Influence of Solvent on Radical Trap-Assisted Dimerization and

Oct 7, 2016 - The extent of dimerization in radical trap-assisted atom transfer radical coupling (RTA-ATRC) was studied as a function of solvent compo...
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Influence of Solvent on Radical Trap-Assisted Dimerization and Cyclization of Polystyrene Radicals Maya M. Arce, Ching W. Pan, Madalyn M. Thursby, Jessica P. Wu, Elizabeth M. Carnicom, and Eric S. Tillman* Department of Chemistry and Biochemistry, Santa Clara University, 500 El Camino Real, Santa Clara, California 95053, United States S Supporting Information *

ABSTRACT: The extent of dimerization in radical trapassisted atom transfer radical coupling (RTA-ATRC) was studied as a function of solvent composition, with accelerated rates of coupling observed in solvent mixtures consisting of THF and hydrocarbons compared to either pure solvent. Aggregation of the nitroso radical trap was speculated to be responsible for the trend in coupling rates of RTA-ATRC reactions, with less polar solvents such as hydrocarbons favoring the active, monomeric form. The mixed solvent system of THF and cyclohexane was found to be transferrable to the synthesis of macrocyclic PS by intramolecular RTAATRC, with 50/50 (v/v) THF:cyclohexane reaction medium giving higher yields of cyclic product compared to reactions performed in the pure solvents.

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INTRODUCTION Atom transfer radical reactions have played an increasingly important role in not only the well-controlled synthesis of linear polymers but also postpolymerization transformations. As shown in eq 1, the rate of atom transfer radical polymerization (ATRP, outlined in Scheme 1, top) is dictated by the rate constant of propagation along with the concentrations of the species involved in the propagation step: the polymer radical and the monomer.1−4 For a given ATRP system, such as the polymerization of styrene (S), the kp term will be the fixed rate constant of a polystyryl radical adding across the monomeric styrene,5 while the initial monomer concentration is chosen by the experimenter. The concentration of the polymer radical is determined by the position of KATRP (eq 2), and this reversible activation/ deactivation process ultimately controls the success of the polymerization6 while also being intimately tied to the rate of polymer formation.7 Extensive studies have been carried out to quantitate the influence of the metal/ligand complex on the position of KATRP, the choice of the halogen, and the structure of the alkyl halide.8−12 R p = k p[Pn•][M] KATRP =

[Cu /L][PBr]

=

kact kdeact

(2)

While it is well-known that polar reactions are influenced by solvent polarity to a far greater extent than radical reactions,13 solvent choice can still affect the rate of ATRP reactions.14,15 In © XXXX American Chemical Society

RATRC = k t[Pn•]2

(3)

RRTA − ATRC = k1[Pn•][R−NO]

(4)

Closely related to ATRP, atom transfer radical coupling (ATRC, Scheme 1, middle) relies on generating polymer radicals via an activation/deactivation process but does so in the absence of monomer to favor radical−radical coupling (kt).18−20 The rate of dimerization, given in eq 3, is second order with respect to the polymer radical and is directly tied to the position of KATRP. The position of the KATRP is purposely pushed further toward the active radical to aid the occurrence of the bimolecular reaction which is accomplished by stronger ligands, higher metal/ligand content, and/or reducing agents to regenerate the active catalyst and prevent a substantial persistent radical effect.18,21 Traditional ATRC can be used to produce simple polymer dimers21 but can also be coerced to produce macrocycles in some cases.22

(1)

[Cu IIBr/L][Pn•] I

this case, it is the stability of the metal−ligand complex in the higher oxidation state (CuIIX/L), and not solvent-driven changes in the stability of the polymer radical, that is the primary driving force for the solvent influence on the position of KATRP.16 Recent work has shown that kact cannot be used to predict the rate of polymerization in ATRP reactions, for both traditional ATRP and those with low catalyst loadings.17

