Modular synthesis of bipyridinium oligomers and corresponding donor-acceptor oligorotaxanes with crown ethers

Article abstract of DOI:10.1021/ol302301r

Donor-acceptor [4]- and [6]rotaxanes have been prepared from bipyridinium (BIPY²⁺) oligomers and 1,5-dinaphtho[38]crown-10 (DN38C10) by a threading-followed-by-stoppering protocol employing click chemistry. An efficient, straightforward route to the BIPY²⁺ oligomers has been developed that requires little to no chromatographic purification. Unlike most donor-acceptor oligorotaxanes that have been reported to date, 100% of the recognition sites on the dumbbells are occupied by rings.

Full text of DOI:10.1021/ol302301r

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Modular Synthesis of Bipyridinium
Oligomers and Corresponding
DonorꢀAcceptor Oligorotaxanes with
Crown Ethers
Chris M. Gothard,† Carson J. Bruns,† Nosheen A. Gothard, Bartosz A. Grzybowski,
and J. Fraser Stoddart*
Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston,
Illinois 60208-3113, United States
stoddart@northwestern.edu
Received August 17, 2012
ABSTRACT
Donorꢀacceptor [4]- and [6]rotaxanes have been prepared from bipyridinium (BIPY2þ) oligomers and 1,5-dinaphtho[38]crown-10 (DN38C10) by
a threading-followed-by-stoppering protocol employing click chemistry. An efficient, straightforward route to the BIPY2þ oligomers has been
developed that requires little to no chromatographic purification. Unlike most donorꢀacceptor oligorotaxanes that have been reported to date,
100% of the recognition sites on the dumbbells are occupied by rings.
Mechanically interlocked molecules (MIMs), such as
catenanes and rotaxanes,1 have been the subject of intensive
investigations over the past few decades because of their
interesting topologies,2 beauty,3 potential applications4 as
switches and machines in nanomechanical systems, and
their synthetic challenge. The noncovalent bonding inter-
actions involved in the templation5 of MIMs, which ‘live
on’ in the molecules, provide a handle to control6 shape,
size, isomerism, and intramolecular motion precisely. This
control over secondary structure is particularly interesting
in the case of polymeric7 MIMs, where minute structural
changes can have dramatic effects on the bulk properties of
the corresponding materials.
† These authors contributed equally.
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Dietrich-Buchecker, C., Eds.; Wiley-VCH: Weinheim, Germany, 1999.
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Breault, G. A.; Hunter, C. A.; Mayers, P. C. Tetrahedron 1999, 55, 5265–
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Inparticular, we have been interested8 in MIMs based on
donorꢀacceptor (DꢀA) interactions between π-electron
ꢀ
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Astumian, R. D.; Stoddart, J. F.; Grzybowski, B. A. Chem. Soc. Rev.
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Rev. 1999, 99, 1643–1663. (d) Takata, T.; Kihara, N.; Furusho, Y. Adv.
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r
10.1021/ol302301r
XXXX American Chemical Society

rich donors such as 1,5-dioxynaphthalene (DNP) units and
π-electron deficient acceptors such as 4,40-bipyridinium
(BIPY2þ) units. We have shown9 previously that oligo-
and polyrotaxanes made from DNP oligomers and the
BIPY2þ-based host cyclobis(paraquat-p-phenylene)10
(CBPQT4þ) tend to form at only ∼50% recognition site
occupancy because they adopt well-defined folded second-
ary structures in solution, made possible by interactions
between CBPQT4þ rings and unencircled ‘alongside’ DNP
units. Here we show that it is possible to create oligorotax-
anes with fully occupied recognition sites, and hence a
higher density of mechanical bonds, using an inverted
recognition system between BIPY2þ oligomers and macro-
cyclic DN38C10. A viable synthetic pathway to fully
occupied mechanically interlocked oligomers and polymers
can help guide the development of functional materials with
novel bulk properties.
The synthesis and purification of a homologous series of
well-defined BIPY2þ oligomers was a formidable synthetic
challenge because they are not amenable to conventional
flash column chromatography (FCC) on account of their
polycationic backbones. Also, there is little precedence in
the literature for synthesizing a series of discrete linear
BIPY2þ oligomers of arbitrary length rationally. Hence,
we sought to develop a modular approach which could
be used to generate BIPY2þ oligomers with a minimal
number of reagents, steps, and purifications. Since benzyl
bromides are highly reactive in nucleophilic substitutions,
we reasoned that their displacement by pyridine groups
would allow us to extend the oligomers in a stepwise manner
efficiently. We designed the diphenylmethane-based linker
L1 to connect BIPY2þ units together in the oligomeriza-
tions, with the expectation that the increased length of the
linker (relative to the p-xylyl group in CBPQT4þ) would
accelerate reaction rates by further separating the repulsive
cationic charges between BIPY2þ units while also removing
the tendency of the corresponding pseudorotaxanes to form
at 50% site occupancy preferentially on account of along-
side interactions with the macrocycles.
Scheme 1. Synthesis of Diphenylmethane Linker L1
We devised a simple modular synthesis of ‘center pieces’
(denoted with the prefix ‘C’) and ‘end pieces’ (denoted by
‘E’ prefixes) using only linker L1 and 4,40-bipyridine
(BIPY) as starting materials. All of the building blocks
were pieced together (Scheme 2) using only three general
transformations: (a) nucleophilic substitution by a pyridyl
unit, (b) bromination of a benzyl alcohol site with PBr3,
and (c) counterion exchange to a PF6 salt by precipitation
Scheme 2. Modular Synthesis of BIPY2þ Building Blocks
L1 was prepared according to Scheme 1, first by com-
bining benzyl bromide 1 and boronic acid 2 in a Suzuki
cross-coupling reaction to form alcohol 3, followed by
bromination of the alcohol with PBr3 and LiBr in DMF
to yield 4 and reduction of the methyl ester with DIBAL
in PhMe and CH2Cl2.11 With the exception of the
(unoptimized) Suzuki cross-coupling that yielded 67%,
these reactions proceeded in excellent (>90%) yields.
of the bromide salts from aqueous NH4PF6 solution. End
piece E1þ was prepared by reacting an excess of BIPY with
3-butynyl p-toluenesulfonate. End piece E22þ was pre-
pared by subsituting E1þ at linker L1. E34þ was synthe-
sized by coupling E22þ with an extended linker L2þ, which
was prepared from L1 and an excess of BIPY. Center piece
C12þ was prepared by reacting BIPY with an excess of L1,
and then it was extended to C24þ with a bromination
followed by an immediate reaction with excess BIPY.
The yields ranged from modest (19%) to excellent (93%),
and no chromatography was needed to isolate pure
(9) (a) Zhang, W.; Dichtel, W. R.; Stieg, A. Z.; Benıtez, D.;
´
Gimzewski, J. K.; Heath, J. R.; Stoddart, J. F. Proc. Natl. Acad. Sci.
U.S.A. 2008, 105, 6514–6519. (b) Basu, S.; Coskun, A.; Friedman, D. C.;
Olson, M. A.; Benıtez, D.; Tkatchouk, E.; Barin, G.; Yang, J.; Fahrenbach,
´
A. C.; Goddard, W. A., III; Stoddart, J. F. Chem.;Eur. J. 2011, 17,
2107–2119.
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Stoddart, J. F.; Williams, D. J. Angew. Chem., Int. Ed. Engl. 1988, 27,
1547–1550. (b) Sue, C.-H.; Basu, S.; Fahrenbach, A. C.; Shveyd, A. K.;
Dey, S. K.; Botros, Y. Y.; Stoddart, J. F. Chem. Sci. 2010, 1, 119–125.
(11) Attempts to reduce 4 with DIBAL in THF returned only starting
material, which was likely caused by the more polar THF molecules
stabilizing DIBAL to render it a weaker reducing agent. See: Winterfeldt,
E. Synthesis 1975, 617–630.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Number of BIPY2þ Units, Starting Materials Used, Isolated Yields, Molecular Weights (MWs), and Characteristic Signals
Observed in the Mass Spectra of BIPY2þ Oligomers
starting materials
no. of BIPY2 (n)
center
end
E1þ
yield (%)
56
MW (g molꢀ1
)
observed ESI-MS signalsa (m/z)
2þ
3BP6þ
5BP10þ
7BP14þ
3
C1Br2
C24þ
1833
1687.16 [M ꢀ PF6]þ
771.31 [M ꢀ 2PF6]2þ
633.36 [M ꢀ 4PF6]4þ
477.79 [M ꢀ 5PF6]5þ
1859.41 [M ꢀ 2TFA]2þ
1202.04 [M ꢀ 3TFA]3þ
5
7
E2Br2þ
E3Br4þ
72
38
3114
4395
C24þ
a 7BP14þ was analyzed by MS as the TFA salt after preparative RP-HPLC purification.
compounds, a fact which was verified (Figure S1 in the
Supporting Information (SI)) by analytical reversed-phase
high performance liquid chromatography (RP-HPLC).
The benzyl bromide intermediates were used immediately
and without purification because they tended to hydrolyze
back to the starting alchohols, especially during RP-HPLC.
The lower isolated yields for certain compounds reflect
multistep reactions that typically involve bromination
(condition b) as well as precipitation from aqueous NH4PF6
(condition c). Condition c enhanced the purity of the crude
products at the penalty of high yields, which can most likely
be attributed to the partial solubility of the PF6 salts in the
Figure 1. RP-HPLC chromatograms (H2OꢀMeCN, 0.1% v/v
TFA, λ = 254 nm) of the BIPY2þ oligomers (a) 3BP6þ, (b)
5BP10þ, and (c) 7BP14þ (0ꢀ60% MeCN in 20 min) and oligorotax-
anes (d) [4]3BP6þ and (e) [6]5BP10þ (80ꢀ100% MeCN in 20 min).
solutions from which they were precipitated.
The center and end pieces were transformed into BIPY2þ
oligomers 3BP6þꢀ7BP14þ under Conditions a and c, as
summarized in Table 1 alongside some of the characteristic
electrospray ionization (ESI) mass spectrometry (MS) data.
Although these reactions also proceed efficiently and do not
necessarily require chromatography, high-purity samples
were obtained after preparative scale RP-HPLC. Analytical
RP-HPLC chromatograms of 3BP6þꢀ7BP14þ are shown in
Figure 1aꢀc. In principle, the present methodology could be
used to extend the oligomers indefinitely, since linker L2þ
can be repeatedly applied to either the center or end pieces to
obtain even larger building blocks.
to form the corresponding pseudorotaxanes, a situation
which was confirmed visually by the red color that ap-
peared because of a charge transfer absorption band from
DNP and BIPY2þ DꢀA interactions. Addition of the
stopper precursor StN3 and catalytic amounts of the TBTA
ligand and Cu(MeCN)4PF6 yielded the target oligorotax-
anes via triazole formation. The ESI-MS data of the crude
reaction suggest that we obtain a statistical mixture of multi-
component rotaxanes, resulting in modest yields (7ꢀ11%)
for the fully occupied targets. However, the oligorotaxanes
We transformed (Scheme 3) 3BP6þ and 5BP10þ into the
with 100% site occupancy ([4]3BPR6þ and [6]5BPR10þ
)
corresponding oligorotaxanes [4]3BPR6þ and [6]5BPR10þ
,
respectively, using the Huisgen12 Cu(I)-catalyzed azideꢀ
alkyne cycloaddition (CuAAC), also known13 as click
chemistry, in a threading-followed-by-stoppering protocol.
The BIPY2þ oligomers were mixed with an excess of
1,5-dinaphtho[38]crown-1014 (DN38C10) in DMF/CHCl3
were easily separated by FCC because they elute much more
quickly on SiO2 in 1% NH4PF6/Me2CO than their smaller
counterparts (which had a tendency to coelute) with ex-
posed BIPY2þ sites. No [8]rotaxane could be isolated from
the statistical mixture when we attempted the same protocol
on 7BP14þ, exposing the limits of the threading-followed-
by-stoppering approach with regard to polyrotaxane synt-
hesis. A kinetically controlled stoppering approach is unlikely
to yield well-defined polyrotaxanes with low polydisper-
sities in the absence of positive cooperativity15 to drive
reactions away from statistical distributions.
(12) (a) Huisgen, R. Angew. Chem. 1963, 75, 604–637. (b) Huisgen,
€
R.; Szeimies, G.; Mobius, L. Chem. Ber. 1967, 100, 2494–2507.
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983–986.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Synthesis of DonorꢀAcceptor Oligorotaxanes in which BIPY2þ Recognition Sites are Fully Occupied by DN38C10 Rings
Using Click Chemistry
The oligorotaxanes were characterized by analytical
RP-HPLC, ESI-MS (Figures S2 and S6 in the SI), and
1H NMR spectroscopy. The significant hydrophobicity
imparted to the oligomers by the rings and stoppers
renders them reluctant to elute even in nearly 100% MeCN
during RP-HPLC, as indicated by the broad traces in
Figure 1dꢀe. The assignments of the aromatic signals in
1
the H NMR spectra (Figure 2bꢀc) of [4]3BPR6þ and
1
[6]5BPR10þ were assisted by multidimensional H NMR
analysis (Sections 4 and 5 of the SI). All BIPY2þ and DNP
protons resonate at lower frequencies than their uncom-
plexed counterparts (Figure 2a and 2d) as a result of
shielding from the local magnetic fields induced by aro-
matic ring currents in the DꢀA stacks that underpin πꢀπ
recognition between DN38C10 and BIPY2þ units. The
spectra also reveal that ‘pirouetting’ motions of the DNP
units (rotations about the central CꢀC bond) occur rap-
idly on the NMR time scale in CD3CN at 293 K, giving
Figure 2. Partial 1H NMR spectra (600 MHz, 293 K, CD3CN) of
the rotaxanes anaveragedD2h symmetry, a conclusion that
(a) 3BP6þ, (b) [4]3BPR6þ, and (c) [6]5BPR10þ as their PF6 salts
and (d) DN38C10. See Scheme 3 for proton labels.
can be drawn from the number of observed BIPY2þ and
DNP signals. For example, DNP protons in the outermost
rings (labeled with ‘o’ prefixes) give rise to single reso-
Acknowledgment. This research was supported by the
nances for pairs of otherwise heterotopic protons (2/6, 3/7,
Non-Equilibrium Energy Research Center (NERC), an
4/8) because they undergo rapid site exchange through
Energy Frontier Research Center funded by the U.S.
pirouetting. Likewise, the C2 symmetry of DNP is not
Department of Energy, Office of Science, Office of Basic
imposed on the terminal BIPY2þ units, since they express
Energy Sciences under Award Number DE-SC0000989.
only two R and β signals.
C.J.B. acknowledges the National Science Foundation for
In summary, we have developed a straightforward syn-
the award of a Graduate Research Fellowship.
thetic route to linear BIPY2þ oligomers of arbitrary length
(in principle) and employed them in the kinetically con-
trolled synthesis of two donorꢀacceptor oligorotaxanes
with fully occupied recognition sites.
Supporting Information Available. Materials and meth-
ods, synthetic procedures, spectroscopic characterization
of new compounds, analytical RP-HPLC traces. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) (a) Belowich, M. E.; Valente, C.; Smaldone, R. A.; Friedman,
D. C.; Thiel, J.; Cronin, L.; Stoddart, J. F. J. Am. Chem. Soc. 2012, 134,
5243–5261. (b) Ke, C.; Smaldone, R. A.; Li, H.; Davis, A. P.; Stoddart,
J. F. Angew. Chem., Int. Ed. 2012DOI: 10.1002/anie.201205087.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX