Programmable High-Throughput Platform for the Rapid and Scalable

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Programmable High-Throughput Platform for the Rapid and Scalable Synthesis of Polyester and Polycarbonate Libraries Binhong Lin,† James L. Hedrick,‡ Nathaniel H. Park,*,‡ and Robert M. Waymouth*,† †

Department of Chemistry, Stanford University, Stanford, California 94305, United States IBM Research-Almaden, 650 Harry Road, San Jose, California 95120, United States

‡

Downloaded by UNIV OF SOUTHERN INDIANA at 18:09:19:412 on May 22, 2019 from https://pubs.acs.org/doi/10.1021/jacs.9b02450.

S Supporting Information *

ABSTRACT: The critical role of composition, architecture, molecular weight, and molecular weight distribution on the functional properties of macromolecular materials underscores the need for reproducible, robust, scalable, and programmable synthetic methods to generate macromolecules that span a systematic and wide range of structure−property space. Herein, we describe the marriage of tunable and highly active organic catalysts with programmed continuous-flow reactors to rapidly generate libraries of polyester and polycarbonate homopolymers and block copolymers with exquisite efficiency and control. Under continuous-flow conditions, highly controlled polymerizations occur with residence times as low as 6 ms (TOF = 24 000 000 h−1) and can be readily scaled-up to generate polymers at a rate of tens of grams per minute. We describe an in-flow catalyst switch strategy to enable the rapid generation of block copolymer libraries (100 distinct polymers in 9 min) from monomers with drastically different reactivity profiles.

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ingredients12,25 as well as polymers and block copolymers.10,11,26−41 For polymerization reactions, the advantages of continuous-flow synthesis include controlled reaction times with uniform heating,10,11 narrow42 and tunable28 molecular weight distributions, and the generation of block copolymers.10,29,33,39,43 Additionally, these systems enable fast and reproducible mixing times with an appropriate reactor design. This permits more consistent control of reaction parameters that govern molecular weight and molecular weight distributions, especially for very fast reactions.10,26−28,39,44 Finally, continuous-flow systems facilitate the programmatic control over reaction development and optimization through the integration of computer controls and in-line monitoring.45 The value of these features has been demonstrated in the optimization of reaction conditions and multistep smallmolecule syntheses.9,46−48 In spite of the advancements and advantages of continuousflow synthesis and previous exploration of the polymerization of cyclic esters in continuous-flow,40,49,50 significant challenges remain. These challenges include the rapid and scalable synthesis of block and multiblock copolymers from monomers that differ widely in their polymerization rates, the facile and reproducible scale-up of polymers, and the preparation of targeted, well-defined material libraries. Herein, we describe a solution to these challenges by combining highly active ringopening polymerization catalysts, an in-flow catalyst switch

INTRODUCTION Recent progress in catalysis1−4 and synthetic methods,5,6 coupled with advances in process chemistry,7−11 are poised to revolutionize synthetic chemistry.6,9,12 New processes to generate well-defined polymeric materials rapidly and reproducibly with a systematic range of structures and compositions10,11,13−15 are critical to illuminate how structure and composition influence the function and performance of macromolecular materials.16−18 The application of synthetic macromolecules for biomedical applications highlights the exquisite sensitivity of the biological functions of degradable, functional polymeric materials to their composition, architecture, and length.19−21 Despite these advancements, the generation of well-defined functional homopolymers and block copolymers remains a time- and labor-intensive process. Even today, heroic synthetic efforts are required to generate libraries of macromolecular structures to illuminate structure− function relationships or to optimize their functional performance. As it is difficult to predict which structures have optimal function,16,22 rapid, robust, and reproducible synthetic processes are needed to generate, evaluate, modify, test, and scale-up promising candidates. Continuous-flow synthesis is a versatile alternative to traditional batch processes due to several notable advantages, including: superior heat transfer, improved mixing, safer handling of hazardous reagents and intermediates, the ability to telescope several synthetic steps into a single system, and a more straightforward path to scale-up.23,24 These benefits facilitated the application of continuous-flow systems for the synthesis of small molecules and active pharmaceutical © XXXX American Chemical Society

Received: March 5, 2019

A

DOI: 10.1021/jacs.9b02450 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Journal of the American Chemical Society

Figure 1. Application of urea anion catalysts and a catalyst switch strategy for the programmed synthesis of polyester and polycarbonate libraries in continuous-flow.

Figure 2. Homopolymerization in continuous-flow.

strategy for block copolymerization, and automated reactor control for precision library generation (Figure 1).

