Water-Tolerant and Atom Economical Amide Bond Formation by Metal-Substituted Polyoxometalate Catalysts

Article abstract of DOI:10.1021/acscatal.9b03415

A simple, safe, and inexpensive amide bond formation directly from nonactivated carboxylic acids and free amines is presented in this work. Readily available Zr(IV)- and Hf(IV)-substituted polyoxometalates (POM) are shown to be catalysts for the amide bond formation reaction under mild conditions, low catalyst loading, and without the use of water scavengers, dry solvents, additives for facilitating the amine attack, or specialized experimental setups commonly employed to remove water. Detailed mechanistic investigations revealed the key role of POM scaffolds which act as inorganic ligands to protect Zr(IV) and Hf(IV) Lewis acidic metals against hydrolysis and preserve their catalytic activity in amide bond formation reactions. The catalysts are compatible with a range of functional groups and heterocycles useful for medicinal, agrochemical, and material chemists. The robustness of the Lewis acid-POM complexes is further supported by the catalyst reuse without loss of activity. This prolific combination of Zr(IV)/Hf(IV) and POMs inaugurates a powerful class of catalysts for the amide bond formation, which overcomes key limitations of previously established Zr(IV)/Hf(IV) salts and boron-based catalysts.

Full text of DOI:10.1021/acscatal.9b03415

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Article
Water Tolerant and Atom Economical Amide Bond
Formation by Metal-Substituted Polyoxometalate Catalysts
Francisco De Azambuja, and Tatjana N. Parac-Vogt
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b03415 • Publication Date (Web): 01 Oct 2019
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Water Tolerant and Atom Economical Amide Bond Formation
by Metal-Substituted Polyoxometalate Catalysts
Francisco de Azambuja and Tatjana N. Parac-Vogt*
Department of Chemistry, KU Leuven, 3001 Leuven, Belgium
*tatjana.vogt@kuleuven.be
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Abstract
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A simple, safe and inexpensive amide bond formation directly from non-activated carboxylic acids and free
amines is presented in this work. Readily available Zr(IV)- and Hf(IV)-substituted polyoxometalates (POM)
are shown to be catalysts for the amide bond formation reaction under mild conditions, low catalyst loading,
and without the use of water scavengers, dry solvents, additives for facilitating the amine attack, or
specialized experimental setups commonly employed to remove water. Detailed mechanistic investigations
revealed the key role of polyoxometalate scaffolds which act as inorganic ligands to protect Zr(IV) and
Hf(IV) Lewis acidic metals against hydrolysis, and preserve their catalytic activity in amide bond formation
reactions. The catalysts are compatible with a range of functional groups and heterocycles useful for
medicinal, agrochemical and material chemists. The robustness of the Lewis acid-polyoxometalate
complexes is further supported by the catalyst reuse without loss of activity. This prolific combination of
Zr(IV)/Hf(IV) and polyoxometalates inaugurates a powerful class of catalysts for the amide bond formation,
which overcomes key limitations of previously established Zr(IV)/Hf(IV) salts and boron based catalysts.
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Keywords
Polyoxometalates, Catalysis, Lewis Acid, Amide bond, Green Chemistry, Atom Economic
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Introduction
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Environmental and economic sustainability in the production of chemicals is a permanent challenge to
process chemists.1 Among many areas of potential improvement, the development of new catalysts and/or
catalytic reactions are the best tools to produce chemicals minimizing waste generation, and decreasing the
energy consumption.2 To overcome these challenges, many heterogeneous and homogeneous catalysts
based on enzymes, metals and/or small organic molecules are intensively researched in industries and
universities around the world. Ideally, catalysts should be stable, inexpensive and widely available materials
able to efficiently convert starting substrates into products without extra additives, and using more simple
experimental protocols. As promising alternatives to meet these challenges, polyoxometalates (POMs),
anionic clusters of early transition metals and oxygen, have been widely explored and/or employed as
catalysts in academic and industrial settings; however, some catalytic manifolds remain scarcely
investigated.3
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The development of new catalysts derived from POMs benefits from their well-defined structure which can
be modified to tune chemical properties such as solubility, acidity and redox potential. POMs basic
structural unit (MOx)n resembles the structure of solids commonly used in heterogeneous catalysis (SiO2,
Al2O3, Ti2O…), providing a rare opportunity to develop (equally or more) efficient metal-oxide based
catalysts bearing advantages of both soluble molecular catalysts and heterogeneous catalytic materials
without the small variations in the catalyst structure often observed among different batches of traditional
heterogeneous catalysts.4 Despite these exciting features, POM-based catalysts are mostly used in
oxidations, reductions and Brønsted acid catalyzed processes while other catalytic modes have been less
investigated.5 In 2006, Malacria, Lacote and Thorimbert demonstrated that lanthanide-substituted
polyoxometalates are catalytically competent Lewis acids in Mannich-like reactions despite being multi-
charged anions, but this groundbreaking concept remained rather underexplored in synthetic chemistry.6
Recently, we expanded the use of such concept by applying Lewis acidic transition-metal substituted POMs
in the selective hydrolysis of peptides,7 proteins8 and other biomolecules.9 The great success in this area
prompted us to further investigate the catalytic activity of the similar Lewis-acid-POM complexes in other
relevant transformations for medicinal and material chemists, such as the formation of amide bonds.
Amide bonds are pivotal structural motifs in biomolecules, drugs and synthetic materials,10 but the synthesis
of amides still faces many challenges.11 From the point of view of sustainable chemical production, the
direct formation of amides from non-activated carboxylic acids and free amines would be ideal because it
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generates only water as a by-product, dramatically limiting the amount of waste generated when traditional
peptide coupling reagents are used.12 However, the high energy barrier hampers the widespread use of this
reaction. Many other option were considered to improve the synthesis of amides, 10, 13 but the catalytic direct
amide bond formation from non-activated carboxylic acids and free amines arguably remains one the most
promising alternatives. Regrettably, it is also among the least developed ones.11a, 14 Considering the
limitations still observed in this area, we set out to examine if the transition-metal-substituted POM catalysts
that accelerated the hydrolytic cleavage of peptide bonds could also catalyze their formation upon
appropriate modification of the reaction conditions. Such reversal in the reactivity observed would be
possible if the water could be replaced by an organic solvent shifting the reaction equilibrium toward the
amide bond formation instead of its cleavage. Further, as the catalytic hydrolytic activity was observed in
aqueous medium, we envisaged the POM framework could prevent hydrolysis of the Lewis acidic metal
providing a highly desirable water and air tolerant catalytic reaction. If successful, this approach would
provide a new class of cost effective, potentially recyclable, stable, and readily available catalysts for the
catalytic formation of amide bond.
