Maldi time-of-flight mass spectrometry of synthetic polymersba333.free.fr/khira/Maldi-tof-ms of synt...

MALDI TIME-OF-FLIGHT MASS SPECTROMETRY OFSYNTHETIC POLYMERS

Michel W.F. NielenAkzo Nobel Chemicals Research, P.O. Box 9300, 6800 SB Arnhem,The Netherlands

Received 26 April 1999; accepted 12 August 1999

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309

II. Matrix Selection for Polymer Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310A. Matrices for UV±MALDI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310B. Matrices for IR±MALDI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317

III. Cationization in Polymer Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319

IV. Sample Preparation Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320

V. Discrimination Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321A. High and Low Mass Discrimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321B. Oligomer Speci®c Discrimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324

VI. MS/MS in MALDI TOF MS of Synthetic Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325

VII. Chromatography/MALDI Coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327

A. Thin Layer Chromatography/MALDI TOF MS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327B. Off-line Size-Exclusion Chromatography/MALDI TOF MS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328C. On-line and Direct Deposition Size-Exclusion Chromatography/MALDI TOF MS . . . . . . . . . . . . . . . . . . . . . 329D. Other Liquid Chromatography Modes Coupled with MALDI TOF MS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330

VIII. Polymer Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331A. Homopolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331B. Blends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333C. Copolymers and Resins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334D. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334

IX. Conclusion and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336

Mass spectrometry of intact synthetic polymers has been limitedto ®eld desorption (FD) MS for many years. More recently, softionization techniques such as electrospray (ESI) and matrix-assisted laser desorption/ionization (MALDI) and the revival oftime-of-¯ight analyzers created new opportunities for thecharacterization of polymers. In this review emphasis is puton MALDI time-of-¯ight mass spectrometry of polymers. Theselection of an appropriate MALDI matrix, cationization saltand sample preparation techniques are critical success factorsfor obtaining a reliable mass spectrum and to infer structuralinformation such as monomer mass(es) and end-groups.However even under optimized conditions mass discriminationin the analysis of polydisperse polymers and speci®c oligomerdiscrimination might occur. Hence hyphenated techniques such

as size exclusion chromatography (SEC)/MALDI have beendeveloped. Many different polymer applications appeared inrecent literature, but most studies deal with homopolymers.Many challenges remain, particularly in the ®elds of haloge-nated polymers, polyole®nes, copolymers, blends, and in thesequencing of block-copolymers. # 1999 John Wiley & Sons,Inc., Mass Spec Rev 18: 309±344, 1999

I. INTRODUCTION

Among the analytical techniques currently used in thecharacterization of synthetic polymers, mass spectro-metry is of increasing importance (Smith et al., 1997). Inthe past, mass spectrometry of synthetic polymers washardly possible: as a rule, polymers had to be degradedthermally or chemically prior to mass spectrometric

Mass Spectrometry Reviews, 1999, 18, 309± 344# 1999 by John Wiley & Sons, Inc. CCC 0277-7037/99/050309-36

ÐÐÐÐCorrespondence to: Michel W.F. Nielen; e-mail: [email protected]

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analysis. For many years, ®eld desorption (FD) on sectorinstruments was the only option for the mass spectro-metric analysis of intact polymers up to 10 kDa (Prokai,1990). Modern soft ionization techniques such aselectrospray, ESI (Fenn et al., 1990), and matrix-assistedlaser desorption/ionization, MALDI (Karas & Hillen-kamp, 1988; Tanaka et al., 1988) had and still have anenormous impact on the analysis of biopolymers such asproteins and peptides. It has been recognized that ESI andMALDI MS are amenable to polymer analysis as well,although the synthetic polymer situation is more complexthan the protein situation due to the coexistence of severaldistributions:

* instead of a single molecular weight, we have todeal with a molecular weight distribution (MWD)as a result of polymer synthesis,

* the polymer chains might have different end-group chemistries due to different initiation andtermination processes, thereby creating a func-tionality type distribution (FTD),

* in case of random copolymers, the polymer chainsshow in addition a chemical composition dis-tribution (CCD),

* in case of block copolymers, additional sequenceand block-length distribution are present,

* (co)polymers show an architecture distribution(linear, cyclic, branched, dendritic).

Despite the complexity of polymer samples, ESI andMALDI MS can contribute to the characterization of all®ve distributions, although so far most studies are limitedto MWD and FTD analyses.

MALDI time-of-¯ight MS is ideally suited forpolymer analysis because of the simplicity of the massspectra which show mainly single-charged quasi mole-cular ions with hardly any fragmentation; the time-of-¯ight (TOF) analyzer in which very high molecularweight polymers can be analyzed, beyond 1 MDa has beendemonstrated (Schriemer & Li, 1996); and the state-of-theart re¯ectron instruments equipped with delayed extrac-tion ion source (Wiley & McLaren, 1955; Brown &Lennon, 1995) which offer resolution in the range of10,000±20,000 (FWHM) thereby allowingÐdependingon the monomer mass and the polymer complexityÐthedetermination of the repeating mass increment (i.e., themonomer mass) and the mass residue (i.e., the end-groupsplus known cation mass) up to 35 kDa.

This review is restricted to MALDI TOF MS ofsynthetic polymers and covers the literature until thebeginning of 1999; short reviews on the same topic can befound elsewhere (Montaudo, 1996; Jackson & Simonsick,1997; Wu & Odom, 1998; Raeder & Schrepp, 1998).

II. MATRIX SELECTION FOR POLYMER ANALYSIS

The ®nal goal of matrix, solvent, salt and samplepreparation in any MALDI experiment is homogeneouscocrystallization of sample and matrix molecules. Incontrast to the peptide and protein situation this is notstraightforward because of the distributions withinpolymer samples as outlined above. Instrument manu-facturers offer automated data acquisition routines(Suckau et al., 1997) which perform quite well in peptideanalysis wherein, as a rule, homogeneous samples arebeing obtained. In MALDI of synthetic polymers,typically rather inhomogeneous sample preparations areobtained and often one has to search not only for thesweet spots showing good resolution and signal intensitybut in cases even for those spots giving any polymersignal.

Water-soluble synthetic polymers such as polyethy-leneglycol and polypropyleneglycol were already studiedin the early days of MALDI MS, simply because the samematrices used in the analysis of peptides could be applied.For other polymers, some general guidelines for matrixselection can be extracted from polymer and matrixsolubility data (Hanton & Owens, 1998):

Matrices Polymers

Hydrophilic

2,5-Dihydroxybenzoic acid Polypropylene glycol

�-Cyano-hydroxycinnamic acid Polyvinyl acetate

Ferulic acid Polytetramethylene glycol

Indoleacrylic acid Polymethylmethacrylate

Dithranol Polystyrene

all trans-Retinoic acid Polybutadiene

Diphenylbutadiene Polydimethylsiloxane

Hydrophobic

Generally, it is recommended to match the matrix polaritywith the polymer under investigation. Nevertheless,matrix selection and optimization for polymer analysisis still often a trial and error process; as a starting point,many suggestions on matrix for UV±MALDI and somehints for IR±MALDI can be found in literature.

A. Matrices for UV±MALDI

An overview of synthetic polymers with documentedMALDI matrices is given in Table 1. The molecularweights indicated therein refer to the high molecularweight end actually observed in the MALDI massspectra. In addition, polymer and matrix solvents areincluded.

Obviously many matrix options are available but oneshould be aware of the incompatibilities and backgroundeffects, e.g., dithranol is successfully used with silver salts

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TABLE 1. Matrices for UV±MALDI mass spectrometry of speci®c synthetic polymers

Polymer Matrix Matrix solvent Polymer solvent MW Reference

PEG SA 1500 Zenobi, 1994

PEG HABA THF 24,000 Montaudo et al.,

1995a

PEG DHB water acetonitrile±water 2400 Pasch & Rode, 1995

PEG DHB ethanol 24,000 Montaudo et al.,

1995c

PEG HABA dioxane methanol 4500 Whittal & Li, 1995

PEG ACA/MSA ethanol methanol 8000 Tang et al., 1995b

PEG DHB dichloromethane 5000 Weidner et al.,

1996b

PEG glycerol/graphite methanol 8000 Dale et al., 1996

PEG NBA/graphite methanol 8000 Dale et al., 1996

PEG hydroxymethoxycinnamic methanol methanol 1000 Fei & Murray, 1996

acid

PEG MBT 14,000 Xu et al., 1997

PEG AMBT EtOH/THF/water EtOH/THF/water 14,000 Xu et al., 1997

PEG K4[Fe(CN)6]/glycerol methanol/glycerol chloroform 8000 Zollner et al. 1997

PEG glassy azodyes 1500 Blair et al., 1998

PEG, pyrene- HABA dioxane methanol Whittal et al., 1996

PEG, derivatized- DHB ethanol/water DMSO 5000 Weidner & Kuhn,

1996

PEG, dimethyl- salicylamide ethanol/water water 1600 Krause et al., 1996

PEG, dimethyl- salicylanilide ethanol water 5200 Krause et al., 1996

PEG, carbonate- CHCA acetone water/acetone 7000 Hagelin et al., 1998

PTMEG DHB 1000 King et al., 1995

PTMEG DHB THF THF 9000 Jackson C et al.,

1996

PPG ACA/MSA 6500 Tang et al., 1995a

PPG DHB methanol±water (1:1) 2400 Barton et al., 1995

Polyether, CHCA acetonitrile/water methylene chloride 5000 Peiris et al., 1998

-azoxyaromatic

Coal SA chloroform/methanol 70,000 Herod et al., 1994a

Coal SA 270,000 Herod et al., 1994b

Coal trihydroxyanthracene 200,000 Herod et al., 1995

Coal, -tar pitch SA, DHB 260,000 John et al., 1994

Coal, -tar various NMP NMP 100,000 Domin et al., 1997

Coal, -tar pitch none 10,000 Johnson et al., 1998

PMMA IAA acetone acetone 260,000 Danis & Karr, 1993

PMMA DHB acetone acetone 260,000 Danis & Karr, 1993

PMMA DHB water/acetonitrile acetone 9000 Danis et al., 1993

PMMA DHB water/ethanol THF 3000 Lehrle & Sarson,

1995

PMMA HABA THF 90,000 Montaudo et al.,

1995a

PMMA DHB THF 9500 Lloyd et al., 1995

PMMA ACA/MSA ethanol toluene 8000 Tang et al., 1995b

PMMA DHB 50,000 Cottrell et al., 1995

PMMA IAA acetone acetone 50,000 Belu et al., 1996

PMMA IAA acetone acetone 7000 Larsen et al., 1996

PMMA DHB ethanol±water THF 4000 Lehrle & Sarson,

1996

PMMA DHB THF THF 15,000 Jackson C et al.,

1996

PMMA DHB THF 3000 Weidner et al.,

1996b

PMMA DHB methanol methanol 6000 Dogruel et al., 1996

PMMA DHB�CsI methanol methanol 6000 Dogruel et al., 1996

(Continued)

MALDI TOF MS OF SYNTHETIC POLYMERS &

311

TABLE 1. (Continued)


PMMA IAA THF THF 110,000 Schweer et al., 1996

PMMA DHB�KtFAc THF THF 10,000 Spickermann et al.,

1996

PMMA MBT Xu et al., 1997

PMMA dithranol� surfactants 6500 Kassis et al., 1996

PMMA dithranol THF THF 20,000 Jackson AT et al.,

1997a

PMMA HABA THF acetone or THF 50,000 Rashidzadeh et al.

1998a

PMMA, end-groups DHB acetone 4000 Maloney et al., 1995

PMMA, end-groups DHB THF 3500 Pasch and Gores,

1995

PMMA, end-groups IAA acetone 9200 Scrivens et al., 1995

PMMA, end-groups DHB acetone acetone 6000 Hunt et al., 1995

PMMA, end groups dithranol HFIP HFIP 13,000 Jackson, AT et al.,

1997b

PBA DHB acetone acetone Easterling et al.,

1998

PBA IAA THF THF 200,000 Nielen & Malucha,

1997

PBMA IAA acetone acetone 100,000 Danis et al., 1995

Polyacrylate, ¯uorinated DHB THF trichlorotri¯uoroethane 25,000 Latourte et al., 1997b

PS IAA THF Danis & Karr, 1993

PS HABA THF 50,000 Montaudo et al.,

1994b

PS none chloroform or THF 1400 Mowat & Donovan,

1995

PS HABA THF 46,000 Montaudo et al.,

1995a

PS dithranol�AgtFAc 10,000 Scrivens et al., 1995

PS 9-Nitroanthracene THF 11,000 Lloyd et al., 1995

�AgtFAc

PS dithranol�AgtFAc chloroform chloroform 40,000 Belu et al., 1996

PS dithranol�AgtFAc THF THF 3500 Thomson et al.,

1996

PS HABA THF THF 35,000 Liu & Schlunegger,

1996

PS 4-(Phenylazo)-resorcinol THF THF 35,000 Liu & Schlunegger,

1996

PS chromoionophor IV THF THF 35,000 Liu & Schlunegger,

1996

PS dithranol�AgtFAc THF THF 7500 Chaudhary et al.,

1996

PS IAA�Agacac THF THF 125,000 Danis et al., 1996a

PS POPOP�Agacac THF THF 22,000 Danis et al., 1996a

PS all-trans-Retinoic THF (puri®ed) THF (puri®ed) 1:5 MDa Schriemer & Li,

acid�AgNO3 1996

PS dithranol�AgtFAc THF THF 35,000 Schweer et al., 1996

PS dithranol� cations THF THF 3000 Deery et al., 1996

PS dithranol�AgtFAc 210,000 Lee & Han, 1996

PS all-trans-Retinoic THF THF 500,000 Brown et al., 1997

acid�AgNO3

PS dithranol�AgtFAc THF THF 200,000 Nielen & Malucha,

1997

PS dithranol� 65Cu(acac)2 THF THF 7000 Burgers & Terlouw,

1998

PS dithranol�Ag/Cu/Pd 4000 Rashidzadeh et al.

1998b

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PS, nitroxide- dithranol�AgtFAc 5000 Beyou et al., 1998

PS, dedtc- dithranol�AgtFAc 5000 Beyou et al., 1998

PS, macrocyclic- dithranol�AgtFAc 4400 Pasch et al., 1997

PS, -methyl 9-nitroanthracene THF THF 1600 Kukulj et al., 1998

�AgtFAc

PVC IAA THF Danis & Karr, 1993

PVC HABA THF Danis & Karr, 1993

PVAc DHB methanol Danis & Karr, 1993

PVAc HABA acetone acetone Cornett et al., 1998

PC HABA THF 17,000 Montaudo et al.,

1995a

PC IAA THF Danis & Karr, 1993

PC HABA THF Danis & Karr, 1993

PC DHB chloroform 5000 Weidner et al.,

1996b

PC HABA 20,000 Montaudo et al.,

1994c

PC IAA THF THF 100,000 Nielen & Malucha,

1997

PC dithranol THF 5000 Pasch et al., 1996

PB none 1300 Mowat & Donovan,

1995

PB POPOP�Agacac THF THF 11,000 Danis et al., 1996a

PB DHB�AgNO3 THF THF 6000 Pastor & Wilkins,

1997

PB all-trans-Retinoic THF THF 300,000 Yalcin et al., 1997

acid�Cu(II)nitrate

PB, hydroxylated- dithranol�AgtFAc THF THF 5000 Latourte et al.,

1997a

Polyisoprene all-trans-Retinoic acid THF THF 150,000 Yalcin et al., 1997

�Cu(II)nitrate

Polyisoprene dithranol�AgtFAc THF THF Cornett et al., 1998

Squalane, Squalene NPOE�AgtFAc toluene toluene 550 Weidner et al., 1997

Squalene, -epoxidized THAP ethanol/water 2000 Kuehn et al., 1997

Paraf®nes, Waxes DHB, NPOE ethanol/water toluene 3000 Kuehn et al., 1996

PDMS DHB THF 280,000 Montaudo et al.,

1995b

PMPS DHB THF THF 2500 Montaudo et al.,

1996c

PMPS IAA THF THF 2000 Montaudo et al.,

1996c

PMPS dithranol THF THF 2500 Montaudo et al.,

1996c

PAN 4-Hydroxy benzylidene acetone DMF 4500 Linnemayr et al.,

malononitrile 1998

Polycaprolactone HABA 14,000 Montaudo et al.,

1994c

Polycaprolactone HABA THF 10,000 Montaudo et al.,

1995a

Polycaprolactone DHB water LC mobile phase: THF 1400 Pasch & Rode, 1995

Polycaprolactone DHB methanol/water ethyl acetate 7000 Cordova et al., 1998

Polycaprolactone, DHB�NaCl 5500 Miola et al., 1998

-benzyl/hydroxy

PEF 2000 Hanton & Parees,

1995

PA6, -aminolized HABA 8000 Montaudo et al.,

1994a

(Continued)


313



PA6, -diamino HABA tri¯uoroethanol 3000 Montaudo et al.,

1995a

PA6, -monoamino HABA tri¯uoroethanol 6200 Montaudo et al.,

1995a

PA6, -dicarboxyl HABA tri¯uoroethanol 6400 Montaudo et al.,

1995a

PA6 HABA tri¯uoroethanol 7000 Montaudo et al.,

1996d

polyamines, Triazine- DHB formic acid formic acid 5000 Braun et al., 1996

Poly(butylene adipate), HABA Montaudo et al.,

-glycolized 1994a

Poly(butylene adipate) HABA THF 4000 Montaudo et al.,

1995a

Poly(butylene adipate) HABA, DHB THF 48,000 Montaudo et al.,

1995d

Poly(butylene adipate) IAA acetone acetone 3000 Williams et al., 1997

Poly(butylene adipate) dithranol�AgtFAc THF THF 6500 Liu & Schlunegger,

1996

Poly(decamethylene DHB water THF/hexane (45:55) 3000 Pasch & Rode, 1995

adipate)

Poly(ethylene DHB, THAP chloroform 3500 Weidner et al., 1995

terephtalate)

Poly(ethylene DHB 5±10 mg/mL chloroform 3000 Weidner et al.,

terephtalate) 1996a

Poly(ethylene DHB chloroform Weidner et al.,

terephtalate) 1996b

Poly(ethylene 3000 Yates et al., 1996

terephtalate)

Poly(ethylene dithranol THF HFIP 4000 Jackson A et al.,

terephtalate) 1997a

Polyester, -aliphatic, DHB, IAA water±methanol, THF water, THF, THF/TFA, TFA 8000 Blais et al., 1995

-aromatic

Poly(trimethylene IAA 4800 Williams et al., 1995

glutarate)

Poly(trimethylene IAA acetone acetone 3000 Williams et al., 1997

glutarate)


adipate)


succinate)

Polyester DHB THF, acetone THF, acetone 5000 Guittard et al.,

1996b

Poly(ethylene DHB THF 4000 Pasch et al., 1996

terephtalate,

-isophtalate)

Poly(dihydroxymethyl- HABA THF THF 120,000 Scampporrino et al.,

benzene/phtalate) 1996

Poly(neopentyl IAA THF THF 40,000 Nielen & Malucha,

terephtalate) 1997

Poly(ethylene adipate) IAA acetone acetone 3000 Williams et al., 1997

Poly(neopentyl sebacate) IAA acetone acetone 3000 Williams et al., 1997

Polyester, -methylated 5-nitrosalicylic acid 2500 Guittard et al., 1997

Polyester, -cyclic 5-CSA 8000 Guittard et al.,

1996a

Poly(diethyl- DHB water/acetonitrile acetone 2000 Feast et al., 1997

3-hydroxyglutarate)

Poly(phenylglycidyl- DHB ethanol THF 6000 Leukel et al., 1996

phtalic anhydride)

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Poly(hydroxystearate) IAA THF Danis & Karr, 1993

Dendrimers, -aromatic DHB water/acetone water/acetone, chloroform, 5200 Sahota et al., 1994

polyester � sodium chloride

Dendrimers, -aromatic IAA THF THF 14,000 Leon & Frechet,

polyether 1995

Dendrimers IAA acetone THF, chloroform Milberg & Garden,

1996

Dendrimers all-trans-Retinoic acid methylene chloride THF, chloroform >20,000 Milberg & Garden,

