Palladium(II)-Schiff base complex immobilized covalently on h-BN: An efficient and recyclable catalyst for aqueous organic transformations

Article abstract of DOI:10.1016/j.tet.2016.11.027

A moisture- and air-stable palladium(II)-Schiff base complex supported on h-BN was simply prepared by using commercially available reagents. This nanomaterial was applied as an excellent and recyclable heterogeneous catalyst for the Suzuki and Heck cross-coupling reactions. And it has been characterized by FT-IR, XRD, SEM, XPS, TG and ICP-AES techniques. High yields, ligand-free, low reaction time, water as solvent, non-toxicity and recyclability of the catalyst are the main merits of these protocols. In addition, a series of pharmacologically relevant products were successfully synthesized using this catalyst. Above all, this work opens up an interesting and attractive avenue for the use of h-BN as an efficient support for heterogeneous catalysts.

Full text of DOI:10.1016/j.tet.2016.11.027

Accepted Manuscript
Palladium(II)-Schiff base complex immobilized covalently on h-BN: An efficient and
recyclable catalyst for aqueous organic transformations
Weijian Li, Guanghui Lv, Xu Cheng, Rui Sang, Xiaojun Ma, Yong Zhang, Ruifang Nie,
Jie Li, Mei Guan, Yong Wu
PII:
S0040-4020(16)31171-1
10.1016/j.tet.2016.11.027
TET 28241
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 31 August 2016
Revised Date: 7 November 2016
Accepted Date: 8 November 2016
Please cite this article as: Li W, Lv G, Cheng X, Sang R, Ma X, Zhang Y, Nie R, Li J, Guan M, Wu Y,
Palladium(II)-Schiff base complex immobilized covalently on h-BN: An efficient and recyclable catalyst
for aqueous organic transformations, Tetrahedron (2016), doi: 10.1016/j.tet.2016.11.027.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Palladium(II)-Schiff base complex
immobilized covalently on h-BN: An efficient
and recyclable catalyst for aqueous organic
transformations
Leave this area blank for abstract info.
a
c
a
a
a
a
a
a
Weijian Li, Guanghui Lv, Xu Cheng, Xiaojun Ma, Yong Zhang, Rui Sang, Ruifang Nie, Jie Li, Mei
b
a
Guan* and Yong Wu*
a
Key Laboratory of Drug Targeting and Drug Delivery System of Education Ministry, Department of Medicinal Chemistry,
West China School of Pharmacy, Sichuan University, No.17, 3th Section, South Renmin Road, Chengdu, 610041, P. R.
China
b
West China Hospital, Sichuan University, No. 37. GuoXue Road, Chengdu, 610041, P. R. China
c
Department of Pharmacy, Taihe Hospital, Hubei University of Medicine, Hubei Shiyan 442000, China

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Palladium(II)-Schiff base complex immobilized covalently on h-BN: An efficient and
recyclable catalyst for aqueous organic transformations
a
c
a
a
a
a
a
a
Weijian Li , Guanghui Lv , Xu Cheng , Rui Sang , Xiaojun Ma , Yong Zhang , Ruifang Nie , Jie Li ,
b
a
Mei Guan * and Yong Wu ∗
a
Key Laboratory of Drug Targeting and Drug Delivery System of Education Ministry, Department of Medicinal Chemistry, West China School of Pharmacy,
Sichuan University, No.17, 3th Section, South Renmin Road, Chengdu, 610041, P. R. China
b
West China Hospital, Sichuan University, No. 37. GuoXue Road, Chengdu, 610041, P. R. China
Department of Pharmacy, Taihe Hospital, Hubei University of Medicine, Hubei Shiyan 442000, China
c
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A moisture- and air-stable palladium(II)-Schiff base complex supported on h-BN was simply
prepared by using commercially available reagents. This nanomaterial was applied as an
excellent and recyclable heterogeneous catalyst for the Suzuki and Heck cross-coupling
reactions. And it has been characterized by FT-IR, XRD, SEM, XPS, TG and ICP-AES
techniques. High yields, ligand-free, low reaction time, water as solvent, non-toxicity and
recyclability of the catalyst are the main merits of these protocols. In addition, a series of
pharmacologically relevant products were successfully synthesized using this catalyst. Above
all, this work opens up an interesting and attractive avenue for the use of h-BN as an efficient
support for heterogeneous catalysts.
Available online
Keywords:
hexagonal boron nitride
heterogeneous catalysis
C-C cross coupling
ligand-free
2
009 Elsevier Ltd. All rights reserved.
water
1
. Introduction
of most reported ligands seems rather laborious and time-
consuming. Therefore, based on the concerns of economic and
green chemistry, the development of mild, simple and efficient
procedures, using heterogeneous phosphorus-free catalysts, is
still a topic of considerable interest in organic synthesis and
industry.
Transition-metal catalyzed cross-coupling reactions have been
used as a powerful method in modern synthetic organic
chemistry for the preparation of natural products, advanced
materials,
biologically active compounds, polymers, UV screens,
hydrocarbons and liquid crystal materials. Among the various
transition-metal catalyzed cross-coupling reactions, the Heck–
Mizoroki and Suzuki–Miyaura reactions are the most important
and highly effective protocols for the construction of carbon–
agrochemicals,
pharmaceuticals,
herbicides,
1
On the other hand, Schiff bases are an important class of
organic ligands in coordination chemistry and have been
extensively used as metal Schiff base complexes to catalyze
organic reactions due to the advantages such as their cost-
effective, ease of synthesis, availability and thermal and chemical
2
3
4
carbon bonds. In the past few years, numerous effective and
9
stability. However, the use of metal Schiff base complexes as
selective homogeneous palladium catalytic systems have been
developed for such reactions, but they have disadvantages such
as tedious separation and contamination of the coupled products
catalyst in homogeneous solution suffers from deactivation
because of formation of µ-oxo and dimeric peroxo- species,
which have been demonstrated to be inactive in various
5
with Pd species. Alternatively, metal catalysts anchored on a
10
reactions. Moreover, difficulties in separation and reusability of
homogeneous metal (particularly expensive metals) Schiff base
complexes have limited the applications of these catalysts. For
overcoming the aforementioned drawbacks, metal Schiff base
complexes can be immobilized on suitable solid supports.
