Turning on catalysis: Incorporation of a hydrogen-bond-donating squaramide moiety into a Zr metal-organic framework

Article abstract of DOI:10.1021/ja511403t

Herein, we demonstrate that the incorporation of an acidic hydrogen-bond-donating squaramide moiety into a porous UiO-67 metal-organic framework (MOF) derivative leads to dramatic acceleration of the biorelevant Friedel-Crafts reaction between indole and

Full text of DOI:10.1021/ja511403t

Article
pubs.acs.org/JACS
Turning On Catalysis: Incorporation of a Hydrogen-Bond-Donating
Squaramide Moiety into a Zr Metal−Organic Framework
C. Michael McGuirk,† Michael J. Katz,† Charlotte L. Stern,† Amy A. Sarjeant,† Joseph T. Hupp,*,†
Omar K. Farha,*,†,‡ and Chad A. Mirkin*,†
†Department of Chemistry and the International Institute for Nanotechnology, Northwestern University, 2145 Sheridan Road,
Evanston, Illinois 60208-3113, United States
‡Department of Chemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
S
* Supporting Information
ABSTRACT: Herein, we demonstrate that the incorporation of an
acidic hydrogen-bond-donating squaramide moiety into a porous
UiO-67 metal−organic framework (MOF) derivative leads to
dramatic acceleration of the biorelevant Friedel−Crafts reaction
between indole and β-nitrostyrene. In comparison, it is shown that
free squaramide derivatives, not incorporated into MOF
architectures, have no catalytic activity. Additionally, using the
UiO-67 template, we were able to perform a direct comparison of
catalytic activity with that of the less acidic urea-based analogue.
This is the first demonstration of the functionalization of a
heterogeneous framework with an acidic squaramide derivative.
lower nucleophilicity of indole.2,3 Overcoming this synthetic
INTRODUCTION
■
barrier is critical, as tryptamine derivatives containing non-N-
The Friedel−Crafts (F-C) reactions between indole and β-
substituted indole backbones are critical precursors in the
nitroalkenes, such as β-nitrostyrene, are of particular interest, as
synthesis of targeted, biologically active alkaloids (Scheme 1A),
this reaction is currently the most widely used approach for the
such as the amino acid tryptophan,4,5 neurotransmitters (e.g.,
synthesis of tryptamine derivatives (Scheme 1A).1 In contrast
serotonin),6,7 anti-tumor drugs (e.g., lavendamycin),8 and
to F-C reactions between β-nitroalkenes and N-alkylated indole
psychedelic compounds (e.g., psilocybin).9 We thus desire to
derivatives (e.g., 1-methylindole), reactions of unsubstituted
find a novel and robust catalyst toward this central trans-
indole with β-nitroalkenes are slow, due to the significantly
formation. One family of catalysts that have shown activity
toward this pivotal reaction is hydrogen-bond-donating (HBD)
Scheme 1. Friedel−Crafts Reactions (A) between Indole and
β-Nitroalkenes for the Synthesis of Alkaloid Derivatives, and
(B) between Indole and β-Nitrostyrene
organocatalysts.3,10,11
Hydrogen-bond-donating organocatalysts are a unique family
of simple pseudo-Lewis-acidic organic compounds, which are
able to activate electrophilic moieties (e.g., β-nitroalkenes)
toward nucleophilic (e.g., indole) addition via cooperative
hydrogen bonding.12−14 This cooperative hydrogen bonding
has been shown to lower the lowest unoccupied molecular
orbital (LUMO) of the electrophile, thus lowering the
activation barrier for nucleophilic attack.12 Due to this effect,
HBD organocatalyts have proven capable of catalyzing a huge
array of bond-forming transformations, including Strecker
reactions,15 Diels−Alder reactions,16 conjugate additions,17
and F-C reactions (Scheme 1B).18,19 In general, the activity
of HBD organocatalysts toward such transformations increases
as a function of acidity, due to the greater dipole moment
across the HBD moiety (i.e., N−H bonds) and the greater
ability to lower the LUMO of the electrophile (e.g., β-
nitroalkene).20,21 Squaramide-based HBD organocatalysts,
Received: November 5, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ja511403t
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
recently developed by Rawal et al., have been shown to be
approximately 6 orders of magnitude more acidic than their
urea counterparts (Figure 1A).20−22 This drastic difference is
tions of different inorganic nodes and organic linkers have
allowed for the synthesis of a diverse array of MOFs with
applications in gas storage and separation,31−33 biomedicine,34
light harvesting,35,36 and heterogeneous catalysis.37 Due to the
extended 3-D ordered structure of these porous crystalline
structures, novel properties (e.g., lack of self-association) can be
imparted to known organic and inorganic moieties by
incorporation into coordinating struts.38 In many such cases,
these unique properties are either inaccessible or synthetically
challenging in the homogeneous state. For example, Lin et al.
have demonstrated the ability to increase the catalytic activity of
an otherwise self-deactivating iridium−bipyridyl catalyst by 3
orders of magnitude via incorporation into the strut of a
MOF.39 Therefore, we hypothesized that by incorporation into
a MOF system (Figure 1C), we could significantly improve the
activity of a squaramide-based HBD organocatalyst, particularly
toward the otherwise dormant F-C reaction between indole and
β-nitrostyrene (Scheme 1B). Namely, by fixing the squaramide
moiety in a 3-D porous framework, detrimental self-association
(such as that shown schematically in Figure 1B) would be
prevented by the ordered structure, thus catalytic activity would
be “turned-on”. To test our hypotheses, we have synthesized a
mixed strut squaramide-functionalized UiO-67 derivative (UiO-
67-Squar/bpdc) (Scheme 2), and studied the activity of this
system toward the F-C reaction between indole and β-
nitrostyrene to produce 3-(2-nitro-1-phenylethyl)-1H-indole
(see Figure 4A, below). The UiO-67 family was chosen for this
study due to their porosity and thermal and chemical
stability.40,41 Using this system, we were able to study the
effects of heterogenization of the HBD organocatalyst into a
porous MOF architecture, as well as how the superior acidity
and unique structure of squaramide derivatives affects catalytic
activity.24 Specifically, by creating a motif in which we are able
to systematically prevent self-association of HBD organo-
catalysts, we can directly probe and compare the relative activity
of different catalysts, without the additional variable of self-
association. Our results demonstrate that upon incorporation of
a catalytically dormant HBD organic moiety into a porous
MOF architecture, we are able to impose truly significant
catalytic activity toward this pivotal organic transformation.
Additionally, in the absence of self-association, the squaramide-
based HBD organocatalyst produces substantially greater
activity relative to a urea-derived counterpart. Therefore, it is
clear that incorporation into a MOF structure is the ideal
Figure 1. (A) Reported acidities of analogous urea and squaramide
derivatives in DMSO. (B) Idealized self-association pattern of
squaramide derivatives. (C) Idealized structure of squaramide-
functionalized UiO-67 MOF derivative.
due to the potential for resonance stabilization of enhanced
electron density by the partially aromatic squaramide ring.23,24
Consequently, squaramide derivatives have been shown to
greatly accelerate key bond-forming transformations relative to
earlier HBD organocatalysts.25 Although this improved acidity
is a promising advancement in HBD organocatalysis, the strong
hydrogen-bonding nature of the squaramide-based catalysts
also drives catalytically detrimental self-association (Figure
1B);26,27 a similar phenomenon occurs for their urea-based
predecessors (see Supporting Information (SI), Figure
S23).28,29 Therefore, we hypothesized that immobilizing the
very acidic HBD squaramide fragments onto the strut of a
metal−organic framework (MOF) would prevent this self-
association, promote hydrogen-bond-accepting substrate rec-
ognition, and improve catalytic activity (Figure 1C).
MOFs are a widely studied class of porous, crystalline
materials that are composed of inorganic nodes connected by
polytopic organic linkers.30 The enormous potential combina-
Scheme 2. Synthesis of 1:1 Mixed Strut MOF UiO-67-Squar/bpdc
B
DOI: 10.1021/ja511403t
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
1
approach to both improve and study the catalytic activity of a
HBD squaramide moiety. To our knowledge, this is the first
demonstration of the functionalization of a heterogeneous
framework with a HBD squaramide motif.42
formula of UiO-67-Squar/bpdc was determined by H NMR
spectroscopy to be Zr6O4(OH)4(Squar)2(bpdc)2 by digesting
the MOF in the presence of an internal standard (Figure S7
and S8). Importantly, the idealized mixed strut UiO-67 formula
is Zr6O4(OH)4(strutA)3(strutB)3, therefore on average there
are two strut vacancies per formula in UiO-67-Squar/bpdc.
These vacancies can potentially aid in the diffusion of substrates
and products in and out of the framework. Powder X-ray
diffraction (PXRD) of UiO-67 and UiO-67-Squar/bpdc (Figure
3) indicates that the desired 3-D architecture is retained upon
RESULTS AND DISCUSSIONS
■
Synthesis and Characterization. Synthesis of the targeted
HBD squaramide-functionalized strut (H2-Squar, Scheme 2)
was achieved by the Lewis-acid catalyzed condensation of
dimethyl 2-aminobiphenyl-4,4′-dicarboxylate with 3-((3,5-bis-
(trifluoromethyl)phenyl)amino)-4-methoxycyclobut-3-ene-1,2-
dione to form Me2-Squar (See SI for structures of precursors),
followed by an acid-catalyzed saponification to cleanly produce
H2-Squar.43,44 Single crystals of the protected precursor, Me2-
Squar, suitable for X-ray diffraction studies were grown via
recrystallization from hot DMSO (Figure 2). Of note, in the
Figure 3. Powder X-ray diffractograms of simulated UiO-67 (black),
UiO-67 (blue), UiO-67-Squar/bpdc (red), and post-catalysis UiO-67-
Squar/bpdc (green). Peaks at 2θ > 10 have been enhanced by 10× for
clarity. The PXRD patterns of the urea-containing derivatives have
been reported elsewhere.45
incorporation of the squaramide-functionalized linker. Addi-
tionally, N2 isotherms of supercritical CO2-dried samples show
that the MOF materials are porous, having Brunauer−
Emmett−Teller (BET) surface areas of 2500 m2/g (UiO-67)
and 1700 m2/g (UiO-67-Squar/bpdc) (Figure S2).
Figure 2. Solid-state X-ray structure of Me2-Squar. Thermal ellipsoids
are drawn to 50% probability. Solvent is omitted for clarity. C, gray; O,
red; N, blue; F, green; H, white.
