Sequence isomerism in [3]Rotaxanes

Article abstract of DOI:10.1021/ja1006838

We describe a strategy for assembling different macrocycles onto a nonsymmetrical rotaxane thread in a precise sequence. If the macrocycles are small and rigid enough so that they cannot pass each other then the sequence is maintained mechanically, affording stereoisomerism in a manner reminiscent of atropisomerism. The method is exemplified through the synthesis of a pair of [3]rotaxane diastereomers that are constitutionally identical other than for the sequence of the different macrocycles on the thread. The synthesis features the iterative binding of different palladium(II) pyridine-2,6-dicarboxamide complexes to a pyridine ligand on the thread followed by their macrocyclization by ring-closing olefin metathesis. Removal of the palladium(II) from the first rotaxane formed frees the pyridine site to coordinate to a second, different, palladium(II) pyridine-2,6-dicarboxamide unit which, following macrocyclization, provides a multiring rotaxane of predetermined macrocycle sequence.

Full text of DOI:10.1021/ja1006838

Published on Web 03/15/2010
Sequence Isomerism in [3]Rotaxanes
Anne-Marie L. Fuller, David A. Leigh,* and Paul J. Lusby
School of Chemistry, UniVersity of Edinburgh, The King’s Buildings, West Mains Road,
Edinburgh, EH9 3JJ United Kingdom
Received January 25, 2010; E-mail: david.leigh@ed.ac.uk
Abstract: We describe a strategy for assembling different macrocycles onto a nonsymmetrical rotaxane
thread in a precise sequence. If the macrocycles are small and rigid enough so that they cannot pass each
other then the sequence is maintained mechanically, affording stereoisomerism in a manner reminiscent
of atropisomerism. The method is exemplified through the synthesis of a pair of [3]rotaxane diastereomers
that are constitutionally identical other than for the sequence of the different macrocycles on the thread.
The synthesis features the iterative binding of different palladium(II) pyridine-2,6-dicarboxamide complexes
to a pyridine ligand on the thread followed by their macrocyclization by ring-closing olefin metathesis.
Removal of the palladium(II) from the first rotaxane formed frees the pyridine site to coordinate to a second,
different, palladium(II) pyridine-2,6-dicarboxamide unit which, following macrocyclization, provides a multiring
rotaxane of predetermined macrocycle sequence.
Introduction
Perhaps less well appreciated is that mechanically linked
molecular level structures,9 such as multiring catenanes and
rotaxanes that contain at least two different macrocycles, can
also exhibit various forms of sequence isomerism, some types
of which are closely analogous to that of covalently linked
systems and some that are less so. Here we report on a strategy
for assembling rotaxanes with constitutionally different mac-
rocycles on a thread in a particular sequence. A pair of
[3]rotaxanes is prepared which differ only in the relative order
of the macrocycles on the rotaxane thread. The rings are
sufficiently small and rigid that the sequence is maintained
mechanically.
Nature famously employs polymeric sequences of only four
DNA bases to encode the genetic information that contains the
instructions for the workings of an entire organism.1 Such
“sequence isomerism” of covalently connected building blockssa
form of constitutional isomerism2sis also intrinsic to RNA,3
proteins,4 and many oligosaccharides5 and is fundamental to
the transfer of information in biological systems. The order of
the sequence is often crucial; even slightly different building
block sequences can have very different meanings6 and poten-
tially disastrous consequences7 for the cell. In fact, any polymer
comprised of two or more monomer units can potentially exhibit
sequence isomerism, and controlling the order of different
covalently linked building blocks still poses a major, largely
unmet, challenge in synthetic polymer chemistry.8
Sequence Isomerism in Catenanes and Rotaxanes. As there
are few examples in the literature of even the simplest types of
catenane and rotaxane sequence isomers, it is worth noting the
different kinds of mechanical isomerism that can potentially arise
(Figure 1). Linear “chain” catenanes10 composed of at least two
distinguishable rings (Figure 1a) can, in principle, exhibit
connectivity sequential isomerism analogous to the ordering of
different building blocks in covalently linked systems.11 Some-
what surprisingly, of the chain [3]catenanes that feature two
different interlocked rings that have been prepared to date, only
a single isomer appears to have been made or isolated in each
case.10 Rotaxanes with multiple rings and “molecular necklace”
catenanes (molecules in which several rings are threaded onto
one ring12) can display a unique alternative form of sequence
isomerism that arises from the order of the interlocked com-
ponents around the cyclic or linear “backbone” component (the
central ring in a catenane or the thread in a rotaxane). In these
cases, purely mechanical,13 not topological, sequence diastere-
oisomers can arise14 (see Figure 1b-e) in which the isomers
(1) For the first time that DNA was implicated as the carrier of genetic
information, see: Hershey, A. D.; Chase, M. J. Gen. Physiol. 1952,
36, 36.