heterogeneous support have received tremendous attention
recently in C–C cross-coupling. Heterogeneous processes have
6
advantages such as ease of separation of the product, reusability
of the catalyst, better steric control of the reaction intermediate
7
and so on. Notably, although C-C cross-coupling reactions
catalyzed by palladium-phosphine systems have achieved great
success over the last decade, however, phosphine ligands are
often quite expensive, air-sensitive, and virulent, which limit
their wide use in large-scale application. Besides, the preparation
Hexagonal boron nitride (h-BN) is defined as material whose
free charges are immobile in one spatial dimension, but mobile in
another two. This property enables h-BN to have novel or
8
∗
Corresponding author. Tel.: +028-85503235; e-mail: meiguan92@163.com; wyong@scu.edu.cn

2
Tetrahedron
ACCEPTED MANUSCRIPT
2
Scheme 1. The synthetic strategy for the synthesis of h-BN@Fur@Pd(OAc) .
1
1
superior functions, distinct from traditional bulk materials. It is
similar in many ways to graphene: it has a stacked sheet
morphology, high thermal conductivity, and excellent mechanical
propyl trimethoxy silane (APTMS) to synthesize amino-
functionalized boron nitride. Thirdly, h-BN@Fur wasformed by
the condensation of furfural with h-BN@APTMS. Ultimately,
the complexation of Pd(OAc)2 onto schiff base generate the
heterogeneous Pd(II) catalyst.
12
strength. However, it is an electrical insulator and is more
chemically inert and temperature stable than graphene. Starting
from reported applications, h-BN have been widely applied in
13
14
15
2.2 Catalyst characterization
hydrogen storage, adsorption of pollutants, drug delivery
16
and water cleanup. In addition, h-BN can be used as very good
catalyst supports because of their high surface area and
insolubility in most solvents. For example, Pt/BN has been
applied in deep oxidation of methanol and benzene. Postole et
al. studied the influence of the preparation methods of Pd/BN
The synthesized nanocatalyst was characterized using several
different microscopic and spectroscopic techniques including FT-
IR, SEM, TGA, ICP, XRD and XPS analysis.
17
Scanning electron microscopy (SEM) has been used in order
to shed light on the presence, distribution, and dimension of the
prepared hybrid nanomaterials. As shown in Fig. 1a-b, no
obvious morphology difference can been found between h-BN
and h-BN@OH. They all exhibit schistose structures with smooth
edge and flat surface. And it can be clearly seen that the size of
palladium(II) loaded nanocatalyst is in range of 50-500 nm.
Notably, after functionalization, the h-BN nanosheets still
arranged in schistose structures and appeared more broken and
aggregated (Fig. 1c).
18
catalysts on the activity for methane oxidation.
The introduction of metal nanoparticles into pristine h-BN has
been widely reported during the past few years, and their
application in organic synthesis have also been investigated.
However, these catalysts often show a broad size distribution and,
in many cases, suffer from severe leaching phenomena. This is
probably due to the lack of sufficient binding sites on the pristine
h-BN surface and the only existent weak non-covalent
interactions between pristine BN and metal nanoparticle. On the
other hand, despite several studies on the morphology, properties
19
20
and preparation of organic modified h-BN, no metal has been
immobilized onto functionalized boron nitride as a heterogeneous
catalyst. Herein, we report the production of Pd catalyst based on
Schiff-base modified h-BN, as a separable and recyclable catalyst
for Suzuki and Heck coupling reactions. All these reactions were
performed in water with high efficiency and excellent yields. To
the best of our knowledge, this is the first report on the
immobilization of palladium(II) on BN for catalytic application
purpose. And, it’s the first time to synthesize a BN-based
heterogeneous catalyst for C-C coupling reactions.
2
2
. Results and discussion
.1 Catalyst preparation
As shown in Scheme 1, the immobilization of Pd(II) onto
furfural-functionalized hexagonal boron nitride was performed in
four steps. Firstly, pristine h-BN was treated with hydroxide
anions, resulting in the formation of free hydroxyl group on the
edge of BN sheets. Secondly, h-BN@OH reacted with amino
Figure 1. SEM of (a) pristine h-BN, (b) h-BN@OH and (c) h-BN@Fur@
2
Pd(OAc) .

3
ACCEPTED MAgr
N
ou
U
ps.
S
B
C
es
R
id
I
es, the weight loss of about 3.6% and 5.5% were
P
T
a
h-BN@OH
observed for h-BN@APTMS and h-BN@Fur, respectively.
These should be mainly attributed to the thermal degradation of
organic components on the BN complex. Moreover, around 1.9%
weight loss was observed when comparing these two samples. It
suggests that furfural was successfully conjugated to h-
BN@APTMS particles. In the curve of h-BN@Fur, the first step
in the curve is associated with the loss of water molecules (below
1
1
1
00
80
60
40
20
3
420 O-H
7
99 B-N
2
00 °C). The second weight loss, starting at 200 °C disintegrates
the supported organic parts with a calculated loss of 3.73%.
Notably, the amount of palladium (1.7%) of h-
BN@Fur@Pd(OAc)2 was determined by inductively coupled
plasma (ICP) analysis. In all, these results corroborate the FT-IR
datas.
0
4
B-N 1395
000 3500 3000 2500 2000 1500 1000 500
-
1
Wavenumber (cm
)
b
h-BN@APTMS
00
1
Si-O
033
80
60
40
20
2928 C-H
100
3
O-H
427
1120
Si-O
1.7 %
1
.7 %
99
98
97
96
8
06 B-N
1.8 %
0
4
h-BN@OH
B-N 1391
h-BN@APTMS
h-BN@Fur
1.9 %
000 3500 3000 2500 2000 1500 1000 500
9
5
4
-
1
)
Wavenumber (cm
9
100
200
300
400
500
600
700
o
c
h-BN@Fur
Temperature ( C)
00
2
928 C-H
Figure 3. TGA thermograms of h-BN@OH, h-BN@APTMS and h-BN@Fur.
