Hydroxy-derivatised emulsion templated porous polymers (PolyHIPEs): Versatile supports for solid and solution phase organic synthesis

Reactive & Functional Polymers 66 (2006) 81–91

REACTIVE & FUNCTIONAL POLYMERS www.elsevier.com/locate/react

Hydroxy-derivatised emulsion templated porous polymers (PolyHIPEs): Versatile supports for solid and solution phase organic synthesis Peter Krajnc a

a,*

, Nermina Leber a, Jane F. Brown b, Neil R. Cameron

b,*

University of Maribor, Faculty of Chemistry and Chemical Engineering, Smetanova 17, SI-2000 Maribor, Slovenia b University of Durham, Department of Chemistry, South Road, Durham DH1 3LE, United Kingdom Available online 12 September 2005

Abstract 4-Hydroxymethyl phenyl (Wang linker) moieties and tris(hydroxymethyl)aminomethane were immobilised onto vinylbenzyl chloride/divinylbenzene porous polymer matrixes via displacement of the chlorine in chloromethyl groups. Both monolithic forms and ground particles of polymerised high internal phase emulsions (PolyHIPE, 90% pore volume) of 4-vinylbenzyl chloride/divinylbenzene (molar ratio of 60/40, 75/25 and 78/22) and also chloromethylated polystyrene beads gave high conversions thus yielding functionalised polymers with a remarkably high loading of OH groups per gram of polymer support (highest obtained loading 8.1 mmol of OH groups per gram of polymer). The reactivity of these novel polymer supports was demonstrated by the immobilisation of 4-iodobenzoic acid, which is frequently used in the preparation of biaryl compounds by Suzuki coupling reactions. Additionally, the emulsionderived polymers were used to scavenge acetyl chloride and a dependence of scavenging ability on the porosity was found (being higher with higher porosity).
2005 Elsevier B.V. All rights reserved. Keywords: PolyHIPE; Polymer scavengers; Solid phase synthesis; Wang linker; Tris(hydroxymethyl)aminomethane

1. Introduction * Corresponding authors. Tel.: +386 2 2294422; fax: +386 2 2527774 (P. Krajnc); Tel.: +44 191 3342008; fax: +44 191 3844737 (N.R. Cameron). E-mail addresses: [email protected] (P. Krajnc), [email protected], [email protected] (N.R. Cameron).

Chloromethylated polystyrene crosslinked with divinylbenzene (DVB) was the material of choice for the first polymer-supported oligomer synthesis, published by Merrifield in 1963 [1]. The versatility of this polymer allows for its vast popularity

1381-5148/$ - see front matter
2005 Elsevier B.V. All rights reserved. doi:10.1016/j.reactfunctpolym.2005.07.023

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among organic chemists even almost 40 years later and many derivatives are now available commercially. The morphology of the majority of polymer supports used to date is still gel-type, where very few if any pores are present in the polymer particle in the dry state. Therefore, the particles must swell in the reaction medium in order to enable contact of the reactants in the solution with the reactive sites in the polymer matrix. This limitation regarding solvent use can be overcome by preparing a support with permanent porosity, which can be achieved with the use of porogenic solvents and a relatively large quantity of crosslinker [2]. Other solutions include grafting [3] onto a formed polymer support, however the disadvantage of this approach is a relative low loading of reactive groups. Recently, novel monolithic polymer supports have appeared with ambitions for use in flow-through polymer assisted solution phase (PASP) methods. Sˇvec and Frechet with coworkers have prepared porous monolithic polymer supports for use in chromatography and PASP chemistry [4]. Since a higher surface area of the polymer in a column usually means a lower permeability, the performance of such monolithic supports has been improved by grafting functional polymers onto the surface [5]. Kirschning et al. [6] recently described a PASP flow through system using a polystyrene/ glass composite in order to avoid any channelling of the solution. An alternative route to porous monolithic polymers is to polymerise the continuous phase of a high internal phase emulsion1 (HIPE) [7]. Reactive monomers, like 4-vinylbenzyl chloride (VBC) can be incorporated into the oil phase of such an emulsion and therefore a functional polymer can be produced via this method [8]. The surface area of the resulting polymers can be enhanced by the addition of porogenic solvents [9]. Styrene based PolyHIPE materials, crosslinked with DVB, have already been used in applications such as the separation of heavy metals [10], precursors for supported species [11], and as biocatalyst supports [12]. In our recent study 4VBC based PolyHIPE monolithic materials

1 A HIPE has an internal (droplet) phase volume ratio of more than 74.05%.

proved promising for functionalisation via reactions with amines [13]. In order to obtain tailored polymer supports for the attachment of various species, linkers can be introduced. A commercially used example of a resin bound linker, derived from chloromethylated polystyrene, is the Wang resin, which has an OH moiety [14]. This resin has been widely adopted by the chemical community and numerous applications have been reported [15]. Whichever type of support is to be used, the loading of reactive groups is of great importance when efficiency is to be taken into account. Not many examples of immobilising species with multiple free OH groups are known. Hodge at al. [16] used a supported diol for removing excess aldehydes and ketones from solution, while recently a diethanolamine support was prepared in order to immobilise boronic acids [17]. In this report, we describe the preparation of Wang and tris(hydroxymethyl)aminomethane derivatives of chloromethylated polystyrene supports. Five different forms of starting support were used, namely in-house prepared 4-vinylbenzyl chloride/DVB PolyHIPE materials of VBC/DVB ratios 60/40 and 75/25 and 78/22, and VBC based polymer beads (gel and macroporous type).

2. Experimental 2.1. Materials and analysis 4-Vinylbenzyl chloride (VBC, Aldrich) and divinylbenzene (DVB, Aldrich, 80%, tech., the rest ethylstyrene) were washed with 5% NaOH (aq) to remove the inhibitors. Dimethylformamide (DMF) (Aldrich; anhydrous and HPLC grade) and methanol (Aldrich; anhydrous) were used as received. THF was freshly distilled over benzophenone ketyl. Dichloromethane (DCM) was freshly distilled over calcium hydride. Azo-bis-isobutyronitrile (AIBN), potassium persulphate, sorbitan monooleate (Span 80), tris(hydroxymethyl)methylamine, acetyl chloride were all purchased from Aldrich and used as received. Chloromethylated polystyrene beads (permanently porous, 10.91% of chlorine) were purchased from Polymer

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Laboratories, while gel type chloromethylated polystyrene beads (7.46% of chlorine) were obtained from Argonaut Technologies. Wang polymer beads were provided by GlaxoSmithKline and were washed with DMF (anhydrous) and DCM (anhydrous) before use. Combustion elemental analysis data (C, H and N) were obtained from an Exeter Analyser CE440. A Dionex Ion Chromatograph Analyser DX-120 was employed for chlorine and iodine determination. FTIR spectra (KBr discs) were recorded on a Perkin Elmer 1600 Series FTIR Spectrometer. UV absorbencies were recorded on a Pye Unicam UV/VIS Spectrophotometer. 2.2. PolyHIPE preparation VBC-containing PolyHIPE materials (1) were prepared as described before [13], with VBC:DVB molar ratios of 60:40, 75:25 and 78:22. A representative procedure is given below. VBC (6.50 g, 0.04 mol), DVB (3.66 g, 0.03 mol) and Span 80 (1.97 g, 4.6 mmol) were mixed in a round-bottomed flask with an overhead stirrer fitted with a D-shaped PTFE paddle. The mixture was purged with nitrogen gas for 15 min. The aqueous phase was prepared separately by dissolving potassium persulfate (0.2 g, 0.74 mmol) and calcium chloride dihydrate (1.0 g, 6.80 mmol) in de-ionised water (90 mL) and the resulting solution was purged with nitrogen for 15 min. The organic solution was stirred under nitrogen at ca. 300 rpm and the aqueous phase was added dropwise under constant mechanical stirring. After complete addition of the aqueous phase, stirring was continued for 1 h to produce a homogeneous emulsion. The emulsion was transferred to a polyethylene (PE) bottle and polymerised in an oven at 60 C for 48 h. The resulting PolyHIPE (1a) was then extracted in a Soxhlet apparatus with de-ionised water for 24 h and IPA for a further 24 h. The monolith was dried in vacuo at 50 C for 48 h. Granular PolyHIPE was obtained by grinding sections of the monolith in a homogeniser. Cubic pieces of PolyHIPE (ca. 1 cm3) were cut from the monolith using a scalpel. Analysis: Found: C, 78.9; H, 7.0; Cl, 9.5%. Calculated for (C9H9Cl)0.64(C10H10)0.29 (C10H12)0.07: C, 77.7; H, 6.6; Cl, 15.7%. IR (KBr

