molecules Review Bio-Based Aromatic Epoxy Monomers for Thermoset Materials FeifeiNg,GuillaumeCouture,CoraliePhilippe,BernardBoutevinandSylvainCaillol* InstitutCharlesGerhardt—UMR5253,CNRS,UniversitédeMontpellier,ENSCM,8ruedel’EcoleNormale, 34296Montpellier,France;[email protected](F.N.);[email protected](G.C.); [email protected](C.P.);[email protected](B.B.) * Correspondence:[email protected];Tel./Fax:+330-467-144-327 AcademicEditors:ThomasFarmerandJamesH.Clark Received:24November2016;Accepted:10January2017;Published:18January2017 Abstract: The synthesis of polymers from renewable resources is a burning issue that is actively investigated. Polyepoxide networks constitute a major class of thermosetting polymers and are extensively used as coatings, electronic materials, adhesives. Owing to their outstanding mechanical and electrical properties, chemical resistance, adhesion, and minimal shrinkage after curing, theyareusedinstructuralapplicationsaswell. Mostofthesethermosetsareindustrially manufactured from bisphenol A (BPA), a substance that was initially synthesized as a chemical estrogen. TheawarenessonBPAtoxicitycombinedwiththelimitedavailabilityandvolatilecost of fossil resources and the non-recyclability of thermosets implies necessary changes in the field ofepoxynetworks. Thus,substitutionofBPAhaswitnessedanincreasingnumberofstudiesboth fromtheacademicandindustrialsides. Thisreviewproposestogiveanoverviewofthereported aromatic multifunctional epoxide building blocks synthesized from biomass or from molecules that could be obtained from transformed biomass. After a reminder of the main glycidylation routes and mechanisms and the recent knowledge on BPA toxicity and legal issues, this review will provide a brief description of the main natural sources of aromatic molecules. The different epoxyprepolymerswillthenbeorganizedfromsimple,mono-aromaticdi-epoxy,tomono-aromatic poly-epoxy, todi-aromatic di-epoxy compounds, and finally to derivatives possessing numerous aromaticringsandepoxygroups. Keywords: epoxidation;aromatic;epichlorohydrin;tannin;lignin;cardanol 1. Introduction Amidst materials widely used in plastic industry nowadays, thermosets (or thermosetting polymers) represent about 20% of plastic production [1]. They are formed from a liquid or solid mixtureofvariousingredientsincludingatleastoneormoremonomers. Oneofthesemonomers at least exhibits a functionality equal or higher than three, thus enabling the creation of a solid three-dimensionalnon-fusiblenetworkviaanexternalactionsuchasheatingorUVirradiation[2]. Thermosets include a wide range of reactive systems such as phenolic and urea formaldehyde resins,unsaturatedpolyesters,andpolyepoxides,thelatteraccountingfornearly70%ofthemarket. Polyepoxidesareoneofthemostversatileclassofcompoundswithdiverseapplications,especially coatings,whichdominatethemarket,butalsowatercontainers,automotiveprimer,printedcircuit boards, semiconductor capsules, adhesives, and aerospace composites. The global production of epoxy prepolymers is estimated to reach 3 million tons by 2017 for a market of US$ 20 billion in 2015. Thissuccessarisesfromtheexcellentmechanicalstrengthandtoughness,outstandingchemical, moisture,andcorrosionresistanceoftheepoxythermosets[3,4]. Thislistdoesnotincludevarious interestingprocess-relatedcharacteristicssuchas: theabsenceofvolatileproductsemittedduringthe Molecules2017,22,149;doi:10.3390/molecules22010149 www.mdpi.com/journal/molecules Molecules2017,22,149 2of48 polymerizationreaction,thelargechoiceofmonomersavailableorthehighadhesionpropertiestoa varietyofsurfaces. Over90%oftheseepoxymaterialsarebasedonbis(4-hydroxyphenylene)-2,2-propane,known asbisphenolA(BPA),apetrol-basedmoleculefirstsynthesizedinthe1890sandusedasasynthetic oestrogen [5]. Aromatic compounds are widely used in organic materials for their stability, their toughness, and above all their ability to structure the matter by π-stacking, thus allowing BPA to confergoodthermalandmechanicalpropertiestotheepoxythermosets. Commercializedformore than50years, BPA, mainly through its epoxy form DiGlycidylEther of Bisphenol A (DGEBA), is nowadaysspreadinmanycoatings,adhesives,laminatesandcomposites,butalsomanydomestic orevenhealthrelated-productssuchasplasticbags,foodcontainersandmetalcans,dentalsealants, soapsandlotions[6,7]. However,epoxythermosetsaresensitivetohydrolysis,whichmaycauseBPAtoleach,leadingto widespreadhumanexposure[6–9]. Unfortunately,ithasbeenclassifiedascarcinogenmutagenand reprotoxic(CMR),andisrecognizedasanendocrinedisruptor[10]. Consequently,manygovernments haverecentlyhardenedthelegislationregardingtheproductionanduseofBPA,especiallyinbaby’s bottles,foodcontainersandmedicalsupplies[11,12]. Moreover,BPAissynthesizedfromoil-based phenolandthe3Dchemicallycrosslinkednetworksofthermosetspreventthemfrombeingrecycled byheating. TheawarenessonBPAtoxicitycombinedwiththelimitedavailabilityandvolatilecost offossilresources,andthenon-recyclabilityofthermosetsimpliesnecessarychangesinthefieldof epoxynetworks. Thus,substitutionofBPAhaswitnessedanincreasingnumberofstudiesbothfrom theacademicandindustrialsides. Overthepastdecades,manybio-basedresourceshavebeentested as potential candidates for replacing BPA in epoxy resins, but very few of them have reached the commercializationstep. Amongthese,epoxidizednaturaloils[13–15]andmodifiedcardanol[16]are theonlytwotypesofepoxyresinsbasedonnaturalandnon-toxicprecursors,commerciallyavailable inthemarket. However, thelowreactivityoftheepoxygroupsalongtheiraliphaticbackbone[1] and the low glass transition temperature caused by the alkyl chain prevent them from competing withBPA-basedmaterialswiththeirhighT valuesandglassymoduli[17]. Forthisreason,many g researcheshavebeendevotedtousingglycidylatedaromaticbio-basedmaterialsassubstitutesfor BPA.Veryinterestingandexhaustivereviewshaverecentlybeenpublishedonbio-basedprecursors forthermosetsandtheirhardeners[1,18–21],buttoourknowledge,noneofthemfocusesespecially onaromaticepoxymonomersbasedonbiomassresources. Infact,onlyaromaticpoly-epoxidesseem tobeabletocompetewithDGEBAintermsofthermo-mechanicalproperties,makingthemofprimary interestforrenewability. Thus,thepresentreviewproposestogiveanoverviewofthereportedaromaticmultifunctional epoxidebuildingblockssynthesizedfrombiomassorfrommoleculesthatcouldbeobtainedfrom transformedbiomass.Afterareminderofthemainglycidylationroutesandmechanismsandtherecent knowledgeonBPAtoxicityandlegalissues,thisreviewwillprovideabriefdescriptionofthemain naturalsourcesofaromaticmolecules. Thedifferentepoxyprepolymerswillthenbeorganizedfrom simple,mono-aromaticdi-epoxy,tomono-aromaticpoly-epoxy,todi-aromaticdi-epoxycompounds, andfinallytoderivativespossessingnumerousaromaticringsandepoxygroups. Foreachone,the curingagentusedandthethermalproperties(especiallyT andthermaldegradation)ofthecrosslinked g materialwillbegivenalongwiththeirDGEBA-basedcounterpartsifavailable. Thepotentialtoxicity oftheepoxyprecursorswillalsobementioned. Tablesgatheringalltheseresultswillbegivenatthe endofeachpartforcomparativepurposes. 