Multifunctional cyclodextrin-based N,N-bidentate ligands for aqueous Heck arylation

Article abstract of DOI:10.1016/j.apcata.2014.04.021

Novel Pd(II) complexes coordinated by N,N-bidentate ligands derived from cyclodextrins have been synthesized by copper-catalyzed azide alkyne 1,3-cycloaddition (CuAAC). Depending on the nature of the N,N-bidentate ligand, fast or slow equilibriums between the free N,N-bidentate ligand and the Pd-species were detected by NMR measurements. The new Pd(II) complexes acted as efficient water soluble catalysts for the Heck reaction of aryl iodides in aqueous medium. The reaction could tolerate aerobic conditions and affords the coupling products in good yields. Once the reaction was complete, the product and the catalyst could be recovered separately by simple decantation.

Full text of DOI:10.1016/j.apcata.2014.04.021

Accepted Manuscript
Title: Multifunctional cyclodextrin-based N,N-bidentate
ligands for aqueous Heck arylation
Author: Jonathan Potier St e´ phane Menuel Jolanta Rousseau
Sigitas Tumkevicius Fr e´ d e´ ric Hapiot Eric Monflier
PII:
S0926-860X(14)00251-8
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.apcata.2014.04.021
APCATA 14794
To appear in:
Applied Catalysis A: General
Received date:
Revised date:
Accepted date:
17-12-2013
28-3-2014
8-4-2014
Please cite this article as: J. Potier, S. Menuel, J. Rousseau, S. Tumkevicius,
F. Hapiot, E. Monflier, Multifunctional cyclodextrin-based N,N-bidentate
ligands for aqueous Heck arylation, Applied Catalysis A, General (2014),
http://dx.doi.org/10.1016/j.apcata.2014.04.021
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Highlights
Two new RAME-β-CD-based N,N-bidentate ligands have been synthesized by click
chemistry.
Their palladium complexes have been synthesized and characterized. One of the phosphane
displayed a hemilabile coordination mode.
High selectivities were measured in Pd-catalyzed Heck reaction of aryl iodides.
The RAME-β-CD-based N,N-bidentate ligands act as multifunctional ligands as they
combined several properties in a single material.
Page 1 of 24

Multifunctional cyclodextrin-based N,N-bidentate ligands for
aqueous Heck arylation
a,b
a,b
a,b
c
Jonathan Potier, Stéphane Menuel, Jolanta Rousseau, Sigitas Tumkevicius,
a,b,
a,b
Frédéric Hapiot, * and Eric Monflier
a
Université Lille Nord de France, F-59000 Lille, France.
b
UArtois, Unité de Catalyse et de Chimie du Solide (UCCS), Faculté des Sciences Jean
Perrin, Rue Jean Souvraz, SP 18 - 62307 Lens Cedex, France. Fax: +33(0)321791755; Tel:
+
33(0)321791773; E-mail: frederic.hapiot@univ-artois.fr
c
Vilnius University, Department of Organic Chemistry, Naugarduko 24, 03225 Vilnius,
Lituania
Abstract: Novel Pd(II) complexes coordinated by N,N-bidentate ligands derived from
cyclodextrins have been synthesized by copper-catalyzed azide alkyne 1,3-cycloaddition
(
CuAAC). Depending on the nature of the N,N-bidentate ligand, fast or slow equilibriums
between the free N,N-bidentate ligand and the Pd-species were detected by NMR
measurements. The new Pd(II) complexes acted as efficient water soluble catalysts for the
Heck reaction of aryl iodides in aqueous medium. The reaction could tolerate aerobic
conditions and affords the coupling products in good yields. Once the reaction was complete,
the product and the catalyst could be recovered separately by simple decantation.
Keywords: cyclodextrins – palladium – aqueous catalysis – Heck reaction
Page 2 of 24

