Kinetics of amide formation through Carbodiimide/N-Hydroxybenzotriazole (HOBt) couplings
Kinetics of amide formation through Carbodiimide/N-Hydroxybenzotriazole (HOBt) couplings
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DOI：
10.1021/jo701558y
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发表时间：
2007-11-09
影响因子：
3.6
通讯作者：
Cox, Brian G.
中科院分区：
文献类型：
--
作者：
Chan, Lai C.;Cox, Brian G.
[图表]在1-甲基-2-吡咯烷酮（NMP）中，使用反应量热法研究了由碳二亚胺EDCI，1和HOBt，2介导的由相应羧酸与甲硫氨酸异丙酯（MIPE）反应形成酰胺4的动力学。反应速率与HOBt的浓度无关，表明反应的速率控制步骤是羧酸与EDCI反应生成相应的O-酰基异脲。所观察到的O-酰基异脲形成的速率常数的pH依赖性与双质子化EDCI（EDCIH 22+，6）和羧酸基团之间的二级反应是一致的。观察到的速率常数急剧下降，在高pH值，EDCI的EDCIH 22+的分数继续强烈下降，而羧酸基团已经完全电离。在20 ℃下，酸3的羧酸根基团与EDCIH 22+之间反应的速率常数k（P）的值为k（P）= 4.1 × 10（4）M-1 s（-1），比在水中测得的类似速率常数高约10（5）倍。随后的催化循环，包括O-酰基异脲与HOBt反应生成HOBt酯，然后HOBt酯与胺反应生成酰胺，HOBt再生，决定了产物分布。在氨基酸3的情况下，O-酰基异脲与MIPE反应生成酰胺4，在较高的pH值下比与碱性较低的内部芳香胺3反应生成二酰胺5更有利。
[GRAPHICS]The kinetics of formation of amide, 4, from the corresponding carboxylic acid by reaction with the isopropyl ester of methionine (MIPE), mediated by carbodiimide EDCI, 1, and HOBt, 2, have been studied in 1-methyl-2-pyrrolidinone (NMP) using reaction calorimetry. The reaction rates have been found to be independent of the concentration of HOBt, showing that the rate-determining step is the reaction between the carboxylic acid and EDCI to give the corresponding O-acylisourea. The pH dependence of the observed rate constants for O-acylisourea formation is consistent with a second-order reaction between doubly protonated EDCI (EDCIH22+, 6) and the carboxylate group. The observed rate constants fall sharply at high pH, as the fraction of EDCI as EDCIH22+ continues to fall strongly, whereas the carboxylic acid group is already fully ionized. The rate constant, k(P), for reaction between the carboxylate group of acid, 3, and EDCIH22+ has a value of k(P) = 4.1 x 10(4) M-1 s(-1) at 20 degrees C, some 10(5) times higher than similar rate constants measured in water. The subsequent catalytic cycle, involving reaction of O-acylisourea with HOBt to give HOBt ester, which then reacts with the amine to give the amide with regeneration of HOBt, determines the product distribution. In the case of the amino acid, 3, reaction of the O-acylisourea with MIPE to give amide, 4, is increasingly favored at higher pH values over that with the less basic internal aromatic amine of 3 to give the diamide 5.