Rational Construction of an Artificial Binuclear Copper Monooxygenase in a Metal-Organic Framework

Monooxygenase in a Metal −Organic Framework

Article

Rational Construction of an Artiﬁcial Binuclear Copper

†

Xuanyu Feng, Yang Song, Justin S. Chen, Ziwan Xu, Soren J. Dunn, and Wenbin Lin*

Cite This: J. Am. Chem. Soc. 2021, 143, 1107 −1118

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sı Supporting Information

ABSTRACT: Artiﬁcial enzymatic systems are extensively studied

to mimic the structures and functions of their natural counterparts.

However, there remains a signiﬁcant gap between structural

modeling and catalytic activity in these artiﬁcial systems. Herein

we report a novel strategy for the construction of an artiﬁcial

binuclear copper monooxygenase starting from a Ti metal−organic

framework (MOF). The deprotonation of the hydroxide groups on

the secondary building units (SBUs) of MIL-125(Ti) (MIL =

Materiaux de l’Institut Lavoisier) allows for the metalation of the

SBUs with closely spaced Cu pairs, which are oxidized by molecular

O to aﬀord the Cu (μ -OH) cofactor in the MOF-based artiﬁcial

binuclear monooxygenase Ti -Cu . An artiﬁcial mononuclear Cu

monooxygenase Ti -Cu was also prepared for comparison. The

MOF-based monooxygenases were characterized by a combination of thermogravimetric analysis, inductively coupled plasma−mass

spectrometry, X-ray absorption spectroscopy, Fourier-transform infrared spectroscopy, and UV−vis spectroscopy. In the presence of

coreductants, Ti -Cu exhibited outstanding catalytic activity toward a wide range of monooxygenation processes, including

epoxidation, hydroxylation, Baeyer−Villiger oxidation, and sulfoxidation, with turnover numbers of up to 3450. Ti -Cu showed a

turnover frequency at least 17 times higher than that of Ti -Cu . Density functional theory calculations revealed O activation as the

rate-limiting step in the monooxygenation processes. Computational studies further showed that the Cu sites in Ti -Cu

cooperatively stabilized the Cu−O adduct for O−O bond cleavage with 6.6 kcal/mol smaller free energy increase than that of the

mononuclear Cu sites in Ti -Cu , accounting for the signiﬁcantly higher catalytic activity of Ti -Cu over Ti -Cu .

31,32

INTRODUCTION

catechol oxidase (Cu−Cu), and tyrosinase (Cu−Cu)

eﬃciently undergo multielectron processes through redox

cooperativity to activate O and oxidize organic substrates.

■

Natural enzymes have evolved over millions of years to provide

extremely powerful catalysts toward a variety of reactions with

excellent activities under mild conditions and exquisite

Owing to the importance of direct activation of O as a

sustainable and inexpensive oxidant,

3−37

−4

many artiﬁcial

substrate speciﬁcity and product selectivity.

However, the

practical use of natural enzymes in synthetic chemistry faces

many challenges, including long-term stability, sensitivity to

reaction conditions, and the diﬃculty in enzyme recovery and

monooxygenases with heme- or ﬂavin-derived cofactors have

been developed but exhibit modest catalytic activity and

substrate/product selectivity. In contrast, few artiﬁcial

monooxygenases with binuclear cofactors have been studied

−7

reuse.

Artiﬁcial enzymes with active metal or organic

5,38−44

cofactors have been constructed to mimic the catalytic

and they exhibited limited catalytic activities.

−17

functions of natural enzymes,

catalytic transformations.

showing promise in many

In-depth studies of these

hypothesized that artiﬁcial binuclear monooxygenases with

well-deﬁned active sites and high monooxygenation activities

can be rationally designed based on crystalline and porous

metal−organic frameworks (MOFs) by taking advantage of

1,18−21

biomimetic artiﬁcial systems have in return provided important

insights into natural enzymes.

Among the diverse family of natural enzymes, monoox-

ygenases (EC 1.13.x.x and EC 1.14.x.x) insert one oxygen

45−52

recent advances in MOF biomimicry (Figure 1).

22−24

atom from molecular oxygen (O ) into organic substrates.

Received: November 13, 2020

Published: January 7, 2021

Monooxygenases with heme-, ﬂavin-, copper-, nonheme iron-,

or other cofactors eﬃciently catalyze a wide range of important

oxidative processes, including hydroxylation, epoxidation,

5−28

Baeyer−Villiger oxidation, sulfoxidation, and others.

particular, natural monooxygenases with multicentered cofac-

tors such as soluble methane monooxygenase (Fe−Fe),

2021 American Chemical Society

J. Am. Chem. Soc. 2021, 143, 1107−1118

107

Article

bridging hydroxide or oxo ligands to form redox-active

cofactors for catalytic transformations.

Ti -OH was synthesized through solvothermal reactions

between Ti(O Pr) ( Pr = isopropyl) and H BDC (terephthalic

acid) based on a modiﬁed literature procedure. Binuclear Cu

species were installed on the SBUs of Ti -OH to aﬀord the

precatalyst Ti -Cu -pre through deprotonation of the hydrox-

ides by LiCH Si(CH ) followed by metalation with excess

3 3

Cu(CH CN) (BF ). Ti -Cu -pre was oxidized by bubbling O

through a MOF suspension in CH CN to aﬀord the binuclear

artiﬁcial monooxygenase Ti -Cu with Cu (μ -OH) cofac-

tors (Figure 2c). Inductively coupled plasma-mass spectrom-

etry (ICP-MS) analysis showed that Ti -Cu -pre and Ti -Cu

had 2.0 and 1.95 Cu centers per SBU, suggesting complete

metalation on all SBUs. By controlling the equivalent of Cu

salts during the metalation process, Ti -Cu with mononuclear

Cu site was also synthesized. ICP-MS analysis showed the

presence of 0.3 Cu per Ti node in Ti -Cu to ensure the

formation of mononuclear Cu species only.

Powdered X-ray diﬀraction (PXRD) studies showed that

crystallinity of the MOF was retained throughout the

metalation and oxidation processes (Figure 2d). Transmission

electron microscopy (TEM) and scanning electron microscope

(

SEM) indicated that Ti -Cu₂maintained the disk-like

Figure 1. Cu active sites with O bonding in (a) the natural enzyme

morphology of Ti -OH of ∼1 μm in diameter and ∼0.4 μm

in thickness (Figures 2f, S3, S4). Installation of Cu centers

reduced the Brunauer−Emmett−Teller (BET) surface area

from 1520 m /g for Ti -OH to 1108 m /g and 1245 m /g for

tyrosinase (PDB code: 1WX2) and (b) the MOF-based artiﬁcial

enzyme Ti -Cu (this work).

Ti -Cu -pre and Ti -Cu , respectively (Figure 2 e), while the

Constructed from metal-oxo secondary building units

SBUs) and organic linkers, MOFs have been used to precisely

install molecular functionalities with good spatial control.

pore sizes and volumes remained similar (Figure S5). Thermal

gravimetric analysis (TGA) results supported the formulations

of Ti (μ -O) [Cu(μ -O) (CH CN)] (BDC) Li and Ti (μ -

(

53−64

The uniform SBUs of MOFs allow the installation of

O) [Cu(μ -O) (μ -OH)] (BDC) Li for Ti -Cu -pre and Ti -

Cu , respectively (Figure S6).

Oleﬁn Epoxidation Catalyzed by MOF-Based Artiﬁcial

Monooxygenases. Natural monooxygenases eﬃciently trans-

8 2 2 2 2 6 2 8 2 8

molecularly precise mono- or multimetallic species as eﬃcient

5−74

cofactors,

while the uniform MOF pores and channels

provide structurally deﬁned microenvironments to confer

75−82

substrate/product selectivities.

As an important class of

fer one oxygen from O to form the mono-oxygenated product

heterogeneous catalysts, MOFs have robust structures and

active sites and can be readily recovered and reused for

with the concomitant oxidation of coreductants such as

NAD(P)H (NAD = nicotinamide adenine dinucleotide,

NADP = nicotinamide adenine dinucleotide phosphate) and

83−86

multiple rounds of catalytic reactions.

the rational design of a binuclear copper cofactor in a Ti-MOF

MIL-125) as an eﬃcient artiﬁcial monooxygenase for the ﬁrst

time. The MOF-based artiﬁcial enzyme, Ti -Cu , displayed

Herein we report

88,89

ascorbate in a four-electron process.

With binuclear Cu

(

cofactors, MOF-based artiﬁcial monooxygenase Ti -Cu₂

displayed excellent catalytic activity toward a broad range of

outstanding reactivity with turnover numbers (TONs) of up to

450 toward a wide range of important monooxygenation

monooxygenation reactions with O as the oxygen source.

Ti -Cu eﬀectively catalyzed epoxidation of oleﬁns to aﬀord

processes, including epoxidation, hydroxylation, Baeyer−

epoxides. We used cyclohexene as a model substrate to screen

the conditions for epoxidation reactions. In the presence of 0.2

mol % Ti -Cu , treatment of cyclohexene with 2 equiv of

Villiger oxidation, and sulfoxidation. Ti -Cu showed excellent

stability and could be readily recycled and reused. Spectro-

scopic studies and computational results revealed the vital role

of cooperativity between binuclear Cu centers in the O₂

activation process.

isobutyraldehyde as the coreductant in 1,2-dichloroethane

(DCE) under atmospheric O at room temperature aﬀorded

cyclohexene oxide in 84% yield along with a small amount of

hydroxylation products 2-cyclohexen-1-ol and 2-cyclohexen-1-

one (13% in total). The reaction also proceeded under

ambient air to aﬀord cyclohexene oxide in 77% yield (entry 3,

Table 1). The absence of Ti -Cu , O , or coreductant shut

RESULTS AND DISCUSSION

Synthesis and Characterization of MOF-Based Artiﬁ-

cial Monooxygenases. We used the Ti (μ -O) (μ -OH)

■

SBUs of MIL-125(Ti), Ti -OH, to support mononuclear and

binuclear Cu cofactors as artiﬁcial monooxygenases. Each SBU

down the monooxygenation reaction, aﬀording no or negligible

amount of cyclohexene oxide (entries 4−6, Table 1).

Replacement of Ti -Cu by homogeneous control, CuCl ,

of Ti -OH features four bridging hydroxides pointing to the

center, along with eight adjacent bridging oxo groups. The

precisely positioned bridging hydroxides were deprotonated to

provide a hydrophilic binding pocket for reactive mononuclear

or binuclear Cu species, while the small cavity in the SBU with

a diameter of 5−6 Å brought the two Cu centers together via

aﬀorded cyclohexene oxide in 7% yield (entries 8 and 9, Table

1), demonstrating the important role of Cu coordination to the

SBU in the monooxygenation activity.

The reaction conditions were further screened with Ti -Cu -

catalyzed epoxidation of cyclohexene. First, several solvents

108

J. Am. Chem. Soc. 2021, 143, 1107−1118

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Figure 2. (a) Synthetic scheme of the MOF-based artiﬁcial monooxygenase Ti -Cu (Ti: light gray; O: red; C: gray). (b) SBU distribution and

channel structure of the Ti MOF Ti -OH. (c) Installation of Cu centers and subsequent treatment with O to aﬀord Ti -Cu . (d) PXRD patterns

of Ti -OH (blue), Ti -Cu -pre (gray), Ti -Cu (red), and the recovered Ti -Cu after reaction (AR, purple) along with the simulated pattern of

MIL-125(Ti) (black). (e) Nitrogen sorption isotherms of Ti -OH (blue), Ti -Cu -pre (gray), and Ti -Cu (red). (f) TEM image of Ti -Cu .

with di ﬀ erent polarities and coordination abilities were tested

products improved from 75% to >99%. However, the highest

epoxidation yield was achieved when 2 equiv of isobutyr-

aldehyde were used (Figure S11). An excess amount of

(Table S5 ). Polar solvents such as DCE, dichloromethane, and

triﬂuorotoluene displayed better monooxygenation perform-

ance than nonpolar solvents such as n-hexane. Notably,

coordinating solvent, e.g. tetrahydrofuran (THF), led to a

poor monooxygenation result, probably due to the strong

solvent coordination to the Cu sites. Second, the eﬀects of

coreductants were also studied. Isobutyraldehyde, cyclo-

hexanecarbaldehyde, and L-ascorbic acid showed 97%, 46%,

and 5% conversions, respectively. Other electron donors such

as 1,3-dimethyl-2-phenyl-2,3-dihydro-1H-benzo[d]imidazole

coreductant likely accelerates the regeneration of Cu (μ-O)

active species to suppress hydroxylation products, but

coreductant also competes with substrate oxidation to decrease

the yield of monooxygenation products.

The reactivity diﬀerence between a binuclear Cu cofactor

and a mononuclear Cu cofactor was studied using Ti -Cu and

Ti -Cu₁as catalysts. As shown in Figure 3a, the time-

dependent curves showed that Ti -Cu catalyzed cyclohexene

(

BIH), N-benzyl-1,4-dihydronicotinamide (BNAH), and

monooxygenation eﬃciently within the ﬁrst few hours with an

initial turnover frequency (TOF) of 175 h and a high

−

tetrahydroxy-1,4-quinone did not work (Table S4 ). Third,

the eﬀects of isobutyraldehyde concentration and equivalents

on the epoxidation reaction were examined. When the amount

of isobutyraldehyde increased from 1 to 10 equiv, the

selectivity of the epoxidation product over the hydroxylation

conversion of 97% in 24 h. In contrast, Ti -Cu showed a

−

much slower reaction rate with an initial TOF of 10 h and a

conversion of 43% in 24 h. This result shows the important

role of binuclear Cu cofactors in the artiﬁcial monooxygenase.

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Table 1. Epoxidation of Cyclohexene Catalyzed by Ti -Cu and Homogeneous Controls

entry

catalyst

reaction condition

conversion (yield)

TON

0.2 mol % Ti -Cu

under O , with 2 equiv of coreductant, 24 h

97 (84)

69 (56)

92 (77)

0 (0)

4 (4)

6 (6)

8 (7)

12 (11)

43 (35)

485

3450

460

0.02 mol % Ti -Cu

under O , with 2 equiv coreductant, 48 h

0.2 mol % Ti -Cu

under air, with 2 equiv of coreductant, 24 h

0.2 mol % Ti -Cu

under N , with 2 equiv of coreductant, 24 h

0.2 mol % Ti -Cu

under O , without coreductant, 24 h

under O , with 2 equiv of coreductant, 24 h

Ti -OH

under O , with 2 equiv of coreductant, 24 h

0.2 mol % CuCl

under O , with 2 equiv of coreductant, 24 h

110

Ti -OH + 0.2 mol % CuCl₂

under O , with 2 equiv of coreductant, 24 h

0.2 mol % Ti -Cu

under O , with 2 equiv of coreductant, 24 h

Reactions were conducted with 0.25 mmol of cyclohexene in 2.0 mL of DCE. The reaction mixture was stirred at room temperature with a

balloon of O , air, or N , and the conversions were determined by GC-MS analysis. Isobutyraldehyde was used as the coreductant. Ti -OH (1.0

mg) was used.

We next examined the substrate scope for Ti -Cu -catalyzed

ketones, lactones, and esters in good to excellent yields (entries

12−15, Table 2). The more diﬃcult substrate ethylbenzene

was oxidized to form acetophenone in 46% yield (entry 16,

Table 2).

oleﬁn epoxidation reactions. At 0.2 mol % of Ti -Cu , various

alkenes were smoothly converted to their corresponding

epoxides in the presence of isobutyraldehyde under atmos-

pheric O . Excellent yields of epoxides were obtained with

Ti -Cu also displayed high activities toward Baeyer−Villiger

cyclic alkenes bearing diﬀerent substituents (entries 1−4,

Table 2). Exclusive epoxidation selectivity was observed for

reactive cyclic oleﬁnic bonds in limonene and 3-carene (entries

reaction and oxidation of thioethers. Speciﬁcally, Ti -Cu (0.2

8 2

mol %) catalyzed Baeyer−Villiger oxidation of 3-phenyl-

cyclobutanone with O as oxidant to aﬀord 4-phenyloxolan-

and 6, Table 2). Noncyclic alkenes, including styrene

derivatives (entries 7 and 8, Table 2) and linear-chain alkenes

entries 9 and 10, Table 2), also underwent epoxidation to

2-one in 70% yield within 48 h (entry 17, Table 2). Ti -Cu₂

catalyzed the oxidation of thioanisole to methyl phenyl

(

sulfoxide in 95% yield under atmospheric O in 72 h (entry

aﬀord epoxides in good to excellent yields. Internal alkenes

displayed reactivity higher than that of terminal alkenes, likely

due to the more electron-rich nature of internal alkenes. As a

heterogeneous catalyst, Ti -Cu was recycled by simple

18, Table 2). These results indicate the eﬀectiveness of MOF-

based artiﬁcial monooxygenases in producing valuable

chemical feedstocks with O as oxidant under mild reaction

conditions.

ﬁltration from the reaction mixture and used in ﬁve

consecutive runs of cyclohexene epoxidation. No signiﬁcant

reactivity drop was observed throughout the recycling

experiments, demonstrating the stability of MOF-based

artiﬁcial monooxygenase under oxygenation reaction con-

ditions (Figure 3b).

Identiﬁcation of the Cu Cofactors. We used Cu K-edge

X-ray absorption near-edge structure (XANES) and extended

X-ray absorption ﬁne structure (EXAFS) spectroscopies to

study the Cu cofactors in MOF-based monooxygenases. The

oxidation states of Cu centers in Ti -Cu -pre and Ti -Cu

were determined by comparing the pre-edge features of their

Other Monooxygenation Reactions Catalyzed by

MOF-Based Artiﬁcial Monooxygenases. Encouraged by

excellent epoxidation activities of Ti -Cu , we examined the

normalized XANES spectra to those of Cu O and CuO (Figure

4a). While Ti -Cu -pre showed a similar pre-edge peak

corresponding to the spin-allowed 1s → 4p electronic

92,93

use of Ti -Cu in other monooxygenation reactions. Direct

transition at 8982−8984 eV to Cu O,

Ti -Cu exhibited

8 2

hydroxylation of alkanes under mild conditions provides an

attractive strategy to construct valuable alcoholic feedstocks

a similar pre-edge peak attributed to the dipole-forbidden Cu

1s → 3d electronic transition at 8977−8979 eV to Cu O.

This pre-edge feature of Ti -Cu also suggests an octahedral

symmetry for Cu centers. Additionally, Ti -Cu showed a

shoulder peak at 8989 eV which is assigned to Cu 1s → 4p +

II 94,95

90,91

which can also be further oxidized to carbonyl compounds.

Ti -Cu displayed excellent reactivity toward hydroxylation of

benzylic substrates and further alcohol oxidation to carbonyl

97,98

compounds. At 0.5 mol % of Ti -Cu , indane was eﬃciently

L shakedown transition.

The XANES studies thus indicate

converted into 1-indanol (8%) and 1-indanone (61%) under

that the Cu centers in Ti -Cu -pre adopt +1 oxidation state

atmospheric O at room temperature in 24 h. Elongating the

while the Cu centers in Ti -Cu exhibit +2 oxidation state.

8 2

reaction time to 48 h increased the yield of 1-indanone to 87%

while reducing the yield of 1-indanol to <1%, which suggests

sequential hydroxylation and oxidation to ketones (entry 11,

Table 2). Several other substrates bearing benzylic C−H bonds

including tetralin, phthalane, isochromane, and (methoxy-

methyl)benzene were successfully converted to corresponding

Density functional theory (DFT) calculations were

performed using the B3LYP functional to determine Cu

coordination environments in Ti -Cu -pre and Ti -Cu . DFT

optimization of Ti -Cu -pre converged at a structure with two

tetrahedral Cu centers slightly above and below the plane of

the Ti node. Each Cu center coordinates to two anionic

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J. Am. Chem. Soc. 2021, 143, 1107−1118

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respectively (Figure 4b), consistent with the existence of Cu₂

species in both Ti -Cu -pre and Ti -Cu . In contrast, no Cu−

Cu single scattering signal was present in the EXAFS spectrum

of Ti -Cu , consistent with the mononuclear Cu species.

Furthermore, Ti -Cu₂showed stronger Cu−Cu single

scattering signal than Ti -Cu -pre, suggesting more intense

interactions between two Cu centers in Ti -Cu due to the

bridging of the Cu centers by two μ -OH groups after

oxidation. This result matches the distance trend observed in

DFT-optimized structures with Cu−Cu distances of 2.86 and

.74 Å for Ti -Cu -pre and Ti -Cu , respectively.

We further ﬁtted the Cu-EXAFS spectra using DFT-

8 2 8 2

optimized structure models (Figure 4c). For Ti -Cu , Cu−O

single scattering pathways contributed most to the ﬁrst and

second peaks of the Cu K-edge EXAFS spectrum to aﬀord

−

Cu−O distances of 2.00, 2.20, and 1.91 Å for a Cu−(μ -O ),

Cu−(μ -O), and Cu−(μ -OH) species, respectively. The third

peak came mainly from the contribution of Cu−Cu interaction

with a Cu−Cu distance of 2.80 Å, which agrees well with the

calculated distance of 2.74 Å. Similarly, the ﬁrst and second

peaks of Ti -Cu -pre were attributed to Cu−O interactions

−

from (μ -O ), (μ -O), and N, while the weak third peak was

mainly assigned to Cu−Cu interactions. These EXAFS results

99,100

are consistent with those reported in the literature.

Fourier-transform infrared (FT-IR) spectroscopy and UV−

vis spectroscopy supported the generation of Cu cofactors in

the MOFs. As shown in Figure 4d, Ti -OH, Ti -Cu -pre, and

−

Ti -Cu displayed similar carbonyl stretching at ∼1550 cm

−

and C −H stretching at ∼3000 cm , but only Ti -OH

sp2

−

showed a shoulder peak at 3645 cm attributable to the O−H

stretching of Ti(μ -OH)Ti species. This peak disappeared

after deprotonation and metalation with Cu in Ti -Cu -pre

−

and Ti -Cu . Interestingly, a new sharp peak at 3670 cm

appeared in Ti -Cu , which is assigned to the O−H stretching

102,103

of the Cu(μ -OH)Cu species.

UV −vis spectra were also

taken on the MOF systems (Figure S10). While Ti -OH

displayed UV absorption at ∼300 nm characteristic of Ti−O

104,105

charge transfer (CT),

Ti -Cu -pre and Ti -Cu showed

8 2 8 2

new bands at 330 and 355 nm, respectively. These bands are

Figure 3. (a) Time-dependent curves of cyclohexene epoxidation

catalyzed by MOF-based artiﬁcial monooxygenases with a binuclear

Cu cofactor (Ti -Cu ) or a mononuclear Cu cofactor (Ti -Cu ) and

assigned to Cu −O and Cu −O CT absorptions, respec-

106

tively.

Energy Proﬁles of Monooxygenation Processes. DFT

calculations with the B3LYP functional were conducted on

SBU-supported Cu cofactors to gain insight into dioxygen

activation and substrate oxidation by the MOF-based

monooxygenases and to understand the drastic reactivity

without a cofactor (Ti -OH). (b) Recycle and reuse of Ti -Cu

catalyst in the epoxidation of cyclohexene.

−

bridging-oxo (μ -O ) groups, one neutral bridging-oxo (μ -O)

group, and one CH CN molecule in a distorted tetrahedral

diﬀerence between Ti

have been made to study O

-Cu

and Ti

activation and utilization by the

8 1

-Cu . Signiﬁcant eﬀorts

−

geometry. The distances of Cu−(μ -O ), Cu−(μ -O), and

Cu−N were 2.13/2.15. 2.23, and 1.95 Å, respectively. DFT

active Cu centers in natural and artiﬁcial Cu-based

monooxygenases. Spectroscopic and computational evidence

optimization of Ti -Cu converged on a Cu (μ -OH)

structure with two Cu centers in the plane of the Ti node.

Each Cu center adopted octahedral geometry by coordinating

to two anionic bridging-oxo (μ -O ) groups in the axial

strongly suggested Cu-oxo species as the key intermediates in

36,40,107−109

the monooxygenation process.

We propose

−

Cu (μ -O) and Cu-oxo species as the active catalysts for the

2 2 2

positions as well as two neutral bridging-oxo (μ -O) groups

monooxygenation processes catalyzed by Ti -Cu and Ti -Cu ,

8 2 8 1

and two bridging μ -OH groups in the equatorial positions.

respectively (Figure 5).

The Cu−O distances were 2.12, 2.45, and 2.03 Å for the

−

Cu(μ -O ), Cu(μ -O), and Cu(μ -OH) moieties, respectively.

EXAFS analyses were performed to determine the local

structures of Cu cofactors. We ﬁrst compared the k -weighted

χ(R) spectra of Ti -Cu -pre, Ti -Cu , and Ti -Cu . No signals

attributable to Cu nanoparticle or CuO are present in these

O )Cu adduct (IN-3). The cleavage of the O−O bond aﬀords

III

EXAFS spectra. Ti -Cu and Ti -Cu -pre showed character-

the highly active Cu (μ -O) intermediate (IN-4). For O

istic Cu−Cu single scattering signals at R ≈ 2.58 and 2.73 Å,

activation on Ti -Cu , O ﬁrst coordinates with Cu (IN-5) to

8 1 2

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J. Am. Chem. Soc. 2021, 143, 1107−1118

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Table 2. Ti -Cu -Catalyzed Monooxygenation Reactions

Reactions were conducted with 0.25 mmol of substrate in 2.0 mL of DCE solvent. The reaction mixture was stirred at room temperature with an

O balloon. Isobutyraldehyde (2 equiv) was applied as coreductant. The conversions were determined by GC-MS analysis.

form an η -O -adduct (IN-6), which is further activated via a

the hydrogen atom abstraction (HAA) from the substrate by

−

one-electron and one-proton (1e /1H ) process (provided by

the Cu-oxo species to form the Cu-hydroxo species and the

carbon radical, followed by a radical rebound step to construct

the C−O bond between the carbon radical and Cu-bonded

hydroxide. Figure 6 shows the key intermediates and transition

states during the hydroxylation processes. The hydroxylation

processes on both Ti -Cu and Ti -Cu are highly exothermic

the coreductant) to form a Cu −OOH intermediate (IN-7).

III

IN-7 loses one H O to aﬀord the active Cu O species (IN-

−

) via another 1e /1H process. Calculations of the free

energies of these key intermediates revealed total free energy

increases of +47.7 kcal/mol for O activation in Ti -Cu to

access IN-4 and +54.3 kcal/mol for O activation in Ti -Cu to

and spontaneous with small activation barriers. Speciﬁcally, the

binuclear Cu cofactor featured a +4.2 kcal/mol activation

barrier for the HAA step and a +1.9 kcal/mol barrier for the

radical rebound to form the benzyl alcohol product. For the

mononuclear Cu cofactor, a +2.6 kcal/mol activation barrier is

calculated for the HAA step and a +9.2 kcal/mol barrier for the

radical rebound step. Both processes are driven by the highly

reactive nature of the Cu-oxo species (IN-4 and IN-8) and the

formation of strong C−O bonds.

access IN-8. Although the cleavage of O−O bond in Ti -Cu

features a lower barrier (IN-7 to IN-8, 23.6 kcal/mol) than in

Ti -Cu (IN-3 to IN-4, 32.8 kcal/mol) with the assistance of

the coreductant, the signiﬁcant stabilization of the dioxygen

species by the Cu species leads to a smaller free energy

increase for the overall transformation by 6.6 kcal/mol. Such a

diﬀerence indicates an easier O activation process on the

binuclear Cu site than the mononuclear Cu site.

DFT studies were also performed on the monooxygenation

processes starting from the active Cu-oxo intermediates in Ti₈-

Cu and Ti -Cu . The hydroxylation of toluene to aﬀord

The DFT results suggest the O activation as the rate-

limiting step in the monooxygenation processes catalyzed by

both Ti -Cu and Ti -Cu . Subsequent substrate oxidation

benzyl alcohol was selected as a model reaction. Typically,

processes by the active Cu-oxo species proceed spontaneously.

hydroxylation of C−H bonds on Cu-oxo species is initiated by

Importantly, the Cu sites in Ti -Cu cooperatively stabilize

112

J. Am. Chem. Soc. 2021, 143, 1107−1118

optimization and EXAFS ﬁtting.

Article

Figure 4. (a) Normalized Cu-XANES spectra of Ti -Cu -pre, Ti -Cu , and reference compounds. The inset shows the pre-edge feature at 8973−

982 eV corresponding to the 1s → 3d electronic transition for Cu . (b) k -weighted Cu-EXAFS χ(R) spectra of Ti -Cu -pre, Ti -Cu , and Ti -

8 2 8 2 8

Cu . SS = single scattering. (c) EXAFS spectra and ﬁts in R-space (within the gray lines) at the Cu K-edge of Ti -Cu with the magnitude (open

circles, red) and real components (open squares, blue) of the Fourier transforms (FT). (d) FT-IR spectra of Ti -OH (blue), Ti -Cu -pre (black),

and Ti -Cu (red). (e) Structural models of Ti -Cu (left), Ti -Cu -pre (middle), and Ti -Cu (right) with the Cu−Cu distances from DFT

Figure 5. (a, b) Monooxygenation processes on (a) the mononuclear Cu cofactor in Ti -Cu and (b) the binuclear Cu cofactor in Ti -Cu . (c)

Energy proﬁles of the O activation processes on Ti -Cu (top) and Ti -Cu (bottom).

the Cu-dioxygen adduct for O−O bond cleavage, leading to a

smaller free energy increase for the dioxygen activation than

the mononuclear Cu sites in Ti -Cu . Although several factors,

8 1

including substrate/product diﬀusions, MOF channels, and Cu

113

J. Am. Chem. Soc. 2021, 143, 1107−1118

Article

Figure 6. Energy proﬁles of the hydroxylation processes on Ti -Cu (up) and Ti -Cu (bottom).