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Results and Discussion
The metal-substituted POM catalyzed amide bond formation derives from our previous work in the
hydrolysis of peptide bonds in the presence of these complexes.7a The formation of minor amounts of the
2,5-diketopiperazine 2a during the hydrolysis of the glycylglycine (GlyGly) (1a) was indicative that it could
be formed using the same catalytic system upon appropriate manipulation of the reaction conditions. We
started our investigation using this intramolecular reaction to probe the effects of reactions conditions and
catalyst structure in the formation of 2a. Next, we demonstrated the equilibrium shift is not limited only to
GlyGly (1a), and it is compatible with several functional group in either intra- or intermolecular fashion.
Further, a preliminary mechanistic investigation outlined the benefits of combining Lewis acids and POMs
in a single catalytic complex.
Perturbing the equilibrium between GlyGly (1a) and c(GlyGly) (2a). Considering the reversibility of
the amide bond formation reaction in the presence of water,7a we examined how the equilibrium between
1a and 2a would be affected if the water was replaced by other commonly used organic solvents (Scheme
1). Whilst most of the solvents tested resulted in no conversion of 1a, and pure water and acetonitrile/water
mixtures showed a small conversion producing similar amounts hydrolysis and cyclization products of 1a,
dimethylsulfoxide (DMSO) provided a 50% yield of the 2a. Further, no hydrolysis of 1 was observed in
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DMSO, and all the substrate converted was transformed into the desired product (ratio yield/conversion =
100%). These findings motivated further evaluation of related metal-POM complexes in DMSO to improve
the yield of 2a.
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a) Zr:Wells-Dawson POM 2:2 complex is effective to favor 2a
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H
N
O
5 mol% [Zr(2-P2W17)]2
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HN
CO2H
H2N
NH
100%
DMSO
O
O
70 °C, 24 h
1a
2a,
b) Summary of screening observations:
 Solvent: DMSO (50%) >> MeCN:H2O (12%)  H2O >>> MeCN, MeOH, PhMe...
 POM structure: 2-Wells-Dawson (100%) > Keggin (38%) > 1-Wells-Dawson
 Metal: Hf4+ (75%)  Zr4+ (36%); Ni2+, Cu2+, Fe3+, Co2+, Ce3+, Ce4+ not active
 Metal-POM ratio: 2:2 (100%) > 1:2 (40%) > 1:1 (3%)
c) Generic structures of the POM catalysts tested
[M(2-P2W17)]2
2-Wells-Dawson 2:2
[M(2-P2W17)2]
2-Wells-Dawson 1:2
[M(1-P2W17)]
1-Wells-Dawson 1:1
[M(PW11)]2
[M(PW11)2]
Keggin 2:2
Keggin 1:2
Hf / Zr
O
[PO4] [WO6]
Scheme 1: a) Best conditions, b) trends, c) and general structure of the metal-POM complexes tested to
favor the formation of 2a. [Zr(α2-P2W17)]2 = (Me2NH2)14[Zr(µ-O)(H2O)(α2-P2W17O61)]2
The metal, the POM structure and the metal:POM ratio also affected the ratio between 1a and 2a (Scheme
1). Using metal-Wells-Dawson POM complexes with the ratio metal:POM = 1:2 in DMSO, only Zr4+ and
Hf4+ formed 2 (40% and 75% of yield, respectively), while Fe3+, Ni2+, Co2+, Cu2+, Ce3+ and Ce4+-substituted
POMs did not provide product 2. The change in POM structure from α2-Wells-Dawson to Keggin or to a
α1-Wells Dawson isomer provided slower conversions of 1a to 2a (28% and 3% of 2a observed,
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respectively). On the other hand, more 2a was formed when a Zr(IV)-Wells-Dawson 2:2 complex was used
instead of the original Zr:POM 1:2 complex. The Zr-Wells-Dawson 2:2 complex completed shifted the
equilibrium, and only 2a was observed after 24 h. Of note, no hydrolysis of 1a was observed in any of these
reactions.
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Other dipeptides and amino acid substrates were also cyclized in the presence of Zr-Wells-Dawson 2:2
complex in DMSO, showing this new lactamization reaction is compatible with challenging substrates
without the need of using protecting groups. (Table 1). To probe the generality of the intramolecular bond
formation observed, other dipeptides were submitted to the same conditions, and the cyclized products were
generally observed in good to excellent yields. Notably, tryptophan, histidine, serine and aspartic acid
containing dipeptides were cyclized without the use of any protecting groups in high yields demonstrating
the excellent compatibility of this catalytic system with (functional) groups widely present in drug
candidates and biomolecules.15 Moreover, the reaction provided similar yields of cyclized products
regardless if Gly-X or X-Gly dipeptides were used as starting materials, even when a secondary amine was
used (Pro-Gly, product 2f). The low yield observed for the Asp-Gly substrate is not fully understood at the
moment but it could be attributed to a preferential coordination of side-chain carboxylic acid group of the
aspartate instead of the one from the glycine moiety generating a stable complex that decreases the catalyst
availability. Further, the cyclization of Phe-Phe (1l) demonstrates the cyclization is not limited to glycine
containing dipeptides, and the formation of 2j,k in excellent yields from non-peptide amino acids shows the
reaction is no limited to the formation of diketopiperazines or products containing six-membered rings. We
isolated products 2b and 2c to check if the substrates epimerized during the reaction, but no change in the
optical purity was detected, highlighting the smoothness of this catalytic reaction (see Supporting
Information for details).
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Table 1. Intramolecular amide bond formation from dipeptides and other amino acid substrates.
