One-Pot Modular Synthesis of Functionalized RAFT Agents Derived

Letter pubs.acs.org/macroletters

One-Pot Modular Synthesis of Functionalized RAFT Agents Derived from a Single Thiolactone Precursor Steven Martens, Frank Driessen, Sofie Wallyn, Oğuz Türünç, Filip E. Du Prez,* and Pieter Espeel Department of Organic and Macromolecular Chemistry, Polymer Chemistry Research Group, Ghent University, Krijgslaan 281 S4-bis, B-9000 Ghent, Belgium S Supporting Information *

ABSTRACT: In this paper, the straightforward preparation of a range of functionalized trithiocarbonates as RAFT chain transfer agents (CTAs) is presented. The crucial step in the one-pot, three-step reaction sequence is the aminolysis of a thiolactone precursor as it introduces the desired functional handle (double bond, hydroxyl, furan, protected amine, ...) and generates the corresponding thiol in situ, facilitating further elaboration of the CTA. Furthermore, the newly synthesized trithiocarbonates were positively evaluated as mediators in the RAFT polymerization of styrene, isobornyl acrylate, and Nisopropylacrylamide, while the presence of the end groups in the heterotelechic polymers was confirmed by NMR and UV− vis analysis.

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derivatives can be isolated. In the case of amidation, careful monitoring, with regard to reaction conditions and stoichiometry, is indispensable as the thiocarbonylthio group is generally sensitive to aminolysis (vide supra).9 This side reaction leads to the erosion of the overall yield, as the amidation is often the last step in a multistep synthetic pathway. Hence, in this contribution, a more generic approach for the synthesis of functionalized CTAs, bearing an amide-linked functionality in the R group, is presented, which has some specific advantages compared to mainstream methods. The innovative aspect is the modular introduction of functionalities in the R group via amidation, prior to the installation of the thiocarbonylthio group, thus completely avoiding CTA lysis and related issues. The synthesis starts with the opening of a thiolactone by amine treatment and subsequent elaboration of the in situ generated thiol to a thiocarbonylthio group, leading to a direct synthesis of the targeted CTAs (Scheme 1). In this atom-efficient and one-pot approach, preactivation and intermediate purification are obsolete, and the desired func-

he reversible addition−fragmentation chain-transfer (RAFT) process1−6 and thiol-based postpolymerization modification (PPM)7 often go hand in hand.8 In general, the thiocarbonylthio (−S−C(S)−) end group, present irrespective of the used chain transfer agent (CTA), is susceptible to aminolysis.9 The recent implementation of thiol-based reactions in synthetic polymeric science10,11 greatly facilitated the PPM of the generated thiol end group, leading to a large variety of derived materials. Although thiols are extremely versatile functional handles, enabling mild and selective modification, stability issues due to disulfide formation might compromise long-term storage and conjugation efficiency. Hence, the appealing features of RAFT as an established controlled radical polymerization (CRP) technique, i.e., wide monomer variety, functional group tolerance, and good control over the molecular weight and dispersity, are combined with other conjugation chemistries in PPM,12,13 by the design of a suitable functionalized CTA.14 Modulation of the R group in the design of RAFT agents (R-S−C(S)-Z) remains particularly interesting and challenging for polymer and materials scientists as the R group holds, in this case, the alternative chemical handle for the application-driven postpolymerization upgrade of the corresponding polymers. Ideally, the functionality in the R group should be connected through stable bonds, like ethers or amides.14 Amide connections are preferred compared to their ester counterparts, as they are more stable toward hydrolysis. In practice, the majority of CTAs with tailored functionalities in the R group are prepared by an esterification or amidation of an acid functional RAFT agent, which is either commercially available or accessible through a short synthetic effort.14 Numerous coupling conditions exist, and activated ester © XXXX American Chemical Society

Scheme 1. One-Pot Synthesis of R Group Functionalized CTAs through Aminolysis of a γ-Substituted Thiolactone (X = Y ≠ H) and Installation of the Thiocarbonylthio Group

Received: June 30, 2016 Accepted: July 20, 2016

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DOI: 10.1021/acsmacrolett.6b00499 ACS Macro Lett. 2016, 5, 942−945

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ACS Macro Letters

with a base and CS2, after which the TTC anion was quenched with ethyl bromide as an electrophile. Reaction solvent, stoichiometry, base, reaction temperature, and time were adapted during optimization. While the benzylamine-derived CTA 2 (Scheme 2) could be isolated in 65% yield, using THF as solvent, overnight heating at 60 °C during the aminolysis, and KOtBu as base,18 consistently higher yields up to 87% were obtained in DMF with NaH as base. As a result, the following conditions were set forth for the preparation of a library of CTAs (Scheme 2): (primary) amine (3 mmol) and γthioisocaprolactone 1 (1.33 equiv) were stirred overnight in DMF (1 M), after which the reaction was cooled and treated with NaH (1.1 equiv) and CS2 (1.33 equiv) for 30′ during which the distinctive yellow color of the TTC anion was observed. The latter was reacted with ethyl bromide (1.2 equiv) for 2 h to finally obtain the corresponding TTCs, which were easily purified and isolated through aqueous workup and flash chromatography (Scheme S1). The γ-thioisocaprolactone 1 was added in excess to guarantee full amine consumption to counter disulfide formation after ring opening on one hand and aminolysis of the targeted TTC on the other hand. NaH is added in a smaller excess to transform thiols to their thiolate anion form. CS2 and ethyl bromide were added in excess to ensure that the thiolate anion is fully converted to the trithiocarbonate functionality. The overall good to excellent yields for the preparation of CTAs 2−16, starting from a wide range of primary amines, demonstrate the robustness of the method in terms of functional group tolerance. Indeed, one could appreciate the installation of numerous functional groups via the described protocol: furan- (5), hydroxyl- (10), allyl- (11), propargyl-(12), cyclohexenyl- (13), Boc-protected amino- (14), and tBuprotected carboxyl- (15) functionalized TTCs were synthesized (Figures S1−14). Moreover, the bis-functional CTA 16 was obtained in similar fashion, starting from the corresponding diamine (Figure S15). The reaction can be scaled up without deterioration of the yield; e.g., the preparation of CTA 6 was repeated on a 9 mmol scale (>3 g of final product). As anticipated, the key step is the aminolysis of 1. Hence, in the case of sterically demanding amines, like cyclopropyl amine (CTA 8) and glycine tert-butyl ester (CTA 15), longer reaction times were required to reach full amine conversion. In the extreme case of 1-adamantylamine, the formation of CTA 9 was impossible due to steric hindrance. Next to primary amines, other N-nucleophiles were evaluated, using the same reaction conditions. Earlier observation19 of the fact that only cyclic secondary amines (CTA 17 and 18) are reactive in the aminolysis of thiolactones was confirmed (Figures S16−18). Furthermore, in the case of phenyl hydrazine (CTA 20) (Figure S19), a poor yield is obtained compared to benzylamine (CTA 2). Less nucleophilic species, like anilines, are not reactive enough to open 1, so the formation of the aniline-derived TTC 21 was impossible, even with overnight heating (100 °C) during the aminolysis. Additionally, hydroxylates (CTA 22 and 23) were also used as O-nucleophiles; however, the isolated yields are poor, and purification is more difficult (Figures S20−21). The unprecedented TTCs have been fully characterized by 1H and 13C NMR, IR, LC-MS, and HR-MS (see SI). In order to evaluate the CTAs as effective mediators in RAFT polymerization, a selection of the library was screened. First, CTA 2 was utilized to mediate the polymerization of N-

tional handle is introduced during the aminolysis. Thus, a library of various CTAs can be prepared by careful selection of the appropriate amines. The choice of the thiolactone as a single precursor for all the functionalized CTAs is particularly important. Until now, practically all synthetic methods based on thiolactone chemistry, recently developed by us and others,15,16 started from the readily available α-substituted homocysteine thiolactone. So far, little to no attention was devoted to the substitution pattern on the five-membered thioester ring. However, for this study, the presence of ring substituents is critical. Specifically, the carbon center adjacent to the sulfur atom (γ position) must be substituted at least once, as it will be converted to a radical stabilizing entity in the R group of CTA (Scheme 1). Thus, screening of the synthetically accessible γsubstituted thiolactones, available in sufficient amounts, resulted in γ-thioisocaprolactone 1 (Scheme 2) as the most suitable compound. It was prepared on gram scale from isobutylene sulfide in two steps,17 purified by distillation and showing a good shelf life (>one year). In order to develop a general protocol, which avails the preparation of various CTAs, careful monitoring of the reaction progress (TLC and LC-MS analysis) at each stage was performed. Benzylamine was selected as a model for primary amines, and we opted for trithiocarbonates (TTCs, --S−C( S)−S--) as CTA. Thus, the in situ generated thiol was treated Scheme 2. Three-Step One-Pot Reaction Sequence for the Synthesis of Functionalized TTCs Derived from γThioisocaprolactone and a Library Overview Mentioning Isolated Yields

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ACS Macro Letters

distinctive signals for the TTC and R groups could be identified in the NMR spectra (Figures S27−30). UV−vis confirms the CTA end group because the absorbance of this functionality could be observed at ca. 310 nm. The full removal of the TTC end group by aminolysis, using octylamine and one-pot thiol scavenging with methyl acrylate,20 was confirmed by UV−vis (Figure 1C) and MALDI-TOF analysis (Figures S31−41). The signal at 310 nm disappeared in the UV spectra after aminolysis, and the latter spectra of these modified polymers clearly reveal the structure of the polymers, including the functional handles introduced through the R group of the selected CTA (Figure 1). In conclusion, this paper describes the preparation of R group functionalized RAFT CTAs through a three-step, onepot reaction sequence starting from the aminolysis of γthioisocaprolactone 1. The procedure is robust; the overall yield is generally good; and a large variety of functional handles can be installed. The preferred nucleophiles to start the process are primary and cyclic secondary amines. In a next stage, the newly synthesized trithiocarbonates were positively evaluated as mediators in the RAFT polymerization of styrene, isobornyl acrylate, and N-isopropylacrylamide, while the presence of the end groups in the heterotelechic polymers was confirmed by MALDI-TOF analysis.

isopropylacrylamide (NIPAM), isobornyl acrylate (iBA), and styrene, highlighting good control of the RAFT polymerization for various monomer types (Table 1 and Figures S22−25), Table 1. RAFT Polymerizations of Different Monomers Applying TTC 2 as Model Experiments TTC

monomer

time (h)

temp. (°C)

Mn,GPC (kDa)

Mw/Mn

conversion (%)

2 2 2 2

NIPAMa iBAb styrenea styrene

6 6 7 6

65 65 70 120

6500 5000 2200 4700

1.25 1.20 1.27 1.17

63 55 26 60

a

[M]/[CTA]/[I] = 75/1/0.11 (I = AIBN). b[M]/[CTA]/[I] = 70/1/ 0.11.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmacrolett.6b00499. Experimental procedures and NMR, LC-MS, HR-MS, and IR data of the CTAs and NMR, SEC, UV−vis, and MALDI data of the polymers (PDF)

Figure 1. (A) ln(M0/Mt) vs time, (B) conversion vs Mn and Đ, and (C) UV−vis spectra of PS with CTA 5 before and after aminolysis.

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Corresponding Author

further evidenced by screening the polymerization kinetics (Figure 1A,B). Next, TTCs 3−6, 10, 11, 13, 14, 16, and 17 were used to synthesize polystyrene, demonstrating the functional group tolerance toward the chemical handles in the R group (Table 2 and Figure S26). Although TTCs 5 and 11 are in principle sensitive for radicals, no side reactions (cross-linking) were observed during polymerization. The presence of the different end groups of the heterotelechelic PS was confirmed by NMR and UV−vis spectroscopy. For a couple of CTAs and their polymers,

*E-mail: fi[email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS All authors are thankful to Ghent University for the financial support. S.M. thanks the Research Foundation-Flanders (FWO) for the funding of his PhD fellowship. F.D. and S.W. thank the Flanders Innovation & Entrepreneurship for a PhD scholarship. F.D.P. acknowledges the Belgian Program on Interuniversity Attraction Poles initiated by the Belgian State, the Prime Minister’s office (P7/05).

Table 2. Polymerization of Styrene Applying Different TTCs via RAFT TTC monomer 2 3 4 5 6 10 11 13 14 16 17

styrene styrene styrene styrene styrene styrene styrene styrene styrene styrene styrene

time (h)

temp. (°C)

Mn,GPC (kDa)

Mw/Mn

conversion (%)

6 6 6 6 6 6 6 6 6 6 6

80 80 80 80 80 80 80 80 80 80 80

4650 4200 4250 4150 4050 4050 3950 4250 4300 3900 4300

1.25 1.23 1.23 1.23 1.23 1.24 1.25 1.23 1.21 1.26 1.26

50 51 50 52 52 48 49 51 45 46 47

AUTHOR INFORMATION

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REFERENCES

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