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Definition and Emergence of SupramolecularChemistry∗

Jonathan W. Steed1, Jerry L. Atwood2, and Philip A. Gale3

1Durham University, Durham, UK2University of Missouri, Columbia, MO, USA3University of Southampton, Southampton, UK

1 Introduction 12 Emergence 23 Conclusion 5References 5

1 INTRODUCTION

Although the word “supramolecular” made an early appear-ance in Webster’s Dictionary in 1903, “Supramolecularchemistry” in its modern sense was introduced only in 1978by Lehn, who defined it as the “. . .chemistry of molecu-lar assemblies and of the intermolecular bond.”1 Classicexplanations of supramolecular chemistry describe it as“chemistry beyond the molecule,” “the chemistry of thenoncovalent bond,” and “nonmolecular chemistry,” or even“Lego chemistry.” The early work in the field concerned theformation of supermolecules comprising two components, ahost and a guest, which interact with one another in a non-covalent manner (Figure 1). The host is a large molecule oraggregate such as an enzyme or synthetic cyclic compoundpossessing a sizeable, central hole, or cavity. The guest may

∗Adapted in part from Supramolecular Chemistry, J. W. Steed andJ. L. Atwood, Wiley: Chichester, 2nd Ed., 2009.

be a monatomic cation, a simple inorganic anion, an ionpair, or a more sophisticated molecule such as a hormone,pheromone, or neurotransmitter. More formally, the host isdefined as the molecular entity possessing convergent bind-ing sites (e.g., Lewis basic donor atoms, hydrogen-bonddonors, etc.). The guest possesses divergent binding sites(e.g., a spherical, Lewis acidic metal cation, or hydrogen-bond-accepting halide anion). In turn, a binding site isdefined as a region of the host or guest capable of takingpart in a noncovalent interaction. The host–guest relation-ship has been defined by Donald Cram2 as follows:

Complexes are composed of two or more molecules or ionsheld together in unique structural relationships by electro-static forces other than those of full covalent bonds . . .

molecular complexes are usually held together by hydro-gen bonding, by ion pairing, by π-acid to π-base interac-tions, by metal-to-ligand binding, by van der Waals attrac-tive forces, by solvent reorganising, and by partially madeand broken covalent bonds (transition states). . .High struc-tural organisation is usually produced only through multiplebinding sites. . . A highly structured molecular complex iscomposed of at least one host and one guest component . . .

A host–guest relationship involves a complementary stereo-electronic arrangement of binding sites in host and guest . . .

The host component is defined as an organic molecule orion whose binding sites converge in the complex . . . Theguest component as any molecule or ion whose binding sitesdiverge in the complex . . .

This description might well be generalized to removethe word “organic,” since more recent work has revealeda wealth of inorganic hosts, such as zeolites3 andpolyoxometallates,4 or mixed metal–organic coordinationcompounds, such as metal–organic frameworks (MOFs)

Supramolecular Chemistry: From Molecules to Nanomaterials, Online 2012 John Wiley & Sons, Ltd.This article is 2012 John Wiley & Sons, Ltd.This article was published in the Supramolecular Chemistry: From Molecules to Nanomaterials in 2012 by John Wiley & Sons, Ltd.DOI: 10.1002/9780470661345.smc002

2 Concepts

+ +

+

Molecular chemistry Supramolecular chemistry

Specific characteristic,

Supermolecule (complex):

Covalent molecule:

Molecularprecursors

Host

GuestChemical natureShapeRedox propertiesHOMO–LUMO gapPolarityVibration and rotationMagnetismChirality

Degree of orderInteractions between subunitsSymmetry of packingIntermolecular interactions

function or properties:RecognitionCatalysisTransport

Figure 1 Definition of traditional supramolecular “host–guest” chemistry according to Lehn.5

(see Zeolitelike Metal–Organic Frameworks (ZMOFs):Design, Structure, and Properties, Supramolecular Mate-rials Chemistry), which perform similar functions and maybe thought of under the same umbrella.

2 EMERGENCE

The original supramolecular host–guest complexesinvolve a host molecule that possesses an intrinsic molecu-lar cavity into which the guest fits; hence, they are, in prin-ciple, stable in all forms of matter (solid, liquid/solution,and the gas phase). The host–guest concept is much olderthan the work by Pedersen6 on hosts for alkali metal ionsin the late 1960s that gave birth to modern supramolecu-lar chemistry and can be dated back to the extensive bodyof clathrate or solid-state inclusion chemistry. This fieldbegins with the twin descriptions of zeolites or “boilingstones” discovered by Axel Cronstedt in 1756 and clathratehydrates or “anomalous ice” prepared by Joseph Priestleyin 1778. The evolution of this area is elucidated later inthis work by Bishop (see Synthetic Clathrate Systems,Supramolecular Materials Chemistry) and forms much ofthe early part of our subjective timeline of supramolecularchemistry (Table 1).

Interspersed among these milestones is the parallel birthof self-assembly as in the formation of self-assembledmonolayers first observed as the spreading of oil on waterby Benjamin Franklin in 1774, and the birth of nanochem-istry (the 1818 recognition of the particle size-dependentcolor of colloidal gold). We can also see the evolution ofcrystal engineering from the early topochemical postulateand molecular engineering of von Hippel in the 1960s to

the supramolecular synthon approach of Desiraju in 1995.The years 1989 and 1995 mark milestones in the designand synthesis of coordination polymer systems that havebrought about the explosion of porous MOF chemistry overthe past decade.

Biological receptor–substrate supramolecular chemistryand, by generalization, the whole of modern host–guestchemistry has its roots in three core concepts:

1. The recognition by Paul Ehrlich in 1906 that moleculesdo not act if they do not bind, Corpora non agunt nisifixata; in this way, Ehrlich introduced the concept of abiological receptor.

2. The recognition in 1894 by Emil Fischer that bind-ing must be selective, as part of the study of recep-tor–substrate binding by enzymes. He described thisby a lock -and -key image of steric fit in which the guest

Lock and key

Induced fit

Enzyme

Complex

Substrate

+

+

(a)

(b)

Figure 2 (a) Rigid lock and key and (b) induced fit models ofenzyme–substrate (and hence host–guest) binding.


Definition and emergence of supramolecular chemistry 3

Table 1 An illustrative timeline charting the development of supramolecular chemistry from its roots in solid-state inclusioncompounds, through the birth of macrocyclic host–guest chemistry in the 1960s to its modern incarnation in self-assembled materialsand nanoscale chemistry.

1756 — Axel Cronstedt: description of “boiling stone” (zeolite)1774 — Benjamin Franklin: spreading of oil on water1778 — Joseph Priestly: “anomalous ice”1810 — Sir Humphrey Davy: discovery of chlorine hydrate1818 — Jeremias Benjamin Richters: particle size explanation for the color of “drinkable gold”; colloidal gold known since antiquity

(e.g., Lycurgus cup, fourth century AD)1823 — Michael Faraday: formula of chlorine hydrate1841 — C. Schafhautl: study of graphite intercalates1849 — F. Wohler: β-quinol H2S clathrate1891 — Villiers and Hebd: cyclodextrin inclusion compounds1891 — Agnes Pockles: the first surface balance, leading to the development of the Langmuir trough and the Langmuir–Blodgett

technique1893 — Alfred Werner: coordination chemistry1894 — Emil Fischer: lock-and-key concept1906 — Paul Ehrlich: introduction of the concept of a receptor1937 — K. L. Wolf: the term Ubermolekule 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 Bond1940 — M. F. Bengen: urea channel inclusion compounds1945 — 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 another1949 — Brown and Farthing: synthesis of [2.2]paracyclophane1953 — Watson and Crick: structure of DNA1956 — Dorothy Crowfoot Hodgkin: X-ray crystal structure of vitamin B12

