1. TOWARDS THE SYNTHESIS OF CYCLOCHIRAL ROTAXANES
BSc IV Dissertation project
Gordon J. Lister
Supervisor Dr Ai-Lan Lee
2010/2011
1
2. Declaration
I, Gordon J. Lister confirm that this work submitted for assessment is my own work and
is expressed in my own words. Any uses made within it of the work of other authors in
any form are properly acknowledged at the point of use.
Signed:
Dated:
2
3. Contents
Contents............................................................................................................................3
1.0 Abstract......................................................................................................................5
2.0 Introduction...............................................................................................................6
2.1 Interlocked molecular architectures .......................................................................6
2.2 Nomenclature of Rotaxanes......................................................................................7
2.3 Applications for Rotaxanes.......................................................................................8
2.4 Overview of strategies for synthesising rotaxanes................................................11
2.4.1 Early statistical approach....................................................................................13
2.4.2 Directed synthesis via covalent bond formation................................................14
2.4.3 Hydrogen bond mediated templating synthesis.................................................16
2.4.4 π-electron donor/ π-electron acceptor interactions...........................................17
2.4.5 Transition metal template synthesis of rotaxanes ............................................18
2.5 Active metal synthesis of rotaxanes.......................................................................20
2.5.1 CuAAc active metal template for rotaxane synthesis.......................................20
2.5.2 Copper mediated alkyne-alkyne heterocoupling...............................................24
2.6 Cyclochirality in rotaxanes ....................................................................................25
3.0 Aim of this project...................................................................................................28
4.0 Results and Discussion ...........................................................................................30
4.1 Synthesis of macrocycle precursor 44....................................................................30
4.2 Synthesis of macrocycle 41.....................................................................................32
5.0 Conclusion................................................................................................................33
6.0 Experimental section...............................................................................................34
6.1 Synthesis of macrocycle precursor.........................................................................34
6.2 Synthesis of macrocycle 41.....................................................................................38
3
4. Abbreviations
δ - chemical shift
mL – millilitres
mmol – millimoles
g – grams
mins – minutes
hrs – hours
EtOAc – ethyl acetate
PE – petroleum ether 40 – 60%
NMR – nuclear magnetic resonance
Hz – Hertz
MHz – mega Hertz
J – NMR coupling constant
s – singlet
d- doublet
t – triplet
q – quartet
m – multiplet
R.T – room temperature (between 12 and 20 o
C)
Me – methyl
Et – ethyl
tBu – tert-butyl
THF – tetrahydrofuran
DMF – dimethylformide
DCM – dichloromethane
TLC – thin layer chromatography
Ph – phenyl
OTf – triflate
Ts – tosyl
OTs – tosylate
o
C – degree Celsius
4
5. 1.0 Abstract
Cyclochirality in rotaxane systems is becoming increasingly important as their uses
become more widespread in nanotechnology. As such, methods of producing pure
samples of one cyclochiral form of a rotaxane are being highly sought after. So far two
methods for producing cyclochiral rotaxanes have so far been found, one where the
rotaxane is synthesised and then reacted to make it cyclochiral. The second method is
to impart the cyclochirality when forming the rotaxane, however this method can
sometimes lead to a racemic mixture of both cyclochiral forms.
5
6. 2.0 Introduction
2.1 Interlocked molecular architectures
Mechanically interlocked molecular architectures are a ubiquitous class of “entwined”
molecules, which exist due to the stability of their topologies. They can neither be
classified as truly supramolecular nor complex-type species, due to the requirement of
covalent bond cleavage to afford their component parts.
Figure 1. Morphology of (a) rotaxane and (b) catenane
There are four main classes of mechanically interlocked molecular architectures, these
are; rotaxanes, catenanes, molecular knots and borromean rings though the latter two
will not be discussed. The term rotaxane is derived from the Latin rota meaning
“wheel” and axle meaning “axis”. Rotaxanes consist of a thread with a bulky stopper
group situated on each end. The resulting dumbbell is threaded through the cavity of a
macrocycle. The stopper groups are present to stop de-threading and the decomposition
into its component parts. Catenane, is derived from the Latin term catena, meaning
“chain”, comprising mechanically interlocked ring systems, which can adopt many
different topologies, however the assembly of extended chain systems is more
synthetically challenging.
6
7. 2.2 Nomenclature of Rotaxanes
The most basic rotaxane morphology (Figure 1) consists of a dumbbell shaped molecule
threaded through a single cyclic moiety. In this case the system is defined as a
[2]rotaxane, characterising the number of interlocked components inherent in the
structure. In more general terms, a [n]rotaxane contains [n-1] ring systems, threaded
onto the dumbbell component. In the case of more elaborate structures, the naming
convention proposed by Vögtle and co-workers is employed.1
Figure 2 shows two
further rotaxane topologies.
The earliest example of a cyclic moiety threaded by a linear chain was first proposed by
Frisch and Wasserman in 1961, when they claimed that a structure of this type could be
kinetically stable. In 1967, both the Harrison and Schill2
groups simultaneously
extended this concept to the synthesis of rotaxanes.
Figure 2. Illustration showing a [4]rotxane and a branched chain rotaxane
7
8. 2.3 Applications for Rotaxanes
The interesting chemical and structural properties of rotaxanes lead to a increased
amount of academic research. Their inherent ability to allow controlled mechanical
motion on the molecular scale has meant they have been exploited for use in the field of
nanotechnology.
Two such applications are molecular switches and molecular machines. In these
examples, an external stimuli controls the mechanical motion of the molecules towards
achieving some overall task. Various external stimuli can be applied to initiate this
movement, examples of this stimuli that have been studied include pH, redox of a co-
ordinated metal centre and light.
Figure 3. Illustration of a [2]rotaxane acting as a molecular switch
One such method for transforming a rotaxane into a molecular switch is by inserting a
copper ion into the macrocycle ring system of the rotaxane. The axle of the rotaxane
system will have one or more “recognition” sites. To make the ring system move from
site to site, the oxidation state of the copper is changed, which in turn would affect the
environment in which the copper resides.
In a 2009 study by Moretto and co-workers showed the use of a helical peptide axle in a
[2]rotaxane3
molecular machines. This study showed how rotaxanes can be “forced”
into making changes in their structure by altering the solvent and the temperature.
They have shown that by changing the solvent that the rotaxane has been dissolved in,
from chloroform to acetonitrile, the macrocycle ring system moves from one
“recognition” site to the other. The reason behind this switch from one “recognition”
site to another upon changing the solvent from chloroform to acetonitrile, is due to the
8
9. hydrogen bonds that are present between the acetonitrile solvent and the nitrogen link
station in the axle.
