, 48H, CH
2
3
J
3
1
2
0
3
1
3
1
respectively, for the C spectrum in CDCl
3
and CD
3
CN). H
1.92-1.76 (m, 4H, H16), 1.76-1.70 (m, 4H, H24), 1.61-1.50 (m,
8H, H13 21), 1.46-1.14 (m, 16H, H14 23);transisomerδ
(ppm) = 8.99 (d, 4H, J
1
1
assignments were deduced from 2D H- H NMR COSY
H
15 22
H H H
13
13
1
3
3
experiments. C assignments were deduced from 2D C- H
NMR HMQC experiments. Coupling constants (J) are reported
in hertz (Hz). Standard abbreviations indicating multiplicity
were used as follows: s (singlet), br (broad), d (doublet), t
=6.7Hz,H ),8.07(d,4H, J
=
H7-H8
7
H8-H7
6.7 Hz, H ), 7.50 (s, 2H, H ), 6.97-6.86 and 6.71-6.60 (2 m, 4H,
8
18
H
26), 6.90-6.70 (m, 12H, H29
H
33
H4 13 H42
H
43
H44), 6.43 (d, 2H,
3
J
H32-H33 = 8.4 Hz, H32), 6.34 (d, 2H, JH1-H2 = 9.0 Hz, H ), 5.57
1
3
(t, 2H, J
3
= J
3
= 3.5 Hz, H ), 5.23 (dd, 2H, J
(
triplet), q (quartet), m (multiplet). Mass spectra (MS) and
=
H3-H2
H3-H4
3
H2-H1
3
high-resolution mass spectra (HRMS) were recorded, respec-
tively, on a ZQ Micromass apparatus and a Q-TOF Micro
apparatus.
9.0 Hz, JH2-H3 = 3.5 Hz, H
2
), 5.13-5.10 (m, 2H, H
= 12.6 Hz, H ), 4.59-4.54 (m, 2H, H
4.59-4.41 (m, 4H, H27), 4.35-4.19 (m, 6H, H 17), 4.35-3.54 (m,
48H, CH O), 3.50 (t, 4H, J = 7.3 Hz, H ), 3.48-3.38 (m,
2 H12-H13
4
), 4.77(dd, 2H,
3
J
2
H6-H5 = 9.2 Hz, JH6-H6
0
6
5
),
0
H
6
3
1. Starting Materials and Monomers. The preparations of the
12
precursor compounds 6a,b and 7 are described in detail in the
Supporting Information. The syntheses of monomers 1au, 1bu,
4H, H25),2.85(s,6H,H11),2.63-2.55(m,4H,H20),2.20and2.15and
2.01 and 1.90 (4*s, 24H, CH CO), 1.92-1.76 (m, 4H, H16),
1.76-1.70 (m, 4H, H ), 1.68-1.61 (m, 4H, H ), 1.61-1.50 (m,
3
2
au, 2bu, 4au, 4bu, 5au, and 5bu are reported in the Supporting
Information.
24
13
1
3
4H, H ), 1.46-1.14 (m, 16H, H
H H H ). JMOD C NMR
21
14 15 22 23
2
. Synthesis of Rotaxane Dimers. 2.1. Rotaxane Dimers 1a
(153 mg, 0.410
(100 MHz, CD
and 170.0 (COCH
148.7 and 147.2 and 147.0 (C C C C C ), 144.1 and 144.1 (C ),
3
CN, 298 K): δ (ppm) = 171.5 and 170.3 and 170.1
and 1b. In a typical procedure, Cu(CH CN) PF
mmol 1 equiv) and 2,6-lutidine (4.4 μL, 0.041 mmol, 0.1 equiv)
were added successively to a solution of the azido compound 6a
3
4
6
3
), 165.8 and 165.6 (C10), 156.8 and 156.6 (C ),
9
19
30 31 40 45
7
127.1 and 126.9 (C
121.6 and 114.2 and 113.0 and 112.7 (C29
89.3 and 89.2 (C ), 78.5 and 78.4 (C ), 73.0 and 71.5 and 71.4 and 71.3
and 71.1 and 68.5 and 68.2 and 68.1 and 68.0 (CH O), 69.7 and 69.7
8
), 126.3 (C28), 122.4 and 122.2 (C18), 123.6 and
(
(
297 mg, 0.410 mmol, 1 equiv) and the alkyne compound 7
300 mg, 0.410 mmol, 1 equiv) in 3 mL of dry dichloromethane.
32 33 41 42 43
C C C C C C
44),
1
5
The mixture was stirred for 24 h at room temperature, after
which time the solvent was evaporated in vacuo. The crude was
then directly purified by chromatography on a silica gel column
2 2
(solvent gradient elution CH Cl /MeOH 98:2 to 85:15) to afford
the rotaxane dimer 1a as a yellow solid.
