Copper(i)-induced amplification of a [2]catenane in a virtual dynamic library of macrocyclic alkenes

Article abstract of DOI:10.1039/c4ob01009d

Olefin cross-metathesis of diluted dichloromethane solutions (≤0.15 M) of the 28-membered macrocyclic alkene C₁, featuring a 1,10-phenanthroline moiety in the backbone, as well as of catenand 1, composed of two identical interlocked C₁

Full text of DOI:10.1039/c4ob01009d

Organic &
Biomolecular Chemistry
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Copper(I)-induced amplification of a [2]catenane
in a virtual dynamic library of macrocyclic alkenes†
Cite this: Org. Biomol. Chem., 2014,
12, 6167
José Augusto Berrocal,a,b Marko M. L. Nieuwenhuizen,b Luigi Mandolini,a
E. W. Meijerb and Stefano Di Stefano*a
Olefin cross-metathesis of diluted dichloromethane solutions (≤0.15 M) of the 28-membered macrocyclic
alkene C1, featuring a 1,10-phenanthroline moiety in the backbone, as well as of catenand 1, composed
of two identical interlocked C1 units, generates families of noninterlocked oligomers Ci. The composition
of the libraries is strongly dependent on the monomer concentration, but independent of whether C1 or 1
is used as feedstock, as expected for truly equilibrated systems. Accordingly, the limiting value 0.022 M
approached by the equilibrium concentration of C1 when the total monomer concentration approaches
the critical value, as predicted by the Jacobson–Stockmayer theory, provides a reliable estimate of the
thermodynamically effective molarity. Catenand 1 behaves as a virtual component of the dynamic
libraries, in that there is no detectable trace of its presence in the equilibrated mixtures, but becomes the
major component – in the form of its copper(I) complex – when olefin cross-metathesis is carried out in
the presence of a copper(I) salt.
Received 15th May 2014,
Accepted 20th June 2014
DOI: 10.1039/c4ob01009d
www.rsc.org/obc
inter alia, by their use in the construction of molecular
Introduction
Dynamic combinatorial chemistry (DCC)1 is a powerful tool for
switches and machines5 for a great variety of functions.
Statistical syntheses of catenanes were of little practical sig-
the synthesis of receptors under thermodynamic control. nificance,6 but the pioneering work of Sauvage7 clearly showed
Efficient receptors may be selected among a family of intercon- that synthetically useful quantities of simple catenanes and
verting members of a dynamic library (DL) upon the addition higher order interlocked macrocycles are easily obtained by
of a suitable template via repeatedly occurring bond dis- metal templation. Since then, hundreds of new [2]catenanes
sociation–recombination processes. A major motivation for have appeared in the literature. Although templating by metal
the intense work dedicated to this research field is the ability ions is commonly used to achieve the synthesis of [2]cate-
of the system to select and produce a good receptor, which nanes, other kinds of intermolecular interactions have been
sometimes is only virtually present,2 i.e. not present at all in exploited as well to direct the closure of the two interlocked
the initial reaction mixture.
cycles into the right topology.8 Very recent developments in
[2]Catenanes are the most popular interlocked systems as the field of DCC have opened the way for templated syntheses
witnessed by the high number of review articles3 and book of [2]catenanes under equilibrium conditions. In a number of
chapters4 devoted to them. They consist of two distinct rings cases catenanes have been isolated as the response of systems
joined together by a mechanical bond, topologically called the to the addition of templates,9 and even self-templated synth-
Hopf link.3c The wide interest in [2]catenanes is motivated, eses of catenanes under equilibrium conditions have also been
reported.10 Thus, DCC provides an alternative access to inter-
locked macrocycles that are generally obtained under kinetic
control.
aDipartimento di Chimica, Sapienza Università di Roma and Istituto CNR di
In our previous studies we have extensively investigated DLs
Metodologie Chimiche (IMC-CNR), Sezione Meccanismi di Reazione, c/o
of macrocycles generated by acid-catalyzed transacetalation of
Dipartimento di Chimica, Sapienza Università di Roma, P.le A. Moro 5, I-00185
cyclophane formaldehyde acetals.11 Many other types of reac-
Rome, Italy. E-mail: stefano.distefano@uniroma1.it
bInstitute for Complex Molecular Systems, Eindhoven University of Technology,
tions can be used for the production of DLs of macrocycles,
among which olefin metathesis plays the most important
role.12
Here, we report our investigations of the fully reversible
ring-opening metathesis13 of dilute dichloromethane solutions
of the 28-membered macrocyclic alkene C1, and the copper(I)-
P.O. Box 513, 5600 MB Eindhoven, The Netherlands
†Electronic supplementary information (ESI) available: 1H NMR and 13C NMR
spectra of new compounds, 2D NMR spectra of 1 and 1·Cu+, stacks of spectra of
the equilibration experiment at 5 mM cmon (Fig. ESI 1) and of selected equili-
bration experiments starting either from C1 or 1 (Fig. ESI 2). See DOI: 10.1039/
c4ob01009d
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induced amplification of the [2]catenane dimer 1. The latter
is totally absent in the reaction mixtures equilibrated in the
absence of copper(I).