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disc) tmax/cm
1 3400br (OH), 2924s and 2853w (CH), 1610w and 1510m (aryl C@C), 1265s (CCl), 835s (p-disubstituted benzene ring). 13C NMR (75.4 MHz, solid state) d 15.8 (–CH2CH3), 29.4 (–CH2CH3), 40.7 (quaternary C), 46.7 (–CH2Cl), 65.5 (–CH2OH), 113.8 (–CH@CH2), 128.3 (aromatic C–H), 135.9 (–CH@CH2), 145.6 (aromatic C–R). 2.3. Wang functionalisation In a 50-mL round-bottomed flask fitted with a reflux condenser, powdered VBC PolyHIPE (0.3 g, 1.35 mmol –CH2Cl groups), 4-hydroxybenzaldehyde (3.38 g, 27.7 mmol), K2CO3 (3.83 g, 27.7 mmol) and NaI (4.15 g, 27.7 mmol) were stirred in acetonitrile (30 mL). The mixture was heated under reflux for 48 h, after which time, PolyHIPE 2 was filtered and washed with DCM (2 · 25 mL), DMF (4 · 25 mL), MeOH (2 · 25 mL) and Et2O (1 · 25 mL). The material was dried in vacuo at 50 C for 72 h to give aldehyde-modified PolyHIPE (0.34 g, 83% conversion by weight). Found: Cl, 0.5%. Calculated: Cl, 0% (97% conversion). IR (KBr disc) tmax/cm
1 3447br (OH), 2923m and 2851w (CH), 2736w (CHO), 1691s (HC@O), 1601s and 1508s (aryl C@C), 1257m (aryl C–O–C), 830m (p-disubstituted benzene ring). The aldehyde-containing material 2 was then reduced with NaBH4. To a 50-mL round-bottomed flask fitted with a rubber septum and vent was charged aldehyde PolyHIPE (0.1 g, 0.31 mmol –C@O groups). Dry THF (4 mL), NMM (2 mL) and ethanol (2 mL) were added to the PolyHIPE via syringe, and the mixture was stirred and degassed with nitrogen gas for 20 min. Sodium borohydride (49.5 mg, 1.31 mmol) was slowly added to the flask, and the mixture was stirred under nitrogen for 24 h. The PolyHIPE was filtered and treated with water (5 · 30 mL), before being washed with MeOH (2 · 30 mL), THF (4 · 30 mL), H2O (2 · 30 mL), THF (2 · 30 mL) and MeOH (2 · 30 mL). The support was dried in vacuo at 50 C for 24 h to provide Wang-functionalised PolyHIPE 3 (70 mg, 70% conversion by weight). IR (KBr disc) tmax/cm
1 3421br (OH), 2922s and 2852w (CH), 1685w (HC@O), 1610m and 1510s

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(aryl C@C), 1243s (aryl C–O–C), 821m (p-disubstituted benzene ring). 2.4. Fmoc number determination Hydroxy-functionalised polymer (30–50 mg), N-a-Fmoc-glycine (Fmoc-Gly-OH) (2.9 equiv.), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) (2.9 equiv), DIPEA (2 eq) and DMF (2 mL) were loaded into 5 mL filter syringe tubes fitted with caps and stoppers. The mixtures were shaken using an agitating device for 2 h. The polymers were filtered and washed with MeOH (5 · 5 mL), THF (2 · 5 mL), and Et2O (2 · 5 mL), before being dried in vacuo at 50 C for 24 h. In 5 mL volumetric flasks, the Fmoc-protected polymers (10 mg) were shaken in a 20% solution of piperidine/DMF (400 lL) for 40 min. Methanol was then added to the flasks to obtain 5 mL solutions. The solutions were diluted with methanol, depending on the loading expected, and UV readings were recorded at 301 and 322 nm (background reading). The Fmoc procedure was performed in duplicate, with each polymer support, in order to obtain an average Fmoc number. Alternative coupling procedure using 1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole and Nmethylimidazole (MSNT/NMI): polymer supports (30–50 mg) were loaded into 5 mL filter syringe tubes and washed with DMF and dry DCM before functionalisation. Fmoc-Glycine (3 equiv.) was placed in a 50-mL round-bottomed flask fitted with a rubber septum and vent. Dry DCM (3– 4 mL) was added via syringe and the solution was degassed with nitrogen for 10 min. NMI (2.25 equiv.) was added via syringe and the solution was transferred to a stoppered 50 mL round-bottomed flask containing MSNT (3 equiv.). This solution was then added immediately via syringe to the filter tubes containing the supports. The tubes were shaken using an agitating device for 2 h. The polymer supports were filtered and washed with MeOH (5 · 5 mL), THF (2 · 5 mL), and Et2O (2 · 5 mL), before being dried in vacuo at 50 C for 24 h. In 5 mL volumetric flasks, the Fmoc-protected polymers (10 mg) were shaken in a 20% solution of piperidine/

DMF (400 lL) for 40 min. Methanol was then added to the flasks to obtain 5 mL solutions. The solutions were diluted with methanol, depending on the loading expected, and UV readings were recorded at 301 and 322 nm (background reading). The Fmoc procedure was performed in duplicate, with each polymer support, in order to obtain an average Fmoc number. Treatment of the Fmoc-loaded resins with piperidine liberates the readily detectable by-product 9-(1-piperidinylmethyl)fluorine [18], which absorbs UV at 301 nm allowing for its quantification through an adaptation of BeerÕs law: concentration in cell

Loading in mmol g
1

zfflfflfflfflfflfflfflfflffl ffl{
ffl}|fflfflfflfflfflfflfflfflffl UV value ¼ Dilution 7800
 Flask volumeðmLÞ  . Wt: of sampleðgÞ

When the molecular weight of the Fmoc group is taken into consideration, a normalised Fmoc value can be obtained. 2.5. Coupling of 4-iodobenzoic acid to Wangfunctional PolyHIPE Example procedure: Wang-functionalised PolyHIPE 3 (80 mg, 0.22 mmol –CH2OH groups) was washed with dry DMF (2 · 5 mL) and dry DCM (2 · 5 mL) and placed in a 25-mL roundbottomed flask, fitted with a rubber septum and vent. In a second 25 mL round-bottomed flask, fitted with a rubber septum and vent, was placed 4iodobenzoic acid (108 mg, 0.44 mmol), dry DCM (2 mL) and NMI (0.14 mL, 1.74 mmol). MSNT (129 mg, 0.44 mmol) was placed in a third 25 mL round-bottomed flask, fitted with a rubber septum and vent. The contents of flask 2, containing the 4iodobenzoic acid solution, were added, via syringe, to flask 3 containing MSNT. The resultant solution was immediately added to the PolyHIPE in flask 1. The reaction was stirred gently at 20 C for 1 h, after which, the PolyHIPE was filtered and thoroughly washed with dry DCM (3 · 5 mL) and dry DMF (3 · 5 mL). The material was dried in vacuo at 50 C for 24 h to give iodine-

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containing support 4 (94 mg, 72% conversion by weight). Found: I, 6.4%. Calculated: I, 21.3% (30% conversion). IR (KBr disc) tmax/cm
1 3421br (OH), 2923s and 2864m (CH), 1718m (C@O), 1610m and 1510s (aryl C@C), 1243m (aryl C–O–C), 821m (p-disubstituted benzene ring), 551br (CI). 2.6. Functionalisation of resins with tris(hydroxymethyl)aminomethane About 1.00 g of VBC/DVB PolyHIPE (1b and c; for quantities of reactive groups see Table 2) was suspended in 30 mL of DMF, tris(hydroxymethyl)methylamine (5 times excess in relation to chloromethyl groups) and triethylamine (5 times excess in relation to chloromethyl groups) were added and the reaction mixture stirred at 90 C under nitrogen for 24 h. The polymer was filtered, washed with DMF, DMF/NEt3 (1:1), MeOH, MeOH/H2O (1:1), tetrahydrofuran and dried in vacuo. All products were submitted to elemental analysis and the loadings of reactive groups calculated from the nitrogen percentage (see Table 2). 2.7. Coupling of 4-iodobenzoic acid to TrisOHfunctional PolyHIPE In a 50-mL round-bottomed glass flask fitted with a rubber septum and vent, (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI, 2.2 g, 11.6 mmol), N-hydroxybenzotriazole (HOBT, 0.32 g, 2.3 mmol), 4-iodobenzoic acid (2.9 g, 11.6 mmol) and finely ground TrisOH PolyHIPE (5, 0.3 g, 2.31 mmol –CH2OH groups) were stirred in DMF (20 mL) at room temperature for 4 h. The PolyHIPE was filtered and washed with DMF (4 · 20 mL), DCM (2 · 20 mL), MeOH (2 · 10 mL), NEt3/MeOH (1:1, 2 · 10 mL) and MeOH (3 · 10 mL). The material was dried in vacuo at 50 C for 24 h to give iodine-containing support 6 (0.57 g). Found: I, 29.7%. Calculated: I, 37.5% (79% conversion). IR (KBr disc) tmax/ cm
1 3421br (OH or NH), 2924 m and 2853w (CH), 1782m and 1719s (C@O), 1637m and 1510s (aryl C@C), 825m (p-disubstituted benzene ring), 555br (CI).

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2.8. Scavenging of acetyl chloride with tris(hydroxymethyl)aminomethane PolyHIPE Powdered trisOH-modified PolyHIPEs (100 mg each) of different nominal porosities, obtained from the corresponding 75/25 VBC PolyHIPEs (90%, 1d; 75%, 1e; 50%, 1f), were suspended in 20 mL of dry DCM, after which acetyl chloride (127 mg, 2 · excess relative to hydroxy groups) was added to each solution and the reaction mixtures stirred at room temperature under nitrogen for 2 h. The resulting polymers (7d–f) were filtered, washed with DCM (4 · 10 mL) and the amount of acetyl chloride remaining in solution determined by measuring the absorption at 269 nm and relating the value to a previously constructed concentration–absorbance relation curve.

3. Results and discussion 3.1. VBC PolyHIPE support preparation and properties VBC-containing PolyHIPEs are well known in the literature [13] and are prepared without difficulties. The morphology is similar to that of poly(styrene-DVB) PolyHIPEs, although a little more irregular (see Fig. 1). The monolithic materials so produced were divided into two sections; one portion was ground into a fine powder using a commercial coffee grinder, the other portion was cut carefully into small (ca. 1 cm3) cubes (Fig. 2). Interestingly, elemental

Fig. 1. SEM of VBC PolyHIPE.

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ring either before (e.g., during washing with NaOH (aq)) or during HIPE preparation. The presence of an –OH stretching band in the FTIR spectrum at around 3400 cm
1 and a peak in the 13 C solid state NMR spectrum at 65.5 ppm suggested the presence of benzyl alcohol residues from chloromethyl group hydrolysis. 3.2. Wang functionalisation

Fig. 2. Processing of monolithic PolyHIPE into cubic and granular forms for derivatisation.

analysis consistently gave lower chloride loadings (typical example: Found: Cl, 9.50%. Calculated: 15.7%) than would be expected based on the VBC content in the monomer mixture. The monomer as supplied is around 90% VBC, however the remaining components are vinyl compounds containing chlorine (information from supplier), so their incorporation into the polymeric material should not result in such a large drop in Cl content. Since no residual monomer could be detected following polymerisation, it was suspected that hydrolysis of benzyl chloride residues was occur-

4-Hydroxymethylphenol (the so-called Wang linker) [14] is an important species for attachment to polymer supports as it facilitates solid phase synthesis then subsequent cleavage of the synthesised molecule by acid treatment. Repeated attempts were made to couple directly 4-hydroxymethylphenol to chloromethyl polystyrene PolyHIPE (1), under both batch and flow-through conditions, however loadings as determined by Fmoc number determination were variable and did not correlate with loadings determined from subsequent esterification reactions. Therefore, an alternative two-step process for the immobilisation of the Wang linker was employed [19]. This involves the initial attachment of 4-hydroxybenzaldehyde, followed by reduction to the primary alcohol (Scheme 1). In a batch reaction, PolyHIPE in granular form (1, 78 mol% VBC, 4.5 mmol –

Scheme 1. Derivatisation of VBC PolyHIPE. Reagents and conditions: (i) 4-HO–Ph–CHO, K2CO3, NaI, CH3CN, reflux, 48 h; (ii) NaBH4, NMM, THF/EtOH (2:1 v/v), r.t., 24 h; (iii) 4-I–Ph–CO2H, MSNT, NMI, DCM, 20 C, 24 h; (iv) TrisOH, DMF, 90 C, 24 h; (v) 4-I–Ph–CO2H, EDCI, HOBT, DMF, r.t., 24 h; (vi) AcCl, DCM, r.t., 2 h.

P. Krajnc et al. / Reactive & Functional Polymers 66 (2006) 81–91

CH2Cl groups g
1) was heated under reflux with 4hydroxybenzaldehyde, K2CO3 and NaI for 48 h. The resultant conversion to 2 was found to be 97% (by elemental analysis, from residual Cl content) and the loading of aldehyde was calculated to be 3.14 mmol –CHO groups g
1. FTIR analysis displayed strong signals at 1691 and 2736 cm
1 representing carbonyl and aldehyde C–H stretching, respectively, and confirmed that the intermediate had been prepared. In order to identify the best agent for carbonyl reduction, the aldehyde polymer was reduced using NaBH4 and NaCNBH4. The latter was employed previously [19], however, NaBH4 was found to be the most successful for PolyHIPE materials, resulting in powdered PolyHIPE 3 with an estimated hydroxymethyl loading of 3.14 mmol –CH2OH groups g
1 (assuming complete reduction of aldehyde groups). An FTIR spectrum of the product displayed a very broad peak at 3421 cm
1, which was attributed to the primary hydroxyl functionality. The carbonyl peak was significantly reduced, however, not completely removed from the spectrum (Fig. 3). This suggested that 100% reduction had not taken place and the actual hydroxymethyl loading was slightly less than that estimated. 4-Iodobenzoic acid is the starting material for a number of synthetic routes particularly Suzuki cross-coupling reactions [20], therefore immobili-

87

sation of the acid onto PolyHIPE would enable solid phase coupling with this support type. This approach has already been demonstrated several times and the advantages outlined [21]. As a first step in this direction, Wang-functionalised PolyHIPE 3 was esterified with p-iodobenzoic acid using carbodiimide coupling chemistry (1-ethyl-3-(3dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and N-hydroxybenzotriazole (HOBT)) [22]. However, after exhaustive washing of the support no iodine was found to be present by elemental analysis. Attention was then switched to 1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole (MSNT) and N-methylimidazole (NMI) as coupling agents, as these have been shown to give improved performance compared to carbodiimides and are particularly useful for substituted amino acids, aromatic and hindered carboxylic acids [23]. MSNT/NMI coupling of 4-iodobenzoic acid to Wang PolyHIPE resulted in a conversion to 4 of 53% (from iodine loading by elemental analysis). The reaction was then optimised by varying first the concentration of MSNT/NMI reagents. In parallel reactions, the PolyHIPE possessing the Wang linker (approx. 3 mmol –CH2OH groups g
1) was stirred at room temperature with 3, 5 and 10 equiv. of MSNT/NMI reagent. The greatest conversion, 69%, was achieved with 3 equiv. (Table 1). The optimum concentration of reagents

Fig. 3. FTIR spectra of aldehyde-(2) and Wang-functionalised PolyHIPEs.

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Table 1 Optimisation of coupling of 4-iodobenzoic acid to WangPolyHIPE using parallel reactionsa MSNT concentration (equiv.)

Temperature (C)

Reaction time (h)

Conversion (%)

2 3 5 10 3 3 3 3 3 3 3

20 20 20 20 20 30 40 20 20 20 20

2 2 2 2 2 2 2 2 4 6 24

53 69 68 68 69 58 73 62 68 64 73

a

Wang loading = 3 mmol g
1, reaction solvent = DCM.

(3 equiv.) was then applied in a temperature study, employing 20 C (room temperature), 30 C and reflux (40 C) conditions. On this occasion, the greatest conversion was achieved when the reaction was performed under reflux (73%), however, this was not considered to be a substantial improvement on the conversion obtained at room temperature (69%) (Table 1). In the final experiment, the effect of reaction time on the conversion to iodine was investigated. MSNT reagent (3 equiv.) was reacted at 20 C with Wang-functionalised PolyHIPE, for 4, 6 and 24 h. The greatest conversion to iodine was obtained after 24 h (Table 1). From these studies, the optimum conditions for the MSNT/NMI coupling of 4-iodobenzoic acid to Wang-functionalised PolyHIPE were found to be 3 equiv. of MSNT reagent, a reaction temperature of 20 C and a duration of 24 h. As mentioned above, Fmoc analysis of Wangfunctionalised PolyHIPE consistently gave poor results, suggesting that the procedure is unsuitable for these materials. The process involves coupling of Fmoc-glycine using PyBOP, which may be incompatible with PolyHIPE. Therefore, the MSNT/NMI route was employed in the attachment of Fmoc-glycine to the Wang-functionalised materials. An Fmoc procedure involving these reagents has been applied successfully to Wang polymer beads [24]. In parallel batch reactions, Fmoc analysis was performed on Wang PolyHIPE (3 mmol –CH2OH groups g
1) and commercial Wang beads (2.7 mmol –CH2OH groups g
1)

O O

N H

O

Polymer support

O

O

Fig. 4. Structure of supports following attachment of Fmocglycine.

using the Fmoc-gly coupling conditions reported in the literature [24] (2 h, 20 C, 3 equiv. MSNT, 2.25 equiv. NMI). The average Fmoc loading of the beads was found to be 1.90 ± 0.15 mmol – CH2OH groups g
1. Unfortunately, the PolyHIPE materials were found to have an average Fmoc loading of only 0.66 ± 0.03 mmol –CH2OH groups g
1, which was substantially lower than the loading estimated from elemental analysis. In a similar batch reaction, the Fmoc coupling was repeated using the optimised MSNT/NMI conditions developed for PolyHIPE (24 h, 20 C, 3 equiv. MSNT, 12 equiv. NMI). However, as in the previous case, the PolyHIPE supports were found to have an average Fmoc loading of 0.65 ± 0.01 mmol –CH2OH groups g
1. Since the Fmoc procedure is performed in two stages, either the coupling of Fmoc-glycine or the cleavage to form the piperidine adduct is unsuccessful. The nitrogen contents of the Fmoc-coupled PolyHIPE and beads (Fig. 4) were determined by elemental analysis. The beads were found to have a nitrogen content of 1.95%, which corresponded to a conversion of 90%. On the contrary, the PolyHIPE material had a nitrogen content of 0.74%, which corresponded to a conversion of 32%. The nitrogen analysis proved that the coupling of Fmoc-glycine to PolyHIPE had failed to take place in high yield. 3.3. Tris(hydroxymethyl)aminomethane immobilization In order to obtain a polymer support with a high loading of hydroxy groups, we decided to try to immobilise, through nucleophilic substitution on the chloromethyl carbon, an amine with pendant hydroxy groups. Chloromethylated poly-

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styrene is still the most frequently used polymer support and both gel and porous type beads of this polymer are commercially available. To react tris(hydroxymethyl)aminomethane (TrisOH) with chloromethylated polystyrene seemed a good choice since the substitution of a chlorine atom yields an amine derivative with three free hydroxy groups. Theoretically, starting with a polymer with the loading of chloromethyl groups of 3 mmol g
1, a product with 7.2 mmol of hydroxy groups per gram (taking into account the increase in mass) could be obtained. We wished to test whether the type of initial polymer support (morphological structure) influences the success of immobilisation. We therefore prepared two different chloromethylated polystyrene PolyHIPE supports, with 25% crosslinking degree (divinylbenzene as a crosslinking agent) (1b) and 40% crosslinking degree (1c), both with 90% nominal pore volume. For the reactions one portion was employed in monolithic form and another part was powdered to see if the support morphology has an effect on the extent of functionalisation. To compare highly porous PolyHIPE supports to commercially available supports of the same chemistry but different morphology and form, we also performed identical transformations on two different types of bead, one of gel-type and one permanently porous. To all supports, the same excess of the amine in DMF was added and identical reaction conditions were applied. All supports performed well; reactions proceeded with high conversions, from 78% for porous beads to 92% for 25% crosslinked PolyHIPE (Table 2). In fact, both powdered and

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monolithic forms of 25% crosslinked PolyHIPE gave the best conversions to the amine derivative. TrisOH modified PolyHIPE (5) was subsequently loaded with 4-iodobenzoic acid. Unlike the Wang-functionalised PolyHIPEs, TrisOH supports were modified efficiently using standard EDCI/HOBT coupling chemistry. A conversion to 6 of 82% was achieved as determined by iodine analysis. 3.4. Scavenging of acetyl chloride with tris(hydroxymethyl)aminomethane-modified PolyHIPE Polymer supports with pendant hydroxy groups can also be utilised as scavengers of excess substrates from solution. A fast reaction of free hydroxy groups with the substrate in solution is required as is good accessibility of the reactive groups. We were intrigued as to whether all the hydroxy groups would be available for the scavenging reaction, the ‘‘concentration’’ of them being quite high. We expected the porosity of the support to play a major role in the scavenging process and therefore tested the influence of the nominal pore volume of the starting PolyHIPE. In a typical experiment, the polymer was reacted with the solution containing excess acetyl chloride, filtered, washed and the amount of remaining acid chloride determined by UV spectroscopy. A series of PolyHIPEs with nominal porosities ranging from 90% (4d) to 50% (4f), all having crosslinking degree of 25% of DVB, was prepared. Tris(hydroxymethyl)aminomethane was then immobilised on

Table 2 Modification of VBC-containing polymers with Tris-OH and subsequent coupling of 4-iodobenzoic acid Support typea

[Cl] (mmol g
1)b

Conversion to 5 (%)b

% Nb

Conversion to 6 (%)b

p-PHP 75/25 (1b) m-PHP 75/25 (1b) p-PHP 60/40 (1c) m-PHP 60/40 (1c) Gel beadsc Porous beadsd

3.95 3.95 3.47 3.47 2.10 3.07

96 96 82 81 83 78

3.92 3.95 3.07 3.05 2.08 2.68

82 – – – – –

a b c d

p denotes powder, m denotes monolith, x/y gives the VBC/DVB ratio; all PolyHIPEs were 90% nominal porosity. Determined by elemental analysis. 1% DVB, purchased from Argonaut Technologies. Permanently porous, from Polymer Laboratories.

90

P. Krajnc et al. / Reactive & Functional Polymers 66 (2006) 81–91

69 60

%T

4000

%T

3200

2400

1200

1800

600

4000

3200

2400

1800

cm-1

1200

600

cm-1

1d

5d

50

%T

7d

4000

3200

2400

1800

1200

600

cm-1

Fig. 5. FTIR spectra of VBC PolyHIPE (1d), TrisOH-modified PolyHIPE (5d) and TrisOH PolyHIPE after scavenging of acetyl chloride (7d).

these as described above. Polymers were powdered and suspended in dry dichloromethane. Approximately 8.1 mmol g
1 –OH groups were estimated to be bound to the support from the nitrogen elemental analysis (3.79%, which corresponds to 2.7 mmol g
1 amine) and all of it was assumed to be from the tris(hydroxymethyl)aminomethane. To test the total capacity of the supports, samples were allowed to react with an excess of acetyl chloride. After thorough washing, the amount of the remaining acid chloride was determined by measuring the absorption at 269 nm. Polymer 5d (90% pore volume) exhibited the highest accessibility of hydroxyl groups, as 5.5 mmol of acetyl chloride per gram of polymer was scavenged, while polymer 5f (50% pore volume) scavenged 3.0 mmol of the acid chloride per gram. Tris(hydroxymethyl)aminomethane derivative 5e (75% pore volume) sequestered 5.0 mmol of the acid chloride per gram of polymer. The resulting polymers 7d–f (with esterified hydroxyl groups)

all show ester carbonyl group peaks in their FTIR spectra confirming scavenging of the acid chloride (Fig. 5). Since the results of the scavenging experiments correlate with the nominal pore volume of the supports, it is our opinion that the more porous structure of the supports also means more accessible hydroxyl groups.

4. Conclusions We have shown that PolyHIPE supports with various loadings of –OH groups can be prepared. Materials possessing the Wang linker, used frequently in solid phase synthesis, were prepared by a two-step procedure by attachment of 4hydroxybenzaldehyde and subsequent reduction. The resulting materials were esterified efficiently with 4-iodobenzoic acid, a component of Suzuki cross coupling reactions. Subsequently, it was shown that tris(hydroxymethyl)aminomethane

P. Krajnc et al. / Reactive & Functional Polymers 66 (2006) 81–91

functionalised PolyHIPE can serve as a linker for attachment via esterification. Various forms of VBC PolyHIPE were used and successful functionalisation was performed on all of them. The majority of the free hydroxyl groups was accessible for immobilisation of 4-iodobenzoic acid, while the utilization of tris(hydroxymethyl)aminomethane derivatives as scavengers of an acid chloride revealed a dependence of accessibility on the porosity of the polymer. It was also shown that Fmoc number analysis is not an appropriate method to determine –OH loadings of these supports.

Acknowledgements The authors thank the European Union for a Marie Curie Individual Fellowship (to P.K.) and the Engineering and Physical Sciences Research Council for a PhD studentship (to JFB). The Ministry of Education, Science and Sport of the Republic of Slovenia and the British Council in Slovenia are also gratefully acknowledged (Partnerships in Science programmes 11/2003 and 12/ 2004).

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