2. EpoxidationMethodsandProcesses Poly-functionalepoxycompoundsareveryreactivebuildingblocksandcanleadtomaterials by chain-growth polymerization or crosslinking with anhydrides, phenols and amines. They are generallypreparedbydirectglycidylation,asshowedinScheme1[1,22,23]. Itconsistsinreacting analcoholoraminederivativewithepichlorohydrin(ECH)inthepresenceofanalkylammonium Molecules2017,22,149 3of48 halideasaphasetransfercatalyst,suchasbenzyltriethylammoniumchloride,tetrabutylammonium bromideorcetyltrimethylammoniumchloride. Sometimes,epibromohydrinisusedinsteadofits chlorideanalogue[24]. Asodiumorpotassiumhydroxidepost-treatmentisusuallyappliedinsame Molecules 2017, 22, 149 3 of 47 pottoincreasethenumberofepoxyrings. Infact, thephenolicoxygenmaydisplacethechlorine Molecules 2017, 22, 149 3 of 47 adteosmiretdo pdrioredcutlcyt vyiiae lad SthNe2 dmeescirheadnipsrmo,d ourc tovpieana thSeN 2epmoexcyh rainnigs mca,uosrinogp ethnet hfoermepaotixoynr oinf ga ccahulsoirningatthede fddoeerrsmiivreaadttii ovpner otohdfauat cccta hvnli oabr eia nc SaloNtse2ed dmd beeycrh iava snattirsiovmne,g t ohbraa tsoepc atehnnr obthueegc hleo paso eSxdNyi bmryineacgh scatarnouisnsmign gb(S atcshheee tmfhorero m2u)a g[t2hio5an,2 S6o]Nf. iSamN ci hescltoahrnaidnnsai stfemodr (SdSuecrbhisvetmaittuievti2eo) tnh[ 2Na5t ,uc2ca6ln]e. obSpeNh ciillsoictsa einnddt ebsrynf oaar ls Satrunodbns gitsi b taua tsnieou ntchleNrooupuchgliheloi acp sShuNibil imsctiietnucthteiaronnnia smlmae n(cSdhcaihsneiamsmneu 2tch)l ae[2to 5ipm,2h6pil]li.ic eSssN uia bs rtsaettnietdunstti ifooonnr mofe ccohnafnigisumrattihoant. impliesaretentionofconfiguration. Substitution Nucleophilic internal and is a nucleophilic substitution mechanism that implies a retention of configuration. ScShcehmeem 1e. S1y.ntheSsyisn othf eespiosxyo fdeerpivoaxtiyveds efrroivma tpihveensolf roorm aniplihnee nboyl doirrecta gnliylicnideylbaytiodn iwreictht egpliycchildoy rolahtyiodnrin. Scwheitmhee p1.i cShylnotrhoehsyisd orfin e.poxy derivatives from phenol or aniline by direct glycidylation with epichlorohydrin. Scheme 2. Mechanism of coupling between phenolic compounds and epichlorohydrin (ECH) in the presence of a phase transfer catalyst (QX) [1,27]. Scheme 2. Mechanism of coupling between phenolic compounds and epichlorohydrin (ECH) in the Scheme2.Mechanismofcouplingbetweenphenoliccompoundsandepichlorohydrin(ECH)inthe presence of a phase transfer catalyst (QX) [1,27]. pTrheese ndcireeocft agplyhcaisdeytrlaatnisofner ocaf taplhysetn(oQl Xh)a[1s, 2p7r].oven to yield several possible side products [28–32] including chlorinated and diol derivatives (Figure 1). Furthermore, the higher reactivity of benzoic acid The direct glycidylation of phenol has proven to yield several possible side products [28–32] may Tlehaed dtoir eacnt ogplyenciidngy loaft itohne oefpopxhye nvoial bhoatshp craorvbeonn atotoymiesl, dlesaedvinegra tlop noeswsi bclhelosridineatperdo d(Bu2c)t, sd[i2o8l –(B323]) including chlorinated and diol derivatives (Figure 1). Furthermore, the higher reactivity of benzoic acid ianncdlu odxinetganceh lorirnign a(tBed1) asnidded-piorlodduercitvs a[t3iv3–e3s7(]F. igAunroeth1e).r Fiumrpthoerrtamnot rsei,dteh-eprhoidguhcetr roebascetrivveidty doufrbienngz othice may lead to an opening of the epoxy via both carbon atoms, leading to new chlorinated (B2), diol (B3) agclyidcimdyalyatlieoand sttoepa nwoitphe neipnigcholforthoheyedproinxy isv iaa bboenthzocdariobxoanna dtoemrivs,alteivaed ionbgtatoinnedew bych alonr iinnatrtae dcy(Bcl2iz),adtiioonl and oxetane ring (B1) side-products [33–37]. Another important side-product observed during the (oBc3cu)arrnindgo wxeittahn tewroin pgh(eBn1o)lisci dgero-purposd iunc otrst[h3o3 p–o3s7i]t.ioAnn (oStchheermime p3)o. rtantside-productobservedduringthe glycidylation step with epichlorohydrin is a benzodioxan derivative obtained by an intra cyclization glycidylationstepwithepichlorohydrinisabenzodioxanderivativeobtainedbyanintracyclization occurring with two phenolic groups in ortho position (Scheme 3). occurringwithtwophenolicgroupsinorthoposition(Scheme3). Figure 1. Common side-products of the direct glycidylation of phenol (A1–A3) and benzoic acid (B 1–B3). Figure 1. Common side-products of the direct glycidylation of phenol (A1–A3) and benzoic acid (B1–B3). Molecules 2017, 22, 149 3 of 47 desired product via a SN2 mechanism, or open the epoxy ring causing the formation of a chlorinated derivative that can be closed by a strong base through a SNi mechanism (Scheme 2) [25,26]. SNi stands for Substitution Nucleophilic internal and is a nucleophilic substitution mechanism that implies a retention of configuration. Scheme 1. Synthesis of epoxy derivatives from phenol or aniline by direct glycidylation with epichlorohydrin. Scheme 2. Mechanism of coupling between phenolic compounds and epichlorohydrin (ECH) in the presence of a phase transfer catalyst (QX) [1,27]. The direct glycidylation of phenol has proven to yield several possible side products [28–32] including chlorinated and diol derivatives (Figure 1). Furthermore, the higher reactivity of benzoic acid may lead to an opening of the epoxy via both carbon atoms, leading to new chlorinated (B2), diol (B3) and oxetane ring (B1) side-products [33–37]. Another important side-product observed during the glycidylation step with epichlorohydrin is a benzodioxan derivative obtained by an intra cyclization Molecules2017,22,149 4of48 occurring with two phenolic groups in ortho position (Scheme 3). Figure 1. Common side-products of the direct glycidylation of phenol (A1–A3) and benzoic acid (B1–B3). Figure 1. Common side-products of the direct glycidylation of phenol (A1–A3) and benzoic acid (B1–B3). Molecules 2017, 22, 149 4 of 47 SScchheemmee 33.. PPrroodduuccttss oobbttaainineedd dduurriningg ththee gglylyccididyylalatitoionn oof fpprorototcoactaetcehcuhiuci cacaicdi dwwithit hepeipcihclholroorhoyhdyrdinri [n38[3].8 ]. To avoid these drawbacks, Meurs et al. [39] developed a process to obtain glycidyl derivatives from Toavoidthesedrawbacks,Meursetal.