Fig. 1 1H NMR spectra of (a) 1·Cu+ and (b) 1 in CD2Cl2 at 25 °C.
protons d, j, vCH and Ha, each pair of signals being in the
ratio of 7 : 1. Pairs of signals are also visible in the less resolved
spectrum of 1 for protons j, vCH, Hb and Hc. Thus, it is likely
that the synthesized catenanes are unresolved mixtures of the
three diolefin isomers EE, EZ and ZZ.
Results and discussion
Synthesis of C1 and 1
The high-field shifts experienced by methylene protons d,
c, e, f and g of 1·Cu+ (Fig. 1) are indicative for the shielding
effect of the phenanthroline moiety of the other interlocked
macrocycle. Also ROE interactions of methylene protons e–j
with aromatic protons Ha and Hc (page ESI 12†) provide strong
indications of the existence of a catenane topology in com-
pound 1·Cu+.
Treatment of 2,9-dimethyl-1,10-phenanthroline (neocuproine)
with 2 mol equiv. of lithium diisopropylamide (LDA), followed
by alkylation with 11-bromoundecene gave the building block
2 in 63% yield (eqn (1)). Ring-closing metathesis (RCM) of
10 mM 2 in CH2Cl2 in the presence of 5 mol% first generation
Grubbs’ catalyst G1 afforded the macrocycle C1 in 79% yield
(eqn (2)).
X-ray analysis on crystals of 1·Cu+, as obtained by slow
diffusion of methanol into a concentrated acetonitrile solu-
tion, was unfortunately not successful.
The confirmation of the interlocked structure of 1 was
obtained from a series of Mass/Mass Collision-Induced Dis-
sociation (MS/MS CID) experiments15 carried out at increasing
collision energy using our ESI-TOF equipment (Fig. 2). The
sole fragment derived from the mass-selected ion, m/z 991
(C68H96N4 + Na+), up to a collision potential as high as 70 V, is
the one at m/z 507 (C34H48N2 + Na+), corresponding to the Na+
complex of the cyclic monomer C1. The latter is most likely
derived from the catenane by the rupture of one covalent
bond, followed by dethreading of the linear fragment of
a labile pseudorotaxane assembly. This behavior is clearly
inconsistent with the dimeric structure of C2, an isomer of 1,
because its fragmentation could hardly produce a single
ion fragment with an m/z value exactly corresponding to its
half.
ð1Þ
5 mol% G1
2 ꢀꢀꢀꢀꢀꢀ! C1
ð2Þ
CH2Cl2
The copper(I) catenate 1·Cu+ was synthesized in 92% yield
via a double RCM of 10 mM (2)2·Cu+ in CH2Cl2 in the presence
of 5 mol% G1 (eqn (3)). Cyanide-induced demetallation of
1·Cu+ afforded catenand 1 in quantitative yield (eqn (4)).
5 mol% G1
ð2Þ2 ꢁ Cuþ ꢀꢀꢀꢀꢀꢀ! 1 ꢁ Cuþ
ð3Þ
ð4Þ
CH2Cl2
KCN
1 ꢁ Cuþ ꢀꢀꢀ! 1
The 1H NMR spectra of 1·Cu+ and 1 are shown in Fig. 1.
Assignment of all methylene proton signals of both com-
pounds was carried out on the basis of 1D-TOCSY, 2D-COSY
and 2D-ROESY experiments (pages ESI 11–13 for 1·Cu+ and
Equilibration experiments under olefin metathesis conditions
pages ESI 16–17† for 1). The more resolved spectrum of 1·Cu+, In a first set of experiments, metathesis of a number of CD2Cl2
in line with the expected mixture of E and Z configurations of solutions of C1 in the concentration range from 10 to 150 mM
the double bond,14 shows two distinct sets of signals for was initiated by addition of
3 mol% second-generation
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Fig. 3 ESI-TOF mass spectrum obtained from equilibrated reaction
mixture of 60 mM cmon starting from C1 (m/z of [Ci + H+] = [i × 484]+1).
Fig. 2 CID experiments at increasing collision energy (from 30 to 90 V)
were carried out on selected peak 1·Na+ (m/z = 991). Peak at m/z = 507
corresponds to the cyclic monomer C1·Na+.
Grubbs’ catalyst G2 at 30 °C. The more robust and catalytically
active G2 was preferred to G1 for increasing the chance to
achieve true equilibrium conditions.16,17 Occasional monitor-
ing of the 1H NMR spectra of the reaction mixtures showed
that after 24 hours equilibrium was reached in all cases. The
ESI-TOF MS spectrum of a typical reaction mixture (Fig. 3)
revealed the presence of
a family of cyclic oligomers,
whose intensities declined progressively with increasing ring
size.
Scheme 1 Ring-opening of one of the two rings of 1 affords a labile
pseudorotaxane intermediate (3·C1). Dissociation of the latter is followed
Catenand 1 (from 2.5 to 50 mM) was the reactant in a
second set of metathesis experiments carried out under
otherwise identical conditions. Interestingly, the most dilute
solution afforded a quantitative transformation of 1 into its
unthreaded macrocyclic component C1 (Fig. ESI 1†), most
likely via the open chain metal–alkylidene intermediate 3, as
schematically depicted in Scheme 1.