Catalysis Studies. With the MOF in hand, we set out to
study the catalytic activity of the squaramide moiety, as well as
the effects of heterogenization into the porous MOF
architecture. Unless otherwise noted, reactions were carried
out at 23 °C in CD2Cl2 at 0.03 M indole and 0.02 M β-
nitrostyrene, with 10 mol% loading of the determined
Zr6O4(OH)4(Squar)2(bpdc)2 formula. The reaction progress
was monitored using 1H NMR spectroscopy. As seen in Figure
4B, UiO-67-Squar/bpdc is capable of achieving approximately
80% yield after 24 h. Conversely, no reaction products were
observed in the absence of the MOF catalyst. Post-catalysis,
UiO-67-Squar/bpdc was isolated via filtration, and PXRD was
performed. Figure 3 (green) shows that the 3-D framework is
preserved. To determine if any product was trapped in the
MOF post-catalysis, a 1H NMR spectrum of thoroughly washed
then digested UiO-67-Squar/bpdc was taken. No product was
solid-state the bis(trifluoromethyl)phenyl group is effectively
coplanar with the squaramide moiety. This conformation is
induced by hydrogen bonding between the squaramide
carbonyl moiety and the ortho C−H bond on the phenyl
substituent, and is known to lower the entropic cost of binding
to a substrate.22 H2-Squar was subsequently incorporated into a
zirconium-cluster-based UiO-67 MOF via a HCl-modulated
preparation, utilizing ZrCl4 as the zirconium source.40 In order
to accommodate the relatively sterically demanding squaramide
motif, and maintain open pores, we utilized a 1:1 molar ratio
mixed-strut approach to the solvothermal synthesis of our UiO-
67 derivative, in which unfunctionalized 4,4′-biphenyldicarbox-
ylate (H2-bpdc) was used in addition to H2-Squar (UiO-67-
Squar/bpdc, Scheme 2).45,46 After digestion of the MOF in
D2SO4 and DMSO, the ratio of H2-bpdc and H2-Squar in UiO-
1
observed. Importantly, this post-catalysis H NMR spectrum
1
67-Squar/bpdc was found to be 1:1 by H NMR spectroscopy
shows that the squaramide moiety is still intact (Figure S20).
Additionally, a recycling experiment was performed (Figure
S19), which showed that UiO-67-Squar/bpdc maintains its
catalytic activity through multiple cycles of catalysis and post-
catalysis isolation. The catalytic activities of multiple different
synthesized batches of UiO-67-Squar/bpdc were tested, and
they demonstrated high consistency and reproducibility, with a
narrow standard deviation after 24 h (Figure 4B).
(see SI). This ratio was found to be consistent throughout
multiple synthesized batches. 13C{1H} NMR spectroscopy also
confirmed the presence of H2-Squar in the synthesized MOF
(Figure S9). Additionally, elemental analysis and 35Cl NMR
spectroscopy were used to determine that no detectable Cl−
(from HCl) was present in the final structure indicating that the
squaramide moiety is not an HCl adduct within the MOF. The
C
DOI: 10.1021/ja511403t
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Table 1. Catalytic Studies for F-C Reaction of Indole and β-
Nitrostyrene
temp
(°C)
time
(h)
yield
(%)
entry
catalyst
solvent
1
none
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
24
24
24
24
24
24
24
24
24
24
24
24
24
24
0
78
38
22
22
19
0
2
UiO-67-Squar/bpdc
UiO-67-Urea/bpdc
UiO-67-Squar
UiO-67
3
4
5
6
UiO-66
a
6
UiO-67 (not SC dried)
Me2-Squar
7
0
b
8
Ethynyl-Squar
0
9
Me2-Urea
0
c
10
11
12
13
UiO-67 + Me2-Squar
21
22
20
0
b,c
UiO-67 + Ethynyl-Squar
b
UiO-67 + Me2-Urea
a
UiO-67 (not SC dried)
Me2-Squar
+
c
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
ZrCl4
DCM
RT
50
24
5
0
74
93
84
95
50
79
33
58
7
UiO-67-Squar/bpdc
UiO-67-Squar/bpdc
UiO-67-Squar/bpdc
1,2-DCB
1,2-DCB
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
ethanol
ethanol
ethanol
ethanol
50
24
5
Figure 4. (A) Reaction conditions for F-C reaction between indole
and β-nitrostyrene. (B) UiO-67-Squar/bpdc (blue) shows drastically
improved catalytic activity over UiO-67-Urea/bpdc (green) and UiO-
67 (red). The MOF-free control shows no detectable yield (black).
Reaction progress was monitored by 1H NMR spectroscopy. Standard
deviation at 24 h determined using multiple synthesized batches of
respective MOFs. Product determined to be racemic by chiral HPLC
(see SI).
