University of Groningen Synthesis and Properties of Starch Based

University of Groningen

Synthesis and properties of starch based biomaterials Sugih, Asaf Kleopas

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record

Publication date: 2008

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA): Sugih, A. K. (2008). Synthesis and properties of starch based biomaterials. s.n.

Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.

Download date: 26-09-2021

Chapter 2 Experimental Studies on the Ring Opening Polymerization of p‐dioxanone using an Al(OiPr)3‐Monosaccharide Initiator System

Abstract The ring opening polymerization (ROP) of p‐dioxanone using a protected i monosaccharide (1,2;3,4‐di‐O‐isopropylidene‐α‐D‐galactopyranose)/Al(O Pr)3 initiator system to yield polydioxanone with a protected monosaccharide end‐ group is described. The products were synthesized at 60‐100°C and characterized by 1H‐ and 13C‐NMR, and MALDI‐TOF mass spectrometry. Besides the desired polydioxanone functionalised with a monosaccharide end‐group, also polydioxanone with an OiPr end‐group was formed (20‐30 %). Systematic studies showed that the polymer yield is a function of the reaction temperature and the reaction time, with higher temperatures (100°C) leading to lower yields. The average chain length of the polymers is between 7 and 58 repeating units and may be tuned by the monomer to monosaccharide ratio (at constant Al(OiPr)3 intake). A statistical model has been developed that successfully describes the experimentally observed relation between the average chain length of the functionalized polymer and reaction parameters.

Keywords: biodegradable, polyesters, ring‐opening polymerization

Chapter 2

2.1. Introduction Aliphatic polyesters, such as polycaprolactone, polyglycolide, and polylactides, are interesting polymers because of their good product performance and biodegradability [1]. Polydioxanone (poly(p‐dioxanone) or poly(1,4‐dioxan‐2‐ one)), accessible by the polymerization of p‐dioxanone (1), has interesting product properties compared to other aliphatic polyesters. Its melting temperature is close to 110 oC, which is a unique compromise between application and processing temperature. This melting point is considerably higher than typically found for polycaprolactone (60 oC) and lower than that of polylactides (at least 175°C). The relatively low melting point of polycaprolactone limits its applicability, whereas the high temperature for polylactides results in thermal degradation and undesirable transfer reactions during synthesis and processing steps [2]. Polydioxanone has a tensile strength close to 48.3 MPa and an elongation at break of 500‐600%, and is tougher than polylactides and even HDPE [3]. From a biodegradability point of view, polydioxanone also shows good performance. It is fully degraded in the body within a period of 180 days [4]. Nishida et al [5] reported that polydioxanone decomposes to non‐toxic gases (CO2 and H2O) by microorganisms. Despite its good properties, only limited information about the synthesis and properties of polydioxanone is available in the open literature, probably because the p‐dioxanone monomer has become commercially available only recently [1]. Biodegradable aliphatic polyesters end‐capped with sugar molecules have been studied extensively for use in biomedical applications, particularly for nano‐ encapsulation systems for drug delivery [6]. The synthesis of protected monosaccharide end‐capped biodegradable polymers is usually performed via Ring Opening Polymerization (ROP). The catalysts are metal alkoxides with Lewis acidic character [8, 9]. The ring‐opening polymerization (ROP) of p‐dioxanone i using metal catalysts such as aluminum isopropoxide [Al(O Pr)3], stannous octoate [Sn(Oct)2], or zinc lactate has been reported. The alkoxide group will end up as an ester end‐group in the polymer and in this way at least one of the end‐groups may be easily controlled and varied. Exchange of the alkoxide group by e.g. reaction of the metal‐alkoxide with an appropriate alcohol allows the synthesis of end‐capped poly‐lactones. Several polymers with bioactive alcoholic and phenolic end‐groups of interest for drug‐related applications were synthesized (for example geraniol, quinine, tocopherol, testosterone, pregnenolone, stigmasterol and ergocalciferol) [10] and also with protected monosaccharides (galactopyranose/ glucofuranose) [6‐7]. This chapter describes experimental studies on the catalytic ROP of p‐ dioxanone in the presence of a protected glucose molecule (1,2;3,4‐di‐O‐ isopropylidene‐α‐D‐galactopyranose, 2), which to the best of our knowledge is the first study to functionalise polydioxanone with a monosaccharide. Besides

Ring Opening Polymerization of p‐dioxanone using an Al(OiPr)3‐Monosaccharide Initiator System potential applications in biomedical products, the results of this study are also of interest for the preparation of starch/polydioxanone polymers using ROP. Particularly interesting in this field are starch polymers grafted with polydioxanone. However, grafting efficiencies are difficult to determine in this system by standard analytical techniques (e.g. NMR) due to the poor solubility of the products in standard organic solvents. As such, the synthetic pathways and the soluble, relatively low molecular weight compounds reported in this study may be viewed as model systems for more complex, poorly soluble heterogeneous systems.

2.2. Materials and Methods 2.2.1. Materials p‐Dioxanone monomer (1, Boehringer Ingelheim, Germany) was purified according to the procedure described by Raquez et al [2, 3]. Toluene (Labscan) was dried and stored on molecular sieves 3 Å (Labscan) under nitrogen. 1,2;3,4‐di‐O‐ isopropylidene‐α‐D‐galactopyranose (2), 97% (Sigma) and aluminum isopropoxide, 98+% (Aldrich) were used as received. Analytical grade dichloroethane (Labscan), heptane (Acros), and diethylether (Labscan) were used as received. CDCl3 was obtained from Sigma and was used as received.

2.2.2. Methods All polymerization experiments were carried out under a protective nitrogen atmosphere using standard Schlenk‐ and glovebox techniques.

2.2.2.1. Typical example for the synthesis of polydioxanone end‐capped with 1,2;3,4‐di‐O‐ isopropylidene‐α‐D‐galactopyranose (2) 2 (1.44 g, 5.5 mmol) was dissolved in toluene (1 ml) at 50 oC. To this solution, 0.8 ml of a solution of an aluminum isopropoxide stock solution was added. This stock solution was prepared by adding 4.07 g, (20 mmol) of aluminum isopropoxide to 20 ml of toluene. The resulting clear solution was stirred for 2 h at 50 oC. Subsequently, part of this solution (350 µl, containing 0.55 mmol of 2 and 0.08 mmol aluminum isopropoxide) was added to pure 1 (0.8 g, 8 mmol), which was pre‐heated till about 60°C to obtain it in a liquid state. The polymerization was allowed to proceed for 16 h at 100 oC. The reaction mixture was clear and colorless during the reaction. After the pre‐determined reaction time, the mixture was brought to room temperature and several drops of HCl (1 N) were added to stop the reaction. Next, hot dichloroethane (20‐25 ml) was added to completely dissolve the partly solid polymer at room temperature. The hot solution was

Chapter 2 precipitated in a heptane/ ether mixture (300‐400 ml, 4:1 by volume) at 4‐8 oC. The white solid was finally separated from the liquid by decantation and dried in a vacuum oven (5 mbar, 40 oC) until constant weight. The isolated yield at this condition was 68%.

2.2.3. Product Analyses

1 13 NMR analyses were performed in CDCl3. H‐ and C‐NMR spectra were recorded on a Varian AMX 400 NMR. 2D‐NMR spectra were recorded on a Varian Unity 500 NMR. Processing of the raw data was performed using VNMR software. MALDI‐TOF spectra were recorded on an Applied Biosystems Voyager DE‐PRO machine using dithranol/ NaI as the matrix (linear mode).

2.2.4. Calculation of Average Degree of Polymerization

theo The Theoretical Average Degree of Polymerization, X n in terms of number of monomer units is calculated as follows [6]:

theo [monomer]0 X n = monomer conversion × [total initiator] (2.1.) [monomer]0 = monomer conversion× i 3[Al(O Pr)3 ] + [sugar]0

Here, it is assumed that all available initiator is used effectively. If the amount of sugar is in excess with respect to the aluminum catalyst, the above equation simplifies to

theo [monomer]0 X n = monomer conversion× (2.2.) [sugar]0

1H‐NMR was applied to determine the experimental average degree of exp polymerization, X n of the product.

exp X n is calculated by comparing the peak area of characteristic end‐group protons with that of a proton of the repeating unit in the polymer (A H‐polymer). As will be shown later, two polymers with different end‐groups are present, one initiated on a galactopyranose molecule and the other on an isopropoxide group. This leads to the following equation:

exp A H-repeating unit X n = (2.3.) A H-galactopyranose end group + A H-isopropoxide end group

Ring Opening Polymerization of p‐dioxanone using an Al(OiPr)3‐Monosaccharide Initiator System

The NMR peaks of the repeating unit overlap partially with those of the galactopyranose end group. To compensate for this effect, eq. 2.3. is rewritten as:

exp [A 3.4−4.7 ppm − 6× A 5.6 ppm ]/ 6 X n = (2.4.) A 5.6 ppm + A 5.1ppm

The ratio of the two different types of polymers (either end‐capped with galactopyranose or an isopropoxide group), Rgp , is calculated using:

A H −galactopyranose end group Rgp = (2.5.) A H −isopropoxide end group or, in term of the NMR resonances :

A 5.6 ppm Rgp = (2.6.) A 5.1ppm

2.3. Results and Discussions 2.3.1. Screening Experiments Initial experiments to synthesize protected galactopyranose end‐capped polydioxanone (3) were performed using 1,2;3,4‐di‐O‐isopropylidene‐α‐D‐ i galactopyranose (2) and Al(O Pr)3 as the catalyst precursor (Scheme 2.1.). Typically, an Al ‐ monosaccharide 2 ‐ monomer 1 mol ratio of 1: 6.6: 96 was applied. The polymerization reaction was performed as a two step process. In the i first step, the protected mono‐saccharide 2 reacts with Al(O Pr)3 to form the actual catalyst for the polymerization reaction. The exchange reaction typically takes place at 50°C for 2 h. To avoid the formation of isopropoxide end groups, an excess of monosaccharide 2 on Al was used (see eq. 2.7.).

O O αβγ α' β' γ' CH2OH O H2C O [ C CH2 O CH2 CH O ] C CH2 O CH2 CH2 OH 6 6 2 n O O O 5 H O 5 H H O Al(OiPr) H 4 α 3 4 1 O H 1 O H H O + n+1 H O O catalyst 3 2 γ 3 2 H O H O β

(2) (1) (3)

Scheme 2.1. Schematic representation of the polymerization reaction including atom numbering scheme

Chapter 2

H O H O O H H O H CH2OH O iPr O O O H H2C O H Al O iPr + 3 + 3OHiPr O H Al O CH2 H O iPr O O H2C O H O O H H O O H O H H H O O H H O H O H O (2.7.)

In the next step, the in‐situ formed catalyst was reacted with p‐dioxanone monomer 1 at 100 oC for 16 h. The off‐white solid reaction product was collected after a dissolution‐reprecipitation process using dichloroethane and a heptane/ diethyl ether mixture. Typical isolated product yields are 68% at these conditions.

2.3.1.1. Product analyses The products were analyzed using 1H‐ and 13C‐ NMR and MALDI‐TOF. Typical 1H‐ and 13C‐NMR spectra of 3 are shown in Figure 2.1 and 2.2., respectively. 1H‐NMR spectra (Figure 2.1.) are not particularly informative, although it is evident that p‐dioxanone polymerisation occurred. The typical proton resonances of the p‐dioxanone (3.78 to 4.40 ppm) unit are broadened and shifted up to 0.1 ppm compared to the monomer. It is difficult to determine the end‐groups of the polymer on the basis of 1H‐NMR. Although the spectra clearly indicate the presence of the monosaccharide 2, it is not possible to determine whether this is truly an end‐group due to overlapping peaks with protons from the poly(p‐ dioxanone) backbone. However, of interest is the presence of a small multiplet at about 5.1 ppm. This multiplet is characteristic for the CH proton of an isopropoxide end‐group. It confirms that polymer initiation not only occurs with the monosaccharide but also with the remaining isopropoxide group of the catalyst precursor (vide infra). Proton resonances of the CH3 group of the isopropoxide end‐group, together with the CH3 groups from the protecting groups of the sugar appear in the range 1.15‐1.51 ppm. The OiPr : 2 end‐group ratio for the standard experiment was 1: 2.67.

Ring Opening Polymerization of p‐dioxanone using an Al(OiPr)3‐Monosaccharide Initiator System

Figure 2.1. 1H‐NMR Spectra of: (a). 1,2;3,4‐di‐O‐isopropylidene‐α‐D‐galactopyranose, 2 (b). p‐dioxanone monomer, 1 (c). 1,2;3,4‐di‐O‐isopropylidene‐α‐D‐galactopyranose‐end‐capped polydioxanone, 3

13C‐NMR (Figure 2.2.) is more informative and clearly shows the presence of a polydioxanone polymer backbone and a monosaccharide end group. The carbon resonances of the polydioxanone backbone are present at δ = 63.8, 68.17 and 69.2 ppm. Carbon resonances arising from the monosaccharide end‐group are present between δ = 66.2 and 96.2 ppm. Particularly the C2‐C6 carbons in the range δ = 66.2‐70.3 ppm are shifted considerably. For instance, C‐6 is shifted from δ = 62.28 ppm in 2 to δ 66.2 ppm in product 3. In addition to the mono‐saccharide end‐ group, characteristic resonances of an ‐O‐C(=O)‐CH2‐O‐CH2‐CH2‐OH end group are present at δ = 61.61 (γ’) and 73.52 ppm (β’).

