1.

Concepts of Supramolecular Chemistry

Definition
Supramolecular chemistry is the chemistry of molecular assemblies and of the intermolecular bond.
More colloquially this may be expressed as ‘chemistry beyond the molecule’.
Originally supramolecular chemistry is defined in terms of the non-covalent interaction between a
‘host’ and a ‘guest’ molecule. i.e.,

Comparison between the scope of molecular and supramolecular chemistry according to J. M. Lehn

Development of supramolecular chemistry

1810 – Sir Humphry Davy: discovery of chlorine hydrate
1823 – Michael Faraday: formula of chlorine hydrate
1841 – C. Schafhäutl: study of graphite intercalates
1849 – F. Wöhler: β-quinol H2S clathrate
1891 – Villiers and Hebd: cyclodextrin inclusion compounds
1893 – Alfred Werner: coordination chemistry
1894 – Emil Fischer: lock and key concept
1906 – Paul Ehrlich: introduction of the concept of a receptor
1937 – K. L. Wolf: the term Übermoleküle is coined to describe organized entities arising from the
association of coordinatively saturated species (e.g. the acetic acid dimer)
1939 – Linus Pauling: hydrogen bonds are included in the groundbreaking book The Nature of the Chemical
Bond
1940 – M. F. Bengen: urea channel inclusion compounds

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1945 – H. M. Powell: X-ray crystal structures of β-quinol inclusion compounds; the term ‘clathrate’ is
introduced to describe compounds where one component is enclosed within the framework of another
1949 – Brown and Farthing: synthesis of [2.2]paracyclophane
1953 – Watson and Crick: structure of DNA
1956 – Dorothy Crowfoot Hodgkin: X-ray crystal structure of vitamin B12
1959 – Donald Cram: attempted synthesis of cyclophane charge transfer complexes with (NC)2C=C(CN)2
1961 – N.F. Curtis: first Schiff’s base macrocycle from acetone and ethylene diamine
1964 – Busch and Jäger: Schiff’s base macrocycles
1967 – Charles Pedersen: crown ethers
1968 – Park and Simmons: Katapinand anion hosts
1969 – Jean-Marie Lehn: synthesis of the first cryptands
1969 – Jerry Atwood: liquid clathrates from alkyl aluminium salts
1969 – Ron Breslow: catalysis by cyclodextrins
1973 – Donald Cram: spherand hosts produced to test the importance of preorganization
1978 – Jean-Marie Lehn: introduction of the term ‘supramolecular chemistry’, defined as the ‘chemistry of
molecular assemblies and of the intermolecular bond’
1979 – Gokel and Okahara: development of the lariat ethers as a subclass of host
1981 – Vögtle and Weber: podand hosts and development of nomenclature
1986 – A. P. de Silva: Fluorescent sensing of alkali metal ions by crown ether derivatives
1987 – Award of the Nobel Prize for Chemistry to Donald J. Cram, Jean-Marie Lehn and Charles J.
Pedersen for their work in supramolecular chemistry
1996 – Atwood, Davies, MacNicol & Vögtle: publication of Comprehensive Supramolecular Chemistry
containing contributions from many key groups and summarizing the development and state of the art
1996 – Award of the Nobel prize for Chemistry to Kroto, Smalley and Curl for their work on the chemistry
of the fullerenes
2003 – Award of the Nobel prize for Chemistry to Peter Agre and Roderick MacKinnon for their discovery
of water channels and the characterisation of cation and anion channels, respectively.
2004 – J. Fraser Stoddart: the first discrete Borromean-linked molecule, a landmark in topological synthesis.
2012 – David Leigh: metal-directed synthesis of a pentafoil knot, the first chemical knot synthesis more
complicated than the simplest knot, the trefoil.
2016 – Award of the Nobel Prize in Chemistry to J. Fraser Stoddart, Jean-Pierre Sauvage, and Ben Feringa
for their design and production of molecular machines.