(2) Stereochemistry of Organic Compounds; Eliel, E. L., Wilen, S. H.,
Mander, L. N., Eds.; John Wiley & Sons: New York, 1994.
(3) For some of the first studies that showed RNA synthesis is templated
by DNA, see: (a) Geiduschek, E. P.; Nakamoto, T.; Weiss, S. B. Proc.
Natl. Acad. Sci. U.S.A. 1961, 47, 1405. (b) Hayashi, M.; Hayashi,
M. N.; Spiegelman, S. Proc. Natl. Acad. Sci. U.S.A. 1963, 50, 664.
For the first deciphering of an RNA three letter codon specifying an
amino acid, see: (c) Matthaei, J. H.; Nirenberg, M. W. Proc. Natl.
Acad. Sci. U.S.A. 1961, 47, 1588. For an account of the role of
ribosomal RNA in protein synthesis, see: (d) Dahlberg, A. E. Cell
1989, 57, 525.
(4) For pioneering work relating protein sequence to structure, see:
Anfinsen, B. C. Science 1970, 181, 223.
(5) Oligosaccharides: Their Synthesis and Biological Roles; Osborn,
H. M. I., Kahn, T. H., Eds.; OUP: New York, 2000.
(6) For example, the sequence of RNA nucleobases AUG is a start codon,
whereas its sequence isomers UAG and UGA are stop codons, see:
Caskey, C. T.; Tompkins, R.; Scolnick, E.; Caryk, T.; Nirenburg, M.
Science 1968, 162, 135.
(8) (a) Badi, N.; Lutz, J.-F. Chem. Soc. ReV. 2009, 38, 3383. (b) Lutz,
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in the amino acid sequence of the ꢀ-chain of hemoglobin can lead to
sickle-cell anemia; see: Ingram, V. M. Nature 1957, 180, 326.
(9) Molecular Catenanes, Rotaxanes, and Knots: A Journey through the
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Eds.; Wiley-VCH: Weinheim, 1999.
9
4954 J. AM. CHEM. SOC. 2010, 132, 4954–4959
10.1021/ja1006838  2010 American Chemical Society

[3]Rotaxane Sequence Isomers
A R T I C L E S
there need only be two distinct types of macrocycle (shown as
blue and green) threaded onto the backbone component (orange)
for sequence isomerism to arise. The fewest number of rings
that must be linked onto the backbone is four (two of each type,
blue and green) for a catenane12 ([5]catenane, Figure 1c) and
three for a rotaxane ([4]rotaxane, Figure 1b).15 When direc-
tionality (one-dimensional asymmetry) is incorporated into the
central component (Figure 1d and 1e), the number of threaded
macrocycles needed to form mechanical sequence isomers
decreases by one to three for a catenane and two for a rotaxane.16
Interestingly, however, a diastereomeric pair of [4]catenane
sequence isomers actually requires three constitutionally dif-
ferent macrocycles (green, blue and red, Figure 1d) locked onto
the central ring,17 one more than for the [5]catenane, Figure
1c, whereas a pair of [3]rotaxane sequence diastereoisomers can
still be achieved with only two distinct macrocycles (green and
blue, Figure 1e).18
Figure 1. Minimum structural requirements for catenane and rotaxane
mechanical sequence diastereomers: (a) linear [3]catenanes consisting of
two different ring types; (b) [4]rotaxane and (c) [5]catenane sequence
isomers on a symmetrical thread/ring; (d) [4]catenane and (e) [3]rotaxane
sequence isomers with an unsymmetrical central ring/thread. In b-e, a
requirement for sequence diastereoisomerism is that each ring is unable to
pass through the cavity of another.
