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Mie UniversityDepartment of Chemistry for Materials
• General Principles and Selected Examples
• in Supramolecular Chemistry
• Prof. Yang Kim
• Kumamoto University
3.1 Introduction
� Self-assembly
The spontaneous and reversible association of molecular species to form larger, more complex
supramolecular entities according to the intrinsic information contained in the components.
(the spontaneous association of two or more molecules or ions to create a larger,
aggregate species through the formation of reversible (generally supramolecular) interactions)
(ex). DNA double-helix via hydrogen bonds and π–π stacking in a self-assembly process.
The strands recognise each other and join together
to form the most thermodynamically stable assembly product.
3.1.1 Self-assembly
Angew. Chem. Int. Ed. Engl. 1983, 22, 565.
� The concepts of self-assembly were originated
from studies on the tobacco mosaic virus (TMV).
� The TMV, after dissociation into its components,
can be reconstituted in vitro leading to the
reconstruction of the intact virus.
H. Fraenkel-Conrat & R.C. Williams,
Proc. Natl. Acad. Sci. USA 1955, 41, 690.
� Synthetic self-assembly process:
� metal–ligand interactions due to their lability
and high degree of directionality as a result of predictable metal-ion coordination environments.
� Metals with well-defined coordination preferences:
1. coupling with rigid ligands to provide predictable self-assemblies.
2. highly directional nature of hydrogen bonds.
� Design of synthetic self-assembling systems: retrosynthetic methodology
Designing a square structure: square-planar metal ion (Pd2+, Pt2+)
3.1.2 Definitions and basic concepts of self-assembly
� In the strictest sense, the term self-assembly:
kinetically rapid and both completely reversible and replicable process
� The reversible nature of the assembly process gives rise
to correct ‘mistakes’ during assembly and the most thermodynamically stable product.
Thermodynamically stable assemble.
Small aggregates are initially formed then go on to form larger assemblies
which are thermodynamically stable and relatively kinetically inert.
1. Single-interaction self-assembly (or single code self-assembly): only one specific interaction
(ex) (1) Pd2+/4,4’-bpy square: solely Pd–N interactions that are all equivalent.
(2) The self-assembly of carboxylic acids in the solid state: only OH···O hydrogen bonds are present.
A single-interaction assembly,
using one specific type of
metal–ligand interaction.
2. Multiple-interaction self-assembly (or multiple-code self-assembly)
2-a. unimediated multiple-interaction assembly
two different metal-ligand interactions
2-b. multimediated multiple-interaction assembly
different categories of interaction (e.g. both metal–ligand bonds and hydrogen bonds)
� ‘n-component self-assembly’, (n: the number of separate parts that combine to make the final product)
Pd2+ /bpy square: 8-component assembly (four Pd2+ corners and four bipyridyl edges)
2-a 2-b
The same terminology applies to hydrogen bonding
interactions to hold the assembly together.
3.1.3 Enthalpic and entropic considerations
� Self-assembling systems selectively produce the most thermodynamically stable products.
� The formation of a self-assembled product is enthalpically favourable.
� However, the formation of aggregate species occurs at an ‘entropic cost’ as many degrees of freedom in the
system are lost. The entropic penalty compensate somewhat by the release of solvent molecules that were
previously interacting with the binding areas of the assembly components.
� Cyclic structures form slightly more interactions per structural unit, as they have no loose ends
and therefore they are more enthalpically favourable.
3.2 Biological self-assembly
� Vital biological processes (ex. replication of DNA, folding of proteins):
countless weak interactions that cause highly complex architectures
� Main non-covalent interactions in biological systems
(1) hydrogen bonding, (2) ion-pair interactions, (3) hydrophobic effects
� In metalloenzymes: metal-coordination interactions (ex. coordination of Zn2+ in carbonic anhydrase)
� Why self-assembling systems play such important biological and biochemical roles?
▸If every biological process required strong chemical bonds to be formed or broken,
then biological systems would consume enormous amounts of energy
and the synthesis of biological molecules would be extremely complex and time-consuming.
▸(ex) Everyday processes such as DNA replication, would involve many thousands of covalent bonds
being broken and reformed for a duplicate of just a single strand to be produced.
▸Nature uses smaller building blocks that are coded with the right information to form the larger species
by themselves.
� Some common supramolecular synthons based on hydrogen bonds.
� Carboxylic acids can form (a) discrete dimers and (b) infinite chains. (c) Amides can form dimers in a similar
manner to carboxylic acids, while (d) urea may form a ‘tape’ motif. Alcohols may also form both (e) infinite
and (f) discrete structures.
Carboxylic acid dimers
3.3 Ladders, polygons and helices3.3.1 Self-assembly using metal templates
� A well-defined coordination geometry is especially important in the synthesis of structures of regular
geometry, such as grids or polygons.
� Convergent components: focus binding sites towards a central point
Divergent components: promote binding in multiple directions
▸Different combinations of convergent and divergent binding sites will give different products,
either discrete complexes or polymeric networks.
3.3.2 Racks, ladders and grids
� Structures that consist of a regular array of metal ions joined by rigid, linear, multidentate ligands.
Nomenclature
� Racks are named according to how many spokes they contain.
(ex) [2]-rack: two monotopic ligands attached to a ditopic ligand
� Ladders takes [2.n]-ladder, whereby n is the number of rungs and the number ‘2’ refers to the two sides
which the rungs connect (the prefix ‘2’ is similar to the naming of grids).
� Grids are named according to the number of ligands that occur in the columns and the rows
(or by the n-topic nature of the ligands), [m×n]-grids.
� square grids: when m and n are equal
rectangular grids: when they are not equal
chiral square grid
[2]-rack [2.2]-ladder [2×2]-square grid chiral [2×2]-grid
� The architectures depend on the selection of metal ion and the ligand design philosophy.
Examples of how ligands can be joined at perpendicular angles templated
by (a) tetrahedral and (b) octahedral metals.
Rack
Racks are described by [n]R, where n refers to the nuclearity of the species.
� The partially blocked Ru2+ (the blocking terpyridyl units become the spokes) are able to sit within the
tridentate pockets in the backbone ligand.
� Counter-anion must be weakly coordinating (e.g. BF4
−, PF6
−, CF3SO
3
−).
[2]-rack constructed using Ru2+ as an octahedral templating ion.
The binding pockets of the free ligands are indicated by arrows.[3]-rack
[3.3]-ladder
multi-compartmental assembly
[2.3]-ladder
Examples of [2.3]-ladder and [3-3]-ladder
using Cu+ as a tetrahedral templating ion.
Cylinders
� Cylinders are a species, which are self-assembled from appropriate metal ions
with two different types of ligand, one planar polytopic ligand and one rigid circular polytopic ligand.
3.3.3 Helicates
� Helicates
▸▸▸▸Metal complexes that possess a helical and therefore chiral structure geometry akin to a screw thread.
▸The ligands are called helicands.
� pitch: The distance between one turn and the next along the screw.
� Double-strand: helicate with two threads (analogous to DNA)
Triple-strand: helicates with three threads
� The specific chirality of helicates is expressed by using the Cahn–Ingold–Prelog notation:
M (left-handed) and P (right-handed), standing for (-) and (+), respectively.
left-handed or M (minus) helicate (left)
right-handed or P (positive) helicate (right).
� Helicates arise due to the use of more flexible threads
when making helicates as the ligands must twist around in order to form the helical structure.
� helicands: Molecular threads that are used in the assembly of helicates
� It is possible to form helicates using either tetrahedral or octahedral metal ions, by applying similar
geometrical arguments as for racks, ladders and grids.
[4 + 4] helicate
A double-stranded helicate templated
by tetrahedral Cu+ ions R = H.
� The nomenclature [m + n] helicate refers to the coordination numbers of two metals that are present.
� 4 being the coordination number for a tetrahedral Cu+ ion.
� Octahedral metal ions form [6+6] helicates.
[6 + 6] helicates
Triple-strand helicate by octahedral Co2+ ions)
� When sexipyridine ligands combine with octahedral metal ions (e.g. Fe2+ , Co2+ , Cd2+ )
→ [6 + 6] double-stranded helicate is formed, with two tridentate binding sites.
� When sexipyridine ligands combine with tetrahedral metal ions (e.g. Cu+),
→ [4 + 4 + 4] double-stranded helix is formed,
(the nomenclature is [m + n + o] as there are now three metals present).
Cd2+-based
[6+6] helicate
three bidentate
binding sites
two tridentate
binding sites
The four discrete supramolecular double-stranded helicates.
Chem. Commun. 2004, 924
Proc. Natl. Acad. Sci. USA, 1993, 90, 5394
3.3.4 Molecular polygons
� If semi-flexible ligands are used, then the geometry around the metal ion may be of lesser importance in
the assembly and polygons.
Chem. Commun. 2013, 49, 1354
� Molecular polygons are hollow, containing a central cavity similar to simple macrocyclic host molecules.
� The assembly processes can be templated around a guest.
� Metal–ligand polygons are positively charged complexes
and therefore templation is brought about by an anionic guest or neutral molecule.
� Different anions during the assembly give different products.
J. Am. Chem. Soc., 2001, 123, 773–774
(a) BF4
- templated molecular square and (b) SbF6
− templated molecular pentagon,
both containing the same ligand and same semiprotected metal vertices.
3.4 Rotaxanes, catenanes and knots
� Rotaxanes & catenanes
▸structurally interlocked molecules in which there is no covalent connection
between the components of each system.
▸synthesized by using various strategies and several effective ways to make complexes have been
developed utilizing template effects.
3.4.1 Topological connectivity
� Mechanical interlocking: One of the most fascinating aspects of self-assembly
� ‘Mechanical interlocking’ :
two or more species become connected to each other,
not via chemical bonds but rather they are threaded through or around one another to form a single entity.
� Species that are linked in this manner are said to be topologically connected.
� Topological Connection: The interlocking of two or more species or the knotting of a single entity
without the need for a chemical bond between the components
– a mechanical interlocking rather than a chemical one.
� Interlocking structures are currently topical
as models for future nanoscale molecular machines and molecular electronic devices.
Eur. J. Org. Chem. 2011, 1763
� Topological connectivity is often represented by using diagrams known as molecular graphs.
� A molecular graph is a simplistic line-drawing of a molecule or species that depicts its connectivity.
Molecular graphs
(a) two unconnected macrocycles are considered to be the topological isomer of two linked macrocycles
as the two situations cannot be interconverted without breaking bonds
(b) topological chirality can be imparted by molecular species becoming entangled.
(a) A metal-linked macrocycle form a discrete molecule (a metallomacrocycle)
(b) Interlocking directly through non-covalent interactions between parts of the ligands
(hydrogen bond or π-interactions)
(c) Interlocking around a templating species (sphere).
� In order for topologically connected species to form,
it is necessary for the templation to occur before the rings are closed.
� In the case of catenanes, this may occur
(a) in a concerted manner (both rings close at the same time) or
(b) in either a stepwise process (one ring forms first and the second is threaded through before sealing).
(c) The template species acts as a kinetic template
with the closing of the rings occurring through the formation of covalent bonds
� The template is referred to as an auxiliary linkage.
� The kinetically templated species can be demetallated to yield a purely organic catenane.
without inter-ring templating interactions.
The ring-closing steps of two components may occur
(a) simultaneously
(b) stepwise manner
(c) kinetic templates by covalent modification and subsequent demetallation.
3.4.2 Rotaxane
� Rotaxanes: Interpenetrating compounds in which one or more macrocycles are threaded onto a linear
molecule and secured in place by the use of bulky terminal groups (−CPh3, PPh
3, porphyrins, fullerenes…).
▸ The ring cannot slip off.
� Pseudorotaxanes: No terminal groups at the ends of the thread to prevent dissociation of the ring.
� The term ‘rotaxane’ is derived from the Latin words rota (wheel) + axis (axel).
� The nomenclature [n]-(pseudo)rotaxane,
where n is the number of components that comprise the complex.
▸[2]-rotaxane: only two components, a ring and a thread
▸[3]-rotaxane: two rings positioned along the same thread
(a) [2]-rotaxane, (b) [2]-pseudorotaxane, (c) [3]-rotaxane
(d) enantiomeric pair of chiral rotaxanes using an asymmetric thread and a macrocycle
The templated synthesis of rotaxanes
Threading.