1
. Introduction
The Pd-catalyzed C-C coupling reaction involving alkenyl or aryl halides and alkenes (Heck
reaction) is currently among the most attractive and powerful tools in modern organic
synthesis [1-4]. The ease of preparation of a wide range of coupling products, the tolerance of
a wide variety of sensitive functionalities and the mild reaction conditions greatly contribute
to the spread of the Heck reaction [5,6,7]. The explanation of such an infatuation mainly lies
in the efficacy of the numerous catalytic systems that have been developed with time. Both
homogeneous and heterogeneous catalysts proved to be suitable candidates [8,9]. Although
the true nature of the Pd-catalyst was questioned [10], the efficacy of these catalysts has been
clearly demonstrated and very high turnover numbers (TON) could be reached in organic
solvents [11]. Efficient catalytic systems have also been developed in non-conventional media
[
12] such as ionic liquids [13, 14]. Tumas and co-workers [15] and Holmes and Carroll [16]
independently reported the application of fluorinated phosphanes coupled with a palladium
source in Heck and Suzuki couplings in scCO . Arai and co-workers reported the use of
2
water-soluble palladium complexes bearing sulfonated phosphanes in scCO with an added
2
polar cosolvent for Heck reactions [17]. Water is also a very attractive solvent for Heck
reactions [18,19,20,21] as it is cheap, environmental-friendly and available in large quantities.
Heck reactions in aqueous media have especially been developed using catalytic systems
based on a simple Pd sources [Pd(OAc) , PdCl , etc.] without any ligand [22]. Palladium
2
2
acetate immobilized on reversed phase amorphous silica gel with the aid of an ionic liquid,
bmim]PF , was highly efficient in the promotion of the Mizoroki-Heck reaction in pure water
[
6
without any ligand up to the sixth re-use, in 95% average yield [23]. In some cases, biphasic
systems were used in combination with palladium salts and water-soluble phosphanes with
the specific aim of aiding catalyst recovery as exemplified in the Heck coupling reactions
studied by Arai et al. [24]. Shaughnessy and co-workers utilized both sterically demanding
water-soluble triaryl-phosphanes in Heck/Suzuki couplings of aryl bromides [25].
Amphiphiles also proved to be effective for Heck reactions in aqueous media [26,27].
In numerous aqueous catalytic systems reported in the literature, the use of ligands was often
required to stabilize Pd catalytic species and avoid the formation of Pd black. To this end,
phosphanes have been mainly considered as ligands to coordinate the metal [28-30]. The
utilization of the resulting phosphane-coordinated Pd-catalysts covered a wide range of
coupling partners [31,32]. Nonetheless, although they still attract much attention nowadays
Page 3 of 24

due to their catalytic performances [33], phosphanes did not constitute a completely
satisfactory solution to stabilize the metal as they are toxic, air-sensitive, expensive, and
subject to P-C bond degradation at elevated temperature [34,35]. Accordingly, oxygen-free
experimental conditions are required thus limiting the scope of their use. Recently, there has
been an increased emphasis on the use of ligands with other donor atoms [36]. Nitrogen-
containing ligands have emerged as promising candidates [37-45]. These ligands are moisture
and air-stable and economically inexpensive. A few years ago, we developed the use of
modified cyclodextrins (CDs) as effective additives to promote the conversion of organic
substrates in water. Modified CDs can act as mass transfer promoters for partially hydrophilic
substrates and as interfacial receptors for hydrophobic substrates [46]. Among modified CDs,
randomly methylated β-CDs (RAME-β-CDs) [47] proved to be especially appropriate in
various biphasic catalytic systems due to their ability to adsorb at the aqueous/organic
interface [46,48,49]. Herein, we detail the synthesis of two new RAME-β-CD-based N,N-
bidentate ligands and their Pd-complexes. The idea is to combine on a unique molecular
platform the coordinating properties of a robust bidentate ligand with the adsorbing properties
of RAME-β-CD. The catalytic performances of the resulting multifunctional Pd-complexes
have been examined in an aqueous C-C coupling reaction between aryl halides and vinyl
derivatives (methyl acrylate or styrene).
2
. Experimental
2.1. General procedures
All chemicals were purchased from Acros and Aldrich Chemicals in their highest purity. All
solvents were used as-supplied without further purification. Distilled water was used in all
experiments. Analytical thin-layer chromatography (TLC) was performed on E. Merck
aluminium-backed silica gel (Silica Gel F254). Reactions were carried out on a Mars
microwave model (CEM Corporation) that delivered 800 W output at a 2450 MHz frequency.
Teflon microwave-transparent XP-1500 vessels (with control temperature conditions inside
sample vessels by RTP-300 Plus temperature sensor) were used. The system regulated the
microwave power output to maintain a selected temperature parameter. Compounds were
identified using UV fluorescence and/or staining with a solution of phosphomolybdic acid in
aqueous sulfuric acid and ethanol. NMR spectra were recorded on a Bruker DRX300
1
13
spectrometer operating at 300 MHz for H nuclei and 75 MHz for C nuclei. CDCl (99.50%
3
isotopic purity), DMSO-d (99.80% isotopic purity) and D O (99.92% isotopic purity) were
6
2
Page 4 of 24

