Analytical Methods

DOI: 10.1002/ange.200600660

Thermal Production and Reactions of OrganicIons at Atmospheric Pressure**

Hao Chen, Zheng Ouyang, and R. Graham Cooks*

Ionization of nonvolatile compounds has been accomplishedby a wide selection of desorption ionization (DI) methods inwhich the sample is converted from the condensed phase intovapor-phase ions by high-energy particles (neutral species orions with energies of 5 keV–100 MeV), photon beams (UVorIR energy range), or high electric fields (ca. 1010 Vm�1).Particular examples include secondary-ion mass spectrometry(SIMS),[1] fast atom bombardment (FAB),[2,3] plasma desorp-tion (PD),[4] laser desorption (LD),[5,6] and field desorption(FD).[7] We now report a simple desorption method in whichorganic ions are generated efficiently by heating organic saltsat atmospheric pressure; we also report reactions of these ionsunder ambient conditions. Although thermal ionization oflow ionization energy elements is well-known,[8, 9] atmos-pheric-pressure thermal desorption ionization (APTDI) oforganic ions, as reported here, is unprecedented. Appropriatechoices of the matrix and solvent strongly increase ion

[*] Dr. H. Chen, Dr. Z. Ouyang, Prof. R. G. CooksDepartment of ChemistryPurdue University560 Oval Drive, West Lafayette, IN 47907 (USA)Fax: (+1)765-494-9421E-mail: cooks@purdue.edu

[**] This work was supported by the US National Science Foundation(CHE04-12782).

Supporting information for this article is available on the WWWunder http://www.angewandte.org or from the author.

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intensities in APTDI. Significantly, atmospheric pressure ion–molecule reactions, which have relied on either radiolysis[10–12]

or special high-pressure mass spectrometers,[13] now can bestudied easily in the atmosphere by using thermally producedions. Reactions in this pressure regime bridge condensed-phase and gas-phase ion chemistry.[10,14]

Figure 1 shows the positive-ion APTDI mass spectra ofrepresentative organic salts recorded after rapidly heatingthem in a nitrogen gas stream which carries the ions to adistant mass spectrometer (see apparatus description in theSupporting Information). The model compounds have either

O-, N-, S-, or P-centered positive charges, as represented by2,4,6-triphenylpyrylium tetrafluoroborate (1+BF4

�), 1,2,4,6-tetraphenylpyridinium perchlorate (2+ClO4

�), methyleneblue (3+Cl�), and tetraphenylphosphonium bromide(4+Br�). In these and related spectra, the cation typicallyappears as the base peak and fragmentation is insignificant.Collision-induced dissociation (CID) can be used to producefragmentation; for example, the thermally generated cation1+ (m/z 309) gives rise to the benzoyl cation PhCO+ at m/z 105 as well as fragment ions of m/z 203 and 231 arising fromthe loss of benzaldehyde and benzene, respectively. Thisresult matches the dissociation behavior seen for the same iongenerated by electrospray ionization (ESI; see the SupportingInformation) or by electron ionization (EI),[15,16] thus con-firming the structure of the cation generated by thermaldesorption at atmospheric pressure.

The hypothesis that ions can be formed in a field-independent thermal desorption process was initially pro-

posed by Holland et al.[17] in connection with a model forionization by field desorption (FD) and it was later unambig-uously observed in the thermal evaporation of quaternaryammonium and phosphonium salts in vacuo by Stoll andRAllgen[18] as well as by Cotter and Yergev.[19] The presentwork, however, appears to represent the first case of thermaldesorption of organic salts at atmospheric pressure. Remark-ably, we find that two popular ionic liquids,[20] 1-ethyl-3-methyl-1,3-imidazolium tetrafluoroborate (5+BF4

� ; see theSupporting Information) and 1,3-dimethylimidazoliummethyl sulfate (6+CH3SO4

�), generate the correspondingimidazolium cations duringheating, despite the fact thationic liquids are known to havenegligible vapor pressures.[20,21]