[39]developedaprocesstoobtainglycidylderivatives phenol, glycidol and propylene carbonate but it requires the use of high temperatures in autoclave and fromphenol,glycidolandpropylenecarbonatebutitrequirestheuseofhightemperaturesinautoclave relatively harsh conditions. A two-step synthesis can also be used to form epoxy compounds: it involves andrelativelyharshconditions. Atwo-stepsynthesiscanalsobeusedtoformepoxycompounds: the O- or N-allylation of the corresponding alcohol or amine derivatives using an allyl halide, followed it involves the O- or N-allylation of thecorresponding alcoholor amine derivatives using an allyl by the oxidation of the resulting double bond (Scheme 4). Unfortunately, allyl chloride and allyl bromide halide,followedbytheoxidationoftheresultingdoublebond(Scheme4). Unfortunately,allylchloride are both toxic derivatives. Moreover, hydrogen peroxide exhibitis low reactivity toward allyl ether andallylbromidearebothtoxicderivatives. Moreover,hydrogenperoxideexhibitislowreactivity oxidation except at high concentrations or in the presence of metal transition catalysts [40]. The use of toward allyl ether oxidation except at high concentrations or in the presence of metal transition stronger, more toxic peracids such as m-chloroperbenzoic acid (mCPBA) is sometimes considered, but catalysts [40]. The use of stronger, more toxic peracids such as m-chloroperbenzoic acid (mCPBA) Aouf et al. [22] found that an excess of peracid is also required and the m-chlorobenzoic acid formed is sometimes considered, but Aouf et al. [22] found that an excess of peracid is also required and during the oxidation of allylated gallic acid is difficult to eliminate. The epoxidation of allyl groups by them-chlorobenzoicacidformedduringtheoxidationofallylatedgallicacidisdifficulttoeliminate. potassium peroxymonosulfate (also known as Oxone) can be considered a sustainable pathway. It is Theepoxidation of allyl groups by potassium peroxymonosulfate (also known as Oxone) can be based on the Shi epoxidation, which uses a fructose-derived organocatalyst with Oxone and ketones to consideredasustainablepathway. ItisbasedontheShiepoxidation,whichusesafructose-derived generate in situ dioxiranes [41], which are strong epoxidation agents. However, the epoxidation of organocatalystwithOxoneandketonestogenerateinsitudioxiranes[41],whicharestrongepoxidation electron-deficient alkenes such as allyl groups by dioxiranes can be very slow [42–44]. The reaction may agents. However,theepoxidationofelectron-deficientalkenessuchasallylgroupsbydioxiranescan require the use of ketones bearing highly electroattractive groups such as 1,1,1-trifluoroacetone to beveryslow[42–44]. Thereactionmayrequiretheuseofketonesbearinghighlyelectroattractive increase the overall yield [22,45]. Enzymatic catalysts have also been developed as greener alternatives groupssuchas1,1,1-trifluoroacetonetoincreasetheoverallyield[22,45]. Enzymaticcatalystshave for the oxidation of carbon-carbon double-bonds. First developed to replace the Prileshajev reaction alsobeendevelopedasgreeneralternativesfortheoxidationofcarbon-carbondouble-bonds. First applied at an industrial scale to produce epoxy vegetable oils [46], one of these catalyst (immobilized developedtoreplacethePrileshajevreactionappliedatanindustrialscaletoproduceepoxyvegetable lipase B from Candida antarctica (Novozym 435)) has also been used by Aouf et al. [40] to obtain epoxy gallic acid and vanillic acid from their allylated precursors in high yields. Scheme 4. Synthetic pathway to obtain epoxy from phenol or aniline using allyl halide and oxidation. Overall, the direct glycidylation remains the main synthetic pathway used for the industrial synthesis of Diglycidyl Ether of Bisphenol A, as it allows the recovery of both monomers and oligomers for tunable properties [23,47]. By reacting bisphenol A with a controlled excess of epichlorohydrin, the “taffy” process yields either monomers or short oligomers of DGEBA (Scheme 5). To increase the chain length of the oligomers, “advancement” (with solvent) or “fusion” (without solvent) processes can be Molecules 2017, 22, 149 4 of 47 Scheme 3. Products obtained during the glycidylation of protocatechuic acid with epichlorohydrin [38]. To avoid these drawbacks, Meurs et al. [39] developed a process to obtain glycidyl derivatives from phenol, glycidol and propylene carbonate but it requires the use of high temperatures in autoclave and relatively harsh conditions. A two-step synthesis can also be used to form epoxy compounds: it involves the O- or N-allylation of the corresponding alcohol or amine derivatives using an allyl halide, followed by the oxidation of the resulting double bond (Scheme 4). Unfortunately, allyl chloride and allyl bromide are both toxic derivatives. Moreover, hydrogen peroxide exhibitis low reactivity toward allyl ether oxidation except at high concentrations or in the presence of metal transition catalysts [40]. The use of stronger, more toxic peracids such as m-chloroperbenzoic acid (mCPBA) is sometimes considered, but Aouf et al. [22] found that an excess of peracid is also required and the m-chlorobenzoic acid formed during the oxidation of allylated gallic acid is difficult to eliminate. The epoxidation of allyl groups by potassium peroxymonosulfate (also known as Oxone) can be considered a sustainable pathway. It is based on the Shi epoxidation, which uses a fructose-derived organocatalyst with Oxone and ketones to generate in situ dioxiranes [41], which are strong epoxidation agents. However, the epoxidation of electron-deficient alkenes such as allyl groups by dioxiranes can be very slow [42–44]. The reaction may require the use of ketones bearing highly electroattractive groups such as 1,1,1-trifluoroacetone to Molecules2017,22,149 5of48 increase the overall yield [22,45]. Enzymatic catalysts have also been developed as greener alternatives for the oxidation of carbon-carbon double-bonds. First developed to replace the Prileshajev reaction oapilpsl[i4e6d] ,aot naen oifntdhuesstericaal tsaclaylset t(oim pmroodbuicliez eedpolixpya sveegBeftarobmle Coialsn d[4id6a],a onntaer cotfi ctah(eNseo cvaotzaylymst 4(3im5)m)hoabsiliazlesdo bliepeanseu Bse fdrobmy ACoaundfiedtaa aln.[t4ar0c]titcoa o(bNtaoivnoezpyomx y43g5a)l)l ihcaasc iadlsaon bdevenan uilsleicda bcyid Afrooumf etth eailr. [a4l0ly] ltaote odbptarienc uerpsooxrys ignalhliicg ahcyidie aldnds. vanillic acid from their allylated precursors in high yields. Scheme 4. Synthetic pathway to obtain epoxy from phenol or aniline using allyl halide and oxidation. Scheme4.Syntheticpathwaytoobtainepoxyfromphenoloranilineusingallylhalideandoxidation. Overall, the direct glycidylation remains the main synthetic pathway used for the industrial Overall, the direct glycidylation remains the main synthetic pathway used for the industrial synthesis of Diglycidyl Ether of Bisphenol A, as it allows the recovery of both monomers and oligomers synthesisofDiglycidylEtherofBisphenolA,asitallowstherecoveryofbothmonomersandoligomers for tunable properties [23,47]. By reacting bisphenol A with a controlled excess of epichlorohydrin, the fortunableproperties[23,47]. ByreactingbisphenolAwithacontrolledexcessofepichlorohydrin,the “taffy” process yields either monomers or short oligomers of DGEBA (Scheme 5). To increase the chain “taffy”processyieldseithermonomersorshortoligomersofDGEBA(Scheme5). Toincreasethechain leMnogletchu loesf 2t0h17e, 2o2l,i g14o9m ers, “advancement” (with solvent) or “fusion” (without solvent) processes c5a onf 4b7e lengthoftheoligomers,“advancement”(withsolvent)or“fusion”(withoutsolvent)processescan b cehcohsoense. nT.hTehy ebyobtho tchoncosinsst iisnt irnearcetainctgi nBgPBAP Awiwthi tahna enxceexscse sosf oaf parpe-rsey-nsythnetshizeesdiz eDdGDEGBAE BmAomnoomneorm teor toexetxetnedn dthteh echchaiani.n .