Mass Spectrometry of Synthetic Polymers - ACS Publications

Anal. Chem. 2010, 82, 4811–4829

Mass Spectrometry of Synthetic Polymers Steffen M. Weidner† and Sarah Trimpin*,‡ Federal Institute for Materials Research and Testing (BAM), D-12489 Berlin, Richard-Willstaetter-Strasse 11, Germany, and Department of Chemistry, Wayne State University, 5101 Cass Avenue, 33 Chemistry, Detroit, Michigan 48202 Review Contents Scope Emerging Technology for Synthetic Polymer Characterization Ion Mobility Spectrometry-Mass Spectrometry Electron Transfer Dissociation Mass Spectrometry New Aspects in Traditional Techniques and Principles Matrix and Matrix-Free Laser Methods Solvent-Free Matrix-Assisted Laser Desorption/ Ionization Methods Electrospray Ionization Methods Atmospheric Pressure Photoionization Methods Traps and Detectors Rapid Measurements Reference Measurements Liquid Chromatography-Mass Spectrometry Surface and Imaging Methods Fragmentation Methods Advanced Degradation Methods General Applications in Polymer Analysis Synthesis of Polymers Homo- and Copolymers Polymer Surface Techniques Polymer Separation by Sophisticated LC-MS Techniques Tandem Mass Spectrometry Polymer Degradation Synthetic Polymers in Biological Applications Outlook Literature Cited

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SCOPE The heart of this review is to give a compact overview of the literature on mass spectrometry (MS) of polymers published in the time period from 2008 to 2009. Identical to the review from 2008, the citations were drawn from SciFinder (January 25, 2010) using the search terms “poly*” and “mass spectrometry” with restrictions to review and journal contributions in the English language. Refined searches in Web of Science were also used again. In these two years more than 750 relevant papers and 5 reviews were published accentuating the importance of MS for polymer analysis. We selected references as an attempt to cover all areas as diverse as “emerging technologies” to “applications”. Decisions are subjective and may not always represent the ideal choice. Additionally, the comprehensiveness and complexity of the field also challenges a clear classification to a single category in some cases but repetition is not a valuable choice. * To whom the correspondence should be addressed. E-mail: strimpin@ chem.wayne.edu. † Federal Institute for Materials Research and Testing (BAM). ‡ Wayne State University. 10.1021/ac101080n  2010 American Chemical Society Published on Web 05/21/2010

EMERGING TECHNOLOGY FOR SYNTHETIC POLYMER CHARACTERIZATION Ion Mobility Spectrometry-Mass Spectrometry. Ion mobility spectrometry (IMS) mass spectrometry (MS) has become increasingly important for the elucidation of the three-dimensional structure of synthetic polymers. Trimpin and Clemmer demonstrated on multidimensional IMSn time-of-flight (TOF) MS prototype instruments (2 and 3 m drift tubes) using electrospray ionization (ESI), the sensitivity gain by efficient separation of polymeric complexity (1). The importance of multiply charged ions for gas-phase separation using IMS-MS technology is exemplified. These multiply charged ions were also beneficially used for bulk activation and fragment ion analysis of polyethylene glycol (PEG) 2-17.9 kDa and even directly from polymer blends as is shown in Figure 1A. The activation approach is achieved by applying voltage in between drift tube segments, leading to charge stripping of the ions (Figure 1.A1) to reduce the surplus energy and providing additional specificity on each polymer system. When the voltage is increased further, bulk fragmentation is induced (Figure 1.A2). The pictorial permits rapid identification of parent, charge stripped and fragment ions and thus in-depth analysis. This bulk fragmentation method increases the fragment ion yield, frequently sparse in tandem mass spectrometry (MS/MS) of polymers, and the speed of analysis by not having to select a specific parent ion. Most importantly, IMS-MS is extremely useful for clean separation of isomeric composition by exploiting the dimension “shape”. This is shown in Figure 1B for a quartinary blend comprised of poly(n-butyl methacrylate) (PnBMA) and poly(tertiary-butyl methacrylate) (PtBMA) isomers, poly(ethyl methacrylate) (PEMA) and PEG, each ∼2 kDa in molecular mass. Isomeric composition is impossible to be distinguished using a solely MS-based approach. A pictorial “snapshot” was used to characterize a number of polymers after detailed characterization has been obtained including those of extreme convolution present in ESI of polyethylene oxide (PEO)/polypropylene glycol (PPG) copolymer (Jeffamine). The IMS-MS data obtained with and without activation is sufficiently distinctive to be used as a pictorial snapshot also overcoming time-restrictions in data interpretation. These snapshots may provide a visual pattern that is sufficiently distinctive that even computer-aided pattern recognition can be used to address process control and regulatory issues in the future. ESI-IMS-TOF-MS using Triwave technology was employed for a number of studies. Large PEGs and PEGylated molecules (>40 kDa) were examined using gas-phase superbases that were introduced to the high-pressure source region of commercial TOF analyzers to manipulate the charge states. This gas-phase protonAnalytical Chemistry, Vol. 82, No. 12, June 15, 2010

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Figure 1. Image analysis of blends of polydisperse macromolecules (here, 3 m drift tube instrument). (A) Binary blend of PEG and PEGDME (∼2000 Da), differing only by two methyl groups located on the end of each polymer chain, doped with cesium chloride. Charge-state families for both components are extracted from the mass spectra, including those of the +3 and +2 series; the latter are charge-reduced families with enhanced td separation (∆ ∼ 1.5 ms). (A.1) Full IMS-a-IMS-MS image (here, 60 V applied at the first activation region). Inset (A.1′) of the most prominent features; dashed lines indicate where mass spectral data were integrated. Slices of one doublet feature, with charge state +3 extracted, showing the two mass spectra overlaid to the right (A.1′′) labeled by charge state/number of repeat units (PEG red, PEGDME blue). (A.2) Full IMS-f-IMS-MS image (here, 200 V applied at the first activation region), (A.2′) inset, (A.2′′) extracted mass spectrum of one slice. (B) Tertiary blend of PEMA, and the two isomers, PtBMA and PnBMA (∼2000 Da), only differing by the side chains doped with sodium chloride along with low-abundance PEG contamination. (B.1) Full IMS-MS image. Inset (B.1′) of the td distribution of the blend against the pure PtBMA sample delineating the clean separation of the two isomeric polymers in the tertiary blend. Reprinted from ref 1. 2008 American Chemical Society. 4812

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transfer based charge stripping process decreased the spectral congestion typically observed in ESI mass spectra of polymers and offers enhanced dynamic range, increased sensitivity, and specificity (2). ESI-IMS-TOF-MS in combination with collisioninduced dissociation (CID) experiments was used to investigate mixtures containing PEG and an active pharmaceutical ingredient (APT) (3). In this study the potential of linear PEGs to serve as internal shift reagent by complexing with the APT was demonstrated enhancing the separation and selectivity without any instrumental modifications. Hilton et al. studied polyether mixtures with the same nominal molecular weights (isobars) by using IMS to separate the precursor ions and employed the MS/MS capability for detailed structural characterization (4). Furthermore, isomeric structures of supramolecular assemblies of hexacadmium macrocycles were distinguished and different charge states were deconvoluted (5). A laser desorption ionization (LDI)-IMS-MS instrument was used for the characterization of asphaltenes and deasphaltened oils. Using the IMS dimension, Becker et al. showed that most of the molecules with MW > 3000 g mol-1 result from gas-phase aggregation related to the LDI process (6). Using matrixassisted laser desorption/ionization (MALDI) ion mobility (IM) TOF-MS, Gies et al. studied linear and branched aramids (7). Molecularly imprinted polymers (MIPs) are extensively crosslinked polymers containing artificial recognition sites with predetermined selectivity for a wide range of target molecules. It was demonstrated by Jafari et al. that MIP-IMS-MS can be used as a powerful technique for preconcentration, separation, and detection of drugs in pharmaceutical and human serum samples (8). Electron Transfer Dissociation Mass Spectrometry. The electron capture dissociation (ECD) and CID of complexes of poly(amidoamine) (PAMAM) dendrimers with metal ions Ag+, Cu2+, Zn2+, Fe2+, and Fe3+ were determined by nanospray ESIFourier transform ion cyclotron resonance (FTICR)-MS (Figure 2). The results suggest that complexes of Fe3+ and Cu2+ are coordinated via both core tertiary amines, whereas coordination of Ag+ involves a single core tertiary amine. The Zn2+ and Fe2+ complexes did not involve coordination by the dendrimer core (9). In addition to ECD, the electron detachment dissociation (EDD) was applied to investigate the effect of the structure (generation) and nature of amino, amidoethanol, and sodium carboxylate surface groups of different PAMAM dendrimers and results were compared to those obtained with CID fragmentation (10). Vincent et al. reported the half- and firstgeneration PAMAM (G0.5 and G1) as well as a totally deuterated dendrimer [G1-d(28)]Na+ were fragmented using a ESI quadrupole ion trap (QIT) mass spectrometer (11). It was shown that the principal fragmentation reaction is a retroMichael rearrangement. NEW ASPECTS IN TRADITIONAL TECHNIQUES AND PRINCIPLES Matrix and Matrix-Free Laser Methods. A review published by Batoy et al. focuses on the search for an ideal matrix covering contributions from the mid 1990s to the 2008 (12). Other authors described the use of ionic liquids as matrixes (13-18). Apart from improving signal intensity and sensitivity, ionic liquids were also used for matrix-enhanced (ME) surface-assisted laser desorption

Figure 2. ECD FTICR mass spectrum (top) and CID FTICR mass spectrum (bottom) of [M + 6H]6+ ions of PAMAMG2OH. Reprinted with permission from ref 9. 2009 Elsevier.

ionization (SALDI) mass spectrometry imaging (MSI). This leads to a reduction of the analyte redistribution during sample preparation and improves matrix vacuum stability during imaging (16). SALDI-MS of low-molecular weight organic compounds and synthetic polymers using zinc oxide (ZnO) nanoparticles was applied by Watanabe et al. (19). They showed that the sensitivity and molecular weight distribution (MWD) is comparable to MALDI mass spectra obtained with the 2,5-dihydroxybenzoic acid (2,5-DHB) matrix. The same group investigated the halohydrination of epoxy resins using sodium halides as cationizing agents in MALDI and desorption ionization on porous silicon (DIOS) MS. With the use of deuterated methanol as the solvent, it was shown that the hydrogen atom source was probably ambient water or residual solvent, rather than being derived from matrixes (20). Another way of obtaining homogeneous sample preparations could be the miniaturization of sample spots (18, 21). Solvent-Free Matrix-Assisted Laser Desorption/Ionization Methods. Hanton et al. used microscopy images and MALDI mass spectra to evaluate the mixing time required for the vortex method. Their results showed that even mixing times of less than 10 s can generate homogeneous thin films that produce highquality mass spectra from relatively low-molecular weight polymers (22). The ability of solid-state 13C-, 133Cs-, and 19F-NMR to explore a possible interaction between the matrix (2,5-DHB) and the cationization agent (cesium fluoride) with grinding times of 10 min was shown by Pizzala et al. (23). With dependence on the matrix/salt molar ratio, a different molecular organization was observed by nuclear magnetic resonance (NMR) data. Analytical Chemistry, Vol. 82, No. 12, June 15, 2010

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Figure 3. Plot of the response surface corresponding to the peak areas under the single oligomer profiles at z ) 1 (n ) 13, m/z ) 1403.3, r ) 0.974) (top) and z ) 5 (n ) 68, m/z ) 1400.8, r ) 0.950) (bottom) against the coded ion source parameters and the time. Isosurface at 95% of maximum. r: correlation coefficient. Reprinted with permission from ref 31. 2008 Wiley Interscience.

Jaskolla et al. investigated the differences between standard dried-droplet (DD) and vacuum sublimed preparations of several cinnamic acid compounds used as matrixes for MALDI-TOF-MS with regard to matrix grain size, internal ion energy, initial velocity, analyte intensity, and analyte incorporation depth. For all sublimed matrixes, a strong increase of the initial ion velocity compared with DD preparations could be found, which might be attributed to very uniform crystal morphologies (24). An alternative way to obtain a quasi-solvent free sample preparation is the “dry spray” of sample solutions in which the solvent is removed prior to the sample molecules reaching the matrix predeposited on the MALDI target. A dual-spray system for intimate dry gas-phase mixing of separately prepared sample and matrix components leading to an increased sample homogeneity was presented by Erb et al. (25). Christadoro et al. applied solvent-free MALDI for the investigation of model systems, such as polycyclic aromatic hydrocarbons (PAHs) and fullerenes. These compounds undergo photoionization and do not require additional cationizing salts. In contrast to the spherical shapes of C60 and C70 buckyballs, which prevent strong aggregation, severe anomalies in the ionization of the hexabenzocoronene (HBC) mixtures were observed (26). The ionization probability is influenced by the strong intermolecular interactions between the aromatic cores of HBCs that cause molecular aggregation hampering both the desorption and the intermolecular charge transfer processes. A solvent-free sample preparation method for the analysis of PEGs with labile end-groups was presented by Mazarin et al. (27). This approach was taken to avoid salt contamination from the solvent traditionally used in the DD MALDI procedure. The solvent-free technique was also employed by Hortal et al. in order to discriminate the gas-phase polymer-cation complex formation mechanism from solvent and cocrystallization effects (28). It was shown that the cohesion energy of the cation precursor has a strong influence on the outcome of the MALDI measurements. 4814


Electrospray Ionization Methods. In the study of Hogan and Biswas, a Monte Carlo based model was developed, which can predict the efficiency of ESI for macromolecules. Precise knowledge of solvent properties, analyte properties, and droplet size are required for model predictions of ESI efficiency (29). ESIMS combined with QIT as well as quadrupole time-of-flight (QTOF) analyzers was used to investigate the incorporation of metal cations into polymer backbones following deprotonation reactions during the ESI process. The results clearly demonstrate that for synthetic polymers the potential detection of polymer-metal cation adducts must be carefully taken into account during spectral data interpretation to avoid erroneous species assignments (30). The “design of experiment” was applied as a tool for the optimization of ionization conditions yielding maximum ionization efficiencies (31). Data were evaluated by a quadratic response surface model, accounting for possible interactions between the individual source settings (Figure 3). This particular methodology was employed to gain the necessary information from a small number of experiments. A derivatization strategy that facilitates selective ionization of polar and nonpolar compounds in complex matrixes without hyphenated techniques or stable-isotope labeled standards in the atmospheric-pressure laser ionization (APLI) TOF-MS was presented by Schieweck et al. (32). Atmospheric Pressure Photoionization Methods. The advantages (compatibility to chromatography) and limitations (insource decomposition) of an atmospheric-pressure chemical ionization (APCI) interface for liquid chromatography (LC) and size exclusion chromatography (SEC) MS analysis of synthetic polymers was investigated by Desmazieres et al. (33). The analysis of very nonpolar samples by MS is of continuing interest. Keki et al. presented a method that involves the chloride ion attachment technique in atmospheric pressure photoionization (APPI) MS (34, 35). Traps and Detectors. A new, wide mass range trapping method for MALDI-FTMS was described and examined for

Figure 4. MALDI TOF cryodetector mass spectrum for polystyrene; Mn 2 MDa; Mw/Mn ) 1.30: (a) no energy filtering, “low” mass range; (b) no energy filtering, “high” mass range; (c) scatter plot of the collision events versus m/z recorded for the 16 channel cryodetector with an energy regions selected to generate the mass spectrum in parts d and e, respectively; (d) mass spectrum resulting from selecting for only low-energy ions between 12.0 and 19.0 keV. The spectrum should be primarily made up of singly charged ions. Some multiply charged ion contribution may be observed at this level of energy filtering; (e) mass spectrum resulting by selecting for only high-energy ions between 27.2 and 45.7 keV. The spectrum should be primarily made up of doubly and higher charged ions. Reprinted with permission from ref 37. 2008 Elsevier.

equimolar PEG mixtures. The results were compared with those obtained from the “integral” trapping method and against reflectron MALDI-TOF-MS results (36). It was shown that the “integral” method provides better results but still failed in the molecular mass region >6000 Da. The authors also came to conclude that a perfectly general trapping method for FTMS has not been achieved. The use of a cryo-detector to explore the high mass-to-charge (m/z) limit of the MALDI-TOF technique for the analysis of polystyrenes (PS), Mn 170, 400, 900, and 2000 kDa, and PMMA, Mn 62.6 and 153.7 kDa, was described (Figure 4) (37). The authors observed a preferential formation of doubly charged even-

numbered aggregates over odd-numbered aggregates for highmolecular mass PS and discussed a potential mechanism for this aggregation. Rapid Measurements. Trimpin et al. extended the multiple solvent-free sample preparation method to samples prepared on disposable microscopy glass slides, thus overcoming cleaning issues of the MALDI plates (38). A TissueLyzer was used for automated solvent-free homogenization and transfer of the matrix/ sample to the glass MALDI plate. Excess sample was removed by air flow and the prepared microscope slide placed in a custommodified or commercial MALDI plate that is conventionally used for tissue imaging. In the same work, a rapid and direct AP Analytical Chemistry, Vol. 82, No. 12, June 15, 2010

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Figure 5. Final oligomer concentrations for Standard Reference Material 2881 with total (type A and type B) uncertainty. Reprinted from ref 40. 2009 American Chemical Society.