Table 1. Continuous-Flow Synthesis of Polycarbonate and Polyester Homopolymersa

RESULTS AND DISCUSSION To take maximum advantage of the fast, programmable, and reproducible mixing times of continuous flow reactors, we employed a recently reported class of highly active and selective urea anion catalysts51 (Figure 2b) whose activities for the ring-opening polymerization of cyclic lactone, carbonate, and phosphoester monomers can be readily tuned by their acidities.52 The fast kinetics exhibited by these catalysts for ring-opening polymerization suggested that they would be ideal candidates for use in continuous-flow systems for controlled polycarbonate and polyester synthesis. Homopolymers. To assess the effectiveness of urea anion catalysts for programmable polycarbonate and polyester synthesis, we first investigated the homopolymerization of lactones and cyclic carbonates in continuous-flow. The homopolymerizations (Table 1) were performed in a flow reactor, where the catalyst/initiator solution and the monomer solution were infused via syringe pumps into the mixer prior to entering the reactor loop for polymerization; the resulting polymers were collected in a THF solution of benzoic acid to quench the catalyst (Figure 2). Under batch conditions, polymerizations with the most active urea anion catalysts with the most reactive monomers are difficult to control due to the very fast rates of polymerization.51,52 The use of high flow rates (15−48 mL/ min) under continuous-flow conditions with millisecond time scale mixing allows the more active urea catalysts to be used

entry

■

1 2 3 4d 5 6 7 8 9 10

monomer L-LA

(0.5 M) L-LA (1 M) L-LA (1 M) L-LA (1 M) L-LA (1 M) VL (1 M) CL (1 M) TMC (1 M) TMC (1 M) TMC-Bn (0.5 M)

conversion (%)b

Mn (kDa)c

Đc

0.32

96

5.4

1.13

3

0.32

98

13

1.09

50

5

0.030

92

14

1.09

50

5

0.10

95

12

1.12

100

3

1.3

98

25

1.11

50 50 50

7 7 7

0.81 2.3 0.0063

86 91 85

7.8 9.1 6.1

1.11 1.14 1.07

50

7

0.010

98

7.0

1.08

50

5

0.040

89

[M]0/ [I]0

urea

25

3

50

τ (s)

11

1.15

a

See Supporting Information for details. Reactor setup and conditions (unless otherwise specified): flow rate = 15, 30, or 48 mL/min at room temperature. Tubing inner diameter = 1 mm (entries 1 to 7) or 0.5 mm (entries 8 to 10). The reaction mixtures were quenched with benzoic acid in THF. bMeasured by 1H NMR. cDetermined by GPC. d Initiated from BnOH using KH as the base to generate the urea anion. [KH]0:[urea]0:[BnOH]0:[L-LA]0 = 1:3:5:250.

with the more reactive monomers, reaching high conversions with excellent control in very short residence times (Table 1, entries 2 and 3). For example, the polymerization of B

DOI: 10.1021/jacs.9b02450 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Journal of the American Chemical Society

Figure 3. Block copolymer synthesis with catalyst switch. (a) Catalyst switch based on proton transfer. (b) Reactor setup for AB diblock copolymer synthesis. (c) Reactor setup for synthesis of ABC triblock copolymer poly(CL)25-block-poly(TMC)25-block-poly(L-LA)25 with sequential catalyst switches. Conversions: 90% (CL), 88% (TMC), 88% (L-LA), Mn GPC = 12 kDa, Đ = 1.08. TMC: trimethylene carbonate.

run at a higher flow rate of 180 mL/min enabled by a more powerful syringe pump (see Supporting Information), the polymerization of L-LA generated 16.5 g of poly(L-LA) in 40 s (Movie S1). Block Copolymers. The synthesis of well-defined block copolymer libraries is important for both fundamental16−18 and practical reasons, including the generation of nanoparticles54,55 and functional bioactive polymers.19−21 Continuous-flow polymerization offers an excellent alternative to batch procedures for block copolymer synthesis as the monomers for each block can be sequentially introduced.10,29,33 However, this approach can be challenging when the blocks are composed of monomers with disparate reactivity profiles, necessitating reactor segments (residence times) that vary drastically, mitigating some of the advantages of flow processes. For the synthesis of a ε-caprolactone (CL) and L-LA diblock copolymer as an example, the reactor segment for CL would be four orders of magnitude longer than the reactor segment for L-LA. The class of highly active and selective ring-opening polymerization (ROP) catalysts derived from urea anions exhibit a broad range of activities that can be predictably tuned based on their acidities, where the more basic anions exhibit