Received: August 17, 2016 Revised: September 28, 2016

A

DOI: 10.1021/acs.macromol.6b01794 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules Scheme 1. (Top) Mechanistic Summary of ATRP Leading to Monobrominated Polymer (kp) while Suppressing Bimolecular Radical−Radical Termination (kt); (Middle) Mechanistic Summary of ATRC of Monobrominated Polymer Chains, Leading to Polymer Dimers;a (Bottom) Mechanistic summary of RTA-ATRC of Brominated Polymers Leading to Polymer Dimers with an Alkoxyamine Unit at the Midpointb

Scheme 2. Equilbrium of Nitroso Dimer (MNP) between the Dimeric Form and the Monomeric Form, with an Equilibrium Constant KRTa

a

Note that only the monomer form is expected to participate in RTAATRC reactions.

In this work, a series of RTA-ATRC reactions of monobrominated polymers were carried out in various pure solvents (THF, hexanes, cyclohexane, monomer, and others) and mixtures of these solvents, with the extent of coupling monitored as a function of reaction time. The results, which indicated superior coupling for RTA-ATRC reactions in mixed solvents compared to analogous reactions in pure solvents, were then applied to macrocyclization reactions by intramolecular RTA-ATRC, showing an identical trend.

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EXPERIMENTAL PART

Materials. Copper(I) bromide (CuBr, 98%, Aldrich), copper metal (Cu0, fine powder, Baker & Adamson), chloroform-D (99.8 atom % D, Aldrich), and cyclohexane (99.5%, Aldrich) were used as received. Tetrahydrofuran (THF, inhibitor free ≥99.9%, Aldrich) was dispensed from the Aldrich Pure-Pac System. Styrene (≥99%, Aldrich), 1bromoethylbenzene (BEB, 97%, Aldrich), and N,N,N′,N″,N″pentamethyldiethylenetriamine (PMDETA, 99%, Aldrich), α,αdibromotoluene (97%, Aldrich), and tris[2-(dimethylamino)ethyl]amine (Me6TREN, 97%, Aldrich) were stored in the refrigerator. Hexanes (96% n-hexane, J.T. Baker), methanol (Burdick and Jackson), and 2-methyl-2-nitrosopropane dimer (Aldrich) were stored in the freezer. Typical Procedure for the Synthesis of Monobrominated Polystyrene Using ATRP. Styrene (2.0 mL, 17.5 μmol), CuBr (50 mg, 0.349 μmol), (1-bromoethyl)benzene (BEB, 47 μL, 0.349 μmols), and THF (2.0 mL) were added into a custom-made Schlenk line round-bottom flask. The flask, capped with a rubber septum, was attached to the Schlenk line. The content of the flask was exposed to three freeze−pump−thawing cycles before being placed on heat plate with custom fit block heaters and equipped with a digital contact thermoregulator (Chemglass CG-1994-V015) set to 80 °C and left to stir for 5 min. PMDETA (73 μL, 0.349 μmol) was then added to the reaction flask via syringe to begin polymerization. After 240 min, the reaction flask was removed from the heat and placed into an ice bath, and the crude product was analyzed by 1H NMR for percent monomer conversion, followed by dilution with THF and precipitation into a white powder using ice-cold methanol (Mn: 2347; Đ: 1.11; percent conversion: 39%). Dibrominated PS (BrPSBr) was synthesized in an identical manner, using BzBr as the difunctional precursor. Typical Procedure for RTA-ATRC and ATRC of PSBr. A representative RTA-ATRC reaction was performed as follows: molar ratio of [CuBr]:[Cu0]:[PMDETA] = 5:5:10 in 50:50 THF:hexanes, PSBr (250 mg, 0.0932 μmol, 2680 g/mol), CuBr (66.7 mg, 0.466 μmol), Cu0 (29.5 mg, 0.466 μmol), 2-methyl-2nitrosopropane dimer (MNP, 8 mg, 0.0466 μmol), THF (3 mL), and hexanes (3 mL) were added into a custom-made Schlenk line round-bottom flask. The reaction flask, sealed with a rubber septum, was attached to the Schlenk line. The flask was exposed to three freeze−pump−thawing cycles before being placed onto a heat plate set to 40 °C. After 5 min of heating and stirring, PMDETA (194 μL, 0.932 μmol) was added into the reaction chamber via syringe. At the 20, 40, and 60 min mark, approximately 500 μL of the reaction solution was removed from the reaction flask via argon-flushed syringe. The aliquots were placed in an

a

The rate of dimerization is given by eq 3. bThe radical trap is a nitroso compound, and the rate-limiting step of the sequence is k1. The rate of dimerization is given by eq 4.

The addition of a radical trap, such as a nitroso compound, alters the mechanism to a stepwise sequence, changing not only the kinetic order with respect to the polymer radical but also increasing the utility of the process.23,24 For example, this socalled radical trap-assisted ATRC (RTA-ATRC), summarized in Scheme 1, bottom, can be used to selectively form diblock copolymers,25 and couple chain ends not compatible with traditional ATRC due to chain end bulkiness 23,26 or unfavorable KATRP positions.27 The addition of the radical trap also allows for “greener” reaction conditions, such as reduced metal content in cyclization reactions28 and coupling reactions without purification of the linear precursor.29 The rate of coupling in these RTA-ATRC examples is tied to the ratelimiting step as given in eq 430 and is first order with respect to the polymer radical. Solvent effects on ATRP reactions would, at first glance, be transferable to RTA-ATRC because the KATRP should be identically affected regardless of being followed by kp or k1 (ATRP or RTA-ATRC, respectively). However, in the case of RTA-ATRC reactions, the nitroso radical trap is known to exist as an equilibrium between a dimer and a monomeric form (Scheme 2).31 The extent of aggregation of the nitroso compound is dependent on the solvent, with more polar solvents favoring the dimeric form due to the stability of the zwitterion in more polar media.32,33 Nitroso compounds must be in the monomeric form to trap alkyl radicals,31 implying that solvent may affect the success of RTA-ATRC reactions beyond simply altering the KATRP value. B

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Macromolecules ice bath to stop the reactions, filtered into a GPC vial, diluted with THF, and analyzed. Other trials were performed in an analogous manner, with reaction conditions adjusted as listed in Tables 1 and 2. The total volume of

Table 2. Results of Dimerization of PSBr via RTA-ATRC in a Variety of Solvents ([PSBr]:[MNP]:[CuBr]:[Cu0]: [PMDETA] Molar Ratio 1:1:2.5:2.5:5)a trialb

Table 1. Results of Dimerization of PSBr via RTA-ATRC in a Variety of Solvents ([PSBr]:[MNP][CuBr]:[Cu0]:[ PMDETA] = 1:1:5:5:10)a trialb 1

2

3

4

RTA-ATRC solvent THF

hexanes

styrene

cyclohexane

5

50THF:50hexanes

6

50THF:50cyclohexane

7

50THF:50styrene

time PSBr 20 40 60 PSBr 20 40 60 PSBr 20 40 60 PSBr 20 40 60 PSBr 20 40 60 PSBr 20 40 60 PSBr 20 40 60

precursor

precursor

precursor

precursor

precursor

precursor

precursor

Mn

Đc

5100 6380 7710 8420 2370 2600 2840 2950 4010 5000 5760 5840 3490 4150 4570 4890 2750 4400 4710 4780 5170 8340 9280 9510 4010 5210 5870 6000

1.08 1.15 1.12 1.09 1.09 1.13 1.18 1.16 1.08 1.16 1.14 1.14 1.09 1.18 1.19 1.18 1.08 1.12 1.09 1.08 1.07 1.15 1.13 1.12 1.08 1.16 1.14 1.13

RTA-ATRC solvent

1

THF

2

hexanes

3

cyclohexane

4

50THF:50hexanes

5

50THF:50cyclohexane

Xcd 0.40 0.68 0.79 0.18 0.33 0.39 0.40 0.61 0.63 0.32 0.47 0.57

time PSBr 20 40 60 PSBr 20 40 60 PSBr 20 40 60 PSBr 20 40 60 PSBr 20 40 60

precursor

precursor

precursor

precursor

precursor

Mn

Đc

5200 5930 7040 7890 2420 2600 2930 3120 5140 5560 5920 6270 1780 2320 2920 3010 5120 6420 7210 7300

