Unusual behavior in the reactivity of 5-substituted- 1H-tetrazoles in a resistively heated microreactor

Article abstract of DOI:10.3762/bjoc.7.59

The decomposition of 5-benzhydryl-1H-tetrazole in an N-methyl-2- pyrrolidone/acetic acid/water mixture was investigated under a variety of high-temperature reaction conditions. Employing a sealed Pyrex glass vial and batch microwave conditions at 240 °, the tetrazole is comparatively stable and complete decomposition to diphenylmethane requires more than 8 h. Similar kinetic data were obtained in conductively heated flow devices with either stainless steel or Hastelloy coils in the same temperature region. In contrast, in a flow instrument that utilizes direct electric resistance heating of the reactor coil, tetrazole decomposition was dramatically accelerated with rate constants increased by two orders of magnitude. When 5-benzhydryl-1H-tetrazole was exposed to 220 ° in this type of flow reactor, decomposition to diphenylmethane was complete within 10 min. The mechanism and kinetic parameters of tetrazole decomposition under a variety of reaction conditions were investigated. A number of possible explanations for these highly unusual rate accelerations are presented. In addition, general aspects of reactor degradation, corrosion and contamination effects of importance to continuous flow chemistry are discussed.

Full text of DOI:10.3762/bjoc.7.59

Unusual behavior in the reactivity of 5-substituted-
1H-tetrazoles in a resistively heated microreactor
Bernhard Gutmann1, Toma N. Glasnov1, Tahseen Razzaq1,
Walter Goessler2, Dominique M. Roberge3 and C. Oliver Kappe*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 503–517.
1Christian Doppler Laboratory for Microwave Chemistry (CDLMC) and
Institute of Chemistry, Karl-Franzens-University Graz, Heinrichstrasse
28, A-8010 Graz, Austria, 2Institute of Chemistry, Analytical
Chemistry, Karl-Franzens-University Graz, Universitätsplatz 1, A-8010
Graz, Austria and 3Continuous Flow/Microreactor Technologies,
Lonza AG, CH-3930 Visp, Switzerland
doi:10.3762/bjoc.7.59
Received: 02 February 2011
Accepted: 31 March 2011
Published: 21 April 2011
This article is part of the Thematic Series "Chemistry in flow systems II".
Guest Editor: A. Kirschning
Email:
C. Oliver Kappe* - oliver.kappe@uni-graz.at
* Corresponding author
© 2011 Gutmann et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
flow chemistry; heterogeneous catalysis; microreactors; palladium;
process intensification
Abstract
The decomposition of 5-benzhydryl-1H-tetrazole in an N-methyl-2-pyrrolidone/acetic acid/water mixture was investigated under a
variety of high-temperature reaction conditions. Employing a sealed Pyrex glass vial and batch microwave conditions at 240 °C, the
tetrazole is comparatively stable and complete decomposition to diphenylmethane requires more than 8 h. Similar kinetic data were
obtained in conductively heated flow devices with either stainless steel or Hastelloy coils in the same temperature region. In
contrast, in a flow instrument that utilizes direct electric resistance heating of the reactor coil, tetrazole decomposition was dramati-
cally accelerated with rate constants increased by two orders of magnitude. When 5-benzhydryl-1H-tetrazole was exposed to
220 °C in this type of flow reactor, decomposition to diphenylmethane was complete within 10 min. The mechanism and kinetic
parameters of tetrazole decomposition under a variety of reaction conditions were investigated. A number of possible explanations
for these highly unusual rate accelerations are presented. In addition, general aspects of reactor degradation, corrosion and contami-
nation effects of importance to continuous flow chemistry are discussed.
Introduction
Microreactor technology has opened up new avenues for syn- temperature conditions in order to conduct highly exothermic
thetic organic chemistry [1-6] and the chemical manufacturing reactions safely [1-9]. More recently, following the concepts of
industry [7,8]. Traditionally, most synthetic transformations “Process Intensification” and “Novel Process Windows” [10-
performed in microreactors have involved ambient or even low- 12], flow chemistry executed in high-temperature and/or high-
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Beilstein J. Org. Chem. 2011, 7, 503–517.
pressure regimes have become increasingly popular [13]. High- addition, often ignored aspects of reactor degradation, corro-
temperature processing offers many distinct advantages as sion and contamination effects in flow chemistry are also
demonstrated by the recent success of microwave-assisted discussed.
organic synthesis [14-18]. In microwave chemistry, reaction
Results and Discussion
times can often be reduced from hours to minutes by efficient
Flow degradation of 5-benzhydryl-1H-tetra-
zole
and rapid direct dielectric heating of the reaction mixture in a
sealed vessel to temperatures far above the boiling point of the
solvent under atmospheric conditions. Since batch microwave
chemistry is inherently difficult to scale up to production quan-
tities [14-16], translating high-speed, high-temperature
microwave chemistry to scalable continuous flow processes is
becoming increasingly important. In the past few years our
research group [19-25] has reported a number of successful case
studies where initial reaction optimization for a variety of syn-
thetic transformations was performed under batch microwave
conditions, followed by translation to high-temperature/high-
pressure scalable continuous flow processes (“microwave-to-
flow” paradigm) [26-28].
As a model system for tetrazole formation the microwave-
assisted cycloaddition of diphenylacetonitrile (1) with NaN3
was studied (Scheme 1). After considerable experimentation
[25] an optimum set of conditions that fulfilled both the require-
ment of reaction homogeneity and reaction rate whilst at the
same time providing clean and complete nitrile to tetrazole
conversion involved the use of NMP as solvent, AcOH as
Brønsted acid and H2O as co-solvent. Thus, 2.5 equiv of NaN3
and a 5:3:2 ratio of NMP/AcOH/H2O at 220 °C (≈15 bar) led to
full conversion of the reactants to the desired 5-benzhydryl-1H-
tetrazole (2) at a 0.69 M nitrile concentration within 15 min,
and furnished the product in 81% isolated yield.
A recent example involves the synthesis of 5-substituted-1H-
tetrazoles via an azide–nitrile cycloaddition pathway, using
sodium azide (NaN3) as an inexpensive azide source and acetic
acid (AcOH) as the reagent/catalyst in a NMP/H2O solvent
mixture [25]. These 1,3-dipolar cycloadditions which involve in
situ generated free hydrazoic acid (HN3) were performed on
small scale (≈1 mL) at 220 °C in a microwave batch reactor
with reaction times of 4–15 min, depending on the reactivity of
the nitrile [25]. Despite the comparatively high reaction
temperatures, virtually no side products were observed in these
Scheme 1: Azide–nitrile cycloaddition under batch microwave condi-
tions.
transformations and the desired tetrazole products were isolated To our surprise, however, we were initially unable to translate
in high yield and purity after a simple work-up procedure [25]. these high-temperature batch conditions obtained in sealed
Since HN3 is not only extremely toxic but also highly explo- Pyrex glass reaction vessel (using either conventional or
sive, a scale-up of this batch protocol is clearly not possible. A microwave heating) [25] to a continuous flow format. The
key advantage of using microreactors compared to conven- microreactor system used for these studies was a high-tempera-
tional batch reactors is the ability to process potentially ture, high-pressure microtubular flow unit that can be used for
hazardous compounds or reagents safely [1-9,29-32]. In a processing homogeneous reaction mixtures [24]. This reactor
continuous flow system, synthetic intermediates can be gener- uses stainless steel coils of variable length (4, 8 or 16 mL
ated and consumed in situ, which eliminates the need to store internal volume) that can be directly heated across their full
toxic, reactive or explosive intermediates and thus makes the length (5–20 m) by electric resistance heating to temperatures
synthetic protocol safer. However, initial attempts to convert the up to 350 °C. Thermocouples are attached to the outer surface
azide–nitrile cycloaddition protocols to a high-temperature of the stainless steel tubing at two different points along the
continuous flow process using a stainless steel microtubular length of the coil to measure the temperature of the coils. In the
flow reactor have failed. Instead of the desired tetrazole actual cycloaddition experiment, the reaction mixture was intro-
products, formation of a number of decomposition products was duced to the reactor block containing a 8 mL stainless steel coil
observed.
(SX 316L, i.d. 1 mm) heated to 220 °C via a standard HPLC
pump at a flow rate of 0.5 mL/min. This translates to a resi-
In this paper the mechanistic details and kinetic profiles of high- dence time of 16 min inside the heated coil, comparable to the
temperature tetrazole decompositions in both microwave batch reaction time in the batch microwave experiment (Scheme 1).
and metal-based microreactors are investigated. A number of However, instead of the anticipated tetrazole 2 the only major
possible explanations for the unusual failure to convert batch to product observed by HPLC-UV monitoring was diphenyl-
flow conditions for this specific transformation are presented. In methane (3) (Figure 1). This very unusual behavior was in stark
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Beilstein J. Org. Chem. 2011, 7, 503–517.
contrast to our previous experience in converting microwave to strong oxidant (E° = 1.96 V) and, in the presence of oxidants, a
flow conditions with the same instrument [19-24], and was not strong reducing agent (E° = −3.09V). It also dissolves metals
limited to nitrile 1 but was also observed for other nitrile such as Fe, Zn, Mn and Cu. Thus, HN3 should in principle be
building blocks.
considered as incompatible with the use of steel reactors [37].
Furthermore, iron nitrides are readily formed from HN3 and Fe
We initially speculated that the observed disintegration of the metal at temperatures around 100 °C which represents a serious
tetrazole nucleus could somehow be connected to the metal safety hazard [38].
surface of the steel reactor. The particularly high surface-to-
volume ratio in a micro structured reactor (the inner surface On the other hand, it has been reported that the decomposition
area of a 16 mL coil with an inner diameter of 1 mm is of tetrazoles can be catalyzed by a whole range of metals. For
640 cm2) may entail pronounced reactor wall effects and unex- example, Cu powder was found to lower the decomposition
pected/undesired side and degradative reactions [33]. The stain- temperature of 1,5-diphenyltetrazole by about 60 °C [39].
less steel reactor contains a variety of metals and the reactor However, in case of the parent tetrazole (CN4H2) itself, differ-
walls could possibly act as heterogeneous catalysts (surface ential scanning calorimetry (DSC) experiments suggest that the
catalysis) [34]. Furthermore, the surface can potentially be decomposition onset temperature does not change significantly
considered as a metal oxide which usually forms surface when the material is contaminated with either Fe or 316 stain-
hydroxyl groups in contact with water. Depending on the pH of less steel [40].
the processed mixture, the surface hydroxides are protonated or
deprotonated and, hence, the surface is uncharged at the isoelec- Whatever the reason for the inability to translate microwave
tric point or positively (negatively) charged at lower (higher) batch conditions optimized in Pyrex glass to a continuous flow
pH values [35]. In this regard, the surface area, the material of regime with a stainless steel coil, the problem was ultimately
construction and the reactor use history have to be considered. solved by employing a passivated silica coated stainless steel
In addition, the stainless steel components of the flow reactor coil (Sulfinert®) mimicking a glass environment [41], in combi-
are prone to corrosion if harsh conditions, such as concentrated nation with the use of a flow reactor that employed a standard
acids are used [36]. Hydrazoic acid itself (pKa 4.7) is both a Al heating block as a coil heater [25]. Using this set-up, a
Figure 1: HPLC-UV chromatograms (215 nm) of crude reaction mixtures from the cycloaddition of diphenylacetonitrile (1) with NaN3 (Scheme 1)
comparing microwave batch (top) and continuous flow conditions (bottom). Reaction parameters: 220 °C, ≈16 min, 2.5 equiv NaN3, NMP/AcOH/H2O
5:3:2.
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Beilstein J. Org. Chem. 2011, 7, 503–517.
general and scalable method for the continuous flow synthesis intramolecular interception leads to the oxadiazole 6. This
of 5-substituted-1H-tetrazoles via the addition of HN3 to mechanism for the degradative acylation of tetrazoles as shown
organic nitriles was developed [25]. For specific substrates the in Scheme 2 was suggested by Huisgen and coworkers in 1958
coil temperature could be raised up to 260 °C (2.5 min resi- [42,43]. An alternative mechanism, whereby the 5-substituted-
dence time) without any significant amounts of decomposition 1H-tetrazole is acetylated at position N1 followed by ring
products being detected in the crude reaction mixture [25].
opening at the 1,2-position, elimination of nitrogen from the
resulting azido group and a subsequent 1,2-migration of the
Control experiments subjecting the isolated pure tetrazole 2 to a acylimido group from carbon to nitrogen to give the same nitril-
NMP/AcOH/H2O solvent mixture quickly revealed that indeed imine intermediate was ruled out by Herbst via 15N labeling
the very low stability of the tetrazole nucleus in the resistively studies [44]. The degradative acylation of 5-substituted-1H-
heated stainless steel flow reactor was responsible for the tetrazoles with acyl halides is in fact an elegant method for the
observed decomposition of the product. The pure tetrazole 2 in synthesis of 1,3,4-oxadiazoles [45,46]. In the NMP/AcOH/H2O
NMP/AcOH/H2O (5:3:2) started to decompose at temperatures solvent mixture, however, the formation of the oxadiazole 6 can
as low as 150 °C after a only few min residence time under flow scarcely compete with the intermolecular addition of water and
conditions and the HPLC-UV traces of the crude reaction oxadiazole 6 was therefore detectable only in minor amounts.
