Template-directed synthesis of mechanically interlocked molecular bundles using dynamic covalent chemistry

Article abstract of DOI:10.1021/ol061262u

Mixing the dipyrido[24]crown-8 derivatives carrying one or two formyl group(s) on the 4 position(s) of their pyridine ring(s) with a 3-fold symmetrical trisammonium ion template in a 3:1 ratio in CD₃NO ₂ results in the formation of t

Full text of DOI:10.1021/ol061262u

ORGANIC
LETTERS
2006
Vol. 8, No. 18
3899-3902
Template-Directed Synthesis of
Mechanically Interlocked Molecular
Bundles Using Dynamic Covalent
Chemistry
Brian H. Northrop, Fabio Arico´, Nick Tangchiavang, Jovica D. Badjic´, and
J. Fraser Stoddart*
Department of Chemistry and Biochemistry and the California NanoSystems Institute,
UniVersity of CaliforniasLos Angeles, 405 Hilgard AVenue,
Los Angeles, California 90095
stoddart@chem.ucla.edu
Received May 23, 2006
ABSTRACT
Mixing the dipyrido[24]crown-8 derivatives carrying one or two formyl group(s) on the 4 position(s) of their pyridine ring(s) with a 3-fold
symmetrical trisammonium ion template in a 3:1 ratio in CD3NO2 results in the formation of thermodynamically stable [4]pseudorotaxanes
which, upon addition of a 1,3,5-trisaminobenzene cap, form mechanically interlocked molecular bundles with one and two caps, respectively,
by virtue of dynamic imine bond formation.
Beginning with the first chemical synthesis of a catenane
by Wasserman1 in 1960, molecular compounds that exhibit
exotic topologies and/or mechanical bonds have been targeted
by synthetic chemists. Mechanically interlocked and knotted
compounds, such as catenanes,2 rotaxanes,3 trefoil knots,4
and Borromean rings5 synthesized usually by template-
directed6 protocols depending on molecular recognition7 and
self-assembly8 processes, represent challenging synthetic
goals that have nonetheless been realized. While much pro-
gress has been made in developing synthetic strategies to
make such compounds, molecules exist9 beyond this first
crop of compounds that need to be accessed by chemical
synthesis.
(3) Rotaxanes are molecules comprised of ring-shaped component(s)
and dumbbell-shaped component(s) that are mechanically interlocked. For
recent examples, see: (a) Stainer, C. A.; Alderman, S. J.; Claridge, T. D.
W.; Anderson, H. L. Angew. Chem., Int. Ed. 2002, 41, 1769-1772. (b)
Andersson, M.; Linke, M.; Chambron, J.-C.; Davidson, J.; Heitz, V.;
Hammarstro¨m, L.; Sauvage, J.-P. J. Am. Chem. Soc. 2002, 124, 4347-
4362. (c) Asakawa, M.; Brancato, G.; Fanti, M.; Leigh, D. A.; Shimizu,
T.; Slawin, A. M. Z.; Wong, J. K. Y.; Zerbetto, F.; Zhang, S. J. Am. Chem.
Soc. 2002, 124, 2939-2950. (d) Nikitin, K.; Long, B.; Fitzmaurice, D.
Chem. Commun. 2003, 282-283. (e) Iijima, T.; Vignon, S. A.; Tseng, H.-
R.; Jarrosson, T.; Sanders, J. K. M.; Marchioni, F.; Venturi, M.; Apostoli,
E.; Balzani, V.; Stoddart, J. F. Chem.-Eur. J. 2004, 10, 6375-6392.
(4) For examples of synthetic trefoil knots, see: (a) Dietrich-Buchecker,
C. O.; Sauvage, J.-P. Angew. Chem., Int. Ed. Engl. 1989, 28, 189-192. (b)
Carina, R. F.; Dietrich-Buchecker, C. O.; Sauvage, J.-P. J. Am. Chem. Soc.
1996, 118, 9110-9116. (c) Ashton, P. R.; Matthews, O. A.; Menzer, S.;
Raymo, F. M.; Spencer, N.; Stoddart, J. F.; Williams, D. J. Liebigs Ann.
Chem. 1997, 2485-2494. (d) Hunter, C. A.; Mayers, P. C. Nature 2001,
411, 763. (e) Lukin, O.; Kubota, T.; Okamoto, Y.; Kaufmann, A.; Vo¨gtle,
F. Chem.-Eur. J. 2004, 10, 2804-2810
(1) (a) Wasserman, E. J. Am. Chem. Soc. 1960, 82, 4433-4434. (b)
Frisch, H.; Wasserman, E. J. Am. Chem. Soc. 1961, 83, 3789-3795.
(2) Catenanes are molecules comprised of two (or more) ring-shaped
components that are interlocked like the links in a chain. See: (a) Schill,
G. Catenanes, Rotaxanes and Knots; Academic Press: New York, 1971.
(b) Molecular Catenanes, Rotaxanes and Knots; Sauvage, J.-P., Dietrich-
Buchecker, C., Eds.; Wiley-VCH: Weinheim, 1999.
10.1021/ol061262u CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/03/2006