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O
R1
R1
HN
[Zr(2-P2W17)]2
H
NH
N
CO2H
H2N
R2
DMSO
O
R2
70 °C, 24 h
O
1b-k
2b-k
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O
O
O
N
Ph
NH
NH
NH
HN
HN
HN
HN
HN
O
O
O
2b
2c
2d
,77%
, 94% (94%)
, 77% (77%)
O
O
O
HO
NH
NH
HO2C
NH
HN
N
HN
O
O
O
2e
2f
2g
from Gly-Ser: 92%
from Ser-Gly: 87%
from Gly-Pro: 76%
from Pro-Gly: 79%
from Gly-Asp: 87%
from Asp-Gly: 34%
O
O
O
Me
NH
Ph
NH
NH
HN
HN
Ph
n
O
O
2h
2i
2j
2k
, 38%
n = 1, >99%
n = 2, >99%
from Gly-Ala: 95%
from Ala-Gly: 89%
Conditions: 1b-k (0.100 – 0.500 mmol), 5.0 mol% [Zr(α2-P2W17O61)]2, DMSO (0.10 mol L-1), 70 °C, 24 h.
1H NMR yields (isolated yields). [Zr(α2-P2W17O61)]2 = (Me2NH2)14[Zr(µ-O)(H2O)(α2-P2W17O61)]2
Intermolecular amide bond formation. The successful conversion of the dipeptide hydrolysis reaction
into an intramolecular amide bond formation reaction under smooth and open-flask conditions prompted us
to investigate the analogous intermolecular coupling. Using phenylacetic acid (3a) and benzylamine (4a) as
model substrates, an optimization based on the intramolecular reaction conditions was carried out, and the
new conditions afforded amide products in good to excellent yields without the use of water scavengers,
dry solvents or any other additives. As observed for the intramolecular reaction, the POM structure was
found to be essential to the catalytic activity, but also the reaction concentration, and the stoichiometry
between the amine and the acid were important.
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Initial screening of the POM structure and the metal:POM ratio showed that metal-Wells-Dawson POM 2:2
complexes were superior catalysts, but only moderate yields of the desired product were observed.
Employing Zr(IV) as the metal, Wells-Dawson and Keggin POM complexes with the ratio metal:POM 1:2
provided the desired product in 14% and 10%, respectively. Changing the ratio metal:POM from 1:2 to 2:2
slightly increased the yields to 29% for the Wells-Dawson complex and 16% for the Keggin complex.
Previously, metal complexes of α1-Wells-Dawson lacunary POMs complex were suggested to be better
Lewis acids,6b but a Zr:[α1-Wells-Dawson] 1:1 complex was ineffective for the formation of the amide 5
(8% yield). While small improvements were obtained using different POM structures, better yields were
observed when Zr(IV) was replaced with Hf(IV) in the metal:POM 2:2 complex. In this case, the desired
product was obtained in 47% yield (Table S3 of Supporting Information).
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Increasing of reaction concentration improved the yield of the desired amide product 5 (Scheme 2). To
perturb the equilibrium coordination of the substrates to the catalyst and tune their concentration nearby the
catalytic active site, different reaction concentrations were evaluated. Using the Hf(IV)-Wells-Dawson
POM 2:2 complex, we varied the reaction concentration from 0.10 mol L-1 to 3.33 mol L-1. A direct
correlation between the concentration and the yield was observed, and 5 was formed in 99% yield at the
highest concentration (3.33 mol L-1). Remarkably, at this highest concentration, the catalyst loading can be
reduced to as low as 0.25 mol% without affecting the yield (Table S6 of Supporting Information). The same
trend was observed for the analogous Zr(IV)-Wells-Dawson 2:2 complex, and this catalyst afforded the
desired product 5 in 82% yield at 1.67 mol L-1 concentration (Table S4 of Supporting Information).
O
[Hf(2-P2W17O61)]2
+
Ph
Ph
CO2H
3a
H2N
Ph
N
Ph
DMSO, 70 °C
H
4a
5
(1.2 equiv.)
Conc. (mol L-1)
0.10
0.20
20
0.42
41
0.83
70
1.67
88
3.33
99
12
5
Yield (%)
Scheme 2. Yield of 5 improves upon increasing reaction concentration Conditions: 3a (0.500 mmol), 4a
(1.2 equiv.), 1.0 mol% [Hf(α2-P2W17O61)]2, DMSO (0.15 – 5.0 mL), 70 °C. [Hf(α2-P2W17O61)]2 =
(Me2NH2)14[Hf(µ-O)(H2O)(α2-P2W17O61)]2
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Considering the excellent yield of amide product 5 observed upon increasing reaction concentration, we
briefly probed the scope of the transformation regarding different amines and carboxylic acids (Table 2).
Primary aliphatic amines efficiently provided the desired amides in good to excellent yields, even bearing
electron-donating or withdrawing groups (5, 6 – 10). The reaction showed sensitivity to steric hindrance
and an increase in the temperature and amine equivalents were needed to achieve good yields with ortho-
substituted benzyl amines (7 – 8) and α-methyl benzylamine (9). Remarkably, the reaction is compatible
with fully unprotected tryptamine providing the desired product 10 in 70% yield. Moreover, 1-
methylpiperazine, i.e., a secondary amine, provided product 11 in 75% yield. Several carboxylic acid
substrates were also efficiently converted to the desired amide products. Products 12 and 13 with extra
substituents at the carbon α were formed in 44% and 79% yield, respectively. The benzyl p-nitrobenzamide
14 was obtained in 95% yield showcasing the compatibility of benzoic acid derivatives. In addition, the
catalyst showed exceptional compatibility with N, S and O-heterocycles. The pyridine-containing nicotinic
acid, a valuable moiety in drug discovery, afforded the desired amide 15 in quantitative yield. Moreover,
the electro-rich and prone to oxidation furan and thiophene substrates were not affected by the well-known
oxidative properties of the POM framework, and the products were obtained high yields without any special
care (16 – 17).5d Similarly, the reaction was also suitable for the formation of amide bonds with Boc-
protected amino acids in excellent yields (18 and 19). Of note, most of the products could be isolated by a
simple acid-base extraction in satisfactory purity to further transformations (>90%) due to the clean reaction
conditions containing only the reactants and a small amount of catalyst, highlighting the simplicity of the
method. The effectiveness of the metal-POM catalyst was also evident from the gram-scale reaction using
41.2 mmol of the acid 3a, in which 8.37 g of amide 5 were produced from a single experiment, without any
modification to the experimental procedure (Scheme 3). The efficiency of this catalyst was further
evidenced by its low Product Mass Intensity16 (PMI) compared to conventional amide coupling reactions
(see Supporting Information for details).11b
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Table 2. Intermolecular bond formation from free amines and non-activated carboxylic acids
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O
[Hf(2-P2W17O61)]2
R2
CO2H
R2
+
R1
H2N
R1
N
DMSO, 70 °C
H
3a-i
4a-g
5-19
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17
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O
O
Cl
O
Ph
Ph
Ph
N
N
H
N
H
Ph
H
Cl
5
6
7
71% (98%)
58% (69%)
71% (92%)
@90 °C
O
OMe
O
Me
NH
O
Ph
Ph
Ph
N
H
N
H
N
H
8
9
10
59% (96%)
@90 °C
88%
@90 °C
70% (81%)
O
N
O
O
N
Ph
Ph
Me
Me
N
H
Ph
Ph
H
N
Ph
12
Me
Me
11
13
, 75%
, 44%
@90 °C
, 79%
@90 °C
O
O
O
O
N
H
Ph
N
Ph
N
H
Ph
H
O2N
N
14
17
15
16
@90 °C
, 95%
, >99%
, 78%
Ph
O
O
H
N
Ph
N
H
Ph
BocHN
BocHN
NH Ph
, 90%
S
O
18
19
, 86%
, 90%
@90 °C
Conditions: 3a-i (0.500 mmol), 4a-g (1.2 – 2.0 equiv.), 1.0 mol% [Hf(α2-P2W17O61)]2, DMSO (0.15 mL),
70 – 90 °C. Isolated yields (crude yields with purity >90%). [Hf(α2-P2W17O61)]2 = (Me2NH2)14[Hf(µ-
O)(H2O)(α2-P2W17O61)]2
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10
0.5 mol%
[Hf(2-P2W17O61)]2
O
+
Ph
Ph
CO2H
3a
H2N
Ph
N
Ph
H
DMSO [3.33M]
70 °C, 24 h
4a
5
(41.2 mmol) (1.2 equiv.)
90% (8.37 g)
PMI
reaction = 3.2
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Scheme 3. Gram-scale synthesis of amide 5 catalyzed by (Me2NH2)14[Hf(µ-O)(H2O)(α2-P2W17O61)]2. PMI
= Product Mass Intensity (see Supporting Information for details)
Mechanistic investigations. The catalytic cycle depicted on Scheme 4 featuring a general Lewis acid
catalysis, is likely the general pathway followed by the reaction, as observed previously in other Zr-
catalyzed amidation reactions17. Based on our previous work,18 we propose a monomeric metal-POM 1:1
complex (A) as the catalytically active species in this reaction. This monomeric form A derives from the
solvent and/or amine induced dissociation of the dimeric metal-POM 2:2 complex added to the reaction.
After dissociation, the carboxylic acid binds A at its metal center, and the carboxylate group is activated to
the amine nucleophilic attack, which forms key tetrahedral intermediate C. At this point, it is not clear if
amine attack occurs through an inner or outer sphere mechanism in the intermolecular reactions. In contrast
to the previous proposals,17 the high concentration of the intermolecular reaction and the concomitant
availability of coordination sites at the metal could indicate that an inner sphere C–N bond formation event
is favored. This is also consistent with our previous studies on the dipeptide hydrolysis where the dipeptide
coordination through both the amine and carboxylate groups were necessary to enable water attack.7a, 18 At
last, release of water from C leads to product formation, and regenerates the catalyst. The catalyst tolerance
to the water formed in the last step of the reaction is attributed to the increased resistance of the metal center
to hydrolytic decomposition when complexed to the POM framework. This proposed pathway and the water
tolerance observed are consistent with the trends observed during reaction development, and several
mechanistic experiments, such as control reactions, kinetic experiments, and 31P NMR investigations
conducted using the intermolecular reaction between 3a and 4a as a model.
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S
H
O
M
M
O
H
S
S = DMSO
7
8
R2NH
9
DMSO
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O
O
R
(HNR2)n
Sn
+ H2O
R'
N
R
2
M
HO
R'
+ H+
– H+
A
R2NH
O
H
R'
O
O
M
R'
NR2
M
O
R2
inner sphere
attack
N
H
R2
C
B
outer sphere
attack
R2NH
Catalyst structure
OH2
H
O
M
M
=
O
H
OH2
[{M(-OH)(H2O)(2-P2W17O61)}2]14–
Hf / Zr
O
[PO4] [WO6]
Scheme 4. Metal-POM complex catalyzed amidation reaction likely follows a general Lewis acid catalysis
pathway
Control experiments. The combination of POM with the Lewis acidic metal in a single complex is essential
to promote the amide bond formation in good yields. Using zirconium as a representative metal, we probed
the catalytic activity of the different components of the catalyst (Table 3, and Tables S9 and S10 of
Supporting Information). In the absence of any catalyst or in the presence of monomeric tungstates (Li2WO4
and Na2WO4) or the lacunary POM (K7P2W17O61) minimal yields were observed. On the other hand, the
Lewis acidity of Zr(IV) salts alone led to the formation of both intra- and intermolecular amide bonds with
limited efficiency as shown by the control experiments done with diverse Zr(IV) salts (Table S10 of
Supporting Information). A potential mechanism involving the lixiviation of the Zr(IV) metal from the POM
framework was disfavored by the low yield of 5 observed when ZrCl4 and K7P2W17O61 were used together.
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Thus, the synergistic actuation of the Zr(IV) Lewis acid and the POM framework in a single compound was
pivotal to the catalytic activity observed.
5
6
7
Table 3. Synergistic combination of Lewis acid and POM framework is evidenced by control experiments
8
9
CO2H
O
O
1–5 mol% Cat.
