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`194 Acc. Chem. Res., Vol. 28, No. 4, 1995
`
`crystals of one handedness, sometimes right, some-
`times left, but not depending on the direction of
`stirring. In checking this result, McBride and Carter“
`showed by video recording that a single nucleation
`event can produce almost all of the crystals formed:
`“...Crystals begin nucleating at random, but the first
`crystal to be struck by the stirrer clones hundreds or
`thousands of new nuclei. Growth of so many nuclei
`soon lowers the concentration of the solute below the
`threshold for spontaneous formation of primary nuclei,
`so that there is no way to begin crystallization of the
`enantiomer.”
`
`Seeding
`
`One way of influencing the crystallization process
`is by seeding, and here we need to differentiate
`between what we may term intentional and uninten-
`tional seeding.
`Intentional seeding is a common
`practice among chemists who wish to coax crystalliza-
`tion of a compound from solution or from the melt;
`small crystals or crystallites of the desired material
`(seeds) are added to the system. In this way, the rate-
`limiting nucleation step, which may be extremely slow,
`is circumvented. For this method to be applied, it is
`of course necessary that a sample of the crystalline
`material is available; that is, the compound must have
`been already crystallized in a previous experiment.
`When polymorphic forms of a substance are known
`to occur, intentional seeding with one of the poly-
`morphs is a useful and often the most successful way
`of preferentially producing it rather than the other.
`Seeding may also occur if small amounts of the
`crystalline material are present as contaminants:
`unintentional seeding.5 Unintentional seeding is often
`invoked as an explanation of phenomena which oth-
`erwise are difficult to interpret. We shall argue in
`favor of this explanation, although there is no con-
`sensus about the size and range of activity of such
`seeds, which have never actually been directly ob-
`served.7 Estimates of the size of a critical nucleus
`range from a few tens of molecules to a few million
`molecules? With a size of about a million molecules,
`even a speck (10‘5 g) of a compound of molecular
`weight 100 contains approximately 1015 molecules,
`sufficient to make 101° such nuclei. One can think of
`local seeding, where the contamination may apply to
`the experimentalist’s clothing, a portion of a room, an
`entire room, a building, or even, with increasing
`degrees of implausibility,
`to a district, a town, a
`country, a continent, and so on. In the limit we have
`what has been proposed as universal seeding (plan-
`etary seeding would be a more accurate expression),
`where the whole planet is assumed to be contami-
`nated.9 A seed that promotes formation of a crystal-
`lization nucleus need not necessarily be composed of
`the same molecules as the compound that is to be
`crystallized. Specks of dust, smoke particles, and
`other small foreign bodies can act as seeds in promot-
`(6) It is well-known that it is often difficult to crystallize a newly
`synthesized compound. Subsequent crystallizations may be easier,
`because of the presence of suitable seeds.
`(7) Chemists and physicists have long become accustomed to postulat-
`ing models as explanations for phenomena that cannot be directly
`observed. The existence of atoms is perhaps the classic example.
`(8) Mullin, J. W. Crystallization, 3rd ed.; Butterworth-Heineman
`Ltd.: Oxford,1993; pp 182-185.
`(9) The claim for “universal seeding”, taken literally, is obviously
`absurd. After all, the universe is estimated to contain about a millimole
`of stars, so one seed per star (per solar system)-not much-would need
`about 100 kg of the compound in question (MW e. 100).
`
`Dunitz and Bernstein
`
`ing crystallization, which is the reason laboratory
`chemists often scratch the walls of a glass vessel with
`a glass rod to encourage a solute to crystallize.”
`
`Polymorphism
`
`We have mentioned the phenomenon of polymor-
`phism, which is commonly understood as connoting
`the ability of a compound (or of an element) to
`crystallize in more than one distinct crystal structure.
`According to McCrone,“ “A polymorph is a solid
`crystalline phase of a given compound resulting from
`the possibility of at least two different arrangements
`of the molecules of that compound in the solid state.”
