Precise, efficient, and effective control of chemical reaction conditions is a viable measure for the environment-conscious time and energy resource management in modern laboratories and in industry. Parameter changes such as surface enlargement, pH, local reactant accumulation by solvent evaporation and polarization effects, etc., have been shown to greatly affect the reaction rate of a chemical reaction. In electrospray (ES) ionization - a soft ionization method often used for mass spectrometry - all these parameters change constantly and with high dynamics during the nebulization process that generates droplets as the ultimate confined μ-reaction vessels. Therefore, high acceleration factors are reported in literature for a manifold of such μ-droplet reactions. Here, the tri-molecular Mannich reaction was identified as a suitable candidate for studying thermal, electronic, and fluidic manipulation of the ES process to achieve high conversion rates with short reaction times and compare them to the batch reaction. Some of these manipulations were conducted separately to better quantify their individual contributions. Here, the keto-enol-tautomerism of the used β-diketones, the high proton concentrations, and the longer reaction times in the μ-droplets are presumed to have the greatest impact on these enhancement factors. Experiments were performed to find ES conditions with small initial droplets and long droplet flight times where the highest reaction conversion rates are obtained. A sharp increase in the product peak was found at large distances between the mass spectrometry (MS) inlet and ES source at high voltages. Moreover, different trends were found for the two ketones studied, acetylacetone (AcAc) and 1,3-cyclohexanedione (Cyclo), by changing the temperature of the heated ES source. Finally, high conversion rates were obtained for the combination of formaldehyde (Fal) and piperidine (Pip) with AcAc and Cyclo, respectively, with over 90%. With respect to the batch reaction, this is mainly due to an increase in reaction kinetics as well as a shift in thermodynamics for the μ-droplet reaction environment.