Master of Science
School Of Science, GSFC University.
Vadodara
Guided by :
Dr.parin kanaiya
Prepared By:
Thakar Twara Pradipkumar
Semester - III
(20MSC01046)
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, 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
non-covalent bonds were understood in gradually more detail, with the hydrogen bond being described by
Latimer and Rodebush in 1920.
 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 Nobel Prize awarded to Jean-Marie Lehn, Donald J Cram, and Charles J Pedersen in 1987, for
‘development and use of molecules with structure-specific interactions of high selectivity’ and established
supramolecular chemistry / as a discipline which is now being explored in various areas such as drug
development, sensors, catalysis, nanoscience, molecular devices etc.
2
What is Supramolecular Chemistry?
 Jean-Marie Lehn, who won the Nobel Prize for his work in the area in 1987 described supramolecular chemistry as
the ‘chemistry of molecular assemblies and of the intermolecular bond’. More colloquially this may be expressed as
‘chemistry beyond the molecule’.
 Other definitions include phrases such as ‘the chemistry of the non-covalent bond’ and ‘non-molecular chemistry’.
 The study of systems involving aggregates of molecules or ions held together by non-covalent interactions, such as
electrostatic interactions, hydrogen bonding, dispersion interactions and solvophobic effects.
 Supramolecular chemistry has been defined by phrases such as ‘chemistry beyond the molecule’, ‘chemistry of
molecular assemblies and of the intermolecular bond’, and ‘non-molecular chemistry’.
Originally supramolecular chemistry was defined in terms of the non-covalent interaction between a ‘host’ and a ‘guest’
molecule as highlighted in Figure, which illustrates the relationship between molecular and supramolecular chemistry in terms
of both structures and function.
Classification of supramolecular Chemistry
 Supramolecular chemistry can be split into two broad categories; host–guest chemistry and self-assembly. The
difference between these two areas is a question of size and shape.
 If one molecule is significantly larger than another and can wrap around it then it is termed the ‘host’ and the
smaller molecule is its ‘guest’, which becomes enveloped by the host.
 One definition of hosts and guests was given by Donald Cram, who said the host component is defined as an
organic molecule or ion whose binding sites converge in the complex.
 The guest component is any molecule or ion whose binding sites diverge in the complex. A binding site is a
region of the host or guest that is of the correct size, geometry and chemical nature to interact with the other
species.
host–guest chemistry
 Figure A describes synthesis and conversion of a cavitand into a cavitate by inclusion of a guest into the cavity of
the host molecule.
 the covalently synthesised host has four binding sites that converge on a central guest binding pocket.
 If one molecule is significantly larger than another and can wrap around it then it is termed the ‘host’ and the
smaller molecule is its ‘guest’, which becomes enveloped by the host.
 Host–guest complexes include biological systems, such as enzymes and their substrates, with enzymes being the
host and the substrates the guest.
 If the host possesses a permanent molecular cavity containing specific guest binding sites, then it will generally act
as a host both in solution and in the solid state and there is a reasonable likelihood that the solution and solid state
structures will be similar to one another.
clathrate
 inclusion of guest molecules in cavities formed between the host molecules in the lattice resulting in conversion
of a clathrand into a clathrate.
 Figure B This process is usually spontaneous but may be influenced by solvation or templation effects or in the
case of solids by the nucleation and crystallisation processes.
self-assembly
 Figure C where there is no significant difference in size and no species is acting as a host for another, the noncovalent joining of two or more species is termed self-assembly. Strictly,
 self-assembly is an equilibrium between two or more molecular components to produce an aggregate with a
structure that is dependent only on the information contained within the chemical building blocks.
 Synthesis and self-assembly of a supramolecular aggregate that does not correspond to the classical host-guest
description.
 A further fundamental subdivision may be made on the basis of the forces between host and guest.
 If the host–guest aggregate is held together by primarily electrostatic interactions (including ion–dipole, dipole–
dipole, hydrogen bonding etc.) the term complex is used.
 On the other hand, species held together by less specific (often weaker), non-directional interactions, such as
hydrophobic, van der Waals or crystal close-packing effects, are referred to by the terms cavitate and clathrate.
Some examples of the use of this nomenclature are shown in Table.
Glimpses of classification in short terms.
 Host–Guest Chemistry: The study of large ‘host’ molecules that are capable of enclosing smaller ‘guest’
molecules via non-covalent interactions.
 Self-Assembly: The spontaneous and reversible association of two or more components to form a larger, noncovalently bound aggregate.
 Binding Site: A region of a molecule that has the necessary size, geometry and functionalities to accept and
bind a second molecule via non-covalent interactions.
 Clathrate: A supramolecular host–guest complex formed by the inclusion of molecules of one kind in cavities of
the crystal lattice of another.
Supramolecular Interactions
 In general, supramolecular chemistry concerns non-covalent bonding interactions. The term ‘non-covalent’
encompasses an enormous range of attractive and repulsive effects. The most important, along with an
indication of their approximate energies.
 When considering a supramolecular system it is vital to consider the interplay of all of these interactions and
effects relating both to the host and guest as well as their surroundings (e.g. solvation, ion pairing, crystal
lattice, gas phase etc.).
 The overall affinity of the host for the guest is unlikely to be due to a single intermolecular interaction but will
come from a combination of forces.
 In the design of supramolecular components it is often possible to manipulate the balance of these forces to
improve host selectivity.
1. Ion–ion Interactions
 Ionic bonding is comparable in strength to covalent bonding (bond energy = 100–350 kJ/mol).
 Complementary cation-anion interactions are usually even stronger than the sharing of electrons in covalent bonds,
however, they are easily disrupted by polar solvents. It is for this reason that simple salts often dissolve easily in water
and yet have melting points higher than many metals.
 A typical ionic solid is sodium chloride, which has a cubic lattice in which each Na+ cation is surrounded by six Cl- anions
(Figure a). It would require a large stretch of the imagination to regard NaCl as a supramolecular compound but this
simple ionic lattice does illustrate the way in which an Na+ cation is able to organise six complementary donor atoms
about itself in order to maximise non-covalent ion–ion interactions.
 A much more supramolecular example of ion–ion interactions is the interaction of the tris(diazabicyclooctane)
host(Figure 1.17) , which carries a 3+ charge, with anions such as [Fe(CN)6]3- (Figure b)
2. Ion-Dipole Interactions
 The bonding of an ion, such as Na+, with a polar molecule, such as water, is an example of an ion– dipole
interaction, which range in strength from ca. 50 – 200 kJ/mol. This kind of bonding is seen both in the solid state
and in solution.
 Ion–dipole interactions also include coordinative bonds, which are mostly electrostatic in nature in the case of
the interactions of nonpolarisable metal cations and hard bases.
 The dative bond formed is weak, and therefore easily reversed, but strong enough for haemoglobin to transport
dioxygen from the lungs to the muscles.
 Can be attractive or repulsive, medium range, weaker than ion-ion interactions,
3. Dipole–Dipole Interactions
 Polar molecules can interact weakly with other polar molecules through the same mechanism.
 Alignment of one dipole with another can result in significant attractive interactions from matching of either a single
pair of poles on adjacent molecules (type I) or opposing alignment of one dipole with the other (type II) with energies
in the range 5–50 kJ/ mol. Organic carbonyl compounds show this behaviour well in the solid state and calculations
have suggested that type II interactions have an energy of about 20 kJ /mol.
4. hydrogen bond
 A hydrogen bond may be regarded as a particular kind of dipole–dipole interaction in which a hydrogen atom attached
to an electronegative atom (or electron withdrawing group) is attracted to a neighbouring dipole on an adjacent
molecule or functional group. Hydrogen bonds are commonly written D–H··A and usually involve a hydrogen atom
attached to an electronegative atom such as O or N as the donor (D) and a similarly electronegative atom, often
bearing a lone pair, as the acceptor (A).
 There are also significant hydrogen bonding interactions involving hydrogen atoms attached to carbon, rather than
electronegative atoms such as N and O (electronegativities: C: 2.55, H: 2.20, N: 3.04, O: 3.44).
 Because of its relatively strong and highly directional nature, hydrogen bonding has been described as the ‘masterkey
interaction in supramolecular chemistry’.
 Hydrogen bonds come in a wide range of lengths, strengths and geometries.
 5. cation-π Interactions
 The interaction is based on the attraction between a positively charged metal ion and the areas of
delocalized electron density that lie above and below the plane of an aromatic ring.
 the cation-π effect is an essential supramolecular interaction not only in simple host-guest systems but
also in protein complexes that incorporate organic or inorganic cations.
 Schematic drawing of the cation–π interaction showing the contact between the two. The quadrupole
moment of benzene, along with its representation as two opposing dipoles, is also shown.
 6. π- π interactions
 Aromatic π- π interactions (sometimes called π - π stacking interactions) occur between aromatic rings, often in
situations where one is relatively electron rich and one is electron poor.
 There are two general types of π-interactions: face-to-face and edge-to-face, although a wide variety of intermediate
geometries are known (Figure).
 Face-to-face π-stacking interactions are responsible for the slippery feel of graphite and its useful lubricant properties.
 Edge-to-face interactions may be regarded as weak forms of hydrogen bonds between the slightly electron defi cient
hydrogen atoms of one aromatic ring and the electron rich π-cloud of another. Strictly they should not be referred to
as π-stacking since there is no stacking of the π-electron surfaces.
7. Van der Waals interactions
 Van der Waals interactions arise from the polarisation of an electron cloud by the proximity of an adjacent nucleus,
resulting in a weak electrostatic attraction. They are non directional and hence possess only limited scope in the
design of specific hosts for selective complexation of particular guests.
