How Ion Pairing Enhances ESI-MS and HPL - ACS Publications

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Triethylamine Solution for the Intractability of Aqueous Gold− Thiolate Cluster Anions: How Ion Pairing Enhances ESI-MS and HPLC of aq-Aun(pMBA)p David M. Black,*,‡ Marcos M. Alvarez,‡ Fangzhi Yan,† Wendell P. Griffith,† Germán Plascencia-Villa,‡ Stephan B. H. Bach,† and Robert L. Whetten*,‡ †

Department of Chemistry and ‡Department of Physics & Astronomy, University of Texas, San Antonio, Texas 78249, United States S Supporting Information *

ABSTRACT: Herein we disclose methods that greatly improve the solution- and gas-phase handling properties of larger aqueous-phase gold−thiolate clusters, which previously presented extreme technical obstacles to molecular analysis and size control, even as they have enjoyed ever-wider applications in materials science and biomedicine. The methods are based upon an analogy between the polyacidic surface structure of the pMBA-protected clusters (pMBA = p-mercaptobenzoic acid) and that of oligonucleotides. A volatile ion-pairing reagent, TEA = triethylamine, greatly improves solution-phase stability near neutral pH and thus facilitates both electrospray generation of the gas-phase ions and the in-line reversedphase ion-pairing HPLC-ESI-MS approach to analyzing complex mixtures of Au-pMBA oligomers and clusters. Previously anticipated but never established compounds, including Au36(pMBA)24, are thereby demonstrated. These results are in accord with recent theoretical simulations of ion pairing of model Au144(pMBA)60 clusters in aqueous solutions. This advance complements our recent work on their nonaqueous (hydrophobic) counterparts, in which redox electrochemistry is sufficient to support the efficient LC-ESI processes, enabling various precise measurements on the intact molecular ions. Here, we report (i) novel conditions for enhanced ESI generation of polyanions of the aqueous clusters and by extension (ii) a notably improved method by which mixtures of these clusters may be successfully separated and detected by ion-pair reversed-phase HPLC-MS.

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INTRODUCTION One special class of larger metal clusters comprises the so-called monolayer-protected clusters (MPCs), which feature (i) a core nanolattice of metal-ion sites that is encapsulated completely by (ii) a set of anionic ligands of the type known to form a selfassembled monolayer (SAM)in which the ligands act as adsorbate groups on the corresponding planar metal surfaces and finally (iii) a charge-compensating number of electrons corresponding to the free electrons of the incipient conduction band of the metallic phase. From a practical standpoint, a critically important feature of noble-metal MPCs is that, with sufficient effort, certain of these clusters can be obtained in substantial quantities, even as compositionally pure forms, which can then be handled and analyzed much as any pure molecular substancei.e., as molecular solids, solutions, and gaseous phasesdespite their great size and complexity.1−3 Several reasons are commonly given for the recently growing interest in the larger noble-metal MPCs, of which we mention but a few: (i) their role in the development of “single-molecule” electron diffraction, as a structure-determination method;4 (ii) their potential as sources of massive ions for gas-phase © XXXX American Chemical Society

explorations; and (iii) their utility in exploring the transition to metallic phase-like behavior in the electronic properties of the metal-rich core. Common to all these purposes is the need for an improved understanding of the fundamental physicochemical properties of these large assemblies that will enable their effective handlingincluding selection (separation) and characterizationfrom the native mixtures in which they are produced. Their solution- and gas-phase handling properties are thought to be determined mainly by their size and by the ligands’ exposed terminal functional groups.1 Herein we report how we exploited an analogy between a prevalent class of gold−thiolate MPCsthose with terminal acidic functionalitiesand a corresponding class of large biomolecules, namely, the oligonucleotides of approximately the same molecular volume. Special Issue: ISSPIC XVIII: International Symposium on Small Particles and Inorganic Clusters 2016 Received: November 30, 2016 Published: December 12, 2016 A

DOI: 10.1021/acs.jpcc.6b12073 J. Phys. Chem. C XXXX, XXX, XXX−XXX

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The Journal of Physical Chemistry C

effective ESI processes provide intriguing clues to the fundamental physicochemical solution-phase properties of these clusters.12,13 Furthermore, our results offer some fascinating insights into this “classic” gold−pMBA series, e.g., the surprise (or delayed) appearance in apparent high abundance of the nonclassical (36,24) species.