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Classification of Supramolecular Host–Guest Compounds
Supramolecular host–guest compounds can be classified as cavitate host-guest complex and lattice
inclusion host-guest complex or clathrate.

Cavitands may be described as hosts possessing permanent intramolecular cavities. This means that
the cavity available for guest binding is an intrinsic molecular property of the host and exists both in solution
and in the solid state. Conversely, clathrands are hosts with extramolecular cavities (the cavity essentially
represents a gap between two or more host molecules) and is of elevance only in the crystalline or solid state.
The host–guest aggregate formed by a cavitand is termed a cavitate, while clathrands form clathrates.

We can also distinguish a third situation in which two molecules associate using non-covalent forces
but do not fit the descriptions of ‘host’ and ‘guest’. Under these circumstances we talk about the self-
assembly of a mutually complementary pair (or series) of molecules.

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.

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CHE 0531 5244 (Supramolecular Chemistry)/Chapter 1 Page 4
Receptors, Coordination and the Lock and Key Analogy
Host–guest (or receptor–substrate) chemistry is based upon three historical concepts:
1. The recognition by Paul Ehrlich in 1906 that molecules do not act if they do not bind, ‘Corpora
non agunt nisi fixata’; in this way Erlich introduced the concept of a biological receptor.

2. The recognition in 1894 by Emil Fischer that binding must be selective, as part of the study of
receptor–substrate binding by enzymes. He described this by a lock and key image of steric fit in which the
guest has a geometric size or shape complementarity to the receptor or host (Figure 1.3a). This concept laid
the basis for molecular recognition, the discrimination by a host between a number of different guests.

3. The fact that selective binding must involve attraction or mutual affinity between host and guest.
This is, in effect, a generalization of Alfred Werner’s 1893 theory of coordination chemistry, in which metal
ions are coordinated by a regular polyhedron of ligands binding by dative bonds.

Figure 1.3 (a) Rigid lock and key and (b) induced fit models of enzyme–substrate binding.

These three concepts arose essentially independently of one another and it was to be many years
before the various disciplines in which they were born grew together to give birth to the highly
interdisciplinary field of supramolecular chemistry.

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Binding Constants
The thermodynamic stability of a host-guest (e.g. metal–macrocycle) complex in a given solvent
(often water or methanol) at a given temperature is gauged by measurement of the binding constant, K.
Strictly the binding constant is dimensionless, but it is often calculated approximately using concentrations
and thus has units of dm3 mol1, or M1, for a 1:1 complex.

The binding constant is also known by the terms formation constant, Kf, association constant, Ka or
stability constant, Ks. In biological systems the dissociation constant, Kd, is commonly used. This quantity is
the reciprocal of the binding constant and has units of concentration. The Kd value is sometimes useful
because it is a direct measure of the concentration below which a complex such as a drug-receptor complex
will dissociate.

Ignoring activity effects, the binding constant is merely the equilibrium constant for the reaction
shown in Equation 1.1 (e.g. between a metal, M, and host ligand, L, in water):

Thus, a large binding constant corresponds to a high equilibrium concentration of bound metal, and
hence a more stable metal–macrocycle complex. Typical binding constants for crown ethers and alkali metal
cations in water are in the range 101–102. In methanol, this increases up to 106 for [K([18]crown-6)]+. The
binding constant for K+ and [2.2.2]cryptand is about 1010. Some other examples are given in Table 1.3.

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Measurement of Binding Constants:
Binding constants can be measured using following methods:
i) Potentiometric Titration
ii) Nuclear Magnetic Resonance Titration
iii) Method of Continuous Variation (Job Plots)
iv) Fluorescence Titration
v) UV-Vis Spectrophotometric Titration
vi) Calorimetric Titration
vii) Extraction Experiments

Cooperativity and the Chelate Effect

Much of the emphasis in the construction of supramolecular host molecules concerns bringing about
summative or even multiplicative interactions. This means that we can construct a stable host–guest
complex using (often weak) non-covalent interactions if we ensure that there are as many as possible of
these interactions stabilizing the complex.

The small amount of stabilization energy gained by any one such interaction when added to all the
other small stabilizations from the other interactions (summative) results in a significant binding energy and
hence complex stability. In some cases, the interaction of the whole system is synergically greater than the

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sum of the parts (multiplicative). When two or more binding sites (A and B) on a host cooperate in this
fashion to bind to a guest the phenomenon is termed cooperativity.

If the overall stability of the complex is greater than the sum of the energies of the interaction of the
guest with binding groups A and B individually then the result is positive cooperativity. On the other hand, if
unfavorable steric or electronic effects arising from the linking of A and B together into one host cause the
overall binding free energy for the complex to be less than the sum of its parts then the phenomenon is
termed negative cooperativity. Binding site cooperativity in a supramolecular host-guest interaction is
simply a generalization of the chelate effect found in classical coordination chemistry.

The chelate effect is well known in coordination chemistry and relates to the observation that metal
complexes of bidentate ligands (such as 1,2-diaminoethane, en) are significantly more stable than closely
related materials that contain unidentate ligands (such as ammonia). For example, in the reaction shown in
Equation 1.24, the value of the equilibrium constant for the replacement of ammonia with 1,2-
diaminoethane indicates that the 1,2-diaminoethane chelate complex is more than 108 times more stable.

Fig.: Supramolecular host–guest complexation stabilized by positive cooperativity between binding sites: Ag+ binding
by 1.12, a host for citrate anion (1.13) and a drug-receptor complex formed by vancomycin (1.14).

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 Fig.: Allosteric (cooperative) enhancement of Na+ binding by preorganisation of the polyether
binding site by Ru(II), and vice versa.

Preorganization and Complementarity

Many supramolecular host–guest complexes are even more stable than would be expected from
cooperative / chelate effects alone. The hosts in these species are usually macrocyclic (large ring) ligands
that chelate their guests, again via a number of binding sites. Such compounds are stabilized additionally by
what is traditionally termed the macrocyclic effect.

This effect relates not only to the chelation of the guest by multiple binding sites, but also to the
organization of those binding sites in space prior to guest binding (i.e. preorganization) such that binding
energy is not expended in the guest having to ‘wrap’ the host about itself in order to benefit from the most
chelation.

Furthermore, the enthalpic penalty associated with bringing donor atom lone pairs into close
proximity to one another (with consequent unfavorable repulsion and desolvation effects) has been ‘paid in
advance’ during the synthesis of the macrocycle. This makes macrocycles difficult to make but stronger
complexing agents than analogous non-macrocyclic hosts (podands). The macrocyclic effect makes cyclic
hosts such as corands (e.g. crown ethers) up to a factor of 104 times more stable than closely related acyclic
podands with the same type of binding sites.

Bicyclic hosts such as cryptands are found to be even more stable than monocyclic corands for much
the same reasons. Historically this further additional stability is referred to as the macrobicyclic effect

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(Figure 1.11) and simply represents the more rigid, preorganised nature of the macrobicycle. The
macrocyclic and macrobicyclic effects make an important contribution to hosts for alkali metal binding.

Fig.: The chelate, macrocyclic and macrobicyclic effects.

Scheme: Comparison of preorganization effects in K+ binding by a macrobicycle, macrocycle and

non-preorganised podand pentaethyleneglycol dimethyl ether.

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 In addition to the degree of host preorganization, the other principal factor in determining the affinity
of a host for a guest is complementarity. In order to bind, a host must have binding sites that are of the
correct electronic character (polarity, hydrogen bond donor/acceptor ability, hardness or softness etc.) to
complement those of the guest. Hydrogen bond donors must match acceptors, Lewis acids must match
Lewis bases and so on. Furthermore, those binding sites must be spaced out on the host in such a way as to
make it possible for them to interact with the guest in the binding conformation of the host molecule. If a
host fulfi ls these criteria, it is said to be complementary. The principle of complementarity has been
summed up by Donald Cram: ‘To complex, hosts must have binding sites which cooperatively contact and
attract binding sites of guests without generating strong nonbonded repulsions.’

The combined effects of preorganization and complementarity are startlingly illustrated by a

comparison of the binding constants under standard conditions for the alkali metal complexes shown in
Figure 1.12. All of the hosts bind through six ether oxygen atoms. The fairly hard (non-polarisable) oxygen
donors are complementary to fairly hard alkali metal cations such as K+. However, the stability constants
range over nearly 14 orders of magnitude, reflecting the increasing preorganization of the oxygen atom
donor array. The amine nitrogen atoms in some hosts do not significantly enhance the binding because the
softer amine is not complementary for alkali metal cations. Thus replacing two oxygen atoms in [18]crown-
6 with two secondary amine nitrogen atoms in diaza[18]crown-6 lowers the binding constant to below the
value found for the podand EG5.

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Figure 1.12 Comparison of the effects of preorganization and complementarity on the magnitudes of the binding
constant of polyether hosts for alkali metal cations. The figure for Li+ is given for the highly preorganised spherand-6
since it is too small to accommodate K+.

Thermodynamic and Kinetic Selectivity

The goal of supramolecular host design, both in nature (enzymes, transport proteins etc.) and in
artificial systems, is the achievement of selectivity; some kind of differentiation of different guests. In the
blood, the iron haem transport protein hemoglobin is fine-tuned to selectively take up O2 in the presence of
N2, water and CO2, and even substances such as CO, which normally bind very strongly to iron. We can
readily assess the affinity of a host for a particular receptor by its binding constant. In thermodynamic terms,
selectivity is simply the ratio of the binding constant for one guest over another:

This kind of selectivity tends to be the most easy to achieve because it is highly susceptible to
manipulation by intelligent application of concepts such as the lock and key analogy, preorganization and
complementarity, coupled with a detailed knowledge of the host–guest interactions. So, we can say that
[18]crown-6, with a binding constant for K+ of 106 M1, is 100-fold selective for K+ over Na+, which it binds
with a binding constant of only ca. 104 M1 under the same conditions.

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 There is another kind of selectivity, however, which relates to the rate of transformation of
competing substrates along a reaction path. This is kinetic selectivity and is the basis for directing the flow of
directional processes such as supramolecular (enzymatic) catalysis and guest sensing and signaling. In this
sense, it is the guest that is transformed fastest, rather than the one that is bound the strongest, that the
system is said to be selective for. Indeed, in such time-resolved processes, large binding constants are
inhibitory to the system since kinetics are slowed down. Many biochemical enzymes are kinetically selective
and examination of their structures reveals that while they are perfectly complementary for the desired
(sometimes transitory) state of the guest at any given instant, they are not generally preorganised in a rigid
way since this would preclude rapid catalysis. In artificial systems, the engineering of time-resolved
selectivity is a much more difficult process since it requires the adaptation of the host to the changing needs
of the guest as the system proceeds along its reactive pathway.

Nature of 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, are explained below. 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.).

i) Ion–ion Interactions: A supramolecular example of ion–ion interactions is the interaction of the

tris(diazabicyclooctane) host (1.17), which carries a 3+ charge, with anions such as [Fe(CN)6]3

ii) 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1. This
kind of bonding is seen both in the solid state and in solution.

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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.

iii) Dipole–Dipole Interactions: 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) (Figure 1.14) with energies in the range 5–50 kJ
mol1. Organic carbonyl compounds show this behavior well in the solid state and calculations have
suggested that type II interactions have an energy of about 20 kJ mol1, comparable to a moderately strong
hydrogen bond.

Dipole–dipole interactions in carbonyls.

iv) Hydrogen Bonding: Hydrogen bonding has tremendous effects on molecular properties. It is the
strong hydrogen bonding in water that makes its boiling point of 100 ºC some 160 ºC higher than the heavier
H2S, simply because of the more polar nature of the O–H bonds. 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 neighboring dipole on an adjacent molecule or functional
group. Hydrogen bonds are commonly written D–HꞏꞏA 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.

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 Various types of hydrogen bonding geometries; (a) linear (b) bent (c) donating bifurcated
(d) accepting bifurcated (e) trifurcated (f) three centre bifurcated.

(a) Secondary interactions providing attractions between neighboring groups between DDD and AAA arrays (primary
interactions in bold) and (b) repulsions from mixed donor/acceptor arrays (ADA and DAD).

(a) Primary and secondary hydrogen bond interactions between guanine and cytosine base pairs in DNA and (b) a
schematic representation.

v) Cation–π Interactions: Transition metal cations such as Fe2+, Pt2+ etc. are well known to form
complexes with olefinic and aromatic hydrocarbons such as ferrocene [Fe(C5H5)2] and Zeise’s salt
[PtCl3(C2H4)]. The bonding in such complexes is strong and could by no means be considered non-covalent,
since it is intimately linked with the partially occupied d-orbitals of the metals.

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.

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 vi) Anion–π Interactions: It is only relatively recently that there has been interest in anion-π
interactions. Intuitively, the interaction of an anion with π-electron density seems like it should be repulsive
and indeed the affinity of the aromatic ring containing cryptand 1.23 for halides rapidly falls off in the order
F >> Cl > Br ~ I because of anion-π repulsions in the case of the larger halides, with all except F
showing a constant anion-ring centroid distance of ca. 3.7 Å. However, there is a charge difference between
an overall neutral aromatic ring and an anion and therefore in principle the possibility exists for an
electrostatic attraction.

vii) 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. Face-to-face π-stacking interactions are responsible for the slippery feel
of graphite and its useful lubricant properties. Similar π-stacking interactions between the aryl rings of
nucleobase pairs also help to
stabilize the DNA double helix. Edge-to-face interactions may be regarded as
weak forms of hydrogen bonds between the slightly electron deficient 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. Edge-to-face interactions are responsible for the characteristic
herringbone packing in the crystal structures of a range of small aromatic hydrocarbons including benzene.

(a) Limiting types of π–π interaction. Note the offset to the face-to-face mode (direct overlap is repulsive). (b) X-ray
crystal structure of benzene showing herringbone motif arising from edge-to-face interactions.

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 Interacting π-quadrupoles.

viii) van der Waals Forces and Crystal Close Packing: Van der Waals interactions arise from the
polarization of an electron cloud by the proximity of an adjacent nucleus, resulting in a weak electrostatic
attraction. They are nondirectional 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. In supramolecular chemistry, they are most important in formation of ‘inclusion’
compounds in which small, typically organic molecules are loosely incorporated within crystalline lattices or
molecular cavities, e.g. the inclusion of toluene within the molecular cavity of the p-tert-butylphenol-based
macrocycle, p-tert-butylcalix[4]arene.

X-ray crystal structure of a typical van der Waals inclusion complex p-tert-butylcalix[4]areneꞏtoluene.

Examples of closed shell interactions (a) Aurophilic interactions in [Au2 (μ-Cl) (PPh3)2](ClO4), (b) halogen bonding in
pyridineꞏꞏꞏI–CCR and I5 and (c) secondary bonding in [{HgCl(C6H4N2Ph)}2].