pyrolysis MS analysis, compatible with identification of almost any polymer, was presented. Bacterial poly(hydroxyalkanoates) were investigated by Grubelnik et al. representing a new and fast HPLCESI-MS method (39). Reference Measurements. Guttman et al. reported the certification of an absolute molecular mass distribution polymer PS Standard Reference Material (SRM 2881). The molecular mass distribution (MMD) was obtained by MALDI-TOF-MS applying a new Taylor’s expansion method for signal-axis intensity calibration of polydisperse materials. This method describes how the molecular mass distributions may be corrected if the degree of mass bias is within certain defined limits (Figure 5). The uncertainty arising from the MALDI sample preparation was found to be the greatest contributor to the overall uncertainty of the measurement (40, 41). A PEG reference intended to calibrate measuring instruments to control measurement precision and to confirm the validity of molecular mass measurement methods, e.g., MALDI-TOF-MS, was presented by Takahashi et al. A wellcalibrated evaporative light-scattering detector (ELSD) coupled with supercritical fluid chromatography (SFC) was used to exactly determine the average mass of the PEG molecular mass fractions (42). Liquid Chromatography-Mass Spectrometry. For the first time, the determination of the critical conditions using ultraperformance liquid chromatography (UPLC) coupled with ESI-TOFMS has been reported by Falkenhagen et al. Without the need to use standards for a calibration of the chromatographic system, this coupling approach was shown to permit adjustment of “critical” separation conditions within a few minutes (43). A novel and powerful high-pressure liquid chromatography (HPLC) ESI-MS methodology using a postcolumn addition of diethylmethylamine or triethylamine was developed and applied to examine high-molecular weight (up to 40 kDa) PEG as well as PEGylated peptide and protein products (44). The authors demonstrated that under these conditions, PEG is diethylmethylor triethyl-ammoniated instead of protonated while the protein or peptide remains protonated. This greatly reduces the number of charges states of PEG and the PEGylated compounds, and there was no convolution among differently charged ions, even for higher mass PEGs. 4816


SEC-ESI was also used for the accurate and absolute determination of MWDs as well as absolute concentrations of the individual macromolecular components in mixtures of polymers of the same monomer class yet differing in their end groups (45). Data were processed by a sophisticated computer algorithm based on the maximum entropy principle. Molecular weights up to 10 kDa are accessible with a conventional mass range limited QIT mass analyzer. The method is applicable to variable polymer systems regardless of the monomer class and without the need for an external calibration but is strongly dependent on the formation of multiply charged ions produced by the ESI source. Surface and Imaging Methods. A partial least-squares model using TOF secondary-ion mass spectrometry (SIMS) and surface energy data from a 496 copolymer micropatterned library was constructed by Taylor et al. (46). High-throughput TOF-SIMS combined with principal component analysis (PCA) was used to identify variations in surface chemistry in a library of 576 novel acrylate-based polymers, synthesized using a combinatorial approach and in a micropatterned format (47). Wood et al. described a novel in situ fracture stage arranged within the preparation chamber of a TOF-SIMS instrument. Comparative surface analysis of polyester resin and an organically modified silica (ormosil) nanoparticulate reinforced polyester resin nanocomposite were used to demonstrate the performance of such a methodology to investigate nanomodified polymer systems and nanocomposites (48). Hiraoka et al. used the electrospray droplet impact (EDI) forming secondary ions measured by an orthogonal TOF mass spectrometer (49). ESI-charged water droplets are introduced in vacuum, accelerated, and allowed to impact a surface covered with a thin layer of PMMA. No fragment ions corresponding to PMMA were detected concluding that EDI is capable of shallow surface etching with little damage of the sample underneath the surface. Similar to other TOF-MS methods coupled to MALDI and ESI, metastable ions can be formed in TOF-SIMS as well. Shard and Gilmore investigated four common polymers, PEO, poly(lactide), PMMA, and poly(tetrafluoroethylene) using a single stage reflectron TOF-SIMS instrument by changing the reflector potentials (50). This analysis provides metastable decay pathways that are a powerful tool for analysts to identify metastable ions and use these to interpret molecular structure and identify complicated molecules. The development of solvent-free sample preparation methods has enabled MALDI-TOF-MS to analyze insoluble materials. Hanton et al. used microscopy tools and TOF-SIMS to image samples prepared using solvent-free methods to examine the morphology of these samples. Their results demonstrated that the relatively simple vortex method for solvent-free sample preparation for MALDI creates remarkably homogeneous and intact thin film samples (51). Similar results were obtained by Weidner and Falkenhagen utilizing MALDI-TOF-MSI imaging a dried spray of polybutyleneoxid (PBO 1000) onto a layer of 2,5DHB matrix (52). Further it was shown that the solvent-based DD preparation not only causes segregation of sample and matrix but also segregation of the oligomer distribution of the polydisperse PBO sample (Figure 6). In contrast, the solvent-free dry spray method showed a homogeneous distribution of the oligomer chain lengths throughout the entire MALDI sample.

Figure 6. Segregation of a polybutyleneoxid 1000 (PBO, in MeOH) in a CCA matrix sample spot (size 3 mm) prepared by the dried droplet method: (left) [PBG]8Na+ ion at m/z 732.2 g/mol and (right) [PBG]14Na+ ion at m/z 1164.5 g/mol; single image spot size 100 µm. Reprinted with permission from ref 52. 2009 Wiley.

Figure 7. Screenshot from the Polymerator software of an annotated ESI-MS/MS spectrum from the lithiated heptamer of poly(propylene glycol) diacrylate (4). Predicted fragment ions are detailed above (left) the spectrum. Reprinted with permission from ref 55. 2008 Springer.

Fragmentation Methods. Fragmentation analysis of biopolymers is routinely used in peptide and protein characterization for determining, for example, the amino acid sequence and/or posttranslational modifications. Similarly, fragment analysis of synthetic polymers can permit information on the repeat unit(s) and end group(s). However, in contrast to biopolymers, where fragmentation typically occurs at the -CO-NH- backbone bonds, resulting in a formation of typical b- and y-fragment ion series, the fragmentation of polymers is much more complex. A polymer fragmentation leads to a variety of fragments caused by complex reactions that may arise from a number of different backbone and side chain cleavages as well as rearrangement reactions (e.g., 1,4 hydrogen shift, etc.). As seen in this review, the potential use of the tandem MS technique is explored increasingly for a more detailed characterization of synthetic polymers. The number of

publications tripled in the reviewed time period as compared to the previous review from 2008. Initial progress toward the construction of a library with common fragments and fragmentation pathways to obtain fast and automated identification, similar to proteomics approaches, were undertaken by Baumgaertel et al. (53, 54). Initial results were presented for PMMA and poly(2-ethyl-2-oxazoline)s employing MALDI-TOF-MS/MS based on CID methodology. An example of how software can be used to significantly reduce the length of time involved in data interpretation was presented by Jackson et al. applying ESI-TOF-MS/MS for PEO end group analysis (Figure 7) (55). Advanced Degradation Methods. Hypervelocity impacts of micrometeoroids, important for the calibration of dust sensors in space applications, were simulated by the impact (3-35 km s-1) Analytical Chemistry, Vol. 82, No. 12, June 15, 2010

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Figure 8. The large area mass analyzer (LAMA) spectrometer with its target section (left) and reflectron housing (right) in the test chamber of the dust accelerator. Dust grains are entering from the right. Reprinted with permission from ref 56. 2009 Wiley.

of submicrometer-sized synthetic dust grains comprising either PS or poly[bis(4-vinylthiophenyl)sulfide] coated with an ultrathin overlayer of an electrically conductive organic polymer (either polypyrrole or polyaniline). The resulting ionic impact plasma was analyzed by TOF-MS using a newly developed large area mass analyzer (LAMA) (Figure 8) (56). With dependence on the projectile type and the impact speed, both aliphatic and aromatic molecular ions and cluster species were identified in the mass spectra with masses up to 400 Da. The results showed that TOF-MS analysis of dust impacts can be used for the identification of organic compounds in planetary, interplanetary, or even interstellar dust. GENERAL APPLICATIONS IN POLYMER ANALYSIS SYNTHESIS OF POLYMERS The synthesis of polymers and copolymers by different synthetic routes represents one of the major MS applications. MS can provide valuable information on end groups and repeat unit structures and, therefore, enables a partial control of reactions. Homo- and Copolymers. CRP: Controlled Radical Polymerization. The synthesis of polymers applying the principles of controlled radical polymerization (CRP) and, moreover, the socalled “click chemistry”, a modular synthetic approach toward the assembly of new molecular entities, was investigated by several authors. The formation of amphiphilic tadpole-shaped copolymers consisting of a PS ring and a PEO tail was described by Dong et al. (57). First, single blocks containing reactive groups were formed via atom transfer radical polymerization (ATRP). These blocks were then coupled to form copolymers by click chemistry and investigated by MALDI-TOF-MS. The same analytical tool was used for investigating the synthesis of [60]fullerene end-capped PSs (58), for the modification of degradable polymers (59) and to monitor the reaction of PMMA, poly(i-butyl methacrylate), poly(2-hydroxyethyl methacrylate), and polymethacrylonitrile bearing organotellurium, organostibine, and organobismuthine ω-living polymer end groups with 2,2,6,6-tetramethylpiperidine 1-oxy (TEMPO) under thermal or photochemical conditions (60). Van Dijk et al. used MALDI in the enzymatic degradation of 4818


peptide triazole-based polymers synthesized via microwave-assisted Click chemistry (61). Among other techniques such as 1H NMR spectroscopy and SEC, MALDI was used for the characterization of difunctionalized PEOs (62). The quantitative introduction of functional groups at both the R and ω positions of the PEO chains and the formation of very narrow molar mass polymers could be confirmed. A study into the stability of 3,6dihydro-2H-thiopyran functionalized PEG under different thermal and pH conditions was performed. ESI-MS was employed to map the generated products (63). A first systematic and experimental comparison of both MALDI- and ESI-MS to analyze PS prepared by five different CRP: nitroxide-mediated polymerization, atom transfer radical polymerization, reversible addition-fragmentation chain transfer polymerization, and reverse iodine transfer polymerization was performed by Ladaviere et al. (64). It was found that the number of chain end-groups detected is higher by ESI-TOF than MALDITOF-MS, whereas the average molecular masses were simultaneously underestimated. The initiator efficiency in controlled radical polymerizations (RAFT) of methyl methacrylate (MMA) in solution was determined by ESI-MS (65). The same group performed the end-group analysis via ESI-MS of PMMA synthesized in free-radical polymerizations in benzene solution. The type of radical that starts chain growth could be unambiguously assigned (66). ESI-MS was also used for the investigation of the synthesis of living stars using a tetra-functional RAFT agent (1,2,4,5-tetrakis-(2-phenyl-thioacetyl-sulfanylmethyl)-benzene). In addition to the ideal stars, various other compounds, like star-star couples with different end groups could be determined (67, 68). Final products and intermediates of the synthesis of mixed-arm star polymers synthesized by ATRP and RAFT sequential polymerization using the “core first” method (69) of maleimide-endfunctionalized stars (70), of amphiphilic poly(lactide)-block-poly(2hydroxyethyl methacrylate) (PLA-b-PHEMA) copolymers with a partially biodegradable and a potentially biocompatible polymer backbone segment (71), and of N-vinylcaprolactam (NVCL) (72) were detected by MALDI-TOF-MS. Tailor-made poly(ethyl acrylate)/clay nanohybrids were prepared by surface-initiated atom transfer radical polymerization (SI-ATRP). In this case, the ATRP initiator was tethered on active hydroxyl groups present on the surface as well as in the organic modifier of the used clay. The control of end-groups was provided by MALDI-TOF-MS analysis (73). Gruendling et al. reported the use of silver tetrafluoroborate as a doping salt for an efficient and soft desorption/ionization of labile end-group-carrying PS in ESI (74). The mechanism of the formation of structurally highly uniform poly(butyl acrylate) macromonomers synthesized via autoinitiated free-radical polymerization without the need to employ any mediating agent was investigated by ESI-MS. Complex addition-fragmentation equilibria, not unlike the RAFT mechanism, effectively resulting in a self-organization of the reaction, were proven by the authors (75). Kavitha et al. described the tailor-made synthesis of hightemperature resistant PMMA. MALDI-TOF-MS and gel permeation chromatography (GPC) analysis showed that the polymers had well-defined molecular weights and the desired amino adamantyl functional groups (76, 77). Well-defined oligo(2-ethyl2-oxazoline) methacrylate (OEtOxMA) macromonomers were

polymerized in a RAFT polymerization yielding a series of comb polymers with varying side chain length and backbone length. These products were characterized by 1H NMR spectroscopy and SEC. Additional information was obtained by MALDI-TOF-MS (78). A kinetic model for RAFT polymerization was extended to include cross-termination between the RAFT intermediate and oligomeric radicals by considering cross-termination between dimeric or shorter chains. The earlier version of the model was experimentally verified by MALDI-TOF-MS (79). Quantum-chemical ab initio calculations were applied for the synthesis of a novel class of RAFT agents featuring extremely strong electron deficient CdS double bonds. These reagents are suitable to undergo rapid hetero Diels-Alder (HDA) reactions with variable dienes under mild (i.e., ambient and catalyst free) reaction conditions. A series of model reactions were performed, whose products were monitored via ESI-MS (80). RAFT was used to synthesize methacrylic acid oligomers and oligo(methacrylic acid)-b-poly(methyl methacrylate) (PMAAb-PMMA) with a targeted length of ∼10 monomer units. The analysis of products by SEC and ESI-TOF-MS was compared (81). The very early stages of the RAFT polymerization (the conversion of the initial RAFT agent into a macroagent) were investigated by ESI-MS, SEC, and electron spin resonance (ESR). The authors could demonstrate that a selective initialization period in which a large percentage of the initial RAFT agent is converted into a macroagent containing one monomer unit took place. After the majority of the RAFT agent had been converted into a first monomer adduct, the addition of a second monomer unit increased significantly (82). ROP (ROMP) Ring-Opening Polymerization. MALDI-TOF-MS was applied for the analysis of the crossover reaction in ringopening metathesis polymerization (ROMP) of various monomers and to present a highly effective and facile end-capping technique for ROMP with living ruthenium carbene chain ends using singleturnover olefin metathesis substrates (83, 84) and in the acyclic diene metathesis (ADMET) polymerization of 2,5-dipropenyl-3hexylthiophene using ruthenium metathesis catalysts (85). The anionic ring-opening polymerization (ROP) of racemic β-(methoxymethyl)-β-propiolactone and β-(ethoxymethyl)-β-propiolactone was monitored by multistage ESI-MSn (86). By careful selection of orthogonal protective groups, Takizawa et al. were able to synthesize monodisperse dimer, tetramer, octamer, 16-, 32-, and 64-mer materials of poly(L-lactic acid) and poly(caprolactone)s. These findings were confirmed by SEC and MALDI-TOF-MS (87, 88). MALDI was also explored in the high-throughput synthesis of poly(ethylene terephthalate) (PET) and poly(butylene terephthalate) using entropically driven ROP (89), in the ROP of lactanes and other cyclic esters (90), of caprolactone (91), and in combination with fast atom bombardment (FAB) for monitoring reaction products of the ROP synthesis of 5,5-dimethyl-1,3,2dioxithiolan-4-one-2-oxide (92). “Living” Ionic Polymerization. MALDI-TOF-MS was used to confirm the structures of thermoreversible π-stacked polymers synthesized by living anionic polymerization of a benzofulvene monomer (93), of trimethoxysilyl-functionalized polymers synthesized by a new general functionalization methodology (94), of chain-end and in-chain cyano-functionalized PS (95), in the anionic synthesis of in-chain-functionalized PS-block-poly(dimethylsilox-

ane) diblock copolymers (96), in the anionic telomerization of poly(buta-1,2-dienes) (97), and in the bismuth catalyzed ringopening polymerization of 2-methoxazoline (98). Three methods for the functionalization of 2-ethyl-2-oxazoline oligomers were compared by Weber et al., and the structure of reaction products was determined by MALDI-TOF-MS (99). Other Polymerizations. Polycondensations of aliphatic dicarboxylic acids with 1,4-butane or 1,6-hexane diol in bulk at 80 or 100 °C were investigated by MALDI-TOF-MS (100). This technique was also used in the synthesis of unique elastic polyesters by a catalyst-free polyesterification of multifunctional nontoxic monomers (1,8-octanediol, citric acid and sebacic acid). The authors demonstrate that the chemical structure, morphology, physical integrity, and surface chemistry of the synthesized copolymer can be controlled by simply varying the initial acid concentration (citric/sabacic) in the prepolymer (101). MALDITOF-MS was also intensively applied in the synthesis of various polyesters by the Kricheldorf group (102-108). ESI- and LDIFT-MSn of glycidyl methacrylate/methyl methacrylate copolymers and polyesters of 12-hydroxystearic acid and stearic acid were performed by Simensick and Petkovska to use the high resolving power to distinguish copolymers by MS and extract sequence information by MS/MS (109). The reaction products of a synthesis of new, conductive, polybenzoxazoles were studied by LC-MS (110). Poly(2,5-dihexyloxy-1,4-phenylene)poly(3-hexylthiophene) (PPF-b-P3HT) diblock copolymers for potential applications in optoelectronics, synthesized by Grignard metathesis polymerization, were characterized by means of SEC and MALDI-TOF-MS (111). Dendrimers and Hyperbranched Polymers. A particular field of interest is the synthesis and physic-chemical properties of dendrimers and hyperbranched polymer structures. A topological approach to the analysis of isomeric dendrimers by considering their “molecular graphs” has been applied by Schubert et al. (112). Various properties of a series of new sulfonamide-based isomeric dendrimers were correlated with their structures. Thus, isomeric dendrimers are referred to as either isographic (having the same graph) or nonisographic. Sets with a different number of peripheral groups have been designed, synthesized, and investigated by means of ESI-FTICR and MALDI-TOF-MS/MS. Because of their different MS/MS patterns, a differentiation of isomers, which could not easily be distinguished by 1H NMR spectroscopy, was possible. A versatile strategy for the synthesis of biodegradable and biomimetic dendron-like polypeptide-based biohybrids synthezised via the combination of controlled ROP of ε-caprolactone, click chemistry, and the ROP of γ-benzyl-L-glutamate N-carboxyanhydride was presented by Hua (113). The principle of click chemistry was also used for the synthesis of azobenzene-containing lineardendritic diblock copolymers and poly(benzyl ether) dendrimers containing tetra(ethyleneoxide) as the core. In addition to spectroscopic methods, such as NMR and FT-IR, these polymers were investigated by MALDI-TOF-MS (114, 115). Because of their well-defined and specific structures, dendrimers are often used in biological applications, e.g., for drug delivery and release. A dendrimer-peptide conjugate was synthesized based on poly(amidoamine) dendrimer generation 5 (PAMAM G5) as a platform and a luteinizing hormone-releasing hormone peptide as Analytical Chemistry, Vol. 82, No. 12, June 15, 2010

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a targeting moiety. Besides other analytical techniques, MALDITOF-MS was used for a complete characterization of the synthesized conjugates (116). MALDI- and ESI-TOF-MS were also applied for systematic investigations of PAMAM dendrimers surface-modified with PEG and potentially useful as anticancer drug delivery agents (117, 118). Laser-induced liquid beam ionization/desorption (LILBID) MS was used for the characterization of synthesized maltose-modified poly(propylene imine) dendrimers (119). The formation of selfassembled structures in organogels of amphiphilic diblock codendrimers consisting of dendrons of hydroxyl-containing poly(methallyl dichloride) (PMDC) and long alkyl-containing poly(urethane amide) or the conjugation of dendrimers was examined by Yang et al. (120). MALDI and ESI-TOF-MS were used by Garcia-Martinez et al. to confirm the synthesis. Lanthanide(III)cored poly(phenylenevinylene) dendrimers and fully conjugated dendrimers with poly(phenylenevinylene) and poly(phenyleneethynylene) scaffolds were applied as active chromophores for a range of optoelectronic applications (121, 122). Liquid SIMS and MALDI-TOF-MS were used to characterize a novel family of dendrimers with amidoferrocenyl units that are attached to diaminobutane-based poly(propyleneimine) surfaces through alkyl chains (123). The synthesis of star-shaped poly(isobornyl acrylate) (PiBA) by atom transfer radical polymerization (ATRP) was confirmed by MALDI-TOF-MS. The end-group of each arm was transformed into a reactive group, which was used to prepare PiBA nanoparticles by intramolecular polymerization (124). The large-scale synthesis of water-soluble nonionic dendrons and their characterization by MALDI-TOF-MS and SEC was reported by Kim et al. (125). Feng et al. described the synthesis of Janus-type dendrimer-like PEOs carrying orthogonal functional groups on their surface (126). The molecular masses as well as the synthesis of asymmetric PEG star polymers with a cholic acid core were verified by MALDI-TOF-MS (127). MALDI-TOF-MS was particularly useful for the characterization of the new hybrid PAMAM dendrimers (G2, 3, 4, and 6) functionalized at their periphery with first- and second-generation poly(phenylenevinylene) (PPV) dendrons, as well as for the estimation of the average number of PPV dendrons attached to the surface (128). Dehydrogenation of tertiary amines in the MALDI process was found to be the reason for the frequently observed [M-H]+ formation of poly(propylene imine) diaminobutane dendrimers. These samples were also studied by ESI-MS where no protonated ions were observed (129). Kassube et al. synthezised two series of peripherally functionalized dendrimers based on poly(ethyleneimine) and PAMAM dendrimers. The dendritic ligands were characterized by NMR spectroscopy, elemental analysis, and for generations G0 to G3, by MALDI-TOF-MS (130). MS was also applied for the investigation of hyperbranched structures. Pastor-Perez et al. incorporated a photosensitizer core in hyperbranched polyether polyols and determined the effect of the branched shell on the core properties (131). Incorporation of the functional core was unequivocally evidenced by MALDI-TOFMS. A detailed reaction mechanism of the formation of hyperbranched poly(L-lactide) copolymers, prepared by ring-opening multibranching copolymerization of L-lactide with a hydroxyl4820


functional (ABB′) lactone inimer, was derived from kinetic studies of the polymerization via NMR spectroscopy, preparative and analytical LC, and MALDI-TOF-MS (132). The SEC-MALDI-TOFMS calibration method was employed to obtain reliable average molar masses of hyperbranched polyesters. Fractions taken from SEC were analyzed by MALDI-TOF-MS and used as narrow standards for calibration. Unexpectedly, the conventional calibration method using PS standards gave very close molar mass and polydispersity values (133). MALDI-TOF-MS was used to confirm the synthesis of star-shaped poly(isobornyl acrylate) by ATRP using multifunctional initiators (124). Oligoethyloxy-modified macromolecules constitute an important type of polymer electrolyte materials for high-performance lithium-ion batteries. The single-molecule behavior of dendritic PEG structures as a receptor for lithium ions was investigated by Tang et al. (134). Nanoparticles. Nanoparticles based on polymer materials are of increasing interest. They are predominantly used for “beads” and “containers” for a controlled release of drugs. Their advantage compared to inorganic materials is their ability to biodegrade in a short time. The synthesis of bionanocomposites based on poly(ε-caprolactone)-grafted cellulose nanocrystals by ROP was described by Habibi et al. The grafting efficiency was evidenced by the longterm stability of a suspension in toluene, confirmed by FT-IR and TOF-SIMS (135). Xiong et al. developed a surfactant-free route to prepare SnO2@PMMA and TiO2@PMMA core-shell nanobeads with controlled size and composition. These nanobeads can effectively enrich extremely low concentrations of peptides and proteins from complex aqueous solutions. MALDI-TOF-MS was applied to monitor this process (136). Similar efforts were undertaken by Shen et al. using ZnO-poly(methyl methacrylate) nanobeads for enriching and desalting low-abundance proteins (137). MALDI-TOF-MS was also used to characterize colloidal platinum nanoparticles. Poly(vinylpyrrolidone) (PVP) was employed as a capping agent to stabilize the synthesized nanoparticles in solution. The findings demonstrate the usefulness of MALDITOF-MS as a technique for fully characterizing nanoscale materials in order to elucidate structure-property relationships (138). MALDI-TOF-MS, SEC, and 1H NMR were applied to analyze poly(N-isopropylacrylamide) used for stabilizing gold nanoparticles (139). The chemical composition of vaccine antigens on the surface of anionic poly(lactide-co-glycolide) (PLG) microparticles before and after adsorption was measured using X-ray photoelectron spectroscopy (XPS) and TOF-SIMS (140). The conjugation yield of the synthesis of biocompatible nanoparticles made of a conjugate of PLG with alendronate was determined by MALDI-TOF-MS analysis (141). Organosilane modified silicon dioxide nanoparticles with different modification levels were synthesized employing microwave and conventional heating (142). In order to analyze the influence of microwave irradiation, the degree of the physically adsorbed and the chemically bound fractions was measured by MALDITOF-MS. The copolymer (poly(2,5-dimethoxyaniline-co-2,5-diaminobenzenesulphonic acid)-platinum nanocomposite film demonstrates better activity and stability toward methanol oxidation than homopolymer-Pt, because they provide more and deeper nucle-

ation sites for the deposition of platinum (Pt) than homopolymers (143). The 3D dispersion of Pt was verified by SIMS analyses. Polymer nanocomposites consisting of PS, poly(4-acetoxystyrene), and poly(4-vinylpyridine) were prepared by blending with polyhedral oligomeric silsesquioxane (POSS) derivatives. The chemical structures of the POSS derivatives were characterized using FT-IR, 1H NMR spectroscopy, and MALDI-TOF-MS (144). Polymer Surface Techniques. Three-dimensional pictures of the chemical morphology of drug eluting coatings before, during, and after drug elution of rapamycin in poly(lactic-coglycolic acid) obtained by TOF-SIMS-MS revealed a gradient of the coating (145). With the use of this method, an excessive increase of Si on the surface of poly(imide-siloxane) block copolymers was determined (146). Another example represents the identification of ions that characterized the curing reactions on the surface of a diglycidyl ether of bisphenol A and diglycidyl ether of bisphenol F epoxy resin blends reacted with the diamine hardener isophorone diamine at different time intervals, including blocking, coupling, branching, and cross-linking (147) and the depth profiling of polycarbonates by using large argon cluster ion beams (148). A micrometer-scale amphiphilic poly(propylene sulfide-block-ethylene glycol) (PPS-PEG) pattern on a gold substrate was produced by Feller et al. and then characterized by TOF-SIMS and atomic force microscopy (AFM). This compound shows a selective adsorption of proteins on gold but not on PPS-PEG areas (149). Lau et al. applied TOF-SIMS to detect different lamellar orientations at the surfaces of semicrystalline polymers, e.g., chain-folded lamellae of poly(bisphenol A-coetheroctane), containing both aliphatic CH2 and aromatic segments (150). Surface morphologies of vapor deposited polycarbonate were investigated using scanning force microscopy (SFM) (151). Changes of the chemical bonding, the molecular weight, as well as the chain length of the polymer films were determined by ESI-QIT-MS. The molecular mass distributions of low polydispersity poly(dimethyl siloxane) was determined by TOF-SIMS using polyatomic primary ions (152). Similar investigations to detect individual fragmentation pattern of poly(4-vinylphenol) and PMMA were undertaken by Straif and Hutter (153). Cluster SIMS employing an SF5+ polyatomic primary ion sputter source in conjunction with a bismuth source revealed similar results regarding the three-dimensional molecular information in polymeric-based drug-eluting stent coatings (154, 155). TOF static SIMS imaging has also been used to visualize the chemical specificity and selectivity of three plasma polymers (acrylic acid, allylamine, and tetraglyme) as substrates for immobilized metal affinity protein separation (156). The attachment of poly(2-(methacryloyloxy)ethyl phosphate) (PMOEP) and poly[2-(acetoacetoxy)ethyl methacrylate (PAAEMA) homoand copolymers to an amine-modified glass slide was studied by Jasieniak et al. (157). The partially preferential orientation of the PMOEP-b-PAAEMA copolymer could have significant implications on interfacial interactions involved in nucleation and the subsequent mineralization in hydroxylapatite formation. This study demonstrates that TOF-SIMS is a powerful tool for the investigation of the surface composition of adsorbed layers and for probing the conformation of adsorbed block copolymers. TOF-SIMS and water contact angle measurements provided evidence for the absence of surface chemical transformations during the imprinting

of polystyrene-block-poly(tert-butyl acrylate) (PS690-b-PtBA(1210) films by means of a soft lithographic technique (inverted microcontact printing) (158). Ogaki et al. used static (S-) SIMS and gentle (G-) SIMS to extract information on the surface monomer unit distribution of polylactide-co-glycolide materials. They demonstrated that G-SIMS successfully identified the structurally important key fragments leading to direct identification (159, 160). A very particular application of MS represents the detection of ions formed in plasma. Beck et al. used a low power atmospheric pressure helium plasma torch to modify the surface chemistry of poly(R-methylstyrene), PS, poly(propylene), and polyethylene. Mass spectra of the positive ions present in the plasma during the treatment showed typical polymers peak series (161). Monomer units and some fragments were detected for cispolyisoprene, PEG, poly(ethylene terephthalate), which allowed identification of the polymer composition by means of flowing afterglow atmospheric pressure glow discharge (APGD) MS (162). Plasma treatment of mica-substrates was used to insert OH groups, which can be used to covalently attach ATRP radical initiators. This was shown using a TOF-SIMS approach (163). Polymer Separation by Sophisticated LC-MS Techniques. The coupling of chromatographic separation with mass spectrometric identification of polymerization products and pathways has been reported by various groups. Several examples on either HPLC or GC methods coupled to MS (predominantly ESI) have already been reviewed in various sections. Thus, the focus here is directed on coupling of less practiced but frequently much more powerful separation techniques such as “critical” chromatography and hyphenated combination providing two-dimensional separation and MS detection. Copolymers synthesized through ROP of ε-caprolactone with polyethylene glycol monomethyl ether using different catalysts were separated from homopolymers and characterized with respect to their molar mass distribution and content of homopolymers using SEC, liquid chromatography under critical conditions (LCCC), and MALDI-TOF-MS (164). This combination was also applied for the characterization of PEO/PO block copolymers (165). The authors showed that two-dimensional chromatography in combination with MALDI-TOF-MS gives information about the purity of reaction products, presence of byproducts, chemical composition, and molar mass distribution of all the products. Julka et al. combined SEC and LCCC for the separation of species in a two-dimensional fashion (according to molecular weight and end group structure) but used ESI-TOFMS for detection (166). They reported the separation and identification of several different functional group families of compounds, e.g., epoxy-epoxy and epoxy-R-glycol functional oligomers, and the determination of their corresponding molecular weight ranges. The microstructure of a PEO-b-PS block copolymer, synthesized by nitroxide-mediated polymerization, were unambiguously characterized in LCCC/ESI-MS/MS by Girod et al. With the application of “critical” separation conditions for PEG, the PS unit could be separated according to its molecular mass (167). Moreover, the structural information was tuned by adjusting different salts and salt concentration in “critical” chromatography coupled with ESI (168). The formation of backbone-linked hydroxy groups by a quantitative conversion of dithioester end groups provides a versatile anchor for the chemical end-group. Analytical Chemistry, Vol. 82, No. 12, June 15, 2010

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This has been investigated by SEC-ESI coupling experiments (169). A hyphenated system for aqueous SEC pyrolysis-gas chromatography (Py-GC) MS based on the transfer of multiple LCfractions to the GC instrument with solvent elimination and subsequent pyrolysis in a programmed temperature vaporization injector was presented by Kaal et al. (170). Molecular masses and chemical composition of a PEG-PPG block copolymer and a random PS-PMMA copolymer were obtained. Tandem Mass Spectrometry. An overview on tandem MS of synthetic polymers covering the time frame 2005-2009 is provided by Crecelius et al. (171). Jackson et al. reported the use of MALDI-MS/MS using CID for PMMA end group analysis (172). Gies et al. examined the influences of structure, molecular weight, and kinetic energy on degradation mechanisms to test the generality of a multichain fragmentation model developed for PS. Additionally, Py-GC/MS experiments were performed, which allow a comparison of the multimolecular free radical reactions in pyrolysis with the unimolecular fragmentation reactions of MS/MS (173, 174). A combination of the evaporation-grinding MALDI sample preparation method, MALDI-MS/MS using CID, and Py-GC/MS to examine the fragmentation mechanisms of polysulfone was reported by Ellison et al. (175). They showed that cyclic species produce previously unreported fragment ions, possibly due to the multiple main-chain cleavage sites required to generate CID spectra and different gas-phase conformations leading to “backbone scrambling”. The fragmentation of cyclic and linear copolyesters was also investigated by Weidner et al. (176). MALDI-TOF-MS/MS using CID permitted unambiguous elucidation of end groups of the linear polymers from each fraction taken from “critical” chromatography using the LACCC method. Further, all of the determined copolyester sequences indicated a random copolymer composition. The principle of “critical” chromatography in combination with ESI tandem MS was also intensively used by Girod et al. for studies of PEO homopolymers and PEO-PS blockcopolymers (167, 177, 178). The structure of the copolymer, synthesized by nitroxide-mediated polymerization, could be unambiguously characterized. Although MS/MS experiments were conducted in a low-collision energy regime, radical cationic fragments were detected and were shown to dissociate further. Results were obtained using hydrogen/deuterium exchange experiments and ab initio calculations. An alternative fragmentation pathway of the radical cation provided structural information on the group between the two blocks of the PEO-PS copolymer. HPLC-ESI-TOF tandem MS was shown to be useful for the analysis of the enzymatic degradation products of 2,2′-bis(2oxazoline)-linked poly(ε-caprolactone) having specific structures. The results showed that ester bonds appear to be most sensitive to enzymatic degradation (179). The fragmentation pathways of poly(ester amide) samples (PEA-Bu) from the melt condensation of sebacic acid and 4-amino-1-butanol were examined by MALDIMS/MS using the TOF/TOF principle. With the use of argon as the collision gas, fragment mass spectra of cyclic and linear oligomers terminated by diamino alcohol groups produced fragment ions in the low-mass range that are diagnostic. Consequently, these ions established the presence of random sequences of ester and amide bonds in the PEA-Bu sample (180). These diagnostic 4822


low-mass range fragment ions were not observed using air as the collision gas. MALDI-MS/MS using CID was also used for the sequence analysis of toluene diisocyanate-methylenediphenyl diisocyanate oligomers obtained by hydrolysis of cross-linked polyurethane (181). Adamus et al. reported the application of QITESI-MS/MS analysis for structural elucidation by establishing fragmentation patterns of (R,S)-3-hydroxybutyrate/(R,S)-3-hydroxy-4-ethoxybutyrate copolyesters with different architectures (182). The sequence distribution of diblock and random copolyester, showing significant differences in the fragmentation patterns, was determined based on the investigation and comparison of the fragmentation product patterns of the individual molecular ions. Polce et al. investigated the decomposition of Ag+ adducts of PS oligomers with different sizes (6-19 repeat units) and initiating (R) or terminating (ω) end groups by ESI-QTOF-MS (183, 184). It was shown that changes in the PS backbone structure can have dramatic effects on the resulting dissociation chemistry. Positive and negative mode ESI-MS/MS was used alone and in combination with 1H- and 13C NMR to analyze poly(methacrylic acid) oligomers and small poly(methacrylic acid)-poly(methylmethacrylate) copolymers. The exact number of MAA units was determined from the number of carbon dioxide molecules successively eliminated from the fully dehydrated precursor ions. Further, Giordanengo et al. reported an inconsistency of copolymer composition data derived from MS and NMR (185-187). This is obviously caused because of strong mass bias well-known to occur during ESI of these polymeric species. Mechanisms for the fragmentation chemistry of PMMA and poly(butyl acrylate) oligomers have been suggested by Alhazmi and Mayer using an ESI triple quadrupole mass spectrometer (188). They demonstrated that the fragmentation behavior of protonated adducts was different from metal ion adducts. The influence of the adducted cation was also investigated by Mazarin et al. comparing MALDI- and ESI-TOF-MS in the fragmentation of nitroxide-terminated poly(ethylene oxide) macroinitiator agents (189) and by Renaud et al. for poly(dimethylsiloxane) oligomers (190). The size of the ester alkyl substituent of alkali-metal cationized polyacrylates strongly influences their fragmentation patterns. This was shown by Chaicharoen et al. using MALDI-QTOF as well as ESI-QIT mass spectrometers. In addition, the investigation of hyperbranched poly(acrylates), carrying ester groups located within and between the branches, showed a release of unique alkenes and alcohols, enabling the determination of the branching architecture (191). Polymer Degradation. Polymer degradation can be obtained by different processes such as thermo-oxidative, photo-oxidative, hydrolytical, ultrasonical, radiological, or plasma chemical exposure of polymers. Degradation strongly influences the stability and durability of polymer materials, which can have dramatic consequences in safety and reliability of products. The degradation predominantly results in the formation of degradation products with lower molecular masses frequently carrying characteristic end groups indicative of specific degradation pathways. MS analysis is especially capable of monitoring these processes. Continuous-wave carbon dioxide laser irradiation and atmospheric pressure nonthermal He plasma treatment on microporous poly(vinylchloride)/silica composites have been investigated and compared with regard to its thermal stability by thermogravimetric

Figure 9. MALDI and SALDI-MS spectra of PEG6000 (average molecular weight 6000): (a) dithranol matrix without UV irradiation, m/z 500-8000; (b) TiO2 nanoparticles without UV irradiation, m/z 500-8000; (c) TiO2 nanoparticles with 30 s UV irradiation, m/z 500-8000; (d) TiO2 nanoparticles without UV irradiation, m/z 1200-1300; and (e) TiO2 nanoparticles with 30 s UV irradiation, m/z 1200-1300. Reprinted with permission from ref 206. 2009 Wiley Interscience.

analysis (TGA) coupled with MS (192). A very dense structure on the surface with very low chlorine content and an chlorine in-depth gradient up to 150 µm in thickness was observed after laser irradiation, whereas the plasma treatment led to a homogeneous decrease of the chlorine in-depth content due to the plasma interpenetration in the porous microstructure. Pulsed radiofrequency glow discharge TOF-MS was used for the molecular depth profiling of PMMA, PET, poly(R-methylstyrene) (PAMS), PS and of multilayered structures of these polymers. Organic fragment ions detected in the afterglow region of the discharge allowed qualitative identification of the polymers (193). Polyurethane coatings exhibiting sustained physicomechanical properties were exposed to a mixed radiation field supplied by a nuclear research reactor. These polymer coatings could be used as an additional barrier in the design of nuclear waste disposal containers (194). Besides FT-IR, differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), and wide-angle X-ray scattering (WAXS), MALDI-TOF-MS was used for determining the degradation products. Similar investigations to predict longterm polymer behavior during a nuclear waste storage time were performed for a segmented aromatic poly(ether-urethane) by Dannoux et al. applying a triple-quadrupole ESI-TOF (195). Identified structures confirmed that extracted degradation products were mainly issued from poly(tetramethylene glycol) soft segment scissions. The ultrasonically induced depolymerization of chitosan was investigated by NMR and MALDI-TOF-MS (196). MALDI-TOFMS was also used in analyzing products formed by the ultrasonic degradation of PMMA (197). Oligomers with up to 16 or 17 glucose units were observed for different tannins using MALDITOF-MS. Apart from a wide distribution of galloyl glucose chains, the results also indicated that these commercial tannin extracts are mainly composed of long chains of mixed di-, tri-, and pentagalloyl glucose repeating units being present in the same chain (198). Shibaev et al. investigated the influence of fullerene

C60 on the thermal degradation of poly(N-vinyl pyrrolidone) by mass spectrometric thermal analysis (199). ESI-QTOF-MS was applied to unambiguously confirm cyclic degradation products by the treatment of poly[(3,3,3-trifluoropropyl)methylsiloxane] with various solvents (200). Low-molar mass species released during hydrolysis of poly(1,5-dioxepan-2-one) (PDXO) were monitored by ESI- and MALDI-TOF-MS (201, 202). The results show that ether bond fragmentation can be used to form a network structure of PDXO. Kjellander et al. studied a number of different commercial grades of polycarbonates with respect to resistance to environmental stress cracking in contact with food using MALDI-TOFMS (203). A low-molar mass material characterized as poly(propylene glycol) was found, which was also confirmed by FT-IR and 1 H NMR. Photo-oxidative degradation processes were investigated by several authors. Malanowski et al. studied the photodegradation of poly(neopentyl isophthalate). The highly informative data provided by MALDI-TOF-MS allowed establishing the pathways of photolysis and photooxidation (204, 205). Watanabe et al. applied TiO2-SALDI-MS for the analysis of PMMA in the presence of PEG (Figure 9) (206). The use of TiO2 nanoparticles combines the advantages of a selective photocatalytic degradation effect of PEG with those of a SALDI matrix for the desorption/ionization of PMMA when irradiated with the UV laser. This approach may be useful for detecting target analytes among multiple components in the future. A comparative investigation of photo- and thermal-oxidation processes in poly(butylene terephthalate) was performed by Corroccio et al. (207). The oxidized compounds were analyzed by MALDITOF-MS. The structural analysis of the oxidation products provided by MALDI allowed construction of an exhaustive scheme of the thermal- and photo-oxidation mechanisms of poly(1,4-butylene terephthalate). MALDI-TOF-MS in combination with 1H NMR was also applied in the study of Romao et Analytical Chemistry, Vol. 82, No. 12, June 15, 2010

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al. investigating the thermo-oxidative and thermo-mechanical oxidation of bottle-grade PET (208). The degradation of a 12-arm starlike polymer with fullerene C-60 core and equal number of PS and PtBMA arms was studied by thermal desorption (TD) MS (209). Thermally induced degradation processes have been extensively studied. A review of synthetic polymer characterization by Py-GC/MS was published by Rial-Otero et al. (210). Sonova et al. applied high-resolution FT-IR, selected ion flow tube (SIFT) MS, and GC/MS for investigating the thermal degradation of PET (211). TGA coupled to single photon ionization (SPI) quadrupole MS was chosen to monitor the chemical signature of the thermal decomposition of PS, polycarbonate, and actylonitrile-butadiene-styrene, polymer mixtures and blends (212). TGA-MS was applied to study the thermal degradation mechanism of poly(vinyl acetate) and poly(ethylene-co-vinyl acetate) copolymers (213) and polychloroprene (214). Direct pyrolysis MS was used by Cetin and Tincer for their studies of the thermal stability and decomposition mechanism of poly(p-acryloyloxybenzoic) acid, p-methacryloyloxybenzoic acid, and their graft coproducts of polypropylene (215). Kurokawa et al. prepared a series of coordination polymers, cobalt(II)[dipicolylamide-propyl poly(dimethylsiloxane)]s (Co-DPPDMS) and studied their thermal behavior by TG and Py-GC/MS (216). This particular technique was also used for the characterization of cross-linking structures in terephthalate polyesters formed during material recycling (217), of synthetic resins used as binding media, paint additives, painting varnishes, coatings, or consolidants in the field of art and conservation (218), and of the thermal degradation of novel ultrafire-resistant polymers and copolymers containing deoxybenzoin units in the backbone (219). A modification is represented by the pyrolysis-silylation GC/MS approach based on “online” silylation-pyrolysis using hexamethyldisilazane as a derivatization reagent in Py-GC/MS. This proposed procedure improves conventional direct Py-GC/MS and led to unambiguous identification of polyvinyl resins, in particular, poly(vinyl acetate) emulsions widely used in contemporary paintings (220, 221). Direct insertion probe pyrolysis MS was applied for monitoring the thermal degradation of electrochemically prepared polyaniline, polypyrrole, their composites/copolymers, and a BF4-doped conducting pyrrole copolymer (222, 223), as well as for studying the thermal degradation characteristics of PS and poly(ε-caprolactone) macromonomers (224, 225). A new application of synchrotron vacuum ultraviolet photoionization MS in the study of the thermal decomposition of poly(vinylchloride) (PVC) and PS were reported by Li et al. (226). The presented data revealed a two-stage thermal decomposition of PVC: the lowtemperature stage to form HCl and benzene and the hightemperature stage to form numerous large aromatic hydrocarbons. PVC was also investigated in the work of Xiao et al. determining the mechano-chemical dechlorination of PVC and poly(vinylidene chloride) by mechanical milling of polymer powder with zinc powder in a planetary ball mill (227). Similarly, German et al. studied the thermal decomposition of poly(oxymethylene) and poly(oxymethylene)-PVC mixtures. In both cases dechlorination products were detected by GC/MS (228). The melt mixing of Nylon-6 and oxazoline-cyclophosphazene units led to the formation of traces of gel determined by MALDI-TOF-MS after acid hydrolysis (229). Direct probe-atmospheric pressure chemical 4824