� Possibly the most common way by
using a pseudorotaxane as a precursor.
� The axel is threaded through the
wheel.
Trapping.
� A thread is blocked at one end, then
only the uncapped end needs to be
capped once the ring is in place.
� The possibility of chirality or
directionality in the products.
Clipping.
� Form rotaxanes by using a fully
assembled axel, complete with bulky
terminal groups, as one of the
starting components.
� The wheel can be formed from two
separate species that combine to
form the complete macrocycle.Slipping.
� A macrocycle to be forced over one
of the blocked ends of a preformed
axel at elevated temperatures.
� This process is referred to as
‘thermally induced slippage’ or
simply ‘slipping’.
3.4.3 Catenanes
� Catenanes: Mechanically interlocked macrocycles or rings, akin to links in a chain.
(from Latin: catena = chain)
� The terminology used for catenanes: m-crossing-[n]-catenane
▸n: the number of rings that are in the catenane
▸m: the number of times that one ring crosses the other along its length
▸2-crossing-[2]-catenane: the ‘2-crossing’ prefix is omitted, giving simply [n]-catenanes.
▸[5]-catenane termed ‘olympiadane’ because of its resemblance to the Olympic symbol
▸Polymeric catenanes are termed [n]-polycatenanes
n: the number of rings
(a) [n]-polycatenanes, (b) poly-[2]-catenanes.
(c) molecular necklaces, (d) pretzelanes
(e) chirality can be imparted by using macrocycles
in which directionality can be defined
by the covalent order of atoms in the ring.
3.4.4 Rotaxanes and catenanes as molecular devices
� Rotaxanes & catenanes:
▸structurally interlocked molecules in which there is no covalent connection
between the components of each system.
▸synthesized by using various strategies and effective ways to make complexes
utilizing template effects.
First Synthesis of Catenanes and Rotaxanes
•Solely based on statistical probability
•Molecules were allowed to self-assemble
•Less than 1 % yield
3.4.4 .2 Synthesis of Catenanes and Rotaxanes
(1). Active Template Strategy
► Hydrogen Bonding
► Metal Ligand Coordination
► Hydrophobic Interactions
► π Donor- π Acceptor Interaction
(2). Click Chemistry
(3). Ring Closing Metathesis
Synthetic Strategy of Catenanes and Rotaxanes
(1)-1. Hydrogen Bonding (1)-2. Metal Ligand Coordination
(1). Active Template Strategy
J. Org. Chem. 1999, 64, 5463.
Angew. Chem. Int. Ed. 1995, 34, 1209
One-pot self-assembly
(eight-molecule condensation)
� Cyclodextrins (CDs)
► cyclic oligosaccharides consisting of six or more α-1,4-linked D-glucopyranose rings.
► rigid conformation , well-defined cavity with a conical shape.
► Hydrophilic exterior, Hydrophobic Interior
► The binding interaction is Van der Waals interactions and hydrophobic binding.
� Click Chemistry is the chemistry tailored to
generate substances quickly and reliably by
joining units together.
� It is a modular reaction which gives very high
yields and has high atom economy.
� Azide Alkyne Cycloaddition using Copper as a
catalyst is one of the widely used click
reactions.
(2). Click Chemistry as an approach for catenane/ rotaxane synthesis
1,2,3 triazole
Template-directed synthesis
Tetrahedron, 57, 2001, 3799
Bipyridinium CyclophaneBPPC34C10 dvts Catenanes
(3). Ring Closing Metathesis
“An assembly of a discrete number of molecular components designed
to perform mechanical-like movements
as a consequence of appropriate external stimuli”
V. Balzani, A. Credi, F.M. Raymo, J.F. Stoddart, Angew. Chem. Int. Ed. 2000, 39, 3348-3391.
What is a molecular machine?
Nobel Prize 2016 in Chemistry Awarded
to the Inventors of World’s Smallest (Molecular) Machine
Feringa’s four-wheel drive nanocar (1999)
Bernard Feringa (1999)
developed a molecular motor.
Jean-Pierre Sauvage (1983)
succeeded in linking two ring-shaped molecules
together to form a chain, called a catenane.
Fraser Stoddart (1991)
developed a rotaxane.
ATP synthase – Rotary MotorKinesin – Linear Motor
Role: vesicle-transport in the cell along
the microtube in linear fashion.
Driving force: ATP hydrolysis
1. Natural Molecular Machines - Biomotors
Rec. Trav. Chim. Pays-Bas, 1967, 86, 755;
ibid, 1970, 89, 673
Propeller Gear
J. Am. Chem. Soc. 1981, 103, 957.
Turnstile
J. Am. Chem. Soc. 1995, 117, 10662.
2. Artificial Molecular Motors
Light-driven unidirectional intramolecular rotation
of a synthetic molecular motor
Phys. Chem. Chem. Phys., 2007, 9, 5067.
� E/Z photoisomerisation of the central
double bond and subsequent helicity
inversion by thermal relaxation.
� Upon irradiation at 355 nm the central
double bond photoisomerises from
the most stable cis conformer (i) to a
higher energy trans conformer (ii).
355 nm
J. Org. Chem. 2000, 65, 1924.
RotaxaneCatenane
“1”“0” “0” “1”
For the switching system:
� The binding constants between the wheel and each station
should be in the following order: A > B > C
� The two states should be reversible and cyclable. (?)
� The process should be easily controllable by external stimuli.
Angew. Chem. Int. Ed. 2003, 42, 2296.
3.1 Chemically Driven Switching Systems
- Acid-Base Reaction
3.2 Photochemically Driven Switching Systems
- Olefin Isomerization
3.3 Electrochemically Driven Switching Systems
- Reduction-Oxidation Reaction
External Stimuli
1) Chemical-Acid-Base
2) Photochemical
3) Electrochemical-Redox
Molecular Shuttling
3.1 Chemically Driven Switching System(a) Acid-Base Reaction Acid-Base Reaction
JACS 1998, 120, 11932.
Chem. Eur. J. 2003, 9, 5348.
Science, 2004, 303, 1845.
Rotaxane
Pseudo-Rotaxane
Molecular Elevator
(b) Molecular (b) Molecular (b) Molecular (b) Molecular MuscleMuscleMuscleMuscle
Angew. Chem. Int. Ed. 2000, 39, 3284.
Chem. Commun. 2003, 1613.
[[[[2]2]2]2]CatenaneCatenaneCatenaneCatenane Molecular Molecular Molecular Molecular SwitchSwitchSwitchSwitch
Nature 2003200320032003, 424, 174.
3.3 Electrochemically Driven Switches - Deduction-Oxidation Reaction
Catenane Switch
Pirouetting-Controlled
Rotaxane Switch
Shuttling-Controlled
Rotaxane Switch
Inorg. Chem. 2000, 39, 1555.
J. Am. Chem. Soc. 1999, 121, 4397.
J. Am. Chem. Soc. 1994, 116, 9399.
3.4.5 Borromeates
� It is possible for three rings to become mutually interlocked without any catenane-like connections.
� This is the situation observed within Borromean rings.
� The Borromean rings were used historically by the Italian Borromeo family as a symbol of unity
– separate parts that are unable to be separated.
� The molecular graph of Borromean rings – no two rings share a link.
Crest of the Borromeo
family of Renaissance Italy
Christian iconography to
represent the Holy Trinity
Norse mythology as the
Walknot (knot of the slain)Shinto symbolism
3.4.6 Knots
� Knots: in everyday life,
both macroscopic world (ties, shoelaces, etc.) and natural systems (DNA can form knotted structures
� Knots in a mathematical and chemical sense:
a single, continuous thread that is interlocked with itself and cannot be untied without being broken,
i.e. without breaking chemical bonds (unlike a tie or shoelace).
� Knots: ‘self-crossing’ macrocycles
� The simplest knot is the trefoil knot.
(Synthesis by two routes: (1) metal-templated helicate,
(2) hydrogen bond-mediated macrocyclisation)
Trefoil knotMӧbius stripIntricate Celtic knotwork
in the 1200-year-old Book of Kells
The endless knot appears
in Tibetan Buddhism
The two distinct chiral trefoil knots; left and right-handed
trefoil knots are illustrated on the left and right, respectively.
Acc. Chem. Res., 2005, 38, 1–9.
synthesised higher order molecular links: (a) a Solomon link, (b) a Borromean ring , (c) a Star of David
catenane and (d) a copper-templated catenane.
(a) The first molecular trefoil knot by Sauvage (b) An organic trefoil knot prepared by Sanders
(c) The first pentafoil knot, synthesised by Leigh (d) Molecular Borromean rings.
(e) Molecular figure-of-eight knot by Sanders (f) A Solomon link
(g) A ‘‘Solomon Cube’’ by Ronson (h) The universal 3-ravel by Lindoy
Hydrogen bonded knots
� Macrocyclisation reaction that utilises appropriate hydrogen bond templating within the macrocycle to
cause interlocking to occur.
� Amide–amide hydrogen bonding interactions are important in the synthesis of molecular knots.
� Standard condensation cyclisation reaction by the elimination of HCl to create amide linkages.
3.5 Self-assembling capsules3.5.1 Molecular containers
� Molecular containers or capsules: three-dimensional cage-like compounds with an internal cavity that is
capable of holding one or more guest species.
� Self-assembled molecular containers/capsules: Discrete, hollow self-assembled structures that are capable
of holding one or more guests.
� Capsules: effective host species being able to completely surround their guest
promising catalytic properties as nanoscale reaction vessels.
�Molecular containers are able to form stable complexes with various guests, including drug molecules,
amino acids and peptides, saccharides, dyes, hydrocarbons, perfluorinated hydrocarbons; even high
molecular weight guests such as proteins (e.g., human insulin) may partially bind to macrocyclic hosts.
Chem. Soc. Rev., 2015, 44, 419
3.5.2 Metal-directed capsules
� Molecular containers are able to form stable complexes with various guests
(1) drug molecules, amino acids and peptides, saccharides, dyes, hydrocarbons, perfluorinated hydrocarbons;
(2) high molecular weight guests such as proteins (e.g., human insulin) may partially bind to macrocyclic hosts.
� Two broad classes of ligands: one-dimensional and two-dimensional.
� One dimensional ligands bridge only between two metal centres.
Such an assembly process is termed molecular scaffolding (Figure (a)).
� Two dimensional ligands bridge between more than two metal atoms.
The assembly of polyhedral capsules using two-dimensional ligands is termed molecular paneling (Figure (b)).
Examples of cages made by (a) molecular scaffolding and (b) molecular panelling.
Molecular scaffolding
� Molecular scaffolding: one-dimensional ligands acting as polyhedral edges
� NiX2
(X = Cl, Br) and amidinothiourea are templated a distorted square-prismatic cage compound
around the halide anion through eight NH· · ·X− interactions.
Angew. Chem., Int. Ed. Engl., 1998, 37, 1258
� The framework of the Ga4
capsule carries a high negative charge (due to quadruple deprotonation of the
ligands) and can therefore act as a host for cations.
� Various tetraalkylammonium cations NR4
+ are able to reside within the capsule with the flexibility of the
ligand allowing the cage to expand and contract to suit guests of differing sizes.
Angew. Chem., Int. Ed. Engl., 1998, 37, 1840
Molecular panelling
� Molecular panelling The assembly of polyhedral capsules using two-dimensional ligands.
� Potentially, this approach can lead to more fully enclosed containers with fewer gaps through which guests can pass,
thereby limiting the rate of guest exchange.
cis-protected
Pd(II) building block
Structure of molecular panels:
(a) triangular,
(b) square
(c) rectangular.
The filled circles represent the binding sites.
3.5.3 Hydrogen bonded capsulesMulti-component assemblies
� Capsules that are held together by hydrogen bonds.
� C-methylcalix[4]resorcinarene with 4,4’-bipyridine through eight OH· · ·N interactions.
� The cavity is large enough to contain two p-nitrobenzene molecules.
Self-complementary capsules
Hexameric hydrogen bonded resorcinarene capsule
In polar media. (Chem. Commun. 2001, 2376)
Dimeric capsule. Encapsulated dichloromethane guest.
J. Org. Chem., 2002, 67, 7091
Unimolecular capsules
J. Am. Chem. Soc., 2002, 124, 10646
Resorcinarene with amide-functionalised arms
templating NMe4
+ guest and Cl- as counter-anion