ReactionChemistry &Engineering

PAPER

Cite this: React. Chem. Eng., 2018, 3,

696

Received 16th April 2018,Accepted 10th July 2018

DOI: 10.1039/c8re00062j

rsc.li/reaction-engineering

Influence of experimental parameters on the sidereactions of hydrosilylation of allyl polyethersstudied by a fractional factorial design†

A. Bouvet-Marchand, ab C. Chatard,a A. Graillot, *a G. Boutevin,a

C. Loubata and D. Grosso b

Even though the hydrosilylation reaction has been the method of choice to produce organosilicon com-

pounds for 70 years, improving its selectivity still remains a current challenge. In this work, a comprehen-

sive study of the influence of experimental parameters on hydrosilylation side reactions was undertaken by

applying a fractional factorial design of experiments. The study was conducted for polyethylene glycol

(PEG, 1000 g mol−1) terminated allyl ether, which is commonly employed as a reactive functional group to-

ward hydrosilylation. In addition, the resulting silane-functionalized PEG happens to be a molecule of inter-

est in various domains such as the biomedical, cosmetic or food industry thanks to its properties in accor-

dance with these sectors' requirements. This methodology enables highlighting an optimized combination

of experimental parameters as well as a cause–effect relationship between the different side reactions,

leading to a better control of the hydrosilylation reaction.

Introduction

An important research effort has been directed these pastyears toward the use of polyethylene glycols (PEGs) and theirderivatives in numerous fields such as biomedical, drug deliv-ery, food industry, cosmetic, and energy. Indeed, their non-toxicity, biocompatibility, high hydrophilic character and solu-bility in water and organic solvents make them particularly rel-evant and appealing for these applications.1–5 In addition,they are available in a wide range of molecular weights (be-tween 200 and over 10 000 g mol−1) and thus, by exhibiting dif-ferent mechanical properties depending on the chain length,PEG can be selected according to the targeted application.6

What makes PEG even more interesting is the possibilityto easily functionalize the hydroxyl end groups of the polymerwith a large range of reactive functional groups, such as vinylether, amine or even proteins and dye conjugates.7 The at-tachment of alkoxysilane moieties to PEG has been particu-larly studied since these reactive functional groups can par-ticipate in sol–gel reactions according to a hydrolysis–condensation mechanism and be bound to most inorganicmaterials bearing hydroxyl functional groups, enabling sur-face modification.8,9 To synthesize alkoxysilane-terminated

monomers or polymers, the hydrosilylation reaction, whichconsists in adding silicon hydrides across multiple bonds, isthe method of choice.10,11 Even though this reaction hasbeen widely used in industry for the production oforganosilicon compounds since its discovery 70 years ago,12

it still suffers from an important lack of selectivity resultingin too low yield, cumbersome purification steps and highproduction costs. Side reactions, such as oligomerization, ad-dition on the β-position, hydrogenation of the double bond,dehydrocondensation and redistribution, have been identi-fied and well-described in the literature.13,14 Hydrosilylationof PEG is commonly achieved on allyl ether end groups thatpresent the advantage of (i) being easily prepared from theWilliamson reaction between allyl bromide and the hydroxylsof PEG and (ii) being highly reactive toward hydrosilylation.15

The overall mechanism is depicted in Scheme 1. However, aswith other platinum-catalyzed hydrosilylation reactions, thesilanization of PEG makes no exception and is also accompa-nied by side reactions which had been highlighted in detailin the work of Lestel et al.16 In addition to decreasing theyield and the purity of the product, the presence of non-functionalized chains in crosslinking polymerizations leadsto lower crosslink density and therefore poorer mechanical

696 | React. Chem. Eng., 2018, 3, 696–706 This journal is © The Royal Society of Chemistry 2018

a SPECIFIC POLYMERS, 34160 Castries, France.

E-mail: alain.graillot@specificpolymers.frb NOVA Team, CNRS, Aix-Marseille Université, Centrale Marseille, IM2NP, UMR

7334, Campus de St. Jérôme, 13397, Marseille, France

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8re00062j

Scheme 1 Schematic illustration of the synthetic pathways leading toPEG bis-silane: (1) Williamson reaction and (2) hydrosilylation withtriethoxysilane.

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properties of the material.17 Moreover, the molecules are thusnot covalently linked to the network which can potentially re-sult in their unwanted release outside the material.

In view of the industrial need for efficient hydrosilylationreactions, an accurate control of the reaction is highly re-quired to reduce at most the by-product content, especiallyfor molecules with very high molecular weights, to be puri-fied by the common distillation process. So far, most of theattempts to limit the undesired reactions of hydrosilylationhave been directed toward the development of sophisticatedcatalysts, using either new Pt systems or low-cost transitionmetal catalysts. Even though important progress has beenmade with these new catalytic systems, in particular with ironcatalyst by Chirik et al.,18 they are still not sufficiently com-petitive with the conventional Pt catalysts, such as Speier'sand Karstedt's catalysts, and thus do not have any industrialapplication yet.13,14,19,20 However, numerous studies havebrought into light the influence of certain experimental pa-rameters on the proportion of by-products during hydro-silylation. The characteristics of the transition metal catalyst,the nature of the alkoxysilane and the olefin,10 the molar ra-tio between the alkoxysilane functional group and the C–Cdouble-bond,21 the catalyst concentration,22,23 the formationof Pt colloids24 and the dilution of the medium25 werereported to impact the nature and the concentration of by-products. However, these factors have only been examinedseparately and on different reactive functional groups,whereas the synthesis involves the whole set of factors duringthe reaction.

Therefore, a novel strategy was implemented here to studyconcomitantly the different experimental conditions knownto have an influence on the hydrosilylation selectivity. For theaforementioned reasons, hydrosilylation of PEG-terminatedallyl ether was at the core of the study since no solutionshave been proposed so far to limit the associated side reac-tions, while the presence of unbound water makes this com-pound particularly vulnerable to them. In order to screen theeffect of the main experimental parameters and their poten-tial interactions on each side reaction, a design of experi-ments (DOE) was applied in this work. Fractional factorial de-signs were chosen as they are particularly powerful tools tounderstand complex systems with a minimum number of ex-periments, thus presenting significant time and costadvantages.