““FFuusisoino”n ”pprorcoecsess sisi sggeenneerarlallyl ypprerefefrerrerde dfofor rtthhee iinndduusstrtriaial lpprroodduucctitoionn oof fDDGGEEBBAA oloilgigoommeersrsa asst thheep puurriifificcaattiioonn sstteeppss aarree eeaassiieerr aanndd ththee chchlolorirnien ecocnotnetnetn otfo tfhteh feinfianl aplropdroudctu icst lioswloewr tehratnh iann inthteh ecacsaes oefo thfeth “eta“ftfayf”f yp”ropcreossc,e wssh,iwchh ricehqurierqeus iarne sexacnesesx ocef sespoicfhelopriochhylodrroinh.y drin. Scheme 5. Two main industrial processes for the synthesis of monomers and oligomers of diglycidyl Scheme5.Twomainindustrialprocessesforthesynthesisofmonomersandoligomersofdiglycidyl ether of vanillyl alcohol (DGEBA): (i) the taffy process with a controlled excess of epichlorohydrin and (ii) etherofvanillylalcohol(DGEBA):(i)thetaffyprocesswithacontrolledexcessofepichlorohydrinand the advancement/fusion process using an excess of a pre-synthesized DGEBA monomer. (ii)theadvancement/fusionprocessusinganexcessofapre-synthesizedDGEBAmonomer. In terms of sustainability, both bisphenol A and epichlorohydrin used for the synthesis of DGEBA Intermsofsustainability,bothbisphenolAandepichlorohydrinusedforthesynthesisofDGEBA are mostly oil-based. BPA is obtained from reaction of acetone and phenol and epichlorohydrin is are mostly oil-based. BPA is obtained from reaction of acetone and phenol and epichlorohydrin synthesized in two steps by reacting hypochlorous acid on allyl chloride and then treating the alcohol is synthesized in two steps by reacting hypochlorous acid on allyl chloride and then treating the mixture obtained with a strong base [48]. In 2007, Solvay designed the EPICEROLTM process to produce alcoholmixtureobtainedwithastrongbase[48]. In2007,SolvaydesignedtheEPICEROLTMprocess epichlorohydrin from bio-based glycerol, thus allowing to reduce the content of fossil resources used for to produce epichlorohydrin from bio-based glycerol, thus allowing to reduce the content of fossil DGEBA production [49–53]. However, the percentage of carbon atoms in the oligomers coming from resources used for DGEBA production [49–53]. However, the percentage of carbon atoms in the ECH is low, thus making the impact limited. Furthermore, whatever synthetic pathway or process is oligomerscomingfromECHislow,thusmakingtheimpactlimited. Furthermore,whateversynthetic chosen, reagents (e.g., epichlorohydrin and allyl halides) are all carcinogen agents (H350). Allyl bromide pathway or process is chosen, reagents (e.g., epichlorohydrin and allyl halides) are all carcinogen is also very toxic for the environment. The toxicity of these reactions is a true issue, and alternatives have agents(H350). Allylbromideisalsoverytoxicfortheenvironment. Thetoxicityofthesereactions to be found over time. Although the production of epoxides is generally well-controlled by the ismaatnruufeacistusureer, aanndd athltee rrnesautlitvinesg hreasvienst oanbde fmouatnedriaolvs edrot inmoet .eAxhltihbiot utgheh ttohxeicpitryo douf cthtieosne orefaecptaonxtisd, etsheis intrinsic toxicity of BPA remains. 3. Toxicity of Bisphenol A and Regulations Bisphenols (BPs) are part of the common class of endocrine disruptors because of their significant hormonal activity, with Bisphenol A being the most famous of them. In fact, BPA exhibits one of the highest production volume of chemicals worldwide [7], with a manufacture of approximately 3.8 million tons per year in 2006 [54]. About 80% of the global production of BPA is used for the synthesis of polycarbonate, 18% for epoxy resins and the remainder for other applications, such as food containers, paper products (e.g., thermal receipts), water pipes, toys, medical equipment, and electronics [6,7]. As a consequence, human beings and environment are constantly exposed to BPA: it has been detected in 95% of human urine samples, which indicates that this compound may leach into food or water [7–9,55]. Furthermore, several studies found that BPA is present in high prevalence in fetuses and infants [7,8,56] and has undeniably an impact on human health leading to precocious puberty, cancer, diabetes, obesity, neurological disorders, and so on. Theoretical and experimental studies can be carried out to forecast the potential toxicity of a compound or to determine the different types of interactions between this compound and estrogen receptors. For example, the “read-across” method, based on analogies between substances is currently developing. It first consists in gathering data on the physical and biological properties of chemicals exhibiting a structure similar to the target molecule. Then, by taking into account previously observed trends, it is considered possible to extrapolate on the target molecule’s behavior [57]. QSAR (Quantitative Structure Activity Relationship) models enable a qualitative and quantitative determination of the endocrine activity in terms of affinity, and give some information about the Molecules2017,22,149 6of48 generallywell-controlledbythemanufacturerandtheresultingresinsandmaterialsdonotexhibitthe toxicityofthesereactants,theintrinsictoxicityofBPAremains. 3. ToxicityofBisphenolAandRegulations Bisphenols(BPs)arepartofthecommonclassofendocrinedisruptorsbecauseoftheirsignificant hormonal activity, with Bisphenol A being the most famous of them. In fact, BPA exhibits one of the highest production volume of chemicals worldwide [7], with a manufacture of approximately 3.8milliontons per year in 2006 [54]. About 80% of the global production of BPA is used for the synthesis of polycarbonate, 18% for epoxy resins and the remainder for other applications, such as food containers, paper products (e.g., thermal receipts), water pipes, toys, medical equipment, andelectronics[6,7]. Asaconsequence,humanbeingsandenvironmentareconstantlyexposedto BPA:ithasbeendetectedin95%ofhumanurinesamples,whichindicatesthatthiscompoundmay leach into food or water [7–9,55]. Furthermore, several studies found that BPA is present in high prevalence in fetuses and infants [7,8,56] and has undeniably an impact on human health leading toprecociouspuberty,cancer,diabetes,obesity,neurologicaldisorders,andsoon. Theoreticaland experimentalstudiescanbecarriedouttoforecastthepotentialtoxicityofacompoundortodetermine thedifferenttypesofinteractionsbetweenthiscompoundandestrogenreceptors. Forexample,the “read-across”method,basedonanalogiesbetweensubstancesiscurrentlydeveloping. Itfirstconsists ingatheringdataonthephysicalandbiologicalpropertiesofchemicalsexhibitingastructuresimilar to the target molecule. Then, by taking into account previously observed trends, it is considered possibletoextrapolateonthetargetmolecule’sbehavior[57]. QSAR(QuantitativeStructureActivity Relationship)modelsenableaqualitativeandquantitativedeterminationoftheendocrineactivity in terms of affinity, and give some information about the underlying mechanism [58]. Recently, Delfosseetal.[59]describedforthefirsttimethemodeofactionofBPAatthemolecularscaleand developedabio-informaticstooltopredicttheinteractionsbetweenbisphenolsandthetargetreceptors (estrogen receptors (ERs) or other members of the nuclear hormone receptor family). Numerous studiesdemonstratedthatbisphenolAhastwomajormodesofactions: steroidrelatedmodeand epigenetic mode. Concerning the latter, Dolinoy et al. [60] have shown the ability of BPA to alter DNA methylation. Regarding the steroid related mode, BPA can act as an estrogen agonist when itbindstonuclearestrogenreceptors(ERαandERβ)[61–64]. Morerecently,Takayanagietal.[65] demonstratedthatBPAalsobindstotheestrogen-relatedreceptor-γ(ERRγ)withhighconstitutive activity. Furthermore,BPAalsobehavesasanandrogenreceptorantagonist(AR)whichaffectsthe activation and function of the AR [66,67]. According to many lines of evidence, BPA acts as an endocrinedisruptorevenatlowdoses. Areview,basedonhundredsofstudies,concludedthatthere issufficientevidenceforlowdoseeffectsofBPA.Indeed,forthesestudies,authorsuseddosesbelow thoseusedfortraditionaltoxicologicalstudies,andfoundnonmonotonicdose-responsecurves[68]. Bisphenolsarecomposedoftwophenolslinkedbyacentralcarbonatom,whichinthecaseof BPAbearstwoadditionalmethylgroups(Figure2B).ThesestructuralfeaturesmakeBPAabletomimic thenaturalestrogen17β-estradiol(Figure3),intermsofbindingabilitytoestrogenreceptors[69,70]. Infact,themaincharacteristicsofthenaturalligandsrequiredforthesteroidactivityarethepresence of phenol groups on a hydrophobic backbone [71,72]. A recent paper has demonstrated that all thestructuralelementsofBPAareprerequisiteforbindingtheestrogen-relatedreceptor-γ(ERRγ), especiallythetwophenolicandmethylgroups[10]. Firstly,theauthorsdemonstratedthatthephenol structureofBPAisanessentialelementtobindERRγandonlyoneofthetwophenolichydroxygroups isrequiredforthefullbinding. Nevertheless,thepresenceofasecondoxygen-basedgroupincreases thesteroidactivity[73]. Molecules 2017, 22, 149 6 of 47 underlying mechanism [58]. Recently, Delfosse et al. [59] described for the first time the mode of action of BPA at the molecular scale and developed a bio-informatics tool to predict the interactions between bisphenols and the target receptors (estrogen receptors (ERs) or other members of the nuclear hormone receptor family). Numerous studies demonstrated that bisphenol A has two major modes of actions: steroid related mode and epigenetic mode. Concerning the latter, Dolinoy et al. [60] have shown the ability of BPA to alter DNA methylation. Regarding the steroid related mode, BPA can act as an estrogen agonist when it binds to nuclear estrogen receptors (ERα and ERβ) [61–64]. More recently, Takayanagi et al. [65] demonstrated that BPA also binds to the estrogen-related receptor-γ (ERRγ) with high cMoonlesctuilteus t2i0v1e7 , a2c2t, i1v4i9t y. Furthermore, BPA also behaves as an androgen receptor antagonist (AR) w6 hoifc 4h7 affects the activation and function of the AR [66,67]. According to many lines of evidence, BPA acts as an underlying mechanism [58]. Recently, Delfosse et al. [59] described for the first time the mode of action of endocrine disruptor even at low doses. A review, based on hundreds of studies, concluded that there is BPA at the molecular scale and developed a bio-informatics tool to predict the interactions between sufficient evidence for low dose effects of BPA. Indeed, for these studies, authors used doses below those bisphenols and the target receptors (estrogen receptors (ERs) or other members of the nuclear hormone used for traditional toxicological studies, and found nonmonotonic dose-response curves [68]. receptor family). Numerous studies demonstrated that bisphenol A has two major modes of actions: steroid related mode and epigenetic mode. Concerning the latter, Dolinoy et al. [60] have shown the ability of BPA to alter DNA methylation. Regarding the steroid related mode, BPA can act as an estrogen agonist when it binds to nuclear estrogen receptors (ERα and ERβ) [61–64]. More recently, Takayanagi et al. [65] demonstrated that BPA also binds to the estrogen-related receptor-γ (ERRγ) with high constitutive activity. Furthermore, BPA also behaves as an androgen receptor antagonist (AR) which affects the activation and function of the AR [66,67]. According to many lines of evidence, BPA acts as an endocrine disruptor even at low doses. A review, based on hundreds of studies, concluded that there is sufficient evidence for low dose effects of BPA. Indeed, for these studies, authors used doses below those Molecules2017,22,149 7of48 used for traditional toxicological studies, and found nonmonotonic dose-response curves [68]. Figure 2. Chemical structures of bisphenol analogues (A); bisphenol A (B); bisphenol F (C) and bisphenol S (D). Bisphenols are composed of two phenols linked by a central carbon atom, which in the case of BPA bears two additional methyl groups (Figure 2B). These structural features make BPA able to mimic the natural estrogen 17β-estradiol (Figure 3), in terms of binding ability to estrogen receptors [69,70]. In fact, the main characteristics of the natural ligands required for the steroid activity are the presence of phenol groups on a hydrophobic backbone [71,72]. A recent paper has demonstrated that all the structural elements of BPA are prerequisite for binding the estrogen-related receptor-γ (ERRγ), especially the two phenolic and methyl groups [10]. Firstly, the authors demonstrated that the phenol structure of BPA is an essential element to bind ERRγ and only one of the two phenolic hydroxy groups is required for the fulFl ibgFiunirgdeu i2rn.e gC2.h .NemCevihceearml tshitcreuallectssustr,r eutshc oteuf rbpeirssepsohefennbcoiesl paohnfea anlo ogslueaceons na(Aldo) g;o buxiesyspgh(eAenn)-o;blba Aisse p(dBh )e;g nbroioslupAhpe ni(nBoc)l ;rFeb (aiCsspe) sah netdnh oeb lissFpteh(reCon)iodal nSa dc(Dtiv).i ty [73]. bisphenolS(D). Bisphenols are composed of two phenols linked by a central carbon atom, which in the case of BPA bears two additional methyl groups (Figure 2B). These structural features make BPA able to mimic the natural estrogen 17β-estradiol (Figure 3), in terms of binding ability to estrogen receptors [69,70]. In fact, the main characteristics of the natural ligands required for the steroid activity are the presence of phenol groups on a hydrophobic backbone [71,72]. A recent paper has demonstrated that all the structural elements of BPA are prerequisite for binding the estrogen-related receptor-γ (ERRγ), especially the two phenolic and methyl groups [10]. Firstly, the authors demonstrated that the phenol structure of BPA is an essential element to bind ERRγ and only one of the two phenolic hydroxy groups is required for the full binding. Nevertheless, the presence of a second oxygen-based group increases the steroid activity [73]. FFigiguurree3 3.. SSttrruuccttuurree ooff 1177ββ--eessttrraaddioiol.l . By analogy with 17β-estradiol, these two hydroxyl groups are essential to establish interactions Byanalogywith17β-estradiol,thesetwohydroxylgroupsareessentialtoestablishinteractions with the hydrophobic pocket created by the receptor [74,75]. This pocket consists of several combining withthehydrophobicpocketcreatedbythereceptor[74,75]. Thispocketconsistsofseveralcombining sites where estrogen or other ligands can bind. The size of the pocket is 440 Å [74–76], which is bigger siteswhereestrogenorotherligandscanbind. Thesizeofthepocketis440Å[74–76],whichisbigger than the natural estrogen molecule size (245 Å) allowing hydrogen binding interactions (Figure 4). Liu et thanthenaturalestrogenmoleculesize(245Å)allowinghydrogenbindinginteractions(Figure4). L iuetal.[77]alsoshowedthatthesubstitutionofoneofthetwoaromaticringsbyamethylorethyl group led to a decrease of the interaction with the hydrophobic part of the receptor, whereas the presenceofchlorinesubstituentsonthe3–5positionsofthefirstaromat icringstrengthensaffinity withthereceptor. Figure 3. Structure of 17β-estradiol. Thepresenceandthedistancebetweenthetwohydroxylgroupsarenottheonlycriticalfactors. OkadBaye atnaal.lo[1g0y] wcleitahr l1y7dβe-emstorandstioral,t ethdetshea ttwthoe haylkdyrolxgyrol ugprosuopns tahree ceesnsternatliacla rtboo enstaatbolmisho finbtiesrpahcteionnosl pwliatyh athkee hyyrdorloepinhosbeilce cptoiockneot fctrheaetehdu mbya nthees rtreocegpetnorr e[c7e4p,7t5o]r. sT:hEiRs RpoγcokretE cRoαn.siEstRs αofp sreevfeerraslt hcoembbuilnkiinegr asinteds mwohreeree leescttrroogpehni loicr aoltkhyelr glirgoaunpdss, wcahne breinads.E TRhReγ sipzree foefr tshteh epolecsksetb iusl k4y40a Ånd [7le4s–s76e]l,e cwtrhoipchh iilsi cbaiglkgyerl gthraonu pthse. Anabtuurlakly egstrroougpeno mnothleeccuelen tsriazle c(a2r4b5o Ån) aatlolomwiisngo bhvyidoruosglyend bisinaddvinagn itnatgeeroauctsioinnst e(Frmigusroef 4b)i. nLdiuin egt BPAtoERRγ’sbindingpocketandreducesitsactivity. Furthermore,itwasshownthatoneofthe twomethylgroupsonthecentralcarbonatomofBPAisinvolvedinthehydrophobicintermolecular interactionwiththereceptorresidue,suchasCH -alkylandCH/πinteractions. 3 The increasing concerns about the detrimental effects of BPA has led governments to enforce regulationsmostlyintheEuropeanUnionandNorthAmericainordertolimittheexpositionoftheir citizenstothissubstance. Forexample,in2014,inlinewiththeopinionadoptedbytheRAC(Risk Assessment Committee), Bisphenol A has been classified in the hazard class reproductive toxicity category1B“maydamagefertility”. IntheframeoftheREACHregulation,theFrenchpropositionof therestrictionofBPAinthermalpaperswasapprovedonthe6July2016bytheREACHCommittee. The BPA European legislation involves different elements such as the restriction of the contact of infantsandyoungpeoplewiththissubstance,throughtoys,feedingbottles,etc.[11,78–80]. BPAis authorizedasadditiveormonomerinthemanufactureofplasticmaterialsandarticlesincontactwith Molecules2017,22,149 8of48 foodandwaterbutaspecificmigrationlimitvalueof0.6mg/kgoffoodhasbeenset[12]. Regarding cosmeticproducts,BisphenolAisrecordedinthelistoftheprohibitedsubstances[81].Alltheproducts Molecules 2017, 22, 149 7 of 47 madeofBPAcan’tbeeligibleforapositiveEco-Label[82]andtheindicativelimitofoccupational eaxl.p [o77s]u arelso[8 s3h]otwoeBdP Athapta trhteic sluesbsitsit1u0timong o/fm on3.e Soof mthee ctwouon atrroiemsastuicc rhinagssF brya nac meehtahvyel oers teatbhlyils hgreoduepv leend mtoo ar edsetcrricetaslee goisf lathtieo ninstetorawctairodns wBPitAh t[h84e ],haynddrotphhisobciocu pnatrrty opfr othpeo sreedceBpPtoAr, awshaeRreEaAs CthHe Rpreegsuenlactei oonf ccahnlodriidnaet esusbusbtisttuaennctes oofnv tehrey 3h–i5g hpocsointicoenrsn o(fS tVhHe fCir)st[ 8a5r]oamnadticco rninfigr mstreednigtsthaednvs earftfionnityth wei3t0h Athueg ruesctep20to1r6. . FFiigguurree 44.. XX--rraayy ssttrruuccttuurree ooff tthhee hhyyddrroopphhoobbiicc ppoocckkeett ooff eessttrrooggeenn rreecceeppttoorr ((EERR))αα [[7766]],, aaccccoorrddiinngg ttoo tthhee wwoorrkkss ooff BBrrzzoozzoowwsskkii eett aal.l .[7[744] ]anandd TaTnanenebnabuamum ete atl.a [l7.5[7].5 ]. The presence and the distance between the two hydroxyl groups are not the only critical factors. FollowingthepublicconcernandthestringentregulationsontheproductionanduseofBPA, Okada et al. [10] clearly demonstrated that the alkyl groups on the central carbon atom of bisphenol play severalbisphenolanalogueshavebeenproducedasalternativesubstances. Thesefollowinganalogues, a key role in selection of the human estrogen receptors: ERRγ or ERα. ERα prefers the bulkier and more BPF (4,4(cid:48)-methylenediphenol) and BPS (4-hydroxyphenyl sulfone) (Figure 2C,D), are frequently electrophilic alkyl groups, whereas ERRγ prefers the less bulky and less electrophilic alkyl groups. A found in most scientific and environmental studies because they are among the main substitutes bulky group on the central carbon atom is obviously disadvantageous in terms of binding BPA to ofBPAinpolycarbonate-basedplasticsandepoxyresins. Availablestudieshavereportedavarietyof ERRγ’s binding pocket and reduces its activity. Furthermore, it was shown that one of the two methyl detrimentaleffectsofthesebisphenolanalogues[86]andshowedthatthetoxicityoftheseanalogs groups on the central carbon atom of BPA is involved in the hydrophobic intermolecular interaction issimilartoorevengreaterthanthatofBPA[87,88]. Thetoxiceffectsincludeendocrinedisruption, with the receptor residue, such as CH3-alkyl and CH/π interactions. cytotoxicity, genotoxicity, reproductive toxicity, neurotoxicity, etc. A recent article by Rochester The increasing concerns about the detrimental effects of BPA has led governments to enforce