Compartmentalized Nanoreactors for One-Pot Redox-Driven

Research Article Cite This: ACS Catal. 2019, 9, 2701−2706

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Compartmentalized Nanoreactors for One-Pot Redox-Driven Transformations Peiyuan Qu,† Michael Kuepfert,† Steffen Jockusch,‡ and Marcus Weck*,† †

Molecular Design Institute and Department of Chemistry, New York University, New York, New York 10003, United States Department of Chemistry, Columbia University, New York, New York 10027, United States

‡

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S Supporting Information *

ABSTRACT: This contribution introduces poly(2-oxazoline)based shell cross-linked micelles (SCMs) as nanoreactors to realize one-pot redox-driven deracemizations of secondary alcohols in aqueous media. TEMPO and Rh-TsDPEN moieties are spatially positioned into the hydrophilic corona and the hydrophobic micelle core, respectively. TEMPO catalyzes the oxidation of racemic secondary alcohols into ketones, while RhTsDPEN catalyzes the asymmetric transfer hydrogenation (ATH) of these ketones to afford enantioenriched secondary alcohols. Both catalysts, the Rh-TsDPEN complex and TEMPO, are incompatible with each other and the SCMs are designed to provide indispensable catalyst site isolation. Kinetic studies show that the SCMs enhance the reactivity of the immobilized catalysts, in comparison to those for the unsupported analogues under the same reaction conditions. Our nanoreactors can perform deracemizations on a broad range of secondary alcohol substrates and are reusable in a continuous manner while maintaining high activity. KEYWORDS: cross-linked micelle, poly(2-oxazoline), deracemization, TEMPO oxidation, asymmetric transfer hydrogenation

R

Deracemization allows for the synthesis of high-value, enantiopure compounds from cheap, racemic mixtures.24−28 Redox-driven deracemizations of racemic secondary alcohols consist of two opposite reactions: the oxidation of the racemic mixture into a nonchiral carbonyl and the enantioselective reduction of the carbonyl group to the desired enantiopure chiral alcohol. In most cases, this process has been achieved via chemoenzymatic catalysis.29−32 Nonenzymatic redox-driven deracemizations that can be carried out in one pot remain scarce and often require harsh reaction conditions in organic solvents.33−36 In this contribution, we report the use of functionalized SCM nanoreactors to catalyze, in water, the redox-driven deracemizations of secondary alcohols in excellent conversions and enantiomeric excesses (ee) (Figure 1). Our research design is based on the use of the organocatalyst TEMPO to oxidize racemic secondary alcohols into ketone intermediates, followed by rhodium (rhodium N-tosylated 1,2diphenyl-1,2-ethylenediamine (Rh-TsDPEN))-catalyzed asymmetric transfer hydrogenation (ATH), to afford enantioenriched secondary alcohols.37,38 We spatially isolate the functionalized TEMPO and rhodium catalysts into the hydrophilic corona and hydrophobic core, respectively, to

edox transformations are essential for many industrial and biological processes: e.g., energy generation and storage, cellular respiration, and photosynthesis. Nature uses subcellular compartments and the assembly of multienzyme complexes to regulate active oxidative and reductive sites.1−3 Motivated by Nature, synthetic strategies for catalyst site isolation include sol−gels,4−6 Pickering emulsion droplets,7 supramolecular metal complex architectures,8,9 and polymers10−15 to facilitate incompatible multistep transformations. Besides photoredox systems and redox-driven electrocatalysis, synthetic compartmentalized nanoractors that enable one-pot oxidative and reductive processes are rare16−19 and are often limited to relatively simple nonorthogonal acid- and basecatalyzed reactions.20 We have introduced compartmentalized shell cross-linked micelles (SCMs) for nonorthogonal multistep cascade catalysis.21−23 The micellar structure contains a hydrophobic core and a hydrophilic corona that provide site isolation for each catalytic transformation. The cross-linking layer restricts diffusion between hydrophobic and hydrophilic domains, preventing mutual deactivation. We envision that compartmentalized SCMs are therefore excellent candidates for isolating both oxidative and reductive active sites into different domains within a single nanostructure. This micellarenabled compartmentalization can mimic natural behaviors on a basic level and realize otherwise nonorthogonal oxidation and reduction steps in one pot. © XXXX American Chemical Society