50
d
UiO-67-Squar/bpdc
50
24
5
UiO-67-Urea/bpdc
UiO-67-Urea/bpdc
UiO-67
50
50
24
5
50
UiO-67
50
24
24
24
24
5
Me2-Squar
50
Me2-Urea
50
4
none
50
0
In comparison to UiO-67-Squar/bpdc, when squaramide-free
UiO-67 is utilized, only 22% conversion is observed (Figure
4B) over the 24 h period. Unsurprisingly, the Lewis-acidic
zirconium clusters of the MOF are able to accelerate the
transformation.47 To probe the necessity of the mixed-strut
MOF approach to create a viable catalytic system, UiO-67-
Squar was synthesized, in which only the H2-Squar strut was
used. The N2 isotherm of the supercritical CO2-dried UiO-67-
Squar gave a BET surface area (530 m2/g) significantly lower
than UiO-67 and UiO-67-Squar/bpdc. In the presence of UiO-
67-Squar the yield decreased significantly (22% in 24 h) (Table
1, entry 4). This yield is attributed to the reactivity of the
zirconium-based nodes. The drastic decrease in activity may be
due to a combination of detrimental intermolecular hydrogen
bonding of the squaramide moieties and/or the shrinking of
pores of the MOF. Importantly, this result demonstrates that
the mixed-strut approach is critical to the activity of the
squaramide moiety. To activate the squaramide moiety to
catalytic activity, the framework must both alleviate the
detrimental self-associative hydrogen bonding, while also
allowing substrates to access the catalyst. Indeed, the mixed-
strut UiO-67-Squar/bpdc does just that. Additionally, filter tests
performed with both UiO-67-Squar/bpdc and UiO-67
confirmed the heterogeneous nature of the catalysts (Figure
S18). Therefore, by incorporating a HBD squaramide moiety
into a mixed-strut UiO-67 derivative we have created an active
catalytic system with high activity toward the pharmaceutically
relevant F-C reaction between indole and β-nitrostyrene.1
To directly investigate how the alleviation of detrimental self-
association events via the incorporation of the squaramide-
based organocatalysts into a porous MOF architecture affects
catalytic activity for the targeted transformation, the catalytic
activities of MOF-free squaramide derivatives were also
UiO-67-Squar/bpdc
UiO-67-Squar/bpdc
none
RT
RT
RT
RT
RT
50
52
91
0
24
24
24
24
24
24
UiO-67-Squar/bpdc
none
8
0
UiO-67-Squar/bpdc
none
35
2
50
Reactions carried out under conditions detailed in Figure 4A using
deuterated solvents unless noted otherwise. MOF not supercritically
dried during synthesis. See SI for structure. 10 mol% MOF and 10
a
b
c
d
mol% HBD moiety used. Conditions used to scale up to isolate over
1 g of product. Reaction progress was monitored by 1H NMR
spectroscopy.
examined (Table 1). Using the same conditions as above,
Me2-Squar (insoluble in CD2Cl2) and the semi-soluble
squaramide derivative 3-((3,5-bis(trifluoromethyl)phenyl)-
amino)-4-((4-ethynylphenyl)amino)-3-ene-1,2-dione (Ethynyl-
Squar) (See SI for structure) fail to produce any detectable
product after 24 h (Table 1, entries 7, 8). These results confirm
our hypothesis that incorporating squaramide-containing struts
into a MOF architecture prevents catalytically detrimental self-
association. Additionally, the catalytic dormancy of the free
squaramide derivatives emphasizes that via incorporation into
the organized, porous 3-D architecture we are able to “turn-on”
the activity of the squaramide moiety. We further ruled out any
cooperative effects between the UiO-67 framework and the
HBD moieties by performing catalytic studies with mixtures of
unfunctionalized UiO-67 and the free HBD squaramide
catalysts; only the 20% conversion attributed to unfunctional-
ized UiO-67 was observed (Table 1, entries 10, 11).
D
DOI: 10.1021/ja511403t
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Having demonstrated the ability to prevent detrimental self-
association via incorporation into a MOF architecture, we
wanted to use this approach to directly compare the catalytic
activity of two different HBD organocatalysts, namely
squaramide and urea derivatives. In using our design principle,
we are able to isolate the substrate activation ability of a HBD
organocatalyst from its otherwise unavoidable self-associative
behavior. Thus, we can directly probe how the structure of the
catalyst affects activity, without the consideration of inter-
homomolecular hydrogen bonding. Therefore, to probe these
effects, the urea-functionalized strut, H2-Urea, was synthesized,
and then incorporated into the analogous mixed-strut UiO-67
derivative UiO-67-Urea/bpdc (Figure S1).45 The structure was
confirmed by PXRD, and the percent loading was determined
pyrrole and β-nitrostyrene (Figure 5). Indeed, under similar
reaction conditions (room temperature (RT), CD2Cl2) as the
Figure 5. Reaction conditions for F-C reaction between pyrrole and β-
nitrostyrene.
first test reactions, we observe a parallel trend in activity (Table
2). After 24 h, UiO-67-Squar/bpdc gives a 51% yield, whereas
1
by H NMR spectroscopy after digestion. UiO-67-Urea/bpdc
Table 2. Catalytic Studies for F-C Reaction of Pyrrole and β-
a
was found to have a similar 1:1 strut ratio as its squaramide-
containing counterpart, as well as a similar formula,
(Zr6O4(OH)4(Urea)2(bpdc)2), which was used to calculate
the loading of the MOF for catalysis experiments. Under the
same reaction conditions reported above, UiO-67-Urea/bpdc
only produced a 38% yield after 24 h, compared to the
approximately 80% yield achieved by UiO-67-Squar/bpdc
(Figure 4B). Clearly, the unique structure of the squaramide
moiety imparts a greater ability to activate the electrophilic β-
nitrosytrene toward nucleophilic attack by indole. Further
controls, analogous to those run with the squaramide-
derivatives, were performed with the urea-based catalysts.
Even though soluble in CD2Cl2, strut precursor Me2-Urea
shows no detectable product after 24 h (Table 1, entry 9).