andBolden[89],focusingonthehormonalactivitiesofBPFandBPSdemonstratedthatthesetwo regulations mostly in the European Union and North America in order to limit the exposition of their analogueshaveahormonalactionsimilartoBPAinvitroandinvivo. HexafluorobisphenolA(BPAF) citizens to this substance. For example, in 2014, in line with the opinion adopted by the RAC (Risk and4,4(cid:48)-(1-methylpropylidene)bisphenol(BPB),twootherssubstituentsofBPA,havealsoshown Assessment Committee), Bisphenol A has been classified in the hazard class reproductive toxicity estrogenicandanti-androgenicactivities[88].Therefore,aharmlessletalonerenewableepoxybuilding category 1B “may damage fertility”. In the frame of the REACH regulation, the French proposition of the blockisstillrequired[90]. Forthisreason,bio-masshasbeenconsideredacheapsourceofpotentially restriction of BPA in thermal papers was approved on the 6 July 2016 by the REACH Committee. The functionalizablemonomersoroligomers. Aspreviouslystated,thealreadycommercializedbio-based BPA European legislation involves different elements such as the restriction of the contact of infants and epoxy monomers cannot compete with DGEBA-based materials in terms of thermo-mechanical young people with this substance, through toys, feeding bottles, etc. [11,78–80]. BPA is authorized as properties,becauseoftheircharacteristicstructureandlowaromaticcontent. Thus,thenextpartwill additive or monomer in the manufacture of plastic materials and articles in contact with food and water brieflypresentthenaturalsourcesofrenewablearomaticcompoundspotentiallycapableofstanding but a specific migration limit value of 0.6 mg/kg of food has been set [12]. Regarding cosmetic products, upforBPAreplacement. Bisphenol A is recorded in the list of the prohibited substances [81]. All the products made of BPA can’t be eligible for a positive Eco-Label [82] and the indicative limit of occupational exposure [83] to BPA 4. MainNaturalSourcesofAromaticMoieties particles is 10 mg/m3. Some countries such as France have established even more strict legislations Thepresentpartwillbrieflysummarizethemainsourcesofaromaticmoietiesbearingreactive towards BPA [84], and this country proposed BPA as a REACH Regulation candidate substance of very groups suitable for the introduction of epoxy moieties. This summary will include resources high concern (SVHC) [85] and confirmed its advert on the 30 August 2016. Following the public concern and the stringent regulations on the production and use of BPA, several bisphenol analogues have been produced as alternative substances. These following analogues, BPF (4,4′-methylenediphenol) and BPS (4-hydroxyphenyl sulfone) (Figure 2C,D), are frequently found in most scientific and environmental studies because they are among the main substitutes of BPA in Molecules 2017, 22, 149 8 of 47 polycarbonate-based plastics and epoxy resins. Available studies have reported a variety of detrimental effects of these bisphenol analogues [86] and showed that the toxicity of these analogs is similar to or even greater than that of BPA [87,88]. The toxic effects include endocrine disruption, cytotoxicity, genotoxicity, reproductive toxicity, neurotoxicity, etc. A recent article by Rochester and Bolden [89], focusing on the hormonal activities of BPF and BPS demonstrated that these two analogues have a hormonal action similar to BPA in vitro and in vivo. Hexafluorobisphenol A (BPAF) and 4,4′-(1-methylpropylidene) bisphenol (BPB), two others substituents of BPA, have also shown estrogenic and anti-androgenic activities [88]. Therefore, a harmless let alone renewable epoxy building block is still required [90]. For this reason, bio-mass has been considered a cheap source of potentially functionalizable monomers or oligomers. As previously stated, the already commercialized bio-based epoxy monomers cannot compete with DGEBA-based materials in terms of thermo-mechanical properties, because of their characteristic structure and low aromatic content. Thus, the next part will briefly present the natural sources of renewable aromatic compounds potentially capable of standing up for BPA replacement. 4. Main Natural Sources of Aromatic Moieties Molecules2017,22,149 9of48 The present part will briefly summarize the main sources of aromatic moieties bearing reactive groups suitable for the introduction of epoxy moieties. This summary will include resources naturally ncoantutarianlilnygc osnmtaailnl,i npghsemnoallilc, pchoemnpoloiucncdo mspuocuh ndass uecuhgeansoelu geexntroalcteixbtlrea cftriobmle frpolamntp lnaanttunraalt uoraills,o iolsr, oprolpyoplhyepnhoelnico clircocssrolisnskleindk pedolypmoleyrms esruschsu acsh taasntnainnns inansda nlidgnliignn tihnatth caatnc abne bdeirdeicrtelcyt lfyunfucnticotnioalnizaelidz eodr odrepdoelpymoleyrmizeerdi zinedto isnmtoalslemr amlloelrecmuloelse cpuriloers tpo reioproxtiodaetpioonx isdteaptiso. nSosmteep isn.foSrommaetioinn foonr mthaetiiro anvaoinlabthileitiyr aovr awiloarblidliwtyidoer pwroodrludcwtioidne wpirlol dbue cgtiivoennw aisl lwbeellg aivs ethnea mswaienl lkansotwhne mchaairnacktneroiwstincsc ohfa rthaectire rsitsrtuiccstuorfe.t hTehier sretraudcetru mrea.yT rheeferre taod tehrem vaasytlrye fdeorctuomtehnetevda srtelvyiedwoc furomme nLtoecdharebv eite wal. f[r9o1m] aLnodc bhoaobke ftroaml. [B9e1l]gaancedmb oanokd fGroamndBineil g[a9c2e] mona nrdenGeawnadbilnei [r9e2s]ouonrcreesn aenwda bnleatruersaolulyr coecscaunrdrinnga tuprhaelnlyoloicc cduerrriinvagtipvheesn tool icodbteariinv amtivoerse tdoetoabilteadin dmatoa.r edetaileddata. 44..11.. LLiiggnniinn LLiiggnniinn iiss tthhee wwiiddeesstt ddiissttrriibbuutteedd aarroommaattiicc bbiiooppoollyymmeerr aanndd tthhee sseeccoonndd mmoosstt aabbuunnddaanntt nnaattuurraallllyy ooccccuurrrriinngg mmaaccrroommoolleeccuulele aafftteerr cceelllululolossee, ,ccoonnstsittiututintign gfrformom 11%% toto 4433%% bbyy wweeiigghhtt ooff tthhee ddrryy lliiggnnoocceelllluulloossicic bbioiommasass,s w, withit ah paotpeontteianlt aiavlaailvabaiilliatbyi elixtcyeeedxcinege d3i0n0g b3il0li0onb itlolniosn [1t7o,n93s–[9157],. 