80
60
40
20
3
O-H
420
1025
Si-O
1119
Si-O
h-BN@APTMS
8
04 B-N
h-BN@Fur@Pd(OAc)
2
0
4
B-N 1390
000 3500 3000 2500 2000 1500 1000 500
-
1
Wavenumber (cm )
Figure 2. FT-IR spectra of (a) h-BN@OH, (b) h-BN@APTMS, (c) h-BN@
Fur.
1
6 20 24 28 32 36 40 44 48 52 56 60 64 68 72
Infra-red spectroscopy was used to characterize the organic
components bound to the surface of h-BN (Fig. 2). The
characteristic absorption band of B-N bonds was observed at
2 θ
-
1
-1
Figure 4. XRD patterns of h-BN@APTMS and h-BN@Fur@Pd(OAc)2.
1
1
2
395 cm and 799 cm (Fig. 2 a), which was slightly shifted to
-1 -1
391 cm and 806 cm after the conjugations with APTMS (Fig.
a vs b). And all the functionalized h-BN showed a strong band
Fig. 4 shows the wide angle XRD patterns of h-BN@APTMS
and h-BN@Fur@Pd(OAc) nanomaterials. These two samples
show the same diffraction peaks at 2θ = 26.7, 41.6, 43.9, 50.1
and 55.1, which correspond to the (002), (100), (101), (102) and
004) lattice planes of a typical hexagonal boron nitride structure
JCPDS no. 34-0421). It suggests that the crystal structure of the
h-BN has not been compromised by the reaction. And in the
process of the coordination between the h-BN@Fur and
palladium ions, the formation of Pd nanoparticles was completely
avoided. No characteristic peaks of palladium particles were
-
1
at around 3420 cm , which was attributed to the stretching
vibrations of O-H bonds (Fig. 2 a-b and c). Comparison studies
on h-BN@OH and h-BN@APTMS reveal additional strong
bands at 1120 and 1033 cm corresponding to characteristic
absorption of Si-O bonds formed through the silylation process.
2
-
1
(
(
-
1
Besides, for the h-BN@APTMS peak at 2928 cm was assigned
to stretching vibration of C-H bonds of the propyl-amine groups
(
Fig. 2 b). Unfortunately, the stretching vibrations of C=N bands,
-1 21
at near 1625 cm , was concealed under the broad absorption
peak of B-N bonds. But the condensation of h-BN@APTMS
with furfural can be confirmed by other techniques.
found in the XRD pattern of h-BN@Fur@Pd(OAc) , which
2
implies that all of the catalytic activity is attributed to divalent
palladium. Moreover, no peaks corresponding to any other
impurity were observed.
For the quantitative analysis, the as-prepared h-BN@OH, h-
BN@APTMS and h-BN@Fur were further observed via TGA,
Detailed surface information of h-BN@APTMS and h-
BN@Fur@Pd(OAc)2 was collected by X-ray photoelectron
spectroscopy (XPS) and the corresponding results are presented
in Fig. 5. The new peaks of O 1s, C 1s and Si 2p can be assigned
in Fig. 5a, indicating that (3-Aminopropyl)-trimethoxysilane
and these results are shown in Fig. 3. The experiments were
o
performed at up to 760 C in an N atmosphere at a heating rate
2
o
-1
of 10 C min . Under these conditions, a weight loss of about
.72% was observed for h-BN@OH, it should be ascribed to the
removal of physically adsorbed solvents and surface hydroxyl
1

4
Tetrahedron
(
APTMS) has successfully attached to the su
A
rfa
C
ce
C
an
E
d
P
ed
T
ges
E
D
of MAev
NU
id
enc
S
e
C
of
R
c
I
h
P
emical bonding between the BN particles and the
T
pristine BN particles. And the spectrum of the h-
BN@Fur@Pd(OAc)2 shows a large increase in the signal
intensity of the O 1s and C 1s peaks, which is attributed to
furfural covalently grafted to the h-BN@APTMS.
silane curing agent, the Si 2p peak can be fitted by a curve with
several component peaks (Fig. 5c). In the de-convoluted Si 2p
spectra, the strong peak at the binding energy of 102.1 eV
represents the bond between silicon and oxygen originating from
the BN particles (B-O-Si), indicating that the surface curing
agent and BN particles are connected through the hydroxyl
groups. The peak at 103.3 eV is attributed to siloxane (Si-O-Si)
resulting from the partial hydrolysis of the silane curing agent
molecules during the silanization reaction. Moreover, the peak at
a)
h-BN@APTMS
h-BN@Fur@Pd(OAc)
2
1
00.8 eV is attributed to Si-C bonding in the silane curing agent
molecules. These results are in agreement with the reaction
mechanism of silane, including the hydrolysis of -OCH3,
condensation to oligomers, hydrogen bonds between oligomer
and hydroxyl groups on the substrate, and the formation of the
covalent linkage between silane and the substrate. The peak at
1
02.5 eV is attributed to Si-OH bonding, indicating that some
1
000
800
600
400
200
0
hydroxyl groups did not hydrolyze and a small amount of
hydroxyl group remained.
Binding Energy (eV)
23
b)
B-N 190.1 eV
1
2000 B 1s
0000
The XPS spectrum of the Pd 3d core level region for the h-
BN@Sal@Pd(OAc)2 nanocomposite displays main peaks at
1
3
38.2 and 343.4 eV which can be attributed to the binding energy
8
6
4
2
000
000
000
000
0
of Pd 3d5/2 and Pd 3d , respectively (Fig. 5d). These values
correspond to the Pd(II) binding energies of Pd(OAc)2.
3/2
B-O
2
.3 Investigation of the catalytic activity of h-BN@Fur@
1
92.0 eV
Pd(OAc) in the Suzuki reaction.
2
Table 1. Optimization of the Suzuki reaction between 4-bromoaceto-
phenone and phenylboronic acid using h-BN@Fur@Pd(OAc) as
catalyst.
1
94
193
192
191
190
189
188
2
a
Binding Energy (eV)
c) 2200
Si 2p
2
1
1
1
1
1
000
800
600
400
200
Si-O-B 102.1 eV
1
02.5 eV
o
b
Si-OH
Entry
Base
Cs CO
KOH
t-BuOK
CO
Et
NaHCO
Pd (.equiv)
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.01
0.1
Temp ( C)
Yield (%)
000 103.3 eV
Si-O-Si
Si-C
1
2
3
4
5
6
2
3
70
70
70
70
70
70
70
70
70
25
50
100
70
70
70
70
70
70
70
70
70
85
90
87
97
88
89
70
85
97
22
73
82
70
98
98
100.8 eV
8
6
4
00
00
00
1
06 105 104 103 102 101 100 99 98
K
2
3
Binding Energy (eV)
3
N
d)
3
3
38.2 eV
5
5
4
4
3
3
2
2
500 Pd 3d
c
7
K
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
000
500
000
500
000
500
000
d
8
K
2
343.4 eV
e
9
K
2
1
1
1
1
1
0
1
2
3
4
K
2
K
2
K
2
K
2
K
2
3
50 348 346 344 342 340 338 336 334 332
Binding Energy (eV)
15
K
2
0.2
g
h
i
f
1
6
K
2
0.05
0.05
0.05
0.05
0.05
/
N.R
f
Figure 5. Full range XPS spectrum of h-BN@APTMS and h-BN@Fur@
Pd(OAc) (a), and the B 1s (b), Si 2p (c), Pd 3d (d) core level region XPS
spectra of the h-BN@Fur@Pd(OAc) nanocomposite.
17
K
2
N.R
f
2
1
1
2
2
8
9
0
1
K
2
N.R
2
j
f
K
2
N.R
k
l
K
2
96
The B 1s spectra of h-BN@Fur@Pd(OAc) showed a strong
2
f
K
2
N.R
binding energy peak for the B-N bond and a weak binding energy
peak for the B-OH bond at 190.1 eV and 192.0 eV, respectively
a
22
Reaction conditions: 1a (1 mmol), 2a (1.5 mmol), h-BN@Fur@Pd(OAc)
2
(Fig. 5b). The B-OH peak resulted from the introduction of a
(
2
0.05 mmol), base (1.5 mmol), H O (1 mL), Ar, 0.5h.
hydroxyl group by the base treatment. In order to provide clearer
b
Isolated yield.

5
c
d
e
f
K
2
CO
CO
CO
3
(0.5 mmol).
(1.0 mmol).
3
(2.0 mmol).
ACCEPTED MA
1
N
5
USC2-
R
OC
I
H
P
3
-
T
Ph
Ph
Ph
3.5
9
3p
3q
87
76
K
2
3
16
2-NH
2
-5-
pyridyl
K
2
1
1
1
7
8
9
2-CHO-Ph
Ph
Ph
Ph
1.5
2.5
5
3r
3s
3t
85
85
88
N.R. = No reaction.
h-BN@Fur@Pd(OAc)
h-BN@Fur@Pd(OAc)
3-NO
2
-Ph
-Ph
g
h
i
2
2
was replaced by 300mg h-BN.
3-COCH
3
was replaced by 300mg h-BN@OH.
was replaced by 300mg h-BN@APTMS.
was replaced by 300mg h-BN@Fur.
a
Reaction conditions: 1 (1 mmol), 2 (1.5 mmol), h-BN@Fur@Pd(OAc)
0.05 mmol), K CO (1.5 mmol), H O (1 mL), Ar.
2
h-BN@Fur@Pd(OAc)
h-BN@Fur@Pd(OAc)
h-BN@Fur@Pd(OAc)
No catalyst.
2
(
b
2
3
2
j
2
Isolated yield
.
k
l
2
2
was replaced by 11.3mg Pd(OAc) .
After the optimization of the reaction conditions, we examined
the catalytic activity of h-BN@Fur@Pd(OAc) for various aryl
2
halides and phenylboronic acids. As shown in Table 2, all the
substrates including electron-donating or electron-withdrawing
functional groups were successfully converted to the
corresponding biphenyls in good to excellent yields. Besides,
synthetically useful naphthyl and pyridyl were well tolerated in
this transformation, giving 3k and 3q in good yields.
Furthermore, the experimental procedure is very simple and
convenient, and has the ability to tolerate a variety of different
functional groups such as OH, OCH , CN, CHO, NO , NH and
Cross-coupling reactions such as Suzuki and Heck reactions
are powerful tools for the preparation of natural products,
advanced materials and biologically active compounds.
Therefore, h-BN@Fur@Pd(OAc) was primarily used as a novel
2
heterogeneous and highly reusable nanocatalyst in the Suzuki
reaction. For this purpose, the coupling of 4-bromoacetophenone
1a) with phenylboronic acid (2a) was selected as a simple model
(
reaction to optimize the reaction conditions, and the results are
summarized in Table 1. First, a range of bases, such as Cs CO ,
3
2
2
2
3
halogen.
KOH, t-BuOK, K CO , Et N and NaHCO , were used in this
2
3
3
3
transformation, however, all of them were unsatisfactory except
for K CO (Table 1, entries 1-6). With respect to the amount of
2.4 Investigation of the catalytic activity of h-BN@Fur@
Pd(OAc) in the Heck reactions.
2
3
2
K CO , 1.5 equivalents was found to be adequate, as neither
2
3
Table 3. Optimization of the Heck reaction between iodobenzene
bigger nor smaller amount showed better yields (Table 1, entries
-9). When the reaction was allowed to proceed in different
a
and styrene using h-BN@Fur@Pd(OAc) as catalyst.
2
7
o
temperatures, an optimal yield of 97% was obtained at 70 C
Table 1, entries 4, 10-12). For the optimization of the amount of
(
Pd used in the model reaction, less than 0.05 equivalent led to the
incompletion of the reaction (Table 1, entry 13). And up to 0.1 or
0
(
.2 equiv. of Pd did not increase the yield of 6a significantly
Table 1, entries 14-15). Above all, aryl halides (1, 1 mmol) in
the presence of a catalytic amount of h-BN@Fur@Pd(OAc)2
o
b
Entry
Base
Cs CO
KOH
t-BuOK
CO
Et
NaHCO3
Pd (.equiv)
Temp. ( C)
Yield (%)
1
2
3
4
5
6
2
3
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.01
0.02
0.1
90
90
90
90
90
90
90
90
90
50
70
100
90
90
90
90
90
90
90
90
90
65
81
84
91
70
72
32
73
87
23
77
79
37
56
91
(
1
0.05 mmol) and K CO (1.5 mmol) with phenylboronic acids (2,
.5 mmol) in water at 70 C was considered to be the ideal
2
3
o
reaction conditions.
K
2
3
Table 2. Investigation of the substrate scope for Suzuki reaction
3
N
a
catalyzed by h-BN@Fur@Pd(OAc)2.
c
7
K
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
3
3
3
d
8
K
2
e
9
K
2
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
K
2
b
Entry
R
1
R
2
Time
Products Yield
(%)
K
2
(h)
K
2
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1
3b
3c
3d
3e
3f
85
90
89
81
90
90
82
K
2
2-CH
3
3
-Ph
-Ph
0.5
0.5
0.5
0.5
0.5
0.5
K
2
3-CH
K
2
3-OH-Ph
4-OCH -Ph
4-C(CH -Ph
g
h
i
f
K
2
0.05
0.05
0.05
0.05
0.05
/
N.R
3
f
K
2
N.R
3
)
3
3g
3h
f
K
2
N.R
3,5-C(CH
3 3
) -
j
f
Ph
19
20
21
K CO3
N.R
2
2
2
k
l
8
9
Ph
4-F-Ph
0.5
0.5
0.5
3.5
2
3i
3j
79
83
87
81
93
82
K CO3
92
f
Ph
3-CN-Ph
K CO3
N.R
1
1
1
1
0
1
2
3
Ph
1-naphthyl
3k
3l
a
Reaction conditions: 4a (1 mmol), 5a (1.5 mmol), h-BN@Fur@Pd(OAc)
2
4-NH
3-NH
2
2
2
-Ph
Ph
Ph
Ph
(
0.05 mmol), base (2 mmol), H
2
O (1 mL), 3.5h.
-Ph
3m
3n
b
Isolated yield.
3-NH
Ph
-4-CH
3
-
2
c
K
2
CO
3
(0.5 mmol).
d
1
4
4-OH-Ph
Ph
2
3o
99
K
2
CO
3
(1.0 mmol).

6
Tetrahedron
b
e
K
2
CO
3
(3.0 mmol).
Isolated yield.
ACCEPTED MANUSCRIPT
f
c
o
N.R. = No reaction.
h-BN@Fur@Pd(OAc)
h-BN@Fur@Pd(OAc)
70 C.
g
h
i
2
2
was replaced by 300mg h-BN.
To further define the scope of this new catalyst for the Heck
reaction, a wide range of aryl halides, styrenes and acrylates were
reacted under the optimized conditions. And the results were
summarized in Table 4. A host of aryl halides bearing either the
electron-donating groups or electron-withdrawing groups were
well tolerated during the course of the reaction, providing the
desired compounds 6b-h in good to excellent yields. Besides, in
addition to stilbenes, the acrylate derivatives 6i-j and 6l-p could
also be obtained in excellent yields. Notably, synthetically useful
heterocyclic groups, such as thienyl (6p), were well tolerated in
this transformation. What's more, a variety of functional groups
such as carbonyl, ether, halogen, amino, nitro and aldehyde
group were well-suited for this reaction.
was replaced by 300mg h-BN@OH.
was replaced by 300mg h-BN@APTMS.
was replaced by 300mg h-BN@Fur.
h-BN@Fur@Pd(OAc)
h-BN@Fur@Pd(OAc)
h-BN@Fur@Pd(OAc)
No catalyst.
2
j
2
k
l
2
2
was replaced by 11.3mg Pd(OAc) .
In order to extend the catalytic applications of h-
BN@Fur@Pd(OAc) , it was then applied for another C-C cross
coupling reaction. At the beginning of our investigation,
experiments were carried out using iodobenzene (4a) and styrene
2
(5a) as the model substrates. Among various bases examined,
K CO turned out to be the best choice, while others such as
2
3
2
.5 Recycling of the catalyst
Cs CO , KOH, t-BuOK, Et N and NaHCO were less effective
2
3
3
3
(
Table 3, entries 1-6). For the optimization of the amount of
For practical applications of catalytic systems, the lifetime of
K CO used in the model reaction, two equivalent was found to
the catalyst and its level of reusability are significant factors. To
clarify this issue, the feasibility of recycling the Pd catalyst was
then examined. After the reaction, the catalyst was simply
separated by filtration and successively washed with water,
dichlormethane and acetone. And in the recycling experiment,
the recovered dry catalyst was recharged with a fresh substrate
for the next run under the same reaction conditions. h-
2
3
be adequate, as neither larger nor smaller amount showed better
yields (Table 3, entries 7-9). Further investigation indicated that
temperature was important for this transformation. An excellent
yield has been obtained when the reaction was carried out at 90
o
C (Table 3, entry 4). However, with the temperature increasing
o
to 100 C, the yield of 6a dropped to 79% (Table 3, entry 12).
Only 23% and 77% yields of 6a were obtained when the reaction
BN@Fur@Pd(OAc) has been reused ten times in the reaction of
2
o
were conducted at 50 and 70 C (Table 3, entries 10-11).
4-bromoacetophenone and phenylboronic acid without
significant loss of its catalytic activity (Fig. 6a). Besides, the
catalyst still remained catalytically active after being reused nine
times in the reaction of 1-iodo-2-nitrobenzene and methyl
acrylate. The Heck reaction at the 8th and 9th runs gave the
desired product in 94% and 92% yields (Fig. 6b). Thus, it is
reasonable to believe that the immobilized catalyst can be
repeatedly used for large-scale production without a significant
loss of its catalytic activity.
Moreover, after extensive screenings, we were pleased to find
that 0.05 mmol of Pd was enough to catalyze this reaction (Table
3
, entries 4, 13-15). Therefore, as observed in this study, the
optimized conditions for the synthesis of 6a tend to be:
iodobenzene (1 mmol), styrene (1.5 mmol), h-BN@Fur@
o
Pd(OAc) (0.05 mmol) and K CO (2.0 mmol) in water at 90 C.
2
2
3
Table 4. Investigation of the substrate scope for Heck reaction
a
catalyzed by h-BN@Fur@Pd(OAc)2.
Entry
R
1
X
R
2
Tim
e (h)
Products Yield
b
(%)
1
2
3
4
2-NH
2
-Ph
I
I
Ph
Ph
5
5
5
5
6b
6c
6d
6e
85
90
84
90
4-Cl-Ph
2-CHO-Ph Br Ph
3
4-CH CO- Br Ph
Ph
5
6
3-CHO-Ph Br Ph
5
5
6f
87
85
3
3-CH CO- Br Ph
Ph
6g
7
3-NO
2
-Ph Br Ph
5
4
6h
6i
95
95
97
70
90
91
95
c
2
Figure 6. Reusability of h-BN@Fur@Pd(OAc) for the synthesis of 3a (a)
8
Ph
I
I
I
I
I
I
COOCH
3
and 6o (b).
9
Ph
CONH
2
4.5
5
6j
1
1
1
1
0
1
2
3
Ph
CN
6k
6l
2.6 Synthesis of pharmacologically relevant compounds via
Suzuki and Heck reactions
4-Cl-Ph
4-Cl-Ph
COOC
2
H
5
2
COOC(CH
3
)
3
2
6m
6n
The synthesis of pharmacologically interesting compounds is
one of the most important applications of C-C coupling reactions.
Inspired by its high efficiency, excellent recyclability and wide
3-OCH
Ph
3
-
COOCH
3
2.5
1
1
4
5
2-NO
2
-Ph
I
I
COOCH
3
2
4
6o
6p
95
92
scope of substrates, h-BN@Fur@Pd(OAc) was utilized in the
synthesis of pharmacologically important products through
Suzuki and Heck reactions (Fig. 7).
2
2-thienyl
COOCH3
a
Reaction conditions: 4 (1 mmol), 5 (1.5 mmol), h-BN@Fur@Pd(OAc)
0.05 mmol) and K CO (2 mmol) in water (1 mL) at 90 C.
2 3
2
o
(

7
ACCEPTED MA (c h
N
ro
U
ma
S
to
C
gr
R
ap
I
h
P
y
T
characterization was performed with silica gel
1
100-200mesh). H NMR spectra were recorded at 400 or 600
MHz and C NMR spectra were recorded at 100 MHz. Fourier
transform infrared (FT-IR) spectra were performed on a Nicolet
13
6
700 FI-IR spectrometer (Nicolet), using KBr pellets. X-ray
photoelectron spectroscopy (XPS) measurements were carried
DLD
out on AXIS Ultra
spectrometer (KRATOS). X-ray
diffractometer (XRD) spectra were recorded with EMPYREAN
spectrometer (Panalytical). The morphologies of h-BN catalyst
were observed by using scanning electron microscopy (SEM,
JSM-7500F). Thermal gravitational analysis (TGA) was
Figure 7. Pharmacologically relevant compounds synthesized by using h-BN
Fur@Pd(OAc) as catalyst.
performed with a thermal analyzer (TGA/DSC2, METTLER
@
2
o
TOLEDO) at rate of 10 C/min under N protection. The loading
2
content of Pd was determinded by inductively coupled plasma
optical emission spectroscopy (ICP-OES, SPECTRO ARCOS).
Felbinac 3u, a non-steroidal anti-inflammatory drug (NSAID),
was first launched in 1993 by Takeda and Wyeth
Pharmaceuticals (now Pfizer) for the treatment of rheumatic and
4
.2 Preparation of the catalyst
24
mild arthritic pain, sprains, strains and other soft tissue injuries.
Felbinac acts as a non-selective inhibitor of the enzyme
cyclooxygenase (COX), and is characterized as non-selective
because it inhibits both the cyclooxygenase-1 (COX-1) and
cyclooxygenase-2 (COX-2) isoenzymes. The Suzuki reaction of
Preparation of hydroxy functionalised h-BN (h-BN@ OH).
First, h-BN (4 g) was dispersed in 5M sodium hydroxide solution
o
(500 mL) at 120 C for 24 h. Then the particles were filtered and
washed with D.I. water (3 x 150 mL) to adjust the pH from basic
to neutral. Finally, the obtained white solid (3.50 g) was dried
4
-bromophenylacetic acid with phenylboronic acid was smoothly
o
conducted, using h-BN@Fur@Pd(OAc) as catalyst under the
under reduced pressure at 80 C for 6 h, and stored in a desiccator
2
optimized conditions, providing Felbinac in 93% yield. On the
other hand, diverse derivatives of cinnamic acid possess various
pharmacological activities. For example, Zhu et al. reported that
compound 6q showed strong antifungal activity by altering the
at room temperature.
Preparation of amino functionalised h-BN (h-BN@
APTMS). The h-BN@OH particles (3 g) were dispersed in dry
toluene (120 mL) and stirred at 25 C for 20 mins. Then, to the
resulting solution, 1.6 mL (3-Aminopropyl)trimethoxy-silane
o
25
permeability of fungal cell membrane. And good antibacterial
activity of compound 6r had been exhibited by Davis and co-
26
(
2
APTMS) was added drop wise. And the mixture was stirred for
4 h at 120 C under argon protection. The resulting particles (h-
works. These two compounds can be easily obtained in 94%
and 90% yields via h-BN@Fur@Pd(OAc)2 catalyzed Heck
reactions.
o
BN@APTMS) were filtered and wished several times with
toluene. Finally, the obtained white solid (3.05 g) was dried
under reduced pressure at 80 C for 6 h.
o
3
. Conclusion
In conclusion, a novel covalently immobilized palladium(II)-
Schiff base complex on hexagonal boron nitride (h-
BN@Fur@Pd(II)) has been synthesized. After its
Preparation of h-BN@Fur@Pd(OAc) . First, the prepared
2
h-BN@APTMS particles (500 mg) were dispersed in 40 mL of
absolute ethanol. Then 2-furfuraldehyde (218.3 mg, 2.27 mmol )
and four drops of acetic acid were added into the suspension.
After refluxing for 5 h. Pale brown solid was got by filtering the
mixture and washing with methanol and DCM each for 3 times.
characterization using various methods, it was used as a new air-
and moisture-stable catalyst for Suzuki and Heck C-C cross
coupling reactions. A wide range of aryl halides were
successfully coupled with aryl-boronic acids, styrenes and
acrylates to generate high yields of the corresponding products in
water. And a series of pharmacologically relevant products have
been successfully synthesized using this catalyst. Furthermore,
the catakyst can be separated easily by filtration and recycled at
least nine runs without appreciable loss of its catalytic activity.
The continued study on the broader scope of this catalyst to other
reaction substrates and other types of chemical reactions will be
on the way.
Then, the particles were mixed with Pd(OAc) (408 mg, 1.8
2
mmol) in DCM (50 mL) and stirred for 24 h under argon
protection at room temperature. The resulting mixture was
filtered and washed with DCM for 5 times to remove unreacted
Pd(OA ) . Finally, the brown solid (417 mg) was dried under
C 2
vacuum at room temperature for 5 h.
4.3 General procedure for the Suzuki reaction
In a typical run, h-BN@Fur@Pd(OAc) (0.05 mmol) was
2
added to a mixture of arylboronic acid 1 (1.0 mmol), aryl
bromide 2 (1.5 mmol) and K CO (1.5 mmol) in water (1 mL).
4
4
. Experimental section
2
3
o
.1 General
The resulting mixture was stirred at 70 C under Ar protection,
and the progress of the reaction was monitored by TLC. After
completion of the reaction, ethyl acetate was added to the
reaction mixture and the catalyst was separated. The organic
phase was washed with water, dried over anhydrous Na SO and
The h-BN powder (99.9%) was obtained from Micxy Regent
Co. Ltd. (Chengdu, China). (3-Aminopropyl) trimethoxysilane
(
(
APTMS, 97%) was purchased from Aladdin Reagent Co.Ltd.
Shanghai, China). Sodium hydroxide (NaOH, 96%) was
2
4
the solvent was evaporated under reduced pressure. Finally, the
residue was isolated by chromatography on a column of silica gel
to afford the corresponding product 3.
collected from Tianjin Ruijinte Chemicals Co. Ltd. (Tianjin,
China). 2-furfuraldehyde (99.0%) was provided by Tianjin Bodi
Chemicals Co. Ltd. (Tianjin, China). Palladous acetate
(
Pd(OAc) , 99.0%) was supplied by Xian Catalyst Chemicals Co.
2
4
.4 General procedure for the Heck reaction
Ltd. (Xian, China). All other materials were commercially
available and used without further purification. Thin layer
chromatography (TLC) characterization was performed with
precoated silica gel GF254 (0.2mm), while column
A mixture of aryl halogen 4 (1.0 mmol), substituted alkene 5
(1.5 mmol), K CO (2.0 mmol) and h-BN@Fur@Pd(OAc) (0.05
2 3 2
o
mmol) was stirred in water at 90 C (progress of the reaction was

8
Tetrahedron
1
1. a) Pakdel, A.; Bando Y.; Golberg, D. Chem. Soc. Rev., 2014, 43,
monitored using TLC). After completion of
A
th
C
e
C
re
E
ac
P
tio
T
n
E
, t
D
he MANUSCRIPT
9
6
34-959; (b) Lin Y.; Connell, J. W. Nanoscale, 2012, 4, 6908-
939.
mixture was cooled to room temperature and then catalyst was
separated and washed with ethyl acetate three times. Then the
filtrate was diluted with water and extracted with ethyl acetate.
The organic layer was dried over anhydrous sodium sulfate and
the solvent was removed under vacuum. Finally, the crude
residue was purified by flash chromatography on silica gel to
give the final product 6.
1
1
2. Lin, Y.; Connell, J. W. Nanoscale, 2012, 4, 6908-6939.
3. Weng, Q. H.; Wang, X. B.; Bando Y.; Golberg, D. Adv. Energy.
Mater., 2014, 4, DOI: 10.1002/aenm.201301525.
14. Xiong, J.; Zhu, W. S.; Li, H. P.; Ding, W. J.; Chao, Y. H.; Wu, P.
W.; Xun, S. H.; Zhang M.; Li, H. M. Green. Chem., 2015, 17,
1
647-1656.
1
1
5. Weng, Q. H.; Wang, B. J.; Wang, X. B.; Hanagata, N.; Li, X.; Liu,
D. Q.; Wang, X.; Jiang, X. F.; Bando Y.; Golberg, D. ACS Nano,
2014, 8, 6123-6130.
6. (a) Lei, W. W.; Portehault, D.; Liu, D.; Qin S.; Chen, Y. Nat.
Commun., 2013, 4, 1777; (b) Yu, Y. L.; Chen, H.; Liu, Y.; Craig,
V. S. J.; Wang, C. M.; Li L. H.; Chen, Y. Adv. Mater. Interfaces,
Supplementary Material
General reaction procedure for the synthesis of 3 and 6,
spectroscopic characterization data of new compounds.
2
015, 2, DOI: 10.1002/admi. 201400529.
7. Lin, C. A.; Wu, J. C. S.; Pan, J. W.; Yeh, C. T. J. Catal. 2002, 210,
9-45.
1
1
3
Acknowledgments
8. (a) Postole, G.; Caldararu, M.; Ionescu, N. I.; Bonnetot, B.;
Auroux, A.; Guimon, C. Thermochim. Acta. 2005, 434, 150-157;
We are grateful for support from the National Natural Science
Foundation of China (NSFC) (grant number 81373259 &
(b) Postole, G.; Gervasini, A.; Guimon, C.; Auroux, A.; Bennetot,
B. J. Phys. Chem. 2006, 110, 12572-12580; (c) Postole, G.;
Gervasini, A.; Auroux, A.; Bonnetot, B. Mater. Sci. Forum. 2006,
8
1573286).
5
18, 203-210.
1
9. (a) Yabe, Y.; Yamada, T.; Nagata, S.; Sawama, Y.; Monguchi Y.;
Sajiki, H. Adv. Synth. Catal., 2012, 354, 1264; (b) Yabe, Y.;
Sawama, Y.; Monguchi Y.; Sajiki, H. Chem. Eur. J., 2013, 19,
484; (c) Uosaki, K.; Elumalai, G.; Noguchi, H.; Masuda, T.;
Lyalin, A.; Nakayama A.; Taketsugu, T. J. Am. Chem. Soc., 2014,
136, 6542; (d) Yabe, Y.; Sawama, Y.; Yamada, T.; Nagata, S.;
Monguchi Y.; Sajiki, H. ChemCatChem., 2013, 5, 2360; (e) Meyer,
L.; Devillers M.; Hermans, S. Catal Today., 2015, 241, 200; (f)
Meyer, N.; Bekaert, K.; Pirson, D.; Devillers, M.; Hermans, S.
Catal Commun., 2012, 29, 170.
References and notes
1
.
(a) Islam, S. M.; Roy, A. S.; Mondal, P.; Salam, N. Appl.
Organomet. Chem., 2012, 26, 625; (b) Pasa, S.; Ocak Y. S.; Temel,
H.; Kilicoglu, T. Inorg. Chim. Acta, 2013, 405, 493; (c) Ghorbani-
Choghamarani, A.; Rabiei, H. Tetrahedron Lett., 2016, 57, 159; (d)
Nadri, S.; Joshaghani, M.; Rafiee, E. Appl. Catal., A, 2009, 362,
1
1
63; (e) Hajipour, A. R.; Rafiee, F. J. Iran. Chem. Soc., 2015, 12,
177.
2
.
(a) Biffis, A.; Zecca, M.; Basato, M. J. Mol. Catal. A: Chem.,
001, 173, 249; (b) Whitcombe, N. J.; Hii K. K.; Gibson, S. E.
Tetrahedron, 2001, 57, 7449.
20. (a) Kumar, R.; Gopalakrishnan, K.; Ahmad I.; Rao, C. N. R. Adv.
Funct. Mater., 2015, 25, 5910; (b) Wu H. C.; Kessler, M. R.; ACS
Appl. Mater. Interfaces., 2015, 7, 5915; (c) Sainsbury, T.; Satti, A.;
May, P.; O’Neill, A.; Nicolosi, V.; Gun’ko Y. K.; Coleman, J. N.
Chem. Eur. J., 2012, 18, 10808; (d) Cui, Z. H.; Oyer, A. J.; Glover,
A. J.; Schniepp H. C.; Adamson, D. H. Small., 2014, 10, 2352; (e)
Oh, K. H.; Lee, D.; Choo, M. J.; Park, K. H.; Jeon, S.; Hong, S. H.;
Park J. K.; Choi, J. W. ACS Appl. Mater. Interfaces., 2014, 6,
7751; (f) Cui, Z. H.; Martinezb A. P.; Adamson, D. H. Nanoscale.,
2015, 7, 10193; (g) Yang, N.; Xu, C.; Hou, J.; Yao, Y. M.; Zhang,
Q. X.; Grami, M. E.; He, L. Q.; Wang N. Y.; Qu, X. W. RSC Adv.,
2016, 6, 18279; (h) Lei, W. W.; Mochalin, V. N.; Liu, D.; Qin, S.;
Gogotsi Y.; Chen, Y. Nat Commun., 2016, 6, DOI:
10.1038/ncomms9849.
2
3
4
.
.
Han, F.-S. Chem. Soc. Rev., 2013, 42, 5270.
(a) Seechurn, C. C. C. J.; Kitching, M. O.; Colacot T. J.; Snieckus,
V. Angew. Chem., Int. Ed., 2012, 51, 5062; (b) Zhong Y.; Han, W.
Chem. Commun., 2014, 50, 3874; (c) Tobisu, M.; Xu, T.;
Shimasaki T.; Chatani, N. J. Am. Chem. Soc., 2011, 133, 19505;
(d) Zhang, R.; Miao, C.; Wang, S.; Xia C.; Sun, W.
ChemCatChem, 2013, 5, 142; (e) Beletskaya I. P.; Cheprakov, A.
V. Coord. Chem. Rev., 2004, 248, 2337; (f) Mao, J.; Guo, J.; Fang
F.; Ji, S.-J. Tetrahedron, 2008, 64, 3905.
Butters, M.; Catterick, D.; Craig, A.; Curzons, A.; Dale, D.;
Gillmore, A.; Green, S. P.; Marziano, I.; Sherlock J.-P.; White, W.
Chem. Rev., 2006, 106, 3002.
5
.
21. Zhao, Q. S.; Bai, C.; Zhang, W. F.; Li, Y.; Zhang, G. L.; Zhang F.
B.; Fan, X. B. Ind. Eng. Chem. Res. 2014, 53, 4232-4238.
22. Kim, K.; Kim, M.; Hwang, Y.; Kim, J. Ceramics International,
2014, 40, 2047-2056.
6
7
.
.
Karimi, B.; Mansouri F.; Vali, H. Green Chem., 2014, 16, 2587.
Zhang, Q.; Su, H.; Luo J.; Wei, Y. Y. Catal. Sci. Technol., 2013, 3,
2
35.
8
.
(a) Phan, N. T. S.; VanDerSluys M.; Jones, C. W. Adv. Synth.
Catal., 2006, 348, 609; (b) Andersen N. G.; Keay, B. A. Chem.
Rev., 2001, 101, 997; (c) Martin R.; Buchwald, S. L. Acc. Chem.
Res., 2008, 41, 1461; (d) Miyaura, N.; Suzuki, A. A. Chem. Rev.,
23. (a) Contarini, S.; Howlett, S. P.; Rizzo, C.; DeAngelis, B. A. Appl
Surf Sci, 1991, 51, 177-1783; (b) Fujita, K.; Oya, A. J. Mater. Sci.
Technol, 1996, 31, 4609-4615.
24. Prous, J.; Castaner, J. Drugs. Fut., 1987, 12, 120.
25. Zhu, J.; Zhu, H.; Kobamoto, N.; Yasuda, M.; Tawata, S. J.
Pesticide Sci., 2000, 25, 263-266.
26. Davis, D. C.; Mohammad, H.; Kyei-Baffour, K.; Younis, W.;
Creemer, C. N.; Seleem, M. N.; Dai, M. J. Eur. J. Med. Chem.,
2015, 101, 384.
1
995, 7, 2457.
Dileep, R.; Badekai, R. B. Appl. Organometal. Chem, 2010, 24,
63.
9
1
.
6
0. (a) Ballus, K. J.; Khanmamedova, A. K.; Dixon, K. M.; Bedioui, F.
Appl. Catal. A, 1996, 143, 159; (b) Heinrichs, C. Holderich, W. F.
Catal. Lett, 1999, 58, 75.