molecules Review Radical Polymerization of Alkyl 2-Cyanoacrylates Review RadicalCormac Duffy Polymerization 1,2, Per B. Zetterlund 3 and of Fawaz Alkyl Aldabbagh 2-Cyanoacrylates 2,4,* 1. Henkel Ireland Operations & Research Limited, Whitestown, Dublin 24, Ireland; [email protected] Cormac2. School Duffy of 1,2Chemistry,, Per B. ZetterlundNational University3 and Fawaz of Ireland Aldabbagh Galway, University2,4,* ID Road, Galway H91 TK33, Ireland 3. Centre for Advanced Macromolecular Design (CAMD), School of Chemical Engineering, The University of 1 Henkel Ireland Operations & Research Limited, Whitestown, Dublin 24, Ireland; [email protected] New South Wales, Sydney, NSW 2052, Australia; [email protected] 2 School of Chemistry, National University of Ireland Galway, University Road, Galway H91 TK33, Ireland 4. Present address: Department of Pharmacy, School of Life Sciences, Pharmacy & Chemistry, Kingston 3 Centre for Advanced Macromolecular Design (CAMD), School of Chemical Engineering, University, Penrhyn Road, Kingston upon Thames KT1 2EE, UK The University of New South Wales, Sydney, NSW 2052, Australia; [email protected] * Correspondence: [email protected]; Tel.: +44-20-8417-2528 4 Present address: Department of Pharmacy, School of Life Sciences, Pharmacy & Chemistry, Received:Kingston University,3 February Penrhyn2018; Accepted: Road, Kingston 17 February upon 2018 Thames; Published: KT1 2EE, 20 February UK 2018 * Correspondence: [email protected]; Tel.: +44-20-8417-2528 Abstract: Cyanoacrylates (CAs) are well-known fast-setting adhesives, which are sold as liquids in Received: 3 February 2018; Accepted: 17 February 2018; Published: 20 February 2018 the presence of stabilizers. Rapid anionic polymerization on exposure to surface moisture is Abstract:responsibleCyanoacrylates for instant (CAs) adhesion. are well-known The more fast-setting difficult adhesives,, but synthetically which are sold more as liquids useful in r theadical presencepolymerization of stabilizers. is only Rapid possible anionic under polymerization acidic conditions on exposure. Recommendations to surface moisture on the ishandling responsible of CAs forand instant the resulting adhesion. polymers The more are difficult, provided but herein. synthetically In this review more article useful, radicalafter a general polymerization description is of onlymonomer possible underand polymer acidic conditions. properties Recommendations, radical homo- and on co thepolymerization handling of CAs studies and the are resulting described, polymersalong with are providedan overview herein. of nanoparticle In this review preparations article, after. A asumm generalary descriptionof our recent ofly monomer reported andradical polymerpolymerization properties, of radical CAs, homo- using and reversible copolymerization addition- studiesfragmentation are described, chain alongtransfer with (RAFT) an overviewpolymerization of nanoparticle, is provided preparations.. A summary of our recently reported radical polymerization of CAs, using reversible addition-fragmentation chain transfer (RAFT) polymerization, is provided. Keywords: cyanoacrylate; instant adhesives; super glue; polymerization; radical Keywords: cyanoacrylate; instant adhesives; super glue; polymerization; radical

1. Introduction 1. Introduction Alkyl 2-cyanoacrylates or cyanoacrylates (CAs) are a family of vinyl monomers renowned for theirAlkyl high 2-cyanoacrylates reactivity, instant or cyanoacrylatesadhesive properties (CAs), an ared awide family-ranging of vinyl applications monomers [1 renowned–6]. Short forchain theirCA highs, like reactivity, methyl instant- and ethyl adhesive 2-cyanoacrylate properties, and have wide-ranging found great applications utility as the [1– 6 major]. Short components chain CAs, of likeindustrial methyl- and and ethyl household 2-cyanoacrylate instant haveadhesives found or great “super utility glues”, as the includingmajor components those manufactured of industrial at andHenkel household under instant the Loctite adhesives brand or (Table “super 1) glues”, [4–6]. including those manufactured at Henkel under the Loctite brand (Table1)[4–6]. Table 1. Structure and commercial uses of common cyanoacrylates (CAs). Table 1. Structure and commercial uses of common cyanoacrylates (CAs). Structure R Uses Structure RMe Loctite Uses 496 super bonder MeEt LoctiteLoctite 496 401 super instant bonder adhesive i-PropylEt Loctite 401Root instant canal adhesive sealant i-Propyl Root canal sealant nn-Butyl-Butyl Skin/surgicalSkin/surgical adhesive adhesive 2-Octyl2-Octyl SkinSkin surgical surgical adhesive adhesive Allyl High temperature adhesive Allyl High temperature adhesive β-Methoxyethyl Low odor adhesive ββ--EthoxyethylMethoxyethyl LowLow odor odo adhesiver adhesive βPhenylethyl-Ethoxyethyl AdhesiveLow odo tapesr adhesive Phenylethyl Adhesive tapes Longer-chain CAs, such as n-butyl and 2-octyl 2-cyanoacrylate (Figure1), have found utility as surgical suture replacements for skin and tissue adhesives [7–10]. Poly(CAs) have gained recognition for numerous biomedical applications due to their favorable biocompatibility, biodegradability, and low toxicity. Colloidal nanoparticles derived from CAs have shown great promise in the field of drug and vaccineMolecules delivery 2018, 23 [, 11465–;16 doi:].10.3390/molecules23020465 CA is used in latent fingerprint development in forensicwww.mdpi.com/journal/ science, wherebymolecules

Molecules 2018, 23, 465; doi:10.3390/molecules23020465 www.mdpi.com/journal/molecules Molecules 2018, 23, 465 2 of 22

Longer-chain CAs, such as n-butyl and 2-octyl 2-cyanoacrylate (Figure 1), have found utility as surgical suture replacements for skin and tissue adhesives [7–10]. Poly(CAs) have gained recognition for numerous biomedical applications due to their favorable biocompatibility,

Moleculesbiodegradability2018, 23, 465, and low toxicity. Colloidal nanoparticles derived from CAs have shown 2 great of 21 promise in the field of drug and vaccine delivery [11–16]. CA is used in latent fingerprint development in forensic science, whereby CA vapors adheres to trace amino acids present in the CAfingerprint vapors adheres [17,18]. to Due trace to amino its unsaturated acids present ester in the group fingerprint, allyl [217-cyanoacrylate,18]. Due to its has unsaturated the ability ester to group,undergo allyl crosslinking 2-cyanoacrylate reactions has theat elevated ability to temper undergoatures, crosslinking a feature reactions that has at found elevated use temperatures, in thermally aresistant feature that adhe hassive founds [5] use. β- inMethoxyethyl thermally resistant- and β adhesives-ethoxyethyl [5]. β2-Methoxyethyl--cyanoacrylate andhaveβ -ethoxyethyl lower vapor 2-cyanoacrylatepressures compared have to lower shorter vapor chain pressures CAs and compared are often to used shorter as low chain odo CAsr adhesives. and are oftenAdditionally, used as lowthese odor adhesives adhesives. avoid Additionally, a phenomenon these adhesivescharacteristic avoid of atheir phenomenon shorter chain characteristic counterparts of their, known shorter as chain“blooming”, counterparts, whereby known polymerized as “blooming”, monomer whereby vapor polymerized is deposited monomer as a fine chalky vapor is powder deposited on the as asurface fine chalky near powderan adhesive on the bond surface-line, nearand anare adhesivesometimes bond-line, referred andto as are “low sometimes-bloom” referredadhesives to [4] as. “low-bloom”Phenylethyl adhesives2-cyanoacrylate [4]. Phenylethyl differs from 2-cyanoacrylate the previously differs named from CA thes in previously that it is named a solid CAs and in is thatutilized it is ain solid industrial and is adhesive utilized intapes industrial and films adhesive [19]. tapes and films [19].

(a) (b) (c)

Figure 1. (a) 2-octyl (b) β-ethoxyethyl (c) phenylethyl 2-cyanoacrylates. Figure 1. (a) 2-octyl (b) β-ethoxyethyl (c) phenylethyl 2-cyanoacrylates.

The general monomer chemistry, synthesis, modes of polymerization, and the physical The general monomer chemistry, synthesis, modes of polymerization, and the physical characteristics of the resulting polymers, along with several toxicological evaluations, have been characteristics of the resulting polymers, along with several toxicological evaluations, have been detailed in a number of reviews [1–15,20–22]. In this review, after a general overview of reactivity and detailed in a number of reviews [1–15,20–22]. In this review, after a general overview of reactivity properties, the focus is the radical polymerization of CAs, with the advantages over the more facile and properties, the focus is the radical polymerization of CAs, with the advantages over the more anionic pathway clearly outlined. facile anionic pathway clearly outlined. 2. General Reactivity and Properties 2. General Reactivity and Properties 2.1. Anionic-Type Polymerizations 2.1. Anionic-type Polymerizations The high reactivity of CAs is attributed to the strong electron-withdrawing nitrile (CN) and ester The high reactivity of CAs is attributed to the strong electron-withdrawing nitrile (CN) and (CO2R) groups attached to the α-carbon of the double bond. The β-carbon of CAs is activated towards nucleophiles,ester (CO2R) groups such as attached anions, as to wellthe α as-carbon weak bases,of the water,double and bond. alcohols The β (Scheme-carbon 1of). CA In ans is adhesive activated context,towards polymerizationnucleophiles, such or curingas anions, occurs as well through as weak rapid bases, initiation water, from and alcohols the thin (Scheme film of moisture 1). In an Moleculescommonlyadhesive 2018 , context, found23, 465 on polymerization the surface of most or curing materials. occurs through rapid initiation from the thin film 3of of 22 moisture commonly found on the surface of most materials. (a) - HO + -

(b) -

Scheme 1. (a) Anionic and (b) zwitterionic initiation. Scheme 1. (a) Anionic and (b) zwitterionic initiation.

Initiation can rapidly occur upon contact with anions, as well as with non-dissociated base species, such as tertiary amines and tertiary phosphines, leading to zwitterionic polymerization [23– 28]. Regardless of whether polymerization is initiated by an anionic or non-dissociated nucleophilic base, a propagating carbanion is formed on the -carbon, which is resonance stabilized through the CN and CO2R groups (Scheme 2).

-

- -

Scheme 2. Resonance stabilization of cyanoacrylate (CA) α-carbanion adduct.

