Selective Heterogeneous C-H Activation/Halogenation Reactions Catalyzed by Pd@MOF Nanocomposites

Article abstract of DOI:10.1002/chem.201502918

A directed heterogeneous C-H activation/halogenation reaction catalyzed by readily synthesized Pd@MOF nanocatalysts was developed. The heterogeneous Pd catalysts used were a novel and environmentally benign Fe-based metal-organic framework (MOF) (Pd@MIL-8

Full text of DOI:10.1002/chem.201502918

DOI: 10.1002/chem.201502918
Full Paper
&
Metal–Organic Frameworks |Very Important Paper|
Selective Heterogeneous CÀH Activation/Halogenation Reactions
Catalyzed by Pd@MOF Nanocomposites
[a, c]
[b, c]
[a, c]
[b, c]
[b, c]
Vlad Pascanu,
Fabian Carson,
Marta Vico Solano,
Jie Su,
Xiaodong Zou,
[d]
[a, c]
Magnus J. Johansson, and BelØn Martín-Matute*
Abstract: A directed heterogeneous CÀH activation/halo-
genation reaction catalyzed by readily synthesized Pd@MOF
nanocatalysts was developed. The heterogeneous Pd cata-
lysts used were a novel and environmentally benign Fe-
based metal–organic framework (MOF) (Pd@MIL-88B-
NH (Fe)) and the previously developed Pd@MIL-101-NH (Cr).
very mild reaction conditions and in short reaction times. A
wide variety of directing groups, halogen sources, and sub-
stitution patterns were well tolerated, and valuable polyhalo-
genated compounds were synthesized in a controlled
manner. The synthesis of the Pd-functionalized Fe-based
MOF and the recyclability of the two catalysts are also pre-
sented.
2
2
Very high conversions and selectivities were achieved under
Introduction
few catalysts have proved capable of realizing this challenging
[
9]
goal efficiently as well as in a selective manner. If such a pro-
tocol could be based on a heterogeneous catalyst, this would
represent an attractive way to synthesize a wide range of func-
tionalized molecules.
CÀH functionalization represents an attractive and straightfor-
ward method to introduce diverse functional groups into
[
1]
a molecule. Not relying on leaving groups to direct a transfor-
[
2]
mation brings significant benefits in terms of time and costs.
This simplifies late-stage transformations in the synthesis of
Metal–organic frameworks (MOFs) are porous materials with
extremely high surface areas that have been shown to be
useful heterogeneous supports for transition-metal nanocata-
[
3]
target molecules, and can positively impact the environmen-
tal output of the chemical industry. However, the activation of
relatively inert CÀH bonds while accurately distinguishing be-
tween several bonds with similar activation energies, is chal-
[
10]
lysts. MOFs can impede the aggregation of supported nano-
[
11]
particles during a reaction, thereby prolonging their lifetime.
The confined environment found inside the pores of MOFs can
lead to surprising reactivity or selectivity, which would other-
[
4]
lenging. Moreover, methods for the activation of CÀH bonds
using heterogeneous catalysts are still scarce.
Halogenated compounds are very useful in various branches
[5]
[12]
wise be difficult to achieve in homogeneous systems. Their
inherent structural features allow MOFs to discern between
substrates of various shapes and sizes, meaning that they
could potentially be used as supports for catalysts for selective
[
6]
[7]
of chemistry (e.g., agrochemistry, pharmaceuticals, supra-
[
8]
molecular chemistry ). They can also be further functionalized
to synthesize more diverse structures. Halogenation through
selective CÀH functionalization is an engaging concept, but
[
13]
CÀH activation reactions. In addition, MOFs can facilitate the
catalyst recycling and prevent metal contamination of the re-
action products.
[
a] V. Pascanu, Dr. M. V. Solano, Prof. B. Martín-Matute
Department of Organic Chemistry, Stockholm University
Stockholm, 10691 (Sweden)
An interesting first report on aromatic CÀH activation/halo-
genation under heterogeneous catalysis was recently pub-
[
14]
E-mail: belen.martin.matute@su.se
lished by Fei and Cohen. A molecular Pd catalyst was immo-
bilized in a modified UiO-66 framework by post-synthetic
ligand exchange. The heterogeneity and recyclability of the
catalyst were demonstrated for a limited number of substrates
that do not raise selectivity issues. For other substrates con-
taining a directing group that allows activation of two equiva-
lent CÀH bonds, such as phenylpyridines and related mole-
cules, it is very challenging to stop the reaction after the first
functionalization, and activation of the second CÀH bond re-
[
b] Dr. F. Carson, Dr. J. Su, Prof. X. Zou
Department of Materials and Environmental Chemistry
Stockholm University, Stockholm, 10691 (Sweden)
[
c] V. Pascanu, Dr. F. Carson, Dr. M. V. Solano, Dr. J. Su, Prof. X. Zou,
Prof. B. Martín-Matute
Berzelii Center EXSELENT on Porous Materials, Stockholm University
Stockholm, 10691 (Sweden)
[
d] Dr. M. J. Johansson
CVMD iMed, Medicinal Chemistry
AstraZeneca R&D, Mçlndal, 43183 (Sweden)
sults in low selectivities towards the monofunctionalized prod-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502918.
