The stability of imine-containing dynamic [2]rotaxanes to hydrolysist

Article abstract of DOI:10.1039/b915864b

Large amounts (> 100 mol equivalents) of water are required to effect by hydrolysis the partial disassembly of the rings from the dumbbell components of two dynamic [2]rotaxanes. The two dynamic [2]rotaxanes are comprised of [24]crown-8 rings-each of which incorporate two imine bonds-encircling a dumbbell component composed of a dibenzylammonium ion in which each of the two benzyl substituents carries two methoxyl groups attached to their 3- and 5-positions. A mechanism for the partial disassembly of the two dynamic [2]rotaxanes, involving the cleavage of the kinetically labile imine bonds by water molecules, is proposed. The most important experimental observation to be noted is the fact that the hydrolysis of the macrocyclic diimines, associated with the templating -CH₂NH₂⁺CH ₂-centres in the middle of their dumbbells, turns out to be an uphill task to perform in the face of the molecular recognition provided by strong [N⁺-H ... O] hydrogen bonds and weaker, yet not insignificant, [C-H ... O] interactions. The dynamic nature of the imine bond formation and hydrolysis is such that the acyclic components produced during hydrolysis of the imine bonds can be enticed to cyclise once again around the -CH ₂NH₂⁺CH₂-template, affording the [2]rotaxanes. The reluctance of imine bonds, present in substantial numbers in larger molecular and extended structures, is significant when it comes to exercising dynamic chemistry in compounds where multiple imine bonds are present. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b915864b

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www.rsc.org/obc | Organic & Biomolecular Chemistry
The stability of imine-containing dynamic [2]rotaxanes to hydrolysis†
Ken Cham-Fai Leung,*a,b Wing-Yan Wong,a Fabio Arico´,b Philip C. Haussmannb and J. Fraser Stoddart*b,c
Received 3rd August 2009, Accepted 8th October 2009
First published as an Advance Article on the web 20th November 2009
DOI: 10.1039/b915864b
Large amounts (>100 mol equivalents) of water are required to effect by hydrolysis the partial
disassembly of the rings from the dumbbell components of two dynamic [2]rotaxanes. The two dynamic
[2]rotaxanes are comprised of [24]crown-8 rings—each of which incorporate two imine
bonds—encircling a dumbbell component composed of a dibenzylammonium ion in which each of the
two benzyl substituents carries two methoxyl groups attached to their 3- and 5-positions. A mechanism
for the partial disassembly of the two dynamic [2]rotaxanes, involving the cleavage of the kinetically
labile imine bonds by water molecules, is proposed. The most important experimental observation to be
noted is the fact that the hydrolysis of the macrocyclic diimines, associated with the templating
+
–CH2NH2 CH2–centres in the middle of their dumbbells, turns out to be an uphill task to perform in the
face of the molecular recognition provided by strong [N+–H ◊ ◊ ◊ O] hydrogen bonds and weaker, yet not
insignificant, [C–H ◊ ◊ ◊ O] interactions. The dynamic nature of the imine bond formation and hydrolysis
is such that the acyclic components produced during hydrolysis of the imine bonds can be enticed to
+
cyclise once again around the –CH2NH2 CH2–template, affording the [2]rotaxanes. The reluctance of
imine bonds, present in substantial numbers in larger molecular and extended structures, is significant
when it comes to exercising dynamic chemistry in compounds where multiple imine bonds are present.
containing macrocycles possess remarkable stabilities in the pres-
ence of water. Other molecular systems,11 involving dative bonds
Introduction
Recently, dynamic covalent chemistry1 (DCC) has attracted in-
creasing attention on account of its usefulness in preparing com-
plex products, such as molecular Borromean rings,2 dendrimers3
and other exotic compounds4 with high efficiencies using one-
pot, templated self-assembly processes.5 The nearly quantitative
formation of the (super)structures with mechanically intertwined
and interlocked entities indicates that a template effect5a is highly
efficient, yielding thermodynamically stable supramolecular inter-
mediates on the way to the desired entities. The main advantage
of the thermodynamic process over the kinetic one is that the
former operates under equilibrium control such that the formation
of undesired, kinetically competitive intermediates can eventually
make their way back to the most energetically-favored product by
means of error checking and proof-reading.1g DCC relies upon the
use of dynamic covalent bonds that form in a reversible manner.