1958 — Daniel Koshland: induced fit model1959 — 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 diamine1964 — Busch and Jager: Schiff’s base macrocycles1965 — Olga Kennard and J. D. Bernal: The Cambridge Structural Database1962 — von Hippel: birth of crystal engineering1967 — Charles Pedersen: crown ethers1968 — Park and Simmons: Katapinand anion hosts1968 — F. Toda: “wheel and axel” inclusion compound hosts1969 — Jean-Marie Lehn: synthesis of the first cryptands1969 — Jerry Atwood: liquid clathrates from alkyl aluminum salts1969 — Ron Breslow: catalysis by cyclodextrins1971 — G. M. J. Schmidt: topochemistry1973 — Donald Cram: spherand hosts produced to test the importance of preorganization1978 — Jean-Marie Lehn: introduction of the term “supramolecular chemistry,” defined as the “chemistry of molecular assemblies and

of the intermolecular bond”1976 — Deliberate clathrate design strategies; “hexahosts” D. D. MacNicol and later in 1982 “coordinatoclathrates” E. Weber1979 — Gokel and Okahara: development of the lariat ethers as a subclass of host1981 — Vogtle and Weber: podand hosts and development of nomenclature1986 — A. P. de Silva: fluorescent sensing of alkali metal ions by crown ether derivatives1987 — Award of the Nobel prize for Chemistry to Donald J. Cram, Jean-Marie Lehn, and Charles J. Pedersen for their work in

supramolecular chemistry1989 — G. M. Whitesides: self-assembled thiol monolayers on gold1989 — R. Robson: 3D coordination polymers based on rod-like linkers1991 — G. M. Whitesides: a chemical strategy for the synthesis of nanostructures1994 — M. Brust: synthesis of thiol-stabilized gold nanoparticles1995 — O. M. Yaghi: first MOF; key coordination polymer papers by M. J. Zaworotko and J. S. Moore1995 — G. Desiraju: supramolecular synthon approach to crystal engineering1996 — Atwood, Davies, MacNicol, and Vogtle: publication of Comprehensive Supramolecular Chemistry containing contributions

from many key groups and summarizing the development and state of the art1996 — J. K. M. Sanders: the first example of a dynamic combinatorial chemistry system1998 — Rowan and Nolte: helical supramolecular polymers from self-assembly1999 — J. F. Stoddart: molecular electronics based on interlocked molecules2004 — J. F. Stoddart: the first discrete Borromean-linked molecule, a landmark in topological synthesis


4 Concepts

has a geometric size or shape complementarity to thereceptor or host (Figure 2a). This concept laid the basisfor molecular recognition, the discrimination by a hostbetween a number of different guests.

3. The fact that selective binding must involve attractionor mutual affinity between the host and guest. Thisis, in effect, a generalization of Alfred Werner’s 1893theory of coordination chemistry, in which metal ionsare coordinated by a regular polyhedron of ligandsbinding by dative bonds.

Receptor–substrate chemistry underwent a hugeparadigm shift in 1958 with Koshland’s “induced fit”model (Figure 2b), and these concepts have since per-meated throughout biological and abiotic supramolecularchemistry.

Supramolecular chemistry as we understand it today hasevolved to encompass not just host and guest chemistrybut also all aspects of self-assembly. It includes the designand function of molecular devices and molecular assem-blies, noncovalent polymers, and soft materials such as

Larger molecule(Host)

Crystallization

Smaller molecule(Guest)

Lattice inclusion host–guest complex or clathrate(Solid-state only)

Small molecules

Small molecules

Covalent

synthesis

Covalentsynthesis

Large ‘‘host’’ molecule

Larger molecule

Small molecular‘‘guest’’

Host–guest complex

Spontaneous

Self-assembledaggregate

(a)

(b)

(c)

Figure 3 Key paradigms in supramolecular chemistry. (a) Solid-state clathrate paradigm, (b) molecular host–guest paradigm, and(c) self-assembly paradigm.


Definition and emergence of supramolecular chemistry 5

liquid crystals, informed nanoscale chemistry, and “bottom-up” nanotechnology. In 2002, Lehn added a functionaldefinition: “Supramolecular Chemistry aims at developinghighly complex chemical systems from components inter-acting by noncovalent intermolecular forces.”7 Hence, thecurrent emphasis is on increasing complexity and henceincreasingly sophisticated functionality and on the infor-mation stored in molecular components that allows thiscomplexity to be achieved.