cofactor concentrations, contributed to the monooxygenation

binuclear Cu cofactors to cooperatively activate O . The strong

reactivities, the 6.6 kcal/mol diﬀerence in ΔG values

oxo ligating ligands and the reticular isolation of Cu cofactors

rationalized the signiﬁcantly higher catalytic activity of Ti -

in the MOF led to a robust artiﬁcial enzyme for

monooxygenation reactions. Ti -Cu catalyzed a wide scope

Cu over Ti -Cu .

of monooxygenation reactions, including epoxidation, hydrox-

CONCLUSION

ylation, Baeyer−Villiger oxidation, and sulfoxidation, with

■

atmospheric O as the oxidant and isobutyraldehyde as the

In this work, we demonstrated a novel strategy to construct an

artiﬁcial monooxygenase, Ti -Cu , starting from a Ti MOF

following the blueprint of natural enzymes. The hydroxides of

the MOF SBUs were deprotonated to support a pair of Cu

coreductant. Ti -Cu eﬃciently catalyzed the epoxidation of

alkenes with TONs as high as 3450 and an initial TOF of 175

−

h , which was more than 17 times higher than the

mononuclear analogue Ti -Cu . Computational studies

revealed the O activation as the rate-limiting step in the

monooxygenation processes catalyzed by both Ti -Cu and

precursors, which were treated with O₂to generate the

Cu (μ -OH) cofactors in the artiﬁcial enzymes. The SBU

provided a precise binding pocket for the installation of

114

J. Am. Chem. Soc. 2021, 143, 1107−1118

Journal of the American Chemical Society

Article

Ti -Cu . The Cu sites in Ti -Cu cooperatively stabilize the

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https://pubs.acs.org/doi/10.1021/jacs.0c11920.

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AUTHOR INFORMATION

Corresponding Author

Wenbin Lin − Department of Chemistry, The University of

orcid.org/0000-0001-7035-7759; Email: wenbinlin@

uchicago.edu

■

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Xuanyu Feng − Department of Chemistry, The University of

orcid.org/0000-0003-1355-1445

Yang Song − Department of Chemistry, The University of

orcid.org/0000-0003-4212-8814

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N. M. Supramolecular catalysis. Part 2: artificial enzyme mimics.

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Justin S. Chen − Department of Chemistry, The University of

orcid.org/0000-0003-0192-3125

Ziwan Xu − Department of Chemistry, The University of

Chicago, Chicago, Illinois 60637, United States

Soren J. Dunn − Department of Chemistry, The University of

Chicago, Chicago, Illinois 60637, United States

(

43), 13957−13963.

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Complete contact information is available at:

https://pubs.acs.org/10.1021/jacs.0c11920

enzymes, “Chemzymes ”: current state and perspectives. Appl.

Microbiol. Biotechnol. 2008, 81 (1), 1−11.

(19) Dong, Z.; Luo, Q.; Liu, J. Artificial enzymes based on

Author Contributions

X. Feng and Y. Song contributed equally to this work.

supramolecular scaffolds. Chem. Soc. Rev. 2012 , 41 (23), 7890 −7908.

(20) Wei, H.; Wang, E. Nanomaterials with enzyme-like character-

istics (nanozymes): next-generation artificial enzymes. Chem. Soc. Rev.

†

Notes

(

013, 42 (14), 6060−6093.

21) Schwizer, F.; Okamoto, Y.; Heinisch, T.; Gu, Y.; Pellizzoni, M.

M.; Lebrun, V.; Reuter, R.; Kohler, V.; Lewis, J. C.; Ward, T. R.

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

Artificial Metalloenzymes: Reaction Scope and Optimization

Strategies. Chem. Rev. 2018 , 118 (1), 142 −231.

This work was supported by NSF and the University of

Chicago. XAS analysis was performed at Beamline 10-BM,

supported by the Materials Research Collaborative Access

Team (MRCAT). Use of the Advanced Photon Source, an

Oﬃce of Science User Facility operated for the U.S. DOE

Oﬃce of Science by ANL, was supported by the U.S. DOE

under contract no. DE-AC02-06CH11357.

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Biotechnol. 2003, 21 (12), 543−549.

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