Additionally, when the reaction was run in the presence of both
UiO-67 and soluble Me2-Urea, no increase relative to the
unfunctionalized MOF was observed (20% yield) (Table 1,
entry 12). Although soluble, the self-associative behavior of the
urea-derivative likely prevents activity toward the F-C reaction
of β-nitrosytrene and indole.
Nitrostyrene
entry
catalyst
solvent temp (°C) time (h) yield (%)
1
2
3
4
none
DCM
DCM
DCM
DCM
RT
RT
RT
RT
24
24
24
24
0
51
28
8
UiO-67-Squar/bpdc
UiO-67-Urea/bpdc
UiO-67
a
All reactions carried out under conditions detailed in Figure 5 using
1
CD2Cl2. Reaction progress monitored by H NMR spectroscopy.
UiO-67-Urea/bpdc and UiO-67 give 28% and 8% yields,
respectively. Interestingly, although pyrrole is significantly
smaller than indole, the electronic effects of the substrate
seem to dictate the relative yield.
CONCLUSION
■
In summary, through the incorporation of a squaramide-based
HBD organocatalyst into the framework of a mixed-strut UiO-
67 derivative, we have created an efficient, and robust
heterogeneous catalyst for F-C reactions between unsubstituted
indole and a β-nitroalkenes. Importantly, we have demonstrated
that via the incorporation of the self-associative HBD
organocatalyst into a MOF, one can “turn on” novel catalytic
activity not seen in the free organocatalyst. By preventing
detrimental self-association, we are able to maintain the active
state of the organocatalyst, thus promoting activity. This is
noteworthy, as it allows for the exploration of HBD
organocatalysis for many other reactions that are critical for
the synthesis of targeted, bioactive molecules. Additionally, by
creating a framework which occludes the self-association of a
HBD organocatalyst, we were able to make a first of its kind
direct comparison of the catalytic activity of different HBD
moieties. Thus, we have shown that the greater acidity of
squaramides promotes significant rate acceleration relative to
the urea counterpart. Significantly, this first demonstration of
the incorporation of an acidic squaramide derivative into a
MOF will allow for the application of more catalytically active
HBD MOFs to various important transformations. Additional
implications of the incorporation of a strongly HBD motif into
a MOF architecture are in anion sensing, substrate detection,
and gas uptake and separation. For example, a targeted toxic
substrate with electron-rich moieties may be selectively up-
taken and sequestered by such HBD structures. Hence, we have
developed a MOF construct, which demonstrates unique and
significant functionality, as well as opens the doors for many
future applications.
In general, the catalytic efficacy of HBD organocatalysts
improves when catalysis is performed in low-polarity solvents
(e.g., 1,2-dichlorobenzene and toluene) and at higher temper-
atures.48 With low-polarity solvents, the propensity for
disruptive interactions with the catalyst is decreased. Therefore,
catalysis was performed with squaramide-functionalized UiO-
67-Squar/bpdc in 1,2-dichlorobenzene-d4 (ET = 0.225) and
N
toluene-d8 (ETN = 0.099) at 50 °C (ETN for CD2Cl2 = 0.309).49
After 5 h, the reaction was 74% and 84% complete, respectively
(TOF = 4.1 × 10−4 s−1 and 4.6 × 10−4 s−1), with nearly
quantitative conversion after 24 h (Table 1, entries 15−18).
Thus, under these conditions we are able to dramatically
improve the catalytic efficacy of UiO-67-Squar/bpdc, allowing
one to achieve nearly complete conversion of this otherwise
sluggish reaction in just a few hours. Importantly, under these
conditions we see that UiO-67-Squar/bpdc is still significantly
more catalytically active than UiO-67-Urea/bpdc (50% yield
after 5 h, Table 1, entry 19) and UiO-67 (33% yield after 5 h,
Table 1, entry 21). For further comparison of reaction
conditions, catalysis was performed in ethanol-d6 at 50 °C.
After 24 h in polar ethanol-d6 (ET = 0.654) the reaction with
N
UiO-67-Squar/bpdc was only 35% complete (Table 1, entry
31), demonstrating that competitive hydrogen bonding by the
solvent with the catalyst deters activity.
To confirm that the difference in activity between UiO-67-
Squar/bpdc, UiO-67-Urea/bpdc, and UiO-67 is not unique to
the reaction of indole and β-nitrostyrene, we examined our
catalysts’ activity for the analogous F-C reaction between
E
DOI: 10.1021/ja511403t
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Ethynyl-Squar. To an anhydrous mixture of toluene:dimethylfor-
mamide (6:1, 10 mL) were added 3-((3,5-bis(trifluoromethyl)phenyl)-
amino)-4-methoxycyclobut-3-ene-1,2-dione (540 mg, 1.59 mmol) and
zinc trifluoromethanesulfonate (115 mg, 0.32 mmol). The suspension
was stirred vigorously for 10 min at RT. 4-Ethynylaniline was added to
the mixture at once (146 mg, 1.25 mmol). The mixture was heated to
50 °C and stirred for 3 days. The reaction was cooled to RT and
filtered. The retentate was washed with toluene and hexanes. The
retentate was then recrystallized from DMSO. The resulting
precipitate was filtered and washed with DMSO and diethyl ether.