O
NH
O
N
H
N
H
NH
O
O
O
NH
H
O
NH
H
H
O
NH
H
H
O
NH
O
NH
O
NH
O
NH
O
NH
O
NH
O
O NH
O
O
NH
H
O
NH
1, macrocycle
stopper
stopper
C - terminal station
N - terminal station
amido - ester junction
310 -helix peptide linker
2, helical peptide axle with stoppers
Figure 4: Chemical structures of macrocycle and helical peptide axle with stopper groups attatched.
Scheme 1: Computer generated structures showing rotaxane switching and a space filling representation
of rotaxane.
However, rotaxanes have also been utilised in the field of nanorecording, where the
rotaxane is applied to a indium-tin oxide coated glass surface as a Langmuir-Blodgett
film.4
When a voltage is applied from the end of a scanning tunnelling microscope
probe, the macrocycle rings present in the area of contact switch to another
“recognition” site and the new overall conformation extrudes the surface by 0.2
nanometres, which is sufficient for a memory dot.
9
10. A final, and more recent, application for rotaxanes is in asymmetric catalysis. The first
example of such an application was developed by Takata and co-workers (shown below
in Scheme 2)5
, in which they utilised rotaxane 3 to catalyse an enantioselective
condensation reaction. They showed that the chemical field of the rotaxanes
components provided a chiral transfer field via non covalent bonding. The study also
showed that axial chirality from the macrocycle can be transferred to the achiral
catalytic site (thiazolium moiety) on the axle. Takata likened the rotaxane field to that
of an enzyme asymmetric reaction field. Although they only achieved a ee of 32% at
this stage, it illustrated the potential of rotaxanes for use in chiral reactions.
Cl
-
OO
OO
OO
OO
N
O
N
+
S
O
O
O
H
O
OH
Et3N
3, catalytic
Up to 90% yield
Up to 32% ee
Scheme 2. Asymmetric benzoin condensation catalysed by chiral rotaxane 1 "through space" chirality
transfer
However, the Nishibayashi group went on to develop a chelating bidentate chiral ligand
which was based on a pseudorotaxane structure, these ligands can be used in rhodium-
catalysed enantioselective hydrogenation of enamides. Their “lassoed” pseudorotaxane
is able to catalyse reactions to high conversions (>99%) and high enantioselectivities
(90-96%).6
Fan and co-workers also reported related pseudorotaxanes for rhodium-catalysed
enantioselective hydrogenation of enamides, the reduced products they report however
are with slightly lower enantioselectivities (68-88% ee) when compared with
Nishibayashi’s “lassoed” pseudorotaxane.7
The synthesis of the Fan “lassoed
pseudorotaxane” 4 is show below in Scheme 3.
10
12. bulky stopper groups to prevent de-threading, thus producing the desired interlocked
species.
Figure 5. Illustration of the threading process.
In a similar way the slipping process requires a macrocycle ring to be threaded onto a
pre-existing stoppered chain (Figure 6). To achieve this requires the cavity of the
macrocycle ring to be able to expand enough to pass over the stopper groups, then
contract once it has reached the desired “recognition” site on the chain, often this
process is thermal in nature. When heated, the macrocycle ring system is able to
expand and pass over the stopper, then upon cooling contracts such that the cavity is
now too small to pass over the stopper groups present in the system.
Figure 6. Illustration of the slipping process.
A third approach used is called clipping, this involves a turn (a large segment of the
macrocycle ring) that has been threaded onto a chain containing both stopper groups, a
macrocyclisation reaction is then carried out to implant the rest of the ring system and
complete the rotaxane (Figure 7).
Figure 7. Illustration of the clipping process.
12
13. Finally the most widely used synthesis process, active metal template, this process
involves a metal ion(active template), this metal ion causes and catalyses the formation
of covalent bonds between two pre-stoppered parts of the “axle” while still threading
the “axle” through the macrocycle cavity simultaneously.
Figure 8. Illustration of the active metal template process.
2.4.1 Early statistical approach
With Frisch and Wasserman first proposing the idea of mechanically interlocked
molecular structures and then their synthesis of the first [2]catenane relying on the
probability of threading through a macrocycles cavity. However it was the Harrison
group which first transferred this concept to rotaxane synthesis, however their approach
of repeatedly treating a Merrifield resin bound macrocycle with decane-1,10-diol and
triphenylmethyl chloride on a column, albeit resulting in a 6% yield of a [2]rotaxane
(reaction show below in Scheme 4).8
O
O
O
O
Resin
O
26
OH
OH
Cl
1. Repeated 70 times
2. NaHCO3, MeOH
O O
26
OH
O
6% yield
Scheme 4. The first synthesis of a [2]rotaxane by the Harrison Group using a Merrifield resin.8
13
14. 2.4.2 Directed synthesis via covalent bond formation
The term “directed synthesis” was first used by Schill and co-workers in 1964 to
describe employing covalent bonding at key stages to template the formation of
[2]catenane in the correct topology, key intermediates of the reaction are shown below
in Scheme 5. This technique although still giving a low yielding (30%) had overcame
the disadvantage of relying only on chance to form interlocked structures, and since this
development many other template strategies have since been developed.
O
O
(H2C)12
(H2C)12
Cl
Cl
NH2
(CH2)24
O
O N
(CH2)11
(CH2)11
(CH2)24
OH
O
O
O(CH2)25
(CH2)11
(CH2)11
Scheme 5. Key intermediates in the synthesis of a [2]catenane by Schill and co-workers.
This method of “directed synthesis” has been transferred and utilised in rotaxane
synthesis. In this synthesis Hiratani and co-workers first synthesised their macrocycle
ring system which as a polyether, contained many oxygen donor atoms, two of the
donor O atoms lay between aromatic ring systems and an unsaturated C-C double bond.
These two donor atoms were easily converted to phenolic hydroxyl groups via tandem
Claisen rearrangements. To obtain this rearrangement a thermal reaction of the
macrocyclic system was carried out in decalin at 160 o
C for 3 hrs, to give one phenolic
hydroxyl group (71% yield obtained), to obtain the second hydroxyl group a further
thermal reaction needed to be carried out, this time no solvent was used, the reaction
was carried out at 195 o
C and under vacuum conditions for 6hrs. This afforded the
required bi-phenolic hydroxyl containing macrocycle, these hydroxyl groups are then
available for the introduction of the axis of the rotaxane system.