1
purchased from Euriso-Top. H NMR data are reported as chemical shift, multiplicity (s,
singlet; d, doublet; m, multiplet), relative integral, coupling constant (J in Hertz). Absorption
spectra were recorded on a Lambda 19 (Perkin Elmer) dual-beam spectrophotometer (1 cm
path cuvette) using the method of standard additions. In a vessel containing 3.5 mL of an
-
4
-1
aqueous solution of modified RAME-β-CD (10 mol.L ) were added successive aliquots (0.1
-
3
-1
equiv.) of an aqueous solution of Na PdCl (20 μL, 1.75 x 10 mol.L ). Mass spectra were
2
4
recorded on a MALDI-TOF–TOF Bruker Daltonics Ultraflex II in positive reflectron mode
with 2,5-DHB as matrix. Surface tension measurements have been carried out using an
Attension Force Tensiometer Sigma 701 with a Wilhelmy plate and two Titronic dispenses.
Gas chromatographic analyses of the organic phase were carried out on a Shimadzu GC-17 A
5
00 gas chromatograph equipped with a polydimethylsiloxane capillary column (30 m×0.32
mm) coupled with a Shimadzu QP-5000 mass spectrometer (GC:MS). Conversions were
determined by GC using undecane as an internal standard and comparison with references.
Conversions were defined from consumption of aryl halide with time. ICP-AES
measurements have been performed using a ICP-AES Vista-Pro VARIAN spectrometer.
2.2. General procedure for the synthesis of randomly methylated mono substituted-β-
CDs (1 and 2)
Randomly methylated mono-6-azido-6A-deoxy-β-D-cyclodextrin (1.8 mmol) and hydrated
copper sulfate (2.1 mmol) were added to a solution of alkynyl precursor (2.1 mmol alkynyl
function) in DMF (90 mL). After subsequent dropwise addition of a freshly prepared solution
of sodium ascorbate (5.2 mmol) dissolved in water (10 mL), the mixture was subjected to
microwave irradiations under vigorously stirring at 60 °C for 2 h. After solvent evaporation,
the crude product was dissolved in an ammoniac solution (10 weight%) and stirred overnight
before being purified by column chromatography on silica gel with water as eluent to give the
product as a pale yellow powder.
2
1
.3. Randomly Methylated 1-(6A-Deoxy-β-D-cyclodextrin)-4-[(dimethylamino)methyl]-
,2,3-triazole (1)
1
Yield 83%. H NMR (300 MHz, D O): δ 8.27 (s, 1 H), 5.19 (m, 4.9 H), 4.98 (m, 50H), 4.44
2
(m, 2.1 H), 4.13 (m, 3.1 H), 3.98–3.88 (m, 13.1 H), 3.68–3.53 (m, 43.9 H), 3.47–3.29 (m, 17.9
1
3
H), 2.82 (s, 6 H) ppm. C NMR (75.5 MHz, D O): δ = 137.4, 135.2, 112.8, 101.4–99.8, 99.0–
2
97.4, 82.7–81.6, 78.5, 73.4, 73.3, 73.1, 72.6, 72.3, 72.2, 70.9, 70.3, 64.4–59.4, 42.4, 30.2,
+
2
0.2, 19.7 ppm. MS: m/z (%) = 1433.51 (11.6) (calcd. 1433.57 for [C H N O + Na] ),
5
9
102
4
34
Page 5 of 24

