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F O C U S A R T I C L E

When did we make our first “crystal bydesign”? There was a moment ofinspiration during the Italo-Israeli Meetingin 1992.1 Peggy Etter had shown in hertalk that benzene could be used to templatethe hydrogen bonding of six 1,3-cyclohexanedione molecules into ahexameric “cyclamer”.2a When, soon after,Fabrizia Grepioni spoke about the packinganalogy between solid benzene andbisbenzene chromium (C6H6)2Cr Peggysuggested the possibility of substitutingbenzene for bisbenzene chromium in thedione cyclamer. The idea was beautifullysimple and we did almost succeed whenwe finally tried it. However, since shape isnot everything in chemistry, the oxidationof (C6H6)2Cr to (C6H6)2Cr+ had led tosomething similar to, but not quite thesame as, Etter’s cyclamer.2b Nonetheless,we had learned that crystal design wasindeed possible and, with this, joined therapidly growing community of crystalmakers.

Various factors drove the emergence ofcrystal engineering during the 1990s.There was a demand for more practicalobjectives for basic research, given therestrictions upon funding. Meanwhile,small molecule crystallography wasbecoming increasingly accessible to non-specialists – so maybe thecrystallographers were looking for a newchallenge. Technically, point detectorswere increasing the speed of datacollection by an order of magnitude, whilecomputers were becoming smaller andcheaper, allowing easy manipulation ofmolecular images on-screen. At the same

time, the Cambridge Structural Database3

was becoming more user-friendly and thestorehouse of intermolecular interactionseasily available for crystal design.

But the cultural factor in the growth ofcrystal engineering was perhaps the mostimportant. The supramolecular perceptionof chemistry generated a true “paradigmshift”: from one focused on atoms andbonds between atoms to one focused uponmolecules and bonds between molecules.Supramolecular chemistry has dissolvedall the traditional barriers between thesubdivisions of chemistry (organic,inorganic, organometallic, biological),focusing attention on the collectiveproperties generated by the assembly ofmolecules and also on the relationship

between such collective properties andthose of the individual components.

The paradigm shiftWhen applied to crystalline solids, theparadigm shift leads directly fromsupramolecular chemistry to crystalengineering. Who could deny that J. M.Lehn’s4 definition of a supermolecule(“organized entity of higher complexityheld together by intermolecular forces”)works just as well for a (molecular)crystal? The collective properties of such agiant supermolecule result from theconvolution of the properties of theindividual molecular/ionic building blockswith the periodical distribution ofintermolecular non-covalent bonding of

Crystal engineering,Wherefrom? Where to?Dario Braga

Dipartimento di Chimica G. Ciamician, Università di Bologna, Via Selmi 2, 40126 Bologna, Italy. E-mail:dbraga@ciam.unibo.it

It is hard to give a definition that does justice to the breadth of crystal engineeringtoday. But a useful working description might see modern crystal engineering asthe bottom-up construction of functional materials from molecular or ionicbuilding blocks. Crystal engineering has its roots in chemistry with importantinterfaces with physics and biology, as well as applications in materials sciences, thedrug industry and nanotechnology. In short, crystal engineering is a rapidlyexpanding global discipline practised by scientists with diverse interests in themodelling, synthesis, evaluation and utilization of crystalline solids.

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Dario Braga is Professor of Chemistry at theUniversity of Bologna in Italy. He has alwaysbeen interested in solids and in therelationship between molecular and crystalproperties. His interests are, at present,focused on making crystalline materials bydesign for applications in solid–solid andsolid–gas solvent-free reactions. Hecollaborates with several companies in Italyand abroad on problems of crystalpolymorphism. Dario Braga is the author ofabout 300 papers and reviews. He is theScientific Editor of CrystEngComm and amember of the Advisory Board ofChemComm. He has been involved in theplanning and organization of severalInternational European Schools and Meetingson crystal engineering.

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the crystal (see Fig. 1). This had beenanticipated in Etter’s papers5 and inDesiraju’s 1988 book,6 and hinted at asearly as 1973 in Kitagorodsky’sinvestigations of molecular crystals.7 Aconcurrence of thoughts and objectivesfostered the birth of modern crystalengineering as the chemistry of periodicalsupermolecules.

The identification of a crystal as aretrosynthetic target8 marked thisevolutionary step: the new crystal engineerwas a chemist, actually a supramolecularsolid state chemist, with interests rangingfrom synthetic chemistry, tocrystallography and solid state chemistry.Though they have their origins in organicchemistry, these ideas have found anextraordinarily fertile soil in the fieldsof metal-organic and coordinationchemistry.9

Put simply, crystal engineering ismaking crystals by design. This definitionimplies the ability to assemble molecularor ionic components into the desiredarchitecture by engineering a target

network of supramolecular interactions.These interactions can be covalent bondsbetween atoms, as well as coordinationbonds between ligands and metal centers,Coulombic attractions and repulsionsbetween ions, and non-covalent bondsbetween neutral molecules (van der Waals,hydrogen bonds, etc.) or – of course – anycombination of these linkages. Thesebonding interactions span a very wideenergy range: from the tiny energiesinvolved in the van der Waals interactionsbetween neutral atoms in neutralmolecules to the high ones involved inbreaking and forming of covalent bonds(see Fig. 2). The difference in bondingtypes offers a practical way to differentiatetarget materials, and hence syntheticstrategies, as a function of the energyinvolved in the bond breaking-bondforming processes that lead from buildingblock to superstructure. On this premise, ajudicious choice of the supramolecularlinks and of the building block features(electronic, spin, charge state andgeometry) allows “bottom-up” preparation

of molecule-based materials for a varietyof applications.10

It is worth stressing that crystal-orientedsynthetic strategies do not differ, in theiressence, from classical chemicalexperiments in which molecules aremodelled, synthetic routes devised,products characterised and their propertiesmeasured. However, this step-wise processneeds, in a sense, to be repeated twice:first, in order to prepare the buildingblocks (whether molecules or ions), andthen to arrange the building blocks in adesired way to attain and/or control crystalproperties. This latter step invariablyrequires the characterisation of a solidproduct for which routine analytical andspectroscopic laboratory tools are muchless useful than in the case of solutionchemistry. In fact, the crystal engineer hasto master methods that are not routine inchemistry labs (DSC, TGA, AFM, STM,SSNMR, XPD, etc.).

Interfaces – crystalengineering and co-ordination chemistry, greenchemistry and drugdiscoveryCoordination chemistry has also gonesupramolecular, evolving from acoordination chemistry focused onmolecular complexes to a periodicalcoordination chemistry focused onnetworks of complexes. The basic idea isthat of expanding coordination in one, twoand three dimensions by means of

CHEM. COMMUN., 2003 This journa l is © The Roya l Soc iety of Chemistry 20032752

Fig. 1 From molecule to periodical supermolecule: the collective properties of molecular crystalresult from the convolution of the properties of the individual molecular/ionic building blocks withthe periodical distribution of intermolecular non-covalent bonding of the crystal.

The term ‘crystal engineering’ is traditionally attributed to G. Schmidt (Pure Appl.Chem., 1971, 27, 647). “...we shall, in the present context of synthetic and mechanisticphotochemistry, be able to ‘engineer’ crystal structures having intermolecular contactgeometries appropriate for chemical reaction…”. However, the proceedings of theAmerican Physical Society Meeting held in Mexico City in August 1955 (Phys. Rev.,1955, 100, 952) report an abstract entitled “Crystal Engineering: a new concept incrystallography”, by R. Pepinsky of the Pennsylvania State University: “Crystallizationof organic ions with metal-containing complex ions of suitable sizes, charges andsolubilities results in structures with cells and symmetries determined chiefly bypacking of complex ions. These cells and symmetries are to a good extent controllable:hence crystals with advantageous properties can be ‘engineered’… Pepinsky’s goalwas that of exploiting complex ions in the application of direct methods for structuredetermination, in particular the absolute structure of optically active ions. Although thescopes of modern crystal engineering are much broader, it is interesting to note that theidea of making crystals by design was there already fifty years ago: the purposedmodification of a crystal structure to enhance anomalous scattering for diffractionimage seeking can be regarded as an early application of the crystal engineeringprinciples.