2
2 4 3 6
(C ), 68.3 (C ), 67.6 and 67.6 (C ), 61.2 and 61.1 (C ), 52.8 (C27), 51.3
(C12cis), 48.0 (C12trans), 50.5 and 50.4 (C17), 49.7 (C25), 37.1 (C12trans),
32.7 (C11cis), 30.9 and 30.7 (C16), 30.1 and 30.0 and 29.2 and 29.1 and
28.3 and 27.3 and 27.2 and 27.1 and 27.0 and 27.0 and 26.8 and 26.8
a. The rotaxane Dimer 1a (R = H) was obtained in a77%
yield. R (CH Cl /MeOH 9:1): 0.26. H NMR (400 MHz,
and 26.7 and 26.3 (C13
C
14
C
15
C
21
C
22
C
23
C
24), 26.0 (C20), 21.0 and
1
f
2
2
20.9 and 20.8 and 20.6 and 20.6 (CH
3
CO). HRMS (ESI): [M -
3
4þ
4þ
] 589.2999, found 589.2994
36
CD CN, 298 K): δ (ppm) 9.04 (d, 4H, J
= 6.6 Hz, H7),
4PF ]
6
calcd for [C120
H
N
172
O
12
3
H7-H8
3
8
7
.35 (d, 4H, JH8-H7 = 6.6 Hz, H
.48 (s, 2H, H18), 6.99-6.85 and 6.73-6.55 (2 m, 4H, H26),
.84-6.70 (m, 12H, H29 44), 6.42 (d, 2H,
H32-H33 = 8.3 Hz, H32), 6.38 (d, 2H, JH1-H2 = 9.0 Hz, H ),
3
.56 (t, 2H, JH3-H2 = JH3-H4 = 3.2 Hz, H ), 5.23 (dd, 2H,
3
8
), 7.66-7.58 (br t, 2H, H11),
2.2. Rotaxane Dimers 2a and 2b. In a typical procedure,
rotaxane dimer 1a (150 mg, 0.0515 mmol) was suspended in
3 mL of iodomethane and stirred for 1 day at room temperature.
Iodomethane was then evaporated under reduced pressure, and
the obtained solid was washed with diethyl ether to give a yellow
solid. NH PF (34 mg, 0.206 mmol, 4 equiv) and 2 mL of dichlo-
6
33 41 42 43
H H H H H
3
3
J
1
3
3
5
3
3
J
H2-H13=9.0 Hz, JH2-H3=3.2 Hz, H
.2 Hz, J = 2.0 Hz, H ), 4.82 (dd, 2H, J = 9.2 Hz,
H6-H5
2
), 5.11 (dd, 2H, JH4-H3
=
4
6
3
3
romethane were added to a suspension of the previous product
in 2 mL of Milli-Q water. The resulting bilayer solution was
vigorously stirred for 30 min. After separation, the aqueous
layer was extracted with 5 mL of dichloromethane. The organic
4
layers were combined, dried over MgSO , and concentrated to
obtain the molecular muscle 2a (135 mg, 81%) as a yellow solid.
a. The rotaxane dimer 2a (R = H) was obtained in 81%
H4-H5
4
2
J
0
= 12.7 Hz, H
), 4.60-4.55 (m, 2H, H
), 4.58-4.40 (m,
H6-H6
6
5
4
3
2
4
1
H, H ), 4.34-4.22 (m, 6H, H
0
H ), 4.17-3.60 (m, 48H, CH O),
27
6
17
2
3
.48-3.33 (m, 8H, H12
H25), 2.58 (t, 4H, JH20-H21 = 7.4Hz, H20),
.20 and 2.16 and 2.00 and 1.86 (4*s, 24H, CH CO), 1.90-1.83 (m,
3
H, H16), 1.77-1.66 (m, 4H, H24), 1.66-1.51 (m, 8H, H13
H21),
13
.46-1.26 (m, 16H, H14
H
15
H22 H ). JMOD C NMR (100
23
1
MHz, CD
(
3
CN, 298 K): δ (ppm) = 171.5, 170.3 and 170.0, 169.9
yield. R (CH Cl /MeOH 9:1): 0.59. 3H NMR (400 MHz,
f
2
2
COCH ), 162.4 (C ), 153.0 (C ), 148.6 and 147.0 and 146.9 (C
3
CD CN, 298 K): δ (ppm)=9.05 (d, 4H, J
H7-H8
=6.9 Hz, H7),
10
9
19
3
3
8.36 (d, 4H, J
C
30
C
31
C
40
C45), 144.1 (C ), 127.2 (C ), 126.2 (C28), 123.5 and
7 8
= 6.9 Hz, H ), 8.09 (s, 2H, H ), 7.72-7.63
H8-H7
8
18
1
23.5 and 121.5 and 121.5 and 114.1 and 112.9 and 112.6 and 112.6
44), 89.0 (C ), 78.7 (C ), 72.9 and 72.9
and 71.4 and 71.3 and 71.2 and 71.0 and 68.4 and 68.4 and 68.1 and
8.0 and 68.0 and 67.8 (CH O), 69.6 (C ), 68.2 (C ), 67.4 (C ), 60.9
) 52.7 (C27), 50.6 (C17), 49.7 (C25), 40.9 (C12), 30.8 (C16), 29.9
and 29.4 and 29.0 and 27.2 and 26.9 and 26.8 and 26.6 (C13
24), 25.9 (C20), 21.0 and 20.9 and 20.8 and 20.4
(br t, 2H, H ), 6.99-6.87 and 6.74-6.64 (2 m, 4H, H ),
1
1
26
(
C
29
C
32
C
33
C
41
C
42
C
43
C
1
5
6.87-6.71 (m, 12H, H
H
H
41
H
42
H
44
H ), 6.45 (d, 2H,
29
33
43
3
3
= 8.4 Hz, H ), 6.38 (d, 2H, J
J
H32-H33
5.57 (t, 2H, J
32
H1-H2 1
= 9.0 Hz, H ),
=
3
3
= J
3
=3.4 Hz, H ),5.23(dd,2H, J
6
2
2
4
3
H3-H2
H3-H4
= 3.4 Hz, H ), 5.11 (dd, 2H, J
3
H2-H1
H4-H3
= 3.4 Hz,
3
9.0 Hz, J
3
(
C
6
H2-H3
= 2.1 Hz, H ), 4.82 (dd, 2H, J
2
3
J
3
2
= 9.2 Hz, J
C
14
C
15
0
=
H4-H5
4
H6-H5
H6-H6
3
C
21
C
22
C
23
C
12.7 Hz, H ),4.61-4.55(m,2H,H ),4.50(t,4H, J
H17-H16
=7.1Hz,
6
5
4þ
3
(
CH CO). HRMS (ESI): [M - 4PF ] calcd for [C118 H168
-
H ), 4.61-4.41 (m, 4H, H ), 4.29 (dd, 2H, J
0
= 3.7 Hz,
3
6
17
27
H6 -H5
4
þ
2
N
12
O
36
]
582.2921, found 582.2929.
J
H6
0
-H6 = 12.7 Hz, H
6
0
2
), 4.19-3.65 (m, 48H, CH O), 4.09 (s,
3
b. The rotaxane dimer 1b (R = Me) was obtained in 74%
yield. R (CH Cl /MeOH 9:1): 0.53. Ratio of isomers cis/trans =
6H, H52), 3.52-3.36 (m, 8H, H12 H25), 2.65 (t, 4H, JH20-H21 =
7.9 Hz, H ), 2.21 and 2.16 and 2.00 and 1.88 (4*s, 24H,
CH CO), 1.99-1.92 (m, 4H, H ), 1.80-1.69 (m, 4H, H ),
f
2
2
20
1
7:53. H NMR (400 MHz, CD
4
3
CN, 298 K): cis isomer δ(ppm) =
3
16
24
3
3
8
.97 (d, 4H, JH7-H8 = 6.7 Hz, H
), 7.47 (s, 2H, H18), 6.97-6.86 and 6.71-6.60 (2 m, 4H,
H ), 6.90-6.70 (m, 12H, H H ), 6.43 (d, 2H,
7
), 8.04 (d, 4H, JH8-H7 = 6.7
1.69-1.53 (m, 8H, H13
H21), 1.48-1.35 (m, 16H, H14
H
15
H
22
1
3
Hz, H
8
3
H23). JMOD C NMR (100 MHz, CD CN, 298 K) δ (ppm) =
H
H
H
H
171.6 and 170.3 and 170.0 and 169.9 (COCH ), 162.5 (C ),
3 10
26
29 33 41 42 43 44
J. Org. Chem. Vol. 75, No. 19, 2010 6529

Romuald et al.
JOCArticle
1
53.0 (C ), 148.7 and 147.1 and 146.9 and 145.5 (C C30 C31 C40
9
layers were extracted with dichloromethane, and the combined
19
C
7
45), 144.1 (C ), 128.4 (C18), 127.2 (C
8
), 126.2 (C28), 123.5 and
4
organics layers were dried over MgSO and concentrated. The
1
C ), 89.1 (C ), 78.7 (C ), 73.0 and 72.9 and 71.5 and 71.3 and
21.6 and 114.1 and 113.0 and 112.7 (C29
C
32
C
33
C
41
C
42
C
43
obtained solid was washed with diethyl ether and purified by
chromatography on a Sephadex LH20 column (eluent CH Cl /
4
4
1
5
2
2
7
1.2 and 71.0 and 68.4 and 68.2 and 68.0 and 67.9 (CH
), 68.3 (C ), 67.5 (C ), 60.9 (C ), 54.4 (C17), 52.8 (C27), 49.6
25), 40.9 (C12), 38.1 (C52), 29.7 (C16), 29.3 and 28.9 and 27.4
2
O), 69.6
MeOH 1:1) to give the desired product 4a (68 mg, 70%) as a
yellow solid.