+
1447.53 (69.9) (calcd.1447.58 for [C60
H
104
N
4
O
34 + Na] ), 1461.55 (16.1) (calcd. 1461.59 for
+
+
[C
61
H
106
N
4
O
34 + Na] ), 1477.05 (2.3) (calcd. 1475.6 for [C62
H
108
N
4
O
34 + Na] ).
2
.4. Randomly Methylated 1-(6A-Deoxy-β-D-cyclodextrin)-4-(2-pyridinyl)-1,2,3-triazole
(
2)
1
Yield 68%. H NMR (300MHz, D 0): δ 8.60 (2H,m), 8.07 (2H, m), 7.53 (1H, m), 5.48-4.99
2
(
m, overlapped with D O), 4.74-4.61 (1H, br. s), 4.40-4.22 (1H, br. s), 4.18-2.93 ( 68.4H, m)
2
1
3
ppm C NMR (75.5MHz, D O): δ 152.0, 148.4, 146.9, 136.8, 129.3, 127.8, 126.3, 104.6,
2
102.3, 85.5, 84.0, 81.4, 76.4, 74.7, 73.5, 70.5, 62.7, 61.7, 55.0 ppm. MS : m/z (%) = 1425.18
+
(
[
(
[
(
2
0.9) (calcd. 1425.14 for [C H N O + Na ]), 1439.19 (4.0) (calcd. 1439.15 for
5
9
94
4
34
+
+
C H N O + Na ]), 1453.21 (19.0) (calcd. 1453.16 for [C H N O + Na ]), 1467.24
6
0
96
4
34
61 98
4
34
+
57.9) (calcd. 1467.17 for [C H N O + Na ]), 1481.26 (14.7) (calcd. 1481.18 for
6
2
100
4
34
+
+
C H N O + Na ]), 1497.26 (2.2) (calcd. 1495.20 for [C H N O + Na ]), 1507.20
6
3
102
4
34
64 104
4
34
+
1.4) (calcd. 1509.20 for [C H N O + Na ]).
6
5
106
4
34
.5. Typical procedure for the Heck reaction
To a stirred solution of aryl halide (1 mmol) in 2.5 mL heptane were added the alkene (1.5
mmol) and the internal standard (undecane, 0.3 mmol). An aqueous solution (2.5 ml)
2 4 3
containing ligand 1 or 2 (0.1 mmol), Na PdCl (0.005 mmol) and NaHCO (1.5 mmol) was
then added. The reaction mixture was heated at 100 °C for 18 h. The reaction mixture was
cooled to room temperature. Once the organic phase has been recovered, the aqueous phase
was washed twice with diethyl ether (2 × 2 mL). The combined organic phases were dried
over anhydrous MgSO and heptane was removed under vacuum. The residue was purified by
4
chromatography over a silica gel column. Elution with 10% ethyl acetate - heptane gave the
expected bisaryl products as colorless oils.
Conversions were calculated on the basis of disappearance of aryl halides, with no visible side
reactions occurring. Conversions were calculated using the following equation,
conversion(t) = ([aryl halide]
0
– [aryl halide]
t
)/[aryl halide]
0
× 100%
is the aryl halide
where ([aryl halide] is initial aryl halide concentration and [aryl halide]
0
t
concentration at time t during the reaction.
Turnover number (TON) was calculated using the following formula,
TON = (moles [aryl halide] converted/mole Pd) × 100.
Turnover frequency (TOF) was calculated as the ratio of,
-
1
TON / time required to achieve TON (TON.h ).
2.6. Reusability of the catalytic system
Page 6 of 24

The reusability of the catalytic system has been carried out as follows. Once the organic phase
of the first run has been removed, fresh reactants and the internal standard (undecane) were
added into the catalyst-containing flask and the reaction was heated at 100 °C for 3 h. The
same work-up as described in the above typical procedure (2.5.) was then applied.
3. Results and discussion
3.1. Synthesis and characterization of CD-based N,N-bidentate ligands
Ligands 1 and 2 (Scheme 1) were synthesized by copper-catalyzed azide alkyne 1,3-
cycloaddition (CuAAC) as follows. The alkynyl precursor (1.3 equiv 3-dimethylamino-1-
propyne or 2-ethynylpyridine, respectively) were mixed in DMF with randomly methylated
4 2
mono-6-azido-β-CD [50] (1.0 equiv) and CuSO .5H O (0.1 equiv). After addition of sodium
ascorbate (0.2 equiv.) at room temperature, the blue solution gradually changed to orange,
color characteristic of the presence of cuprous acetylide [51]. The mixture was then subjected
to microwave irradiations under vigorously stirring at 60 °C for 2 h. After DMF evaporation,
the crude products were submitted to purification. Addition of an ammoniac solution (10
weight%) entrapped the Cu-ions in the form of tetraamminecopper(II) sulfate which was
removed by chromatography on a silica column using water as eluent. The deep blue Cu-
complex remained at the top of the column whereas the CD-based products migrated to give 1
or 2 in 83 and 68% yields, respectively.
As described below, the availability of the CD cavity was crucial in our catalytic system to
promote the conversion of the substrate. Indeed, examples from the literature usually
described a CD platform substituted by hydrophobic substituents capable of interacting with
the CD cavity [52]. 1 and 2 behaved very differently. As clearly shown in their 2D T-ROESY
spectra realized in D O at 25 °C (ESI), no correlation could be observed between the protons
2
of the CD-substituent (N,N-dimethylaminotriazolyl or pyridyltriazolyl) and the inner CD
protons (H3 and H5). The molecular recognition of a guest molecule by the CD cavity thus
remained possible. To complete the analysis of 1 and 2, surface tension measurements have
been carried out in water. The regular decrease in surface tension γ was indicative of their
-
5
interfacial adsorption in the 10 –1 mM concentration range (Fig. 1). 1 and 2 were more
surface active than RAME-β-CD, thus demonstrating their higher ability to interact with the
air–water interface. Note that no critical micellar concentration could be observed in the
studied concentration range. 1 and 2 could be considered hydrotropic. Their water-solubility
was similar to that measured for RAME-β-CD (>500 g/L).
Page 7 of 24

