Polarizability: a promising descriptor for selecting di-substituted arene supercharging reagents used during electrospray ionization mass spectrometry (ESI-MS); A DFT Study

During electrospray ionization mass spectrometry (ESI-MS) analysis of proteins, the addition of supercharging agents allows for adjusting the maximal charge state, affecting the charge state distribution, and increases the number of ions reaching the detector thus, improving signal detection. Supercharging reagents with higher polarizability values should generate greater signal intensity and increase multiple charging. Molecular polarizability is a vital descriptor for explaining intermolecular interactions.
Method
We employed DFT-derived descriptors and computed molecular polarizability for ten sets of di-substituted (ortho, meta, para isomers) arene supercharging reagents, with reported use during ESI experiments. Calculations employed the density functional/Hartree-Fock hybrid model, B3LYP and the 6-311++G (2df, 2p) basis set as implemented in the Gaussian 09 program. All structural optimizations were done without symmetry restrictions. All optimized structures were subjected to normal mode analysis to verify the nature of the stationary points located. The geometries of the supercharging compounds were optimized as either the neutral or the anion species. The atomic inputs were ionization potential (IP), electron affinity (EA), electronegativity (χ), hardness (ƞ), chemical potential (µ), and dipole moment (D). We determined that the para isomers showed the highest polarizability values in nine out of the ten sets (Table 1). Polarizability also increased with increasing complexity of the substituents on the benzene ring. Polarizability correlated positively with IP, EA, χ, ƞ, and D, and negatively with chemical potential (Figure 1). Our DFT study predicts that the para isomers of di-substituted arene isomers will elicit the strongest ESI responses. Future experiments to compare the isomers are planned to establish this premise.

在蛋白质的静电喷雾电离质谱（ESI-MS）分析过程中，加入超充电剂能够调节最大电荷状态，影响电荷状态分布，并增加达到探测器的离子数量，从而提升信号检测的灵敏度。具有较高极化率的超充电试剂能够产生更强的信号强度，并增加多重充电。分子极化率是解释分子间相互作用的关键描述符。

研究方法：本研究采用密度泛函理论（DFT）导出的描述符和计算分子极化率，针对十组二取代（邻位、间位、对位异构体）芳烃超充电试剂，这些试剂在ESI实验中有应用报道。计算采用Gaussian 09程序中的密度泛函/Hartree-Fock混合模型B3LYP和6-311++G（2df, 2p）基组。所有结构优化均未施加对称性限制。所有优化后的结构均经过正常模式分析，以验证驻点性质。超充电化合物的几何形状优化为中性或阴离子物种。原子输入包括电离能（IP）、电子亲和力（EA）、电负性（χ）、硬度（ƞ）、化学势（µ）和偶极矩（D）。研究发现，在对位异构体中，九组中的极化率值最高（见表1）。极化率与电离能、电子亲和力、电负性、硬度和偶极矩呈正相关，与化学势呈负相关（见图1）。我们的DFT研究预测，二取代芳烃异构体的对位异构体将引发最强的ESI响应。计划进行未来实验以比较异构体，以确立这一前提。