Mixtures of increasing complexity were obtained at higher
concentrations, whose 1H NMR spectra (Fig. ESI 2†) turned out
to be indistinguishable from those of the reaction mixtures
derived from C1. This was expected for a truly reversible
system, whose composition at equilibrium should be indepen-
dent of the oligomer used as feedstock, but solely dependent
on the total concentration of monomer units, cmon. No signal
ascribable to catenand 1 was detected in the spectra of the
equilibrates in the whole range of cmon values (Fig. ESI 2†),
showing that catenand 1 is thermodynamically unstable with
by the exclusive ring-closure of 3 in an extremely dilute solution (cmon
2 × [1]0 = 5 mM).
=
respect to the mixture of unlocked macrocyclic members of
the DLs generated by metathesis of either C1 or 1.
It is unfortunate that all attempts at analyzing the reaction
mixtures by gel permeation chromatography failed and
reversed-phase HPLC analysis was prevented by solubility pro-
blems. However, deconvolution and integration of the aro-
matic singlet at δ = 7.72 (Fig. ESI 2†) allowed at least the
determination of the equilibrium concentration of C1 as a
function of the concentration of monomer units cmon
(Table 1).
The distribution of cyclic and linear polymers in ring-chain
equilibria is ruled by the Jacobson–Stockmayer (J–S) theory.18
Accordingly, the concentration of each cyclic species increases
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Table 1 Concentrations of C1 in the equilibrated mixtures obtained
from C1 or catenand 1
Starting material
cmona (mM)
[C1] (mM)
1
1
5.0
10
5.0
9.1
C1
1
C1
C1
1
1
C1
10
15
30
50
60
100
150
9.1
11.0
16.8
20.5
21.2
22.0
22.1
Scheme 2 DL of oligomeric macrocycles generated by ring-opening
metathesis of either C1 or 1.
a cmon = [C1]0 or 2 × [1]0.
fitted to a single, smooth curve thanks to the establishment of
true equilibrium conditions.
upon increasing cmon, until a critical value c*mon is reached.
Such a critical concentration is a real cut-off point, below
which the system is composed of cyclic species only, and
above which the total monomer concentration of cyclic species
remains constant, eqn (5),19 whereas the concentration of
linear polymers Pi increases on increasing the total monomer
concentration in excess to c*mon, eqn (6). The limiting value [Ci*]
coincides with the thermodynamically effective molarity EMi
of the given cyclic oligomer.20
The concentration profile in Fig. 4 does not allow the cm* on
value to be obtained with any precision, because [C1]
approaches asymptotically its limiting value. Nevertheless, the
shape of the profile suggests that c*mon should lie somewhere
in the neighborhood of 0.15 M, a value that compares well
with literature data related to macrocyclization equilibria
based on olefin metathesis,22 transacetalation,11,21,23 trans-
esterification,24 and quadruple hydrogen bonding inter-
actions,25 for which cm* on values in the range of 0.13–0.25 M
were reported.
X
i½C*i ꢂ ¼ c*mon
ð5Þ
ð6Þ
The thermodynamically effective molarity of C1, EM1
=
i
0.022 M, compares well with a large body of EM values
reported for the formation of large, strainless rings of similar
size,26 and this leads to the conclusion that the G2 catalyzed
transformation of C1 into a mixture of cyclic oligomers is a
pure entropy driven reaction, or very nearly so.27
To sum up, well-behaved DLs composed of macrocyclic
oligomers only were obtained upon treatment of either C1 or 1
with G2 at cmon values not exceeding the critical value cm* on
(Scheme 2). Catenand 1 is a virtual component of the DL,
namely, one whose equilibrium concentration is too low to
measure.
X
i½P*i ꢂ ¼ cmon ꢀ cm* on
i
A plot of [C1] against cmon indeed shows a negative curva-
ture (Fig. 4) and a definite tendency to approach a limiting
value in the high concentration region, in full agreement with
the J–S theory. Incidentally, data points could be fitted to a
good precision (rms = 0.17 × 10−3 M) to a simple exponential
function, as found in analogous instances,11b,c,21 although no
theoretical explanation for such a behavior is available at
present. In any event, it is worth noting that the concentration
data derived from two distinct sets of experiments could be
A copper(I)-driven amplification experiment
An important feature of DLs is their ability to readjust the
product distribution dictated by the initial conditions when
the variables that rule the equilibrium change. Notably,
addition of a template, e.g. a metal ion that binds to the
various members of the library with differential affinities, will
strongly perturb the equilibrium composition.
The following two-step experiment was aimed to illustrate
the adaptability of a DL to the equilibrium perturbation
caused by the addition of copper(I), in view of its ability to
form strong tetrahedral complexes of 1 : 2 stoichiometry with
1,10-phenanthroline ligands.28
In the first step a dilute solution of 1 in CD2Cl2 (2.5 mM)
was treated with 3 mol% G2 and left to stand at room tempera-
1
ture for 24 hours. The H NMR spectrum of the final reaction
mixture (Fig. 5b) revealed the presence of the macrocycle C1 as
the sole detectable product, as expected for the limiting com-
position of the DL in the very low concentration domain.
