Thermodynamic Synthesis of Rotaxanes by Imine Exchange

Article abstract of DOI:10.1021/ol991047w

(Matrix Presented) By utilizing the dynamic nature of imine bonds, it is possible to construct [2]rotaxanes from a ring and a preformed dumbbell under thermodynamic control. These dynamic [2]rotaxanes, which exhibit reversible supramolecular-like behavior

Full text of DOI:10.1021/ol991047w

ORGANIC
LETTERS
1999
Vol. 1, No. 12
1913-1916
Thermodynamic Synthesis of Rotaxanes
by Imine Exchange
Stuart J. Rowan† 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 September 15, 1999
ABSTRACT
By utilizing the dynamic nature of imine bonds, it is possible to construct [2]rotaxanes from a ring and a preformed dumbbell under thermodynamic
control. These dynamic [2]rotaxanes, which exhibit reversible supramolecular-like behavior in the presence of appropriate catalysts, can be
“fixed” by reduction of their imine bonds.
Although thermodynamic control dominates the chemistry
of noncovalently bonded systems and allows spontaneous
access to intricate supramolecular entities, with a few notable
and spectacular exceptions,1 many molecular aggregates are
difficult to characterize in solution because of a lack of
sufficient cooperativity between their noncovalent bonding
arrays. The prospect of being able to synthesize more robust
analogues of these noncovalently bonded systems is an
appealing one. In a recent Letter,2 we outlined the synthesis
of a rotaxane utilizing thermodynamically controlled revers-
ible covalent chemistry involving imine bond formation. In
this Letter, we describe the construction of two dynamic
rotaxanes in which the ring component is cyclobis(paraquat-
p-phenylene)3 (CBPQT4+), with its π-electron-deficient bi-
pyridinium units, and a dumbbell component which contains
either a π-electron-rich 1,5-dioxynaphthalene or 1,4-dioxy-
benzene ring system centrally located within a polyether
chain, terminated by large aromatic stoppers containing imine
bonds produced as a result of either imine formation or
exchange.4,5 We show how these two rotaxanes can be
equilibrated in the presence of an excess of the appropriate
dumbbell component. Furthermore, we also demonstrated
that we can “fix” the dynamic [2]rotaxanes by reduction of
the imine bonds present in their dumbbell components.
The syntheses of the dynamic dumbbells 5NP/5BZ in both
the 1,5-dioxynaphthalene (NP) and 1,4-dioxybenzene (BZ)
series are outlined in Scheme 1. The account given here
(3) Asakawa, M.; Dehaen, W.; L′abbe´, G.; Menzer, S.; Nouwen, J.;
Raymo, F. M.; Stoddart, J. F.; Williams, D. J. J. Org. Chem. 1996, 61,
9591-9595.
(4) In imine-forming reactions, it is H2O that is either produced or
required as a nucleophile, to establish the equilibrium between the aldehyde,
the amine, and the imine. In imine-exchange reactions, it is a “second”
amine that reacts with the imine, resulting in “second” imine, thus
establishing an equilibrium between two amines and two imines.
(5) In order that the equilibrium is driven toward rotaxane formation,
the dumbbell component has to interact strongly with CBPQT4+ as well as
contain the appropriate imine functionality within its stoppers. The 1,5-
dioxynaphthalene derivative carrying two methoxyethoxyethoxy side chains
has been shown3 to form a strong 1:1 complex with Ka > 5000 M-1 in
MeCN at room temperature with CBPQT‚4PF6, cf., Ka ) 2220 ( 240 M-1
for the analogous 1:1 complex in which 1,4-dioxybenzene replaces 1,5-
dioxynaphthalene.
† Current address: Department of Macromolecular Science, Case Western
Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-7202.
Fax: (216) 368-4202.
(1) (a) MacDonald, J. C.; Whitesides, G. M. Chem. ReV. 1994, 94, 2383-
2420. (b) Zimmerman, S. C.; Zeng, F. W.; Reichert, D. E. C.; Kolotuchin,
S. V. Science 1996, 271, 1095-1098. (c) Sijbesma, R. P.; Beijer, F. H.;
Brunsveld, L.; Folmer, B. J. B.; Hirschberg, J. H. K. K.; Lange, R. F. M.;
Lowe, J. K. L.; Meijer, E. W. Science 1997, 278, 1601-1604. (d) Jolliffe,
K. A.; Timmerman, P.; Reinhoudt, D. N. Angew. Chem. Int. Ed. 1999, 38,
933-937. (e) Rebek, J., Jr. Acc. Chem. Res. 1999, 32, 278-286.
(2) Cantrill, S. J.; Rowan, S. J.; Stoddart, J. F. Org. Lett. 1999, 1, 1363-
1366 and references therein.
10.1021/ol991047w CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/16/1999

in MeCN. Treatment of 4NP with 3,5-di-tert-butylaniline in
the presence of either MgSO4 or powdered 4 Å molecular
sieves resulted in the formation of the dynamic dumbbell
5NP in almost quantitative yield. Reduction (NaBH4/MeOH)
of this diimine 5NP gave (83%) the “fixed” dumbbell 6NP.
A threadlike analogue (7NP) of 5NP, in which the two 3,5-
di-tert-butylphenyl groups in 5NP have been replaced by two
p-methyphenyl groups, was also prepared from 4NP by
reacting it with p-toluidine (p-MeC6H4NH2). The [2]pseudo-
rotaxane [7NP‚CBPQT]‚4PF6 is formed spontaneously when
equimolar amounts of 7NP and CBPQT‚4PF6 are mixed
together in MeCN.
Scheme 1
The synthesis of the purple-colored dynamic [2]rotaxane
9NP‚4PF6 in ca. 90% yield was performed initially using a
threading, followed-by-stoppering approach (a in Scheme 2),
Scheme 2
relates only6 to the NP series, starting from the known7 diol
1NP, which was converted (TsCl/NEt3/ DMAP/CH2Cl2) into
the bistosylate 2NP in 88% yield. Reaction (K2CO3/MeCN)
of 2-hydroxymethylphenol with 2NP afforded (90%) 3NP
which was oxidized (PCC/CH2Cl2) to the dialdehyde 4NP
in 70% yield. 4NP was shown to bind8 to CBPQT‚4PF6 with
a Ka value of ca. 1.7 ( 0.4 × 104 M-1 for this 1:1 complex
whereby 3,5-di-tert-butylaniline was added to a 10 mM
MeCN solution of 4NP and CBPQT‚4PF6 containing an
excess of powdered 4 Å molecular sieves. Next, we at-
tempted to prepare 9NP‚4PF6 utilizing the reversible nature
of imine bond formation (b in Scheme 2). Thus, addition of
equimolar amounts9 of the preformed dumbbell 5NP to
CBPQT‚4PF6 in CD3CN (9.5 mM) did result in the formation
of 9NP‚4PF6 during a 2-week period. To confirm that it is
the imine functions in 5NP that are responsible for rotaxane
(6) In the BZ series, the bistosylate 2BZ, prepared in 63% yield by
treatment of the diol 1BZ with TsCl/Et3N/DMAP in CH2Cl2, was reacted
(K2CO3/DMF) with salicylaldehyde to yield (33%) the dialdehyde 4BZ.
The diiminess5BZ and 7BZswere prepared by reacting 4BZ with the
appropriate arylamine in the presence of MgSO4. Reduction (NaBH4/MeOH)
of these diimines afforded the diamine dumbbellss6BZ and 8BZ.
(7) Bravo, J. A.; Raymo, F. M.; Stoddart, J. F.; White, A. J. P.; Williams,
D. J. Eur. J. Org. Chem. 1998, 2565-2571.
(8) The Ka value was determined by varying the concentration of CBPQT‚
4PF6 in the presence of a known concentration of 4NP and measuring the
absorbance of the charge-transfer band. CBPQT‚4PF6 (MeCN, 10 mM)
containing 4NP (0.2 mM) was titrated with 4NP (MeCN, 0.2 mM) until
the concentration of CBPQT‚4PF6 reached 0.1 mM. The binding constant
was obtained by curve fitting the experimental absorbance values using
the ULTRAFIT 2.11 program [see: Connors, K. A. Binding Constants;
Wiley: New York, 1987; Chapter 4]. Previously, we had shown [ref 3]
that CBPQT‚4PF6 can bind a 1,5-dioxynaphthalene derivative carrying two
methoxyethoxyethoxy side chains in a 1:2 ratio at concentrations >10-3
M and in a 1:1 ratio at concentrations <10-3 M. By keeping the
concentration of 4NP < 10-3 M, and starting with a large excess of CBPQT‚
4PF6, we can estimate a value of Ka for the 1:1 complex of ca. 1.7 ( 0.4
× 104 M-1
.
1914
Org. Lett., Vol. 1, No. 12, 1999

formation, the “inert” diamine 8NP was added to CBPQT‚
4PF6. Although the CD3CN solution turned pale pink,
presumably on account of some weak association of the 1,5-
dioxynaphthalene ring system in 8NP with the outside of
CBPQT4+, no binding of 8NP inside its cavity was observed,
even after addition of an acid (e.g., NH4PF6) or a nucleophile
(e.g., p-MeC6H4NH2).
pathway for the production of 9NP‚4PF6. Thus, the reaction
was repeated using 5% of p-MeC6H4NH2 as a catalyst. Figure
2 shows the partial H NMR spectrum in the region where
1
The mechanism (Figure 1) of the formation of 9NP‚4PF6
presumably involves imine hydrolysis, as a result of small
Figure 2. Partial 1H NMR (400 MHz, CD3CN) spectra of the t-Bu
region during the dynamic [2]rotaxane 9NP·4PF6 formation. This
reaction was carried out at 9.5 mM using 5% p-MeC6H4NH2 as
catalyst. The small peak observed downfield of the rotaxane peak
is believed to correspond to a semirotaxane wherein one end of
the “dumbbell” carries a 3,5-di-tert-butylaryl group and the other
end is occupied by either an aldehyde or a p-methylaryl group.
the protons on the tert-butyl groups resonate. Monitoring the
reaction using these signals indicated that equilibrium was
reached within 2 days (cf. 2 weeks with no amine catalyst
present), implying that, in this particular reaction, the major
pathway to the formation of the dynamic [2]rotaxane is imine
exchange.
Figure 1. Formation of the [2]rotaxane 9NP·4PF6.
To exploit the reversible nature of imine exchange even
further, we have assembled the BZ-dynamic [2]rotaxane
9BZ‚4PF6 utilizing the stoppering methodology in a manner
analogous to that used to obtain 9NP‚4PF6 (a in Scheme 2).
The yield (65%) of 9BZ‚4PF6 was lower compared with that
(90%) of 9NP‚4PF6, reflecting the weaker association
(Ka ) 1.8 ( 0.4 × 103 M-1) of 4BZ with CBPQT‚4PF6. On
account of the differences in the noncovalent bonding
interactions between the dumbbell and the ring components
of these two [2]rotaxanes, we decided to see if we could
exchange (c in Scheme 2) the BZ dumbbell for the NP
dumbbell and so convert 9BZ‚4PF6 into 9NP‚4PF6 under
thermodynamic control. This objective was achieved by
adding 1 equiv11 of 5NP to a CD3CN solution containing
65% of the BZ-dynamic [2]rotaxane 9BZ‚4PF6 and 35% of
free CBPQT‚4PF6 and 5BZ.
amounts of H2O being present, followed by threading and
then formation of the imine once again. Since acid is known10
to catalyze imine hydrolysis and formation, the reaction was
carried out in the presence of 5% of a weak acid (NH4PF6).
This modification resulted in an increase in the rate of
formation of the [2]rotaxane, such that equilibrium was
reached inside 3 h.
Next, it was decided to try and establish if a similar result
could be obtained during an imine exchange process. And
so, p-MeC6H4NH2 (5%) and NH4PF6 (5%) were added9 to
the dynamic dumbbell 5NP and CBPQT‚4PF6. Addition of
both the acid and the nucleophile increased the rate of [2]-
rotaxane formation such that equilibrium was attained inside
2 h. This observation, however, does not rule out the
possibility of imine hydrolysis/formation being the major
The reaction was followed (Figure 3) by monitoring the
relative intensities of signals for the tert-butyl protons in the
various different species. On addition of 5% of both NH4-
PF6 and p-MeC6H4NH2, the proportion of 9NP‚4PF6 in-
creased gradually at the expense of 9BZ‚4PF6 until an
(9) In the formation of the 9NP‚4PF6, via the dynamic process, stock
solutions (20 mM) of CBPQT‚4PF6 and 5NP in CD3CN were prepared
and partially dried with freshly activated 4 Å molecular sieves. CBPQT‚
4PF6 (300 µL) and 5NP (300 µL) were added to an NMR tube (note that
the resulting concentration of the reactants at this point is 10 mM). Catalyst
(if any) (15 µL, 5%) was then added to the NMR tube from 20 mM stock
solutions of either NH4PF6 or p-MeC6H4NH2 in CD3CN. In the case where
nosor only onescatalyst was used, then an extra 30 µL (or 15 µL) of
CD3CN was added to the NMR tube in order to make the concentration of
all the samples 9.5 mM. 1H NMR spectroscopy was then used to follow
the reactions at room temperature.
(11) The exchange reaction was carried out by addition of 5NP in CD3-
CN (300 µL, 20 mM) to a CD3CN (300 µL, 20 mM) solution containing
the [2]rotaxane 9BZ‚4PF6 (65%) and free CBPQT‚4PF6 and 5BZ (35%).
Then 15 µL of the catalyst p-MeC6H4NH2/NH4PF6 (20 mM of each in CD3-
CN) was added to the reaction mixture (final concentration 9.8 mM) and
1
(10) Layer, R. W. Chem. ReV. 1963, 63, 489-510.
the reaction monitored by H NMR spectroscopy.
Org. Lett., Vol. 1, No. 12, 1999
1915

(d in Scheme 2). Eventually, we discovered that reduction
of 9NP‚4PF6 can be achieved by using the BH3‚2,6-lutidine
complex, followed by hydrolysis, to afford the “fixed” [2]-
rotaxane 10NP‚4PF6 in 40% yield.14
The research reported here has shown how [2]rotaxanes
with dynamic structures can be assembled under equilibrium
control. These dynamic species represent a halfway house
between rotaxanes and pseudorotaxanes. Although their
components are covalent in nature, under certain conditions,
e.g., in the presence of a small nucleophile and/or an acid
catalyst, they can equilibrate and exchange their components
as if they were their supramolecular counterparts, namely,
the pseudorotaxanes. In this respect, dynamic rotaxanes have
some of the hallmarks of the “rotaxanes” which have been
obtained using the slippage methodology15 where, in nonpolar
solvents at low temperatures, they behave like rotaxanes
while, at higher temperatures in more highly solvating polar
solvents, they assume the characteristics of pseudorotaxanes.
In the case of the dynamic rotaxanes, it is the presence of
the appropriate catalyst which imparts upon them their
pseudorotaxane characteristics. These new dynamic rotax-
anes, however, have the added advantage that they can be
transported out of a thermodynamic regime and transferred
into a kinetic one, simply by reduction of their imine bonds.
Figure 3. Partial 1H NMR (400 MHz, CD3CN) spectra of the t-Bu
region during the exchange reaction of 9NP·4PF6 with 9BZ·4PF6.
This reaction was carried out at 9.8 mM using 5% p-MeC6H4NH2/
1
NH4PF6 as catalysts. Time ) [0] indicates the H NMR spectrum
taken before any catalyst was added. The small peak observed just
upfield of the rotaxane peaks is believed to correspond to the
semirotaxane wherein one end of the “dumbbell” carries a 3,5-di-
tert-butylaryl group and the other end is occupied by either an
aldehyde or the p-methylaryl group.
Acknowledgment. The authors thank Stuart J. Cantrill
for producing the final version of this manuscript and UCLA
for generous financial support.
Supporting Information Available: Experimental pro-
cedures and characterization data for 1NP-10NP and 4BZ-
5BZ. 1H NMR spectra for 4NP-8NP, 10NP‚4PF6, 4BZ, and
equilibrium was reached after 14 h, i.e., the equilibrium takes
a lot longer to reach than in the previous experiments
involving only one dumbbell at a time. This difference in
time scale is not unexpected.12 The ratio of the dynamic
rotaxanes 9NP‚4PF6:9BZ‚4PF6, at equilibrium, is ca. 6:1,
reflecting the stronger binding of the naphthalene-derived
components over the benzene derivatives. Thus, this experi-
ment reveals all the subtlety and attractions of using
thermodynamic control13 exclusively in the self-assembly of
interlocked molecular compounds.
1
5BZ. H NMR spectra of the reaction mixtures formed in
the synthesis of 9NP‚4PF6 and 9BZ‚4PF6 and VT 1H NMR
of these two compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL991047W
(13) (a) Rowan, S. J.; Sanders, J. K. M. Chem. Commun. 1997, 1407-
1408. (b) Hamilton, D. G.; Feeder, N.; Teat, S. J.; Sanders, J. K. M. New.
J. Chem. 1998, 1019-1021. (c) Sanders, J. K. M. Chem. Eur. J. 1998, 4,
1378-1383. (d) Kidd, T. J.; Leigh, D. A.; Wilson, A. J. J. Am. Chem. Soc.
1999, 121, 1599-1600. (e) Tam-Chang, S.-W.; Stehouwer, J. S.; Hao, J.
J. Org. Chem. 1999, 64, 334-335. (f) Ipaktschi, J.; Hosseinzadeh, R.; Schalf,
P. Angew. Chem. Int. Ed. 1999, 38, 1658-1660. (g) Weck, M.; Mohr, B.;
Sauvage, J.-P.; Grubbs, R. H. J. Org. Chem. 1999, 64, 5463-5471. (h)
Fujita, M. Acc. Chem. Res. 1999, 32, 53-61. (i) Cousins, G. R. L.; Poulsen,
S.-A.; Sanders, J. K. M. Chem. Commun. 1999, 1575-1576.
(14) The yield is based on the assumption that the starting material
consists of only 90% 9NP‚4PF6.
One challenge remained. It was to show that the imine
functions in the dynamic [2]rotaxanes can be reduced without
losing the interlocking between their dumbbells and rings
(12) The increased reaction time reflects the fact that there are now an
increased number of reactions that are required to occur before 5NP can
exchange with 5BZ in the [2]rotaxane. The first step in the process is
presumably imine exchange (or hydrolysis) of 9BZ‚4PF6, resulting in a
semirotaxane (Figure 1) which can then undergo decomplexation of the
BZ thread component revealing “free” CBPQT‚4PF6. This “free” cyclophane
can then form 9NP‚4PF6 with 5NP by means of the process depicted by b
in Scheme 2.
(15) Raymo, F. M.; Houk, K. N.; Stoddart, J. F. J. Am. Chem. Soc. 1998,
120, 9318-9322.
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Org. Lett., Vol. 1, No. 12, 1999