mixtures became fairly complicated (Figure 2). On increasing Using NMP/AcOH as the solvent system, 2-benzhydryl-5-
the reactor temperature or applying longer residence times, methyl-1,3,4-oxadiazole (6) became one of the major products
however, all peaks except the diphenylmethane (3) signal in the flow reactor under these reaction conditions. The
vanished. At 220 °C, the temperature contemplated for the tetra- resulting hydrazide 7 can be expected to have a weak N–N
zole synthesis, diphenylmethane (3) was the only detectable bond, however, the products obtained from the decomposition
product after ≈10 min of residence time.
of diacylhydrazides are generally considered to arise via polar
pathways rather than via a radical path [47]. Under the
Apparently, the degradation of tetrazole 2 in the NMP/AcOH/ employed reaction conditions the hydrazide apparently
H2O solvent mixture involves various consecutive reactions hydrolyzes to diphenylacetic acid (8) which finally decarboxy-
and/or parallel pathways that finally channel to diphenyl- lates to yield diphenylmethane (3). Decarboxylation may
methane (3). We have identified virtually all the peaks in the proceed via an intramolecular, concerted mechanism as
HPLC chromatograms and therefore have a rather complete proposed for β,γ-unsaturated acids [48].
picture of the complex degradation processes (Scheme 2, Figure
S1 in Supporting Information File 1). The main degradation In addition to these structures, a different set of intermediates
path starts with the N-acetylation of the tetrazole nucleus at resulting from a second decomposition pathway were identified,
position 2. The resulting N-acetyltetrazole 4 looses nitrogen to although in much smaller quantities. The second path possibly
form nitrilimine 5. Interception of the nitrilimine dipolar inter- involves cyclo-reversion of the tetrazole to the nitrile 1, hydrol-
mediate by water produces N’-acetyl-diphenylacetohydrazide ysis of the nitrile to the amide 9 and then further to the
(7) (the first detectable intermediate in this sequence), while carboxylic acid 8, which again finally decarboxylates to
Figure 2: HPLC-UV chromatogram (215 nm) showing the decomposition of tetrazole 2 in NMP/AcOH/H2O 5:3:2 (0.125 M) after heating in a stainless
steel flow coil at 180 °C for 5.3 min.
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produce diphenylmethane (3) (Scheme 2) [49]. Further details be increased to 240 °C, but even at 240 °C the decomposition
and control experiments supporting the proposed decomposi- process required many hours. The intermediates from the
tion pathways are discussed in the Supporting Information “second path” (Scheme 2) were hardly detectable and the
File 1.
resulting experimental data could be fitted nicely with the rate
law shown in Scheme 3 with each step assumed to be (pseudo)
Notably, exactly the same decomposition pathway involving the first order. A least square fit revealed k1 = 1.11 × 10−3, k2 =
identical set of intermediates as in the stainless steel reactor 0.432 × 10−3 and k3 = 0.0832 × 10−3 s−1 at 240 °C (Figure 3).
were indeed also observed in a microwave batch reactor using a Control experiments in a microwave reaction vial constructed
Pyrex glass vessel, but the reactions were nowhere near as fast. from strongly microwave absorbing silicon carbide (SiC),
In the microwave reactor equipped with an accurate internal which shields the vessel contents from the electromagnetic field
fiber-optic temperature probe [50] there was no appreciable and therefore mimics a conventionally heated autoclave experi-
disintegration of tetrazole 2 in the NMP/AcOH/H2O system at ment, provided identical results and demonstrates that the
220 °C after 30 min. In order to obtain reasonable decomposi- observed decomposition in the microwave reactor was the result
tion rates for a kinetic analysis, the reaction temperature had to of purely thermal effects [51,52].
Scheme 2: Possible decomposition mechanisms for tetrazole 2 in NMP/AcOH/H2O.
Scheme 3: Reaction steps for the degradation of tetrazole 2 and the corresponding rate equations.
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Beilstein J. Org. Chem. 2011, 7, 503–517.
Figure 4: Decomposition of tetrazole 2 in a 4 mL resistance heated
stainless steel coil at a nominal temperature of 220 °C in a NMP/
AcOH/H2O 5:3:2 mixture (0.125 M) (points: experimental results; solid
lines: predicted with a rate law according Scheme 3 on the assump-
tion that the rate constants are proportional to the residence time ki =
ai · t (i.e., inversely proportional to the flow rate ki = ai · V ∙ v−1, t = resi-
dence time, V = reactor volume, v = flow rate) with a1 = 0.169 × 10−3,
a2 = 0.166 × 10−3 and a3 = 0.0207 × 10−3 s−2). Conversions in percent
were derived from HPLC-UV (215 nm) peak area integration without
correction for response factors. Similar curves for different coils are
shown in Figure S5 in the Supporting Information File 1.
Figure 3: Decomposition of tetrazole 2 at 240 °C in a NMP/AcOH/H2O
5:3:2 mixture (0.125 M) (points: experimental results; solid lines:
predicted with a rate law according Scheme 3 with k1 = 1.11 × 10−3, k2
= 0.432 × 10−3 and k3 = 0.0832 × 10−3 s−1). Conversions in percent
were derived from HPLC-UV (215 nm) peak area integration without
correction for response factors. The corresponding conversions for
250 °C and 260 °C and additional data are shown in the Supporting
Information File 1 (Figures S2–S4).
A comparison of the batch and flow data presented above shows
that the tetrazole decomposition in the stainless steel flow coil is
≈100 times faster than decomposition in the Pyrex vial at the decomposition steps in solution. Indeed, for example, deliber-
same temperature. The rate constants for the decomposition ately added stoichiometric amounts of Fe2O3 markedly acceler-
process in the resistively heated flow reactor are apparently not ated the decarboxylation of diphenylacetic acid (8) under batch
simple first order and appear to depend on the flow rate/resi- microwave conditions, so that the acid no longer accumulated.
dence time and show decreasing rate constants with increasing The other degradation steps, however, remained virtually unaf-
flow rates/decreasing residence times. For example, the experi- fected (Figure S6, Supporting Information File 1).
mental data obtained in a 4 mL stainless steel coil can be fitted
nicely with the rate law shown in Scheme 3 assuming that the The detected individual amounts of metals in the solvent mix-
rate constants are inversely proportional to the flow rate ture after treatment in coils of different length varied signifi-
(k ~ v−1) (Figure 4). Although some differences in the rate of cantly and correlated somewhat with the age and history of the
decomposition between individual coils (4, 8, 16 mL internal coils. The decomposition rates, on the other hand, did not show
volume, different age and history) were noticeable (Figure S5, a correlation with the detected quantity of any of the released
Supporting Information File 1), in all cases the disintegration of metals (Figure S5, Supporting Information File 1). Furthermore,
the tetrazoles was dramatically faster compared to the decomposition of tetrazole 2 under batch microwave conditions
microwave batch conditions.
in Pyrex using a NMP/AcOH/H2O mixture pre-treated as
described in the stainless steel reactor was not appreciably
In order to investigate if the enhanced tetrazole decomposition faster compared to the decomposition in “fresh” NMP/AcOH/
in the stainless steel coils is connected to metal contamination H2O (Figure S7, Supporting Information File 1). It thus appears
as a result of steel corrosion phenomena, a series of inductively that the surprisingly fast degradation of tetrazole 2 in the resis-
coupled plasma mass spectrometry (ICPMS) experiments were tively heated steel reactor compared to the microwave batch
performed. ICPMS analysis of a NMP/AcOH/H2O (5:3:2) mix- experiment at the same temperature is not the result of homoge-
ture pumped through the continuous flow reactor at 220 °C nous catalysis by some of the released metals.
