Macromolecular Coupling in seconds of Triazolinedione End-functionalized Polymers prepared by RAFT PolymerizationStef Vandewalle, Stijn Billiet, Frank Driessen, Filip E. Du Prez*Department of Organic and Macromolecular Chemistry, Polymer Chemistry Research Group, Ghent University, Krijgslaan 281 S4-bis, B-9000 Ghent, BelgiumSupporting Information Placeholder

ABSTRACT: The ultrafast and additive-free triazolinedione-click reaction with electron rich (di)enes is a powerful method for the ultrafast ligation of polymer segments. A versatile method is described for the introduction of clickable TAD end groups in various polymer segments, using reversible addition fragmentation chain transfer polymerization. These triazolinedione-functionalized prepolymers were subsequently used for macromolecular functionalization with a low molecular weight diene and block copolymer synthesis of different types within seconds, at ambient conditions, through the coupling with diene-functionalized polymers such as poly(ethylene glycol) and poly(isobornyl acrylate).

In polymer science nowadays, the synthesis of advanced macromolecular structures with increasing complexity in terms of functionality and architecture is receiving much attention as this results in tailor-made polymers for a range of high-end applications.1-4 To achieve this, polymer chemists continuously get inspired by the click philosophy,5-7 a concept that was introduced by Sharpless and co-workers as a class of reliable reactions that allow efficient covalent coupling, in high yields.8 The copper-catalyzed azide-alkyne cycloaddition (CuAAC)9,10

reaction served as a primary inspiration for the development of new reactions that can complement the wide “click” chemistry toolbox containing already a range of synthetic methodologies such as the well-known thiol-X,11-14

Diels-Alder cycloaddition15,16, tetrazine-norbornene17 and other recently reported efficient ligations18,19 to design (high-tech) polymers with desirable functionality20-22 and advanced architectures such as star,16,23 cyclic,24 hyperbranched,25-27 graft and block (co)polymers28-30.

Nevertheless, in order to perform coupling reactions in more demanding systems, like the conjugation of two polymer segments in equimolar conditions, a significant amount of “click”-based reactions struggle with synthetic limitations such as rather moderate kinetics, the use of (metal) catalysts and undesired side-reactions. Since the density of reactive moieties in this system is rather low, a high reaction rate

coefficient for the ligation method is essential to obtain an efficient and clean polymer-polymer coupling. In addition, the reaction should preferably proceed additive-free and follow a single reaction trajectory yielding only one characteristic adduct, avoiding laborious purification procedures after coupling.6,7

Recently, our research group revisited a powerful reaction, based on the reactivity of a 1,2,4-triazoline-3,5-dione (TAD) component, which is characterized by all aforementioned indispensable click features.31,32 The heterocyclic TAD moiety consists of an azo functionality, which favors ultrafast and additive-free Diels-Alder and ene-type reactions with diene and ene moieties respectively, at ambient conditions. More specifically, if a substituted double bond or a diene is present as “click” partner in the reaction mixture, a Diels-Alder or ene-type adduct is selectively formed due to the high kinetic selectivity of the TAD moiety for such reactions.31 Moreover, the reaction progress can be monitored by a discoloration of the characteristic red color of the TAD moiety during reaction, even at low concentrations. These valuable characteristics gives this conjugation approach huge opportunities in polymer synthesis such as polymer functionalization,33,34 surface modification,35,36 network formation31,37,38 and modular synthesis of block copolymers.31

Up to now, the challenge of implementing TAD chemistry in the modular synthesis of block copolymers was the efficient and scalable

introduction of the clickable TAD moiety into polymer segments. Indeed, besides their high reactivity towards electron rich delocalized π-cloud type substrates, TAD-based chemicals can also participate in a whole range of other reactions.31,32 In order to avoid these side reactions, stable urazole moieties (i.e. TAD precursors, Scheme 1a, 1) are generally introduced in polymer segments, which are subsequently oxidized, prior to use, to a reactive TAD functionality (Scheme 1a, 2). In order to implement this approach, the requirement for a scalable synthesis method of urazole compounds with a functional handle is indispensable.