Few examples of rotaxanes that contain constitutionally
different macrocycles have been prepared to date.19
A
pseudo[3]rotaxane was prepared19a by adding differently sized
macrocycles to a thread using different assembly routes, the
smaller via a “threading” strategy and the larger using a
differ only by the sequence of the different rings on the
backbone component, provided their order is conserved (i.e.,
the rings are sufficiently small and/or rigid that they are
prevented from slipping past each another).
If all the interlocked components of a rotaxane (Figure 1b)
or molecular necklace catenane (Figure 1c) are symmetrical
(13) The sequence isomerism that arises through steric blocking in
mechanically interlocked structures (e.g., Figure 1b-e), as opposed
to sequence isomerism that arises through connectivity/topolological
differences (e.g., Figure 1a), is conceptually similar to atropisomerism,
which formally only refers to restricted rotation about single bonds.
(14) These types of isomers are topologically trivial since deformation of
one or more of the rings would allow scrambling of the sequence
without changing the molecular graph.
(15) The linear [4]rotaxanes prepared to date all incorporate only consti-
tutionally identical rings: (a) Tuncel, D.; Steinke, J. H. G. Chem.
Commun. 2002, 496. (b) Parham, A. H.; Schmieder, R.; Vo¨gtle, F.
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Chem. Soc. 1996, 118, 4931. (e) Amabilino, D. B.; Ashton, P. R.;
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(16) Interlocked structures that incorporate symmetrical central components
and macrocycles that are constitutionally identical but have prochiral
faces can also exhibit diastereoisomerism: (a) Chang, S. Y.; Jeong,
K. S. J. Org. Chem. 2003, 68, 4014. (b) Schmieder, R.; Hubner, G.;
Seel, C.; Vo¨gtle, F. Angew. Chem. Int. Ed. 1999, 38, 3528. (c) Kishan,
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(17) There does not appear to be any examples of this type of structure in
the literature.
(18) Since the two faces of a cyclodextrin molecule are different, rotaxanes
and catenanes featuring two or more cyclodextrins threaded onto an
axle or ring can exhibit diastereoisomerism, not as a consequence of
the different sequence of the rings but rather through their differing
relative orientations. (a) Cheetham, A. G.; Claridge, T. D. W.;
Anderson, H. L. Org. Biomol. Chem. 2007, 5, 457. (b) Saudan, C.;
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A R T I C L E S
Fuller et al.
“slippage” strategy.20 However, a symmetrical thread was
employed, and consequently, the structure displays no isomer-
ism. A pseudo[3]rotaxane with an unsymmetrical thread has
been synthesized from two different crown ethers and a thread
with ammonium groups of differing hydrogen-bond-donating
ability.19b Two different template interactions have been used
to assemble a [3]rotaxane with two constitutionally different
rings.19c The thread incorporated a π-acceptor-π-donor site as
well as a hydrogen-bonding template site, and as a result, two
macrocycles, one specific for each site, were interlocked around
the unsymmetrical thread in a spatial arrangement determined
by the positions of the template sites. In general, however,
having the order of macrocycles on a thread dependent on the
template sequence on the thread is not conducive to the
preparation of different mechanical sequence isomers since
aligning the macrocycles in different orders would imply
constitutionally different threads.
Scheme 1. Synthesis of Building Block [L1Pd(CH3CN)] and
[2]Rotaxane H2L4a
[3]Rotaxane Sequence Isomers: Synthesis. We were intrigued
by the possibility of preparing sequence isomers by the iterative
addition21 of different macrocycles onto a single template site
of a rotaxane thread. Our approach was to utilize a square-planar
geometry Pd(II)-based “clipping” methodology that has been
successfully used to make [2]catenanes and [2]-, [3]-, and
[4]rotaxanes.21–23 The metal ion is bound to a tridentate 2,6-
pyridinedicarboxamide ligand (e.g., L1 or L2 in Schemes 1 and
2). Significantly, this involves deprotonation of the ligand amide
groups. The resulting complex [L1/L2Pd(CH3CN)] is coordi-
nated to a monodentate pyridine unit on a thread such that
subsequent macrocyclization by ring-closing metathesis (RCM)
occurs around the thread to generate an interlocked architecture.
