Supramolecular

chemistry

An example of a supramolecular assembly[1]

Supramolecular complex of a chloride ion,
cucurbit[5]uril, and cucurbit[10]uril[2]

An example of a mechanically interlocked molecular

architecture, in this case a rotaxane[3]
An example of a host-guest chemistry[4]

host-guest complex with a p-xylylenediammonium

bound within a cucurbituril[5]
Intramolecular self-assembly of a foldamer.[6]

3D interpenetrated network in the crystal structure of

silsesquioxane.[7]

Supramolecular chemistry is the domain

of chemistry beyond that of molecules
that focuses on the chemical systems
made up of a discrete number of
assembled molecular subunits or
components. The forces responsible for
the spatial organization may vary from
weak (intermolecular forces, electrostatic
or hydrogen bonding) to strong (covalent
bonding), provided that the degree of
electronic coupling between the molecular
component remains small with respect to
relevant energy parameters of the
component.[8][9] While traditional
chemistry focuses on the covalent bond,
supramolecular chemistry examines the
weaker and reversible noncovalent
interactions between molecules. These
forces include hydrogen bonding, metal
coordination, hydrophobic forces, van der
Waals forces, pi-pi interactions and
electrostatic effects. Important concepts
that have been demonstrated by
supramolecular chemistry include
molecular self-assembly, folding,
molecular recognition, host-guest
chemistry, mechanically-interlocked
molecular architectures, and dynamic
covalent chemistry.[10] The study of non-
covalent interactions is crucial to
understanding many biological processes
from cell structure to vision that rely on
these forces for structure and function.
Biological systems are often the
inspiration for supramolecular research.

Supermolecules are to molecules and the

intermolecular bond what molecules are to
atoms and the covalent bond.

History
The existence of intermolecular forces
was first postulated by Johannes Diderik
van der Waals in 1873. However, Nobel
laureate Hermann Emil Fischer developed
supramolecular chemistry's philosophical
roots. In 1894,[11] Fischer suggested that
enzyme-substrate interactions take the
form of a "lock and key", the fundamental
principles of molecular recognition and
host-guest chemistry. In the early
twentieth century noncovalent bonds were
understood in gradually more detail, with
the hydrogen bond being described by
Latimer and Rodebush in 1920.

The use of these principles led to an

increasing understanding of protein
structure and other biological processes.
For instance, the important breakthrough
that allowed the elucidation of the double
helical structure of DNA occurred when it
was realized that there are two separate
strands of nucleotides connected through
hydrogen bonds. The use of noncovalent
bonds is essential to replication because
they allow the strands to be separated and
used to template new double stranded
DNA. Concomitantly, chemists began to
recognize and study synthetic structures
based on noncovalent interactions, such
as micelles and microemulsions.

Eventually, chemists were able to take

these concepts and apply them to
synthetic systems. The breakthrough
came in the 1960s with the synthesis of
the crown ethers by Charles J. Pedersen.
Following this work, other researchers
such as Donald J. Cram, Jean-Marie Lehn
and Fritz Vögtle became active in
synthesizing shape- and ion-selective
receptors, and throughout the 1980s
research in the area gathered a rapid pace
with concepts such as mechanically
interlocked molecular architectures
emerging.

The importance of supramolecular

chemistry was established by the 1987
Nobel Prize for Chemistry which was
awarded to Donald J. Cram, Jean-Marie
Lehn, and Charles J. Pedersen in
recognition of their work in this area.[12]
The development of selective "host-guest"
complexes in particular, in which a host
molecule recognizes and selectively binds
a certain guest, was cited as an important
contribution.

In the 1990s, supramolecular chemistry

became even more sophisticated, with
researchers such as James Fraser
Stoddart developing molecular machinery
and highly complex self-assembled
structures, and Itamar Willner developing
sensors and methods of electronic and
biological interfacing. During this period,
electrochemical and photochemical motifs
became integrated into supramolecular
systems in order to increase functionality,
research into synthetic self-replicating
system began, and work on molecular
information processing devices began.
The emerging science of nanotechnology
also had a strong influence on the subject,
with building blocks such as fullerenes,
nanoparticles, and dendrimers becoming
involved in synthetic systems.

Control
Thermodynamics

Supramolecular chemistry deals with

subtle interactions, and consequently
control over the processes involved can
require great precision. In particular,
noncovalent bonds have low energies and
often no activation energy for formation.
As demonstrated by the Arrhenius
equation, this means that, unlike in
covalent bond-forming chemistry, the rate
of bond formation is not increased at
higher temperatures. In fact, chemical
equilibrium equations show that the low
bond energy results in a shift towards the
breaking of supramolecular complexes at
higher temperatures.

However, low temperatures can also be

problematic to supramolecular processes.
Supramolecular chemistry can require
molecules to distort into
thermodynamically disfavored
conformations (e.g. during the "slipping"
synthesis of rotaxanes), and may include
some covalent chemistry that goes along
with the supramolecular. In addition, the
dynamic nature of supramolecular
chemistry is utilized in many systems (e.g.
molecular mechanics), and cooling the
system would slow these processes.