a. The rotaxane dimer 4a (R = H) was obtained in 70% yield
(
C
2
4
3
6
(
C
1
and 27.2 and 26.9 and 26.1 (C13 C14 C15 C21 C22 C23 C ), 23.5
24
after 62 h of reaction R (CH Cl /MeOH 9:1): 0.59. H NMR
f
2
2
3
(
C
20), 21.0 and 20.9 and 20.8 and 20.4 (CH
3
CO). HRMS (ESI):
(400 MHz, CD
6.4 Hz, H ), 8.99 (d, 4H, JH7-H8 = 6.4 Hz, H
2H, H ), 7.49 (s, 2H, H ), 7.04-6.79 (m, 14H, H
3
CN, 298 K): δ (ppm) = 9.35 (d, 4H, JH8-H7 =
3
þ
3þ
3
[
M - 3PF
found 931.3714
b. The rotaxane dimer 2b (R = Me) was obtained in 83%
yield. R (CH Cl /MeOH 9:1): 0.46. Ratio of isomers cis/trans
3:57. H NMR (400 MHz, CD CN, 298 K): cis isomer δ (ppm)
= 6.8 Hz, H ), 8.06 (s, 2H, H ), 8.05 (d,
6
]
calcd for [C120
H
174
N
12
O36 3PF
6
]
931.3693,
8
7
), 7.96-7.88 (br t,
H
H H
1
1
18
29 32 33 41
3
H
H
H ), 6.34 (d, 2H, J
= 9.2 Hz, H ), 5.45 (t, 2H,
4
2
43 44
3
H1-H2 1
3
3
f
2
2
JH3-H2 = JH3-H4 = 3.5 Hz, H ), 5.27 (dd, 2H, JH2-H1 = 9.2
3
1
3 3
2
4
=
3
Hz, JH2-H3 = 3.5 Hz, H
), 5.00 (dd, 2H, JH4-H3 = 3.5 Hz,
3
3
8.97 (d, 4H, J
J
H4-H5
= 1.6 Hz, H ), 5.02-4.92 (m, 2H, H ), 4.40-4.25 (m,
H7-H8
7
18
4
6
3
3
4
H, JH8-H7 = 6.7 Hz, H
8
), 7.03-6.86 and 6.74-6.63 (m, 4H,
26), 6.87-6.71 (m, 12H, H29 44), 6.45 (d, 2H,
),
= 3.5 Hz, H ), 5.22 (dd, 2H,
6H, H
(m, 18H, H
3.25-2.96 (m, 20H, H12
7.3 Hz, H ), 2.16 and 2.12 and 2.00 and 1.84 (4*s, 24H,
5
H
27), 4.21 (t, 4H, JH17-H16 = 7.0 Hz, H17), 4.17-3.99
51), 3.80-3.50 (m, 20H, CH O),
O), 2.61 (t, 4H, JH20-H21 =
H
H
33
H
41
H
42
H
43
H
6
0
H
34
H
39
H
46
H
2
3
3
3
J
H32-H33 = 8.4 Hz, H32), 6.34 (d, 2H, JH1-H2 = 8.9 Hz, H
1
H
25 CH
2
3
3
5
.58 (t, 2H, J
= J
H3-H2
H3-H4
3
20
3
3
J
H2-H1 = 8.9 Hz,
J
J
H2-H3 = 3.5 Hz, H
H4-H5 = 2.2 Hz, H
2
4
), 5.11 (dd, 2H,
), 4.80 (dd, 2H,
CH
3
CO), 1.73-1.64 (m, 4H, H16), 1.63-1.53 (m, 4H, H21),
3
3
3
J
H4-H3 = 3.5 Hz,2
1.44 (s, 18H, H ), 1.49-1.37 (m, 4H, H ),1.36-1.18 (m, 8H,
2
6
24
13
J
= 8.6 Hz, J
0
= 12.8 Hz, H ), 4.60-4.54 (m,
H
H ), 1.16-1.01 (m, 12H, H
13 14 15
H ). JMOD C NMR
H
H6-H5
H6-H6
6
22 23
3
2
H, H ), 4.60-4.40 (m, 4H, H ), 4.45 (t, 4H, J
= 7.3
(100 MHz, CD CN, 298 K): δ (ppm) = 171.7 and 170.2 and
5
27
H17-H16
3
Hz, H17), 4.33-4.25 (m, 2H, H
4
H ), 3.04 (s, 6H, H ), 2.69-2.61 (br t, 4H, H ), 2.20 and 2.16
and 2.02 and 1.90 (4*s, 24H, CH
1
6
0
), 4.22-3.64 (m, 48H, CH
2
O),
170.0 and 169.8 (COCH ), 163.0 (C ), 152.3 and 148.7 and
3
10
.08 (s, 6H, H ), 3.50-3.41 (m, 4H, H ), 3.14-3.07 (br t, 4H,
9 19
148.6 and 148.5 and 148.4 and 147.6 (C C C30 C31 C40 C45
NCOO), 142.8 (C ), 133.2 (C ), 130.2 (C ), 122.5 and 122.3 and
7 28 8
52
25
1
2
11
20
3
CO), 2.00-1.90 (m, 4H, H16),
122.1 and 121.1 and 112.8 and 112.7 and 112.5 and 112.5 (C29
C32 C33 C41 C42 C43 C ), 88.6 (C ), 79.9 (C ), 79.0 (C(CH ) ),
.79-1.70 (m, 4H, H24), 1.63-1.50 (m, 4H, H13
H
21), 1.49-1.35
44
1
5
3 3
(
H
H
m, 8H, H14 H ), 1.34-1.25 (m, 4H, H ), 1.22-1.13 (m, 4H,
71.3 and 71.0 and 70.5 and 70.3 and 70.1 and 69.7 and 69.6 and
69.3 and 69.2 and 69.1 and 69.0 (CH O), 68.8 (C ), 68.2 (C ),
23
15
3
22); trans isomer δ (ppm) = 8.98 (d, 4H, JH7-H8 = 6.8 Hz,
), 8.09 (s, 2H, H18), 8.07 (d, 4H, JH8-H7 = 6.1 Hz, H
2
2
4
3
7
8
), 7.03-
67.3 (C ), 60.3 (C ), 50.5 (C ), 50.4 (C ), 47.3 (C ), 40.6 (C ),
3 6 17 27 25 12
6.86 and 6.74-6.63 (m, 4H, H26), 6.87-6.71 (m, 12H, H29
H41
H
33
= 8.4 Hz, H ), 6.34 (d,
30.7 and 30.1 and 29.4 and 29.4 and 27.2 and 26.5 (C13 C14 C15
C16 C21 C22 C23 C ), 26.0 (C ), 27.4 ((CH ) C), 21.0 and 20.9
3
H ), 6.45 (d, 2H, J
H
H
42
43 44
H32-H33 32
24
20
3 3
3
3
3
4þ
2
3
H, JH1-H2 = 8.9 Hz, H
.5 Hz, H
1
3
), 5.58 (t, 2H, JH3-H2 = JH3-H4
=
and 20.8 and 20.7 (CH CO). HRMS (ESI): [M - 2PF þ 2H]
4þ
128 184 12 40
3
6
3
3
), 5.23 (dd, 2H, JH2-H1 = 8.9 Hz, JH2-H3 = 3.5 Hz,
calcd for [C
H
N O ] 632.3150, found 632.3179.
