Kinetic Control of Protonation in Electrospray Ionization
Kinetic Control of Protonation in Electrospray Ionization
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DOI：
10.1007/s13361-010-0037-0
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发表时间：
2011-02-01
影响因子：
3.2
通讯作者：
Richards, Don S.
中科院分区：
文献类型：
--
作者：
Joyce, J. Richard;Richards, Don S.
质子化在分子中的位置对产物离子MS/MS图谱中观察到的碎片有很大影响。在电喷雾正电离质谱中，质子化通常主要发生在分子上最碱性的位置，以产生热力学上有利的质子化物种。然而，文献中并不清楚是液相热力学还是气相热力学的影响更大。本文描述了克里佐替尼及其两种杂质的质子化和碎裂行为。Crizotinib有两个可能的质子化位置，一个是吡啶氮，一个是仲胺，即哌啶氮；前者是气相中的有利位置，后者是液体中较有利的位置。这些杂质含有哌啶氮上的烷基取代，生成叔胺物种。文献表明，在液相中，哌啶氮仍然是最碱性的中心，但在气相中，吡啶氮和哌啶氮具有非常相似的碱性。这三个分子的碎裂数据表明，仲胺和叔胺优先且几乎完全在不同的位置发生质子化。我们认为仲胺质子化在哌啶氮上(受溶液热力学的影响)和两个叔胺结构质子化在吡啶氮上是因为分子最基本位置的空间位阻，这使得质子化过程可以进行动力学控制。
The site of protonation in a molecule can greatly affect the fragments observed in product ion MS/MS spectra. In electrospray positive ionization mass spectra, protonation usually occurs predominantly on the most basic site on the molecule to produce the thermodynamically favored protonated species. However, the literature is unclear whether liquid phase or gas phase thermodynamics has the greater influence. This paper describes the protonation and fragmentation behavior of crizotinib and two of its impurities. Crizotinib has two possible protonation sites, a pyridine nitrogen and a secondary amine, piperidine nitrogen; the former is the favored site in the gas phase and the latter the more favored site in the liquid phase. The impurities contain alkyl substitution on the piperidine nitrogen, producing tertiary amine species. Literature precedence suggests that in the liquid phase, the piperidine nitrogen is still the most basic site but, in the gas phase, the pyridine nitrogen and the piperidine nitrogen have very similar basicities. Fragmentation data for the three molecules suggest that the secondary and tertiary amines protonate preferentially and almost exclusively on different sites. We propose that the secondary amine protonates on the piperidine nitrogen (influenced by solution thermodynamics) and the two tertiary amine structures protonate on the pyridine nitrogen because of steric hindrance at the most basic site of the molecule, allowing kinetic control of the protonation process.