(residence time 5 min) revealed that a range of metals are
released from the coil under these conditions. Especially Fe (up In order to obtain further insights into this remarkable enhance-
to 113 ± 6 mg/L) but also Ni (up to 21.0 ± 1.0 mg/L), Cr (up to ment of tetrazole decomposition, the same reaction was subse-
32.3 ± 1.5 mg/L) and Mn (up to 4.9 ± 0.3 mg/L) were found in quently carried out in flow devices using metal coils made from
the processed solvent (Table S1, Supporting Information different materials heated either in an oil bath or with an Al
File 1). We hypothesized that several of these metals liberated heating block. Remarkably, the stability of tetrazole 2 in a
from the stainless steel capillary may catalyze some of the 5.21 mL Hastelloy C-4 coil (i.d. 2.0 mm) at 240 °C was very
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Beilstein J. Org. Chem. 2011, 7, 503–517.
close to the stability observed in the microwave batch experi- decomposition, whilst with electric resistance heating, complete
ment (Figure S8, Supporting Information File 1). The superior disintegration of the tetrazole occurred at even lower tempera-
resistance of the Hastelloy material toward the NMP/AcOH/ tures (Figure S11, Supporting Information File 1).
H2O mixture at high temperature was also evident from an
ICPMS analysis of the solvent mixture processed in the At the moment we have no compelling explanation for the
Hastelloy C-4 capillary at 220 °C (5 min residence time, dramatic discrepancies observed in tetrazole decomposition
1.0 mL/min flow rate). Hastelloy is a high-performance Ni-Cr- rates comparing different heating principles. One possible
Mo alloy with enhanced corrosion stability compared to stan- reason for the exceptionally fast disintegration of the tetrazoles
dard steel materials under high temperature conditions [53]. in flow reactors utilizing direct electrical resistance heating
Therefore, only comparatively small amounts of released Ni would be the occurrence of extreme hot spots or uneven
(5.3 ± 1.1 mg/L), W (2.4 ± 0.6 mg/L) and Mo (2.0 ± 0.4 mg/L) temperature distributions along the capillary. To explain the
were detected in the processed solvent mixture. The amounts of observed degradation rates, however, average temperatures well
other metals, including Fe, were negligible compared to the above 300 °C in the resistively heated reactor have to be
background values (Table S1, Supporting Information File 1). assumed (Figure S10, Supporting Information File 1). This
appears unlikely taking our previous experience in microwave-
In an additional experiment, we demonstrated that the decom- to-flow translations into account, where the same instrument
position of the pure tetrazole 2 in a stainless steel capillary and coils were used, but inconsistencies as seen in the tetrazole
heated on an Al heating block was only marginally faster than decomposition have never been observed [19,24]. As the exper-
the decomposition in the microwave reactor at the same iments in the resistively heated flow reactor were typically
measured reaction temperature. A least square fit of the performed at a higher pressure (140 bar) than the corres-
obtained experimental data with the kinetic model depicted in ponding experiments in a conductively heated flow instrument
Scheme 3 gave k1 = 2.52 × 10−3, k2 = 1.15 × 10−3 and k3 = (34 bar), the influence of reaction pressure on tetrazole decom-
0.184 × 10−3 s−1. All reaction steps are hence about two times position was also investigated. Although some differences could
faster than under microwave conditions (Figure S9, Supporting be observed performing flow decomposition experiments at 50
Information File 1). This rather small difference in the decom- and 140 bar in the resistively heated flow reactor, respectively
position rate (compared to the factor 100 found in the resis- (Figure S12, Supporting Information File 1), these differences
tively heated coils) can be explained by an inaccurate tempera- were not large enough to suggest a genuine pressure effect.
ture calibration of the Al block coil heating system used for Finally, the possibility of electrochemical phenomena, as a
heating the stainless steel capillary. If metal/surface catalysis result of the electric current passing through the steel coil inter-
would be involved it could be expected that the individual reac- acting with the reaction mixture, were considered (Figure S13,
tion steps of the decomposition pathway would be affected to Supporting Information File 1) [54]. Comparative experiments
different extents. However, the rate constants for all consecu- for the tetrazole decomposition carried out in batch mode at
tive reactions in the flow reactor at a measured temperature of 220 °C for 10 min in a short stainless steel loop (≈300 µL)
240 °C were very close to those found under microwave batch heated either by direct electrical resistance heating with a
conditions at 250 °C (Figure S10, Supporting Information DC-switching power supply (Figure S14, Supporting Informa-
File 1). These results strongly suggest that the degradation tion File 1), or by immersion into an oil bath, support the notion
process for tetrazoles of type 2 is indeed not influenced by the that the enhanced decomposition is somehow related to the
stainless steel material and thus does not involve heterogeneous/ electric current. While the batch experiment in the conductively
surface catalysis phenomena.
heated coil showed little to no tetrazole decomposition,
diphenylmethane (3) and diphenylacetic acid (8) were the main
Ultimate proof that the enhanced tetrazole decomposition in the products in the resistively heated run (Figure S15, Supporting
resistively heated coils is related to the method of heating and Information File 1).
not to the coil material itself was obtained from a control
Corrosion effects influencing flow chemistry
experiment where the very same 8 mL stainless steel coil
initially used in the dedicated flow reactor employing electric in steel reactors
resistance heating [24] was subsequently used in a conduc- Extreme care is required in the selection of the reactor ma-
tively heated experiment. This was achieved by immersing the terials when solutions containing even relatively dilute concen-
complete reactor block containing the steel coil and accessories trations of HCl or other Brønsted acids are handled in a flow
into a well agitated silicone oil bath. Remarkably, with a 10 min environment [36]. The corrosion results described earlier
residence time for both types of flow experiments, the conduc- involving comparatively benign mixtures of NMP/AcOH/H2O
tively heated flow run at 192 °C showed no sign of tetrazole (5:3:2) passed through stainless steel coils at 220 °C provide
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Beilstein J. Org. Chem. 2011, 7, 503–517.
testimony to the fact that even mild acids (the pKa of AcOH is
4.75) can act as corrosive reagents on stainless steel in an
elevated temperature regime. Aqueous HCl is a much stronger
acid and lacks the oxidizing properties that stainless steel
requires to maintain its “passive” corrosion resistant surface
layer [55]. Furthermore, chloride containing acidic solutions
will in many situations show a corrosive nature similar to HCl
itself. The corrosion attack of HCl, as with most acids, is highly
dependent on the temperature but all common stainless steel
types should be considered non-resistant to HCl at any concen-
tration and temperature [36]. Hastelloy type reactor materials in
turn are known to offer better corrosion resistance in both
reducing and oxidizing environments [53].