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Hydrophobic Effects and Solvation
A. Hydrophobic Effects
Although occasionally mistaken for a force, hydrophobic effects generally relate to the exclusion
from polar solvents, particularly water, of large particles or those that are weakly solvated (e.g. via hydrogen
bonds or dipolar interactions). The effect is obvious in the immiscibility of mineral oil and water. Essentially,
the water molecules are attracted strongly to one another resulting in a natural agglomeration of other
species (such as non-polar organic molecules) as they are squeezed out of the way of the strong inter-solvent
interactions. This can produce effects resembling attraction between one organic molecule and another,
although there are in addition van der Waals and π–π stacking attractions between the organic molecules
themselves. The hydrophobic effect is very important in biological systems in the creation and maintenance
of protein and polynucleotide structure and in the maintenance of phospholipid bilayer cell walls.
Hydrophobic effects are of crucial importance in the binding of organic guests by cyclodextrins and
cyclophane hosts in water and may be divided into two energetic components: enthalpic and entropic.

The enthalpic hydrophobic effect involves the stabilization of water molecules that are driven from a
host cavity upon guest binding. Because host cavities are often hydrophobic, intracavity water does not
interact strongly with the host walls and is therefore of high energy. Upon release into the bulk solvent, it is
stabilized by interactions with other water molecules. The entropic hydrophobic effect arises from the fact
that the presence of two (often organic) molecules in solution (host and guest) creates two ‘holes’ in the
structure of bulk water. Combining host and guest to form a complex results in less disruption to the solvent
structure and hence an entropic gain (resulting in a lowering of overall free energy). The process is
represented schematically in Figure 1.26.

Hydrophobic binding of organic guests in aqueous solution.

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B. Solvation
The importance of solvent in supramolecular chemistry can hardly be overstated. In the solid-state
solvent is often included as a guest in the crystal lattice and usually mediates the nucleation and deposition
of a crystalline (or otherwise) compound from solution. In solution all complexation phenomena are in
competition with solvation interactions and the solvent is almost invariably in a huge molar excess. Polar
solvents, particularly water, compete very effectively for binding sites, particularly hydrogen bonding
functionality, making hydrophobic (or solvophobic) effects of paramount importance. In non-polar solvents
and in the gas phase specific host-guest dipolar and hydrogen bonding interactions are much more
significant. It is thus essentially meaningless to discuss the magnitude of binding constants without mention
of solvent and impossible to compare binding constants or even relative affinity across different solvent
media. Indeed, a common ‘trick’ to differentiate the affinity of a host for various guests is to lower the
apparent binding constants by moving to a more competitive (generally more polar) solvent. Thus binding
constants that are too high to measure in one solvent become lower and hence experimentally accessible in a
more competitive one.

A fuller picture of both the energetics and kinetics of the complexation process must take into
account the desolvation of both host and guest upon binding and the resolvation of the resulting complex,
often with release of free solvent and consequent formation of solvent-solvent interactions, Figure 1.27.

Figure 1.27 Solvation considerations during the host-guest complexation of a metal cation.

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Supramolecular Chemistry of Life
A. Alkali Metal Cations in Biochemistry

Energy-releasing dephosphorylation of ATP to ADP and dihydrogen phosphate. Mg2+ acts as a catalyst for the
reaction.

Mode of signal transduction of nerve system: Under concentration gradients, generated by Na+/K+-ATPase, opening of
an ion channel causes the passive efflux of K+ and the influx of Na+ resulting in a small burst of electrical current
(nerve impulse) and a change in the membrane potential. At the end of the nerve cell (axon) the electrical signal is
transformed into a chemical signal by triggering the ejection of a hormone such as acetylcholine. The hormone, in turn,
triggers the opening of a ligand-gated ion channel in the next nerve axon and restarts the nerve impulse as an electrical
current by allowing passive flow of K+ and Na+ across the next membrane.

Schematic diagram of a phospholipid biological membrane (5–6 nm in width).