For the first time, under controlled conditions of the reac-tive medium, isomerization of the double bond, cleavage ofthe resulting propenyl ether and hydrogenation of the carbondouble bond were observed. A better understanding of the in-tricate relation between experimental parameters and side re-actions was then obtained due to the DOE analysis. In partic-ular, this study brought into light a cause–effect relationshipbetween the side-reactions which was presented as a comple-mentary part of the well-known Chalk–Harrod cycle. Withthis new information, a favorable combination of experimen-tal parameters was then proposed to increase the selectivityof the hydrosilylation of PEG allyl ether.

Experimental sectionMaterials

Polyethylene glycol 1000 (PEG 1000, Sigma-Aldrich) wastreated by azeotropic distillation in tetrahydrofuran at 60 °Cunder vacuum in order to remove the water from the prod-uct.26 Sodium hydride (NaH, 95%), allyl bromide (99%), HCl(36.5–38%), anhydrous sodium sulfate, triethoxysilane (95%),platinumIJ0)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complexsolution (Karstedt, in xylene, Pt ∼2%) were purchased fromSigma-Aldrich and used as such without any further purifica-tion. Tetrahydrofuran (≥99.9%, Sigma-Aldrich) and toluene(99.8%, Sigma-Aldrich) were used as received. A solution ofSpeier’s catalyst (99.9%, Alfa Aesar) was prepared by mixing0.2 g of chloroplatinic acid hydrate (0.49 mmol) with 400 μLof isopropanol (≥99.7%, Sigma-Aldrich) under argon. Acti-vated carbon (untreated, granular, 4–8 mesh) was purchasedfrom Aldrich and used as it is.

Synthesis

Synthesis of diallyl PEG. Allyl-terminated PEG (120 g; 0.13mol) was prepared according to the Williamson procedure.An azeotropic distillation was carried out beforehand on PEG1000 in tetrahydrofuran (THF) until a drying extract of 25wt% was reached. The mixture was then added in a two-neckflask and NaH (11.52 g; 0.52 mol) was added under a largeflow of nitrogen with all the preventive measures required.The mixture was stirred at room temperature for 1 h. Allylbromide (58 g; 0.52 mol) was introduced dropwise into thereactive medium. The reaction was carried out until the com-plete disappearance of hydroxyl functional groups, easilydetected by 1H NMR spectroscopy in the presence oftrifluoroacetic anhydride. The excess NaH was neutralizedwith a solution of 37 wt% HCl (26 g; 0.26 mol) addeddropwise under nitrogen. THF was then evaporated with a ro-tary evaporator. The crude material was poured intodichloromethane and washed several times with distilled wa-ter, and then dried over anhydrous Na2SO4. After filtration,the solvent was removed using a rotary vacuum evaporator at40 °C.

PolyIJethylene glycol) bis allyl ether (95%, yellowish wax,1.78 mmol of allyl ether per gram): 1H NMR (CDCl3, 300MHz): δ 3.85 (m, 94.8H), 4.02 (m, 4H), 5.22 (m, 4H), 5.89 (m,2H).

Hydrosilylation of PEG allyl ether. All the reactions fromthe DOE were carried out according to the procedure de-scribed as follows.

PolyIJethylene glycol) bis allyl ether (5 g, 4.4 mmol) was in-troduced into a single-neck round bottom flask and solubi-lized in toluene. An azeotropic distillation was then carriedout until the selected drying extract (25 wt% or 100 wt%) wasreached. Triethoxysilane (1.44 g; 8.8 mmol or 5.78 g; 35.2mmol) was then added to the reaction flask fitted with a con-denser tube. The reaction was stirred at the selected tempera-ture (60 °C or 90 °C) under nitrogen. Catalyst,hexachloroplatinic acid (3.1 g dl−1 in isopropanol) or

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Karstedt, was then added by means of a calibrated micropi-pette for the right amount of Pt per allyl ether function (100or 200 ppm [Pt]/[allyl ether]). The reaction was carried out un-til the complete disappearance of allylic groups, easilydetected by 1H NMR spectroscopy (after 30 minutes, exceptin run 2′ for which the reaction was terminated after 3hours). The platinum catalyst was treated with pellets of acti-vated charcoal added into the reactive medium, previously di-luted with toluene when necessary (i.e. for the experimentscarried out without solvent). Na2SO4 was also added to re-move any potential residue of water from the reactive me-dium. After 2 h, the mixture was filtered and evaporated witha rotary vacuum evaporator at 60 °C.

A description of the NMR of the run 8 is given since allside products are visible on this spectrum. PolyIJethyleneglycol) bis-triethoxysilane (yellow wax, purity varying from66% to 74%; the content of triethoxysilane functions was be-tween 1.02 and 1.13 mmol per gram depending on the run).1H NMR (CDCl3, 300 MHz): δ 0.62 (t, 3.3H), 0.9 (t, 0.1H), 1.10(t, 0.1H), 1.21 (t, 19H), 1.55 (m, 0.7H), 1.62 (m, 0.07H), 1.69(m, 3.0H), 2.48 (m, 0.2H), 3.42 (t, 3.9H), 3.64 (m, 94.8H), 3.79(q, 12.7H), 4.38 (m, 0.3H), 4.76 (m, 0.1H), 5.97 (m, 0.1H),6.24 (m, 0.1H), 9.8 (s, 0.1H).

Methods1H NMR spectra were obtained using a Bruker Advance 300(300 MHz) spectrometer equipped with a QNP probe at roomtemperature. For 1H NMR, chemical shifts were referenced tothe peak of residual non-deuterated solvent at 7.26 ppm forCDCl3. The alkoxysilane index (AI, number of moles ofalkoxysilane functional groups per gram) was determined bythe 1H NMR titration method. The method consisted in solu-bilizing a known mass of the product and an internalstandard (1,3,5-trioxane – 6 equivalent H) in CDCl3. The num-ber of moles of alkoxysilane functional groups per gram ofproduct was measured by comparing the integration of thestandard (6H) with the integration of the CH2 in alpha of thegrafted silane (2H).

Size exclusion chromatography (SEC) analyses wereconducted on a Varian PL-GPC-50 equipped with a polypore(polystyrene) column in THF.

Results and discussionMethodology of the design of experiments

Exploitation of the design of experiments was proved to behighly profitable for manufacturing industries since intricatesystems can be apprehended in a global way with a mini-mum of resources. Nevertheless, the hydrosilylation reactionhas only been investigated so far using the OFAT (one factorat a time) method.22,23,27,28 The OFAT strategy consists inmodifying one variable while keeping the others fixed andtherefore does not enable a precise estimate of the effectsand more particularly of their interactions.29,30 In order toget a full picture of the PEG allyl ether hydrosilylation, the

DOE approach was thus preferred and applied in the form ofa two-level fractional factorial design.

