Polymorphism and Desmotropy in Heterocyclic Crystal Structures

PERSPECTIVE pubs.acs.org/crystal

Polymorphism and Desmotropy in Heterocyclic Crystal Structures Jos
e Elguero* Instituto de Química M
edica, Consejo Superior de Investigaciones Científicas (CSIC), Juan de la Cierva, 3, E-28006 Madrid, Spain ABSTRACT: There is some confusion about concepts such as polymorphism, tautomerism, tautomeric polymorphism, and desmotropy. This perspective review tries to clarify them by defining their boundaries. Most examples are from heterocyclic compounds and differentiate between NH/OH tautomers (fast prototropy) and CH ones (slow prototropy). In the case of “tautomeric polymorphism” and “desmotropy” it is strongly recommended to use desmotropy. The different possibilities of crystallization of tautomers are examined in the conclusion.

’ INTRODUCTION In this perspective review desmotropy, also called tautomeric polymorphism, will be discussed in order to definitely establish that desmotropy is not a case of polymorphism. But first, we need definitions of polymorphism, tautomerism, and desmotropy. For polymorphism, this is not an easy task. Like many notions in chemistry (aromaticity1 and hydrogen bond2,3 being paradigmatic examples), polymorphism is a controversial concept. Bernstein reported several definitions:4,5 the older one of McCrone “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”; this definition includes conformational polymorphs and excludes dynamic isomerism and tautomerism because they involve the formation of different molecules. The “safe” criterion for classification of a system as polymorphic would be if the crystal structures were different but lead to identical liquid and vapor states; the problem with this definition is, as Dunitz pointed out, that it involves a time factor. We propose to complete the definition by adding a final sentence “polymorphism concerns crystal structures that are different but lead to identical liquid and vapor states with the condition that no bonds are broken or created”. This excludes E/Z isomerism (too slow) and tautomerism as well as valence isomerism (new bonds). This definition is close to that proposed by Gavezzotti: “Polymorphs are a set of crystals (a) with identical chemical composition; (b) made of molecules with the same molecular connectivity, but allowing for different conformations by rotations about single bonds; (c) with distinctly different three-dimensional translationally periodic symmetry operations.”6 According to the IUPAC, tautomerism is a part of isomerism of the general form:

O, or S, and G is a group which becomes an electrofuge or nucleofuge during isomerization. The commonest case, when the electrofuge is H+, is also known as “prototropy”. Desmotropy is an old German term coined by Jacobson in 1887
18887 at the beginning of organic chemistry. It was formed from the Greek meaning change of bonds. Citing Holczbauer, F
abian, Csom
os, Fodor, and K
alman:7a “The term desmotropy or
bond, τFoπ
oς change) was introdesmotropism (Gr. δεσμoς 7b duced by Jacobson in an attempt to improve the hypothesis deduced by Laar8 from the dualistic behavior of acetoacetic ester in the chemical reactions studied at that time in different laboratories. It was found that with certain reagents it acts as if it contained a hydroxyl group, while with other substances it behaves as if it were a pure ketonic compound. Laar proposed to call this phenomenon
τ
o the same, με
Foς part). To differentiate tautomerism (ταυ between tautomerism and desmotropy, Hantzsch and Herrmann9 suggested that if a substance could be isolated in two stable forms it should be called desmotropic, while if it could not be isolated it should be termed tautomeric. Although there are no examples of desmotropy involving three tautomeric forms, the above definition would cover this case. Desiraju has asked the question “Are tautomers the same or different molecules?”10 He discussed the case of omeprazole where both benzimidazole tautomers (5- and 6-methoxy) are present in variable proportions (solid solution). He concludes that if the tautomers are different, the so-called tautomeric polymorphs are not polymorphs at all but crystals of different compounds. In what concerns omeprazole, Desiraju’s conclusions are not fully consistent with a 13C and 15N NMR cross polarization magic angle spinning (CPMAS) study that concludes that omeprazole in the solid state consists uniquely of the 6-methoxy tautomer11 (see also12 and a more detailed discussion below).