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(a) Carrier, (b) channel and (c) gated channel mechanisms of ion transport across a biological membrane. The carrier
encapsulates the alkali metal cation, stripping away most or all of the water molecules bound to it. The carrier then
presents a lipophilic surface, moving across the membrane and releasing the ion back into aqueous solution at the
other end. The channel is, primarily, an aqueous hole running through the membrane. Ions can traverse swiftly through
the channel without losing their solvent sphere throughout most of their journey, as long as the gate (activated by
potential changes or hormones) is open and the ion can pass through the selectivity filter (which discriminates between
Na+ and K+).

Mechanism of the enzymatic action of ATPase.

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B. Porphyrins and Tetrapyrrole Macrocycles
Common examples are:
i) Chlorophylls, which contain otherwise labile Mg2+, and are important as energy harvesters in
photosynthesis.

ii) Cobalamins, the active form of vitamin B12, which involves a partially conjugated ‘corrin’ ring
system.

iii) Heme complexes, which consist of an iron centre and a substituted porphyrin ligand, as in iron
protoporphyrin IX, the active O2 binding site found in haemoglobin; hemes are also found in a variety of
enzymes such as cytochromes, which rely upon O2 as a substrate.

iv) A porphyrinoid nickel(II) complex, coenzyme F450, found in methane-producing

microorganisms; the independence of the function of this species from proteins makes it a good candidate
for ‘first-hour’catalysis, i.e. the origins of life.

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CHE 0531 5244 (Supramolecular Chemistry)/Chapter 1 Page 23
Uptake of Oxygen by Haemoglobin

(a) Irreversible μ-oxo dimer formation in nonprotein iron porphyrin complexes. (b) A rare example of reversible O2
binding in a simple inorganic complex. The formally Ir(III)/O22 complex is destabilized by the π-acceptor properties
of the phosphine and CO ligands.

(a) Porphyrin doming relaxes upon O2 binding. (b) Oxygenated haem showing immediate protein environment
including stabilizing hydrogen bonds.

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 Improved selectivity for O2 over CO is enforced by the protein environment.

Enzymes and Coenzymes

Enzyme structure can be divided into primary (amino acid sequence), secondary (chain folding), tertiary (full 3D
conformation) and quaternary (association of more than one protein chain) features.

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 Modular construction of holoenzymes.

Neurotransmitters and Hormones

In addition to the bioinorganic chemistry involving metal cations in various forms, there exists a vast
amount of biological chemistry that, in a supramolecular sense, involves molecular species and anions as the
guests. Hormones and neurotransmitters, which broadly speaking, act as messengers and activating agents.

Hormones such as the human sex hormones, oestrogen and testosterone, and the pregnancy hormone,
progesterone, are household names. A range of testosterone derivatives, the anabolic–androgenic steroids,
are capable of altering human physical performance significantly and as a result are highly topical within the
context of their illegal use in competitive sports. Similarly, levels of neurotransmitters such as dopamine and
acetylcholine may have dramatic effects on brain chemistry and hence behavior, and imbalances are
implicated in a number of mental disorders such as schizophrenia and Parkinson’s disease, highlighting the
chemical nature of even our very thought processes.

To illustrate the supramolecular biological role of such molecular species we will look at the mode of
action of acetylcholine (ACh, 2.8) in particular since this example highlights the profound effect that the
non-covalent binding of a small molecular guest may have on a biological system.

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 Acetylcholine is a key neurotransmitter molecule. Nerve pulses are passed on from nerve fiber to
nerve fiber across the synapses (the gaps between nerve cells, about 30–40 nm thick) by transfer of
acetylcholine from one nerve cell to the next. The role of acetylcholine is to bind to, and hence open, a gated
sodium ion channel, which forms part of the nicotinic acetylcholine receptor protein (nAChR). This large
transmembrane protein is composed of five subunits (two labelled α, and the others labelled β, δ, γ, Figure
2.25) with similar amino acid sequences, which encircle a central channel.

The membrane-bound nicotinic acetylcholine receptor (nAChR).

