Accelerated C–N Bond Formation in Dropcast Thin Films on Ambient Surfaces
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The aza-Michael addition and the Mannich condensation occur in thin films deposited on ambient surfaces. The reagents for both C–N bond formation reactions were transferred onto the surface by drop-casting using a micropipette. The surface reactions were found to be much more efficient than the corresponding bulk solution-phase reactions performed on the same scale in the same acetonitrile solvent. The increase in rate of product formation in the thin film is attributed to solvent evaporation in the open air which results in reagent concentration and produces rate acceleration similar to that seen in evaporating droplets in desorption electrospray ionization. This thin film procedure has potential for the rapid synthesis of reaction products on a small scale, as well as allowing rapid derivatization of analytes to produce forms that are easily ionized by electrospray ionization. Analysis of the derivatized sample directly from the reaction surface through the use of desorption electrospray ionization is also demonstrated.
Key wordsC–N bond formation Aza-Michael addition Mannich reaction Surface chemistry Solvent effects Ion chemistry Microdroplets Mass spectrometry
Solvent evaporation leading to rate enhancement of chemical reactions has recently been reported for charged microdroplets reactor systems generated in reactive desorption electrospray ionization (DESI) [1,10,11] and ambient ion soft landing [12, 13, 14] experiments. Traditionally, the advantages of microreactor systems are recognized to include rapid mixing of reagents, effective control of reaction time, and the ability to control interfacial chemistry . It has also become apparent that the larger surface areas associated with microreactor systems favor physical processes such as evaporation (when this is allowed) and partitioning of solutes from the bulk to the surface [16, 17, 18], which should increase those reactions that are dependent on surface active species. In the special case of charged microdroplets, the increase in product yield is ascribed to solvent evaporation, which causes moderate pH values in the starting droplet to reach extreme values while reagent concentrations also increase [1,19]. Such a system might be particularly suitable for accelerating acid/base catalyzed bimolecular reactions. Aside from microreactors, solid films of reactants containing microscopic quantities of solvent have been reported to serve as efficient reaction media in which organic reactions can be accelerated [12,20]. Otera and coworkers generated solid films through the use of a rotary evaporator , and reaction was observed to be more efficient than that under the corresponding bulk solution-phase conditions when the solid film was allowed to stand under ambient conditions. This procedure was applied to imine synthesis, the Wittig reaction, and quaternization of tertiary phosphine, and pyridine . Gentle deposition of electrospray [21,22] droplets at ambient surfaces has been shown to afford organic solid films in which the Girard condensation is accelerated compared with the bulk solution-phase reaction conducted on the same scale . In this paper, we show that similar enhancement in product yield can be achieved for C–N bond forming reactions in nominally dry mixtures generated by simple drop-casting of reactant solutions onto ambient surfaces. The drop-casted products are easily collected or directly analyzed using surface analysis techniques such as DESI without dissolution.
Chemicals and Reagents
Acrylamide, acrylonitrile, methyl acrylate, morpholine, piperidine, cycloheptylamine, benzaldehyde, cyclohexanone, and chloroform were purchased from Sigma-Aldrich (Milwaukee, WI, USA), ethanolamine was obtained from Acros Organics (Geel, Belgium), and methanol and acetonitrile (HPLC grade) from Mallinckrodt Baker Inc. (Phillipsburg, NJ, USA). Deionized/distilled water was obtained using a Barnstead/Thermolyne deionizer unit (Barnstead Mega-Pure System, Dubuque, IA, USA).
Nanospray Ionization Mass Spectrometry for Product Analysis
Surface reaction was achieved by depositing appropriate volumes (typically 2 μL) of each of the reagent solutions to be reacted separately (but at the same spot) onto a surface, and allowing the resulting drop to dry under ambient conditions. After surface reaction, the dried material was dissolved into 10 μL of methanol/ water (1:1, vol/vol) and characterized using nanoelectrospray ionization-MS (nanospray-MS or nESI-MS). A nanospray was generated using an emitter (E Series Microelectrode Holder, with Ag wire electrode; Warner Instruments, LLC, Hamden, CT, USA) and applying a voltage of 1.8 kV (~20 nL/min flow rate). These sample analysis conditions involve short ionization periods, and so significant reaction cannot occur during analysis. All MS experiments were performed using a Thermo Fisher Scientific LTQ mass spectrometer (San Jose, CA, USA). Typical MS parameters used included averaging of 3 microscans, 100 ms maximum ion injection time, 15 V capillary voltages, 150 °C capillary temperature, and 65 V tube lens voltage. Data were acquired and processed using Xcalibur 2.0 software (Thermo Fisher Scientific, San Jose, CA, USA). The identification of analyte ions was confirmed by tandem mass spectrometry using collision-induced dissociation (CID). An isolation window of 1.5 Th (mass/charge units) and a normalized collision energy of 30 %–35 % (manufacturer’s unit) was selected for the CID experiments. Reagent (e.g., piperidine) consumption was calculated based on normalized product ion intensities [IP/(IP + IR)], where IP and IR represent protonated product and reagent ion intensities, respectively.
3 Results and Discussion
Acrylamide Reaction with Amines (in acetonitrile solution) at Ambient Surface in the Open Air
The possibility of there being surface effects on reaction efficiency were also investigated. First, chemical effects in the form of possible structural changes of reagent at surfaces due to the absence of solvent were investigated using infrared spectroscopy (Thermo-Nicolet Nexus FTIR, with ATR optics). FTIR spectrum recorded on the nominally dry acrylamide (in the absence of amine) showed a band at about 1670 cm–1, which is attributed to C = O stretching of amides  (Figure S1, Supporting Information) just as is observed in solution-phase and indicating no structural changes at the surface in the absence of solvent. This result suggests that the increase in surface product yield compared with that obtained under bulk conditions is simply due to solvent evaporation leading to reagent concentration. In this regard, the influence of the physical properties of the surface itself on solvent evaporation was further investigated by utilizing gold, Teflon, stainless steel, paper, and aluminum foil as substrates for the aza-Michael addition. (Highly hydrophilic surfaces like glass could not be used because of the extent to which the solvent acetonitrile spreads, making collection of product from the surface particularly difficult). Again, all surfaces provided the expected reaction product, indicating the lack of chemical effects, except for the differences in efficiency of the surface reaction. For example, more products were collected from the inert gold surface than from Teflon (see Figure S2, Supporting Information for detail). Different surfaces yielded products at distinctive rates because hydrophilic surfaces such as gold produced larger surface areas than Teflon, which in turn afforded faster solvent evaporation and, eventually, reagent concentration and more effective collisions in a unit time.
An interfacial version of the aza-Michael addition has been achieved through drop-casting, which yielded rate enhancement over the conventional bulk solution-phase reactions performed on the same scale with no added catalyst. The increase in reaction yield is attributed to reagent concentration in the thin film as solvent evaporates. The expected reaction products were collected from all types of surfaces used, including inert gold substrates and others such as stainless steel and aluminum foil, indicating no apparent chemical surface effects. However, the physical properties of the surfaces employed were found to be important as higher reaction efficiencies were achieved on surfaces that allowed rapid solvent evaporation. A more efficient form of indirect Mannich reaction was also achieved at ambient surfaces through the use of the drop-casting procedure. This thin film method may be a simple, efficient, and practical method for preparing reaction products or intermediates for use in the synthesis of diverse chemical species, including various amino ketones. It is, however, recommended that this protocol should be used for small scale chemical synthesis, a condition in which evaporation of large volumes of organic solvents can be avoided. The drop-casting method may also advance sample analysis via MS by allowing rapid and effective sample derivatization compared with wet chemistry. Direct analysis of the surface product is also achievable using desorption electrospray ionization and (presumably) by other ambient ionization techniques. Moreover, the accelerated reaction products can be collected from the surface for subsequent use, or analysis by other analytical techniques such as nuclear magnetic resonance.
The authors acknowledge funding for this work by the National Science Foundation (CHE NSF 0848650 and 0852740).
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