Glucose as a clean and renewable reductant in the pd-nanoparticle-catalyzed reductive homocoupling of bromo- and chloroarenes in water

Article abstract of DOI:10.1021/jo1005729

Figure presented An efficient and highly sustainable Ullmann-type homocoupling of bromo- and chloroarenes, including the more challenging electron-rich chloroarenes (e.g., 4-chloroanisole), catalyzed by in situ generated Pd colloids, is carried out in aqueous medium under relatively mild conditions (temperatures ranging from 40 to 90 °C). Glucose is used as a clean and renewable reductant, while tetrabutylammonium hydroxide (TBAOH) acts as base, surfactant, and phase-transfer agent, creating a favorable environment for the catalyst. Pd nanoparticle sizes, morphology, and chemical composition are ascertained by TEM and XPS analyses.

Full text of DOI:10.1021/jo1005729

pubs.acs.org/joc
Besides the classic general Ullmann,7 Suzuki,8 and Stille9
Glucose as a Clean and Renewable Reductant
in the Pd-Nanoparticle-Catalyzed Reductive
Homocoupling of Bromo- and Chloroarenes in Water
coupling reactions, the Pd-catalyzed reductive coupling of
haloarenes has gained great attention as a useful route to the
formation of aryl-aryl bonds. This simple method for
preparing symmetrical biaryls is of ongoing interest, as it
prevents the use of stoichiometric amounts of expensive or
moisture-sensitive organometallic compounds (i.e., boronic
acids, stannanes, Grignard reagents, etc.).
Antonio Monopoli,*,† Vincenzo Calo,
ꢀ †
Francesco Ciminale,† Pietro Cotugno,† Carlo Angelici,†
Nicola Cioffi,† and Angelo Nacci*,†,‡
†Department of Chemistry and ‡CNR-ICCOM,
Department of Chemistry, Universitaꢀ degli Studi Aldo Moro,
Via Orabona 4, 70126 Bari, Italy
This approach may be particularly attractive for industrial
applications provided that it can be carried out in eco-
friendly solvents, employing cheap and renewable raw ma-
terials. From this standpoint, of special interest is the use of
chloroarenes as substrates, safe and clean reducing agents,
and water as the most desirable green solvent. In addition to
that, the use of metal nanoparticles as catalyst is gaining
interest due to the enhanced ability of colloids to transfer
electrons because of the large surface area-to-volume ratio.10
As part of our ongoing program aimed at finding new eco-
efficient synthetic solutions,10a,11 we were attempting to
develop a highly sustainable catalyst system to perform the
reductive coupling of aryl chlorides in water by replacing the
most commonly used reductants, Zn powder, formate salts,
and hydrogen gas, with safer and cleaner reducing agents.
Among these, sugars were thought to be suitable candidates
because they are cheap, inexhaustible base chemicals and
highly soluble in water.
Although several reductive aryl-aryl coupling protocols
have been studied in water,10b,12 no examples have been
reported on the use of sugars as stoichiometric reductants.
Among several monosaccharides, we focused our attention
particularly on glucose, which is known to reduce many
metals in colloidal form smoothly.13
Our investigations started by checking the ability of
glucose to generate catalytically active Pd nanoparticles
(Pd-NPs) in situ. To this end, a series of model reductive
antomono@libero.it; nacci@chimica.uniba.it
Received March 25, 2010
An efficient and highly sustainable Ullmann-type homo-
coupling of bromo- and chloroarenes, including the more
challenging electron-rich chloroarenes (e.g., 4-chloroanisole),
catalyzed by in situ generated Pd colloids, is carried out
in aqueous medium under relatively mild conditions (tem-
peratures ranging from 40 to 90 °C). Glucose is used as a
clean and renewable reductant, while tetrabutylammonium
hydroxide (TBAOH) acts as base, surfactant, and phase-
transfer agent, creating a favorable environment for the
catalyst. Pd nanoparticle sizes, morphology, and chemical
composition are ascertained by TEM and XPS analyses.
(7) (a) Fanta, P. E. Synthesis 1974, 9. See also: (b) Beletskaya, I. P.;
Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337–2364.
(8) For reviews, see: (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Tetrahedron
2008, 64, 3047–3101. (b) Phan, N. T. S.; Van Der Sluys, M.; Jones, C. W. Adv.
Synth. Catal. 2006, 348, 609–679.
In the past decade, the biaryl scaffold has received inc-
reased attention as a privileged structure by the agrochemical
and pharmaceutical industries.1 The core of many types of
natural products,2 advanced materials,3 polymers,4 sensors,5
and ligands for asymmetric catalysis6 contains the biaryl
moiety. Consequently, the development of new and efficient
methods of synthesizing these structures is crucial to the
work of a broad area of organic chemistry.
(9) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. See also:
(b) De Souza, M. V. N. Curr. Org. Synth. 2006, 3, 313–326.
ꢀ
(10) See, for example: (a) Calo, V.; Nacci, A.; Monopoli, A.; Cotugno, P.
Chem.;Eur. J. 2009, 15, 1272–1279. (b) Gallon, B. J.; Kojima, R. W.; Kaner,
R. B.; Diaconescu, P. L. Angew. Chem., Int. Ed. 2007, 46, 7251–7254.
ꢀ
(11) (a) Calo, V.; Nacci, A.; Monopoli, A.; Montingelli, F. J. Org. Chem.
2005, 70, 6040–6044. (b) Calo, V.; Nacci, A.; Monopoli, A. Eur. J. Org.
ꢀ
ꢀ
Chem. 2006, 3791–3802. (c) Calo, V.; Nacci, A.; Monopoli, A.; Cotugno, P.
Angew. Chem., Int. Ed. 2009, 48, 1–4.
(12) (a) Wan, Y.; Wang, H.; Zhao, Q.; Klingstedt, M.; Terasaki, O.;
Zhao, D. J. Am. Chem. Soc. 2009, 131, 4541–4550. (b) Wang, H.; Wan, Y.
J. Mater. Sci. 2009, 44, 6553–6562. (c) Li, H.; Chai, W.; Zhang, F.; Chen, J.
Green Chem. 2007, 9, 1223–1228. (d) Ram, R. N.; Singh, V. Tetrahedron Lett.
2006, 47, 7625–7628. (e) Li, J.-H.; Y. Liang, W.-J.; Liu, S.; Tang, Y.; Xie, X.
Chin. J. Chem. 2004, 22, 1432–1435. (f) Li, J.-H.; Xie, Y.-X.; Yin, D.-L.
J. Org. Chem. 2003, 68, 9867–9869. (g) Mukhopadhyay, S.; Joshi, A. V.;
Peleg, L.; Sasson, Y. Org. Proc. Res. Dev. 2003, 7, 44–46. (h) Venkatraman,
S.; Huang, T.; Li, C.-J. Adv. Synth. Catal. 2002, 344, 399–405. (i) Mukhopadhyay,
S.; Rothenberg, G.; Gitis, D.; Sasson, Y. Org. Lett. 2000, 2, 211–214.
(j) Mukhopadhyay, S.; Rothenberg, G.; Wiener, H.; Sasson, Y. Tetrahedron
1999, 55, 14763–14768.
(1) (a) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 2419–2440.
(b) Matheron, M. E.; Porchas, M. Plant Dis. 2004, 88, 665. (c) Horton, D. A.;
Bourne, G. T.; Smythe, L. M. Chem. Rev. 2003, 103, 893–930.
(2) (a) Baudoin, O.; Gueritte, F. Stud. Nat. Prod. Chem. 2003, 29, 355–
417. (b) Bringmann, G.; Gunther, C.; Ochse, M.; Schupp, O.; Tasler, S. In
Progress in the Chemistry of Organic Natural Products; Herz, W., Falk, H.,
Kirby, G. W., Moore, R. E., Eds.; Springer: New York, 2001; Vol. 82, pp 1-293.
(3) (a) Lightowler, S.; Hird, M. Chem. Mater. 2005, 17, 5538–5549.
(b) Zhan, X.; Wang, S.; Liu, Y.; Wu, X.; Zhu, D. Chem. Mater. 2003, 15,
1963–1969.
(4) (a) Kertesz, M.; Choi, C. H.; Yang, S. Chem. Rev. 2005, 105, 3448–
3481. (b) Roncali, J. Chem. Rev. 1992, 92, 711–738.
(5) Mei, X.; Wolf, C. J. Am. Chem. Soc. 2006, 128, 13326–13327.
(6) (a) Brunel, J. M. Chem. Rev. 2005, 105, 857–897. (b) Berthod, M.;
Mignani, G.; Woodward, G.; Lemaire, M. Chem. Rev. 2005, 105, 1801–1836.
(13) (a) Xu, L.; Wu, X.-C.; Zhu, J.-J. Nanotechnology 2008, 19, 305603.
(b) Panigrahi, S.; Kundu, S.; Ghosh, S. K.; Nath, S.; Pal, T. Colloids Surf., A
2005, 264, 133–138. (c) Mayya, K. M.; Jain, N.; Gole, A.; Langevin, D.;
Sastry, M. J. Colloid Interface Sci. 2004, 270, 133–139.
3908 J. Org. Chem. 2010, 75, 3908–3911
Published on Web 05/12/2010
DOI: 10.1021/jo1005729
r
2010 American Chemical Society

Monopoli et al.
JOCNote
TABLE 1. Optimization of the Reaction Conditions in the Pd Colloid-
Catalyzed Reductive Homocoupling of 4-Chloroanisole in Watera
run
reductant
glucose
base
T [°C] convb (%) selectivityc
1
2
3
4
5
6
7
8
9
TBAOH
TBAOH
TBAOH
TBAOH
TBAOH
TBAOH
KOH
40
60
90
110
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
35
45
92
91
93
93
<1
16
15
32
15
20
56
>99
13
7
88
89
93
90
96
50
glucose
glucose
glucose
glucosed
glucosee
glucose
glucose
glucose
KOHf
K2CO3
NaHCO3
62
66
75
80
90
68
27
23
30
39
5
f
f
10 glucose
11 glucose
12 glucose
13 fructose
14 HCOONa
15 propanal
16 hydroquinone
17 Zn powder
18 NaBH4
Et4NHCO3
TBAOHg
TBAOH
TBAOH
TBAOH
TBAOH
TBAOH
TBAOH
FIGURE 2. Pd 3d XP spectrum of Pd-NPs chemically synthesized
in aqueous solution in the presence of glucose and tetrabutyl-
ammonium hydroxide. Before XPS analysis, the colloidal suspension
was deposited on an inert Pt substrate. BE(Pd3d5/2) values for nano-
Pd(0) and Pd(II) were obtained via curve fitting and were, respec-
tively, equal to 335.6 ( 0.2 and 337.8 ( 0.2 eV.
33
39
66
96
19 glyceraldehyde TBAOH
20 ascorbic acid TBAOH
83
95
aReaction conditions: 4-chloroanisole (0.5 mmol), reductant (0.5 mmol),
base (1.5 mmol), and Pd acetate (3 mol %) in 1 mL of H2O, heated under
stirring for 6 h. bConversions based on GLC areas by using biphenyl
as external standard. cPercentage of the coupling with respect to the
reduction product. In some cases, small percentages (<2%) of the
regioisomeric homocoupling product 3,40 were also observed. dWith
The surface chemical composition of Pd nanocolloids
was assessed by means of X-ray photoelectron spectroscopy
(XPS). The main palladium XP signal, the Pd3d high resolu-
tion region, is reported in Figure2. Two doublets, corres-
ponding to two chemical states, were detected on the NP surface,
namely nanostructured Pd(0)14 and Pd(II) oxide and/or
hydroxides.15
f
0.25 mmol of glucose. eWith 1 mmol of glucose. In the presence of
1.5 mmol of di-Bu4NBr as PTC. gIn the presence of 1.5 mmol of KBr.
The oxidized palladium species always showed a low
relative abundance(10(4%inthecasereportedinFigure2).
The presence of this chemical environment can probably be
interpreted in terms of air-oxidation induced by the ex situ
characterization of Pd-NPs, although we cannot exclude that
residual Pd(II) ions derived from the NPs precursors have
formed traces of oxide/hydroxide species in the basic colloi-
dal suspension.
To avoid use of organic cosolvents, a phase-transfer agent
(PTC) was exploited to facilitate solvation of the aryl halide
in neat water. In line with our previous findings,11a the PTC
was properly chosen among the quaternary ammonium
salts by virtue of their ability to stabilize colloids. Because
a base was necessary, we decided to use tetrabutylammo-
nium hydroxide (TBAOH).
Preliminary experiments showed that conversions of the
chloroarene increased with temperature until a plateau was
reached at 90 °C, while selectivity remained roughly constant
throughout the reaction (Table 1, runs 1-4).
FIGURE 1. TEM pictures and core diameter distribution of Pd-NPs
chemically synthesized in aqueous solution in the presence of glucose
and tetrabutylammonium hydroxide.
Interestingly, due to the capacity of glucose to release
many reducing equivalents, the coupling was found to
be complete with a half-equimolar amount of reductant
(0.25 mmol), obtaining simultaneously almost complete
couplings of 4-chloroanisole were carried out under varied
conditions in terms of temperature, base, and additive (Table 1).
At the same time, the reaction mixture was analyzed by
the transmission electron microscopy technique to ascertain
both NP core morphology and size dispersion. Colloidal Pd-
NPs shape was almost spherical, and nanoparticles showed
an appreciable dimensional homogeneity with a mean core
diameter of 15 ( 3 nm and a slightly tailed size distribution
(see Figure 1 for typical TEM pictures and quantitative core
size information).
(14) (a) Cioffi, N.; Torsi, L.; Losito, I.; Sabbatini, L.; Zambonin, P. G.;
Bleve-Zacheo, T. Electrochim. Acta 2001, 46, 4205–4211. (b) Cioffi, N.;
Farella, I.; Torsi, L.; Valentini, A.; Sabbatini, L.; Zambonin, P. G. Sens.
Actuators, B 2003, 93 (1-3), 181–186.
(15) Moulder, J. F.; Stickle, W. F.; Sobol; P. E.; Bomben, K. D. In
Handbook of X-ray Photoelectron Spectroscopy; Perkin-Elmer Corp.: Eden
Prairie, 1992.
J. Org. Chem. Vol. 75, No. 11, 2010 3909

Monopoli et al.
JOCNote
selectivity (Table 1, run 5). On the contrary, with an excess of
glucose (twice the equimolar amount with respect to the
chloroarene), selectivity toward the homocoupling product
was lowered drastically (Table 1, run 6).
TABLE 2. Pd-Catalyzed Homocoupling of Aryl Halides Promoted by
Glucose in Watera
To date, the reduction mechanism of palladium with
glucose has not been thoroughly investigated. It is known
that under alkaline conditions the initial step should be the
formation of gluconic acid and then, the gluconate.13a
However, it is known also that under heating at 100 °C a
complete alkaline degradation of glucose can occur in only
30 min, leading, via the enediol intermediate, to a number of
byproducts with shorter chains.16 Among them, formic acid,
lactic acid, and glyconic acid are the most abundant, some of
which can act as reducing agents for palladium. This is the
rationale for using less than equimolar amounts of glucose.
Next, the effect of other bases and the role of TBAOH
were examined more deeply. To this end, both inorganic
carbonates and hydroxides were used in place of TBAOH,
adding to the reaction mixture Bu4NBr as phase-transfer
agent. All of them gave disappointing results (Table 1, runs
7-10).
At the same time, low conversions were also observed
when other tetraalkylammonium bases (Table 1, run 11) were
employed or when the same TBAOH was used but in the
presence of KBr as an additive (Table 1, run 12).
These results clearly demonstrate that TBAOH plays a
special role in creating a favorable environment for the
catalyst. Indeed, into the emulsioned mixture generated by
the surfactant, reactions presumably occur into the special
layer surrounding the nanoparticles surface, which contains
the organic species, Bu4Nþ cations, and the anionic counter-
part. Under these conditions, in the presence of TBAOH as
the sole surfactant, a high concentration of the base OH-
should be reached on the colloidal surface, with a corre-
sponding increase of the reaction rate. Otherwise, the pre-
sence of other anions, such as, for example, the Br- ions
arising from additives or other PTCs, should decrease the
[OH-] in close proximity to the active catalyst sites, lowering
the catalyst performances. Moreover, besides the role of
base, OH- chemisorbed13a on the nanoparticles surface is
expected to increase the electron density on palladium in so
much that the less reactive electron-rich chloroarenes can
also be coupled.17 Preliminary investigations were completed
by comparing, under the same reaction conditions, the
performances of glucose with those of the most common
reductants used in this process (Table 1, runs 13-20):
ascorbic acid was the sole reagent capable of providing yields
and selectivity comparable with those of glucose (Table 1,
run 20).12d
aReaction conditions: haloarene (0.5 mmol), glucose (0.25 mmol),
TBAOH (1.5 mmol), and Pd acetate (3 mol %) in 1 mL of H2O, heated
under stirring for 6 h. bIsolated yields. Selectivity of the coupling vs the
reduction product is higher than 95%. cTetrabutylammonium acetate in
0.1 mL of water was used as base instead of the TBAOH aqueous
Having established the optimal reaction conditions
(glucose/chloroarene 1:2 molar ratio, Pd source 3 mol %
and TBAOH 3 equiv with respect to chloroarene), the
protocol was extended to other aryl chlorides and bromides
to verify scope and limitations of the method (Table 2).
Notably, the results showed that this catalyst system
proved to be so active that bromoarenes, such as bromoben-
zene, 4-bromotoluene, 4-bromoanisole, and the heteroaryl
3-bromothiophene, were coupled in excellent yields under
d
e
solution. A GLC 15% of benzonitrile was detected. A GLC 13% of
acetophenone was detected.
extremely mild conditions (T = 40 °C, Table 2, runs 1-4),
with the exception of 2-bromotoluene which required the
slightly higher temperature of 60 °C (Table 2, run 5).
Instead, the reaction conditions suitable to couple chloro-
arenes were found to be dependent on the nature of the
substituent on the aromatic ring. In particular, neutral and
electron-poor chloroarenes were reacted smoothly at 60 °C
(Table 2, runs 6-10) and the electron-rich chloroarenes
required the minimum temperature of 90 °C (Table 2, runs
(16) (a) Yang, B. Y.; Montgomery, R. Carbohydr. Res. 1996, 280, 27–45.
(b) Yang, B. Y.; Montgomery, R. Carbohydr. Res. 1996, 280, 47–57.
(17) Choudary, B. M.; Madhi, S.; Chowdari, N. S.; Kantam, M. L.;
Sreedhar, B. J. Am. Chem. Soc. 2002, 124, 14127–14136.
3910 J. Org. Chem. Vol. 75, No. 11, 2010

Monopoli et al.
JOCNote
12-13), while for substrates bearing functional groups sus-
ceptible to the extreme basic conditions, such as 4-chloro-
benzonitrile and 4-chloroacetophenone, the replacement of
TBAOH with a weaker base such as tetrabutylammonium
acetate (TBAA) was necessary (Table 2, runs 7, 11).
It is worth mentioning that all of the reactions in Table 2
occurred, with few exceptions (Table 2, runs 7 and 11), with a
selectivity higher than 95% toward the coupling product
with respect to the reduction product.
To further verify the sustainability of our method, we
checked the feasibility of the catalyst recycling. To this end,
we decided to work on a larger scale by processing 10 mmol
of aryl halide (chlorobenzene). After completion of the reac-
tion, the coupling product was extracted with cyclohexane,
and fresh reagents were added to the reaction mixture for the
next run. Results18 showed that the aqueous catalyst solu-
tion was active for 3 runs, after which yields dropped
drastically. This clearly indicates that during the workup
operations nanoparticles undergo a rapid aggregation that
causes the loss of activity. Work aimed at anchoring colloids
on a solid support to improve the catalyst robustness is in
progress.
In conclusion, homocoupling of bromo- and chloroarenes
under moderate conditions can be achieved in water in the
presence of Pd colloids generated in situ by glucose as re-
ductant. This method proved to be highly efficient and green
for the following reasons: (i) the use of a green a renewable
reagent such as glucose provides a great advantage in terms
of safety, economy, and sustainability, (ii) more challenging
substrates, including the less reactive electron-rich chloro-
arenes (e.g., 4-chloroanisole), are activated without use of
special additives or ligands under relatively mild conditions
(reaction temperatures ranging from 40 to 90 °C), and (iii)
the combined activating and stabilizing effects of both
glucose and TBAOH provide a favorable environment for
the catalyst.
To the best of our knowledge, this is the first example of
using glucose as reagent in the biaryl homocoupling of aryl
halides. A comparison with the literature data on the reduc-
tive coupling in water12 shows how this method can compete
with the most efficient known protocols, and we anticipate
that it will find wide applicability due to its simple operating
procedure.
Experimental Section
General Procedure for the Reductive Homocoupling in Water.
In a 1 mL gastight vial, equipped with a screw cap and a mag-
netic bar, were placed chloroarene (0.5 mmol), glucose (0.25 mmol),
TBAOH (1.5 mmol), and Pd acetate (3 mol %). For a better
reproducibility of experiments, the use of a gastight vial having a
proper capacity (leaving a very small head space) to avoid the
formation of droplets of the reaction mixture on the walls of vial
is recommended. The flask was heated under air and under
stirring at the reaction temperature for a maximum of 6 h (see
Tables 1 and 2). The reaction mixture was washed with HCl 5%
and extracted with dichloromethane. To the organic phase was
added a known amount of an external standard (in almost all
cases biphenyl), and the mixture was examined by GLC and
GC-MS, providing both conversion and product identification
by comparison with spectral data reported in the literature.
Isolated yields in Table 2 were determined by purification of the
extracted dichloromethane solutions after evaporation of the
solvent in vacuo with a short pad of silica gel (eluent: petroleum
ether).
Acknowledgment. This work was financially supported,
ꢀ
in part, by the Ministero dell’Universita e della Ricerca
Scientifica e Tecnologica, Rome, and the University of Bari.
(18) Results on the recycling experiments of the aqueous catalyst solu-
tion in the honocoupling of chlorobenzene(10 mmol) are summarized
below. Experimental details on the recycling tests are given in the Support-
ing Information.
Supporting Information Available: Experimental details and
spectroscopic XPS and NMR data for colloids and the coupling
products, respectively. This material is available free of charge
via the Internet at http://pubs.acs.org.
run
first recycle second recycle third recycle fourth recycle
94 91 62 21
yield (%)
J. Org. Chem. Vol. 75, No. 11, 2010 3911