Metastable tautomers

It was shown that the cocrystallization yielded both the target stable and metastable tautomers of 1-deazapurine. In the case of halogen-bond donors, 1-deazapurine occurs as the >H tautomer and the predicted synthon pattern is dominant in the stabilization of their crystal architectures, with >H dimer intact. In the remaining four structurally characterized cocrystals with urea coformers, the H is obtained as an exclusive tautomeric species, with urea appearing at the predicted position, acting as a bridge between two H molecules (Scheme 13.6). As indicated by FTIR spectroscopy, the H tautomer was present in 6 out of 14 cocrystals obtained by milling. 

Compound 6 crystallizes from cyclohexane as colorless needles which have no definite melting point there is a change of color to yellow at 128-134 C and the compound then melts sharply at 187-189 r C. When the colorless form is kept for a long time or recrystallized from pyridine or dimethyl sulfoxide it is changed into the yellow modification of mp 187-189 C recrystallization from cyclohexane reverses the process. It has been suggested that the yellow stable form has structure 6A and that the colorless metastable compound is the tautomer 2-methyl-l//-pyrido[2,3-6][l, 4]diazepin-4(5//)-one (6B). There is evidence from 1H NMR spectroscopy that the isomeric pyridodiazepin-2-one, yellow crystals, mp 195—197 " C, exists as an inseparable mixture of the tautomers 4-methyl-l//-pyrido[2,3-6][l,4]diazepin-2(3//)-one (7 A) and 4-methyl-l H-pyrido[2,3-6][l, 4Jdiazepin-2(5//)-one (7B) in the ratio 1 3. 

Despite patient and exhaustive effort by many researchers, all attempts to isolate or trap a benzazirine intermediate (214) have so far failed, and unequivocal evidence for their participation in either the photolytic or thermal decomposition of aryl azides is still awaited. Evidence in favor of the proposed reaction pathway (Scheme 22) comes from the work of Sundberg and coworkers, who succeeded in identifying 3-alkyl-2-diethylamino-lff-azepines as oxygen-sensitive, metastable intermediates in the photolysis of o-alkylphenyl azides in diethylamine (72JA513). Later studies on the flash photolysis of aryl azides in dialkylamine solution provided kinetic data which not only confirmed the Iff- to 3/f-azepine tautomer-ism, but also strongly supported the involvement of a benzazirine intermediate (74JA7491). 

The kinetic energy release associated with the decomposition of metastable ions has been used to differentiate between the hydroxypyridines and their pyridone tautomers in the gas phase. The hydroxy forms were found to be favored for 2-hydroxypyridines (88JCS(P2)347). 

The mass spectra of seven 2-thio- and four 2-oxo-l,3,4-benzotriazepines, for example (128), have been recorded and the fragmentation patterns elucidated by exact mass measurement and metastable ion analysis <90JHC259>. The x-ray crystallographic analysis of the imidazo[l,5-fe]-l,2,4-triazepine (129) showed that a double bond possesses a 1 and 2 linkage (C=N 1.276 A) with no evidence of an alternative tautomer in which the double bond is between the 2 and 3 positions (C—C 1.490 A) <93AX(C)I693>. 

One important aspect of the bases is that they also exist in forms which involve a change in the position of a H atom relative to those described above. These forms are called tautomers and have slightly higher energy than the stable forms described already, that is, the tautomers are metastable. The stable forms are referred to as keto, when the H atom in question is part of an NH group that has two more... 

Here we aim to present some of the recent advances in crystal engineering concerning the synthesis of metastable solid tautomers by design, usually by complexation with suitable counter-molecules (later called coformers), forming the multicomponent molecular solids. We will also discuss the methods and supramolecular rules that can be used for design and controllable synthesis of such solids. Finally, we will present some of the most illustrative examples of cocrystal systems comprising more tautomeric forms reported to date. 

The calculation of the interaction modes between two Schiff base molecules showed the preference for the formation of (R2 (18)) dimers, stabilized by the O-H- O hydrogen bond, thus leaving the pyridine nitrogen without any significant hydrogen bond contacts (Scheme 13.8a). When one carries in mind the robustness of O-H- -N(py) synthon [83], such stabilization is not intuitively expected. However, the same dimeric substructure already occurred in similar metastable keto-amino tautomers of nonmethoxy Schiff base derivative IX [45]. To accomplish these dimers, it would be energetically favorable for both participating Schiff base molecules to take the keto-amino form. 

In the polymorphs 1, II, and III, molecules of H3BA are present exclusively in the keto form. Form I corresponds to the kinetically favored metastable phase, form II is the commercially available phase (which was originally considered as a thermodynamically stable form) [109c], while form 111 corresponds to the high-temperature phase. It should be noted that the solid-state structures of polymorphs I and II were determined by SC-XRD [109a, b], whereas the structure of form III was solved from PXRD data which revealed its close relationship with the crystal structure of form II [110]. In 2011, the structure of the solid form IV, obtained exclusively by milling or grinding of the commercial form II, was finally unveiled and was shown to contain the enol tautomer of HjBA [78]. 

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