1.08 1.14 1.14 1.11 1.09 1.13 1.16 1.18 1.07 1.12 1.15 1.17 1.13 1.23 1.15 1.17 1.07 1.15 1.13 1.17

Xcd 0.25 0.52 0.68 0.14 0.35 0.45 0.15 0.26 0.36 0.47 0.78 0.82 0.40 0.58 0.60

a

Reactions were performed in approximately 15 mM concentrations of PSBr in 6 mL of solvent at 40 °C. bData for the PSBr precursor and for a single RTA-ATRC run sampled at different times. cWeightaverage (Mw) divided by number-average (Mn) molecular weights. d Extent of coupling at a given time interval of RTA-ATRC reaction, as calculated by eq 5.

0.75 0.83 0.85 0.76 0.89 0.91

some of the pressure built up in the 250 mL Schlenk flask. The syringe containing the polymer solution was then added dropwise to the redox-active flask using a Cole Parmer syringe pump at a rate of 5.0 mL/h. Once the addition had completed, the contents of the flask were allowed to stir for an additional hour before the flask was placed in an ice bath and opened to the atmosphere to terminate the reaction. The contents of the flask were then concentrated using rotary evaporation, and a small aliquot was removed for GPC analysis: Mn = 6800, Mp = 4800, Đ = 1.88, ⟨G⟩ = 0.77, 64% cyclic. Characterization. Raw reaction mixtures were diluted in chloroform-D and characterized by 1H NMR (Bruker 400 MHz). All time point and crude product samples were removed from the flask, filtered, and diluted with THF before characterization by gel permeation chromatography (GPC). GPC analysis was done on a Shimadzu prominence UFLC HPLC system including a CBM-20A communications module, a DGU-20A degassing unit, a SIL-20A autosampler, a LC-20AD pump, a SPD-M20 diode array detector, and a RID-20A refractory index detector. Separations were performed using Shodex KF-804L columns housed inside a CTO-2A column oven set to 30 °C. THF was used as an eluent at an optimized flow rate of 1 mL/min, and a 10-point calibration was performed using Agilent EasiCal PS standards. The data analysis was performed using the Shimadzu Lab Solutions software. Cyclic polymers samples were analyzed on an EcoSEC GPC system (Tosoh Biosciences LLC) connected to a PC running EcoSEC data analysis software. The system was equipped with an UV detector, a dual flow RI detector, and two TSK gel super HZ3000 columns, and the whole system was temperature controlled at 40 °C. A seven-point calibration, obtained with polystyrene standards (TOSOH, Mp range: 2.66 × 102 to 3.79 × 104 g/mol), was used to obtain molecular weight characteristics and dispersity index (Đ) values for all polymers. THF solvent was used as the mobile phase for the GPC system at a flow rate of 0.35 mL/min. The extent of coupling in dimerization reactions (Tables 1 and 2) was calculated by taking two times the difference between 1 and the

0.46 0.63 0.66

a

Reactions were performed in approximately 15 mM concentrations of PSBr in 6 mL of solvent at 40 °C. bData for the PSBr precursor and for a single RTA-ATRC run sampled at different times. cWeightaverage (Mw) divided by number-average (Mn) molecular weights. d Extent of coupling at a given time interval of RTA-ATRC reaction, as calculated by eq 5. solvent and the concentration of PSBr remained consistent at 6 mL and approximately 15 mM, respectively. The volume of ligand was adjusted to match the total equivalents of CuBr and Cu0. Samples were taken at the 20, 40, and 60 min time points. ATRC reactions followed a similar procedure as the RTA-ATRC, but the radical trap was omitted. Typical Procedure for Intramolecular RTA-ATRC of BrPSBr To Form Macrocyclic PS. To an oven-dried 50 mL Schlenk flask was added BrPSBr (300 mg, 0.049 mmol) and 50 mL of THF. The flask was sealed with a Schlenk valve, rubber septum, and copper wire and was placed on the Schlenk line for four freeze−pump−thaw cycles. The contents of the flask were then transferred to a plastic syringe under argon. To a separate oven-dried 250 mL Schlenk flask was added a magnetic stir bar, CuBr (35 mg, 0.24 mmol), Cu(0) (16 mg, 0.24 mmol), Me6TREN (130 μL, 0.49 mmol), 2-methyl-2-nitrosopropane (8.5 mg, 0.097 mmol), 25 mL of THF, and 25 mL of cyclohexane. The flask was then sealed with a Schlenk valve, rubber septum, and copper wire and was placed on the Schlenk line for four freeze−pump−thaw cycles. Argon gas was then bubbled through the contents of the 250 mL flask for ∼5 min. The flask was then placed in a 60 °C oil bath, and once equilibrated, a needle was used to relieve C

DOI: 10.1021/acs.macromol.6b01794 Macromolecules XXXX, XXX, XXX−XXX

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Figure 1. GPC traces of PSBr precursor prepared by ATRP and the RTA-ATRC product after 20 min. [PSBr] = 30 mM; [PSBr]:[MNP]:[CuI]: [Cu0]:[PMDETA] = 1:1:5:5:10.

Figure 2. Percent dimerization of PSBr via RTA-ATRC as a function of time in a variety of pure solvent conditions ([PSBr]:[MNP]:[CuBr]:[Cu0]: [PMDETA] molar ratio = 1:1:5:5:10). quotient of Mn(precursor) and Mn(coupled product), as shown in eq 5.18

■

⎛ M (precursor) ⎞ Xc = 2⎜1 − n ⎟ M n(product) ⎠ ⎝

cyclization, the concentrations of the polymer and redox components were lowered, and a series of reactions using PSBr precursors were carried out first in pure solvents. The molar equivalents of the components were consistently held at [PSBr] = 15 mM: [PSBr]:[MNP]:[Cu I ]:[Cu 0 ]:[PMDETA] = 1:1:5:5:10. Characteristics of the PSBr precursors and product of the RTA-ATRC reactions are summarized in Table 1, trials 1−5 (for pure solvents). The coupling success of these reactions as a function of time for each solvent is illustrated in Figure 2. In all cases dimerization was observed, with the more polar solvent THF giving rise to higher amounts of coupling than the less polar hydrocarbons (hexanes and cyclohexane). Note that the radical trap MNP was used in the coupling reaction, allowing for even

(5)

RESULTS AND DISCUSSION To preface the study presented here, PSBr can be quantitatively dimerized by RTA-ATRC in THF after only 20 min even though the coupling temperature was only 40 °C (Figure 1). This is superior to traditional ATRC reactions, which require increased temperatures and time to generate similar amounts dimerization.18 To gauge the solvent’s influence on RTAATRC reactions and better represent conditions amenable to D

DOI: 10.1021/acs.macromol.6b01794 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules Scheme 3. Detailed Mechanism of RTA-ATRC Reactions Using PSBr and MNP (tBuNO) as the Radical Trap

Figure 3. GPC traces of PSBr RTA-ATRC products dimerized in pure THF (bottom), pure hexanes (middle), and a 50:50 mixture THF:hexanes (top); ([PSBr]:[MNP]:[CuBr]:[Cu0]:[PMDETA] molar ratio 1:1:5:5:10).

styrene itself to serve as a medium to carry out the dimerization.29 The fact that ATRP does not compete with RTA-ATRC under these conditions demonstrates that the k1 pathway (Schemes 1, bottom, and Scheme 3) occurs preferentially over k p (Scheme 1), even though the concentration of styrene was >2 orders of magnitude higher than MNP when styrene was used as the solvent for the RTAATRC reaction.34 Typical GPC traces of the precursors and the RTA-ATRC products at each time interval can be found in Figure 3 (for THF and hexanes) and Figure S1 (for others). When THF and hexanes were mixed 50/50 by volume and the RTA-ATRC reaction was performed in an otherwise identical manner, accelerated extents of coupling were observed compared to either pure solvent alone (Table 1, trial 6). Figure 3 shows the GPC traces of precursor and the RTA-ATRC products at 20, 40, and 60 min in the pure solvents (bottom and middle) and for the mixed solvent (top). Even at only 20 min, substantial dimerization occurred in the THF:hexanes mixture (Table 1, trial 6), while neither pure solvent exceeded

50% coupling at this time point (note that Figure 1 shows near complete coupling at 20 min for the RTA-ATRC because the concentrations of the components was 2-fold higher). When cyclohexane was used in the RTA-ATRC reaction in place of hexanes, the identical trend was observed, with higher extents of coupling occurring for the 50/50 mixture than for either pure solvent. These trends can be visualized in Figure 4, with the results listed in Table 1. Additional RTA-ATRC reactions were carried out with the amounts of metal (CuI and Cu0) and ligand (PMDETA) cut in half to ensure that the redox activity of the reaction mixture does not play a role in the solvent effects as were observed in Figure 3. Listed in Table 2 are the characteristics of the PSBr precursors along with the RTA-ATRC products at different time intervals, again revealing the enhanced coupling rates in the mixed solvent systems. The trends of mixed solvents showing coupling rate enhancement for these reactions are illustrated in Figure S2, and the GPC traces are shown in Figure S3. E

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Figure 4. Percent dimerization of PSBr via RTA-ATRC as a function of time in a variety of solvent conditions ([PSBr]:[MNP]:[CuBr]:[Cu0]: [PMDETA] molar ratio 1:1:5:5:10).

Scheme 4. Possible Fate of a PS Radical Depending on Reaction Conditions and Rate Constants for ATRP, ATRC, and RTAATRCa

a

The metal/ligand complex is omitted from the KATRP equilibrium for clarity.

radical with monomeric nitroso would be several orders of magnitude higher,36 near 9 × 109 L mol−1 s−1. Mechanistic Evaluation. As the solvent polarity increases, the KATRP generally increases,37 leading to an enhanced rate for ATRP reactions. However, for RTA-ATRC to occur the radical trap MNP must be in its monomeric form to trap the polymer radical,38 which means the position of KRT affects the rate of dimerization. As stated earlier, the extent of dissociation of nitroso compounds from the dimeric form to the monomeric form is solvent dependent, with less polar solvents favoring the monomeric form.32,33 Thus, the effect of solvent on KATRP and the effect on KRT (Scheme 4) would be inversely related, consistent with mixed solvents giving superior results in a reaction sequence whose rate is tied to both equilibria. The mixed solvent system apparently represents a scenario that allows for the greatest concentration of the PS radical while also

While ATRP is commonly carried out in mixed solvents, with one of the cosolvents being the monomer itself, ATRC-type reactions would typically fail if monomer was used as a cosolvent because ATRP would simply compete with coupling. As seen in Figure S4, mixed solvents of THF and styrene showed substantial coupling with no observable competition from ATRP (bottom), while an analogous traditional ATRC reaction in the absence of the radical trap lead to monomer consumption due to the ATRP process. (The PSBr simply served as a macroinitiator for ATRP, which was uncontrolled due to high KATRP values under ATRC conditions.) This nicely illustrates the utility and robustness of RTA-ATRC compared to traditional ATRC and also shows the k1 must be much greater than kp (Scheme 1). This is expected from literature values, with the kp of styrene35 in a radical chain polymerization at 80 °C ∼6 × 102 L mol−1 s−1, while k1 for trapping an alkyl F

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Figure 5. Proton NMR spectra of MNP in (a) benzene-d6, (b) THF-d4, and (c) 50/50 v/v of solvents in (a) and (b). [MNP] = 0.0172 M in all cases.

allowing for dissociation of the nitroso dimer into the reactive monomeric nitroso group. To gain insight and confirm that aggregation of the nitroso compound could be in fact affecting the extent of dimerization in RTA-ATRC reactions studied, 1H NMR of MNP was carried out in benzene-d6 and THF-d4, as well as mixtures, at concentrations approximating t = 0 of an RTA-ATRC reaction (0.0172 M MNP). Benzene was used as the nonpolar solvent, rather than hexanes-d14, to avoid the solvent peaks interfering with the signal of the tBu group on the MNP (which has signals near 1 and 1.5 ppm for monomer and dimer, respectively39). As shown in Figure 5a (top), in benzene-d6 two signals can be seen corresponding to the dimeric and monomeric form of the radical trap. When the same spectrum was obtained in THF-d4, the percentage of the monomeric form of tBu-NO was reduced, and a new signal was found near 2.5 ppm. At this point, it is unclear if this peak near 2.5 ppm corresponds to higher aggregates of MNP or simply diastereotopic forms of the dimer (for example, the dimer can exist as E or Z). When the same spectrum was obtained in a 50/50 mixed THF/benzene solvent system (Figure 5c, bottom), the species at the higher ppm was still seen. The signals corresponding to THF in the mixed solvent system with benzene were assigned using established ppm values, while the signal due to benzene is easily identified as a singlet at 7.16 ppm.40 Tabulated in Table 3 is the percentage of the monomeric form of the MNP as a function of solvent conditions. Consistent with the RTA-ATRC results, the mixed solvent showed higher amounts of monomeric MNP compared to pure THF. While the exact percentages of the monomeric species would likely differ in the RTA-ATRC reaction mixtures of

Table 3. Percentage of Monomeric Form of MNP as a Function of Solvent solventa

% monomeric for R-NOb

benzene THF 50/50 benzene:THF

82 53 58

a Deuterated solvent, with 0.0172 M NMP. bCalculated as the percentage of monomer compared to all forms (dimer and aggregate appearing near 2.5 ppm in THF and mixed solvent).

hexanes or cyclohexane with THF compared to the benzene in the NMR study, the trends would almost certainly hold true. Pure benzene had the highest percentage of MNP in the monomeric form due to its low dielectric constant being poor at stabilizing the charges in the dimeric form. At this point, it is unclear the nature of the MNP aggregates in polar solvents, but for this study only the monomeric form is of interest as it is the active form in trapping alkyl radicals. The data indicate that the mixed solvent of THF/ hydrocarbons give accelerated rates of dimerization at early time points in the RTA-ATRC reactions, yet the more polar THF tends to nearly match the extent of coupling by the 60 min time mark (Figure 4 and Figure S2). As the RTA-ATRC progresses, the radical trap is consumed, and its concentration in the reaction mixture becomes progessively lower. Therefore, the rate of RTA-ATRC would decrease with increasing extents of coupling, and ATRC may eventually begin to compete or even become the dominant pathway for coupling in more polar solvents like THF. Qualitatively using GPC analysis, we have shown that the nitroso group is incorporated in coupled product as a thermally cleavable alkoxyamine, readily underG

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Scheme 5. Synthesis of Macrocyclic PS by Intramolecular RTA-ATRC (k2), with Competition from Intermolecular Chain Elongation (k2, Intermolecular)

Figure 6. GPC traces of BrPSBr and RTA-ATRC products formed under pseudo high dilution pure THF, pure cyclohexane, and solvent mixtures.

Table 4. Results of Cyclization of BrPSBr via Intramolecular RTA-ATRC in a Variety of Solvents RTA-ATRCa product triala

Mn

Mp (cyclic)

Đb

⟨G⟩c

% cyclicd

ratio of THF:cyclohexane

precursor 1 2 3e

6000 9950 7200 6400

6200 5000 4800 4750

1.05 1.85 1.68 1.81

0.81 0.77 0.77

34 54 64

0:100 100:0 50:50

All trials had an addition rate of 0.044 mmol BrPSBr per hour with 50 mL of polymer solution added to a redox active flask with 50 mL of solvent. Weight-average (Mw) divided by number-average (Mn) molecular weights. cCalculated by taking the ratio of the Mp for the BrPSBr precursor and the Mp for the cyclic product. dCalculated by taking the area under the peak in the GPC trace corresponding to cyclic product and comparing the value to the total area for all coupled product. eThe syringe had 25 mL THF/25 mL cyclohexane and the redox active flask had 25 mL THF/25 mL cyclohexane. a b

and used as the linear precursor in pseudo high dilute RTAATRC reactions to favor ring closure (Scheme 5). The results of the reactions were analyzed with no precipitation or fractionation of any kind in order to gauge the success of the conditions in the creation of macrocycles. The solvents chosen were THF, cyclohexane (a theta solvent for PS41), and mixtures of the two solvents. Conditions were not necessarily optimized to give the highest extents of cyclic product possible but rather

going thermolysis and reverting back to the size of the precursor.23,28 Further studies are needed to quantitate the extent of nitroso incorporation as a function of solvent, progress of dimerization, and concentration of nitroso group. Macrocylic Formation by Intramolecular RTA-ATRC. To evaluate if this solvent insight would be useful in the synthesis of macrocyclic PS by intramolecular RTA-ATRC, a single dibrominated PS precursor (BrPSBr) was synthesized H

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to relate the fraction of cyclic product to the entire RTA-ATRC product as a function of solvent. Note that in cyclization reactions each chain end can only have a single reaction partner, and thus solvent-induced conformation changes could also play a role in the extent of cyclization. If this were the case, poorer solvents (like alkanes) would give rise to greater extents of cyclic polymers because smaller end-to-end distances would favor intramolecular coupling.42 However, based on the earlier results, dimerization in RTA-ATRC reactions occurs faster (especially at the early stages) in equal volume mixed solvent systems which would be favorable for cyclic formation by end-to-end coupling. Figure 6 shows the GPC traces of intramolecular RTAATRC cyclization reactions performed in an identical manner with only the solvent makeup differing, with a solution of BrPSBr added dropwise into a redox-active flask (results are tabulated in Table 4). The same BrPSBr precursor was used in all trials to allow for an easier comparison of the extent of cyclization. The shift to lower apparent molecular weight values is indicative of cyclization,43−46 while the peaks at higher molecular weights are due to intermolecular coupling and “step”-type reactions. As expected, coupling occurred in all cases, but the ratio of intramolecular (cyclic) to intermolecular product varied greatly. In agreement with the results on RTAATRC reactions listed in Tables 1 and 2, the 50/50 mixed solvent system gave superior results to pure THF or cyclohexane. Consistent with dimerization rates, the extent of cyclization in cyclohexane was the poorest, with intermolecular coupling being dominant. Our group has previously shown that in THF intramolecular RTA-ATRC reactions do indeed involve the nitroso compound, as thermolysis of the alkoxyamine within the cycle reverted the product back to its linear form.26,28 The increased amounts of intramolecular (cyclic) vs intermolecular (“step”) product in mixed solvent conditions where RTA-ATRC was accelerated is expected because chain end coupling must be fast to maintain the pseudo high dilute conditions required for cyclization. If coupling reactions are slower, the concentration of chains (and chain ends) builds up, giving each activated chain end radical more available partners and increasing the likelihood of intermolecular competition.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] (E.S.T.). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Science Foundation (Award # 1307133), a DeNardo Science Scholar Award (supporting Maya Arce), and the Fletcher Jones Foundation (via an endowed professorship).

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REFERENCES

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CONCLUSIONS Equal volume mixed solvents were found to give greater extents of dimerization in RTA-ATRC reactions of PSBr compared to pure solvents in all cases studied. This suggests that the KATRP value alone was not responsible for coupling efficiencies in RTA-ATRC sequences, and the aggregation of the nitroso radical trap is important in the rate of chain end coupling. Importantly, the mixed solvent results were transferrable to intramolecular RTA-ATRC reactions, with the highest extents of cyclization (compared to chain extension) found in 50/50 solvent mixtures of THF:cyclohexane.

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.6b01794. Additional GPC traces and dimerization data (PDF) I

DOI: 10.1021/acs.macromol.6b01794 Macromolecules XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.macromol.6b01794 Macromolecules XXXX, XXX, XXX−XXX