Dynamic covalent chemistry10 (DCC) has emerged as an
efficient and versatile strategy for the synthesis of complex
molecular structures. Whereas early examples of supramo-
lecular assistance to covalent synthesis11 relied heavily on
kinetically controlled reactions for postassembly covalent
modification, DCC takes advantage of the reversible nature
of acetal,12 disulfide,13 ester,14 and imine15 bond formation,
as well as carbon-carbon bond formation during methasis16
and metal-ligand coordination,17 to allow the formation of
the new covalent bonds to be thermodynamically controlled.
The reversible formation of covalent bonds provides a means
of proofreading and editing intermediate structures to
achieve, with time, the most thermodynamically stable prod-
uct. When coupled with templation, DCC has been shown
to provide a highly efficient route to mechanically interlocked
molecules. Recent examples include a calix[4]arene-based
[8]catenane,16d multiple rotaxanes,18 interlocked dendrimers,19
and molecular Borromean rings.5 In some cases, the dynamic
covalent structures have been fixed5,18,19 through reduction
of their imine bonds to kinetically stable amine ones. Here,
we describe the use of DCC in the context of imine bond
formation, along with computational modeling, in the
template-directed synthesis of two mechanically interlocked
molecular bundles from five and six components, respec-
tively. The pool of structures from which these components
have been drawn is shown in Figure 1, and the manner in
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G. W. V.; Atwood, J. L.; Stoddart, J. F. Science 2004, 304, 1308-1312.
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VCH: Weinheim, 1999. (f) Stoddart, J. F.; Tseng, H.-R. Proc. Natl. Acad.
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Figure 1. Structural formulas of the trisammonium ion template
TAT-H3‚3PF6, the formyl derivatives (CHO)-DP24C8 and (CHO)2-
DP24C8 of dipyrido[24]crown-8 (DP24C8), and 1,3,5-trisami-
nobenzene (TAB). The proton descriptors employed in Figures 2
and 4 are defined on the four structural formulas.
(8) (a) Lindsey, J. S. New J. Chem. 1991, 15, 153-180. (b) Philp, D.;
Stoddart, J. F. Angew. Chem., Int. Ed. 1996, 35, 1154-1195. (c) Fujita, M.
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Ockwig, N. W.; Chae, H. K.; Eddaoudi, M.; Kim, J. Nature 2003, 423,
705-714.
which they have been employed in the two syntheses is
outlined in Scheme 1. The supramolecular assistance to
covalent synthesis11 is provided by hydrogen bonding
between crown ether derivatives and secondary dialkylam-
monium ion centers, and the DCC uses imine bond formation
to link together three individually derivatized crown ethers,
carrying either one or two formyl groups, singly or doubly,
with a trigonal capping reagent20 displaying the three
matching amine functions.
(9) For a preliminary discussion of the mechanically interlocked mol-
ecules beyond catenanes and rotaxanes, see: Chang, T.; Heiss, A. M.;
Cantrill, S. J.; Fyfe, M. C. T.; Pease, A. R.; Rowan, S. J.; Stoddart, J. F.;
Williams, D. J. Org. Lett. 2000, 2, 2943-2946.
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Stoddart, J. F. Angew. Chem., Int. Ed. 2002, 41, 898-952.
(11) For examples of the kinetic approach, see: (a) Fyfe, M. C. T.;
Stoddart, J. F. Acc. Chem. Res. 1997, 30, 393-401. (b) Rowan, S. J.;
Cantrill, S. J.; Stoddart, J. F. Org. Lett. 1999, 1, 129-132.
Complexation occurs immediately upon addition of 3.0
equiv of (CHO)-DP24C8 to TAT-H3‚3PF6 in CD3NO2, as
(12) (a) Fuchs, B.; Nelson, A.; Star, A.; Stoddart, J. F.; Vidal, S. Angew.
Chem., Int. Ed. 2003, 42, 4220-4242. (b) Cacciapaglia, R.; Di Stefano, S.;
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Chem.-Eur. J. 2005, 11, 4655-4666.
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121, 1599-1600. (b) Weck, M.; Mohr, B.; Sauvage, J.-P.; Grubbs, R. H.
J. Org. Chem. 1999, 64, 5463-5471. (c) Kilbinger, A. F. M.; Cantrill, S.
J.; Waltman, A. W.; Day, M. W.; Grubbs, R. H. Angew. Chem., Int. Ed.
2003, 42, 3281-3285. (d) Wang, L.; Myroslav, O. V.; Bogdan, A.; Bolte,
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(20) While the templating effect of -CH2NH2+CH2- centers located in
dumbbell components have been used to activate the formation of two imine
bonds in macrocyclic polyethers to form rotaxanes in a process known as
clipping (Glink, P. T.; Oliva, A. I.; Stoddart, J. F.; White, A. J. P.; Williams,
D. J. Angew. Chem., Int. Ed. 2001, 40, 1870-1875. Horn, H.; Ihringer, I.;
Glink, P. T.; Stoddart, J. F. Chem.-Eur. J. 2003, 9, 4040-4054.), the
capping process described in this letter is more reminescent of forming
rotaxanes under thermodynamic control by imine exchange (Rowan, S. J.;
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3900
Org. Lett., Vol. 8, No. 18, 2006