Received: November 20, 2018 Revised: February 3, 2019

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entire redox catalysis in aqueous media and can be reused in a continuous manner. The synthesis of the SCM nanoreactor is shown in Scheme 1. The side-chain-functionalized poly(2-oxazoline) triblock copolymer 1 was synthesized via cationic ring-opening polymerization (CROP) using methyl triflate as the initiator.39 The polymerization was monitored by 1H NMR spectroscopy. After completion, the final triblock copolymer was analyzed by gel-permeation chromatography (GPC). The apparent molecular weight (Mnapp) and dispersity (Đ) were 8.7 kDa and 1.25, respectively (see the Supporting Information). Hydrolysis of the ester block yielded the free carboxylic acids in 2, which increases hydrophilicity to promote micelle formation and provided a functional site to immobilize the hydroxylfunctionalized TEMPO catalysts. Disappearance of the characteristic methyl ester signal and the presence of an acid peak in the 1H NMR spectrum (see the Supporting Information) confirmed the successful reaction. Dynamic light scattering (DLS) proved the assembly of 2 in water into nanostructures with an average hydrodynamic radius (Rh) of 62 ± 4 nm. A multivalent tetrathiol linker was used to crosslink the terminal vinyl groups via a thiol click addition to afford SCM 3. To yield higher functionalization of free TEMPO radicals, free thiols were capped with 1-octene before attaching the TEMPO to the free carboxylic acid groups through DIC/ DMAP coupling to afford 5-TEMPO. The percent of TEMPO functionalization of 5-TEMPO was determined via electron paramagnetic resonance (EPR). On average seven TEMPO

Figure 1. Schematic representation of our research design: compartmentalized nanoreactors for one-pot redox-driven deracemization of racemic secondary alcohols.

avoid mutual destruction and enable oxidative and reductive catalysis in one pot. The SCMs are designed to carry out the Scheme 1. Synthesis of SCM Nanoreactors

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TEMPO-mediated oxidation of 1-phenylethanol afforded only trace amounts of the desired ketone after 16 h. The reaction rate and the conversion of the TEMPO oxidation using 5TEMPO were depressed during the first 3 h, likely owing to substrate diffusion. After substrate enrichment into the nanoreactors, the oxidation process accelerated and went to completion in 10 h. The ATH using Rh-TsDPEN in water was reported to be efficient.38 Unsupported heterogeneous Rh-TsDPEN catalyzed the ATH of acetophenone in water in 99% conversion in 12 h with excellent enantioselectivity (98% ee). Using nanoreactor 6-Rh and the same catalyst loading, the ATH accelerated with complete conversions in 3 h and excellent enantioselectivities (98% ee). We attribute this increase in catalyst activity to the dense nanoenvironment inside the polymeric micelles, which play a dominant role in localizing catalysts and substrates to speed up the reaction under pseudohomogeneous conditions.42,43 Before investigating the activity of our SCM nanoreactors in the deracemization step, a series of control experiments were performed with the respective unsupported catalysts. 4-OHTEMPO showed poor catalytic performance either under aqueous conditions or using a mixture of solvents (Table 1, entries 1 and 2). However, oxoammonium salts that are widely used under biphasic oxidations can catalyze the oxidation reaction with quantitative conversions in a mixture of solvents (Table 1, entry 3). ATH using Rh-TsDPEN in a DCM/H2O mixed solvent system yielded 99% conversion with 98% ee (Table 1, entry 4). The one-pot unsupported redox deracemization, however, failed (Table 1, entry 5) because (i) the reaction between the oxidant (aqueous NaOCl) and the reductant (aqueous HCOONa) is kinetically faster than the TEMPO-catalyzed oxidation of secondary alcohols and (ii) components (e.g., basic NaOCl and potential intermediate NaOBr) from the TEMPO oxidation process deactivate the Rh catalyst. These control experiments prove that the RhTsDPEN-catalyzed step is incompatible with the reaction conditions of the TEMPO-catalyzed oxidation reaction. Spatial confinement of the free radical TEMPO into nanoreactors enables the catalytic oxidation under aqueous conditions (Table 2, entries 1 and 2). The micellar structure efficiently prevents catalyst deactivation and allows for the desired redox reaction to proceed (Table 2, entries 2 and 3).