Electrospray ionization (ESI) is a key enabling process well suited to the generation of intact gas-phase ions from large and complex solution-phase species, including heavy metal MPCs. Transfer of these ions from the ambient-pressure gas phase into high vacuum enables the precise analysis of redox-active, acid/ base, and other compounds that form adducts or metal−ion complexes in dilute electrolyte solutions.5−8 Among these various compound types, the polyanions, produced by electrospray of polyacids, have historically presented special difficulty for ESI: First, their high metal-ion affinity and propensity for water-cluster formation cause ion suppression that must be reduced by compound-specific sample cleanup and thoughtful preparation procedures prior to analysis.9 Second, as high-polarity polyacids, they require special ionpairing agents to obtain satisfactory liquid chromatographic (LC) behavior.10 Closely related mixtures of these species present proportionately problematic chromatographic analyses. Aqueous, polyacid monolayer protected gold clusters (AuMPC) share these LC and ESI difficulties. They are frequently handled as high-pH (>11) solutions to improve solubility and colloidal stability,11 but this (alkalinity) is incompatible with many kinds of measurements. Recent investigations point to the role played by counterions12 which mediate Au−MPC interactions with solvent molecules, with surrounding (nonpairing) electrolyte, with each other, as well as with stationary phases. Villareal et al. found that sodium (Na+) counterions, and by extension other small hydrophilic cations, create strong salt bridges linking aq-Au144(pMBA)60 (pMBA = paramercaptobenzoic acid) clusters.13 Subsequently, they predicted the strong ion pairing that results when these alkali ions are replaced by bulky quaternary ammonium cations, namely, tetramethylammonium (TMA+) counterions,12 which thereby prevents the attractive salt-bridge interaction between clusters. However, TMA+ is nonvolatile and thus ineligible for ESI-MS. Here, we report the use of mass spectrometry compatible triethylammonium (TEAH+) counterions for improved aqueous-solution properties relating directly to intrinsic ESI processes of desolvation and ion depairing (e.g., evaporation) for improved mass spectral quality and as a mobile phase modifier for reversed-phase LC separation. Quite apart from improving the applicability to well-defined aqueous noble-metal MPCs, there are fundamental issues related to the ESI process itself. Here we disclose a range of early results on the ESI of aqueous MPCs of the gold−pMBA series, aq-Aun(SR)p = (n,p), n = 10−146, employing an in-line capillary HPLC-ESI-MS approach to go far beyond what has been previously reported. The LCMS approach described here offers practical advantages not only for the immediate analytical questions of the presence and abundance of MPC components but also to expedite thermochemical and kinetic analyses of MPC formation processes. The applicability of this method is broad, lending itself to analysis of clusters varying in size and protecting ligand structure. Our principle interest has thus been to improve the ESI properties of larger noble-metal MPCs, both to make them amenable to routine analyses of synthetic samples and of their modified (ligand exchanged and bioconjugated) products and to facilitate gas-phase ion experiments. The wide range of Au−pMBA clusters investigatedranging from aurous-thiolate oligomers (∼2−4 kDa) to classic smaller metallic clusters like (25,18), at ∼8-kDa, all the way to the classic larger (144,60) at ∼37-kDamay serve as model systems of comparatively high rigidity and (surface) charge density. The specific solution parameters required for