The solid was dried to give a pale yellow/white solid (318 mg, 60%
yield). 1H NMR (400.16 MHz, 25 °C, DMSO-d6): δ 10.37 (br s, 1H),
10.17 (br s, 1H), 8.05 (s, 2H), 7.75 (s, 1H), 7.49 (d, JH−H = 8 Hz, 2H),
7.43 (d, JH−H = 8 Hz, 2H), 4.15 (s, 1H). ESIMS (m/z): 424 [M]−;
found 423.
General Procedure for Synthesis of UiO-67 and Derivatives. All
UiO-67 materials were synthesized using the following general
procedure. An 8-dram vial was loaded with ZrCl4 (67 mg, 0.29
mmol), which was purchased from Aldrich and kept in an Ar(g)
glovebox, one-third of the DMF, and 0.5 mL of HCl before being
sonicated for 20 min until fully dissolved. The mixture of ligands
(Table S1) and the remainder of the DMF were then added, and the
mixture was sonicated an additional 20 min before being heated at 80
°C overnight (bpdc was not completely soluble under these
conditions). For UiO-67, the resulting solid was filtered and washed
first with DMF (2 × 30 mL) and then with EtOH (2 × 30 mL). UiO-
67 was subsequently heated at 90 °C under vacuum until a pressure of
100 mTorr was reached. The samples were then heated to 150 °C
under vacuum for 24 h. For all the other samples, the reaction mixture
was centrifuged and the solvent exchanged for DMF several times in
order to remove any unreacted starting material. Subsequently, the
MOF was soaked in EtOH for 3 days, replacing both at the beginning
and end of the day to ensure complete solvent exchange. Samples were
subsequently dried under supercritical CO2.
EXPERIMENTAL SECTION
■
General Methods. All reactions were carried out under a nitrogen
atmosphere in oven-dried glassware with magnetic stirring unless
otherwise stated. All solvents were purchased from Sigma-Aldrich, and
were degassed with argon and dried using 3 or 4 Å sieves where
appropriate. All reagents were purchased from Aldrich Chemical Co.,
and used as received unless otherwise stated. Dimethyl-2-amino-
biphenyl-4,4′-dicarboxylate was prepared using a slight modification of
the procedure previously reported.43 H2-Urea was prepared as
previously reported.45 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-
methoxycyclobut-3-ene-1,2-dione was prepared as previously re-
ported.44 Deuterated solvents were purchased from Cambridge
1
Isotope Laboratories. For recording H NMR spectra for character-
ization, the solvents were used as received. For catalysis experiments,
the solvents were dried over 3 Å sieves. 1H NMR spectra were
1
recorded on a Bruker Avance III 400 MHz spectrometer. H NMR
spectra were referenced internally to residual protons in the deuterated
solvents (dichloromethane-d2 = δ 5.32 ppm, dimethyl sulfoxide-d6 = δ
2.50 ppm). Data are reported as (s = singlet, d = doublet, t = triplet, q
= quartet, m = multiplet; coupling constant(s); integration).
Electrospray ionization (ESI) mass spectra were recorded on a Bruker
AmaZon SL LC-MS instrument in either positive or negative ion
mode. Samples were sent to Intertek Pharmaceutical Services
(Whitehouse, NJ) for elemental analysis.
Powder X-ray diffraction (PXRD) patterns were collected on a
Bruker AXS APEX2 diffractometer equipped with a CCD detector and
a Cu Kα IμS mircrofocus source with MX optics. Samples were
mounted in nylon cryoloops on a goniometer head. Data was collected
with an area detector as rotation frames over 180° in φ at 2θ values of
12°, 24°, 36°, and 48° and exposed for 10 min for each frame. At a
distance of 150 mm, the detector area covers 24° in 2θ. Powder
pattern data were treated for amorphous background scatter (EVA 16,
Copyright Bruker-AXS 1996−2010).
Supercritical CO2 drying was performed using a Tousimis Samdri
PVT-30 critical point dryer. N2 adsorption and desorption isotherm
measurements were performed on a Micromeritics Tristar II 3020
(Micromeritics, Norcross, GA) at 77 K.
UiO-66. The general procedure for synthesis of UiO-67 was
followed, but replacing bpdc with terephthalic acid (see SI).
ASSOCIATED CONTENT
Synthesis. Me2-Squar. To an anhydrous mixture of toluene:dime-
thylformamide (19:1, 20 mL) were added 3-((3,5-bis-
(trifluoromethyl)phenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione
(1.08 g, 3.18 mmol) and zinc trifluoromethanesulfonate (230 mg, 0.63
mmol). The suspension was stirred vigorously for 10 min at RT.
Dimethyl 2-aminobiphenyl-4,4′-dicarboxylate was added to the
mixture at once (1.00 g, 3.50 mmol). The mixture was heated to
100 °C and stirred overnight. The reaction was cooled to −20 °C and
filtered. The retentate was washed with toluene and hexanes. The solid
was dried to give a yellow solid (980 mg, 52% yield). 1H NMR (400.16
MHz, 25 °C, DMSO-d6): δ 10.19 (br s, 1H), 9.69 (br s, 1H) 8.05 (d,
JH−H = 8 Hz, 2H), 7.94 (d, JH−H = 4 Hz, 2H), 7.86 (m, 2H), 7.71 (d,
JH−H = 8 Hz, 2H), 7.68 (br s, 1H), 7.53 (d, JH−H = 8 Hz, 1H), 3.89 (s,
3H), 3.88 (s, 3H). ESIMS (m/z): 592 [M]+; found 593.