molecules are attached to each polymer chain (see the Supporting Information). To obtain the SCM nanoreactor 6Rh, we started with SCM 3 and reacted the remaining free thiol groups on 3 with alkene-functionalized Rh-TsDPEN catalysts via a second thiol−ene reaction. The immobilized Rh catalyst loading was determined by ICP-MS. Approximately six Rh-TsDPEN complexes are attached to each polymer chain (see the Supporting Information). Micelle 6-Rh was further functionalized with TEMPO via TBTU/DIPEA coupling, yielding the bifunctional SCM nanoreactor 7-TEMPO-Rh. DLS confirmed the presence of the nanostructures in water with Rh = 61 ± 2 nm. CryoTEM imaging further confirmed the formation of spherical micelles with a radius of 45 ± 3 nm. Kinetic studies of oxidation and ATH involving SCM nanoreactors 5-TEMPO and 6-Rh, respectively, were conducted using chiral gas chromatography (GC) (Figure 2).

Figure 2. Plot of conversion vs time for the TEMPO-mediated oxidation of 1-phenylethanol (black squares, 4-OH-TEMPO; blue squares, nanoreactor 5-TEMPO) and the Rh-catalyzed ATH of acetophenone (green triangles, unsupported Rh-TsDPEN; red solid circles, nanoreactor 6-Rh). Oxidation conditions: [S] = 0.0136 M, [KBr] = 0.00680 M, [NaOCl] = 0.163 M, [TEMPO] = 0.000136 M, room temperature. ATH conditions: [S] = 0.0136 M, [HCOONa] = 0.0680 M, [Rh] = 0.00177 M, 40 °C.

Comparative studies of unsupported catalysis using the homogeneous catalysts under the same reaction conditions were performed in parallel. TEMPO-catalyzed oxidation has been carried out in a two-phase system using a phase transfer catalyst.40,41 Without any phase transfer catalysts, the 4-OH-

Table 1. Catalytic Tests of Unsupported TEMPO and Rh Catalysts

entry

reactiona

catalyst

solvent

cat. loading (mol %)

conversion (%)c

ee (%)c

1 2 3 4 5

I I I II IIIb

4-OH-TEMPO 4-OH-TEMPO oxoammonium salt Rh-TsDPEN oxoammonium salt + Rh

H2O DCM/H2O DCM/H2O DCM/H2O DCM/H2O

10 10 10 5 5/1

trace trace 99 99 trace

98 n.d.

All reactions were carried out with [S] = 0.0136 M. The oxidation was carried out at room temperature and the ATH reaction at 40 °C. bReaction was carried out at room temperature. After completion of the oxidation step, HCOONa (5 equiv) was added and the reaction mixture was heated to 40 °C. cDetermined by chiral GC analyses.

a

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ACS Catalysis Table 2. Catalytic Tests of Micelle-Supported TEMPO and Rh Catalysts entry

a

reaction

1

I

2

I

3

II

4

IIIb

5

IIIb

catalyst nanoreactor 4 + 4-OHTEMPO nanoreactor 5TEMPO + Rh nanoreactor 6-Rh + 4-OHTEMPO nanoreactor 5-TEMPO + nanoreactor 6Rh nanoreactor 7TEMPO-Rh

cat. loading (mol %) 1

time (h)

conversion (%)c

12

trace

Table 3. Substrate Scope for the One-Pot Redox-Driven Deracemization Using SCM Nanoreactor 7-TEMPO-Rh

ee (%)c

1/13

8

99

13/20

4

99

98

1/13

48

95

98

1/13

12

97

98

a

All reactions were carried out with [S] = 0.0136 M in water (micelle concentration 4 mg/mL). The oxidation was carried out at room temperature and the ATH reaction at 40 °C. bFirst, reactions were carried out at room temperature. After completion of the oxidation reaction, HCOONa (5 equiv) was added and the reaction mixture was heated to 40 °C. cDetermined by chiral GC analyses with mesitylene as internal standard.

While the one-pot reaction cascade using two different nanoreactors can also be carried out with each individual catalyst in a separate micelle, our strategy to engineer two catalysts into a single nanoreactor efficiently shortens the reaction time from 48 to 12 h by taking advantage of intramicellar diffusion (Table 2, entries 4 and 5). The successful redox-driven deracemization proves that our compartmentalized nanoreactors are capable of mimicking a simple metabolism process by performing oxidative and reductive processes in one pot. We then investigated the substrate scope of our reaction sequence using the bifunctional SCM nanoreactor 7-TEMPORh (Table 3). Aromatic substrates, substituted with either electron-withdrawing or -donating groups, can be converted in high yields and ee values (Table 3, entries 1−3). However, the use of solid substrates resulted in poor conversions and lower ee values (Table 3, entry 4). Heteroaromatic substrates, e.g. furan derivatives, also yielded good conversion with excellent ee (Table 3, entry 5). Nonaromatic substrates, e.g. cycloalkyl and linear alkyl secondary alcohols, can be deracemized in high conversions, albeit lower ee values of 42% were observed using 2-octanol (Table 3, entries 6 and 7). The deracemization can be carried out successfully with a racemic diol (97% conversion, dl/meso ratio of 89/11 and 98% ee) (Table 3, entry 8). Additionally, enantioenriched starting materials can be converted to the opposite enantiomer. When (S)-(−)-1phenylethanol was used as reactant, the antipode (R) was isolated in excellent yield (91%) and enantiomeric excess (95%) (Table 3, entry 9). To demonstrate the recyclability of our nanoreactors, the catalytic transformations were carried out in a continuous manner without tedious recovery processes. After the products were extracted into organic solvents from the aqueous micelle solution and the two phases were separated, a fresh batch of starting materials and reagents was added. Nanoreactors 5TEMPO and 6-Rh can be reused multiple times while maintaining high reactivity (Figures S7 and S8). Nanoreactor 7-TEMPO-Rh can process the deracemization of racemic 1-

a

Reactions were carried out with [S] = 0.0136 M in water (micelle concentration 4 mg/mL). HCOONa (5 equiv) was added after completion of the oxidation reaction. bDetermined by chiral GC analyses with mesitylene as internal standard. cThe conversion and % ee of the deracemization on a 40 mg substrate scale are shown in parentheses. dDetermined by chiral HPLC analyses. edl/meso = 89/ 11.

phenylethanol twice continuously without any major loss of reactivity (Scheme 2 and Figure S9). Scheme 2. Recycling of Nanoreactor 7-TEMPO-Rh in Water

