A Metal–Organic Framework with Exceptional Activity for C?H Bond Amination

Article abstract of DOI:10.1002/anie.201709420

The development of catalysts capable of fast, robust C?H bond amination under mild conditions is an unrealized goal despite substantial progress in the field of C?H activation in recent years. A Mn-based metal–organic framework (CPF-5) is described that promotes the direct amination of C?H bonds with exceptional activity. CPF-5 is capable of functionalizing C?H bonds in an intermolecular fashion with unrivaled catalytic stability producing >10⁵ turnovers.

Full text of DOI:10.1002/anie.201709420

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Accepted Article
Title: A Metal-Organic Framework with Exceptional Activity for C-H
Bond Amination
Authors: Le Wang, Douglas W Agnew, Xiao Yu, Joshua S Figueroa,
and Seth Mason Cohen
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201709420
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Angewandte Chemie International Edition
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COMMUNICATION
A Metal-Organic Framework with Exceptional Activity for C–H
Bond Amination
Le Wang, Douglas W. Agnew, Xiao Yu, Joshua S. Figueroa,* Seth M. Cohen*
Abstract: The development of catalysts capable of fast, robust C–H
bond amination under mild conditions is an unrealized goal despite
substantial progress in the field of C–H activation in recent years.
Here we describe a Mn-based metal-organic framework (CPF-5) that
state matrix. The synthetic flexibility of metal-organic frameworks
(MOFs) allows for the preparation of metal active sites that are
[
6]
immobilized and separated within
a
porous lattice.
Site
isolation via immobilization as part of the MOF lattice can relax
promotes the direct amination of C–H bonds with exceptional activity. the need to introduce steric encumbrances (as commonly found
CPF-5 is capable of functionalizing C–H bonds in an intermolecular
in molecular catalysts), allowing for facile substrate access to
the reactive sites. The use of site isolation within a MOF matrix
offers the potential to obtain a catalyst that is resistant to
autodegradation, without sacrificing catalytic activity as often
5
fashion with unrivaled catalytic stability producing an unrivaled >10
turnovers.
[
7]
required with molecular catalysts. Lin et al. have recently
reported MOF-based C–H amination systems where a molecular
catalyst is constructed on the MOF linkers. This approach has
Amine functional groups are of critical importance for bioactive
molecules, polymer precursors, and other commodity chemicals.
Selective methods for their formation, especially those that
reduce synthetic steps and waste generation, have been of long
been demonstrated to increase C–H amination catalysis activity
[8]
3
- to 5-fold relative to homogeneous counterparts. Alternatively,
[
1]
standing interest to the synthetic community. With the advent
of late first-row transition-metal catalysts capable of mediating
C–H amination of saturated hydrocarbons, direct routes to
the secondary-building units (SBUs) of the MOFs can act as the
catalytic active site for multi-electron transformations such as C–
H bond amination. This strategy is a departure from embedding
molecular-type catalysts into a MOF, and potentially offers both
high catalytic activity (i.e. an open active site) and long catalytic
lifetimes (i.e. active site stability and isolation) in a single system.
Herein, we describe here a C–H amination MOF catalyst, based
on SBU active sites, with exceptional activity and immortal-like
[
2]
highly-diversified amine products have become available.
These methods have been inspired by biological systems, most
notably the cytochrome P450 class of enzymes that use reactive
metal oxo units to effect the activation of hydrocarbon
[
3]
substrates. These systems also rely on isolation of the reactive
metal-oxo center within a buried protein active site. Accordingly,
molecular complexes that perform these transformations must
rely on the use of encumbering substituents and highly-active
metal-element multiple bonds to achieve reasonable turnover
numbers (TONs) before catalyst decomposition. To date, the
most active homogenous catalysts for direct amination of
hydrocarbon bonds perform with TONs as high as several
[9]
durability.
Our search for a MOF with suitable active sites was
inspired by first-row transition metal amination catalysts that
[5, 10]
utilize facially coordinating tripodal ligands,
and studies on
MOF catalysts for olefin oligomerization that use related active
[11]
sites.
coordination porous framework) that has the molecular formula
Mn21(TZBA)12(HCO CPF-5 is prepared from 4-
tetrazolate-benzoic acid (TZBA), ammonium formate, and MnCl
Based on these criteria we selected CPF-5 (CPF =
[
1, 4]
hundred per active site.
Strategies for improving molecular
2 2
)18(H O)12.
catalysts rely on ancillary-ligand redesign that can increase
catalyst stability and lifetime. However, such efforts can also
potentially sacrifice substrate accessibility to catalyst active sites.
Indeed, in some C–H amination catalysts, increasing steric bulk
results in reduced catalyst activity and promotes facile
2
[12]
to give a MOF with SBUs containing unsaturated Mn(II) sites.
As shown in Fig. 1, three framework tetrazolate rings bind one
Mn(II) center on each corner of the SBU to form an isolated,
tripodal Mn(II) site. Balancing the overall charge of CPF-5
indicates that these Mn(II) sites possess no net charge,
indicating that the framework acts as a dianionic ‘ligand’ to the
Mn(II) ion. To the best of our knowledge, this dianionic ligand
environment is distinct when compared to related
tris(pyrazolyl)methane (Tpm, neutral) and tris(pyrazolyl)borate
[
5]
intramolecular catalyst decomposition.
An alternative approach to the use of elaborate ligand
architectures is isolation of catalytic sites within a robust, solid-
[*]
Dr. L. Wang, D. W. Agnew, Prof. Dr. J. S. Figueroa, Prof. Dr. S.
M. Cohen
[
5, 10, 13]
(
Tp, monoanionic) ligands.
Being charge neutral, the
Department of Chemistry and Biochemistry,
University of California, San Diego
La Jolla, California, 92093, USA
vacant coordination sites on the Mn(II) center in CPF-5 are
capped by three water molecules (Fig. 1). The bound water
molecules can be exchanged by solvents, such as acetonitrile,
or substrates for achieving catalysis. Importantly, because
these Mn(II) sites are immobilized within the MOF, steric
protection is not required to avoid catalyst dimerization,
decomposition, etc., making substrate access, binding, and
turnover facile.
E-mail: scohen@ucsd.edu
Xiao Yu
Department of Nanoengineering,
University of California, San Diego
La Jolla, California, 92093, USA
[**]
This work was supported by a grant from the National Science
Foundation, Division of Chemistry (CHE-1359906, S.M.C.) and
the Department of Energy, Office of Basic Energy Sciences (DE-
SC0008058, J.S.F.). We thank Y. Ma, M.J. Drance, C.C.
Mokhtarzadeh, and M.L. Neville for helpful discussions, and M.
Gembicky, C.E. Moore, and Prof. A.L. Rheingold for assistance
with crystallography.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201xxxxxx.
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Angewandte Chemie International Edition
10.1002/anie.201709420
COMMUNICATION
benzylic C–H substrates, such as 1,3-dihydroisobenzofuran
(
BzTHF) resulted in near quantitative conversion of PhI=NTs to
the expected amination products (Fig. S4). 2-Methyl-
tetrahydrofuran (2-MeTHF) resulted in selective amination at 2°
C–H bond (73% yield), thereby showing a preference for less
sterically hindered sites. Similarly, the less sterically hindered
product was favored when employing 3-methyl-tetrahydrofuran
(
3-MeTHF) as the substrate, which produced two product
isomers (Fig. S5). The overall yield of 3-MeTHF amination
products is ~65%, with 36% selectivity for the 2-substituted
amination product (Fig. 2) and 64% selectivity for 5-substituted
product. Treatment of weaker Lewis basic cycloether substrates,
such as tetrahydropyran (THP) afforded the α-aminated product
in ~50% yield. 3,4-Dihydro-2H-pyran (DHP) resulted in 56%
yield of amination product (Fig. S6). However, more reactive
substrates, such as and 3,4-dihydro-1H-2-benzopyran (BzTHP)
and dioxane (performed neat) gave the desired amination
products in >90% yield (Fig. 2). Amination of nitrogen and sulfur
heterocycles was also examined, but the PhI=NTs reagent
dissolved immediately upon addition of these substrates, even in
the absence of catalysis, suggesting a rapid reaction between
the substrates and PhI=NTs (potentially oxidation into imines or
sulfilimide). However, C–H activation was achieved with
dibenzyl-methyl-amine (DBMA), where the methylaminated
product was formed in 35% yield. Consistent with the amination
of 2-MeTHF, the product obtained also suggests the sterically
less hindered methyl C–H bond is favored for activation.
Figure 1. The CPF-5 contains complex SBUs, but results in
large 13.6
A
pores (top left).
The SBUs contain four
crystallographic independent Mn(II) ions (top right, labeled as
Mn1-4), with the tripodal active (Mn1) active site highlighted in
brighter colors. The facially coordinated Mn(II) in CPF-5
possesses open coordination sites for substrate binding (bottom,
depicted as different colored shapes). Mn, orange; C, gray; H,
white; N, blue; O, red; Cl, green.
To demonstrate the viability of CPF-5 as a catalyst for
intermolecular C–H amination, we treated CPF-5 with the nitrene
precursor phenyl-N-tosyliodinane (PhI=NTs,
1
equiv) in
acetonitrile solution with THF as a substrate (1.0 equiv). The
MOF catalyst was used in 1.0 mol% (based on tripodal Mn(II)
1
sites) relative to PhI=NTs. After 30 min at room temperature, H
NMR (Fig. S3) and gas chromatography-mass spectrometry
(
GC-MS) analysis revealed 85% yield of THF to the a-amination
product N-(tetrahydro-2-furanyl)-4-toluenesulfonamide (Fig. 2,
Table S1). The yield is based on the productive transfer of
[
5, 10]
PhI=NTs to form the a-amination product
stoichiometry of PhI=NTs to THF. CPF-5 after catalysis was
proved to be intact by PXRD (Fig. S1) and N gas sorption (Fig.
S2). To test the heterogeneity of CPF-5, hot filtration
with a 1:1
2
Figure 2. Reaction scheme and substrate scope for C–H
amination by CPF-5. Yield for 3-MeTHF is the combined yield of
two isomers. Isolated yields are shown under each amination
product with the solvent system indicated.
a
experiment was conducted after 30 min of catalysis, after which
no further conversion of substrate was observed. In addition,
ICP-MS shows that the concentration of Mn ion was <5 ppb in
the filtered solution, indicating no significant Mn leaching during
the reaction. By comparison, similar molecular, homogeneous
Mn(II) complexes require 5 mol% catalyst to produce between
CPF-5 can aminate non-coordinating substrates in lower
yields, but requires longer reaction times (6 h) and a non-
[5]
coordinating solvent (CHCl
Using CHCl
3
instead of acetonitrile used above).
3
2-38% yield of the amination product after 1 h under similar
3
, the benzylic hydrogens of indane and 1,2,3,4-
conditions and generally require a large excess of organic
tetrahydronaphthalene (THN) could be aminated in 32% and 35%
yield. Similarly, cyclohexene is selectively aminated at the allylic
position in 53% yield (Fig. S7). This is notable, as many
molecular C–H amination catalysts based on reactive metal-
nitrene species effect both aziridination and C–H amination with
[
5]
substrate to achieve efficient nitrene transfer. As rudimentary
control reactions, a variety of Mn(II) and Mn(III) salts, as well as
several other MOFs, were examined, but none yielded the
desired product under identical conditions (Table S1).
To explore the catalytic scope of CPF-5, we examined its
reactivity with a variety of substrates (Fig. 2). Secondary
[5]
olefin substrates. CPF-5 is capable of olefin aziridination when
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COMMUNICATION
relatively weak C–H bonds are absent in the substrate, e.g. t-
butylethylene (tBE, Fig. S8), trimethylsilylethylene (TMSE), and
styrene, all of which can be converted by CPF-5 to the
corresponding aziridines in modest yields (Fig. 2). However,
conversion of benzene or toluene were unsuccessful,
suggesting a C–H bond dissociation energy threshold required
for productive amination with CPF-5.
5
crystals were exposed to fresh THF and PhI=NTs in
acetonitrile. Amination of THF dropped slightly with each fresh
addition of substrate (Fig. 3), perhaps due to the introduction of
[
5]
water during catalyst isolation, but could be fully recovered by
the addition of molecular sieves to the reaction mixture. Similar
experiments were carried out with BzTHF and BzTHP, which
gave >90% yield over 20 reaction cycles (Fig. S10), while
leaving the CPF-5 single-crystals intact (Table S2). Taken
together, these experiments further support our conclusion that
Despite the limited substrate scope, the catalytic activity of
CPF-5 is most remarkable with respect to catalyst longevity and
turnover with coordinating substrates. In this respect, CPF-5
serves as a prototype for site immobilization and isolation of a
molecular type species capable of carrying out a difficult,
multielectron transformation with high efficiency. To demonstrate
catalyst activity and stability, a large-scale reaction involving 50
g of PhI=NTs (1.0 equiv), 24 g of BzTHF (1.5 equiv), and ~1.0
[
8a]
CPF-5 is a reusable, immortal C–H amination catalyst.
It is
also notable that CPF-5 does not show any apparent product
inhibition, which may be due to the formation of a high-spin Mn(II)
species that are known to exhibit fast ligand dissociation
[
16]
kinetics.
An initial examination of the catalytic mechanism was
performed using the isotope effect on C–H amination between
-
4
mg of CPF-5 catalyst (~7´10 mol% of active sites) was
performed. Remarkably, the PhI=NTs nitrene precursor was fully
consumed after ~2.5 h and 34 g (89% yield) of the desired
amination product was recovered. This corresponds to a TON of
THF and THF-d
formation from parallel THF/THF-d
in a k /k = 4.5(2) (Fig. S11). A similar value was obtained (k
= 4.6(1)) when competitive amination of a 1:1 mixture of
THF/THF-d was conducted. These isotope effect results
indicate that C–H bond cleavage is the critical initial step in the
8
. Measurement of rate constants for product
amination reactions resulted
/k
8
H
D
H
D
-
1
~
120,000 and turnover frequency (TOF) of ~48,000 h . The
CPF-5 crystals remained highly active even after this large-scale
reaction and could be recovered and reused. These
observations suggest that CPF-5 can be regarded as an
immortal-like C–H amination catalyst in a manner consistent with
8
[
17]
product formation process.
The isotope effect for
intermolecular C–H amination by CPF-5 is lower than some Fe-
[
14]
some polymerization systems.
homogeneous C–H activation catalysts, the TON obtained for
Compared to many
nitrene systems that function by
a
hydrogen-atom
[
4b, 15b]
abstraction/radical rebound pathway,
but are comparable
systems that have
[
10, 15]
[15c]
[18]
[19]
CPF-5 is 3- to 4-orders of magnitude greater.
In addition,
to other Mn-,
Cu-,
and Ru-nitrene
CPF-5 outperformed previously reported MOF-based C–H
amination catalysts, which only show a 3- to 5-fold improvement
been proposed to operate similarly. Notably, the preferential C–
H amination, rather than aziridination, of cyclohexene by CPF-5
mirrors the chemoselectivity of other Mn- and Fe-based
amination catalysts where reactive metal-nitrene species are
[
8]
[11a]
in TON or TOF
when compared to their homogeneous
analogues. Indeed, the TON for the amination of BzTHF
exceeds that measured in this large-scale experiment, as
turnover was limited by the quantity of PhI=NTs available. This
suggested to us that with lower yielding substrates, greater
product generation could be achieved by continued addition of
PhI=NTs. Indeed, when the reaction between cyclohexene and
PhI=NTs stalled at lower conversions (Fig. 2), successive
additions of PhI=NTs continued to drive formation of the
amination product (Fig. S9). To the best of our knowledge, CPF-
[
15c, 20]
proposed as the catalytically relevant intermediates.
5
demonstrates record high TON and TOF for a C–H amination
catalyst that is unmatched by any other homogenous or
heterogeneous catalysts.
To further demonstrate the immortal nature of C–H
amination catalysis by CPF-5 a series of experiments involving
tandem reactions was performed. Using THF as a substrate,
GC-MS was used to monitor product formation (Fig. 3). In the
first experiment, amination of THF with 100 mg of PhI=NTs was
completed (~90% yield based on consumption of PhI=NTs)
using 1.0 mg of CPF-5 in ~10 min. The reaction mixture was
stirred for an additional 20 min, after which another aliquot of
THF and PhI=NTs was added. This was repeated four times
using the same 1.0 mg of CPF-5 catalyst, with no loss in
catalytic activity (Fig. 3). Continuous catalytic activity was
observed even when the dwell time between addition of
substrate was extended from 20 min to one day (Fig. 3).
Similarly, catalytic activity was maintained when different
substrates were added to the reaction mixture (THP and THF,
Fig. 3). Finally, upon catalytic amination of THF with PhI=NTs
Figure 3. Evidence for CPF-5 as an immortal C–H amination
catalyst. Using 1.0 mg of CPF-5: (top left) Addition of PhI=NTs
and THF resulted in conversion to the desired amination product
after ~10 min, which could be replicated by addition of fresh
reactants added in 30 min intervals (in last two runs, the quantity
of reactants was doubled); (top right) The same experiment as
performed in ‘A’ but with the addition of fresh reactants every 24
(
for ~20 min), the liquid phase was removed and the same CPF-
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COMMUNICATION
h; (bottom left) The use of two different substrates, THP (red)
and THF (blue) did not impact the activity of the catalyst; (bottom
right) The CPF-5 catalyst was isolated between additions of
fresh reactant in 25 min intervals, showing essentially no change
in reaction rate. Arrows indicate the removal of reaction mixture.
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2
)
3
(MeTet)Mn] (MeTet = 5-
methyl-tetrazolate) as a model platform, the Mn-nitrene THF
+
adduct [Zn(OH
found to optimize to
bipyramidal geometry (Fig. S12). Broken-symmetry DFT
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)
3
(MeTet)Mn(NTs)(THF)] (m1; m = model) was
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abstraction/radical rebound mechanism.
the putative THF-radical
2 3
Zn(OH ) (MeTet)Mn(N(H)Ts)(THF)] (m2), in which an a-
amination
catalysis
through
a
hydrogen-atom
Calculations on
intermediate,
[
4b, 15b, 20]
[
[
[
9]
+
[
hydrogen atom is transferred to the Mn-nitrene unit, converged
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surmountable for coordinating substrates such as THF. Whereas
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a simple Mn-iminoiodane adduct (i.e.
[
22]
Mn¬RI=NR') capable nitrene transfer cannot be ruled out,
especially for the aziridination of olefin substrates lacking allylic
C–H bonds, the similar chemoselectivity and kinetic isotope data
to other C–H amination catalysts systems suggest that the
[
[
12]
13]
tripodal Mn(tetrazolate)
3
15c]
sites of CPF-5 can form an active
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The unprecedented activity of CPF-5 is attributed to a
combination of effects, including site isolation of the dianionic,
[
12, 23]
facial coordinating, sterically unencumbered active site.
In
addition, unlike homogenous molecular species or flexible
[
24]
[16]
17]
MOFs,
the highly interconnected metal clusters in CPF-5
3
210
result in a rigid framework that may inhibits dynamic, stabilize
reactive centers, and isolate these centers. Although the
substrate scope of CPF-5 is rather limited, it is also known that
tripodal Mn complexes are inferior to their Fe analogues for C–H
[
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[18]
[19]
[
5]
amination. Therefore, we anticipate that by modifying CPF-5,
including by postsynthetic ion exchange, we will produce highly
activity catalysts with a broader utility. Nevertheless, CPF-5
achieves unprecedented activity in Mn catalyzed C–H amination
and represents the first example of a C–H amination catalyst
with immortal-like characteristics.
[20]
[
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Angewandte Chemie International Edition
10.1002/anie.201709420
COMMUNICATION
Hudson, J. Rodriguez, J. E. Bachman, M. I. Gonzalez, A.
Cervellino, A. Guagliardi, C. M. Brown, P. L. Llewellyn, N.
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This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201709420
COMMUNICATION
COMMUNICATION
Le Wang, Douglas W. Agnew, Xiao Yu,
Joshua S. Figueroa,* and Seth M.
Cohen*
Page xx. – Page xx.
A Metal-Organic Framework Catalyst
with Exceptional Activity for C–H
Bond Amination
A Mn-based metal-organic framework (MOF) with a unique active site catalyzes C–H amination under mild conditions.
Importantly, the catalyst displays an exceptional and unprecedented TON of >120,000, which is ~4-orders of magnitude
greater than any other state-of-the-art C–H amination catalysts.
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