Thus, thermodynamics is an important

tool to design, control, and study
supramolecular chemistry. Perhaps the
most striking example is that of warm-
blooded biological systems, which entirely
cease to operate outside a very narrow
temperature range.
Environment

The molecular environment around a

supramolecular system is also of prime
importance to its operation and stability.
Many solvents have strong hydrogen
bonding, electrostatic, and charge-transfer
capabilities, and are therefore able to
become involved in complex equilibria
with the system, even breaking complexes
completely. For this reason, the choice of
solvent can be critical.

Concepts
Molecular self-assembly
Molecular self-assembly is the
construction of systems without guidance
or management from an outside source
(other than to provide a suitable
environment). The molecules are directed
to assemble through noncovalent
interactions. Self-assembly may be
subdivided into intermolecular self-
assembly (to form a supramolecular
assembly), and intramolecular self-
assembly (or folding as demonstrated by
foldamers and polypeptides). Molecular
self-assembly also allows the construction
of larger structures such as micelles,
membranes, vesicles, liquid crystals, and
is important to crystal engineering.[13]
Molecular recognition and
complexation

Molecular recognition is the specific

binding of a guest molecule to a
complementary host molecule to form a
host-guest complex. Often, the definition
of which species is the "host" and which is
the "guest" is arbitrary. The molecules are
able to identify each other using
noncovalent interactions. Key applications
of this field are the construction of
molecular sensors and
catalysis.[14][15][16][17]

Template-directed synthesis
Molecular recognition and self-assembly
may be used with reactive species in order
to pre-organize a system for a chemical
reaction (to form one or more covalent
bonds). It may be considered a special
case of supramolecular catalysis.
Noncovalent bonds between the reactants
and a "template" hold the reactive sites of
the reactants close together, facilitating
the desired chemistry. This technique is
particularly useful for situations where the
desired reaction conformation is
thermodynamically or kinetically unlikely,
such as in the preparation of large
macrocycles. This pre-organization also
serves purposes such as minimizing side
reactions, lowering the activation energy
of the reaction, and producing desired
stereochemistry. After the reaction has
taken place, the template may remain in
place, be forcibly removed, or may be
"automatically" decomplexed on account
of the different recognition properties of
the reaction product. The template may be
as simple as a single metal ion or may be
extremely complex.

Mechanically interlocked
molecular architectures

Mechanically interlocked molecular

architectures consist of molecules that are
linked only as a consequence of their
topology. Some noncovalent interactions
may exist between the different
components (often those that were
utilized in the construction of the system),
but covalent bonds do not.
Supramolecular chemistry, and template-
directed synthesis in particular, is key to
the efficient synthesis of the compounds.
Examples of mechanically interlocked
molecular architectures include
catenanes, rotaxanes, molecular knots,
molecular Borromean rings[18] and
ravels.[19]

Dynamic covalent chemistry

In dynamic covalent chemistry covalent
bonds are broken and formed in a
reversible reaction under thermodynamic
control. While covalent bonds are key to
the process, the system is directed by
noncovalent forces to form the lowest
energy structures.[20]

Biomimetics

Many synthetic supramolecular systems

are designed to copy functions of
biological systems. These biomimetic
architectures can be used to learn about
both the biological model and the
synthetic implementation. Examples
include photoelectrochemical systems,
catalytic systems, protein design and self-
replication.[21]

Imprinting

Molecular imprinting describes a process

by which a host is constructed from small
molecules using a suitable molecular
species as a template. After construction,
the template is removed leaving only the
host. The template for host construction
may be subtly different from the guest that
the finished host binds to. In its simplest
form, imprinting utilizes only steric
interactions, but more complex systems
also incorporate hydrogen bonding and
other interactions to improve binding
strength and specificity.[22]

Molecular machinery

Molecular machines are molecules or

molecular assemblies that can perform
functions such as linear or rotational
movement, switching, and entrapment.
These devices exist at the boundary
between supramolecular chemistry and
nanotechnology, and prototypes have been
demonstrated using supramolecular
concepts.[23] Jean-Pierre Sauvage, Sir J.
Fraser Stoddart and Bernard L. Feringa
shared the 2016 Nobel Prize in Chemistry
for the 'design and synthesis of molecular
machines'.[24]

Building blocks
Supramolecular systems are rarely
designed from first principles. Rather,
chemists have a range of well-studied
structural and functional building blocks
that they are able to use to build up larger
functional architectures. Many of these
exist as whole families of similar units,
from which the analog with the exact
desired properties can be chosen.

Synthetic recognition motifs

The pi-pi charge-transfer interactions of
bipyridinium with dioxyarenes or
diaminoarenes have been used
extensively for the construction of
mechanically interlocked systems and in
crystal engineering.
The use of crown ether binding with
metal or ammonium cations is
ubiquitous in supramolecular chemistry.
The formation of carboxylic acid dimers
and other simple hydrogen bonding
interactions.
The complexation of bipyridines or
tripyridines with ruthenium, silver or
 other metal ions is of great utility in the
construction of complex architectures
of many individual molecules.
The complexation of porphyrins or
phthalocyanines around metal ions
gives access to catalytic, photochemical
and electrochemical properties as well
as complexation. These units are used a
great deal by nature.