Based on previous experiments performed in our labora-tory and reported in the literature, five experimental factors,which were proved to have an influence on the molar percent-age of the different side reactions of the allyl ether hydro-silylation, were selected as the main effects of the DOE. These5 factors, whose variables are respectively denominated X1,X2, X3, X4 and X5 are the following: drying extract, proportionof the catalyst, nature of the catalyst, proportion ofalkoxysilane and nature of the alkoxysilane. Two levels, corre-sponding to the limits of the range covered by each factor,were studied. They are defined as “high” and “low” and re-spectively coded 1 and −1. Each variable is then described bya column of an alternation of 1 and −1 (simplified as + and −)with a number of lines corresponding to the number of exper-iments.31 If a full factorial two-level design was chosen tostudy the interactions and combined effect of these 5 factors,it would have required 32 experiments (25), leading to 5 mainfactor interactions, 10 two-factor and three-factor interactions,5 four-factor interactions and 1 five-factor interaction.According to the effect hierarchy principle, the influence ofthe third and higher factor interaction is most of the timenegligible and fractional factorial design can be used to onlyestimate lower-order effects, which greatly limits the numberof experiments needed.32 In this study, the following polyno-mial equation was employed:

y = b0 +P

biXi +P

bijXiXj

where y is the response and X the variables, coded +1 and −1.bi are the coefficients corresponding to the effect of each fac-tor and are the unknown parameters. The method to con-struct and analyze the fractional factorial design is describedin detail in the ESI† (see section S1†). The DOE implementedhere required 16 experiments.

In order to get suitable information from this DOE and bein accordance with the experimental field usually employedfor the hydrosilylation reaction, the value of each factor'slevels was carefully chosen. Proportions of the platinum cata-lyst generally comprised between 5 and 200 ppm per reactivefunctional group.33,34 However, Meister et al.22 recently dem-onstrated the negative influence of a very high concentrationof platinum on the total conversion and reaction rate. For[Pt] ≥250 ppm, formation of colloid particles was observedby dynamic light scattering corresponding to the deactivationof the catalyst, whereas maximum activation was obtained at125 ppm. Thereby, two concentrations on both sides of thethreshold value of 125 ppm were tested. Since the reactionstudied here is apprehended from an industrial point of view,the two prevailing catalysts, Speier and Karstedt's catalysts,were compared here.35,36 Karstedt's catalyst was developed in1973 by chemical modification of the Speier catalyst with disil-oxane and has been preferentially used in industry since thenbecause of its higher activity and selectivity.37 Selected temper-atures correspond to classic conditions for the hydrosilylation

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of allyl ethers and were chosen so as not to exceed the boilingtemperature of the triethoxysilane.38 In particular, the twotemperatures 60 °C and 90 °C were studied since it has beendemonstrated that they gave different results in terms of thekinetics of conversion of SiH.39 The influence of the reactivemedium dilution was investigated as well since the additionof solvent can be required in case the reaction leads to an exo-therm or high viscosity. In addition, it has been proved that ahigh dilution increases the probability of an intramolecularoxidative addition on the Pt centre of the alkoxysilane andthus favors the catalytic cycle reaction of hydrosilylation.40

The two opposite drying extracts, 25 wt% and 100 wt%, werethen chosen as the two levels of this factor. Regarding the Si–H/allyl ratio, it has been proved to be a key parameter for lim-iting the isomerization reaction. However, the proportion ofalkoxysilane required to decrease by two the proportion ofisomerized by-products is very high (Si–H/allyl ratio equal to16.5) which has a direct impact on the reaction cost.21 Here, aratio of 4 was chosen as the high level and compared to thestoichiometric ratio usually employed in industry to avoid theprocedure of treatment of the reactive medium. The differentlevels of each factor are summarized in Table 1.

Influence of experimental conditions on side reactions

Determination of the side reactions. Synthesis of the inter-mediate PEG bis allyl ether was conducted by the reaction be-tween PEG (1000 g mol−1) and allyl bromide in the presenceof NaH. From this intermediate, 22 hydrosilylations, corre-sponding to each run of the DOE and six replicated runs,were then carried out according to the experimental condi-tions set by the fractional factorial design.

The progress of the reaction was analyzed by 1H NMR byfollowing the conversion of the allyl ether functionalities(ESI,† Fig. S2). The 1H NMR spectra obtained at the end ofthe reaction enabled identification of the main product ofthe hydrosilylation, whose attributions are presented in Fig. 1and correspond to the PEG bis-silane compound.

Integrations of the signals in Fig. 1 were established fromthe number of protons belonging to the PEG motif (indicatedby the number 4 on the spectrum) obtained in the intermedi-ate compound. Indeed, the number of PEG repetitive motifsremains the same after hydrosilylation since no significantpolymerization by condensation reactions was observed inSEC (see Fig. 2).

The integration of the signal corresponding to the CH2 inthe alpha position of the alkoxysilane (indicated by the num-ber 1) is equal to 3.0, whereas an integration of 4.0 shouldhave been obtained. This inconsistency as well as the observa-tion of other non-identified peaks on the 1H NMR spectrumclearly demonstrates the presence of by-products (Fig. 3a).Further investigations were then carried out from the NMRspectra to determine the nature and the proportion of theseside-products and were achieved for each run of the DOE.

The peaks observed at 1.56, 4.38, 4.77, 5.97 and 6.25 ppmare characteristic of the cis and trans structures of the PEG-terminated propenyl ether resulting from the isomerizationof the allyl ether in the presence of Pt catalyst (see Fig. 3b).Three other peaks, defined in Fig. 3c by the numbers 12, 13and 14, are consistent with a propionaldehyde (or propanal)structure and correspond to one of the products formed aftercleavage of the propenyl ether. The other molecule obtainedby cleavage is the hydroxyl-terminated polyethylene glycol butis not visible on the 1H NMR since the chemical shifts are

Table 1 Factors of the fractional factorial design

Variable Factors Level −1 Level +1 Ref.

X1 Catalyst ratioa 100 200 22X2 Catalyst Speierb Karstedt 37, 41X3 Temp. 60 °C 90 °C 38, 39X4 Drying extractc 25 wt% 100 wt% 40X5 Silane ratiod 1 4 21

a nIJPt) :nIJallyl ether) in ppm. b Speier solution. c Drying extract =(mPEG + msilane)/(mPEG + msilane + mtoluene).

d nIJSi–H) :nIJallyl ether).

Fig. 1 General 1H NMR spectrum obtained in run 1 before treatment andschematic representation of the chemical structure of the main product.

Fig. 2 SEC chromatograms of PEG before (black curve) and afterhydrosilylation (grey curve).

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similar to those of PEG bis-silane. Finally, the two peaks No.15 and 16, respectively at 0.90 and 1.60 ppm in Fig. 3d (partlyoverlapped by peak No. 2) were proved to be correlated to an-other peak located under peak No. 3. A 2D-HSQC-DEPT 135

spectrum, which (i) shows the correlations between the reso-nance of 1H and 13C having one-bond scalar couplings (1JCH) and (ii) distinguishes the methylenes from the methyland methine correlations by the sign of the peaks, was car-ried out to provide information on the nature of these threepeaks (see the ESI,† S2). From this information, it was de-duced that these three signals correspond to the hydroge-nated form of the PEG allylether.

Results of the DOE

The proportions of each by-product were calculated for eachrun based on the integrations determined in 1H NMR andaccording to the equations presented in the ESI,† S3. Threeresponses, corresponding to the percentage of isomerization,cleavage of the propenyl ether and hydrogenation, were thenobtained with only 16 experiments. The magnitude of eachresponse and the results obtained from the replicated runsare given in Table 2.

Three replicated experiments were performed at centerpoints for each catalyst (runs 9 to 14 in Table 2). Similar pro-portions of by-products were obtained in both cases. Thestandard deviation calculated from the by-product's response,which corresponds to the estimation of the experimental er-ror, is low (σby-products = 0.26 with Karstedt and 0.12 withSpeier). Therefore, it can be assessed that the variations ob-served in the side-product's proportions for each run dependon the selected factors and not on the dispersion ofmeasurements.

The contents of by-products varied from 14.1 to 20.7mol%, 0 to 5.0 mol% and 0 to 3.0 mol%, for the reactions of

Fig. 3 (a) Schematic representation of the chemical structure of theby-products and 1H NMR spectrum of the peaks corresponding to the(b) PEG-terminated propenyl ether, (c) propanal and (d) hydrogenatedPEG.

Table 2 Responses from the 2-level fractional factorial design corresponding to the molar percentage of the different by-products. The abbreviations Sand K correspond respectively to Speier's and Karstedt's catalyst. Runs 9 to 14 correspond to replicated runs at the center points of the field of study,i.e. the average value between the low and the high levels of each factor for each catalyst

Runs X1 X2 X3 X4 X5 % Isoa % Clb % Hydc % by-products

1 100 S 60 100 4 15.6 5.0 1.8 22.42 200 S 60 25 1 19.9 0.8 1.1 21.83 100 K 60 25 4 16.8 0.0 1.2 18.04 200 K 60 100 1 19.3 0.0 0.7 20.05 100 S 90 100 1 17.3 1.2 0.7 19.26 200 S 90 25 4 20.7 0.0 0.0 20.77 100 K 90 25 1 18.6 1.9 0.8 21.38 200 K 90 100 4 14.4 2.8 1.4 18.61′ 100 S 60 25 1 19.9 0 0.0 19.92′ 200 S 60 100 4 16.3 0.8 1.8 18.93′ 100 K 60 100 1 15.7 0 0.6 16.34′ 200 K 60 25 4 14.4 1.9 0.2 16.55′ 100 S 90 25 4 17.4 0.8 1.7 19.96′ 200 S 90 100 1 16.7 2.9 0.7 20.37′ 100 K 90 100 4 13.3 3.1 1.8 18.28′ 200 K 90 25 1 14.7 1.8 0.0 16.59 150 K 75 62.5 2.5 13.8 0.0 2.9 16.710 150 K 75 62.5 2.5 14.2 0.0 3.0 17.211 150 K 75 62.5 2.5 14.1 0.0 3.0 17.112 150 S 75 62.5 2.5 19.3 0.0 0.4 19.713 150 S 75 62.5 2.5 18.8 0.0 0.9 19.714 150 S 75 62.5 2.5 18.9 0.0 0.6 19.5

a Isomerization of allyl ether. b Cleavage of propenyl ether. c Hydrogenation of the carbon double bond.

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isomerization, cleavage and hydrogenation, respectively. Itcan be noticed that isomerization is the predominant side re-action since the proportion of by-products formed by this re-action is much higher than the proportions of hydrogenatedand cleaved allyl ether. From these three sets of responses,the coefficients bn were estimated according to the methodol-ogy described in the ESI† S1 for each side reaction anddiscussed in the following section. For the sake of clarity, theanalysis of the interrelationships between the main effectsare illustrated according to a three-dimensional surfacegraph in which each axis corresponds to one parameter ofthe DOE. The studied area is delimited by the low and highlevels of each of these parameters. For each side reaction, thestandard deviations of the estimates bn are presented by errorbars, highlighting the most significant factors.

To go further in the interpretation of these previous re-sults and better understand the behavior of each parameterin the presence of the others, the response of each individualparameter was treated alternatively at the highest and lowestlevels while keeping all other factors constant at their middlelevel. These results brought complementary information forthe DOE analysis without requiring any additional experi-ments. The respective responses are presented in Table 3 andare discussed for each side reaction in the following section.

Interpretations and discussions

Isomerization of the allyl ether. The isomerization corre-sponds to the migration of the allylic double bond from a ter-minal to an internal position leading to the formation ofPEG-terminated propenyl ether.10 Because the kinetics of for-mation of propenyl ethers is similar to that of hydro-silylation, isomerization of the double bond is observed sys-tematically in the presence of platinum catalyst.22 Theproportion of isomerized by-products is commonly between10 and 30 mol%.42 Moreover, propenyl ether functions wereproved to be unable to react by hydrosilylation despite theirsimilar structure with vinyl ethers23,43 and, as demonstratedby Meister et al., the kinetics of reversibility of isomerizationis too slow to enable a complete conversion in a reasonabletime of reaction.22 Over the years, important efforts were

made by academic researchers and several actors of the sili-con industry to limit this side reaction, using for instancespecific additives, different reaction processes or new catalystsystems.20,38,42 Even though technical solutions were broughtforward to improve the hydrosilylation efficiency, no solutioncompliant with industrial requirements and suitable with allsorts of compounds has been established yet.

Estimation of the main effect's and interaction's coeffi-cients for the isomerization response is presented in Fig. 4a.For factors with a positive bn coefficient, the by-product'scontent will be reduced by selecting the experimental condi-tions corresponding to their lowest level, and inversely. b2, b4and b5, equal to −1.0, −0.9 and −0.8, respectively, are the coef-ficients with the highest values. Then, the nature of the cata-lyst, the drying extract and the proportion of alkoxysilane arethe predominant effects influencing the propenyl ether's con-tent. Interestingly, the coefficient b1 corresponding to the cat-alyst ratio has no influence whatsoever on the isomerization.In order to see some possible interrelationships betweenthese factors, the interactions 2/4, 2/5 and 4/5 were studiedusing a 3D surface graph representation. It can behighlighted from Fig. 4b that using Karstedt's catalyst insteadof Speier's limits the isomerization reaction. This result isconfirmed by the analysis of responses at mid-level for whichthe most important decrease in isomerized by-products isobtained by employing the Karstedt's catalyst (see Table 3,#2, level +). In addition, it can be observed that whatever thecatalyst employed or the dilution of the solution, a high Si–H/allyl ether ratio is always favorable to the reduction of theisomer content (see factor X5, Fig. 4c and d). This result is inagreement with previous observations made in the litera-ture.21 However, new conclusions arise from these represen-tations such as the positive influence of a high drying extracton the reduction of propenyl content (see factor X4,Fig. 4b and d) and the favorable synergetic effect between a

Table 3 Responses at high and low level for each factor. The abbrevia-tions S and K correspond to Speier's and Karstedt's catalyst, respectively

# Factors Levels % Isoa % Clb % Isoa + % Clb % Hydc

1 X1 100 16.8 1.50 18.3 1.08200 17.1 1.38 18.4 0.74

2 X2 S 18.0 1.44 19.4 0.98K 15.9 1.44 17.3 0.84

3 X3 60 17.2 1.06 18.3 0.9390 16.6 1.81 18.5 1.81

4 X4 25 17.8 0.90 18.7 0.63100 16.1 1.98 18.1 1.19

5 X5 1 17.8 1.08 18.8 0.584 16.1 1.80 17.9 1.24

a Isomerization of allyl ether. b Cleavage of propenyl ether.c Hydrogenation of the carbon double bond.

Fig. 4 (a) Estimation of the effect's coefficients for the isomerization'sresponse. (b) 3D representation of the interaction catalyst ratio–dryingextract. (c) 3D representation of the interaction catalyst–alkoxysilane ratio.(d) 3D representation of the interaction alkoxysilane ratio–drying extract.

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high alkoxysilane ratio and a high drying extract (see factorX4 and X5, Fig. 4d). These conclusions are consistent with thefact that applying these experimental conditions increasesthe probability of reaction between the olefins and thealkoxysilanes. Thereby, hydrosilylation is expected to be fa-vored over isomerization.

Cleavage. As observed previously on certain 1H NMR spec-tra of the DOE (Fig. 3c), another side reaction can occur con-comitantly to the isomerization, corresponding to the cleav-age of the propenyl ether. Indeed, under acidic conditionsand in the presence of water, PEG-terminated propenyl etheris susceptible to hydrolysis, leading to the formation ofpropanal and polyethylene glycol.44 In addition to a loss ofalkoxysilane functionality, the presence of propanal presentsnumerous additional drawbacks such as a distinctive odorand a coloration of the polymer.

Estimation of the effect's coefficients for the cleavage's re-sponse are presented in Fig. 5a. The highest values areobtained for the coefficients b23 + b45, b24 + b35, b4, b3 and b5.

In the sum b23 + b45, which is the predominant coefficient,two interactions are at stake, 2/3 and 4/5. Their respective in-fluences have to be distinguished in order to interpret the ef-fect of the sum b23 + b45. The interaction 4/5 corresponds totwo coefficients with a high effect, whereas the coefficient b2is low and the coefficient b3 is high. Based on the hypothesisof interpretation for fractional factorial design, the interac-tion 2/3 will be considered weak compared to the interaction4/5.45 Therefore, the interaction between the drying extract(X4) and the Si–H/allyl ether ratio (X5) was investigated ratherthan the interaction 2/3. Nevertheless, since the coefficient b3is almost equal to b5, the effect of the temperature (X3) wasalso considered to be significant and its interaction with thepredominant main effect (X4) was also studied.

As can be observed in Fig. 5b, for a stoichiometricalkoxysilane ratio, the influence of the drying extract is notsignificant. However, for a high alkoxysilane ratio, it isrecommended to dilute the solution to limit the formation ofpropanal. One can notice that this result is in contradictionwith the observations made previously on the reduction ofthe isomerization content. This point will be discussed herebelow. As suggested by the 3D representation of the interac-tion 3/4, the temperature also has an effect on the propanalcontent (Fig. 5c). The proportion of aldehyde is sensibly re-duced by decreasing the temperature and this result is alsoconfirmed by the fact that the propanal content is almost de-creased by two when the temperature is lowered to 60 °C (seeTable 3, #3, level −). A favorable synergetic effect between alow temperature and a high dilution of the reactive mediumcan also be highlighted in Fig. 5c.

Because propanal can alter the quality of the product,evaporation at first via a rotary evaporator and then by distil-lation was carried out at 50 °C. The boiling temperature forpropanal is 48.8 °C.46 1H NMR was carried out at differenttimes of the evaporation process in order to follow the disap-pearance of the aldehyde. It was observed that the molar ra-tios of the PEG-propenyl ether and of the propanal variedwith an inverse tendency, while the proportion of these twoby-products remained constant all throughout the process.This result indicates that a reversible reaction exists betweenthese two forms. A mechanism of this reaction is proposed inScheme 2. It involves in a first step the formation of a hemi-acetal by the reaction between the propanal and the PEG-terminated hydroxyl. Under acidic conditions, a molecule ofwater is liberated which leads to the re-generation of thepropenyl ether.

As highlighted previously, the drying extract has an oppo-site effect on these two by-products' content. By increasing it,the isomerization reaction is reduced while cleavage is fa-vored. Because of the equilibrium between these two forms,it is not possible to draw clear conclusions on the favorableeffect of the experimental parameters. Indeed, it will not bepossible to differentiate between cases where the experimen-tal parameters are indeed favorable to limit the by-products'content and one where the other reversible form is preferen-tially formed keeping the amount of by-products constant. Toavoid this problem, the influence of the experimental param-eters was then studied for the sum of responses, correspond-ing to the isomerization and cleavage reactions, using theanalysis at mid-factors.

Even though the main influencing parameter is the cata-lyst nature, it can be observed that a high drying extract anda high alkoxysilane ratio reduce the proportion of these twoby-products (see Table 3, #4 and 5, levels +). These conditions

Fig. 5 (a) Estimation of the effect's coefficients for the cleavage'sresponse. (b) 3D representation of the interaction alkoxysilane ratio–drying extract. (c) 3D representation of the interaction temperature–drying extract.

Scheme 2 Reversible reaction occurring between propanal andpropenyl ether with R, polyIJethylene glycol).

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are actually the same ones that were proved to limit the isom-erization. This result is consistent with the fact that propanalis formed by cleavage of the propenyl ether. Therefore, bylimiting in the first place the isomerization reaction, theamount of cleaved products is also expected to be reduced.

Hydrogenation. 1H NMR of some DOE runs shows thepresence of saturated PEG formed by hydrogenation of the al-lyl ether functions and their proportions for each run arereported in Table 2. From the hydrogenation responses, itwas highlighted that the coefficients with the highest valueswere b4 and b5, associated to the drying extract and thealkoxysilane ratio effects, respectively (Fig. 6a).

As a matter of fact, the drying extract significantly impactsthe proportion of hydrogenated products as can be seen inTable 3 (#4, level −), where the content of hydrogenated PEGis divided by two for a highly diluted solution. Similarly, theproportion of hydrogenation is also reduced by two for stoi-chiometric alkoxysilane ratios (Table 3, #5, level −). In addi-tion, the analysis of the interaction between these two factorspinpoints that a combination of a high proportion ofalkoxysilane with a high drying extract is even more detri-mental (Fig. 6b). From the Table 3 (#3, level +), it can also beobserved that a high temperature will result in a higher con-tent of hydrogenated PEG. Indeed, the proportion of sideproducts is doubled when the temperature is raised from 60°C to 90 °C.

Hydrogenation occurs when H2 reacts with a carbon dou-ble bond. Since the hydrosilylation of allyl ether happens veryfast, it can be supposed that the PEG hydrogenated form ob-served in this study comes from the hydrogenation of thepropenyl ethers. The reactive medium was carefully made in-ert before the reaction; thus, it can be assessed that H2 iscoming from the reactions occurring in the flask. Water orcompounds bearing alcohol functions can react withalkoxysilane compounds and form H2 by condensation.16,23

Thereby, it can be assumed that the presence of bound waterin PEG as well as the formation of hydroxyl-terminated PEGafter cleavage favors the hydrogenation.47 In addition,according to Lewis et al.,48 the release of H2 can also comefrom the formation of a Si–Si bond in the presence of an ex-cess of alkoxysilane. In each scenario, it clearly appears thatan excess of alkoxysilane leads to the formation of saturated

PEG. This observation is in accordance with the conclusionof the DOE for which less hydrogenated by-products areobtained for low alkoxysilane ratio. It can also be noted thatthe effects leading to a high proportion of hydrogenated PEGare the same as for the cleavage which is consistent with thefact that this reaction can generate H2. Moreover, the high di-lution of the reactive medium contributes to the reduction ofthe probability of reaction with an excess of alkoxysilane andthen limits the proportion of hydrogenated PEG. Contrary tothe isomerization and the cleavage reaction, hydrogenation isnot reversible and therefore has to be avoided at all costs.The results obtained from the DOE analysis are summarizedin Table 4, stating the best combination of experimental pa-rameters to limit each side reaction of the PEGhydrosilylation.

Influence of the treatment procedure on side reactions.The analysis of this design of experiment was undertaken onthe reactive medium after complete conversion of the reac-tant in order to study the only influence of the experimentalparameters on the by-product content.

After each run, the reactive medium was treated accordingto the same protocol (see the Experimental section) in orderto remove platinum traces. The crude products were then an-alyzed by 1H NMR and the same methodology as before wasapplied to determine the proportion of each by-product (seeTable 5).

Interestingly, in most runs, the proportion of side-products decreases after treatment. Since hydrogenation is ir-reversible, the only possibility is that propenyl ethers areconverted back into allyl ethers and are hydrosilylated. As amatter of fact, the runs (1, 3, 2′ and 7′) showing the impor-tant decrease of by-product amount after treatment are thoseperformed with an excess of alkoxysilane (4 equivalents ofalkoxysilane by allyl ether). This implies that a high contentof alkoxysilane into the reactive medium is beneficial to in-crease the functionalization of the PEG allyl ether.

Extended Chalk–Harrod cycle for PEG hydrosilylation.From these results, a cause–effect relationship was proposed be-tween these three side reactions on the fringe of the well-established Chalk–Harrod mechanism (see Scheme 3). Whilethe isomerization reaction has been widely studied and hasbeen considered as one of the steps of the Chalk–Harrod mecha-nism, it has not been the case for the other side reactions so far.

The different steps of the Chalk–Harrod cycle are the fol-lowing: (I) oxidative addition of the alkoxysilane, (II) coordi-nation of the olefin, (III) insertion of the olefin into the Pt–Hbond and (IV) reductive elimination of the alkoxysilane.

The isomerization is represented by the steps described inthe literature: (V) migratory olefin insertion, (VI) β-H elimina-tion, (VII) elimination of isomerized product and (VIII) re-versibility of the isomerization.22 An extended mechanism ofthe hydrosilylation reaction and its associated side reactionsis proposed and illustrated by the following steps. Step IXcorresponds to the reversible reaction that was demonstratedto occur between the isomerized products and the propanaland PEG formed during the cleavage reaction. The formation

Fig. 6 (a) Estimation of the effect's coefficients for the hydrogenationresponse. (b) 3D representation of the interaction alkoxysilane ratio–drying extract.

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of hydroxyl-terminated PEG leads to the release of H2 by con-densation with alkoxysilane compounds (step X) which con-tributes afterward to the hydrogenation of the PEG-terminated propenyl ether (step XI).

Because the two other by-products are generated from theisomerized PEG, by limiting in the first place its proportion,the hydrosilylation selectivity is expected to be enhanced.Nevertheless, based on the results obtained after treatment,it appears necessary to limit the hydrogenation since this re-action is not reversible. As demonstrated, the parameters lim-iting the proportion of hydrogenation by-products are a lowtemperature, a high dilution and a low alkoxysilane ratio.However, it was proved that a high alkoxysilane ratio was fa-vorable to increase the amount of PEG-functionalizedalkoxysilane thanks to the hydrosilylation of allyl-ethersformed after the reversible isomerization of propenyl etherduring the treatment step. Therefore, a low temperature, alow drying extract and a high alkoxysilane ratio in presenceof Karstedt was chosen as the best combination of parame-ters. This combination is actually the one corresponding torun 3 exhibiting the lowest proportion of by-products aftertreatment (15.4 mol%) and run 4′, with only 16.5 mol% ofnon-functionalized PEG.

Analysis of variance of the DOE. The significance of thefactors and their relative coefficients was assessed byperforming an analysis of variance for all the three responses.The analysis was performed with Statistical Software usingANOVA based on the p-value with 95% confidence level.

The model fits the data with an R2 equal to 78, 74% and89%, respectively, for the isomerization, cleavage and hydro-genation responses. The p-values of the studied effects of theDOE are presented in the ESI† (see section S4) for each re-sponse. These values are either inferior or close to 0.05,which indicate their significance. However, two p-values, cor-responding to the temperature and silane ratio effects on thecleavage response, are superior to 0.2, which might questionthe real influence of such parameters on this side reaction.Nevertheless, these two factors were taken into considerationsince they were proved to have an important influence on thecleavage at the middle level of the remaining factors.

From a statistical point of view, some improvements couldbe achieved to obtain a better correlation to the model bystudying additional factors or selecting more relevant experi-mental parameters. However, the objective of this work wasto evaluate the influence of the catalyst ratio and nature, thetemperature, the drying extract and the alkoxysilane ratio

Table 4 Overview of the results obtained from the DOE analysis describing the most favorable parameters to limit the by-product's content for eachside reaction

Factors Isoa Clb Isoa + Clb Hydc

Catalyst ratio No influence 200 ppmCatalyst Karstedt No influence Karstedt No influenceTemp. No influence 60 °C No influence 60 °CDrying extract 100 wt% 25 wt% 100 wt% 25 wt%Silane ratio 4 eq. 1 eq. 4 eq. 1 eq.

a Isomerization of allyl ether. b Cleavage of propenyl ether. c Hydrogenation of the carbon double bond.

Table 5 Responses from the DOE corresponding to the molar percent-age of the different by-products after treatment and compared to thepercentages obtained before treatment

Runs

Before treatment After treatment

% by-products % Isoa % Clb % Hydc % by-products

1 22.4 19.1 0.0 1.7 20.82 21.8 17.2 0.0 2.2 19.43 18.0 13.2 0.0 2.2 15.44 20.0 19.0 0.0 1.0 20.05 19.2 16.4 0.8 0.9 18.16 20.7 17.3 0.0 2.2 19.57 21.3 19.3 0.0 1.6 20.98 18.6 12.9 3.6 2.0 18.51′ 19.9 17.4 0.0 0.9 18.32′ 18.9 4.9 0.6 9.9 15.43′ 16.3 15.7 0.0 0.6 16.34′ 16.5 14.4 1.9 0.2 16.55′ 19.9 17.4 0.8 1.7 19.96′ 20.3 17.7 0.9 0.9 19.57′ 18.2 9.6 0.9 6.1 16.68′ 16.5 8.4 6.2 1.0 15.6

a Isomerization of allyl ether. b Cleavage of propenyl ether.c Hydrogenation of the carbon double bond.

Scheme 3 Proposed extended Chalk–Harrod mechanism for thehydrosilylation of the PEG-terminated allyl ether.

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which are the main variables governing the hydrosilylationreaction. Moreover, the conclusions arising from this DOEanalysis explaining the cause–effect relationships betweenthe experimental parameters and the side reactions areconsistent with chemical mechanisms which show thatthe fractional factorial design implemented here was suit-able. In addition, this work led to the determination ofthe main significant effects influencing the side reactionsof the PEG hydrosilylation and, thereby, will allow the se-lection of the most relevant factors in further DOEinvestigations.

Conclusions

Better control of hydrosilylation and its associated side reac-tions is a key challenge for the production of organosilanes.During the past decades, this topic has been at the centerof numerous industrial and academic research studies. To-day's trend is oriented towards the synthesis of new cata-lysts showing high selectivity and a reduced price comparedto the conventional platinum catalysts. However, developedcatalysts are still not able to compete with the current sys-tems. Therefore, another strategy was proposed here basedon the observation that some experimental parameters wereproved to impact the proportion of by-products. A fractionalfactorial design of experiments was implemented instead ofthe classic OFAT approach in order to obtain an overall vi-sion of the phenomena happening during the reaction. Theinfluence of the nature and proportion of the catalyst, thetemperature and dilution of the reactive medium and theproportion of alkoxysilane were studied concomitantly onthe model reaction of the hydrosilylation of PEG bis-allylether. Identification of the nature and proportion of by-products was achieved by 1H NMR for each combination ofparameters and enabled the estimation of the effect of eachfactor and associated interactions via the analysis of theDOE. For the first time, it was possible to (i) highlight themain influencing parameters contributing to each side reac-tion, (ii) observe synergistic interactions between the differ-ent factors and (iii) demonstrate the influence of the treat-ment on the evolution of by-product content for thisparticular reaction. Finally, it was demonstrated that theuse of the Karstedt rather than the Speier catalyst, at 60 °C,with a high dilution and a high alkoxysilane content werethe experimental conditions leading to the highest hydro-silylation selectivity for PEG. In addition, based on the DOEresults, a cause–effect relationship between the side reac-tions was brought into light, while until now these reactionshave always been studied apart from one another. This re-sult enables the proposal of an extended version of theChalk–Harrod cycle for hydrosilylation of PEG.

By using the powerful tool of a DOE, a better understand-ing of PEG hydrosilylation was then achieved, enabling us topropose optimized experimental conditions to increase theselectivity of this classic reaction of the silicon industry.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

SPECIFIC POLYMERS is greatly thanked for financial support.

Notes and references

1 C. Fruijtier-Pölloth, Toxicology, 2005, 214, 1–38.2 S. Zalipsky, C. Gilon and A. Zilkha, Eur. Polym. J., 1983, 19,

1177–1183.3 J. M. Harris, PolyIJethylene glycol) chemistry: biotechnical

and biomedical applications, Plenum Press, New York,1992.

4 K. Knop, R. Hoogenboom, D. Fischer and U. S. Schubert,Angew. Chem., Int. Ed., 2010, 49, 6288–6308.

5 N. Lago, O. Garcia-Calvo, J. M. L. del Amo, T. Rojo and M.Armand, ChemSusChem, 2015, 8, 3039–3043.

6 M. A. Al-Nasassrah, F. Podczeck and J. M. Newton, Eur. J.Pharm. Biopharm., 1998, 46, 31–38.

7 J. M. Harris, J. Macromol. Sci., Rev. Macromol. Chem. Phys.,1985, C25, 325–373.

8 C. Sanchez, L. Rozes, F. Ribot, C. Laberty-Robert, D. Grosso, C.Sassoye, C. Boissiere and L. Nicole, C. R. Chim., 2010, 13, 3–39.

9 S. Khoee and A. Kavand, J. Nanostruct. Chem., 2014, 4, 111.10 B. Marciniec, Comprehensive handbook on hydrosilylation,

Pergamon Press, Oxford, New York, 1992.11 S. J. Clarson, Silicon, 2009, 1, 57–58.12 L. H. Sommer, E. W. Pietrusza and F. C. Whitmore, J. Am.

Chem. Soc., 1947, 69, 188.13 Y. Nakajima and S. Shimada, RSC Adv., 2015, 5, 20603–20616.14 D. Troegel and J. Stohrer, Coord. Chem. Rev., 2011, 255,

1440–1459.15 J. V. Crivello and G. Lohden, Chem. Mater., 1996, 8, 209–218.16 L. Lestel, H. Cheradame and S. Boileau, Polymer, 1990, 31,

1154–1158.17 G. Martin, C. Barres, P. Cassagnau, P. Sonntag and N.

Garois, Polymer, 2008, 49, 1892–1901.18 A. M. Tondreau, C. C. H. Atienza, K. J. Weller, S. A. Nye,

K. M. Lewis, J. G. P. Delis and P. J. Chirik, Science,2012, 335, 567–570.

19 X. Y. Du and Z. Huang, ACS Catal., 2017, 7, 1227–1243.20 I. E. Marko, S. Sterin, O. Buisine, G. Mignani, P. Branlard, B.

Tinant and J. P. Declercq, Science, 2002, 298, 204–206.21 T. D. H. Nguyen, F. X. Perrin and D. L. Nguyen, Beilstein J.

Nanotechnol., 2013, 4, 671–677.22 T. K. Meister, K. Riener, P. Gigler, J. Stohrer, W. A.

Herrmann and F. E. Kuhn, ACS Catal., 2016, 6, 1274–1284.23 G. Torres, P. J. Madec and E. Marechal, Makromol. Chem.,

1989, 190, 2789–2803.24 J. Stein, L. N. Lewis, Y. Gao and R. A. Scott, J. Am. Chem.

Soc., 1999, 121, 3693–3703.25 M. Mirza-Aghayan, R. Boukherroub, M. Bolourtchian, M.

Hoseini and K. Tabar-Hydar, J. Organomet. Chem., 2003, 678,1–4.

Reaction Chemistry & Engineering Paper

Publ

ishe

d on

13

July

201

8. D

ownl

oade

d by

Uni

vers

ity o

f M

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r on

4/8

/201

9 1:

50:2

0 PM

. View Article Online

706 | React. Chem. Eng., 2018, 3, 696–706 This journal is © The Royal Society of Chemistry 2018

26 L. Kinard, K. Kasper and A. Mikos, Protocol exchange, 2012.27 L. N. Lewis, J. Am. Chem. Soc., 1990, 112, 5998–6004.28 D. W. Chung and T. G. Kim, J. Ind. Eng. Chem., 2007, 13,

979–984.29 D. C. Montgomery, Design and analysis of experiments, John

Wiley & Sons, Hoboken, NJ, 6th edn, 2005.30 V. Czitrom, Am. Stat., 1999, 53, 126–131.31 P. R. Nelson, M. Coffin and K. A. F. Copeland, Introductory

statistics for engineering experimentation, Academic Press,Amsterdam, Boston, 2003.

32 C.-F. Wu and M. Hamada, Experiments: planning, analysis,and optimization, Wiley, Hoboken, N. J., 2nd edn, 2009.

33 J. S. L. N. Lewis, Y. Gao, R. E. Colborn and G. Hutchins,Platinum Met. Rev., 1997, 41, 66–75.

34 L. N. Lewis, US Pat., 4705765, 1987.35 J. L. Speier, in Advances in Organometallic Chemistry, ed. F.

G. A. Stone and R. West, Academic Press, 1979, vol. 17, pp.407–447.

36 B. Karstedt, US Pat., 3715334, 1973.37 M. F. Lappert and F. P. A. Scott, J. Organomet. Chem.,

1995, 492, C11–C13.

38 R. A. Drake, US Pat., 5359112, 1994.39 A. D'Amore and G. E. Zaikov, New topics in monomer and

polymer research, Nova Science Publishers, New York,2007.

40 X. Coqueret and G. Wegner, Makromol. Chem., 1992, 193,2929–2943.

41 I. E. Marko, S. Sterin, O. Buisine, G. Berthon, G. Michaud, B.Tinant and J. P. Declercq, Adv. Synth. Catal., 2004, 346,1429–1434.

42 S. Westall, A. Surgenor and T. Bunce, WO Pat.,WO2003014129 A1, 2003.

43 J. V. Crivello and G. Lohden, Macromolecules, 1995, 28,8057–8064.

44 G. Tersac, Polym. Int., 2007, 56, 820.45 J. Goupy, Methods for experimental design: principles and

applications for physicists and chemists, Elsevier, Amsterdam,New York, 1993.

46 Boiling Point Data, ed. S. E. S. R. L. Brown, 2017.47 S. Lusse and K. Arnold, Macromolecules, 1996, 29, 4251–4257.48 L. N. Lewis and N. Lewis, J. Am. Chem. Soc., 1986, 108,

7228–7231.

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