3
3
H
2
), 5.11 (dd, 2H, JH4-H3 = 3.5 Hz, JH4-H5 = 2.2 Hz, H
4
),
b. The rotaxane dimer 4b (R = Me) was obtained in 75%
yield after 16 days of reaction. R (CH Cl /MeOH 9:1): 0.59.
Ratio of isomers cis/trans 47:53. H NMR (400 MHz, CD CN,
3
J
2
4
.81 (dd, 2H,
= 9.0 Hz,
J
0
= 12.8 Hz, H6),
H6-H5
H6-H6
f
2
2
1
4
J
(
3
.60-4.54 (m, 2H, H
5
), 4.60-4.40 (m, 4H, H27), 4.51 (t, 4H,
H17-H16 = 7.3 Hz, H17), 4.33-4.25 (m, 2H, H ), 4.22-3.64
m, 48H, CH O), 4.09 (s, 6H, H ), 3.54-3.45 (br t, 4H, H ),
3
3
0
298 K): cis isomer δ (ppm) = 9.92-9.82 (br s, 4H, H ), 8.01 (d,
6
7
3
4H, J
H29 H32 H33
5.50-5.38 (m, 2H, H ), 5.17 (t, 2H, J
2
52
12
H8-H7
= 5.7 Hz, H ), 7.45 (s, 2H, H ), 7.10-6.70 (m, 14H,
8
18
.50-3.41 (m, 4H, H ), 2.86 (s, 6H, H ), 2.69-2.61 (br t, 4H,
H
H
H
H ), 6.35 (s, 2H, H ), 5.90 (br s,2H, H ),
2
5
11
41 42 43 44
1
2
3
3
= J = 8.0 Hz,
H
20), 2.20 and 2.16 and 2.01 and 1.90 (4*s, 24H, CH
3
CO),
3
H4-H3
H4-H5
2
4
.00-1.90 (m, 4H, H16), 1.79-1.70 (m, 4H, H24), 1.70-1.63 (m,
H, H ), 1.63-1.50 (m, 4H, H ), 1.49-1.35 (m, 12H, H
H ), 4.39-4.20 (m, 6H, H H ), 4.20-4.07 (m, 4H, H H
0
),
4
5
17
6
6
H
14 15
4.39-3.83 (m, 20H, H
27 34 39 46 51
H H H
H ), 3.81-3.51 (m, 16H,
13
21
1
3
H
CD
(
1
1
23), 1.22-1.13 (m, 4H, H22). JMOD C NMR (100 MHz,
CN, 298 K): δ (ppm) = 171.5 and 170.3 and 170.0 and 170.0
COCH ), 165.7 and 165.6 (C10), 156.7 and 156.5 (C ), 148.7 and
47.1 and 146.9 and 145.5 (C19 C30 C31 C32 C40 C ), 144.1 and
35 38 47 50
H H H H ), 3.51-3.33 and 3.21-3.02 (m, 16H, H H H
36 37 48
3
H ), 3.21-3.02 (m, 8H, H H ), 3.01 (s, 6H, H ), 2.65-2.53 (m,
49
12 25
11
3
9
20 3
4H, H ), 2.12 and 1.81 and 1.78 and 1.76 (4*s, 24H, CH CO),
45
1.88-1.73 (m, 4H, H ), 1.43 (s, 18H, H ), 1.63-1.05 (m, 28H,
16
26
44.0 (C
7
), 128.4 (C18), 127.0 and 126.9 (C
8
), 126.2 (C28), 123.5
H
H H H H H H ); trans isomer δ (ppm) = 9.95 (d,
1
3
14 15 21 22 23 24
3
4H, J
3
= 5.8 Hz, H ), 8.05 (d, 4H, J
and 121.6 and 114.1 and 113.0 and 112.7 and 112.7 (C29
44), 89.1 (C ), 78.4 and 78.4 (C ), 72.9 and 72.9 and
1.4 and 71.3 and 71.2 and 71.0 and 68.4 and 68.1 and 68.0 and
7.9 (CH O), 69.7 and 69.6 (C ), 68.2 (C ), 67.5 (C ), 61.0 and
1.0 (C ), 54.4 and 54.3 (C17), 52.8 (C27), 51.3 (C12cis), 47.8
C
32
C
33
= 5.8 Hz, H8),
H7-H8
7
H8-H7
C
41
C
42
C
43
C
1
5
7.48 (s, 2H, H ), 7.15-6.70 (m, 14H, H H32 H33 H41 H42 H43
18
29
7
6
6
H ), 6.35 (s, 2H, H ), 5.95 (br s, 2H, H ), 5.50-5.38 (m, 2H, H ),
4
4
1
3 3
H4-H3
2
3
2
2
4
3
5.17 (t, 2H, J
= J
H4-H5
= 8.0 Hz, H ), 4.39-4.20 (m, 6H,
4
H H ), 4.20-4.07 (m, 4H, H H ), 4.39-3.83 (m, 20H, H H
5
17
6
6
0
27 34
6
(
C12trans), 49.6 (C ), 38.1 (C ), 37.0 (C11trans), 32.7 (C11cis), 29.7
25
H
39 46 51
H
H ), 3.81-3.51 (m, 16H, H
H
H
H ), 3.51-3.33
52
35 38 47 50
and 29.6 and 28.9 and 28.9 and 28.2 and 27.4 and 27.2 and 26.9
and 26.9 and 26.6 and 26.2 (C13
3.5 (C20), 21.0 and 20.8 and 20.8 and 20.8 and 20.5 and 20.5
and 3.21-3.02 (m, 16H, H36
H
H48 H ), 3.51-3.33 (m, 4H,
37
49
C
14
C
15
C
16
C
21
C
22
C
23
C24),
H ), 3.21-3.02 (m, 4H, H ), 2.82(s,6H, H ), 2.65-2.53 (m, 4H,
12
25
11
2
20 3
H ), 2.12 and 1.81 and 1.78 and 1.76 (4*s, 24H, CH CO),
4
þ
(CH CO). HRMS (ESI): [M - 4PF ] calcd for [C122H178N -
O36 2PF ] 669.2938, found 669.2930.
1.88-1.73 (m, 4H, H ), 1.43 (s, 18H, H ), 1.63-1.05 (m, 28H,
3
6
12
16
26
4
þ
13
6
H
13
H
14
H
15
H
21
H
22
H
23 24
H ). JMOD C NMR (100 MHz,
2.3. Rotaxane Dimers 4a and 4b. In a typical procedure,
Boc O (120 mg, 0.550 mmol, 16 equiv) and DIEA (36 mg,
CD CN, 298 K): δ (ppm) = 171.0 and 170.3 and 169.9 and 169.8
3
2
and 169.7 (COCH
148.4 and 148.1 and 147.5 (C19
(C ), 133.0 (C ), 125.6 and 125.0 (C ), 122.0 (C ), 122.2 and
3 9
), 166.8 (C10), 153.6 and 153.3 (C ), 148.5 and
0.275 mmol, 8 equiv) were added to a solution of 1a (100 mg,
0.0344 mmol, 1 equiv) in 1 mL of dry acetonitrile. After 62 h at
30 31 40
C C C C45 NCOO), 147.7
7
28
8
18
rt, the solvent was evaporated, and the mixture was dissolved in
0 mL of dichloromethane. The organic layer was washed twice
with 10 mL of an aqueous solution of HCl 1 M and twice with
0 mL of a NaHCO saturated aqueous solution. The aqueous
121.0 and 113.3 and 113.2 and 113.0 and 112.9 (C29
44), 93.4 and 92.9 (C ), 79.9 (C ), 72.7 and 72.5 and 71.3
and 71.2 and 69.4 and 69.3 and 69.2 (CH O), 68.8 (C ), 68.8 (C ),
66.5 (C ), 61.6 (C ), 51.5 (C12cis), 47.4 (C12trans), 50.4 and 50.3
32 33 41
C C C
1
C
42
C
43
C
1
5
2
2
3
1
3
4
6
6
530 J. Org. Chem. Vol. 75, No. 19, 2010

Romuald et al.
JOCArticle
(
C ), 50.3(C ), 47.4 (C ), 37.1(C11trans), 32.6(C11cis), 30.7 (C16),
27
1.69-1.55 (m, 8H, H H ), 1.43 (s, 18H, H ), 1.54-1.09 (m,
17
25
13 21
26
30.2 and 30.1 and 29.5 and 29.4 27.2 and 27.1 and 27.0 and 26.8
and 26.7 and 26.6 (C13
14 15 22 23
H H H H H24); trans isomer δ (ppm) = 9.01 (d, 4H,
3
C
14
C
15
C
21
C
22
C
23
C24), 28.6 (C26), 26.1
J
H7-H8 = 6.7 Hz, H
7
), 8.77-8.57 (br s, 2H, H18), 8.05 (d, 4H,
3
and 26.0 (C ), 20.8 and 20.6 (CH CO). HRMS (ESI): [M - 2PF
J
= 6.7 Hz, H ), 6.98-6.64 (m, 14H, H H32 H33 H41
2
0
3
6
H8-H7
42 43 1
H44), 6.40 (d, 2H, JH1-H2 = 8.8 Hz, H ), 5.57 (t, 2H,
3 3
8
29
4þ
4þ
3
þ 2H] calcd for [C130
H N
188 12
O
40
]
639.3262, found 639.3235.