Modern supramolecular systems are beginning to dis-play complex emergent properties based on the nonlinearinteractions between the molecular component parts. It isclear that there are certain properties and features thatemerge according to the length scale on which a systemassembles, and indeed on which it is studied. Thus, theway in which ostensibly easily understood molecular-levelsupramolecular interactions scale up into the nanoworldis not always predictable and represents the frontiers andfuture of supramolecular science. As direct microscopicimaging and manipulation on the multinanometer scalebecome increasingly technologically feasible, it is increas-ingly possible to study the fascinating consequences ofchemical emergence —the “arising of novel and coherentstructures, patterns, and properties during the process ofself-organization in complex systems.”8

Fundamentally, supramolecular chemistry concerns themutual interaction of molecules or molecular entities withdiscrete properties. This interaction is usually of a nonco-valent type (an “intermolecular bond” such as a hydrogenbond, dipolar interaction, or π-stacking). Key to many def-initions of supramolecular chemistry is a sense of modu-larity. Supermolecules, in the broad sense, are aggregatesin which a number of components (of one or more type)come together, either spontaneously or by design, to form alarger entity with properties derived from those of its com-ponents. These aggregates can be of the host–guest typein which one molecule encapsulates the other or they caninvolve mutually complementary, or self-complementary,components of similar size in which there is no host orguest. We can thus trace the evolution of supramolecularchemistry from the original solid-state “clathrate” paradigm(Figure 3a), through the molecular host–guest paradigm(Figure 3b) to the self-assembly paradigm (Figure 3c).

As it is currently practiced, supramolecular chemistry,with its emphasis on the interactions between molecules,underpins a very wide variety of chemistry and materialsscience impinging on molecular host–guest chemistry,solid-state host–guest chemistry, crystal engineering andthe understanding and control of the molecular solid state(including crystal structure calculation), supramolecular

devices, self-assembly and self-organization, soft materials,nanochemistry and nanotechnology, complex matter, andbiological chemistry. Dario Braga has summed up theimpact of supramolecular concepts in the following way9:

The supramolecular perception of chemistry generated atrue “paradigm shift”: from the one focused on atoms andbonds between atoms to the one focused on molecules andbonds between molecules. In its burgeoning expansion thesupramolecular idea abated, logically, all traditional bar-riers between chemical subdivisions (organic, inorganic,organometallic, biological) calling attention to the collec-tive properties generated by the assembly of molecules andto the relationship between such collective properties andthose of the individual component.

3 CONCLUSION

It is clear that the molecular-level approach to understand-ing binding phenomena that gave rise to supramolecularchemistry has found application in a vast array of phenom-ena and is to a great extent fueling the concepts and growthof a vast swathe of chemically related science. For example,future applications of supramolecular chemistry in biologi-cal systems may include new treatments for disease by theinhibition of protein–protein interactions or by the pertur-bation via synthetic channels or carriers of chemical andpotential gradients within cancer cells triggering apoptosis.

From molecules to supramolecular assemblies, to nano-materials and complex molecular biosystems, the ensuingchapters in these volumes capture in detail the backdropand current state of the art in all of these fields that aredriven or informed by supramolecular concepts.

REFERENCES

1. J.-M. Lehn, Angew. Chem. Int. Ed. Engl., 1988, 27, 89.

2. D. J. Cram, Angew. Chem. Int. Ed. Engl., 1986, 25, 1039.

3. R. Szostak, Molecular Sieves, Van Nostrand Reinhold, NewYork, 1989.

4. A. Muller, E. Krickemeyer, J. Meyer, et al., Angew. Chem.Int. Ed. Engl., 1995, 34, 2122.

5. J.-M. Lehn, Supramolecular Chemistry, 1st edn, Wiley-VCHVerlag GmbH, Weinheim, 1995.

6. R. M. Izatt, Chem. Soc. Rev., 2007, 36, 143–147.

7. J.-M. Lehn, Proc. Nal. Acad. Sci. U.S.A., 2002, 99, 4763.

8. J. Goldstein, Emergence: Complex. Organ., 1999, 1, 49.

9. D. Braga, Chem. Commun., 2003, 2751.


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