Ion neutral reactions in the gas phase in mixtures of ROH/CO 2 , R ϭ CH 3 , C 2 H 5 , and 2-C 3 H 7 were studied by supercritical fluid chromatography-mass spectrometry (SFC-MS). Three main reaction series were found for this system; ionization followed by ␣-cleavage, formation of ␣ clusters, and formation of protonated dialkyl ethers from the corresponding alcohol. The ion chemistries were similar for the three alcohols, but that of 2-propanol was somewhat more complex. (J Am Soc Mass Spectrom 2007, 18, 2173-2179 [6]. When SFC is coupled to MS, the modifiers can form several reagent ions. The variety of reagents of different Brönsted acids gives the possibility to choose the correct reagent for a particular type of analysis [14,15]. The chemistry of ion-molecule interactions in the gas phase may provide an elegant substitute for the chromatographic preseparation step in conventional MS analysis. Pure CO 2 has been reported to act as a reagent gas for charge exchange (CE) with solute molecules [16 -18]. Using modified CO 2 , mixed CE/CI mechanisms can be reflected in the mass spectra [19]. This work presents results of the ionneutral reactions in the gas phase, which take place when mixtures of polar modifiers (methanol, ethanol, and 2-propanol) are introduced into the CO 2 mobile phase and expand through the direct fluid interface. The structure of the reagent ions were studied by collision induced dissociation (CID) and deuterium labeling. Previous reports of ion-neutral reactions in these alcohols [20 -24] provided an excellent basis for our study. ExperimentalInstrumentation SFC-MS data were collected by using an Isco 100DX syringe pump (Isco Inc., Lincoln, NE) attached to a double focusing mass spectrometer with EB geometry (DX303; JEOL, Tokyo, Japan). The SFC column was installed in a Carlo Erba high-resolution gas chromatograph (HRGC/MS; Instrument Teknikk Scandinavia AS, Oslo, Norway). The total ion chromatograms (TIC), reconstructed ion chromatograms (RIC), and mass spectra were recorded using Shrader interface and software (Shrader Analytical and Consulting Laboratories, Inc. Detroit, MI). Chromatography was performed using a 60 cm long, 450 m o.d., 320 m i.d., fused silica column packed with 5 m Intersil C 18 particles (Keystone Scientific Inc., Bellefonte, PA). The column outlet and the union connected to the column entrance were both equipped with a stainless steel frit with 2 m pore size (2400 Keystone Scientific). Valco zero dead volume unions (1/16 in. to 1/16 in.) were used. The injector (Valco C14W; Valco Instruments Co. Inc., Houston, TX) with 0.5 L injection loop was connected to the column by 7 cm long deactivated 50 m fused silica capillary tubing. Constant pressure in the chromatographic system was maintained by a 12 cm long, 15 m i.d. linear restricter. The temperature on the restricter tip was kept at 200°C, and the flow rate was 1.8 cm/s. The ion source temperature was 150°C and the column oven was held at 100°C. The electron energy used was 230 eV in CI mode. The pressure in the ion ...