.4. Rotaxane dimer 5a. The rotaxane dimer 5a was obtained
H
H
3
2
in 96% yield from 4a using the typical methylation procedure
JH3-H2 = JH3-H4 = 3.5 Hz, H ), 5.23 (dd, 2H, JH2-H1 = 8.8
3
3 3
2
Hz, JH2-H3 = 3.5 Hz, H
), 5.12 (dd, 2H, JH4-H3 = 3.5 Hz,
3
described in section 2.2.
R
2
8
2
J
= 2.2 Hz, H ), 5.06-4.86 (br s, 4H, H ), 4.81 (dd, 2H,
H4-H5
2
4
17
1
/MeOH 9:1): 0.33. H NMR (400 MHz, CD
3
(CH
2
Cl
2
3
CN,
JH6-H5 = 9.0 Hz, JH6-H6
0
= 12.8 Hz, H
6
), 4.60-4.53 (m, 2H,
f
3
98 K): δ (ppm) = 9.02 (d, 4H, JH7-H8 = 6.9 Hz, H
7
), 8.75-
H
5
), 4.33-4.25 (m, 2H, H
6
0
), 4.33-4.16 (m, 4H, H27), 4.15-3.89
.63 (br s, 4H, H ), 8.55-8.44 (br s, 2H, H ), 7.79-7.72 (br t,
(m, 16H, H H ), 3.87-3.71 (m, 16H, H
H
39
H
46
H
38 47
H ), 3.67 (s, 6H, H ),
H
8
18
34
51
35
H, H ), 6.94-6.66 (m, 14H, H
H
H
H
H
H
H ),
=
H ), 3.71-3.46 (m, 16H, H
H
H
11
29
32
33
41
42
43
44
50
36 37 48 49 52
3
3
6
.37 (d, 2H, JH1-H2 = 9.1 Hz, H
1
), 5.53 (t, 2H, JH3-H2
3.46-3.39 (br t, 4H, H12), 3.19-3.04 (m, 4H, H25), 2.82 (s, 6H,
3
3
J
H3-H4 = 3.4 Hz, H
3
), 5.24 (dd, 2H,
= 3.4 Hz, H ), 5.08 (dd, 2H,
JH2-H1 = 9.1 Hz,
H11), 2.79-2.68 (m, 4H, H20), 2.21 and 2.16 and 2.01 and 1.90
3
3
2
3
3
J
J
J
J
= 3.4 Hz,
(4*s, 24H, CH CO), 2.00-1.90 (m, 4H, H ), 1.69-1.56 (m, 8H,
H2-H3
2
H4-H3
3
16
H4-H5 = 1.9 Hz, H
= 12.8 Hz, H
), 4.35-4.17 (m, 4H, H27), 4.21 (dd, 2H,
4
), 4.88 (dd, 2H,
J
H6-H5 = 9.5 Hz,
H
H
13 15 22 23
H21), 1.43 (s, 18H, H26), 1.54-1.09 (m, H14 H H H
13
0
), 4.81-4.68 (br s, 4H, H17),
24). JMOD C NMR (100 MHz, CD
CN, 298 K): δ (ppm) =
), 165.7
and 165.5 (C ), 156.7 and 156.5 (C ), 148.7 and 148.7 and 148.6
H6-H6
6
3
4
.53-4.47 (m, 2H, H
5
171.5 and 171.5 and 170.3 and 170.1 and 170.0 (COCH
3
3
2
J
0
= 3.4 Hz, J
0
= 12.8 Hz, H
0
), 4.34-3.93 (m,
H6 -H5
6H, H34
H6 -H6
6
10
9
1
3
3
2
H
H
1
H
39
H
46
H
51), 4.83-3.58 (m, 16H, H35
H
38
H
H
47
H
H
50),
49),
and 148.6 and 148.5 and 148.4 and 147.7 (C19
30 31 32 40
C C C C
.75 (s, 6H, H52), 3.50-3.14 (m, 24H, H12
H
25
H
36
H
37
48
C
(C ), 122.4 and 122.3 and 121.6 and 115.1 and 112.5 and 111.9
45 NCOO), 144.1 (C ), 132.4 (C28), 129.4 (C18), 127.0 and 126.9
7
.14-3.03 (br s, 4H, H ), 2.18 and 2.11 and 1.99 and 1.86 (4*s,
2
0
8
4H, CH CO), 2.12-2.00 (m, 4H, H ), 1.56-1.37 (m, 12H, H
(C29 C32 C33 C41 C42 C43 C ), 89.1 and 89.0 (C ), 80.0
44
3
16
13
1
21
H
24), 1.43 (s, 18H, H26), 1.36-1.10 (m, 16H, H14
H
15
H
22
3 3 5
(C(CH ) ), 78.5 and 78.5 (C ), 71.9 and 71.7 and 71.2 and 70.8
1
3
23). JMOD C NMR (100 MHz, CD
3
CN, 298 K): δ (ppm) =
and 70.6 and 70.3 and 70.2 and 69.8 and 69.4 and 69.1 and 69.0
and 68.9 (CH O), 69.7 and 69.6 (C ), 68.2 (C ), 67.5 (C ), 61.1
71.7 and 170.3 and 170.0 and 169.9 (COCH ), 162.6 (C ),
C
3
10
2
2
4
3
1
52.8 (C
9
), 148.7 and 148.6 and 148.5 and 147.7 (C19
C
30
31
C
40
(C
47.0 (C25), 38.1 (C52), 37.1(C11trans), 32.8 (C11cis), 28.7
(C(CH ), 27.4 and 27.3 and 27.0 and 26.9 and 26.9 and 26.2
and 23.6 and 23.6 and 23.3 (C13 C14 C15 C16 C21 C22 C23 C24),
23.2 (C20), 21.0 and 20.9 and 20.8 and 20.6 and 20.5 (CH CO).