The key to extending this protocol so that further, different,
ligands can be cyclized around the template after the first is
decomplexed is that while complexes of the type [L1/
L2Pd(CH3CN)] will readily exchange the labile coordinated
acetonitrile molecule for a pyridine unit, they do not undergo
tridentate ligand exchange with protonated (that is, metal-free)
versions of the 2,6-pyridinedicarboxamide system. Thus, a pyridine
group on a thread can repetitively be used to replace acetonitrile
ligands of complexes of the type [L1/L2Pd(CH3CN)], with the
resulting coordinated ligands being macrocyclized, providing the
rings in a defined order on the thread.
In order to access a pair of [3]rotaxane sequence isomers,
two constitutionally different macrocycles need to be used
interchangeably in the synthesis. Building block [L2Pd-
(CH3CN)] has previously been used21 to construct [2]rotaxane
H2L5 (Scheme 2). Building block [L1Pd(CH3CN)], identical
to [L2Pd(CH3CN)] other than having an isopropyl ether attached
to the 4-position of the pyridine group, was chosen as a precur-
sor to the other macrocycle. Complex [L2Pd(CH3CN)] was
a Reagents and conditions: (i) (1) pentafluorophenol, 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide (EDCI), CH2Cl2, 0 °C, (2) (4-(hex-5-
i
enyloxy)phenyl)methamine, CHCl3, 0 °C, 89% over two steps; (ii) PrI,
K2CO3, butan-2-one, ∆, 95%; (iii) Pd(OAc)2, CH3CN, 70%; (iv)
[L1Pd(CH3CN)], CH2Cl2, 97%; (v) (1) PhCHdRu(PCy3)2Cl2 (0.12 equiv),
CH2Cl2, (2) 2-nitrobenzenesulfonyl hydrazide (NBSH),24 NEt3, CH2Cl2, 70%
(over two steps); (vi) KCN, CH2Cl2/MeOH, 98%.
(20) Structures formed by “slippage” are not formally rotaxanes; rather,
they are pseudorotaxanes that are kinetically stable under some
conditions. Rotaxanes are “molecules in which a ring encloses another,
rod-like molecule having end groups too large to pass through the
ring opening, and thus holds the rod-like molecule in position without
covalent bonding”: McNaught, A. D.; Wilkinson, A. The IUPAC
Compendium of Chemical Terminology, 2nd ed.; Blackwell Science:
London, 1997.
prepared in three steps from chelidamic acid 1 and elaborated
into [2]rotaxane H2L4 as shown in Scheme 1. Amide bond
formation via the pentafluorophenol ester of chelidamic acid
afforded 2 which was O-alkylated (with no competing N-
alkylation at the pyridine or amide nitrogen atoms) to give L1
in 85% overall yield. Treatment of L1 with Pd(OAc)2 in
acetonitrile gave the key building block [L1Pd(CH3CN)], which
was combined with thread L3 in dichloromethane to generate
complex [L1PdL3] as the only product formed (Scheme 1, iv).
Subjecting [L1PdL3] to ring closing metathesis with Grubbs’
first generation olefin metathesis catalyst, followed by hydro-
(21) Fuller, A. M. L.; Leigh, D. A.; Lusby, P. J. Angew. Chem., Int. Ed.
2007, 46, 5015.
(22) Fuller, A. M.; Leigh, D. A.; Lusby, P. J.; Oswald, I. D. H.; Parsons,
S.; Walker, D. B. Angew. Chem., Int. Ed. 2004, 43, 3914.
(23) Fuller, A. M. L.; Leigh, D. A.; Lusby, P. J.; Slawin, A. M. Z.; Walker,
D. B. J. Am. Chem. Soc. 2005, 127, 12612.
(24) Myers, A. G.; Zheng, B.; Movassaghi, M. J. Org. Chem. 1997, 62,
7507.