1996

Dendrimers, -carbosilane, DHB water Wu & Biemann,

-t-amino 1997

Dendrimers, -carbosilane, DHB� ammonium citrate water Wu & Biemann,

-sulfonated (1:1) 1997

Dendrimers, IBU- dithranol THF THF 11,000 Srinivasan et al.,

1998

Dendrimers, -aromatic- benzyloxycyano-cinnamic 5000 Gooden et al., 1998

polyether acid

PU HABA 10,000 Tang et al., 1995a

PU, -pyrolysate 5500 Lattimer, 1998

PU, dendritic wedges CHCA acetone acetone 6500 Puapaiboon &

Taylor, 1999

PI dithranol�AgtFAc chloroform chloroform 5000 Belu et al., 1996

Polysul®de, -linear 9-Nitroanthracene THF THF 2800 Mahon et al., 1998

�AgtFAc

PAA Danis et al., 1992

PAA, -¯uorinated end DHB THF THF 2000 Latourte et al.,

1997b

PSS SA 180,000 Danis et al., 1992

PSS DHB, SA, CSA water, water, THF 100,000 Raeder et al., 1995

PSS SA water 450,000 Danis & Karr, 1995

Polylactide DHB THF THF 6000 Montaudo et al.,

1996b

Polylactide HABA THF THF 10,000 Montaudo et al.,

1996b

Polydextrane DHB/HIC (3:1) water/acetonitrile water 2000 Bornsen et al., 1995

Copolymers and resins

PVP/PVAc IAA THF Danis & Karr, 1993

PVP/PVA 3500 Schaer, 1995

EO/PO DHB water acetonitrile±water 1400 Pasch & Rode, 1995

EO/PO Kalinoski et al.,

1995

EO/PO dithranol HFIP HFIP Scrivens et al., 1998

PO/EO/PO, HABA dioxane 2000 Schriemer & Li,

-diaminopropylether 1995

EO/PO/EO, PO/EO/PO CHCA � potassium iodide 8600 Lacey et al., 1996

EO/pyrene HABA 1,4-dioxane methanol 10,000 Lee et al., 1996

Jeffamine ACA/MSA ethanol methanol 2000 Tang et al., 1995b

Jeffamine HABA dioxane dioxane 3000 Schriemer et al.,

1997

Jeffamine DHB methanol methanol Goldschmidt &

Owens, 1997

PPE-b-PEO dithranol THF 3500 Francke et al., 1998

PS/PMeS IAA�AgIAA THF THF 5000 Wilczek-Vera et al.,

1996

PMMA/MeSTY, IAA acetone acetone 9000 Guttman et al., 1997

-block(SRM 1487)

(Continued)


315



PMMA/PBMA DHB acetone THF 2500 Suddaby et al., 1996

PMMA/PBMA DHB acetone 4500 Haddleton et al.,

1997

PMMA/PMAA IAA THF THF 150,000 Nielen & Malucha,

1997

PDMS/PHMS NPOE THF THF 15,000 Servaty et al., 1998

Copoly(aryletherketone/ dithranol chloroform chloroform 4000 Wang et al., 1997

arylethersulfone),

-cyclic

Copoly(arylether/ether dithranol�AgtFAc 6000 Wang & Hay, 1997

sul®des)

Copolycarbonate/copper HABA THF THF 3000 Vitalini et al., 1996

complex

Copolyether-bisphenolA/ HABA THF THF 4000 Vitalini et al., 1996

copper complex

Copolybisphenol HABA 1,4-dioxane dioxane 10,000 Schriemer et al.,

A/epichlorohydrin 1997

Copolyester PBA/PBS HABA, DHB THF 80,000 Montaudo et al.,

1995d

Copolyester PBA/PBSe HABA THF/chloroform SEC fraction THF or 30,000 Montaudo et al.,

chloroform 1998a

Copolyester PBSu/PBA HABA THF/chloroform SEC fraction THF or 30,000 Montaudo et al.,

chloroform 1998a

Copolyester PBSu/PBSe HABA THF/chloroform SEC fraction THF or 30,000 Montaudo et al.,

chloroform 1998a

Copolyester HABA THF/chloroform SEC fraction THF or 30,000 Montaudo et al.,

PBSu/PBA/PBSe chloroform 1998a

Copolyester HABA THF/chloroform chloroform 15,000 Montaudo et al.,

1998c

Epoxy resin DHB acetone acetone 3500

Epoxy resin, DHB SEC fractions 6000 Lo & Huang, 1998

-thiodiphenol

Poly(cresylglycidyl/ 1,3-diphenylbutadiene acetone 2800 Schriemer & Li,

formaldehyd) �AgNO3 1995

Poly(cresylglycidyl/ 1,4-diphenylbutadiene acetone acetone 3500 Schriemer et al.,

formaldehyde) �AgNO3 1997

PF resin, -epoxy DHB acetone 2000 Pasch et al., 1996

PF resin DHB acetone 4000 Pasch et al., 1996

PF resin, -alkyl dithranol chloroform chloroform 2000 Mandal & Hay,

1997b

PF resin, -polycyclic 2700 Mandal & Hay,

carbonate of- 1997a

PF resin, t-Butyl-, cyclic dithranol�AgtFAc chloroform�THF chloroform 2500 Mandal & Hay,

siloxanes 1998a

PF resin, Phenyl-, dithranol�AgtFAc chloroform�THF chloroform 2500 Mandal & Hay,

cyclic siloxanes 1998a

PF resin, -cyclic dithranol chloroform chloroform 2700 Mandal & Hay,

phosphonate 1998b

Miscellaneous

Fullerene CHCA benzene benzene 800 Cordero et al., 1996

Fullerenes MSA 756 Rogner et al., 1996

Fullerenes CHCA acetone chloroform Linnemayr &

Allmaier, 1997

Fullerenes sulfur carbon disul®de 992 Brune, 1999

Calixarenes HPA water/acetonitrile chloroform Linnemayr &

Allmaier, 1997

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in MALDI of polystyrenes but the stability of this mixtureis limited to a few minutes only. Matrices such as IAA andall-trans-retinoic acid show self-polymerization uponstanding and ®nally might obscure the mass spectrum upto several thousand Daltons. Initially promising matricessuch as HABA (Montaudo et al., 1994b) showedsigni®cant mass discrimination in later studies (Rashid-zadeh & Guo, 1998a; Nielen & Malucha, 1997). Some ofthe matrices listed in Table 1 should be considered`̀ experimental'' and are less suitable for routine applica-tions: graphite (Dale et al., 1996) and liquid matrices suchas 2-nitrophenyl octylether, NPOE, (Williams et al., 1996)might cause severe contamination of the ion source.Physical-chemical data are only known for a fewgenerally used matrices and are summarized in Table 2.Most of the data in Table 2 originate from peptide and

protein studies; as a consequence, proton af®nity data areinvestigated while cation af®nity data are actuallyrequired in the synthetic polymer situation. Nevertheless,some idea about the energetics can be obtained and shouldbe considered in practice. It has been shown that matriceswith low PA values induce more fragmentation of peptidesthan matrices with high PA values (Jorgensen et al., 1998).

B. Matrices for IR±MALDI

Only one signi®cant study in the ®eld of IR±MALDI ofsynthetic polymers is known so far, see the data in Table3. Infrared lasers such as the Nd±YAG laser (3.27 mm,equivalent to 3050 cmÿ1) excite the C±H stretch vibra-tions, so, many matrices for UV±MALDI can be appliedin IR±MALDI as well. In addition, matrix-less, i.e., IR±



Calix[3]indoles SA dichloromethane 1200 Lidgard et al., 1996

Triton X305 K4[Fe(CN)6]/glycerol chloroform 2000 Zollner et al., 1996

Tween 85 HABA acetonitrile/water acetonitrile/water 2000 Giang & Chang,

1997

Tween 20 CHCA acetonitrile/water water or isopropanol 2000 Cumme et al., 1997

Sorbitols, methyl, FA Kim et al., 1998

benzylidene-

Surfynol DHB methanol methanol 1600 Parees et al., 1998

Alkylphenolethoxylate, DHB methanol 1000 Barry et al., 1997

-derivatized

Surfactants, -ethoxylated CHCA ethanol iso-propanol or water 1800 Bartsch et al., 1998

Azodyes, polysulfonated- HABA� diammonium ethanol water 1400 Sullivan & Gaskell,

citrate 1997

TABLE 2. Physical-chemical data of UV±MALDI matrices

�®lm (cmÿ1)Matrix MW at 337 nm PA (kJ/mol) Reference

2,5-DHB 154 0.79� 105 ± Allwood et al., 1996841ÿ 866 Jorgensen et al., 1998854� 14 Steenvoorden et al., 1997854� 16 Burton et al., 1997

�-CHCA 189 2.18� 105 ± Allwood et al., 1996841 Jorgensen et al., 1998933� 9 Steenvoorden et al., 1997766� 8 Burton et al., 1997

Sinapinic acid 224 1.10� 105 ± Allwood et al., 1996887 Jorgensen et al., 1998894� 13 Steenvoorden et al., 1997

Dithranol 226 ± 874� 8 Burton et al., 1997IAA 187 ± 900� 16 Burton et al., 1997HABA 242 ± 943 Jorgensen et al., 1998

766� 8 Burton et al., 1997


317

LDI, has potential for the characterization of rather apolarsamples such as waxes (Weidner et al., 1998). FT±IRspectra of the matrices in Table 3 are given in Fig. 1: inall cases, excitation of the matrix by a 3.27 mm IR-laser isfeasible. For proteins and peptides, a lower degree ofprompt and metastable fragmentation has been observedas compared to corresponding UV±MALDI measure-ments (Berkenkamp et al., 1997; Zhang et al., 1998).

However, one should also note some disadvantages whenconsidering IR±MALDI. First, one IR±laser shot willdesorb more material than a corresponding UV±laser shotdue to its greater penetration depth, thus only a few massspectra can be acquired from a speci®c spot and morefrequent spot change is required. Second, the pulse lengthof the IR±laser is generally longer, for example 10±20 nsfor a YAG pumped OPO laser vs. 3±5 ns for a

TABLE 3. Matrices for IR±MALDI mass spectrometry of synthetic polymers (Weidner et al.,

1998)

Polymer Matrix Matrix solvent Polymer solvent MW

PMMA CCA THF THF 3500PMMA SA THF THF 3500PMMA DHB THF THF 3500PMMA THAP THF THF 3500PEG CCA THF THF 14,000PEG SA THF THF 14,000PEG DHB THF THF 14,000PEG THAP THF THF 14,000

FIGURE 1. FT±IR spectra of IR±MALDI matrices: grey bars cover the absorption region for an infraredlaser at 3.27 mm. Reproduced from Weidner et al., 1998, with permission from John Wiley & Sons, Ltd.

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conventional 337 nm nitrogen laser. These disadvantagesexplain, at least partly, the much lower (7±20 times)resolution obtained in IR±MALDI of polymers. The peakwidth due to the initial velocity distribution might beeffectively reduced by delayed-extraction techniques(Weidner et al., 1998; Zhang et al., 1998), similar toUV±MALDI experiments. Nevertheless, it was con-cluded that in general UV±MALDI is to be preferredfor the analysis of synthetic polymers (Weidner et al.,1998), but there might be potential for some interestingniche applications too, such as the characterization ofhalogenated polymers, which often show extensiveprompt fragmentation in UV±MALDI (McEwen et al.,1998), and in the analysis of polymers absorbing at337 nm by themselves.

III. CATIONIZATION IN POLYMER ANALYSIS

Contrary to MALDI of biopolymers, the ®nal ionizationof synthetic polymers is usually by cationization ratherthan protonation. Consequently, matrix optimizationalone is not suf®cient and should be considered togetherwith cationization issues. For relatively polar polymerssodium and/or potassium adduct ions might be observedin the MALDI mass spectrum, even when they were notintentionally added (Danis & Karr, 1993). These cationsare present as impurities in glassware, solvents, reagents,etc., and polymers having relatively high cation af®nitiesdo not necessarily require high cation concentrations inthe MALDI sample. Most of the synthetic polymershaving heteroatoms will show cationization after additionof sodium or potassium salts, e.g., polyethers (King et al.,1995), polyacrylates, polyesters, polyamides. Use of thedelayed ion extraction technique allows more time forcation attachment, and a substantial increase in signalintensity of cationized polymers might be obtained(Mowat et al., 1997). Apolar synthetic polymers withoutheteroatoms such as polystyrene, polybutadiene, andpolyisoprene can be successfully ionized after theaddition of silver or copper salts, which interact withthe double-bonds of these polymers (Mowat & Donovan,1995). Polymers without hetero-atoms and without anydouble bonds such as polyethylene and polypropylene arestill not amenable to MALDI analysis because of theextremely low binding energy of the cation-oligomercomplexes (Reinhold et al., 1998); in these cases ®elddesorption MS or medium-energy electron ionization MSmight be an alternative to some extent (Prokai, 1990;Ludanyi et al., 1999).

Cationization has been studied by several groups butsystematic approaches and cation af®nity data aregenerally lacking and remain interesting research oppor-tunities for the near future. As exceptions to this general

observation, some papers deal with conformations andenergetics and compare theoretical ®ndings with experi-mentally observed MALDI data. The experimentallyobserved absence of sodium cationized poly(ethyleneglycol) oligomers below n� 5 has been attributed to toolow binding energies and the requirement of multipleinteractions, i.e., folded oligomer conformations (Heldenet al., 1995; Reinhold et al., 1998). Also, for polyestertrimers, folded conformations are energetically morefavorable, but the difference was smaller for sodium vs.lithium cations (Gidden et al., 1997). Actually, differentcations such as lithium, sodium, and cesium ef®cientlywrap the polymer around them but the detailed structureof the inner coordination sphere of polyether oxygenatoms around the cation was found to be cation dependent,i.e., the larger cesium cations prefer higher (11-fold)coordination (Wyttenbach et al., 1997). Varying the cationtype and size in the analysis of polymethacrylates showedmolecular weight distribution (MWD) shifts as much as20±35%, and higher mass averages with the largercations, these effects being more pronounced for poly-disperse samples (Dogruel et al., 1996; Scrivener et al.,1996). It was concluded that larger cations should be ableto form a more stable conformation with a larger oligomeras more oxygens should be available for coordination withthe cation. Similar MWD shifts were observed whenpoly(ethylene terephtalate) was measured in the presenceof lithium, sodium, potassium, rubidium and, cesium(Jackson et al., 1997a).

Polyesters are less ¯exible than polyethers andpolyacrylates, and consequently the most favorableinteractions with the cation are expected to occur athigher molecular weight oligomers. Cationization ofpolystyrene was investigated using silver, zinc, copper,cobalt, aluminum, palladium, and platinum salts. Itwas found that silver, copper, and palladium yieldedef®cient cationization of polystyrene oligomers and it wasargued that cationization occured by gas phase ion±molecule reactions rather than pre-formed ions from thecondensed phase (Deery et al., 1996; Hoberg et al., 1997;Rashidzadeh & Guo, 1998b). The disadvantage of thesilver and copper cation option are their two signi®cantisotopes which complicate the isotope patterns of thecationized polystyrene oligomers. Therefore, the use of amonoisotopic cation, 65Cu(II)acetylacetonate, was advo-cated (Burgers & Terlouw, 1998).

Only one study dealt with effects of the counter ionsin MALDI. In all cases the cation was sodium and thepolymer was poly(methyl methacrylate) but the counterions were iodide, bromide, or chloride. Decreasing ionyields were observed in the order I > Br > Cl. It was arguedthat the counter ion in¯uences the amount of gas phasecations available for cationization in the expanding plume(Hoberg et al., 1998).


319

IV. SAMPLE PREPARATION TECHNIQUES

Before using a particular sample preparation technique,solvent(s) must be selected for the matrix, sample, andcationization salt solutions; suggestions are included inTable 1. Ideally only one solvent is present in the ®nalmixture which reduces the risk of segregation duringcrystallization on the MALDI target. However, salts arehardly soluble in organic solvents used for nonpolarsynthetic polymers. Typically, a stock solution of the saltin an intermediate solvent such as propanol can beprepared and subsequently diluted with the matrix andpolymer solvent. However, even relatively low concen-trations of a polymer nonsolvent in the ®nal mixture canaffect ®nal signal reproducibility and cause errors in theMWD data obtained. The effect of the water andmethanol content in THF used for the MALDI analysisof PS 7000 was studied and the data showed very poorreproducibility and 13% lower Mn values when 5% waterwas present in the ®nal mixture (Yalcin et al., 1998).Similar phenomena were observed for PMMA (Chen &Guo, 1997; Yalcin et al., 1998). Note that water is anonsolvent for PS and methanol for PMMA. If actually amixture of solvents is used in the sample preparation thenthe solvent composition will change during the solventevaporation process because of differences in volatility.As a consequence, the solubility of the polymer changesas well, thus when some less volatile non-solvent ispresent in the preparation, the polymer might precipitatebefore matrix crystal formation. In these cases, even aninitial clear sample preparation might change into aproblematic situation during the drying process. The bestway is to select a solvent system that will allow matrixcrystallization to take place simultaneously or prior topolymer precipitation.

Of course, the molar ratio of polymer sample/matrix/salt in the sample preparation determines whether a massspectrum will be obtained or not. However, in the highmass range, multimer formation might occur which is asource of errors in the MWD calculations. Increasing thematrix to polymer ratio might improve such an unintendedsituation (Schriemer & Li, 1997a).

Following the selection of MALDI matrix, cationiza-tion salt and solvent(s) for sample, matrix and salt, severaloptions are available for transferring the mixture onto theMALDI target. The oldest procedure is the so-calleddried-droplet method (Karas & Hillenkamp, 1988). In thismethod the three solutions are mixed by volume andapproximately 0.5±1 mL of the mixture is applied to thetarget and air-dried at room temperature. The crystal-lization is relatively slow, thereby increasing the risk ofsegregation between sample and matrix and cationizationsalt, or segregation within one of the distributions of thesynthetic polymer (cf. INTRODUCTION). Later on, the

fast crystallization method was introduced (Weinbergeret al., 1993; Nicola et al., 1995) in which the target is putin a vacuum chamber in order to promote rapid crystal-lization, typically within a few seconds. As a result,smaller crystals are obtained with less segregation, givingenhanced reproducibility, signal intensity and resolution.Accelerated drying using a stream of high-purity nitrogengas is an alternative means for reaching similar goals(Castoro et al., 1992; Gusev et al., 1995a). Improvedhomogeneity and better sensitivity were also obtained byspin-coating sample preparation techniques (Perera et al.,1995). In the thin-layer method, ®rst a matrix layer isprepared and allowed to crystallize and next the sample isadded and dried. Particularly in the analysis of peptidesand proteins (Vorm et al., 1994) but also in the analysis ofan aromatic polyester (Guittard et al., 1995) and organicdendrimers (Milberg & Garden, 1996) improved resultswere reported.

One of the most promising techniques for samplepreparation of synthetic polymers is electrospray deposi-tion (Axelsson et al., 1997). A typical experimental set-upis shown in Fig. 2. Using an applied potential of 8 kV, adistance from needle to sample slide (target) of 2±4 cmand a ¯ow rate of 10±100mL/min, a 1 cm diametercircular spot on the target was obtained. A comparisonwas made for PS and other polymers, using both the drieddroplet (i.e., one-layer) and the thin-layer (i.e., two-layer)technique, with and without electrospray deposition. Thedried-droplet technique without electrospray depositionshowed large variations in shot-to-shot reproducibility andsignal intensities ranging between zero and the maximumobserved. The thin-layer method without electrosprayingyielded a large number of spectra without any polymerdistribution. Electrospray deposition on the other handwith either the one-layer or the two-layer approachyielded much higher signal intensities and much bettershot-to-shot and spot-to-spot reproducibility, slightlyfavoring the one-layer electrospraying approach. Theimproved results of the electrospray deposition methodcan be explained by the small and evenly-sized cocry-stals formed (Axelsson et al., 1997; Sadeghi & Vertes,1998).

Recently, microscopy and surface analysis techniquessuch as scanning electron microscopy (SEM), confocal¯uorescence microscopic imaging, X-ray photoelectronspectroscopy (XPS) and time-of-¯ight secondary ion massspectrometry (TOF±SIMS) have been successfullyapplied to study the homogeneity of the ®nal MALDIsample preparations. The microscopy techniques showedbetter homogeneity of the sample preparation for fastcrystallization methods (Westman & Barofsky, 1995; Daiet al., 1996). Evidence for segregation of cationization saltfrom matrix crystals was obtained by TOF±SIMS imagesboth for slow drying preparations such as for a PEG 1500

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sample with DHB and sodium cations dissolved inmethanol/water, as well as for a fast drying system ofPMMA 2900 with DHB and sodium dissolved in acetone(Hanton et al., 1999). Upon changing from the drieddroplet to the electrospray deposition method homoge-neous cocrystallization occurred and very homogeneouschemical images were obtained. Similarly, XPS analysisshowed improved sample homogeneity in MALDI ofproteins for the so-called crushed crystal method vs. thedried droplet method (Smith et al., 1997).

Negative ion MALDI analysis of polymeric acidssuch as sulphonated polystyrene and poly(acrylic acid)requires desalting and conversion into the hydrogen form,thereby putting an additional demand on sample prepara-tion. The addition of ion exchange beads to the sample/matrix mixture might be adequate for the purpose ofdesalting but one should be aware of different solubilitiesof the polymer in its neutralized form vs. the original saltform. Precipitation of the neutralized polymer onto the ionexchange beads might occur thereby obstructing the ®nalanalysis. More sophisticated desalting options such asmembrane desalting (Bornsen et al., 1995; Worrall et al.,1998) and on-probe desalting using self-assembledmonolayers (Brockman et al., 1997) are currentlyinvestigated for MALDI of biomolecules and might yieldsome valuable spin-off for the analysis of acidic syntheticpolymers in the negative ion mode.

V. DISCRIMINATION ISSUES

A. High and Low Mass Discrimination

Discrepancies between MWD data of polymers ascalculated from MALDI TOF MS and size exclusion

chromatography (SEC) forced several groups to searchfor explanations of mass discrimination in MALDI MS.But before going into more detail of these massdiscrimination phenomena, one has to consider thefundamental differences between SEC and MS (Jacksonet al., 1996): A narrow MWD as typically obtained byanionic `̀ living'' polymerizations can be theoreticallydescribed by a Poisson distribution. The calculatednumber fraction distribution, as to be expected in MSwhere each oligomer chain acquires ideally one chargeindependent of its molecular weight, is shown in Fig. 3a.In SEC, on the other hand, a weight fraction distributionvs. the logarithm of the molecular weight will be obtainedas shown in Fig. 3b. In this case the peak molecularweight values, Mp, of both distributions are theoreticallyvery similar and only two monomer units higher in SECvs. MS. In fact, excellent comparisons between MALDIMS and SEC data for narrow-distributed (polydispersity<1.1) polymers have been experimentally observedindeed in several studies where sample preparation and/or instrumental discrimination factors could be success-fully ruled out (e.g., Cottrell et al., 1995). For wideMWDs as obtained in many polymer syntheses, thesituation can be described by a Schulz or Florydistribution. The comparison of the theoretical resultsfor a condensation polymer is given in Fig. 4. A decayingnumber fraction distribution is to be expected in MS andMp will be the monomer mass, in sharp contrast to theSEC situation where Mp will be equal to the weight-average molecular weight, Mw. So the huge discrepancybetween MS and SEC data in Fig. 4 originates simplyfrom how the data are being displayed. In theory,examination of the decaying mass spectrum up to veryhigh m/z values, smoothing, and background subtractionwould be suf®cient to obtain reliable MWD data directly

FIGURE 2. Electrospray sample deposition set-up employed for preparation of MALDI sample slides.Reproduced from Axelsson et al., 1997, with permission from John Wiley & Sons, Ltd.


321

from the mass spectrum, even in the case of polydispersesynthetic polymers (Montaudo et al., 1996a).

In practice, however, baseline subtraction on a verynoisy and decaying signal is not trivial, and signi®canterrors and poor reproducibility of MWD data areobtained. Moreover, such a data treatment assumes thatno mass discrimination occurs in sample preparation,desorption/ionization, transmission, and detection. Uponrealizing that a polymer with a polydispersity >2 willhave masses over an m/z range of a few hundred Da up to afew hundred thousand Da, it becomes obvious that it isunrealistic to expect discrimination-free experiments inMALDI MS of polydisperse synthetic polymers. More-

over, the high molecular weight end in the mass spectrumwill disappear much earlier into the baseline noise than thehigh molecular weight side of the SEC distribution(compare Figs. 4a and b): a few high molecular weightmolecules represent only a few ions in the MS but stillshow a signi®cant bulk property as detected by therefractive index detector in a SEC apparatus. As a result,too low MWD data are to be expected in such a situation.On the other hand, experimentally obtained MALDI massspectra showing a decaying pattern as in Fig. 4aimmediately show that the polymer sample underinvestigation is polydisperse (>1.1) and that directMWD calculation from the mass spectrum will be biased

FIGURE 3. Simulated narrow distribution of oligomers for 20.5monomers reacted per initiator: (a, top) plotted on a linear and (b,bottom) plotted on a logarithmic scale. Reproduced from Jackson Cet al., 1996, with permission from the American Chemical Society.

FIGURE 4. Simulated distribution for a wide polymer distributionfrom, e.g., a polycondensation reaction: (a, top) plotted on a linear and(b, bottom) plotted on a logarithmic scale. Reproduced from Jackson Cet al., 1996, with permission from the American Chemical Society.

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to (far) too low values and pre-fractionation will berequired (cf. Section VII).

Basically, two different origins for mass discrimina-tion in MALDI TOF MS can be distinguished: samplepreparation on the one hand and instrumental factors onthe other. Both contributors can be minimized, yieldingreliable and reproducible mass spectra for narrowdistributed synthetic polymers having average masses upto several hundred thousands Da. Sample preparationissues were covered in the previous sections: one shouldselect the right MALDI matrix, the right salt forcationization, preferably use one type of solvent, optimizemixing ratios, and apply the best preparation technique,e.g., electrospray deposition. Each of these samplepreparation factors might ruin the ®nal goal of homo-geneous cocrystallization of polymer, matrix and salt.

With regards to the instrumental factors, desorption/ionization, transmission, and detection might be respon-sible for mass discrimination. Channel plate detectorshave a limited dynamic range and can get saturated easilyby low molecular weight components such as matrix ionsand/or oligomers; particularly in the case of polydispersepolymers where the majority of the ions (cf. Fig. 4) will below molecular weight (McEwen et al., 1996; Schriemerand Li, 1997b; Zhu et al., 1998). When the more abundantlower mass ions in polydisperse polymers are de¯ectedfrom reaching the detector, then the high-mass ions can beobserved indeed which proves that at least in partsaturation of the detector is responsible for high massdiscrimination in MALDI TOF MS (McEwen et al.,1997). But the sensitivity at the high molecular weight endof the MWD will be insuf®cient anyway due to the lowerimpact velocity of a high MW ion vs. a low MW ion whichgenerally causes a lower number of secondary electrons(Axelsson et al., 1996; Larsen et al., 1996). Instrumentmanufacturers coped with the detector problem indifferent ways. For example, using a conversion dynodeplus a microchannel plate and a cesium iodide scintillatormounted on the entrance window of a photomultiplier.Unfortunately, most of the solutions compromise theresolving power of the detection system. Alternatively, aprocedure might be considered in order to correct for thedecreasing detector response with increasing mass(Scamporrino et al., 1998).

Ideally the laser power should be so chosen that theionization probability is the same for all ions, but the laserpower is not so high as to cause fragmentation. In practice,however, higher laser powers are required in order to reachthe threshold ¯uence for the observation of highermolecular weight oligomer ions (Lloyd et al., 1995).Many authors observed mass discrimination effectsrelated to the applied laser power: Equimolar amountsof monodisperse PMMA's were mixed and the effect oflaser power was studied. A typical example is shown in

Fig. 5 (Sakurada et al., 1998). An increase in laser powerresults in an increase of ion intensities of the highmolecular weight species, accompanied by an increase inthe matrix peak intensity. Higher laser powers can alsoinduce dimerization by clustering in the gas phase,yielding an MWD shift towards higher masses (Axelssonet al., 1996). Moreover, higher laser power can initiateunintended scissions in the polymer structure, as shownfor example in the characterization of hyperbranchedpolyesters (Feast et al., 1997) and in the degradation ofPMMA (Lehrle and Sarson, 1995; 1996).

FIGURE 5. The effect of laser power on the MALDI±MS ofmonodisperse PMMA (an equimolar mixture of n� 20, 35, and 50).Reproduced from Sakurada et al., 1998, with permission from JohnWiley & Sons, Ltd.


323

The ion transmission in MALDI TOF MS has beenreported as a source of mass discrimination as well,particularly when a polydisperse polymer is analyzed byan instrument having a long ¯ight tube and a detector of asmall detection area (Guo et al., 1997b). Mixtures ofnarrow disperse PS were used to investigate similardiscrimination effects. It was shown that the lensing actionprovided by the source electrodes in TOF MS isresponsible for a mass-dependent distribution of the ionsin the plane of the detector (Schriemer & Li, 1997b). Indelayed-extraction instruments the lensing properties canbe altered by adjusting the amplitude of the pulse voltage.However, depending on the pulse voltage and time delayapplied, only a narrow mass range will be focussed, i.e.,only a part of the molecular weight distribution will have abetter resolution. Depending on the calculation method,peak areas of the unfocused peaks are overestimatedcompared to the well-focused ion peaks and, as aconsequence, different molecular weight averages arecalculated (Zhu & Li, 1998).

Also, on the low molecular weight end of the polymerdistribution, mass discrimination might occur, yieldingtoo high MWD values for MALDI mass spectrometry vs.alternative methods (Barry et al., 1997). This phenomenoncan be at least partly explained by the lower bindingenergy of cations for shorter oligomers (cf. Section III)and losses of low molecular weight components byevaporation. Derivatization has been successfully appliedto reduce the low-mass discrimination in ethoxylatepolymers (Barry et al., 1997).

In summary, it has to be concluded that MALDI±TOFmass spectrometry cannot be considered as an absolutemethod in the measurement of polymers with highpolydispersity, whereas it can be really an absolutemethod in the analysis of narrowly distributed polymersamples (Martin et al., 1996).

B. Oligomer Speci®c Discrimination

Apart from high- and low mass discrimination in themolecular weight distribution (MWD), speci®c discrimi-nation might occur in the functionality type distribution(FTD). Oligomers having chemically different end groupstructures might in¯uence their respective cocrystalliza-tion behavior during sample preparation and/or mightshow different cationization ef®ciencies as such. Surpris-ingly, very limited data have been published concerningthis topic. The relative ion yields of two differentlyfuntionalized polystyrenes, terminated with a dimethyl-phenylsilyl end group and with a per¯uoroalkylsilyl endgroup, were compared relative to the standard proton-terminated PS. By ratioing the signals of the functiona-lized to unfunctionalized oligomers at each degree ofpolymerization, the effect of the end group on ion yield

was investigated. A typical result for the per¯uoroalk-ylsilyl-PS is shown in Fig. 6. The impact of the end groupon the cationization ef®ciency will be more pronouncedfor the lower oligomers. Obviously, the end groupmodi®cation allows these oligomers to ionize moreeasily. The improved ionization at higher oligomernumbers as shown in Fig. 6 has probably resulted fromimproved interaction of the functionalized PS with thematrix (Belu et al., 1996). In a second example, oligomerspeci®c mass discrimination both from end groupfunctionality and from different oligomer architecture isdemonstrated. The MALDI mass spectrum of an aromaticpolyester based on terephthalic acid (TPA) and neopen-tylglycol (NPG) is given in Fig. 7. The spectrum showsions of cyclic(TPA/NPG)n oligomers, linear (TPA/NPG)n

oligomers and linear (TPA/NPG)nTPA oligomers. Directcalculation from the mass spectrum yields the followingcomposition: 14 Mol% cyclic (TPA/NPG)n oligomers, 20Mol% linear (TPA/NPG)n oligomers, and 66 Mol% linear(TPA/NPG)nTPA oligomers. However, according toestablished reference methods, only 6 Mol% cyclic(TPA/NPG)n oligomers are present in this sample (Nielen& Buijtenhuijs, 1999) and only 3% linear (TPA/NPG)n

oligomers (based on titration and on NMR). Thusoligomer speci®c mass discrimination in MALDI offunctionalized and/or differently shaped oligomers isresponsible for signi®cant errors in composition calcula-tions and conclusions based thereon. Much more researcheffort is required in this ®eld in order to establish theimpact of end group chemistry on cationization yield andto derive suitable response correction functions which

FIGURE 6. Comparison of relative ion yields of an equimolar mixtureof per¯uoroalkylsilyl- and H-terminated polystyrene oligomers byMALDI TOF MS. Reproduced from Belu et al., 1996, with permissionfrom the American Society for Mass Spectrometry.

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would ideally allow composition calculations directlyfrom the mass spectrum.

VI. MS/MS IN MALDI TOF MS OF SYNTHETICPOLYMERS

Being a soft ionization method, fragmentation isgenerally not very pronounced in MALDI mass spectro-metry. However, under speci®c instrumental and experi-mental conditions, different types of fragments can beobserved in MALDI TOF MS. At high laser ¯uences,fragmentation might occur in the ion-source region, oftenreferred to as `̀ prompt fragmentation''. In addition, indelayed extraction ion sources, fast metastable fragmen-tation might occur during the delay time beforeextraction, i.e., on the �100±1200 ns time scale, referredto as in-source decay (ISD). The increase in ISDfragmentation with laser energy at a ®xed delay time iscaused by a greater number of collisions in the expandingplume leading to a greater amount of collisionalactivation in the source. Prompt and ISD fragmentationyield fragment ions in the mass spectra from both thelinear and the re¯ector detector. In contrast, metastablefragmentation in the ®eld-free region, referred to as post-source decay (PSD), occurs on the �10ms time scale andyields fragment ions in the mass spectrum from there¯ector detector only. With the aid of a suitable

precursor ion selector in the ®eld-free region of thelinear ¯ight path and a scanning re¯ectron voltage, a PSDMS/MS daughter spectrum can be obtained. Despite thelow internal energy and low fragmentation ef®ciencyobtained, MALDI PSD is very useful for controlledfragmentation such as required in, e.g., peptide sequen-cing. In addition, a pulsed collision gas cell can bemounted in the ®eld-free region of MALDI TOF systemsfor high energy (keV) collisions thus yielding additionalfragments in peptide analysis (PSD/CID). In contrast tothe large number of references on MALDI PSD (andPSD/CID) of peptides, only a few MS/MS data ofsynthetic polymers can be found in MALDI TOFliterature. A good example of a PPG mass spectrumincluding ISD fragment ions is shown in Fig. 8 (Mowatet al., 1997). ISD fragmentation was also observed in theMALDI analysis of hyperbranched polyesteramideswhich showed rapid dissociation of higher oligomersinto lower oligomers minus a water molecule (Kwak-kenbos et al., 1999). Next, PSD/CID of mass-selectedions was applied in order to discriminate between theseISD fragment ions and the isobaric cyclic oligomers.From these results and reference data obtained bytechniques as NMR, titration, and FD MS, it was obviousthat MALDI TOF MS yielded wrong conclusions aboutthe chemical composition distribution and functionalitytype distribution for these hyperbranched samples.Structural information of dendritic polyurethanes was

FIGURE 7. Delayed extraction re¯ectron MALDI TOF mass spectrum of a terephthalic acid/neopentylglycol polyester sample. Matrix, 2,5-dihydroxybenzoic acid. Reproduced from Nielen &Malucha, 1997, with permission from John Wiley & Sons, Ltd.


325

obtained by PSD experiments (Puapaiboon et al., 1999).Most of the fragment ions were sodium adducts arisingfrom the cleavage of the ester or amide bond, see Fig. 9.A MALDI/PSD spectrum of the 10-mer of PMMA isshown in Fig. 10, and a proposal for the origin of

fragments from direct cleavage (labeled A and B) is givenin Fig. 11. The formation of fragment ions was comparedwith high energy MALDI±CID experiments in aMALDI/hybrid sector oaTOF instrument (Scrivens et al.,1997). Despite the different time-scales for dissociation,

FIGURE 8. MALDI-ISD TOF MS/MS spectrum of PPG 2000 under delayed extraction and high laserintensity conditions. (4 kV extraction pulse, 1.21ms delay time, laser power 120 mJ). The symbolsrepresent the following series: *58nÿ1, � 58n� 10,� 58n� 23, �58n� 39, 458n� 41. Reproducedfrom Mowat et al., 1997, with permission from John Wiley & Sons, Ltd.

FIGURE 9. Proposed mechanism for the fragments observed in the MALDI±PSD TOF MS/MSspectrum of a third generation polyurethane dendritic wedge. Reproduced from Puapaiboon et al., 1999,with permission from John Wiley & Sons, Ltd.

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the main difference between Fig. 10 and the massspectrum obtained in the hybrid instrument when nocollision gas was applied, is the ratio of the fragment ionpeaks arising from direct cleavages (A and B series) andrearrangement processes (C,D,E, and F series). The samecomparison for the 15-mer of PEG yielded similarconclusions: both MS/MS spectra may be readilyinterpreted in terms of polymer structure but enhancedresolution and signal-to-noise ratio was observed in theMALDI/hybrid sector oaTOF instrument (Jackson et al.,1996). Actually, these authors applied the MALDI/hybridsector oaTOF to a variety of synthetic polymers andstudied high-energy MALDI±CID spectra of polyacry-lates, polyethylene glycols, polystyrenes, and polyesters.PSD MALDI TOF MS was successfully used in order todifferentiate between linear and branched PEG (Kowalskiet al., 1998). Using a precursor ion selector having aresolution of 150, the MS/MS spectra of mass selectedlinear PEG 2000 oligomers showed fragmentation bycleavage on both sides of the oxygen atoms, while theMS/MS spectra of mass selected branched PEG 2000showed a dominant single cleavage of intact ethyleneoxide monomer. PSD fragmentation patterns were alsoreported for mass selected oligomer ions of polyisobu-tylene (Varney et al., 1997).

A very important and challenging application ofMALDI TOF MS/MS in polymer analysis would be thesequencing of block copolymers and the mass spectro-metric determination of the block length distribution.Obviously, much more effort is required in order to reachthis goal.

VII. CHROMATOGRAPHY/MALDI COUPLING

A. Thin Layer Chromatography/MALDI TOF MS

The coupling of thin layer chromatography (TLC) withMALDI mass spectrometry has been realized via anextraction method (Gusev et al., 1995b): following TLCseparation a drop of extraction solvent was added and the(peptide) analyte was extracted from the TLC spot intothe solvent. Next, the MALDI matrix was added, mixedwith the extracted analyte and allowed to cocrystallize onthe TLC plate. Finally, MALDI measurements werecarried out directly onto the plate using a modi®edLAMMA 1000 laser microprobe instrument. The mainadvantage of such a direct measurement is the direct TLCimaging capability. Later on, the authors modi®ed thematrix deposition method in order to reduce the analytespreading, by using a method in which pre-dried matrixwas pressed onto the TLC gel, and an ultimate spatialresolution of 50mm for TLC imaging was obtained(Gusev et al., 1995c). A further improvement was re-ported recently by electrospraying the matrix materialonto the TLC plate (Mowthorpe et al., 1999). The authorsused a modi®ed commercial MALDI±TOF instrumentfor direct measurements on the cocrystallized spots andapplied their method on rapid impurity testing ofpharmaceuticals. As a simple alternative to these directmethods, off-line coupling of TLC and MALDI TOF MSwas reported for the analysis of pitch fractions (Herodet al., 1996). The silica spots containing the fractionatedanalytes were scraped from the plates and extracted using

FIGURE 10. MALDI±PSD TOF MS/MS spectrum of the 10-mer of PMMA. Reproduced from Scrivenset al., 1997, with permission from Elsevier Science B.V.


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1-methyl-2-pyrrolidinone in an ultrasonic bath. Finally,the extracted material was deposited on the MALDI targetand measured without the addition of a matrix, i.e., thesample acted as its own matrix. A similar TLC/MALDIapproach was used for the analysis of organic reactionssuch as the base-catalyzed condensation between benzal-dehyde and cyclohexanone (Hilaire et al., 1998).

B. Off-Line Size-Exclusion Chromatography/MALDITOF MS

The coupling of matrix-assisted laser desorption/ioniza-tion to liquid separations such as capillary electrophoresis(CE) and liquid chromatography (LC) has been reviewedvery recently (Murray, 1997). A good description ofmethods and their applications in the biochemicalanalysis ®eld was given but polymer data were ratherscarce. The most relevant separation technique to be

coupled with MALDI TOF MS is size-exclusionchromatography (SEC) or gel permeation chromatogra-phy (GPC). As outlined in Section V, the characterizationof polydisperse synthetic polymers is obstructed by massdiscrimination issues. A practical solution to this problemis the pre-fractionation of a polydisperse polymer sampleinto several fractions each having a narrow MWD(polydispersity <1.2) by SEC. The fractions on theirturn can be very well characterized by MALDI TOF MSprovided an optimized sample preparation protocol isused. Finally, the mass-measured fractions can be used asabsolute calibration points (Log M vs. elution volume ortime) for the SEC chromatogram and the absolute MWDaverages calculated from the calibrated chromatogramwith the aid of a classical SEC software package.Actually, this is an ideal marriage overcoming theshortcomings of both components: SEC is obstructed bythe very limited availability of well-characterized cali-

FIGURE 11. Proposed mechanism for the formation of the direct cleavage ion series A and B in Fig. 10.Reproduced from Scrivens et al., 1997, with permission from Elsevier Science B.V.

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bration standards while MS of polydisperse samples isquantitatively limited by discrimination issues; nowpolydisperse synthetic polymers can be characterizedusing an absolute calibration method based on theinvestigated polymer sample itself. Moreover, the massspectra of the low molecular weight fractions can be usedto infer structural information from the polymer such asthe monomer(s), from the repeating mass increment(s),and, following extrapolation to zero monomer(s) andsubtraction of the cation mass, the combined end-groupmass. In a series of papers, this approach was applied tothe analysis of polydisperse synthetic polymers such aspoly(dimethylsiloxane)s (Montaudo et al., 1995b); poly-(butylene adipate) and poly(butylene adipate-co-butylenesuccinate), (Montaudo et al., 1995d); PMMA, poly(vinylacetate) and poly(N-vinylpyrrolidone-co-vinyl acetate),(Danis et al., 1996b); PS, polybutylacrylate, polycarbo-nate, terephthalic acid/neopentylglycol polyester andpoly(methylmethacrylate-co-methacrylic acid), (Nielen& Malucha, 1997); PMMA, poly(dimethylsiloxane) andseveral copolyesters, (Montaudo et al., 1998b; Montaudoet al., 1998a). A comparison of MWD data calculatedfrom off-line SEC/MALDI TOF MS with reference datafrom manufacturers, from SEC with conventional cali-bration using narrow standards, and from SEC with on-line intrinsic viscosity (IVD)- and light scatteringdetection (RALLS), is given for a vareity of polydispersepolymers in Table 4. Generally, a very good agreementwith reference data is obtained. It is also obvious thatsamples such as polybutylacrylate cannot be analyzed byconventional SEC with calibration based on PMMAnarrow standards, thereby underlining that SEC columnsshould be calibrated by the investigated polymer itself, asobtained by off-line SEC/MALDI coupling. In addition,structural data of monomers and end groups could beinferred from the isotopically-resolved oligomer spectraof the low molecular weight fractions, as recorded by

MALDI TOF MS in the delayed-extraction re¯ectronmode (Nielen & Malucha, 1997).

C. On-Line and Direct Deposition Size-ExclusionChromatography/MALDI TOF MS

On-line coupling of SEC and MALDI MS has beenpresented, both in a continuous ¯ow set-up (Li et al.,1993) and in an aerosol MALDI set-up (Fei & Murray,1996). The former approach utilizes liquid MALDImatrices and shows similarities with continuous ¯owFAB but might suffer from typical ion source contamina-tion problems. The latter, aerosol approach, utilizes polarsolvents such as methanol, instead of the more generalSEC solvent tetrahydrofuran (THF).

It can be argued that off-line coupled SEC/MALDIMS is more attractive than on-line combinations since itallows MALDI optimization (e.g., detector settings) forindividual narrow fractions of the polymer distribution,particularly the more demanding high molecular weightparts. However, off-line SEC/MALDI MS, as outlinedabove, involves fraction collection, evaporation, pipetting,etc. and is de®nitely laborious and time-consuming. So,direct deposition methods in which SEC fractions andMALDI matrix are directly and automatically depositedonto the MALDI target are to be preferred. The feasibilityof such a direct deposition was demonstrated by spray-deposition of approximately 15% of a SEC ef¯uent onto acontinuous rotating matrix-coated substrate using amodi®ed LC-TransformTM Series 100 IR interface (Kassiset al., 1997). The resulting polymer `̀ trail'' could beanalyzed directly by MALDI MS but the mass spectraobtained were summed in order to calculate MWDaverages instead of using the MS data as calibrationpoints in the SEC chromatogram. As a consequence, themethod still suffered from discrimination issues asdiscussed in Section V.

FIGURE 12. Set-up for mSEC/MALDI TOF MS using a robotic interface. Inset (right): Close-up of theneedle tip. Reproduced from Nielen, 1998, with permission from the American Chemical Society.


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Following some early developments (Dwyer &Botten, 1996), a direct deposition interface has becomecommercially available. In this system, the eluent from aconventional-sized SEC system is sprayed through aheated nozzle and spotted or track-deposited on MALDItargets equipped with foils containing precoated MALDImatrix. The disadvantages of this system are the highsheath gas consumption (300±900 L/h) and the signi®cantvolumes of hazardous solvents which evaporate. Toovercome these shortcomings, a miniaturized methodwas developed featuring the use of a mSEC system with aTHF ¯ow of only 5 mL/min, UVabsorbance detection, anda robotic interface in which the MALDI matrix iscoaxially added to the SEC ef¯uent and directly spottedonto the MALDI target without the use of heat and sheathgas, see Fig. 12 (Nielen, 1998). Despite the extremely

small quantities of polymer in each 10 sec spot, and theabsence of optimization of the polymer/matrix ratio,MALDI TOF MS data were successfully used ascalibration points for the mSEC/UV chromatogram andallowed the calculation of absolute molecular weightaverages by using regular SEC software. The MWDaverages thus determined for polydisperse poly(bisphenolA carbonate) and an aromatic copolyester resin, were ingood agreement with reference data from manufacturerand off-line SEC fractionation/MALDI analysis. More-over, the method still allowed the characterization of end-groups and the chemical composition distribution in thecopolyester using (isotopically-)resolved mass spectra ofoligomers.

Recently, an automated SEC/MALDI method waspresented using a SEC system consisting of a 4.6 mm i.d.SEC column, a THF ¯ow of 0.3 mL/min, an analogrefractive index (RI) or UV detector, and a post-columnsplit 10:1 to a microfraction collector (Danis et al., 1998).Every 4 sec a SEC fraction was collected and MALDI datawere acquired in the linear mode using an automated dataacquisition and data analysis protocol. The mass spectrawere smoothed to a high degree, the derivative of thesmoothed data was taken, and the Mp of the spectra at zerointensity was used vs. retention time (from fractionnumber) in the data output table. Thus a SEC calibrationcurve could be constructed and used for the calculation ofabsolute MWD data of a polydisperse poly(bisphenol Acarbonate) sample. As an alternative, a less sophisticatedlow-cost direct deposition interface might be constructedfrom a modi®ed pen plotter, programmed to apply 1.5mLspots from a microLC system onto the MALDI target(Stevenson & Loo, 1998).

D. Other Liquid Chromatography Modes Coupledwith MALDI TOF MS

In principle, all LC modes in polymer analysis can beinterfaced with MS. Recently, size-exclusion chromato-graphy (SEC), gradient polymer elution chromatography(GPEC) and liquid chromatography at the critical point ofadsorption (LCCC) were on-line coupled with ESI TOFMS, in a single experimental set-up (Nielen & Buijten-huijs, 1999). Of course, coupling of GPEC and LCCCwith MALDI TOF MS, either off-line or on-line, can berealized simply by using a gradient LC system and one ofthe SEC/MALDI couplings discussed above. In an earlyexample of off-line LCCC/MALDI TOF MS, a fattyalcohol ethoxylate sample was separated into three maingroups and fractionated for MALDI analysis (Pasch &Rode, 1995). According to the mass spectra, the LCCCseparation was proven to be controlled mainly by end-group interactions showing the elution order PEG, C13-terminated PEG and C15-terminated PEG.

FIGURE 13. Mass spectra of three poly(styrene) samples withnominal molecular weights of (A) 330,000 (B) 600,000 and (C)900,000. Reproduced from Schriemer & Li, 1996, with permissionfrom the American Chemical Society.

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VIII. POLYMER APPLICATIONS

A. Homopolymers

In Table 1 several polymer applications of MALDI TOFMS are summarized. Homopolymers, in particular PEG,PMMA, and PS, are being studied frequently for thepurpose of matrix- and instrument optimization. Further-more, absolute molecular weights have been determinedfor narrow-distributed (homo)polymers. An example ofthe determination of absolute molecular weights byMALDI TOF MS is given in Fig. 13. The three massspectra of poly(styrene) were obtained in a linear TOFinstrument after careful sample preparation with all-trans-retinoic acid as the matrix and silver nitrate forcationization. The PS oligomers remained unresolved atthese high masses and the distributions appeared as broadpeaks. At higher masses, multiple charged distributions of[M� nAg]n� ions dominated the MALDI spectra. Thisfeature was successfully applied in the MALDI analysisof PS having a nominal molecular mass of 1.5 million Da(Schriemer & Li, 1996). The application of MALDI TOF

MS to the determination of absolute molecular weights ofpolydisperse polymers has been discussed already inSection VII and typical results of MWD calculationswere summarized in Table 4.

The determination of end-groups in homopolymersrequires resolution of the oligomers and suf®cient massaccuracy. Time-lag focusing (in this review also referredto as `̀ delayed extraction'') provides both improvedresolution and signal-to-noise ratio, as well as enhancedmass accuracy in MALDI TOF of polymers, thus enablingthe differentiation of end groups (Whittal et al., 1997;Jackson AT et al., 1997b). In a linear TOF mass spectro-meter equipped with a time-lag focusing ion source,oligomer resolution was obtained for PEG of masses up to25 kDa and for polystyrene (PS) even up to 55 kDa(Whittal et al., 1997). MALDI TOF with time-lag focus-ing in the re¯ector mode yielded a resolution of almost9000, as can be seen in the mass spectrum of PMMA inFig. 14 (Jackson AT et al., 1997b). At lower molecularweights, isotopically-resolved mass spectra were obtainedin the delayed-extraction re¯ector mode and used for end-group analysis of a variety of polymers (Nielen &

TABLE 4. Comparison of molecular weight distribution data of polymers (Nielen & Malucha,

1997)

Polymer and data source Mw Mn Mz Mp PD Note

Polystyrene 48 kDaManufacturer 48,000 22,500 78,000 2.13SEC (PS) 47,700 22,300 83,500 45,100 2.14 aSEC/MALDI 47,000 23,600 78,600 45,100 1.99SEC/IVD 47,500 18,000 81,100 43,400 2.64

Polybutylacrylate 62 kDaManufacturer 59,200 19,900 2.98SEC (PMMA) 78,200 17,400 187,000 44,800 4.49 bSEC/MALDI 62,200 16,500 138,400 38,000 3.76SEC/IVD 63,600 19,000 131,900 3.35SEC/RALLS 57,200 25,000 98,900 2.29

Aromatic polyester 8 kDaSEC/MALDI 7300 3900 11,400 6800 1.88SEC/IVD 8100 4400 10,700 9000 1.83

Polycarbonate 29 kDaManufacturer 28,800 17,300 1.66SEC/MALDI 28,500 15,800 43,200 30,400 1.81SEC/IVD 28,800 16,700 39,800 31,900 1.72SEC/RALLS 30,500 19,200 40,500 32,300 1.59

Poly(methylmethacrylate-co-methacrylic acid) 34 kDaManufacturer 34,000 15,000 2.27SEC/MALDI 36,300 18,500 56,600 35,300 1.97 cSEC/MALDI 34,300 19,300 50,700 34,100 1.78 d

aConventional calibration of the SEC column using narrowly-distributed PS standards.bConventional calibration of the SEC column using narrowly-distributed PMMA standards.cData based on MALDI measurements in the positive ion mode using IAA with sodium formate asmatrix.

dData based on MALDI measurements in the negative ion mode using DHB as matrix.


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FIGURE 14. MALDI time-lag focusing spectrum of a speci®c PMMA obtained in the re¯ectron mode ofoperation (the inset shows the expansion of the molecular adduct ion [M�Na]� peak region for the 36-mer of this PMMA and the theoretical isotope pattern). Reproduced from Jackson AT et al., 1997b, withpermission from John Wiley & Sons, Ltd.

FIGURE 15. Detail of the delayed-extraction re¯ectron MALDI mass spectrum of a mSEC fraction ofpolycarbonate. Reproduced from Nielen, 1998, with permission from the American Chemical Society.

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Malucha, 1997). In Fig. 15, a detail of the isotopically-resolved MALDI mass spectrum of a polycarbonate isshown, featuring [M�Na]� and [M�K]� ions of oligo-mers (Nielen, 1998). The repeat unit mass of the poly-carbonate, 254.1 Da, was con®rmed and after subtractionof the cation and n-times the repeat unit mass, the endgroups were inferred from the mass residues (214, 0, and94 Da) yielding the structure proposals phenylcarbonate(bisphenol A carbonate)nphenyl, cyclic poly(bisphenol Acarbonate)n and (bisphenol A carbonate)n phenyl. So far,end group analysis by MALDI TOF has been successfullyused in a variety of reactivity studies in polymerchemistry, and these data are usually found in polymer-,rather than mass spectrometry journals.

B. Blends

Blends of the same narrow-distributed polymers, but ofdifferent molecular weights, were used in several studiestowards discrimination phenomena in MALDI TOF MS(Spickermann et al., 1996; Goldschmidt & Owens, 1997).MALDI applications concerning blends of different typesof polymers are scarce, probably because of signi®cantdifferences in cationization ef®ciencies and other dis-

crimination effects. As an example, two narrow stan-dards, PS 10200 and PMMA 9200, were dissolved inTHF and mixed by volume in several ratios. Next,samples were prepared using either indoleacrylic acid(IAA) matrix with sodium formate, or dithranol matrixwith silver tri¯uoracetate. In a ®rst set of experiments thevolumetric ratio of PS vs. PMMA was increased from 0:1up to 199:1, and the matrix was IAA/Na in these cases,i.e., optimized for PMMA. The striking result is shown inFig. 16: even when PMMA is present only as a 0.5%impurity in a blend with PS, the mass spectrum is stilldominated by the [M�Na]� ions of the PMMAdistribution. In a second set of experiments, thevolumetric ratio of PS vs. PMMA was decreased from1:0 down to 1:9, and the matrix was dithranol/Ag in allcases, i.e., optimized for PS. In any mixture tested, thePMMA distribution is dominant and when PS is presentas a 10% impurity relative to PMMA, the mass spectrumwill not show PS ions any longer but only the PMMAdistribution. Of course, this general discrimination infavor of PMMA might be exploited in an application forqualitative trace analysis of acrylates in PS samples, butfrom these results it is obvious that quantitative analysisof blends with MALDI is far from reality.

FIGURE 16. MALDI TOF of PMMA and blends of PMMA and PS, applying a matrix recipe optimizedfor PMMA, i.e., indoleacrylic acid and sodium formate for cationization. For conditions, see Section VIII.B.


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C. Copolymers and Resins

In Table 1 several copolymer and resin applications ofMALDI TOF MS are included: from ethylene oxide/propylene oxide (EO/PO) copolymers, copolystyrenesand copolyacrylates, to several copolyesters, and epoxy-and phenol-formaldehyde resins. In copolymer spectrathe number of masses observed increases dramatically,hence oligomer resolution is usually limited to relativelylow molecular weights. Provided that this resolution isachieved, that the masses of the different monomers usedare suf®ciently different from each other, and that nooligomer-speci®c discrimination occurs, the chemicalcomposition distributions (CCD) can be calculateddirectly from the MALDI mass spectra. Thus, evidencemight be obtained for the presence (or absence) of achemical composition drift as a function of oligomermass. An example of the complexity of a copolymer massspectrum, obtained after separation by micro size-exclusion chromatography (mSEC), is given in Fig. 17(Nielen, 1998).The aromatic copolyester investigated wasbased on the building blocks, dipropoxylated bisphenol A(D), adipic acid (A) and isophthalic acid (I); proposals forthe chemical composition of the [M�Na]� ions in Fig.17 are given in Table 5. Note that without the use of themSEC preseparation one would encounter an even morecomplex situation caused by additional overlap due to thepresence of [M�Na]� ions of cyclic oligomers; inmSEC/MALDI MS cyclic oligomers show up later indifferent spots/fractions.

MALDI TOF MS can also be successfully applied toblock-copolymers. Knowledge of the distribution ofblocks in a copolymer is very important for the ®nalproperties and to conclude whether the random couplinghypothesis is valid for the system being studied, i.e., do

long blocks of one monomer preferably grow from shortblocks of the other monomer or is there no correlationbetween block sizes. An example is the MALDI analysisof block copolymers of �-methylstyrene and vinylpyr-idine (Danis et al., 1997). The mass spectra of the blockcopolymers prepared with varying molar ratios ofmonomers are shown in Fig. 18. With increasing relativeamounts of the 4-vinylpyridine monomer, the averagemass increased as well as the spectra became morecomplex. Nevertheless, the resolution and mass accuracyof MALDI TOF in the re¯ector mode with additional useof a delayed extraction ion source, allowed unambiguousassignment of the composition of the [M�Ag]� ionsobserved. Finally, the distributions of the �-methylstyreneunits were plotted for different numbers of vinylpyridineunits and from the similarity of the distributions it couldbe concluded that there was no correlation between thesize of the ®rst block and the size of the second block; i.e.,the random coupling hypothesis was found to be valid.Some mass spectrometric studies about copolymers claimblock-length distribution data; however, one should notethat MALDI TOF allows conclusions about the chemicalcomposition of the copolymer chains only, i.e., differ-entiation between random-, alternating-, and block-copolymers is not obtained! Such information about theblockiness of copolymers would require a kind of massspectrometric sequencing, similar as in peptide analysis.Tandem MS/MS approaches have to be developed for thefull characterization of synthetic copolymers.

D. Miscellaneous

Among the miscellaneous applications of MALDI TOFMS in the ®eld of synthetic (macro)molecules, data canbe found in literature dealing with, a.o., fullerenes,calixarenes, and alkylethoxylate surfactants, see Table 1.

IX. CONCLUSION AND OUTLOOK

In a period of six years MALDI TOF MS has gained wideacceptance as a tool for polymer characterization. Thisspeci®c application ®eld can be considered as a spin-offof MALDI activities in the traditional ®eld of peptidesand proteins. However, signi®cant differences have beenobserved: sample preparation is less straightforward dueto the coexistence of several distributions, and homo-geneous cocrystallization between matrix and syntheticpolymer is not so easily achieved. These seriously hinderautomated spectra acquisition of large numbers ofpolymer samples. Nevertheless, impressive results instructure elucidation of polymers are documented inliterature: identi®cation of monomers, end groups, andchemical composition distributions of copolymers in

FIGURE 17. Detail of the delayed-extraction re¯ectron mass spec-trum of fraction nr. 15 of dipropoxylated bisphenol A/adipic acid/isophthalic acid copolyester resin after mSEC/MALDI MS. Repro-duced from Nielen, 1998, with permission from the AmericanChemical Society.

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chemically complex mixtures. Some polymers showed tobe less amenable to MALDI: polyole®nes, which lackunsaturation and heteroatoms for stable cationization;chlorinated and brominated polymers, which often showphotochemical fragmentation in the ion source; andpolyamine dendrimers, which show signi®cant prompt

fragmentation in MALDI (in contrast to electrosprayionization). Possibly, the use of IR±MALDI yields betterresults for these polymers.

For some years it was thought that MALDI TOF MSwould be a simple and fast method for the determinationof the molecular weight distribution and the molecular

FIGURE 18. Details of the MALDI±TOF mass spectra of block poly(�-methylstyrene-co-vinylpyr-idine) samples prepared from different molar ratios of monomers. Reproduced from Danis et al., 1997,with permission from the American Society for Mass Spectrometry.

TABLE 5. Chemical composition of oligomers in the mass spectrum of Fig. 17 (Nielen, 1998)

[M�Na]� ion at m/z Functionality Structure proposal

1858, 1878, 1898, 1918, 1938 HO. . . . . . COOH (DA)4, (DA)3DI, (DA)2(DI)2, DA(DI)3, (DI)4

1880, 1900, 1920, 1940 HO. . . . . . COONa (DA)4, (DA)3DI, (DA)2(DI)2, DA(DI)3

2006, 2026, 2046, 2066, 2086 HOOC. . . . . . COOH I(DA)4, I(DA)3DI, I(DA)2(DI)2, IDA(DI)3, I(DI)4

2028, 2048, 2068, 2088 HOOC. . . . . . COONa I(DA)4, I(DA)3DI, I(DA)2(DI)2, IDA(DI)3

2184, 2204, 2224, 2244, 2264 HO. . . . . . OH (DA)4D, (DA)3DID, (DA)2(DI)2D, DA(DI)3D, (DI)4D2332, 2352, 2372, 2392, 2412 HO. . . . . . COOH (DA)4DI, (DA)3(DI)2, (DA)2(DI)3, DA(DI)4, (DI)5

2354, 2374, 2394, 2414 HO. . . . . . COONa (DA)4DI, (DA)3(DI)2, (DA)2(DI)3, DA(DI)4


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weight averages Mw, Mn, and Mz. Nowadays, it has beenadmitted that MALDI TOF MS is quantitatively much lessreliable than chromatography and that, apart fromdifferent manners of data presentation, mass discrimina-tion occurs during ionization, transmission, and detectionof wide polymer distributions. As a way out, sampleshaving a polydispersity>1.2 are characterized by off-line,or semi on-line, coupling of SEC and MALDI TOF MS(SEC/MALDI). Thus the mass spectrometer is used as amass detector and provides both absolute calibrationpoints for the SEC column based on the polymer itself,and the structural data about monomers and end groups.

Many MALDI studies assume uniform cationizationef®ciencies for polymers and copolymers, having differ-ent end group chemistries and chain lenghts. Most likely,this is far from reality and more research efforts arerequired in this ®eld. The feasibility of MALDI/CID/PSDof polymers has been demonstrated. Controlled MS/MSfragmentation of copolymers (sequencing) is extremelyimportant in order to establish the type of copolymer(block-, random-, alternating-); the position of the blocks,and the block length distribution. Obviously, a lot of workstill has to be done since hardly any data are found inliterature.

Although outside the scope of this review, alternativemass spectrometric techniques have shown promisingresults for the characterization of polymers. Among themare MALDI MS/MS studies using a hybrid sectorinstrument with an oaTOF as MS2; MALDI FTICR; andSIMS. Of course, the mass range of these alternativetechniques is limiting their application to low molecularweight polymers. Recently, ESI TOF MS has becomecommercially available, featuring an m/z range of 13,000and the inherent ability of multiple-charging. Besides, on-line LC/ESI TOF MS is performed very easily (Nielen &Buijtenhuijs, 1999); consequently, some overlap withMALDI TOF MS of polymers is foreseen. Apart fromthis, MALDI TOF MS is expected to be increasinglyapplied to characterize synthetic polymers, copolymers,and resins. Moreover, very interesting research opportu-nities remain in the exciting ®eld of MALDI massspectrometry of polymers.

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