6
), 54.3 and 54.2 (C17), 51.4 (C12cis) 48.0 (C12trans), 50.0 (C27),
C
45 NCOO), 143.7 (C
and 112.5 and 111.9 (C29
C(CH ) ), 78.8 (C ), 71.4 and 71.2 and 70.7 and 70.5 and 69.1
7
), 132.6 (C28), 128.3 (C
8
), 121.8 and 112.7
C
32
C
33
C
41
C
42
C
43
C
44), 88.9 (C ), 80.0
1
3 3
)
(
3
3
5
and 69.0 and 68.9 (CH
), 54.3 (C17), 50.0 (C25), 49.1 (C27), 40.8 (C12), 37.3 (C52), 29.5
and 27.0 and 26.5 (C13 24), 28.7 (C26),
3.4 (C ), 21.0 and 20.9 and 20.8 and 20.6 (CH CO). HRMS
2
2 4 3
O), 69.4 (C ), 68.2 (C ), 67.4 (C ), 60.7
3
(
C
6
2.6. Reprotonation Procedure of Rotaxane Dimers 4a,b and 5a,
b. In a typical procedure, the rotaxane dimer 4a (12 mg,
C
14
C
15
C
16
C
21
C
22
C
23
C
-
6
2
4.26.10
mol) was suspended in 1 mL of a solution of
20
3
4þ
4þ
639.3262,
(
ESI): [M - 4PF
found 639.3242.
.5. Rotaxane Dimer 5b. The rotaxane dimer 5b was obtained
6
]
calcd for [C130
H
188
N
12
O
40
]
HCl (2 M) in diethyl ether and stirred for 30 min at room
temperature. After evaporation, the solid was washed with
-
5
2
diethyl ether. Then, NH PF (3.5 mg, 2.130.10 mol, 5 equiv)
4 6
in 91% yield from 4b using the typical methylation procedure
described in section 2.2. It could be as well obtained in a 73%
yield from 2b after 5 days using the typical carbamoylation
procedure described in section 2.3. R (CH Cl /MeOH 9:1):
and 1 mL of dichloromethane were added to a suspension of the
previous product in 1 mL of Milli-Q water. The resulted bilayer
solution was vigorously stirred for 30 min. After separation, the
aqueous layer was extracted with 5 mL of dichloromethane. The
organic layers were combined, dried over MgSO , and concen-
4
trated to obtain the rotaxane dimer 1a (11 mg, 89%) as a yellow
solid.
f
2
2
1
0
CD
.64. Ratio of isomers cis/trans 42:58. H NMR (400 MHz,
3
3
CN, 298 K): cis isomer δ (ppm) = 9.01 (d, 4H, JH7-H8
=
=
3
6
6
6
.7 Hz, H
7
), 8.77-8.57 (br s, 2H, H18), 8.03 (d, 4H, JH8-H7
.7 Hz, H ), 6.98-6.64 (m, 14H, H H32 H33 H41
.42 (d, 2H, JH1-H2 = 8.8 Hz, H
H3-H4 = 3.5 Hz, H
H H43 H44),
42
8
29
3
3
1
), 5.57 (t, 2H, JH3-H2
=
Acknowledgment. This research was supported by the
Ligue National Contre le Cancer (LNCC). We thank Professor
Jean Martinez (Director of the Institut des Biomol ꢀe cules Max
Mousseron) for his help in finding Doctoral Fellowship and for
support.
3
3
J
J
J
3
), 5.21 (dd, 2H,
= 3.5 Hz, H ), 5.12 (dd, 2H,
JH2-H1 = 8.8 Hz,
3
3
3
J = 3.5 Hz,
H4-H3
H2-H3
2
= 2.2 Hz, H ), 5.06-4.86 (br s, 4H, H ), 4.82 (dd,
H4-H5
4
2
17
3
2
2
4
H, JH6-H5 = 8.8 Hz, JH6-H6
H, H
0
= 12.8 Hz, H
), 4.33-4.25 (m, 2H, H
.15-3.89 (m, 16H, H
6
), 4.60-4.53 (m,
0
), 4.33-4.16 (m, 4H, H27),
5
6
H
39
H46 H ), 3.87-3.71 (m, 16H,
50), 3.71-3.46 (m, 16H, H36
3
4
51
H
35
H
38
H
47
H
H
37
H
48
H49), 3.67 (s,
Supporting Information Available: Characterization data
with full experimental procedures for starting materials, mono-
mers, and [c2]daisy chains. This material is available free of
charge via the Internet at http://pubs.acs.org.
6
3
H, H52), 3.19-3.04 (m, 4H, H25), 3.06-2.96 (br t, 4H, H12),
.00 (s, 6H, H11), 2.79-2.68 (m, 4H, H20), 2.21 and 2.12 and 1.99
and 1.88 (4*s, 24H, CH CO), 2.00-1.90 (m, 4H, H ),
3
16
J. Org. Chem. Vol. 75, No. 19, 2010 6531