Table 1: Conversion of nitrobenzene (10) to aniline (11) in different
flow environments.a
HCl equivb
Conversion (%)c
Hastelloy
Stainless
steel
PTFE
0.0
0.5
1.0
2.0
0
5
0
2
0
0
0
0
14
31
7
19
In order to evaluate the relative corrosiveness of HCl at
different concentrations and in different reactor environments, a
test reaction was developed that can readily reflect the level of
corrosion. For this purpose a 0.5 M solution of nitrobenzene
(10) in EtOH containing varying amounts of aqueous conc. HCl
(0–1.0 M) was flowed through reactor coils made out of PTFE,
aReaction conditions: conductively heated (150 °C, 20 min) stainless
steel (20 mL, flow rate 1.0 mL/min), Hastelloy (5.21 mL, flow rate 0.26
mL/min) and high-temperature PTFE (14 mL, flow rate 0.7 mL/min)
coils. bHCl equiv with respect to nitrobenzene (10). cConversions were
obtained by GC-FID monitoring.
SX 316L stainless steel or Hastelloy C-4 at 150 °C (≈20 min otherwise quite stable materials. The potential disintegration
residence time) (Table 1). The “nascent” hydrogen formed in may be further enhanced by material and/or surface phenomena
the corrosion process causes unwanted reduction reactions resulting from the high surface-to-volume ratio in a micro-
when susceptible groups, e.g., nitro groups, are in the molecule. reactor environment. Since, in most cases, microreactors or
The reduction of nitro compounds with Fe in the presence of related flow devices (coils, tubular reactors) for high-tempera-
HCl is known as the Bechamp reduction and large amounts of ture/high-pressure applications are made out of non-transparent
aniline from nitrobenzene are produced by this reaction [56]. As materials (i.e., stainless steel, alloys, ceramics) [13], the
expected, the reduction of nitrobenzene (10) to aniline (11) in problem is further aggravated since reactor contamination may
metal coils increased steadily with increasing HCl concentra- not be immediately obvious. As flow devices are generally
tion. With R–NO2 + 6 H+ + 6 e− → R–NH2 + 2 H2O, the reac- designed for long-term use, the inadvertent accumulation of
tions were more or less quantitative with respect to HCl after chemical contaminants inside of these reactors must always be
20 min at 150 °C in a stainless steel coil. Significant reduction taken into account when interpreting the results from flow
to aniline was, however, also observed in a Hastelloy coil under chemistry experiments. In the case of the tetrazole decomposi-
these conditions. As expected, no reduction was experienced in tion discussed above (Scheme 2), a careful inspection of the
reactor coils made out of chemically inert PTFE, which unfortu- individual kinetic profiles obtained in stainless steel coils that
nately lacks the temperature and pressure resistance to perform had been exposed to different chemistries over several months
genuine high-temperature/high-pressure flow chemistry (the of usage (Figure 4 and Figure S5 in Supporting Information
autogenic pressure in the Bechamp reduction at 150 °C was File 1) clearly reveals that the age/history of the reactor can
≈9 bar) [13]. The corrosion in steel and Hastelloy coils was also have an influence on the chemical transformations occurring
clearly evident as strongly colored solutions, probably due to inside these flow devices.
dissolved FeII/III, exited the coil (Figure S16, Supporting Infor-
mation File 1).
The use of transition metal catalysts for carbon–carbon or
carbon–heteroatom bond formation under continuous flow
conditions represents an interesting opportunity for studying the
effects of metal contaminations inside of microreactors, as
Reactor contamination by catalytically active
transition metals
Another critical issue in flow chemistry that is often over- many of these coupling reactions proceed in the presence of
looked is reactor contamination (fouling) as a result of sub- extremely small quantities of transition metal catalysts in
strate, solvent, reagent or catalyst degradation inside the flow so-called “homoeopathic” doses [57,58]. In a recent publication
device. In high-temperature flow chemistry, the problem is we reported the Mizoroki–Heck coupling of 4-iodobenzonitrile
particularly serious as the sometimes rather extreme tempera- (12) with n-butyl acrylate (13) under high-temperature contin-
tures on the reactor walls may lead to the decomposition of uous flow conditions (150–190 °C) employing Pd(OAc)2 as a
510

Beilstein J. Org. Chem. 2011, 7, 503–517.
homogeneous pre-catalyst and a stainless steel-based coil flow used without additional amounts of catalyst being added, 15 mL
system (Scheme 4) [59]. With only 0.01 mol % of Pd(OAc)2 as of reaction mixture containing 1.125 g of aryl iodide 12
catalyst, MeCN as solvent and triethylamine as base gave (8.45 mmol) were processed through the coil under the same
cinnamic ester 14 in very high yield (≈95%) and good selec- reaction conditions (180 °C, 1.6 mL/min flow rate). The analyt-
tivity. It can be assumed that at the comparatively high reaction ical results clearly demonstrated that after processing ≈7 mL of
temperatures applied in the high-temperature flow reactor, the reaction mixture conversions started to decrease and ultimately
homogeneous Pd pre-catalyst will be rapidly converted into Pd reached almost 0% after 12 mL.
colloids/nanoparticles with high catalytic activity [57,58].