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(8) Wang, Z. J.; Clary, K. N.; Bergman, R. G.; Raymond, K. N.; Toste, F. D. A Supramolecular Approach to Combining Enzymatic and Transition Metal Catalysis. Nat. Chem. 2013, 5, 100−103. (9) Ueda, Y.; Ito, H.; Fujita, D.; Fujita, M. Permeable SelfAssembled Molecular Containers for Catalyst Isolation Enabling Two-Step Cascade Reactions. J. Am. Chem. Soc. 2017, 139, 6090− 6093. (10) Chi, Y.; Scroggins, S. T.; Fréchet, J. M. J. One-Pot MultiComponent Asymmetric Cascade Reactions Catalyzed by Soluble Star Polymers with Highly Branched Non-Interpenetrating Catalytic Cores. J. Am. Chem. Soc. 2008, 130, 6322−6323. (11) Helms, B.; Guillaudeu, S. J.; Xie, Y.; McMurdo, M.; Hawker, C. J.; Frechet, J. M. One-pot Reaction Cascades Using Star Polymers with Core-confined Catalysts. Angew. Chem., Int. Ed. 2005, 44, 6384− 6387. (12) Xiong, L.; Zhang, H.; Zhong, A.; He, Z.; Huang, K. Acid- and base-functionalized Core-confined Bottlebrush Copolymer Catalysts for One-pot Cascade Reactions. Chem. Commun. 2014, 50, 14778− 14781. (13) Runge, M. B.; Mwangi, M. T.; Miller, A. L., 2nd; Perring, M.; Bowden, N. B. Cascade Reactions Using LiAlH4 and Grignard Reagents in the Presence of Water. Angew. Chem., Int. Ed. 2008, 47, 935−939. (14) Yang, Y.; Liu, X.; Li, X.; Zhao, J.; Bai, S.; Liu, J.; Yang, Q. A Yolk-shell Nanoreactor with a Basic Core and an Acidic Shell for Cascade Reactions. Angew. Chem., Int. Ed. 2012, 51, 9164−9168. (15) Tan, H.; Guo, S.; Dinh, N.-D.; Luo, R.; Jin, L.; Chen, C.-H. Heterogeneous Multi-compartmental Hydrogel Particles as Synthetic Cells for Incompatible Tandem Reactions. Nat. Commun. 2017, 8, 663. (16) Fukuzumi, S.; Lee, Y.-M.; Nam, W. Immobilization of Molecular Catalysts for Enhanced Redox Catalysis. ChemCatChem 2018, 10, 1686−1702. (17) Li, F.; Fan, K.; Xu, B.; Gabrielsson, E.; Daniel, Q.; Li, L.; Sun, L. Organic Dye-Sensitized Tandem Photoelectrochemical Cell for Light Driven Total Water Splitting. J. Am. Chem. Soc. 2015, 137, 9153−9159. (18) You, B.; Liu, X.; Jiang, N.; Sun, Y. A General Strategy for Decoupled Hydrogen Production from Water Splitting by Integrating Oxidative Biomass Valorization. J. Am. Chem. Soc. 2016, 138, 13639− 13646. (19) Sato, H.; Hummel, W.; Gröger, H. Cooperative Catalysis of Noncompatible Catalysts through Compartmentalization: Wacker Oxidation and Enzymatic Reduction in a One-Pot Process in Aqueous Media. Angew. Chem., Int. Ed. 2015, 54, 4488−4492. (20) Womble, C. T.; Kuepfert, M.; Weck, M. Multicompartment Polymeric Nanoreactors for Non-Orthogonal Cascade Catalysis. Macromol. Rapid Commun. 2019, 40, 1800580. (21) Lu, J.; Dimroth, J.; Weck, M. Compartmentalization of Incompatible Catalytic Transformations for Tandem Catalysis. J. Am. Chem. Soc. 2015, 137, 12984−12989. (22) Lee, L.-C.; Lu, J.; Weck, M.; Jones, C. W. Acid−Base Bifunctional Shell Cross-Linked Micelle Nanoreactor for One-Pot Tandem Reaction. ACS Catal. 2016, 6, 784−787. (23) Kuepfert, M.; Cohen, A.; Cullen, O.; Weck, M. Shell Crosslinked Micelles as Nanoreactors for Enantioselective Three-Step Tandem Catalysis. Chem. - Eur. J. 2018, 24, 18648−18652. (24) Rachwalski, M.; Vermue, N.; Rutjes, F. P. J. T. Recent Advances in Enzymatic and Chemical Deracemisation of Racemic Compounds. Chem. Soc. Rev. 2013, 42, 9268−9282. (25) Faber, K. Non-Sequential Processes for the Transformation of a Racemate into a Single Stereoisomeric Product: Proposal for Stereochemical Classification. Chem. - Eur. J. 2001, 7, 5004−5010. (26) Gruber, C. C.; Lavandera, I.; Faber, K.; Kroutil, W. From a Racemate to a Single Enantiomer: Deracemization by Stereoinversion. Adv. Synth. Catal. 2006, 348, 1789−1805. (27) Turner, N. J. Deracemisation methods. Curr. Opin. Chem. Biol. 2010, 14, 115−121.

In summary, this contribution introduces micellar-based compartmentalized nanoreactors as supports for incompatible oxidation and reduction reactions. The SCMs provided indispensable catalyst site isolation and enhanced catalyst reactivity. The one-pot redox-driven deracemizations using our catalyst-functionalized SCMs yielded outstanding conversions and enantioselectivities for various substrates. Our nanoreactors can be reused in a continuous manner while maintaining high reactivities. Future research in our group will focus on preparing advanced tunable multicompartmentalized SCM nanoreactors to regulate the order of multistep redox-driven transformations and to construct useful synthetic building blocks.

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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/acscatal.8b04667.

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Synthetic procedures, experimental details of micellesupported catalytic tests, DLS details, ICP-MS, and cryoTEM and SEM images (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail for M.W.: [email protected]. ORCID

Steffen Jockusch: 0000-0002-4592-5280 Marcus Weck: 0000-0002-6486-4268 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Funding provided by the U.S. Department of Energy, Office of Basic Energy Sciences, through Catalysis Science Contract DEFG02-03ER15459, is gratefully acknowledged. We thank Kristen Dancel-Manning from the OCS Microscopy Core at New York University Langone Medical Center for obtaining the cryo-TEM images.

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