The stabilization of the negative charge through delocalization at the α-carbon atom, in combination with the sterically unhindered and highly electrophilic nature of the β-carbon, makes the cyanoacrylate molecule uniquely reactive. The carbanion adds to another monomer molecule to generate a dimeric species, which in turn reacts with more monomer until high molecular weight polymer is formed, typically in the range of 105–107 g·mol−1 (Scheme 3) [29]. The poly(CA) molecular weights are not greatly affected by temperature, but can be affected by pH [30]. Solution polymerizations of n-butyl 2-cyanoacrylate in tetrahydrofuran (THF) at 20 °C using tetrabutylammonium salts as initiators gave extremely high rates of polymerization, with propagation rate coefficient (kp) values close to 106 L·mol−1 s−1 [28]. The kp values for CAs are significantly greater than that for the anionic polymerization of methyl methacrylate (MMA), with kp = 775 L·mol−1 s−1 being initiated by a tetraphenylphosphonium salt under similar experimental conditions of 20 °C in THF [31]. Rapid initiation of CA polymerization leads to characteristics close to those of ideal living polymerization, with molecular weights in approximation to theoretical values, based on the monomer/initiator ratio [32].

Propagation - - + ( )n n = 40-80000

n

Scheme 3. Anionic polymerization: Propagation.

Propagation of CA polymerization will continue until all available monomers are consumed or until a chain transfer or termination step intervenes. It is believed that some chain-transfer reactions can occur in the presence of weak acids, such as the carboxylic acids formed from the hydrolysis of CA monomers [1]. Transfer of a proton to the propagating carbanion will terminate the growth to

Molecules 2018, 23, 465 3 of 22

Molecules 2018, 23, 465 3 of 22 (a) - HO + - (a) - HO + -

(b) - (b) -

Scheme 1. (a) Anionic and (b) zwitterionic initiation . Molecules 2018, 23, 465 3 of 21 Scheme 1. (a) Anionic and (b) zwitterionic initiation. Initiation can rapidly occur upon contact with anions, as well as with non-dissociated base species,Initiation such as tertiary can rapidly amines occur and upon tertiary contactcontac phosphinest with anions, anions,, leading as well to zwitterionic as as with with non-dissociated non polymerization-dissociated base [23 – 28species,]. Regardless suchsuch asas of tertiarytertiary whether amines amines polymerization and and tertiary tertiary phosphines,is phosphines initiated by leading, leading an anionic to to zwitterionic zwitterionic or non- polymerizationdissociated polymerization nucleophilic [23 –[2328–]. base,Regardless28] .a Regardless propagating of whether of whethercarbanion polymerization polymerization is formed is initiatedon is the initiated - bycarbon, an by anionic an which anionic or is non-dissociated resonanceor non-dissociated stabilized nucleophilic nucleophilic through base, the base, a propagating carbanion is formed on the -carbon, which is resonance stabilized through the CNa propagatingand CO2R groups carbanion (Scheme is formed 2). on the α-carbon, which is resonance stabilized through the CN and CN and CO2R groups (Scheme 2). CO2R groups (Scheme2). - -

- - - -

Scheme 2. Resonance stabilization of cyanoacrylate (CA) α-carbanion adduct. Scheme 2. Resonance stabilization of cyanoacrylate (CA)(CA) α-carbanion-carbanion adduct.adduct.

The stabilization of the negative charge through delocalization at the α-carbon atom, in The stabstabilizationilization of of the the negative negative charge charge through through delocalization delocalization at at the the α-carbonα-carbon atom atom,, in combinationincombination combination with with withthe the sterically thesterically sterically unhindered unhindered unhindered and highly and highly electrophilicelectrophilic electrophilic nature nature nature of of the the ofβ -βcarbon the-carbonβ-carbon,, makes, makes themakesthe cyanoacrylate cyanoacrylate the cyanoacrylate molecule molecule moleculeuniquely uniquely uniquely reactive.reactive. The reactive. carbanioncarbanion The adds carbanionadds to to another another adds m to monomer anotheronomer molecule monomermolecule to to generatemoleculegenerate a adimeric to dimeric generate species, species, a dimeric which which species,inin turnturn r whicheacts with in turn moremore reacts monomermonomer with until moreuntil high monomerhigh molecular molecular until weight highweight polymermolecularpolymer is isformed, weightformed, typically polymer typically in isin the formed,the range range typically ofof 105–10 in77 g·mol the range−−11 (Scheme (Scheme of 10 53 –103) )[2 [297 ]9g.] The·. molThe poly(− poly(1 (SchemeCACA) molecular) molecular3)[ 29]. weightsTheweights poly(CA) are are not not molecular greatly greatly weightsaffected affected are by by nottemperatempera greatlyture, affected but but canby can temperature, be be affected affected but by by canpH pH be[ 30[30 affected]. ]Solution. Solution by polymerizationspHpolymerizations [30]. Solution of polymerizations of nn-b-buutyltyl 2 2--cyanoacrylate ofcyanoacrylaten-butyl 2-cyanoacrylate inin tetrahydrofurantetrahydrofuran in tetrahydrofuran (TH (THF)F) (THF) atat 20 at 20 20 °C◦ °C C using using tetrabutylammoniumtetrabutylammonium salts salts salts as as initiators as initiators initiators gave gave gaveextremely extremely high rates highhigh of polymerization, ratesrates of of polymerization polymerization with propagation, with, with 6 −1 −1 66 −1−1 −1−1 propagationratepropagation coefficient rate rate (k p coefficient ) coefficient values close (k (kp top)) values10 valuesL·mol close close·s to [28 10 10]. L TheL··molmolkp values ss [2[28 for8].] .The CAsThe arek pk pvalues significantlyvalues for for CA greaterCAs ares are −1 −1 significantlythansignificantly that for greater greater the anionic than than that polymerization that for for the the anionicanionic of methyl polymerization methacrylate of of methyl methyl (MMA), methacrylate methacrylate with kp = 775 (MMA), (MMA), L·mol with with·s kp kp −1 −1 ◦ = being 775= 775 L · initiated Lmol·mol−1 s −s1 by being being a tetraphenylphosphonium initiated initiated by by a a tetraphenylphosphonium tetraphenylphosphonium salt under similar experimental salt salt under under similar conditionssimilar experi experi ofme 20mentalCntal conditionsinconditions THF [ 31of ].of 20 Rapid20 °C °C in in initiationTHF THF [ 31[31] of.] .R R CAapidapid polymerization initiationinitiation of CACA leads polymerizationpolymerization to characteristics leads leads closeto to characteristics characteristics to those of idealclose close to livingto those those polymerization, of of ideal ideal living living with polymerization polymerization molecular weights,, withwith inmolecular approximation weights weights to in theoretical in approximation approximation values, to based to theoretical theoretical on the valuesmonomer/initiatorvalues, based, based on on the the monomer/initiator ratio monomer/initiator [32]. ratioratio [32].

Propagation - Propagation - - + ( )n - + n = 40-80000 ( )n n = 40-80000

n n Scheme 3. Anionic polymerization: Propagation.Propagation. Scheme 3. Anionic polymerization: Propagation. Propagation of CA polymerization will continue until all available monomers are consumed or Propagation of CA polymerization will continue until all available monomers are consumed or untilPropagation a chain transfer of CA or polymerization termination step will intervenes. continue It untilis believed all available that some monomer chain-transfers are consumed reactions or until a chain transfer or termination step intervenes. It is believed that some chain-transfer reactions untilcan a occur chain in transfer the presence or termination of weak acids, step intervenes.such as the carboxylicIt is believed acids that formed some fromchain the-transfer hydrolysis reactions of can occur in the presence of weak acids, such as the carboxylic acids formed from the hydrolysis of canCA occur monomer in thes presence[1]. Transfer of weak of a proton acids, suchto the as propagating the carboxylic carbanion acids formedwill terminate from the the hydrolysis growth to of CA monomers [1]. Transfer of a proton to the propagating carbanion will terminate the growth to CA monomers [1]. Transfer of a proton to the propagating carbanion will terminate the growth to produce a dead-chain; however, the resulting conjugate base (carboxylate anion) is able to initiate a new growing polymer chain by addition onto a monomer (Scheme4). Strong acids will act as chain terminators by protonation of the anion and will rapidly kill the polymerization (Scheme5). In the case of strong mineral acids (e.g., sulfuric acid), the conjugate base is not nucleophilic enough to initiate further anionic polymerization. The investigations carried out by Pepper et al. demonstrated that in the absence of strong acid, the polymerization has no intrinsic termination reactions, and the poly(CA) carbanions are stable enough to remain active, even after addition of small amounts of common terminating agents, such as water, oxygen or CO2 [23–28,32]. The stability of the propagating species is in stark contrast to other common monomers like styrenics or (meth)acrylates, for example, where, in the Molecules 2018, 23, 465 4 of 22

produce a dead-chain; however, the resulting conjugate base (carboxylate anion) is able to initiate a new growing polymer chain by addition onto a monomer (Scheme 4). Strong acids will act as chain terminators by protonation of the anion and will rapidly kill the polymerization (Scheme 5). In the case of strong mineral acids (e.g., sulfuric acid), the conjugate base is not nucleophilic enough to initiate further anionic polymerization.

- ( )n + ( )n -

Carboxylate Molecules 2018, 23, 465 Anion 4 of 21 case of organolithium-initiated anionic polymerizations, the introduction of trace amounts of air or moisture terminates polymer growth by reacting with the active chain-end anions or the (often + - - Moleculesorganometallic) 2018, 23, 46 initiator.5 With the latter conventional anionic polymerizations stringent experimental4 of 22 conditions, including inert atmospheres and glove boxes are a requirement [33,34]. It is noteworthy produce a dead-chain; however, the resulting conjugate base (carboxylate anion) is able to initiate a that the recent advances in the synthesis of well-defined complex macromolecular architectures using new growing polymer chain by addition onto a monomer (Scheme 4). Strong acids will act as chain anionic polymerizations (including star, comb/graft, cyclic, branched, hyperbranched, dendritic and terminators by protonationScheme of the anion4. Chain and-transfer will rapidlyin anionic kill polymerization the polymerization. (Scheme 5). In the multi-block multi-component polymers [35]) are yet to be achieved with the highly reactive monomer case of strong mineral acids (e.g., sulfuric acid), the conjugate base is not nucleophilic enough to subject of this review. initiateThe further investigations anionic polymerization. carried out by Pepper et al. demonstrated that in the absence of strong acid, the polymerization has no intrinsic termination reactions, and the poly(CA) carbanions are stable enough to remain active, even after addition of small amounts of common terminating agents, such - as water, oxygen( or CO)n 2 [23–28,32+ ]. The stability of the( propagating)n species -is in stark contrast to

other common monomers like styrenics or (meth)acrylates, for example, where,Carboxylate in the case of organolithium-initiated anionic polymerizations, the introduction of trace amountsAnion of air or moisture terminates polymer growth by reacting with the active chain-end anions or the (often organometallic) initiator. With the latter conventional anionic polymerizations stringent experimental conditions, including inert atmospheres and glove boxes are a requirement [33,34]. It is - noteworthy that the recent advances+ - in the synthesis of well-defined complex macromolecular architectures using anionic polymerizations (including star, comb/graft, cyclic, branched, hyperbranched, dendritic and multi-block multi-component polymers [35]) are yet to be achieved with the highly reactive monomerScheme 4.subjectChain-transfer of this review. in anionic polymerization. Scheme 4. Chain-transfer in anionic polymerization.