Common dynamic equilibrating (reversible) reactions exploited in
such syntheses include olefin metathesis,6 and disulfide7 and imine
formation.8
between imines and transition metal ions,12 can also experience
increased imine stabilities in water. It follows that a careful
investigation of the dissociative mechanisms associated with the
formation and hydrolysis of dynamic rotaxanes containing imine
bonds is important in the context of the design of functional
rotaxanes13 that can be obtained in high yields by DCC and possess
potentially useful applications.14
In this paper, we report an investigation of the dissociation of
dynamic, imine-containing rotaxanes8a in the presence of an excess
of water. It transpires that not only is the hydrolysis far from
complete, but also that the dissociated molecular components
obtained at equilibrium can be assembled rather easily to afford
the original [2]rotaxanes by removing the water from the aqueous
solutions with appropriate drying agents.
Results and discussion
By employing DCC associated with reversible imine bond for-
mation, we reported8c previously that the dynamic [2]rotaxane
1a–H·PF6 can be formed (Scheme 1) by condensation between
three different components in a 1 : 1 : 1 ratio—the diformylpyridine
2, the diamine 3a and the already stoppered dialkylammonium
salt 4–H·PF6—in dry MeCN (60 mM) in over 90% yield in
one pot. Similarly, another dynamic [2]rotaxane 1b–H·PF6 can
also be formed using the same condensation method with 2,
the diamine 3b and 4–H·PF6 in a 1 : 1 : 1 ratio. Moreover, we
found out experimentally that the condensations occur effectively
in both MeCN and MeNO2 (60 mM). The encirclement of
a dialkylammonium ion by the imine-containing [24]crown-8
macrocycle can be regarded as a thermodynamically controlled
template-directed self-assembly and amplification process. Since
Generally, imines are relatively unstable since they are sus-
ceptible to rapid hydrolysis in the presence of water.9 Sag-
giomo and Lu¨ning10 have reported recently, however, that imine-
aCenter of Novel Functional Molecules, Department of Chemistry, The
Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, P. R. China.
E-mail: cfleung@cuhk.edu.hk; Fax: (+852) 2603-5057
bCalifornia NanoSystems Institute and Department of Chemistry and
Biochemistry, The University of California, Los Angeles, 405 Hilgard
Avenue, Los Angeles, California, 90095, USA
cDepartment of Chemistry, Northwestern University, 2145 Sheridan Road,
Evanston, Illinois, 60208, USA. E-mail: stoddart@northwestern.edu;
Fax: (+1) 847-491-1009
† Electronic supplementary information (ESI) available: NMR and mass
spectra. See DOI: 10.1039/b915864b
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Scheme 1 Equilibrium for the self-assembly and dissociation of the dynamic [2]rotaxanes 1a/b–H·PF6 and their components 2, 3a/b and 4–H·PF6
depending on the concentration of water present in the reaction mixture.
the dialkylammonium ion template 4–H·PF6 fits well into the
macrocycle, which is generated from the [1 + 1] condensa-
tion between 2 and 3a/b, the [2]rotaxanes 1a/b–H·PF6 can be
amplified as the major products in the dynamic competitive
equilibrium mixture. Subsequently, the [2]rotaxanes 1a/b–H·PF6
were characterised by 1H NMR spectroscopy and matrix-assisted
laser-desorption ionization mass spectrometry (HR-MALDI-MS)
(d = 10.12 ppm), the free (f) pyridine ring (d = 8.22 ppm)
and the free (f) dimethoxyaryl ring (d = 6.58 and 6.62 ppm) in
separate cyclic (or acyclic) and dumbbell components were found
to have their relative intensities increase, while those signals arising
from the rotaxane decreased. The low intensity aldehyde signal at
10.10 ppm can be attributed to the intermediate monoaldehyde
5a/b formed during the hydrolysis of 1a/b–H·PF6. The results
indicate that the dynamic [2]rotaxane dissociates slowly into its free
