Форум хімфаку КНУ

IB

Користувач

Реєстрація: 08.02.2006

К-ть повідомлень: 217

Детективные истории - исчезающие полиморфы (для студентов)

Извечно актуальная проблема для наших органиков (особенно пасочников), как закристаллизовать соединение, полученное на скорую руку в полумикро- и микроколичествах. Над этой проблемой потеют затирщики, не давая проходу ультразвуковым баням . Предлагаю внеклассное чтиво - две выдержки из классической статьи Дуница и Бернштейна (Dunitz and Bernstein  Acc. Chem. Res. 1995,28, 193-200) об исчезающих полиморфах, который подтверждает поверье о том,  что переезд из одной лаборатории в другую негативно сказывается на шансах закристаллизовать сходу свеженькую паску .

Seeding
One way of influencing the crystallization process is by seeding, and here we need to differentiate between what we may term intentional and unintentional seeding. Intentional seeding is a common practice among chemists who wish to coax crystallization 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 ratelimiting 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 polymorphs 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.Unintentional seeding is often invoked as an explanation of phenomena which otherwise are difficult to interpret. We shall argue in favor of this explanation, although there is no consensus about the size and range of activity of such seeds, which have never actually been directly observed .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 (10-6 g) of a compound of molecular weight 100 contains approximately 10^l6 molecules, sufficient to make 10^10 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 (planetary seeding would be a more accurate expression), where the whole planet is assumed to be contaminated. A seed that promotes formation of a crystallization 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 promoting 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.

Vanishing Polymorphs
Woodard and McCrone 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 chemists 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 Virtually the same melting point was measured for material prepared by a different method in Jena by Bredereck and Hepfner .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 Viserfurst 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, Zinne obtained a mixture of two tetraacetyl derivatives, one the ribopyranose and the other the ribofuranose, 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 difference 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 meantime, 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 Groshens (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 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 orientation 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 A^3; B, 392.5 A^3). In the early 1950s it would have been a major undertaking to determine the atomic arrangement in these noncentrosymmmetric crystals by X-ray analysis, 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, 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 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 orientations of the acetyl groups about the bonds. According to force-field calculation the intramolecular 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. 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 transform spontaneously to B, we can infer that the transition point lies somewhat below normal laboratory 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 crystallize 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. 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 experiments 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 laboratories “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.32 Besides, the immediate postwar period was marked by severe fuel shortages in Europe. British and German laboratories at that time must often have been considerably colder than 25 “C, except in warm summer weather. Was form A obtained in Cambridge and Jena during cold weather conditions, when the ambient temperature fell below the thermodynamic transition 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 phenomena. The accounts of the optical rotation measurements are particularly confusing. For example, Davoll, Brown, and Vissee reported that when a methanolic solution of A was inoculated with a minute amount of B, the specific rotation [alphaD] 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 alpha, beta  isomerism at the anomeric carbon atom to be unlikely (although we shall encounter examples later). In contrast, Farrar found that solutions of the two forms in chloroform had nearly the same specific rotation [alphaD] 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.

Відредаговано IB (22.11.2006 02:12:09)