With the purpose of investigating the nature of the Pd leaching
In the course of these investigations, we noticed that catalyti- from the coil in more detail a freshly “palladated” coil was
cally active Pd species were apparently retained inside the steel subjected to a similar series of experiments, measuring the
reactor coil on performing these Pd-catalyzed high-temperature amount of leached Pd by ICPMS analysis (Table 2). While the
coupling transformations, despite an extensive washing regime background leaching for pure solvent at room temperature and
with pure solvent. This became very obvious, since running the at the reaction temperature was relatively low (Table 2, entries 1
Mizoroki–Heck coupling shown in Scheme 4 without any added and 2), significantly higher levels of Pd were found in samples
Pd catalyst still led to complete conversion in subsequent flow derived from the Mizoroki–Heck reaction mixture (Table 2,
experiments utilizing the same coil. Control experiments in entry 3). These results, both in terms of decreasing conversion
batch mode confirmed that the untreated steel material itself and Pd leaching are therefore analogous to the experiments
(SX 316L) cannot catalyze Mizoroki–Heck couplings of this using Pd/C as a heterogeneous pre-catalyst in continuous flow
type, despite of the fact that Ni and even Fe-catalyzed Mizoroki–Heck chemistry [59]. Catalysis essentially proceeds
carbon–carbon bond forming reactions are well known in the via dissolution/re-adsorption of Pd from the support (here from
literature [60,61]. Furthermore, very low levels of conversion the steel coil). The mechanism is quasi-homogeneous with
were obtained in this coupling when using a pristine, unused small Pd0 species (colloids/nanoparticles) in solution acting as
stainless steel coil in the flow reactor without the addition of a the catalytically active species. Presumably, the heterogeneous
Pd catalyst.
“Pd-on-steel” pre-catalyst is initially solubilized by oxidative
addition of the aryl iodide and enters the catalytic cycle in the
In order to investigate these phenomena in more detail, a new form of a soluble Pd species. Therefore, significant levels of Pd
set of experiments involving “palladated” steel coils was leaching are observed for the reaction mixture, not for pure
designed. For this purpose, a 16 mL internal volume stainless solvent [59].
steel coil (≈20 m of 1.0 mm i.d. coil) was “loaded” with Pd by
processing ≈2 mL of the Mizoroki–Heck reaction mixture
Table 2: Leaching of Pd from a “palladated” steel coil for the
through the coil under reaction conditions (180 °C, 1.6 mL/min
flow rate) with 1 mol % of the Pd(OAc)2 as pre-catalyst. As
expected, the desired product 14 was obtained in 94% isolated
yield after chromatographic purification. To clean the instru-
ment extensive washing at 170 °C for 20 min with MeCN was
performed. The so conditioned steel coil was then used for
processing a new portion of the reaction mixture that did not
contain any Pd catalyst. Remarkably, analysis of the reaction
mixture by GC-MS demonstrated full conversion to cinnamic
ester 14 in the initial product fractions exiting the flow reactor.
To establish for how long this “palladated” steel coil could be
Mizoroki–Heck coupling of aryl iodide 12 with n-butyl acrylate (13)
(Scheme 4).a
Entry Reaction mixture composition
Leaching [μg Pd]b
1
2
3
MeCN at rt
4.9
10.9
52.9
MeCN at 180 °C
Reaction mixture at 180 °C
aComplete reaction mixture composition: 0.65 mmol aryl iodide 12,
1.5 equiv n-butyl acrylate (13), 1.5 equiv Et3N, 2 mL MeCN. Condi-
tions: 16 mL stainless steel coil, 180 °C, 1.6 mL/min flow rate. bDeter-
mined by ICPMS analysis of the product contained in a 10 mL fraction.
Scheme 4: Mizoroki–Heck coupling under continuous flow conditions.
511

Beilstein J. Org. Chem. 2011, 7, 503–517.
We suspect that the Pd metal inside the steel coil is allows the influence of pressure on the rate of chemical trans-
present in the form of a thin film of nanometer-sized Pd crystal- formations under continuous flow conditions to be studied.
lites, very similar to the highly porous and catalytically active While in the tetrazole decomposition described earlier, reaction
Pd films that can be generated very easily inside glass pressure apparently had no significant influence, there are some
capillaries by the decomposition of Pd(OAc)2 under somewhat transformations that can potentially be influenced by reaction
similar elevated temperature conditions [62]. Work by Organ pressure under these flow conditions. In general, the rate and
and coworkers has demonstrated, that these Pd-on-glass equilibrium of many chemical reactions can be influenced when
films (and other metal-coated glass capillaries) can be pressures in the range of 1–20 kbar are applied. Typically, reac-
used for a variety of synthetically important flow chemistry tions that are accompanied by a decrease in molar volume can
applications in an elevated temperature regime [63,64], be accelerated by increasing pressure (ΔV≠ < 0) and the equi-
including Mizoroki–Heck chemistry [62]. It should be libria are shifted towards the side of the products (reaction
emphasized that our interest in this steel-based immobilized volume ΔV < 0) [69,70]. A variety of high-pressure flow chem-
catalytic Pd system was mainly to demonstrate reactor contami- istry examples have been reported in the literature, but the
nation/fouling and not of a preparative nature. After all, only number of cases where a pressure influence is seen in the
1.5 mg of Pd(OAc)2 were used to load a 20 m long stainless medium pressure range (50–200 bar) accessible in standard
steel coil, a procedure clearly not suitable to sustain catalytic flow reactors is rather limited [69,70]. One transformation
activity of the “palladated” reactor coil for an extended time where pressure-dependent rate enhancements (1–600 bar) have
[65-67].
been observed in a 3 μL fused-silica capillary, albeit not under
continuous flow conditions, is the nucleophilic aromatic substi-
Since the “Pd-on-steel” catalyst cannot be easily removed by tution reaction of 4-fluoro-1-nitrobenzene (15) with pyrrolidine
washing with pure solvent and steel coils for most flow instru- (16) in THF (ΔV≠ = −58 cm3/mol) (Scheme 5) [71]. In order to
ments are designed for multiple usage, a cleansing procedure confirm that these pressure enhancements can also be experi-
was developed. After considerable experimentation, we found enced in a stainless steel mesofluidic flow reactor, the nucleo-
that the use of a KCN/m-nitrobenzenesulfinic acid sodium salt philic substitution was repeated in an X-Cube Flash instrument.
mixture in water [68] at 80 °C effectively removes all Pd from Employing an 8 mL steel coil and an overall flow rate of 1 mL/
the surface of the steel coils as these coils were not catalytically min (two individual reagent streams at 0.5 mL/min each, resi-
active in subsequent Mizoroki–Heck chemistry. Only renewed dence time = 8 min), the conversion of the substitution reaction
loading of the coil by running a Mizoroki–Heck reaction with at 40 °C was determined at 60, 120 and 180 bar pressure.
Pd(OAc)2 or by simply processing a Pd(OAc)2 solution through Indeed, for this transformation a higher reaction pressure
the coil at elevated temperature regenerated the “palladated” increases the reaction rate as previously observed in a fused-
stainless steel coils.
silica capillary (Figure 5) [71]. Since the mesofluidic reactor not
only allows variation of pressure but also temperature, a series
of experiments was designed in which temperature and pres-
sure were increased at the same time. As the data presented in
Influence of pressure on reaction rate in flow
reactors
In the resistively heated flow reactor used in this work, the pres- Figure 5 demonstrate, a significant influence of reaction pres-
sure during a flow experiment can be set in a range of sure on reaction rate is no longer observable at a temperature of
50–180 bar with the help of a back-pressure valve [24]. This 70 °C.
