Organic Ring-Opening Polymerization Catalysts: Reactivity Control by

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Organic Ring-Opening Polymerization Catalysts: Reactivity Control by Balancing Acidity Binhong Lin and Robert M. Waymouth* Department of Chemistry, Stanford University, Stanford, California 94305, United States S Supporting Information *

ABSTRACT: Organocatalysts derived from thioureas and amines exhibit high functional group tolerance and extraordinary selectivities for ring-opening relative to chain transesterification. The modest activities of the thiourea/ amine catalysts prompted a detailed investigation of ureas and thiourea with organic bases for the ring-opening polymerization of lactones. An array of ureas or thioureas and organic bases were evaluated to assess the effect of the acidity of the urea (thiourea) and the basicity of the base cocatalyst on the activity for ring-opening polymerization. These studies reveal that for a given urea or thiourea stronger bases lead to faster rates. For a given base, the observed catalytic activity is highest when the acidity of the (thio)urea is closely matched with that of the B−H+. For ureas and thioureas of comparable acidity, the urea/base catalyst systems are considerably more active than the corresponding thiourea/base systems. These results are consistent with two mechanisms: one mediated by deprotonated (thio)urea anions when (thio)ureas are combined with bases of sufficient basicity and one mediated by neutral (thio)ureas when the base is incapable of deprotonating the (thio)urea. Opposing trends in reactivity for (thio)urea anions and neutral (thio)ureas as a function of (thio)urea acidity lead to the maximal activity when the acidities of the (thio)ureas are closely matched with that of the protonated base (B−H+). These findings provide the basis for understanding the reactivity of ring-opening polymerization cocatalysts as well as guidelines for the rational design of other acid/base catalyst pairs.

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INTRODUCTION Organocatalytic ring-opening polymerization (ROP)1−9 is a versatile method for generating well-defined biodegradable polyesters and polycarbonates. Ring-opening polymerization, and other modern controlled polymerization methods,9−14 have evolved to provide robust and versatile methods to generate functional macromolecules for applications in chemistry, materials science, physics, biology, and medicine.15,16 The broad functional group tolerance of many organocatalysts, the lack of heavy-metal contaminants, and the facile removal of catalyst residues from the resulting polymers have proven useful for the generation of bioactive oligomers and polymers for a variety of biomedical applications.17−25 Organocatalysts derived from thioureas and amines,5,26,27 introduced in 2005 as ring-opening-polymerization catalysts,28−30 have been widely adopted due to their high functional group tolerance and extraordinary selectivities for ring opening relative to chain transesterification, allowing for the precise control of the molecular weight and the molecular weight distribution of the resultant polymers. Nevertheless, one of the major limitations of these catalyst systems is their modest activities, which has stimulated efforts to develop more active organocatalysts that retain high selectivities.8,9,31−34 We recently reported a class of catalysts derived from urea or thiourea anions.8,9 Treatment of (thio)ureas with strong bases © XXXX American Chemical Society

such as potassium methoxide generates (thio)urea anions that are highly active ring-opening polymerization catalysts. Mechanistic and computational studies indicate8 that these anionic species behave as bifunctional catalysts that simultaneously activate the alcohol initiator (or polymer chain-end) and the monomer (Figure 1a).1 In contrast, treatment of thioureas with weaker amine bases in the presence of alcohol initiators generates bifunctional cooperative systems where the amine base (H-bond acceptor) was proposed to activate the alcohol initiator (chain-end), and the thiourea (H-bond donor) activates the monomer (Figure 1b).28−30,35 As these two approaches differ only by the choice of the base to generate the active catalysts, herein we report a systematic investigation28−30 of these cocatalyst systems to assess the effect of the acidity of the (thio)urea and the basicity of the base cocatalyst on the activity for ring-opening polymerization. Herein we describe a family of highly selective catalyst pairs that are easy to prepare and utilize for the rapid generation of polymeric materials. This study reveals that for a given (thio)urea stronger bases lead to faster polymerizations, while for a given base the maximal activity is observed when the acidity of the (thio)urea is closely matched to that of the Received: March 14, 2018

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DOI: 10.1021/acs.macromol.8b00540 Macromolecules XXXX, XXX, XXX−XXX

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substituents on their aryl substituents.38 Structurally related ureas and thioureas, 4, 7, and 8, were also included. The bases were chosen to span a range of basicities (the pKa values of their conjugate acid B−H+ listed are reported either in DMSO or MeCN; see Table S1 in the Supporting Information). While strong bases such as BEMP and DBU can mediate the polymerization of VL in bulk,39,40 control experiments reveal that, in the absence of ureas or thioureas, BEMP, MTBD, and DBU are inactive for the polymerization of valerolactone ([VL]0 = 2.5 M) in THF (Table S2). The carbene IMes exhibits activity for VL polymerization under these conditions (kobs = 5.9 × 10−3 min−1, where d[monomer]/ dt = kobs[monomer]), but this activity is considerably lower than that observed in the presence of urea 1-O (kobs = 8.33 × 10 −1 min−1). On the other hand, weaker bases such as Protonsponge (N,N,N′,N′-tetramethyl-1,8-naphthalenediamine), DMAP (N,N-(dimethylamino)pyridine), pyridine, and triethylamine are inactive for the polymerization of VL in THF even in the presence of 1-O, likely due to their low effectiveness in the activation of alcohol. Earlier studies reported that solvents such as THF and DMF significantly hindered ring-opening polymerizations with the amine-tethered thiourea cocatalyst systems.28,29 Therefore, many subsequent organocatalytic ring-opening polymerizations were carried out in chloroform, dichloromethane, or aromatic solvents.28 Because of the low solubilities of ureas in the solvents used,29 ureas were perceived to be ineffective as ringopening polymerization catalysts. Subsequent reinvestigation of the solvent effects by us9 and others33,36 reveals this not to be the case. Here we show that THF is an effective solvent for ring-opening polymerizations with both ureas and thioureas in the presence of appropriate bases. For example, the polymerization of VL with DBU/4-S proceeded smoothly in THF (Table 1, entry 12, and Figure S1), reaching 93% conversion in 7 h with excellent control over the molecular weight distribution of the polymer (Đ = Mw/Mn = 1.03). Toluene

Figure 1. (a) Proposed dual activation mechanism of bifunctional urea (thiourea) anions, where the anionic portion of the urea (thiourea) activates the alcohol and the urea (thiourea) N−H activates the monomer. (b) Proposed cooperative H-bond activation mechanism of the thiourea/amine cocatalyst system, where DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) activates the alcohol and the thiourea activates the monomer.

protonated base (B−H+). For ureas and thioureas of comparable acidity, the urea/base catalyst systems are considerably more active than the corresponding thiourea/ base systems.9,33,36 More importantly, these results provide a basis for understanding the activities of these (thio)urea/base cocatalyst systems and useful principles for the rational design of catalyst pairs.

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RESULTS AND DISCUSSION An array of ureas and thioureas with varying electronic substituents (Figure 2a) were paired with several organic bases (Figure 2b) for the polymerization of cyclic esters, including L-lactide (LA), δ-valerolactone (VL), and εcaprolactone (CL) (Figure 2c). The acidities of several of the ureas and thioureas have been measured in DMSO37,38 and are indicated in Figure 2a. Diarylureas and thioureas, 1, 3, 5, and 6, have been demonstrated to exhibit pKaDMSO values that vary linearly with the number of CF3 electron-withdrawing

Figure 2. (a) Ureas and thioureas with their respective pKa values in DMSO.37,38 (b) Organic bases (basicity: DBU < MTBD < BEMP < IMes; see Table S1 in the Supporting Information) with the respective pKa values of their conjugate acids B−H+ in DMSO/MeCN. (c) Monomers studied. B

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Macromolecules Table 1. Representative Polymerization Reactionsa entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14

monomer LA (1 M)

VL (2.5 M)

CL (2.5 M)

urea/TU

base

solvent

target DP

time (s)

convb (%)

Mn,GPCc (kDa)

Đ

1-O 1-O 1-O 1-O 1-O 1-O 2-O 6-O 4-O 1-S 3-S 4-S 6-S 6-O

DBU DBU DBU DBU DBU BEMP BEMP IMes DBU DBU DBU DBU DBU IMes

THF THF THF THF toluene toluene toluene THF THF THF THF THF THF THF

50 100 200 100 100 100 100 100 100 100 100 100 100 100

6 20 160 600 420 45 20 4 25000 64800 74000 25000 7500 60

92 89 94 91 92 93 94 91 94 4 24 93 16 90

10.5 20.7 34.8 11.0 11.3 10.7 10.8 11.1 11.8

1.02 1.02 1.02 1.02 1.02 1.02 1.03 1.07 1.02

10.2

1.03

9.7

1.05

a

Unless otherwise specified, reaction conditions are [base]0:[H-bond donor]0:[PyOH initiator]0:[monomer]0 = 2.5:2.5:1:100 in THF at room temperature. Reactions were quenched with excess benzoic acid. bConversions were determined using NMR by determining the ratios of the integrations of the protons associated with the monomer and the polymer. cPolystyrene calibrated Mn,GPC (determined in THF). For a complete list of kobs of ureas (thioureas) with different bases, see Table 2 and Table S3.

Table 2. kobs for δ-Valerolactone Polymerization with Different Diaryl Ureas and Basesa

a

Reaction conditions: [base]0:[urea]0:[PyOH]0:[VL] = 2.5:2.5:1:100 in THF, [urea]0 = [base]0 = 0.0625 M, [PyOH]0 = 0.025 M, and [VL]0 = 2.5 M. Additionally, urea 4-O with DBU has a kobs of 0.0060 ± 0.0006 min−1, and urea 7-O with IMes has a kobs of 9.5 ± 0.1 min−1.

Figure 3. (a) kobs (log scale) of VL ROP vs number CF3 groups on diaryl ureas. (b) Data of Figure 3a normalized to the maximum kobs observed for each base.

can also be used with ureas if δ-valerolactone and εcaprolactone are used as monomers, in which the ureas are soluble, leading to reproducible polymerization rates. Base Plus Urea: A Class of Fast and Selective Catalytic Partners. With the appropriate combinations, catalysts derived from ureas and organic bases exhibit extraordinary activities for ring-opening polymerization (Table 1). The polymerization of L-lactide (LA) in THF from the initiator 1-pyrenebutanol (PyOH) with catalytic amounts of DBU and urea 1-O reached

high conversion within seconds (Table 1, entry 2). The polymerization of a less reactive monomer VL with the same catalyst combination was also fast, reaching 91% conversion in just 10 min (Table 1, entry 4), a substantial time decrease from the 7 h required for the benchmark catalyst pair DBU/4-S (Table 1, entry 12). The same VL polymerization can be further decreased to merely 4 s with 6-O and IMes (Table 1, entry 8), translating to an ∼7000-fold increase in rate relative to DBU/4-S. The polymerization of the less reactive monomer C

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for the polymerization of valerolactone in THF (note the log scale in Figure 3a). For a given base, the rates depend sensitively on the nature and acidity of the urea (Figure 3). For the strongest base IMes, the activity increases with decreasing acidity (decreasing number of CF3 substituents),37 ranging from kobs = 0.833 min−1 (1-O/IMes) to kobs = 36.6 min−1 (6O/IMes). In contrast, for the weaker bases DBU and MTBD, the rates are lower but decrease with decreasing acidity of the urea. The most revealing trend is that observed for BEMP, which has intermediate basicity: the activity exhibits a maximum with the ureas of intermediate acidity (2-O with three CF3 substituents and 3-O with two CF3 substituents). Significantly, the acidity of 3-O (pKaDMSO = 16.1) is slightly lower than that of BEMP-H+ (pKaDMSO = 16.5).37 A similar trend was observed for the rates of valerolactone polymerization with a series of thioureas (Figure 4 and Table S3). Analysis of the catalytic activities of a variety of thioureas with DBU in THF reveals that the maximum activity (Figure 4, blue diamonds) is observed for thioureas 4-S (pKaDMSO = 13.2, kobs = 5.5 × 10−3 min−1) and 6-S (pKaDMSO = 13.4, kobs = 1.2 × 10−3 min−1), whose pKaDMSO values are slightly lower than that of DBU-H+ (pKaDMSO = 13.9, dashed line). The catalytic activity falls off as the acidity of the thiourea (3-S, pKaDMSO 10.7, kobs = 2.0 × 10−4 min−1; 8-S, pKaDMSO 20.3, kobs = 1.5 × 10−4 min−1) deviates from that its optimally matched basic cococatalyst (DBUH+ pKa 13.9). These data indicate that for a given base the maximum activity in THF correlates to the DMSO acidity and is observed when the urea (or thiourea) is slightly more acidic than the conjugate acid of the base. The relative polymerization activities of structurally similar ureas and thioureas (1-S/1-O, 3-S/3-O, 4-S/4-O, and 6-S/6O) with a given base do not exhibit consistent trends, as they vary considerably (Figure 4, DBU as base). The structurally similar urea 4-O (kobs = 0.0060 min−1) and thiourea 4-S (kobs = 0.0055 min−1) exhibit comparable rates under the tested reaction conditions (see also Table 1, entries 9 and 12). In contrast, urea 1-O (kobs = 0.239 min−1) is significantly more active than its structurally similar thiourea 1-S (kobs = 0.000 042 min−1), and urea 3-O (kobs = 0.114 min−1) is significantly more active than thiourea 3-S (kobs = 0.000 20 min−1). The data in Figure 4 indicate that the structure of the thiourea or urea is not the appropriate descriptor to compare activities. For a given urea or thiourea, the acidity of the urea or thiourea relative to the basicity of the cocatalyst defines which urea or thiourea will be the most active. The similar activities of 4-S and 4-O are coincidental as a consequence of the close acidity matching of thiourea 4-S with DBU-H+ and the poor matching of the acidity of 4-O with DBU-H+. If ureas are compared to thioureas of similar pKaDMSO with DBU as the base (Figure 4), urea 1-O (pKa = 13.8, kobs = 0.239 min−1) is significantly more active than 6-S (pKa = 13.4, kobs = 0.0012 min−1) or 4-S (pKa = 13.2, kobs = 0.0055 min−1). These data indicate that provided the relative acidities of the urea or thiourea are matched appropriately with the base, the ureas are more active ring-opening polymerization catalysts. The observed trend that the ureas are more active than the thioureas (Figure 4) is consistent with trends reported by Kozlowski46 that when cross-correlated with acidity, diarylureas are better H-bond donor catalysts than diarylthioureas.46,47 Kozlowski46 quantified the electrophilic activation of carbonyl compounds by H-bond donor catalysts and showed that for ureas and thioureas of similar acidity ureas exhibit stronger binding than thioureas to carbonyl compounds and that this

CL also reached 90% conversion in just 1 min (Table 1, entry 14). These rates are competitive with some of the most active metal-based catalysts.41,42 Polymerization reactions with these organic base/urea cocatalysts are highly controlled. The living behavior of this polymerization system is evidenced by the linear first-order dependence of the rate on monomer concentration (d[monomer]/dt = kobs[monomer]), the linear increase in molecular weight with conversion, and the narrow molecular weight distribution of the polymer up to very high conversion (Figure S3). Also, the absence of ions separated by m/z = 72 in the MALDI spectra (Figure S5) of the poly(L-lactide) (Table 1, entry 1) reveals minimal transesterification of the polymer backbone. Moreover, the 1H homonuclear decoupled NMR spectrum of a poly(L-lactide) sample prepared under similar conditions reveals a highly isotactic microstructure, indicative of minimal epimerization (Figure S6). As shown in Tables 1 and 2, combinations of a variety of common organic bases and ureas provide a versatile platform of catalysts for the rapid and controlled ROP reactions. Reactivity Trends: Role of Acidity of (Thio)urea and Basicity of Cocatalyst. The rate of valerolactone polymerization was investigated for a series of diaryl ureas with a series of bases (Table 2 and Figure 3). The rates of all polymerizations are first-order in monomer; the relative activities can be quantified by comparison of the first-order rate constant kobs (d[monomer]/dt = kobs[monomer]). For these experiments, diaryl ureas substituted with zero to four CF3 substituents were chosen, as Schreiner had observed that the acidities of ureas and thioureas (pKa in DMSO) increase linearly with the number of CF3 substituents.37,38 A series of strongly basic cocatalysts were chosen to span a range of basicities (the pKaDMSO of their conjugate acids in parentheses): DBU (13.9)43 < MTBD < BEMP (16.5)44 < IMes (18 < pKaDMSO < 24).45 As shown in Table 2, Figure 3, and Figure 4, the observed rate constants (kobs) exhibit some revealing trends: the catalytic activities in THF are strongly influenced by the acidity of the ureas (thioureas) and the strength of the base. For a given urea H-bond donor, stronger bases yield faster rates (IMes > BEMP > MTBD > DBU, Table 2 and Figure 3)

Figure 4. Observed rate constant kobs (log scale) for δ-valerolactone polymerization with of DBU/thiourea (blue diamonds) and DBU/ urea (red circles) plotted against the pKaDMSO of thioureas or ureas. Reaction conditions: [base]0:[urea (thiourea)]0:[PyOH]0:[VL]0 = 2.5:2.5:1:100 in THF, [urea (thiourea)]0 = [base]0 = 0.0625 M, [PyOH]0 = 0.025 M and [VL]0 = 2.5M. (a) The pKaDMSO of DBU-H+ is shown in the dotted line. D

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Macromolecules was correlated to their relative activities in Diels−Alder reactions of methyl vinyl ketone. Mechanistic Implications. Prior studies had implicated two mechanisms for urea (thiourea)/base catalysts for ringopening polymerizations (Figure 1): For sufficiently strong bases (such as KOMe, KH, and IMes) capable of deprotonating the urea or thiourea, an anionic mechanism was proposed where the urea (thiourea) anion simultaneously activates the alcohol and the lactone for ring-opening (Figure 1a).8,9 For weaker bases whose pKa would render them incapable of deprotonating the urea (thiourea), the base was proposed to form a hydrogen bond to activate the alcohol, while the urea or thiourea was proposed to activate the lactone (Figure 1b). Two key observations provided by this study include (1) for a given base the maximum activity is observed when the acidity of the (thio)urea is closely matched to that of the protonated base (B−H+) and (2) for a given urea stronger bases lead to faster polymerizations. One interpretation of these observations is that the mechanism of polymerization changes depending on the deprotonation state of the ureas or thioureas, as dictated by the acidity of the ureas (thioureas) and the basicity of the base. When the pKa values of the (thio)ureas are significantly lower than the pKa of the B−H+, deprotonation of the (thio)ureas generates (thio)urea anions, and polymerization proceeds by the anion mechanism (Figure 1a). This is consistent with the trends observed for the strongest organic base studied IMes (IMes-H+: 18 < pKaDMSO < 24) and ureas (pKaDMSO < 18) 1-O, 2-O, 3-O, and 5-O, as well as for DBU (DBU-H+: pKaDMSO = 13.9) and thioureas (pKaDMSO < 13.4) 1S, 3-S, 4-S, 5-S, and 6-S. In both cases, the polymerization activity increases with decreasing acidity of the ureas (Figures 3 and 4, respectively). This trend is similar to that observed with urea anions generated with KOMe,9 where the activities of the urea anions decrease with increasing acidity of the ureas (decreasing basicity of urea anions). To correlate the trends indicated in Figure 3 with those observed previously for urea anions, the kinetics of the polymerization of VL using IMes/1O and using the anion generated by KOMe/1-O were compared.9 When IMes and 1-O were combined in the presence of an initiating alcohol ROH, the rate of VL polymerization (kobs is 0.0828 min−1) was similar to that catalyzed by the urea anion of 1-O (prepared with KOMe/1-O, kobs = 0.0825 min−1) under similar reaction conditions. Moreover, the catalytic activities of the IMes/urea/ROH catalyst system exhibit a similar linear free energy relationship with that of KOMe/urea catalyst system (Figure 5). For urea anions in the KOMe/urea catalytic system,9 the increase in activity with decreasing acidity of the ureas was previously proposed to be a result of stronger activation of the alcohol nucleophile with more basic urea anions. In contrast, when the pKa values of the ureas (thio)ureas are significantly higher than the pKa of the B−H+, the polymerization activity decreases with decreasing acidity of the (thio)urea (Figure 4, kobs 3-O > 4-O > 6-O, and kobs 7-S > 8-S). Under these conditions, prior studies had implicated that ring-opening proceeds by the H-bond cooperative mechanism (Figure 1b), where the base activates the alcohol instead of deprotonating the urea (thiourea). The decrease in activity with decreasing acidity of the urea (thiourea) could be rationalized as a consequence of the weaker activation of the lactone as the H-bond donated by the neutral (thio)ureas is less effective with less acidic (thio)ureas.

Figure 5. Free energy relationship between ln(kobs) and the number of CF3 substituents for IMes/initiator/urea and KOMe/urea under similar reaction conditions. IMes/urea conditions: [IMes]:[PyOH (initiator)]:[urea]:[VL]0 = 1:1:3:100. [VL]0 = 1 M. KOMe/urea conditions: [KOMe (base and initiator)]:[urea]:[VL]0 = 1:3:100. [VL]0 = 1 M.

Thus, according to the change in mechanism hypothesis, the maximum activity observed occurs at the point where both mechanisms become competitive, where the acidity of the (thio)ureas and the basicity of base are closely matched. As illustrated for BEMP (Figure 3), the activity increases with decreasing acidity of the urea (1-O < 2-O), as expected for urea anions (Figure 1a) until the acidity of the urea is slightly lower than that of the base (kobs, max with 2-O and 3-O); as the acidity of the urea decreases beyond this point, the activity decreases (kobs: 3-O > 5-O > 6-O) as the ureas ares less acidic and lesseffective H-bond donors (Figure 1b). A similar effect is observed for the thioureas with DBU, where the maximum activity is observed for 4-S and 6-S (pKaDMSO = 13.2 and 13.4, respectively), but decreases as the acidity of thiourea deviates from that of 4-S. When pKa of (thio)urea is comparable to that of the protonated base, the concentrations of the free (thio)ureas or (thio)urea anions cannot be trivially predicted from their relative pKa values due to multiple coupled equilibria that include (thio)urea binding to the base, deprotonation of the (thio)urea by the base, and ion-pairing of the (thio)urea anion and the protonated base.48−50 Nevertheless, the increase in activity for (thio)urea anions and decrease in activity for neutral (thio)ureas with decreasing (thio)urea acidity provide a rationale to explain why the maximal activity is observed when the acidities of the (thio)urea are closely matched with that of the protonated base (B−H+). The change from a neutral (thio)urea mechanism to a (thio)urea anion is also consistent with the increase in activity as the strength of the base increases for a given (thio)urea. As seen in Figure 3, the activities of the urea catalysts increase as the strength of the base increases (IMes > BEMP > MTBD > DBU), but the influence of the different bases on the relative rates is much more dramatic for urea 6-O than it is for urea 1O. For urea 6-O, the much more significant increase in activity with base strength (relative to 1-O) can be explained by a change in mechanism for this urea from a neutral urea/base (Figure 1b) for 6-O/DBU to the more active urea anion (Figure 1a)9 in the presence of the strong base IMes.

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CONCLUSION In summary, H-bond donors derived from ureas or thioureas in the presence of basic cocatalysts are a broad class of active and selective ring-opening polymerization catalysts whose activities span 6 orders of magnitude. Previous studies proposed E

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in the preparation of aliphatic polycarbonate materials. Prog. Polym. Sci. 2014, 39 (6), 1144−1164. (5) Thomas, C.; Bibal, B. Hydrogen-bonding organocatalysts for ring-opening polymerization. Green Chem. 2014, 16 (4), 1687−1699. (6) Vaca, B. M.; Bourissou, D. O-Carboxyanhydrides: Useful Tools for the Preparation of Well-Defined Functionalized Polyesters. ACS Macro Lett. 2015, 4 (7), 792−798. (7) Hu, S. Y.; Zhao, J. P.; Zhang, G. Z.; Schlaad, H. Macromolecular architectures through organocatalysis. Prog. Polym. Sci. 2017, 74, 34− 77. (8) Zhang, X.; Jones, G. O.; Hedrick, J. L.; Waymouth, R. M. Fast and selective ring-opening polymerizations by alkoxides and thioureas. Nat. Chem. 2016, 8 (11), 1047−1053. (9) Lin, B.; Waymouth, R. M. Urea Anions: Simple, Fast, and Selective Catalysts for Ring-Opening Polymerizations. J. Am. Chem. Soc. 2017, 139 (4), 1645−1652. (10) Grubbs, R. B.; Grubbs, R. H. 50th Anniversary Perspective: Living PolymerizationEmphasizing the Molecule in Macromolecules. Macromolecules 2017, 50 (18), 6979−6997. (11) Matyjaszewski, K. Atom Transfer Radical Polymerization (ATRP): Current Status and Future Perspectives. Macromolecules 2012, 45 (10), 4015−4039. (12) Perrier, S. 50th Anniversary Perspective: RAFT PolymerizationA User Guide. Macromolecules 2017, 50 (19), 7433−7447. (13) Nicolas, J.; Guillaneuf, Y.; Lefay, C.; Bertin, D.; Gigmes, D.; Charleux, B. Nitroxide-mediated polymerization. Prog. Polym. Sci. 2013, 38 (1), 63−235. (14) Ouchi, M.; Terashima, T.; Sawamoto, M. Transition MetalCatalyzed Living Radical Polymerization: Toward Perfection in Catalysis and Precision Polymer Synthesis. Chem. Rev. 2009, 109 (11), 4963−5050. (15) Lutz, J. F.; Lehn, J. M.; Meijer, E. W.; Matyjaszewski, K. From precision polymers to complex materials and systems. Nature Rev. Mater. 2016, 1 (5), 16024. (16) Ober, C. K.; Cheng, S. Z. D.; Hammond, P. T.; Muthukumar, M.; Reichmanis, E.; Wooley, K. L.; Lodge, T. P. Research in Macromolecular Science: Challenges and Opportunities for the Next Decade. Macromolecules 2009, 42 (2), 465−471. (17) McKinlay, C. J.; Vargas, J. R.; Blake, T. R.; Hardy, J. W.; Kanada, M.; Contag, C. H.; Wender, P. A.; Waymouth, R. M. Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals. Proc. Natl. Acad. Sci. U. S. A. 2017, 114 (4), E448− E456. (18) McKinlay, C. J.; Waymouth, R. M.; Wender, P. A. CellPenetrating, Guanidinium-Rich Oligophosphoesters: Effective and Versatile Molecular Transporters for Drug and Probe Delivery. J. Am. Chem. Soc. 2016, 138 (10), 3510−3517. (19) Cooley, C. B.; Trantow, B. M.; Nederberg, F.; Kiesewetter, M. K.; Hedrick, J. L.; Waymouth, R. M.; Wender, P. A. Oligocarbonate Molecular Transporters: Oligomerization-Based Syntheses and CellPenetrating Studies. J. Am. Chem. Soc. 2009, 131 (45), 16401−16403. (20) Cheng, J. C.; Chin, W.; Dong, H. H.; Xu, L.; Zhong, G. S.; Huang, Y.; Li, L. J.; Xu, K. J.; Wu, M.; Hedrick, J. L.; Yang, Y. Y.; Fan, W. M. Biodegradable Antimicrobial Polycarbonates with In Vivo Efficacy against Multidrug-Resistant MRSA Systemic Infection. Adv. Healthcare Mater. 2015, 4 (14), 2128−2136. (21) Venkataraman, S.; Tan, J. P. K.; Ng, V. W. L.; Tan, E. W. P.; Hedrick, J. L.; Yang, Y. Y. Amphiphilic and Hydrophilic Block Copolymers from Aliphatic N-Substituted 8-Membered Cyclic Carbonates: A Versatile Macromolecular Platform for Biomedical Applications. Biomacromolecules 2017, 18 (1), 178−188. (22) Yang, C.; Krishnamurthy, S.; Liu, J.; Liu, S. Q.; Lu, X. H.; Coady, D. J.; Cheng, W.; De Libero, G.; Singhal, A.; Hedrick, J. L.; Yang, Y. Y. Broad-Spectrum Antimicrobial Star Polycarbonates Functionalized with Mannose for Targeting Bacteria Residing inside Immune Cells. Adv. Healthcare Mater. 2016, 5 (11), 1272−1281. (23) Lim, Y. H.; Tiemann, K. M.; Heo, G. S.; Wagers, P. O.; Rezenom, Y. H.; Zhang, S.; Zhang, F.; Youngs, W. J.; Hunstad, D. A.; Wooley, K. L. Preparation and in Vitro Antimicrobial Activity of Silver-

mechanisms for DBU/thiourea and for (thio)urea anions; this study provides correlations for understanding and interpreting the relationship between the nature of H-bond donors and the base cocatalysts based on the relative acidity of the (thio)urea and strength of the base. For a given base, maximum activities are observed when the acidity of the urea or thiourea is closely matched to that of the protonated base (B−H+), a result of two competing mechanisms. For a given urea, higher activities are observed with more basic cocatalysts as stronger bases drive the formation of more anions and are better activators of the nucleophilic chain end. These findings not only offer a quantitative means of choosing the optimal catalyst partners for polymerizations of interest but also provide useful insights and criteria for the rational design of H-bond donor/acceptor catalysts. In addition, as ureas and thioureas have been widely employed both as anion binders50−52 and as H-bond donor catalysts26,53−56 for a diverse scope of organic reactions, these insights should inform further developments for more active Hbond catalysts for other reactions.

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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/acs.macromol.8b00540. Experimental details; Tables S1−S3 and Figures S1−S7 (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail [email protected] (R.M.W.). ORCID

Binhong Lin: 0000-0003-1996-9287 Robert M. Waymouth: 0000-0001-9862-9509 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Science Foundation (NSF-CHE 1607092). We gratefully thank Yan Xia and his group for the use of their GPC.

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ABBREVIATIONS DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; MTBD, 7-methyl1,5,7-triazabicyclo[4.4.0]dec-5-ene; BEMP, 2-tert-butylimino-2diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine; IMes, 1,3-bis(2,4,6-trimethylphenyl)-1,3-dihydro-2H-imidazol2-ylidene.

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REFERENCES

(1) Kiesewetter, M. K.; Shin, E. J.; Hedrick, J. L.; Waymouth, R. M. Organocatalysis: Opportunities and Challenges for Polymer Synthesis. Macromolecules 2010, 43 (5), 2093−2107. (2) Kamber, N. E.; Jeong, W.; Waymouth, R. M.; Pratt, R. C.; Lohmeijer, B. G. G.; Hedrick, J. L. Organocatalytic ring-opening polymerization. Chem. Rev. 2007, 107 (12), 5813−5840. (3) Ottou, W. N.; Sardon, H.; Mecerreyes, D.; Vignolle, J.; Taton, D. Update and challenges in organo-mediated polymerization reactions. Prog. Polym. Sci. 2016, 56, 64−115. (4) Mespouille, L.; Coulembier, O.; Kawalec, M.; Dove, A. P.; Dubois, P. Implementation of metal-free ring-opening polymerization F

DOI: 10.1021/acs.macromol.8b00540 Macromolecules XXXX, XXX, XXX−XXX

Article

Macromolecules Bearing Degradable Polymeric Nanoparticles of Polyphosphoesterblock-Poly(l-lactide). ACS Nano 2015, 9 (2), 1995−2008. (24) Elzeny, H.; Zhang, F. W.; Ali, E. N.; Fathi, H. A.; Zhang, S. Y.; Li, R. C.; El-Mokhtar, M. A.; Hamad, M. A.; Wooley, K. L.; Elsabahy, M. Polyphosphoester nanoparticles as biodegradable platform for delivery of multiple drugs and siRNA. Drug Des., Dev. Ther. 2017, 11, 483−496. (25) Brannigan, R. P.; Dove, A. P. Synthesis, properties and biomedical applications of hydrolytically degradable materials based on aliphatic polyesters and polycarbonates. Biomater. Sci. 2017, 5 (1), 9− 21. (26) Doyle, A. G.; Jacobsen, E. N. Small-molecule H-bond donors in asymmetric catalysis. Chem. Rev. 2007, 107 (12), 5713−5743. (27) Lippert, K. M.; Hof, K.; Gerbig, D.; Ley, D.; Hausmann, H.; Guenther, S.; Schreiner, P. R. Hydrogen-Bonding Thiourea Organocatalysts: The Privileged 3,5-Bis(trifluoromethyl)phenyl Group. Eur. J. Org. Chem. 2012, 2012 (30), 5919−5927. (28) Dove, A. P.; Pratt, R. C.; Lohmeijer, B. G. G.; Waymouth, R. M.; Hedrick, J. L. Thiourea-Based Bifunctional Organocatalysis: Supramolecular Recognition for Living Polymerization. J. Am. Chem. Soc. 2005, 127 (40), 13798−13799. (29) Pratt, R. C.; Lohmeijer, B. G. G.; Long, D. A.; Lundberg, P. N. P.; Dove, A. P.; Li, H.; Wade, C. G.; Waymouth, R. M.; Hedrick, J. L. Exploration, Optimization, and Application of Supramolecular Thiourea−Amine Catalysts for the Synthesis of Lactide (Co)polymers. Macromolecules 2006, 39 (23), 7863−7871. (30) Lohmeijer, B. G. G.; Pratt, R. C.; Leibfarth, F.; Logan, J. W.; Long, D. A.; Dove, A. P.; Nederberg, F.; Choi, J.; Wade, C.; Waymouth, R. M.; Hedrick, J. L. Guanidine and Amidine Organocatalysts for Ring-Opening Polymerization of Cyclic Esters. Macromolecules 2006, 39 (25), 8574−8583. (31) Kazakov, O. I.; Datta, P. P.; Isajani, M.; Kiesewetter, E. T.; Kiesewetter, M. K. Cooperative Hydrogen-Bond Pairing in Organocatalytic Ring-Opening Polymerization. Macromolecules 2014, 47 (21), 7463−7468. (32) Kazakov, O. I.; Kiesewetter, M. K. Cocatalyst Binding Effects in Organocatalytic Ring-Opening Polymerization of l-Lactide. Macromolecules 2015, 48 (17), 6121−6126. (33) Dharmaratne, N. U.; Pothupitiya, J. U.; Bannin, T. J.; Kazakov, O. I.; Kiesewetter, M. K. Triclocarban: Commercial Antibacterial and Highly Effective H-Bond Donating Catalyst for Ring-Opening Polymerization. ACS Macro Lett. 2017, 6 (4), 421−425. (34) Coady, D. J.; Engler, A. C.; Horn, H. W.; Bajjuri, K. M.; Fukushima, K.; Jones, G. O.; Nelson, A.; Rice, J. E.; Hedrick, J. L. Catalyst Chelation Effects in Organocatalyzed Ring-Opening Polymerization of Lactide. ACS Macro Lett. 2012, 1 (1), 19−22. (35) Zhu, R. X.; Wang, R. X.; Zhang, D. J.; Liu, C. B. A Density Functional Theory Study on the Ring-Opening Polymerization of DLactide Catalyzed by a Bifunctional-Thiourea Catalyst. Aust. J. Chem. 2009, 62 (2), 157−164. (36) Fastnacht, K. V.; Spink, S. S.; Dharmaratne, N. U.; Pothupitiya, J. U.; Datta, P. P.; Kiesewetter, E. T.; Kiesewetter, M. K. Bis- and TrisUrea H-Bond Donors for Ring-Opening Polymerization: Unprecedented Activity and Control from an Organocatalyst. ACS Macro Lett. 2016, 5 (8), 982−986. (37) Blain, M.; Yau, H.; Jean-Gérard, L.; Auvergne, R.; Benazet, D.; Schreiner, P. R.; Caillol, S.; Andrioletti, B. Urea- and ThioureaCatalyzed Aminolysis of Carbonates. ChemSusChem 2016, 9 (16), 2269−2272. (38) Jakab, G.; Tancon, C.; Zhang, Z.; Lippert, K. M.; Schreiner, P. R. (Thio)urea Organocatalyst Equilibrium Acidities in DMSO. Org. Lett. 2012, 14 (7), 1724−1727. (39) Zhang, L.; Nederberg, F.; Pratt, R. C.; Waymouth, R. M.; Hedrick, J. L.; Wade, C. G. Phosphazene bases: A new category of organocatalysts for the living ring-opening polymerization of cyclic esters. Macromolecules 2007, 40 (12), 4154−4158. (40) Pothupitiya, J. U.; Dharmaratne, N. U.; Jouaneh, T. M. M.; Fastnacht, K. V.; Coderre, D. N.; Kiesewetter, M. K. H-Bonding Organocatalysts for the Living, Solvent-Free Ring-Opening Polymer-

ization of Lactones: Toward an All-Lactones, All-Conditions Approach. Macromolecules 2017, 50 (22), 8948−8954. (41) Guillaume, S. M.; Kirillov, E.; Sarazin, Y.; Carpentier, J.-F. Beyond Stereoselectivity, Switchable Catalysis: Some of the Last Frontier Challenges in Ring-Opening Polymerization of Cyclic Esters. Chem. - Eur. J. 2015, 21 (22), 7988−8003. (42) Hillmyer, M. A.; Tolman, W. B. Aliphatic Polyester Block Polymers: Renewable, Degradable, and Sustainable. Acc. Chem. Res. 2014, 47 (8), 2390−2396. (43) Schwesinger, R.; Schlemper, H.; Hasenfratz, C.; Willaredt, J.; Dambacher, T.; Breuer, T.; Ottaway, C.; Fletschinger, M.; Boele, J.; Fritz, H.; Putzas, D.; Rotter, H. W.; Bordwell, F. G.; Satish, A. V.; Ji, G.-Z.; Peters, E.-M.; Peters, K.; von Schnering, H. G.; Walz, L. Extremely Strong, Uncharged Auxiliary Bases; Monomeric and Polymer-Supported Polyaminophosphazenes (P2−P5). Liebigs Annalen 1996, 1996 (7), 1055−1081. (44) Bug, T.; Lemek, T.; Mayr, H. Nucleophilicities of Nitroalkyl Anions. J. Org. Chem. 2004, 69 (22), 7565−7576. (45) Martin, D.; Illa, O.; Baceiredo, A.; Bertrand, G.; Ortuño, R. M.; Branchadell, V. Theoretical and Experimental Investigation of the Basicity of Phosphino(silyl)carbenes. J. Org. Chem. 2005, 70 (14), 5671−5677. (46) Walvoord, R. R.; Huynh, P. N. H.; Kozlowski, M. C. Quantification of Electrophilic Activation by Hydrogen-Bonding Organocatalysts. J. Am. Chem. Soc. 2014, 136 (45), 16055−16065. (47) Ho, J. M.; Zwicker, V. E.; Yuen, K. K. Y.; Jolliffe, K. A. Quantum Chemical Prediction of Equilibrium Acidities of Ureas, Deltamides, Squaramides, and Croconamides. J. Org. Chem. 2017, 82 (19), 10732− 10736. (48) Perez-Casas, C.; Yatsimirsky, A. K. Detailing hydrogen bonding and deprotonation equilibria between anions and urea/thiourea derivatives. J. Org. Chem. 2008, 73 (6), 2275−2284. (49) Gomez, D. E.; Fabbrizzi, L.; Licchelli, M.; Monzani, E. Urea vs. thiourea in anion recognition. Org. Biomol. Chem. 2005, 3 (8), 1495− 1500. (50) Baggi, G.; Boiocchi, M.; Fabbrizzi, L.; Mosca, L. Moderate and Advanced Intramolecular Proton Transfer in Urea-Anion HydrogenBonded Complexes. Chem. - Eur. J. 2011, 17 (34), 9423−9439. (51) Zhang, Z. G.; Schreiner, P. R. (Thio)urea organocatalysis - What can be learnt from anion recognition? Chem. Soc. Rev. 2009, 38 (4), 1187−1198. (52) Bregovic, V. B.; Basaric, N.; Mlinaric-Majerski, K. Anion binding with urea and thiourea derivatives. Coord. Chem. Rev. 2015, 295, 80− 124. (53) Grayson, M. N.; Houk, K. N. Cinchona Urea-Catalyzed Asymmetric Sulfa-Michael Reactions: The Brønsted Acid−Hydrogen Bonding Model. J. Am. Chem. Soc. 2016, 138 (29), 9041−9044. (54) Auvil, T. J.; Schafer, A. G.; Mattson, A. E. Design Strategies for Enhanced Hydrogen- Bond Donor Catalysts. Eur. J. Org. Chem. 2014, 2014 (13), 2633−2646. (55) Li, X.; Deng, H.; Zhang, B.; Li, J. Y.; Zhang, L.; Luo, S. Z.; Cheng, J. P. Physical Organic Study of Structure-Activity-Enantioselectivity Relationships in Asymmetric Bifunctional Thiourea Catalysis: Hints for the Design of New Organocatalysts. Chem. - Eur. J. 2010, 16 (2), 450−455. (56) Zhao, W.; Gnanou, Y.; Hadjichristidis, N. Organocatalysis by hydrogen-bonding: a new approach to controlled/living polymerization of alpha-amino acid N-carboxyanhydrides. Polym. Chem. 2015, 6 (34), 6193−6201.

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DOI: 10.1021/acs.macromol.8b00540 Macromolecules XXXX, XXX, XXX−XXX