DMSO, 70 °C
HN
or
Ph
N
Ph
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NH
O
H
NH2
2a
5
2a
5
Catalyst
no catalyst
Yield
(%)
Yield (%)
0%
0%
3%
Li2WO4 or Na2WO4
---
K7(P2W17O61
ZrCl4
)
0%
5%
32%
---
27%
26%
82%
ZrCl4 + K7(P2W17O61
)
[Zr(2-P2W17O61)]2
99%
Behavior of the metal-POM catalyst in solution. The behavior of the metal-POM 2:2 complexes in solution
is influenced by the concentration, and the presence of substrates as evidenced by 31P NMR. Using DMSO
solutions of metal-POM complexes reproducing the same nominal concentrations of catalyst used in the
reactions, e.g., a solution of 0.02 mmol of metal-POM 2:2 complex in 0.60 mL of DMSO reproduces the
reaction conducted at a 3.33 mol L-1 concentration of 3a (see Supporting Information for details), we
observed a concentration dependent equilibrium between two species for both the Zr(IV)- and Hf(IV)-
Wells-Dawson POM 2:2 complex (Figures S3 and S4 of Supporting Information, respectively). These two
species are likely the monomeric and the dimeric forms of the complexes, based on Le Chatelier’s principle
and previous reports for similar metal-POM systems.18-19 At the highest concentration, the equilibrium
heavily favors the dimeric species. Upon addition of acid or amine substrates (100 equivalents to reproduce
reaction stoichiometry) to the most concentrated solution of Hf-POM complex (0.03 mol L-1 of catalyst),
different species are formed (Figure S5 of Supporting Information). While benzylamine induces the
formation of a monomeric species like the one observed upon dilution, the addition of acid generates a new
species that could be either monomeric or dimeric in nature. As the excess of carboxylic acid substrate
negatively impacts the initial reaction rate (Figure S6 of Supporting Information), this species is presumably
an off-cycle resting state of the catalyst similarly to previously proposed in a similar Zr(IV)-catalyzed
amidation reaction.17b Interestingly, addition of 0.5 equivalent of benzylamine to this acid solution reverted
this species back to the putative monomeric one (Figure S5 of Supporting Information). Considering the
beneficial effect of an excess of amine in the initial rate of reaction (Figure S6 of Supporting Information),
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these equilibria observed for the Hf(IV)-POM in the presence of substrates are consistent with a monomeric
complex, i.e., Hf(IV)-POM 1:1 complex, as the active catalyst.18, 20
5
6
7
8
9
Tolerance to water. The reaction tolerates the addition of water up to 13% of the reaction volume without a
significant decrease in the yield of 5 (Table 4). Early on in the optimization of both the intra- and
intermolecular reactions, we realized the presence of molecular sieves was not improving the yield, in sharp
contrast with the sensitivity to water reported previously in the literature,10, 13 including Zr(IV) and Hf(IV)
catalyzed reactions.17b, 21 To better understand this unique feature, we performed control and kinetic
experiments using external water additions under controlled conditions to evaluate the effect of water in the
product yield and reaction kinetics. The reaction tolerated the addition of water up to 13% of the reaction
volume (a >220 molar excess of water) before a significant drop in the product yield was observed (entries
3 – 4, Table 4), thus explaining why the water formed in the reaction does not affect the yield. The yield
decrease due to the addition of external water might derive from the slower reaction kinetics, as observed
through the initial reaction rates (Figure S7 of Supporting Information), showing the water is tolerated by
the reaction,22 as opposed to being part of the active catalytic species.21b, 23
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Table 4. POM framework preserves the high activity of the catalyst in the presence of up to a >220 molar
excess of water
[Hf(2-P2W17O61)]2
O
(0.005 mmol)
+
Ph
Ph
CO2H
H2N
4a
Ph
N
Ph
H
DMSO [3.33 M], 70 °C
3a
0.5 mmol
5
H2O (table)
(1.2 equiv.)
c
5
H2O (mmol)
0
nH2O / nCat
0
Yield (%)
Entry
>99%
94
1
2
0.55
110
1.11
222
90
3
1.39
278
69
4
1.67
334
71
5
4.17
834
46
6
7b
1.67
334
76
Conditions: 3a (0.500 mmol), 4a (1.2 equiv.), 1.0 mol% [Hf(α2-P2W17O61)]2, DMSO (0.15 mL), 70 °C (GC
a
b
yields). [Hf(α2-P2W17O61)]2 = (Me2NH2)14[Hf(µ-O)(H2O)(α2-P2W17O61)] 0.12 mL DMSO as solvent
(reaction concentration ~3.33 M), c nH2O / nCat = mmol H2O / mmol Catalyst.
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The POM framework likely act as a “molecular shield” to protect the catalytic metal center from the water
formed in the reaction preventing its hydrolysis and stabilizing the catalytic complex against decomposition.
It is well known that Zr(IV) and Hf(IV) salts hydrolyze in aqueous medium to form many species, some of
which are in the form of extended polymeric chains that hinder experimental handling and product
isolation.24 To probe the effect of water in the Hf(IV)-POM 2:2 complex behavior in DMSO, stepwise
addition of water was done to the most concentrated solution of Hf(IV)-POM complex (0.03 mol L-1 of
catalyst) used in the NMR study (vide supra). Upon gradual addition of water, the putative Hf(IV)-POM 2:2
dimer complex forms a monomeric species similar to what is observed upon addition of benzylamine
(Figure S8 of Supporting Information). However, this water induced dissociation was not observed when
the carboxylic acid and amine substrates were present, thus water is a labile ligand compared to the
substrates, and its influence on the catalyst monomer-dimer equilibrium is probably not relevant for the
reaction outcome (Figure S9 of Supporting Information). On the other side, Zr(IV) and Hf(IV) can
coordinate up to 8 ligands, and the transient coordination of water molecules to the metal center is not
enough to account for the water tolerance observed. The crystallographic structures of the catalyst,25 the
behavior of metal-substituted POM complexes,7a, 18, 20 and the hygroscopic properties of polyoxometalates26
strongly suggest that part of the water is also trapped/adsorbed by the POM through H-bonding/polar
interactions, thus decreasing the amount of water available to interfere with the reaction. Further attempts
to correlate the amount of water with the catalyst loading revealed a non-linear relationship, indicating the
complexity in the equilibria present in solution enabling this ‘shielding effect’. Finally, the POM-conferred
robustness of the catalyst to the water formed in the reaction was further supported by the catalyst recycle
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for three times without a decrease in the reaction efficiency. P NMR analysis of the recovered catalysts
showed the catalyst did not decompose or changed its structure after the reaction, underlining the robustness
of the metal-POM combination (see Supporting Information for details).
Conclusion
In summary, a new class of robust catalysts based on the synergic combination of Zr(IV) or Hf(IV) and
Wells-Dawson POM frameworks for the direct formation of amide bonds from non-activated acids and free
amines are reported. Products bearing a range of functional groups and heterocycles useful for medicinal,
agrochemical and material chemists deriving from intra- and intermolecular reactions were obtained in good
to excellent yields. Remarkably, water scavengers or specialized experimental setups employed to remove
water, dry solvents, additives, and inert atmosphere were not necessary to observe high yields. Moreover,
the catalyst could be recycled without loss of efficiency due to the robustness conferred to the Lewis acid
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by the POM framework. Mechanistic experiments showed the POM framework likely inhibits the hydrolysis
of the Lewis acidic metal by the water formed in the reaction, and a high catalytic activity is obtained even
in the presence of a >220 molar excess of externally added water. This ligand induced robustness without
impacting the reactivity is strikingly different from previous protocols in which the rigorous exclusion of
water was necessary to achieve high conversions. Given the diversity of POMs known, along with its
structural versatility, ready availability and low cost, the water tolerance observed in the amide bond
formation strongly suggests the POMs are promising ligands to develop many other safer, greener and robust
homogeneous catalytic processes.
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AUTHOR INFORMATION
Corresponding Author *E-mail: tatjana.vogt@kuleuven.be
ASSOCIATED CONTENT
Supporting Information. Experimental procedures, supplementary experiments and copy of NMR spectra.
This information is available free of charge on the ACS Publications website.
ACKNOWLEDGMENTS
We thank KU Leuven and Research Foundation Flanders (FWO) for financial support.
REFERENCES:
1.
Rossen, K., Greening Organic Chemistry with Process Chemistry. J. Org. Chem. 2019, 84, 4580-
4582.
2.
a) Sheldon, R. A., E Factors, Green Chemistry and Catalysis: an Odyssey. Chem. Commun. 2008,
3352-3365; b) Sheldon, R. A., Fundamentals of Green Chemistry: Efficiency in Reaction Design. Chem.
Soc. Rev. 2012, 41, 1437-1451.
3.
2.
4.
Kozhevnikov, I., Catalysis by Polyoxometalates. Chichester : Wiley, c2002.: Chichester, 2002; Vol.
Day, V. W.; Klemperer, W. G., Metal Oxide Chemistry in Solution: The Early Transition Metal
Polyoxoanions. Science 1985, 228, 533-541.
16
ACS Paragon Plus Environment

Page 17 of 21
1
ACS Catalysis
2
3
5.
a) Hill, C. L.; Prosser-McCartha, C. M., Homogeneous Catalysis by Transition Metal Oxygen Anion
Clusters. Coord. Chem. Rev. 1995, 143, 407-455; b) Kozhevnikov, I. V., Catalysis by Heteropoly Acids and
Multicomponent Polyoxometalates in Liquid-Phase Reactions. Chem. Rev. 1998, 98, 171-198; c) Mizuno,
N.; Kamata, K.; Yamaguchi, K., Liquid-Phase Selective Oxidation by Multimetallic Active Sites of
Polyoxometalate-Based Molecular Catalysts. In Bifunctional Molecular Catalysis, Ikariya, T.; Shibasaki,
M., Eds. Springer Berlin Heidelberg: Berlin, Heidelberg, 2011; pp 127-160; d) Wang, S.-s.; Yang, G.-y.,
Recent Advances in Polyoxometalate-Catalyzed Reactions. Chem. Rev. 2015, 115, 4893-4962.
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6.
a) Boglio, C.; Lemière, G.; Hasenknopf, B.; Thorimbert, S.; Lacôte, E.; Malacria, M., Lanthanide
Complexes of the Monovacant Dawson Polyoxotungstate [α1-P2W17O61]10− as Selective and Recoverable
Lewis Acid Catalysts. Angew. Chem. Int. Ed. 2006, 45, 3324-3327; b) Dupré, N.; Rémy, P.; Micoine, K.;
Boglio, C.; Thorimbert, S.; Lacôte, E.; Hasenknopf, B.; Malacria, M., Chemoselective Catalysis with
Organosoluble Lewis Acidic Polyoxotungstates. Chem. Eur. J. 2010, 16, 7256-7264.
7.
a) Absillis, G.; Parac-Vogt, T. N., Peptide Bond Hydrolysis Catalyzed by the Wells–Dawson Zr(α2-
P2W17O61)2 Polyoxometalate. Inorg. Chem. 2012, 51, 9902-9910; b) Vanhaecht, S.; Absillis, G.; Parac-
Vogt, T. N., Amino Acid Side Chain Induced Selectivity in the Hydrolysis of Peptides Catalyzed by a
Zr(IV)-Substituted Wells–Dawson Type Polyoxometalate. Dalton Trans. 2013, 42, 15437-15446; c) Ly, H.
G. T.; Absillis, G.; Parac-Vogt, T. N., Influence of the Amino Acid Side Chain on Peptide Bond Hydrolysis
Catalyzed by a Dimeric Zr(IV)-Substituted Keggin Type Polyoxometalate. New J. Chem. 2016, 40, 976-
984; d) Sap, A.; Van Tichelen, L.; Mortier, A.; Proost, P.; Parac-Vogt, T. N., Tuning the Selectivity and
Reactivity of Metal-Substituted Polyoxometalates as Artificial Proteases by Varying the Nature of the
Embedded Lewis Acid Metal Ion. Eur. J. Inorg. Chem. 2016, 2016, 5098-5105.
8.
Ly, H. G. T.; Absillis, G.; Janssens, R.; Proost, P.; Parac-Vogt, T. N., Highly Amino Acid Selective
Hydrolysis of Myoglobin at Aspartate Residues as Promoted by Zirconium(IV)-Substituted
Polyoxometalates. Angew. Chem. Int. Ed. 2015, 54, 7391-7394.
9.
a) Luong, T. K. N.; Govaerts, I.; Robben, J.; Shestakova, P.; Parac-Vogt, T. N., Polyoxometalates
as Artificial Nucleases: Hydrolytic Cleavage of DNA Promoted by a Highly Negatively Charged Zr(IV)-
Substituted Keggin Polyanion. Chem. Commun. 2017, 53, 617-620; b) Van Rompuy, L. S.; Parac-Vogt, T.
N., Polyoxometalates as Sialidase Mimics: Selective and non-Destructive Removal of Sialic Acid from a
Glycoprotein Promoted by Phosphotungstic Acid. Chem. Commun. 2017, 53, 10600-10603.
10.
11.
Pattabiraman, V. R.; Bode, J. W., Rethinking Amide Bond Synthesis. Nature 2011, 480, 471.
a) Wang, X., Challenges and Outlook for Catalytic Direct Amidation Reactions. Nat. Catal. 2019,
2, 98-102; b) Sabatini, M. T.; Boulton, L. T.; Sneddon, H. F.; Sheppard, T. D., A Green Chemistry
Perspective on Catalytic Amide Bond Formation. Nat. Catal. 2019, 2, 10-17.
17
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ACS Catalysis
Page 18 of 21
1
2
3
12.
a) Valeur, E.; Bradley, M., Amide Bond Formation: Beyond the Myth of Coupling Reagents. Chem.
Soc. Rev. 2009, 38, 606-631; b) El-Faham, A.; Albericio, F., Peptide Coupling Reagents, More than a Letter
Soup. Chem. Rev. 2011, 111, 6557-6602; c) Dunetz, J. R.; Magano, J.; Weisenburger, G. A., Large-Scale
Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals. Org. Proc. Res. Dev. 2016,
20, 140-177.
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13.
a) Allen, C. L.; Williams, J. M. J., Metal-Catalysed Approaches to Amide Bond Formation. Chem.
Soc. Rev. 2011, 40, 3405-3415; b) de Figueiredo, R. M.; Suppo, J.-S.; Campagne, J.-M., Nonclassical Routes
for Amide Bond Formation. Chem. Rev. 2016, 116, 12029-12122.
14.
a) Lundberg, H.; Tinnis, F.; Selander, N.; Adolfsson, H., Catalytic Amide Formation from Non-
Activated Carboxylic Acids and Amines. Chem. Soc. Rev. 2014, 43, 2714-2742; b) Noda, H.; Furutachi,
M.; Asada, Y.; Shibasaki, M.; Kumagai, N., Unique Physicochemical and Catalytic Properties Dictated by
the B3NO2 Ring System. Nat. Chem. 2017, 9, 571; c) Sabatini, M. T.; Boulton, L. T.; Sheppard, T. D.,
Borate Esters: Simple Catalysts for the Sustainable Synthesis of Complex Amides. Science Advances 2017,
3, e1701028.
15.
Vitaku, E.; Smith, D. T.; Njardarson, J. T., Analysis of the Structural Diversity, Substitution Patterns,
and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 2014,
57, 10257-10274.
16.
Jimenez-Gonzalez, C.; Ponder, C. S.; Broxterman, Q. B.; Manley, J. B., Using the Right Green
Yardstick: Why Process Mass Intensity Is Used in the Pharmaceutical Industry To Drive More Sustainable
Processes. Org. Proc. Res. Dev. 2011, 15, 912-917.
17.
a) Han, C.; Lee, J. P.; Lobkovsky, E.; Porco, J. A., Catalytic Ester−Amide Exchange Using Group
(IV) Metal Alkoxide−Activator Complexes. J. Am. Chem. Soc. 2005, 127, 10039-10044; b) Lundberg, H.;
Tinnis, F.; Zhang, J.; Algarra, A. G.; Himo, F.; Adolfsson, H., Mechanistic Elucidation of Zirconium-
Catalyzed Direct Amidation. J. Am. Chem. Soc. 2017, 139, 2286-2295.
18.
Mihaylov, T. T.; Ly, H. G. T.; Pierloot, K.; Parac-Vogt, T. N., Molecular Insight from DFT
Computations and Kinetic Measurements into the Steric Factors Influencing Peptide Bond Hydrolysis
Catalyzed by a Dimeric Zr(IV)-Substituted Keggin Type Polyoxometalate. Inorg. Chem. 2016, 55, 9316-
9328.
19.
a) Sadakane, M.; Dickman, M. H.; Pope, M. T., Chiral Polyoxotungstates. 1. Stereoselective
Interaction of Amino Acids with Enantiomers of [CeIII(α1-P2W17O61)(H2O)x]7-. The Structure of dl-
[Ce2(H2O)8(P2W17O61)2]14. Inorg. Chem. 2001, 40, 2715-2719; b) Boglio, C.; Hasenknopf, B.; Lenoble,
G.; Rémy, P.; Gouzerh, P.; Thorimbert, S.; Lacôte, E.; Malacria, M.; Thouvenot, R., Sensing the Chirality
of Dawson Lanthanide Polyoxometalates [α1-LnP2W17O61]7− by Multinuclear NMR Spectroscopy. Chem.
18
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2
3
4
5
Eur. J. 2008, 14, 1532-1540; c) Carabineiro, H.; Villanneau, R.; Carrier, X.; Herson, P.; Lemos, F.; Ramôa
Ribeiro, F.; Proust, A.; Che, M., Zirconium-Substituted Isopolytungstates:ꢀ Structural Models for Zirconia-
Supported Tungsten Catalysts. Inorg. Chem. 2006, 45, 1915-1923.
6
7
8
20.
Luong, T. K. N.; Shestakovaꢀ, P.; Mihaylov, T. T.; Absillis, G.; Pierloot, K.; Parac-Vogt, T. N.,
9
Multinuclear Diffusion NMR Spectroscopy and DFT Modeling: A Powerful Combination for Unraveling
the Mechanism of Phosphoester Bond Hydrolysis Catalyzed by Metal-Substituted Polyoxometalates. Chem.
Eur. J. 2015, 21, 4428-4439.
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21.
a) Lundberg, H.; Tinnis, F.; Adolfsson, H., Direct Amide Coupling of Non-activated Carboxylic
Acids and Amines Catalysed by Zirconium(IV) Chloride. Chem. Eur. J. 2012, 18, 3822-3826; b) Lundberg,
H.; Adolfsson, H., Hafnium-Catalyzed Direct Amide Formation at Room Temperature. ACS Catal. 2015,
5, 3271-3277.
22.
a) Shteinberg, L. Y.; Kondratov, S. A.; Shein, S. M.; Marshalova, V. V., Effect of water on the
kinetics of the catalytic reaction between benzoic acid and aniline. Kinet. Catal. 2007, 48, 632-635; b) Allen,
C. L.; Chhatwal, A. R.; Williams, J. M. J., Direct Amide Formation from Unactivated Carboxylic Acids and
Amines. Chem. Commun. 2012, 48, 666-668; c) Li, N.; Wang, L.; Zhang, L.; Zhao, W.; Qiao, J.; Xu, X.;
Liang, Z., Air-stable Bis(pentamethylcyclopentadienyl) Zirconium Perfluorooctanesulfonate as an Efficient
and Recyclable Catalyst for the Synthesis of N-substituted Amides. ChemCatChem 2018, 10, 3532-3538;
d) Lundberg, H.; Tinnis, F.; Adolfsson, H., Zirconium Catalyzed Amide Formation Without Water
Scavenging. Appl. Organomet. Chem. 2019, 33, e5062.
23.
Gernigon, N.; Al-Zoubi, R. M.; Hall, D. G., Direct Amidation of Carboxylic Acids Catalyzed by
ortho-Iodo Arylboronic Acids: Catalyst Optimization, Scope, and Preliminary Mechanistic Study
Supporting a Peculiar Halogen Acceleration Effect. J. Org. Chem. 2012, 77, 8386-8400.
24.
a) Johnson, J. S.; Kraus, K. A., Hydrolytic Behavior of Metal Ions. VI. Ultracentrifugation of
Zirconium(IV) and Hafnium(IV); Effect of Acidity on the Degree of Polymerization. J. Am. Chem. Soc.
1956, 78, 3937-3943; b) Singhal, A.; Toth, L. M.; Lin, J. S.; Affholter, K., Zirconium(IV) Tetramer/Octamer
Hydrolysis Equilibrium in Aqueous Hydrochloric Acid Solution. J. Am. Chem. Soc. 1996, 118, 11529-
11534; c) Fang, Z.; Dixon, D. A., Hydrolysis of ZrCl4 and HfCl4: The Initial Steps in the High-Temperature
Oxidation of Metal Chlorides to Produce ZrO2 and HfO2. J. Phys. Chem. 2013, 117, 7459-7474; d) Kalaji,
A.; Skanthakumar, S.; Kanatzidis, M. G.; Mitchell, J. F.; Soderholm, L., Changing Hafnium Speciation in
Aqueous Sulfate Solutions: A High-Energy X-ray Scattering Study. Inorg. Chem. 2014, 53, 6321-6328.
25.
a) Saku, Y.; Sakai, Y.; Nomiya, K., Relation among the 2:2-, 1:1- and 1:2-type complexes of
hafnium(IV)/zirconium(IV) with mono-lacunary α2-Dawson polyoxometalate ligands: Synthesis and
structure of the 2:2-type complexes [{α2-P2W17O61M(μ-OH)(H2O)}2]14− (M=Hf, Zr). Inorg. Chim. Acta
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2010, 363, 967-974; b) Sokolov, M. N.; Izarova, N. V.; Peresypkina, E. V.; Mainichev, D. A.; Fedin, V. P.,
Zirconium and Hafnium Aqua Complexes [(H2O)3M(P2W17O61)]6−: Synthesis, Characterization and
Substitution of Water by Chiral Ligand. Inorg. Chim. Acta 2009, 362, 3756-3762.
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7
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26.
a) Uehara, K.; Nakao, H.; Kawamoto, R.; Hikichi, S.; Mizuno, N., 2D-Grid Layered Pd-Based
9
Cationic Infinite Coordination Polymer/Polyoxometalate Crystal with Hydrophilic Sorption. Inorg. Chem.
2006, 45, 9448-9453; b) Helen, M.; Viswanathan, B.; Murthy, S. S., Synthesis and Characterization of
Composite Membranes Based on α-Zirconium Phosphate and Silicotungstic Acid. J. Membr. Sci. 2007, 292,
98-105; c) Teli, S. B.; Gokavi, G. S.; Sairam, M.; Aminabhavi, T. M., Highly Water Selective Silicotungstic
Acid (H4SiW12O40) Incorporated Novel Sodium Alginate Hybrid Composite Membranes for Pervaporation
Dehydration of Acetic Acid. Sep. Purif. Technol. 2007, 54, 178-186; d) Liu, H.; Xue, N.; Peng, L.; Guo, X.;
Ding, W.; Chen, Y., The Hydrophilic/Hydrophobic Effect of Porous Solid Acid Catalysts on Mixed Liquid
Phase Reaction of Esterification. Catal. Commun. 2009, 10, 1734-1737; e) Chen, J. H.; Zheng, J. Z.; Liu,
Q. L.; Guo, H. X.; Weng, W.; Li, S. X., Pervaporation Dehydration of Acetic Acid Using Polyelectrolytes
Complex (PEC)/11-Phosphotungstic Acid Hydrate (PW11) Hybrid Membrane (PEC/PW11). J. Membr. Sci.
2013, 429, 206-213.
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TOC Figure
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High water tolerance
Lewis acid
+
polyoxometalate
Readily available
Recyclable
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O
Zr(IV)/Hf(IV)-POM
Open-flask
O
H
R2
+
N
R1
N
R2
R2
R1
OH
R2
No dry solvents
No chromatography
Low catalyst loading
No water scavengers
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