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[3]Rotaxane Sequence Isomers
A R T I C L E S
Scheme 2. Parallel Syntheses of [3]Rotaxane Sequence Isomers H2L6 and H2L7a
a Reagents and conditions (i) CH2Cl2; (ii) (a) PhCHdRu(PCy3)2Cl2 (0.12 equiv), CH2Cl2, (b) NBSH, NEt3, CH2Cl2; (iii) KCN, CH2Cl2/MeOH.
genation24 of the resulting internal double bond, afforded the
palladium-complexed [2]rotaxane [L4Pd] in 70% yield over two
steps.
The two [2]rotaxanes H2L4 and H2L5 were elaborated into
[3]rotaxanes possessing the same macrocycles in a different
sequence by coordinating each [2]rotaxane with the comple-
mentary building block for the other macrocycle followed by
the macrocyclization procedure (Scheme 2). Thus, H2L5 was
treated with [L1Pd(CH3CN)] (Scheme 2, i), generating a single
positional isomer [L1PdH2L5] with the macrocycle located on
the alkyl chain of the thread since it is sterically unfavorable17
for it to reside between the coordinated building block and the
closest stopper. Ring-closing metathesis and hydrogenation
(Scheme 2, ii) afforded the palladium-complexed [3]rotaxane
[L6Pd] in 72% yield, which was demetalated with KCN to give
the metal-free [3]rotaxane H2L6. Following a complementary
procedure, [2]rotaxane H2L4 was elaborated into [3]rotaxane
H2L7 by coordination with building block [L2Pd(CH3CN)]
(Scheme 2, i), macrocyclization, hydrogenation, and demeta-
lation (Scheme 2, ii and iii).
The structures of [L4Pd] and the metal-free rotaxane, H2L4,
1
were confirmed by mass spectrometry and H NMR spectros-
copy. Protons Hc and Hg protons of the thread (Figure 2a) exhibit
characteristic changes in chemical shift in the rotaxanes (Figures
2b and 2c) caused by the ring currents of the aromatic rings of
the macrocycle. The appearance of the benzylic protons (H*D
and H*D′) of the macrocycle in [L4Pd] as an AB system (Figure
2b), and the corresponding ABX system in H2L4 (Figure 2c),
are a consequence of the two faces of the macrocycle experienc-
ing different magnetic environments as a result of the threading
with an unsymmetrical axle. The large downfield shift amide
protons (H*C) at 9.3 ppm in H2L4 are indicative of intercom-
ponent hydrogen bonding between the macrocycle and the
pyridine group of the thread.25
[3]Rotaxane Sequence Isomers: Characterization. [3]Rotax-
anes H2L6 and H2L7 gave very similar molecular ions of
m/z ) 2372.49202 (H2L6) and m/z ) 2372.49443 (H2L7) by
(25) Bifurcated hydrogen bonding between the amides and the pyridine
groups of interlocked molecules has previously been observed: (a)
Leigh, D. A.; Lusby, P. J.; Slawin, A. M. Z.; Walker, D. B. Angew.
Chem., Int. Ed. 2005, 44, 4557. (b) Leigh, D. A.; Lusby, P. J.; Slawin,
A. M. Z.; Walker, D. B. Chem. Commun. 2005, 4919.
high-resolution mass spectrometry consistent with the anticipated
molecular formulas (calculated [MH]+ for
C
13CH196N7O12
156
12
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A R T I C L E S
Fuller et al.
Figure 2. 1H NMR spectra (400 MHz, CD2Cl2, 298 K) of (a) thread L3; (b) palladium-complexed [2]rotaxane [L4Pd]; and (c) metal-free [2]rotaxane H2L4.
The lettering refers to the assignments in Scheme 1.
) 2372.49756). Intriguingly, the sequence isomers H2L6 and
H2L7 exhibit slightly different fast atom bombardment (FAB)
mass spectrometry fragmentation patterns. Both sets of spectra
show the daughter ion peaks (m/z ) 1800 and 1858) corre-
sponding to the [2]rotaxanes H2L4 and H2L5, respectively.