Figure 5: Nucleophilic aromatic substitution reaction of 1-fluoro-4-nitrobenzene (15) with pyrrolidine (16) in THF (Scheme 5) at different temperatures
and three different pressures performed in a 8 mL stainless steel coil at a flow rate of 1 mL/min.
512

Beilstein J. Org. Chem. 2011, 7, 503–517.
Experimental
General remarks: 1H NMR spectra were recorded on a Bruker
300 MHz instrument. Melting points were determined on a
Stuart™ SMP3 melting point apparatus. Low resolution mass
spectra were obtained on an Agilent 1100 LC/MS instrument
using atmospheric pressure chemical ionization (APCI) in posi-
tive or negative mode. Analytical HPLC analysis was carried
out on a Shimadzu LC-20 system with a LiChrospher 100 C18
reversed–phase analytical column (119 × 3 mm, 5 µm particle
size) at 25 °C, using mobile phase A (water/MeCN 9:1 (v/v) +
0.1% TFA) and phase B (MeCN + 0.1% TFA), with linear
gradient from 30% B to 100% B in 8 min and 2 min with 100%
Scheme 5: Nucleophilic aromatic substitution of 4-fluoro-1-nitroben-
zene (15) with pyrrolidine (16) under continuous flow conditions.
Conclusion
In summary, we have demonstrated that the high-temperature phase B. GC-FID analysis was performed on a Trace-GC (Ther-
decomposition of 5-benzhydryl-1H-tetrazole (2) in a NMP/ moFisher) with a flame ionization detector with an HP5 column
AcOH/H2O 5:3:2 mixture is remarkably accelerated when (30 m × 0.250 mm × 0.025 μm). After 1 min at 50 °C the
performed in a resistively heated stainless steel coil as temperature was increased in 25 °C/min steps up to 300 °C and
compared to either microwave batch experiments using Pyrex kept at 300 °C for 4 min. The detector gas for the flame ioniza-
vessels or flow experiments where stainless steel or Hastelloy tion was H2 and compressed air (5.0 quality). GC–MS condi-
coils are heated by conductive techniques. Through a series of tions were as follows: injection temperature 250 °C, HP-5 MS
control experiments, effects of homogeneous metal catalysis as column (30 m × 0.250 mm ID, 0.25 μm film); carrier gas
a result of reactor corrosion, and heterogeneous catalytic effects helium 5.0, flow 1 mL min−1, temperature gradient
derived from the large metal surface area in the microreactor programmed from 60 to 300 °C at 20 °C min−1 after an initial
environment (wall effects) were excluded from being respon- time of 6 min.
sible for these unusual phenomena. Although no obvious ex-
planation for these dramatic enhancements in reaction rates can The MS conditions were as follows: positive EI ionization,
be offered at this time, the results presented herein clearly ionization energy 70 eV, ionization source temperature 280 °C,
demonstrate that the conversion of batch to flow chemistry can emission current 100 μA. Flash chromatography separations
sometimes be a non-trivial affair and great care must therefore were performed on a Biotage SP1 instrument with petroleum
be taken in the interpretation of results.
ether/ethyl acetate mixtures as eluent. Microwave irradiation
experiments were carried out in an Anton Paar Monowave 300
In this context, we have also presented results of microreactor instrument with appropriate internal fiber-optic temperature
fouling studies that highlight the fact that reactor contamination, control [50-52]. All products synthesized in this study are
for example, by deposition of catalytically active transition known in the literature and have been characterized by 1H NMR
metals inside a microreactor, must also be carefully considered and MS analysis. All solvents and chemicals were obtained
in executing flow chemistry. In the case of a Mizoroki–Heck from standard commercial vendors and were used without any
coupling, we have demonstrated that small amounts of Pd metal further purification.
retained inside a stainless steel reactor can exhibit catalytic
activity in subsequent chemical transformations. As most Pd concentrations from the leaching experiments of a
microreactors for high-temperature applications are made out of “palladated” steel coil and the metal screening of the “NMP/
non-transparent materials, reactor contamination may not be AcOH/H2O mixtures” were determined after microwave
immediately obvious.
assisted acid digestion in an MLS UltraClave III. The tempera-
ture was ramped up in 30 min to 250 °C and kept at this
Finally, the fact that stainless steel or Hastelloy-based flow temperature for a further 30 min. Pd was quantitatively deter-
reactors are sensitive to acids, even in small quantities, is mined at m/z 105 with an Agilent 7500ce inductively coupled
sometimes disregarded. In particular at high temperatures, plasma mass spectrometer. A calibration was performed with an
significant corrosion of the reactor material can result, leading external calibration curve established from 1.000 g Pd/L stan-
to unwanted side reactions. In addition, in specific cases dard (CPI International). Indium was used as the internal stan-
reaction pressure can influence reaction rates as evidenced dard. The element screening in the digests of the “NMP/AcOH/
by the nucleophilic aromatic substitution reaction of H2O mixtures” was performed in the semi-quantitative analysis
1-fluoro-4-nitrobenzene with pyrrolidine in the 60–180 bar mode using the Merck VI ICPMS standard for calibration. For
pressure range.
both measurements, the samples were dispatched from the
513

Beilstein J. Org. Chem. 2011, 7, 503–517.
autosampler via an integrated sample introduction system (ISIS) stirrer bar was heated in the microwave reactor (Monowave
from Agilent Technologies to an Ari Mist HP nebulizer 300) at the indicated temperature (Figure 3 and Figures S1–S4,
(Burgener Research International) and further into the ICPMS. Supporting Information File 1). For reaction monitoring the vial
was cooled to 60 °C. After a defined time, 40 μL samples were
Continuous flow experiments
taken with a transfer pipette, the sample diluted with 1.0 mL of
The flow experiments described herein were performed in a MeCN and analyzed by HPLC at 215 nm. The experiments
Thales X-Cube Flash reactor (electric resistance heating) [24], a were carried out either in a standard 10 mL Pyrex tube or a
Uniqsis FlowSyn instrument (conductive heating) [25] or in a vessel made from sintered silicon carbide and gave identical
self-made flow device constructed by immersing the corres- results.
ponding coil material – connected to a HPLC pump and back-
pressure regulator – into a pre-heated oil bath. The flow reac- Bechamp reduction (Table 1)
tors were equipped with coils made from different materials A 0 M, 0.25 M, 0.5 M and 1 M aqueous HCl solution in ethanol
(SX 316L steel, Hastelloy C-4 or PTFE), of variable lengths and was prepared from conc. HCl and ethanol. A sample of 1 mmol
inner diameters. A system pressure of 140 bar was applied for (123.1 mg) of nitrobenzene (10) was added in a graduated
all experiments in the X-Cube Flash reactor while a pressure of cylinder and the volume was made up to 2 mL with the respec-
≈34 bar was selected for all experiments in the FlowSyn instru- tive HCl solution to obtain a 0.5 M solution of nitrobenzene.