Scheme 1: a) Preparation and modification of clickable TAD end-capped polymer. b) Synthesis of urazole-functionalized chain transfer agent for RAFT polymerization.

In 2013, Barbas and co-workers reported a 5 kDa poly(ethylene glycol) (PEG) chain with a TAD end group, starting from an azide-functionalized urazole.39 Although this polymer was used for successful PEGylation of proteins in complex reaction media, this functionalization approach cannot be used for ‘bulk’ applications such as polymer-polymer coupling, as a result of limited scalability. Another approach for the introduction of TAD end groups in macromolecular structures was recently reported in a preliminary study by ourselves.31 For this, a poly(butyl acrylate) (PnBA) chain with TAD end group was prepared through Cu-mediated controlled polymerization, by applying a urazole-functionalized ATRP initiator. After oxidation, the PnBA was used to prepare block copolymers via click coupling. However, later on, the corresponding polymerizations turned out to be difficult to reproduce, often with low initiator efficiencies and until now only applicable to butyl acrylate as monomer. Those issues are attributed to complexation interactions of the copper catalyst with the urazole moiety due to its acidic nature (pKa~5).32

Herein, first a versatile method is described to introduce clickable TAD end groups in various polymer segments, which is based on reversible addition fragmentation chain transfer (RAFT) polymerization. This metal-free controlled polymerization technique enabled the synthesis of well-defined urazole end-functionalized polymers (1) by using a urazole containing chain transfer agent (CTA) (Scheme 1b, 6), which after successful oxidation leads to TAD end-functionalized polymers (2). Additionally, the potential of TAD chemistry for the efficient design of (complex) macromolecular structures was demonstrated, including block copolymer synthesis (3), by polymer-polymer

coupling with different polymer segments within seconds (Scheme 1a).

In a RAFT process, addition of a suitable chain transfer agent, e.g. a thiocarbonylthio compound, to the reaction mixture of a conventional free radical polymerization affords control over polymerization of a wide range of monomers in different solvent systems.40 An important feature of RAFT is the ability to introduce end group functionalities at the α-chain of the polymer segment using a functional CTA,41,42 in this particular case the introduction of a urazole functional handle. Accordingly, the first step in the presented work was the design of a urazole-functionalized trithiocarbonate (Ur-TTC), a class of thiocarbonylthio compounds that affords control over the polymerization of acrylates, acrylamides and styrene derivatives. (Scheme 1b, Figure S1).

The Ur-TTC was prepared through coupling of an aliphatic amino-functionalized urazole (4), prepared in a 3-step reaction, to 2-([butylsulfanyl-carbonothioyl]sulfanyl)-propanoic acid (BuPAT), a trithiocarbonate containing a carboxylic acid functional handle, frequently used for the preparation of functional RAFT agents.43 In a first attempt, BuPAT was reacted with the urazole (4) but side-reactions occurred due to the acidity of the protons of the urazole moiety. Likewise, the amine could induce aminolysis, destroying the trithiocarbonate moiety. Therefore, an activated ester of BuPAT (5) was prepared, favoring esterification over aminolysis, which was efficiently coupled with the amino-functionalized urazole to yield the pure Ur-TTC (6) after column chromatography on multigram scale (Figure S2).

The synthesized Ur-TTC proved to be effective as chain transfer agent in the RAFT polymerization of acrylates, acrylamides and styrene and enabled the introduction of a urazole functionaltiy at the α-chain end of a variety of polymers. Urazole-functionalized poly(butyl acrylate) (Ur-PnBA), poly(N,N-dimethyl acrylamide) (Ur-PDMA) and poly(styrene) (Ur-PS) were successfully obtained, applying typical RAFT conditions ([M]/[CTA]/[AIBN] = 100/1/0.1, 3M DMF, 70°C) (Figure 1, Figures S3-5). For a detailed analysis, we mainly focused on the monomer n-butyl acrylate (nBA) to explore the potential of TAD-chemistry in combination with RAFT polymerization for the synthesis of advanced macromolecular structures. The data of the kinetic analysis for this monomer is depicted in Figure 1 and S3. A linear first order kinetic plot and a linear increase in molecular weight with monomer conversion was observed, while maintaining low dispersity indices. At high conversions, a small deviation from the linear relationship could be observed for both the first order kinetic plot and the molecular weight as a function of conversion, indicating the occurrence of transfer and termination reactions. To ensure a maximal urazole end group functionality, monomer conversions during the RAFT polymerizations were thus kept below 70%. Based on the kinetic data, various batches of Ur-PnBA with different degrees of polymerization (DP) were synthesized (Table 1; Entries 1-3) which were applied for end group

functionalization and synthesis of block copolymers via polymer-polymer coupling.

Figure 1: RAFT polymerization of nBA with the urazole-functionalized CTA, at 70°C, in 3M DMF and AIBN, [nBA]/[CTA]/[AIBN] = 100/1/0.1. Molecular weight and dispersity (Đ) evolution with monomer conversion (left). First-order kinetic plot and monomer conversion evolution with reaction time (right).

In order to implement the aforementioned PnBA polymers in the synthesis for advanced macromolecular structures through click conjugations, including end group functionalization and efficient polymer-polymer coupling, the urazole end group should be oxidized to its corresponding 1,2,4-triazoline-3,5-dione functionality. Numerous easy procedures are available in literature for this oxidation reaction.32 In this work, the tetrameric complex of 1,4-diazabicyclo[2.2.2]octane and bromine (DABCO−Br) was used as a mild and heterogeneous oxidizing agent for the urazole

end groups, which proved already its relevance in a preliminary study.31

The oxidation procedure of the urazole end groups by the DABCO-Br complex was optimized in a model study with the Ur-PnBA (Entry 1). As already mentioned before, triazolinedione components can undergo undesired side reactions, such as hydrolysis, generating the corresponding amine and urazole as decomposition products.32 To investigate the hydrolytic stability of hydrophobic TAD compounds in organic solvents, a UV/vis experiment was performed on a 4-butyl-TAD model component (Figure S6). By comparing the evolution of the characteristic absorbance of the TAD moiety (at 540 nm) over time of a solution of 4-butyl-TAD in dry DCM to the same solution in the presence of a small amount of water, it could be concluded that the hydrolysis of hydrophobic components is negligible within the measured time frame. However, the oxidation was performed under dry conditions to guarantee the stability of the generated TAD moiety during oxidation. After oxidation, the TAD-PnBA polymers were purified (see supporting information) and used directly in coupling experiments or could be stored for a couple of days under inert atmosphere, in the dark at -18°C. Table 1 : Mn and conversion for all polymeric structures. Polymers prepared via RAFT polymerization using Ur-TTC under same conditions: [M]/[CTA]/[AIBN] = 100/1/0.1 at 70°C in 3M DMF. aCalculated by SEC (THF, PS standards). bCalculated by 1H NMR or GC. Ur-PDMA (Entry 4): RAFT polymerization at 65°C and Mn calculated by SEC (DMA with LiBr, PMMA standards). c[M]/[CTA]/[AIBN] = 200/1/0. dBlock copolymer in entries 2a-2b and 3a-3b.

The Ur-PnBA polymer, dried prior to use, was oxidized for 3 hours in dry dichloromethane in the presence of DABCO-Br. The discoloration of the polymer solution from yellow to red indicated successful generation of the corresponding clickable TAD-PnBA polymer. This polymer was easily purified by filtration of the oxidant to obtain a clear red polymer solution, which was instantaneously reacted with a low molecular weight diene, trans,trans-2,4-hexadien-1-ol (HDEO), in the same solvent (Figure 2a).

The model study provided more information about the quality of the polymer end group oxidation and its corresponding functionalization with the low molecular weight diene. The reaction rate for this polymer end group functionalization was comparable with earlier investigations with corresponding low molecular weight analogues,31 namely in a matter of seconds, as could be followed by a visual discoloration from red to yellow during reaction. The effectiveness of this end group functionalization was also demonstrated by UV/vis spectroscopy (Figure S7), since the characteristic absorbance of the triazolinedione

Entry

Polymer Polymer-b-Polymer

Mn

[kDa]a

(Đ)

Conv.b

(%)1 Ur-PnBA - 3.2

(1.31)18

1a HDEO-PnBA

- 3.6 (1.28)

-

2 Ur-PnBA - 4.8 (1.35)

32

2a - PiBA-b-PnBA

5.2 (1.39)

-

2b - PEO-b-PnBA

5.4 (1.38)

-

3 Ur-PnBA - 7.1 (1.26)

62

3a - PiBA-b-PnBA

7.7 (1.40)

-

3b - PEO-b-PnBA

8.7 (1.30)

-

4 Ur-PDMA

- 3.0 (1.20)

28

5 Ur-PSc - 4.4 (1.28)

11

6 PiBA-diene

d 2.9 (1.23)

-

7 PEO-diene

d 2.6 (1.12)

-

end group at 540 nm disappears instantaneously upon reaction with the diene functionality. Furthermore, a unimodal shift of the SEC trace could be observed after coupling (Table1, Figure S8).

The completion of the oxidation and coupling reaction was also confirmed by the evaluation of distinct signals in 1H NMR spectroscopy with DMSO-d6, a solvent in which the protons of the urazole moiety are clearly visible. Indeed, after oxidation and coupling, the distinctive urazole singlet at 10 ppm disappeared completely, while new signals between 3-6 ppm, which can be assigned to the coupled HDEO end group, arose in the spectrum (Figure 2a and S9)

Additionally, MALDI-TOF analysis of the PnBA polymers provided full evidence for complete oxidation and successful coupling reaction (Figure 2b, Figures S10-11). The MALDI spectrum of the urazole-PnBA is characterized by a main distribution P1, attributed to the urazole-PnBA, evidenced by the similarity in theoretical mass and isotopic distribution (Figure 2b and S12). The small distributions P2 and P3 can respectively be attributed to a single charged urazole-PnBA fragment, with an extra sodium atom bound to a deprotonated urazole moiety,

and an unknown fragmentation product, with a mass difference of 24 Da between main distribution P1, originating from the ionization process during analysis. After coupling with HDEO, the main distribution P1* is clearly shifted to a mass that can be readily assigned to the clicked HDEO-PnBA (Figure 2b and S13), indicating successful and selective oxidation of the urazole end group, retaining the characteristic trithiocarbonate end group. Moreover, both distributions P1 and P2, ascribed to the urazole precursor polymer, are absent in the spectrum. In resemblance with the urazole-PnBA, a similar fragmentation product P3*, with an identical mass difference of 24 Da between the main distribution, was detected. As these fragments (P3 and P3*) were detected for both polymers, they should be attributed to an undesired fragmentation of PnBA during MALDI analysis, rather than to defects in the starting material.

Thus, this model study on PnBA demonstrated successful oxidation of the urazole end group to the corresponding triazolinedione moiety, which was quantitatively functionalized with a low molecular weight diene in a matter of seconds at ambient conditions.

Figure 2: 1H NMR analysis (in DMSO-d6 as solvent, 400 MHz) (A) and MALDI-TOF spectra (B) of Ur-PnBA entry 1 before and after oxidation/coupling with HDEO.

Based on these results, the potential of TAD click reactions was further explored as a promising strategy for the ultrafast and upscalable preparation of block copolymers via polymer-polymer coupling. In this context, the clicking of various macromolecular chains on TAD end-functionalized PnBA was investigated. For this purpose, a hydrophilic diene end-functionalized PEO (PEO-diene) (Mn = 2.6 kDa, Đ = 1.12) and a hydrophobic diene end-functionalized poly(isobornyl acrylate) (PiBA-diene) (Mn = 2.9 kDa, Đ = 1.23) were synthesized (Figures S14-16) and reacted with different TAD-PnBA polymers, obtained via the reaction protocol as optimized in the model study (Table 1).

After mixing TAD-PnBA with the diene end- functionalized polymers in equimolar amounts (in dichloromethane), the distinctive red color corresponding to the TAD end group disappeared

immediately, again demonstrating an ultrafast polymer-polymer ligation reaction for both the PEO-diene and PiBA-diene polymers. In agreement with the model study, the polymer-polymer coupling could be examined by following the TAD absorbance in a UV/vis experiment (Figure S17). As an example, to a solution of TAD-PnBA (Entry 2), PiBA-diene was added in fractions that react immediately with the triazolinedione moiety, decreasing the absorbance at 540 nm. Evolution of this absorbance with the addition of PiBA-diene demonstrated effective polymer-polymer coupling in equimolar amounts (Table S1). Similar results could be obtained for the conjugation between the hydrophilic PEO-diene and hydrophobic PnBA polymer segments.

The SEC-traces of the starting polymers and the PiBA-b-PnBA and PEO-b-PnBA block copolymers confirmed successful polymer-polymer ligation for both diene end-functionalized

polymers and TAD-PnBA polymers of different molecular weights (Table 1 and Figures 3a, S18-20). In each case, the distribution of the SEC traces, before and after coupling, are unimodal with comparable dispersity indices, while the peak corresponding to the characteristic block copolymer shifts to lower retention times, revealing a clear increase in Mn value compared to the initial polymers. As an example, TAD-PnBA (Mn = 7.1 kDa, Đ = 1.26) was successfully coupled with the PEO-diene in equimolar amounts, generating the PEO-b-PnBA block copolymer (Mn = 8.7 kDa, Đ = 1.3) at room temperature within seconds in the absence of any additive (Figure 3a). In order to confirm the efficiency of the polymer-polymer conjugation in-depth, the PEO-b-PnBA (Entry 3b) block copolymer was analyzed with LCxSEC chromatography (Figure 3b), a technique in which separation occurs in two dimensions, respectively based on polarity (y-axis) and hydrodynamic volume (x-axis) of the polymer. The hydrophobic Ur-PnBA (Mn = 7.1 kDa) and the hydrophilic PEO-diene (Mn = 2.7 kDa) starting polymers differ clearly in hydrodynamic volume and polarity, which is clearly visible in the elugram. After coupling, it shows only one signal with a hydrodynamic volume higher than the Ur-PnBA and PEO-diene precursor polymers and a polarity that is intermediate between that of the starting materials. This gives conclusive proof that the polymer-polymer conjugation reaction between the TAD-PnBA and PEO-diene proceeds equimolar and quantitative.

NN

N

O

O

NH6

OS S

Sn

O O O OO

On

NN

N OO

O

OO

O= PEO-diene

= PnBA-TAD OO

=

=

(7)

(3)

= PEO-b-PnBA (3b)

< 5 secondsroom temperature

A B

Figure 3: a) SEC traces of PEO-diene (Entry 7), Ur-PnBA (Entry 3) and the PEO-b-PnBA block copolymer (Entry 3b). b) LCxSEC data for the starting materials and the corresponding block copolymer prepared in less than 5 seconds in equimolar conditions.

In summary, the present work describes a robust method for the introduction of a clickable triazolinedione end group in polymer segments of different types on a multigram scale. For this, well-defined urazole end-functionalized polymers based on acrylate, acrylamide and styrene monomers, were synthesized using a functional urazole-trithiocarbonate as control agent in a RAFT polymerization. The synthetic potential of using these urazole-prepolymers for the modular preparation of macromolecular structures was demonstrated starting from PnBA prepolymers. For this polymer class, a triazolinedione end

group was successfully generated by an orthogonal oxidation of the urazole moiety, which subsequently was functionalized, in seconds, with respectively a low molecular weight diene and diene end-functionalized polymers, yielding end-functionalized PnBA polymers and block copolymers of different types and molecular weights.

ASSOCIATED CONTENT Supporting InformationExperimental procedures; synthesis of Ur-TTC RAFT CTA and polymers; kinetic study and NMR, UV/VIS, MALDI-TOF, SEC data are included in the Supporting Information. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATIONCorresponding AuthorsFilip.Duprez@UGent.be

NotesThe authors declare no competing financial interests.

ACKNOWLEDGMENT Bernhard De Meyer is acknowledged for the LCxSEC analysis. S.V. acknowledges Ghent University for funding. S.B. and F.D. thank the Flanders Innovation & Entrepeneurship for a Ph.D. scholarship. F.D.P. acknowledges Ghent University and the Belgian Program on Interuniversity Attraction Poles initiated by the Belgian State, the Prime Minister’s office (P7/05).

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