`Because polymorphs have different structures, they
`may differ greatly in density, hardness, solubility, and
`optical and electrical properties; e.g., diamond and
`graphite are two polymorphic forms (allotropes) of
`carbon. Many compounds are known to crystallize in
`polymorphic forms. In the inorganic and mineralogi-
`cal fields, these sometimes have different names, e.g.,
`ZnS, wurtzite and sphalerite; CaCO3, calcite, arago-
`nite, and vaterite; TiO2, rutile, brookite, and anatase;
`but, more generally, different polymorphic forms are
`denoted by letters, A, B, C or 0., ,6, y, etc., or by Roman
`numerals, I, II, III, etc., depending on the preference
`of the discoverer. McCrone“ has provocatively sug-
`gested that “every compound has different polymor-
`phic forms, and that, in general, the number of forms
`known for a given compound is proportional to the
`time and money spent in research on that compound.”
`In support of this, McCrone observes that many
`compounds of industrial importance (i.e., those on
`which a great deal of time and money are spent) are
`known to exhibit polymorphism: silica, iron, calcium
`silicate, sulfur, soap, pharmaceutical products, dyes,
`and explosives. Such compounds, unlike the vast
`majority of compounds that are isolated, are prepared
`and crystallized not just once but repeatedly, under
`conditions that may vary slightly from time to time.
`Similarly, in the biomolecular area, where much time
`and effort is invested in attempts to crystallize pro-
`teins under many slightly different conditions, poly-
`morphism is frequently observed.” The universality
`suggested by McCrone’s statement may, however, be
`considerably tempered by the fact that fewer than 5%
`of the compounds in the Cambridge Structural Data-
`base (CSD) are known to be polymorphic (although it
`must be admitted that crystallographers typically
`choose one crystal specimen from their sample and
`leave it at that). Moreover, some very widely studied
`compounds have shown no evidence of polymorphic
`behavior, even though they have been crystallized and
`handled for many years under a far-ranging variety
`of conditions; naphthalene is an example that im-
`mediately comes to mind.
`Here we shall be concerned exclusively with molec-
`ular crystals, where the molecule may have the same
`shape in the two polymorphs or it may have a different
`shape, resulting in what has been termed “conforma-
`(10) “Auch das Reiben mit einem Glasstab an der Wandung des
`Gefasses schaffi Keime, an deren Vorhandensein die Kristallisation
`gebunden ist.” Organikum; VEB Deutscher Verlag der Wissenschaften:
`Berlin, 1977; p 46.
`(11) McCrone,W. C. Polymorphism In Physics and Chemistry of the
`Organic Solid State; Fox, D., Labes, M. M., Weissberger, A., Eds;
`Interscience: New York, 1965; Vol, II, pp 726—767.
`(12) For example, according to the Protein Data Bank (distributed
`by Brookhaven National Laboratory, Upton, NY), the extensively studied
`human hemoglobin is known in monoclinic, orthorhombic, and tetragonal
`modifications; lysozyme in triclinic, monoclinic, orthorhombic, trigonal,
`tetragonal, and hexagonal ones.
`
`Page 2 of 8
`
`
`
`Disappearing Polymorphs
`
`Acc. Chem. Res., Vol. 28, No. 4, 1995
`
`195
`
`
`
`FreeEnergy
`
`
`
`FreeEnergy
`
`Te mperot ure
`Figure 1. Free energy vs temperature diagrams for two polymorphs, with crossing points where their free energies cross:
`enantiotropic system; right, monotropic system.
`
`Temperature
`
`left,
`
`tional polymorphism”.13 McCrone’s criterion“ is that
`polymorphs are different in crystal structure but
`identical in the liqu.id or vapor states. This implies
`that crystals containing molecules with different
`atomic arrangements are to be classed as polymorphs
`if the molecules concerned interconvert rapidly in the
`melt or in solution to give the same equilibrium
`mixture. Thus, this definition would encompass not
`only conformational isomers but all kinds of isomers
`in dynamic equilibrium. In phase-rule terminology,“
`the various polymorphs and the liquid obtained by
`melting them constitute a one-component system (or
`a two-component system if we consider solution of the
`polymorphs in a given solvent).
`Clearly, this definition is not completely satisfactory
`and leaves several kinds of borderline cases open: are
`syn- and anti-oximes in the solid state to be classed
`as polymorphs or as separate compounds? What
`about the various molecular species involved in the
`complex equilibria among open-chain and cyclic forms
`of saccharides (constitutional and configurational poly-
`morphs)? How long are we supposed to wait for
`equilibrium to be established? Should different hy-
`drates or solvates of a given compound be classified
`as polymorphs? (The term pseudopolymorphism has
`been proposed to cover such cases.) Definitive answers
`to these and similar questions cannot be given; they
`depend on one’s point of view. In the same way, there
`seems to be no unequivocal way of distinguishing
`between polymorphic transformations and solid-state
`chemical reactions. There are borderline cases that
`show characteristic features of both.
`In molecular crystals, free energy differences be-
`tween polymorphs are usually quite small, a matter
`of a few kilocalories/mole at most,‘5 and depend on
`temperature, mainly because of the entropic contribu-
`tion to the free energy. Because of the thermodynamic
`relation G = H - TS, the form with the higher entropy
`will
`tend to become the thermodynamically more
`stable form as the temperature is raised (Figure 1).
`Thus, over a small temperature range, and particu-
`larly between room temperature and the melting
`point, one polymorph or another can change from
`being the stable form to being metastable.
`If the
`
`(13) Bernstein, J.; Hagler, A. T. J. Am. Chem. Soc. 1978, 100, 673.
`Bernstein, J. Conformational Polymorphism In Organic Solid State
`Chemistry; Desiraju, G., Ed.; Studies in Organic Chemistry, Vol. 32;
`Elsevier: Amsterdam, 1987; pp 471-518.
`(14) See, for example: Findlay, A.j. Campbell, A. N.; Smith, N. The
`Phase Rule and its Applications, 9th ed.; Dover: New York, 1951.
`(15) Kitaigorodskii, A. I. Adv. Struct. Res. Diffr. Methods 1970, 3, 173.
`
`- thermodynamic transition temperature is below the
`melting point, the polymorphic system is known as
`enantiotropic (not to be confused with enantiotopic, a
`term applied to atoms or groups in a molecule that
`are related by an improper symmetry operation but
`not by a proper one, e.g., the two methylene H atoms
`in ethanol) and the transition is in principle reversible;
`if the transition temperature is above the melting
`point, then the system is monotropic and the transi-
`tion can take place only in one direction. A metastable
`form can persist for years, or it can undergo spontane-
`ous transformation to the stable form.
`
`Mechanisms of Polymorphic Transformations
`
`The title of this section promises more than it can
`deliver, because the mechanisms of polymorphic trans-
`formations in molecular crystals are largely unknown.
`The one type of transformation for which some level
`of understanding can be claimed is order—disorder
`transformations, where the high- temperature phase
`has essentially the same molecular arrangement as
`the low-temperature one and differs from it only by
`an increase in the crystallographic site symmetry of
`the structural units. This increase in apparent mo-
`lecular symmetry is due to an increase in crystal
`disorder such that the space-averaged, time-averaged
`distribution of matter has a higher symmetry than the
`instantaneous distribution in an individual unit cell.
`The reverse transformation corresponds to the onset
`of an ordering process. Such transitions are usually
`classified as “second-order” from the thermodynamic
`point of view, and, since they are virtually the only
`ones that can be handled on a theoretical basis, they
`receive the most attention in textbooks. From reading,
`one might even get the impression that order-—disorder
`transformations are the prototype of phase transitions
`in general, but this is not the case.
`Presumably, as in the primary crystallization proc-
`ess, the mechanisms of most so1id—solid transforma-
`tions involve the formation of critical nuclei of the new
`phase, followed by their growth. According to My-
`nukh,” the nucleation step is critically dependent on
`the presence of “suitable” defects. Depending on the
`nature of these defects, nuclei of the new phase may
`be formed at different temperatures and grow at
`different rates. Thus, defects in the initial crystal
`structure may be necessary for initiating (or cata-
`(16) Mynukh, Yu. V. J. Cryst. Growth 1974, 38, 284; Mol. Cryst. Liq.
`Cryst. 1979, 52, 467, 505.
`
`Page 3 of 8
`
`
`
`196 Acc. Chem. Res., Vol. 28, No. 4, 1.995
`
`lyzing) nucleation of the new phase. Indeed, in some
`cases, the transformation can be induced by mechani-
`cally introducing defects, for example, by scratching
`the surface of the crystal with a pinpoint. On the
`other hand, there are also examples where the trans-
`formation is virtually instantaneous (and in one case
`even reversible), causing the crystals to “jump”.17
`Solid-state transformations in molecular crystals
`often show a high degree of hysteresis.
`It may be
`necessary to heat the low-temperature form to a
`temperature well above the thermodynamic transition
`temperature before signs of phase transformation can
`be detected. Even when no solid-solid transformation
`of the low-temperature form occurs below the melting
`point, this is not sufficient proof that the system is
`monotropic; the transformation may simply be too
`sluggish to be observed. Similarly, transformations
`in the reverse direction, produced by cooling the high-
`temperature form, are also invariably accompanied by
`hysteresis. This can be so severe that a high-temper
`ature form can sometimes be kept indefinitely at
`temperatures well below the transition point. Thus,
`X-ray structure analyses at 100 K have been made of
`crystal phases more than 200 K below their thermo-
`dynamic range of stability.”
`
`Vanishing Polymorphs
`
`Woodard and McCrone19 described several cases
`where, after nucleation of a more stable crystal form,
`a previously prepared crystal form could no longer be
`obtained. Other examples were described by Webb
`and Anderson,” who wrote, “Within the fraternity of
`crystallographers anecdotes abound about crystalline
`compounds which, like legendary beasts, are observed
`once and then never seen again.” In a sober comment
`on these views, Jacewicz and Nayler” criticized some
`of the more exaggerated claims. While admitting the
`role of seeding in promoting nucleation, they argue
`that the disappearance of the metastable form is a
`local and temporary phenomenon and conclude that
`“any authentic crystal form should be capable of being
`re-prepared, although selection of the right conditions
`may require some time and trouble.”
`In most of the examples cited by these authors,
`relevant questions are left unanswered. Many chem-
`ists remain skeptical about a subject that calls into
`question the criterion of reproducibility as a condition
`for acceptance of a phenomenon as being worthy of
`scientific inquiry. Nevertheless,
`there are well-
`documented cases of crystal forms that were observed
`over a period of time but not thereafter, having been
`apparently displaced by a more stable polymorph. The
`relevant literature is scattered and almost impossible
`to find by subject searches.
`In the remaining space
`
`(17) Gigg, J.; Gigg, R.; Payne, S.; Conant, R. J. Chem. Soc., Perkin
`Trans. 1, 1987, 2411. Ding, J.; Herbst, R.; Praefke, K.; Kohne, B.;
`Saenger, W. Acta Crystallogn, Sect. B 1991, 47, 739. Steiner, T.; Hinrichs,
`W.; Saenger, W.; Gigg, R. Ibid., in press. Zamir, S.; Bernstein, J.;
`Greenwood, D. J. Mol. Cryst. Liq. Cryst. 1994, 242, 193. Etter, M. C.;
`Seidel, A. R. J. Am. Chem. Soc. 1983, 105, 641. Kohne, B.; Praefke, K.;
`Mann, G. Chimia 1988, 42, 139.
`(18) For example, the white high-temperature modification of dimethyl
`3,6—dichloro-2,5-dihydroxyterephthalate, unstable below about 340 K,
`crystal structure analysis at 98 K. Yang, Q.-C.; Richardson, M. F.; Dunitz,
`J. D. Acta Crystallogr., Sect. B 1989, 45, 312. Richardson, M. F.; Yang,
`Q.-C.; Novotny-Bregger, E.; Dunitz, J. D. Ibid. 1990, 46', 653.
`(19) Woodard, G. D.; McCrone, W. C. J. Appl. Crystallogr. 1975, 8,
`342.
`(20) Webb, J.; Anderson, B. J. Chem. Educ. 1978, 55, 64-4.
`(21) Jacewicz, V, W.; Nayler, J. H. C. J. Appl. Crystallogr. 1979, 12,
`396.
`
`Dunitz and Bernstein
`
`we review published examples, present some new
`results, and try to put the subject into perspective. We
`begin with one of the best-studied examples.
`1,2,3,5-Tetra-O-acetyl-/3-I)-ribofuranose (I). The
`early history of this compound reads like a mystery
`story. As first prepared in 1946 in Cambridge, Eng-
`land, by Howard, Lythgoe, and Todd,” the compound
`had melting point 58 °C.
`
`AcO
`
`OAC
`
`O
`
`I
`
`Virtually the same melting point was measured for
`material prepared by a different method in Jena by
`Bredereck and Hoepfner.“ When several batches of
`the same material were prepared soon afterward
`(1949) in a different laboratory on the other side of
`the Atlantic, in New York, by Davoll, Brown, and
`Visser,“ the first three preparations had melting point
`56-58 ‘’C, but the fourth run yielded material with a
`distinctly higher melting point, 85 °C. Around the
`same time, in Jena, by direct acetylation of ribose,
`Zinner25 obtained a mixture of two tetraacetyl deriva-
`tives, one the ribopyranose and the other the ribo-
`furanose, with a melting point of 82 °C for the latter.
`The two high-melting compounds appeared to be
`identical, although the nature of the structural dif-
`ference between them and the low-melting form was
`unknown. So far, so good; innumerable examples of
`polymorphism are known. The low-melting form can
`be called A, the high-melting one B.
`After some time, however, the melting points of the
`early New York preparations had risen to 85 °C, and
`it was no longer possible to prepare the A form.“ A
`sample of A was sent from Cambridge, but when it
`was exposed to the air in New York, in a laboratory
`that contained samples of B, the crystals of A rapidly
`became opaque and transformed to B.
`In the mean-
`time, transformation of A to B was also found to have
`taken place in Cambridge. Since the A form could no
`longer be obtained in the New York laboratory, further
`experiments involving this form were moved to distant
`Los Angeles, where it was shown that when 1 g of A
`(melting point 57 °C) was inoculated with 1 mg of B
`(melting point 85 °C), the melting point of the sample
`was raised to 75-77 °C within 2 h and to 77-79 °C
`overnight.“ Similar phenomena were observed in
`Manchester.“ Low-melting A was first obtained, but
`when B was introduced into the laboratory, the whole
`of the material had the higher melting point and the
`low-melting form could no longer be prepared.”
`The scene now changes to Philadelphia, where
`Patterson and Groshenszs (the same Patterson as in
`the Patterson function used in crystallography) took
`on the task of measuring X-ray diffraction data for the
`two crystalline forms. Low-melting A was found to
`be monoclinic, space group P21, and the crystal was
`(22) Howard, G. A.; Lythgoe, B.; Todd, A. R. J. Chem. Soc. 1947, 1052.
`(23) Bredereck, H.; Hoepfner, E. Chem. Ber. 1948, 81, 51.
`(24) Davoll, J.; Brown, B. B.; Visser, D. W. Nature (London) 1952,
`170, 54.
`(25) Zinner, H. Chem. Ber. 1950, 83, 153.
`(26) Farrar, K. R. Nature (London) 1952, 170, 896.
`
`Page 4 of 8
`
`
`
`Disappearing Polymorphs
`
`Acc. Chem. Res., Vol. 28, No. 4, 1995
`
`197
`
`Figure 2. Stereoviews of the two forms of I. In both cases the View is on the plane of C1-O—C4 of the furanose ring: upper,
`monoclinic A form; lower, orthorhombic B form. For clarity, only carbon atoms are labeled.
`
`sufficiently stable to last for 7 weeks. At the end of
`this time, crystals of B were introduced into the room.
`After three days, the A crystal was unchanged, but
`when powdered B was sprinkled over the A crystal,
`the latter transformed completely to B in a few
`minutes. The transformed material still had the
`external shape of the original A crystal, but it was
`opaque and polycrystalline with no preferred orienta-
`tion of the crystallites. Crystals of B were found to
`be orthorhombic, space group P212121, with quite
`different cell dimensions from A. Patterson and
`Groshens noted that the molecular volume increased
`
`by about 2% during the A to B transformation (A,
`383.9 A3; B, 392.5 A3).