The investigations carried out by Pepper etTermination al. demonstrated that in the absence of strong acid, - H+ the polymerization has( no intrinsic)n termination+ reactions, and the( poly()nCA) carbanions are stable n = 40-80000 enough to remain active, even after addition of small amounts of common terminating agents, such as water, oxygen or CO2 [23–28,32]. The stability of the propagating species is in stark contrast to other common monomersScheme like 5. Termination styrenics or of (meth)acrylatespropagating chain, withfor example strong acid., where, in the case of organolithium-initiatedScheme anionic 5. Termination polymerizations, of propagating the introduction chain with strong of traceacid. amounts of air or moisture terminates polymer growth by reacting with the active chain-end anions or the (often 2.2.2.2. Polymer Properties and Stability organometallic) initiator. With the latter conventional anionic polymerizations stringent experimentalThe glass conditions transition, including temperatures inert ( Tatmospheresg)) of of common common and poly( poly(CAs) gloveCA boxess) are are areshown shown a requirement in in Table 22.. [33,34 InIn general,general,]. It is noteworthythe Tg values that decrease the recent with advances increasing in ester the chainsynthesis length of and well steric-defined bulk.bulk. complex Tg values macromolecular can can,, however however,, architecturesvary to some some extent extentusing depending depending anionic polymerizationson on the the method method employed employed (including for fordetermination star, determination, comb/graft,, such such as cyclic, dilatometry as dilatometry branched, and hyperbranched,anddynamic dynamic thermal thermal dendritic analysis analysis. and. Additionally, multi Additionally,-block themulti the means-component means of of polymer polymer polymers sample sample [35] ) preparation preparationare yet to be (anionic (anionic achieved or withradical the polymerization),polymerization), highly reactive monomer polymerization polymerization subject temperature temperature of this review. and and resulting resulting molecular molecular weight weight can can impact impact on Tong valuesTg values [36 [36,37,37]. ].

Table 2. Glass transitionTermination temperatures (Tg) of poly(CAs). - H+ ( )n + ( )n n = 40-80000 ◦ Poly(CA) Tg, C Ref. MeCA 160 [36] EtCA 150 [38] Schemen -BuCA5. Termination (isobutylcyanoacrylate) of propagating chain 130 with strong [37] acid. 2-OctylCA 10 [1] 2.2. Polymer Properties and Stability AllylCA 90 [37] β-MethoxyethylCA 85 [1] The glass transition temperatures (Tg) of common poly(CAs) are shown in Table 2. In general, the Tg values decrease with increasing ester chain length and steric bulk. Tg values can, however, Poly(CAs) have relatively poor thermal stability [39–48], and start to degrade slightly above their vary to some extent depending on the method employed for determination, such as dilatometry and T , which is significantly less than their ceiling temperature (T )[42,45]. The latter is the temperature at dynamicg thermal analysis. Additionally, the means of polymerc sample preparation (anionic or which the rates of polymerization and depolymerization are equal [49]. Thermal behavior of isolated radical polymerization), polymerization temperature and resulting molecular weight can impact on polymers, however, can be very complex, and degradative reactions other than depolymerization will Tg values [36,37]. often occur at temperatures below the Tc. Poly(ethyl 2-cyanoacrylate), for example, begins to degrade

Molecules 2018, 23, 465 5 of 22

Table 2. Glass transition temperatures (Tg) of poly(CAs).

Poly(CA) Tg, °C Ref. MeCA 160 [36] EtCA 150 [38] n-BuCA 130 [37] (isobutylcyanoacrylate) 2-OctylCA 10 [1] AllylCA 90 [37] β-MethoxyethylCA 85 [1]

Poly(CAs) have relatively poor thermal stability [39–48], and start to degrade slightly above their Tg, which is significantly less than their ceiling temperature (Tc) [42,45]. The latter is the temperature at which the rates of polymerization and depolymerization are equal [49]. Thermal behavioMolecules r2018 of ,isolated23, 465 polymers, however, can be very complex, and degradative reactions other 5than of 21 depolymerization will often occur at temperatures below the Tc. Poly(ethyl 2-cyanoacrylate), for example, begins to degrade at around◦ its Tg of approximately 150 °C, whereas its◦ Tc has been at around its Tg of approximately 150 C, whereas its Tc has been measured as 276 C[38]. Rather measured as 276 °C [38]. Rather than a random chain scission, thermal degradation occurs through a than a random chain scission, thermal degradation occurs through a depolymerizing or “unzipping” depolymerizing or “unzipping” mechanism that starts at the chain terminus, whereby the polymer mechanism that starts at the chain terminus, whereby the polymer chains undergo retro-polymerization chains undergo retro-polymerization to reform monomers (Scheme 6) [43–47]. to reform monomers (Scheme6)[43–47].

 / Base - ( )n ( )n-1 +

Scheme 6. Degradation of poly(CAs). Scheme 6. Degradation of poly(CAs).

Poly(Poly(CAs)CAs) are very susceptible to degradation following contact contact with with water water [41,44,47 [41,44,47]],, but the rate of degradation is greatly accelerated under basic solutions [[44,4544,45].]. AdventitiousAdventitious base bases,s, present as impurities in common organic solvents solvents,, are are suffi sufficientcient to promote degradation [4 [466]].. HanHan and and Kim stored a solution of poly(ethylpoly(ethyl 22-cyanoacrylate)-cyanoacrylate) in in acetone at room temperature and periodically testedtested the the solution by g gelel permeationpermeation c chromatographyhromatography (GPC), demonstrating the the polymer peak to gradually disappear with time [47 [47]].. Ryan Ryan and and McCann McCann showed showed the the addition addition of of tetrabutylammonium tetrabutylammonium hydroxide (TBAOH) (TBAOH) to to poly( poly(nn-butyl-butyl cyanoacrylate cyanoacrylate)) in inTHF THF at 21 at °C 21 deprotonated◦C deprotonated the chain the chain end and end ledand to led ato rapid a rapid depo depolymerizationlymerization process process [45 [45]. ].The The unzipped unzipped monomer monomer is is then then instantly repolymerized in in the the presence of the base to form much lower molecular weight,weight, so so-called-called “daughter” polymers,polymers, in a a depolymerization–repolymerization depolymerization–repolymerization reaction. reaction. Similarly, Similarly, solutions of n--butylbutyl cyanoacrylate cyanoacrylate monomer monomer in in THF THF underwent underwent instantaneous instantaneous polymerization polymerization upon upon addition addition of millimolarof millimolar quantities quantities of TBAOH of TBAOH to give to giveinitially initially high highmolecular molecular weight weight polymer polymers,s, followed followed by rapid by depolymerizationrapid depolymerization and subsequent and subsequent repolymerization repolymerization to give to give lower lower molecular molecular weight weight daughter daughter polymerpolymers.s. This depolymerization depolymerization–repolymerization–repolymerization reaction was confirmed confirmed by Robello et al. in in their their studies into into the the degradation degradation of of various various poly(CAs) poly(CAs [46)]. [46 In] this. In case this the case added the baseadded was base not was a necessity not a necessityas degradation as degradation was observed was observed in acetonitrile in acetonitrile and acetone and acetone containing conta poly(CA)ining poly(CA) incubated incubated at 50 ◦ atC. 50The °C. degradation The degradation could could be effectively be effectively inhibited inhibited by addition by addition of acetic of acetic acid. acid. As As with with the the findings findings of ofthe the previous previous McCann McCann and Ryanand Ryan degradation degradation study, study, the initial the high initial molecular high molecular weight peak weight observed peak observedby GPC gradually by GPC disappeared gradually disappear over timeed and over was time accompanied and was accompanied by the simultaneous by the appearance simultaneous of appearancelower molecular of lower weight molecular peaks, indicating weight peaks, that the indicating polymer that chains the are polymer in dynamic chains equilibrium are in dynamic with etheirquilibrium monomers. with their monomers.

3. Conventional (Non-Living) Radical Polymerizations

3.1. Inhibitors and Precautions Anionic polymerization is routinely inhibited by addition of parts per million of strong organic or mineral acids. These act by proton transfer to terminate anionic or zwitterionic species, before significant chain growth occurs. Anionic inhibitors have included Lewis acids, such as BF3 complexes [48], as well as, acetic acid [50–53], dichloroacetic acid [54], trifluoroacetic acid [55], methanesulfonic acid [47], and 1,3-propanesultone [51,56–58]. Excessive acidity should, however, be avoided, due to the potential for the hydrolysis of the monomer/polymer ester functionality leading to interference with the polymerization (see above). Commercial CAs will often contain radical inhibitors, such as hydroquinone, catechol, p-methoxyphenol, butylated hydroxyanisole, and related phenolic compounds to suppress radical polymerization, which can be triggered with high temperatures or UV-light. In order to study the radical polymerization of CAs, inhibitors should be removed by distillation prior to commencing the reaction [58]. Any glassware that will come in contact with CAs should be acid washed, acetone rinsed, and oven dried before use. Distilled monomers should ideally be stored in tightly closed, high-density, polyethylene (HDPE) containers, at sub-zero temperatures. For solution polymerizations, attention Molecules 2018, 23, 465 6 of 21 should be paid to the inhibitor contained within commercial solvents which can often be nucleophilic in nature [46]. Similarly, any non-solvents used to isolate poly(CAs) by precipitation should be inhibited with strong acid (e.g., MeSO3H) to prevent anionic polymerization of residual monomers [58].

3.2. General Mechanism Once the appropriate inhibitor for anionic polymerization is added, CAs can be polymerized radically (Scheme7). Initiation takes place in two steps, as is normal in radical polymerization; the first involves the thermal homolysis of the initiator to give a pair of radicals. The initiator depicted is 2,20-azobis(2-methylpropionitrile) (AIBN), an azo-initiator frequently used with CAs. After thermal decomposition into a pair of cyanoisopropyl radicals, the second step is the addition of the initiating radical onto the CA monomer to form a propagating radical. Rapid addition onto successive monomers occurs hundreds or even thousands of times, increasing the polymer chain length with each addition until terminating events take place. The process of initiation, propagation and termination take place for each propagating species, typically in the order of less than one second, or at most, a few Molecules 2018, 23, 465 7 of 22 seconds [59].

(a)  2 + N2 Decomposition

Cyanoisopropyl Radical

NC(CH ) C Addition 3 2

NC(CH3)2C

(b)

NC(CH ) C 3 2 Propagation ( )n n = 20-8000

n Propagating Radical (c)

( )n ( )m

Coupling

( )n ( )m

( )n ( )m

Disproportionation

( )n ( )m

Scheme 7. Conventional radical polymerization: (a); Initiation (b) Propagation; and (c) Termination. Scheme 7. Conventional radical polymerization: (a); Initiation (b) Propagation; and (c) Termination.

(a)

ktr ( )n + ( )n

(b)

kri

Scheme 8. Chain transfer in radical polymerization: (a) Transfer and (b) Reinitiation.

Molecules 2018, 23, 465 7 of 22

(a)  2 + N2 Decomposition

Cyanoisopropyl Radical

NC(CH ) C Addition 3 2

NC(CH3)2C

(b)

NC(CH ) C 3 2 Propagation ( )n n = 20-8000

n Propagating Radical (c)

( )n ( )m

Coupling

( )n ( )m

Molecules 2018, 23, 465 7 of 21 ( )n ( )m

There are two different means of termination: couplingDisproportionation and disproportionation. Termination by coupling occurs when two growing chains combine to give a single dead chain. Termination by disproportionation takes place when a β-hydrogen atom is abstracted from one propagating chain, resulting in a chain with a hydrogen terminus and the other with an unsaturated chain-end. ( )n ( )m An additional occurrence in radical polymerization is chain transfer reactions (ktr), whereby a propagating radical is terminated, usually by hydrogen atom abstraction, and a new radical species is created (Scheme8). The newly created radical can then add to a monomer unit ( kri) and reinitiate polymerization. The chain transfer agent (TrH) can be the initiator, monomer, a solvent molecule Scheme 7. Conventional radical polymerization: (a); Initiation (b) Propagation; and (c) Termination. or polymer.

(a)

ktr ( )n + ( )n

(b)

kri

Molecules 2018, 23, 465 8 of 22 Scheme 8. Chain transfer in radical polymerization: (a) Transfer and (b) Reinitiation. Scheme 8. Chain transfer in radical polymerization: (a) Transfer and (b) Reinitiation. 3.3. Mechanism and Kinetics of Radical Homopolymerization 3.3. Mechanism and Kinetics of Radical Homopolymerization Various common azo- and peroxide radical initiators have been employed to initiate CA Various common azo- and peroxide radical initiators have been employed to initiate CA polymerization. AIBN and benzoyl peroxide (BPO) are the most frequently used, with the former polymerization. AIBN and benzoyl peroxide (BPO) are the most frequently used, with the former being preferred. When BPO is used as a radical initiator, both benzoyloxy and phenyl radicals being preferred. When BPO is used as a radical initiator, both benzoyloxy and phenyl radicals participate in initiation as the benzoyloxy radical decomposes to give a phenyl radical through loss participate in initiation as the benzoyloxy radical decomposes to give a phenyl radical through loss of of carbon dioxide (Scheme 9). Methyl 2-cyanoacrylate showed low reactivity towards the carbon dioxide (Scheme9). Methyl 2-cyanoacrylate showed low reactivity towards the benzoyloxy benzoyloxy radical, with initiation occurring largely through the addition of the more nucleophilic radical, with initiation occurring largely through the addition of the more nucleophilic phenyl radical, phenyl radical, as detected using doubly isotopically labelled BPO with carbon-14 and hydrogen-3 as detected using doubly isotopically labelled BPO with carbon-14 and hydrogen-3 (tritium, T) [56]. (tritium, T) [56]. For the polymerization at 60 °C, the number of phenyl α-end groups on the polymer For the polymerization at 60 ◦C, the number of phenyl α-end groups on the polymer was found to be was found to be approximately twice that of benzoyloxy end groups. approximately twice that of benzoyloxy end groups.

60  C 2 Benzoyloxy Radical

- 14

Phenyl Radical

Scheme 9. Initiation with doubly isotopically labelled benzoyl peroxide (BPO). Scheme 9. Initiation with doubly isotopically labelled benzoyl peroxide (BPO). Chappelow et al investigated the use of tri-n-butyl borane oxide (TBBO) as the radical initiator Chappelow et al investigated the use of tri-n-butyl borane oxide (TBBO) as the radical initiator for several highly reactive monomers: ethyl 2-isocyanatoacrylate, 2-isocyanatoethyl methacrylate, for several highly reactive monomers: ethyl 2-isocyanatoacrylate, 2-isocyanatoethyl methacrylate, and ethyl 2-cyanoacrylate [60]. The initiating radical was generated from the auto-oxidation of the alkylboron compound with air to give the alkyl borane peroxide and butyl radicals [61]. Homopolymerizations were carried out using 1.8 wt% of TBBO in THF at room temperature. After 21 h, poly(ethyl 2-cyanoacrylate) was isolated by precipitation into hexane at greater than 70% conversion, however, polymer formation via anionic polymerization cannot be ruled out since no anionic inhibitor was employed. The earliest report on the kinetics for the radical polymerization of CAs was by Canale et al. in 1960, who carried out polymerizations of methyl 2-cyanoacrylate using a boron trifluoride acetic acid complex as an anionic inhibitor and AIBN as the initiator [48]. The bulk parameter, kp/kt0.5, (where, kp and kt are the rate coefficients for propagation and termination, respectively) was determined to be 0.021 L·mol−1 s−1 at 60 °C. This was significantly greater than the kp/kt0.5 = 0.0144 L·mol−1 s−1 for MMA and kp/kt0.5 = 0.00166 L·mol−1 s−1 for styrene (St), measured in the same study, under the same conditions. Poly(methyl 2-cyanoacrylate) was found to be insoluble in common aromatic solvents, such as benzene and toluene. The homopolymer was also reported to be insoluble in alcohols, ketones (acetone, 2-butanone) and chlorinated solvents (chloroform, 1,2-dichloroethane). Bevington et al. used 1,3-propanesultone (0.3 wt%) as an inhibitor in the radical polymerization of methyl 2-cyanoacrylate in bulk and in solutions of 1,4-dioxane at 60 °C using AIBN and BPO as initiators [57]. The inhibitor was reported to have negligible effects on the rate of polymerization at 60 °C, even at high concentrations, above 2.6 × 10−2 M. Although the polymer was found to be insoluble in dioxane, it was deemed an acceptable diluent for the polymerization at 60 °C. In a more recent study, looking at the preparation of highly branched CA containing polymers, the homopolymerization of ethyl 2-cyanoacrylate in two different solvents at 65 °C was carried out [55].

Molecules 2018, 23, 465 8 of 21 and ethyl 2-cyanoacrylate [60]. The initiating radical was generated from the auto-oxidation of the alkylboron compound with air to give the alkyl borane peroxide and butyl radicals [61]. Homopolymerizations were carried out using 1.8 wt% of TBBO in THF at room temperature. After 21 h, poly(ethyl 2-cyanoacrylate) was isolated by precipitation into hexane at greater than 70% conversion, however, polymer formation via anionic polymerization cannot be ruled out since no anionic inhibitor was employed. The earliest report on the kinetics for the radical polymerization of CAs was by Canale et al. in 1960, who carried out polymerizations of methyl 2-cyanoacrylate using a boron trifluoride acetic acid 0.5 complex as an anionic inhibitor and AIBN as the initiator [48]. The bulk parameter, kp/kt , (where, kp and kt are the rate coefficients for propagation and termination, respectively) was determined to be −1 −1 ◦ 0.5 −1 −1 0.021 L·mol ·s at 60 C. This was significantly greater than the kp/kt = 0.0144 L·mol ·s for 0.5 −1 −1 MMA and kp/kt = 0.00166 L·mol ·s for styrene (St), measured in the same study, under the same conditions. Poly(methyl 2-cyanoacrylate) was found to be insoluble in common aromatic solvents, such as benzene and toluene. The homopolymer was also reported to be insoluble in alcohols, ketones (acetone, 2-butanone) and chlorinated solvents (chloroform, 1,2-dichloroethane). Bevington et al. used 1,3-propanesultone (0.3 wt%) as an inhibitor in the radical polymerization of methyl 2-cyanoacrylate in bulk and in solutions of 1,4-dioxane at 60 ◦C using AIBN and BPO as initiators [57]. The inhibitor was reported to have negligible effects on the rate of polymerization at 60 ◦C, even at high concentrations, above 2.6 × 10−2 M. Although the polymer was found to be insoluble in dioxane, it was deemed an acceptable diluent for the polymerization at 60 ◦C. In a more recent study, looking at the preparation of highly branched CA containing polymers, the homopolymerization of ethyl 2-cyanoacrylate in two different solvents at 65 ◦C was carried out [55]. The polymerization was 50% faster in toluene than in acetonitrile due to an apparent poorer solubility of the polymer in the former, less polar solvent. In 1983 Yamada et al. reported the first determination of absolute kp and kt for the radical polymerization of ethyl 2-cyanoacrylate using the rotating sector method [51]. The rotating sector method is so named as it refers to a rotating disc from which a sector-shaped portion is cut out; the disc is placed in between the reaction system and a non-laser light source to cause periodic interruption of light [62]. The cycling of light and dark periods allowed the parameter τs, known as the average lifetime of a growing radical under steady-state conditions, to be calculated. Once τs is known, from Equation (1), kp and kt values can be determined.

kp[M] τs =
(1) 2kt Rp

The values of kp and kt were determined for the bulk polymerization of ethyl 2-cyanoacrylate at 30 ◦C in the presence of two different anionic inhibitors. Using 7.0 wt% acetic acid, −1 −1 8 −1 −1 −1 −1 kp = 1622 L·mol ·s and kt = 4.11 × 10 L·mol ·s , and similar values of kp = 1610 L·mol ·s 8 −1 −1 and kt = 4.04 × 10 L·mol ·s were obtained when using 0.5 wt% 1,3-propanesultone. The close proximity of these values indicated that anionic polymerization was adequately suppressed by both inhibitors, and the rate coefficients were representative of the radical polymerization. The kp values for ethyl 2-cyanoacrylate were close to those determined at 30 ◦C using the same method for ethyl 2-chloroacrylate and were attributed to the nitrile group attached to the α-carbon of the double bond having a similar stabilization effect on the propagating radical as the chlorine substituent at the same position [52]. Table3 gives a comparison of experimentally measured kp values using the rotating sector method. The kp values for ethyl 2-cyanoacrylate are over five times higher than those measured for MMA and n-butyl methacrylate (n-BuMA) (Table4). Yamada’s determination of kp for the polymerization of ethyl 2-cyanoacrylate is in agreement with data derived from more recent density functional theory (DFT) computational modelling [63]. Molecules 2018, 23, 465 9 of 21

◦ Table 3. Propagation rate coefficient (kp) values at 30 C using the rotating sector method.