Fig. 4 Concentrations of C1 in the equilibrated reaction mixtures start-
ing either from 1 (crosses) or C1 (yellow dots) (data from Table 1).
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Scheme 3 From catenane to the unlocked macrocycle and back again.
Only the clockwise route is allowed.
increases upon increasing the total monomer concentration
cmon, and approaches a limiting value when cmon approaches
its critical value c*mon. The limiting value of 0.022 M provides a
genuine measure of the thermodynamic EM of C1. This value
indicates that C1 is a strainless ring, or very nearly so. No
visible traces of catenand 1 are found in the equilibrated
mixtures. The thermodynamic sink featured by the strong
complexation with the copper(I) ion results in a tremendous
amplification of 1 under copper(I) ion template action. These
results provide an additional illustration of the potential of
well-behaved DLs, arising from their ability of “proof reading
and editing” via repeated bond dissociations and recombina-
tions, and of amplification of even a virtual component via
strong interaction with a suitable template.
Fig. 5 Partial 1H NMR spectrum of the (b) product of the first step of
the experiment (see text), (c) the product of the second step of the
experiment (see text). 1H NMR spectra of pure C1 (a) and 1·Cu+ (d) are
shown for comparison.
In the second step, (CH3CN)4CuPF6 (2.5 mM) and a fresh
portion of G2 (3 mol %) were added to the above solution. The
1H NMR spectrum, taken after 24 hours (Fig. 5c), showed a
reaction mixture in which catenate 1·Cu+ was the major com-
ponent (60%), accompanied by C1 (13%) and minor presum-
ably copper(I)-complexed unidentified species (27%). It
appears therefore that the dynamic system dramatically read-
justed its composition in response to the presence of the
copper(I) template. It is evident that catenand 1 is the best
binder, most likely on account of the enforced proximity of the
two phenanthroline units. The extra stabilization provided by
metal coordination transforms a thermodynamically unstable,
virtual component of the DL into the most stable metal–ligand
species. Thanks to the adaptability of dynamic systems, the
metal template performs the assembly of the optimal partner,
whose concentration rises from a negligibly low value to 60%
of the available monomeric units. Notably, a catenane struc-
ture is directly obtained from a macrocyclic monoolefin, rather
than from an α,ω-diolefin precursor.14
Experimental section
Instruments and general methods
1D NMR spectra were recorded on either a 300 or 500 MHz
spectrometer. 2D NMR spectra were recorded on a 500 MHz
spectrometer. The spectra were internally referenced to the
residual proton solvent signal. HR-ES mass spectra were
obtained on either an ESI-TOF or a MALDI-TOF spectrometer.
UV-vis spectra were performed on a double-ray spectro-
photometer using a standard quartz cell (light path = 1 cm) at
298 K.
Addition of a third step, namely, the cyanide induced de-
metallation of 1·Cu+ completes the cycle depicted in Scheme 3,
in which any of the three species involved can be used as a
starting point of a clockwise route.
Materials
All reagents and solvents purchased were of the highest com-
mercial quality and were used without further purification,
unless otherwise stated. Deuterated halogen solvents were
flashed through basic alumina immediately prior to use.
Conclusions
General procedure for the untemplated olefin
cross-metatheses
We have shown that ring-opening metathesis of dilute solu-
tions of macrocyclic alkene C1, catalyzed by second-generation Either catenand 1 or cyclic monomer C1 was weighed in
Grubbs’ catalyst G2, yields well-behaved DLs of cyclic oligo- a NMR tube in order to prepare solutions in CD2Cl2 at the
mers Ci that are indistinguishable from those obtained from desired total monomer concentration cmon. To such solutions,
catenand 1 under the same equilibrium conditions. As pre- a calculated volume of a stock solution of 2nd generation
dicted by J–S theory, the equilibrium concentration of C1 Grubbs’ catalyst G2 in CD2Cl2 was added to reach final catalyst
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concentrations of 3 mol%. Reaction runs were monitored by isomers). 1H-NMR (300 MHz, CD2Cl2, δ): 1.18–1.56 (m, 28H),
1H-NMR spectroscopy.
1.83–2.04 (m, 8H), 3.12 (t, J = 8 Hz, 4H), 5.32–5.38 (m, 2H),
7.50 (d, J = 8 Hz, 2H), 7.72 (s, 2H), 8.16 (d, J = 8 Hz, 2H).