[15]
uct.
Indeed, excellent conversions can be achieved using
[
16]
[15a]
Pd(OAc)2 or even Cu salts
as the catalyst, but a mixture of
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mono- and difunctionalized products is formed under these
conditions, which necessitates tedious purification steps. To-
Chem. Eur. J. 2016, 22, 3729 – 3737
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wards this goal it is still necessary to develop methods that
afford the synthesis of either mono- or dihalogenated aromat-
ics selectively, and that could be scaled up and applied in
large-scale processes.
cording to a procedure previously developed and reported by
[
10i,j]
our group.
For cat. 2 a new procedure was developed. The supporting
framework, MIL-88B-NH (Fe), was synthesized by adapting
2
[
18]
Our group has developed efficient procedures for Suzuki
a protocol reported by Serre et al. using ethanol as the sol-
vent and without hazardous additives. The stability of the MOF
in acidic and basic aqueous solutions (ranging from pH 1 to
14) was investigated in order to determine the appropriate
functionalization conditions. According to the X-ray powder
diffraction (XRPD) data, the material is stable between pH 1 to
11. At higher pH (pH 12 to 13), significant mass loss was ob-
served, which correlated with a decrease in crystallinity and
a color change from dark brown to pale orange. At pH 14, the
structure transformed into another crystalline phase, possibly
a MIL-53-type structure (see the Supporting Information, Fig-
[
10i–j]
[10k]
cross-coupling
and alcohol oxidation reactions
using Pd
nanoparticles supported in the MIL-101-NH (Cr) and MIL-88B-
2
NH (Cr) MOFs, respectively. Although these systems show ex-
2
tremely low metal leaching and very good recyclability, the
presence of Cr clusters in the frameworks raises concerns over
health issues in potential industrial large-scale applications. To
address this issue, in this paper we report the synthesis of a re-
lated catalyst based on a benign Fe MOF, dubbed Pd@MIL-
8
8B-NH (Fe). This new heterogeneous catalyst is cheaply and
2
easily synthesized, which makes it extremely attractive for cata-
lytic applications.
ure S1). This behavior makes MIL-88B-NH (Fe) an ideal hetero-
2
We report here a reliable and selective heterogeneous CÀH
halogenation method using palladium nanoparticles immobi-
geneous support for applications that require stability under
acidic conditions such as CÀH activation reactions, which are
typically carried out in an acidic environment.
lized into porous heterogeneous MOFs, Pd@MIL-88B-NH (Fe)
2
and Pd@MIL-101-NH (Cr). Both MOFs showed excellent selec-
Despite the flexible nature of the MOF, impregnation with
a palladium precursor was successfully achieved, using a strat-
egy that we had previously developed for the Cr analogue of
2
tivity for the formation of monofunctionalized products from
starting materials in which two competing positions were
available, under exceptionally mild and environmentally friend-
ly conditions. Conversely, the difunctionalized products could
also be obtained selectively by adjusting the reaction parame-
ters. This heterogeneous system is considerably more efficient
in terms of yields, and even more importantly selectivity, using
lower catalyst loadings and temperatures than any of those
[
10k]
MIL-88B-NH2.
Na PdCl4 was found to be an optimal Pd
2
source, and MeOH proved to be an adequate solvent for keep-
ing the flexible structure of the MOF in an open conformation
during the impregnation process. Analysis of the impregnated
II
material, Pd @MIL-88B-NH (Fe), by inductively-coupled-plasma
2
optical emission spectrometry (ICP-OES) confirmed the success-
ful loading of Pd (10.89 wt% Pd) and the complete removal of
[14,15,16b,17]
previously described.
We found the reaction to have
a wide substrate scope, which demonstrates both catalysts are
versatile, and can be used with various directing groups, sub-
stitution patterns, and halogen sources. We also investigated
the recyclability of the two MOFs, which revealed some differ-
ences in their behavior.
Na (see the Supporting Information, Section S2 for a detailed
II
procedure). The use of NaBH to reduce the Pd resulted in
4
amorphization of the material, even when the reaction was
carried out at À58C. This led us to explore milder reducing
agents. We found that the crystallinity of the MOF was pre-
served when either a mixture of Na citrate/l-ascorbic acid or
NaBH(OAc) were used as the reducing agents. To verify the ef-
3
ficiency of these conditions for the synthesis of Pd nanoparti-
cles and the ability of these reagents to access the Pd sites
within the pores of the MOF, XPS was carried out after the re-
Results and Discussion
0
II
duction step. This revealed Pd /Pd ratios of 70:30 and 90:10,
1. Catalysts synthesis
respectively, when sodium citrate/l-ascorbic acid and NaB-
The two catalysts utilized for this study, Pd@MIL-101-NH (Cr)
H(OAc) were used as reducing agents (Figure 2b, top right).