−1 −1 Monomer kp (L·mol ·s ) Ref. EtCA 1610–1622 [51] Ethyl chloroacrylate 1660 [52] Ethyl fluoroacrylate 1120 [53]

In 2015, the kp for n-butyl 2-cyanoacrylate was estimated to be about seven times lower −1 −1 (kp = 226 ± 32 L·mol ·s ) than that reported by Yamada et al for ethyl 2-cyanoacrylate [54]. The kp was obtained by extrapolation of experimental data for the copolymerization of the CA with MMA using the more accurate pulsed-laser polymerization coupled with size exclusion chromatography (PLP-SEC) technique. PLP uses pulsed laser irradiation to oscillate between the light and dark periods; however, the pulse width is greatly shorter (nanoseconds) compared to the cycle time of the rotating sector method (seconds). The key advantage of PLP is that it allows for kp to be calculated directly without the need to couple it to kt, and has led to greater reproducibility of kinetic results; compared to the discrepancies in experimental data observed for the rotating sector method. Consequently, PLP is now the International Union of Pure and Applied Chemistry (IUPAC) preferred method for kp determination [64]. Table4 gives a comparison of experimentally measured kp for n-butyl 2-cyanoacrylate and other common monomers using PLP, and the reader is directed to benchmark Arrhenius parameters in authoritative reports [64,65]. It is difficult to draw direct comparisons between kp values obtained from the rotating sector method and those obtained by PLP, since variations in experimentally reported kp values from different studies can reflect differences in data interpretation and the dependence of kinetic parameters on polymerization conditions. The discrepancy in the kp measured for the two different CA monomers by two different techniques is, however, significant, but, it is worth highlighting that the value obtained by Rooney et al. is an extrapolation rather than a direct PLP measurement [54].

Table 4. kp values using the pulsed-laser polymerization coupled with size exclusion chromatography ◦ (PLP-SEC) method of n-butyl cyanoacrylate at 30 C and critically evaluated kp values of common vinyl monomers at 20 ◦C.

−1 −1 Monomer kp (L·mol ·s ) Ref. n-BuCA a 226 ± 32 [54] methyl methacrylate 270 [66] n-BuMA 310 [67] MA 15,851 [65] St a 107 [68] a Measured at 30 ◦C.

As with radical polymerization of methacrylate monomers, termination in CA polymerizations is thought to predominantly occur by disproportionation. The hydrogen-atom terminated (non-functionalized) polymer chains are susceptible to the same degradation by base-catalyzed unzipping that occurs with anionically formed poly(CAs), where the chains with the unsaturated terminus do not unzip and are more stable [45,46]. Consequently, radically formed poly(CAs) exhibit greater stability than those formed by anionic polymerization. This improved stability was noted by Robello et al. during degradation studies of poly(CAs) [46]. Samples of poly(CA) derived from nucleophilic initiation completely degraded when incubated in acetonitrile at 50 ◦C for 24 h whereas only a small portion of samples derived from radical polymerization degraded under the same conditions. Manipulation of GPC data using a Gaussian numerical algorithm function for peak fitting enabled deconvolution of the GPC curves, which allowed an approximation that 80% of these polymer samples were terminated through disproportionation and 20% by combination. Molecules 2018, 23, 465 10 of 22

Table 4. kp values using the pulsed-laser polymerization coupled with size exclusion chromatography (PLP-SEC) method of n-butyl cyanoacrylate at 30 °C and critically evaluated kp values of common vinyl monomers at 20 °C.

Monomer kp (L·mol−1 s−1) Ref. n-BuCA a 226 ± 32 [54] methyl methacrylate 270 [66] n-BuMA 310 [67] MA 15,851 [65] St a 107 [68] a Measured at 30 °C.

As with radical polymerization of methacrylate monomers, termination in CA polymerizations is thought to predominantly occur by disproportionation. The hydrogen-atom terminated (non-functionalized) polymer chains are susceptible to the same degradation by base-catalyzed unzipping that occurs with anionically formed poly(CAs), where the chains with the unsaturated terminus do not unzip and are more stable [45,46]. Consequently, radically formed poly(CAs) exhibit greater stability than those formed by anionic polymerization. This improved stability was noted by Robello et al. during degradation studies of poly(CAs) [46]. Samples of poly(CA) derived from nucleophilic initiation completely degraded when incubated in acetonitrile at 50 °C for 24 h whereas only a small portion of samples derived from radical polymerization degraded under the same conditions. Manipulation of GPC data using a Gaussian numerical algorithm function for peak fitting enabled deconvolution of the GPC curves, which allowed an approximation that 80% of these polymerMolecules 2018 samples, 23, 465 were terminated through disproportionation and 20% by combination. 10 of 21

3.4. Mechanism and Kinetics of Radical Copolymerization 3.4. Mechanism and Kinetics of Radical Copolymerization One key benefit of radical polymerization, which is difficult to achieve through anionic means, One key benefit of radical polymerization, which is difficult to achieve through anionic means, is the ease of copolymerization with other monomers, generating polymers with unique and varying is the ease of copolymerization with other monomers, generating polymers with unique and varying properties. CAs form alternating head-to-tail copolymers when radically copolymerized with properties. CAs form alternating head-to-tail copolymers when radically copolymerized with electron-rich monomers, such as vinyl ethers (Scheme 10) [69,70]. electron-rich monomers, such as vinyl ethers (Scheme 10)[69,70].

AIBN, 60  C ( )n Benzene

R = alkyl Head-to-tail copolymer

Scheme 10 10.. RadicalRadical copolymerization of ethyl 2 2-cyanoacrylate-cyanoacrylate and vinyl ether ether..

For a vinylvinyl monomer,monomer, M M1,1, being being copolymerized copolymerized with with monomer monomer M M2, the2, the reactivity reactivity ratios, ratios r1, andr1 and r2, rrepresent2, represent the tendencythe tendency of the of propagating the propagating chain-end chain species-end species to self-propagate to self-propagate with its ownwith monomer its own monomerover that ofover the that other of monomer.the other monomer. Although Although it has been it has met been with met criticism, with criticism, historically, historically the Q and, thee Qscheme and e has scheme been usedhas been as a measureused as ofa measure monomer of and monomer radical reactivityand radical on areactivity quantitative on a basis, quantitative in terms basisof correlating, in termsstructure of correlating with reactivity,structure with and canreactivi be usedty, and to can predict be us reactivityed to predict ratios reactivity [71,72]. TheratiosQ [71,72and e ]values. The Q are and related e values to theare extentrelated of to resonance the extent stabilization of resonance and stabilization polarity of and the polarity monomer of andthe monomerare approximated and are approximated from its copolymerization from its copolymerization kinetic data, whereby kinetic data the, parameterwhereby theQ describesparameter the Q describesresonance the factor resonance (and to a factor certain (and degree to the a certain steric factor) degree of the the steric monomer factor) and of the the parameter monomere describes and the parameterthe polar factor. e describesQ and thee values polar assignedfactor. Q toand monomers e values assigned are correlated to monomers against theare arbitrarilycorrelated selectedagainst thereference arbitrarily values selected of Q = 1reference and e = − value0.80 fors of St. Q The= 1 and values e = of−0.80Q and fore Stincrease. The values with increasingof Q and e monomer increase withreactivity increasing and increasing monomer electron reactivity deficiency and increasing of the carbon–carbon electron deficiency double of bond.the carbon Negative–carbon values double of e bond.indicate Negative an electron-rich values double of e indicate bond. The an values electron for- methylrich double 2-cyanoacrylate bond. The were values reported for by methyl Otsu 2and-cyanoacrylate Yamada as Q were= 17 and reportede = 2.48 by from Otsu the bulkand copolymerization Yamada as Q = with 17 and MMA e in= the 2.48 presence from the of acetic bulk copolymerizationacid in a sealed tube with at 60MMA◦C usingin the AIBN presence as the of initiatoracetic acid [50 in]. Thea sealed authors tube noted at 60 that °C using the monomers AIBN as showed a high tendency for alternation, with rates of copolymerization decreasing as the CA monomer concentration increased. The modes of derivation for Q and e values without the necessity for an arbitrary assignment or without equating the polarities of conjugate monomers and radicals have led to improved methods of assessment for reactivity ratios [73,74]. Recent values of Q and e for methyl 2-cyanoacrylate have been reported as 4.91 and 0.91, respectively [75]. The values of Q and e for some common monomers are shown in Table5.

Table 5. Q and e values for methyl 2-cyanoacrylate (MeCN) and common monomers.

Monomer Q e MeCA 4.91 0.91 Vinyl Acetate (VAc) 0.026 −0.88 St 1.00 −0.80 Isoprene 1.99 −0.55 1,3-Butadiene 1.70 −0.50 MMA 0.78 0.40 Acrylamide 0.23 0.54 MA 0.45 0.64 Ethyl vinyl ether 0.018 −1.80 Acrylonitrile (AN) 0.48 1.23

Kinsinger et al. examined the radical copolymerization of methyl 2-cyanoacrylate with a wide variety of monomers [76]. The reactivity ratios for methyl 2-cyanoacrylate (M1) with a number of reference monomers in benzene at 60 ◦C using AIBN as the initiator were determined, the most Molecules 2018, 23, 465 11 of 21

important of which was that of MMA (M2), reported as r1 = 0.25 and r2 = 0.04, given that MMA has been one of the more frequently studied co-monomers with CAs. In 2016, the reactivity ratios of ethyl 2-cyanoacrylate and MMA were simulated on PROCOP software by Tang and Tsarevsky, based on their experimental copolymerization data in toluene at 65 ◦C[55]. The terminal kinetic model was used, and the theoretical kinetic curves were fitted to the experimental data. The values reported were r1 = 0.15 and r2 = 0.02, which are not too dissimilar to those reported by Kinsinger. Over the years, a series of reactivity ratios for CAs with a variety of monomers have been reported, which are summarized in Table6.

Table 6. Reactivity ratios of CAs with vinyl monomers at 60 ◦C.

CA (M1) Monomer (M2) r1 r2 Medium Ref. MeCA MA 1.2 0.1 Benzene [76] MeCA MMA 0.25 0.04 Benzene [76] MeCA St 0.03 0.01 Benzene [76] MeCA α-Methyl St 0.001 0.05 Benzene [76] MeCA VAc c 0.5 0.005 Benzene [76] MeCA MMA 0.13 0.10 Bulk [50] EtCA MMA 0.85 0.41 Bulk [47] EtCA MMA 0.16 0.08 a Bulk [51] n-BuCA MMA 0.236 0.057 b Bulk [54] a Measured at 30 ◦C, b Measured at 50 ◦C, c VAc is vinyl acetate.