13C-NMR (75 MHz, CD2Cl2, δ): 27.14, 28.66, 29.22, 29.24, 29.27,
General procedure for the templated olefin cross-metatheses
Catenand 1 was weighed in a NMR tube in order to prepare 29.29, 29.33, 29.36, 29.57, 29.64, 29.75, 30.07, 30.14, 32.41,
solutions in CD2Cl2 at 5 mM cmon. To such solutions, a calcu- 39.21, 39.26, 122.72, 122.84, 125.52, 127.19, 129.96, 130.59,
lated volume of a stock solution of 2nd generation Grubbs’ 136.43, 162.91. HRMS-ESI TOF (m/z): [M + Na+] calcd for
catalyst G2 in CD2Cl2 was added to reach final catalyst concen- C34H48N2, 507.3715; found, 507.3703. UV-vis (CH2Cl2) λmax, nm
trations of 3 mol%. After the equilibrium was reached, a (ε): 234 (41 657); 271 (24 392); 283 sh (15 970).
weighed amount of the solid Cu(CH3CN)4PF6 was added to
Bis[2,9-di(dodec-11-en-1-yl)-1,10-phenanthroline]copper(I)
(1.5 g,
reach a final template concentration of 2.5 mM. Then, an hexafluorophosphate ((2)2·Cu+). Compound
2
additional portion of a stock solution of the catalyst G2 in 2.93 mmol) was dissolved in CH2Cl2 (50 mL) and the resulting
CD2Cl2 was added (3 mol% again) to ensure the efficiency of solution was degassed by the freeze–pump–thaw technique,
the metathetical process. Reaction runs were monitored by and then a previously degassed solution of [Cu(CH3CN)4]PF6
1H-NMR spectroscopy.
(550 mg, 1.46 mmol) in CH3CN was added to it. The resulting
2,9-Di(dodec-11-en-1-yl)-1,10-phenanthroline
(2). Neo- mixture changed from colourless to red and was kept under
cuproine (6.5 g, 31.2 mmol) was dissolved in dry THF (260 mL) stirring at room temperature for 24 hours, after which the
and the obtained solution was degassed and the temperature solvent was evaporated. The red residue was filtered, washed
was brought to −78 °C. A 1.5 M solution of LDA in cyclohexane with water and dried to afford complex (2)2·Cu+ (red solid,
(42 mL, 63 mmol) was slowly added to this solution at −78 °C. 1.8 g, 1.46 mmol, 100% yield). mp 57.3–58.1 °C. 1H-NMR
After 4 hours, the reaction mixture was brought from −78 °C (300 MHz, CD2Cl2, δ): 0.53–0.69 (m, 16H), 0.74–0.95 (m, 16H),
to 10 °C, and then back to −45 °C. At this temperature, a 1.05–1.27 (m, 16H), 1.31–1.39 (m, 16H), 2.02–2.09 (m, 8H),
degassed solution of BrCH2(CH2)8CHvCH2 (16.3 mL, 2.74 (t, J = 8 Hz, 8H), 4.95–5.06 (m, 8H), 5.79–5.92 (m, 4H),
75 mmol) in dry THF (325 mL) was added in 30 minutes to the 7.80 (d, J = 8 Hz, 4H), 8.06 (s, 4H), 8.53 (d, J = 8 Hz, 4H).
reaction mixture. The reaction mixture was kept at 0 °C for 13C-NMR (75 MHz, CD2Cl2, δ): 28.89, 28.99, 29.15, 29.28, 29.35,
12 hours, after which the reaction was quenched by adding 29.37, 29.40, 29.43, 29.93, 33.87, 40.51, 113.99, 125.01, 126.18,
water until no gas evolution was observed. THF was evaporated 127.90, 137.46, 139.32, 143.32, 162.03. HRMS-ESI TOF (m/z):
and the residue was dissolved in CH2Cl2–H2O 1 : 1. The two [M + Cu+] calcd for C72H104N4, 1087.7557; found, 1087.7584.
phases were separated and the water phase was extracted three UV-vis (CH2Cl2) λmax, nm (ε): 229 (67 490); 243 sh (34 180);
times with CH2Cl2. The organic phases were dried over 276 (55 086); 296 sh (31 730); 459 (6807).
Na2SO4, filtered and evaporated to obtain 19.3 g of the crude
Catenate 1·Cu+. Complex (2)2·Cu+ (1.05 g, 0.85 mmol) was
product (yellow wax), which was subjected to column chromato- dissolved in CH2Cl2 (85 mL) and the resulting solution was
graphy (neutral Al2O3, hexane 100%→hexane–ethyl acetate degassed. 1st generation Grubbs’ catalyst G1 (35 mg,
5 : 1) to give 2 as a white solid, 10 g, 19.5 mmol, 62.5% yield, 0.04 mmol) was then added and the resulting mixture was
recrystallizable from hexane. mp 67.1–67.7 °C. 1H-NMR kept under stirring at room temperature for three days (the
(300 MHz, CDCl3, δ): 1.26–1.43 (m, 28H), 1.80–1.88 (m, 4H), reaction was monitored by ESI-TOF MS). The solution was fil-
1.99–2.06 (m, 4H), 3.17 (t, J = 8 Hz, 4H), 4.89–5.02 (m, 4H), tered through a short path of silica gel and the solution was
5.74–5.85 (m, 2H), 7.53 (d, J = 8 Hz, 2H), 7.72 (s, 2H), 8.18 (d, evaporated to afford complex 1 (orange solid, 920 mg,
J = 8 Hz, 2H). 13C-NMR (75 MHz, CDCl3, δ): 28.89, 29.10, 29.45, 0.76 mmol, 92% yield). mp 268.3–270.1 °C. 1H-NMR
29.49, 29.52 (br), 29.54, 29.75, 33.78, 39.21, 114.04, 122.53, (300 MHz, CD2Cl2, δ): 0.46–0.67 (m, 24H), 0.98–1.05 (m, 8H),
125.48, 127.09, 136.51, 139.21, 144.76, 163.20. HRMS-ESI TOF 1.24–1.48 (m, 28H), 1.73–1.84 (m, 6H), 2.12–2.29 (m, 8H),
(m/z): [M + H+] calcd for C36H52N2, 513.4209; found, 513.4158; 2.65–2.78 (m, 8H), 5.71–5.78 (m, 4H), 7.77 (d, J = 8 Hz, 4H),
[M2 + Na+] calcd for C72H104N4 1047.8183; found, 1047.8129. 8.03 (s, 4H), 8.49 (d, J = 8 Hz, 4H). 13C-NMR (75 MHz, CD2Cl2,
UV-vis (CH2Cl2) λmax, nm (ε): 234 (53 340); 271 (31 200); 283 sh δ): 29.05, 29.39, 29.41, 29.63, 29.73, 29.76, 30.60, 32.07, 33.21,
(19 290).
