Interaction of allylic carbocations with benzene: a theoretical model of carbocationic intermediates in terpene biosynthesis

Abstract

Carbocátions atuam de formas diferentes quando interagem com anéis aromáticos. É interessante como na biosíntese de terpenos, os intermediários carbocatiônicos não alquilam a cadeia lateral aromática de aminoácidos presentes no sítio ativo, como seria esperado para outros carbocátions, como o cátion terc-butila. Neste trabalho, a interação entre benzeno e diferentes carbocátions alílicos é analisada, mimetizando carbocátions terpenóides, para melhor compreender como esta interação ocorreria. Cálculos em nível de teoria do funcional da densidade (DFT) mostram que para carbocátions alílicos secundários e terciários (como os encontrados na natureza), a forma não ligada da interação é mais estável energeticamente do que a alquilação do anel aromático, justificando a escolha da natureza por esses carbocátions mais estabilizados.Carbocations act in different ways when interacting with aromatic rings. It is interesting that in terpene biosynthesis, the carbocationic intermediates do not alkylate the aromatic side chain of the amino acids present in the enzymatic active site, as would be expected by other carbocations such as the tert-butyl cation. In this study, the interaction between benzene and different allylic carbocations, mimicking terpenoid cations, is analysed in order to better understand how this interaction would occur. Density-functional-theory (DFT) calculations show that for secondary and tertiary allylic carbocations (as found in nature), the non-covalent interaction is energetically favoured with respect to alkylation of the aromatic ring.Keywords: density-functional calculations, DFT, electrophilic substitution, cation-π interaction IntroductionThe study of noncovalent interactions has been gaining interest due to their broad applications in diverse fields such as ligand recognition, catalysis 1 and supramolecular chemistry.2 However, the importance of noncovalent interactions, such as π stacking, 3,4 charge-dipole 5,6 and cation-π interactions, 4,7-10 has only been recognized recently. A cation-π interaction is defined as a strong, attractive, noncovalent and quite specific interaction between a cation and a π-system.11 The cation-π interaction, which is of the same magnitude or even stronger than a typical hydrogen bond, 9,12 has a key role in protein folding, 13 selectivity of potassium channels 14 and several types of intermolecular recognition. 1,13,[15][16][17] The nature of the cation in the cation-π interaction can be metallic, 11,18 of ammonium derivatives, [19][20][21][22] which are very common in biological systems, 23,24 or carbocationic, 25-30 among others. Most of the available information for cation-π complexes has been obtained from coordinatively saturated cations, such as Na + and NH 4 + . 11,[18][19][20][21][22] In the case of carbocations, cation-π interactions are found as intermediates in many enzymatic reactions, e.g. elongation and cyclization reactions in terpene biosynthesis. [31][32][33] The study of the interaction of such cations with aromatic side chains of amino acids is...

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