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<\/a><\/figure><\/div>\n\n\n\nAbstract<\/h3>\n\n\n\n
The search for more sustainable solutions for plastics production, moving away from petrochemical feedstocks as today’s major raw material basis, is a research area of increasing interest. This task goes far beyond the issue of designing greener polymers and their related monomers as tailor-made plastics require, besides the polymer itself, further components. These additives also need to be switched from typically fossil-based to bio-renewable raw materials. One of such necessary components for many applications are plasticizers, and a major application of them is related to polyvinyl chloride (PVC) as one of the leading polymers with a wide range of applications. Typically today\u2018s plasticizers are based on fossil feedstocks, and some of them such as specific ortho-phthalates as the most important product class of plasticizers are now subject to restrictions and authorization by the EU’s REACH legislation due to their toxicological profile. In this contribution, we report the synthesis and technical evaluation of alternative, novel bicyclic plasticizer candidates, which are fully accessible from renewable feedstocks. In detail, these new plasticizer target molecules are based on the use of the furan-derivative 2-methylfuran, maleic anhydride and 2-ethylhexanol as bio-based starting materials. The synthetic concept consists of an initial Diels-Alder reaction with 2-methylfuran and a subsequent hydrogenation and optional esterification step. The applied reactions are well-known as economic and sustainable technologies. Thus, not only the starting materials (being of bio-based origin) but also the selected reaction technologies for the syntheses of the target molecules are sustainable. Furthermore, a range of performance tests enabled an insight into structure-performance relationships and revealed promising plasticizing properties of this new bio-based plasticizer generation with, e.\u2009g., an attractive solution temperature fulfilling the criterium for a \u201cfast fuser\u201d as well as good compatibility with PVC.<\/p>\n\n\n\n
Introduction<\/h3>\n\n\n\n
Although plastics are currently controversially discussed for pollution issues, the use of polymers is still inevitable for numerous applications, e.\u2009g., in the construction and automotive industry or as vital disposables for medical use.1<\/a><\/sup> They are often superior compared to common materials like wood, metal or glass due to their combination of low cost, low weight and durability as well as, at least in part, sustainability.2<\/a><\/sup> At the same time, the search for more sustainable solutions moving away from petrochemical feedstocks as the major raw material basis for today’s plastics is ongoing. However, when addressing the challenge of sustainable plastics production, this task (and vision as graphically outlined in Figure\u20051<\/a>) goes far beyond the issue of designing greener polymers and their related monomers. Today, tailor-made plastics require, besides the polymer itself, further components. These additives also need to be switched from typically fossil-based to bio-renewable raw materials. One of such necessary components for many applications are plasticizers, and a major application of them is related to polyvinyl chloride (PVC) as one of the leading polymers in the European polymer market.3<\/a><\/sup> After the polyolefins polyethylene (PE) and polypropylene (PP), PVC is accounted for the third-largest share of European production volume of plastics in 2018.3a<\/a><\/sup> PVC has a wide range of applications as its properties can be modified by additives.4<\/a><\/sup> Furthermore, very recently an industrial scale production of PVC being fully based on a renewable feedstock has been realized, thus addressing an important sustainability issue in this field of plastics.3b<\/a><\/sup> For their use in PVC, plasticizers represent the most important category of additives by weight.5<\/a><\/sup><\/p>\n\n\n\n Traditionally, ortho-phthalates have represented the most important and well-known product class of plasticizers. However, some of these molecules are now subject to restrictions and authorization by the EU’s REACH legislation (Regulation (EC) No. 1907\/2006) due to their toxicological profile, and by now have mostly been replaced.6<\/a><\/sup> For so-called low molecular weight phthalates (LMW) like di(2-ethylhexyl) phthalate (DEHP), reproductive toxicity with presumed endocrine-disrupting activity was shown.7<\/a><\/sup> These LMWs are restricted in all articles not explicitly exempted in Annex XVII, entry\u200551 of REACH (Regulation (EC) No. 1907\/2006). With the market launch of dioctyl terephthalate (DEHT) and diisononyl 1,2-cyclohexane dicarboxylate Hexamoll\u00ae DINCH, two alternative plasticizers are now available that can be regarded as suitable alternatives and due to their eco-\/toxicological profiles, they are used in critical applications such as toys as well as medical and food contact applications.8<\/a>, 9<\/a><\/sup><\/p>\n\n\n\n However, up to now these plasticizers used on bulk scale are based, at least to the most extent, on fossil feedstocks. With the goal to find more sustainable products based on bio-renewable raw materials, much effort has been made in recent years to develop such bio-based alternatives.10<\/a><\/sup> As raw materials, citric acid11<\/a><\/sup> as well as soybean oil,12<\/a><\/sup> castor oil13<\/a><\/sup> or cardanol14<\/a><\/sup> play an important role. Another possible feedstock is based on platform chemicals from bio-renewable resources like lignocellulose for either the synthesis of known compounds or the design of new candidates.15<\/a><\/sup>Further prominent building blocks are furfural and 5-hydroxymethylfurfural (5-HMF) as well as derivatives thereof.16<\/a><\/sup>For example, the esters of furan dicarboxylic acids showed good compatibility with PVC and low cytotoxicity. However, bad low-temperature properties and higher volatility compared to DEHP hamper their technical application.17<\/a><\/sup>Furthermore, the synthesis of 1,2-cyclohexane dicarboxylates and derivatives starting from bio-based fumarates by means of an one-pot cycloaddition of isoprene and hydrogenation was reported.18<\/a><\/sup> Complementing these efforts, we recently could show the suitability of a 3-methyl-substituted DEHP derivative, which is available from bio-based feedstocks, as a plasticizer.19<\/a><\/sup> In spite of promising performance properties such as the solution temperature in the PVC test, a drawback of this type of bio-based plasticizer is its too high viscosity.<\/p>\n\n\n\n Thus, in spite of all these efforts and the strong demand, a novel generation of plasticizers fulfilling the criteria of a bio-renewable feedstock basis, reduced toxicity, unchanged excellent performance features and favored economic access (which certainly is a strong advantage of the current fossil-based plasticizer product portfolio besides excellent performance data) has not been developed yet.<\/p>\n\n\n\n Addressing this challenge of such a bio-based novel plasticizers generation, in this work we present the synthesis and technical evaluation of novel bicyclic plasticizer candidates 1<\/strong> and 2<\/strong>, which are fully accessible from renewable feedstocks (Scheme\u20051<\/a>). The comparison of the performance tests also enables an insight into structure-performance relationships. In this performance test study, we also included the non-biomass derived, non-methyl-substituted heterocyclic compound 3<\/strong> for comparison.<\/p>\n\n\n\n he synthetic concept for the first bio-based plasticizer target molecule 1<\/strong> is based on the use of the furan-derivative 2-methylfuran, maleic anhydride and 2-ethylhexanol as starting materials. It is noteworthy that all these involved starting materials and the reagent, in detail 2-methylfuran, maleic anhydride, molecular hydrogen and 2-ethylhexanol (resulting from bio-based n<\/em>-butanol being currently planned for production on pilot plant scale)20<\/a><\/sup> can be prepared from renewable feedstocks. As will be outlined more in detail below (Scheme\u20052<\/a>), the total (three-step) synthesis of 1<\/strong> consists of an initial Diels-Alder reaction of 2-methylfuran with maleic anhydride, followed by hydrogenation and esterification with 2-ethylhexanol (Scheme\u20052<\/a>). These three individual reactions are in general well-known as economic and sustainable technologies. Thus, not only the starting materials (being of bio-based origin) but also the selected reaction technologies for the syntheses of the target molecules are sustainable.<\/p>\n\n\n\n When carrying out the Diels-Alder reaction of 2-methylfuran with bis<\/em>(2-ethylhexyl) maleate instead of maleic anhydride, subsequent hydrogenation then leads to the second plasticizer molecule 2<\/strong> showing an opposite diastereopreference compared to 1<\/strong>. The availability of both diastereomers enables a deeper insight into the structure-activity relationship. Besides the bio-based 2-ethylhexyl diesters 1<\/strong> and 2<\/strong>, we also included the related non-bio-based and non-methyl-substituted diester 3<\/strong> in our study, which should provide information about the effect of the methyl-substituent in the target molecules 1<\/strong> and 2<\/strong> on their plasticizer performance based on criteria such as, e.\u2009g., solution temperature and viscosity data as well as compatibility with PVC. For all the synthesized diester compounds 1<\/strong>–3<\/strong> in our study, a bis<\/em>(2-ethylhexyl) ester subunit was chosen as structural diester motiffor reasons of comparability when investigating the effect of the bicyclic subunit. We will demonstrate that the new bio-based bicyclic diester molecules open up the perspective towards new lead structures of bio-based plasticizers that go beyond \u201cjust representing\u201d replacements of the state-of-the-art commercial plasticizer compounds.<\/p>\n\n\n\n The synthetic pathways to both bio-based diastereomers 1<\/strong> and 2<\/strong> are fully based on the utilization of biorenewable raw materials, and all the reactions leading to 1<\/strong> and 2<\/strong> starting from such biorenewable sources are shown in Scheme\u20052<\/a>.<\/p>\n\n\n\n As a starting material, bio-based furfural is one of the top 30 biomass-derived platform chemicals, which is annually produced today with more than 200,000\u2005tons. Bio-based materials already serve as the main source of this production of furfural, which is readily available from natural pentose sources. For example, agricultural waste streams based on oat hulls, corn cobs, and sugar cane bagasse can be used.21<\/a><\/sup> When converting 2-methylfuran (4<\/strong>, being readily accessible from furfural) in a Diels-Alder reaction with maleic anhydride (5<\/strong>), which also represents a bio-based building block being accessible by fermentation, the resulting cycloalkene derivative 6<\/strong> is formed, which can subsequently be transformed via<\/em> hydrogenation into the desired cyclic anhydride 7<\/strong>. Final ring-opening and esterification with 2 equivalents of 2-ethylhexanol (8<\/strong>) then furnishes the first desired bio-based plasticizer exo<\/em>-candidate 1<\/strong>. The formation of the thermodynamically more stable exo<\/em>-diastereomer 6<\/strong> (over the kinetically favored endo<\/em>-diastereomer) in this type of Diels-Alder reaction is in accordance with experimental and theoretical literature studies for the related Diels-Alder reaction of furan with maleic anhydride.22<\/a><\/sup> In this study it has been shown that the preference for the exo<\/em>-product is due a low thermodynamic stability of the Diels-Alder adduct, which results in a retro<\/em>-Diels-Alder reaction, thus favoring then the formation of the thermodynamically more stable exo<\/em>-product.22<\/a><\/sup> For the subsequent ring-opening and esterification step, the alcohol 8<\/strong> was chosen to allow a comparison with the standard plasticizer DEHP. The stereochemically opposite endo<\/em>-compound 2<\/strong> as a second target molecule is obtained through an initial Diels-Alder reaction of 2-methylfuran (4<\/strong>) and maleate 9<\/strong> and subsequent hydrogenation of the resulting cycloalkene 10<\/strong>, yielding the endo<\/em>-product 2<\/strong>. Note that maleate 9<\/strong> is also fully available from bio-based raw materials (Scheme\u20052<\/a>).<\/p>\n\n\n\n When realizing these synthetic concepts in our laboratory, the initial Diels-Alder reaction of 2-methylfuran (4<\/strong>) with maleic anhydride (5<\/strong>) was carried out analogously to our previous studies and literature under solvent-free conditions.19<\/a>, 23<\/a>, 24<\/a><\/sup> Without isolating the formed Diels-Alder adduct 6<\/strong>, subsequent hydrogenation at 80\u2005bar of H2<\/sub> in the presence of 2\u2005wt% of Pd\/C as a catalyst and 2-methylfuran as a solvent (leading to a substrate concentration of 2.5\u2005M) gave anhydride 7<\/strong> in 52\u2009% yield after recrystallization. This intermediate 7<\/strong> was then further converted with alcohol 8<\/strong> to the desired methyl-substituted bicyclic exo<\/em>-type diester 1<\/strong>, which was obtained after a straightforward work-up (for details, see Supporting Information) in 58\u2009% yield and with a purity of 96\u2009% according to GC analysis (Scheme\u20053<\/a>). Note that this compound 1<\/strong> has been obtained as an oil as the preferred form for an application as a plasticizer.<\/p>\n\n\n\n To gain insight into the relationship of the stereochemistry and plasticizer performance of the new bio-based plasticizer candidates, we then focused on the synthesis of the analogous endo<\/em>-isomer 2<\/strong> (Scheme\u20054<\/a>). As in the Diels-Alder reaction of 2-methylfuran (4<\/strong>) and maleic anhydride (5<\/strong>) running under kinetic control25<\/a><\/sup> exclusively the exo<\/em>-adduct 6<\/strong> is formed, we changed the reagent from anhydride 5<\/strong> to the maleic diester 9<\/strong>, which is easily accessible from bio-based raw materials (as shown in Scheme\u20052<\/a>). When starting from 9<\/strong> in the presence of a Lewis acid catalyst, the resulting Diels-Alder reaction preferably gives the endo<\/em>-isomer 2<\/strong> (Scheme\u20054<\/a>).<\/p>\n\n\n\n Since different properties are expected with an altered stereochemical configuration,26<\/a><\/sup> the different selectivities of the synthetic routes provide a good way to evaluate the influence of the endo<\/em>\/exo<\/em> configuration later in the plasticizer performance tests. In order to identify the most suitable Lewis acid for the desired endo<\/em>-selective Diels-Alder reaction of 4<\/strong> and 9<\/strong> and having been inspired by the work of Hayashi et\u2005al<\/em>.,27<\/a><\/sup> an initial catalyst screening of different types of Lewis acids was carried out (results not shown). The highest conversion (85\u2009%) to the desired product 10<\/strong> with an endo<\/em>\/exo<\/em>-selectivity of 9\u2009:\u20091 was found for Er(OTf3<\/sub>) when using this Lewis acid at a catalyst loading of 6\u2005mol% in 10 equivalents of furan 4<\/strong> at 0\u2009\u00b0C for 24\u2005h.<\/p>\n\n\n\n From the crude product of 10<\/strong>, the remaining furan substrate 4<\/strong> was evaporated under reduced pressure and Pd\/C as well as THF were added for the subsequent hydrogenation step. A hydrogen atmosphere of 1\u2005bar was applied, and the mixture was stirred for 24\u2005h at room temperature. After solvent removal and filtration, the obtained crude product of 2<\/strong>was purified via<\/em> column chromatography.<\/p>\n\n\n\n However, this turned out to be a bottleneck for further scale-up, as a simple and scalable separation of the side product di(2-ethylhexyl) succinate (being formed in the hydrogenation step from unreacted maleate 9<\/strong>) from the desired product 2<\/strong> turned out to be challenging. We could solve this issue by removing the unreacted maleate 9<\/strong> in the crude intermediate product of 10<\/strong> via<\/em> an aza<\/em>-Michael addition with pentane-1,5-diamine (12<\/strong>, which also represents a bio-based compound) and simple silica gel filtration of adduct 13<\/strong> after the Diels-Alder reaction (Scheme\u20054<\/a>). This method turned out as an efficient way for the purification of 10<\/strong> prior to column chromatography. The aza<\/em>-Michael reaction only occurred with the maleate 9<\/strong> and interestingly not with its corresponding fumarate 11<\/strong> (which represents a non-converted impurity component from the maleate substrate 9<\/strong>, which is a commercial sample with a purity of 97\u2009%) or the desired Diels-Alder endo<\/em>-intermediate 10<\/strong>. As the commercially available maleate contains 3\u2009% of fumarate 11<\/strong>, this impurity remains in the purified product. The desired endo<\/em>-type plasticizer product 2<\/strong> could be finally isolated after hydrogenation at first 0\u2009\u00b0C for 3\u2005h and then 22\u2005h at room temperature, and obtained in 105\u2005g (corresponding to 43\u2009% yield) with 97\u2009% purity (determined by 1<\/sup>H NMR spectroscopy).<\/p>\n\n\n\n For comparative studies in the subsequent plasticizer performance tests, we also prepared the non-methyl-substituted (and non-bio-based) exo<\/em>-type furan derivative 3<\/strong> (Scheme\u20051<\/a> and Scheme\u20055<\/a>) as a further product. This synthesis is based on the use of commercially available norcantharidin as starting material. The conversion with 2-ethylhexanol under acid catalysis furnished this reference compound 3<\/strong> in 80\u2009% yield and with a purity of 96\u2009% according to GC analysis. The work-up was done in analogy to our protocol developed for the exo<\/em>-product 1<\/strong>, and the whole synthesis of 3<\/strong> is described in detail in the Supporting Information. It is noteworthy that this non-methylated compound 3<\/strong> crystallized already below 35\u2009\u00b0C in contrast to the bio-based candidate 1<\/strong>, which was obtained as an oil. This illustrates the positive impact of the methyl-substituent (as a result of the structure of the bio-based raw material for 3<\/strong>) for reaching the desired oily form for an application as a plasticizer product.<\/p>\n\n\n\n Having the new bio-based plasticizer candidates 1<\/strong> and 2<\/strong> as well as the non-methylated derivative 3<\/strong> as a reference compound in hand, the properties and processibility were investigated. Furthermore, the performance in PVC was tested. For norcantharidin diester 3<\/strong>, some properties, as the viscosity at 20\u2009\u00b0C, could not be measured because of the high melting point. However, all compounds were tested for their suitability as a plasticizer for PVC. The obtained values are compared with the properties of the standard plasticizers DEHP, DEHA (DOA) and DINCH (and the structures of these commercial compounds are also shown in Scheme\u20055<\/a>).<\/p>\n\n\n\n First, physical parameters were tested to investigate the processability of the new bio-based plasticizers 1<\/strong> and 2<\/strong>. As an important indicator for the gelating properties of a plasticizer, the solution temperature of 1<\/strong>, 2<\/strong> and 3<\/strong> has been determined and compared to those of DEHP, DINP (diisononyl phthalate), DINCH (diisononyl 1,2-cyclohexane dicarboxylate; cis<\/em>\/<\/a><\/a><\/a>Results and Discussion<\/h3>\n\n\n\n
<\/a><\/a><\/a>