Sulfa drugs are an important class of pharmaceuticals in the treatment of bacterial infections. The amido/imido tautomerism of these molecules in their neutral form has been widely discussed in the literature. Here, we study the protonation preferences of sulfa drugs upon electrospray ionization (ESI) using IR action spectroscopy of the ionized gas-phase molecules in a mass spectrometer. Our set of molecules includes sulfanilamide (SA), the progenitor of the family of sulfa drugs, and the actual, sulfonamide nitrogen substituted, sulfa drugs sulfamethoxazole (SMX), sulfisoxazole (SIX), sulfamethizole (SMZ), sulfathiazole (STZ), sulfapyridine (SP) and sulfaguanidine (SG). IR multiple photon dissociation (IRMPD) spectra were recorded for the protonated sulfa drugs using a Fourier transform ion cyclotron resonance mass spectrometer (FT-ICR-MS) and an optical parametric oscillator/amplifier (OPO/OPA) as well as the FELIX free electron laser (FEL) as IR sources. The OPO provides tunable IR radiation in the NH stretch region (3100–3700 cm\(^{-1}\)), while the FEL covers the fingerprint region (520–1750 cm\(^{-1}\)). Comparison of experimental IR spectra with spectra predicted using density functional theory allowed us to determine the gas-phase protonation site. For SA, the sulfonamide NH\(_2\) group was identified as the protonation site, which contrasts the situation in solution, where the anilinic NH\(_2\) group is protonated. For the derivative sulfa drugs, the favored protonation site is the nitrogen atom included in the heterocycle, except for SG, where protonation occurs at the sulfonamide nitrogen atom. The theoretical investigations show that the identified protonation isomers correspond to the lowest-energy gas-phase structures.

磺胺药物是治疗细菌感染的重要药物类别。这些分子以中性形式的酰胺基/酰亚胺基互变异构现象已在文献中广泛讨论。在这里，我们使用质谱仪中离子化气相分子的红外作用光谱研究了电喷雾电离（ESI）时磺胺类药物的质子化偏好。我们的分子集包括磺胺类药物的祖先磺胺（SA），以及实际的磺酰胺氮取代的磺胺类药物磺胺甲恶唑（SMX），磺胺异恶唑（SIX），磺胺甲唑（SMZ），磺胺噻唑（STZ），磺胺吡啶（SP）和磺胺胍（SG）。使用傅立叶变换离子回旋共振质谱仪（FT-ICR-MS）和光学参量振荡器/放大器（OPO / OPA）以及FELIX自由电子记录质子化磺胺药物的IR多光子解离（IRMPD）光谱激光（FEL）作为红外光源。OPO在NH拉伸区域（3100–3700厘米）中提供可调的IR辐射\（^ {-1} \），而FEL覆盖指纹区域（520–1750厘米\（^ {-1} \））。实验红外光谱与使用密度泛函理论预测的光谱的比较使我们能够确定气相质子化位点。对于SA，磺酰胺NH \（_ 2 \）基团被确定为质子化位点，这与溶液中苯丙胺NH \（_ 2 \）基团被质子化的情况相反。对于衍生的磺胺类药物，首选的质子化位点是杂环中包含的氮原子，但SG除外，SG质子化发生在磺酰胺的氮原子上。理论研究表明，确定的质子化异构体对应于最低能量的气相结构。