Rotaxane in the synthesis of a complete rotaxane

Rotaxane Synthesis



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Rotaxanes definition

Molecular machines are currently at the forefront of
research in chemistry, with the Nobel prize being awarded to Sauvage et al, in 2016. A crucial component of
molecular machines are rotaxanes and pseudorotaxanes. Rotaxanes are dissimilar
to any other molecules, as they are mechanically interlocked molecular
structures, they most often consist of 3 components; a long axel like molecule
(also known as the guest), threaded through a ring-like macrocycle (also known
as the host) which is then “stoppered” at each end through the addition of
bulky groups to prevent extrusion from the chain, 1, 2  the threaded structure is maintained through
non-covalent host-guest interactions.

Semirotaxane, pseudorotaxanes

A pseudorotaxane is commonly the first step in the synthesis
of a complete rotaxane (though not always e.g. the slipping method which will
be discussed later), it consists of only the axel like alkyl chain molecule,
threaded through the macrocycle, without the bulky groups added to stopper it,
pseudorotaxanes are often the synthetic precursor to rotaxanes as the lack of
bulky end groups allows for threading.

 If only one of the
end of the axel is stoppered it can be known as a semi rotaxane, these semi
rotaxanes can either be stoppered with a bulky group or “clipped” / “snapped”
to another semi rotaxane to form a complete rotaxane. Representations of the
previously mentioned rotaxanes can be found in figure 1.



Figure 1 Cartoon representations of pseudorotaxane,
semirotaxane, and rotaxane. (Microsoft Word 2018)



1 rotaxanes, 2 rotaxanes, n rotaxanes,
polyrotaxanes, daisy chains

It is possible to classify rotaxanes into two general
types:” macromolecular” or “discrete rotaxanes”. “Macromolecular rotaxanes”,
“polymeric rotaxanes”, or “polyrotaxanes” contain a macromolecular or polymeric
component. comparatively, rotaxanes without a macromolecular or polymeric
component are generally referred to simply as “rotaxanes”. However, in some circumstances
this can lead to confusion, as rotaxane can be considered an umbrella term,
therefore the terms “low-molar-mass rotaxanes” and “discrete rotaxanes” have
been used.  The current nomenclature of
rotaxanes appears as nrotaxane, with n referring to the number of species
making up the completed rotaxane be they linear or cyclic 3, 4.

A 2rotaxane is the simplest form and can only comprise of
one linear axel component threaded through one cyclic component, very similar
to this is the 1 rotaxanes which is comprised of the same components however
the macrocycle and linear species are structurally linked.

A 3rotaxane can be comprised of either two linear species
threaded through one cyclic component, or just the one linear species threaded
through two cyclic components, as can be seen in figure 2. This nomenclature
continues to apply as n increases, and current research has taken this as far
as a 7rotaxane 5

Figure 2 Cartoon representation of different types of
3rotaxanes (Microsoft Word 2018)


There are many kinds of polymeric rotaxanes that can be
found in the literature 6.  A specific example of a polymeric rotaxane is
the daisy chain type 7;
which consists a macromolecule that features a linear species covalently bonded
to a macrocycle, which is threaded with the linear species of another
macromolecule so they interlock, like a daisy chain as can be sin in figure 3.They
can be homopolymeric or copolymeric.


Figure 3 Cartoon representation of a “Daisy
Chain” rotaxane (Microsoft Word 2018)

Similar to rotaxanes are catenanes, which are mechanically-interlocked
molecules consisting of two or more
interlocked macrocycles. Only breaking
the covalent bonds of the macrocycles will separate the interlocked rings. They
are conceptually related to other mechanically interlocked molecules, as such
their syntheses require similar techniques to rotaxanes however
that is beyond the scope of this research.


As with many
technologies at the forefront of science there are far more potential
applications currently than current real world applications however there are
many possibilities. As mentioned previously, the 2016 Nobel prize was awarded
for the development of molecular machines based on rotaxanes such as
a molecular lift, a molecular muscle and a molecule-based computer chip.

 A molecular motor has
been developed which molecular rotor blade to spin continually in the same
direction 8. Molecular machines will most likely be used to develop such
things as novel materials, sensors and energy storage systems.


Synthesis Methods


Initial strategies for rotaxane synthesis were developed
using a statistical threading method,
i.e. when a large enough macrocyclic molecule and linear species are placed in
aqueous solution, statistically a percentage will combine in the desired

This method was first employed by Harrison in 1967 1,
in this case, the macrocycle was bound to a resin and treated with decane-I,
10-diol (linear species/axel) and triphenylmethyl chloride (bulky end
group/cap) this resulted in trace amounts of the desired complex, to increase
yield beyond this, the process was repeated 70 times for an eventual yield of


Scheme 1 Initial Rotaxane synthetic approach 1




This early synthesis method of threading a macrocycle before
adding bulky end groups was the precursor of today’s more developed capping method.  Synthesis via the statistical method does not make use of any
attractive forces between the linear and cyclic elements, the use of these
non-covalent attractive forces has allowed for template strategies to be used
for a variety of increasingly complex rotaxanes. These non-covalent forces include, ?–? stacking
interactions, hydrogen bonding, hydrophobic interactions,
metal ion coordination, and anion templates 9 It is these
non-covalent interactions which pre-organise the components prior to the next
stage of the reaction, therefore these reactions are known as self-assembling

template relied upon for the capping method is a thermodynamically driven
template effect. In this case, the linear species is threaded through and held
within the macrocycle by non-covalent forces, the nature of these forces is
most commonly dependent on the macrocycle involved.

 Cyclodextrins (CDs) are popular macrocycles
for the rota in rotaxane synthesis as  they are easily  functionalised through variety of methods they can be
functionalized by a wide variety of synthetic methods 10.  CD’s have a predisposition to form host–guest
or inclusion complexes in aqueous solution through hydrophobic interactions in part due
to their funnel like shape and the presence of many hydroxyl groups (therefore they are
also water-soluble and biocompatible). The hydroxyl groups are also responsible
for increased preorganization through hydrogen bond donors and acceptors. As
mentioned previously CDs can be easily functionalised to provide additional
non-covalent interactions.

successful CD rotaxane synthesis requires specific
conditions due to the hydrophobic driving forces, which require a polar solvent
or aqueous conditions, without high reaction temperatures. First, the bulky
substituents should be hydrophilic. Second, the pseudorotaxane-like structure
should not be dissociated in aqueous media. Third, the coupling reactions
should be carried out under and inert, anhydrous demand

relies upon the end cap being a suitable size to prevent extrusion or rethreading,
these are covalently bonded to the linear species for increased stability, for
higher yields and to prevent dethreading the end cap size has to be
complimentary to the macrocycle to be threaded. Historically bulky transition
metal complexes such as CoIII, RuIII and FeII
were used and resulted in relatively high yields of CD based rotaxanes, however
other organic groups such as trinitrophenyl groups have also been used. Harada
found that 2-bromophenyl groups provided a suitable
end cap (Scheme 20) however similar phenyl groups without the bromine present
were not effective, suggesting the bulk of the larger halide group was responsible
for the capping preventing dethreading.  Saccharidic ligands have also been used as capping
groups as well as adding bio recognition function to the rotaxane. Cyclodextrins
themselves have been used as an end cap with a trinitrophenyl group capping the
other end 11


Scheme 2. One-Pot Synthesis of 3 Rotaxane 1 from
1,12-Diaminododecane and ?-CD via the Urea End-Capping Method12

Hydrophobic forces and
Hydrogen bonding are not the only forces which direct capping synthetic
strategies, for the synthesis of rotaxanes using cyclobis(paraquat-p-phenylene)2 (CBPQT4+)
and other linear molecules containing ?-electron-rich components, ?- ?
interactions are crucial. With Molecular electronic devices at the forefront of
technology, there is a need to synthesise molecular switches, and (CBPQT4+)  based switchable donor acceptor rotaxanes have
been found to be suitable 13. Initial methods relied on
the “clipping” technique however this requires very precise reaction condition
and is hard to achieve in high yields. A capping strategy has therefore been developed
which operates under mild conditions thanks to click chemistry and 2-, 3-,
and 4rotaxanes have been successfully prepared.

 This synthetic strategy relies upon, ?- ?
interactions driving the ?-electron-deficient CBPQT4+ ring to thread a linear species containing ?-electron-rich moieties
to form pseudorotaxanes. These are terminated by azide and/or alkyne groups.
These pseudorotaxanes then undergo Cu(I)-catalyzed Huisgen9 1,3-dipolar cycloadditions forming rotaxanes
incorporating 1,2,3-triazole units. The  CBPQT4+ ring,
which can be electrochemically induced to move between tetrathiafulvalene (TTF)
and 1,5-dioxynaphthalene (DNP) recognition units12 located
along its dumbbell component. This bistable compound was characterized by (i)
electrospray ionization mass spectrometry (ESI-MS) and (ii) 1H NMR spectroscopy, and its switching
behavior was demonstrated by using (iii) cyclic voltammetry (CV), (iv)
differential pulse voltammetry (DPV), and (v) UV?vis spectroelectrochemistry