Template-directed dynamic synthesis of mechanically interlocked dendrimers

Article abstract of DOI:10.1021/ja0501363

The versatility and efficiency of dynamic covalent chemistry (DCC) has been exploited in the convergent synthesis of mechanically interlocked dendrimers that are based upon the mutual recognition expressed between secondary dialkylammonium ions and crown

Full text of DOI:10.1021/ja0501363

Published on Web 03/29/2005
Template-Directed Dynamic Synthesis of Mechanically Interlocked
Dendrimers
Ken C.-F. Leung, Fabio Arico´, Stuart J. Cantrill, and J. Fraser Stoddart*
California NanoSystems Institute and Department of Chemistry and Biochemistry, The UniVersity of California,
Los Angeles, 405 Hilgard AVenue, Los Angeles, California 90095-1569
Received January 9, 2005; E-mail: stoddart@chem.ucla.edu
Recently, the versatility of dynamic covalent chemistry (DCC)1
has been demonstrated2 in the multicomponent construction of
complex mechanically interlocked compounds, such as molecular
bundles3 and nanoscale Borromean rings,4 as well as in the highly
efficient template-directed synthesis5 of [2]rotaxanes.6 Previously,
we have reported7 that, by employing DCC in the form of reversible
imine bond formation, [2]rotaxanes with dialkylammonium ion
(-CH2NH2+CH2-) recognition sites8 encircled by [24]crown-8
macrocycles can be prepared in high yields by a thermodynamically
controlled, templated self-assembly process, that is, a kind of
clipping procedure (Figure 1), as a result of the mixing together of
three different components, namely, a dialdehyde, a diamine, and
a dumbbell compound containing a -CH2NH2+CH2- center to
template the [2]rotaxane formation.7 In the context of constructing
mechanically interlocked dendrimers9,10 by employing a convergent
templation procedure, we have explored11 the feasibility of using
DCC to introduce dendrons onto multivalent cores carrying
-CH2NH2+CH2- centers on their sidearms to act as “hooks” round
which “eyes” in the shape of diimine-containing [24]crown-8
macrocycles can be constructed in an activating environment. We
report herein that dendritic dialdehydes 1a-c from generation zero
[G0] to generation two [G2], the diamine 2, and the trisammonium
salt 3-H3‚3PF6 can be self-assembled (Scheme 1) as three collections
of seven components, each in one-pot, under equilibrium conditions
to afford the imine-containing [G0]-[G2] mechanically interlocked
dendrimers 4a-c-H3‚3PF6 in yields in excess of 90%. These
dynamic dendrimers can be converted into their kinetically stable,
neutral amine-containing dendrimers 5a-c by reduction (fixation)
of the imine bonds using the BH3‚THF complex as the reducing
agent, and then subsequently isolated as their fully protonated
counterparts 5a-c-H3‚3TFA after acidification with trifluoroacetic
acid (H-TFA).
of dendritic dialdehydes 1a-c with 3 molar equiv of the diamine
2 and 1 molar equiv of the dialkylammonium salt 3-H3‚3PF6 in
either CD3CN or CD3NO2 (concentration ∼35 mM) at room
temperature. Such clipping experiments were monitored directly
by 1H NMR spectroscopy. By way of an example, Figure 2 shows
1
(upper trace) the H NMR spectrum (500 MHz, CD3NO2, 298 K)
of the dynamic [G2]-dendrimer 4c-H3‚3PF6 recorded 5 min after
mixing the three components in the requisite amounts (3:3:1 for
1:2:3-H3‚3PF6). The spectrum can be interpreted in terms of trace
amounts of the starting materials plus the dynamic [G2]-dendrimer
Scheme 1. Seven-Component Self-Assemblies in One-Pot
Procedures of the Dynamic Dendrimers 4a-c-H3‚3PF6
Figure 1. Graphical representation of the template-directed synthesis of
mechanically interlocked dendrimers.
While the [G0]-[G2] dendritic dialdehydes 1a-c were obtained
from their corresponding [G0]-[G2] dendritic bromides12 (see
Supporting Information), the diamine 27 and the trisammonium salt
1m
3-H3‚3PF6 were prepared according to procedures already de-
scribed in the literature. The template-directed formation5 of the
[G0]-[G2] dendrimers requires only the mixing of 3 molar equiv
9
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J. AM. CHEM. SOC. 2005, 127, 5808-5810
10.1021/ja0501363 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. ESI-MS Data for the Dynamic (4a-c-H3‚3PF6), the
Neutral (5a-c), and Protonated (5a-c-H3‚3TFA) Dendrimers
calcd
m/z
found
m/z
structure
molecular formula
3+
[4a-H3]3+
[4b-H3]3+
[4c-H3]3+
5a
C168H189N12O24
C222H249N12O30
C330H369N12O42
C168H198N12O24
C222H258N12O30
C330H378N12O42
C168H201N12O24
C222H261N12O30
C330H381N12O42
919.4646
1187.6109
1723.9036
2767.4637
3571.9031
5180.7812
923.4959
919.4623
1187.6109
1723.9803
2767.4680
3572.0780
5181.0500
923.4968
3+
3+
5b
5c
3+
3+
3+
[5a-H3]3+
[5b-H3]3+
[5c-H3]3+
1191.6422
1727.9349
1191.6762
1727.9941
significant changes even after standing for more than 24 h at room
temperature. This collective behavior demonstrates the remarkable
stabilities of these mechanically interlocked dynamic compounds,
presumably as much because of the numerous stabilizing [N+-
H‚‚‚O] hydrogen bonds and [C-H‚‚‚O] interactions as from the
favorable charge transfer and other interactions involving π-donating
and π-accepting aromatic rings.
On account of their six readily hydrolyzable imine bonds, the
three kinetically labile [G0]-[G2]-dendrimers were fixed (Scheme
2) in each case by reduction (BH3‚THF), followed by deprotonation
(NaOH/H2O) to give the kinetically stable, neutral dendrimers 5a-
c. In all cases, the reductions with the borane complex were a little
less than quantitative. In general, however, mass spectrometry and
1H NMR spectroscopy confirmed the presence of 5a-c as the major
products, which were also characterized as their fully protonated
derivatives 5a-c-H3‚3TFA. The average yield for the conversion
of 4a-c-H3‚3PF6 through 5a-c-H3‚3TFA was around 80%. For
5a-c-H3‚3TFA, they can be deprotonated with triethylamine into
their corresponding 5a-c to switch off the numerous [N+-H‚‚‚O]
hydrogen bonds and [C-H‚‚‚O] interactions.
Figure 2. Partial 1H NMR spectra (500 MHz, CD3NO2, 298 K) of the
dynamic dendrimer 4c-H3‚3PF6 in addition to the precursors 1c, 2, and
3-H3‚3PF6 from which it is self-assembled.
4c-H3‚3PF6 present in more than 90% yield. Specifically, the
formation of 4c-H3‚3PF6 is supported by the appearance of a sharp
(singlet) resonance (δ ) 8.12 ppm) for the equivalent imine protons
along with the disappearance of the singlet peak (δ ) 9.95 ppm)
for the formyl protons in the [G2]-dialdehyde 1c. On the basis of
their multiplicities and relative integrations, all of the other 1H NMR
signals in 4c-H3‚3PF6 can be assigned to protons in the [G2]-
dendrimer. Similar characterizations were obtained for the [G0]-
and [G1]-dendrimers 4a-H3‚3PF6 and 4b-H3‚3PF6. In general, the
1H NMR spectra of these dynamic dendrimers did not undergo any
Electrospray ionization mass spectrometry (ESI-MS) proved to
be a particularly useful technique for the mass analyses (Table 1)
of 4a-c-H3‚3PF6 and 5a-c-H3‚3TFA and, hence, their character-
ization.13 By way of an example, the ESI-MS of the dynamic
dendrimer 4c-H3‚3PF6 revealed (Figure 3) a high-intensity signal
at m/z ) 1724.9738 corresponding to the ion mass of [4c-H3]3+
,
that is, the loss of 3PF6 ions from the salt.
Scheme 2. Fixing of the Kinetically Labile Dendrimers to Give the
Neutral Dendrimers 5a-c and Their Protonation to Yield
5a-c-H3‚3TFA.
Figure 3. ESI-MS analysis of the dynamic dendrimer 4c-H3‚3PF6.
We have found that, by taking advantage of dynamic covalent
chemistry,1 dendrons from generation zero to two can be self-
assembled in near quantitative yields into, first of all, kinetically
labile and, then, kinetically stable mechanically interlocked den-
drimers. These results demonstrate the potential for a modular
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C O M M U N I C A T I O N S
Moorefield, C. N. Dendrimers and Dendrons: Concepts, Syntheses,
Applications; VCH: New York, 2001. (c) Chow, H.-F.; Mong, T. K.-K.;
Nongrum, M. F.; Wan, C.-W. Tetrahedron 1998, 8543-8660. (d)
Matthews, O. A.; Shipway, A. N.; Stoddart, J. F. Prog. Polym. Sci. 1998,
23, 1-56. (e) Bosman, A. W.; Janssen, H. M.; Meijer, E. W. Chem. ReV.
1999, 99, 1665-1688. (f) Stoddart, F. J.; Welton, T. Polyhedron 1999,
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approach to the convergent synthesis of dendrimers wherein the
components can be mixed and matched according to the require-
ments of an even larger equilibrating system wherein the dynamic
portion can, in principle, be altered and adapted to suit environ-
ments. A way of making mechanically interlocked dendrimers that
is of practical value has been discovered.
(10) For examples of dendritic pseudorotaxanes/rotaxanes, see: (a) Amabilino,
D. B.; Ashton, P. R.; Balzani, V.; Brown, C. L.; Credi, A.; Fre´chet, J. M.
J.; Leon, J. W.; Raymo, F. M.; Spencer, N.; Stoddart, J. F.; Venturi, M.
J. Am. Chem. Soc. 1996, 118, 12012-12020. (b) Yamaguchi, N.;
Hamilton, L. M.; Gibson, H. W. Angew. Chem., Int. Ed. 1998, 37, 3275-
3279. (c) Hu¨bner, G. M.; Nachtsheim, G.; Li, Q. Y.; Seel, C.; Vo¨gtle, F.
Angew. Chem., Int. Ed. 2000, 39, 1269-1272. (d) Osswald, F.; Vogel,
E.; Safarowsky, O.; Schwanke, F.; Vo¨gtle, F. AdV. Synth. Catal. 2001,
343, 303-309. (e) Gibson, H. W.; Yamaguchi, N.; Hamilton, L. M.; Jones,
J. W. J. Am. Chem. Soc. 2002, 124, 4653-4665. (f) Jones, J. W.; Bryant,
W. S.; Bosman, A. W.; Janssen, R. A. J.; Meijer, E. W.; Gibson, H. W.
J. Org. Chem. 2003, 68, 2385-2389.
Acknowledgment. The research was conducted as part of an
NSF-NIRT award (ECS-0404458). We are grateful to the Croucher
Foundation (HKSAR) for a postdoctoral fellowship to K.C.-F. L.
Supporting Information Available: Preparative procedures, spec-
troscopic data for all compounds reported in this communication, and
complete ref 12. This material is available free of charge via the Internet
at http://pubs.acs.org.
(11) The history of this exploration in our laboratory has been frustrating,
dominated as it has been, by both intricate and attractive procedures, but
all lacking ultimately the efficiencies required to render them useful in a
practical context. An approach which involves “threading-followed-by-
stoppering”, and then, thereafter, “stopper exchange”, has been used
(Elizarov, A. M.; Chiu, S.-H.; Glink, P. T.; Stoddart, J. F. Org. Lett. 2002,
4, 679-682) in a template-directed synthesis of a precursor bis[2]rotaxane
that requires that a bisdibenzo[24]crown-8 core is threaded with a bis-
(bromomethyl)-substituted dibenzylammonium ion derivative before stop-
pering is achieved with an excess of Ph3P. The best yield obtained in this
sequence of reactions was 37% overall, a major byproduct being the
intermediate mono[2]rotaxane isolated in 28% yield. Subsequent treatment
of the bis[2]rotaxane with Fre´chet-type wedge-shaped aldehydes (G1 and
G2) effected Wittig reactions affording isomeric mixtures of tetraolefins,
which were hydrogenated catalytically. The combined efficiencies of these
final two steps were 70 and 75% for the G1 and G2 dendrimers,
respectively. Thus, in a multistep synthesis that involves four separate
steps, the first of which is the lowest yielding one, the best yield that has
been obtained for dendrimers with rotaxane-like mechanical branching is
below 30%. In an attempt to find a more efficient route to mechanically
interlocked dendrimers, we turned our attention (Elizarov, A. M.; Chang,
T.; Chiu, S.-H.; Stoddart, J. F. Org. Lett. 2002, 4, 3565-3568) to the
“slippage” approach in the knowledge (Ashton, P. R.; Baxter, I.; Fyfe,
M. C. T.; Raymo, F. M.; Spencer, N.; Stoddart, J. F.; White, A. J. P.;
Williams, D. J. J. Am. Chem. Soc. 1998, 120, 2297-2307) that, in CH2Cl2
at 40 °C, bis(cyclohexylmethyl)ammonium hexafluorophosphate (50 mM)
is converted 98% of the way to a [2]rotaxane in the presence of 150 mM
of dibenzo[24]crown-8 (DB24C8). In the event, this thermodynamically
controlled self-assembly process lost all its remarkable efficiency on going
from the model system to one that involves a Fre´chet-type benzyl ether
wedge and a DB24C8 unit which links another two such wedges. The
best yield of a mechanically interlocked dendrimer that could be obtained
in this single slippage experiment was 19%, and this result involved a 90
day reaction period, followed by chromatography! This outcome was not
exactly encouraging, and it took a considerable act of faith not to abandon
a thermodynamically controlled approach to the synthesis of dendrimers
containing mechanical bonds. It was against this background that we
decided to explore the convergent template procedure, involving DCC in
the context of imine bond formation. The fact that this one-step procedure
goes in excess of 90% tells us that finally, at the third attempt, we have
come up with a method that works that is sufficiently efficient to be of
practical use in the synthesis of mechanically interlocked dendrimers.
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