Han and Kim carried out extensive studies on the stability and degradation of copolymers from ◦ the radical copolymerization of ethyl 2-cyanoacrylate and MMA using AIBN at 60 C with MeSO3H as an anionic inhibitor [47]. These copolymers were found to be random in nature with a strong alternating tendency. Due to this alternation in the copolymer system, the inclusion of MMA units in the polymer backbone close to the chain terminus was believed to be the reason for suppressing theMolecules unzipping 2018, 23, degradation465 of the polymer. The copolymers were found to have increasing thermal12 of 22 stability with increasing MMA content. Like CAs,CAs, methylene esters of malonic acid are a group of electron deficientdeficient monomers which can be polymerized both anionically and radically. Polyakova et al. studied the anionic and radical copolymerization of of a series a series of alkyl of and alkyl fluoroalkyl and fluoro methylenealkyl malonates methylene with malonates ethyl 2-cyanoacrylate with ethyl using2-cyanoacrylate a molar feed using of 5–50%a molar [77 feed]. Bulk of 5 anionic–50% [77 copolymerizations]. Bulk anionic copolymerizations were carried out usingwere carried a tert-BuLi out asusing the a initiator tert-BuLi at 20as ◦theC, whereasinitiator bulkat 20 radical°C, whereas copolymerizations bulk radical copolymerizations were carried out using were dicyclohexyl carried out peroxydicarbonateusing dicyclohexyl (DCHPC) peroxydicarbonate and BPO at 40(DCHPC)◦C and 60and◦C, BPO respectively, at 40 °C to generate and 60 °Crandom, respectively, copolymers to (Schemegenerate 11random). The fluoroalkyl copolymers methylene (Scheme malonates11). The fluoroalkyl were observed methylene to have malonates the highest w reactivityere observed toward to ethylhave the 2-cyanoacrylate, highest reactivity as determined toward ethyl by elemental 2-cyanoacrylate analysis., as The determined mechanical by andelemental chemical analysis. properties The ofmechanical cured poly(CA) and chemical based adhesiveproperties formulations of cured poly(CA) containing based 10% adhesive of alkyl formulations and fluoroalkyl containing methylene 10% malonatesof alkyl and were fluoroalkyl tested. Formulations methylene malonates containing were fluoroalkyl tested. Formulations methylene malonate containing were fluoroalkyl found to havemethylene improved malonate thermal were and found hydrolytic to have stability, improved compared thermal toand the hydrolytic control formulation stability, compared based on to ethyl the 2-cyanoacrylatecontrol formulation alone. based on ethyl 2-cyanoacrylate alone.

DCHPC / BPO + ( )m ( )n 40  C / 60  C

R = Et, Pr, n-Bu, Hept, CH (CF ) H n = 2, 4, 6 2 2 n Scheme 11. Copolymerization of CA with alkyl/fluoroalkyl methylene malonates. Scheme 11. Copolymerization of CA with alkyl/fluoroalkyl methylene malonates.

Kinsinger et al. detailed a lack of success in attempting to copolymerize 1-octene with methyl 2-cyanoacrylate, which largely resulted in CA homopolymer being formed [76]. Sperlich and Eisenbach overcame this issue by employing CF₃CO₂H or ZnCl2.OEt2 as complexing agents in the copolymerization of ethylene with ethyl 2-cyanoacrylate to form alternating copolymers [78]. Copolymerizations were carried out in a pressure reactor using DCHPC as initiator, with reaction components added together at −80 °C before being heated to 40 °C and maintained at that temperature for 15 h. The concentration of complexing agent was found to have a significant influence on the degree of alternation of the copolymer. Dikov et al. reported on the radical graft copolymerization of ethyl 2-cyanoacrylate onto poly(butadiene-co-AN) using bulk polymerizations at 60–80 °C in the presence of up to 2 wt% of the dissolved polymer with BPO as the initiator and TsOH (1 wt%) as an anionic inhibitor [79]. Graft polymerizations are useful as they allow combination of two polymers which would otherwise be incompatible. Solution copolymerizations were also carried out in toluene at 80–90 °C with up to 75 wt% poly(butadiene-co-AN) present. IR spectra of the resulting polymers gave superposition of the individual polymer spectra and were considered a good indication of a successful graft copolymerization. Polymers can act as piezoelectric materials whereby polymers’ functionality can repel or attract each other when an electrical field is applied. Hall Jr et al. synthesized a large number of nitrile containing copolymers and studied their piezoelectric properties in terms of their pyroelectric coefficients [80]. Copolymers of CA with vinyl acetate (VAc) and isopropenyl acetate were prepared using AIBN in benzene at 60–65 °C with 7 wt% of acetic acid. A copolymer of ethyl 2-cyanoacrylate and VAc gave a value of p = 6.7 μC·m−2K−1, one of the highest values recorded in the study, in contrast to the value of p = 1.94 μC·m−2K−1 measured for a copolymer of acrylonitrile (AN) and VAc. When CAs are added directly to certain electron-rich vinyl monomers, spontaneous copolymerization can occur without the requirement of an external initiator, even at room temperature—this is believed to occur through the formation of diradical intermediates (Scheme 12) [81,82]. After the formation of the intermediate diradical species, the electron-deficient CA radical rapidly adds onto another St monomer to form a new benzylic radical, which, in turn, further reacts with an CA monomer, and an alternating copolymer is generated.

Molecules 2018, 23, 465 12 of 21

Kinsinger et al. detailed a lack of success in attempting to copolymerize 1-octene with methyl 2-cyanoacrylate, which largely resulted in CA homopolymer being formed [76]. Sperlich and Eisenbach overcame this issue by employing CF3CO2H or ZnCl2.OEt2 as complexing agents in the copolymerization of ethylene with ethyl 2-cyanoacrylate to form alternating copolymers [78]. Copolymerizations were carried out in a pressure reactor using DCHPC as initiator, with reaction components added together at −80 ◦C before being heated to 40 ◦C and maintained at that temperature for 15 h. The concentration of complexing agent was found to have a significant influence on the degree of alternation of the copolymer. Dikov et al. reported on the radical graft copolymerization of ethyl 2-cyanoacrylate onto poly(butadiene-co-AN) using bulk polymerizations at 60–80 ◦C in the presence of up to 2 wt% of the dissolved polymer with BPO as the initiator and TsOH (1 wt%) as an anionic inhibitor [79]. Graft polymerizations are useful as they allow combination of two polymers which would otherwise be incompatible. Solution copolymerizations were also carried out in toluene at 80–90 ◦C with up to 75 wt% poly(butadiene-co-AN) present. IR spectra of the resulting polymers gave superposition of the individual polymer spectra and were considered a good indication of a successful graft copolymerization. Polymers can act as piezoelectric materials whereby polymers’ functionality can repel or attract each other when an electrical field is applied. Hall Jr et al. synthesized a large number of nitrile containing copolymers and studied their piezoelectric properties in terms of their pyroelectric coefficients [80]. Copolymers of CA with vinyl acetate (VAc) and isopropenyl acetate were prepared using AIBN in benzene at 60–65 ◦C with 7 wt% of acetic acid. A copolymer of ethyl 2-cyanoacrylate and VAc gave a value of p = 6.7 µC·m−2·K−1, one of the highest values recorded in the study, in contrast to the value of p = 1.94 µC·m−2·K−1 measured for a copolymer of acrylonitrile (AN) and VAc. When CAs are added directly to certain electron-rich vinyl monomers, spontaneous copolymerization can occur without the requirement of an external initiator, even at room temperature— this is believed to occur through the formation of diradical intermediates (Scheme 12) [81,82]. After the formation of the intermediate diradical species, the electron-deficient CA radical rapidly adds onto another St monomer to form a new benzylic radical, which, in turn, further reacts with an CA Molecules 2018, 23, 465 13 of 22 monomer, and an alternating copolymer is generated.

0  C, Bulk

( )n

Scheme 12. Spontaneous copolymerization of St and ethyl 2-cyanoacrylate. Scheme 12. Spontaneous copolymerization of St and ethyl 2-cyanoacrylate. 3.5. Synthetic Copolymerization Studies 3.5. Synthetic Copolymerization Studies Branched ethyl 2-cyanoacrylate copolymers were recently reported using small amounts Branched ethyl 2-cyanoacrylate copolymers were recently reported using small amounts of of haloethyl methacrylates in the presence of CBr4 and bis(2-methacryloyloxyethyl) disulfide haloethyl methacrylates in the presence of CBr4 and bis(2-methacryloyloxyethyl) disulfide ((MAOE)2S2), a disulfide-based dimethacrylate crosslinker (Scheme 13) [55]. Highly branched poly(CAs) are of special interest due to unique characteristics, like enhanced solubility and reduced viscosity, in comparison to their linear analogues with the same molecular weight. AIBN was used as the initiator at 65 °C, CF₃CO₂H as an anionic inhibitor and CBr4 was employed as a chain transfer agent to limit the polymer chain growth, inhibit gelation, and provide bromide functionality to the chain ends. Typical relative ratios were [AIBN]0:[CBr4]0:[ECA]0:[HaloEMA]0:[(MAOE)2S2]0 = 1:200:500:300:100, and by varying the amount of chain-transfer agent, crosslinker and comonomer, the point of gelation was modified for different conversions and reaction times. The resulting highly branched copolymers were selectively degraded by treatment with Bu3P to reductively cleave the disulfide bridges.

AIBN, CBr + + 4 PhCN, 65  C

( )

Scheme 13. Preparation of disulfide-containing branched CA-based copolymers.

3.6. Nanoparticles Colloidal nanosystems for drug delivery alter the pharmacokinetics of numerous drugs, which can often improve their therapeutic indexes [83]. These colloids are usually spherical, submicron in size, stable in bodily fluids, biodegradable, and have no systematic toxicity or immune response.

Molecules 2018, 23, 465 13 of 22

0  C, Bulk

( )n

Scheme 12. Spontaneous copolymerization of St and ethyl 2-cyanoacrylate.