 In general, van der Waals interactions provide a general attractive interaction for most ‘soft’ (polarisable) species
with an interaction energy proportional to the surface area of contact.
 Van der Waals, or London, forces are extremely weak and less easy to control than most others.
8. Hydrophobic Effects
 Many molecules do not possess the ability to form hydrogen bonds or other attractive interactions based on
complementary charges. These are often compounds composed of carbon and hydrogen, typical examples being
linear hydrocarbons and aromatic ring systems. Although some interactions such as π-π stacking can occur, the
main effect of these molecules is to interact by excluding charged or polar groups.
Compared to most non-covalent interactions
Very High energies
Very short distance
Highly dependent on orientation
Factors affecting the interaction and binding
Selectivity
 For a host–guest interaction to occur the host molecule must posses the appropriate
 binding sites for the guest molecule to bind to.
 The binding of one guest, or family of guests, significantly more strongly than others, by a host molecule. Selectivity is
measured in terms of the ratio between equilibrium constants
 Lock and key analogy
 Emil Fisher developed the concept of the lock and key principle in 1894, from his work
on the binding of substrates by enzymes, in which he described the enzyme as the lock
and the substrate as the key; thus, the substrate (guest) has a complementary size and
shape to the enzyme (host) binding site. Figure shows a schematic diagram of the lock
and key principle; the key is exactly the correct size and shapefor the lock.
 The lock and key principle, where the lock represents the receptor in which the
grooves are complimentary to the key, which represents the substrate.
 The induced-fit analogy
 Daniel Koshland postulated that the mechanism for the binding of the substrate by an enzyme is more of an
interactive process, whereby the active site of the enzyme changes shape and is modified during binding to
accommodate the substrate (Figure). An induced fit has occurred and as a consequence the protein backbone
or the substrate binding site itself changes shape such that the enzyme and the substrate fit more precisely
 The induced-fit model of substrate binding. As the enzyme and substrate approach each other, the binding site
of the enzyme changes shape, resulting in a more precise fit between host and guest.
Complementarity: Both the host and guest must have mutual spatially and electronically complementary binding sites to
form a supermolecule.
Co-operativity: Two or more binding sites acting in a concerted fashion to produce a combined interaction that is
stronger than when the binding sites act independently of each other. The sites are co-operating with each other. In the
case of binding two guests, co-operativity also represents the effect on the affinity of the host for one guest as a result of
the binding of the other.
Chelate Effect: The observation that multidentate ligands (by extension, hosts with more than one binding site) result in
more stable complexes than comparable systems containing multiple unidentate ligands, a result of co-operativity between
interacting sites.
Preorganisation: A host is said to be preorganised when it requires no significant conformational change to bind a guest
species.
Macrocyclic Effect: Host systems that are preorganised into a large cyclic shape form more stable complexes as there is
no energetically unfavourable change in conformation in order to bind a guest.
Binding Constant, K: The equilibrium constant for the interaction of a host with one or more guests. The binding
constant provides a quantitative representation of the degree of association and is also called the association constant.
Molecular Recognition in
Supramolecular Systems
Chemists have demonstrated that artificial
supramolecular systems can be designed
that exhibit molecular recognition. One of
the earliest examples of such a system is
crown ethers which are capable of
selectively binding specific cations.
The crown ethers are among the simplest
and most appealing macrocyclic (large ring)
ligands,
and
are
ubiquitous
in
supramolecular chemistry as hosts for both
metallic and organic cations. They consist
simply of a cyclic array of ether oxygen
atoms linked by organic spacers, typically —
CH2CH2— groups. While the metal binding
ability of unidentate ethers such as the
common solvent diethyl ether is very poor,
the crown ethers are much more effective
by virtue of the chelate effect and the
partial preorganisation arising from their
macrocyclic structure
The discovery of the crown ethers in 1967 gained a share of the
1987 Nobel Prize for Chemistry for Charles Pedersen, a chemist
working at the American du Pont de Nemours company. Oddly,
however, Pedersen’s initial synthesis of the first crown ether,
dibenzo[18]crown-6 was accidental.
Applications
 Materials technology
Supramolecular chemistry has found many applications, in particular molecular self-assembly processes 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. Many smart materials are based on molecular recognition.
 Catalysis
A major application of supramolecular chemistry is the design and understanding of catalysts and catalysis. Non-covalent
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 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. 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.
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.
 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.
References
 Reference Books: Core Concepts in Supramolecular Chemistry and Nano chemistry by Jonathan W. Steed, David R. Turner, Karl J. Wallace.
 Supramolecular Chemistry by Jonathan W. Steed, Jerry L. Atwood Second Edition.
 Supramolecular Chemistry From Biological Inspiration to Biomedical Applications by Peter J. Cragg.
 Overview of Bioorganic Chemistry NPTEL – Chemistry – Bio-Organic Chemistry (Module)
 Website:- http://www.wiley.com/go/steed , google scholar.