Practical implications of some recent studies in electrospray ionization fundamentals

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I. Introduction 363 II. The Mechanics of ESI‐MS 363 III. Analyte Characteristics and Selectivity 365 A. Charging the Analyte 366 1. Ionization Through Charge Separation 366 2. Adduct Formation 366 3. Ionization Through Gas‐Phase Reactions 366 4. Ionization Through Electrochemical Oxidation or Reduction 368 B. Analyte Surface Activity and Its Effect on ESI Response 368 1. Surface Activity and the Fissioning Process 369 2. Predicting ESI Response from Other Parameters 369 C. The Role of Analyte pKa and Solvent pH 370 D. Improving ESI Response Through Derivatization 371 IV. The Working Curve and Dynamic Range 373 A. Detection Limits With ESI 373 1. Background Interferences 373 2. Random Noise 374 3. Ion Transmission and Sensitivity 374 B. Sources of Signal Saturation at High Concentrations 375 1. Limited Amount of Excess Charge 375 2. Limited Space on Droplet Surfaces 375 3. Suppression and Competition at High Concentrations 376 C. Improving the Detection Limit and Linear Dynamic Range 376 1. Extending to Higher Concentrations 376 2. Extending to Lower Concentrations 376 V. Instrumental Parameters and Stability 377 A. Current–Voltage Curves 377 B. Effect of Instrumental Parameters on the Current–Voltage Curve 378 C. Self‐Stabilizing Operation 379 D. Non‐Conductive vs. Conductive Spray Capillaries 379 VI. Solution Characteristics 380 A. The Ideal ESI Solvent 380 B. Solvent Choice for Analysis in the Positive Ion Mode 381 C. Solvent Choice for Analysis in the Negative Ion Mode 381 D. Compatibility Between ESI and Liquid Separation Techniques 382 VII. Summary 382 VIII. Acknowledgment 383 References 383 In accomplishing successful electrospray ionization analyses, it is imperative to have an understanding of the effects of variables such as analyte structure, instrumental parameters, and solution composition. Here, we review some fundamental studies of the ESI process that are relevant to these issues. We discuss how analyte chargeability and surface activity are related to ESI response, and how accessible parameters such as nonpolar surface area and reversed phase HPLC retention time can be used to predict relative ESI response. Also presented is a description of how derivitizing agents can be used to maximize or enable ESI response by improving the chargeability or hydrophobicity of ESI analytes. Limiting factors in the ESI calibration curve are discussed. At high concentrations, these factors include droplet surface area and excess charge concentration, whereas at low concentrations ion transmission becomes an issue, and chemical interference can also be limiting. Stable and reproducible non‐pneumatic ESI operation depends on the ability to balance a number of parameters, including applied voltage and solution surface tension, flow rate, and conductivity. We discuss how changing these parameters can shift the mode of ESI operation from stable to unstable, and how current–voltage curves can be used to characterize the mode of ESI operation. Finally, the characteristics of the ideal ESI solvent, including surface tension and conductivity requirements, are discussed. Analysis in the positive ion mode can be accomplished with acidified methanol/water solutions, but negative ion mode analysis necessitates special constituents that suppress corona discharge and facilitate the production of stable negative ions. © 2002 Wiley Periodicals, Inc., Mass Spec Rev 20: 362–387, 2001; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mas.10008