14
15. O
O
ONa
Cl
Cl
O O
O
Cl
O
O
OH
NaH, DMF
OH
O
O
OH
O
O
O
TsO
O
TsO
O
O
O
O
O
O
O
O
O
OH
O
O
O
O
O
O
Decalin
160
o
C
3 hrs
O
OH
OH
O
O
O
O
O
195
o
C
6 hrs
5 6 7
CsCO3, KI, DMF
Scheme 6: Synthesis of macrocycle used by Hiratani and co-workers.
This macrocycle 7 is then reacted with an acid chloride 8 in THF at room temperature
(35% yield), giving a racemic mixture of monoesters 9 at either of the previously
hydroxyl positions. These monoester systems, were then reacted via an aminolysis
reaction with 10 carried out in a small amount of DMF at room temperature to afford
the desired rotaxane products 11.
NH
O
O
Cl
7
8
t-BuOK, THF
O
O
OH
O
O
O
O
O
NH
O
O
O
OH
O
O
O
O
O
O
NH
O
O
monoester isomers, 9
NH210
DMF
O
OH
OH
O
O
O
O
O
NH
O
O
NH
O
OH
OH
O
O
O
O
O
NH
O
O
NH
racemic mix of [2]rotaxanes 11
Scheme 7: Synthesis of [2]rotaxane 11 used by Hiratani and co-workers utilising covalent bond formation
to template the rotaxane formation.
15
16. 2.4.3 Hydrogen bond mediated templating synthesis
The first report of hydrogen bonding in connection with the templating of mechanically
interlocked structures was by Hunter, when they discovered a [2]catenane, in a 34%
yield, as a by-product of a macrocyclisation reaction.11
The [2]catenane results from
the macrocyclic precursors clipping around an existing molecule of the targeted
macrocycle, hydrogen bonding between the precursors amide groups and the
macrocycles carbonyl groups held the precursor in place while macrocyclisation
occurred to afford a [2]catenane.
The Leigh group also went on to utilise this phenomenon in the synthesis of a
[2]rotaxane, containing an amide macrocycle over an amide axle, using the clipping
methodology.12
The [2]rotaxane 12 formed satisfies the hydrogen bonding
requirements of both the axle and the macrocycle, this leads to the rotaxane being 105
times more soluble in chloroform than the free macrocycle.
R
O
Cl
O
Cl
NH2NH2
OO
NHNH
O O
O
O
CHPh2
CHPh2
R
O
N
H
O
N
H
NH
N
O
O H
O
O
NH
O
O
N
H
O
O
Ph2HC
NEt3
CHCl3
12
Scheme 8. Hydrogen bond assisted clipping of a macrocycle around an axle to afford corresponding
[2]rotaxane.12
16
17. 2.4.4 π-electron donor/ π-electron acceptor interactions
During the design of a receptor unit for parquat (a molecule containing π-electron
deficient bipyridinium rings), Stoddart and co-workers discovered that certain
bipyridinium salts complex efficiently with benzo crown ethers.13, 14
The parallel
aromatic rings of the π-electron rich benzo crown ethers coordinate with the π-electron
deficient paraquat-based salts, resulting in the production of pseudorotaxane type
structures, which can then be stoppered to give the equivalent rotaxane 13 (Scheme 7).
OO O O OHOOOH
SiTfO
N
N
+
N
+
N
+
N
+
4PF6
-
N
+
N
+
N
+
N
+
OO O OOOSi Si
5% yield
13
Scheme 9. Synthesis of a [2]rotaxane 13 by Stoddart and co-workers utilising π-π interactions.14
The development of π-π interactions as a viable route towards mechanically interlocked
structures has led to a large library of catenane and rotaxane systems being synthesised
with two15-20
, three21-25
and more23, 26
aromatic donor sites, thus with the potential to be
used as a molecular switch.
17
18. 2.4.5 Transition metal template synthesis of rotaxanes
The use of a transition metal to hold ligands in the precise orientation, directing bond
formation to favour an interlocked product, is extremely attractive to the synthetic
chemist. As well as the interactions being strong, the nature of the resulting
supramolecular complexes are frequently highly ordered, and often dictated by the
preferred geometry of the transition metal. The transition metal in this methodology
only aids the formation of the molecule but it is not essential once the molecule has
been synthesised.
The use of a metal template was first introduced by Sauvage and co-workers in 1983,
when they used tetrahedral Cu(I) to hold two 1,10-phenanthroline fragments orthogonal
to each other to allow the formation of a [2]catenane27
. When they first proposed this,
they were using a Williamson ether synthesis to close the ring systems27
,with this first
synthesis process they were obtaining a catenane yield of 27% which was surprising as
various other routes to catenanes at the time were only obtaining yields of <1%, they
then followed up this work by investigating the use of ring closing metathesis and first
published this in 199728
and then a fully completed paper was published on the subject
in 199929
reaction shown below in Scheme 10.
N
N
OH
OH
[Cu(NCCH3)4]+
N
N
OH
OH
N
N
OH
OH
Cu
+
[CH2(CH2OCH2)4CH2]
Cs2CO3
N
N
O
O
N
N
O
Cu
+
O
O
O
O
O
O
O
O
O27% yield
14
Scheme 10. [2]catenane 14 formation using a transition metal template methodology as employed by
Sauvage and co-workers.29
However it was Gibson and co-workers who first extended this concept to rotaxane
synthesis, using a similar Cu(I)-phenanthroline type ligand complex. They reported that
they obtained a [2]rotaxane, 15, in a 42% yield (Scheme 11).30
Since then the technique
has grown to not only incorporate copper but also to include many over transition
metals such as Fe, Co, Ni, Zn, Cd and Hg. The study of all these systems has led to a
much greater understanding of the mechanism associated with the synthesis.
18
20. 2.5 Active metal synthesis of rotaxanes
Although the introduction of transition metal template synthesis revolutionised the
synthesis of catenanes, rotaxanes and various other mechanically interlocked structures,
they did not fully utilise the chemistry intrinsically available to metal ions. As
previously discussed, the metal is only used to hold the reactive precursors in position
for as to allow for covalent bond formation. In the case of active metal template
synthesis, which is an extension of the previous concept, the metal has a dual role in the
synthesis, the metal acts as a template for holding the precursors together and to
catalyse the covalent bond formation which interlock the structure.
When synthesising rotaxanes using this methodology a metal is chosen such that it
promotes the formation of covalent bonds between two pre-functionalised “half-thread”
units, while still threading those “half-threads” through the cavity of the macrocycle.
The first active metal template synthesis was reported by the Leigh group in 2006, they
utilised a copper(I)-catalysed terminal alkyne-azide 1,3-cycloaddition (CuAAc) to
synthesis a [2]rotaxane, this model has now been extended to include other reactions
that utilise transition metals (Scheme 12).
2.5.1 CuAAc active metal template for rotaxane synthesis
Even with there being little knowledge of the mechanism of the CuAAc reaction at the
time, the mild reaction conditions and high yields obtained made it encouraging for
investigation, which lead to the gathering of proof of the active metal template concept.
However it was already known that the addition of Cu(I) exponentially accelerated the
reaction rate, as a result of this it was thought that the coordination of a tetrahedral Cu(I)
ion to the inner cavity of a monodentade or bidentate macrocycle would improve
coordination of an azide and terminal alkyne to the copper ion, through either face of
the macrocycle, the resulting coupling reaction results in the formation of a [2]rotaxane.
20
21. The Leigh group have reported yields of up to 94% for selected [2]rotaxanes, when the
reactions were carried out using a stoichiometric amount of the copper active species.31
With this they then investigated the use of sub-stoichiometric amounts of the copper
active species, while investigating this they found that the copper was able to both
template the reaction and also catalyse the cycloaddition reaction, when the reaction
mixture has a competitive ligand present (such as pyridine). Once optimised the sub-
stoichiometric reaction led to a slightly lower yield of 82% however this was achieved
using only 4mol% of the Cu(I) catalyst with respect to each “half-thread” precursor.32
The synthesis of [2]rotaxane 16 by CuAAc template is shown below in Scheme 12.
N
OO
(CH2)n
N
OOHO
(CH2)n
Cu
+
L4 F P
F
F-
-L
H
OR
Cu
+(IV)
L
L
L
N
OO
(CH2)n
ORCu
+(IV)
L
L-L
-HPF6
N3 OR
N
OO
(CH2)n
N
+
N
N
-
RO
OR
Cu
+(IV)
L
N
OO
(CH2)n
+L
+HPF6
L
Cu
+(IV)
L
N
RO
N
N
OR
+ pyridine
R = (t
-
BuC6H4)3CC6H4
-
L = MeCN, H2O, CH2Cl2, alkyne, azide, pyridine (catalytic version) or a donor from another rotaxane, macrocycle or thread.
N
OOHO
(CH2)n
N
N
N
O
O
16
Scheme 12. Cycle of a CuAAc reaction conducted by the Leigh group, used to investigate the effect of
macrocycle ring size on [2]rotaxane formation.
21
22. A study by Stoddart and co-workers in 2008 showed that consecutive CuAAc reactions
can be used to synthesis branched [4]rotaxanes in one pot reactions with reasonable
yield 44% (Scheme 13).33
The macrocycle used in the reaction is the charged species
CBPQT4+
, with a counter ion that is PF6
-
. Before being placed into the reaction the
stopper 19 and central axle unit 17 must first be activated from their corresponding
chlorides (shown below in Figure 9).
N3
N3
N3
O
O
O
OSiMe3
O
O
O
O
17
18
N
+
N
+
N
+
N
+
20
4PF6
-
N3
O
O
O
O
O
O
O
OMe
O
OMe
O
MeO
19
Figure 9: Starting materials for rotaxane synthesis, central axle component, 17, axle chain, 18, stopper
group, 19, macrocycle and counter ion, 20.
22
23. CH3
O
O
O
O
CH3
O
O
O
O
X =
N
N
N
N
N
N
N
N N
X
R
X
R
X
R
21 R = SiMe3
22 R = H
17 + 18
O
O
O
O
O
O
O
OMe
O
OMe
O
MeO
Y =
CuSO4.5H2O
Ascorbic acid
DMF
25
o
C
AgPF6
H2O
DMF
40
o
C
N
N
N
Y
N
N
N Y
N
N
N
N
N
N
N
N N
O
O
(CH2CH2O)3
O
O
(CH2CH2O)3
O
O
(CH2CH2O)3
(OH2CH2C)3
(OH2CH2C)3(CH2CH2O)3
N
N
N
Y
N
+
N
+
N
+
N
+
N
+
N
+
N
+
N
+
N
+
N
+
N
+
N
+
23
19 + 20
Cu nanopowder
[Cu(MeCN)4]PF6
DMF
-5
o
C
Scheme 13: One-pot rotaxane synthesis by Stoddart and co-workers.
23
24. 2.5.2 Copper mediated alkyne-alkyne heterocoupling
After their successful application of the CuAAc reaction, the Leigh group went on to
develop a copper-catalysed alkyne-alkyne heterocoupling active template synthesis,
which has its basis in a Cadiot-Chodkiewicz procedure (Scheme 14).32
Importantly, the
rotaxane products obtained contain unsymmetrical axles and unlike products of the
classical synthetic procedures, do not leave strong intercomponent binding motifs in the
final product. With this reaction procedure the group were able to synthesis rotaxanes
with excellent selectivity (>98%) and high yields (up to 85%), which makes the Cadiot-
Chodkiewicz one of, if not the most, efficient active template syntheses available to the
synthetic chemist to date.
RO
Cu
+
L
N N
O O
O O
RO
Cu
+
L
N
+
N
+
O O
O O
Br RO
Oxidative addition
RO
Cu
3+
N
+
N
+
O O
O O
RO
Br
Reductive elimination
-CuBr
N N
O O
O O
O
O
R = (t-BuC6H4)3CC6H4
L = I, THF
24
Scheme 14. Stoichiometric Cadiot-Chodiewicz active template synthesis of [2]rotaxane 24.32
24
25. 2.6 Cyclochirality in rotaxanes
Cyclochirality as a feature of mechanically interlocked systems has not as yet been
exploited to a great degree. The concept of cyclochirality is closely linked to that of
chirality in covalently linked systems, however in a covalent system a chiral molecule is
described as one that cannot be deformed to give its mirror image without the breaking
of chemical bonds. Whereas in a rotaxane system the macrocycle ring can be caused to
expand its cavity to allow the macrocycle ring to pass over the stopper group and allow
de-threading and re-threading to produce its mirror image, thus the rotaxane is not
topologically chiral but is instead termed cyclochiral. A graphical representation of
cyclochirality is show below in Figure 10.
Figure 10. Graphical representation of cyclochirality.
The first reported synthesised racemic mixture of pure cyclochiral rotaxanes was by
V gtle and co-workers in 1997.ӧ 34
The cyclochirality of their produced rotaxanes comes
from differing sequences of sulphonamide and amine groups on the macrocycle ring.
This, along with unsymmetrical stopper groups gives directionality to the rotaxane
system and as such cyclochirality. The resulting racemic mixture ([2]rotaxanes 25a and
25b) was able to be separated by HPLC with a chiral column.
25
26. Figure 11: Cyclochiral [2]rotaxanes synthesised by V gtle and co-workers which were then separated byӧ
HPLC with a chiral column.
In a more recent study by Hiratani and co-workers they were able to synthesis and
resolve the mixture of rotaxane 11 (shown in Scheme 7)35
that has the ability to
recognise chirality in covalent species so they can be exploited as amino acid chiral
sensors. However they also reported that not all racemic mixtures of rotaxanes could be
resolved using chiral HPLC, they propose that this stems from the structure of the
rotaxane “axle”, with the stopper and chain length being the primary factor that
influences the efficiency of the separation by this technique. This approach to
producing cyclochiral rotaxanes does have its drawbacks, in that the maximum yield
that is applicable is 50%, which limits the scale on which cyclochiral rotaxanes can be
produced.
NH
SO2
NH
O
NH
SO2
NH
O
O O
NH NH
NH
S
O
NH
OO
NHNH
NH
S
O
NH
26
27. A more promising possible strategy is to adopt an asymmetric synthesis, where only the
desired enantiomer is synthesised, which therefore does not then have the same
problems in purification and yield as the racemic mixture strategy. However the
synthesis of a single enantiomer is extremely challenging and only one success has so
far been reported (synthesis shown below in Scheme 15)36
. The yield however is not
impressive (48%) shows that this strategy is a reasonable alternative, with an
enantiomeric excess of only 4.4% also being produced shows that although in theory it
is possible to produce just one enantiomer it is very hard to reproduce synthetically.
O
O
O
O
O
O
O
O
NHCOCH3
NH2
+
OH
PF6
-
+
CO O
2
P
P
catalyst, 99% ee
NH2
+
O
O
OO
O
O
OO
O O
NHCOCH3
PF6
-
26
Scheme 15: Synthesis of cyclochiral [2]rotaxane 26 by Takata and co-workers.
27
28. 3.0 Aim of this project
Previous work within the Lee group has led to the synthesis of the macrocycle shown
below in Scheme 16.
O
O
O
O
O
O
O
O
O
O O
OHOH
O O
O
I I
O
I I
O
N N
O O
O
O
OO
N N
O O
OH OH
N N
O O
O O
N
H
+
N
OH OH
Cl
-
Br
O
OH
O
OH
OH
N BrBr NBr
O
H
NBr
OH
N
H
+
N
OH OHCl
-
(i) n-BuLi, THF, -78
o
C
(ii) DMF, -78
o
C to R.T
74 %
86 % 85 %
79 % 83 %
80 % 82 %
76 % 90 %
82 %
82 %19 %
NaBH4, MeOH, 0
o
C
(i) NiCl2.6H2O, PPh3, Zn, 50
o
C
(ii) 29
(iii) HCl(g), DCM
K2CO3, Allyl bromide, KI
Acetone, Reflux
48% HBr(aq), DCM
Pd(PPh3)4, Aniline, THF, 50
o
C
In(OTf)3, Ethylene glycol,
Benzene, Dean-Stark,
Reflux LiAlH4, THF, 0
o
C to R.T
PPh3, I2, Toluene,
Reflux
In(OTf)3, Ethylene glycol,
Benzene, Dean-Stark,
Reflux
NaH, 33, DMF, 0
o
C to R.T
35, K2CO3
DMF (0.0024 molL
-1
), 80
o
C
27
28
29 30
31 32 33
30
34
35
36 37
38
39
40
41
Scheme 16: Synthesis of macrocycle and its precursors used within Lee group
28
29. The problems with this synthesis are that when forming the diiodo compound 39. The
compound upon formation (as shown in Scheme 16) loses the acetal group and therefore
requires re-acetylation. Although the formation of 40 is high yielding the compound is
not stable enough to be stored for long periods of time.
This project was set up to synthesis a new macrocycle precursor to replace 40. The
conditions that must be satisfied for the new macrocycle precursor are:
a) There must have 7 carbons between leaving groups as a shorter chain hinders
macrocycle formation.
b) The leaving groups X must be easily removable.
c) A five-membered acetal must be present to protect the ketone, as the ketone reactivity
is needed for making the rotaxane cyclochiral.
The new macrocycle precursor must be either formed in one step from the acetal diol 38
shown in Scheme 16 and Scheme 17, or be much higher yielding than the previous
precursor 40.
OO
OH OH
OO
X X
N N
O O
O
O
OO
N N
O O
OH
OH
OO
X X
+
38
35
41
Scheme 17: Overall aim of the project
29
30. 4.0 Results and Discussion
4.1 Synthesis of macrocycle precursor 44
The overall synthetic strategy adopted for the formation of a macrocycle precursor is
shown below in Scheme 18.
OO
O O
O O
O
O O
O O
OO
OH OH
OO
TsO OTs
O
BrBr
O
Br Br
O
383736
42 43
44
Scheme 18: Overall synthetic route explored for macrocycle precursor.
Many different acetals are possible in synthesis, however in this case a five-membered
acetal was chosen because of its ease of cleavage, this is important for revealing
cyclochirality in a rotaxane system comprising the precursor formed.
OO
O O
O O
O
O O
O O
36 37
Scheme 19: 2 mol% In(OTf)3, Ethylene Glycol, Benzene, Dean Stark reflux, 100 o
C, 18 hrs, 88%
The first step of the synthesis is an acetalation, of commercially available Diethyl 4-
oxopimelate, this reaction was carried out under normal Dean Stark conditions. This
reaction proceeded with an 88% yield after purification by column chromatography.
OO
O O
O O
OO
OH OH
37 38
Scheme 20: LiAlH4, dry THF, N2, 18 hrs, R.T, 64%
30
31. With the acetal ester successfully synthesised the next step was to reduce the ester to an
alcohol using LiAlH4 as the reducing agent. The reaction went to completion however a
Fieser workup (1 mL of H2O for every gram of LiAlH4 used followed by 1 mL of 15%
NaOH for every gram of LiAlH4 used then finally 3 mL of H2O for every gram of
LiAlH4 used) was necessary as the acetal diol is soluble in water. After filtration to
remove the salts the solvent was removed using a rotary evaporator, once all solvent had
been removed the pure product would crystallise.
OO
OH OH
O
BrBr
38 42
Scheme 21: PPh3, Br2, Toluene, 18 hrs, 21%
Following on from previous work within the group, the acetal diol was reacted with
bromine to form a dibromo compound (shown above in Scheme 15), however due to the
acidic conditions of the reaction the acetal of the diol is cleaved, because the acetal is
vital for the macrocycle the dibromo compound has to be re-acetalised.
O
BrBr
O
Br Br
O
42 43
Scheme 22: 2 mol% In(OTf)3, Ethylene Glycol, Benzene, Dean Stark reflux, 100 o
C, 18 hrs, 43%
This reaction utilised normal Dean-Stark conditions also, however in this case a poor
yield of only 43% was obtained, I think this may have been due to the relative
instability of the dibromo ketone at the temperatures required for the reaction to
proceed.
OO
OH OH
OO
TsO OTs
38 44
Scheme 23: KOH, TsCl, dry THF, -10 - 0 o
C, 66%
The new shorter final step of the synthesis is the conversion from an alcohol group to a
tosylate group without removing the acetal. This was performed under extremely mild
31
32. conditions to protect the acetal from being removed. The reaction proceeds via a
deprotonation of the alcohol to produce an alkoxide this then reacts via an SN2
mechanism to produce the OTs group from reaction with TsCl. The product was
recrystallised from MeOH/hexane to give a 66% yield of pure product.
4.2 Synthesis of macrocycle 41
N N
O O
O
O
OO
N N
O O
OH OH
OO
TsO OTs
+
413544
Scheme 24: Cs2CO3, dry DMF, N2, high dilution, 18 hrs, 37%
A high dilution set up was used for the macrocyclisation reaction. Both macrocycle
precursors (44 and 35) were dissolved up in dry DMF and transferred into syringes.
The Cs2CO3 was dissolved in dry DMF in a 3 necked round bottom flask with the
syringes containing the macrocycle precursors on an injection pump set to add into the
flask. This method compared with the previous method of adding all reactants in at
once gave a twice as high yield of 37% (versus the 21% yield obtained within group).
The macrocycle product was characterised by 1
H and 13
C-NMR, with a 1
H-13
C
correlation taken to resolve the many overlapping peaks.
32
33. 5.0 Conclusion
The main aim of the project was to synthesis a new macrocycle precursor which was
able to be stored for long periods unlike the precursor used by the group at the moment
(compound 40) this aim was achieved with the formation of precursor 44 as this is
stable for long periods and is able to be stored under air with no problems.
The secondary aim of the project was to make the precursor in fewe steps, this was also
successfully achieved with the formation of 44, because of the mild conditions the Ts
group can be added under the acetal is not cleaved and as such saves one step from the
synthesis.
Finally and most importantly the new precursor 44 was reacted with the other premade
precursor 35 to give the desired macrocycle, this process was also an improvement over
previous methods within the group, such that an almost doubled percentage yield was
obtained from the reaction (37% compared with 21% from previous work within the
group).
33
34. 6.0 Experimental section
1
H NMR spectra were recorded on Bruker AVIII and DPX 400 at 300 MHz and 400
MHz respectively and referenced to the residual solvent. 13
C NMR spectra were
recorded at 75.5 MHz and 100 MHz on the same spectrometers. Chemical shift data is
given in parts per million (δ in ppm), J values are given in Hz.
Flash chromatography was carried out using Matrix silica gel 60a from Fisher
Chemicals and TLC was performed using Merck silica gel 60 F254 pre-coated sheets
with detection by CAM or permanganate dips depending upon reaction being studied.
The inference room temperature (RT) refers to an ambient temperature of 12 – 20 o
C.
All chemicals used were purchased from either Aldrich or Fischer chemical companies.
THF was dried by distillation from sodium as was toluene and DMF was dried using
vacuum distillation from sodium. PE refers to petroleum ether (40-60%). EtOAc refers
to ethyl acetate.
6.1 Synthesis of macrocycle precursor
Preparation of diethyl 3,3'-(1,3-dioxolane-2,2-diyl)dipropanoate 37
OO
O O
O O
Ha
Hb
Hb
Hc Hc
HdHd
He
He
He
Ha
O
O O
O O
36 37
Solution of diethyl 4-oxoheptanedioate (16.5 g, 71.5 mmol) and ethylene glycol (20
mL/22.3 g) in Benzene (330 mL) was stirred before indium triflate (0.819 g, 1.46
mmol) was added to the solution. The reaction mixture was then heated at reflux until
the reaction was complete (approximately 18 hrs) before being cooled to room
temperature. The solvent was then removed in vacuo to afford a crude yellow oil
product which was subsequently dissolved in a minimum amount of EtOAc. The
organics were then washed consecutively with H2O, saturated NaHCO3, H2O and brine
before being dried over Na2SO4. This was concentrated to a pale yellow oil, the oil was
pre-adsorbed onto silica and then purified by flash chromatography eluting with a
mixture of PE:EtOAc of 15:1 to 6:1 to yield (17.3 g, 63 mmol, 88%) of clean product
37 as a colourless oil.
34
35. δ H (300 MHz, CDCl3) 4.11 (4 H, q, J 7.1, Ha), 3.92 (4 H, s, Hb ), 2.40 – 2.31 (4 H, m,
Hc/Hd), 2.00 – 1.91 (4 H, m, Hc/Hd), 1.28 – 1.20 (6 H, m, He).
δ C (75 MHz, CDCl3) 173.4 (C x2), 110.1 (C), 65.1 (CH2 x2), 60.3 (CH2 x2), 32.4 (CH2
x2), 28.9 (CH2 x2), 14.2 (CH3 x2).
Preparation of 3,3'-(1,3-dioxolane-2,2-diyl)dipropan-1-ol 38
OO
O O
O O
OO
OH OHk
Hf
Hf
Hg
Hg
Hi Hi
Hj Hj
37 38
Solution of 37 (3.054 g, 11.1 mmol) in dry THF (130 mL) was stirred under N2, LiAlH4
(2.14 g, 56.3 mmol) was added portion wise at 0 o
C. The reaction was then stirred for
18 hrs at room temperature. The reaction was quenched using a minimum volume of
saturated Na2SO4 followed by EtOAc (20mL). The solution was then filtered and the
salts were washed with EtOAc, the solvent was removed from the filtrate in vacuo. The
residue obtained was dissolved in DCM (75 mL) and dried over Na2SO4. This was
concentrated to afford crude product, the crude product was pre-adsorbed onto silica
and then purified by flash chromatography eluting with a mixture of PE:EtOAc of 9:1 to
1:1 to yield (1.37 g, 7.2 mmol, 64%) of clean product 38 as a white solid.
δ H (300 MHz, CDCl3) 3.90 (4 H, s, Hf), 3.55 (4 H, t, J 6.1, Hg), 2.95 (2 H, s, Hk), 1.71 –
1.62 (4 H, m, Hi/Hj), 1.62 – 1.51 (4 H, m, Hi/Hj).
δ C (75 MHz, CDCl3) 111.8 (C), 65.2 (CH2 x2), 63.3 (CH2 x2), 33.8 (CH2 x2), 27.3 (CH2
x2).
Preparation of 1,7-dibromoheptan-4-one 42
OO
OH OH
O
BrBr
Hl
Hm Hm
Hn HnHl
38 42
A solution of 38 (0.502 g, 2.64 mmol) in dry toluene (40 mL) was stirred under an N2
atmosphere. PPh3 (1.81 g, 6.91 mmol) was added and reaction was heated to 130 o
C
and the Br2 (0.2 mL/0.62 g, 7.77 mmol) was added portion wise. The reaction was then
refluxed in darkness for 18 hrs. Absolute ethanol (0.25 mL) was added in 2 portions, 30
mins apart from each other. The solvent was then removed in vacuo before the residue
35
36. was taken up in a minimum DCM. The crude product was pre-adsorbed onto silica and
then purified by flash chromatography eluting with a mixture of PE:EtOAc of 10:1 to
yield (0.149 g, 0.55 mmol) of clean product 42 as a dark yellow/brown oil.
δ H (300 MHz, CDCl3) 3.47 (2 H, t, J 6.4, Hn), 2.66 (2 H, t, J 7.0, Hl), 2.15 (2 H, p, J 6.7,
Hm).
δ C (75 MHz, CDCl3) 110.5 (C), 35.7 (CH2 x2), 34.1 (CH2 x2), 27.4 (CH2 x2).
Preparation of 2,2-bis(3-bromopropyl)-1,3-dioxolane 43
O
BrBr
O
Br Br
O
Ho
Ho
Hp Hp
Hq Hq
Hr Hr
42 43
Solution of 42 (0.26 g, 0.96 mmol) and ethylene glycol (0.25 mL/0.28 g) in Benzene (7
mL) was stirred before indium triflate (0.013 g, 0.023 mmol) was added to the solution.
The reaction mixture was now heated at reflux until completion of the reaction
(approximately 18 hrs) before being cooled to room temperature. The solvent was then
removed in vacuo and the crude product dissolved in a minimum amount of EtOAc.
The organics were then washed consecutively with H2O, saturated NaHCO3, H2O and
brine before being dried over NaSO4. This was concentrated to a pale yellow oil, the oil
was pre-adsorbed onto silica and then purified by flash chromatography eluting with a
mixture of PE:EtOAc of 15:1 to yield (0.13 g, 0.41 mmol, 43%) of clean product 43 as a
brown solid.
δ H (300 MHz, CDCl3) 3.96 (4 H, s, Ho), 3.44 (4 H, t, J 6.6, Hr), 2.02 – 1.90 (4 H, m,
Hp), 1.81 – 1.72 (4 H, m, Hq).
δ C data was not obtained as not enough product was formed for analysis.
36
37. Preparation of 2,2-bis(3-tosyloxypropyl)-1,3-dioxolane 44
OO
OH OH
OO
TsO O
Hs
Hs
Ht Ht
Hu Hu
Hv Hv S
O
O
Hw
Hw
Hx
Hx
Hy
Hy
Hy
38 44
A solution of 38 (1.73 g, 9.07 mmol) in dry THF (20 mL) was cooled to -10 o
C under an
N2 atmosphere, TsCl (4.35 g, 22.8 mmol) and powdered KOH (5.1 g, 90.9 mmol) were
then added over portion wise over 20 mins. The reaction was allowed to stir for 30
mins before being allowed to reach 0 o
C and left to stir for 18 hrs. The solution was
then added to an ice/water mixture and extracted with EtOAc, the solution were then
washed 3 times with EtOAc. The organics were then washed with brine and dried with
MgSO4. The solvent was then removed in vacuo to afford a crude solid product, the
crude product was then recrystallised from hot MeOH and extracted using hexane to
yield (2.97 g, 5.97 mmol, 66%) of pure crystalline macrocycle precursor 44.
δ H (300 MHz, CDCl3) 7.76 (4 H, d, J 8.3, Hw), 7.32 (4 H, d, J 8.0, Hx), 4.00 (4 H, t, J
6.3, Hv), 3.82 (4 H, s, Hs), 2.43 (6 H, s, Hy), 1.69 – 1.61 (4 H, m, Ht/Hu), 1.58 – 1.53 (4
H, m, Ht/Hu).
δ C (75 MHz, CDCl3) 145.0 (C x2), 133.4 (C x2), 130.1 (CH x4), 128.1 (CH x4), 110.6
(C), 70.7 (CH2 x2), 65.2 (CH2 x2), 33.1 (CH2 x2), 23.6 (CH2 x2), 21.9 (CH3 x2).
37
38. 6.2 Synthesis of macrocycle 41
N N
O O
O
O
OO
Haa Hbb
Hcc
Hdd
Hdd
Hee
Hee
Hff
Hgg
Hff
Hgg
Hhh
Hhh
HiiHii
Hjj
Hjj
Hkk
Hkk
N N
O O
OH OH
OO
TsO OTs
+
413544
A solution of CsCO3 (0.383 g, 1.17 mmol) in dry DMF (50 mL) at 65 o
C was stirred
under N2. 44 (0.059 g, 0.012 mmol) was dissolved in dry DMF (5 mL) and put in
syringe, macrocycle precursor 35 (0.0502 g, 0.012 mmol) was dissolved in dry DMF (5
mL) and put in a syringe. Both syringes were put on a syringe pump set with a flow
rate of 0.5 mL/hr. Once all starting material had been added solution was stirred for a
further 24 hrs. The solvent was removed in vacuo then the residue was taken up in
EtOAc (100 mL). This solution was then washed with H2O (100 mL) and the aqueous
re-extracted using DCM (300 mL). This was concentrated to a brown oil, the oil was
pre-adsorbed onto silica and then purified by flash chromatography eluting with a
changing solvent system (DCM to DCM:MeOH 99.5:0.5 to DCM:MeOH 99:1) to yield
(0.025 g, 0.043 mmol, 37%) of clean macrocycle product 41 as a white solid.
δ H (400 MHz, CDCl3) 7.88 (2 H, d, J 7.7, Haa/Hcc), 7.70 (2 H, t, J 7.8, Hbb), 7.40 (2 H, d,
J 7.7, Haa/Hcc), 7.20 – 7.11 (4 H, m, Hgg), 6.75 – 6.68 (4 H, m, Hff), 4.63 (8 H, d, J 4.3,
alkyl CH2’s), 3.97 – 3.89 (8 H, m, alkyl CH2’s), 1.79 – 1.66 (8 H, m, alkyl CH2’s).