G—X—YdZ h XdY—Z—G where the isomers (called tautomers) are readily interconvertible; the atoms connecting the groups X, Y, Z are typically any of C, H, r 2011 American Chemical Society

Received: July 27, 2011 Revised: September 6, 2011 Published: September 12, 2011 4731

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Chart 1. Examples of Desmotropy

Cruz-Cabeza and Groom carried out a survey of the Cambridge Structural Database (CSD) concerning the identification, classification, and relative stability of tautomers.13 They prefer the name “tautomeric polymorphs” to “desmotropes” on the grounds that this last term is not widely known or used within the crystallographic community. On the other hand, Braga, Grepioni, and Maini wrote that “desmotropy” would be more appropriate than “tautomeric polymorphism”.14 On questions related to polymorphism, pseudopolymorphism, and tautomerism several important papers have been published in recent years: disappearing polymorphs,15 pseudopolymorphism,16,17 polymorphic perversity, 18 predicting polymorphs,19 polymorphism,5,20,21 and annular tautomerism (experimental observations and quantum mechanics calculations).22 Zwitterionic Compounds/Zwitterions. Neutral compounds having formal unit electrical charges of opposite sign. Some chemists

restrict the term to compounds with the charges on nonadjacent atoms, for example, H3N+CH2C(dO)O
ammonioacetate (glycine), (CH3)3N+
O
trimethylamine oxide, C5H5NO pyridinium-3-olate.

’ PAPERS REPORTING DESMOTROPY Since prototropic tautomerism is especially important in heterocyclic chemistry, the examples we have selected are from this field. Chart 1 reports compounds described as showing desmotropy. The double arrow means that both tautomers are connected through proton transfer from one heteroatom to the other. Prototropy occurs in solution assisted by solvent molecules and in some rare cases in the solid state. The first studies were based on solid-state IR spectroscopy. With this method, the desmotropy of hydantoins (1),23 thiohydantoins (2),24 4732

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Chart 2. Desmotropy in 4-Acylpyrazolin-5-ones

imidazolinones (3),25 and imidazolinthiones (4)26 was established. The result concerning hydantoins (1) was later confirmed by X-ray crystallography; the authors wrote: “This is the first established case of annular desmotropy in the azole field”.27 A combination of IR and NMR was used in the case of pyridoxal (5)28 (see also ref 29). The first example of desmotropy concerning the annular tautomerism of pyrazoles (6) was determined by X-ray crystallography and CPMAS NMR in 1994.30
32 The desmotropy of thiohydantoin anions (7) was studied by X-ray crystallography.33 A combination of crystallography and CPMAS NMR was used by Harris et al. to study the desmotropy of irbesartan (8).34 Since this is one of the cases where the prototropy between 8a and 8b occurs in the crystal, theoretical studies were devoted to this phenomenon.35,36 The crystal structure of 8a was determined in the Sanofi pharmaceutical industry.37,38 Russian authors reported the desmotropy of rhodanine (9) based on IR studies.39,40 Both tautomers of 3(5)-phenylpyrazole (10) were isolated and their structures were determined by crystallography as well as by 13C and 15N CPMAS NMR.41 The desmotropy of compounds 8 and 10 was discussed in a review.42 A patent claims the desmotropy of aminoquinolines (11).43 The case of 3(5)-phenyl-5(3)-methylpyrazole (12) constitutes an interesting case of desmotropy. Two desmotropes were isolated, both being tetramers linked by N
H 3 3 3 N bonds. The first one 12a has two 3-phenyl-5-methyl tautomers and two 3-methyl-5phenyl ones, while the second 12b is formed by four 3-phenyl-5methyl tautomers. Only 12a present solid-state proton transfer (SSPT) because after four proton transfers an identical structure was obtained; on the contrary 12b does not show SSPT.44,45

Chart 3. Desmotropy in 1,4-Benzothiazepines

Two kinds of compounds have been studied in detail: 4-acylpyrazolin-5-ones and 1,4-benzothiazepines. Holzer et al. reported that 4-acylpyrazolin-5-ones could exist in six different tautomers (Chart 2).46 They prepared a compound 14 (orange crystals) to which they assigned the 14f tautomeric structure based in NMR in solution. When orange crystals were crystallized in EtOH 96% a metastable light yellow compound was obtained, assumed to be a desmotrope. These conclusions were proven wrong by Guard and Steel,47 who determined the X-ray structure of both forms: the orange one is 14e and the yellow one, the hydrate of 14b (N
H 3 3 3 OH2). Some time after, Japanese authors reported another example of desmotropy in the related series 15 (15e and 15b) based on crystallography and Raman spectroscopy.48,49 Finally, a paper entitled “A Study in Desmotropy” using solid-sate 13C and 15N NMR as well as theoretical calculations, described a new example of desmotropy in these compounds, the pair 16e and 16b.50 Hungarian and Finnish authors explored the behavior of 4,1benzothiazepines (Chart 3). They reported the first evidence for the desmotropy of seven-membered heterocycles. These desmotropes could be separated by column chromatography and are stable in solution allowing their structures to be proven by means 4733

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Crystal Growth & Design of NMR and mass spectrometry.51 This result deserves two comments. The first one is a question: is this an example of desmotropy or is it not because it is too slow? The second one is an explanation for why these compounds tautomerize so slowly: contrary to all examples reported so far, this involves not an heteroatom
H bond but the bond breaking of a C
H bond, a process requiring much more energy. These studies were extended to phenyl-substituted derivatives.52 In contrast with 4,1-benzothiazepines derivatives, desmotropy was not observed for the 1,4-benzothiazepines.53

’ PAPERS REPORTING TAUTOMERIC POLYMORPHISM One very interesting example of tautomers very stable in the solid state (1 year at room temperature) and even in solution (24 h at room temperature in CDCl3) was reported by Schulenberg in 1968 (Chart 4).54 2-(20 ,40 -Dinitrobenzyl)-3-methylpyridine (19) presents an interesting behavior that their authors have named tautomerism (Chart 5).55 The CH tautomer 19a presents three polymorphs; two of them by irradiation afforded the NH tautomer 19b that, although it has not been characterized by X-ray crystallography, is a different tautomer (13C, 15N CPMAS NMR, DSC). 2-Thiobarbituric acid (20) (Chart 5) is probably the most beautiful example of this perspective because all the possibilities have been found and studied by X-ray crystallography as well as by 1H, 13C and 15N CPMAS NMR.56 Three polymorphs of the CH tautomer 20a, one tautomeric polymorph of the NH tautomer 20b, a crystal containing both tautomers 20a and 20b in 50:50 proportion, and a hydrate (not a true polymorph) of 20b have been described. Note that in compounds 18, 19, and 20 tautomerization involves CH bond breakings, and thus prototropy is expected to be slow. The pharmaceutical importance of racemic omeprazole (21) and its eutomer,57 esomeprazole (22),58 cannot be stressed enough (only AstraZeneca sales of omeprazole in 2010 amounted to $986 million). Therefore, the study of their polymorphism has reached enormous proportions, including many patents.59 Here, our concern is limited to 5-methoxy/6-methoxy tautomerism (Chart 6). Remember that a CPMAS NMR study concluded that only the 6-methoxy tautomer, 21b, is present in the solid state.11 Desiraju et al. published two papers on omeprazole (21) (Chart 6).10,60 In that of 2007, they obtained single crystals ranging from pure 21b to a 15:85 mixture of 21a/21b (substitutional solid

PERSPECTIVE

solution).60 This led them to question the concept of polymorphism. In the 2008 paper, Desiraju continued his reflection about this problem using as example omeprazole. Studying the structure of 4,5,6,7-tetrabromobenzimidazoles by 13 C and 15N solid-state NMR, Zawada, Wolniak, Kazimierczuk, and Waver concluded that for some derivatives two independent molecules are present in the unit cell but that probably they do not correspond to N1
H and N3
H tautomers, Chart 6).61 In a subsequent work, Kazimierczuk with other authors reported the study of a series of polyhalogenated benzimidazoles.62 They recall that benzimidazole itself (23, R4 = R5 = R6 = R7 = H) presents polymorphism but being “symmetrical” it has only one tautomer. By a combination of crystallography, nuclear quadrupole double resonance (NQDR) and density functional theory (DFT) calculations, these authors conclude that some polyhalogenated benzimidazoles (for instance, 23, R4 = R6 = Cl, R5 = R7 = I and 23, R4 = R6 = Br, R5 = R7 = I) contain both tautomers, 23a and 23b, in a 50:50 ratio in the crystal, the possibility of proton transfer being less clear. In summary, the compounds of Chart 5 are not examples of tautomeric polymorphism. Although not discussed in detail in this survey, there are several reports on non-heterocyclic examples of desmotropy: 2-amino-3hydroxy-6-phenylazopyridine (not named desmotropy nor tautomeric polymorphism),63 acetohexamide (named tautomeric polymorphism),64 ortho-anthraquinones (named desmotropy),65 salicylideneamines (named tautomeric polymorphism),66 plumbagins (named desmotropy),67 Schiff bases (named tautomeric forms);68 sulfamethazine (sulfadimidine, named tautomeric polymorphism),69 and glybenclamide (glyburide, different names).70
74

’ COCRYSTALS75,76 VS SALTS determinedIn all the examples reported so far, the proton migrates between two positions of the same neutral molecule in an intramolecular shift (independently if other molecules, Chart 6. The Tautomerism of Omeprazole and Esomeprazole

Chart 4. The Case of the Keto/Enol Tautomers 18a and 18b

Chart 5. Examples of Tautomeric Polymorphism

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Crystal Growth & Design Chart 7. Other Situations

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Chart 9. Salts and Cocrystals of Picric Acid

Chart 8. The Tautomerism of Histidine

Chart 10. The Two Desmotropes of Piroxicam

for instance, water, are involved). In heterocyclic tautomerism, there are cases where the first rule does not apply, 24a and 24b (1H-pyridinium-3-olate), and, in general, tautomerism may correspond to an intermolecular situation, 25a and 25b (Chart 7). For instance, an amino acid such as histidine (Chart 8) presents five tautomers, the one found in the solid-state 26d being framed. If crystals of another form, zwitterionic 26c and 26e, or neutral, 26a or 26b, were to be found, they would constitute examples of desmotropy. For the pharmaceutical industry, a very important case of desmotropy involves the equilibrium between a complex or a cocrystal (A
H 3 3 3 B, 25a) and the corresponding salt (A
3 3 3 H
B+, 25b) of active pharmaceutical ingredient (APIs).77 We will closely follow Stahly’s opinion:76 Formation of salts of organic compounds involves proton transfer from an acid A
H to a base B. The study of crystal structures reveals that the possibility for a proton to be transferred from one component to another depends on the crystalline environment and cannot be predicted from ΔpKa values alone.78 Thus, it is reasonable to consider crystalline salts and cocrystals as species that exist at either end of a continuum of multicomponent crystal structures. At the salt end, proton transfer is complete, and at the cocrystal end proton transfer is absent. When a pair of ionizable components crystallizes, both the ΔpKa value and the crystalline environment determine the extent of proton transfer and therefore the placement of the structure on the continuum. Childs, Stahly, and Park have solved crystal structures of an anhydrous form and a monohydrate form of aminophylline. In one structure, there is proton transfer 25b and in the other there is protonsharing 25a (Chart 7).79 The importance of ΔpKa in deciding if the proton will be transferred from A
H to B has been named by Gilli et al. “the pKa slide rule”.80 The same team studied the existence of picric acid complexes vs picrates;81 in 13 of 15 examples they are picrates (as, for instance, 27), and in one case the compound (with 4-nitropyridine-N-oxide) is a cocrystal (28) (Chart 9). No example of desmotropy was found [the picrate of 1,8-bis(dimethylamino)naphthalene presents polymorphism].82 13C and 15N CPMAS NMR was used to determine that the crystals obtained by mixing equimolar amounts of diethyl 1H-pyrazole3,5-dicarboxylate (29, R3 = R5 = CO2Et, R4 = H) and the primary

amines phenethylamine and homoveratrylamine are ammonium pyrazolate salts 29a and not cocrystals 29b (Chart 8).83 Combined 15N solid-state NMR and X-ray photoelectron spectroscopy (XPS) was used to differentiate theophylline cocrystals (oxalic acid) from theophylinium salts (salicylic-5-sulfonate monohydrate salt).84 The anti-inflammatory drug piroxicam 30 shows many polymorphs, but only relevant for this perspective is that two tautomers one neutral and one zwitterionic have been characterized (Chart 10).85

’ TWO TAUTOMERS IN THE SAME CRYSTAL Although this phenomenon is not related to desmotropy, some compounds close to those previously discussed show in their unit cells two tautomers: 12a (Chart 1),44,45 21 (Chart 6),58 23 (Chart 6),62 and the compounds of Chart 11: 1-phenyl-3methyl-3-pyrazolin-5-one 31a/1-phenyl-3-methyl-5-hydroxypyrazole 31b,86 (30 ,40 -dimethoxyphenyl)-3(5)-pyrazole (32) hydrate,87 3(5)-phenyl-4-bromo-5(3)-methylpyrazole (33),88 3(5)-methylpyrazole (34) (four trimers formed by 34a and 34b),89 4(5)nitro-5(4)-methoxyimidazole 35,90 and 2-amino-6-methylpyrimidin-4-one 36.91 ’ TRUE POLYMORPHISM OF A TAUTOMERIC COMPOUND Obviously, tautomeric compounds are able to present classical polymorphism without any change in the tautomerism. We have already noted some cases: 19a (Chart 5),55 20a (Chart 5),56 and 23 (Chart 6) (R4 = R5 = R6 = R7 = H).62 Other examples are gathered in Chart 12: 4-aminopyrazole (37),92 diiminoisoindoline (a conformational isomorph with a 50:50 mixture of 38b and 38c and a conformational polymorph containing only 38b),93 sibenadet (39) (three polymorphs).94 1,2,4-Triazino[2,3-a]benzimidazol-5(4)H-3-ones (40) present polymorphism but both polymorphs contain the 5H-tautomer (40b),95 and indazolin-3-one (41) has two polymorphs of tautomer 41a.96 4735

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Chart 11. Two Tautomers in the Same Crystal

Chart 12. Polymorphism of a Single Tautomer

Chart 13. The Four Possible Situations

’ DESMOTROPY IN COCRYSTALS AND WITH COFORMERS With the rapid increase of cocrystals and coformers (also called counter-molecules, where one component is molecular and a solid at room temperature),96 problems of desmotropy should appear, for instance, tautomer a with a coformer c and tautomer b with the same coformer. Maybe even 12a could be

considered a cocrystal formed by two tautomers as well as the examples of Chart 10. Cocrystals of azoles presenting polymorphism have been described.98

’ CONCLUSIONS Chart 13 summarizes the four possible situations of crystal formed by tautomers. The first situation, desmotropy, is clearly defined. When there are two tautomers in a single crystal, this may be considered a cocrystal but never a case of desmotropy. If both tautomers show fast prototropy (SSPT) like irbesartan (8) they do not belong to desmotropy. Individual tautomers often show polymorphism. How to distinguish a polymorph from a desmotrope? (i) Localize the X
H by crystallography, either X-ray at low temperature or neutron diffraction (X
D); (ii) use the bond lengths of the non-hydrogen atoms that change considerably between tautomers; (iii) use CPMAS NMR: this is not always definite because polymorphism, especially the conformational, also alters the chemical shifts significantly; (iv) CPMAS NMR plus chemical shifts theoretical calculations: better but still not definitive. 4736

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Crystal Growth & Design In conclusion, we are of the opinion that desmotropy should be preferred to tautomeric polymorphism.

’ AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected].

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