Acetylcholine binds to the two α-subunits, causing a conformational change in the channel external
region, which allows access to Na+ ions located in the synapse. These then flow rapidly into the cell in
accordance with the prevailing concentration gradient, resulting in a current flow. The binding of the agonist
acetylcholine to its receptor is highly selective and involves cation–π interactions between the quaternary
ammonium moiety and a particular tryptophan amino acid residue. Interestingly, acetylcholine activity is
affected severely by nicotine (2.9), which also possesses a quaternary ammonium residue, and it is likely
that this is the basis for nicotine addiction in smokers. Once the membrane has depolarized and the neural
current has been generated, acetylcholine is removed by another acetylcholine-binding protein, acetylcholine
esterase, which hydrolyses the ester functionality preventing the molecule from binding to nAChR.

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Semiochemistry in the Natural World
Semiochemistry is the chemistry of signalling and sensing and, like the binding of neurotransmitters
and hormones, a great deal of sensing and signalling in the natural world makes use of chemical recognition
events, usually between a chemical messenger molecule such as a hormone or pheromone and a protein-
based receptor.

Hormones are responsible for intercellular signaling in the body where they are involved in the
regulation of cell function. Pheromones can be used by insects as well as reptiles and mammals to induce
particular kinds of behavior or to signal information such as the whereabouts of food or sexual availability.
There are numerous classes of pheromone including aggregation, alarm and epideictic (signal the presence
of insect eggs) pheromones; releaser, primer, territorial, trail and sex pheromones. The sense of smell is also
based on molecular recognition with odourants dissolving in nasal mucus where they bind to and activate
odourant binding proteins or, in insects, chemosensory proteins generating a nerve signal to the brain.

A good example of a pheromone is bombykol, (10E,12Z)-hexadeca-10,12-dien-1-ol (2.10), a

pheromone which is used by the female silkworm moth to attract a mate (Figure 2.26a). It’s predominantly
hydrocarbon structure makes it water insoluble and thus it remains localized near the source. Bombykol was
one of the first pheromones to be isolated (in 1959) and is used in minute quantities to confuse male moths
as to the location of females and thus control numbers.

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DNA
DNA (deoxyribonucleic acid) is well known as the molecule that bears all of the genetic information
necessary to construct and operate a living organism. The cell nuclei of all eucaryotic organisms contain
DNA and each cell contains all the genetic code needed to assemble the entire organism – a remarkable
duplication of information.

(a) The DNA double helix. Dotted lines represent hydrogen bonded base–pair interactions; (b) Idealized views of the
three most common forms of DNA: B, A and Z. Structures B and A have right-handed helicity with 10 and 11
phosphate residues per turn, respectively. The Z form is left-handed with 12 phosphates per turn.

Biochemical Self-Assembly
As an example of protein self-assembly, take the protein ribonuclease, a 124-residue protein
containing four disulfide (SS) bonds. Reduction of these linkages gives a reduced protein containing
eight SH groups that is entirely denatured (i.e., enzymatically inactive). Reoxidation of the protein in the
presence of urea (which acts as a denaturing agent by virtue of its versatile hydrogen-bonding ability) results
in a mixture of scrambled (incorrectly folded) proteins containing most (if not all) of the 105 possible
combinations of disulfide bonds. Addition of β-mercaptoethanol causes the disulfide bonds to break slowly
and reform in an equilibrium process; if the urea is removed and β-mercaptoethanol added, the proteins
unscramble to give the native ribonuclease with full enzymatic activity, (Figure 2.41). The conclusion is that
the native protein represents the structure with the lowest Gibb’s free energy, and that all the information
required to assemble the protein is encoded into the amino acid sequence.

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Figure 2.41: Denaturing and self-reassembly of ribonuclease. The correct folding occurs only when disulfide bond
formation is made reversible by the addition of β-mercaptoethanol (RSH) allowing the system to equilibrate.

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