2
3
and Pd@MIL-88B-NH (Fe), are shown in Figure 1. Pd@MIL-101-
Therefore we chose to use NaBH(OAc) as the reducing agent
2
3
NH (Cr) containing 8 wt% of Pd (cat. 1) was synthesized ac-
for the synthesis of the nanoparticles (see the Supporting In-
formation for further details). TEM micrographs confirmed the
formation of Pd nanoparticles with an average size of 2 nm
that were uniformly distributed throughout the MOF (Fig-
ure 2c, bottom). Specific rod-shaped crystals could be ob-
2
served, ranging in size from 500 nm to several micrometers.
0
Pd @MIL-88B-NH (Fe) synthesized in this way had a Pd loading
2
of 11.46 wt%.
The XRPD data confirmed that the framework remained crys-
talline after the functionalization procedure (Figure 2a, top
left). The peaks progressively shifted to lower 2q angles and
II
the unit cell volume increased in Pd @MIL-88B-NH (Fe) and
2
Figure 1. Illustrative representation of palladium nanoparticles supported in
0
Pd @MIL-88B-NH (Fe) compared to MIL-88B-NH (Fe), which in-
MIL-101-NH
2
(Cr) cages (left, green), and MIL-88B-NH
2
(Fe) channels (right, red)
2
2
(
note: The nanoparticles in both materials are of similar dimensions).
dicates that the framework expanded during the impregnation
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with excellent selectivity. Com-
plete details of the optimization
procedure are given in the Sup-
porting Information (Section S4).
The first experiments were
aimed at obtaining 2-(2-iodo-
phenyl)pyridine (2). The choice
of acetic acid as an environmen-
tally friendly and cheap solvent
also simplifies the protocol as
addition of an acid additive is
therefore not needed. Moreover,
it creates a polar environment,
which favors the diffusion of the
reagents into the pores of MIL-
1
01-NH . After 7 h, a good con-
2
version and high selectivity were
achieved, even though the tem-
perature was as mild as 508C
(
Table 1, entry 1). Surprisingly,
along with traces of dihalogenat-
ed product 3, small amounts of
II
0
Figure 2. a) XRPD patterns of MIL-88B-NH
2
(Fe), Pd @MIL-88B-NH
2
(Fe), and Pd @MIL-88B-NH
2
(Fe); b) XPS analysis of
a
dimeric product (4) were
0
0
Pd @MIL-88B-NH
2
(Fe); c) TEM micrographs of Pd @MIL-88B-NH
2
(Fe).
[
19]
formed.
This result could be
significantly improved by using
with Pd and again during the
formation of the Pd nanoparti-
cles. LeBail fitting of the XRPD
data gave unit cell parameters of
[a]
Table 1. Optimization of the selective mono a di-iodination of 2-phenylpyridine (1).
a=10.891(1), c=19.181(2) Š; V=
3
1
970.4(3) Š for MIL-88B-NH (Fe);
2
a=11.691(2), c=18.705(4) Š; V=
Entry
Catalyst
T [8C]
t [h]
NIS [equiv]
Solvent
Additive
Yield [%]
3
II
2
214.2(6) Š for Pd @MIL-88B-
2
3
4
NH (Fe); and a=12.243(3), c=
2
1
2
3
4
5
6
7
8
Pd@MIL-101-NH
Pd@MIL-101-NH (Cr)
Pd@MIL-101-NH
Pd@MIL-101-NH
Pd@MIL-101-NH
Pd@MIL-88B-NH
Pd@MIL-88B-NH (Fe)
Pd/C (10 wt%)
2
(Cr)
50
50
40
80
80
50
80
50
7
7
7
1.2
2.3
3.0
3.0
3.0
2.3
3.0
2.3
AcOH
AcOH
AcOH
THF
DCE
AcOH
DCE
–
–
–
58
74
52
0
0
81
0
2
1
0
93
98
7
99
0
8
3
0
3
0
3
0
0
3
1
8.429(6) Š; V=2392.1(9) Š for
2
0
Pd @MIL-88B-NH (Fe)
using
a hexagonal space group (P 6¯ 2c)
see the Supporting Information,
Figures S2–S4). TGA results con-
2
(Cr)
2
(Cr)
2
(Cr)
2
2.25
16
7
16
7
PTSA
PTSA
–
PTSA
–
(
2
(Fe)
2
II
0
firmed that Pd @ and Pd @MIL-
8B-NH (Fe) were thermally
AcOH
16
8
2
[a] Experiments were carried out under an air atmosphere on a 0.1 mmol scale, using Pd@MOF or Pd/C
(4 mol% Pd) and 3 mL of solvent. Conversions were monitored by GC. 0.5 mmol additive was used in entries 4,
5
stable up to 3008C in air, which
is similar to the thermal stability
, and 7. PTSA=p-toluenesulfonic acid; DCE=1,2-dichloroethane.
of MIL-88B-NH (Fe) (see the Sup-
2
porting Information, Figure S6).