δ C (101 MHz, CDCl3) 159.0 (C x2), 158.6 (C x2), 137.5 (CH x2) , 130.3 (CH x4),
130.0 (C x2), 121.5 (CH x2), 120.5 (CH x2), 114.9 (CH x4), 111.5 (C x2), 77.4 (C),
73.0 (CH2 x2), 72.1 (CH2 x2), 68.1 (CH2 x2), 65.2 (CH2 x2), 33.6 (CH2 x2), 23.6 (CH2
x2).
38
39. Acknowledgements
I would like to thank my supervisor Dr Ai-Lan Lee for a very interesting project and all
the feedback I have received throughout it. I would also like to thank James O’Neill for
his considerable contribution during my time in the lab. Also thanks are extended to
Jamie Jordan-Hore and Pauline Glen for guidance when I have required it.
39
40. References
1. O. Safarowsky, B. Windisch, A. Mohry and F. Vogtle, J. Prakt. Chem., 2000,
342, 437-444.
2. G. Schill and H. Zollenkopf, Journal of the American Chemical Society, 1967,
15, 149.
3. A. Moretto, I. Menegazzo, M. Crisma, E. J. Shotton, H. Nowell, S. Mammi and
C. Toniolo, Angewandte Chemie-International Edition, 2009, 48, 8986-8989.
4. M. Feng, X. F. Guo, X. Lin, X. B. He, W. Ji, S. X. Du, D. Q. Zhang, D. B. Zhu
and H. J. Gao, Journal of the American Chemical Society, 2005, 127, 15338-
15339.
5. Y. Tachibana, N. Kihara and T. Takata, Journal of the American Chemical
Society, 2004, 126, 3438-3439.
6. G. Hattori, T. Hori, Y. Miyake and Y. Nishibayashi, Journal of the American
Chemical Society, 2007, 129, 12930-+.
7. Y. Li, Y. Feng, Y. M. He, F. Chen, J. Pan and Q. H. Fan, Tetrahedron Letters,
2008, 49, 2878-2881.
8. I. T. Harrison and S. Harrison, Journal of the American Chemical Society, 1967,
89, 5723-5724.
9. A. Harada, J. Li and M. Kamachi, Nature, 1993, 364, 516-518.
10. E. Mezzina, M. Fani, F. Ferroni, P. Franchi, M. Menna and M. Lucarini, Journal
of Organic Chemistry, 2006, 71, 3773-3777.
11. C. A. Hunter, Journal of the American Chemical Society, 1992, 114, 5303-5311.
12. A. G. Johnston, D. A. Leigh, A. Murphy, J. P. Smart and M. D. Deegan, Journal
of the American Chemical Society, 1996, 118, 10662-10663.
13. P. R. Ashton, A. M. Z. Slawin, N. Spencer, J. F. Stoddart and D. J. Williams,
Journal of the Chemical Society-Chemical Communications, 1987, 1066-1069.
14. E. Cordova, R. A. Bissell, N. Spencer, P. R. Ashton, J. F. Stoddart and A. E.
Kaifer, Journal of Organic Chemistry, 1993, 58, 6550-6552.
15. P. L. Anelli, N. Spencer and J. F. Stoddart, Journal of the American Chemical
Society, 1991, 113, 5131-5133.
16. R. A. Bissell, E. Cordova, A. E. Kaifer and J. F. Stoddart, Nature, 1994, 369,
133-137.
17. A. C. Benniston, A. Harriman and V. M. Lynch, Journal of the American
Chemical Society, 1995, 117, 5275-5291.
18. P. R. Ashton, M. R. Johnston, J. F. Stoddart, M. S. Tolley and J. W. Wheeler,
Journal of the Chemical Society-Chemical Communications, 1992, 1128-1131.
19. P. R. Ashton, R. A. Bissell, N. Spencer, J. F. Stoddart and M. S. Tolley, Synlett,
1992, 914-918.
20. P. R. Ashton, R. A. Bissell, R. Gorski, D. Philp, N. Spencer, J. F. Stoddart and
M. S. Tolley, Synlett, 1992, 919-922.
21. P. R. Ashton, M. A. Blower, S. Iqbal, C. H. McLean, J. F. Stoddart, M. S. Tolley
and D. J. Williams, Synlett, 1994, 1059-1062.
22. P. L. Anelli, P. R. Ashton, N. Spencer, A. M. Z. Slawin, J. F. Stoddart and D. J.
Williams, Angewandte Chemie-International Edition in English, 1991, 30, 1036-
1039.
23. P. R. Ashton, D. Philp, N. Spencer and J. F. Stoddart, Journal of the Chemical
Society-Chemical Communications, 1991, 1677-1679.
24. P. R. Ashton, R. A. Bissell, N. Spencer, J. F. Stoddart and M. S. Tolley, Synlett,
1992, 923-926.
25. P. R. Ashton, D. Philp, N. Spencer, J. F. Stoddart and D. J. Williams, Journal of
the Chemical Society-Chemical Communications, 1994, 181-184.
40
41. 26. M. Seiler, H. Durr, I. Willner, E. Joselevich, A. Doron and J. F. Stoddart,
Journal of the American Chemical Society, 1994, 116, 3399-3404.
27. C. O. Dietrichbuchecker and J. P. Sauvage, Tetrahedron Letters, 1983, 24, 5091-
5094.
28. B. Mohr, M. Weck, J. P. Sauvage and R. H. Grubbs, Angewandte Chemie-
International Edition in English, 1997, 36, 1308-1310.
29. M. Weck, B. Mohr, J. P. Sauvage and R. H. Grubbs, Journal of Organic
Chemistry, 1999, 64, 5463-5471.
30. C. Wu, P. R. Lecavalier, Y. X. Shen and H. W. Gibson, Chemistry of Materials,
1991, 3, 569-572.
31. E. R. Kay, D. A. Leigh and F. Zerbetto, Angewandte Chemie-International
Edition, 2007, 46, 72-191.
32. J. D. Crowley, S. M. Goldup, A. L. Lee, D. A. Leigh and R. T. McBurney,
Chemical Society Reviews, 2009, 38, 1530-1541.
33. J. M. Spruell, W. R. Dichtel, J. R. Heath and J. F. Stoddart, Chemistry-a
European Journal, 2008, 14, 4168-4177.
34. C. Yamamoto, Y. Okamoto, T. Schmidt, R. Jager and F. Vogtle, Journal of the
American Chemical Society, 1997, 119, 10547-10548.
35. N. Kameta, Y. Nagawa, M. Karikomi and K. Hiratani, Chemical
Communications, 2006, 3714-3716.
36. Y. Makita, N. Kihara, N. Nakakoji, T. Takata, S. Inagaki, C. Yamamoto and Y.
Okamoto, Chemistry Letters, 2007, 36, 162-163.
41
