Proton Transfer in the Solid State

For acid-base complexes, the lone difference between a salt and a co-crystal is the location of the acidic H atom(s) in the crystal structure. While it is generally accepted that proton transfer will occur between an acid and base to form a salt in solution when the difference between their acid ionization constants (pXa of base - pXa of acid or ApXa) is greater than two or three units, crystallization may yield salts, co-crystals, or disordered solid forms that exhibit partial proton transfer when the ApXa is less, with the exact location of the acidic proton being strongly dependent on the specific crystal packing environment. Here, it must be understood that the value is a solution property that is not specifically defined in crystals and as such, cannot be transferred to the solid state in a general way.  

While Aakeroy et al. have noted dramatically different structural behavior between carboxylic acid co-crystals and carboxylate salts, what effect, if any, the location of the proton specifically has on the physical properties relevant to delivering a drug in a controlled manner is unclear. Indeed for all intents and purposes, whether the form is unionized, a salt or co-crystal should not matter as long as its physicochemical properties are suitable for the drug product. That said, from a regulatory perspective, the jury is still out. Today, the 

N centers. Peresypkin et al. differentiated protonated and non-protonated sites using low power decoupling to eliminate signals effectively from the strongly coupled NH groups.  

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E. Reguera, Proton Transfer in the Solid State Reactions of Organic Acids and Amines,... 

The deuterium isotope effect on the rate constant of the double-proton transfer in the solid state can be used as a criterion to judge whether the double-proton transfer proceeds in a simultaneous or in a stepwise manner. The difference between ratios of rate constants /chh/ hd and /chd/ dd depends on the mechanism of the double-proton transfer. If a double-proton transfer occurs in a stepwise manner, the slower step in the /chd process, that is, a deuteron transfer, becomes rate-determining. Consequently the ratio/chh/ hd should be large. On the other hand, since deuteron transfers are ratedetermining in both /chd and /cdd processes, the ratio /chd/ dd is expected to be small. By contrast, if a proton transfer and a deuteron transfer occur simultaneously, the ratios of /chh/ dd and /chd/ dd should be of the same order. The observed ratios for benzoic acid dimers in crystals were found to be /chh/ hd = 23, / hd/ dd = 10 at 15 K (Stbckli et ai, 1990). Accordingly, the double-proton transfer is considered to occur concertedly in benzoic acid dimers [16]. 

Desiraju, G. R. (1983).Intermolecular proton transfers in the solid state. Conversion of the hydroxyazo into the quinone hydrazone tautomer of 2-amino-3-hydroxy-6-phenylazopyridine. X-ray crystal structures of the two forms. J. Chem. Soc., Perkin Trans. 2,1983, 1025-30. [84]... 

Two related compounds were prepared afterwards <93ccii39> and one of them, a 1 1 complex of the host and pyrazole (7) crystallizes in the form of a tetramer which presents proton transfer in the solid state involving nitrogen and oxygen atoms. The system has been studied by a combination of x-ray crystallography and dynamic high resolution solid state NMR spectroscopy. 

For comparison, let us compare the methanol data with those obtained by Horsewill et al. [80] who have reported an intramolecular quadruple proton transfer in the solid state between the four OH groups of solid calix[4]arene. Almost temperature independent rate constants were observed, which are again indicative of tunneling. An Arrhenius curve can be calculated using reasonable parameters (Table 6.4) which can reproduce both the pure methanol and the calix[4]arene data. It would be interesting to know more about the kinetic isotope effects in both systems. 

Raman and IR spectroscopy have both been used extensively in the characterization of salts and co-crystals to identify functional groups corresponding to the individual components, to characterize proton transfer in the solid state and to confirm the presence of new binary phases based on unique IR/Raman fingerprints. Confirmation of the latter is achieved simply through comparison with the pure component spectra, as shown for an indomethacin-saccharin co-crystal in Figure 10.5. In this case, not only were the Raman carbonyl... 

As mentioned earlier, only prototropic tautomerism is expected to occur in the solid state. Furthermore, as the motion of molecules is restricted to vibration about their equilibrium positions, the transfer of atoms from one part of a molecule to another must occur via a direct contact, that is, with the donor and the acceptor of the transferred atoms in immediate proximity. This is most easily satisfied when the atom that is to be transferred is a hydrogen atom, and the atoms donor and the acceptor are the donor and acceptor of an intra- or intermolecular hydrogen bond. Therefore, in the solid state tautomerization is equivalent to proton transfer in the solid state. 

Ionization reactions can occur under vacuum conditions at any time during this process but the origin of ions produced in MALDI is still not fully understood [27,28], Among the chemical and physical ionization pathways suggested for MALDI are gas-phase photoionization, excited state proton transfer, ion-molecule reactions, desorption of preformed ions, and so on. The most widely accepted ion formation mechanism involves proton transfer in the solid phase before desorption or gas-phase proton transfer in the expanding plume from photoionized matrix molecules. The ions in the gas phase are then accelerated by an electrostatic field towards the analyser. Figure 1.15 shows a diagram of the MALDI desorption ionization process. 

Polarization transfer has also been observed between HP supercritical xenon and organic solutes. HP xenon was collected as a solid and then transferred to a 3 mm borosilicate tube containing the organic molecule (toluene or biphenyl) at a field of 1 T to avoid relaxation. Proton enhancements were observed to be three (biphenyl) or seven (toluene) times the Boltzmann equilibrium level as measured at 2T and with the xenon polarization at 2%. Several proton acquisitions could be made because the xenon Ty was approximately 7.5 min. The authors suggest that the low cross-relaxation rates observed in both the liquid and now supercritical phases could lead to better polarization transfer in the solid state, albeit with a highly dispersed xenon, such as provided by freezing a supercritical or liquid solution. 

Allavena, M. and Kassab, E. (1993) Molecular interactions in solid state and quantum chemistry A model problem, the proton transfer in zeolites. Solid State Ionics, 61,33-39. 

The imbalance between and NMR studies in the solid state (Section VI,F) partly reflects the fact that it is easier to introduce N than into heterocyclic compounds, particularly azoles (DNMR in the solid state usually requires isotopic enrichment). Compared to solution studies, solid-state intermolecular proton transfer between tautomers has the enormous advantage that the structure of the species involved is precisely defined. 

The first observation of the proton transfer in pyrazoles in the solid state was made for the intermolecular tautomerism in 3,5-dimethylpyrazole 10b (85JA5290). The degenerate rearrangement was recorded using the... 

No proton transfers were observed in linear oligomers (catemers) of pyrazoles 8 in the solid, a fact which was understandable because such rearrangements would require a very high activation energy [97JCS(P2)101]. A possible exception to this rule is a catemer 8f, for which slow proton transfer was observed in the solid state [97JCS(P2)1867]. 

Tliere are several reasons for this great interest in the tautomerism of porphyrins (which could justify its own review) (1) their biological significance, (2) their applications in material science ( hole burning is related to their tautomerism), (3) the simplicity of the system (annular tautomerism involving intramolecular proton transfer both in solution and in the solid state), and (4) the possibility of elucidating the kinetic processes in great detail. 

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