components—2, 3a and 4–H·PF6—until the dissociation process
has reached equilibrium after 24 h. Furthermore, the broad signal
1
(mass spectra not shown). The H NMR spectra were obtained
after 15 min of mixing between the free components. The 1H NMR
spectra of the dynamic [2]rotaxanes reveal that the characteristic
benzylic methylene proton signals, adjacent to the ammonium
ion centre, observed at 3.8–3.9 ppm of 4–H·PF6 are shifted
downfield to 4.5–4.6 ppm upon rotaxane formation. Moreover,
the characteristic peaks for the protons on the ethyleneglycol
chain are shifted upfield (see the ESI†). The [2]rotaxanes are stable
+
(d = 9.98 ppm) for the NH2 centre became diminished with
time on account of proton/deuterium exchange. With particular
reference to 1a–H·PF6, there were 52, 41 and 14% of the dynamic
[2]rotaxane remaining in the mixture after 24 h following the
additions, in turn, of 100, 200 and 500 equivalents of D2O. On
the other hand, in the case of the dissociation of 1b–H·PF6, there
were 19, 8 and 4% of the dynamic [2]rotaxane remaining in the
mixture after 24 h following the additions, in turn, of 100, 250 and
+
+
=
entities on account of [N –H ◊ ◊ ◊ O] and [N –C–H ◊ ◊ ◊ X] (X O or
N) hydrogen bonds, in addition to electrostatic and p–p stacking
interactions.8c Thereafter, they were redissolved in MeCN prior
to carrying out dissociation studies in the presence of different
amounts of water.
1
500 equivalents of D2O. Moreover, the H NMR spectra reveal
that the residual dynamic [2]rotaxanes 1a/b–H·PF6 are stable in
the CD3CN–D2O mixture after 24 h, reflecting a situation that is
able to maintain the integrity of the [2]rotaxane constitution, even
in the presence of water.
Our investigations have shown that the dissociation of dynamic
[2]rotaxanes 1a/b–H·PF6 requires large amounts of water. Thus,
1H NMR spectroscopy was employed for investigating the disso-
ciation of 1a/b–H·PF6, following addition15 of 100, 200, 250 and
500 equivalents of D2O. Whether or not equilibration has been
reached, sharp signals in the 1H NMR spectra of the [2]rotaxanes
indicate that they are relatively stable kinetically on the NMR
timescale at 500 MHz. The stability is presumably the result of the
stabilizing multiple noncovalent bonding interactions. By way of
an example, Fig. 1 shows the stacked 1H NMR spectra (500 MHz,
CD3CN, 298 K, aromatic region, 16.6 mM, b = bound rotaxane
and f = free components) of the [2]rotaxane 1a–H·PF6 in the
presence of 200 equivalents of D2O. Initially, the NMR spectra
of [2]rotaxane 1a–H·PF6 (at 0 min) reveal the proton signals at
d = 7.71 ppm and d = 8.02 ppm for the bound (b) pyridine
ring, at d = 6.9–7.5 ppm for the bound (b) N,O-substituted aryl
ring, and at d = 6.10 ppm and d = 6.45 ppm for the bound (b)
dimethoxyaryl ring. With increasing time in the presence of water,
the characteristic proton signals originating from the aldehyde
By comparing the integrations of characteristic signals arising
from the dynamic rotaxanes 1a/b–H·PF6 and the dissociated
free dumbbell 4–H·PF6 from the dissociation study, plots of the
[Rotaxane]-1 versus time can be obtained. The data, which were
obtained (Fig. 2) from dissociations lasting 4–6 h, were best
fitted to straight lines in agreement with second-order kinetics for
both the a and b series. Rate constants (k2 and k-2), dissociation
rates and half-lives (t1/2) for the breakdown of 1a/b–H·PF6
were calculated and are listed in Table 1. When comparing
similar starting concentrations of the dynamic rotaxanes, in
most cases, the stability to water dissociation of 1a–H·PF6 is
higher than that of 1b–H·PF6. This observation may account
for the enhanced template binding induced by translocational
freedom involving the tetraethyleneglycol chain in 3a than
that involving the more rigid 2,6-disubstituted pyridyl moiety
in 3b.
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Fig. 1 Partial 1H NMR spectra (aromatic region, 500 MHz, CD3CN, 298 K, 200 mol equivalents of D2O, total conc. = 16.6 mM) showing the
dissociation of the dynamic [2]rotaxane 1a–H·PF6 with time (b = bound rotaxane and f = free components). With increasing time, the characteristic
proton signals originating from the aldehyde (d = 10.12 ppm), the free (f) pyridine ring (d = 8.22 ppm) and the free (f) dimethoxyaryl ring (d = 6.62
and 6.58 ppm) in separate cyclic (or acyclic) and dumbbell components were found to have their relative intensities increase while those signals arising
from the rotaxane decreased. The results indicate that the dynamic [2]rotaxane dissociates slowly into its free components—2, 3a and 4–H·PF6—until the
dissociation process has reached equilibrium after 24 h. With particular reference to 1a–H·PF6, there was 41% of the dynamic [2]rotaxane remaining in
the mixture after 24 h.
Table 1 Dissociation data of the dynamic [2]rotaxanes 1a/b–H·PF6 in the presence of water calculated from the 1H NMR spectroscopic results
1a–H·PF6
1b–H·PF6
Equivalents of water (total concentration) 100 (17.2 mM) 200 (16.6 mM) 500 (15.2 mM) 100 (16.6 mM) 250 (15.9 mM) 500 (14.9 mM)
k2/M-1 h-1
k-2/M-1 h-1
rate/mM h-1
247.4 1.2
268.0 1.3
73.2
14.1
52
355.9 1.8
247.3 1.2
98.1
10.2
41
1091.2 5.4
177.6 0.9
252.1
3.6
14
606.7 2.9
145.0 0.7
179.5
5.8
19
1298.5 6.5
115.4 0.6
357.8
2.8
8
2354.2 11.7
82.2 0.4
543.9
1.7
4
t
1/2/min
% Remaining [2]rotaxane in the
water–acetonitrile mixture
From a mechanistic point of view, the ring associated with
the [2]rotaxanes 1a/b–H·PF6 will eventually open up (Scheme 2)
with only one equivalent of H2O present in the solution to give
the monoaldehyde intermediates 5a/b, allowing the dumbbell 4–
H·PF6 to dethread from these intermediates on account of the loss
of the crown ether’s integrity and the associated pre-organisation.
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DMF-d7 (9 : 1), CD3CN–CD3OD (2 : 1) and pure CD3CN. No
1
significant changes were observed in the H NMR signals, from
which it was concluded that dissociation of the dumbbell 4–H·PF6
does not occur even after standing for over 12 h in the presence
of solvents that do not sustain hydrogen bonding. Secondly, since
imine hydrolysis and formation can be catalysed by nucleophiles,8b
as well as by acids,8f ,16 the dissociations of the rotaxanes were
investigated after adding a nucleophile—p-toluidine—as an imine
exchange partner. On adding one equivalent of toluidine to the
[2]rotaxane solutions, dissociation was found to occur on account
of imine exchange, which results in the fast opening of the
[24]crown-8 macrocycles to give the podand-like compounds 6a/b.
Toluidine plays an important role in serving as a relatively bulky
imine exchange partner with the macrocycle to give a disrupted
open crown (podand), which cannot be easily converted back
to the [24]crown-8 derivative. As a consequence, the [2]rotaxanes
dissociate rapidly on simply adding one equivalent of toluidine.
The reversible formation of the [2]rotaxanes 1a/b–H·PF6 from
their separate components has been demonstrated (Fig. 3) by 1H
NMR spectroscopy. For example, from the dissociated mixture of
the dynamic [2]rotaxane 1a/b–H·PF6 achieved on the addition
of 200 equivalents of H2O (i.e., with 41% of the [2]rotaxane
remaining in the mixture), after treatment with anhydrous MgSO4,
the percentage of the corresponding dynamic [2]rotaxane 1a/b–
H·PF6 is restored (Fig. 3a) to ~70%. Somewhat surprisingly,
Fig. 2 A plot of [Rotaxane]-1 versus time, showing the dissociation profile
of the dynamic [2]rotaxanes 1a/b–H·PF6 in the presence of different
amounts of D2O. For the a series, the concentration of [2]rotaxane is 17.2,
16.6 and 15.2 mM when 100, 200 and 500 equivalents D2O were added,
respectively. For the b series, the concentration of [2]rotaxane is 16.6,
15.9 and 14.9 mM when 100, 250 and 500 equivalents D2O were added,
respectively. Data points were obtained from analyzing their 1H NMR
spectra (500 MHz, CD3CN, 298 K). The data, which were obtained from
dissociations lasting 4–6 h, were best fitted to straight lines in agreement
with second-order kinetics for both the a and b series.
Subsequently, the monoaldehyde intermediates 5a/b will be
hydrolysed even further right down to the diformylpyridine 2, as
well as into the diamines 3a/b with one additional equivalent
of H2O. However, the template effect offered by the multiple
noncovalent interactions and also the stopper effect may retain
the relative stability and integrity of the rotaxanes. That is,
at equilibrium, relatively large amounts of H2O are required
to hydrolyse the imine bond(s) and to solubilise the cleaved
components.
˚
molecular sieves (4 A) are not useful for drying these systems,
since the dynamic [2]rotaxanes 1a/b are unstable in their presence.
Moreover, treatment with anhydrous Na2SO4, followed by evap-
oration and the redissolving of the dry MeCN (three consecutive
cycles), gives (Fig. 3b) the corresponding dynamic [2]rotaxane
1a–H·PF6. This reversibility of the equilibrium was found to
be adjustable many times over, without destroying either the
individual components or the dynamic [2]rotaxanes.
Two control experiments were performed. Firstly, the dynamic
[2]rotaxanes were dissolved separately in pre-dried CD3CN–
Scheme 2 Plausible mechanism for the dissociation of the dynamic [2]rotaxanes 1a/b–H·PF6 into their components 2, 3a/b, 4–H·PF6, 5a/b and 6a/b. The
ring associated with the [2]rotaxanes 1a/b–H·PF6 eventually opens up with only one equivalent of H2O present in the solution to give the monoaldehyde
intermediates 5a/b, allowing the dumbbell 4–H·PF6 to dethread from these intermediates on account of the loss of the crown ether’s integrity and the
associated pre-organisation. Subsequently, the monoaldehyde intermediates 5a/b will be hydrolysed even further right down to the diformylpyridine 2,
as well as into the diamines 3a/b with one additional equivalent of H2O. On the other hand, on adding one equivalent of toluidine to the [2]rotaxane
solutions, dissociation occurs on account of imine exchange, which results in the fast opening of the [24]crown-8 macrocycles to give the podand-like
compounds 6a/b. Toluidine plays an important role in serving as a relatively bulky imine exchange partner with the macrocycle to give a disrupted open
crown (podand) that cannot be easily converted back to the [24]crown-8 derivative.
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Fig. 3 Partial 1H NMR spectra (500 MHz, CD3CN, 298 K, aromatic region) of the dissociated dynamic [2]rotaxane 1a–H·PF6 (b = bound and f = free)
after treatment with (a) anhydrous MgSO4 and (b) anhydrous Na2SO4, evaporated and redissolved in MeCN through three consecutive cycles.
Conclusions
Experimental
The separation of the dynamic [2]rotaxanes 1a/b into their
dumbbell and cleaved ring components in the presence of different
concentrations of water has been demonstrated. Large amounts
(>100 equivalents) of water are required for the degradation of half
of the molecules of the [2]rotaxanes. The stability of the [2]rotaxane
1a–H·PF6 towards the hydrolysis is higher than that of 1b–H·PF6.
A mechanism for the hydrolysis, involving the hydrolytic cleavage
of one of the two imine bonds in the [24]crown-8 ring, has been
proposed. It involves the formation of an acyclic intermediate
following hydrolysis of one of the kinetically labile bonds in the
ring. The separate components are also relatively stable in the
presence of large amounts of water and can even be re-assembled
to afford the dynamic [2]rotaxanes 1a/b–H·PF6, once again by
eliminating water from their aqueous solutions. In principle, the
concentrations of the dynamic [2]rotaxanes in the mixture can be
controlled by the addition and subtraction of appropriate amounts
of water. It is possible that by covalent attachment with fluorescent
probes (reporter groups), such as anthracene or naphthalene
moieties, detailed hydrolysis mechanisms for the degradation of
these dynamic rotaxanes in the presence of various stimuli—
e.g., water, acids, nucleophiles, etc.—could be investigated by
monitoring the fluorescence quenching effects in the rotaxanes.
Materials and methods
All reagents were purchased from Aldrich or Cambridge
Isotopes Laboratories, Inc. 2,6-Pyridinedicarboxaldehyde (2)
is commercially available, while tetraethyleneglycol bis(2-
aminophenyl)ether (3a) and bis-3,5-dimethoxybenzyl ammonium
hexafluorophosphate (4–H·PF6) were prepared according to lit-
erature procedures.8c The dynamic [2]rotaxanes were prepared
according to the literature procedure,8c and were then dried in
vacuo and isolated. Compound 3b was synthesized as illustrated
in Scheme 3. Acetonitrile-d3 (99.8% D), N,N-dimethylformamide-
d7 (99.8% D) and methanol-d4 (99.8% D) were dried with activated
˚
molecular sieves (4 A). Deuterium oxide (99.9% D) was used. Thin-
layer chromatography (TLC) was carried out using aluminium
sheets, precoated with silica gel 60F (Merck 5554). The plates were
inspected by UV light, prior to their development with iodine
vapor. Melting points were determined on an Electrothermal
9200 apparatus and are uncorrected. Column chromatography
was performed on silica gel 60F (Merck 9385, 0.040–0.063 mm).
All nuclear magnetic resonance (NMR) spectra were recorded on
a Bru¨ker Advance 500 (1H at 500 MHz and 13C at 126 MHz).
Chemical shifts are reported in parts per million (ppm) downfield
Scheme 3 Synthesis of the diamine compound 3b through an intermediate compound 8.
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1
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8. NaH
(0.13 g, 5.6 mmol) was added to a DMF (20 mL) solution of
2-(hydroxyethoxy)nitrobenzene17 (7) (0.86 g, 4.7 mmol) and
2,6-bis(p-toluenesulfonyl)methylpyridine (1.0 g, 2.2 mmol) in a
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2H), 7.51 (t, J = 7.6 Hz, 2H), 7.76 (t, J = 7.7 Hz, 1H), 7.82 (d,
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15359.
7 For rotaxane-containing disulfide units in their dumbbell-shaped
components that are formed by riveting and stoppering approaches, see:
(a) A. G. Kolchinski, N. W. Alcock, R. A. Roesner and D. H. Busch,
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2,6-Bis-[2-(2-aminophenoxy)ethoxymethyl]pyridine 3b. The
bisnitro compound 8 (0.40 g, 0.80 mmol) was dissolved in
CH2Cl2–MeOH (10 mL/10 mL) in a 50 mL round-bottomed
flask. Diethylamine (0.4 mL) and Pd/C (50% water, 0.05 g) were
added, the reaction vessel was degassed and filled with H2, and
the pressure was maintained at 1 atm for 4 h. The catalyst was
removed by filtration and the solution was evaporated in vacuo
to give the title compound 3b as a clear oil (0.33 g, 95% yield); 1H
NMR (500 MHz, CDCl3): d = 3.93–3.94 (m, 4H), 4.22–4.20 (m,
4H), 4.72 (s, 4H), 6.67–6.72 (m, 4H), 6.78–6.81 (m, 4H), 7.38 (d,
J = 7.7 Hz, 2H), 7.70 (t, J = 7.7 Hz, 1H); 13C NMR (126 MHz,
CDCl3): d = 68.1, 69.3, 73.9, 112.6, 115.2, 118.3, 120.1, 121.7,
136.6, 137.4, 146.2, 157.6; HRMS (HR-MALDI): calcd for
C23H28N3O4 m/z = 410.2080 and C23H27N3O4Na m/z = 432.1899;
found m/z = 410.2096 [M + H]+ and 432.1910 [M + Na]+.
General procedure for investigating the dissociation of [2]rotax-
anes. Typically, the [2]rotaxane (10.0 mg, 0.0107 mmol for 1a–
H·PF6; 0.0103 mmol for 1b–H·PF6) was dissolved in CD3CN
(0.600 mL) in an NMR tube. Prescribed amounts of D2O were
1
added with a microsyringe. H NMR spectra were recorded at
specific times following the addition of water.
Acknowledgements
This material is based upon work supported by the National
Science Foundation under CHE0924620 in the United States and
by the RGC-GRF (CUHK401808) of Hong Kong SAR.
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Notes and References
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88 | Org. Biomol. Chem., 2010, 8, 83–89
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The Royal Society of Chemistry 2010
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