40.47, 125.08, 126.37, 127.80, 131.03, 137.54, 143.25, 162.07.
Cyclic monomer C1. Compound 2 (400 mg, 0.78 mmol) was HRMS-ESI TOF (m/z): [M + Cu+] calcd for C68H96N4, 1031.6931;
dissolved in CH2Cl2 (78 mL) and the resulting solution was found, 1031.6919. HRMS-MALDI TOF (m/z): [M + Cu+] calcd for
degassed. First generation Grubbs’ catalyst G1 (32 mg, C68H96N4Cu, 1031.6931; found, 1031.6938. UV-vis (CH2Cl2)
0.04 mmol) was then added and the resulting mixture was λmax, nm (ε): 232 (59 630); 244 sh (31 110); 276 (49 210); 293 sh
kept under stirring at room temperature for one day (the reac- (29 310); 324 (4490); 467 (6030).
tion was monitored by ESI-TOF MS). The solution was filtered
Catenand 1. Catenate 1·Cu+ (920 mg, 0.76 mmol) was dis-
through a short path of silica gel and the solution evaporated solved in wet CH3CN (200 mL). Excess KCN (33 g, 500 mmol)
to afford 440 mg of the crude material, which was subjected to was added at room temperature. The heating was turned on
column chromatography (neutral Al2O3, hexane–ethyl acetate and the refluxing suspension was kept under stirring for
20 : 1) to afford compound C1 (white wax, 300 mg, 0.62 mmol, 4 hours, and the colour changed from red to colourless. The
79% yield). mp 127.3–132.2 °C (mixture of cis and trans solvent was removed and the residue was dissolved in CH2Cl2.
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The organic phase was washed three times with an ammonia
solution (0.1 M, 100 mL), dried over Na2SO4, filtered and evap-
orated to afford compound 1 (white wax, 735 mg, 0.76 mmol,
100% yield). mp 164.2–170.1 °C. The 1H-NMR spectrum shows
additional signals related to a chemical exchange in the NMR
time scale due to protonation of 1. 1H-NMR (300 MHz, CD2Cl2,
δ): 1.18–1.36 (m, 56H), 1.65–1.82 (m, 8H), 1.86–2.05 (m, 8H),
3.02–3.09 (m, 8H), 5.41–5.47 (m, 4H), 7.44 (d, J = 8 Hz, 4H),
7.67 (s, 4H), 8.10 (d, J = 8 Hz, 4H). 13C-NMR (75 MHz, CD2Cl2,
δ): 29.10, 29.24, 29.44, 29.49, 29.55, 29.70, 29.97, 30.49, 30.72,
32.82, 39.91, 40.21, 122.08, 122.25, 125.41, 127.08, 130.32,
135.96, 145.83, 162.81. HRMS-ESI TOF (m/z): [M + H+] calcd for
C68H96N4, 969.7713; found, 969.7711; [M + Na+] calcd for
C68H96N4, 991.7533; found, 991.7526. HRMS-MALDI TOF
(m/z): [M + H+] calcd for C68H96N4, 969.7713; found, 969.7747.
UV-vis (CH2Cl2) λmax, nm (ε): 234 (97 910); 271 (58 420); 283 sh
(37 560).
pp. 249–307; (d) G. Podoprygorina and V. Böhmer, in Tetra-
urea Calix[4]arenes – From Dimeric Capsules to Novel Cate-
nanes and Rotaxanes in Modern Supramolecular Chemistry,
ed. F. Diederich, P. Stang and R. R. Tykwinski, Wiley-VCH,
Weinheim, 2008, pp. 143–184; (e) A. J. Wisner and
A. B. Blight, in Rotaxanes and Catenane Synthesis in Modern
Supramolecular Chemistry, ed. F. Diederich, P. Stang and
R. R. Tykwinski, Wiley-VCH, Weinheim, 2008, pp. 349–387.
5 V. Balzani, A. Credi, S. Silvi and M. Venturi, Chem. Soc.
Rev., 2006, 35, 1135–1149.
6 (a) E. Wasserman, J. Am. Chem. Soc., 1960, 82, 4433–4434;
(b) G. Schill and A. Lüttringhaus, Angew. Chem., 1964, 76,
567–568; (c) R. Wolovssky, J. Am. Chem. Soc., 1970, 82,
2132–2133; (d) D. A. Bem-Efraim, C. Batich and
E. Wasserman, J. Am. Chem. Soc., 1970, 82, 2133–2135.
7 C. O. Dietrich-Buchecker, J.-P. Sauvage and J.-P. Kintzinger,
Tetrahedron Lett., 1983, 24, 5095–5098.
8 (a) C. A. Hunter, J. Am. Chem. Soc., 1992, 114, 5303–5311;
(b) F. Vögtle, S. Meier and R. Hoss, Angew. Chem., Int. Ed.
Engl., 1992, 31, 1619–1622; (c) A. Harada, J. Li and
M. Kamanuci, Chem. Commun., 1997, 1413–1414;
(d) C. Seel and F. Vögtle, Chem. – Eur. J., 2000, 6, 21–24;
(e) D. B. Amabilino and J. F. Stoddart, Chem. Rev., 1995, 95,
2725–2828; (f) M. S. Vickers and P. D. Beer, Chem. Soc. Rev.,
2007, 36, 211–225.
Acknowledgements
Thanks are due to the Ministero dell’Istruzione, dell’Università
e della Ricerca (MIUR, PRIN 2010CX2TLM). This work was
also partially supported by Università di Roma La Sapienza
(Progetti di Ricerca 2011 and Avvio alla Ricerca 2012).
9 (a) R. T. S. Lam, A. Belenguer, S. L. Roberts, C. Naumann,
T. Jarrosson, S. Otto and J. K. M. Sanders, Science, 2005,
308, 667–669; (b) M. E. Belowich and J. F. Stoddart, Chem.
Soc. Rev., 2012, 41, 2003–2024 and references cited therein;
(c) F. B. L. Cougnon, N. A. Jenkins, G. Dan Pantoş and
J. K. M. Sanders, Angew. Chem., Int. Ed., 2012, 51, 1443–
1447.
Notes and references
1 (a) P. T. Corbett, J. Leclaire, L. Vial, K. R. West, J.-L. Wietor,
J. K. M. Sanders and S. Otto, Chem. Rev., 2006, 106, 3652–
3711; (b) Dynamic combinatorial chemistry, ed. J. Reek and
S. Otto, Wiley-VCH Verlag GmbH
& Co. KGaA Inc., 10 (a) T. J. Kidd, D. A. Leigh and A. J. Wilson, J. Am. Chem.
Weinheim, 2010; (c) Dynamic combinatorial chemistry: in
drug discovery, bioorganic chemistry and material science, ed,
B. L. Miller, Wiley and Sons Inc., Hoboken New Jersey,
2009; (d) S. Ladame, Org. Biomol. Chem., 2008, 6, 219–226;
(e) Y. Jin, C. Yu, R. J. Denman and W. Zhang, Chem. Soc.
Rev., 2013, 42, 6634–6654; (f) J. Li, P. Nowak and S. Otto,
J. Am. Chem. Soc., 2013, 135, 9222–2239; (g) A. Herrmann,
Chem. Soc. Rev., 2014, 43, 1899–1933.
Soc., 1999, 121, 1599–1600; (b) H. Y. Au-Yeung, G. Dan
Pantoş and J. K. M. Sanders, Proc. Natl. Acad. Sci. U. S. A.,
2009, 106, 10466–10470; (c) H. Y. Au-Yeung, G. Dan Pantoş
and J. K. M. Sanders, J. Am. Chem. Soc., 2009, 131, 16030–
16032; (d) F. B. L. Cougnon, N. Ponnuswamy, N. A. Jenkins,
G. Dan Pantoş and J. K. M. Sanders, J. Am. Chem. Soc.,
2012, 134, 19129–19135.
11 (a) S. Di Stefano, J. Phys. Org. Chem., 2010, 23, 797–805;
(b) J. A. Berrocal, R. Cacciapaglia and S. Di Stefano, Org.
Biomol. Chem., 2011, 9, 8190–8194; (c) J. A. Berrocal,
R. Cacciapaglia, S. Di Stefano and L. Mandolini, New
J. Chem., 2012, 36, 40–43; (d) A. Ruggi, R. Cacciapaglia,
S. Di Stefano, E. Bodo and F. Ugozzoli, Tetrahedron, 2013,
69, 2767–2774.
2 J.-M. Lehn, Chem. – Eur. J., 1999, 5, 2455–2463.
3 (a) J. F. Stoddart, Chem. Soc. Rev., 2009, 38, 1802–1820;
(b) J. E. Beves, B. A. Blight, C. J. Cambell, D. A. Leigh and
R. T. McBurney, Angew. Chem., Int. Ed., 2011, 50, 9260–
9327; (c) J.-C. Chambron and J.-P. Sauvage, New J. Chem.,
2013, 37, 49–57.
4 (a) Molecular Catenanes, Rotaxanes and Knots, ed. 12 (a) S. Monfette and D. E. Fogg, Chem. Rev., 2009, 109,
J.-P. Sauvage and C. O. Dietrich-Buchecker, Wiley-VCH,
Weinheim, 1999; (b) F. M. Raymo and J. F. Stoddart, in
Switchable Catenanes and Molecular Shuttles in Molecular
Switches, ed. B. Feringa, Wiley-VCH, Weinheim, 2001, pp.
