We advance the concept that tautomerism is crucial for the understanding of the chemical behavior of tetracycline. Indeed, considering four deprotonations, there are 64 different possible tautomers to be considered for tetracycline. Our results indicate that tetracycline is a very adaptive molecule, capable of easily modifying itself through tautomerism in response to various chemical environments. Indeed, its situation in solution can be more accurately pictured as an equilibrium among a diversity of tautomeric species-an equilibrium that can be easily displaced depending on the various possible chemical perturbations, such as varying the pH or the dielectric constant of the solvent. Moreover, we also show that tetracycline could undergo four deprotonations and predict for it a fourth pKa of 13 and refer to our experimental determination of this parameter, which yielded the value of 12. We conclude that tautomerism is essential to the comprehension of the chemical behavior of tetracycline as determined by the semiempirical method AM1 as well as by the self-consistent reaction field method, which estimates the effects of the solvent on the tautomers. All tautomers in their different conformations have been fully optimized for each of the possible degrees of protonation of this molecule. Thus, the relative stabilities of the different tautomeric species have been computed.

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