3.5. Synthetic Copolymerization Studies MoleculesBranched2018, 23, 465ethyl 2-cyanoacrylate copolymers were recently reported using small amounts13 of of 21 haloethyl methacrylates in the presence of CBr4 and bis(2-methacryloyloxyethyl) disulfide ((MAOE)2S2), a disulfide-based dimethacrylate crosslinker (Scheme 13) [55]. Highly branched ((MAOE)2S2), a disulfide-based dimethacrylate crosslinker (Scheme 13)[55]. Highly branched poly(CAs) are of special interest due to unique characteristics, like enhanced solubility and reduced poly(CAs) are of special interest due to unique characteristics, like enhanced solubility and reduced viscosity, in comparison to their linear analogues with the same molecular weight. AIBN was used viscosity, in comparison to their linear analogues with the same molecular weight. AIBN was used as as the initiator at◦ 65 °C, CF₃CO₂H as an anionic inhibitor and CBr4 was employed as a chain transfer the initiator at 65 C, CF3CO2H as an anionic inhibitor and CBr4 was employed as a chain transfer agent agent to limit the polymer chain growth, inhibit gelation, and provide bromide functionality to the to limit the polymer chain growth, inhibit gelation, and provide bromide functionality to the chain ends. chain ends. Typical relative ratios were [AIBN]0:[CBr4]0:[ECA]0:[HaloEMA]0:[(MAOE)2S2]0 = Typical relative ratios were [AIBN]0:[CBr4]0:[ECA]0:[HaloEMA]0:[(MAOE)2S2]0 = 1:200:500:300:100, 1:200:500:300:100, and by varying the amount of chain-transfer agent, crosslinker and comonomer, and by varying the amount of chain-transfer agent, crosslinker and comonomer, the point of gelation the point of gelation was modified for different conversions and reaction times. The resulting highly was modified for different conversions and reaction times. The resulting highly branched copolymers branched copolymers were selectively degraded by treatment with Bu3P to reductively cleave the were selectively degraded by treatment with Bu P to reductively cleave the disulfide bridges. disulfide bridges. 3

AIBN, CBr + + 4 PhCN, 65  C

( )

Scheme 13. Preparation of disulfide-containing branched CA-based copolymers. Scheme 13. Preparation of disulfide-containing branched CA-based copolymers. 3.6. Nanoparticles 3.6. Nanoparticles Colloidal nanosystems for drug delivery alter the pharmacokinetics of numerous drugs, which can Colloidal nanosystems for drug delivery alter the pharmacokinetics of numerous drugs, which often improve their therapeutic indexes [83]. These colloids are usually spherical, submicron in can often improve their therapeutic indexes [83]. These colloids are usually spherical, submicron in size, stable in bodily fluids, biodegradable, and have no systematic toxicity or immune response. size, stable in bodily fluids, biodegradable, and have no systematic toxicity or immune response. Ideally, these nanoparticles can be loaded with various drugs and targeted to a specific location in the body, allowing drugs to be delivered to certain organs or cells but not to others. Site-specific targeting gives increased drug concentration to infected or abnormal cells and low concentration to normal cells, thus decreasing drug toxicity and undesirable side effects. Many synthetic polymers, such as poly(lactic acid) and poly(caprolactone), have found utility in the preparation of various drug nanocarriers, with poly(CA) becoming an established colloidal delivery system, since its introduction almost 40 years ago [84]. Poly(CA) is a favoured nanocarrier due to its ease of polymerization, biodegradability, and relatively low toxicity. Broadly speaking, polymeric nanoparticles used for drug delivery are either solid particles or hollow particles, and can be prepared by a wide variety of methods. In the case of solid particles, the drug would typically be distributed throughout the particle or located at/near the interface. In the case of hollow particles (capsules), the drug is normally solubilized in a liquid core of either water or oil, surrounded by a polymer shell (Figure2). Poly(CA) nanospheres are classically prepared by anionic emulsion or mini-emulsion polymerizations of the monomer in an acidic aqueous medium, typically of pH ≈ 3, containing a surfactant as a colloidal stabilizing agent. This relatively simple process was first reported by Couvreur et al. in 1979 [84], and numerous studies have investigated the polymerization parameters and kinetics [85–87]. Alternatively, poly(CA) nanospheres can be produced by radical polymerization using traditional radical initiators, such as AIBN, though at a very low pH of close to 1 [88]. These radical mini-emulsion polymerizations have the advantage of achieving high molecular weight poly(CAs), whereas, in the case of anionic polymerization, the molecular weight is strongly Molecules 2018, 23, 465 14 of 22

Ideally, these nanoparticles can be loaded with various drugs and targeted to a specific location in the body, allowing drugs to be delivered to certain organs or cells but not to others. Site-specific targeting gives increased drug concentration to infected or abnormal cells and low concentration to normal cells, thus decreasing drug toxicity and undesirable side effects. Many synthetic polymers, such as poly(lactic acid) and poly(caprolactone), have found utility in the preparation of various drug nanocarriers, with poly(CA) becoming an established colloidal delivery system, since its Moleculesintroduction2018, 23 almost, 465 40 years ago [84]. Poly(CA) is a favoured nanocarrier due to its ease14 of 21of polymerization, biodegradability, and relatively low toxicity. Broadly speaking, polymeric nanoparticles used for drug delivery are either solid particles or hollow particles, and can be dependent on the pH of the medium and typically results in polymers below 8000 g·mol−1. Typically, prepared by a wide variety of methods. In the case of solid particles, the drug would typically be nanoparticles have a hydrophilic shell based on poly(ethylene oxide, PEO) and hydrophobic core, distributed throughout the particle or located at/near the interface. In the case of hollow particles based on poly(n-butyl 2-cyanoacrylate). [88,89] PEO can not only impart hydrophilicity on polymers, (capsules), the drug is normally solubilized in a liquid core of either water or oil, surrounded by a but modify toxicity (see below). polymer shell (Figure 2).

Figure 2.2. TypesTypes ofof nanoparticles.nanoparticles.

ChauvierrePoly(CA) nanospheres et al. employed are redox classically radical prepared polymerization by anionic using emulsion cerium ammonium or mini-emulsion nitrate, (NHpolymerizations4)2Ce(NO3)6 ,of (CAN) the monomer in HNO3 toin initiate an acid polymerizationic aqueous medium, in the presence typically of of various pH ≈ polysaccharides,3, containing a suchsurfactant as dextran, as a colloidal heparin stabilizing or chitosan agent. [90]. T Initiationhis relatively and propagationsimple process of isobutylcyanoacrylatewas first reported by (Couvreuri-BuCA) occurredet al. in 1979 as the[84] monomer, and numerous was added studies to have the polysaccharideinvestigated the andpolymerization CAN mixture parameters to form theand polysaccharide-poly( kinetics [85–87]. iAlternatively,-BuCA) copolymer poly( (SchemeCA) nanospheres 14). The rate can of polymerizationbe produced b wasy radical found topolymerization be high due tousing the traditional fast initiation radical step. initiators The high, such radical as AIBN, initiation though rate at ata very a low low pH pH renders of close any to anionic1 [88]. These polymerization radical mini negligible-emulsion within polymerization the timescales ha ofve the the reaction advantage and of allows achieving radical high propagation molecular toMoleculesweight predominate. poly(2018, 23CA, 46s),5 This whereas initiation, in the process case of has anionic since beenpolymerization, applied to emulsionthe molecular polymerizations weight is strongly15 in of the 22 preparationdependent on of the poly(CA)-based pH of the medium nanospheres and typically with various results polysaccharidesin polymers below on 8000 the surface g·mol−1 [.91 Typically,92]. , nanoparticles have a hydrophilic shell based on poly(ethylene oxide, PEO) and hydrophobic core, based on poly(n-butyl 2-cyanoacrylate). [88,89] PEO can not only impart hydrophilicity on polymers, but modify toxicity (see below).

Chauvierre et al. employed redox radical polymerization using cerium ammonium nitrate, CAN, HNO3, 40 C (NH₄)₂Ce(NO₃)₆, (CAN) in HNO3 to initiate polymerization in the presence of various Radical Formation polysaccharides, such as dextran, heparin or chitosan [90]. Initiation and propagation of isobutylcyanoacrylate (i-BuCA) occurred as the monomer was added to the polysaccharide and CAN mixture to form the polysaccharide-poly(i-BuCA) copolymer (Scheme 14). The rate of polymerization was found to be high due to the fast initiation step. The high radical initiation rate at a low pH renders any anionic polymerization negligible within the timescale of the reaction and allows radical propagation to predominate. This initiation process has since been applied to emulsion polymerizations in the preparation of poly(CA)-based nanospheres with various polysaccharides on the surface [91,92]. i-

Propagation

Scheme 14. CAN-initiated radical polymerization of CA. Scheme 14. CAN-initiated radical polymerization of CA. Poly(CA) nanocapsules are typically prepared by anionic interfacial polymerization techniques in water-in-oilPoly(CA) nanocapsules or oil-in-water are emulsion typically systems prepared [93 by,94 ];anionic however, interfacial nanocapsules polymerization can also techniques be formed in water-in-oil or oil-in-water emulsion systems [93,94]; however, nanocapsules can also be formed by nanoprecipitation. Based on the nanoprecipitation method, preformed polymers (such as those made by radical polymerization) are dissolved in an organic solvent, typically acetone, and then added dropwise to an aqueous solution of surfactant where self-assembly gives nanocapsules [95]. Using this approach, poly[α-maleic anhydride-ω-methoxypoly(ethylene glycol, PEG)-co-EtCA] copolymers were prepared by radical solution copolymerization of a PEG macromonomer with ethyl 2-cyanoacrylate at 60 °C using AIBN (Scheme 15) [96]. The polymer formed by precipitation was added to acetone containing the drug (ibuprofen), which successfully self-assembled upon addition to water to encapsulate the drug (Figure 3) [97]. PEGylated particles (also termed “stealth” nanoparticles) are of great significance as they can escape immuno-recognition to give long-circulating drug delivery vehicles [98,99].

AIBN, 60  C + ( )x( )y Toluene

n n

Scheme 15. Polymerization of a PEG macromonomer with ethyl 2-cyanoacrylate.

Molecules 2018, 23, 465 15 of 22

 CAN, HNO3, 40 C Radical Formation

i-

Propagation

Scheme 14. CAN-initiated radical polymerization of CA.

MoleculesPoly(CA2018, 23), nanocapsules 465 are typically prepared by anionic interfacial polymerization techniques15 of 21 in water-in-oil or oil-in-water emulsion systems [93,94]; however, nanocapsules can also be formed by nanoprecipitation. Based on the nanoprecipitation method, preformed polymers (such as those by nanoprecipitation. Based on the nanoprecipitation method, preformed polymers (such as those made by radical polymerization) are dissolved in an organic solvent, typically acetone, and then made by radical polymerization) are dissolved in an organic solvent, typically acetone, and then added added dropwise to an aqueous solution of surfactant where self-assembly gives nanocapsules [95]. dropwise to an aqueous solution of surfactant where self-assembly gives nanocapsules [95]. Using this Using this approach, poly[α-maleic anhydride-ω-methoxypoly(ethylene glycol, PEG)-co-EtCA] approach, poly[α-maleic anhydride-ω-methoxypoly(ethylene glycol, PEG)-co-EtCA] copolymers were copolymers were prepared by radical solution copolymerization of a PEG macromonomer with prepared by radical solution copolymerization of a PEG macromonomer with ethyl 2-cyanoacrylate at ethyl◦ 2-cyanoacrylate at 60 °C using AIBN (Scheme 15) [96]. The polymer formed by precipitation 60wasC added using to AIBN acetone (Scheme containing 15)[96 ]. the The drug polymer (ibuprofen), formed which by precipitation successfully was self added-assembled to acetone upon containing the drug (ibuprofen), which successfully self-assembled upon addition to water to addition to water to encapsulate the drug (Figure 3) [97]. PEGylated particles (also termed “stealth” encapsulatenanoparticles) the are drug of (Figure great3 )[ significance97]. PEGylated as particlesthey can (also escape termed immuno “stealth”-recognition nanoparticles) to give are of great significance as they can escape immuno-recognition to give long-circulating drug delivery long-circulating drug delivery vehicles [98,99]. vehicles [98,99].

AIBN, 60  C + ( )x( )y Toluene

n n

Molecules 2018, 23Scheme, 465 15. Polymerization of a PEG macromonomer with ethyl 2-cyanoacrylate. 16 of 22 Scheme 15. Polymerization of a PEG macromonomer with ethyl 2-cyanoacrylate.

Figure 3. Formation of nanocapsules by polymer self-assembly. Figure 3. Formation of nanocapsules by polymer self-assembly.

Nanoparticles based based on on CAs CAs are areconsidered considered promising promising polymer polymer colloidal colloidal drug delivery drug deliverysystems, andsystem haves, and been have significantly been significantly studied for studied cancer therapyfor cancer with therapy certain with formulations certain formulations reaching Phases reaching III in clinicalPhases III trials in clinical [100]. trials [100].

3.7. Controlled/Living Radical Polymerizations 3.7. Controlled/Living Radical Polymerizations There has been onlyonly oneone reportreport onon controlled/livingcontrolled/living radical polymerization of CAs,CAs, which used reversiblereversible addition-fragmentationaddition-fragmentation chain transfer (RAFT) [[5588].]. RAFT is perhaps the most most versatile versatile reversible deactivation deactivation (controlled/living) (controlled/living) radical radical polymerization polymerization technique technique for for making precision polymers [101101].]. Given that CA propagates via a tertiary radical,radical, poly(MMA), a reasonably bulky macroRAFT agent was used to make the first block copolymers containing poly(CAs) (Scheme 16). macroRAFT agent was used to make the first block copolymers containing poly(CAs) (Scheme 16). ACN (1,1’-azobis(cyclohexanenitrile)) and 1,3-propanesultone were used as the respective radical initiator and anionic stabilizer at 90–95 °C.

m

( )n ACN, ( )n( )m 1,3-propane sultone, 90-95 C

poly(MMA) macroRAFT poly(MMA)-block-poly(CA)

Scheme 16. RAFT polymerization of CAs using a macroRAFT (reversible addition-fragmentation chain transfer) agent.

Controlled/living character in CA polymerizations were indicated by a shift in the molecular weight distributions (MWDs) to higher MW with increasing conversion, with the MWD remaining mono-modal and relatively narrow throughout. However, the refractive index (RI) GPC MWDs disguised an underlying problem, which was the inherent instability of the CA block copolymers through self-elimination of the RAFT end group to generate dithiobenzoic acid (Scheme 17). The degradation of the RAFT end group, which was not apparent by RI detection of GPC, could be visualized by UV analysis of polymer samples. UV showed several low MW peaks that were absent in the RI data, which increased in intensity with increasing conversion.

Molecules 2018, 23, 465 16 of 22

Figure 3. Formation of nanocapsules by polymer self-assembly.

Nanoparticles based on CAs are considered promising polymer colloidal drug delivery systems, and have been significantly studied for cancer therapy with certain formulations reaching Phases III in clinical trials [100].

3.7. Controlled/Living Radical Polymerizations There has been only one report on controlled/living radical polymerization of CAs, which used reversible addition-fragmentation chain transfer (RAFT) [58]. RAFT is perhaps the most versatile

Moleculesreversible2018 , deactivation23, 465 (controlled/living) radical polymerization technique for making precision16 of 21 polymers [101]. Given that CA propagates via a tertiary radical, poly(MMA), a reasonably bulky macroRAFT agent was used to make the first block copolymers containing poly(CAs) (Scheme 16). ACNACN (1,1’-azobis(cyclohexanenitrile)) (1,1’-azobis(cyclohexanenitrile)) and and 1,3-propanesultone 1,3-propanesultone were were used used as as the the respective respective radical radical ◦ initiatorinitiator and and anionicanionic stabilizer stabilizer at at 90–95 90–95 °C.C.

m

( )n ACN, ( )n( )m 1,3-propane sultone, 90-95 C

poly(MMA) macroRAFT poly(MMA)-block-poly(CA) Scheme 16. RAFT polymerization of CAs using a macroRAFT (reversible addition-fragmentation chain Scheme 16. RAFT polymerization of CAs using a macroRAFT (reversible addition-fragmentation transfer) agent. chain transfer) agent.

Controlled/livingControlled/living character in CA polymerizations werewere indicated by aa shiftshift inin thethe molecularmolecular weightweight distributionsdistributions (MWDs)(MWDs) toto higherhigher MWMW withwith increasingincreasing conversion,conversion, withwith thethe MWDMWD remainingremaining mono-modalmono-modal and and relativelyrelatively narrownarrow throughout.throughout. However,However, the the refractiverefractive index index (RI)(RI) GPC GPC MWDs MWDs disguiseddisguised anan underlyingunderlying problem,problem, whichwhich waswas thethe inherentinherent instabilityinstability ofof thethe CACA blockblock copolymerscopolymers throughthrough self-eliminationself-elimination of of the the RAFT RAFT end end group group to to generate generate dithiobenzoic dithiobenzoic acid acid (Scheme (Scheme 17). 17 The). Thedegradation degradation of the of the RAFT RAFT end end group group,, which which was was not not apparent apparent by by RI RI detection detection of ofGPC, GPC, could could be bevisualized visualized by by UV UV analysis analysis of of polymer polymer samples samples.. UV UV showed showed several several low low MW peaks that werewere absentabsent Molecules 2018, 23, 465 17 of 22 inin thethe RIRI data,data, whichwhich increasedincreased in in intensity intensity with with increasing increasing conversion. conversion.

Degradation

Poly(CA)-RAFT "Dead Polymer" Dithiobenzoic Acid

SchemeScheme 1 17.7. EliminationElimination of of the the RAFT RAFT end end group group..

ItIt seems seems that that the the acidity acidity of of the the methylene methylene at at the the chain chain terminus terminus is is enhanced enhanced by by the the inductively inductively electronelectron-withdrawing-withdrawing nitrile nitrile and and ester ester functionalities functionalities,, leading leading to to the the formation formation of of an an unsaturated unsaturated endend group. group. The The polymerization polymerization is is then then complicated complicated by by the the many many possible possible combination combinationss and and disproportionationdisproportionation reactions reactions between between propagating propagating and/or and/or dithiobenzoic dithiobenzoic acid acid-derived-derived radicals, radicals, whichwhich account account f foror the the observed observed increase increase in in the the number number of of polymer polymer chains chains obtained obtained through through analysis analysis ofof GPC GPC RI RI data data.. For For all all three three CAs investigated ( (ethylethyl 2 2-cyanoacrylate,-cyanoacrylate, nn--butylbutyl 2 2-cyanoacrylate-cyanoacrylate and and phenylethylphenylethyl 2 2-cyanoacrylate),-cyanoacrylate), loss loss of of livingness livingness wa wass about about 70% by the end of the polymerizations.

44.. Conclusions Conclusions OverOver the the years years researchers researchers have have found found the the instant instant adhesive adhesive action action of of CAs CAs to to be be a a significant significant impedimentimpediment when when it it comes comes to to realizing their synthetic potential. Clearly Clearly,, this this is is a a challenging challenging monomermonomer class class for for radical radical ho homopolymerization,mopolymerization, with with dispute disputedd po polymerizationlymerization rate rate coefficients. coefficients. CCopolymerizationopolymerization viavia radical radical means means is facile,is facile in, contrast in contrast to anionic to anionic copolymerization, copolymerization, and the and derived the derivedcopolymers copolymers are more are stable more due stable to suppression due to suppression of the unzipping of the process. unzipping The process greater. stabilityThe greater over stabilitypolymers over made polymers by the anionic made pathway by the is anionic due to the pathway greater is preponderance due to the greater of unsaturated preponderance end groups, of unsaturatedand the incorporation end groups, of alternative and the incorporation monomer repeat of alternative unit using monomer radical polymerization. repeat unit using Alternating radical polymerizationcopolymers are. Alternating formed by CA copolymers radical copolymerizations are formed by CA with radica electron-richl copolymerizations and non-activated with electronmonomers,-rich withand non initiator-free-activated spontaneousmonomers, with copolymerizations initiator-free spon alsotaneous possible. copolymerizations Copolymers of also CAs possible.with electron-rich Copolymers vinyl of monomers CAs with offer electron superior-rich piezoelectricvinyl monomers properties, offer comparedsuperior topiezoelectric analogous properties, compared to analogous copolymers with AN. RAFT enabled the preparation of the first block copolymers containing poly(CA), although control/living character was limited by the inherent instability of the resultant polymer chains that eliminate the RAFT end group. Nevertheless, the low toxicity and biocompatibility of poly(CA) materials provides stimulus for continued research, especially in the area of controlled drug release. Particularly notable are nanoparticle formations via mini-emulsion radical copolymerizations with PEG.

Acknowledgments: Authors thank Henkel Ireland for funding the PhD of Cormac Duffy.

Author Contributions: Cormac Duffy wrote this Review article, as part of his PhD thesis, directed by Prof F. Aldabbagh. Prof P. B. Zetterlund and F. Aldabbagh reviewed and corrected the manuscript. All authors contributed substantially, and with the sponsors authorized the final published version.

Conflicts of Interest: The authors declare no conflict of interest.

References

1. Klemarczyk, P.; Guthrie, J. Advances in anaerobic and cyanoacrylate adhesives. In Advances in Structural Adhesive Bonding, 1st ed.; Dillard, D., Eds.; Woodhead Publishing Limited: Cambridge, UK, 2010; pp. 96– 131, ISBN: 978-1-84569-435-7. 2. Shantha, K.L.; Thennarasu, S.; Krishnamurti, N. Developments and applications of cyanoacrylate adhesives. J. Adhes. Sci. Technol. 1989, 3, 237–260, doi:10.1163/156856189X00191. 3. Fink, J.K. Chapter 13—Cyanoacrylates. In Reactive Polymers Fundamentals and Applications, 2nd ed.; Fink, J.K., Ed.; Elsevier: London, UK, 2013; pp. 317–330, ISBN: 978-1-4557-3149-7. 4. Burns, B. Polycyanoacrylates. In Encyclopedia of Polymer Science and Technology, 4th ed.; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2016; Volume 4, pp. 1–27, ISBN: 9780471440260, doi:10.1002/0471440264.pst256.pub2.

Molecules 2018, 23, 465 17 of 21 copolymers with AN. RAFT enabled the preparation of the first block copolymers containing poly(CA), although control/living character was limited by the inherent instability of the resultant polymer chains that eliminate the RAFT end group. Nevertheless, the low toxicity and biocompatibility of poly(CA) materials provides stimulus for continued research, especially in the area of controlled drug release. Particularly notable are nanoparticle formations via mini-emulsion radical copolymerizations with PEG.

Acknowledgments: Authors thank Henkel Ireland for funding the PhD of Cormac Duffy. Author Contributions: Cormac Duffy wrote this Review article, as part of his Ph.D. thesis, directed by F. Aldabbagh. P. B. Zetterlund and F. Aldabbagh reviewed and corrected the manuscript. All authors contributed substantially, and with the sponsors authorized the final published version. Conflicts of Interest: The authors declare no conflict of interest.

References

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