3.2. Synthesis and characterization of Pd-complexes.
The complexing properties of 1 and 2 towards Na PdCl were assessed at room temperature in
2
4
D O by NMR spectroscopy. The stoichiometry of the obtained Pd-complexes was determined
2
using a continuous variation method (Job plot) [53]. Two mother solutions of equal
concentration were prepared, one containing the free ligand (1 or 2) and the other one
containing Na PdCl . Aliquots of each solution were added in a NMR tube so that the total
2
4
concentrations [Na PdCl + ligand] remained constant while the concentration of each
2
4
compound was varied. Chemical shifts variations (Δδ) were recorded for each sample in the
1
H NMR spectra. Using 1 as a ligand, average NMR signals (ESI) were detected, illustrative
of a fast equilibrium between the free ligand and the Pd-species. In that case, the chemical
shifts variations observed for the triazolyl proton and the methylene group attached to the
amino group were translated into a Job plot which revealed a maximum around 0.66
characteristic of a 2:1 stoichiometry (two ligands 1 for one Pd). The resulting Pd-complex (3)
was described in Fig. 2. Conversely, distinct resonances were observed for the free ligand 2
and two different Pd-complexes depending on the concentrations (Figure 3). With ligand 2 in
excess, the metal was stabilized by two ligands 2, resulting in the formation of the Pd-
complex 4 containing tetradentate-nitrogen donor ligands, as already observed in the literature
[54,55]. However, a fluxional coordination behavior (equilibrium between 4 and a Pd-center
coordinated by three nitrogens and one chloride) could not be ruled out at this stage.
Conversely, when ligand 2 is in default, only one ligand 2 could then coordinate the metal
resulting in the formation of Pd-complex 5. Note that the observation of three sets of
1
resonances in the H spectra revealed a slow equilibrium between the free ligand 2 and the
Pd-complexes 4 and 5 (at least on the NMR time scale). The difference in behavior between 1
and 2 resulted from the hemilability of the amino group of 1. Indeed, it has previously been
shown that -NR exhibited a strong hemilabile character [56]. Thus, average NMR signals
2
were observed for mixtures of 1 and Na PdCl while distinct NMR resonances were observed
2
4
for mixtures of 2 and Na
2 4
PdCl . No cross-peaks could be detected in 2D T-ROESY spectra of
mixtures containing 1 or 2 and Na PdCl . Accordingly, the CD cavities of Pd-complexes 3, 4
2
4
and 5 remained available for the molecular recognition of appropriate substrates (ESI).
Indeed, 2D T-ROESY experiments realized using mixtures of 1 (or 2), Na PdCl and phenyl
2
4
iodide (chosen as a model substrate) clearly showed that cross-peaks were detected between
the aromatic protons of the substrate and the CD protons, indicative of the inclusion of phenyl
iodide within the CD cavity, even after coordination of the nitrogens onto the Pd center (ESI).
Page 8 of 24

