Modelagem computacional da reação da pirrolidina com piridina-n-óxido ativada por sal de fosfônio: controle eletrostático da regiosseletividade
Aminopyridines belong to an important class of compounds in organic chemistry, due to their applications in the construction of drugs particularly related to neurological diseases. In 2010 an alternative, general, easy and one-pot method was presented for the synthesis of 2-aminopyridines from py...
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| Formato: | Dissertação |
| Idioma: | pt_BR |
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Universidade Federal do Rio Grande do Norte
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| Endereço do item: | https://repositorio.ufrn.br/handle/123456789/47096 |
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| Resumo: | Aminopyridines belong to an important class of compounds in organic chemistry, due to their
applications in the construction of drugs particularly related to neurological diseases. In 2010 an
alternative, general, easy and one-pot method was presented for the synthesis of 2-aminopyridines
from pyridine-N-oxides activated with phosphonium salts. This alternative method showed high
efficiency and selectivity when compared to the conventional preparation method. In this work, the
mechanism of this synthesis was elucidated through quantum calculations of electronic structure,
using the density functional theory and the continuous solvation model. We are proposing that the
mechanism of this reaction be described in four steps and that the regioselectivity be kinetically
controlled, but not thermodynamically. First, the pyridine-N-oxide is added to the phosphonium salt
from a nucleophilic displacement, forming a first reaction intermediate (a phosphonium complex with
a double positive charge). Second, this first intermediate undergoes an amine attack, which can occur
either at position 2 or at position 4 of the activated pyridine-N-oxide. Finally, two subsequent proton
abstractions must produce 2- and/or 4-aminopyridines. Our computational results suggest that
counterions, which are derived from the phosphonium salt, play a key role in the regioselectivity of
these reactions. We found that 4-aminopyridine formation is slightly favorable when the reaction path
is modeled without the presence of counterions. However, when counterions were considered in the
reaction mechanism, we observed that the pathway related to the attack at position 2 of pyridine-Noxide becomes preferential, presenting more accessible reaction barriers and exergonic reaction
intermediates. The regiochemical preference for the addition of the 2-position can be attributed to a
charge association that occurs between the reactional intermediate of the phosphonium complex and
the counterions. Furthermore, we verified a critical dependence of the evolution of this reaction with
some characteristics of the phosphonic additive. In this case, the phosphonium salt must have a good
leaving group for the pyridine-N-oxide activation step to occur easily. |
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