ment and in the self-made device. Experiments in PTFE coils The flow experiments were performed at 150 °C in coils made
were limited to system pressures of ≤ 14bar.
from stainless steel, Hastelloy or PTFE. The flow rates for the
different coils were selected in order that the residence time was
20 min in every coil. The feed was switched between pure
Tetrazole decomposition in flow
The reactor was heated to the selected temperature while the ethanol and reagent solutions.
solvent mixture (e.g., NMP/AcOH/H2O 5:3:2) was pumped
through the reactor at the desired flow rate. After the tempera- Heck–Mizoroki coupling using palladated steel coils.
ture was stable, the feed was switched from pure solvent to Loading procedure
reagent (e.g., 0.125 M solution of tetrazole 2 in NMP/AcOH/ 4-Iodobenzonitrile (150 mg, 0.65 mmol), n-butyl acrylate
H2O 5:3:2). A defined volume (≈1 mL) of the reagent solution (126 mg, 142 mL, 0.98 mmol, 1.5 equiv), Pd(OAc)2 (1.5 mg,
was introduced into the reactor and the feed was then changed 0.0065 mmol, 1 mol %) and triethylamine (100 mg, 137 mL,
back to pure solvent. The outcoming processed reagent solution 0.98 mmol, 1.5 equiv) were mixed together with MeCN (2 mL)
was collected. For the kinetic analysis of the decomposition into a 5 mL glass vial and stirred for 2 min. The X-Cube
process (Figure 4 and Figure S5, Supporting Information Flash instrument was equipped with a stainless steel
File 1), the flow rate was varied and, after equilibration, the reaction coil (16 mL volume, 10 min residence time at
feed was switched back from pure solvent to reagent. The 1.6 mL/min flow rate). The reaction parameters – temperature
processed mixture was collected and the procedure repeated (180 °C), flow rate (1.6 mL/min), and pressure (55 bar) –
until enough data points were collected. For reaction moni- were selected on the flow reactor and processing was
toring and kinetic analysis, 100 µL samples were taken from the started, whereby only pure solvent was pumped through
collected mixtures, diluted with 0.9 mL MeCN and analyzed by the system until the instrument had achieved the desired reac-
HPLC-UV at 215 nm. A detailed description of the isolation tion parameters and stable processing was assured. At
and characterization of decomposition products (Scheme 2) is that point, the inlet tube was switched to the vial containing
given in the Supporting Information File 1.
the freshly prepared reaction mixture. After processing through
the flow reactor, the inlet tubing was dipped back into a vial
with pure solvent and processed for further 10 min, thus
Tetrazole synthesis in flow (Scheme 1)
The first attempts to synthesize tetrazole 2 (Figure 1) were washing the system from any remaining reaction mixture.
performed in a resistively heated 8 mL coil at 220 °C with a The processed reaction mixture was then combined with
residence time of 16 min (0.5 mL/min flow rate). The reagent the washings and the solvent was removed under vacuum.
mixture was a 0.67 M solution of diphenylacetonitrile (1) with The residue was dissolved in acetone (2 mL) and transferred
2.5 equiv of NaN3 in NMP/AcOH/H2O 5:3:2.
to a silica-samplet, dried for 2 h at 70 °C in a drying oven, and
then subjected to automated flash chromatography with
petroleum ether/ethyl acetate (0 to 45% gradient) as eluent to
provide 141 mg (94%) of cinnamic ester 14, identical in all
Tetrazole decomposition using microwave condi-
tions
A 2.5 mL sample of a 0.125 M solution of tetrazole 2 in NMP/ respects with a previously prepared sample in our laboratories
AcOH/H2O (5:3:2) in a 10 mL microwave process vial with a [20].
514

Beilstein J. Org. Chem. 2011, 7, 503–517.
Pd leaching studies
appropriate time. To a 100 µL portion of this collected sample,
An identical experiment was performed in the loading proce- 500 µL of 2 M HCl were immediately added to quench the
dure, but in the absence of the Pd catalyst employing the “palla- reaction. Then 500 µL of water and 600 µL DCM were added to
dated” coil described earlier. After complete processing through extract the product and unreacted nitrobenzene. After vigorous
the flow reactor, the inlet tubing was dipped back into a vial shaking and settling, 100 µL of the organic layer was then
with pure solvent and processed for further 10 min, thus diluted with 1 mL of MeCN before injecting into the HPLC for
washing any remaining reaction mixture from the system. A 10 an offline analysis. The pressure was increased to 120 bar and
mL sample was collected and the solvent removed under then to 180 bar to collect two more samples at 40 °C. Similarly,
vacuum before submission for ICPMS analysis. Conversion was the above steps were repeated to collected data for tempera-
determined by the means of GC-MS. In a similar manner 10 mL tures of 50, 60 and 70 °C (Figure 5).
fractions of solvent were collected at room temperature and at
180 °C, the solvent evaporated and the residues submitted to
Supporting Information
ICPMS analysis.
Supporting Information File 1
Details of experimental procedures, kinetic analysis and
spectral data.
Pd cleaning procedure
The X-Cube Flash instrument was equipped with a “palladated”
stainless steel reaction coil (16 mL volume, 10 min residence
time at 1.6 mL/min flow rate). The reaction parameters –
temperature (80 °C), flow rate (1.6 mL/min), and pressure
(55 bar) – were selected on the flow reactor and processing was
started, whereby only distilled water was pumped through
the system until the instrument had achieved the desired reac-
tion parameters and stable processing was assured. At
that point, the inlet tube was switched to the vial containing 100
mL freshly prepared mixture of KCN (10 g/L) and m-nitroben-
zenesulfinic acid sodium salt (10 g/L) in water. After processing
of the 100 mL through the flow reactor (ca. 60 min), the inlet
tubing was dipped back into a vial with distilled water and
processed for a further 10 min. The process was repeated two
more times with fresh 100 mL portions of KCN/m-nitroben-
zenesulfinic acid sodium salt in water mixture before the reactor
was finally washed with distilled water for 30 min to remove
any remaining residues of the KCN/m-nitrobenzenesulfinic acid
sodium salt in water mixture.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-59-S1.pdf]
Acknowledgements
This work was supported by a grant from the Christian Doppler
Research Society (CDG). We thank J.-P. Roduit (Lonza) for
helpful comments. T. R. thanks the Higher Education Commis-
sion of Pakistan for a Ph. D. scholarship.
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