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EXPERIMENTAL METHODS

Liquid chromatographic experiments were carried out on an Eksigent nanoLC 2D system. The binary liquid chromatography pump was interfaced with a Bruker micrOTOF time-offlight mass spectrometer. Separations were performed using a Hypersil Gold (ThermoFisher Scientific, San Jose California) C18 HPLC column (0.5 × 150 mm, 5 μm particle size). Mobile phase was prepared as follows: Mobile phase A was prepared by adding 10 mM each of triethylamine and acetic acid to HPLCgrade deionized water. Similarly, mobile phase B was prepared by adding 10 mM each of triethylamine and acetic acid to HPLC-grade methanol. The pH of an equimolar solution of triethylammonium acetate is approximately 7.75. Various 10, 20, and 30 min linear gradients were used to analyze each sample for comparison of elution characteristics. Each gradient varied the contribution of mobile phase B from 5 to 30%. For each method, the gradient was followed by a 2 min hold at 100% mobile phase B to clear the column of any nonpolar compounds followed by a re-equilibration period of 10 min at initial mobile phase conditions. Total mobile phase flow rate was 15.0 μL per minute (μL/min). Injections (1 μL) were carried out via a six-port Rheodyne injection valve and 1 μL sample loop. Samples were dissolved in 10 mM ammonium acetate or 10 mM triethylamine. The Supporting Information section provides details on cluster synthesis and sample preparation. The time-of-flight instrument was tuned prior to LC-MS experiments to improve transmission and detection high-mass cluster ions using a mixture of cesium triiodide. Two different sets of source conditions were used to analyze the mixtures described here. Mass spectra were acquired in the negative-ion mode over a range of m/z 1000−8000. 10K individual spectra were summed per spectrum displayed, and the rolling average function was selected and set to three. Mass Spectrometer Source Conditions 1. Electrospray emitter −4 kV, capillary exit −120 V, skimmer 1−40 V, hexapole 1−23 V, hexapole rf 800 V, skimmer 2−23 V, lens 1 transfer time 50 μS, and lens 1 prepulse storage 100 μs were used. The MCP detector voltage increased to 2350 V (from a standard setting of 2100 V for small molecule work). Nebulizer pressure and sheath gas settings were 1.5 bar and 1.5 L/min, respectively. These conditions were optimal for the smaller clusters found in the Au25(pMBA)18 sample. Mass Spectrometer Source Conditions 2. Electrospray emitter −4 kV, capillary exit −35 V, skimmer 1−33 V, hexapole 1−23 V, hexapole rf 800 V, skimmer 2−23 V, lens 1 transfer time 50 μS, and lens 1 prepulse storage 100 μs were used. The MCP detector voltage increased to 2350 V (from a standard setting of 2100 V for small-molecule work). Nebulizer pressure and sheath gas settings were 1.5 bar and 10.0 L/min, respectively. Drying gas temperature was set to 150 °C. These conditions were optimal for the larger clusters found in the Au102(pMBA44) sample. B


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Figure 1. Direct infusion electrospray ionization mass spectra of a Au102(pMBA)44 gel electrophoresis isolate. The effects of different sample preparation procedures are compared. See text for description of these procedures and interpretation of the effects. (Savitzky−Golay31 smoothing and background subtraction were applied to each spectra as appropriate to optimize spectral quality.)

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RESULTS AND DISCUSSION

ments in solution stability and in mass spectral quality evidenced in the example of Figure 1, which shows minimized adduct formation, sharpened MS peaks, enhanced signal-tonoise, and simple charge-state envelopes. Absent such cleanup, trace salts produce broad peaks, 10 to 100 s of Th wide. The results reported in Bruma et al. 15 on PAGE-purified Au102(pMBA)44 are typical of those obtained by several laboratories.16 More recently, Plascencia et al.17 reported conditions under which high-resolution MS were effectively

In contrast to ESI of the hydrophobic homologues of these aqueous clusters,14 satisfactory ESI of these aqueous species requires removal from the sample solution of alkali salts introduced during cluster synthesis or in the buffers used for gel electrophoretic (GE) separation. As for polyacid biomolecules (oligonucleotides, phospholipids, etc.), removal of alkali ions via formation of ammonium salts results in marked improveC


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Figure 2. Base peak chromatograms (m/z 1000−8000) showing the effect of HPLC mobile phase gradient on retention times and separation of a mixture of Au36(pMBA)24, Au25(pMBA)18, and byproducts. [See text and SI section for description and interpretation.] Similarly, the effect of the mobile phase gradient on the retention time of Au102(pMBA)44 is shown in Figure S1.

is evidenced by broad and overlapping peaks (∼110 Th at fwhm) with low S/N ratios which are attributed mainly to Na+ and H2O adduct and cluster formation. Spectral quality is similar in Figure 1b, which was acquired from a sample to which an equal volume of 10 mM of triethylamine in water was added. The peaks in Figure 1b are slightly narrowed (∼50 Th at fwhm) and with less overlap compared to Figure 1a, but S/N improves negligibly. The improved spectrum in Figure 1c was acquired by adding an equal volume of 50:50 H2O:CH3CN solution of TEA (10 mM). Peaks are significantly narrower (∼2 Th at fwhm), reflecting reduced adduct and cluster formation, but the minor Na-adduct formation remains evident during analysis. This improvement may be attributed to increased volatility of the diluting solvent as well as the inhibiting effect acetonitrile may have on Na-adduct formation. Finally, Figure 1d reveals the benefit of careful sample washing and precipitation, using NH4OAc and ethanol for effective removal of Na+ and other byproducts, followed by reconstitution in 10 mM TEA. Again, significant reduction in peak widths (∼2 Th at fwhm) and minimal evidence of broadening from sodium adduct formation is noted, allowing precise assignment of m/z not previously reported of larger aqueous Au clusters (∼1.6 nm in diameter). Spectra are sufficiently clean to identify minor related MPC byproducts in the sample (see below). Recently, we reported reversed-phase LC analysis of a size series of hydrophobic gold MPCs in complex mixtures at the ∼10 ng level.22,23 This LC development work follows the great strides and continuing progress made by Negishi et al.1,24−26 Analogously, an LC-MS method described here was developed to separate and detect hydrophilic Au-MPCs via ion-pair reversed-phase chromatography using a Hypersil Gold (ThermoFisher Scientific, San Jose California) C18 HPLC column (150 mm long × 0.5 mm i.d.). Method details are provided in the Supporting Information. Because pMBAprotected clusters are both highly polar and acidic, one adds to the mobile phases an ion-pairing agent, triethylammonium acetate (TEAH+−AcO−, pH ∼ 7.75), in order to increase column retention time, via ion pairing with the carboxylate functionalities of the protecting ligands, and to maintain the

obtained for purified or mixed aqueous (102,44) and larger (130−170 Au atom) polyanionic compounds, and these analyses revealed not only the expected species but also the ubiquity of adducts (especially sodium alkali ion and others) in congesting these spectra. Subsequently, Alvarez et al.18 employed a heated electrospray source and Orbitrap mass spectrometry to achieve much higher resolution spectra showing isotopic resolution in the case of (102,44) clusters. However, the spectra remained negatively impacted by the effect of sodium ions remaining in solution. We found that effective washing or cleaning of as-obtained aq-MPC solutions could be carried out by either (1) precipitation using dropwise addition of glacial acetic acid followed by reconstitution in either 10 mM ammonium acetate or 10 mM triethylamine (TEA) or (2) addition of 10 M ammonium ammonium acetate, cold absolute ethanol precipitation, and reconstitution. [See SI section for a detailed description of methods and instrumental procedures.] The procedures were adapted from well-established oligonucleotide preparations,19−21 which convert alkali oligonucleotides to alternative salt forms. Generally, we find that ammonium salt analogues greatly improve mass-spectral quality of Au clusters. Whereas equivolume addition of a base (few-percent ammonia, TEA, etc.) to the as-obtained aqueous samples can enhance signal level, the best results are obtained after complete sodium removal by a series of wash cycles. The larger the molecule of interest, the more cycles are required for satisfactory sodium removal from the −COO− group of the pMBA ligands. The largest clusters studied here benefited most from a minimum of three cycles for effective replacement of the sodium counterions. The ESI-MS results from the different preparation procedures are shown in Figure 1. The four mass spectra were acquired via ESI of a Au102(pMBA)44 sample (∼0.1 mg/ mL), infused at 15 μL/min. Each spectrum represents an average of no fewer than 10 individual mass spectra. The spectrum in Figure 1a represents a typical mass spectrum acquired with no additional sample preparation, following aqueous extraction of Au-pMBA from PAGE gels. Poor quality D


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Figure 3. Capillary HPLC-MS separation, 30 min gradient, and detection of a mixture of Au−pMBA MPCs. The separate identified components are as follows: (1, red) Au36L24; (2, orange) Au25L18; (3, green) MW 7810 Da; (4, blue) MW 7657 Da; (5, violet) Au10L10 and several other smaller oligomeric gold species. Corresponding electrospray ionization mass spectra of Au36(pMBA)24 and Au25(pMBA)18 are shown to the left and right of peaks 1 and 2, respectively.