9I3t –is9 5a] c.elIlt-wisaall cceolml-wpoanllecnotm bopnodnienngt bceolnlsd tionggectehlelsr tiong tehteh ewroinodthye swteomosd, ypsrotevmidsi,npgr othveidmin wgitthhe tmhewir itwhetlhl-ekinrowwenll -rkingiodwitny raingdid iimtypaancdt rimespisatacntcrees. iAstlatnhcoeu.gAhl tihtso uabgshoiltustea bsstorulucttuerset rruecmtuariensr eumnakinnoswunn kannodw vnaarineds vacacroiersdaincgco trod itnhge tpolatnhte pitl aonrtigitinoartiegsi nfartoemsf raonmd aintsd ietnsveinrovnirmonemnte, nlti,glniginn inis isanan aammoorrpphhoouuss tthhrreeee--ddiimmeennssiioonnaall ppoollyymmeerr nneettwwoorrkk ooff tthhrreeee mmaaiinn mmeetthhooxxyyllaatteedd pphheennyyll pprrooppaannee uunniittss ((FFiigguurree 55)) wwiitthh sseevveenn mmaajojorr lliinnkkaaggeess:: ββ--OO--44 ((aarryyll eetthheerr)),, αα--OO--44,, ββ--ββ ((ppiinnoorreessiinnooll)),, ββ--55 ((pphheennyyllccoouummaarraann)),, ββ--11 ((ddiipphheennyyllmmeetthhaannee)), ,55,,55 aanndd 44--OO--55 ((ddiipphheennyyll eetthheerr)) lliinnkkaaggeess.. IItt eexxhhiibbiittss vvaarriioouuss ffuunnccttiioonnaall ggrroouuppss ssuucchh aass aalliipphhaattiicc aanndd pphheennoolliicc hhyyddrrooxxyyll,, ccaarrbbooxxyylliicc,, ccaarrbboonnyyl laanndd mmeeththooxyxy mmoioeiteietise. s. Figure 5. Main aromatic subunits found in lignin. Figure5.Mainaromaticsubunitsfoundinlignin. Usually,ligninisviewedasawastematerialderivedfromthewoodpulpinthepaperindustry andavailableinlargequantity(50–70millionoftonsestimated)[96]. Unfortunately,only1%to2%of overallligninisusedformorespecificapplications,theremainingprimarilyservingasa(bio)fuelfor thecelluloseextraction[97]. Ligninisextractedfromlignocellulosicbiomassbytwomaincategories ofprocesses: (i)sulfurprocessesyieldinglignosulfateandKraftligninand(ii)sulfur-freeprocesses yieldingorganosolvandsodalignin. Theseextractionmethodsgreatlyinfluencethealreadycomplex structure of the polymer, sometimes making it difficult to directly use it as a chemical precursor. Forthisreason,workshavebeencarriedouttodepolymerizeligninintosmaller,simpleraromatic moleculessuitableforchemicalmodificationand/orpolymerization. Forexample,whenligninis depolymerized,compoundssuchasvanillin,phenolsderivatives,cresols,ferulicandcoumaricacids arereleased(Figure6). Allthesemoleculesarealreadyoil-basedbutthispathwayoffersaninteresting solutionfortheirrenewability,thusincreasingthermosetsrenewability. Molecules 2017, 22, 149 9 of 47 Usually, lignin is viewed as a waste material derived from the wood pulp in the paper industry and available in large quantity (50–70 million of tons estimated) [96]. Unfortunately, only 1% to 2% of overall lignin is used for more specific applications, the remaining primarily serving as a (bio)fuel for the cellulose extraction [97]. Lignin is extracted from lignocellulosic biomass by two main categories of processes: (i) sulfur processes yielding lignosulfate and Kraft lignin and (ii) sulfur-free processes yielding organosolv and soda lignin. These extraction methods greatly influence the already complex structure of the polymer, sometimes making it difficult to directly use it as a chemical precursor. For this reason, works have been carried out to depolymerize lignin into smaller, simpler aromatic molecules suitable for chemical modification and/or polymerization. For example, when lignin is depolymerized, compounds such as vanillin, phenols derivatives, cresols, ferulic and coumaric acids are released (Figure 6). All these Mmoolelceucluesl2e0s1 7a,r2e2 ,a1l4r9eady oil-based but this pathway offers an interesting solution for their renewa1b0iolift4y8, thus increasing thermosets renewability. Figure 6. Various aromatic moieties obtained from lignin depolymerization [93,94]. Figure6.Variousaromaticmoietiesobtainedfromlignindepolymerization[93,94]. 4.2. Tannins 4.2. Tannins Tannins are the second bio-based source of natural phenolic moieties and the third most abundant Tanninsarethesecondbio-basedsourceofnaturalphenolicmoietiesandthethirdmostabundant compounds extracted from wood biomass, with 160,000 tons bio-synthesized each year [98,99]. They can compoundsextractedfromwoodbiomass,with160,000tonsbio-synthesizedeachyear[98,99]. They be found mainly in the soft tissues such as wood, bark, leaves or needles of all vascular and some canbefoundmainlyinthesofttissuessuchaswood,bark,leavesorneedlesofallvascularandsome non-vascular plants, in which they play a protective role against outside aggressions and in plant growth non-vascular plants, in which they play a protective role against outside aggressions and in plant regulation [100]. Tannins are polyphenol derivatives with low molecular weights and can be divided growthregulation[100]. Tanninsarepolyphenolderivativeswithlowmolecularweightsandcanbe into three main categories: hydrolysable tannins, condensed tannins and complex tannins, the latter dividedintothreemaincategories: hydrolysabletannins,condensedtanninsandcomplextannins,the being a combination of the first two. latterbeingacombinationofthefirsttwo. Hydrolysable tannins are a mixture of phenolic esters of sugars (Figure 7A) readily hydrolyzed by Hydrolysabletanninsareamixtureofphenolicestersofsugars(Figure7A)readilyhydrolyzed acids, alkalis or enzymes, and present a low availability (less than 10% of the world’s commercial byacids,alkalisorenzymes,andpresentalowavailability(lessthan10%oftheworld’scommercial production) [101]. They are mainly used in the tanning industry. The condensed tannins may represent production)[101]. Theyaremainlyusedinthetanningindustry. Thecondensedtanninsmayrepresent the most interesting derivatives with 90% of global production. They are based on four types of the most interesting derivatives with 90% of global production. They are based on four types of repeating flavonoid units: profisetinidin, procyanidin, prorobinetidin, and prodelphinidin linked by C4– repeating flavonoid units: profisetinidin, procyanidin, prorobinetidin, and prodelphinidin linked C6 or C4–C8 bonds (Figure 7B). Thanks to their availability, aromatic moieties and rigid structure, their by C4–C6 or C4–C8 bonds (Figure 7B). Thanks to their availability, aromatic moieties and rigid numerous functionalizable hydroxyl functions and nucleophilic sites, condensed tannins may represent structure, their numerous functionalizable hydroxyl functions and nucleophilic sites, condensed an interesting candidate for BPA substitution. Similarly to lignin, some studies are conducted on the tanninsmayrepresentaninterestingcandidateforBPAsubstitution. Similarlytolignin,somestudies depolymerization of tannins to obtain phenolic monomers as building units for thermosets [98,102,103]. areconductedonthedepolymerizationoftanninstoobtainphenolicmonomersasbuildingunits For example, Roumeas et al. [102] successively used thiol and furan derivatives as nucleophiles for the for thermosets [98,102,103]. For example, Roumeas et al. [102] successively used thiol and furan derivativesasnucleophilesfortheacid-assisteddepolymerizationofcondensedtanninsintocatechin andthioetherorfuranderivativesofcatechin. Finally,alastclassoftannins,phlorotannins,canbefoundinnon-vascularplantssuchasalgaeand arebasedonpolymerizedphloroglucinol(1,3,5-trihydroxybenzene)withalargerangeofmolecular weights [98]. They play a role similar to condensed tannins in vascular plant and can as well be dividedintocategoriesaccordingtothelinkbetweenphloroglucinolunitse.g.,ether,phenylbonds, acombinationofboth,oradibenzo-p-dioxinbond(Figure8).