`In the early 1950s it would have been a major
`undertaking to determine the atomic arrangement in
`these noncentrosymmmetric crystals by X-ray analy-
`sis, and it was only some 20 years later that the crystal
`structure of form B was determined.” The authors
`made no mention of the other polymorph. Essentially
`the same structure was found by Poppleton,3° who
`commented that an attempt to prepare the “rare” A
`form by application of high pressure was unsuccessful.
`Comparison of the structures of the two forms only
`became possible when the elusive A form was obtained
`
`(27) The state of affairs was summarized by Brown et al. (Brown, G.
`B.; Davoll, J.; Lowy, B. A. Biochem. Prep. 1955, 4, 70) as follows: “The
`form first reported melted at 58° or 56“ and the form melting at 84“ was
`initially termed the B form. A number of laboratories have observed the
`transformation of the low melting into the high melting form and once
`the latter is obtained the former is not encountered.” For another
`contemporary account of the confusion, see: Overend, W. G.; Stacey, M.
`In The Nucleic Acids; Chargaff, E., Davidson, J. N., Eds.; Academic
`Press: New York, 1955; Vol. 1, p 44.
`(28) Patterson, A. L.; Groshens, B. P. Nature (London) 1954, 173, 398.
`(29) James, V. J.; Stevens, J. D. Cryst. Struct. Commun. 1973, 2, 609.
`(-30) Poppleton, B. J. Acta Crystallogn, Sect. B 1976, 32, 2702.
`
`in Budapest and its crystal structure determined.“
`There is no simple structural relationship between the
`two polymorphs; the crystal packing is quite different,
`and although the ribose ring and its directly attached
`atoms are nearly superimposable, the molecules adopt
`different conformations with respect to the orienta-
`tions of the acetyl groups about the bonds C2—O2,
`C3—O3, and C5—O5 (Figure 2).
`According to force-field calculations?“ the intra-
`molecular nonbonded potential energy of the form A
`conformation is lower than that of the B conformation
`by 15.7 kJ mol"1; that is, the more stable molecular
`structure is found in the low-melting polymorph. This
`is reasonable, because, as mentioned earlier,
`the
`thermodynamic stability of a high-temperature form
`must be due to its higher entropy rather than to its
`lower potential energy (see Figure 1). The increase
`in molecular volume on going from the A to the B form
`is consistent with this.
`In spite of all the work done on this system, we still
`do not know the thermodynamic transition point,
`where the two free energy curves cross. From the
`many instances where A has been reported to trans-
`form spontaneously to B, we can infer that the
`transition point lies somewhat below normal labora-
`tory temperature. Thus, form A is likely to have been
`present as a metastable species during most of its
`existence.
`In spite of its thermodynamic instability
`with respect to form B, it may have tended to crystal-
`lize first from solution because of a more rapid rate
`of nucleation, a kinetic factor. Once formed,
`the
`crystals of A may endure for a longer or shorter period,
`depending on the local temperature and other factors.
`(31) Czugler, M.; Kzilrnén, A.; Kovacs, J.; Pinter, l. Acta Crystallngn,
`Sect. B 1981, 37, 172.
`
`Page 5 of 8
`
`
`
`198 Acc. Chem. Res., Vol. 28, No. 4, 1995
`
`The solid-state transformation to B may take place
`spontaneously, or it may be catalyzed by the presence
`of seeds of B.
`In subsequent crystallization experi-
`ments in the same laboratory the presence of B seeds
`will circumvent the kinetic advantage of form A; once
`such seeds are present in the laboratory atmosphere,
`the lower solubility of thermodynamically stable B
`must tip the balance in its favor, resulting in the
`virtual “disappearance” of metastable A from labora-
`tories “contaminated” by B.
`It is also possible that, when first prepared, the A
`form was preferred thermodynamically as well as
`kinetically. Although normal laboratory temperature
`is nowadays taken as around 25 °C, this can by no
`means be taken as typical of former times.” Besides,
`the immediate postwar period was marked by severe
`fuel shortages in Europe. British and German labo-
`ratories at that time must often have been consider-
`ably colder than 25 °C, except
`in warm summer
`weather. Was form A obtained in Cambridge and
`Jena during cold weather conditions, when the ambi-
`ent temperature fell below the thermodynamic transi-
`tion point? After so many years it is difficult to find
`out.
`
`There are clearly many questions left unanswered,
`and this is typical of the information that can be
`gathered today from the literature about these phe-
`nomena. The accounts of the optical rotation meas-
`urements are particularly confusing. For example,
`Davoll, Brown, and Visser34 reported that when a
`methanolic solution of A was inoculated with a minute
`amount of B, the specific rotation [o.]D changed from
`about —3.5° (the normal value for solutions of A) to
`about -13.5“ (the normal value for solutions of B). The
`authors were somewhat at a loss to explain this, since
`they considered on, ,6 isomerism at the anomeric carbon
`atom to be unlikely (although we shall encounter
`examples later).
`In contrast, Farrarzs found that
`solutions of the two forms in chloroform had nearly
`the same specific rotation [otlp of about -12°, the value
`expected for B. From this result, correctly as we now
`know, Farrar considered the difference between the
`two forms to be merely one of dimorphism in the solid
`state; equilibrium among the various conformational
`states is attained rapidly in chloroform solution,
`regardless of whether the solution is prepared from
`the A or the B form. What about the different results
`in methanolic solutions of A and B? It seems most
`unlikely that interconversion would be slow enough
`to be observable from optical rotation measurements.
`Our tentative conclusion is that these measurements
`are unreliable.
`Benzylidene-dl-piperitone (II). The compound
`was first prepared in Sydney, Australia, in 1921 as
`large pale yellow prisms (mp 59-60 °C, 0. form). After
`a second form appeared (mp 63-64 °C, yellow rhombic
`prisms,
`/3 form),
`it was difficult to reproduce the
`
`O
`
`11
`
`original 0. form, and the conditions leading to each
`
`Dunitz and Bernstein
`
`form were carefully determined.” Several years later,
`in St. Andrews, Scotland, only a third polymorph (mp
`69-70 °C, faintly yellow small needles, )2 form) could
`be obtained,“ and it was found that 0. and fl transform
`readily into )2 “by inoculation” (seeding). Once seeds
`of )2 were present, even intentional seeding of solutions
`or melts with 0L or [3 seeds yielded only the y form.
`The authors Wrote, “It seems clear, however, that the
`fortuitous presence of a nucleus of the y form is
`sufficient to suppress the production of the 0L and fl
`forms: such nuclei may have been carried from one
`building to another in the two sets of St. Andrews
`experiments-for example, on the clothes of the
`operators—in spite of precautions.”
`In 1987,
`the same compound was prepared in
`Bangalore, India,35 by the same method as used in
`Sydney.33 Only the (1 form was obtained and used in
`solid-state photochemical reactions. The authors wrote,
`“lnnumerable attempts to obtain the fl form were
`met with failure”, and they did not even mention the
`)2 form.
`Benzocaine Picrate (III). A low-melting (132 °C)
`form has been used as a pharmacopeial standard.“ A
`higher-melting ( 162-163 °C) form is obtained by
`drying this material at 105 “C for at least 1 h or by
`vacuum drying/sublimation (100 °C/ 0.1 mmHg).37
`Experiments in two laboratories showed that, once the
`
`cooc2H,
`
`N02
`
`NH2
`
`[1]
`
`latter form had been obtained, the lower-melting form
`could no longer be prepared.
`It was realized that
`drastic measures were called for. All samples were
`discarded, equipment and laboratory benches were
`washed, and, following a waiting period of 8-12 days,
`the low-melting form could again be obtained. This
`“purging” procedure was followed several times with
`reproducible results.
`Melibiose (IV) and Mannose (V). The Pfanstiehl
`Chemical Company, in Waukegan, IL, specialized in
`isolating and purifying natural products. One of these
`was the disaccharide /3-melibiose IV, with crystalliza-
`tion as the final purification step. The production ran
`into a problem?“ “Then one day, for no apparent
`reason, the melibiose turned out to be of the 0. Variety.
`Try as they might, the Pfanstiehl chemists could not
`get a batch of melibiose to crystallize in the [3 form.
`They finally concluded that mere traces of the or form
`in the air or on the equipment were enough to seed
`the solutions, but where it came from was never
`
`(32) As an indication of earlier typical laboratory temperatures, it may
`be recalled that the calorie was defined as the amount of heat necessary
`to raise 1 g of water by 1 °C at 15 °C.
`(33) Read, J.; Smith, G. S. J. Chem. Soc. 1921, I19, 779.
`(34) Dewar, J.; Morrison, D. R.; Read, J. J. Chem. Soc. 1936, 1598.
`(35) Kamagapushna, D.; Ramamurthy, V.; Venkatesan, K. Acta
`Crystallogr., Sect. C 1987, 43, 1128.
`(36) Pharmcopoea Nardica. See also The Merck Index, 8th ed., mp 134
`°C.
`(37) Nielsen, T. K.; Borka, L. Acta Pharm. Sues. 1979, 9, 503.
`(38)Ina'. Eng Chem. December 1953, p lla.
`
`Page 6 of 8
`
`
`
`Disappearing Polymorphs
`
`H0 H2
`
`determined. They gave up the manufacture of that
`particular item, but are convinced that in some other
`locality in which there is not a trace of or-melibiose, it
`could be possible to crystallize the £3 sugar.” 39
`Similar problems arise with mannose V. Once the
`or anomer was obtained, recrystallization from alcohol
`was no longer a suitable method for purifying the ff
`anomer,4° which could still be obtained from the
`mixture by extraction at 0 °C with 80% alcohol.“
`We include these two cases involving epimerization
`at the anomeric carbon atom as examples of polymor-
`phism because they fit McCrone’s criterion; once
`dissolved, 0.- and ,6-melibiose equilibrate rapidly, and
`so do (1- and fl-mannose. Of course, each pair is
`usually regarded as two separate,
`isomeric com-
`pounds. We are here in one of those borderline areas
`where insistence on precise definitions may not be
`productive.
`N-(4’-Methylbenzylidene)-4-methylaniline (VI).
`Over the years, we have been interested in benzyl-
`ideneanilines.
`In 1968 J.D.D. reported the cell con-
`stants of several derivatives, among them the subtitle
`compound.“ This work was repeated in J.B.’s labora-
`
`VI
`
`tory in 1973.43 After a break of about 8 months the
`original crystals did not diffract Well, and recrystal-
`lization experiments were undertaken to prepare
`crystals suitable for structure determination. For
`(39) The problem may still exist. From a survey of chemical catalogs,
`including those of Merck, Fluka, BDH, Aldrich, and Sigma, only the (1
`form seems to be available.
`(40) Levene, P. A. J. Biol. Chem. 1935, 108, 419.
`(41) Powers, H. E. C. Z. Zuckerind. 1971, 21, 272.
`(42) Biirgi, H.-B.; Dunitz. J. D.; Zust, C. Acta Crystallogr, Sect. B
`1968, 21. 463.
`(43) Izak, I. Senior Thesis, Ben-Gurion University of the Negev, Beer
`Sheva, 1973.
`
`Acc. Chem. Res., Vol. 28, No. 4, 1995
`
`199
`
`nearly three years, many recrystallization experi-
`ments, often preceded by the synthesis of fresh batches
`of the compound, were undertaken, resulting in the
`discovery of two new polymorphic forms, but the
`original one could not be obtained.“ Suspecting that
`our laboratory had been “infected” by seeds of the two
`newer polymorphs, we took advantage of the opening
`of a new laboratory about a kilometer away, to try
`again from scratch, using new reagents, virgin glass-
`ware, and a “new” student, whose contact with the old
`laboratory and its inhabitants was forbidden. The
`first attempt to prepare the original form under these
`conditions was successful.
`3-Phenyl-1-p-tolylprop-2-enone (p’-Methy1chal-
`cone) (VII). Experiments made in 1988-89 at the
`ETH provide another example. Following earlier
`reports that p’-methylchalcone was polymorphic,“ the
`compound was obtained