Macrocycles

Macrocycles are very useful in

supramolecular chemistry, as they provide
whole cavities that can completely
surround guest molecules and may be
chemically modified to fine-tune their
properties.

Cyclodextrins, calixarenes, cucurbiturils

and crown ethers are readily
synthesized in large quantities, and are
therefore convenient for use in
supramolecular systems.
More complex cyclophanes, and
cryptands can be synthesised to provide
more tailored recognition properties.
Supramolecular metallocycles are
macrocyclic aggregates with metal ions
in the ring, often formed from angular
and linear modules. Common
metallocycle shapes in these types of
 applications include triangles, squares,
and pentagons, each bearing functional
groups that connect the pieces via "self-
assembly."[25]
Metallacrowns are metallomacrocycles
generated via a similar self-assembly
approach from fused chelate-rings.

Structural units

Many supramolecular systems require

their components to have suitable spacing
and conformations relative to each other,
and therefore easily employed structural
units are required.
Commonly used spacers and
connecting groups include polyether
chains, biphenyls and triphenyls, and
simple alkyl chains. The chemistry for
creating and connecting these units is
very well understood.
nanoparticles, nanorods, fullerenes and
dendrimers offer nanometer-sized
structure and encapsulation units.
Surfaces can be used as scaffolds for
the construction of complex systems
and also for interfacing electrochemical
systems with electrodes. Regular
surfaces can be used for the
construction of self-assembled
 monolayers and multilayers.

Photo-/electro-chemically
active units

Porphyrins, and phthalocyanines have

highly tunable photochemical and
electrochemical activity as well as the
potential for forming complexes.
Photochromic and photoisomerizable
groups have the ability to change their
shapes and properties (including
binding properties) upon exposure to
light.
TTF and quinones have more than one
stable oxidation state, and therefore can
be switched with redox chemistry or
 electrochemistry. Other units such as
benzidine derivatives, viologens groups
and fullerenes, have also been utilized in
supramolecular electrochemical
devices.

Biologically-derived units

The extremely strong complexation

between avidin and biotin is
instrumental in blood clotting, and has
been used as the recognition motif to
construct synthetic systems.
The binding of enzymes with their
cofactors has been used as a route to
produce modified enzymes, electrically
 contacted enzymes, and even
photoswitchable enzymes.
DNA has been used both as a structural
and as a functional unit in synthetic
supramolecular systems.

Applications
Materials technology

Supramolecular chemistry and molecular

self-assembly processes in particular have
been applied to the development of new
materials. Large structures can be readily
accessed using bottom-up synthesis as
they are composed of small molecules
requiring fewer steps to synthesize. Thus
most of the bottom-up approaches to
nanotechnology are based on
supramolecular chemistry.[26]

Catalysis

A major application of supramolecular

chemistry is the design and understanding
of catalysts and catalysis. Noncovalent
interactions are extremely important in
catalysis, binding reactants into
conformations suitable for reaction and
lowering the transition state energy of
reaction. Template-directed synthesis is a
special case of supramolecular catalysis.
Encapsulation systems such as micelles,
dendrimers, and cavitands[27] are also
used in catalysis to create
microenvironments suitable for reactions
(or steps in reactions) to progress that is
not possible to use on a macroscopic
scale.

Medicine

Design based on supramolecular

chemistry has led to numerous
applications in the creation of functional
biomaterials and therapeutics.[28]
Supramolecular biomaterials afford a
number of modular and generalizable
platforms with tunable mechanical,
chemical and biological properties. These
include systems based on supramolecular
assembly of peptides, host-guest
macrocycles, high-affinity hydrogen
bonding, and metal-ligand interactions.

A supramolecular approach has been used

extensively to create artificial ion channels
for the transport of sodium and potassium
ions into and out of cells.[29]

Supramolecular chemistry is also

important to the development of new
pharmaceutical therapies by
understanding the interactions at a drug
binding site. The area of drug delivery has
also made critical advances as a result of
supramolecular chemistry providing
encapsulation and targeted release
mechanisms. In addition, supramolecular
systems have been designed to disrupt
protein-protein interactions that are
important to cellular function.[30]

Data storage and processing

Supramolecular chemistry has been used

to demonstrate computation functions on
a molecular scale. In many cases,
photonic or chemical signals have been
used in these components, but electrical
interfacing of these units has also been
shown by supramolecular signal
transduction devices. Data storage has
been accomplished by the use of
molecular switches with photochromic
and photoisomerizable units, by
electrochromic and redox-switchable units,
and even by molecular motion. Synthetic
molecular logic gates have been
demonstrated on a conceptual level. Even
full-scale computations have been
achieved by semi-synthetic DNA
computers.

See also
Organic chemistry
 Nanotechnology

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External links
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2D and 3D Models of Dodecahedrane

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