trimethylene carbonate (TMC) with KOMe/7 reached 85% conversion in 0.0063 s (Table 1, entry 8), corresponding to a residence time that is 3 orders of magnitude faster than what is achievable in batch and a catalyst turnover frequency of 24 000 000 h−1. Shown in Table 1 are some example polymerizations of a representative series of monomers. For the resulting polymers, their molecular weight distributions are narrow (Table 1); molecular weights increase with increasing [M]0/[I]0 (Table 1, entries 1, 4, 5), and the experimental degree of polymerization determined via 1H NMR analysis matches well with the targeted degree of polymerization (see Supporting Information). Continuous-flow processes can be scaled-up either by running the flow reactor for a longer period of time or using multiple reactors in parallel.53 Here, the combination of the high activity of this class of catalysts and the efficient mixing of continuous-flow enables the generation of narrowly dispersed polymers at the rate of multiple grams per minute (Table 1). As a demonstration for scale-up synthesis, L-lactic acid (L-LA) (1.0 M) was polymerized using potassium hydride (KH, 4.0 mM), urea 5 (12.0 mM), and benzyl alcohol (20.0 mM) as the catalyst/initiator to afford 5.2 g of well-defined poly(L-LA) after a reactor run time of 50 s (Table 1, entry 4). In a larger C

DOI: 10.1021/jacs.9b02450 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Journal of the American Chemical Society Table 2. Examples of Block Copolymer Syntheses in Continuous-Flow (or Batch)a block 1

final polymer

block 2

entry

M

[M]0/[I]0

urea

τ (s)

conv. (%)b

M

[M]0/[I]0

urea

τ (s)

conv. (%)b

Mn GPC(kDa)c

Đc

1 2 3d 4 5 6 7 8 9

VL VL VL VL CL CL TMC L-LA CL

50 50 50 50 50 25 50 50 50

7 7 7 7 7 7 6 3 7

0.81 0.81 0.81 0.81 2.27 2.27 0.45 0.32 2.27

89 88 87 88 92 89 90 (95) (84)

L-LA

50 50 50 25 50 25 50 50 50

3

0.43 0.43 0.43 0.43 0.43 0.70 0.43 0.43 0.61

93 97 96 95 94 89 97 (95) (84)

23 15 22 16 17 7.1 17 29 18

1.09 1.36 1.21 1.12 1.13 1.09 1.11 1.08 1.12

L-LA L-LA L-LA L-LA TMC L-LA D-LA VL

3 3 3 6 3

a See Supporting Information for details. Tubing inner diameter = 1 mm. bConversion was measured by 1H NMR. NMR signals of the blocks in entries 8 and 9 overlap. cDetermined by GPC analysis using THF as the eluent and calibrated with polystyrene standards. dIn batch.

Figure 4. Programmed library generation of (a) poly(L-LA) with chain lengths from 10 to 50 with increments of 1 and (b) poly(VL)-block-poly(LLA) with block sizes of 10 to 46 with increments of 4 (using catalyst switch). DP: degree of polymerization (number of monomer repeat units).

higher activities.51,52 This enables the activity of the catalyst to be matched optimally with the reactivity of the monomer, allowing for high conversions with excellent polymerization control for a wide variety of monomers. We envisioned that the pKa-based activity of the urea anions51,52 would facilitate an inflow catalyst switching strategy to ensure the appropriate matching of the catalyst activity with that of the different monomers in a telescoped block polymerization process. This concept is outlined in Figure 3a, where a more active and more basic urea anion is used to polymerize a low activity monomer; addition of a more acidic urea simultaneously with the second (less reactive) monomer quenches the first catalyst by rapid proton transfer and generates a less active urea anion that is optimally matched to the reactivity of the second monomer. While several other catalyst switching strategies are known,56,57 the wide range of acidity-dependent catalytic activity of the

urea anions enables multiple catalyst switches to be carried out under continuous-flow conditions (Figure 3, Table 2). The catalyst switch strategy was first tested in the synthesis of poly(VL)50-block-poly(L-LA)50 (Figure 3a and 3b). For the polymerization of the VL block, the highly active anion of urea 7 was utilized. For the second block, L-LA and the more acidic urea 3 were coinjected immediately before the second reactor loop (Figure 3b). When the catalyst from the anion of urea 7 was switched to 3, a well-defined AB diblock copolymer was obtained with excellent control (Đ = 1.09, Table 2, entry 1). In contrast, when no catalyst switch was employed, a broader molecular weight distribution was obtained (Đ = 1.36, Table 2, entry 2). The catalyst switch strategy was utilized to successfully access other narrowly dispersed block copolymers from monomers with very different reactivity profiles (Table 2, D

DOI: 10.1021/jacs.9b02450 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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In summary, the rapid and controlled synthesis of polycarbonates and polyesters was enabled by exploiting the unique advantages of continuous-flow, a class of highly active and selective urea anion catalysts, and an in-flow catalyst switch strategy. With benefits such as very short residence times and rapid synthesis of multiblock copolymers, our approach enables the facile access to libraries of homopolymers and block copolymers. Moreover, the high rate of production offers a straightforward solution for scaling up the synthesis of new material candidates. Overall, the versatile catalyst platform, diverse polymer compositions, and seamless automation represent a practical solution for the truly programmable, on-demand synthesis of functional materials for accelerated material discovery, evaluation, and scale-up.

entries 4−7). When the appropriate urea anions for each monomer are selected, comparable retention times of the blocks can be achieved while minimizing transesterification of the polymer backbone (Figure 3, Table 2). Because of the decreasing activities of new anions generated with each switch, this approach is most effective for the polymerization of the less reactive monomer before the more reactive monomer. However, this requirement does not limit the number of diblock copolymers that can be synthesized, unless a specific head−tail direction of the repeat units is required. While the catalyst switch is straightforward to employ, it is not necessary when the polymer consists of monomers of relatively similar reactivities such as L-LA and D-LA (Table 2, entry 8) or CL and VL (Table 2, entry 9). Characterization of these copolymers via NMR and DSC analysis (see Supporting Information) shows minimal random sequences and high fidelity of the individual polymer blocks. Sequential catalyst switches for accessing triblock copolymers is also feasible. Here, the synthesis of poly(CL)25-blockpoly(TMC)25-block-poly(L-LA)25 was facilitated by three catalysts and two catalyst switches, generating the triblock copolymer in 3.5 s with excellent control, a challenging feat given that CL is approximately 6000 times less reactive than LLA43,44 (Figure 3c). Despite the short block sizes, DSC revealed sharp melting peaks for the CL and L-LA segments (Figure S52), indicating minimal transesterification of the polymer backbone and high integrity of the individual blocks. Automated Library Generation. While continuous-flow systems are readily operated manually, they also offer the advantage of automation via computer control. This facilitates systematic variation of polymer compositions through modulation of the relative stoichiometry between the monomer and initiator, rapidly generating well-defined material libraries. To demonstrate this process, we developed software (see Supporting Information) to programmatically control the flow system for the automated synthesis of homopolymer and block copolymer libraries. Shown in Figure 4a is the reactor setup for the synthesis of a homopolymer library of poly(L-LA)s with degrees of polymerization ranging from 10 to 50 in increments of 1 repeat unit. By programmatically varying the flow rates of the THF and the monomer solution inlets, the ratio of the monomer to initiator can be accurately varied. With this reactor, 41 well-defined polymers were generated in 6 min (approximately 0.04 mmol each) with precisely the programmed number of monomer repeat units (Figure 4). The high degree of control is also evident in the evolution of monomodal GPC traces, where these polymer samples illustrate the progressive increase in molecular weight (Figure S3, Table S3, Supporting Information). This program and flow reactors were also adapted for the generation of block copolymer libraries by incorporating and programming a catalyst switch (Figure 4b). When a catalyst switch was applied and the appropriate modifications to the reactor were made, a 2-dimensional library of 100 AB diblock poly(VL)-block-poly(L-LA) copolymers was generated under computer control with a total run time of less than 9 min. The block sizes ranged from DP 10 to DP 46 in increments of 4 repeat units (DP = degree of polymerization, Figure 4b). The experimental total DPs map well with the target total DPs (Figure 4), and the molecular weight distribution of the polymers remain narrow with an average Đ of 1.13.

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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/jacs.9b02450. Supplemental figures and information regarding materials used, instrumentation, synthetic procedures, and characterization data (PDF) Movie S1 showing the scale-up synthesis of L-LA in continuous-flow (180 mL/min) (MP4) Python script used for making material libraries (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Binhong Lin: 0000-0003-1996-9287 James L. Hedrick: 0000-0002-3621-9747 Nathaniel H. Park: 0000-0002-6564-3387 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), the Office of Naval Research (ONR N000141410551, R.M.W.), and IBM Research-Almaden. We thank Andy Tek for obtaining the DSC data.

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DOI: 10.1021/jacs.9b02450 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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DOI: 10.1021/jacs.9b02450 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX