J. Phys. D: Appl. Phys. 2s (1993) 1366-376. Printed ln the UK
`
`Crystal growth, polymorphism and
`structure-property relationships in
`
`organic crystals
`
`Joel Bernstein
`
`Department of Chemistry, Ben-Gurion University of the Negev, PO Box 653,
`Beer Sheva 84105, Israel
`
`Abstract. Understanding the role of structure in determining the properties of
`materials is a crucial aspect of the design of new materials. The existence of
`polymorphic crystal structures provides a unique opportunity to study structure-
`property relationships, since the only variable among polymorphic forrns is mat
`of structure, and variation in properties must be due to differences In structure.
`Systematic characterization of the polymorphic forms and acquisition of the
`ability to grow crystals of a desired term are additional elements in the design
`strategy of new materials. The conditions and techniques required to obtain a
`particular polymorph, combined with knowledge of the crystal structures. can also
`provide information on the relative stability of the different structures. Studies
`of representative systems which illustrate the intimate connections between
`polymorphism, structurt-:—-property relations and crystal growth are presented.
`
`1. Introduction
`
`The design and preparation of materials with desired
`properties is one of the principal goals of chemists,
`physicists and structural biologists. Achieving that
`goal depends critically on understanding the relationship
`between the structure of a material and the properties
`in question. Systematic studies of structure—property
`relationships generally require eliminating as many as
`possible of the structural variables in an attempt to
`isolate the one or few structural parameters which play
`the most
`important role in determining the particular
`property under investigation. For organic molecules at
`typical strategy might involve, for instance. a systematic
`variation in the mode or type of substitution on one part
`of the molecule in order to test a particular hypothesis.
`Variations in substituents, while they do often result in
`changes in structure, and the corresponding changes in
`properties. also lead to perturbations in the electronic
`structure of the molecules in question.
`In such cases.
`changes
`in properties cannot always be correlated
`directly with changes in structure. The existence of
`polymorphic fonns provides a unique opportunity for the
`investigation of structure—property relationships, since
`by definition the only variable among polymorplis is
`that of structure. For a polymorphic system, differences
`in properties among the polymorphs must be due
`to differences in structure. As a corollary to this
`principle, a constancy in properties for a polymorphic
`system indicates a lack of structural dependence on that
`property, at least within the limitations of the structural
`
`lJU?2-3727l93.l’8B0066+11$0T.5D © 1993 IOP Publishing Lll:l
`
`variations through that particular series of polymorphic
`structures.
`
`For organic materials, studies of structure-property
`relations fall into two broad categories.
`In the first,
`the properties under investigation are due to strong
`interactions between neighbouring molecules. and we
`wish to study the changes in bulk properties resulting
`from differences in the spatial
`relationships between
`molecules in the crystal.
`i.e. the crystal structure.
`In
`the second category we seek information related to
`variations in molecular structure, generally molecular
`conformation.
`The existence of difi'erent molecular
`
`structures.
`in different polymorphic
`confonnations
`known as conformational polymorphism, also provides
`an opportunity for the study of the influence of crystal
`forces on the molecular conformation, since variations
`in conformation must be a result of different crystalline
`environments.
`
`Our intention in this paper is to provide a brief
`overview, with suitable examples, of the utilization
`of polymorphism in organic materials to investigate
`structure-—properl:y relations.
`
`2. How widespread is polymorphism in organic
`materials?
`
`Although the phenomenon of polymorphism was
`recognized by Mitscherlich (1822, 1823) at the dawn of
`modern chemistry, relatively little effort was devoted
`to the systematic search for and investigation of
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`polymorphic forms of organic materials until the last
`twenty-five years or sol‘. The extent of the phenomenon
`is evident in the fact that over 3000 of the entries in
`the Cambridge Strucnrral Database (Allen et ai 1991)
`contain qualifying descriptions as being members of
`polymorphic systems.
`While most examples of polymorphism are still
`discovered through serendipity,
`there are a number
`of areas of chemical research and development where
`full characterization of solid materials is critical
`in
`the determination of
`their ultimate use.
`These
`
`include pharmaceuticals (I-Ialeblian and McCrone 1969,
`Haleblian 1975, Clements 1976). dyes (Walker et at
`1972, Griffiths and Monahan 1976, Etter er al 1984.
`Tristani-Kendra et al 1983, More] er al 1984) and
`explosives (Karpowicz er al 1983). Various aspects
`of the subject have been treated in books (Vama and
`Krishna 1966, Bym I983, Kulmert-Brandstatter i971)
`and a number of reviews (McCrone 1963, Haleblian and
`McCrone 1969, I-Ialeblian 1975).
`The proliferation of examples of polymorphism in
`these areas would seem to lend credence to the widely
`quoted statement by McCrone (1963) that
`‘Virtually
`all compounds are polymorphic and the number of
`polymorphs of a material depends on the amount of
`time and money spent in research on that compound’.
`However,
`it is still not possible to predict with any
`reasonable level of confidence the crystal structure
`of an organic material, much less the existence of
`polymorphism, although considerable progress is being
`made in these endeavours (Roberts 1992. Sato I992.
`Desiraju 1991, Gavezzotti 1989, I991, Maddox 1988,
`Scaringe and Perez 1987, Fagan and Ward 1992).
`Moreover, since scientists do not make a practice of
`reporting negative results, we are generally not aware of
`unsuccessful systematic searches for polymorphs. When
`required, a systematic search for polymorphic forms
`should be carried out on solid materials,
`involving a
`wide variety of techniques and conditions for growing
`crystals and enlisting a diversified arrnoury of analytical
`techniques to detect them. The range and combinations
`of crystal growth conditions are virtually infinite, and
`there is no way to guarantee the preparation of additional
`polymorphs of a substance, much less the generation of
`‘all’ of them.
`
`In spite of the considerable efforts and progress in
`understanding and controlling polymorphic behaviour
`(Weissbuch er al 1987) the phenomenon still seems to be
`at least pa.r1:ially shrouded in mystery and folklore, with
`tales of metastable crystal forms ‘disappearing’ in favour
`of more stable ones (Woodard and McCrone 1975,
`Iaeewicz and Nayler 1979, Webb and Anderson 1978,
`Scheidt er at 1983). To fuel this debate there have been
`reports of successful attempts (Catti and Ferraris 1976,
`Czugler er a1 1981, Bar and Bernstein 1982), after
`considerable efi"or1s, to overcome the ‘poisoning’ of a
`laboratory or even vast areas of the earth (Woodard and
`McCrone 1975).
`
`T One notable exception is the relatively obscure but very useful
`compilation by Delfet (1942) of polymorphic organic materials.
`
`Structure-—property relationships in organic crystals
`
`3. Comparing polymorphic crystal structures
`
`The crystal structure representation containing most
`infonnation is a stereo diagram of the packing, with a
`suitably chosen view of a central reference molecule and
`its immediate surroundings. Comparison of polymorphic
`structures is best made by preparing the same type of
`drawing on the same reference plane of the reference
`molecule for all of the polymorphs. While this pictorial
`approach is very helpful to a viewer it is difficult to
`translate the graphic infomration into a form which can
`be communicated to others. The traditional method of
`
`doing so involves the preparation of a listing of the
`‘short’ inten-nolecular contacts (ie. those less than the
`sum of the van der Waals radii) including the symmetry
`operations relating the neighbouring molecules. This
`representation falls at the opposite end of the information
`spectrum:
`it contains all the necessary analytical data,
`but is virtually impossible for the reader to visualize.
`A solution to this dilemma may lie in the use
`of graph sets which have been developed recently to
`represent the patterns of hydrogen bonds (Etter 1990,
`Etter er al 1990), but which,
`in principle, may be
`applied to any type of intermolecular interaction.
