Tautomeric polymorphism

There are some confusions about concepts such as polymorphism, tautomerism, tautomeric polymorphism, and desmotropy. J. Elguero tried to clarify them by defining their boundaries in an excellent review published in 2011 (2011CGD4731) by discussing examples taken from heterocyclic compounds, differentiating between NH/OH-tautomers (fast prototropy)... 

Two desmotropes (tautomeric polymorphs) of 2,6-dichloropurine (30) have been crystallized and identified as the 9H- (30a) and the 7H-tautomers (30b)... 

In 2007, Bhatt and Desiraju reported that the five different solid forms of opremazole have varying proportions of the 5-methoxy and 6-methoxy tautomers. Only one form is the pure 6-methoxy tautomer, while all other forms are mixture of 5- and 6-methoxy tautomers ranging from pure to a 15 85 mixture of 5-methoxy- 6-methoxy opremazole (2007CC2057). Solid-solution hardening of molecular crystals in connection with tautomeric polymorphs of opremazole has been discussed (2015JA1794). 

When different configurations of the same molecule crystallize in separate crystalline forms, they are termed as configurational polymorphs. As a caveat, since configurational isomers can be considered to be separate chemical entities, these solids may not be strictly classified as polymorphs. Yet another classification of polymorphs that is closely related to confignrational polymorphism is tautomeric polymorphism which occurs when different tautomers of a compound exist in different polymorphs. There are cases where confignrational isomers or tautomers can interconvert in solution, and the fact that their relative population and stability depends on factors such as temperature, solvent, pH, and so on makes them appear as different crystalline polymorphs. In contrast to other, previously described classes of polymorphs, tautomeric polymorphs are rare. An early report of tautomeric polymorphism by Desiraju is the compound 2-amino-3-hydroxy-6-phenylazopyridine, which exists as hydroxyazo and quinonehydrazone crystals of different colors. Polymorphs of the antiulcer drug omeprazole (Figure 6) also represent tautomeric polymorphs that were characterized by SC-XRD. ... 

Figure 3 Solid-state conversion processes between tautomeric polymorphs of 2-thiobarbituric acid.

Also, tautomeric polymorphism in the solid state was reported. The CP-MAS NMR spectra of sahcylideneimine derivatives 4 demonstrated a tautomeric equilibrium in the same crystal (Scheme 5.2) and allowed the quantitative estimation of the tautomeric equilibrium (by employing the characteristic 5(C-2) values of the tautomers, the presence of 47% of the quinoid tautomer 4b proved significant] [14a,bj. And residual dipolar coupling effects, which were not mentioned... 

Most authors consider tautomerism to be a minor phenomenon that can be included in polymorphism [32, 33]. This is not our opinion and we prefer to use desmotropy instead of tautomeric polymorphism [34-36]. Tautomers can also be present in co-crystals [37]. 

In 2007, Bhatt and Desiraju [27] reported that in the solid state omeprazole yields five different forms that were described as tautomeric polymorphs. One of the forms, called form I, contains exclusively 6-methoxy tautomer while the remaining four forms have different proportions of the 5-methoxy (Tl) and 6-methoxy (T2) tautomers (Figure 13.1). Namely, form II comprises Tl and T2 tautomers in a 8 92 ratio form III in a 10 90 ratio form IV in a 12 88 ratio and form V in a 15 85 ratio. It is interesting to note that except those, other ratios of Tl and T2 tautomers in the solid state have not been observed [104]. All five forms crystallize in the triclinic space group P-1 with one molecule per asymmetric unit... 

In a recent study of twenty disperse and solvent dyes, data for water solubility, octanol/ water partition coefficient, entropy of fusion and melting point were subjected to regression analysis. Complicating factors such as impurities, polymorphism, tautomerism, polarisation and hydrogen bonding precluded the development of reliable predictions of solubility and partition coefficient. Anthraquinone dyes exhibited much lower entropy of fusion than many of the azo dyes [64,65]. 

Dibenzoylmethane (8b) has been the subject of much interest as regards the possibility that its polymorphism is associated with keto-enol tautomerism. Chemical and spectroscopic studies showed that this is not so (33a). This compound had previously been reported to be trimorphic (33b), but one form appears, in fact, to be a eutectic mixture of the other two. The molecules in these two polymorphs are both in the same state of tautomerism they differ in the torsional angle about the (CH)-(CO) bond and in the type of hydrogen bonding in which they participate. It is noteworthy that solutions prepared from these forms at low temperature have differences in chemical and spectroscopic properties that are maintained for some time. For example, such solutions prepared and held at —35° react at different rates with FeCl3. 

Desmotropes - Desmotropes are prototropic tautomers in which both tautomeric forms have been isolated. They should not be confused with polymorphs in which the same molecule (tautomer) crystallizes in two or more crystal forms <2008SSNMR68>. For examples see Sections 2.4.34 and 24.5.1.1. 

Tautomerization of porphyrins in crystals exhibits diverse patterns of behaviour. There are polymorphic crystal structures of tetraphenylporphyrin (TPP) [19] the tetragonal and the triclinic forms (Silvers and Tlilinsky, 1967 Codding and Tulinsky, 1972 Tblinsky, 1973). In the tetragonal form. X-ray... 

At first glance this definition seems straightforward. What are some of the complications For flexible molecules McCrone would include conformational polymorphs, wherein the molecule can adopt different conformations in the different crystal structures (Corradini 1973 Panagiotopoulis et al. 1974 Bernstein and Hagler 1978 Bernstein 1987). But this is a matter of degree dynamic isomerism or tautomerism... 

As noted above, the characterization of polymorphs by SSNMR is by no means limited to spectra. For instance, Bauer et al. (1998), showed that CPMAS could easily distinguish between the two polymorphs of Irbesartan 4-1 and could be used to study the difference of the tautomeric behaviour in the tetrazole ring of the two polymorphic forms. Variable temperature spectra indicate that the ring in Form B is involved in an exchange process that does not occur in Form A (Fig. 4.37). 

First, it is necessary to eliminate tautomerism or dynamic isomerism by determining that the two materials give identical melts. X-ray diffraction can determine that crystal strain (which can be mistaken for polymorphism) is not a factor. Then, McCrone... 

Takla PG, Dakas CJ. Infrared study of tautomerism in acetohexamide polymorphs. J Pharm Pharmacol 1989 41 227-230. 

In 1989, Etter published an excellent paper on the complementary use of solid-state NMR and X-ray crystallography to study the structure of pharmaceutical solids (57). Crystallographic effects such as polymorphism, multiple molecules per asymmetric unit cell, disorder, intra- and intermolecular H-bonding, tautomerism, and solvation were all investigated by solid-state NMR. 

Takla and Dakas (1989) have also shown that IR spectroscopy can be used to detect polymorphism due to the keto-enol tautomerism of acetohexamide. 

Tautomerism of 2-Aminothiazoles. - The imino-form (101) predominates only when the S02Ar group is bonded to the exocyclic nitrogen atom In all other cases the amino-form (102) is prevalent. The and Hn.m,r., i.r., and u.v. spectra of 4- or 5-substituted 4-thiazolin-2-ones and their N-or 0-Me derivatives were studied. The i.r. and n.m.r. spectra show that the parent compounds exist entirely or predominantly in the 2-oxo-form in solution. In contrast, u.v. and n.m.r. spectroscopy did not clearly distinguish between the 2-oxo- and 2-hydroxy-stnictures. The kinetics and mechanism of spontaneous acid-, base-, and metal-ion-induced hydrolyses of A salicylidene-2-aminothiazole were also described. Studies on the polymorphism of sulphathiazole and its crystallographic behaviour under pressure have also been reported. ... 

However, it is clear that vibrational spectroscopy has considerable use beyond the identification of polymorphs and solvates. The infrared spectra obtained on the polymorphs of acetohexamide and selected derivatives has been used to study the tautomerism of the drug compound [127]. It was deduced in this work that Form A existed in the enol form, stabilized by the intramolecular bonding between the O—H and groups that produces a six-membered ring. Form B was characterized by the existence of the keto form, with the urea carbonyl group being intermolecular bonding to a sulfonamide N—H functionality. This behavior can be contrasted with that noted for spironolactone, where no evidence was found for the existence of enolic tautomers in any of the four polymorphs [128]. 

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