Combinatorial Methods for Polymer Science.pdf

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COMBINATORIAL METHODS

FOR POLYMER SCIENCE

Introduction

Fundamental research of the synthesis and characterization of polymeric materi-

als is driven by their use in applications including structural materials, packag-

ing, microelectronics, coatings, biomedical materials, and nanotechnology. Current

trends demand ﬁner control of chemistry, morphology, and surface topography at

the micrometer and nanometer scales. To achieve these goals, there are increasing

needs for the synthesis and processing of multicomponent mixtures, composites,

and thin ﬁlms. However, these systems are inherently complex due to the interac-

tions of phase transitions, microstructure, interfaces, and transport behavior that

occur during synthesis and processing. The synthesis of polymers by emulsion

polymerization, for example, involves colloid chemistry, micellization, transport

between phases, and complex rate relationships. In the case of coatings and thin

ﬁlms, the mechanical and optical properties, microstructure, and phase and wet-

ting behavior are sensitive and poorly understood functions of thickness. In ad-

dition to the complex phenomena involved in polymer synthesis and processing,

there is a large variable space involving parameters whose effects often coun-

teract one another. These include reactant composition and structure, synthetic

sequence, solvent, temperature, annealing history, pressure, and thickness (eg,

in ﬁlms). Conventional microscopy, spectroscopy, and analytical tools for polymer

synthesis and characterization were designed for one-sample-one-measurement

utilization, and are suited for detailed characterization over a limited set of vari-

able combinations. This conventional approach is preferred when the most rele-

vant variable combinations are known a priori or can be reliably predicted from

theory. However, the complex phenomena and large variable spaces present in

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Fig. 1. Schematic of the combinatorial experimental method, as applied to the prepara-

tion of thickness and temperature gradient ﬁlm libraries, high throughput screening with

optical microscopy, and informatic analysis of image data as a function of temperature,

thickness, and time. Adapted with permission from Ref. 22.

multicomponent, multiphase, bioactive or thin-ﬁlm polymers often exceed the ca-

pabilities of current theory and conventional measurements. Therefore, a strong

need exists for experimental techniques capable of highly efﬁcient synthesis and

characterization of complex polymeric systems over large numbers of variable

combinations.

Combinatorial methods (CM) use experimental design, library creation, high

throughput screening, and informatics to efﬁciently and rapidly develop new mate-

rials and measure properties over large numbers of variable combinations (Fig. 1).

This is accomplished by preparing samples not one at a time, but rather as

sample “libraries” containing hundreds to thousands of variable combinations

each. High throughput measurements of relevant chemical and physical prop-

erties, combined with informatic data analysis, allow efﬁcient development of

structure–processing–property relationships. The beneﬁts include efﬁcient char-

acterization of novel regimes of thermodynamic and kinetic behavior (knowledge

discovery) and accelerated development of functional materials (materials syn-

thesis and discovery). Although historically applied to pharmaceutical research,

there is an increasing interest in applying CM to materials science, as indicated

by recent reports of combinatorial methodologies for a wide range of inorganic

(1–8) and organic/polymeric materials (7,9–24).

Early combinatorial materials research used sputtering methods to prepare

composition gradient libraries for measuring the phase behavior of ternary metal

alloys (20) and other inorganic materials (25). However, limitations in computing

capacity and instrument automation overshadowed the beneﬁts of combinatorial

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morphology, physical form, thickness ( h ), and temperature ( T ). This article is a

review of recent advances in applying CM to polymer synthesis and characteriza-

tion. Applications of CM to the synthesis of a wide range of polymeric materials,

including sensors, dendrimers, and biodegradable polymer are presented. Several

novel methods developed for the preparation of T ,

, h , and surface energy contin-

uous polymer ﬁlm libraries are discussed. There is particular focus on the novel

library preparation and high throughput screening steps, since these have been

the principal limiting factors in CM development for polymers. The use of continu-

ous gradient libraries in the measurement of fundamental properties is described

for polymer blend phase behavior, block copolymer segregation, and dewetting

transitions.

Combinatorial Polymer Synthesis

θ w ), and ﬁbroblast proliferation during

cell culture. Fibroblast proliferation was found to decrease with increased hy-

drophobicity except for the main-chain oxygen containing polymers that served

as uniformly good growth substrates regardless of the hydrophobicity.

The results of the above study were utilized (13) to test informatic methods

for designing diverse and focused combinatorial libraries. Molecular topology and

genetic-algorithm-optimized quantitative structure–property relationships were

used to design libraries. These techniques allowed selection of a representative

subset of library members for rapid study of the entire library (a diverse subset) or

concentration on a speciﬁc property of interest (a focused subset). Each monomer

pair of the 112-member library was represented by a 2-D topological descriptor,

used by the algorithm to select a structurally diverse and representative subset

of the library. This subset was utilized to create models for the T g and

θ w , which

θ w of the entire library. Focused libraries

of polymer structures predicted to meet certain T g and

θ w speciﬁcations were also

designed. Good agreement was reported between the calculated and experimental

T g and

θ w values, even for polymers not included in the subset library. Additionally,

the focused libraries were shown to be effective in identifying polymer structures

within speciﬁc T g and

θ w ranges.

Gravert and co-workers (9) used parallel synthesis to design polymeric

supports for liquid-phase organic synthesis. In this work, three polymerization

materials’ characterization until only recently. The primary limitation to char-

acterizing polymers, as bulk material or ﬁlms, with CM has been a shortage

of techniques for preparing libraries with systematically varied composition (

Despite the recent increase in combinatorial inorganic materials research (2–

7,14,15), there are still relatively few studies reporting CM for the synthesis of

polymeric materials. One example is the work of Brocchini and co-workers (10,11),

where a 112-member combinatorial library of biodegradable polyarylates was pre-

pared by copolymerizing all possible combinations of 14 tyrosine-based diphenols

and 8 diacids. The pendant chain and backbone structures were systematically

varied by the addition of methylene groups, substitution of oxygen for the methy-

lene, and addition of branched or aromatic structures. The library products dis-

played diverse properties, as indicated by measurements of the glass-transition

temperature T g , air–water-contact angle (

were tested by comparing to the T g and

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-nitrile diazene cores were utilized for block copolymer

synthesis, while a functionalized methacrylate initiator was used to produce graft

copolymers. Five vinyl monomers were used in combination with the initiators

to produce approximately 50 block and graft copolymers. Copolymer products

were characterized by size exclusion chromatography, nuclear magnetic reso-

nance, and solubility in a range of solvents. Based upon this characterization,

a4- tert -butylstyrene- b -3,4-dimethoxystyrene block copolymer was selected and

used successfully as a support in subsequent liquid-phase syntheses.

Takeuchi and co-workers (18) coupled combinatorial techniques with molec-

ular imprinted polymers to develop sensors for triazine herbicides. The library

consisted of a 7

7 array containing different fractions of monomers methacrylic

acid (MAA) and 2-(triﬂuoromethyl)acrylic acid (TFMAA) with constant concen-

trations of the imprint molecules ametryn or atrazine. After UV-initiated poly-

merization, the products from the sensor library were characterized by HPLC

measurement of herbicide concentration. The receptor efﬁciency was observed to

vary with monomer type: the atrazine receptor efﬁciency increased with MAA

composition and the ametryn receptor was enhanced by increased fractions of

TFMAA. Although only monomer concentration was varied in the libraries, the

authors conclude that the CM synthetic approach would be useful in analyzing

other variables such as solvent, cross-linking agent, and polymerization conditions

to produce optimum molecularly imprinted polymer sensors.

Dickinson and co-workers (12) reported CM synthesis of a sensor library

consisting of solvatochromic dyes dissolved in polymer. Permeation of the polymer

by volatile solvents induced changes in the dye’s solvation environment, which

were detectable by the ﬂuorescence signal. A combination of methyl methacrylate

and dimethyl(acryloxypropyl) methylsiloxane monomers was used to create two

sensor libraries. A discrete library was prepared by photo-polymerizing constant

concentration solutions of the dye and monomers to produce cones of polymer at

different locations on the end of a ﬁber-optic bundle. A second, continuous library

was created by adding methyl methacrylate to the copolymer monomer as UV light

was scanned across the ﬁber-optic bundle, producing a copolymer concentration

gradient across the bundle end. Both the discrete and the continuous libraries

were characterized by monitoring the ﬂuorescence response (via the ﬁber-optic

cables) as a function of exposure to saturated organic vapors. The deposition of

the library directly onto the measurement probe (ﬁber optic) makes this work a

good example of a combined CM polymer synthesis and characterization. For the

particular dye and monomer used, the ﬂuorescence response was found to be a

nonlinear function of the concentration.

Newkome and co-workers (26) report, a combinatorial strategy for synthe-

sizing dendrimers with modiﬁed structure and surface chemistry. Mixtures of

three branched isocyanate-based monomers, mixed over a wide range of compo-

sitions, were used to synthesize a combinatorial library of dendritic molecules.

Based upon 13 C NMR spectra, the dendrimer products displayed varying degrees

of peripheral heterogeneity, adjustable by controlling the ratios of the three iso-

cyanate monomer groups. The methodology provides for the rapid modiﬁcation

of dendritic properties based upon the chemistry and distribution of peripheral

surface groups; for example, some of the dendrimers were amphiphilic, display-

ing solubility in CH 3 OH, H 2 O, and CHCl 3 . The degree of amphiphilicity can be

initiators containing

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adjusted to favor solubilization in one of the solvents by varying the proportion of

amino vs benzyl ether surface moieties, based upon the ratio of monomer building

blocks.

Combinatorial Polymer Characterization

m) polymer ﬁlms and coatings. Here, the pri-

mary goal is not to produce new materials, but rather to use CM to measure rel-

evant phase behavior, wetting, and microstructural properties over a large range

of parameter combinations. The variables of primary importance in characteriz-

ing the physical and chemical properties of polymers in the bulk and ﬁlm state

include the composition in multicomponent mixtures and composites, thickness,

temperature (eg, annealing, curing, melt processing), and substrate energy (

≈

1to

≈

m) and thin (

γ so ).

While preparing polymer ﬁlms and coatings libraries with variations in

γ so , we found that the deposition of ﬁlms with continuous gradients in

each of these properties is a convenient and practical alternative to the deposition

of libraries containing discrete regimes. Of course the introduction of chemical,

thickness, and thermal gradients drives nonequilibrium transport processes that

will eliminate the gradients over time. The timescale and lengthscale over which

gradient library measurements are valid are determined in part by the magnitude

of these transport ﬂuxes. In most cases high molecular mass ( M w >

10,000 g/mol)

polymers have relatively low transport coefﬁcients, eg, diffusivity and viscosity.

(According to ISO 31–8, the term “molecular weight” has been replaced by “relative

molecular mass,” symbol “Mr”. The conventional notation, rather than the ISO

notation, has been employed for this publication.) Thus the mass transport and

ﬂow lengthscale and timescale are often orders of magnitude lower than those of

the measurements, allowing properties to be measured near equilibrium.

Preparation of Polymer Coating and Thin-Film Libraries.

Thickness Gradient Libraries. A velocity-gradient knife coater (21–24), de-

picted in Figure 1, was developed to prepare coatings and thin ﬁlms containing

continuous thickness gradients. A 50-

L drop of polymer solution (mass frac-

tion 2–5%) was placed under a knife-edge with a stainless steel blade width

of 2.5 cm, positioned at a height of 300

m and at a 5 ◦ angle with respect to

the substrate. A computer-controlled motion stage (Parker Daedal) moves the

substrate under the knife-edge at a constant acceleration, usually 0.5–1 mm/s 2 .

This causes the substrate coating velocity to gradually increase from 0 to a

maximum value of 5–10 mm/s. The increase in ﬂuid volume passing under the

knife-edge with increasing substrate velocity results in ﬁlms with controllable

thickness gradients. Figure 2 shows h -gradients for polystyrene (PS) and blends

of polystyrene/poly(vinylmethylether) (PS/PVME) ﬁlms on Si substrates as a

function of solution composition. Thin-ﬁlm-thickness-dependent phenomena can

The previous section focused on CM studies in which the production or synthesis

of new polymeric materials was the primary goal. In those examples the synthesis

steps were combinatorial, but subsequent characterization steps were noncombi-

natorial. One exception is the ﬂuorescent sensor libraries prepared on ﬁber-optic

bundles, discussed above (12). In this section we describe library preparation and

high throughput screening methods for the combinatorial characterization of both

thick (

h , T , and

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