The emission of ions from theviscous ionic liquids at moder-ately elevated temperatureindicates that the strong ionicinteractions in the liquid can bebroken thermally. Collision-induced dissociation of 5+ (m/z 111) yields a fragment ion ofm/z 83 through loss of ethylene,the same process as observedfor the ESI-generated imidazo-lium ion. The present observa-tions on ion desorption fromheated ionic liquids corrobo-rate a very recent report[22] onthe distillation and volatility ofionic liquids that we learned ofafter completing this study.Besides these nonmetallicorganic salts, we also investi-gated the thermal ionization oforganometallic salts andobserved the formation ofintact cations from organome-tallic salts by APTDI (see theSupporting Information for the

example of bis(cyclopentadienyl)cobalt(iii) hexafluorophos-phate (7+PF6

�)). Anions were also observed (for example, theproduction of a perchlorate ion (m/z 99 and 111) fromAPTDI of the salt 2+ClO4

� ; see the Supporting Information).In other cases, adduct ions accompanied the observed intactcations, for example, from tertiary and quaternary ammoniumsalts (see the Supporting Information).

Favorable effects of matrix on ion yields were observed inAPTDI, analogous to those seen in conventional desorptionionization, including MALDI. The intensity of the signalcorresponding to the 2+ ion (m/z 384) generated from2+ClO4

� was enhanced by more than 20 times in the presenceof 1+BF4

� (Figure 2). It is rationalized that the addition of thematrix decreases the thermal decomposition of 2+ClO4

� ,probably by decreasing the sublimation temperature. Arelated observation is that doping of the nitrogen carrier gaswith a polar solvent such as methanol also greatly increasesthe ion yield. For example, the signal for the 1+ ion at m/z 309

Figure 1. APTDI mass spectra of organic salts: a) 1+BF4� , b) 2+ClO4

� , c) 3+Cl� , and d) 4+Br� .

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from salt 1+BF4� was increased by about 30 times using

methanol-doped N2 carrier gas (see the Supporting Informa-tion). It is likely that methanol effectively solvates thegenerated cations/anions and prevents their recombination.The solvated ions subsequently undergo complete desolva-tion before mass analysis.

Strong ion signals are seen for organic salts such as2+ClO4

� and tetrapropylammonium bromide (8+Br�) evenusing amounts as small as 200 pg (see the SupportingInformation). The relatively low efficiency of ionizationachieved in previous vacuum thermal evaporation experi-ments[23,24] (large quantities of sample were used, for example,1 mg) limited their applicability as an analytical method.Counterintuitively, desorption is more efficient when heatingis carried out at atmospheric pressure, probably because thenumerous collisions at atmospheric pressure favor chargeseparation.

The most distinctive feature of the APTDI method is thation desorption occurs at atmospheric pressure. Chargeseparation and ion formation in the gas phase occur outsidethe mass spectrometer, as demonstrated by the drop in ionintensity when a deflecting electrical field (which can bethought of as an ion switch, see the Supporting Information) isplaced ahead of the ion-sampling atmospheric-pressure inter-face of the mass spectrometer. A demonstration of thecomplete removal of a strong stable signal by the simple “ionswitch” is shown in the Supporting Information.

The dramatic solvent-doping effect encouraged us toperform an experiment in which thermal evaporation of aneutral base was followed by gas-phase protonation[25] using aprotic-solvent-doped carrier gas. As shown in Figure 3,successful ionization of neutral 2,4,6-triphenylpyridine wasobserved.

The reactivity of thermally produced ions has also beenexamined. Since APTDI usually generates intact cations/anions from salts and gives very simple mass spectra, it ispossible to perform atmospheric pressure ion–moleculereactions without mass-selection of the reactant ions—currently a formidable task outside the mass spectrometer.

Gas-phase ion chemistry under conditions of very highpressure (0.01� 10 atm)[12,13] gives kinetic, structural, andstereochemical information which allows meaningful corre-lations between gas-phase and condensed-phase ion chemis-try.[10] To perform atmospheric pressure ion–molecule reac-tions we generated reactant ions by APTDI in the presence ofa neutral reagent in a nitrogen gas stream which served tocarry the ion–molecule reaction products into the massspectrometer. The reaction of cation 1+ with aniline to give2+ represents an example. In addition to such homogeneousion/molecule reactions, heterogeneous reactions can also bestudied (for example, the reaction of thermally generated gas-phase reactant ions in a gas stream with condensed-phaseneutral reagents present on a surface). Such reactions[26] differin several important characteristics from conventional ion–molecule reactions: 1) they take place at the heterogeneousgas–solid interface; 2) the neutral analyte molecule can beheavy, polar, and nonvolatile; 3) in situ derivatization of theanalyte on the surface allows its fast selective detection. Theinset of Figure 4 displays the ion–molecule reaction of 1+ (m/z309) generated by APTDI of 1+BF4

� with solid d-lysinepresent on a metal surface to yield the norleucyl-substitutedpyridinium product ion of m/z 437 (Figure 4a). The conver-sion of pyrylium into pyridinium ions[27–29] is an importantroute for the conversion of primary amino groups into avariety of other functionalities such as halide, ester, alcohol,nitrate, thiocyanate, and azide. The structure of the production (m/z 437) was confirmed by its CID spectrum, whichshowed the formation of a signal at m/z 308 arising from theloss of 2-amino-5-hexenoic acid.

An alternative general approach for carrying out hetero-geneous or homogeneous ion–molecule reactions at atmos-pheric pressure is to label the reactant with a charge sitewhich is responsible for thermal desorption but is remotefrom the active functional group at which ion–moleculereactions can occur. As a demonstration, 1-(4-aminophenyl)-2,4,6-triphenylpyridinium cation (9+, m/z 399) was chosen asthe reactant ion (charge-labeled aniline, shown in Figure 5).The organic salt 9+BF4

� used in this study was synthesized

Figure 2. Relative ion currents of the 2+ ion (m/z 384) recorded duringAPTDI of salt 2+ClO4

� with (trace a) and without a matrix of salt1+BF4

� (trace b). During APTDI, the signal corresponding to the matrixion 1+ was also observed at m/z 309.

Figure 3. Mass spectrum recorded on heating neutral 2,4,6-triphenyl-pyridine with methanol/water-doped nitrogen carrier gas. The heatertemperature was set at 100 8C. The inset shows the intact cationregion.

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from 1+BF4� and para-phenylenediamine following the stan-

dard procedure for the synthesis of pyrydinium salts[27]

(characterization data are shown in the Supporting Informa-tion). In this case, thermally generated ions 9+ were trans-

ported in a pure nitrogen gas stream into a reactor where theyreacted with benzaldehyde vapor. The reactor volume isoutside the mass spectrometer and the Schiff base product iscarried into the instrument by the nitrogen stream and isobserved at m/z 487 (Figure 5). When benzaldehyde wasreplaced by propionaldehyde or para-tolualdehyde, thecorresponding product ions of m/z 439 or 501 were observed,respectively (see the Supporting information).

In conclusion, we have shown a new atmospheric pressuremethod (APTDI) to generate gas-phase ions as well as novelprotocols for performing ion–molecule reactions at atmos-pheric pressure. Organic salts are readily available and thesimplicity of direct thermal evaporation at atmosphericpressure together with the possibility of studying the reac-tivity of the thermally produced ions gives these findingspotential to have a significant impact in gas-phase ionchemistry as well as to have promising applications forin situ chemical analysis. These results, including the generallack of fragmentation in the reported spectra, point to theunexpected possibility that manymaterials, when heated in aninert atmosphere at an appropriate rate, will sublime ratherthan decompose or polymerize.

Received: February 20, 2006Published online: April 26, 2006

.Keywords: analytical methods · ionic liquids · ion–moleculereactions · mass spectrometry · thermal desorption

[1] A. Benninghoven, H. W. Werner, F. G. Rudenauer, SecondaryIon Mass Spectrometry: Basic Concepts, Instrumental Aspects,Applications, Wiley-Interscience, New York, 1986.