I am grateful to Dr. K. Larsson (Chalmers University of Technology, Göteborg,Sweden) for informing me of this “ancient literature” discovery.

Fig. 2 Bonding interactions between buildingblocks span a very wide energy range: thedifference in bonding types offers a practical wayto differentiate target materials, and hencesynthetic strategies, as a function of the energyinvolved in the bond breaking-bond formingprocesses that lead from building block tosuperstructure.

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polydentate ligands which, instead ofconvergent chelation, could give divergentpolydentation joining metal centres inextended networks as schematicallyrepresented in Fig. 3. Coordinationnetworks (also called coordinationpolymers) constitute by far the largestclass of engineered crystal structures.

A popular motivation for this work isthe design and preparation of zeolite-typenanoporous structures with voids andchannels that can be used for sensing,trapping, and storing small molecules (seeFig. 4).11 There is a catch, though, and thisis the self-filling of voids in the structuresby network interpenetration. Even wheninterpenetration does not occur, the edificemay not resist removal of solvent or guestmolecules. Therefore, the two main designchallenges in this sub-area are:• understanding the factors controllingself-entanglement• designing nanoporous materials thatwithstand uptake and release ofsubstances9

Solvent-free reactions betweenmolecular crystals and gases, as well asbetween two molecular solids, to yieldmolecular crystalline products are also ofinterest in the quest for environmentallyfriendly processes (green chemistry).12

Examples of both types of processes areshown in Fig. 5.13 Both uptake/release ofsmall molecules by a nanoporous materialand the reaction between a molecularcrystal and molecules (whether from gasphase or in the solid state) to yield a newcrystalline material are supramolecularreactions whereby non-covalentinteractions between guest and the host arebroken and formed.

Solid-state covalent reactions, on theother hand, bring back Schmidt’spioneering ideas of pre-arrangingmolecules in the solid state in order toobtain reactions.14 This topochemicalapproach, however, is not a dogma: inmany cases molecules need to travel along distance within crystals in order toreact.15

Meanwhile, fuelled by patentingconcerns, the interest of pharmaceuticalcompanies in the appearance (ordisappearance) of polymorphic forms of agiven substance has increasedtremendously.16 Crystalline polymorphs,e.g. different periodical supermolecules ofthe same component molecule, could havedifferent physico-chemical properties(solubility, thermal resistance, workability,particle size etc.) and could thus be treatedas different substances for many practicalpurposes. The controlled preparation andcharacterization of different crystal formshas thus become a major issue of solid-state chemistry, and not only for organicsubstances. However, one may wonderwhether the existence of a multiple answerto the crystal design and constructionparadigm could be seen as the “dark side”of crystal engineering.

Learning how to generate polymorphson purpose by a judicious choice of thecrystallization conditions is a way tomaster non-covalent interactions. Thereare also notable implications in theoreticalsolid-state chemistry where the challengebecomes that of predicting the outcome ofa crystallization process (see J. D. Dunitzrecent Focus Article17).

Crystal engineering, whereto?Where is crystal engineering going? Itcontinues to expand across scientific

borders. Having grown from its “organic”cradle, crystal engineering now spans allareas of chemistry, with relevantinterdisciplinary interactions with biology,informatics and physics.

In the area of biology, for example,crystal engineering involves theinvestigation of the interaction betweenbiological matrices and crystalline phasesand the transfer of this knowledge to labpractice.18

Clearly, the motivation behind a crystalengineering project may be utilitarian andeconomical or, equally, aesthetic and/orfuelled by quintessential scientificcuriosity. Crystal engineering is a globaldiscipline practised by scientists withdiverse interests but all sharing the idea of“making crystals with a purpose”.

Needless to say, crystals were prepared“with a purpose”, and thoroughlyinvestigated, long before the advent ofmodern crystal engineering. What waslacking, perhaps, was a common scientificlanguage and a unifying perception ofcrystals not as something different frommolecules but rather as giganticsupermolecules that could be manipulatedwith the tools of chemistry. In this respect,while topological analysis of weak andstrong non covalent interactions, designstrategies with hydrogen and coordinationbonds, characterization of solidcompounds are all well charted areas, thequest for novel properties engineered at

2753This journa l is © The Roya l Soc iety of Chemistry 2003 CHEM. COMMUN., 2003

Fig. 3 The transition from molecular to periodicalcoordination chemistry. From coordinationcomplexes (top) to coordination networks(bottom): the use of bidentate ligand spacersallows construction of periodical coordinationcomplexes.

Fig. 4 Coordination networks: (a) “Paddle wheel” clusters M(O2CR)4 have been used to produce low-density structures that can take up a large amount of guest molecules; the large sphere indicates theempty space in the crystal structure. Reproduced by permission of the Royal Society of Chemistry.11a

(b) “Sponge-like” behaviour of the coordination network obtained from 2,4,6-tris-(4-pyridyl)triazineand ZnI2: the network shrinks/swells upon release/uptake of guest molecules.11b

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molecular and supramolecular levels hasonly recently begun.10 One can expectdevelopments in diverse andcomplementary areas: nano-computing,catalysis (in nano- and meso-cavities),protonics (fuel cells), storage (fuelstorage), biomimesys and implantology,sieves, sensors and traps (environmentalchemistry), polymorphism (drugs deliveryand uptake) just to mention a few.Focusing research on these topics will alsohelp directing basic research towards longterm practical applications and willincrease co-operation between theacademic and industrial sectors.

However, the “black magic” ofcrystallization19a remains a challenge. Norecipe exists to predict the shape or size,let alone space group, of the crystals thatwill eventually form from a solution of anew chemicals, nor whether the crystalswill be thermodynamically stable ormetastable, or will undergo phase changeswith temperature or pressure, or includesolvent molecules upon crystallization. Weare unable to predict whethercrystallization will yield a powder, orsingle crystals, or amorphous materials, orall these together. Everything can be solidbut not every solid obeys Bragg’s law.Indeed, many of the most interestingmaterials are disordered or amorphous18c

and their characterization and evaluation isan open challenge.

Engineering requires transferability andreproducibility. There is no doubt thatcrystals can be engineered at the molecularlevel, but in order for a crystal to “exist”,to have any practical meaning, it mustgrow to size. Even the smallest fragment,visible only under a microscope, requiresthe self-arrangement of billions ofmolecules.19b This is the fascination thatnever ends.

AcknowledgementsFor reasons of space I am unable tocite relevant contributions of manycolleagues. I hope all those who havecontributed to make crystal engineeringfascinating and diverse will accept acollective acknowledgment. I would alsolike to express my thanks to FabriziaGrepioni for her help and usefulsuggestions.

References and Notes1 Italo-Israeli Meeting on “The Influence of

Steric and Electronic Effects on Molecularand Crystalline Structure”, Tel-Aviv, 1992.

2 (a) M. C. Etter, Z. Urbonczyck-Lipkowska, D. A. Jahn and J. S. Frye, J.Am. Chem. Soc., 1986, 108, 5871. Etter’scyclamer has been chosen as a logo, forCrystEngComm, the RSC journal devotedto crystal engineering(http://www.rsc.org/CrystEngComm). (b)D. Braga, F. Grepioni, J. J. Byrne and A.Wolf, J. Chem. Soc., Chem. Commun,1995, 1023.

3 F. H. Allen and O. Kennard, Chem. Des.Autom. News, 1993, 31, 8.

4 J. M. Lehn, Angew. Chem., Int. Ed. Engl.,1990, 29, 1304.

5 With her studies of solid state organicchemistry and purposeful utilization ofintermolecular interactions Etter madesignificant contributions to the definitionof modern crystal engineering. With greatforesight, in 1988, she wrote: “Organizingmolecules into predictable arrays is thefirst step in a systematic approach todesigning solid-state materials” (T. W.Panunto, Z. Urbanczyk-Lipkowska, R.Johnson and M. C. Etter, J. Am. Chem.Soc., 1987, 109, 7786).

6 G. R. Desiraju, Crystal Engineering: TheDesign of Organic Solids; Elsevier:Amsterdam, 1989. This book remains, to

date, the only single author book on thesubject.

7 See, for instance A. I. Kitagorodsky,Molecular Crystals and Molecules,Academic Press, New York, 1973.

8 G. R. Desiraju, Angew. Chem. Int. Ed.,1995, 34, 2311.

9 See, for instance:(a) D. Braga, F. Grepioniand G. R. Desiraju, Chem. Rev., 1998, 98,1375; (b) R. Robson, J. Chem. Soc. DaltonTrans, 2000, 3735; (c) S. R. Batten,CrystEngComm, 2001, 1; (d) B. Moultonand M. J. Zaworotko, Chem. Rev., 2001,101, 1629; (e) A. J. Blake, N. R.Champness, P. Hubberstey, W. S. Li, M. A.Withersby and M. Schroder, Coord. Chem.Rev, 1999, 183, 117; (f) J. Chem. Soc.Dalton Trans., 2000, pp. 3705–3998reports the papers presented at the DaltonDiscussion on “Inorganic crystalengineering”, which was the first scientificmeeting in Europe entirely devoted tocrystal engineering.

10 D. Braga, F. Grepioni and A. G. Orpen,Crystal Engineering: from Molecules andCrystals to Materials, Kluwer AcademicPublishers, Dordrecht, 1999.

11 (a) N. L. Rosi, M. Eddaoudi, J. Kim, M.O’Keeffe and O. M. Yaghi,CrystEngComm, 2002, 4, 401; (b) K.Biradha and M. Fujita, Angew. Chem. Int.Ed., 2002, 41, 3392.

12 (a) K. Tanaka and F. Toda, Chem. Rev,2000, 100, 1025; (b) F. Toda,CrystEngComm, 2002, 4, 215; (c) G. W. V.Cave, C. L. Raston and J. L. Scott, Chem.Commun., 2001, 2159 and referencestherein.

13 (a) van Koten M. Albrecht, M. Lutz, A. M.M. Schreurs, E. T. H. Lutz, A. L. Speckand G. van Koten, Dalton Trans, 2000,3797; (b) M. Albrecht, M. Lutz, A. L.Speck and G. van Koten, Nature, 2000,406, 970; (c) D. Braga, L. Maini, M.Polito, L. Miralo and F. Grepioni, Chem.Commun, 2002, 24, 2960.

14 G. M. J. Schmidt, Pure Appl. Chem, 1971,27, 647. See also L. R. McGillivray,CrystEngComm, 2002, 4, 37 for a recentsurvey of topochemical reactions.

15 G. Kaupp, in, ComprehensiveSupramolecular Chemistry, edited by J. E.D. Davies (Elsevier, Oxford), 1996 , 8,381.

16 J. Bernstein, Polymorphism in MolecularCrystals, Oxford University Press, Oxford,2002.

17 J. D. Dunitz, Chem. Commun., 2003,545.

18 (a) S. Mann, Biomineralization. Principlesand Concepts in Bioinorganic MaterialsChemistry, Oxford University Press,Oxford, 2001; (b) L. Addadi andM. Geva, CrystEngComm, 2003, 5, 140;(c) J. Aizenberg, G. Lambert, S. Weinerand L. Addadi, J. Am. Chem. Soc., 2002,124, 32.

19 (a) P. Ball, Nature, 1996, 381, 648; (b) In acrystal of ice of 0.01 mm3 the number ofwater molecules is roughly 1013!

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Fig. 5 Solid-gas and solid-solid reactions. (a) the Pt(II) complex reversibly binds gaseous SO2 in thesolid state by Pt–S bond formation and cleavage. Uptake and release of SO2 does not destroy thecrystalline ordering.13a,b (b) Mechanochemical and gas–solid assembly of a hybridorganic–organometallic solid compound accompanied by reorganization of the hydrogen bondingpattern.13c

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