However, for H2L7 the 1858 signal intensity is 40% greater
than that of the 1800 peak, while the relative peak intensities
are reversed for H2L6: the signal intensity of the m/z ) 1800
ion is 73% greater than that of the m/z ) 1858 ion. This suggests
that the macrocycle nearest to the stopper that bears the pyridine
group is more likely to fragment and be lost under the FAB
conditions. This “sequence fingerprint” by mass spectrometry
is reminiscent of different amino acid arrangements showing
different fragmentation patterns that can be diagnostic of a
particular polypeptide sequence. The Pd(II) complexes of the
two [3]rotaxane isomers, [L6Pd] and [L7Pd], have distinctive
differences in their 1H NMR spectra above 7.5 ppm (i.e., protons
HA, H*A, HB and H*B) as a result of constitutionally different
macrocycles being coordinated to the thread in each rotaxane
(Figure 3a,d). For example, in [L7Pd] the (blue) macrocycle
lacking the isopropyl ether is coordinated to palladium and its
HB pyridine protons appear at 7.8 ppm, whereas in [L6Pd] (in
Figure 3. 1H NMR Spectra (400 MHz, CD2Cl2, 298 K) of (a) palladium-complexed [3]rotaxane [L7Pd]; (b) metal-free [3]rotaxane H2L7; (c) metal-free
[3]rotaxane H2L6; (d) palladium-complexed [3]rotaxane [L6Pd]. The lettering refers to the assignments in Schemes 1 and 2.
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4958 J. AM. CHEM. SOC. VOL. 132, NO. 13, 2010

[3]Rotaxane Sequence Isomers
A R T I C L E S
which the other macrocycle is the one coordinated to the metal)
the equivalent protons resonate at 8.4 ppm. Conversely, the H*B
protons of the noncomplexed isopropyl ether macrocycle (green)
appear at 7.9 ppm in [L7Pd] but in [L6Pd] the protons are
shifted upfield to 7.2 ppm as a result of the coordinated
palladium. As expected, the resonances of the alkyl region of
the thread in [L6Pd] and [L7Pd] show increased shielding due
to the presence of metal-free macrocycle, and in particular, the
aliphatic protons are significantly shifted nearly a whole ppm
upfield compared to the analogous [2]rotaxanes (see Figure 2).
Although the two metal-free rotaxane isomers have very similar
1H NMR spectra (Figure 3b,c), close inspection reveals very
subtle differences in the shifts of certain protons. For example,
the aromatic stopper protons (Hb) are shifted slightly downfield
in H2L7 compared to H2L6, and the benzylic resonances of both
macrocycles appear at slightly different shifts in each isomer.
After several months on the bench, there was no sign of any
interconversion from one [3]rotaxane isomer to the other as
evidenced by 1H NMR (no doubling of signals) and mass
spectrometry (no change in the fragmentation pattern ratios).
sequence isomers. Successive ligand complexation, macrocy-
clization, and demetalation reactions were used to assemble
different macrocycles onto an asymmetric thread in different
orders. As far as we are aware, the resulting [3]rotaxane
sequence isomers are the first pair of diastereoisomers to be
prepared in which the distereomerism arises from mechanical
sequence isomerism, a counterpart of atropisomerism in co-
valently bonded systems. The physical and spectroscopic
characteristics of the [3]rotaxanes are very similar, although the
1
palladium-complexed [3]rotaxanes show differences in the H
NMR spectra characteristic of the order of the macrocycles on
the thread. The synthetic strategy could potentially be extended
to add multiple different rings to a rotaxane thread, in any
desired order, thus enabling the synthesis of single isomer higher
order rotaxanes with a defined macrocycle sequence.
Acknowledgment. P.J.L. is a Royal Society University Research
Fellow. D.A.L. is an EPSRC Senior Research Fellow and holds a
Royal Society-Wolfson research merit award.
Supporting Information Available: Experimental procedures
and spectral data for all compounds. Complete ref 10n. This
material is available free of charge via the Internet at http://
pubs.acs.org
Conclusions
The challenge of precisely controlling the order and number
of constitutionally different macrocycles in rotaxane syntheses
has been addressed through the synthesis of a pair of [3]rotaxane
JA1006838
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