The ability to control the chemical composition of surfaces is of fundamental interest and growing technological importance due to developments in nanotechnology, biotechnology, organic electronics, and functionalized materials.[1] The motivation behind this study is to generate new materials at surfaces, including new covalently bound surface coatings, by using molecular ions in the ambient environment as chemical reagents. In particular, we are interested in generating twoand three-dimensional peptidic macromolecular structures by cross-linking the linear peptide chains generated by conventional solid-phase synthesis [2] using suitable ambient ionic reagents. There is already a substantial literature on peptide cross-linking [3] but our approach is unique in that we use ionic reagents generated by mass spectrometry (MS) to effect rapid, small-scale derivatization. In pursuit of this larger aim, the present study focuses on cross-linking of oligolysines (K n , n = 3, 5) and on the model derivatization reaction of aromatic aldehydes with Girard T reagent. The results indicate that exposure of a nominally dry derivatizing agent (e.g., Girard T or an N-hydroxysuccinimide (NHS) ester reagent) present at a surface to a stream of charged microdroplets containing the analyte (e.g. an aldehyde or a peptide) is a rapid and efficient method of small-scale chemical synthesis.There is a growing interest in the study of the reactions of organic ions outside of the mass spectrometer, both at surfaces and in the gas phase. For example, [4] dry pyrylium ions react in air at surfaces bearing amines to give the pyridinium derivatives. This reactive scattering experiment at atmospheric pressure is the analog of typical vacuum-based ion/surface reactions performed with mass-selected ions at surfaces inside a mass spectrometer.[5] As examples of gasphase reactions, organic ions generated by electrospray ionization (ESI) and dried in a heated metal tube [6] undergo atmospheric pressure ionic reactions like the Fischer indole synthesis, the Borsche-Drechsel cyclization, and the pinacol rearrangement outside the mass spectrometer. Charged microdroplets are used to interrogate surfaces in desorption electrospray ionization (DESI), a method of ambient surface analysis. [7, 8] If a reagent is included in the primary spray solvent, then chemical reactions occur at greatly accelerated rates in the secondary droplets splashed [9] from the surface.For example, the rate of derivatization of ketones by the Girard T reagent is accelerated by two to three orders of magnitude in the droplet/surface process compared to conventional bulk solution. [10,11] The reactive DESI experiment also facilitates identification of reaction intermediates, [12] something also achieved with ESI.[13]Ambient peptide cross-linking was examined in two ways, in one experiment the cross-linking reagent was ionized and delivered in charged microdroplets to the peptide present on an ambient glass surface. In the other experiment, the reagents were interchanged and the pep...