Synthesis of Macrocyclic Polymers Formed via Intramolecular Radical Trap-Assisted Atom Transfer Radical Coupling

Abstract

The synthesis of cyclic polystyrene (PSt) with an alkoxyamine functionality has been accomplished by intramolecular radical coupling in the presence of a nitroso radical trap. Linear α,ω-dibrominated polystyrene, produced by the atom transfer radical polymerization (ATRP) of styrene using a dibrominated initiator, was subjected to chain-end activation via the atom transfer radical coupling (ATRC) process under pseudodilute conditions in the presence of 2-methyl-2-nitrosopropane (MNP). This radical trap-assisted, intramolecular ATRC (RTA-ATRC) produced cyclic polymers in greater than 90% yields, possessing ⟨G⟩ values in the 0.8−0.9 range as determined by gel permeation chromatography (GPC). Thermal-induced opening of the cycles, made possible by the incorporated alkoxyamine, resulted in a return to the original apparent molecular weight, further supporting the formation of cyclic polymers in the RTA-ATRC reaction. Liquid chromatography−mass spectrometry (LC-MS) provided direct confirmation of the cyclic architecture and the incorporation of the nitroso group into the macrocycle. RTA-ATRC cyclizations carried out with faster rates of polymer addition into the redox active solution and/or in the presence of a much larger excess of MNP (up to a 250:1 ratio of MNP:C−Br chain end) still yielded cyclic polymers that contained alkoxyamine functionality. C yclic polymers present not only a synthetic challenge for polymer chemists but also offer a set of properties that often differ substantially from linear polymers. 1,2 The most well-known differences include reduced hydrodynamic radii, 3,4 increased glass transition temperatures, 5−7 and advantageous spatial orientations of pendent groups in terms of energy transfer applications. 8−11 Very recently, it has also been reported that macrocycles may be potentially useful as drug delivery vehicles, owing to increased circulation times and greater accumulation into tumors compared to otherwise identical linear polymers. 12−14 While cyclic polymers have been produced by both ring closing 15−17 and ring expansion methods, 18−20 there remains substantial interest in both new routes and improving existing methods of their production. Controlled radical polymerization techniques have found their way into synthetic routes of several macromolecular architectures, 21−25 and macrocycles are no exception. For example, a linear precursor polymer can be produced by atom transfer radical polymerization (ATRP) and then subjected to intramolecular ring closure once the chain ends have been appropriately modified to be compatibly reactive. 26,27 Our group recently introduced a relatively simple method for producing cyclic polymers via a pseudodilute, intramolecular atom transfer radical coupling (ATRC) reaction of an α,ω-dibrominated precursor produced by ATRP using a dibrominated initiator (Scheme 1, bottom). 28 While this cyclization pathway could be adjusted to obtain near-quantitative yields of macrocycles, this closure reaction was necessarily carried out by the very slow addition of th...

Synthesis of Nitroxide End‐Labeled Polymers by Capturing Polystyrene Radicals with Spin Traps

“…These results indicate that even in a large excess, substantial dimerization competes with end‐capping when MNP is used as the radical trap. This is not unexpected, as high amounts cyclization of dibrominated PS was found even in a much larger excess of MNP as the radical trap …”

“…Two radical traps, MNP and nitrosobenzne (NBz) were added in varying equivalents to redox active solutions of PSBr. Previous research by our group has shown that both MNP and/or NBz act as radical traps in ATRC‐like reactions leads to high amounts of coupling for end‐halogenated polystyrene (PS), poly(methyl methacrylate), and poly(methyl acrylate), producing either coupled polymer dimers or cyclic polymers. This so‐called RTA‐ATRC is summarized in Scheme , along with the desired nitroxide‐capped intermediate (boxed).…”

“…As shown in Figure and tabulated in Table 3 , a substantial amount of the PS‐nitroxide did not participate in the coupling reaction and remained in the reaction mixture of the product, with the extent of coupling ( X c ) not exceeding 30%. The relative ineffectiveness of the nitroxide‐capped polymer to trap another polymer radical, when it is well known to do so in RTA‐ATRC sequences, suggests that not all the nitroxide label was active. This may be consistent with the EPR spectrum in Figure , which showed unusual fine detail not necessarily expected in nitroxide‐labeled macromolecules.…”

Effect of Trapping Agent and Polystyrene Chain End Functionality on Radical Trap-Assisted Atom Transfer Radical Coupling

“…Cyclic polymers can be prepared directly from dibrominated precursors, prepared by ATRP, in both ATRC [15] or RTA-ATRC [16,17] reactions. We have shown, as well, that RTA-ATRC can be successful in instances where ATRC fails.…”

Macrocyclic poly(methyl acrylate) and macrocyclic poly(methyl acrylate-block-styrene) synthesized by radical trap-assisted atom transfer radical coupling

“…As an example, the conversion of the terminal alkyl bromide into an azide group when an alkyne-containing ATRP initiator is used allows for ring closure by "click" chemistry [45e48]. By choosing a dibrominated initiator, ATRP can be used to produce telechelic polymers that can be directly employed in end-to-end coupling reactions either by ATRC [49] or RTA-ATRC [50] resulting in cyclic (Scheme 2), or even dicyclic, polymers [27,51]. Ring closing by traditional ATRC to produce macrocycles is problematic due to the following: i) chain end radicals must terminate by head-to-head coupling and ii) chain end radicals must be sufficiently present (large K ATRP value) that a bimolecular reaction is feasible in which each chain end radical has only one allowable partner.…”