Figure 4. Capillary HPLC-MS separation, 20 min gradient, and detection of a mixture of Au−pMBA MPCs. The separated and tentatively identified components are as follows: (1, red) Au99L42, (1, orange) Au100L42, (2, green) Au101L42, (2, light blue) Au76L37, (2, blue) Au88L40, (3, dark blue) Au76L38 and Au77L37, and (4, violet) Au65L32. The mass spectrum corresponding to peak 2 is shown in the inset in the figure. All other corresponding mass spectra are shown in Figure S2. Tentative structural assignments for many of the components observed in this sample are listed in Tables S1− S4.

relatively higher mobile phase pHs, as required for cluster solubility and colloidal stability. In Figure 2, the effects of three different LC gradients, 5− 30% MeOH over (a) 10 min, (b) 20 min, and (c) 30 min at ambient temperature, were compared for impact on retention time and separation. Each of the two mobile phases contained 10 mM TEAH+−AcO−. The sample diluent was 10 mM NH4+−AcO−. As the gradient is shallowed, all peaks elute at longer retention times and become increasingly separated, while elution order remains constant. Products identified as Au36(pMBA)24 and Au25(pMBA)18, separated partially by the 10 min gradient (RT = 9.3 and 10.0 min), are well resolved by the 20 min gradient (13.8 and 15.1 min) and completely by the 30 min method (17.9, 19.8 min), albeit with some broadening of the peaks corresponding to the elusive Au36(pMBA)2427 and Au 25 (pMBA) 18 . [Figure S1 shows data from gradient comparison experiments run using a sample of Au102(pMBA)44.] Figures 3 and 4 each show a color-coded extracted-ion chromatogram with major peaks numbered in order of elution. The base peak chromatogram (m/z 1000−8000) in each figure is shown in black. A capillary HPLC-MS separation of a mixture containing the main components observed in Figures 3 and 4 is shown in Figure S3.

Similar retention behavior is evident for both gold samples. In each case, the largest clusters present in the sample eluted first, followed by successively smaller ones. Although this trend might, by first consideration, seem to be consistent with a sizeexclusion mechanism, we believe that the separation observed here is directed solely by a reversed-phase, ion-pair mechanism. This indicates either that the largest clusters are of higher polarity directly influenced by the number of surface ligands per cluster, which reduces retention, or that separation is directed by the combination of ion-pairing agent with reversed-phase chromatography. Whereas purely reversed-phase separations are predominantly the result of a hydrophobic interaction between analyte and stationary phase, ion-pairing agents introduce a second, ion-exchange-like, interaction. The interaction between the anionic cluster analytes and “cationic ion-pairing agents sorbed to the stationary phase” is such that analytes with lower pKa values are retained longer than those with higher ones.28 A macroscopic pKa value for the Au102(pMBA)44 cluster has been reported and may be consistent with the trend of elution observed here.11 Experimental data from the gradient and diluent variation experiments shown in Figures 2 and S1 are also consistent with the reversed-phase ion-pair mechanism. While size-exclusion separations are not affected by LC method gradient, the E


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basic and applied research and development toward marketed products and applications, particularly in biomedicine as delivery systems or contrast agents. Ongoing effort is directed toward improving separations and widening the scope of analytical samples to include MPC derivatives including functional bioconjugates (proteins, antibodies, nucleic acids, and fluorophores).29,30

separations reported here reveal a shift to longer retention times for all clusters as the gradient is shallowed from 10 to 30 min. Figure S4 shows the effect of diluent composition on retention times of Au25(pMBA)18 and related components. Here, we note that a diluent-containing ion-pairing agent causes an increased retention of these compounds under identical chromatographic conditions relative to what is observed when an ion-pairing agent is not present. These results all serve to illustrate how TEA solutions enhance the essential analytical capabilities of the aqueous gold−thiolate oligomers and clusters of up to 102 Au atoms. To these we add brief mention of a series of extensions that indicate the directions of ongoing research enabled by these new capabilities: (i) Identification of previously unknown species that add significantly to the panorama of compositions to be explained theoretically, notably the Au36(pMBA)24, but also compositions that are consistent with 40e and 32−34e shell closings. Without the two-dimensional capabilities of in-line LC-MS, the detection of these ions might have been attributed to fragmentation (ion-dissociation) processes, whereas their diagnostic retention times establish them as distinct species of appreciable abundance that will attract efforts to isolate and determine their molecular structure and electronic characteristics. (ii) Collision-induced dissociation of the components of the mixture of intermediate-sized clusters (Au25 and Au36) uses the in-line HPLC-ESI source to obtain ion beams of a single component but in varying charge states. Figures S5 and S6 demonstrate this method and the early results obtained. (iii) Extension by these methods of the mass range to access larger clusters, above Au102, in the Au130 to Au146 range has also been explored and found to achieved improvements over previously obtained spectra18 but not yet for the combined inline HPLC-ESI method; this indicates an important direction of future research, following the polyacid oligonucleotide−nanoparticle analogy, replacing the acetic acid component (of the ion-pairing TEAH−acetate system) with a higher volatility one.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpcc.6b12073. Detailed descriptions of data collection and analysis, cluster synthesis and sample preparation procedures, additional HPLC-MS separations and method condition comparisons, mass spectra corresponding to peaks in Figure 4 (along with corresponding maximum entropy deconvoluted mass spectra), in-source collision-induced dissociation spectra of each of the two clusters, and tentative mass spectral peak assignments (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

David M. Black: 0000-0003-2757-447X Author Contributions

DMB designed the project, carried out the experiments and analysis, and cowrote the manuscript. GPV and FY carried out the experiments to synthesize the monolayer protected cluster mixtures analyzed for this manuscript. MA carried out data analysis and interpretation. WG provided key insights and guidance as well as mass spectrometer parameter optimization. RLW participated in the analysis and interpretations and cowrote the manuscript. All these coauthors (DMB, RLW, SBHB) participated in the conception and initiation of the project and have reviewed and approved the final manuscript.

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CONCLUSIONS Here we have demonstrated how to greatly enhance the solution-phase stability of a large and previously intractable class of aqueous Au-MPCs, namely those with acidic ligand Rgroups, leading to improved direct infusion mass spectral analysis and then to efficient separation and detection by ionpair reversed-phase capillary LC-MS. Our procedures were adapted from those developed for oligonucleotides,5,6 consistent with the notion that these classes of aqueous polyacids share key acid−base and ion-pairing properties and the results of realistic theoretical simulations of the ion-pairing in aqueous electrolyte solutions. This interpretation will be explored in continuing research. The presented results reveal the bright promise of hyphenated LC techniques, specifically LC-MS, for detailed compositional analysis of these novel and promising nanomaterials with superatom structure arrangements. The combined procedures accomplish rapid analysis of these materials, resolving all the main species present in complex mixtures, as well as previously undetected minor components, including the elusive aqueous-phase analogue of Au36(SCH2CH2Ph)24,27 while consuming only minute sample amounts (∼100 ng) per injection. These methods will thus facilitate further analytical characterization of these novel nanomaterials in

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to acknowledge support from the National Institute on Minority Health and Health Disparities (G12MD007591), PREM: NSF PREM Grant #DMR 0934218; ‘‘Oxide and Metal Nanoparticles − The Interface Between Life Sciences and Physical Sciences”, and the Welch-Foundation Grant (AX-1857); and encouragement and advice from Prof. Miguel Yacaman, Prof. Borries Demeler (University of Texas Health Science Center San Antonio) and Prof Yuichi Negishi (Tokyo University of Science).

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REFERENCES

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