ionization (DP-APCI) MS and MS/MS of cross-linked copolymers and copolymer blends (amphiphilic conetworks), (Figure 10) were applied to reveal information about the thermal stability of the different domains within the copolymer (230). This study demonstrated that the DP-APCI method can successfully be used to characterize the chemical composition of synthetic polymers that are too large or too complex for direct analysis by MS. Biodegradable polymers gain an increasing importance for medical and environmental use. Aoyahi et al. used an excimer laser to generate long thin holes on biodegradable polylactic acid. These materials were used for blood collection. Gaseous degradation products were detected by GC/MS (231). ESI-MS gave valuable insights into the hydrolysis of biodegradable homo- and copolyesters of 1,5-dioxepan-2-one and ε-caprolactone and showed that hydrophilicity of the polymer as well as copolymer architecture both greatly influenced the water-soluble degradation product patterns (232). The molecular mass dependent degradation of PEGs (up to 57 800 Da) in wastewater and seawater was investigated by LC-MS and MALDI-TOF-MS (233). The results showed that all PEGs were completely biodegradable in freshwater media within 65 days, whereas higher mass PEGs (> 7.400 Da) were not degraded in artificial seawater for a period of 135 days. The influence of poly(ethylene glycol) monoacrylate (PEGA) macromonomer grafted on preoxidized poly(methyl methacrylate) (PMMAox) films on marine compounds (proteins and phospholipids) adsorption was evidenced by TOF-SIMS and XPS. The authors showed that the antifouling efficiency of the PEGA-grafted surfaces increases with both PEGA concentration and PEG chain length (234). The fabrication of uniform arrays of substrate-bound poly(caprolactone) nanowires, used for tissue-engineered scaffolds to promote the natural healing process of bones, was described by Porter et al. (235). MALDI-TOF-MS was applied to characterize the biodegradation of nanowire surfaces. The chemical and enzymatic degradation of monodisperse oligo(ε-caprolactone) (OCL) and its amphiphilic block oligomer with methoxy poly(ethylene glycol) (mPEG) was investigated as function of the pH and dielectric constant of the medium, at different enzyme and substrate concentrations. The results indicate that mPEG-b-OCL micelles are very stable in vitro, but their susceptibility to enzymes such as lipase makes these systems suitable for the hydrolysis controlled release of drugs in vivo (236). The hydrolytic degradation of glycolide/L-lactide/ε-caprolactone terpolymers was verified by Kasperczyk et al. (237). ESI-MS and 1H NMR have been used to investigate the hydrolytic degradation of these polymers. Biodegradation of poly(butylene succinate) powders in a controlled compost at 58 °C was studied using a microbial oxidative degradation analyzer based on the ISO 14855-2 method. Formed CO2 was transformed to graphite, which was analyzed by accelerated MS to determine the percent modern carbon based on the C-14 radiocarbon concentration (238). Polymer recycling becomes increasingly important to save resources and to protect the environment. The influence of multiple recycling of high-density polyethylene and polypropylene crates on the migration and formation of degradation products was investigated by Coulier et al. using thermodesorption GC/ MS. The proposed analytical protocol is suitable to examine the influence of (multiple) recycling on the food safety of plastic

Figure 10. Structure of a graft copolymer (PDMAAm-g-PDMS) and cross-linked APCN resulting after reaction of the graft with pentamethylcyclopentasiloxane and a typical DP-APCI mass spectrum. Reprinted from ref 230. 2008 American Chemical Society.

materials and can be applied to other plastics used for food contact materials as well (239). Flame protection of polymers represents a major issue and can be achieved using a number of different strategies. Ishikawa et al. investigated the influence of oxides in polymer blends of PET on its flame retardancy and flammability by means of PyGC/MS and TGA (240). Price et al. used covalently bonded phosphonate to introduce flame retardancy in PMMA polymers. A range of MS techniques including laser pyrolysis (LP)-TOF MS and isothermal Py-GC/MS was used to gain information pertinent to the mechanisms of their flame-retardant behavior (241). With the use of LP/TOF-MS, the presence of phosphorus containing species in the pyrolysis product plume from the samples containing phosphonate fire retardants could be identified. The thermal decomposition of carbonaceous material from biomass (soft and hard wood), fossil fuel (crude oil and coal) as well as a complex polymer (ABS) was investigated online using a TGA/DSC coupled to SPI MS for evolved gas analysis (242). Kim et al. investigated the effect of metal compounds on the thermal degradation of poly(3-hydroxybutyric acid), poly(4-hydroxybutyric acid), and poly(ε-caprolactone) (243). Using TGA and Py-GC/MS, they showed that the presence of Na and Ca compounds induced an

acceleration of random chain scission to generate ω-crotonyl chain ends, resulting in a lower shift of decomposition temperature, whereas Zn, Sn and Al compounds were considered not to be effective in accelerating the pyrolysis process. The results of the flash pyrolysis of pure PEG and a mixture of PEG with nano nickel powders indicate that nano Ni powders have remarkable effects on bond cleavage and free radical annihilation. GC/MS and FTIR were employed to detect the volatile products formed (244). Polymer degradation processes can also occur in the synthesis of macromolecules. The importance of initiator choice for synthesis of poly(acrylics) under higher temperature conditions was shown by Wang et al. using a MALDI-QTOF mass spectrometer. In addition to the expected polymer species, an additional peak was found, possibly formed by methacrylate backbiting and scission with long alkyl side chains (245). A detailed mass spectrometric analysis of the degradation products generated during storage of PMMA and PS carrying cumyldithiobenzoate end groups was presented by Gruendling et al. Using highresolution ESI-MS, they proved an unexpected radical degradation mechanism for the PMMA macro-RAFT agent stored in tetrahydrofuran. On the basis of these findings, a substitution of cyclic Analytical Chemistry, Vol. 82, No. 12, June 15, 2010

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ethers as solvents for RAFT polymers in synthesis and analysis is strongly suggested (246). Synthetic Polymers in Biological Applications. Although this review is focused on applications of MS for synthetic polymers, a clear separation from biopolymers is not always possible. Only a few examples are included demonstrating the close relationship between synthetic and biopolymers. Frequently synthetic polymers such as PEG and poly(hydroxylbutyrates) homo- and copolymers but also other polymers, such as polyamidoamine dendrimers decorated with PEGs, are used for drug or gene delivery applications and the controlled release of drug or enzymes (117, 247-249). MALDI-TOF-MS was exclusively applied in these experiments. Other applications are the synthesis of polymers by enzymatic reactions, sometimes referred to as “green chemistry” (250-254). For these investigations, GC/MS and MALDI-TOF-MS were used. Polymer coatings can be used as biosensors, e.g., for selective detection of explosives in water (255, 256). This was accomplished using GC/MS and focused ion beam (FIB) SIMS. Segmented polyurethanes are widely used in medical devices because of their desirable physical and chemical properties and proven biocompatibility. A method for the functionalization of polyurethane scaffolds to enable subsequent coupling with dextran and recombinant peptides was shown by Jozwiak et al. SIMS was used for surface analysis (257). Other examples deal with polylactides and their migration from food-contact materials, monitored by LC-ESIMS (258), and of poly3-hydroxybutyrate isolated from commercial baker’s yeast cells and monitored by MALDI-TOF-MS (259). Finally, positive and negative mode MALDI-TOF-MS were applied to investigate the structure of various tannins (260). OUTLOOK An astonishing number of challenges associated with, for example, polymer structure, degree of polymerization, degradation mechanisms, and identification of additives, could be solved using more traditional methods and technologies. These applications range from academic fundamental research to real world industrial challenges. The continuous improvements made to more traditional technology used for polymer analysis by MS demonstrates that there is still room for improvements. Numerous exciting new technologies are emerging such as IMS-MS and ETD, promising an even wider and more detailed view of synthetic polymers including those of three-dimensional structures (topologies). ACKNOWLEDGMENT The authors are grateful for financial support from the National Science Foundation (NSF CAREER ID 0955975), DuPont Young Investigator Award, Wayne State University (start-up funds), and technical support by the Bundesanstalt fuer Materialforschung and pruefung (BAM) and R. Laging. Sarah Trimpin joined the faculty in the Department of Chemistry at Wayne State University 2008. She is a member of the American Chemical Society, American Society for Mass Spectrometry, and the German Society for Mass Spectrometry. Prof. Trimpin is the author and coauthor of numerous scientific journal publications and book chapters as well as coeditor of a book. Her interest is to provide new tools to study diverse materials ranging from obstinate small to fragile large molecules using mass spectrometry in areas such as cell biology and material sciences. She received a Diplom degree in chemistry from the University of Konstanz and a doctor rerum naturalium from the Max-Planck-Institute for Polymer 4826


Research granted by the Department of Chemistry, University of Mainz, Germany. She held a postdoctoral position at Oregon State University/ Oregon Health & Science University. Prior to starting her independent faculty position, she was as a senior research associate at Indiana University. Recently, Prof. Trimpin received the NSF CAREER Award, the ASMS Research Award, and the DuPont Young Investigator Research Award.

Steffen Weidner joined the Federal Institute for Materials Research and Testing (BAM) in 1990. He is head of the “Polymer Analysis” group at the BAM and a member of the German Society for Mass Spectrometry and the American Society for Mass Spectrometry. Dr. Weidner is the author and coauthor of numerous scientific journal publications and book chapters as well as coeditor of a book. He is chairperson of the annual German workshop on the analysis of synthetic polymer by MALDI-TOF mass spectrometry. His research is driven from a regulatory perspective having strong ties to academia and industry. His particular interest is focused on the application of MALDI-TOF-MS of synthetic polymers by developing suitable hyphenated chromatography approaches for efficient reduction of complexity. He received a Diplom degree in chemistry from the Berlin Humboldt-University and a doctor rerum naturalium in chemistry from the Technical University of Berlin.

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