H2-Squar. To 50 mL of acetic acid (99%) was added 800 mg (1.35
mmol) of Me2-Squar, and the mixture was stirred for 5 min at RT. To
the mixture was added 50 mL of H2SO4 (98%). With vigorous stirring,
10 mL of water was added dropwise, in order to maintain one
homogeneous phase. The reaction was stirred at 50 °C for 48 h. The
reaction was cooled to 0 °C, and ice water was added dropwise with
vigorous stirring. Upon cooling, the mixture was filtered over a glass
frit. The retentate was washed with water (3 × 200 mL). The solid
retentate was dried under high vacuum to yield H2-Squar as a yellow
solid (343 mg, 45% yield). 1H NMR (400.16 MHz, 25 °C, DMSO-d6):
δ 10.21 (br s, 1H), 9.66 (br s, 1H), 8.04 (d, JH−H = 8 Hz, 2H), 7.84
(m, 2H), 7.68 (br s, 1H), 7.67 (d, JH−H = 8 Hz, 2H), 7.57 (d, JH−H = 8
Hz, 1H), 7.51 (d, JH−H = 8 Hz, 1H), 7.46 (d, JH−H = 8 Hz, 1H).
13C{1H} NMR (100.6 MHz, 25 °C, DMSO-d6): δ 185.3, 183.0, 167.5,
167.4, 167.1, 167.0, 142.4, 141.9, 137.2, 135.5, 131.5, 130.8, 130.5,
130.1, 129.9, 126.3, 125.6, 122.4, 119.4, 116.0. ESIMS (m/z): 582 [M
+H2O]+; found 583.
■
S
* Supporting Information
Ligand structures, MOF synthesis table, porosity measure-
ments, procedure for catalytic experiments, filter tests, 1H NMR
1
spectra of digested MOFs for ratio study, H NMR spectra of
digested MOFs with standards for formula and loading
calculations, recycling experiment, filter tests, ORTEP diagrams
and crystallographic data tables for single-crystal studies, CIF
files, and diagrams of urea self-association. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*J.H.: j-hupp@u.northwestern.edu
*O.F.: o-farha@northwestern.edu
*C.M.: chadnano@northwestern.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
O.K.F. and J.T.H. gratefully acknowledge the ARO (project no.
W911NF-13-1-0229) for financial support (grant HDTRA-1-
10-0023). C.A.M. gratefully acknowledges the NSF (CHE-
1149314) and the U.S. Army (W911NF-11-1-0229) for
financial support. We thank J. Reddel and Dr. W. Morris for
experimental assistance.
F
DOI: 10.1021/ja511403t
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(38) Roberts, J. M.; Fini, B. M.; Sarjeant, A. A.; Farha, O. K.; Hupp, J.
T.; Scheidt, K. A. J. Am. Chem. Soc. 2012, 134, 3334.
(39) Manna, K.; Zhang, T.; Lin, W. J. Am. Chem. Soc. 2014, 136,
6566.
(40) Katz, M. J.; Brown, Z. J.; Colon, Y. J.; Siu, P. W.; Scheidt, K. A.;
Snurr, R. Q.; Hupp, J. T.; Farha, O. K. Chem. Commun. 2013, 49, 9449.
(41) Cavka, J. H.; Jakobsen, S.; Olsbye, U.; Guillou, N.; Lamberti, C.;
Bordiga, S.; Lillerud, K. P. J. Am. Chem. Soc. 2008, 130, 13850.
(42) Kasapla, P.; Rodriguez-Escrich, C.; Pericas, M. A. Org. Lett.
2013, 15, 3498.
(43) Ol’khovik, V. K.; Pap, A. A.; Vasilevskii, V. A.; Galinovskii, N. A.;
Tereshko, S. N. Russ. J. Org. Chem. 2008, 44, 1172.
(44) Yang, W.; Du, D.-M. Org. Lett. 2010, 12, 5450.
(45) Siu, P. W.; Brown, Z. J.; Farha, O. K.; Hupp, J. T.; Scheidt, K. A.
Chem. Commun. 2013, 49, 10920.
REFERENCES
■
(1) Lancianesi, S.; Palmieri, A.; Petrini, M. Chem. Rev. 2014, 114,
7108.
(2) Jia, Y.-X.; Zhu, S.-F.; Yang, Y.; Zhou, Q.-L. J. Org. Chem. 2005, 71,
75.
(3) Dessole, G.; Herrera, R. P.; Ricci, A. Synlett 2004, 2004, 2374.
(4) Lalonde, J. J.; Bergbreiter, D. E.; Wong, C. H. J. Org. Chem. 1988,
53, 2323.
(5) Majchrzak, M. W.; Zobel, J. N.; Obradovich, D. J. Synth. Commun.
1997, 27, 3201.
(6) Glennon, R. A.; Lee, M.; Rangisetty, J. B.; Dukat, M.; Roth, B. L.;
Savage, J. E.; McBride, A.; Rauser, L.; Hufeisen, S.; Lee, D. K. H. J.
Med. Chem. 2000, 43, 1011.
(7) Loh, C. C. J.; Raabe, G.; Enders, D. Chem.Eur. J. 2012, 18,
13250.
(46) Wang, C.; Xie, Z.; deKrafft, K.; Lin, W. J. Am. Chem. Soc. 2008,
133, 13445.
(8) Cai, W.; Hassani, M.; Karki, R.; Walter, E. D.; Koelsch, K. H.;
Seradj, H.; Lineswala, J. P.; Mirzaei, H.; York, J. S.; Olang, F.; Sedighi,
M.; Lucas, J. S.; Eads, T. J.; Rose, A. S.; Charkhzarrin, S.; Hermann, N.
G.; Beall, H. D.; Behforouz, M. Bioorg. Med. Chem. 2010, 18, 1899.
(9) Marek, G. J.; Aghajanian, G. K. Drug Alc. Dep. 1998, 51, 189.
(10) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem.,
Int. Ed. 2005, 44, 6576.
(47) Vermoortele, F.; Bueken, B.; Le Bars, G.; Van de Voorde, B.;
Vandichel, M.; Houthoofd, K.; Vimont, A.; Daturi, M.; Waroquier, M.;
Van Speybroeck, V.; Kirschhock, C.; De Vos, D. E. J. Am. Chem. Soc.
2013, 135, 11465.
(48) Zhang, H.; Liao, Y.-H.; Yuan, W.-C.; Zhang, X.-M. Eur. J. Org.
Chem. 2010, 2010, 3215.
(11) Tran, N. T.; Wilson, S. O.; Franz, A. K. Org. Lett. 2011, 14, 186.
(12) Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289.
(13) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299.
(14) Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217.
(15) Tsogoeva, S. B.; Yalalov, D. A.; Hateley, M. J.; Weckbecker, C.;
Huthmacher, K. Eur. J. Org. Chem. 2005, 2005, 4995.
(16) Wittkopp, A.; Schreiner, P. R. Chem.Eur. J. 2003, 9, 407.
(17) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170.
(18) Lancianesi, S.; Palmieri, A.; Petrini, M. Chem. Rev. 2014, 114,
7108.
(49) Reichardt, C. Chem. Rev. 1994, 94, 2319.
(19) Qian, Y.; Ma, G.; Lv, A.; Zhu, H.-L.; Zhao, J.; Rawal, V. H.
Chem. Commun. 2010, 46, 3004.
(20) Ni, X.; Li, X.; Wang, Z.; Cheng, J.-P. Org. Lett. 2014, 16, 1786.
(21) Jakab, G.; Tancon, C.; Zhang, Z.; Lippert, K. M.; Schreiner, P.
R. Org. Lett. 2012, 14, 1724.
(22) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc.
2008, 130, 14416.
(23) Rostami, A.; Colin, A.; Li, X. Y.; Chudzinski, M. G.; Lough, A. J.;
Taylor, M. S. J. Org. Chem. 2010, 75, 3983.
(24) Aleman
2011, 17, 6890.
́
, J.; Parra, A.; Jiang, H.; Jørgensen, K. A. Chem.Eur. J.
(25) Lu, T.; Wheeler, S. E. Chem.Eur. J. 2013, 19, 15141.
(26) Silva, C. E.; Dos Santos, H. l. F.; Speziali, N. L.; Diniz, R.; de
Oliveira, L. F. C. J. Phys. Chem. A 2010, 114, 10097.
(27) Busschaert, N.; Kirby, I. L.; Young, S.; Coles, S. J.; Horton, P.
N.; Light, M. E.; Gale, P. A. Angew. Chem., Int. Ed. 2012, 51, 4426.
(28) McGuirk, C. M.; Stern, C. L.; Mirkin, C. A. J. Am. Chem. Soc.
2014, 136, 4689.
(29) Etter, M. C.; Urbanczyk-Lipkowska, Z.; Zia-Ebrahimi, M.;
Panunto, T. W. J. Am. Chem. Soc. 1990, 112, 8415.
(30) Furukawa, H.; Cordova, K. E.; O’Keeffe, M.; Yaghi, O. M.
Science 2013, 341, No. 6149.
(31) Suh, M. P.; Park, H. J.; Prasad, T. K.; Lim, D.-W. Chem. Rev.
2011, 112, 782.
̈
(32) Farha, O. K.; Ozgur Yazaydın, A.; Eryazici, I.; Malliakas, C. D.;
Hauser, B. G.; Kanatzidis, M. G.; Nguyen, S. T.; Snurr, R. Q.; Hupp, J.
̈
T. Nat. Chem. 2010, 2, 944.
(33) Farha, O. K.; Eryazici, I.; Jeong, N. C.; Hauser, B. G.; Wilmer, C.
̈
E.; Sarjeant, A. A.; Snurr, R. Q.; Nguyen, S. T.; Yazaydın, A. O.; Hupp,
J. T. J. Am. Chem. Soc. 2012, 134, 15016.
(34) Morris, W.; Briley, W. E.; Auyeung, E.; Cabezas, M. D.; Mirkin,
C. A. J. Am. Chem. Soc. 2014, 136, 7261.
(35) Lee, C. Y.; Farha, O. K.; Hong, B. J.; Sarjeant, A. A.; Nguyen, S.
T.; Hupp, J. T. J. Am. Chem. Soc. 2011, 133, 15858.
(36) Zhang, T.; Lin, W. Chem. Soc. Rev. 2014, 43, 5982.
(37) Lee, J.; Farha, O. K.; Roberts, J.; Scheidt, K. A.; Nguyen, S. T.;
Hupp, J. T. Chem. Soc. Rev. 2009, 38, 1450.
G
DOI: 10.1021/ja511403t
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX