Template-directed synthesis of multiply mechanically interlocked molecules under thermodynamic control

Article abstract of DOI:10.1002/chem.200500148

The template-directed construction of crown-ether-like macrocycles around secondary dialkylammonium ions (R₂NH₂⁺) has been utilized for the expedient (one-pot) and high-yielding synthesis of a diverse range of mechanically

Full text of DOI:10.1002/chem.200500148

FULL PAPER
Template-Directed Synthesis of Multiply Mechanically Interlocked Molecules
Under Thermodynamic Control
Fabio Aricó, Theresa Chang, Stuart J. Cantrill, Saeed I. Khan, and J. Fraser Stoddart*[a]
Abstract: The template-directed con-
struction of crown-ether-like macrocy-
cles around secondary dialkylammoni-
um ions (R2NH2+) has been utilized
for the expedient (one-pot) and high-
yielding synthesis of a diverse range of
mechanically interlocked molecules.
The clipping together of appropriately
designed dialdehyde and diamine com-
pounds around R2NH2+-containing
dumbbell-shaped components proceeds
through the formation, under thermo-
dynamic control, of imine bonds. The
reversible nature of this particular re-
action confers the benefits of “error-
checking” and “proof-reading”, which
one usually associates with supramolec-
ular chemistry and strict self-assembly
processes, upon these wholly molecular
systems. Furthermore, these dynamic
covalent syntheses exploit the efficient
templating effects that the R2NH2
to give kinetically stable species, a pro-
cedure that can be performed in the
same reaction vessel as the inital ther-
modynamically controlled assembly.
Isolation and purification of the me-
chanically interlocked products formed
by using this protocol is relatively
facile, as no column chromatography is
required. Herein, we present the syn-
+
ions exert on the macrocyclization of
the matched dialdehyde and diamine
fragments, resulting not only in rapid
rates of reaction, but also affording
near-quantitative conversion of starting
materials into the desired interlocked
products. Once assembled, these “dy-
namic” interlocked compounds can be
“fixed” upon reduction of the reversi-
ble imine bonds (by using BH3·THF)
thesis and characterization of 1)
[2]rotaxane, 2) [3]rotaxane, 3)
a
a
a
branched [4]rotaxane, 4) a bis [2]ro-
taxane, and 5) a novel cyclic [4]ro-
taxane, demonstrating, in incrementally
more complex systems, the efficacy of
this one-pot strategy for the construc-
tion of interlocked molecules.
Keywords: dynamic
covalent
chemistry · imine formation · mo-
lecular recognition · noncovalent
interactions · reductive amination
Introduction
tive,[9] and noncovalent[10] templating[11] strategies under
both kinetic[12] and thermodynamic[13–17] control.
For the past 45 years now, the synthesis of exotic molecular
compounds, such as catenanes,[1] rotaxanes,[2] knots,[3] and
Borromean rings,[4,5] with aesthetically appealing[5] and po-
tentially useful[6] structures have been proceeding apace.
During the same period of time, the synthetic protocols em-
ployed by chemists have evolved from being all but statisti-
cal[7] in the beginning, to progressively covalent,[8] coordina-
In general, the syntheses of interlocked and intertwined
molecular compounds that rely upon coordinative and non-
covalent templating strategies come about with the aid of
molecular-recognition motifs[18] that induce the self-assem-
bly[19] of certain components to first of all form a complex.
Although the formation of such complexes are more often
than not under thermodynamic control, the final and crucial
step in the synthesis of compounds with one or more me-
chanical bonds is usually kinetically controlled. This se-
quence of events has been described[20] as supramolecular
assistance to covalent synthesis. One hopes the majority of
the final product, which is kinetically “fixed”, is the desired
product, for, if not, there is no going back from unwanted
byproducts lacking mechanical bonds. In essence, the fate of
the synthesis is sealed once and for all.
[a] Dr. F. Aricó, Dr. T. Chang, Dr. S. J. Cantrill, Dr. S. I. Khan,
Prof. J. F. Stoddart
California NanoSystems Institute and
Department of Chemistry and Biochemistry
University of California, Los Angeles
405 Hilgard Avenue, Los Angeles, CA 90095–1569 (USA)
Fax : (+1)310-206-1843
Dynamic covalent chemistry[21] has been exploited in the
template-directed syntheses[11] of both catenanes[16,17] and ro-
taxanes[16,17] and it comes into its own in the construction of
E-mail: stoddart@chem.ucla.edu
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2005, 11, 4655 – 4666
DOI: 10.1002/chem.200500148
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4655

more intricate mechanically interlocked molecular com-
pounds.[5,6] The chief attribute of the thermodynamic ap-
proach over the kinetic one is the fact that the former oper-
ates under equilibrium control. As such, the formation of
undesired kinetic byproducts can be recycled in the direc-
tion of the most stable mechanically interlocked molecular
compound. Proof reading and error checking operate in
conjunction with synthesis in a remarkably efficient manner.
Numerous successes[15–17] during the past 10 years have dem-
onstrated the potential of dynamic covalent chemistry[21] for
synthesizing compounds consisting of two or more compo-
nents that are associated with one another by virtue of me-
chanical linkages only. Particularly when it is template-di-
rected,[11] the appeal of this particular brand of synthesis lies
in the fact that dynamic covalent bonds combine the robust-
ness of covalent bonds with the reversibility of noncovalent
bonding. And so it is for these reasons that the reversible
and/or exchangeable character of acetal,[13] ester,[14] and di-
sulfide[15] bond formation, of labile metal–ligand coordina-
tion[16] and carbon–carbon bond formation during metathe-
sis[17] have, among others, played a key role in the develop-
ment of the chemistry of the mechanical bond.
Despite the fact that there are now numerous exam-
ples[13,15–18] reported in the literature describing the use of re-
versible reactions for the preparation of [2]catenanes and
[2]rotaxanes, the application of dynamic covalent chemis-
try[21] to the construction of higher order catenanes and ro-
taxanes, as well as mechanically interlocked compounds
beyond catenanes and rotaxanes,[22] has remained largely un-
explored[23] up until imine bond[24] formation and exchange
(Scheme 1) was exploited by us.[25,26] Following our recent
water is produced. In the presence of water, the reaction is
reversible, that is, the imine is hydrolyzed to give back its
amine and aldehyde precursors. In the presence of another
amine, imines can undergo reversible exchange reactions to
yield different imines.[26,27] Finally, the imine bonds can be
“fixed” by reducing them to secondary amines that are ki-
netically stable.
In our first investigations[25,26] of [2]rotaxane formation
under thermodynamic control, we used dynamic dumbbell
components, in which both stoppers were attached to the
rod section by imine bonds, in the presence of matching ring
components. The yields of the rotaxanes never exceeded
50%. By contrast, a more efficient pathway for the forma-
tion of a [2]rotaxane involves a clipping process[28,29] in
which a kinetically stable dumbbell component recognizes
and binds the macrocyclic precursors and, in so doing, tem-
plates the formation of the macrocycle around the dumbbell
component. The dynamic pathway that prevails during the
formation of such a macrocycle containing two imine
bonds[28] is much more efficient, with the outcomes being
near-quantitative ones. In competition experiments, kinetic
control is often found[29] to dominate in the initial stages of
a reaction, giving way to thermodynamic control in the full-
ness of time.
The repercussions of going from forming two imine bonds
remote from the recognition site in a dialkylammonium ion/
crown ether based rotaxane to one in which the secondary
dialkylammonium center facilitates the formation of the two
imine bonds is illustrated graphically in Figure 1. In the first
Figure 1. Formation of a [2]rotaxane a) by a dynamic-stoppering and b)
by a dynamic-clipping approach.
case, imine bond formation is not activated during the pro-
cess of mechanical bond construction, whereas in the second
case, the formation of the two imine bonds is part of the
templation process leading to rotaxane formation.
Scheme 1. An example of imine formation, exchange and reduction
(“fixing”).
In this full paper, we report the template-directed synthe-
ses (in all cases >95%) and characterization by mass spec-
trometry in the gas phase and by NMR spectroscopy in solu-
tion of 1) a [3]rotaxane (with X-ray crystal structure), 2) a
branched [4]rotaxane, 3) a bis[2]rotaxane (with X-ray crystal
structure) and 4) a novel, jumbo-sized cycle incorporating a
bismacrocycle mechanically interlocked with a bisammoni-
um dication. In addition, we announce the use of BH3·THF
to “fix” the thermodynamically stable products as kinetically
stable ones without the need for time-consuming purifica-
tion procedures, such as chromatography: yields of 75–96%
are reported.
demonstration[4,5] of the near-quantitative self-assembly of a
Borromean ring compound from 18 components by the tem-
plate-directed formation of 12 imine and 30 dative bonds as-
sociated with the coordination of three interlocked macrocy-
cles, each tetranucleating and decadentate overall to a total
of six zinc(ii) ions, our confidence in the ability of imine
chemistry to further the structural potential[27] of the me-
chanical bond is considerable. When an imine bond is
formed by the condensation of an amine with an aldehyde,
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Supramolecular Chemistry
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Results and Discussion
toxicity of BH3·lutidine, which has led to its removal from
the market, and purification procedures, which become in-
creasingly difficult to perform with higher order rotaxanes,
were limiting the exploitation of this otherwise efficient
imine clipping protocol for the construction of more com-
plex mechanically interlocked
In 2001 we reported[28] the synthesis of the [2]rotaxane [4-
H]PF6 as outlined in Scheme 2. In this template-directed[11]
reaction, a macrocyclic diimine with a [24]crown-8 construc-
molecular structures based
upon the dialkylammonium ion/
crown
ether
recognition
motif.[30] We have found recent-
ly, however, that the BH3·THF
complex (1.8m BH3 in THF) is
an excellent substitute for
BH3·lutidine for the reduction
of imine bonds in thermo-
dynamically labile compounds.
When the formation and subse-
quent “fixing” of the dynamic
[2]rotaxane [4-H]PF6 was re-
peated using BH3·THF (ca.
2 equiv for each imine bond)
complete reduction of the
imine bonds was observed by
1H NMR spectroscopy after
only two hours instead of two
Scheme 2. Synthesis of the [2]rotaxane [5-H]PF6 by dynamic covalent chemistry.
days. Moreover, the kinetically
stable [2]rotaxane [5-H]PF6 was
tion is formed by condensation in nitromethane (MeNO2) of
2,6-pyridinedicarboxaldehyde (1) and tetraethyleneglycol
bis(2-aminophenyl)ether (2) around bis(3,5-dimethoxyben-
zyl)ammonium hexafluorophosphate ([3-H]PF6) as the
active dumbbell. Well-resolved peaks were observed in the
1H NMR spectrum of the reaction mixture, indicating that
the [2]rotaxane [4-H]PF6 is by far the most thermodynami-
isolated as a pure crystalline powder in 86% yield after de-
protonation of the secondary dialkylammonium center by
extraction with a mixture of aqueous sodium hydroxide so-
lution and chloroform, followed by reprotonation of the res-
idue from the chloroform extract with trifluoroacetic acid
and anion exchange with a saturated aqueous solution of
ammonium hexafluorophosphate.[31] The purification proce-
dure does not require any time-consuming chromatography.
When a similar experiment was carried out using dibenzyl-
ammonium hexafluorophosphate [6-H]PF6 as the template,
the components assembled spontaneously (Scheme 3) to
form the pseudorotaxane [7·6-H2]PF6. Reduction of the two
imine bonds in [7·6-H2]PF6 with BH3·THF and deprotona-
tion of the secondary dialkylammonium center of the tem-
plate resulted in the isolation of the free macrocycle 8 in a
yield of 80%. The 1H NMR spectrum (Figure 2) of the
white crystalline product can be interpreted in terms of the
constitution 8. Slow evaporation of a solution of 8 in di-
cally stable product, presumably as a result of N+ H···N hy-
ꢀ
ꢀ
drogen bonding, C H···O interactions and, most likely, also
aromatic p···p stacking interactions between the macrocyclic
diimine and the active dumbbell component.[28] The imine
bonds in [2]rotaxane [4-H]PF6 were reduced with BH3·luti-
dine during a period of two days, to yield, after an involved
workup procedure that included chromatography, the
“fixed” [2]rotaxane [5-H]PF6 in 70% yield.
This protocol represents an efficient way of assembling a
new class of mechanically interlocked molecular compounds
from easily accessible starting materials. However, the acute
Scheme 3. Synthesis of the amine-based macrocycle 8.
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J. F. Stoddart et al.
a syringe to this mixture and
the reaction was monitored
by
1H NMR
spectroscopy
(Figure 4, bottom) until the
peak associated with the four
imine protons in the dynamic
[3]rotaxane had disappeared
(4 h) to yield [10-H2][PF6]2. This
compound was isolated as a
pure crystalline powder in 80%
yield after the deprotonation/
reprotonation procedure previ-
ously discussed.[32] Single crys-
tals, suitable for X-ray crystal-
lography, were grown by liquid
1
Figure 2. Partial H NMR spectrum (500 MHz) of the amine-based macrocycle 8.
diffusion of EtOH into a solu-
chloromethane and hexane yielded single crystals suitable
for X-ray crystallographic analysis (Figure 3) which estab-
lished the structure of the macrocycle beyond any doubt.
tion of the [3]rotaxane [10-H2][PF6]2 in CHCl3. Its solid-state
structure (Figure 5) has crystallographic inversion symmetry.
The inversion center lies at the middle of the p-phenylene
ring in the dicationic dumbbell component. Each end of the
centrosymmetric dumbbell component is threaded through
the central cavity of one of the two ring components. Stabili-
+
zation is achieved by a combination of N+ H···N, N
ꢀ
ꢀ
ꢀ
H···O, C H···O hydrogen-bonding and aromatic p–p stack-
ing interaction. The hydrogen atoms on both of the amino-
phenol-derived nitrogen atoms of the macrocycle were lo-
cated by means of the difference maps and were found to
be out-of-plane, giving a distorted tetrahedral geometry
around both of these nitrogen atoms, which enter, one into
Figure 3. Solid-state structure of the macrocycle 8.
N+ H···N hydrogen bonding, and the other into a C H···N
interaction with the dumbbell component. The NH2 center
ꢀ
ꢀ
+
in the dumbbell component has both of its hydrogen atoms
involved in hydrogen bonding, one with the ether oxygen
atom of the macrocycle and the other with an aminophenol-
derived nitrogen atom, as mentioned already. The centro-
symmetric p-phenylene ring in the dumbbell is probably in-
volved in rather weak p–p stacking interactions (centroid–
centroid separation, 4.72 Š and mean inter-planar separa-
tion 4.15 Š) with one of the aminophenol-derived rings in
each of the macrocyclic components. The planes of the two
aromatic rings are inclined at approximately 188 to each
other.
To establish the generality of this improved synthetic pro-
tocol, we have explored the synthesis of much more com-
plex mechanically interlocked structures, such as a [3]ro-
taxane, a branched [4]rotaxane, and a bis[2]rotaxane. The
bisammonium salt [9-H2][PF6]2 was obtained by using a
well-established procedure[32] from commercially available
p-xylylenediamine and 3,5-dimethoxybenzaldehyde. Subse-
quent addition of two equivalents of each of 1 and 2 to [9-
H2][PF6]2 in CD3NO2 resulted in the rapid assembly of a dy-
1
namic [3]rotaxane (Scheme 4), as indicated by the H NMR
spectrum (Figure 4, top) of the sample recorded after a few
minutes. Immediately thereafter, BH3·THF was added with
Next, we applied the dynamic clipping-followed-by-
“fixing” methodology in the synthesis of a branched [4]ro-
Scheme 4. Synthesis of the [3]rotaxane [10-H2][PF6]2.
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Supramolecular Chemistry
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taxane (Scheme 5). Using the
trifurcated trisammonium salt[23]
[11-H3][PF6]3 as a template and
three equivalents of each of 1
and 2, it is possible to assemble
the dynamic branched [4]ro-
taxane quickly (5 min in
CD3NO2) and efficiently (vide
supra). The dynamic branched
[4]rotaxane can be reduced
readily with BH3·THF to
afford, after the usual workup,
the kinetically stable [12-H3]-
[PF6]3 in an impressive 87%
yield overall from a one-pot re-
action. This conclusion was con-
1
firmed by H NMR spectrosco-
py. Assignment of the proton
resonances was consistent with
the proposed structure for the
branched [4]rotaxane [12-H3]-
[PF6]3. Moreover the high-reso-
lution electrospray mass spec-
Figure 4. Partial 1H NMR spectra (500 MHz, CD3NO2) of the dynamic [3]rotaxane formation (top) and of its
related kinetically stable [3]rotaxane [10-H2][PF6]2 after reduction of the imine bonds (bottom).
trum of [12-H3][PF6]3 is reproduced in Figure 6. A compari-
son between the calculated mass distribution for the triply-
charged species and the experimental data confirms the au-
thenticity of [12-H3][PF6]3.
The simple and efficient access to the branched [4]ro-
taxane is particularly interesting, since it opens the way to
the convergent construction of mechanically interlocked
dendrimers.[33] Indeed, by using a 2,6-pyridinedicarboxalde-
hyde incorporating in its 4-position a dendritic wedge, it is
possible to obtain dendrimers by the clipping-followed-by-
“fixing” approach in which each of the new branches is asso-
ciated with a mechanically-bonded junction.[34]
With a branched [4]rotaxane coming within our grasp so
easily, we were curious to see if we could make jumbo-sized
Figure 5. Solid-state structure of the [3]rotaxane [10-H2][PF6]2.
Scheme 5. Synthesis of the dendritic [4]rotaxane [12-H3][PF6]3.
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J. F. Stoddart et al.
Scheme 6. Synthesis of the tetraaldehyde 16.
tion, its terphenylene-based structure brings with it solubili-
ty problems. The compound is slightly soluble in pyridine,
nitrobenzene, and nitromethane, and only sparingly soluble
1
in acetonitrile and toluene. A H NMR spectrum of 16 re-
corded in C6D5NO2 reveals three extremely weak signals rel-
ative to the intense resonances corresponding to the residual
solvent. The tetraaldehyde is virtually insoluble in all the
other solvents, including Me2SO. Nonetheless, clipping reac-
tions involving 16, 2, and the dumbbell template [3-H]PF6
gave very encouraging results (Scheme 7). Since 16 is only
partially soluble in CD3NO2, the clipping reaction was initi-
ated by heating a suspension containing all three compo-
nents for a few seconds with a heat gun. After heating and
Figure 6. High resolution mass spectrum of the [4]rotaxane [12-H3][PF6]3.
The experimental isotopic distribution (lower trace) corresponds to
[Mꢀ3PF6]+ and it matches the calculated one (upper trace) having
0.33 m/z differences caused by the triple charge on the species.
cycles by linking two 2,6-pyridi-
nedicarboxaldehyde units to-
gether and reacting the subse-
quent tetraaldehyde with bis-
ammonium salts, such as [9-H2]-
[PF6]2.
The synthesis of the tetraal-
dehyde 16, which was selected
for this particular investigation,
was carried out as shown in
Scheme 6 following
a proce-
dure similar to that reported by
Hosseini et al.[35] for the synthe-
sis of a bis-tridentate ligand
based on a combination of two
pyridine and four thioether
Scheme 7. Synthesis of the bis[2]rotaxane [17-H2][PF6]2.
groups. Phosphorus pentabro-
mide was generated in situ from phosphorous tribromide
and bromine. The resulting yellow solid was added to cheli-
demic acid (13), and the two solids were heated to 1208C
with thorough mixing. The reaction was quenched by the ad-
dition of MeOH to convert the acid bromide into the corre-
sponding methyl ester 14. The ester functions were reduced
(NaBH4) and the resulting diol was oxidized using SeO2 to
afford the dialdehyde 15. Coupling two of these dialdehydes
by using a modified Suzuki reaction and p-phenylenebisbor-
onic acid gave the tetraaldehyde 16 in good yield.
Even although the tetraaldehyde 16 was easily accessible
synthetically by using a high-yielding Suzuki coupling reac-
sonication, the solution became bright yellow and no solid
residue remained in the flask. The resulting H NMR spec-
1
trum (Figure 7) indicates that the dynamic bis[2]rotaxane is
formed in almost quantitative yield: in particular, the ap-
pearance of a sharp imine proton resonance (d=8.27 ppm)
is accompanied by the disappearance of the aldehyde
proton signal at d=10.14 ppm. Finally, reduction of the dy-
namic bis[2]rotaxane led to the isolation of the kinetically
stable bis[2]rotaxane [17-H2][PF6]2 in a remarkable 96%
yield. High-resolution electrospray mass spectrometry and
NMR spectroscopy confirmed the structural identity of this
compound.
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Supramolecular Chemistry
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Figure 7. Partial 1H NMR spectrum (500 MHz) of the dynamic bis[2]rotaxane prior to the reduction of the imine bonds (a, b, g, d-OCH2 correspond to
the protons of the ethylene glycol chain as labeled in Scheme 3).
Slow evaporation of a solution of the bis[2]rotaxane [17-
H2][PF6]2 in CH2Cl2/EtOH yielded single crystals suitable
for X-ray structural analysis. Its solid-state structure is
shown in Figure 8. The structure has a crystallographic in-
H···O interactions are between both CH2 groups in the
dumbbell-shaped component and two of the oxygen atoms
in the macrocycles. These interactions are further supple-
ꢀ
mented by C H···p bonds between the 3,5-dimethoxyphenyl
rings of the dumbbell and the two CH2 groups adjacent to
the aminophenol in the ring component.
These results have encouraged us to try and assemble a
yet more exotic mechanically interlocked molecular struc-
ture in which eight components cooperate to form a jumbo-
sized cycle [18-H4][PF6]4 (Scheme 8) The tetraaldehyde 16
(2 equiv), the bis-aniline 2 (4 equiv) and the secondary di-
alkylammonium salt [9-H2][PF6]2 were mixed together in
CD3NO2. As in the previous case, the clipping reaction
needs to be initiated by heating the suspension containing
the components. As a consequence of the nature of the pre-
cursors, polymeric materials or non-templated products
could easily be the outcome. The 1H NMR spectrum
(Figure 9) showed, however, no evidence for the presence of
other compounds; only the dynamic mechanically inter-
locked compound is observed. All the proton signals can be
assigned easily within the context of a dynamic jumbo-sized
cycle. Reduction of the imine bonds by BH3·THF resulted in
the isolation of the kinetically stable interlocked compound
[18-H4][PF6]4. The crude product could be further purified
by recrystallization from EtOH to achieve a very pure
sample of the branched [4]rotaxane. A portion of the
1H NMR spectrum of the kinetically stable product is shown
in Figure 9. High-resolution electrospray mass spectrometry
confirmed the proposed constitution of the mechanically in-
terlocked compound.
Figure 8. Solid-state structure of the bis[2]rotaxane [17-H2][PF6]2.
version center at the middle of the phenylene ring connect-
ing the two halves of the bis[2]rotaxane. The centrosymmet-
ric phenylene ring is disordered between two orientations
(rotated about 378 along the axis) in an 80:20 ratio. A simi-
lar disorded distribution of the two orientations is also pres-
ent around one of the oxygen atoms of the macrocycles. The
dicationic dumbbell-shaped component is threaded through
the central cavity of the crown ether and the resulting co-
Conclusion
conformation is stabilized by N+ H···N hydrogen bonds and
ꢀ
+
ꢀ
ꢀ
C H···O interactions. The N H···N hydrogen bonds are
Simple and efficient syntheses are the key to taking a piece
of chemistry from being just a curiosity to being something
more substantial. The importance of the research described
+
between the NH2 centers on the dumbbell-shaped compo-
ꢀ
nent and the aminophenol-derived nitrogen atoms. The C
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J. F. Stoddart et al.
Scheme 8. Synthesis of the [4]rotaxane [18-H4][PF6]4.
two secondary amine functions
in their ring components can be
isolated by a bulk extraction
procedure without us having to
resort to the use of chromatog-
raphy. We have
a way of
making multiply mechanically
interlocked molecular com-
pounds on a gram scale.
Experimental Section
General methods: Reagents were pur-
chased from Aldrich or synthesized as
described in the literature. 2,6-Pyri-
dinedicarboxaldehyde (1), tetraethyle-
neglycol bis(2-aminophenyl) ether[28]
(2), bis-3,5-dimethoxybenzylammoni-
Figure 9. Partial 1H NMR spectra (500 MHz, CD3NO2) of the dynamic cyclic [4]rotaxane formation (upper
trace) and of its related kinetically stable cyclic [4]rotaxane [18-H4][PF6]4 (lower trace) after reduction of the
imine bonds.
um hexafluorophosphate[28] ([3-H]-
PF6), the trifurcated trisammonium
salt[23] [11-H3][PF6]3 and 4-bromo-2,6-
pyridinedicarboxyaldehyde[36] were all
prepared according to literature proce-
dures. Solvents were purified accord-
ing to literature procedures.[37] Thin-layer chromatography (TLC) was
carried out using aluminum 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. Proton and carbon nuclear magnetic
resonance spectra (1H NMR and 13C NMR) spectra were recorded on
Bruker Avance 500 or ARX500 spectrometers, using the deuterated sol-
vent as lock and the residual protonated solvent as internal standard. All
chemical shifts are quoted using the d scale, and all coupling constants
(J) are expressed in Hertz (Hz). Electrospray mass spectra (ESI-MS)
were measured on a VG ProSpec triple focusing mass spectrometer.
in this full paper rests very much on this premise. We have
found that, by using supramolecular assistance—which relies
+
upon N+ H···O and N H···N hydrogen bonds and C
ꢀ
ꢀ
ꢀ
ꢀ
H···O, C H···N, and p···p stacking interactions—to reversi-
ble imine bond formation, the mechanical bond can be in-
corporated quickly and near-quantitatively at numerous dif-
ferent sites in mechanically interlocked molecules under
thermodynamic control. The further discovery that
BH3·THF can be employed to carry out repeated reductive
aminations with speed and accuracy overall represents yet
another advance on the previous available methodologies. It
[2]Rotaxane [5-H]PF6: A solution of 1 (10 mg, 0.074 mmol), 2 (27.9 mg,
0.074 mmol), and [3-H]PF6 (34.3 mg, 0.074 mmol) in CD3NO2 (1.5 mL)
was stirred at room temperature for 5 min. A solution of 1.8m BH3·THF
in THF (170 mL, 0.306 mmol) was added to the mixture and it was al-
lowed to stir at room temperature for further 2 h. The solvent was then
evaporated off and the residue was distributed between 2m aqueous
NaOH solution and CHCl3. The organic extracts were dried (MgSO4)
and the solvent was evaporated. The residue was dissolved in Me2CO
+
seems likely that the NH2 centers, which act as templates
for the production of the macrocycles with their two imine
bonds, also activate imine bond formation, that is, the ster-
eoelectronics associated with the whole process are good if
not excellent. Last, but by no means least, the products with
4662
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chem. Eur. J. 2005, 11, 4655 – 4666

Supramolecular Chemistry
FULL PAPER
and TFA (few drops) was added to the solution. After evaporation of the
solvent, the residual oil was dissolved in a mixture of H2O and Me2CO
and saturated aqueous solution of NH4PF6 was added. The Me2CO was
then removed and the aqueous solution was extracted with CH2Cl2 sever-
al times. The organic extracts were dried (MgSO4) and the solvent was
evaporated to dryness to yield the [2]rotaxane [5-H]PF6 as a white
powder (60 mg, 86%). Characterization of this compound is consistent
with that reported in the literature.[28]
128.9, 146.7, 161.0 ppm; HRMS (ESI): m/z calcd for C80H100F12N8O14P2
[MꢀPF6]+: 1541.6995; found: 1541.7012. Single crystals, suitable for X-
ray crystallography, were grown by liquid diffusion of EtOH into a solu-
tion of [10-H2][PF6]2 in CHCl3.
[4]Rotaxane [12-H3][PF6]3:
A solution of 1 (9.5 mg, 0.07 mmol), 2
(26.5 mg, 0.07 mmol), and the trifurcated trisammonium salt [11-H3][PF6]3
(30 mg, 0.023 mmol) in CD3NO2 (2 mL) was stirred at room temperature
for 5 min. BH3·THF (1.8m in THF, 90 ml, 0.162 mmol) was added to the
mixture, and the resulting solution was allowed to stir at room tempera-
ture overnight. The solvent was then evaporated off, and the residue was
partitioned between 2m aqueous NaOH and CHCl3. The organic extracts
were dried and concentrated to give a solid, which was dissolved in
Me2CO and few drops of TFA were added to the solution. The solvent
was evaporated off, the residual oil was dissolved in a mixture of H2O
and MeOH, and a saturated aqueous solution of NH4PF6 was added. The
MeOH was then removed, and the aqueous solution was extracted with
CH2Cl2 several times. The organic extracts were dried (MgSO4) and the
solvent was evaporated to dryness to yield the [4]rotaxane [12-H3][PF6]3
Macrocycle 8:
A solution of 1 (40 mg, 0.29 mmol), 2 (110 mg,
0.29 mmol), and [7-H]PF6 (100 mg, 0.29 mmol) in MeNO2 (5 mL) was
stirred at room temperature for 5 min. BH3·THF (1.8m in THF, 0.6 mL,
1.08 mmol) was added to the mixture, which was left stirring at room
temperature for 2 h. The solvent was then evaporated off and the residue
was partitioned between 2m aqueous NaOH solution and CHCl3. The or-
ganic extracts were dried (MgSO4) and the solvent was evaporated again.
The residue was dissolved in warm MeOH and filtered to recover the
macrocycle 8 (115 mg, 80%) as a white crystalline powder. M.p. 143–
1448C; 1H NMR (CDCl3, 500 MHz, 298 K): d=3.60–3.62 (m, 4H), 3.78–
3.79 (m, 4H), 3.88–3.89 (m, 4H), 4.20–4.21 (m, 4H), 4.56 (d, J=5 Hz,
4H), 5.84 (brs, 2H), 6.66–6.71 (m, 4H), 6.91 (d, J=7.7 Hz, 2H), 6.96 (t,
J=7.7 Hz, 2H) 7.25 (d, J=7.7 Hz, 2H), 7.63 ppm (t, J=7.7 Hz, 1H);
13C NMR (CDCl3, 125 MHz, 298 K): d=48.9, 68.9, 70.2, 70.6, 70.7, 110.3,
114.2, 116.2, 119.6, 122.8, 136.9, 139.9, 146.0 158.2 ppm; HRMS (EI): m/z
calcd for C27H33N3O5: 479.2420; found: 479.2413. Slow evaporation of a
solution of 8 in CHCl3 and hexane yielded a single crystal suitable for X-
ray crystallography.
(55 mg, 87%) as
a
yellow powder. M.p. 130–1318C; 1H NMR
(CD3COCD3, 500 MHz, 298 K): d=3.41 (s, 18H), 3.79–4.05 (m, 16H),
4.12–4.22 (m, 48H), 4.10–4.20 (m, 12H), 4.70–4.80 (m, 12H), 6.23 (d, J=
1.8 Hz, 6H), 6.33–6.34 (m, J=1.9, 3H), 6.45 (d, J=7.6 Hz, 6H), 6.59–6.70
(m, 18H) 7.11 (d, J=7.8 Hz, 6H), 7.40 (d, J=8.0 Hz, 6H), 7.49 (d, J=
7.6 Hz, 6H), 7.66 (s, 3H), 7.86 (t, 7.5 Hz, 3H), 9.03 ppm (brs, 6H);
13C NMR (CD3COCD3, 125 MHz, 298 K): d=49.6, 52.4, 54.7, 67.3, 70.3,
71.0, 71.3, 100.8, 106.6, 110.0, 112.3, 119.4, 121.0, 122.0, 124.7, 127.2, 129.3
137.0, 138.2, 140.6, 141.2, 146.8, 158.9, 161.1 ppm; HRMS (ESI): m/z
calcd for C135H159F18N12O21P3 [Mꢀ3PF6]+: 761.3921; found: 761.3908.
Bisammonium salt [9-H2][PF6]2: A solution of p-xylylenediamine (1.00 g,
7.34 mmol) and 3,5-dimethoxybenzaldehyde (2.44 g, 14.68 mmol) in
PhMe (120 mL) was heated under reflux for 20 h using a Dean-Stark ap-
paratus. The resulting solution was evaporated to dryness, the residue dis-
solved in MeOH (250 mL), and NaBH4 (1.85 g, 50 mmol) was added por-
tionwise during 10 min. After stirring the reaction mixture under ambient
conditions for 12 h, the solvents were removed in vacuo, and the residue
was partitioned between H2O and CH2Cl2 (250 mL). The aqueous layer
was further extracted with CH2Cl2 (3”250 mL), the combined organic ex-
tracts were dried (MgSO4), and the resulting solution was evaporated to
dryness to yield a colorless oil. The oil was subsequently dissolved in
MeOH (200 mL), and TFA (10 mL) was added carefully. After stirring
for about 10 min, the solvents were removed in vacuo to give a white
solid, which was then dissolved in a mixture of H2O and Me2CO. Addi-
tion of an excess of saturated aqueous NH4PF6 to this solution resulted in
the precipitation of the desired compound, which was collected and dried
to give [9-H2][PF6]2 (3.6 g, 70%) as a white solid. M.p. 224–2258C;
1H NMR (500 MHz, CD3COCD3): d=3.76 (s, 12H), 4.51 (s, 4H), 4.63 (s,
4H) 6.54 (t, J=2.1 Hz, 2H), 6.70 (d, J=2.1 Hz, 4H), 7.68 ppm (s, 4H);
13C NMR (CD3COCD3, 125 MHz, 298 K): d=51.0, 51.7, 54.8, 99.9, 107.7,
130.7, 132.4, 132.7, 161.3 ppm; HRMS (ESI): m/z calcd for
C26H34F12N2O4P2 [Mꢀ2PF6]2+: 437.2434; found: 427.2453.
Tetraaldehyde 16: Pd(PPh3)4 (0.50 g, 0.31 mmol) was added to a degassed
solution of 2,6-diformyl-4-bromopyridine (1.50 g, 7.01 mmol) in THF
(80 mL). A degassed solution of Na2CO3 (20% aq) and p-phenylbisbor-
onic acid (0.58 g, 3.51 mmol) in EtOH (10 mL) was injected into the solu-
tion. The resulting mixture was heated at 808C for 2 days. After cooling
down to room temperature, the solvent was evaporated and the residue
was filtered and washed with Me2SO, H2O, Me2CO, and hexanes to give
the tetraaldehyde 16 (1.0 g, 80%) as
a
white powder. 1H NMR
(400 MHz, CD3NO2): d=7.86 (s, 4H), 8.34 (s, 4H), 10.16 ppm (s, 4H).
Bis[2]rotaxane [17-H2][PF6]2: A solution of the tetraaldehyde 16 (30 mg,
0.087 mmol), 2 (66 mg, 0.174 mmol), and [3-H]PF6 (80.7 mg, 0.174 mmol)
in CD3NO2 (6 mL) was stirred at room temperature for 5 min. BH3·THF
(1.8m in THF, 260 ml, 0.468 mmol) was added to the mixture, which was
stirred at room temperature overnight. The solvent was then evaporated
off, and the residue was partitioned between 2m aqueous NaOH and
CHCl3. The organic extracts were dried and the solvent removed. The
residue was dissolved in Me2CO and few drops of TFA were added to
the solution. The solvent was evaporated off, the oily residue was dis-
solved in a mixture of H2O and Me2CO, and a saturated aqueous solution
of NH4PF6 was added. The Me2CO was then removed and the aqueous
solution was extracted with CH2Cl2 several times. The organic extracts
were dried (MgSO4) and the solvent concentrated to dryness to yield the
bis[2]rotaxane [17-H2][PF6]2 (163 mg, 96%) as a light yellow powder.
M.p. 132–1338C; 1H NMR (CD3COCD3, 500 MHz, 298 K): d=3.44 (s,
12H), 3.82–3.85 (m, 16H), 4.03–4.05 (m, 8H), 4.10–4.20 (m, 16H), 4.71
(brs, 8H), 6.24–6.26 (m, 8H), 6.31–6.33 (m, 4H), 6.55–6.75 (m, 16H),
8.01 (s, 4H), 8.17 (s, 4H), 8.85 ppm (brs, 4H); 13C NMR (CD3COCD3,
125 MHz, 298 K): d=49.7, 52.4, 54.6, 67.3, 70.4, 71.0, 71.3, 100.7, 106.7,
107.7, 109.9, 112.2, 119.2, 119.7, 121.1, 127.9, 134.1, 136.9, 146.5,
160.9 ppm; HRMS (ESI): m/z calcd for C96H116F12N8O18P2 [Mꢀ2PF6]+:
834.4193; found: 834.4229. Slow evaporation of a solution of [17-H2]-
[PF6]2 in CH2Cl2/EtOH yielded single crystals suitable for X-ray crystal-
lography.
[3]Rotaxane [10-H2][PF6]2:
A solution of 1 (14.5 mg, 0.1 mmol), 2
(40 mg, 0.1 mmol) and the bisammonium salt [9-H2][PF6]2 (38.7 mg,
0.05 mmol) in CD3NO2 (3 mL) was stirred at room temperature for
5 min. BH3·THF (1.8m in THF, 300 ml, 0.540 mmol) was added to the
mixture, which was left stirring at room temperature for 4 h. The solvent
was then evaporated off and the residue was partitioned between 2m
aqueous NaOH and CHCl3. The organic extracts were dried and the sol-
vent evaporated again. The residue was dissolved in Me2CO, and few
drops of TFA were added to the solution. The solvent was evaporated
off, the residual oil was dissolved in a mixture of H2O and Me2CO, and a
saturated aqueous solution of NH4PF6 was added. The Me2CO was then
removed and the aqueous solution was extracted with CH2Cl2 several
times. The organic extracts were dried (MgSO4) and concentrated to dry-
ness to yield the [3]rotaxane [10-H2][PF6]2 (71 mg, 80%) as a white
powder. M.p. 160–1628C; 1H NMR (CD3COCD3, 500 MHz, 298 K) : d=
3.47 (s, 12H), 3.68–4.10 (m, 32H), 4.19 (brs, 8H), 4.62 (brs, 8H), 6.24–
6.26 (m, 4H), 6.38–6.39 (m, 2H), 6.47 (d, J=7.5 Hz, 4H), 6.54 (s, 4H),
6.66–6.75 (m, 12H), 7.56 (d, J=7.5 Hz, 4H), 7.96 (t, J=7.5 Hz, 2H),
8.97 ppm (brs, 4H); 13C NMR (CD3COCD3, 125 MHz, 298 K): d=49.8,
54.6, 67.4, 70.3, 71.0, 71.4, 100.8, 106.7, 109.9, 112.5, 119.7, 121.0, 122.0
[4]Rotaxane [18-H4][PF6]4: A solution of the tetraaldehyde 16 (11.8 mg,
0.034 mmol), 2 (25.9 mg, 0.068 mmol), and the bisammonium salt [9-H2]-
[PF6]2 (25 mg, 0.034 mmol) in CD3NO2 (2 mL) was stirred at room tem-
perature for 5 min. BH3·THF (1.8m in THF, 100 ml, 0.180 mmol) was
added to the mixture, which was stirred at room temperature overnight.
The solvent was then evaporated and the residue was partitioned be-
tween 2m NaOH aqueous and CHCl3. The organic extracts were dried
Chem. Eur. J. 2005, 11, 4655 – 4666
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ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4663

J. F. Stoddart et al.
and the solvent evaporated off. The residue was dissolved in Me2CO and
few drops of TFA were added to the solution. The solvent was evaporat-
ed off, the residual oil was dissolved in a mixture of H2O, and MeCN and
a saturated aqueous solution of NH4PF6 was added. The MeCN was re-
moved and the aqueous solution was extracted with CH2Cl2 several
times. The organic extracts were then dried (MgSO4) and the solvent was
concentrated dryness to yield the [4]rotaxane 18–4H·4PF6 (45 mg, 75%)
as a yellow powder. A portion of the product was further purified by
washing with hot EtOH to recover [18-H4][PF6]4 as an off-white solid.
M.p. > 3008C (decomp); 1H NMR (CD3CN, 500 MHz, 298 K): d=3.37
(s, 24H), 3.47–3.80 (m, 40H), 4.09–4.17 (m, 24H), 4.30–4.45 (m, 24H),
4.79 (brs, 8H), 5.88 (d, J=2.1 Hz, 8H), 6.28 (t, J=2.1 Hz, 4H), 6.49 (t,
J=7.5 Hz, 8H), 6.55 (d, J=7.7 Hz, 8H), 6.79 (t, J=7.5 Hz, 8H), 7.01–
7.03 (m, J=16H), 7.40 (s, 8H), 7.77 (s, 8H), 9.13 ppm (brs, 8H);
13C NMR (CD3NO2, 125 MHz, 298 K): d=54.6, 67.6, 70.4, 70.8, 71.1,
100.9, 107.0, 110.4, 113.1, 119.6, 120.3, 120.9, 127.8, 130.0, 137.0, 138.0
147.1, 159.1 161.0 ppm; HRMS (ESI): m/z calcd for C172H204F24N16O28P4
[Mꢀ4PF6]4+: 735.3723; found: 735.3752.
Acknowledgements
This research was supported by a National Science Foundation (NSF)
grant (CHE 0317170) and two NSF equipment grants (CHE 9974928 and
CHE 0092036).
[1] Catenanes are molecules comprised of two (or more) ring-shaped
components that are interlocked like links in a chain, see: a) G.
Schill, Catenanes, Rotaxanes and Knots, Academic Press, New York,
1971; b) Molecular Catenanes, Rotaxanes and Knots (Eds.: J.-P. Sauv-
age, C. Dietrich-Buchecker), Wiley-VCH, Weinheim, 1999; for
recent examples of kinetic syntheses of catenanes, see: c) D. G.
Hamilton, M. Montalti, L. Prodi, M. Fontani, P. Zanello, J. K. M.
Sanders, Chem. Eur. J. 2000, 6, 608–617; d) Q. Y. Li, E. Vogel, A. H.
Parham, M. Nieger, M. Bolte, R. Frçhlich, P. Saarenketo, K. Rissa-
nen, F. Vçgtle, Eur. J. Org. Chem. 2001, 4041–4049; e) L. Z. Yan,
P. E. Dawson, Angew. Chem. 2001, 113, 3737–3739; Angew. Chem.
Int. Ed. 2001, 40, 3625–3627; f) P. R. Ashton, V. Baldoni, V. Balzani,
A. Credi, H. D. A. Hoffmann, M.-V. Martínez-Diµz, F. M. Raymo,
J. F. Stoddart, M. Venturi, Chem. Eur. J. 2001, 7, 3482–3492; g) F.
Biscarini, M. Cavallini, D. A.
X-ray crystallography: Table 1 summarizes the crystallographic data. The
intensity data were collected on Bruker Smart 1000 CCD-based X-ray
diffractometer, radiation MoKa (l=0.71073 Š); absorption correction:
Leigh, S. León, S. J. Teat, J. K. Y.
Wong, F. Zerbetto, J. Am. Chem.
Soc. 2002, 124, 225–233; h) L.
Raehm, J.-M. Kern, J.-P. Sauvage,
C. Hamann, C. Palacin, J.-P.
Bourgoin, Chem. Eur. J. 2002, 8,
2153–2162; i) H.-R. Tseng, S. A.
Vignon, P. C. Celestre, J. F. Stod-
dart, A. J. P. White, D. J. Williams,
Chem. Eur. J. 2003, 9, 543–546;
j) P. Mobian, J.-M. Kern, J.-P.
Sauvage, J. Am. Chem. Soc. 2003,
125, 2016–2017; k) P. Mobian, J.-
M. Kern, J.-P. Sauvage, Angew.
Chem. 2004, 116, 2446–2449;
Angew. Chem. Int. Ed. 2004, 43,
2392–2395; l) J. V. Hernandez,
E. R. Kay, D. A. Leigh, Science
2004, 306, 1532–1537.
Table 1. Crystal data, and refinement parameters for compounds 8, [10-H2][PF6]2, and [17-H2][PF6]2.
8
[10-H2][PF6]2
[17-H2][PF6]2
formula
solvent
Mr
C27H33N3O5
–
479.56
C80H100N8O14P2F12
2CH2Cl2
1857.47
C96H116N8O18P2F12
CH2Cl2·4C2H6O
2229.11
color, habit
crystal size [mm]
T [K]
colorless, prism
0.60”0.03”0.03
120(2)
colorless, block
0.20”0.20”0.20
120(2)
colorless, prism
0.40”0.20”0.10
120(2)
crystal system
space group
a [Š]
b [Š]
c [Š]
orthorhombic
Pbca (no. 61)
12.447(2)
7.801(1)
49.623(8)
90
90
90
4818(1)
8
1.322
0.092
1.64–28.31
28365
5837
0.997/0.890
316
triclinic
P1 (no. 2)
triclinic
P1 (no. 2)
¯
¯
11.856(3)
12.214(3)
17.628(4)
93.068(4)
107.538(4)
117.122(3)
2110.9(8)
1[a]
1.461
0.273
1.92–26.43
16991
8562
13.040(1)
13.712(1)
16.017(2)
94.527(2)
96.019(2)
99.526(2)
2795.3(5)
1[b]
1.324
0.178
1.51-26.38
22498
11308
a [8]
b [8]
g [8]
V [Š
3
Z
1calcd [Mgmꢀ3
]
[2] Rotaxanes are molecules com-
prised of one (or more) wheel-
shaped component(s) that is (are)
trapped mechanically along the
axle(s) of one (or more) dumb-
bell-shaped component(s). See
references [1a,b]. For recent ex-
amples of the kinetic syntheses of
rotaxanes, see: a) C. A. Schalley,
G. Silva, C. F. Nising, P. Linnartz,
Helv. Chim. Acta 2002, 85, 1578–
1596; b) C. A. Stainer, S. J. Alder-
man, T. D. W. Claridge, H. L. An-
derson, Angew. Chem. 2002, 114,
m [mmꢀ1
q range [8]
]
reflections collected
independent reflection
max/min transmission
parameters
0.947/0.902
552
0.98/0.91
744
R1/wR2 [I>2s(I)]
R1/wR2 (all data)
0.065/0.113
0.158/0.137
0.062/0.147
0.116/0.168
0.078/0.224
0.147/0.262
[a] The complex has crystallographic Ci symmetry. R1 =ꢀjjFo jꢀjFc jjꢀjFo j ; wR2 ={ꢀ[w(F2oꢀFc2)2]/ꢀ[w(Fo2)2]}1/2
;
wꢀ1 =s2(F2o)+(aP)2 +bP. [b] The complex has crystallographic Ci symmetry.
semiempirical. The frames were integrated with the Bruker SAINT-pro-
1847–1850; Angew. Chem. Int. Ed. 2002, 41, 1769–1772; c) M. An-
dersson, M. Linke, J.-C. Chambron, J. Davidson, V. Heitz, L. Ham-
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kawa, G. Brancato, M. Fanti, D. A. Leigh, T. Shimizu, A. M. Z.
Slawin, J. K. Y. Wong, F. Zerbetto, S. Zhang, J. Am. Chem. Soc.
2002, 124, 2939–2950; g) J. O. Jeppesen, K. A. Nielsen, J. Perkins,
S. A. Vignon, A. Di Fabio, R. Ballardini, M. T. Gandolfi, M. Venturi,
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3007; h) K. Nikitin, B. Long, D. Fitzmaurice, Chem. Commun. 2003,
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J. K. M. Sanders, F. Marchioni, M. Venturi, E. Apostoli, V. Balzani,
gram system[38a] by using a narrow-frame integration algorithm. The
structures were solved by direct methods and refined based on F2 using
the SHELXTL software package.[38b] CCDC-263073–CCDC-263075 con-
tain the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
4664
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 4655 – 4666

Supramolecular Chemistry
FULL PAPER
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853; d) D. A. Leigh, A. Murphy, Chem. Ind. 1999, 178–183; e) P.
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Received: February 10, 2005
Published online: May 11, 2005
4666
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www.chemeurj.org
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