Self-assembly of dendrimers by slippage

Article abstract of DOI:10.1021/ol026479c

(graph presented) A dendrimer with rotaxane-like characteristics has been assembled under thermodynamic control from complementary wedge-shaped precursors by slippage in CH₂Cl₂. The driving force for the self-assembly process is the molecular recognition that exists as a result of [N⁺-H...O] and [C-H...O] hydrogen bonds between an NH₂⁺ center in one Frechet-type benzyl ether wedge and a dibenzo[24]crown-8 unit that links the other two such wedges.

Full text of DOI:10.1021/ol026479c

ORGANIC
LETTERS
2002
Vol. 4, No. 21
3565-3568
Self-Assembly of Dendrimers by
Slippage
Arkadij M. Elizarov, Theresa Chang, Sheng-Hsien Chiu, and J. Fraser Stoddart*
Department of Chemistry and Biochemistry, UniVersity of California, Los Angeles,
405 Hilgard AVenue, Los Angeles, California 90095-1569
stoddart@chem.ucla.edu
Received July 8, 2002
ABSTRACT
A dendrimer with rotaxane-like characteristics has been assembled under thermodynamic control from complementary wedge-shaped precursors
by slippage in CH Cl2. The driving force for the self-assembly process is the molecular recognition that exists as a result of [N+−H‚‚‚O] and
2
[C−H‚‚‚O] hydrogen bonds between an NH + center in one Fre´chet-type benzyl ether wedge and a dibenzo[24]crown-8 unit that links the other
2
two such wedges.
Although dendrimers containing mechanically interlocked
components are known,1 they are far from commonplace.
Usually, they have been prepared by template-directed
protocols wherein, at some point in the synthesis, a supra-
molecular species is formed that is then modified covalently2
to introduce either the catenane or rotaxane architecture.3
Recently, for example, we described4 the construction of a
dendrimer that contains two identical covalently linked bis-
dendrons and a core unit fused to two rings that encircle the
two bis-dendrons. In this work, the dendrons were introduced
into an already interlocked molecular compound by Wittig
chemistry5 that allows no less than four surrogate stoppers
to be replaced by dendrons. The resulting dendrimer with
its mechanical branching points is kinetically stable in
contrast with the so-called supramolecular dendrimers6 and
their assemblies7 which are subject to thermodynamic control
and are usually kinetically labile, in common with most
noncovalently bonded superstructures. An intermediate situ-
ation between mechanically interlocked molecular dendrim-
(5) Rowan, S. J.; Stoddart, J. F. J. Am. Chem. Soc. 2000, 122, 164-
165.
(1) (a) Amabilino, D. B.; Ashton, P. R.; Belohradsky, M.; Raymo, F.
M.; Stoddart, J. F. J. Chem. Soc., Chem. Commun. 1995, 751-753. (b)
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. (c) Hu¨bner, G.
M.; Nachtsheim, G.; Li, Q. Y.; Seel, C.; Vo¨gtle, F. Angew. Chem., Int. Ed.
2000, 39, 1269-1272. (d) Reuter, C.; Pawlitzki, G.; Wo¨rsdo¨rfer, U.;
Plevoets, M.; Mohry, A.; Kubota, T.; Okamoto, Y.; Vo¨gtle, F. Eur. J. Org.
Chem. 2000, 3059-3067. (e) Kim, K. Chem. Soc. ReV. 2002, 31, 96-107.
(2) Fyfe, M. C. T.; Stoddart, J. F. Acc. Chem. Res. 1997, 30, 393-401.
(3) (a) Schill, G. Catenanes, Rotaxanes and Knots; Academic: New
York, 1971. (b) Molecular Catenanes, Rotaxanes and Knots; Sauvage, J.-
P., Dietrich-Buchecker, C., Eds.; VCH-Wiley: Weinheim, Germany, 1999.
(4) Elizarov, A. M.; Chiu, S.-H.; Glink, P. T.; Stoddart, J. F. Org. Lett.
2002, 4, 679-682.
(6) Supramolecular dendrimers are comprised of noncovalently bonded
subunits: (a) Zimmerman, S. C.; Zeng, F.; Reichert, D. E. C.; Kolotuchin,
S. V. Science 1996, 271, 1095-1098. (b) Emrick, T.; Fre´chet, J. M. J.
Curr. Opin. Colloid Interface Sci. 1999, 4, 15-23. (c) Percec, V.; Cho,
W.-D.; Ungar, G. J. Am. Chem. Soc. 2000, 122, 10273-10281. (d) Lee, J.
W.; Ko, Y. H.; Park, S.-H.; Yamaguchi, K.; Kim, K. Angew. Chem., Int.
Ed. 2001, 40, 746-749. (e) Zeng, F.; Zimmerman, S. C.; Kolotuchin, S.
V.; Reichert, D. E. C.; Ma, Y. Tetrahedron 2002, 58, 825-843.
(7) Noncovalently bonded aggregates wherein each component is
considered to be a dendrimer: (a) Percec, V.; Cho, W.-D.; Mosier, P. E.;
Ungar, G.; Yeardley, J. P. J. Am. Chem. Soc. 1998, 120, 11061-11070.
(b) Uppuluri, S.; Swanson, D. R.; Piehler, L. T.; Li, J.; Hagnauer, G. L.;
Tomalia, D. A. AdV. Mater. 2000, 12, 796-800. (c) Percec, V.; Cho, W.-
D.; Ungar, G.; Yeardley, D. J. P. Chem. Eur. J. 2002, 8, 2011-2025.
10.1021/ol026479c CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/24/2002

ers and supramolecular dendrimers is provided by dendritic
pseudorotaxanes8 where the components of the superstructure
are not only noncovalently bonded with one another, but also
interpenetrate each other.
to have dissociated completely into its components inside
18 h on standing at 25 °C.
In the knowledge of these remarkable experimental find-
ings, it occurred to us that a possible approach to the
preparation of mechanically bonded dendrimers might be
provided by using the slippage protocol involving one
dendron carrying a DB24C8 ring and another dendron that
is attached to one side of an NH2+ center, leaving the other
side free to support a cyclohexylmethyl group, i.e., a slippage
stopper for the DB24C8 ring. For the dendrons, we chose
Fre´chet-type benzyl ether wedges because (i) they are readily
available and soluble in solvents such as CH2Cl2 and (ii) we
surmised that the phenolic ether functions would not interfere
with the [N+-H‚‚‚O] hydrogen bonds and [C-H‚‚‚O]
interactions that constitute most of the noncovalent bonding
The slippage methodology9 provides a bridge between
kinetically stable, mechanically interlocked compounds and
kinetically labile, supramolecular assemblies. Some time ago,
we established10 that the secondary dialkylammonium ion
+
(RCH2)2NH2 , where R is a cyclohexyl group and the
-
counterion is PF6 , will form a kinetically stable [2]rotaxane
when the salt and dibenzo[24]crown-8 (DB24C8) are heated
(Figure 1) under reflux (at 40 °C) in CH2Cl2 (50 mM in salt
+
in the recognition motif involving a CH2NH2 CH2 center
and a DB24C8 ring.
The preparations of (i) a dialkylammonium salt 2-H‚PF6,
carrying a dendritic wedge and bearing a cyclohexylmethyl
+
group, respectively, on either side of its NH2 center, and
(ii) a bis-dendron 5 containing a DB24C8 recognition site
are summarized in Scheme 1. The synthesis of the benzyl
Scheme 1. Preparation of Dendritic Wedges for Assembly by
Slippage
Figure 1. A slippage system par excellence!
and 150 mM in DB24C8) for 32 days.11 An almost 98%
conversion to the rotaxane in this experiment is reflected in
a 90% yield of a crystalline product which showed no
tendency to dissociate in CDCl3/CD3CN (3:1) solution upon
standing for several weeks at 20 °C. However, when this
crystalline product was dissolved in CD3SOCD3, it was found
(8) (a) Yamaguchi, N.; Hamilton, L. M.; Gibson, H. W. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 3275-3279. (b) Gibson, H. W.; Yamaguchi, N.;
Hamilton, L.; Jones, J. W. J. Am. Chem. Soc. 2002, 124, 4653-4665.
(9) The slippage methodology was exploited early on when rotaxanes
were prepared in a statistical manner. For examples see: (a) Harrison, I. T.
J. Chem. Soc., Chem. Commun. 1972, 231-232. (b) Schill, G.; Beckmann,
W.; Schweikert, N.; Fritz, H. Chem. Ber. 1986, 119, 2647-2655. The first
successful template-directed synthesis of rotaxanes by slippage was reported
in 1993. See: (c) Ashton, P. R.; Belohradsky, M.; Philp, D.; Stoddart, J. F.
J. Chem. Soc., Chem. Commun. 1993, 1269-1274. For a discussion of the
phenomenon see: (d) Fyfe, M. C. T.; Raymo, F. M.; Stoddart, J. F. In
Stimulating Concepts in Chemistry; Shibasaki, M., Stoddart, J. F., Vo¨gtle,
F., Eds.; VCH-Wiley: Weinheim, Germany, 2000; pp 211-220. For recent
examples see: (e) Sohgawa, Y. H.; Fujimori, H.; Shoji, J.; Furusho, Y.;
Kihara, N.; Takata, T. Chem. Lett. 2001, 8, 774-775. (f) Jeppesen, J. O.;
Becher, J.; Stoddart, J. F. Org. Lett. 2002, 4, 557-560.
ether-based dendritic aldehyde 1, which serves as a common
intermediate in the preparation of both 2-H‚PF6 and 5, was
carried out according to a literature procedure.12 Reductive
amination of 1 with aminomethylcyclohexane, followed by
(10) 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.
(11) An initial slippage experiment, which was performed (ref 10) with
the concentrations of both components at 10 mM, afforded the [2]rotaxane
in appreciable quantities after 16 weeks! As expected, increasing the
concentrations and using an excess of DB24C8 resulted in a higher yield
of the [2]rotaxane in a shorter time.
(12) Pollak, K. W.; Sanford, E. M.; Fre´chet, J. M. J. J. Mater. Chem.
1998, 8, 519-527.
3566
Org. Lett., Vol. 4, No. 21, 2002

protonation of the resulting amine and counterion exchange,
produced 2-H‚PF6 in 75% yield overall. The bis-dendron 5
incorporating the crown ether was prepared by reducing the
aldehyde 1, brominating the benzyl alcohol, and reacting the
benzyl bromide with Ph3P to generate the triphenylphos-
phonium salt 3‚Br in 63% yield overall. Wittig olefination
of 3‚Br with the syn-diformyl-DB24C8 derivative 413 af-
forded a mixture of cis and trans olefins which were then
subjected to catalytic hydrogenation, yielding 5 in 73% yield
overall.
On account of the fact that the dialkylammonium ion 2+
carries a large π-electron-rich dendritic wedge, it was decided
to perform a model slippage experiment (Scheme 2) first of
Scheme 2. Slippage and Deslippage
1
Figure 2. Partial H NMR spectra (500 MHz, CD2Cl2) of the
dendritic wedge-shaped [2]rotaxane 8-H‚PF6 formed by slippage
between 2-H‚PF6 and DB24C8: (a) free DB24C8, (b) the [2]-
rotaxane 8-H‚PF6, and (c) free 2-H‚PF6.
its free components, namely 2-H‚PF6 and DB24C8, supports
the fact that it has a [2]rotaxane architecture. In particular
(i) the downfield shifts of the signals for the methylene group
+
protons adjacent to the NH2 center and (ii) the separating
out of the signals for both the R-OCH2 and γ-OCH2 protons
into two pairs of well-resolved multiplets, reflecting their
diastereotopicities in the [2]rotaxane, should be noted. The
FAB mass spectrum afforded further strong evidence for the
interlocked nature of the components of 8-H‚PF6 with the
presence in it of a base peak at m/z 1288.6, corresponding
to the 8-H+ ion alongside a much less intense peak for the
2-H+ ion at m/z 840.4. These experiments prove convincingly
that, not only is the dendritic dumbbell 2-H‚PF6 able to
undergo slippage through the DB24C8 ring, but also the
product formed in the process is stable enough to be isolated
by chromatography without undergoing dissociation. Thus,
it may be safely concluded that, under relatively nonpolar
conditions, 8-H‚PF6 behaves as a molecular species, i.e., it
is a [2]rotaxane.
With both the wedge-shaped components in hand, and in
the knowledge that slippage can be performed between 2-
H‚PF6 and DB24C8, we decided to investigate the self-
assembly of the triply branched dendritic [2]rotaxane 9-
H‚PF6 from 2-H‚PF6 and 5. We used conditions similar to
those employed in the preparation of 8-H‚PF6 with the
exception that 2-H‚PF6 and 5 were present in the reaction
mixture in a 3:1 molar ratio. The reaction proceeded very
slowly. After 90 days, the reaction mixture was subjected
to silica gel column chromatography and the most apolar
component, which turned out to be the [2]rotaxane 9-H‚PF6,
was isolated pure in 19% yield. The interlocked nature of
all with DB24C8. Consequently, a CH2Cl2 solution (10 mM)
of 2-H‚PF6 was heated under reflux with DB24C8 (100 mM),
resulting in the appearance in the 1H NMR spectrum,
recorded in CD2Cl2, of a new set of signals which increased
in their intensities with time and have chemical shifts (see
below) commensurate with the formation of a [2]rotaxane.
When the slippage kinetics had slowed significantly (after
10 days), the mixture was separated into its components by
preparative TLC (SiO2: CH2Cl2/THF, 95:5). The [2]rotaxane
8-H‚PF6 was isolated in 39% yield in its pure form, along
with unreacted 2-H‚PF6 and DB24C8. Comparison (Figure
2) of the 1H NMR spectrum of 8-H‚PF6 with the spectra of
(13) The synthesis of 4 is also outlined in Scheme 1. In the reaction of
triethyleneglycol bistosylate (6) with 3,4-dihydroxybenzaldehyde in the
presence of a base, only one pure isomer, namely 7, is isolated. The
regioselectivity, expressed doubly in this nucleophilic substitution, is
believed to be dictated by the stabilization of the phenoxide ion in the
position para to the formyl group. See: (a) Reitz, A.; Avery, M. A.;
Verlander, M. S.; Goodman, M. J. Org. Chem. 1981, 46, 4889-4863. (b)
Allwood, B.; Kohnke, F. H.; Slawin, A. M. Z.; Stoddart, J. F.; Williams,
D. J. J. Chem. Soc., Chem. Commun. 1985, 311-314. (c) Bourgeois, J.-P.;
Echegoyen, L.; Fibbioli, M.; Pretsch, E.; Diederich, F. Angew. Chem., Int.
Ed. 1998, 37, 2118-2121. The 1H NMR spectrum recorded in CD3SOCD3
(see Supporting Information) is consistent with the presence of only one
isomer, i.e., compound 7, as already reported in the literature.
Org. Lett., Vol. 4, No. 21, 2002
3567

the two components of 9-H+ was confirmed by FAB mass
spectrometry and by 1H NMR spectroscopy. The mass
spectrum revealed a base peak at m/z 2770 corresponding
components is not as favorable as that observed (Figure 1)
in the model system10 could find its explanation in a number
of different factors present (Scheme 2) in both the dumbbell-
shaped component 2-H‚PF6 and the ring component 5 that
are absent in the bis(cyclohexylmethylammonium) ion and
DB24C8. The dendritic wedges present in 2-H‚PF6 and 5
contain six phenolic oxygen atoms and seven benzenoid
rings, all of which are going to enter into a competition with
the DB24C8 core oxygen atoms to accept hydrogen bonds
1
to the 9-H+ ion. The H NMR spectrum (Figure 3) of
+
from the single, all-important CH2NH2 CH2 center, i.e., the
immediate molecular and supramolecular environments
around this hydrogen bond donating center impair the
strengths of the [N+-H‚‚‚O] hydrogen bonding and [C-H‚
‚‚O] interactions at the recognition site. Presumably, if we
were to employ wedges containing only saturated hydrocar-
bon building blocks, we could anticipate a much more highly
efficient slippage “reaction”. Given this scenario, which we
are testing currently, there is good reason to suppose that
dendrimers containing mechanical bonds can be assembled
and disassembled with close to 100% efficiencies, depending
upon their immediate environments, where solvent, temper-
ature, and pH are all parameters that can be manipulated at
will.14 The prospect of being able to trap guest molecules
within a closed dendritic host system, which can subsequently
be broken apart in a controlled manner, is one that has very
obvious implications for the slow release15 of drugs in
patients.
1
Figure 3. Partial H NMR spectra (500 MHz, CD2Cl2) of the
dendritic [2]rotaxane 9-H‚PF6 self-assembled by slippage between
2-H‚PF6 and the crown ether-based bis-dendron 5: (a) free ring 5,
(b) the [2]rotaxane 9-H‚PF6, and (c) free 2-H‚PF6.
9-H‚PF6 displays signals reminiscent of those observed in
the spectrum of 8-H‚PF6, especially those for the methylene
protons in the CH2NH2 CH2 and R-, â-, and γ-OCH2 units,
that are consistent with a “rotaxane-like complex”. Thus,
under certain conditions, this “complex” may be considered
to be a rotaxane. Yet, under different conditions, this
“complex” behaves like a pseudorotaxane. When 9-H‚PF6
was dissolved in CD3SOCD3, a solvent which acts as a very
good hydrogen bond acceptor, the dissociation of the
“rotaxane-like complex” into its components, 2-H‚PF6 and
Acknowledgment. We thank the National Science Foun-
dation (CHE-9910199) and the Petroleum Research Fund,
administered by the American Chemical Society (PRF-
35071-AC4), for generous financial support. This material
is based upon work supported by the National Science
Foundation under equipment grant number CHE-9974928.
+
Supporting Information Available: 1H and 13C NMR
and mass spectra of compounds 2-H‚PF6, 4, 5, 7, 8-H‚PF6,
and 9-H‚PF6, experimental procedures for their preparation,
and the calculations of t1/2 for both 8-H‚PF6 and 9-H‚PF6 in
CD3SOCD3 at 25 °C. This material is available free of charge
via the Internet at http://pubs.acs.org.
1
5, took place slowly and could be followed by H NMR
spectroscopy. The half-life for the first-order decay14 of this
“complex” was 17.7 h, a t1/2 that is considerably longer than
that observed10 for the “complex” shown in Figure 1. When
this same experiment was carried out on 8-H‚PF6, we found
that it dissociated into its two components, 2-H‚PF6 and
DB24C8, with a t1/2 of 7.8 h.
OL026479C
(14) The ability to assemble and disassemble dendrimers where hydrogen
bonding between the components is complemented by a mechanical bond
renders the rotaxane-like dendrimer much more stable than a conventional
supramolecular dendrimer where multiple hydrogen bonds, even when they
act cooperatively, lead to dynamic superstructures for the most part, i.e.,
the mechanical bond can be employed to bring added stability to supramo-
lecular dendrimers based on hydrogen-bonding interactions.
(15) (a) Park, K. Controlled Drug DeliVery. Challenges and Strategies;
American Chemical Society: Washington, DC, 1997. (b) Ooya, T.; Yui,
N. J. Controlled Release 1999, 58, 251-269. (c) Chiu, S.-H.; Rowan, S.
J.; Cantrill, S. J.; Glink, P. T.; Garrell, R. L.; Stoddart, J. F. Org. Lett.
2000, 2, 3631-3634.
To date, this investigation has established the principle
that mechanically interlocked dendrimers can be self-
assembled under thermodynamic control by using the slip-
page protocol.9 The major driving force for the rotaxane
formation in refluxing dichloromethane is believed to arise
from [N+-H‚‚‚O] hydrogen bonding and [C-H‚‚‚O] inter-
actions. The fact that the equilibrium for the formation
(Scheme 2) of the dendritic [2]rotaxane 9-H‚PF6 from its
3568
Org. Lett., Vol. 4, No. 21, 2002