219–248; (c) J.-P. Collin, J.-M. Kern, L. Raehm and
J.-P. Sauvage, in Metallo-Rotaxanes and Catenanes as Redox
3783–3816 and cited references; (b) D. J. Nelson,
I. W. Ashworth, I. H. Hillier, S. H. Kyne, S. Pandian,
J. A. Parkinson, J. M. Percy, G. Rinaudo and M. A. Vincent,
Chem. – Eur. J., 2011, 17, 13087–13094; (c) K. R. Prasad and
S. M. Kumar, Tetrahedron, 2013, 69, 6512–6518;
(d) P. Hodge, Chem. Rev., 2014, 114, 2278–2312.
Switches: Towards Molecular Machines and Motors in Mole- 13 Ring-opening metathesis polymerizations (ROMP) of con-
cular Switches, ed. B. Feringa, Wiley-VCH, Weinheim, 2001,
centrated solutions of macrocyclic olefins are quite popular
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among polymer chemists (ref. 12a and d). In the present
work the notation ring-opening metathesis cyclooligomeri-
that Ki = EMi within the usual approximation of reactivity
of the end group independent of chain length.
zation (ROMCO) would be appropriate, for all equilibration 21 (a) R. Cacciapaglia, S. Di Stefano and L. Mandolini, J. Am.
reactions were carried out at monomer concentrations not
exceeding the critical monomer concentration (see further
on).
Chem. Soc., 2005, 127, 13666–13671; (b) R. Cacciapaglia,
S. Di Stefano, L. Mandolini, P. Mencarelli and F. Ugozzoli,
Eur. J. Org. Chem., 2008, 186–195.
14 (a) M. Weck, B. Mohr, J.-P. Sauvage and R. H. Grubbs, 22 L. Reif and H. Höcker, Macromolecules, 1984, 17, 952–
Angew. Chem., Int. Ed. Engl., 1997, 36, 1308–1310; 956.
(b) M. Weck, B. Mohr, J.-P. Sauvage and R. H. Grubbs, 23 (a) Y. Yamashita, J. Mayumi, Y. Kawakami and K. Ito,
J. Org. Chem., 1999, 64, 5463–5471.
15 (a) C. A. Schalley, J. Hoernschemeyer, X.-Y. Li, G. Silva and
P. Weis, Int. J. Mass Spectrom., 2003, 228, 373–388;
Macromolecules, 1980, 13, 1075–1080; (b) R. Cacciapaglia,
S. Di Stefano, G. Ercolani and L. Mandolini, Macromol-
ecules, 2009, 42, 4077–4083.
(b) C. A. Schalley, P. Ghosh and M. Engeser, Int. J. Mass 24 K. Ito, Y. Hashizuka and Y. Yamashita, Macromolecules,
Spectrom., 2004, 249, 232–233; (c) C. A. Schalley, Analytical 1977, 10, 821–824.
Methods in Supramolecular Chemistry, Wiley-VCH Verlag, 25 A. T. ten Cate, H. Kooijman, A. L. Spek, R. P. Sijbesma and
Weinheim, 2007; (d) S. Pasquale, S. Di Stefano and
B. Masci, New J. Chem., 2010, 34, 426–431.
E. W. Meijer, J. Am. Chem. Soc., 2004, 126, 3801–3808.
26 C. Galli and L. Mandolini, Eur. J. Org. Chem., 2000, 3117–
3125.
16 G. C. Vougioukalakis and R. H. Grubbs, Chem. Rev., 2010,
110, 1746–1787.
27 An admittedly crude estimate of the strain energy (SE) of
C1 can be given as follows: SE = −RT ln(0.022/0.061) =
0.6 kcal mol−1 where 0.022 M is the given experimental
EM1 from Fig. 4 and 0.061 M is the ideal EM1 predicted for
a strainless ring whose ease of formation is solely deter-
mined by the conformational entropy loss upon cyclization
of a chain precursor composed of 22 rotatable single bonds
(see ref. 26). Although too much emphasis cannot be
placed on exact figures, the picture which emerges is one
where the SE of C1, if any, should amount to a fraction of a
17 The syntheses of C1 and 1·Cu+ were performed in the pres-
ence of the less active G1 to minimize subsequent cross-
metathesis of cyclic products.
18 (a) H. Jacobson and W. H. Stockmayer, J. Chem. Phys., 1950,
18, 1600–1606; (b) P. J. Flory, Statistical Mechanics of
Chain Molecules, Wiley Interscience, New York, 1969;
(c) G. Ercolani, L. Mandolini, P. Mencarelli and S. Roelens,
J. Am. Chem. Soc., 1993, 115, 3901–3908.
19 [C*i ] is the limiting value approached by [Ci] when cmon
approaches c*mon
.
kcal mol−1
.
20 Polymer chemists usually refer to macrocyclization equili- 28 H. Irving and D. H. Mellor, J. Chem. Soc., 1962, 5222–
brium constant Ki (see ref. 18b). It was shown (see ref. 18c) 5237.
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