Chapter 2

Figure 2.2. 13C‐ NMR Spectra of: (a). 1,2;3,4‐di‐O‐isopropylidene‐α‐D‐galactopyranose, 2 (b). p‐dioxanone monomer, 1 (c). 1,2;3,4‐di‐O‐isopropylidene‐α‐D‐galactopyranose‐end‐capped polydioxanone, 3

Carbon resonances of the isopropoxide groups from the by‐product (isopropoxide end‐capped polydioxanone) are present at δ = 68.48 ppm (‐CH‐ (CH3)2) and between δ = 21.76‐25.97 ppm (‐CH‐(CH3)2). The resonances of the protecting group of the sugar appears at δ = 108.73 and 109.70 (>C‐(CH3)2) and between δ = 21.76‐25.97 (>C‐(CH3)2). 2D‐NMR (HSQC) was applied for complete peak assignment of the product. A typical example of a part of the 2D‐NMR spectra is given in Figure 2.3. An overview of the data is given in Tables 2.1. and 2.2., the numbering scheme of carbons and protons is given in Scheme 2.1.

Ring Opening Polymerization of p‐dioxanone using an Al(OiPr)3‐Monosaccharide Initiator System

Figure 2.3. HSQC 13C‐1H spectra of 3

Table 2.1. 1H‐NMR peak assignments a

Reactant peaks (ppm) Product peaks (ppm)

Galactopyranose p‐dioxanone Poly(p‐dioxanone) end‐capped Monomer with protected galactopyranose (2) (1) (3) H‐1 5.54 H‐1 5.50 H‐2 4.31 H‐2 4.32 * H‐3 4.59 H‐3 4.60

H‐4 4.25 H‐4 4.09 H‐5 3.74 H‐5 4.16* H‐6 3.83 H‐6 4.00 H‐α 4.26 H‐α 4.17 H‐β 3.77 H‐β 3.78 H‐β’ 3.68

H‐γ 4.301 H‐γ 4.40 H‐γ’ 3.732 H‐OH broad, around 1.8 a all values were determined using 1H NMR, except values with *, which were determined from HSQC spectrum due to overlapping resonances.

Chapter 2

Table 2.2. 13C‐NMR peak assignments

Reactant Peaks (ppm) Product Peaks (ppm)

Galactopyranose p‐dioxanone Poly(p‐dioxanone) end‐capped monomer with protected galactopyranose (2) (1) (3) C‐1 96.28 C‐1 96.21 C‐2 70.75 C‐2 70.31 C‐3 70.58 C‐3 70.63

C‐4 68.10 C‐4 68.33 C‐5 71.57 C‐5 70.92 C‐6 62.28 C‐6 66.2 C‐α 61.92 C‐α 68.17 C‐β 69.2 C‐β 68.09 C‐β’ 73.52 C‐γ 63.80 C‐γ 65.54 C‐γ’ 61.61 C‐carbonyl 170.00 C‐carbonyl 166.21 C‐carbonyl‐iPr/gal 171.11/ 170.07

NMR analyses also allow calculation of the molecular weight of the products. For this purpose, the ratio of the intensity of the end groups and the polymer backbone peaks is determined. A detailed procedure is given in the experimental section. The product obtained at screening conditions (16 h reaction time at 100°C) contains on average 13 monomer units, corresponding with an average number molecular weight (Mn) of about 1600. MALDI‐TOF was also applied to characterize the products. An example of a MALDI‐TOF spectrum of 3 recorded in a dithranol/NaI matrix is given in Figure 2.4. A typical molecular weight distribution is observed. The difference in molecular weight between the main peaks is 102 g/mol, which is the molecular weight of a repeating dioxanone unit. The molecular weight distribution of the major peaks may be represented by the following relation: m / z = 23+ 260 +102n (2.8.)

This series represents a dioxanone polymer end capped with 2 and an additional Na ion. The latter likely stems from the matrix used to ionize the sample.

Ring Opening Polymerization of p‐dioxanone using an Al(OiPr)3‐Monosaccharide Initiator System

100 1098.5

90 +102

40 %-Intensity

0 600 800 1000 1200 1400 1600 1800 2000 2200 2400 Mass (m/z)

Figure 2.4. Typical MALDI‐TOF spectra of 3

A second molecular weight distribution is also clearly visible when enlarging the spectra, see Figure 2.5. for details. This series may be described by the following relation: m / z = 23+ 60 +102n (2.9.)

This relation is indicative for the presence of a polydioxanone polymer containing an isopropoxide end‐group, in line with the NMR data. Furthermore, two other distributions are present, although both with a very low intensity (Figure 2.5.). These distributions may be represented by equation (2.10.) and (2.11.) and imply the presence of dioxanone polymers with carboxylic end groups, ionized with either Na+ or H+. m / z = 23+18 +102n (2.10.) m / z = 1+18 +102n (2.11.)

