Dendrimer-encapsulated Pd nanoparticles as catalysts for C-C cross-couplings in flow microreactors

Article abstract of DOI:10.1039/c5ob00289c

The inner walls of glass microreactors were functionalized with dendrimer-encapsulated Pd nanoparticles. The catalysts were efficient for the Heck-Cassar (copper-free Sonogashira) and Suzuki-Miyaura (SMC) cross-coupling reactions. For the Heck-Cassar reaction between iodobenzene and phenylacetylene, the catalytic system exhibited a high turnover frequency (TOF) and on average required milder reaction conditions as compared to other continuous flow cross-couplings. A study of the substituent effect of para-substituted aryl halides revealed a beneficial effect of electron-withdrawing side groups for the SMC. Moreover, a reaction constant (ρ) of 1.5, determined from the Hammett plot, indicated a possible rate-determining step other than the oxidative addition.

Full text of DOI:10.1039/c5ob00289c

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DOI: 10.1039/C5OB00289C
ARTICLE
Dendrimer-encapsulated Pd nanoparticles as
catalysts for C-C cross-couplings in flow
microreactors
Cite this: DOI: 10.1039/x0xx00000x
Roberto Ricciardi, Jurriaan Huskens and Willem Verboom*
Received 00th January 2012,
Accepted 00th January 2012
The inner walls of glass microreactors were functionalized with dendrimer-encapsulated Pd
nanoparticles. The catalysts were efficient for the Heck-Cassar (copper-free Sonogashira) and
Suzuki-Miyaura (SMC) cross-coupling reactions. For the Heck-Cassar reaction between
iodobenzene and phenylacetylene, the catalytic system exhibited a high turnover frequency
(TOF) and on average required milder reaction conditions as compared to other continuous
flow cross-couplings. A study of the substituent effect of para-substituted aryl halides revealed
a beneficial effect of electron-withdrawing side groups for the SMC. Moreover, a reaction
constant (ρ) of 1.5, determined from the Hammett plot, indicated a possible rate-determining
step other than the oxidative addition.
DOI: 10.1039/x0xx00000x
www.rsc.org/
of reagent diffusion limitation, promotes conversion rates that
can be much higher than in batch operations.9 The use of
Introduction
Carbon-carbon (C-C) cross-couplings are among the most used
and studied reactions, especially for their importance in
industrial processes.1 In fact, biaryls and heterobiaryls are
intermediates in many pharmaceuticals, natural derivatives, and
dyes.2 Palladium is the metal of choice for these reactions and
several homogeneous catalysts rely on Pd(II) and Pd(0) species,
mostly in the form of Pd complexes.3 Depending on the reagent
involved, several examples of C-C cross-couplings have been
developed since the early 1970s, such as the Suzuki-Miyaura,
the Mizoroki-Heck, the Sonogashira, the Stille reactions, etc.4
Transition metal nanoparticles (NPs) have gained a lot of
interest over the last decade for a variety of applications, with
catalysis exerting a central role.5 These nanometer species are
considered ideal candidates for improving the sustainability of
catalytic processes, blending together the advantages of
homogeneous and heterogeneous catalysts.6 In this respect, Pd
NPs are widely utilized as catalyst for C-C cross-coupling
reactions, as witnessed by the numerous reviews present in the
literature.7
continuous flow microreactors, however, necessitates stable
NPs which can be reused for many cycles. A variety of
strategies has already been shown in literature for the
stabilization of Pd NPs within microchannels and has been
employed mainly in Suzuki-Miyaura and Heck reactions.10
Examples of continuous-flow Sonogashira,11 Negishi,12 and
Stille13 reactions have been based on different Pd catalysts.
The leaching of metal species associated with the use of Pd
NPs for C-C cross-couplings under flow conditions represents
an important issue. The debate is centered on whether the Pd
catalysts act in a heterogeneous or a homogeneous manner.14
Meanwhile, the accepted mechanism for Pd cross-couplings,
independently from the type of catalyst used, involves the
formation of Pd2+ after the oxidative addition of an aryl halide.
These molecular species, even in very small quantities, can
catalyze cross-coupling reactions.15 Usually Pd2+ atoms
redeposit on the mother NPs at the end of the catalytic cycle,
while the application of continuous flow eventually leads to the
washing out of dissolved Pd and hence loss of catalyst.16 To this
regard, Kappe et al 17
have conducted a comparative study of
.
A stable heterogeneous catalytic system making use of
supported Pd NPs would undoubtedly allow to carry out cross-
coupling reactions in continuous flow systems.8 In this way, the
high local concentration of catalyst, together with the absence
some of the most common immobilized diarylphosphine- and
triarylphosphine-based Pd catalysts, with particular attention to
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the leaching resistance for continuous flow Suzuki-Miyaura and confirmed the formation of homogeneously dispersed 2.4 nm
Mizoroki-Heck reactions. Under the reaction conditions used, Pd NPs within the dendrimer templates (see supporting
View Article Online
the SiliaCat DPP-Pd catalyst gave the best results in terms of information).20a The detailed description of the analytical
DOI: 10.1039/C5OB00289C
catalyst efficiency and leaching resistance.18
procedures has been presented elsewhere.19 The total amount of
Recently, we have presented the synthesis of dendrimer- catalyst within the microreactor was 0.12 µg of Pd metal as
encapsulated Pd NPs (Pd DENs) anchored onto the inner walls measured by total reflection X-ray fluorescence (TXRF). This
of flow microreactors.19 The thus formed catalytic platform was value indicates the Pd retained by the dendrimer templates
successfully used in a test Suzuki-Miyaura cross-coupling attached to the surface of the microreactor. The quantity of
(SMC) reaction of iodobenzene with p-tolylboronic acid. The metal atoms within the microreactor volume (13 µL) is thus 1.1
choice of this system was motivated by the advantageous nmol.
feature of dendrimers as a template for NP formation and
activity.20 The G3 PAMAM dendrimer exhibited the best
activity as compared to higher dendrimer generations. With a
turnover frequency (TOF) as high as 11340 h-1, the system
outperformed many other flow-supported Pd NP reactors as
well as Pd DENs used in batch scale studies. Additionally,
dendrimers were demonstrated to have good stabilizing
properties towards metal leaching.21 In fact, the reactor was run
over seven consecutive days showing a minimal Pd leaching
(1.2 ppm).19
Herein, we expand the scope of Pd DENs as catalysts for
cross-coupling reactions under continuous flow. Therefore, the
Heck-Cassar coupling (the copper-free Sonogashira) reaction
was investigated. Additionally, we studied the influence of
Scheme 1 Microreactor surface functionalization with dendrimer‐encapsulated
para-substituted aryl iodides on the overall SMC reactivity. In
this way, through a Hammett plot of the aryl iodides
substituents, we aimed at gaining insight into some catalytic
mechanistic aspects, such the rate-determining step of the
reaction.
Pd NPs.
Heck-Cassar coupling (copper-free Sonogashira reaction)
The Sonogashira cross-coupling has become one of the
most useful tools for the synthesis of alkyl-aryl- and diaryl-
substituted acetylenes.23 Generally, this reaction is carried out
with Pd as the catalyst and a copper salt as a co-catalyst.24 The
Cu(I) salt is usually used in the same mixture as the reagents to
increase the reactivity through the formation of a copper(I)
acetylide with the terminal alkyne.23b However, the addition of
copper, although for some aspects beneficial, poses some
problems such as avoiding the presence of oxygen that can lead
to the formation of alkyne dimers (Glaser-type reactions).25
Moreover, heterogeneous Pd catalysts should ensure a minimal
contamination of the final product, another reason to avoid a
homogeneous co-catalyst. The solution to address these
problems is the use of only a Pd catalyst in the so-called
‘copper-free’ Sonogashira, or Heck-Cassar coupling, as it is
usually referred to.26 However, the Heck-Cassar coupling is
more difficult to carry out with Pd NPs than the SMC reaction.
The reaction usually requires high temperatures and a large
excess of base.23 Nevertheless, the coupling of iodobenzene and
phenylacetylene was efficiently carried out in the Pd DEN-
functionalized microreactor (Scheme 2).
Results and discussion
Microreactor functionalization
For the functionalization of the microreactor surface we
followed the methodology described in
publication.19 Briefly, the inner surface of a glass microreactor
was first modified with reactive monolayer of (3-
aminopropyl)triethoxysilane (APTES) followed by -phenylene
a
previous
a
p
diisothiocyanate (DITC). In this way the exposed
isothiocyanate groups were used for the covalent anchoring of
G3-NH2 and G3-OH PAMAM dendrimers. Two different
methodologies for the formation of Pd NPs were employed, as
depicted in Scheme 1. In one approach NH2- and OH-
terminated dendrimers were first attached to the monolayer-
functionalized surface and thereby Pd NPs were formed in situ
,
using K2PdCl4 as a Pd source followed by reduction by NaBH4.
In the other approach, Pd DENs were preformed in solution,
based on the procedure developed by Crooks in which Gn-OH
dendrimers contained 40-atom Pd NPs,22 and subsequently
anchored to the reactive monolayer. The characterization of the
Pd DENs was carried out on silicon dioxide surfaces
functionalized in the same way as the microchannel interior.
Contact angle, UV-vis spectroscopy, X-ray photoelectron
spectroscopy (XPS), transmission electron microscopy (TEM),
and high-resolution scanning electron microscopy (HRSEM)
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of temperatures, residence times, and less environmentally
friendly solvents such as DMF and NMP.
View Article Online
DOI: 10.1039/C5OB00289C
Substituent effect for the Suzuki-Miyaura cross-coupling
reaction
Pd DEN-functionalized microreactors were also used in the
SMC, with particular attention to the role of different electron-
withdrawing and electron-donating substituents on the aryl
halide counterpart. All aryl halides were cross-coupled with a
Scheme 2 Sonogashira coupling of iodobenzene and phenylacetylene catalyzed
by Pd DEN‐microreactors.
The catalytic system reached almost quantitative conversion
in less than 15 min of residence time (Fig. 1). The temperature
was set at 100 °C and tetrabutylammonium hydroxide was used
as base. The formation of diphenylacetylene was monitored by
GC and no side products were formed in the course of the
reaction (Figure S24). Because the two reagents are present in
almost stoichiometric amounts, a second order rate constant of
1.3 × 10-1 M-1 s-1 was calculated from the initial rates (see linear
fit in Fig. 1).
slight excess of phenylboronic acid or p-tolylboronic acid in
ethanol. Tetrabutylammonium hydroxide was used as a base
and the temperature was set at 80 °C (Table 1). The reaction
conditions were kept the same for all the experiments to
exclude any external influence on the catalytic activity.
Table 1 Suzuki-Miyaura cross-coupling reactions catalyzed by Pd DEN-
microreactors.a
Entry
Ar-X
R2
Yieldb
(%)
Conversionb
(%)
1
2
H
CH3
H
93
96
91
92
91
96
96
94
95
70
65
65
60
30
28
50
40
96
>99
>99
>99
>99
>99
>99
74
3
4
CH3
H
5
Fig. 1 Diphenylacetylene formation in a G3‐NH2(Pd)‐functionalized microreactor.
[Iodobenzene] = 10 mM, [phenylacetylene] = 15 mM, [Bu4NOH] = 20 mM. The
line indicates a linear fit through the first data points to estimate the initial rate.
6
CH3
H
7
8
CH3
H
Considering a catalyst loading of 1.1 nmol, the turnover
frequency number (TOF) for the continuous flow Pd DEN-
catalyzed Sonogashira reaction was 800 h-1. To this regard,
9
10
11
12
13
14
15
16
CH3
H
69
Astruc and co-workers27 developed recently
a dendritic
70
CH3
H
75
nanoreactor with hydrophilic triethylene glycol termini and a
hydrophobic interior for the stabilization of small Pd NPs. This
catalytic system was very efficient for a variety of C-C cross-
coupling reactions. The highest TOF obtained for the
Sonogashira coupling of iodobenzene and phenylacetylene was
375 h-1, comparable to the value obtained with our catalytic
system. In addition, our DEN-functionalized microreactor
exhibits a higher TOF as compared to other Pd NP-catalyzed
33
CH3
H
35
54
CH3
45
17
18
19
H
52
10
40
55
15
45
Sonogashira
couplings
between
iodobenzene
and
Br
phenylacetylene,27 with only a few exceptions.28 The majority
of examples of Sonogashira couplings under continuous flow
make use of Pd catalysts other than supported NPs.8b Different
approaches, ranging from ionic liquids,29 monoliths,30 surface
thin layers,11b,31 and perovskite catalysts,11a have been used in
the coupling of several terminal alkynes with aryl halides. In
most of the cases, however, harsher reaction conditions were
generally used as compared to our microfluidic reactor, in terms
CH3
CH3
a [Ar-X] = 10 mM; [Ar-B(OH)2] = 15 mM; [Bu4NOH] = 20 mM; res. time 13
min. b The yield and conversion data were obtained by GC (see Experimental
section and Supporting information)
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Fig. 2 Formation of 1‐R1‐biphenyls using Pd DENs‐functionalized microreactors.
R1 = ( ) OCH3. [4‐R1‐iodobenzene] = 10 mM, [phenylboronic acid] =
) COCH3; (
150 mM, [Bu4NOH] = 160 mM.
As expected, electron-withdrawing groups enhanced the
■

overall reactivity, with very high yields (92-96%) and
conversions > 99% (Table 1, entries 3-8).32 Electron-donating
groups, on the other hand, showed a reduced reactivity within
the reaction time selected, with yields ranging from 40 to 70%
(Table 1, entries 9-17). Aryl bromides are much less reactive as
compared to aryl iodides (Table 1, entries 18-19), as is common
for SMC reactions. Moreover, little difference in reactivity was
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DOI: 10.1039/C5OB00289C
observed between phenylboronic- and p-tolylboronic acid. The
disparity between the yields and the conversions for all entries
is due to the presence of some degree of homocoupling and
dehalogenated side products (~ 5%).
To assess the electronic substituent effects in a quantitative
manner, the apparent rate constants, kobs, for a variety of
substituted aryl iodides were calculated by using a large excess
of phenylboronic acid. In this way pseudo-first-order conditions
were obtained and the kobs values were calculated from the
corresponding kinetic curves (two examples for electron-
withdrawing and electron-donating para-substituents are shown
in Fig. 2). The logarithms of the thus obtained kobs values were
Fig.
3 Hammett plot for Suzuki‐Miyaura cross‐couplings using Pd DEN‐
functionalized microreactors showing the effect of para‐substituted
iodobenzenes on the reaction rate.
Conclusions
plotted against the Hammett parameter
σ
(Fig. 3).33 Although it
Continuous-flow microreactors functionalized using small
dendrimer-encapsulated Pd NPs were employed in the catalysis
of C-C cross-coupling reactions. This same approach has been
presented in a recent study for the efficient catalysis of a model
is problematic to obtain relevant mechanistic information from
this analysis whenever multistep reactions are involved, it is
possible to gain useful information, especially about the
electronic state of the transition state of the rate-determining
step.34 The catalytic cycle of transition-metal-catalyzed cross-
coupling reactions, including the SMC, consists of three steps:
oxidative addition, transmetalation, and reductive elimination.3a
In most cases, the oxidative addition represents the rate-
determining step of the catalytic cycle for the SMC.32 In our
study, a linear Hammett plot was obtained with a positive
Suzuki-Miyaura
cross-coupling
(SMC)
reaction,19
demonstrating also the influence of dendrimers in the
stabilization of the Pd NPs with low metal leaching. Here, the
reaction scope of the Pd DEN microreactors was expanded,
including the Sonogashira coupling of iodobenzene and
phenylacetylene, carried out in the absence of a copper co-
catalyst (Heck-Cassar coupling) and at milder reaction
conditions than other Pd catalysts used in flow. The calculated
TOF of 800 h-1 was comparatively higher than many other Pd
DEN platforms used for the batch scale Sonogashira synthesis.
Furthermore, the beneficial effect of electron-withdrawing
groups was proved for the SMC of substituted aryl iodides. The
Hammett plot analysis confirmed the influence of the
substituent on the kinetics and thus on the transition state of the
rate-determining step, which is most likely not represented by
the oxidative addition as common, but possibly the
transmetalation or reductive elimination steps.
reaction constant (ρ = 1.5). This result indicates the presence of
a negative charge at the reaction center in the transition state of
the rate-determining step, with electron-withdrawing
substituents at aryl iodides that increase the reaction rate.35
Usually, the SMC reactions of substituted aryl bromides and
aryl tosylates show low, positive
ρ values (for ArBr: 0.48,
0.66,36 0.18,37 and 1;38 for ArOTs: 0.8039), suggesting that the
aryl halide oxidative addition is not the rate-determining step in
this process, but possibly the transmetalation or the reductive
elimination. In contrast, higher
ρ values were obtained for the
oxidative addition of aryl chlorides to Pd(0) complexes (5.2,40
and 2.341).
Further work is needed to extend the applicability of the Pd
DENs microreactors to other C-C cross-couplings, such as the
Mizoroki-Heck and the Stille reactions. Nevertheless, the
anchoring of DENs within microreactors would allow the easy
screening of several mono- and bimetallic nanoparticles for a
variety of catalytic reactions.
Experimental section
Materials and equipment
The chemicals and solvents were purchased from Sigma
Aldrich unless otherwise stated and were used without
purification unless specified. Single-side-polished silicon
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wafers were purchased from OKMETIC with (100) orientation. Technologies) by means of Upchurch Nanoport™ assembly
Methanol and ethanol (VWR, analytical reagent grade) were parts (i.e., Nano-Tight™ unions and fittings, Upchurch
used without further purification, water was purified with the Scientific Inc. USA). During the experiments, theVmiewicArrtoicrleeaOcntlioner
DOI: 10.1039/C5OB00289C
Milli-Q pulse (millipore, R = 18.2 MΩ cm) ultrapure water was placed in a home-built chip holder designed for fitting
system, toluene was purified through a solvent purification fused silica fibers into the inlet/outlet chip reservoirs by means
system dispensing ultra dry solvents (MBraun, MB-SPS-800). of commercially available Upchurch Nanoport™ assembly
Contact angles were measured on a Krüss G10 contact angle parts. Glass microreactors with a residual volume of 13 μL
measuring instrument, equipped with a CCD camera. Gas (dimensions: 150 µm width and 150 µm depth) were purchased
chromatography (GC) experiments were performed with an from Micronit Microfluidics.
Agilent DB-5MS UI column (30 m × 0.32 mm i.d., 25 μm film
thickness) with a constant pressure of 11.9 psi. GC samples
were prepared by collecting 50 µL of reaction mixture. The
Dendrimer-encapsulated Pd NP functionalization of flat surfaces
and microreactors
oven temperature was held at 50 °C for 1 min and increased Deposition of a monolayer of APTES and DITC. Both the SiO2
linearly at a rate of 30 °C min-1 to 290 °C with a final hold of 1 surface and the microreactor channels were cleaned with a
min. The conversions were determined from the area under the Piranha solution (H2SO4:H2O2 3:1) and then copiously rinsed
curve of the peaks corresponding to reagents, products and with water and dried with a stream of nitrogen. (CAUTION:
possible side products. The peaks were identified by injecting Piranha solution is a very strong oxidant and reacts violently
the corresponding reaction products which were commercially with many organic materials). The clean surface was
available. The yields were calculated with reference to functionalized
with
a
monolayer
of
(3-
calibration curves calculated injecting the commercially aminopropyl)triethoxysilane (APTES) and
p
-phenylene
available compounds at three different concentrations (5 mM, diisothiocyanate (DITC, Acros Organics) following a slightly
10 mM, and 15 mM). For all the experiments Bu4NOH was modified literature procedure.43 First, the silicon surface was
used as internal standard because the area under its peak soaked in a 10 mM solution of APTES in dry toluene for 15 h.
remained constant during the course of the reaction, unless For functionalization in the device the same solution was
specified otherwise. For X-ray photoelectron spectroscopy flowed for 15 h at a flow rate of 0.05 µL min-1. Silicon wafers
(XPS) a Quantera Scanning X-ray Multiprobe instrument was and microchannels were rinsed with dry toluene and ethanol to
used, equipped with a monochromatic Al Kα X-ray source remove the unreacted reagent and dried with a stream of
producing approximately 25 W of X-ray power. XPS-data were nitrogen. Subsequently, the APTES-modified flat surface was
collected from a surface area of 1000 × 300 μm with a pass reacted with a 50 mM solution of DITC in dry toluene for 5 h.
energy of 224 eV and a step energy of 0.8 eV for survey scan The same solution was flowed within the microreactor for 5 h
and 0.4 for high resolution scans. For quantitative analysis, high at 0.05 µL min-1. Silicon wafers and microchannels were rinsed
resolution scans were used. Absorption spectra were recorded with dry toluene and ethanol to remove the unreacted reagent
on a Perkin Elmer Lambda 850 UV-vis spectrophotometer. The and dried with a stream of nitrogen.
optical path length was 10 mm, and deionized water was used Formation and anchoring of Pd DENs. In situ procedure. A
as reference. For high resolution scanning electron microscopy methanolic solution of 150 µM G3 PAMAM dendrimer
(HRSEM) characterization a Zeiss 1550 FE-SEM was used. (ethylenediamine core) was reacted with the APTES-DITC-
Transmission electron microscopy (TEM) was performed using functionalized silicon surface for 10 h at room temperature.
a Philips CM300 microscope operating at 300 kV. Samples for After rinsing with methanol and water, the surface was soaked
imaging were deposited onto a 200 mesh copper grid and the in a 5 mM solution of K2PdCl4 for 2 h after which it was rinsed
liquid was allowed to dry in air at room temperature. The with water. Afterwards, the reduction of Pd particles was
nanoparticle dimensions were obtained from TEM images with obtained by reaction with a 20 mM aqueous solution of NaBH4
ImageJ software, for each sample at least 50 particles were (20 min). The same procedure was followed for the
measured. Total reflection X-ray fluorescence (TXRF) microreactor functionalization by flowing the dendrimer,
measurements were carried out on a S2-PICOFOX™ (Bruker palladium salt, and reducing agent solutions at 0.05 µL min-1
AXS, Karlsruhe, Germany) system with a low power Xray tube for the respective times.
by means of a Mo source and an energy-dispersive, 50 Peltier- Preformed in solution procedure. The formation of Pd DENs
cooled silicon drift detector (SDD, XFlash™). The software in solution was accomplished by following a slightly modified
SPECTRA version 6.1.5.0 (Bruker AXS, Karlsruhe, Germany) literature procedure.22 First, a 150 µM aqueous solution of G3
was used for data evaluation.42
PAMAM-OH dendrimers was prepared and stirred for 30 min.
A 40-fold excess of palladium was introduced by means of
K2PdCl4 and the mixture was left for 2 h at room temperature.
Flow apparatus
In all microreactor experiments, the sample solutions were Pd NPs were obtained by reduction with a 10-fold excess of
mobilized by means of a PHD 22/2000 series syringe pump NaBH4. The so-formed G3-OH(Pd) NPs were anchored onto
(Harvard Apparatus, United Kingdom) equipped with 500 μL the APTES-DITC-functionalized silicon surface by dipping the
flat tip syringes (Hamilton). Syringes were connected to fused wafer into the dendrimer solution for 15 h and subsequently
silica capillaries (100 μm i.d., 362 μm o.d., Polymicro rinsing it with water and ethanol. The same solution was flowed
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within the microchannel for 15 h at 0.05 µL min-1 followed by
thorough rinsing with water and ethanol.
3
(a) K. Köhler, K. Wussow and A. S. Wirth, in Palladium-Catalyzed
Coupling Reactions, ed. A. Molnár, 2013, Wiley-VCH, Weinheim,
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DOI: 10.1039/C5OB00289C
Continuous flow Sonogashira (Heck-Cassar) cross-coupling
reaction
2320.
4
5
6
X.-F. Wu, P. Anbarasan, H. Neuman and M. Beller, Angew. Chem.
Int. Ed., 2010, 49, 9047-9050.
Iodobenzene (0.10 mmol) was reacted with phenylacetylene
(0.15 mmol) in ethanol (10 mL) at 80 °C using
tetrabutylammonium hydroxide as base (0.20 mmol, 1.0 M
solution in methanol). This solution was passed through the
catalytic microreactor at different flow rates and the reaction
product was collected and analyzed off-line by GC (Fig. S24).
The second order rate constant was determined from the initial
rate according to the equation: initial rate = k * [iodobenzene]0
* [phenylacetylene]0. The turnover frequency (TOF) was
calculated based on the moles of product per unit time per
moles of catalyst within the microreactor volume (13 µL). The
moles of catalyst are based on the total amount of metal atoms
(1.1 nmol of Pd).
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Continuous flow Suzuki-Miyaura cross-coupling reactions
For all the experiments described aryl halides (0.10 mmol) were
reacted with p-tolylboronic acid or phenylboronic acid (0.15
8
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We gratefully acknowledge the Netherlands Organization for
Scientific Research (NWO) for financial support (project
ECHO.09.TD.024). Michael Holtkamp and Uwe Karst
(University of Münster, Germany) are gratefully thanked for
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