Activated Polyacrylamides as Versatile Substrates for

Letter Cite This: ACS Macro Lett. 2018, 7, 122−126

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Activated Polyacrylamides as Versatile Substrates for Postpolymerization Modification Michael B. Larsen,† Shannon E. Herzog,† Helena C. Quilter,‡ and Marc A. Hillmyer*,† †

Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States Doctoral Training Centre in Sustainable Chemical Technologies, University of Bath, Bath BA2 7AY, U.K.

‡

S Supporting Information *

ABSTRACT: The displacement of an activated leaving group in polymeric repeat units is a powerful method of postpolymerization modification. This strategy enables the synthesis of polymers otherwise unobtainable by direct polymerization as well as the preparation of a diverse array of macromolecular structures. We demonstrate that the activation of acrylamide through the introduction of two tert-butyloxycarbamate (Boc) groups followed by radical polymerization leads to a new class of activated polyacrylamides analogous to well-known activated polyacrylates. Transamidation of poly(di(Boc)-acrylamide) utilizing primary amines proceeds to high conversion under mild conditions, and the products can be readily purified. Less nucleophilic secondary amines and alcohols require more forcing conditions. We demonstrate the utility of this approach by preparing copolymers capable of on-demand gel formation and the synthesis of block polymers using controlled radical polymerization.

T

tolerance toward a wide variety of polymerization conditions; however, these polymers still exhibit some degree of hydrolytic sensitivity that can lead to deleterious effects.9 Amidesand by extension poly(meth)acrylamidesare generally much less reactive toward nucleophilic substitution (including hydrolysis), largely due to molecular orbital overlap between the HOMO (dominated by nonbonding electrons on nitrogen) and the π* LUMO, which increases the electron density on the carbonyl carbon, rendering it less electrophilic and thus less susceptible to nucleophilic attack and displacement.10,11 This interaction can be disrupted via conformational restrictions,12 steric interactions,13 or electronic modification14 and can result in so-called “twisted amides” that are substantially more active toward solvolysis and other nucleophilic substitution reactions. These types of electronic modifications in particular have become useful strategies for activating a variety of amides toward Ni-catalyzed C−N insertion and cross-coupling for transamidation reactions and transformation of amides into esters.15,16 Additionally, recent studies have examined organocatalytic postpolymerization modification of polyacrylates using a nucleophilic guanidine,17 which involves a twisted amide intermediate in the reaction pathway.18 Along with amides, similar concepts extend to moieties such as ureas, which can react as masked isocyanates when electronic modifications are incorporated.19 We were inspired by a recent report detailing metal-free conditions for transamidation of electronically activated amides through acyl substitution20 to extend this concept to the

he past quarter century has seen growth in the preparation of functional macromolecules with diverse architectures. This is in large part due to the development of controlled polymerization techniques broadly tolerant of functional groups and useful for preparing precise macromolecular structures. A complementary approach involves the functionalization of reactive polymers, known as postpolymerization modification, which enables the synthesis of (co)polymers unobtainable by direct polymerization, facile polymer architecture modifications, and precision tuning of properties.1 Whether due to the incompatibility of functional groups with the selected synthesis method or the intrinsic reactivity ratios of different monomer units resulting in undesirable comonomer distributions, some linear sequences are unobtainable directly and thus require a postpolymerization modification approach. Additionally, the modification of polymer properties, such as glass transition temperature or rheological parameters, is readily accomplished using this strategy,2 and the preparation of a single type of reactive polymer followed by its transformation into a diverse array of architectures via grafting or cross-linking reactions can have tremendous utility.3 The use of nucleophilic substitution to modify polymers containing activated carbonyl compounds is among the most versatile methods of postpolymerization modification.4 In small-molecule organic synthesis, acid halides are generally used for similar reactions; however, due to the relative hydrolytic sensitivity of this functional group,5 activated esters have been much more extensively investigated in a macromolecular context.6 Polymers such as poly(N-hydroxysuccinimide-(meth)acrylate)7 and poly(pentafluorophenyl(meth)acrylate)8 have emerged as broadly useful and versatile platforms for postpolymerization modification due to their © XXXX American Chemical Society

Received: November 13, 2017 Accepted: December 19, 2017

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DOI: 10.1021/acsmacrolett.7b00896 ACS Macro Lett. 2018, 7, 122−126

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ACS Macro Letters macromolecular realm as a new platform for postpolymerization modification for nucleophilic substitution under mild conditions. Compared to other types of polymers with activated carbonyls, simple heating or acid treatment should allow for a more facile purification of the desired polymeric products given that the byproducts are gases at room temperature (Figure 1).

Scheme 1. Synthesis of DBAm Monomer, Free-Radical Polymerization Yielding Poly(DBAm), and Substitution of Poly(DBAm) with Generic Nucleophile NuH

Figure 1. Postpolymerization modifications utilizing activated esters (top) and activated amides (bottom).

Here we present a new twisted acrylamide monomer and demonstrate its controlled polymerization and subsequent displacement with amines and alcohols. Activation of amides via electronic modification is generally accomplished by the introduction of π-electron-withdrawing groups on the amide nitrogen using, for example, tertbutyloxycarbamate (Boc) or tosylate groups. Increased electron delocalization through such substituents lessens the donating ability of the nonbonding nitrogen electrons into the π* LUMO,14 rendering the carbonyl more electrophilic and also enhancing the effectiveness of the leaving group. These factors render activated amides both kinetically and thermodynamically much more susceptible to nucleophilic substitution. To take advantage of these effects, we synthesized a new activated acrylamide monomer, di(Boc)-acrylamide (DBAm), using a one-step double acylation of acrylamide that could be carried out on a multigram scale (Scheme 1). X-ray crystallography revealed a twisted amide structure (Figure 2), with a modest twist angle (τ) of 12.6° and pyramidalization at nitrogen (χ) of 1.5°. While these parameters are smaller than typical twisted amides utilized for C−N activation and cross-coupling (τ ∼ 20−40°, χ ∼ 5−20°),14 the C(3)−N(1) bond between the original carbonyl C and amide N is still significantly lengthened to 1.40 Å, in line with other similar activated amides (1.39−1.45 Å). In contrast, typical acyclic amides exhibit C−N bond lengths of ∼1.33−1.35 Å due to partial double-bond character of the C−N bond.21 Interestingly, the C(4)−N(1) bond length is more elongated to 1.46 Å, indicating even less effective orbital overlap. Despite this, we still observed excellent regioselectivity of the nucleophilic substitution reaction in most cases, potentially due to increased steric encumbrance associated with the tert-butyl group (see below). Thus, DBAm exhibits structural characteristics typical of activated amides.

Figure 2. Solid-state structure of DBAm and definitions of twist angle τ and pyramidalization at nitrogen χ. Ellipsoids are shown at the 50% probability level. Selected bond lengths (Å) and angles (deg): O(1)− C(3) 1.2166(18), N(1)−C(3) 1.400(2), N(1)−C(4) 1.4610(19), N(1)−C(9) 1.4038(19), C(3)−N(1)−C(4) 114.80(12), C(3)− N(1)−C(9) 125.68(12), C(4)−N(1)−C(9) 118.06(12), C(4)− N(1)−C(3)−O(1) 4.3(2), C(9)−N(1)−C(3)−C(2) 20.8(2).

Free-radical polymerization of DBAm initiated with AIBN yielded an amorphous polyacrylamide with a glass transition temperature Tg = 92 °C (Scheme 1). All molecular characterization data were consistent with successful polymerization to give the repeat unit shown in Scheme 1 (Figures S1−S5). Thermogravimetric analysis of the polymer indicated a 70 wt % loss at 158 °C, consistent with thermal decomposition of two Boc groups on each repeat unit. Infrared spectroscopy exhibited CO stretching frequencies consistent with the presence of 123

DOI: 10.1021/acsmacrolett.7b00896 ACS Macro Lett. 2018, 7, 122−126

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ACS Macro Letters Boc (1777 cm−1) and amide (1747 cm−1) carbonyl stretches; the amide stretch was shifted to a higher wavenumber compared to typical amides (1630−1690 cm−1). SEC analysis showed a broad, monomodal distribution typical for normal free radical polymerizations. While poly(DBAm) is not water soluble, examination of potential hydrolysis in wet (10 equiv of water per DBAm repeat unit) THF-d8 indicated no measurable hydrolysis over multiple days (Figure S6). We investigated the postpolymerization nucleophilic substitution of the activated poly(DBAm) using a variety of nucleophiles (Scheme 1, Table 1). Exposure of poly(DBAm) to

Selectivity for transamidation was further diminished by increasing the nucleophilicity of the amine (i.e., pyrrolidine), which exhibited single Boc removal as the primary reaction (Figures S25−S28). Sterically encumbered 2° amines as well as alcohols required more forcing conditions. Prolonged heating to 60 °C in DMF in the presence of DMAP as a transacylation catalyst resulted in full conversion of the polymeric Boc group; however, the final polymer contained the desired acrylamide or acrylate repeat unit and a putative cyclic imide repeating unit, likely a result of DMAP-promoted cyclization of adjacent DBAm units (Figures S29−S36). This poly(imide) structure could be obtained exclusively when poly(DBAm) was heated in the presence of DMAP with no external nucleophile (Figures S37−S38). Control of molar mass and achieving low dispersity is essential for the preparation of more complex polymeric architectures. To probe the potential for controlled radical polymerization, DBAm was subjected to reversible addition− fragmentation chain transfer (RAFT) polymerization utilizing (S)-1-dodecyl-(S′)-(α,α′-dimethyl-α″-acetic acid) trithiocarbonate as the chain transfer agent (CTA). SEC analysis with multiangle light scattering indicated that the resulting polymer exhibited low dispersity values as compared to poly(DBAm) synthesized via normal free radical polymerization (Mw = 14 kDa, Đ = 1.27 versus Mw = 46 kDa, Đ = 2.19, respectively), and RAFT polymerization also enabled synthesis of poly(DBAm) of controlled molar mass through tuning of the initial monomer:CTA ratio (Figure S39). Transamidation with benzyl amine resulted in the expected decrease in Mw to 11 kDa due to the lower molar mass of the repeat unit, while maintaining a low dispersity value of 1.33 (Figure 3), confirming that transamidation only alters the polymer side chains and not the overall architecture; however, the terminal trithiocarbonate was removed due to reaction with amine. Thus, to form block polymers, chain extension with another monomer must be accomplished prior to transamidation. Upon heating poly(DBAm) synthesized by RAFT in neat styrene, a clean shift in the SEC to lower retention volumes as well as increased Mw were observed (Figure 3), indicative of block polymer formation (Mw = 36 kDa, Đ = 1.44). The mild conditions and high fidelity of transamidation of DBAm with 1° amines enables the synthesis of (co)polymers capable of on-demand gelation via transamidation with nucleophilic diamines, even in the presence of hydroxycontaining nucleophiles. Statistical copolymer samples were prepared by radical polymerization containing varying ratios of DBAm and N,N-dimethylacrylamide (DMAm). In each case, the initial monomer loading was approximately maintained in the final polymer, as characterized by 1H NMR spectroscopy (Figure S40). To monitor the gelation of DBAm-containing copolymers with diamines, rheological experiments were conducted using small-amplitude oscillatory shear measurements at sufficiently low strain amplitudes to probe the linear viscoelastic regime. Kinetics of gelation were probed by monitoring the dynamic storage modulus (G′) and loss modulus (G″) of polymer solutions with diamine cross-linking agents in MeOH at 25 °C over time. To investigate the influence of cross-linker rigidity on the gelation process, two different diamine crosslinkers were investigated: ethylene diamine and p-xylylene diamine. Figure 4 shows the onset of gelation for a copolymer with [DBAm]:[DMAm] loading = 1:1, using both diamines at initial [DBAm]0:[NH2]0 of 1:1 and a polymer concentration of

Table 1. Nucleophilic Substitution of Poly(DBAm) nucleophile benzyl amine cyclohexyl amine allyl amine ethanolamine pyrrolidine dibenzyl amine benzyl alcohol

conversion a

>99% >99%a 98%a 90%b 13%b,e 62%b,f 76%b,f

c

yield

98% 96% 63% 88% 70% 58% 65%

d

Tg (°C) 90 −g 79 91 −g 123 45

a To desired repeat unit, determined by 1H NMR spectroscopy-scale transamidation reactions with internal standard. bTo desired repeat unit, determined by 1H NMR analysis of the final obtained polymer. c Isolated yield after workup. dSecond heating ramp, 10 °C/min. e Removal of a single Boc group observed as the primary reaction. f Boc group in poly(DBAm) fully converted, but a side reaction resulting in cyclic imide formation limited conversion to the desired repeat unit. gNo Tg detected by DSC up to 150 °C (Figures S14 and S28).

1° amines resulted in full transamidation in 20 h under mild conditions; the reaction was also effective with α-branched amines (e.g., cyclohexyl amine) (Figures S7−S18), and full conversion could be obtained with stoichiometrically equivalent amounts of poly(DBAm) repeat units and amine. In each case (except for ethanolamine; see below), high selectivity for transamidation versus “trans-Bocylation” was observed; the latter would likely deactivate the repeat unit toward further substitution, and NMR analysis during the course of the reaction indicated clean transamidation and generation of Boc2NH as the primary byproduct (Figure S19). The product polymers were purified by heating to 150 °C under reduced pressure to remove any residual amine. The Boc2NH byproduct was also thermally decomposed at this temperature, likely to isobutylene, CO2, and NH3. Thus, no precipitation is required for purification, and isolated yields of product acrylamides were >95%. 1H NMR spectra of purified polyacrylamides obtained by transamidation of poly(DBAm) were identical to spectra of the same polymer produced from the authentic monomer (e.g., N-benzyl acrylamide), further indicating the high conversion and high fidelity of the transamidation reaction (Figure S20). In the case of allyl amine, cross-linking precluded thermal purification, and Boc2NH byproduct was decomposed upon treatment with 10% trifluoroacetic acid. This method requires multiple precipitations to obtain clean polymer, and the yield of the final polymer was somewhat lower. The use of ethanolamine resulted in transamidation with no evidence of cross-linking, as hydroxy nucleophiles exhibit little reactivity under these conditions. However, a small degree of Boc removal was observed, resulting in singly Boc-protected repeat units that were inactive toward further nucleophilic substitution and limiting conversion to the desired poly(N-hydroxyethyl acrylamide) to 90% (Figures S21−S24). 124

DOI: 10.1021/acsmacrolett.7b00896 ACS Macro Lett. 2018, 7, 122−126

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ACS Macro Letters

the modulus of the obtained polymer gel may be tuned through the choice of nucleophilic diamine. The onset of gelation was much more rapid with the rigid cross-linker over the more flexible ethylene diamine linker, with crossover occurring at ca. 23 and 42 min, respectively. As the relative nucleophilicities of these diamines are similar,22 this is potentially due to competing intramolecular transamidation occurring between adjacent DBAm units with the flexible ethylene diamine backbone, which would be disfavored with the rigid p-xylylene diamine. The gelation time may also be adjusted by tuning the copolymer composition to increase the number of cross-linkable DBAm units present (Figures S41−S42). Gel formation using both diamines was investigated with copolymer samples prepared with [DBAm]:[DMAm] loadings of 1:1, 1:2, and 1:3. Gel formation is more rapid with higher concentrations of reactive DBAm sites for both diamine cross-linking agents. In crosslinking reactions with the more effective p-xylylene, diamine gelation occurred at very similar time points for both the [DBAm]:[DMAm] = 1:1 and 1:2 samples, at ca. 23 and 25 min (Figure S42); however, copolymers with [DBAm]:[DMAm] = 1:3 required ca. 102 min. This is in agreement with the expected critical extent of conversion of DBAm units required for gel formation (pcrit), calculated for the copolymers to be 0.11, 0.10, and 0.18 for [DBAm]:[DMAm] = 1:1, 1:2, and 1:3, respectively (see Supporting Information). Plateau moduli, as estimated by the last collected data point, increase by an order of magnitude in each case with increasing cross-linking content. Varying the amount of diamine also affects the kinetics of gelation (Figure S43). Using the same copolymer ([DBAm]:[DMAm] = 1:1) and ethylene diamine as cross-linker, gel formation occurred much faster with [DBAm]0:[NH2]0 = 1:1 (37 min) than with [DBAm]0:[NH2]0 = 1:2 (57 min), in agreement with calculated pcrit values of 0.11 and 0.16. In conclusion, we have introduced an activated amide monomer (DBAm) and corresponding polymer, poly(DBAm), capable of facile postpolymerization modification via nucleophilic substitution. Poly(DBAm) reacts with both amines and alcohols to yield the corresponding poly(acrylamides) and poly(acrylates). RAFT polymerization and subsequent transamidation indicate that the polymer architecture remains intact during modification, and poly(DBAm) can be incorporated into block polymers. We also demonstrated on-demand gelation with tunable kinetics and rheological properties by reacting DBAm-containing copolymers with nucleophilic diamines. Poly(DBAm) expands the potential chemistries available for postpolymerization modification using activated carbonyl compounds.

Figure 3. Transamidation of poly(DBAm) synthesized by RAFT to obtain poly(benzyl acrylamide) (red) and block polymer formation via chain extension with styrene (blue). The clean shift in the retention volume in both cases indicates a lack of secondary reactions that would alter dispersity, as well as clean initiation from the CTA-terminated poly(DBAm). The end group of poly(benzyl acrylamide) is likely a thiol due to aminolysis of the trithiocarbonate; however, no direct evidence for this end group was observed.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmacrolett.7b00896. X-ray structure and crystallographic information file for C13 H21 N O5 (CIF) Experimental details, characterization (1H NMR, ATR-IR, TGA, and DSC) of polymers, and additional rheological data (PDF)

Figure 4. Determination of gel points using shear rheometry. Storage (G′) and loss (G″) moduli as a function of time determined for poly(DBAm-co-DMAm) with copolymer [DBAm]:[DMAm] loading = 1:1 and [DBAm]0:[NH2]0 = 1:1, using ethylene diamine (black) and p-xylyene diamine (blue) at polymer concentration in MeOH of 250 mg/mL. Frequency = 1 rad/s, strain = 5%, 40 mm parallel plate geometry, T = 25 °C.

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250 mg/mL in MeOH. The gel prepared with the more rigid p-xylylene diamine exhibited crossover and plateau moduli values that were approximately an order of magnitude higher than for the analogous ethylene diamine gel. This indicates that

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. 125

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ACS Macro Letters ORCID

N-Acyl-tosylamides (Ts): Twisted Amides of Relevance to Amide N-C Cross-Coupling. J. Org. Chem. 2016, 81, 8091−8094. (15) Hie, L.; Fine Nathel, N. F.; Shah, T. K.; Baker, E. L.; Hong, X.; Yang, Y.-F.; Liu, P.; Houk, K. N.; Garg, N. K. Conversion of amides to esters by the nickel-catalyzed activation of amide C-N bonds. Nature 2015, 524, 79. (16) Baker, E. L.; Yamano, M. M.; Zhou, Y.; Anthony, S. M.; Garg, N. K. A two-step approach to achieve secondary amide transamidation enabled by nickel catalysis. Nat. Commun. 2016, 7, 11554−11558. (17) Easterling, C. P.; Kubo, T.; Orr, Z. M.; Fanucci, G. E.; Sumerlin, B. S. Synthetic upcyclic of polyacrylates through organocatalyzed postpolymerization modification. Chem. Sci. 2017, 8, 7705−7709. (18) Kieswetter, M. K.; Scholten, M. D.; Kirn, N.; Weber, R. L.; Hedrick, J. L.; Waymouth, R. M. Cyclic Guanidine Organic Catalysts: What Is Magic About Triazabicyclodecene? J. Org. Chem. 2009, 74, 9490−9496. (19) Hoff, E. A.; Abel, B. A.; Tretbar, C. A.; McCormick, C. L.; Patton, D. L. RAFT Polymerization of ‘Splitters’ and ‘Cryptos’: Exploiting Azole-N-carboxamides As Blocked Isocyanates for Ambient Temperature Postpolymerization Modification. Macromolecules 2016, 49, 554−563. (20) Liu, Y.; Shi, S.; Achtenhagen, M.; Liu, R.; Szostak, M. MetalFree Transamidation of Secondary Amides via Selective N-C Cleavage under Mild Conditions. Org. Lett. 2017, 19, 1614−1617. (21) Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen, A. G.; Taylor, R. Tables of Bond Lengths determined by X-Ray and Neutron Diffraction. Part 1. Bond Lengths in Organic Compounds. J. Chem. Soc., Perkin Trans. 2 1987, S1−S19. (22) Brotzel, F.; Chu, Y. C.; Mayr, H. Nucleophilicities of Primary and Secondary Amines in Water. J. Org. Chem. 2007, 72, 3679−3688.

Michael B. Larsen: 0000-0002-2511-0922 Marc A. Hillmyer: 0000-0001-8255-3853 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the University of Minnesota for support of this research. This work was supported partially by the Research Experiences for Undergraduates (REU) Program of the National Science Foundation under Award Number DMR1559833. HCQ thanks the EPSRC Doctoral Training Centre in Sustainable Chemical Technologies, University of Bath (EP/ G03768X/1), for funding. We acknowledge Dr. Victor G. Young, Jr. and the X-ray Crystallographic Laboratory at the University of Minnesota for data collection and crystal structure solution. The authors thank Aditya Banerji and Prof. Chris Ellison for access to DMF SEC instrumentation.

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REFERENCES

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DOI: 10.1021/acsmacrolett.7b00896 ACS Macro Lett. 2018, 7, 122−126