2
.3 equivalents of NIS, which gave a higher conversion while
keeping products 3 and 4 in trace amounts (entry 2). Remark-
ably, the product (2) could also be obtained at a temperature
as low as 408C (entry 3). These are some of the mildest condi-
tions ever reported for an efficient Pd-catalyzed CÀH activa-
tion. Further experiments carried out at 50 and 608C with vari-
ous reaction times and equivalents of reagents did not give
improved product distributions (see the Supporting Informa-
tion, Table S2).
2
. Reaction optimization
The iodination of unsubstituted 2-phenylpyridine using N-iodo-
succinimide (NIS) as a halogenating agent was chosen as
a model reaction to explore the reactivity and selectivity ob-
tained with the two Pd@MOF catalysts. Preliminary investiga-
tions were carried out using Pd@MIL-101-NH (Cr) (Table 1). A
2
step-by-step approach led to the identification of suitable reac-
tion conditions for the synthesis of either 2-(2-iodophenyl)pyri-
dine (2) or 2-(2,6-diiodophenyl)pyridine (3) in high yields and
We then set out to find optimal conditions that would favor
the formation of the dihalogenated product, 2-(2,6-diiodophe-
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nyl)pyridine (3). Increasing the temperature to 808C promoted
the activation of the monohalogenated ring for a second func-
tionalization step. Switching to THF, which is a less polar sol-
vent, along with p-toluenesulfonic acid as an additive was also
an important step in the right direction, and the balance of
products shifted considerably towards 3 (see the Supporting
Information, Table S2). Increasing the excess of halogenating
agent to 3 equivalents was decisive, and the reaction proceed-
ed to full conversion into 3. It was interesting to observe that
in THF at 808C, the reaction was extremely fast, and it was
complete in approximately 2 h (Table 1, entry 4) due to the
high pressure created in the sealed vial, at a temperature
above the boiling point of the solvent (THF b.p.=668C).
Switching to 1,2-dichoroethane (DCE b.p.=848C) led to a de-
crease in the rate, and the reaction required overnight stirring
to reach completion, but formation of byproduct 4 was inhibit-
ed and complete selectivity for 3 was achieved (entry 5). Other
solvents and additives were screened, but none of them im-
proved the reaction outcome (see the Supporting Information,
Table S2), while with Pd/C only a modest conversion was ob-
tained (entry 8).
periments confirmed that in the absence of a catalyst, as well
as in the presence of MOFs without supported Pd, no conver-
sion was observed for either the first or the second halogena-
tion step.
It can therefore be concluded that the selective synthesis of
either monohalogenated 2 or dihalogenated 3 compounds
can be well controlled with both cat. 1 and cat. 2. The selectivi-
ty is mostly dependent on the reaction temperature, the polar-
ity, and pH of the reaction solvent. It is also influenced by the
excess of the halogenating agent, albeit to a far lesser extent.
We then investigated the influence of various substitution pat-
terns on the functionalization of 2-phenylpyridine derivatives
under these optimized reaction conditions (5a–d, Scheme 1a).
3. Scope in terms of symmetrical phenylpyridines
The activation of the CÀH bond in electron-poor 2(4-formyl-
phenyl)pyridine (5a) proved to be more difficult, and the reac-
tions were allowed to stir overnight. This lower reactivity
meant that we obtained conversions of approximately 60%
with both catalysts, but a complete selectivity for the desired
product (6a) could be achieved (Scheme 1a). 2-(4-Tolyl)pyri-
dine (5b) was more reactive, giving up to 10% of 7b at 508C.
However, by decreasing the temperature to 408C the selectivi-
ty could be completely restored while maintaining a very good
conversion (74%) (Scheme 1a). The electron-rich 2-(4-meth-
oxylphenyl) pyridine (5c) was converted into 6c in 81 and
92% yield with both catalysts (Scheme 1a). A functional group
grafted on the pyridyl moiety did not affect its directing prop-
The optimal conditions for the formation of both mono- and
di-iodinated products were also tested in experiments using
Pd@MIL-88B-NH (Fe). At 508C in AcOH, the Fe-based catalyst
2
(
(
cat. 2) was found to be even more reactive than the Cr one
cat. 1), and the selectivity was marginally lower (Table 1,
entry 6). At 808C in DCE, the Fe-based catalyst gave a full and
clean conversion within 16 h, and no traces of dimer 4 were
found in the reaction mixture (entry 7). Importantly, control ex-
Scheme 1. a) Selective monoiodination of substituted 2-phenylpyridines; b) Selective diiodination of substituted 2-phenylpyridines. Unless otherwise specified,
1
experiments were carried out on a 0.1 mmol scale, using 3 mL of solvent. Conversions were monitored by H NMR spectroscopy. Reactions were scaled up to
0
.4 mmol for isolation purposes. Isolated yields are reported in parentheses. [a] Low isolated yields of monoiodinated products due to difficult separation
from the remaining starting material. [b] 3.5 equiv NIS was used. [c] DCE was used as the solvent, 24 h.
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erties and 6-phenylnicotinonitrile (5d) gave the monoiodinated
product in high yields (78 to 85%, Scheme 1a). These results
tions, brominated products could be obtained in excellent
yields within much shorter reaction times than their iodinated
counterparts. 6-Phenylnicotinonitrile (5d) could be selectively
monobrominated (Scheme 2, 8-Br) using N-bromosuccinimide
(NBS) and cat. 1. A 73% yield was achieved within 2 h.
(
Scheme 1a) show that the outcome of the reaction is not
highly dependent on the electronic nature of the substituents,
and both electron-withdrawing and -donating groups are well
tolerated. The variations in reactivity observed are most likely
caused by the differences in size and polarity between the
substrates; this behavior is typical with porous catalysts such
as the ones investigated.
Pd@MIL-88B-NH (Fe) (cat. 2) gave a similar high yield and se-
2
lectivity. The analogous chlorination reaction using N-chloro-
succinimide (NCS) and cat. 1 gave significantly worse results.
Only 21% of the product (8-Cl) could be obtained after 4 h,
and the reaction did not progress further. Replacing the halo-
Under the second set of reaction conditions (Scheme 1b), all
the substrates (5a–d) were quantitatively converted into diio-
[
20]
genating agent with the newly developed Palau’chlor led to
a more efficient chlorination, but it also triggered the decom-
position (disolution) of both MOFs.
dinated products using Pd@MIL-101-NH (Cr) (cat. 1). For the
2
second MOF (cat. 2), dichloroethane (DCE) proved again to be
a more suitable solvent and a quantitative yield was achieved
in all cases within 24 h. The formation of dimers was not ob-
served with these larger substituted 2-phenylpyridines, which
is expected for a reaction carried out in a size-limiting environ-
ment.
We also investigated the behavior of other directing groups
in the reaction. Substrates bearing rigid directing groups (9,
10) were readily halogenated. 7,8-Benzoquinoline (9), which
showed no reactivity in iodination reactions due to steric limi-
tations (9-I), could be rapidly and efficiently brominated yield-
ing 9-Br and even chlorinated (9-Cl). N-acetyl-2-methylindoline
(
10) is another interesting target molecule for directed CÀH ac-
tivation, but it is highly susceptible to oxidation yielding unde-
sired indole-type products. We were pleased to see that the
mild conditions used in the methodology described here en-
abled C7-iodination and bromination of 10 efficiently, yielding
products 10-I and 10-Br for the first time in very good yields.
Both catalysts showed a good tolerance towards the amide-di-
recting group and they displayed similar levels of performance.
Iodine (to give 10-I, at 508C) and bromine (to give 10-Br, at
4
. Bromination and chlorination reactions and diverse di-
recting groups
The next step in our investigation was to test whether our
method was also applicable to bromination and chlorination
reactions (Scheme 2). We found that under similar mild condi-
4
08C) atoms could be successfully grafted onto the phenyl
ring using either of the two catalysts. All four of these reac-
tions proceeded to completion in a directed fashion and
within very short reaction times. On the other hand, only
traces of desired product were formed in the corresponding
chlorination reactions (10-Cl).
5. meta-Substituted substrates
A more interesting case in our study was that of meta-substi-
tuted phenyl rings (Scheme 3, 11 a–c). With these substrates
three halogenated products may be formed: the functionaliza-
tion at either one of the two available positions ortho to the
directing group would lead to the formation of two different
monohalogenated isomers, and in addition, the corresponding
dihalogenated arene can be formed.
As expected, at low temperatures the introduction of a large
iodine substituent proceeded exclusively through activation of
the less crowded CÀH bond (i.e., H ). This behavior was ob-
A
served with all the substrates tested, regardless of the size or
the electronic properties of the R group (Scheme 3). Products
12a-I and 12b-I could be isolated in very good to excellent
yields from the standard conditions (AcOH, 508C). When the R
group was replaced by a bulkier bromine atom, as in the case
of N-(3-bromophenyl)pyrrolidin-2-one (11 c), the substrate
became less reactive. Little or no product formation could be
observed in either AcOH or THF. This behavior, which contrasts
with that observed for phenylpyridines, may be explained by
the coordinating nature of THF. This solvent did not affect the
Scheme 2. Evaluation of other halogenation agents and different directing
groups. Unless otherwise specified, experiments were carried out under an
air atmosphere, on a 0.1 mmol scale, using 3 mL of solvent. Conversions
were monitored by H NMR spectroscopy. Isolated yields are reported in pa-
rentheses. DG=directing group. [a] MOF decomposition leading to a homo-
1
geneous reaction mixture; [b] 18% oxidation to indole-type byproducts;
[
c] 14% oxidation to indole-type byproducts.
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Figure 3. Selectivity in the functionalization of N-(3-bromophenyl)pyrrolidin-
2-one (11 c). Experiments were carried out under an air atmosphere, on
a 0.1 mmol scale, using 3 mL of solvent. Conversions were monitored by
1
H NMR spectroscopy. [a] 2.3 equiv NBS was used. At 508C, a ratio of 73:27:0
was recorded. [b] 0.5 equiv PTSA and 3.0 equiv NCS were used. No conver-
sion was recorded in AcOH at 508C.
Scheme 3. meta-Substituted substrates 11 a–c (top); synthesis of products
2a-I to 12c-I (bottom). Unless otherwise specified, all experiments were
1
carried out under an air atmosphere, on a 0.1 mmol scale, using 3 mL of sol-
1
vent. Conversions were monitored by H NMR spectroscopy. Isolated yields
in parentheses. [a] 2.3 equiv NIS was used. [b] Low isolated yield of 12b-I
due to difficult separation from remaining starting material; [c] 0.5 equiv
PTSA and 3.0 equiv NIS were used. Only 17% conversion in AcOH at 508C.
DG=directing group.
Figure 4. Synthesis of diiodinated, meta-substituted products 14a-I to 14c-I.
Experiments were carried out under an air atmosphere, on a 0.1 mmol scale,
1
using 3 mL of solvent. Conversions were monitored by H NMR spectrosco-
py. Isolated yields in parentheses. [a] 0.5 equiv PTSA and 3.0 equiv NIS were
used. [b] 0.5 equiv PTSA and 3.5 equiv NIS were used.
reactivity of the strongly coordinating pyridines, but it can
compete with the less strongly coordinating amides and lac-
tams, disrupting their directing ability. Gratifyingly, when the
solvent was replaced with DCE, a non-coordinating solvent,
the function of the directing group was restored, and product
14a-I in excellent yield in THF at 808C in only 5 h (Figure 4,
top). We tested N-(3-chlorophenyl)acetamide (11 b), and a di-
functionalized product (14b-I) was also obtained here. Howev-
er, upon closer inspection, we found that in this case the inser-
tion of the second iodine atom took place in an undirected
fashion at the para position (Figure 4, middle). This was further
confirmed in a control experiment performed in the absence
of palladium, which afforded similar yields of the product. Fi-
nally, in the case of 11 c, a diiodinated product was not ob-
served under any of the conditions tested (Figure 4, bottom).
Observing the different preferences in substitution patterns
for different halogen atoms, we attempted to illustrate the util-
ity of this protocol by synthesizing a polyhalogenated amine
product 16, which is a highly valuable synthetic intermediate.
Each one of the four different anchors present on the aromatic
ring can be selectively targeted in order to access an immense
variety of functionalized molecules. After the initial directed io-
dination step catalyzed by Pd@MOF, product 12b-I was bromi-
nated under similar conditions in the absence of a Pd catalyst.
A mixture of regioisomers 15 and 15’ was obtained in a ratio
1
2c-I was obtained quantitatively at 658C.
Intrigued by this behavior, we attempted the corresponding
bromination of N-(3-bromophenyl)pyrrolidin-2-one (11 c).
Indeed, the smaller and more reactive Br atom could access
and functionalize both of the CÀH bonds ortho to the directing
lactam group (Figure 3, top). At 508C in AcOH, full conversion
was recorded within 4 h, but both regioisomers 12c-Br and
1
3c-Br were present in the reaction mixture in a ratio of ap-
proximately 2.7:1. When the temperature was decreased to
08C, the bromination could still be carried out efficiently, al-
though 6 h were necessary for full conversion to be achieved
Figure 3, top). However, the selectivity was only slightly im-
4
(
proved. Similarly, a mixture of the two chlorinated regioiso-
mers was obtained when NCS was used, and slightly harsher
conditions were required (Figure 3, bottom).
By a strategy similar to that described above (Section 3), we
attempted to switch the selectivity towards the formation of
diiodinated products. This approach proved suitable for sub-
strate 11 a, which gave 2-(2,6-diiodo-3-methylphenyl)pyridine
Chem. Eur. J. 2016, 22, 3729 – 3737
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was found to be slightly higher than expected for both of the
catalysts. This is due to small amounts of Pd that are inevitably
present on the surface of the MOFs (Table 2, entries 1 and 6).
During further runs leaching was kept to a minimum in the
case of the Cr-MOF (cat. 1), which could easily withstand the
change of reaction solvent between the iodination (i.e., 658C,
PTSA, DCE; Table 2 entries 2 and 5) and bromination conditions
(
i.e., 408C, AcOH; entries 3 and 4).
The Fe MOF (cat. 2) was also stable under the iodination
conditions (Table 2, entry 7). However, when the solvent was
switched to AcOH for the bromination reaction, the Pd leach-
ing increased despite the reaction being run at a lower tem-
perature (entries 8 and 9). Interestingly, when the conditions
were reverted to the iodination protocol, the MOF was capable
of regaining control over the Pd leaching (entry 10). Despite
the loss of small amounts of Pd during runs 3 and 4, the cata-
lyst was still active, and full conversion was obtained in all
runs. This behavior suggests that the Fe framework is not de-
stroyed during the reaction, but that it is less effective at pro-
tecting Pd nanoparticles in the presence of polar solvents. In
Scheme 4. Synthetic route to multifunctionalized amine 16. [a] Experiment
carried out on a 0.1 mmol scale under an Ar atmosphere. 2 equiv Zircono-
cene chloride hydride and 1 mL THF were used.
of 5:3 (Scheme 4). The major
component (15) was isolated
and subjected to a mild diacetyl-
ation reaction using Schwartz re-
Table 2. Recyclability of Pd@MOF catalysts.
[
21]
agent,
which gave the poly-
halogenated amine 16 in a very
high isolated yield. The experi-
ments described in this section
demonstrate the wide applicabil-
ity of our protocol for selective
CÀH activation/halogenation re-
actions using Pd@MOF catalysts.
Entry
Catalyst
cat. 1
Conditions
Run
X
Conv. [%] Pd leaching [ppm]
[a]
[a]
[b]
1
2
3
4
5
for X=I:
658C, 6 h
2.5 equiv NIS,
0.5 equiv PTSA, DCE
or
1
2
3
4
5
I
I
Br
Br
I
>99%
>99%
98%
0.5
0.1
0.3
0.2
0.3
[b]
[a]
97%
>99%
6. Recyclability
We studied the stability of the
catalysts upon repeated recy-
cling, under the conditions de-
scribed above (Section 5). N-(3-
Bromophenyl)pyrrolidin-2-one
[
[
a]
a]
6
7
8
9
cat. 2:
1
2
3
4
5
I
I
Br
Br
I
>99%
>99%
>99%
>99%
>99%
1.5
0.3
5.0
6.7
0.9
for X=Br:
408C 6 h
2.5 equiv NBS, AcOH
[b]
[
b]
a]
[
10
(
11 c) was chosen as a model
substrate, using Pd@MIL-101-
NH (Cr) (cat. 1) and Pd@MIL-88B-
2
NH (Fe) (cat. 2) in
a parallel
2
[
a] Selective formation of 11 c-I; [b] Mixture of products 11 c-Br and 12c-Br formed.
study. The two catalysts were
subjected to iodination and bro-
mination reactions alternatively
to test their ability to withstand changes in the reaction envi-
ronment. The results are described below in Table 2. The de-
tailed procedure is available in the Supporting Information
this situation, the different behaviors of the two materials (en-
tries 3 and 4 for cat. 1 vs. entries 8 and 9 for cat. 2) may be ex-
plained by the different structural features of the two MOFs;
cages (MIL-101) are more suitable for protecting Pd nanoparti-
cles than channels (MIL-88B). Additionally, Cr-MOFs are in gen-
(
Section S5).
Both MOFs were capable of giving full conversion for several
[
22]
runs. Since in the presence of coordinating directing groups,
some metal leaching can be expected, the Pd content in the
reaction solution was measured after each run by ICP-OES
analysis. In the first run, the amount of Pd in the supernatant
eral more stable than Fe-MOFs.
XRPD analysis of the recycled catalysts revealed changes in
the crystallinity of the materials. Pd@MIL-88B-NH (Fe) remained
2
crystalline after catalysis, with the peaks in the XRPD pattern
Chem. Eur. J. 2016, 22, 3729 – 3737
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shifting to lower 2q angles, which suggests an expansion of
Conclusion
the framework. In contrast, most of the peaks in the XRPD pat-
tern of Pd@MIL-101-NH (Cr) after catalysis had disappeared, in-
We present in detail the development of one of the first effi-
cient and highly selective heterogeneous procedures for CÀH
activation/halogenation reactions. For this purpose we also
report the facile synthesis of a catalyst based on a benign and
2
dicating loss of long-range order (see the Supporting Informa-
tion, Figure S8).
The recycled materials were also studied by TEM. In both
cases, significant agglomeration of Pd could be observed on
the surface of the MOF crystals (see the Supporting Informa-
tion, Figures S11 and S12). The aggregated Pd nanoparticles
suggest that a rapid leaching–redeposition mechanism could
be predominant. This hypothesis was supported by additional
hot filtration experiments (Supporting Information, Figures S13
and S14), which are consistent with the results of the recycling
study. Thus, in the case of 2-phenylpyridine (1), which is a non-
recyclable substrate, a hot-filtration test from AcOH at 508C
led to just a partial inhibition of the reaction rate and a moder-
ate yield could still be achieved. In contrast, under identical
conditions (AcOH, 508C) a hot-filtration experiment performed
for a substrate bearing an amide directing group (11 b), led to
a nearly complete inhibition of the reaction. This result sug-
gests that the rate of the redeposition process is strongly influ-
enced by the coordinating strength of the directing group and
is consistent with the behavior observed during recycling stud-
ies (see the Supporting Information, Section S5.4). A weaker
coordinating directing group leads to a much faster redeposi-
tion process, which in turn makes the recycling of the catalyst
robust Fe MOF, namely Pd@MIL-88B-NH (Fe). This composite
2
material together with the well-known Pd@MIL-101-NH (Cr)
2
were used to catalyze the directed CÀH halogenation of
a wide range of aromatic substrates. Both Pd@MOF catalysts
perform remarkably well. Excellent conversions can be achiev-
ed under very mild conditions, and the selectivity between
mono- and dihalogenated products can be fully controlled.
