Chemical modification of macroreticular 2-hydroxyethyl methacrylate polymers

Reactive Polymers, 8 (1988) 105-111

105

Elsevier Science Publishers B.V., Amsterdam - Printed in The Netherlands

REVIEW

CHEMICAL MODIFICATION OF MACRORETICULAR 2-HYDROXYETHYL METHACRYLATE POLYMERS J. KAHOVEC 1 and J. (~OUPEK 2

i Institute of Macromolecular Chemistry, Czechoslovak Academy of Sciences, 162 06 Prague 6 (Czechoslovakia) 2 Laboratory Instruments Works, 162 03 Prague 6 (Czechoslovakia) (Received May 3, 1987; accepted July 24, 1987)

Chemical reactions on the commercially available reactive polymer, macroreticular 2-hydroxyethyl methacrylate-ethylene dimethacrylate ( H E M A - E D M A ) resin, are reviewed. The review covers both scientific and patent literature. Several H E M A - E D M A derivatives are applied as ion exchangers in biochemistry and for metal ion separations.

INTRODUCTION

One speciality polymer which has recently become commercially successful is crosslinked poly(2-hydroxyethyl methacrylate), a copolymer of 2-hydroxyethyl methacrylate (HEMA) and ethylene dimethacrylate (EDMA). Due to their hydrophilicity and other favourable properties, lightly crosslinked gel copolymers of HEMA are suitable as biomedical polymers for contact lenses, prostheses and the like. Highly crosslinked macroreticular copolymers of H E M A - E D M A and their derivatives, known under the generic commercial names Spheron * (Lachema, Brno) and Separon ® (Laboratory Instrument Works, Prague), have been applied in a number of different ways; they are useful as sorbents, as carriers of biologically active substances, or as ion exchangers for various types of chromatography. Although the unmodified Spherons and their simple chemical derivatives have found 0167-6989/88/$03.50

these types of application, their potential as reactive polymers has not yet been widely explored. For example HEMA copolymers containing primary alcohol groups are intrinsically reactive and, by chemical transformation of the hydroxy groups, many new polymers with various functional groups may be obtained. In this paper we have chosen macroreticular H E M A - E D M A copolymers to present a brief review of their chemical modifications as described in scientific and patent literature.

HEMA-EDMA

Unmodified macroreticular HEMAEDMA copolymers, containing 39 or 24% EDMA, were characterized by the determination of their degree of swelling, inner surface area, exclusion limits and pore volume [1]. These characteristics are important in consid-

© 1988 Elsevier Science Publishers B.V.

106

ering the accessibility of reactive hydroxy groups, which, in turn, determines the attainable degree of conversion in chemical transformations. Generally, it can be said that only 40-60% of the hydroxy groups present are accessible to a chemical reagent, the other hydroxy groups are buried in the heavily crosslinked mass of microparticles. A great advantage of HEMA-EDMA is its high resistance to acid and alkaline hydrolysis as a result of the steric shielding of carboxylic groups by the polymer chain. Of course, this considerably extends the range of reaction conditions which can be used in chemical modification of these polymers. This review is limited to the chemistry of HEMA-EDMA (denoted as (~)-OH in the reaction schemes). A general bibliography on HEMA-EDMA has already been published [2]. HEMA-EDMA derivatives are further classified by their characteristic functional groups.

Esters with inorganic and sulfonic acids These are readily available by reaction of HEMA-EDMA with inorganic acid chlorides and sulfonic acid chlorides. Thus, with chlorosulfonic acid, phosphorus oxychloride and aromatic sulfochloride, the corresponding polymeric alkylsulfuric acid [3], monoalkyl phosphate (after hydrolysis) [4], and arenesulfochloride [5] are obtained, respectively: CISO3 H POCl3 R ' ~

~

OSO2OH

~

OPO(OH)2

SO2C[

halogenating agents (SOC12, SOBr2) [6,7]: -OH laX or SOX2.)@ - X (X = C1, Br).

Esters with carboxylic acids The hydroxy groups in HEMA-EDMA are easily acylated by carboxylic acid chlorides or anhydrides, especially in pyridine as the medium, yielding polymer esters: (~) - O H RCOC1 or (RCO)20) @ -OCOR Thus, acetate, butyrate, caprylate, laurate, stearate, 4-nitro- and 3,5-dinitrobenzoate were obtained from the corresponding acid chlorides [8]; also, the succinyl derivative (R = CHzCH2COOH; SUC-Spheron®) [9] was prepared by reaction with succinic anhydride. The methoxycarbonyl derivative, i.e., mixed carbonic acid ester (R=OCH3), was obtained by a reaction with methyl chloroformate [10]. The corresponding complexon esters can be prepared by a reaction with complexon (EDTA, DTPA) anhydrides [11]. In the patent literature [12], a mixed carbonate of HEMA -EDMA and N-hydroxy-5-norbornene-2,3dicarboximide is described. This active ester may be used in the preparation of polymerimmobilized amino acids.

Sulfur derivatives The thiol derivative of HEMA-EDMA was prepared by a three-step procedure via the thiuronium salt [13]: @ - O H epichlorohydrin) BF3 • Et 20

(R=H,CH 3 )

(~-OCH

2 C H C H 2 C1 CS(NH2)2 >

I Halogen derivatives Polymer chloro or bromo derivatives can be obtained by a reaction of HEMA-EDMA with hydrohalogenic acids (HC1, HBr) or with

OH NH~(~)-OCH2 CHCH2 SC~// C1[ NH2 OH

107 OH

From carboxylic acid obtained by the oxidation of HEMA-EDMA, esters may be prepared by acid-catalyzed esterification [18], by a reaction with diazomethane [19], or by condensation with an alcohol in the presence of dicyclohexylcarbodiimide (DCCI) [20]. By the latter method, active esters, derivatives of N-hydroxyphthalimide and of substituted phenols were obtained [20]:

) (~)_OCH2 CH_C H2S H

I

OH (Spheron®-Thiol) The sulfonic acid derivative of H E M A EDMA, ( ~ ) - C H z C H ( O H ) C H z S O 3 H , is easily obtained by a reaction of the 2,3epoxypropyl derivative of H E M A - E D M A with sodium hydrogen sulfite [3]. Polymeric alkylsulfuric acid, (S)-OSO2OH, is an alkylating reagent and hence, it can also be used for the preparation of sulfonic acid [14]:

@

COOH<

SO2 @ - O H + (CH2),,~ I O

NaOH >@ _O(CH2 ),,SO3Na

(n = 3 or 4).

(~

N-hydroxyphthalimide ( ~ DCCI

(~)-OSO2OH + NazSO 3 ~ @ - S O 3 H

Alternatively, sulfonic acids can also be obtained by a reaction of H E M A - E D M A with propane- or butanesultone [3,15] (Note: the latter are carcinogens):

CH3OH/HCI or CH2N2

COOCH3 CO COO-- N/ ~CO

Aldehydes Aldehydes may be obtained by mild oxidation of primary alcohol groups of the polymer by selective reagents, such as dimethyl sulfoxide or pyridine-chromium trioxide. The conversions to aldehyde groups are very low, however [21]: (~) - O H oxidation) ~ ) - C H = O

Carbox>'lic acids and esters The primary alcohol groups of HEMAEDMA can be oxidized to carboxylic groups with potassium permanganate in an acid medium [9,16,17]: (~) - O H --* (~) - C O O H (C-Spheron®) Alternative methods for the preparation of carboxylic acids are carboxymethylation of hydroxy groups with chloroacetic acid [9,16]:

Aliphatic amino derivatioes These compounds are most often prepared indirectly, by reaction of an alkylating derivative of HEMA-EDMA, e.g., halogenide, tosylate and sulfate, with ammonia or an amine [6,11,22-24]: R

(~)-X + R N H - R ' ~ ( ~ ) - N ~ R '

@ - O H CICH2COOH~@ -OCH2COOH NaOH

(CM-Spheron~) and their reaction with dicarboxylic acid anhydrides (maleic anhydride, phthalic anhydride) [9,16]: (~)-OH +

( CO / O CO

~ (~)-OCO COOH

or by a reaction of H E M A - E D M A with alkylating amines. For example, the 2-(diethylamino)ethyl derivative (DEAE-Spheron®) is prepared by a r e a c t i o n w i t h 2(diethylamino)ethyl chloride [25-27]. The reaction of the 2,3-epoxypropyl derivative of H E M A - E D M A is particularly convenient in this respect:

108 (~)-CH 2 C H - C H 2 + R - N H - R ' \O /

R (~)-CH2 CHCH2 N~/

I

"R'

OH

Using these methods, H E M A - E D M A polymers with immobilized ethylamine, ethylene-, tetramethylene- and hexamethylenediamine, ethanolamine, 6-aminocaproic acid, imidazole, L-lysine and peptide [28-30] groups, as well as with straight-chain oligo(iminoethylene) and branched polyethylenimine [11], were prepared. Immobilized amines can also be prepared by a direct reaction of amine with H E M A - E D M A after the activation of weakly reactive hydroxy groups with cyanogen bromide [23] or carbonyldiimidazole [31]. If the primary amine, (~)-NH2, without secondary and tertiary amino group contaminants is required, it is advantageous to use reduction of the corresponding azide derivative [5] or the Del6pine reaction, i.e., alkylation of hexamethylenetetramine and subsequent hydrolysis of the hexamethylenetetraminium salt which is formed [11]:

@ -OZO2C6n5 NAN3)@ - -.I N SnCI 3~ 2 @-NH2

The conversion of hydroxy groups is rather low, the greater part of the reagent is hydrolyzed in the alkaline medium. According to the second method [33], a polymeric carboxylic acid is condensed with an aromatic diamine (e.g., benzidine) in the presence of dicyclohexylcarbodiimide:

(~COOH + H 2 N ~ ~ - - N H

2 DCCI"

(~--- CONH~

NH2

Diazotation of these amines and azo coupling with various analytical reagent--phenols, aromatic amines or other pi-electron systems--leads to immobilized analytical reagents from ortho-hydroxyazo dyes, formazane and other moieties [33,34]. Immobilized 8-hydroxyquinoline (Spheron~-Oxin) and salicylic acid (Spheron®-Salicyl) are commercially available: NaNO2 ( ~ OCH2CH2sO2 NH2 HCl

( ~ OCH2CH2SO2~ ~

OCH2CH2SO2~

N2+CIN=N'-~

? ' 1. (CH2)rN4

/

Other nitrogen derivatives

J

2. aq. HC1

The hydrazide derivative of H E M A EDMA may be obtained by ester hydrazinolysis [18,19]:

Aromatic amino derivatives

An aromatic primary amino group can be introduced into the polymer in two ways. The first method is analogous to the functionalization of cellulose fibers using reactive dyes [32,331: (~OH + H2N-~SO2CH2CH2OSO3H

OH-~

( ~ OCH2CH2SO2~ (Spheron~--ArA)

NH2

@ -COOCH3N2H4"n20_)@

-CONHNH2

Polymer hydrazide may also be obtained by the direct hydrazinolysis of H E M A - E D M A during which methacryloyl hydrazide units, -CH2C(CH3)(CONHNH2)- , are formed in the polymer [10]. Hydrazinolysis of the polymeric methoxycarbonyl derivative leads to half-carbohydrazide [10]: (~)-OCOOCH 3 N2H4"H20 ) @ - O C O N H N H 2

109

Miscellaneous

An important derivative of HEMA-EDMA is 2,3-epoxypropyl or glycidyl ether, easily obtainable by a reaction of the basic polymer with epichlorohydrin [28] (cf. the related glycidyl methacrylate resin [35,36]): CH 2

(~)-OH

CHCHzC1

\ °NaOH /

)

(~)-OCH2 q%%H 2 (Spheron®-E)

tose, D-mannose, L-fucose, N-acetyl-D-glucose and N-acetyl-D-galactosamine. The polymers obtained may be used as carriers in affinity chromatography of lectins [29]. The derivative of HEMA-EDMA with oligo(N-acetyliminoethylene) grafts, (~)(N(COCHa)CHECH2)n, may be obtained by the reaction of an alkylating derivative of HEMA-EDMA (bromide, tosylate, glycidyl ether) with 2-methyloxazoline. By hydrolysis, a chelating polymer with oligo(iminoethylene) units was obtained [11,40].

The epoxide ring is readily opened by various nucleophiles (Null). (~) - O C H 2 CHCH 2 + Null \O / @-OCH2

CHCH2Nu

I

OH This is the reason why this derivative is much used as a reactive polymer in the preparation of other derivatives of HEMAEDMA [25,28-30], and for the immobilization of 8-hydroxyquinoline [37] and enzymes [28]. In contrast, the acid-catalyzed (BF3" Et20 ) reaction of HEMA-EDMA with epichlorohydrin leads to the 3-chloro-2-hydroxypropyl derivative, (~)-OCH2CH(OH)CH2C1 (cf. p. 106) [13,38]. Alkylation of HEMA-EDMA with 2,4-dinitrochlorobenzene and 4-chloromethylpyridine yields 2,4-dinitrophenyl [8] and 4-picolyl [27] ethers, respectively: @-o.

__ NO 2

Glycosidic derivatives of HEMA-EDMA

@-

o-c )

are readily obtainable by an acid-catalyzed condensation (HC1, BF3) of the polymer with monosaccharides, such as D-glucose, D-galac-

CONCLUSION It has been shown, using many examples taken from the scientific and patent literature, that commercial macroreticular copolymers of 2-hydroxyethyl methacrylate-ethylene dimethacrylate are promising polymers. Their ion exchange derivatives are already much used in the chromatography of biopolymers [41], and their chelating derivatives in the analysis of trace amounts of metals [13,42-45]. The possibilities offered by a purposeful functionalization of HEMA-EDMA are far from exhausted, and many new products offering remarkable properties and uses may be expected in the future.

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