`In
`this representation all hydrogen bonds may be classified
`as belonging to one of only four different patterns:
`intramolecular,
`finite dimeric,
`finite ring, or infinite
`chain. A complete definition of the pattern is given by
`specifying the number of donors (hydrogens) and the
`number of acceptors (basic atoms) as well as the total
`number of atoms contained in the pattern. The hydrogen-
`bond networks may then be summarized in a concise
`shorthand way which carries a great deal of information
`that may be used to compare readily the structures of
`polymorphic systems. Examples of such a treatment are
`given for the trimorphic system of irninodiacetic acid
`(Bernstein eta! 1990) and the dimorphic Lrglutarrric acid
`(Bernstein 1991a).
`as
`Because of
`their highly directional nature,
`compared with other types of interactions, this approach
`has been applied initially to hydrogen-bonded structures.
`Other intermolecular atom-atom interactions also exhibit
`characteristic patterns (Desiraju 1991) which are now
`much more amenable to study because of the ready
`accessibility of the structural data from the Cambridge
`Structural Database and the analytical and statistical
`software associated with it. The extension of the graph
`set approach for cataloguing structures from hydrogen-
`bond systems to other types of interaction is a natural one
`which should allow for much more facile understanding
`and comparison of polymorphic systems.
`
`4. Examples of struoture—property studies on
`polymorphic systems
`
`4.1. Bulk properties
`
`For historical reasons, the properties of organic materials
`have been considered in terms of the molecular structure.
`This was a natural result of the fact that most of the
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`J Bernstein
`
`chemistry of these materials was carried out in solution,
`where molecules might interact or react in a pairwise
`fashion. Even three-body interactions were considered
`quite unusual. The last two decades have witnessed
`a revolution in this point of view, as the wealth of
`possibilities for designing and utilizing the solid state
`properties of organic materials have become evident.
`These properties intrinsically depend on both the nature
`of the molecules and the way in which they interact with
`each other in the solid.
`Important information about
`the role of these solid state interactions can be obtained
`
`from the study of polymorphic materials, and variation
`of physical properties from one polymorph to another.
`Moreover,
`the recognition of the conditions required
`for the growth of the different polymorphs can provide
`additional
`information on the energetic relationships
`among them, and the crystallization conditions necessary
`to obtain the crystal architecture with the desired
`intermolecular
`interactions required for a particular
`physical property. Two examples from the realm of bulk
`properties will serve to illustrate these points.
`
`4.1.1. Electrical conductivity. Organic materials are
`traditionally considered to be electrical insulators, but the
`discovery twenty years ago of metallic conductivity in
`crystals of the Jr molecular complex of terrathiafulvalcne
`I and tetracyanoquinotlimethan II
`
`s
`
`E
`
`s
`
`i
`53
`
`>——("-
`
`1
`
`are
`
`N
`
`N
`
`C>=<:>==(
`on
`
`I!
`
`(Ferraris er at 1973, Coleman et at 1973) led ‘to a
`revolution in thinking about these materials in particular
`and the potential
`for organic materials in general,
`as the basis for
`the next generation of electronic
`components (Wudl 1984. Williams at al 1985).
`In
`contrast
`to the vast majority of known 2: molecular
`complexes that crystallize with plane-to-plane stacks
`of alternating donors and acceptors
`(mixed stack,
`figure 1(a)) (Herbstein 1972),
`the complex of I and
`II crystallized with segregated stacks of molecules
`along the same crystallographic axis (but not mutually
`parallel). each stack containing only one type of
`molecule.
`feature has been shown to be
`structural
`This
`a necessary condition for electrical conductivity in
`these materials, although the mixed mode of stacking
`is generally the
`thermodynamically preferred one
`(Shaik 1982). What means do chemists have at their
`disposal to overcome the tendency to form mixed stacks
`rather than segregated stacks? One method is to choose
`either a donor or acceptor with a completely different
`molecular shape. - The principles of close packing in
`organic crystals (Kitaigorodskii 1973) then suggest that
`molecules will pack in segregated stacks in order to
`most efficiently fill the space. Such reasoning led, for
`instance, to the 2:1 ‘Bechgaard salts‘ (Bechgaard er al
`1930, 1981) based on III as a donor. and a similar series
`based on IV (‘ET’) as a donor, in which the acceptors are
`
`T B68
`
`..U>UJ>U:v--
`
`J=c::r>U>c:
`
`E 3.2-3.5 it
`
`OUUUUU
`
`--:=-:=-:t=->>>--
`
`
`Hi xed stocks
`
`Segregated slacks
`
`lnl
`
`(bl
`
`Figure 1. Upper part: schematic diagram of the mixed
`slack and segregated stack motifs for packing of molecular
`charge-transfer complexes; lower part: views of the two
`polymorphic structures of lI:lll.
`in both cases the view
`is on the plane of the retro molecule (ii). (a) The red,
`transparent, mixed stack complex, a semiconductor; (b)
`the black, opaque, segregated slack complex. a conductor.
`{From Bernstein {1991b) with permission.)
`
`nearly spherical (i.e. octahedral or tetrahedral) or short
`linear anions that fill the voids between stacks of donors.
`
`c:I}~<rf9
`
`The 2:1 stoichiometry ensures the partial charge on
`the donor
`stack,
`another necessary condition for
`conductivity, and many of these salts are conductors or
`superconductors.
`Proof of the relative stability of the mixed and
`segregated stack packing motifs and a recipe for
`obtaining crystals of the latter came with the discovery
`of a pair of polymorphic 1:1 complexes of II with El
`(Bechgaard at al 1977. Kistenrnacher et al 1982). The
`red,
`transparent, mixed stack form of the complex is
`a semiconductor, while the black, opaque, segregated
`stack is a conductor
`(figure
`l(b)).
`This
`finding
`demonstrated conclusively that
`the segregated stacks
`are a necessary condition for electrical conductivity.
`Reflecting the relative stabilities for the two stacking
`modes noted above, crystals of the red semiconductor
`form are obtained by a ‘thermodynamic’ or ‘equilibrium’
`crystallization: equimolar solutions of the donor and
`acceptor
`in acetonitr-lie are mixed and allowed to
`evaporate slowly.
`Crystals of the black form are
`obtained by a ‘kinetic’ or nonequilibrium crystallization:
`hot equimolar solutions of the donor and acceptor
`in acetonitrile are mixed and cooled rapidly.
`Some
`microcrystals of the resulting black powder are then used
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`
`Figure 2. Network of ET (V) molecules in two phases of
`the salt (ET}§|5. The unit cell is included in each figure
`and thin lines indicate short intennolecular S-- -8 contacts.
`(a) 5 tom; (12) x lorm. (From Williams et all (1991) with
`pennission.)
`
`as seeds to obtain larger crystals of the mixed staclr
`black form. Non—equil.ibrium crystallization methods,
`in particular electrochemical techniques, have become
`standard procedure for obtaining crystals of organic
`conductors, in part because of the ability to control and
`reproduce the crystallization conditions. However, as
`we indicate below, control and reproducibility do not
`guarantee obtaining a single or unique crystal phase.
`The role of polymorphism in understanding the
`connection between structure and properties is most
`poignantly represented by the ET;X salts of IV. No
`fewer than 20 have been reported to be superconductors,
`having among them the highest known Tc values
`(Williams et at 1991). For X:-I3‘ alone,
`there are at
`least fourteen known phases, and learning to understand
`and control
`the crystal growth conditions in these
`polymorphic systems is one of the greatest challenges
`facing workers in this rapidly expanding field. As above,
`crystals are typically obtained by electrccrystallization
`methods, using Pt electrodes and an H tube, and a
`constant cun'ent of ~ 1 p.A cm‘3. Crystal growth
`experiments can extend up to periods of months. with
`a number of polymorphs simultaneously appearing on
`the same electrode, in many cases with indistinguishable
`colours or crystal habits. For instance, Kobayashi e: at’
`(1987) identified the presence of the ot,fl,y,6,9 and
`it polymorphs of (ET);"I;'
`in the same crystallization
`experiment.
`Intense activity in this field has led to the definition
`of some conditions for preferentially obtaining one, or
`a limited number, or phases (Williams er al 1991), but
`very often the isolation and identification of the various
`phases
`requires characterization of each individual
`crystal (Karo era! 1987).
`As an example of the type of variation observed, we
`can compare the 13 and x phases of (ET);I; (figure 2).
`The former, apparently favoured by thermodynamic
`crystallization conditions (eg. low current density) is a
`centrosymmetric triclinic structure with one formula unit
`of the salt in the unit cell. The symmetry arguments
`require that the anion lie on a crystallographic inversion
`centre, and that the donor molecules all be parallel, as
`shown in figure 2(a). The structure is thus characterized
`by stacks along the diagonal of the unit cell, with strong
`intermolecular S- - IS interactions between stacks. Tc for
`
`this phase is 1.4 K.
`together with the
`The rc phase may be obtained,
`or and 9 phases,
`in a THF solution under N; with
`
`Stnlcture-property relationships in organic crystals
`
`a mixed supporting electrolyte of (n-C41-l9)4Nl3 and
`(H.-C4J.'I9)4.N.AlJIz at 20 ‘C and constant current of 1.0 ,u.A
`(Kato et al 1987). It is characterized by the formation
`of dimers, but a number of different salts exhibit more
`variability in this type of structure than in the it phase
`(Williams at at 1991).
`ic-(E'l")§I;‘ is centrosymmetric,
`with one layer per unit cell in a P21/c structure (Kato
`et at 1937) (figure 2(b)) and has a. Tc of 3.6 K.
`Understanding the structure—propet‘ty relationship in
`these materials is crucial to the rational development of
`organic conductors and superconductors with increas-
`ingly high Tc values. The plethora of polymorphic
`structures can easily lead the unwary investigator astray,
`but it provides an opportunity not available in many
`other systems for isolating the structural characteristics
`required for a very specific physical property. Williams
`at al (1991) have also pointed out that the isostrucnrral
`series of salts are important for the information they
`can yield. In this case, the structural parameter is kept
`nearly fixed (or only slightly perturbed) and the effect
`of chemical perturbations can then be evaluated.
`
`The aggregation of
`4.1.2. Aggregation of dyes.
`organic dye molecules has held the attention of dye
`chemist; since its discovery over half a century ago
`(Smith 1974, Hem 1974). A lack of understanding of
`the phenomenon did not prevent extensive use being
`made of it,
`for instance,
`in the spectral
`‘tuning’ of
`the response of photographic silver halide emulsions
`(Nassau 1983).
`Jelley (1936) found that when the
`solution concentration of many dyes is increased,
`the
`intensity of the characteristic molecular absorption band
`decreases in favour of the growth of a new intense,
`narrow absorption band on the long-wavelength side of
`the original molecular absorption band (figure 3). The
`new absorption, called a 1 band after its discoverer,
`is commonly attributed to the formation of aggregates
`of dye molecules, and results from the coupling of
`transition dipoles within the aggregate structure.
`Since the aggregates are generally believed to contain
`only a few tens of molecules (Smith 1974) it has been
`difficult to study directly the relationship between their
`structure and spectral properties. While there is no
`certainty that a crystal structure represents the structure
`of the aggregate, the existence of polymorphic structure
`of a dye does allow one to probe directly the relationship
`between structure and spectral properties. For many
`years great difficulty was encountered in obtaining
`crystals of most dyes, to say nothing of polymorphic
`forms. However, as a result of the energy crises during
`the 19705, considerable research effort was expended on
`many dyes with potential applications as photovoltaic
`materials (Morel er al 1978, Morel 1979, Forster and
`Hester 1982). True to McCrone’s dictum some were
`found to be polymorphic. and one,
`the squarylium
`dye V was the subject of a combined crystallographic
`and spectroscopic study to investigate the relationship
`between the structure and spectral properties of such
`dyes.
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`
`J Bernstein
`
`lnluvenurnber I103 tm"l
`
`Figure 3. Solution spectra of a dye exhibiting J banding.
`Solutions numbered 1-9 range in concentration from
`8.8 x 10-7 M to 1.4 x 10 M. The molecular absorption band
`is on the left; the J band on the right (see text). (From
`Bernstein (1991b) with permission.) A. 8.31 x 10*‘ M‘.
`B, 1.76 x 10-‘ M: C, 2.20 x 10-6 M, D, 2.54 x 10-3 M;
`E, 3.08 x 10"‘ M; F. 3.53 x 10*“ M; G. 4.40 x 10*‘ M:
`H, 6.16 x 104 M; l. 1.44 x10‘3 M.
`0'!-l0
`
`El
`
`\
`
`at’
`
`oH o-
`V
`
`‘9 Q "
`
`E1
`I
`
`‘E:
`
`The material is dimorphic, forming well developed
`crystals of both a violet triclinic structure and a green
`triclinic structure. Representative views of the crystal
`structures are given in figure 4.
`Here again. "the
`crystal growth process is instructive in understanding
`the energetic relationships between the two observed
`phases. The two polyrnorphs appear simultaneously in
`the same beaker, and hence they grow under identical
`conditions,
`indicating that
`they are of very similar
`energies. The energetic similarity would appear to be
`coincidental since the difference in space groups and
`crystal structures indicated by figure 4(a) and (b) would
`suggest at least some difference in lattice energy and
`hence different crystallization conditions. The key to
`this conundrum lies,
`in part at least.
`in the way the
`crystal structures are viewed. When the reference plane
`is the molecular plane (figure 4(c) and (d)) it is clear
`that the plane-to-plane stacking in the two structures is
`essentially identical. This apparently is the dominant
`interaction, and the one that governs the crystallization
`process.
`The only difference between the trlclinic
`and monoclinic structures.
`then,
`is
`the relationship
`between the stacks, a translation in the tdclinic structure,
`and a screw axis in the monoclinic structure. These
`
`must be either subsidiary to the plane-to-piano stacking
`interaction or equal
`to each other for the crystals to
`appear simultaneously (Bernstein and Chosen 1988).
`What are the spectroscopic mariifcstations of these
`structural differences? The molecule is essentially flat
`in both structures, so differences in the spectroscopic
`
`B70
`
`tal stnrctura of the
`figure 4. Stereo views of the crys
`squaryliurn dye V: (a) triclinic structure, (100) face; (is)
`monoclinic structure, (100) face (from Tristani-Kendra
`et at (1983) with permission): (c) view of the molecular
`plane, triclinic structure; (d) view of the molecular plane.
`monoclinlc Blluclure. (From Bernstein and Chosen (1988)
`with pennisslon.)
`
`properties must be an expression of the differences of
`intermolecular relationships in the two structures. The
`polarized normal incidence reflcction spectra of the two
`crystals are given in figure 5, and it can be readily
`seen that the spectra are significantly different between
`the two forms for light polarized along the long axis
`of the molecules.
`This must be a consequence of
`the difference in the interaction of a single molecule
`with its sunnundings. The reflection spectrum of the
`band in the monoclinic form has been interpreted as
`being composed of two oscillators, while that of the
`triclinic form contains three, or possibly four, oscillators
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`
`Rafle:
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Energy llo’ :rn'1l
`
`iivityPI.)
`
`
`10
`
`‘I5
`
`20
`
`25
`
`30
`
`Energy I103 rm‘ '1
`Figure 5. Normal incidence reflection spectra at the two
`forms of V.
`In each case there are two spectra measured
`with the light polarized along each of the two directions
`(the so-called principal directions), as indicated in the
`upper right-hand corner. which also shows the projection of
`the rnoleoule(s) onto the crystal face studied. (a) Triclinic
`pclymorph, (100) face; (bl monoclinlc polyrnorph, (100)
`face. (From Tristani-Kendra er al (1983) with permission.)
`
`('I'ristan.i-Kendra a.nd Eclchar-dt I984, Tristani-Kendra et
`al 1935).
`
`4.2. Molecular properties
`
`At the other extreme in the range of interaction between
`molecules, organic crystals may be considered as simply
`a matrix for holding molecules in a specific juxtaposition
`with respect to each other. The interactions among
`molecules are ignored, at least to a first approximation.
`and the properties of the crystal reflect to a large extent
`the properties of the molecule, albeit with the three-
`dimensional ordering imposed by the very fact that it
`is a crystal.
`When the molecule in question is conforrnationally
`flexible with a number of energetically accessible
`conformations (differing by less than ~ 2 icon] moi")
`then different crystallization conditions may lead to
`conformational polymorphs. An almost classic example
`is the dichloro—benzylideoeani1ine VI (X=Y=Cl).
`
`Vi (X,'r' = Cl. Br. Cl-lg)
`
`The molecule has only two degrees of conformational
`freedom, designated as and ,6. The planar conformation
`
`StnJcture—property relationships in organic crystals
`
`of the molecule is known to be more energetic than
`the conformation in which at 2 50°, fi 2:. 0° (Buergi
`and Dunitz 1971, Bernstein at al 1981) by about
`1.5 kcal mol“. Two polyntorphs are known: a n-icllnic
`form in which the molecule adopts a planar conformation
`(ct = ,8 5: 0°) (Bernstein and Schmidt 1972), and
`an orthorhombic form in which the conformation is
`a: 9: 25°,
`:9 9: —25° (Bernstein and Izak l9‘i’6).
`Hence this system is an example of conformational
`polymorphism where the crystal environment of the
`triclinic form is sufficient to stabilize the higher-energy
`planar conformation of the molecule (Bernstein and
`Hagler 1973).
`The treatment of the energetics of this system
`have been described in detail elsewhere (Bernstein
`and Hagler
`I978, Bernstein 1987).
`However.
`in
`the present context
`it
`is of interest
`to review the
`crystallization behaviour.
`The triclinic form was
`discovered serendipitously in the course of a search
`for clichloro-substituted molecules which might have
`a 4 A translation axis (Loser er al 1969, Green and
`Schmidt 1971, Desiraju 1989). A single oscillation
`photo of one crystal unambiguously indicated the
`presence of a 4 A axis, but that crystal did not diffract on
`the second photo, and all subsequent attempts to obtain
`such crystals were unsuccessful.
`Recrystallizations
`carried out under equilibrium conditions yielded only
`the pale yellow orthorhombic form.
`The tziclinic
`form was finally obtained under kinetic conditions by
`rapidly cooling a boiling saturated ethanoiic solution in
`a desiccator freshly charged with CaCl2. The white
`(actually colourless when viewed individually under the
`microscope) needles, characteristic of :2 structure with
`a 4 A axis. proved to be metastable, and often upon
`standing for a few days would spontaneously revert to
`a pale yellow powder. The trarrsforrnation could also
`be initiated by cleaving the crystals perpendicular to the
`needle axis, and sometimes could be followed visually
`by a gradual clouding of the crystal accompanied by
`a failure to extinguish polarized light. All of these
`phenomena are consistent with a metastable crystal form.
`and it is clear why somewhat unconventional methods
`were required to grow crystals of that form.
`The trimorphic dimethyl derivative VI (X=Y=CI-I3)
`represents an example of the ‘disappearing’ crystal form.
`Apparently unaware of the existence of polymorphism,
`Buergi e! at
`(1968)
`reported cell constants for the
`compound (fortn I). We had no trouble preparing the
`compound and repeating their determination (lzait 1973).
`After an interim of about eight months these crystals did
`not diffract well. Over a three-year period, subsequent
`recrystallization experiments, often preceded by a fresh
`synthesis of the material, resulted in the discovery of two
`previously unknown polymorphs (forms 11 and ill) (Bar
`and Bernstein 1977, 1982, Bemstein et all 1976), but
`failed to yield form I. suspecting that our laboratory had
`been ‘poisoned’ by forms 11 and III we tools: advantage
`of the opening of a new laboratory about a kilometre
`away to try again from scratch, using new reagents.
`new glassware, and a ‘new’ student-—this time with
`
`B71
`
`Janssen Ex. 2022
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
`
`(Page 6 of 11)
`
`

`
`
`
`J Bemstein
`
`
`
`Figure 6. Solution absorption spectra of benzylideneaniline
`(Vi, X=Y=H) (-—). azobenzene VII (— — —-) and stilbene
`VIII (— - —) in ethanolic solutions. (From Bernstein er al
`(1979) with pennissiorr.)
`
`success. While the ‘entire universe‘ was not poisoned
`by forms II and III,
`there clearly is some basis to
`the claims of McCrone and Woodard regarding the
`difficulties in crystallizing metastable polymorphic forms
`in an environment in which a more stable form has been
`obtained.
`
`The slight, but certainly visually distinguishable,
`difference in the colour of the two polymorphs of the
`dichloro-derivative suggested using the two forms to
`make a direct examination of a problem which had
`occupied spectroscopists for nearly three decades (H_asel-
`bnch and Heilbronner 1968, and references therein).
`Benzylideneaniline VI (X=Y=H) is isoelectronic with
`azobenzene VII and stilbene VIII
`
`V1!
`
`V1“
`
`but its solution absorption spectr11m differs significantly
`from them (figure 6). The difference in the absorption
`spectra between stilbene and azobenzene on the one
`hand. and benzylideneaniline on the other, has been
`attributed to a difference in molecular conformation in
`
`the former were believed to be essentially
`solution:
`planar on the average, while the latter is not (I-Iasselbach
`and I-leilbronner 1968). The non-planarity of VI is due to
`a repulsion between the hydrogen on the bridge and one
`of the ortha-hydrogens on the aniline ring. The bridge
`hydrogen is absent from VII and the increased length of
`the C=C bond in VIII alleviates that steric effect. For
`
`the tendency towards nonplanarity
`benzylideneanilinc,
`due to the hydrogen repulsion is balanced in part by the
`n:—electron conjugation, leading to the minimum energy
`conformation of or L’ 50”.
`
`The existence of the two polymorphic structures
`of VI (X=Y=Cl), and the corresponding planar and
`nonplanar conformations
`found therein, provides a
`unique opportunity to examine directly the relationship
`
`B72
`
`between molecular conformation and the electronic
`structure, as manifested in the absorption spectrum.
`Assuming that the two crystal structures merely serve
`to hold the molecule in the two different conformations.
`the absorption spectra should reflect the difference in
`conformation:
`that measured on the triclinic structure,
`with a planar molecular conformation, should closely
`resemble that of VII and VIII, while that for the
`orthorhombic stnrcture, with the nonplanar molecular
`conformation, should retain the characteristics of VI in
`solution.
`
`The measurement of the crystal absorption spectra
`of highly absorbing materials
`(in this case E 2
`20000) would normally require the preparation of very
`thin samples. However.
`the use of polarized nearly
`normal
`incidence reflection spectroscopy on single
`crystals not only overcomes this problem but provides
`some additional advantages (Anex 1966. Pennelly and
`Eckhardt 1976).
`The use of polarized light allows
`one to gain information on the directional properties
`of the electronic transitions as well as information on
`the energies and intensities.
`Second,
`the fact
`that
`measuremen