Chapter 2

792.7 40

796.7

30 %-Intensity 20

858.3

10 836.1

0 600 700 800 900 1000 1100 1200 Mass (m/z)

Figure 2.5. Enlarged MALDI‐TOF spectra for 3

Although MALDI‐TOF clearly demonstrated the presence of various types of end‐groups in the product, it proved not suitable to determine the average molecular weight of the products. Various samples with, according to NMR, different molecular weights were analysed. The observed differences in the molecular weight distributions of the various samples were only marginal. Most likely the matrix (dithranol/NaI), although successfully applied for galactopyranose‐end‐capped polycaprolactone [6], is not particularly suitable for polydioxanone. Various other matrices were tested (e.g. 2‐(4′‐ hydroxybenzeneazo)benzoic acid (HABA)), but in all cases poor quality, low resolution spectra were obtained.

2.3.1.2. Mechanistic aspects Both NMR and MALDI‐TOF measurements imply that the main product is indeed the desired monosaccharide end‐capped polydioxanone. In addition, small but significant amounts (20‐30%‐mol) of polydioxanone chains with an OiPr end group are present. A mechanistic proposal for the ROP of p‐dioxanone with i Al(O Pr)3 as the catalyst precursor leading to the desired monosaccharide end‐ capped polydioxanone is given in Figure 2.6. [6,13]. In the first step, the catalyst precursor is treated with monosaccharide 2 resulting in an alcohol exchange

Ring Opening Polymerization of p‐dioxanone using an Al(OiPr)3‐Monosaccharide Initiator System reaction and the formation of the desired active catalyst with preferentially all three OiPr exchanged with 2. Next, a p‐dioxanone molecule will coordinate to the Lewis acidic aluminium center followed by an insertion step. Subsequent coordination and insertion of dioxanone molecules leads to the formation of a polymer chain with a monosaccharide end‐group. During the reaction, termination of the chain growth may occur by reaction with an alcohol. The resulting Al‐alkoxide may again initiate a polymerisation reaction. The termination reaction is known to be reversible and the formed polymer may again react with an aluminum center and continue to grow [18]. Irreversible termination of the polymerisation is performed at the end of reaction period by adding dilute acid to the polymerisation mixture. The termination reactions lead to the formation of ‐O‐C(=O)‐CH2‐O‐CH2‐CH2‐OH end groups.

iPr O Al O iPr + ROH(in excess) iPr O

O O Al O R + iPr OH Al O iPr O O

+ + O O

O n O l O O

O O Al [O CH2 CH2 O CH2 C ] OR n O O

O + m O O R-OH O Al [O CH2 CH2 O CH2 C] OR n+m O + HX (termination)

O O Al O R Al X O O + + O O O H [O CH CH O CH2 C ] OR H [O CH CH O CH C ] OR ] O iPr 2 2 n 2 2 2 n+m H [O CH2CH2 O CH2 C l

product by-product

Figure 2.6. Simplified reaction scheme for the ROP of p‐dioxanone catalyzed by i Al(O Pr)3. (R = monosaccharide 2)

Chapter 2

The minor product, OiPr‐end‐capped poly(p‐dioxanone), will be formed when the polymerization starts with an aluminum alkoxide with a remaining Al‐OiPr group (eq. 2.7.). These may be present in the reaction mixture because the i exchange reaction between Al(O Pr)3 and 2 was incomplete, despite the excess of 2. However, the end group may also be formed by a termination reaction with free isopropanol, formed in the first step of the polymerisation reaction (eq. 2.7.).

2.3.2. Systematic Studies The effect of important process variables (temperature, time and the mol ratio of monomer to monosaccharide) on the yield, degree of polymerisation of the product and the end group distribution was determined. A total of 15 experiments were performed at two polymerization temperatures (60 and 100 oC), two different reaction times (1.5 hrs and 16 hrs) and a p‐dioxanone to monosaccharide 2 molar ratio ranging between 3.3 and 62.5. An overview of the experiments and the i results are given in Table 2.3. In all cases, a (nearly) fixed Al(O Pr)3 : monosaccharide ratio of 1 : 6.3‐6.6 was applied.

Table 2.3. Overview of experiments a

Processing Condition Product Properties

Set dioxanone/ Avg. Chain 2/OiPr ratio 2/Al ratio t T Yieldb Sample 2 ratio Length Rgp (mol/mol) (h) (°C) exp (%) (mol/mol) ( X n ) (mol/mol) S111 6.6 16 100 3.29 7.22 30.5 2.8 S112 6.6 16 100 14.45 13.10 67.6 2.7 1 S113 6.6 16 100 19.93 15.28 81.6 2.4 S114 6.6 16 100 37.53 33.21 80.5 3.1 S115 6.6 16 100 59.78 54.49 81.3 3.1 S211 6.3 16 60 10.22 13.74 81.6 2.5 S212 6.3 16 60 16.74 18.50 86.0 2.4 2 S213 6.3 16 60 23.12 25.16 87.6 2.6 S214 6.3 16 60 42.70 46.74 91.6 2.4 S215 6.3 16 60 58.93 52.85 96.2 2.8 S221 6.3 1.5 60 8.81 14.36 91.5 3.3 S222 6.6 1.5 60 16.11 17.04 92.5 3.1 3 S223 6.6 1.5 60 22.50 19.08 84.1 2.8 S224 6.6 1.5 60 35.30 30.22 86.6 2.9 S225 6.6 1.5 60 62.55 57.96 89.4 2.9 a For each experiment, the exchange reaction between the catalyst and the protected sugar was performed for 2 hours at 50°C b The yield is the isolated yield of product 3

Ring Opening Polymerization of p‐dioxanone using an Al(OiPr)3‐Monosaccharide Initiator System

2.3.2.1. Product yield The isolated yields of the reactions are all but one between 67 and 96% (see Table 2.3.). One of the experiments (S111) resulted in a very low yield (31%) compared to the other reaction. For this particular experiment, a low dioxanone: monosaccharide 2 ratio was applied, leading to a low average chain length of the dioxanone polymer (7.2, see Table 2.3.). It is likely that this relatively low molecular weight compound dissolves partly during isolation/ purification procedure leading to lower isolated yields. The effect of the reaction temperature (60 and 100°C) on the product yield at three different dioxanone: 2 ratios is given in Table 2.3. Clearly, the yields for reactions conducted at 60 oC are always higher than those performed at 100 oC. The effect of temperature on the yield of the bulk polymerization of dioxanone i using Sn(Oct)2 and Al(O Pr)3 as catalysts (without the use of a second alcohol) has been studied by Nishida et al [5] and Esteves, et al [11]. Higher polymerisation yields were obtained at lower temperatures. For instance, the equilibrium conversion of dioxanone at 80oC was about 80%, which reduced to 75% when increasing the temperature to 120oC. These results were explained by assuming that the reaction is an equilibrium polymerisation and that the equilibrium is shifted to the monomer side at higher temperatures. The latter is due to the slight exothermicity of the reaction [14], with an enthalpy of polymerization of approximately ‐15 kJ/ mol [5]. Another possibility is the occurrence of polymer crystallization, which is expected to be more pronounced at lower temperatures. On the basis of our experimental data and in line with literature data, we conclude that equilibrium conversion is achieved after 16 h and that the lower polymer yields at higher temperatures are due to the slight exothermicity of the reaction. The effect of the reaction time on the product yield may be derived from the data provided in Table 2.3. and particularly when comparing the data in set 2 and 3 (60oC, 1.5 and 16 h reaction time). For the two experiments with a dioxanone: 2 ratio higher than 16 (≅ 23 and 60), the yields are higher when performing the reaction at 16 h reaction times. Evidently, equilibrium conversion is not yet achieved within 1.5 h. However, when the reaction is performed at a low dioxanone: 2 ratio (≅ 16), the yield at 1.5 h is higher than the yield at 16 h. Similar observations were made by Raquez et al [3] and Kricheldorf et al [1] for dioxanone i polymerisations using Al(O Pr)3 in the absence of a external alcohol or using benzyl alcohol. It was shown that at lower monomer to catalyst ratios, the monomer conversion reaches a maximum value before going down to the equilibrium monomer conversion. To the best of our knowledge, no detailed explanation has been put forward to explain this anomalous behaviour. A more detailed analysis on the actual nature and composition of the polymerization products, as suggested by Raquez et al [3], will be required.

Chapter 2

exp 2.3.2.2. Effects of process conditions on the average chain length ( X n ) and end group distribution The effects of the p‐dioxanone: 2 ratio, reaction time and temperature on the exp exp X n of the products is shown in Figure 2.7. The X n increases linearly with respect to the dioxanone : 2 ratio, as expected for a typical ring opening theo polymerisation [18]. In Figure 2.7., the X n (eq. 2.2.) as a function of the dioxanone : 2 ratio at 90% and 100% monomer conversion is also provided. Most experimental points are scattered along these lines, in line with the theoretical predictions.

60 Temperature: 100oC, time: 16 hr

Temperature: 60oC, time: 16 hr

50 Temperature: 60oC, time: 1.5 hr

X theo (90%-conversion) n

X theo (100%-conversion) 40 n exp

n 30 X

0 0 10 20 30 40 50 60 70 dioxanone : 2 ratio (mol/mol)

exp Figure 2.7. Average Chain Length ( X n ) of the product as a function of the dioxanone : 2 mol ratio

The end group distribution was determined using NMR and is expressed in terms of Rgp (eq. 2.5. and 2.6.). The Rgp values (Table 2.3.) for all experiments are scattered randomly between 2.4 and 3.3. A clear trend between Rgp and the process conditions (temperature, time, and dioxanone/ 2 mol ratio) is absent. A i possible strategy to increase the Rgp values i.e. to reduce the number of O Pr endgroups in the product may be the removal of isopropyl alcohol formed in step

Ring Opening Polymerization of p‐dioxanone using an Al(OiPr)3‐Monosaccharide Initiator System

1 of the polymerisation process (eq. 2.7.) from the reaction mixture by e.g. vacuum distillation before adding the dioxanone monomer [6].

2.3.2.3. Statistical Data Analysis Quantification of the influence of the experimental factors (temperature, time exp and dioxanone/ 2 ratio) on the X n has been performed by multivariable linear regression [12] on the data given in Table 2.3. The 2/ Al ratio was not included in the model as the experimental range (6.3‐6.6) was too limited to draw sound conclusions. A linear model proved adequate to describe the effects of the exp independent variables on the X n :

exp X n = 8.49 + 0.854× (dioxanone : 2 ratio) + 0.177 × (t) − 0.097 × (T ) (2.12.) where t and T are respectively the polymerization time and temperature. The analysis of variance for the model is given in Table 2.4. The low P‐value clearly indicates that the model is statistically significant. The R2 value for the model is 0.977 (with an adjusted R2 value of 0.974), indicating that the model describes the experimental data reasonably well. A parity plot of the modeled versus experimental values of the average chain length Xn confirms this statement (Figure 2.8.).

exp Table 2.4. Analysis of variance (ANOVA) for linear model of X n as a function of experimental parameters

SS DF MS F P‐value Model 4103 3 1337 173.543 3.459*10‐7 Error 93 12 7.703 Total 4010 15

Chapter 2

model 30

n X

0 0 10 20 30 40 50 60 X exp n

Figure 2.8. Modeled versus experimental values for the average chain length Xn

The model predicts that the X n is a clear function of the p‐dioxanone : 2 mol ratio, with high ratios leading to a higher average chain length. In addition, the exp model predicts that the X n is positively influenced by the polymerization time, which is in agreement with the available data on ring opening polymerization [15, exp 16, 17]. Furthermore, the X n is negatively influenced by temperature. This is in line with literature data [5, 11] and due to the fact that the reaction is an equilibrium polymerization with a slight exothermic effect. Within the experimental ranges, the model allows determination of the process variables to obtain a product with the desired degree of polymerization.

2.4. Conclusions The ROP of p‐dioxanone in the presence of a monosaccharide (1,2;3,4‐di‐O‐ isopropylidene‐α‐D‐galactopyranose, 2) with Al(OiPr)3 as the catalyst is reported. The isolated yields of the off‐white solid products were between 30 and 96%. Molecular weights (NMR) of the product were between 970 and 6200 and are a clear function of the p‐dioxanone/2 ratio (at constant Al(OiPr)3 intake), with higher ratios leading to higher molecular weights. Both NMR and MALDI‐TOF measurements indicate that the products are mixtures of polymers and significant

Ring Opening Polymerization of p‐dioxanone using an Al(OiPr)3‐Monosaccharide Initiator System amounts of p‐dioxanone polymers with an isopropoxide end group (20‐30%) were present. A statistical model has been developed to quantify the effects of process exp variables (time, temperature and monomer: monosaccharide ratio) on the X n . Moreover, the findings of this study have proven to be valuable input for synthetic studies on the preparation of novel biodegradable polymers consisting of polydioxanones and polycaprolactones grafted on oligo‐ and polysaccharides (e.g. starch). These studies will be reported in the next chapter.

2.5. Nomenclature

1 A H : peak area of certain proton in H‐NMR spectra [‐]

1 A x− y ppm : peak area of certain peak at x until y ppm in H‐NMR spectra [‐]

Rgp : mol ratio of galactopyranose end‐capped polydioxanone and isopropoxide‐end‐capped polydioxanone [‐] n : number of monomer unit in the polymer products [‐] t : time [hour] T : temperature [oC]

exp X n : experimental average degree of polymerization the polymer products [monomer units]

theo X n : theoretical average degree of polymerization of the polymer products [monomer units]

2.6. References [1]. H.R. Kricheldorf, D.O. Damrau: Polylactones, 42. Zn‐lactate‐catalyzed polymerizations of 1,4‐dioxan‐2‐one. Macromol. Chem. Phys. 1998, 199, 1089‐ 1097. [2]. J.M. Raquez, P. Degee, R. Narayan, P. Dubois: ʺCoordination‐insertionʺ ring‐ opening polymerization of 1,4‐dioxan‐2‐one and controlled synthesis of diblock copolymers with epsilon‐caprolactone. Macromol. Rapid Commun. 2000, 21, 1063‐1071. [3]. J.M. Raquez, P. Degee, R. Narayan, P. Dubois: Some thermodynamic, kinetic, and mechanistic aspects of the ring‐opening polymerization of 1,4‐dioxan‐2‐ one initiated by Al((OPr)‐Pr‐i)(3) in bulk. Macromolecules 2001, 34, 8419‐8425. [4]. H.L. Lin, C.C. Chu, D.J. Grubb: Hydrolytic degradation and morphologic study of poly‐p‐dioxanone. Biomed. Mater. Res. 1993, 27, 153‐166.

Chapter 2

[5]. H. Nishida, M. Yamashita, T. Endo, Y. Tokiwa: Equilibrium polymerization behavior of 1,4‐dioxan‐2‐one in bulk. Macromolecules 2000, 33, 6982‐6986. [6]. T. Hamaide, M. Pantiru, H. Fessi, P. Boullanger: Ring‐opening polymerisation of epsilon‐caprolactone with monosaccharides as transfer agents. A novel route to functionalised nanoparticles. Macromol. Rapid Commun. 2001, 22, 659‐663. [7]. K. Bernard, P. Degee, P. Dubois: Regioselective end‐functionalization of polylactide oligomers with D‐glucose and D‐galactose. Polym. Int. 2003, 52, 406‐411. [8]. H.R. Kricheldorf: Syntheses and application of polylactides. Chemosphere 2001, 43, 49‐54. [9]. H.R. Kricheldorf, M. Berl, N. Scharnagl: Poly(lactones). 9. Polymerization mechanism of metal alkoxide initiated polymerizations of lactide and various lactones. Macromolecules 1988, 21, 286‐293. [10]. H.R. Kricheldorf, I. Kreisersaunders: Polylactones. 30. Vitamins, hormones and drugs as co‐Initiators of AlEt3‐initiated polymerizations of lactide. Polymer 1994, 35, 4175‐4180. [11]. L.M. Esteves, L. Marquez, A.J. Muller: Optimization of the coordination‐ insertion ring‐opening polymerization of poly(p‐dioxanone) by programmed decrease in reaction temperatures. J. Appl. Polym. Sci. 2005, 97, 659‐665. [12]. D.C. Montgomery: Design and Analysis of Experiments, 5th Edition, John Wiley & Sons Inc., New York, USA, 2001. [13]. P. Dubois, R. Jerome, P. Teyssie: Aluminum alkoxides ‐ A family of versatile initiators for the ring‐opening polymerization of lactones and lactides. Makromol. Chem. Macromol. Symp. 1991, 42/43, 103‐116. [14]. A. Duda, A. Kowalski, J. Libiszowski, S. Penczek: Thermodynamic and kinetic polymerizability of cyclic esters. Macromol. Symp. 2005, 224, 71‐84. [15]. A. Kowalski, A. Duda, S. Penczek: Polymerization of L,L‐lactide initiated by aluminum isopropoxide trimer or tetramer. Macromolecules 1998, 31, 2114‐ 2122. [16]. A. Duda, A. Kowalski, S. Penczek, H. Uyama, S. Kobayashi: Kinetics of the ring‐opening polymerization of 6‐, 7‐, 9‐, 12‐, 13‐, 16‐, and 17‐membered lactones. Comparison of chemical and enzymatic polymerizations. Macromolecules 2002, 35, 4266‐4270. [17]. A. Duda: Polymerization of epsilon‐caprolactone initiated by aluminum isopropoxide carried out in the presence of alcohols and diols. Kinetics and mechanism. Macromolecules 1996, 29, 1399‐1406.

Ring Opening Polymerization of p‐dioxanone using an Al(OiPr)3‐Monosaccharide Initiator System

[18]. S. Penczek, T. Biela, A. Duda: Living polymerization with reversible chain transfer and reversible deactivation: The case of cyclic esters. Macromol. Rapid Commun. 2000, 21, 941‐950.