The catalysts show high versatility, tolerating various halogen
sources, directing groups, and different reaction conditions. In
most cases, the Fe MOF and Cr MOF give similar results and
show similar catalytic activity, which demonstrates that robust
heterogeneous procedures can also be developed using less
harmful materials. The MOFs can also be recycled, maintaining
their activity for several runs.
Experimental Section
Procedure for the monohalogenation experiments
Typically, in a 10 mL vial the starting material (0.1 mmol), NXS
(
2.3 equiv; X=I, 52 mg; X=Br, 41 mg or X=Cl, 31 mg) and
possible. N2 sorption isotherms of Pd@MIL-101-NH (Cr) after
2
Pd@MOF (4 mol% Pd) (5.0 mg of 8.40 wt%-Pd@MIL-101-NH (Cr) or
2
catalysis revealed that the material was still porous, although
3
.7 mg of 11.46 wt%-Pd@MIL-88B-NH (Fe)) were added together
2
2
À1
the BET surface area and pore volume were now 332 m g
with a magnetic stirring bar. AcOH (3 mL glacial) was added, and
the vial was sealed with a lid and stirred vigorously at 508C. The
progress of the reaction was monitored until completion by regu-
3
À1
and 0.20 cm g (see the Supporting Information, Figure S9).
We anticipated that the MOFs could undergo halogenation
during catalysis, therefore, in a separate experiment, Pd@MIL-
1
lar sampling followed by GC or H NMR analysis.
8
8B-NH (Fe) (cat. 2) was subjected to three consecutive iodina-
2
tion runs (i.e. under the reaction conditions shown in Table 2
but in the absence of the substrate). The material was then
thoroughly washed, dried, and subsequently digested for anal-
Procedure for the dihalogenation experiments
Typically, in a 10 mL vial the starting material (0.1 mmol), NXS
(
3.0 equiv; X=I, 68 mg; X=Br, 54 mg or X=Cl, 40 mg), PTSA
1
ysis. H NMR analysis of the digested MOF revealed incorpora-
monohydrate (0.5 equiv, 9.5 mg) and 4 mol% Pd cat. (5.0 mg
tion of one iodine atom into 68% of the linker molecules (see
the Supporting Information, Section S5 for a detailed proce-
dure of the digestion experiments). As a control experiment,
we also subjected dimethyl aminoterephthalate to the to the
same conditions and observed that a full conversion into di-
methyl 2-iodoaminoterephthalate was obtained after 12 h.
8.40 wt% Pd@MIL-101-NH (Cr) or 3.7 mg 11.46 wt% Pd@MIL-88B-
NH (Fe)) were added together with a magnetic stirring bar. THF or
2
2
DCE (3 mL) was added, and the vial was sealed with a lid and
stirred vigorously at 808C. The progress of the reaction was moni-
tored until completion by regular sampling followed by GC or
1
H NMR analysis.
Pd@MIL-101-NH (Cr) is a rigid MOF and iodination of the
2
For isolation or recycling purposes, the reactions were scaled up to
framework seems to result in partial collapse of the framework,
whereas introduction of iodine into the linker of Pd@MIL-88B-
0
.4 mmol of starting material. The crude reaction mixture was ex-
tracted in an appropriate organic solvent (EtOAc or CHCl depend-
3
NH (Fe) leads to a swelling of the flexible MOF structure to ac-
ing on the solubility of the product) and washed with brine. The
2
commodate the bulky iodine group. This is consistent with ob-
servations by Serre and co-workers who showed that function-
alization of the linker in MIL-88B(Fe) with halogen atoms (Cl, Br
organic phase was separated, dried over MgSO , and the volatiles
4
were evaporated under reduced pressure. The solid residue was
purified by column chromatography. Mixtures of petroleum ether/
EtOAc were used as the standard mobile phase but in cases of in-
[
19]
and F) led to expansion of the respective frameworks. This
highlights the benefit of using a flexible MOF as an advanced
catalytic material. The halogenation of the framework linkers
sufficient solubility, CHCl was added as a coeluent.
3
also explains the need for an excess of halogenating agent in Acknowledgements
the catalytic tests. Fortunately, halogenation of the Pd@MOF
composites does not reduce their catalytic properties.
This project was supported by the Swedish Governmental
Agency for Innovation Systems (VINNOVA) and AstraZeneca
Chem. Eur. J. 2016, 22, 3729 – 3737
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Full Paper
through the Berzelii Center EXSELENT, by the Swedish Research
Council (VR), the MATsynCELL project through the Rçntgen
1085; d) N. Schrçder, F. Lied, F. Glorius, J. Am. Chem. Soc. 2015, 137,
1448–1451.
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Published online on October 20, 2015
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3737
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim