Simple chip-based interfaces for on-line monitoring of supramolecular interactions by nano-ESI MS.

Two simple interfaces were designed and realized, enabling on-line coupling of microfluidics reactor chips to a nanoflow electrospray ionization (NESI) time-of-flight (TOF) mass spectrometer (MS). The interfaces are based on two different approaches: a monolithically integrated design, in which ionization is assisted by on-chip gas nebulization, and a modular approach implying the use of commercially available Picospray tips. Using reserpine as a reference compound in a 1ratio1 mixture of acetonitrile and water revealed that both interfaces provide a remarkably stable mass spectrometric signal (standard deviations lower than 8% and 1% for the monolithic and modular approaches, respectively). Glass microreactors, containing mixing zones, were fabricated and coupled to the modular interface with perfluoroelastomer Nanoport fluidics connectors, providing a tool to study chemical reactions on-line. Investigation of the mixing dynamics showed that complete on-chip reagents mixing is achieved within a few tens of milliseconds. Metal-ligand interactions of Zn-porphyrin with pyridine (2), 4-ethylpyridine (3), 4-phenylpyridine (4), N-methylimidazole (5), and N-butylimidazole (6) in acetonitrile as well as host-guest complexations of beta-cyclodextrin (7) with N-(1-adamantyl)acetamide (8) or 4-tert-butylacetanilide (9) in water were studied by mass spectrometry using the modular NESI-chip interface. From on-chip dilution-based mass spectrometric titrations of Zn-porphyrin 1 with pyridine (2) or 4-phenylpyridine (4) in acetonitrile Ka-values of 4.6 +/- 0.4 x 10(3) M(-1) and 6.5 +/- 1.2 x 10(3) M(-1), respectively, were calculated. The Ka-values are about four times larger than those obtained with UV/vis spectroscopy in solution, probably due to a higher ionization efficiency of complexed compared to uncomplexed Zn-porphyrin. For the complexation of N-(1-adamantyl)acetamide (8) with beta-cyclodextrin (7), a Ka-value of 3.6 +/- 0.3 x 10(4) M(-1) was obtained, which is in good agreement with that determined by microcalorimetry.

[1]  I. Mezić,et al.  Chaotic Mixer for Microchannels , 2002, Science.

[2]  Troy D Wood,et al.  Reproducibility in fabrication and analytical performance of polyaniline-coated nanoelectrospray emitters. , 2003, Analytical chemistry.

[3]  Monica Veszelei,et al.  Poly(dimethylsiloxane) microchip: microchannel with integrated open electrospray tip. , 2004, Lab on a chip.

[4]  B. D. Berezin.  Coordination Compounds of Porphyrins and Phthalocyanine , 1981 .

[5]  S. Jacobson,et al.  Novel microfabricated device for electrokinetically induced pressure flow and electrospray ionization mass spectrometry. , 2000, Journal of Chromatography A.

[6]  M. Mann,et al.  Electrospray ionization for mass spectrometry of large biomolecules. , 1989, Science.

[7]  B. Ganem,et al.  Detection of noncovalent receptor-ligand complexes by mass spectrometry , 1991 .

[8]  D R Knapp,et al.  Microfabrication of polydimethylsiloxane electrospray ionization emitters. , 2001, Journal of chromatography. A.

[9]  R. Aebersold,et al.  Identification of proteins by capillary electrophoresis-tandem mass spectrometry. Evaluation of an on-line solid-phase extraction device. , 1997, Journal of chromatography. A.

[10]  J. Henion,et al.  Demonstration of direct bioanalysis of drugs in plasma using nanoelectrospray infusion from a silicon chip coupled with tandem mass spectrometry. , 2003, Analytical chemistry.

[11]  J. Rossier,et al.  Polymer microspray with an integrated thick-film microelectrode. , 2001, Analytical chemistry.

[12]  Robert L. White,et al.  Disposable Emitters for On‐line Capillary Zone Electrophoresis/Nanoelectrospray Mass Spectrometry , 1997 .

[13]  Klavs F. Jensen,et al.  Microchemical systems: Status, challenges, and opportunities , 1999 .

[14]  Javier Ramirez,et al.  Chiral recognition in gas-phase cyclodextrin: Amino acid complexes—Is the three point interaction still valid in the gas phase? , 2001, Journal of the American Society for Mass Spectrometry.

[15]  P. Zavracky,et al.  Multichannel microchip electrospray mass spectrometry. , 1997, Analytical chemistry.

[16]  E. Verpoorte.  Microfluidic chips for clinical and forensic analysis , 2002, Electrophoresis.

[17]  F. Hirayama,et al.  Cyclodextrin Drug Carrier Systems. , 1998, Chemical reviews.

[18]  C. Enke,et al.  Practical implications of some recent studies in electrospray ionization fundamentals. , 2001, Mass spectrometry reviews.

[19]  Klavs Jensen,et al.  Chemical kinetics: Smaller, faster chemistry , 1998, Nature.

[20]  Gwo-Bin Lee,et al.  Micro devices integrated with microchannels and electrospray nozzles using PDMS casting techniques , 2002 .

[21]  Jun Kameoka,et al.  An electrospray ionization source for integration with microfluidics. , 2002, Analytical chemistry.

[22]  D. Reinhoudt,et al.  Anion complexation by glycocluster thioureamethyl cavitands: novel ESI-MS-based methods for the determination of Ka values. , 2004, Chemistry.

[23]  M. Mann,et al.  Of protons or proteins , 1988 .

[24]  Göran Stemme,et al.  Development of micromachined hollow tips for protein analysis based on nanoelectrospray ionization mass spectrometry , 2002 .

[25]  Keiko Takahashi,et al.  Organic Reactions Mediated by Cyclodextrins. , 1998, Chemical reviews.

[26]  C. Henry.  Micro Meets Macro: Interfacing microchips and mass spectrometers , 1997 .

[27]  Renato Zenobi,et al.  Quantitative determination of noncovalent binding interactions using soft ionization mass spectrometry , 2002 .

[28]  D. DeVoe,et al.  Efficient electrospray ionization from polymer microchannels using integrated hydrophobic membranes. , 2004, Lab on a chip.

[29]  Paul Watts,et al.  The application of micro reactors to synthetic chemistry , 2001 .

[30]  D. Jed Harrison,et al.  Analytical microdevices for mass spectrometry , 2000 .

[31]  J. Szejtli.  Introduction and General Overview of Cyclodextrin Chemistry. , 1998, Chemical reviews.

[32]  C. Lebrilla,et al.  Evidence for the Formation of Gas-Phase Inclusion Complexes with Cyclodextrins and Amino Acids , 2000 .

[33]  Stephane Mouradian,et al.  Lab-on-a-chip: applications in proteomics. , 2002, Current opinion in chemical biology.

[34]  A. Neyer,et al.  A new on-chip ESI nozzle for coupling of MS with microfluidic devices. , 2004, Lab on a chip.

[35]  A. D. Mello,et al.  Focus DNA amplification: does ‘small’ really mean ‘efficient’? , 2001 .

[36]  C. Lebrilla.  The gas-phase chemistry of cyclodextrin inclusion complexes. , 2001, Accounts of chemical research.

[37]  P. Kebarle,et al.  On the mechanisms by which the charged droplets produced by electrospray lead to gas phase ions , 2000 .

[38]  R. Aebersold,et al.  A microfabricated device for rapid protein identification by microelectrospray ion trap mass spectrometry. , 1997, Analytical chemistry.

[39]  B. Pramanik,et al.  Electrospray ionization mass spectrometry for the study of non-covalent complexes: an emerging technology. , 1998, Journal of mass spectrometry : JMS.

[40]  J. Ramsey,et al.  Generating electrospray from microchip devices using electroosmotic pumping. , 1997, Analytical chemistry.

[41]  D. Reinhoudt,et al.  Capped biscalix[4]arene-Zn-porphyrin: metalloreceptor with a rigid cavity , 1995 .

[42]  Niels Lion,et al.  On-chip protein sample desalting and preparation for direct coupling with electrospray ionization mass spectrometry. , 2003, Journal of chromatography. A.

[43]  J. Khandurina,et al.  Bioanalysis in microfluidic devices. , 2002, Journal of chromatography. A.

[44]  Sequential electrospray analysis using sharp-tip channels fabricated on a plastic chip , 2001 .

[45]  Jan B. F. N. Engberts,et al.  Hydrophobic Effects. Opinions and Facts , 1993 .

[46]  A. Hedges.  Industrial Applications of Cyclodextrins. , 1998, Chemical reviews.

[47]  Paul Yager,et al.  Simple quantitative optical method for monitoring the extent of mixing applied to a novel microfluidic mixer , 2004 .

[48]  S. Gaskell.  Electrospray: Principles and Practice , 1997 .

[49]  C. Robinson,et al.  Use of a microchip device coupled with mass spectrometry for ligand screening of a multi-protein target. , 2003, Analytical chemistry.

[50]  B. Karger,et al.  Microfabricated devices for capillary electrophoresis-electrospray mass spectrometry. , 1999, Analytical chemistry.

[51]  A J de Mello,et al.  Microchip-based synthesis and analysis: control of multicomponent reaction products and intermediates. , 2001, The Analyst.

[52]  P. Kebarle.  A brief overview of the present status of the mechanisms involved in electrospray mass spectrometry. , 2000, Journal of mass spectrometry : JMS.

[53]  L. Benson,et al.  In line desalting mass spectrometry for the study of noncovalent biological complexes. , 2003, Analytical chemistry.

[54]  Jun Kameoka,et al.  Chip-based P450 drug metabolism coupled to electrospray ionization-mass spectrometry detection. , 2003, Analytical chemistry.

[55]  A. Jaffrezic,et al.  Correlation Between Solvation Energies and Electrospray Mass Spectrometric Response Factors. Study by Electrospray Mass Spectrometry of Supramolecular Complexes in Thermodynamic Equilibrium in Solution , 1996 .

[56]  C. Schalley.  Supramolecular chemistry goes gas phase: the mass spectrometric examination of noncovalent interactions in host–guest chemistry and molecular recognition , 2000 .

[57]  A. Manz,et al.  TECHNICAL NOTE: A miniaturized glow discharge applied for optical emission detection in aqueous analytes , 2002 .

[58]  M. Wilm,et al.  Analytical properties of the nanoelectrospray ion source. , 1996, Analytical chemistry.

[59]  Paul Watts,et al.  Micro reactors: principles and applications in organic synthesis , 2002 .

[60]  John B. Fenn,et al.  Electrospray ionization–principles and practice , 1990 .

[61]  M. Vincenti.  Special feature: Perspective. Host–guest chemistry in the mass spectrometer , 1995 .

[62]  D. Reinhoudt,et al.  Influencing the binding selectivity of self-assembled cyclodextrin monolayers on gold through their architecture. , 2001, Chemistry.

[63]  Paul Watts,et al.  The application of micro reactors for organic synthesis. , 2005, Chemical Society reviews.

[64]  R. E. Oosterbroek,et al.  Surface effects in the esterification of 9-pyrenebutyric acid within a glass micro reactor. , 2003, Chemical communications.

[65]  Y. Tai,et al.  A micromachined chip-based electrospray source for mass spectrometry. , 2000, Analytical chemistry.

[66]  H. Löwe,et al.  Chemistry in microstructured reactors. , 2004, Angewandte Chemie.

[67]  Terry D. Lee,et al.  A microscale electrospray interface for on-line, capillary liquid chromatography/tandem mass spectrometry of complex peptide mixtures. , 1995, Analytical chemistry.

[68]  Yuehe Lin,et al.  Microfabricated isoelectric focusing device for direct electrospray ionization‐mass spectrometry , 2000, Electrophoresis.

[69]  D. Figeys,et al.  Proteomics on a chip: Promising developments , 2001, Electrophoresis.

[70]  B. Karger,et al.  Integrated multichannel microchip electrospray ionization mass spectrometry: analysis of peptides from on-chip tryptic digestion of melittin. , 1997, Rapid communications in mass spectrometry : RCM.

[71]  P. Vouros,et al.  False positives and the detection of cyclodextrin inclusion complexes by electrospray mass spectrometry , 1995, Journal of the American Society for Mass Spectrometry.

[72]  R. Cole,et al.  Dication induced stabilization of gas-phase ternary beta-cyclodextrin inclusion complexes observed by electrospray mass spectrometry , 2003, Journal of the American Society for Mass Spectrometry.

[73]  J. Peter-Katalinic,et al.  Fully automated chip-based mass spectrometry for complex carbohydrate system analysis. , 2004, Analytical chemistry.