Buyens Dominique M S, Pilcher Lynne A, Roduner Emil
Department of Chemistry, University of Pretoria, Pretoria, 0002, Republic of South Africa.
Institute of Physical Chemistry, University of Stuttgart, D-, 70569, Stuttgart, Germany.
Chemphyschem. 2024 Dec 2;25(23):e202400561. doi: 10.1002/cphc.202400561. Epub 2024 Nov 5.
The factors governing the regio-selectivity of the alkylation of adenine have been of interest for many years due to the biological importance of adenine derivatives, however, no reaction kinetic studies have been conducted. Herein, we report the rate constants and activation parameters of the benzylation of adenine under basic conditions in DMSO in the absence and presence of 15-crown-5 ether using real-time H NMR spectroscopy. The reaction is second-order for the formation of the N9- and N3-benzyladenine products, with a regio-selectivity factor 2.3 in favour of the N9-adduct. The Gibbs free energy of activation amounts to 87±2 kJ mol for both reactions. The formation of the N9-adduct is more activated by 7 kJ mol, but its effect is offset by a less negative activation entropy, demonstrating that the long-contested reason for the regioselectivity in the benzylation of adenine is dominated by compensation of entropy and enthalpy in the transition state. The kinetic parameters obtained in the presence of the 15-crown-5 ether indicate that the crown ether forms a complex with an adenine-sodium ion-pair, increasing the activation barrier. However, the Gibbs free energy in the absence and presence of the crown ether remains constant.
由于腺嘌呤衍生物具有生物学重要性，多年来，影响腺嘌呤烷基化区域选择性的因素一直备受关注，然而，尚未开展反应动力学研究。在此，我们利用实时¹H NMR光谱法，报道了在DMSO碱性条件下，有无15-冠-5醚存在时腺嘌呤苄基化反应的速率常数和活化参数。该反应生成N9-和N3-苄基腺嘌呤产物的反应为二级反应，区域选择性因子为2.3，有利于N9-加合物的生成。两个反应的活化吉布斯自由能均为87±2 kJ mol⁻¹。N9-加合物的生成活化程度高7 kJ mol⁻¹，但其影响被较小的负活化熵抵消，这表明腺嘌呤苄基化区域选择性长期存在争议的原因是过渡态中熵和焓的补偿起主导作用。在15-冠-5醚存在下获得的动力学参数表明，冠醚与腺嘌呤-钠离子对形成络合物，增加了活化能垒。然而，有无冠醚存在时的吉布斯自由能保持不变。