UV/vis spectra were also recorded to characterize the Pd-complexes (ESI). When the
absorbance vs wavelength curves related to mixtures of 1 (or 2) and Na PdCl were translated
into a plot representing the absorbance vs the amount of Na PdCl the ruptures in the slope at
2
4
2
4,
0.5 equiv. confirmed the 2:1 stoichiometry of complexes 3 (two ligands 1 for one Pd) and 4
(
two ligands 2 for one Pd).
3.3 Catalytic results
Heck reactions involving aryl halides and methyl acrylate were performed at 100 °C in a
water/heptane mixture (2.5 mL each) using Na PdCl (0.005 mmol%) as a Pd precursor.
2
4
Blank runs were carried out using the randomly methylated β-CD (RAME-β-CD), one of the
best additive so far in aqueous organometallic catalysis (Table 1).[47] Only very small
fractions of aryl iodide (<1%) could be converted in that case (Table 1, entry 1) due to the
instability of the active monomeric Pd(0) species. Indeed, the catalytic system rapidly evolved
to Pd black. In fact, whatever the amount, RAME-β-CD was not able to stabilize the
palladium species in water. Ligand coordination was then required to sustain monomeric
Pd(0) in water. As expected, the chelation effect inherent in 1 and 2 ensured the stability of
the Pd-species in water. Excess ligand (at least 10 equiv.) was added to Na PdCl in water to
2
4
favor the in situ formation of Pd-complexes 3 or 4. As usually observed for the Heck reaction,
aryl iodides were more readily converted than aryl bromides (Table 1, entries 2-7). No
conversion could be measured with aryl chlorides. With aryl iodides (Table 1, entries 6-25),
-
1
low turnover frequencies (TOF) were measured (up to 39.6 h ). It should be noted that in all
1
13
cases only the trans products could be selectively obtained as confirmed by H and C NMR
(
(
ESI). Complex 3 (Pd coordinated by 1) proved to be a more effective catalyst than complex 4
Pd coordinated by 2) presumably because of the hemilabile character of 1 (as revealed by the
fast equilibrium in the NMR spectra, see above). Indeed, the amino group of 1 being partially
coordinated onto the metal, the oxidative addition of aryl halide was favored leading to an
enhanced catalytic activity. Conversely, ligand 2 was more strongly coordinated to the Pd
center (as revealed by the slow equilibrium in the NMR spectra). The stability of Pd-species
coordinated by ligand 2 then slowed down the oxidative addition of aryl halides, thus
decreasing the catalytic activity.
Both aryl iodides bearing electron-donating or electron-withdrawing groups could be
converted into coupling products with conversions ranging from poor to excellent (up to
9
9%). No correlation could be found when comparing the substrates water solubility (W) and
the catalytic activity. For example, phenyl iodide (W = 70 mg/L) gave higher TOFs (entries 6
Page 9 of 24

and 7) than p-iodophenol (W = 428 mg/L, entries 10 and 11). Similarly, 4-iodobenzonitrile
W = 82 mg/L) gave comparable TOFs (entries 8 and 9) than 3,4-dimethylphenyl iodide (W =
mg/L, entries 18 and 19). Interestingly, a recognition process between the CD cavity and the
(
7
substrate greatly contributed to the catalytic efficacy. Indeed, as already observed for RAME-
β-CD,[27] 1 and 2 were capable of adsorbing at the aqueous/organic interface as confirmed
by surface tension measurements (Fig. 1). Consequently, the CD cavity of 1 or 2 could
interact with the organic phase to promote the conversion of a substrate molecule into a
product. Moderate to poor conversions were achieved with hindered aryl iodides (2-
methylphenyl iodide and 3,4-dimethylphenyl iodide). While the bad results obtained with 2-
methylphenyl iodide (Table 1, entries 22 and 23) could be explained by a lower oxidative
addition of the substrate on the Pd-center (hindered coordination sphere), the results obtained
with the 3,4-dimethylphenyl iodide were clearly related to a complicated recognition process
with the CD cavity. Due to the bulkiness of the methyl substituents, 3,4-dimethylphenyl
iodide was unable to enter the CD cavity as clearly shown by the absence of correlations in
the 2D T-ROESY spectrum (ESI). Less hindered substrates such as p-methoxyphenyl iodide,
p-tolyl iodide or m-tolyl iodide led to higher conversions (Table 1, entries 12, 13, 16, 17, 20
and 21) due to a better inclusion of the substrate in the CD cavity as exemplified by the
presence of intense cross-peaks in the 2D T-ROESY spectrum of a stoichiometric mixture of
1
and p-methoxyphenyl iodide (Figure 4). Thus, through both Pd-coordination and molecular
recognition, 1 and 2 confined the catalyst and the substrate in a restricted volume resulting in
enhanced capacity to maximize the C-C coupling reaction. Additionally, whatever the
substrates, no by-products could be detected indicative of a very selective catalytic process.
Also note that no variation in the catalytic performance could be noticed when the reaction
proceeded under anaerobic conditions thus highlighting the robustness of the studied catalytic
system.
The catalytic results obtained with methyl acrylate were confirmed with styrene as a substrate
(
Table 2). The superiority of 3 over 4 was even more marked as the conversions were always
better using 1 as a ligand. Here again, the water solubility of the substrate could not be
incriminated to explain the catalytic results. The catalytic performance was dependent on the
recognition process between the substrates and the CD cavity. As expected, the linear p-tolyl
iodide, which was well recognized by the β-CD cavity, led to better TOF than the hindered 2-
methylphenyl iodide, 3-methylphenyl iodide and 3,4-dimethylphenyl iodide (Table 2,
compare entries 6, 7 with 8-13). We believe that, in that case, the catalytic activity was
influenced by both the inclusion of aryl iodide within the CD cavity and by the recognition of
Page 10 of 24

styrene within another CD cavity. A kinetic monitoring realized with phenyl iodide and
styrene as substrates and 1 as a ligand showed that the conversions levelled off after 5 h
(
Figure 5). This observation probably resulted from the increasing amount of C-C coupling
products in the solution. Indeed, the proportion of product included within the CD cavity
regularly increased with time, thus limiting the supramolecular recognition of remaining
substrate. However, poisoning of the CD cavity by the reaction product could be excluded as
the catalytic system could be recycled (Table 2, runs 16). Thus, once the reaction was
complete, a rapid decantation took place and the organic phase was recovered by cannula. The
aqueous catalyst-containing solution recovered from run 2 was filtered at 80 °C on Celite to
remove any heterogeneous Pd-catalysts (such as Pd-particles). Fresh phenyl iodide and
styrene were then added into the catalyst-containing flask and the Heck reaction then
proceeded under the same experimental conditions as described above. The equilibriums were
then displaced to the formation of CD/substrate complexes and the residual product was
excluded from the CD cavity. For the second run, 68% phenyl iodide were converted within 5
h vs 74% for the first run. The slight decrease in conversion observed between the first and
the second run was likely a consequence of the increasing amounts of salts (NaI) in the
aqueous compartment. Indeed, addition of NaI (1 equiv. regarding the substrate) in the
reaction mixture at the beginning of the reaction led to a comparable conversion in C-C
coupling product (66% after 5 h). As such, the advantage of the present catalytic system lies
more in the easy separation of the coupling product and the Pd-catalyst once the reaction was
complete than in its reusability. Finally, the recovered organic phases were analyzed by ICP-
AES. No trace of metal could be detected (< 0.2 ppm) thus highlighting the efficacy of the
current process. Indeed, although the catalytic steps at Pd proceeded smoothly, the
multidentate character of the CD-based ligand led to higher coordination states. As such, the
Pd(0) intermediates were never underligated during the catalytic cycle. Accordingly, 1 and 2
acted as stabilizing ligands of Pd-species in water, thus avoiding aggregation of Pd into
inactive clusters.
4
. Conclusions
In summary, RAME-β-CD was used as a platform to access N,N-bidentate ligands 1 and 2 by
click chemistry (CuAAC). 1 and 2 were successfully used as ligands to stabilize Pd(0)-species
in water. The latter were effective in phosphane-free Heck reaction of a wide range of aryl
iodides (and to a less extent aryl bromides) bearing electron-donating or electron-withdrawing
groups with moderate activity and good stability in aerial atmosphere. The N,N-
Page 11 of 24

dimethylaminotriazolyl-substituted β-CD (1) was a better ligand than the N,N-
pyridyltriazolyl-substituted β-CD (2) because of the hemilabile character of the N,N-
dimethylamino group towards the palladium center. 1 and 2 acted as multifunctional ligands
as they combined several properties in a single material: i) they stabilized the reactive metal
center in water during the course of the Heck reaction (easy separation of the product and the
catalyst once the reaction is complete), ii) they allowed for a significant increase of the
substrate concentration in water or at the aqueous/organic interface, iii) they increased the
local concentrations of substrate and catalyst in a confined environment. Thus, 1 and 2 could
be considered as versatile catalysts for aqueous organometallic catalysis. Actually, both
hydrophobic and partially hydrophilic aryl halides and alkenes could be readily converted into
substituted alkenes. This study is a new illustration of the efficacy of CD-based
supramolecular edifices for the transformation of organic substrates in aqueous media.
Acknowledgements
The authors are grateful to Roquette Frères (Lestrem, France) for a gift of β-cyclodextrin.
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Page 15 of 24

Scheme 1 Synthesis of RAME-β-CD-based N,N-bidentate ligands 1 and 2. R = H or CH
substitution degree = 1.8 per glucopyranose unit).
3
(
Page 16 of 24

Fig. 1 Surface tension measurements of RAME-β-CD, 1 and 2 as a function of their
concentration in water at room temperature.
Page 17 of 24

Fig. 2 Continuous variation plot (Job’s plot) derived from chemical shift variations of the
triazolyl proton of ligand 1.
Page 18 of 24

1
Fig. 3 Partial 300 MHz H NMR spectra (triazolyl and aromatic region) of 2/Na PdCl
2 4
mixtures in D O at 25 °C. The total concentration of species is 10 mM. The 2/Na PdCl ratios
2
2
4
are given on each spectrum. ♣ free ligand 2. ♥Pd-complex 4. ♦Pd-complex 5.
Page 19 of 24

Fig. 4 2D T-ROESY spectrum of a stoichiometric mixture of 1 and p-methoxyphenyl iodide
-
1
(
2
5 M each) in D O at 25 °C.
Page 20 of 24

Fig. 5 Kinetic monitoring of the Heck reaction using phenyl iodide and styrene as substrates.
Reaction conditions: phenyl iodide (1.0 mmol), styrene (1.5 mmol), ligand 1 (0.1 mmol),
Na PdCl (0.005 mmol), NaHCO (1.5 mmol), water (2.5 mL), heptane (2.5 mL), 100 °C.
2
4
3
Conversions
were
determined
by
GC-MS
analysis.
Page 21 of 24

Table 1 Scope of the Heck reaction between aryl halides and methyl acrylate using 1 or 2 as a
a
water-soluble ligand.
R2
R3
R2
R3
O
O
O
ligand, Na PdCl
2
4
O
R1
X +
R1
NaHCO , H O
3
2
1
00°C
1
2
3
b
c
d
e
Entry Additive
X
I
R
R
R
W (mg/L)
70
Conv(%)
<1
0
0
3
TOF
-
0
TON
-
0
0
6
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
RAME-β-CD
H
H
H
H
H
H
H
CN
CN
OH
OH
OCH
OCH
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
Cl
Cl
Br
Br
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
400
400
197
197
70
70
82
82
428
428
49
49
28
28
24
24
7
7
24
24
24
24
126
126
0
1.2
0.8
22.8
12
2
4
57
30
5
114
60
10
8
2
4
1.6
20.4
6.4
26
10.4
12.8
8
14.8
6.4
3.2
1.6
14.4
5.6
1.6
0.8
39.6
21.2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
51
16
65
26
32
20
37
16
8
102
32
130
52
64
40
74
32
16
8
72
28
8
4
198
106
3
3
NO
NO
2
2
CH
CH
CH
CH
H
H
H
H
H
3
3
3
3
H
CH
CH
CH
CH
H
H
NH
NH
3
3
3
3
4
36
14
4
2
99
53
CH
CH
H
3
3
2
2
H
2
H
a
2 4
Reaction conditions: aryl halide (1.0 mmol), methyl acrylate (1.5 mmol), ligand (0.1 mmol), Na PdCl (0.005 mmol),
b
NaHCO
3
(1.5 mmol), water (2.5 mL), heptane (2.5 mL), 100 °C, 5 h. Estimated water solubility at 25 °C (from Log Kow
c
d
using the WsKow v1.41 software). Conversions were determined by GC-MS analysis. TOF = turnover frequency (number
e
of molecules of substrate converted per catalytic site and per hour). TON = turnover number (number of molecules of
substrate converted per catalytic site).
Page 22 of 24

Table 2 Scope of the Heck reaction between aryl halides and styrene using 1 or 2 as a water-
a
soluble ligand.
R2
R3
R2
R3
ligand, Na PdCl4
2
R1
I
+
R1
NaHCO , H O
3
2
100°C
1
2
3
b
c
d
e
Entry
Additive
RAME-β-CD
R
R
R
W (mg/L)
70
70
70
49
49
24
24
7
7
24
24
24
Conv(%)
<1
74
16
60
55
87
42
14
12
64
17
44
24
28
9
68
TOF
-
29.6
6.4
24
22
34.8
16.8
5.6
4.8
25.6
6.8
17.6
9.6
11.2
3.6
27.2
26.4
TON
-
148
32
120
110
174
84
28
24
128
34
88
48
56
18
136
132
(1.5
1
2
3
4
5
6
7
8
9
H
H
H
OCH
OCH
CH
CH
CH
CH
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH
CH
CH
CH
H
H
H
H
H
H
H
H
H
H
H
H
CH
CH
H
H
H
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
1
3
3
3
3
3
3
3
3
3
3
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
3
3
H
24
NH
NH
H
2
126
126
70
2
f
g
1
H
H
70
66
a
2 4 3
Reaction conditions: aryl halide (1.0 mmol), styrene (1.5 mmol), ligand (0.1 mmol), Na PdCl (0.005 mmol), NaHCO
b
mmol), water (2.5 mL), heptane (2.5 mL), 100 °C, 5 h. Estimated water solubility (W) at 25 °C (from Log Kow using the
c
d
WsKow v1.41 software). Conversions were determined by GC-MS analysis. TOF = turnover frequency (number of
e
molecules of substrate converted per catalytic site and per hour). TON = turnover number (number of molecules of substrate
f
converted per catalytic site). performed using the aqueous catalytic phase recovered from run 2 after filtration on Celite.
g
Addition of NaI (1 mmol).
Page 23 of 24

*Graphical Abstract (for review)
Page 24 of 24