Scheme 1. Addition of Either (CHO)-DP24C8 or (CHO)2-DP24C8 to TAT-H3‚3PF6 in a 3:1 Ratio Leads to the Formation of the
[4]Pseudorotaxanes MFPR-H3‚3PF6 and DFPR-H3‚3PF6, Respectivelya
a Capping of these two complexes with 1.0 and 2.0 equiv, respectively, of TAB results in the formation of the mechanically interlocked
molecular bundles MFB-H3‚3PF6 and DFB-H3‚3PF6, respectively.
1
indicated (Figure 2) by H NMR spectroscopy. As is char-
partially complexed, as well as fully complexed, species.
Integration of these peaks suggests that MFPR-H33+ accounts
for >95% of the species present in solution. Isothermal
titration microcalorimetry (ITC) indicates a “binding con-
stant” per binding site of 11 800 M-1 (∆G° ) -5.5 kcal/
+
acteristic of the binding of -CH2NH2 CH2- centers by
crown ethers, the two pairs of benzylic methylene protons
in TAT-H3 are shifted upfield from δ ) 4.5 and 4.6 pm
3+
3+
to δ ) 3.9 and 4.4 pm, respectively. Moreover, MFPR-H3
3+
is a kinetically stable complex on the 1H NMR timescale at
298 K because peaks can be identified for uncomplexed and
mol) between TAT-H3 and (CHO)-DP24C8 in MeNO2.
Computational force-field modeling (Figure 3a) reveals that
the three NH2 functions in TAB should be capable of forming
imine bonds with the CHO groups in three complexed
1
(CHO)-DP24C8 macrocycles. Indeed, although H NMR
spectroscopy reveals the formation of a number of products
initially when 1.0 equiv of TAB is added to MFPR-H3‚3PF6,
after 2 h these kinetic intermediates converge21 to the most
stable thermodynamic productsMFB-H3‚3PF6 with 3-fold
(C3V) symmetryscontaining three imine bonds. This out-
come22 is supported (Figure 3a) by high-resolution electro-
spray ionization (HR-ESI) mass spectrometric analysis: m/z
) 1131.52 for [M - 2PF6]2+ compared with the calculated
value of 1131.28.
Formation of DFPR-H3‚3PF6 was observed (Figure 4) by
1H NMR spectroscopy to occur spontaneously upon mixing
of (CHO)2-DP24C8 and TAT-H3‚3PF6 in CD3NO2 in a 3:1
ratio. ITC measurements indicate a binding constant per
binding site23 of 3520 M-1 (∆G° ) -4.8 kcal/mol) between
TAT-H33+ and (CHO)2-DP24C8 in MeNO2. Computational
force-field modeling (Figure 3b) reveals that 2.0 equiv of
TAB is capable of linking all six formyl functions of the
(21) Within 10 min of the addition, one witnesses a decrease in the
intensity of the peak at δ ) 9.95 ppm for formyl protons as the intensity
of the singlet at δ ) 8.10 ppm for imine protons increases simultaneously.
(22) All attempts to obtain X-ray quality single crystals of MFB-H3‚
3PF6 and DFB-H3‚3PF6 or to reduce (e.g., with BH3-THF and BH3-lutidine)
the three and six imine bonds, respectively, have been unsuccessful to date.
Hence, the evidence for the formation of these two mechanically interlocked
compounds rests primarily on 1H NMR spectroscopy and mass spectrometry
for the present.
1
Figure 2. Partial H NMR spectra (CD3NO2, 13.8 mM) of (a)
(CHO)-DP24C8, (b) TAT-H3‚3PF6, (c) MFPR-H3‚3PF6, and (d)
MFB-H3‚3PF6. For a definition of the proton (H) descriptors, see
Figure 1.
Org. Lett., Vol. 8, No. 18, 2006
3901

Figure 4. Partial 1H NMR spectra (CD3NO2, 8.8 mM) of (a)
(CHO)2-DP24C8, (b) TAT-H3‚3PF6, (c) DFPR-H3‚3PF6, and (d)
DFB-H3‚3PF6 and other unidentified minor products. For a defini-
tion of the proton (H) descriptors, see Figure 1.
was confirmed (Figure 3b) by HR-ESI mass spectrometric
analysis: m/z ) 758.40 for [M - 3PF6]3+, compared with
the calculated value of 756.91.
The mechanically interlocked molecular bundles are
distinguishable9 from regular rotaxanes. Once either the
3+
3+
singly capped MFB-H3 or doubly capped DFB-H3 has
been formed, it is the mutual linking together, by a com-
bination of supramolecular and dynamic covalent chemistry,
of either five or six components, respectively, that results in
the mechanically interlockingsnot the addition of large
stoppers to rods to constrain the movement of rings trapped
thereupon. This alternative mode of construction24 of me-
chanically interlocked compounds represents another way
of exploiting the mechanical bond at the molecular level in
chemistry.
Figure 3. HR-ESI mass spectra showing the [M - 2PF6]2+
and [M - 3PF6]3+ peaks at m/z ) 1131.52 and 705.70 for (a)
MFB-H3‚3PF6 as well as the [M - 3PF6]3+ peak at m/z ) 758.40
for (b) DFB-H3‚3PF6 along with the computed lowest-energy
structures displayed alongside and the isotopic patterns inset within
each spectra.
Acknowledgment. One (B.H.N.) of us thanks the ACS
Division of Organic Chemistry for a graduate fellowship,
sponsored by the Nelson J. Leonard ACS DOC Fellowship,
sponsored by Organic Synthesis, Inc.
three (CHO)2-DP24C8 macrocycles in such a way that each
equivalent of TAB reacts with the three formyl groups
positioned on either side of TAT-H33+. Double capping of
Supporting Information Available: Synthesis of com-
pounds, ITC, HR-ESI, and computational modeling proce-
dures. This material is available free of charge via the Internet
at http://pubs.acs.org.
3+
DFPR-H3 was achieved by adding 2.0 equiv of TAB to
the reaction mixture containing the [4]pseudorotaxane. While
3+
capping of MFPR-H3 requires only 2 h, double capping
3+
1
of DFPR-H3 requires a lot longer. Although H NMR
spectra (Figure 4) obtained 5 h after addition of TAB showed
some initial sharpening of peaks corresponding to the high-
symmetry (D3h) product DFB-H33+, a peak at δ ) 9.84 ppm
for aldehydic protons could still be observed after 48 h. In
the event, it took 8 days for the mechanically interlocked
OL061262U
(24) Mechanically interlocked molecular bundles have been synthesized
previously by kinetically controlled postassembly modification from triply
threaded, two-component superbundles with a trifurcated trication wherein
three dibenzylammonium ions are linked to a central benzenoid core. See:
(a) Fyfe, M. C. T.; Lowe, J. N.; Stoddart, J. F.; Williams, D. J. Org. Lett.
2000, 2, 1221-1224. (b) Balzani, V.; Clemente-Leon, M.; Credi, A.; Lowe,
J. N.; Badjic´, J. D.; Stoddart, J. F.; Williams, D. J. Chem.-Eur. J. 2003, 9,
5348-5360. (c) Badjic´, J. D.; Balzani, V.; Credi, A.; Lowe, J. N.; Silvi,
S.; Stoddart, J. F. Chem.-Eur. J. 2004, 10, 1926-1935. This particular
synthetic approach expressed itself ultimately in the making of molecular
elevators. See: (d) Badjic´, J. D.; Balzani, V.; Credi, A.; Silvi, S.; Stoddart,
J. F. Science 2004, 303, 1845-1849. (e) Badjic´, J. D.; Ronconi, C. M.;
Stoddart, J. F.; Balzani, V.; Silvi, S.; Credi, A. J. Am. Chem. Soc. 2006,
128, 1489-1499.
3+
molecular bundle DFB-H3 to become (Figure 4d) the
1
dominant product in the H NMR spectrum. Its formation
(23) The additional formyl group in (CHO)2-DP24C8, compared to
(CHO)-DP24C8, appears to have a disruptive effect upon its binding to
3+
the TAT-H3 trication, possibly as a result of the increased electron-
withdrawing influence of the additional formyl group upon the electron-
donating ability of the heteroatoms in the DP24C8 macrocycles.
3902
Org. Lett., Vol. 8, No. 18, 2006