Faculty of Pharmacy and Biochemistry , University of Zagreb , Ante Kovačića 1 , 10000 Zagreb , Croatia.
Faculty of Food Technology and Biotechnology , University of Zagreb , Pierottijeva 6 , 10000 Zagreb , Croatia.
J Org Chem. 2019 Oct 4;84(19):12471-12480. doi: 10.1021/acs.joc.9b01944. Epub 2019 Sep 12.
In the reaction of purines with ferrocenoyl chloride in dimethylformamide (DMF), a regioselective acylation occurred. The two products have been isolated and, according to detailed NMR analysis, identified as - and -ferrocenoylated isomers. In a more polar solvent, for example, in dimethylsulfoxide (DMSO), the two isomers interconvert to each other. The / isomerization was followed by H NMR spectroscopy, until dynamic equilibrium was reached. Both kinetics and thermodynamics of the transacylation process are governed by a C6-substituent on the purine ring (R = NH, Me, NHBz, OBz). The observed rate constant for the /-isomerization in the adenine system (R = NH) is = 0.3668 h, whereas the corresponding process in the C6-benzyloxypurine is 56 times slower. By use of density functional theory calculations and molecular dynamics simulations, several reaction pathways were considered and explored. Only the reaction mechanism involving DMSO as a nucleophilic reactant is in harmony with the experimental kinetic data. The calculated barrier (Δ = 107.9 kJ/mol; at the M06L/6-311+G(d,p)/SDD level of theory) for this S2-like reaction in the adenine system agrees well with the experimental value of 102.7 kJ/mol. No isomerization was detected in other organic solvents, for example, acetonitrile, ,-dimethylformamide, or acetone, which indicated the exceptional nucleophilicity of DMSO. Our results raise a warning when treating or dissolving acylated purines in DMSO as they are prone to isomerization. We observed that the /-group transfer was specific not only for the organometallic moiety only, but for other acyl groups in purines as well. The relevance of this isomerization may be expected for a series of nucleobases and heterocyclic systems in general.
在嘌呤与二甲基甲酰胺（DMF）中的二茂铁酰氯反应中，发生了区域选择性酰化。已经分离出两种产物，并根据详细的 NMR 分析，将其鉴定为-α和-β-二茂铁酰化异构体。在更极性的溶剂中，例如在二甲基亚砜（DMSO）中，两种异构体可以相互转化。通过 1H NMR 光谱法跟踪 / 异构化，直到达到动态平衡。嘌呤环上的 C6-取代基（R = NH、Me、NHBz、OBz）决定了 transacylation 过程的动力学和热力学。腺嘌呤系统（R = NH）中 /-异构体异构化的观察到的速率常数为 = 0.3668 h，而相应的 C6-苯氧基嘌呤的过程慢 56 倍。通过使用密度泛函理论计算和分子动力学模拟，考虑并探索了几种反应途径。只有涉及 DMSO 作为亲核试剂的反应机制与实验动力学数据一致。在腺嘌呤体系中，这种 S2 样反应的计算能垒（Δ = 107.9 kJ/mol；在 M06L/6-311+G(d,p)/SDD 理论水平）与实验值 102.7 kJ/mol 非常吻合。在其他有机溶剂中，例如乙腈、二甲基乙酰胺或丙酮，没有检测到异构化，这表明 DMSO 具有异常的亲核性。当在 DMSO 中处理或溶解酰化嘌呤时，我们的结果警告人们它们容易发生异构化。我们观察到 /-基团转移不仅对有机金属部分，而且对嘌呤中的其他酰基都具有特异性。这种异构化的相关性可能适用于一系列核苷碱基和杂环系统。