[2] M. Barber, R. S. Bordoli, R. D. Sedgwick, A. N. Tyler, J. Chem.Soc. Chem. Commun. 1981, 325.

[3] C. Fenselau, R. J. Cotter, Chem. Rev. 1987, 87, 501.[4] C. J. McNeal, R. D. Macfarlane, J. Am. Chem. Soc. 1981, 103,

1609.[5] M. Karas, U. Bahr, U. Giessmann, Mass Spectrom. Rev. 1991, 10,

335.[6] F. Hillenkamp, M. Karas, R. C. Beavis, B. T. Chait, Anal. Chem.

1991, 63, 1193A.[7] H. D. Beckey, Principles of Field Ionization and Field Desorp-

tion in Mass Spectrometry, Pergamon, Oxford, 1977.[8] D. W. Koppenaal, Anal. Chem. 1988, 60, 113R.[9] D. H. Smith, Pract. Spectrosc. 2000, 25, 1.[10] F. Cacace, Acc. Chem. Res. 1988, 21, 215.[11] M. Attina, F. Cacace, P. Giacomello, M. Speranza, J. Am. Chem.

Soc. 1980, 102, 6896.[12] M. Speranza, Mass Spectrom. Rev. 1992, 11, 73.[13] W. B. Knighton, E. P. Grimsrud,Adv. Gas Phase Ion Chem. 1996,

2, 219.[14] R. G. Cooks, H. Chen, M. N. Eberlin, X. Zheng, W. A. Tao,

Chem. Rev. 2006, 106, 188.[15] K. L. Busch, B.-H. Hsu, K. W. Wood, R. G. Cooks, J. Org. Chem.

1984, 49, 764.[16] A. M. Deffield, C. Djerassi, A. T. Balaban, Org. Mass Spectrom.

1971, 5, 87.[17] J. F. Holland, B. Soltmann, C. C. Sweeley, Biomed. Mass

Spectrom. 1976, 3, 340.[18] R. Stoll, F. W. RAllgen, J. Chem. Soc. Chem. Commun. 1980, 789.[19] R. J. Cotter, A. L. Yergey, J. Am. Chem. Soc. 1981, 103, 1596

Figure 4. a) Schematic representation of the desorption ionization ofd-lysine by the thermally produced 1+ ion (m/z 309) at atmosphericpressure; b) mass spectrum showing the generation of norleucyl-substituted pyridinium ion (m/z 437) in a heterogeneous ion/moleculereaction.

Figure 5. Mass spectrum showing the ion–molecule reaction of thethermally generated 9+ ion and benzaldehyde in the homogeneousphase to form a Schiff base at atmospheric pressure.

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[20] J. Dupont, J. Spencer, Angew. Chem. 2004, 116, 5408; Angew.Chem. Int. Ed. 2004, 43, 5296.

[21] T. Welton, Chem. Rev. 1999, 99, 2071.[22] M. J. Earle, J. M. S. S. Esperanc, M. A. Gilea, J. N. C. Lopes,

L. P. N. Rebelo, J. W. Magee, K. R. Seddon, J. A. Widegren,Nature 2006, 439.

[23] B. L. MilMman, Zh. Anal. Khim. 1986, 41, 1934.[24] R. Stoll, F. W. Rollgen, Org. Mass Spectrom. 1981, 16, 72.[25] For methods of studying atmospheric pressure proton transfer

reactions, see Z. TakNts, J. M. Wiseman, B. Gologan, R. G.Cooks, Anal. Chem. 2004, 76, 4050.

[26] H. Chen, I. Cotte-Rodriguez, R. G. Cooks, Chem. Commun.2006, 597.

[27] A. R. Katritzky, D. E. Leahy, J. Chem. Soc. Perkin Trans. 2 1985,171.

[28] A. R. Katritzky, R. H. Manzo, J. M. Lloyd, R. C. Patel, Angew.Chem. 1980, 92, 315; Angew. Chem. Int. Ed. Engl. 1980, 19, 306.

[29] A. R. Katritzky, Tetrahedron 1980, 36, 679.

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