Thiazolium-functionalized polystyrene monolithic microreactors for continuous-flow umpolung catalysis

Article abstract of DOI:10.1039/c3gc41284a

Thiazolium salt pre-catalysts have been immobilized on silica and monolithic polystyrene and their activity was tested under batch conditions in three model umpolung reactions, namely the benzoin condensation of benzaldehyde, the acyloin-type condensation of biacetyl, and the Stetter reaction of biacetyl with trans-chalcone. A prerequisite of the study has been the utilization of environmentally benign water and ethanol solvents. After having established the higher performance of polystyrene monolithic thiazolium carbene catalysts, their effectiveness has been tested under the flow regime by fabricating the corresponding monolithic microreactors (pressure-resistant stainless-steel columns). Importantly, it has been demonstrated by a brief substrate scope study that the polymeric matrix and the continuous flow regime synergistically contribute to preserve the activity of the carbene catalysts over time, thus permitting the long-term operation (up to 7 days) of the prepared monolithic reactors for the production of valuable compounds via the umpolung strategy.

Full text of DOI:10.1039/c3gc41284a

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Page 1 of 26
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DOI: 10.1039/C3GC41284A
Thiazolium-Functionalized Polystyrene Monolithic Microreactors for
Continuous-Flow Umpolung Catalysis
Olga Bortolini,a Alberto Cavazzini,a Paolo Dambruoso,*b Pier Paolo Giovannini,a Lorenzo
Caciolli,a Alessandro Massi,*a Salvatore Pacifico,a and Daniele Ragnoa
aDipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, Via Fossato di
Mortara 17-27, I-44121 Ferrara (Italy)
bISOF-CNR, Area della Ricerca di Bologna, Via P. Gobetti 101, I-40129 Bologna (Italy)
alessandro.massi@unife.it - paolo.dambruoso@isof.cnr.it
Thiazolium salt pre-catalysts have been immobilized on silica and monolithic polystyrene and their
activity tested under batch conditions in three model umpolung reactions, namely the benzoin
condensation of benzaldehyde, the acyloin-type condensation of biacetyl, and the Stetter reaction of
biacetyl with trans-chalcone. A prerequisite of the study has been the utilization of the
environmentally benign water and ethanol solvents. After having established the higher
performance of polystyrene monolithic thiazolium carbene catalysts, their effectiveness has been
tested under flow regime by fabricating the corresponding monolithic microreactors (pressure-
resistant stainless-steel columns). Importantly, it has been demonstrated by a brief substrate scope
study that the polymeric matrix and the continuous flow regime synergistically contribute to
preserve the activity of the carbene catalysts over the time, thus permitting the long-term operation
(up to 7 days) of the prepared monolithic reactors for the production of valuable compounds via the
umpolung strategy.
Introduction
The generation of acyl anions by the polarity reversal of carbonyl compounds through N-
heterocyclic carbene (NHC) catalysis is today a well-established methodology, which provides
access to unconventional strategies for the successful synthesis of target molecules such as natural
products and drugs.1 The unique catalytic activity of NHCs has therefore spurred intense research
on the fixation of this valuable class of catalysts onto different types of solid2,3 and soluble
supports,4 with the aim not only to simplify work-up procedures but also to improve NHCs stability
towards air and moisture.5,6 Surprisingly, although the advantages associated to continuous-flow
techniques have been amply demonstrated in different chemistries,7 process intensification by the
assistance of flow strategies has been almost ignored in the field of polarity inversion.8 On the other
1

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hand, heterogeneous catalysis in microstructured flow reactors appears a well suited synthetic
platform for NHC-based processes,9 offering advantages over conventional batch systems in terms
of mechanical degradation of supports, stability of the sensitive carbene species and thus,
ultimately, in terms of process productivity. Recently, our10 and other groups11 have demonstrated
the high synthetic potential of organocatalytic packed-bed microreactors in the continuous-flow
production of valuable (chiral) molecules. Ease of product purification, high (stereo)selectivity,
reproducibility, and absence of metal contamination, which is a problematic issue especially in
pharmaceutical applications, were the most striking features of the disclosed procedures.
As part of our ongoing studies in the fields of NHC-catalysis12 and flow-chemistry,10 we herein
describe the synthesis of thiazolium salt pre-catalysts immobilized on silica and monolithic
polystyrene, and their utilization in fundamental benzoin, acyloin-type, and Stetter reactions. Initial
batch investigations were propaedeutic for selecting polystyrene over silica as the support; the
macroporous polymeric matrix, in fact, imparted higher activity to fixed NHC catalysts when water
and the ecofriendly alternative ethanol were used as the solvents.13 The study culminated with the
fabrication of the corresponding polystyrene monolithic microreactors,14 and the subsequent
analysis of productivity and long-term stability thereof. Monolithic columns of the type first
described by Fréchet and Svec15 were preferred to randomly packed reactors for their improved
flow characteristics16 and, specifically, for avoiding stagnation zones and hot-spot formation that
we envisaged could be detrimental for carbene stability. Indeed, the results of this study clearly
indicate that the polymeric support and the flow regime of the process contribute in a synergic way
to preserve the activity of the monolithic carbene catalysts over the time (up to 7 days on-stream),
thus making them suitable tools for continuous-flow applications in the field of umpolung catalysis.
Results and discussion
The synthesis of the styryl thiazole derivatives 4a (R = Bn) and 4b (R = Et) was initially considered
for the preparation of the target silica-supported thiazolium salts S7a,b (Scheme 1) and the
polystyrene monolithic counterparts M9a,b (Scheme 2).
2

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-
Br
Bn
Me
+
N
S
2
Cl
O
BnBr
4a
CH3CN,
70 °C, on
Me
O
>95%
Me
N
NaH,
2
N
-
Br
S
2
Et
Me
+
N
DMF, 0 °C to RT, 16 h
75%
S
2
OH
1
S
2
O
EtBr
3
4b
CH3CN,
70 °C, on
>95%
SiO2
SH
photoinduced
TEC
S5 TEC
S5 (f: 1.29 mmol g-1
)
-
-
Br
Br
Bn
Me
O
Et
Me
O
Me
+
+
N
N
N
S
S
2
2
S
2
O
BnBr
EtBr
CH3CN,
70 °C, on
CH3CN,
70 °C, on
S
S
S
SiO2
SiO2
SiO2
2
2
2
S6 (f: 1.07 mmol g-1
)
S17a (f: 1.05 mmol g-1
S27a (f: 0.78 mmol g-1
S37a (f: 0.47 mmol g-1
)
)
)
S17b (f: 1.00 mmol g-1
S27b (f: 0.75 mmol g-1
S37b (f: 0.44 mmol g-1
)
)
)
Thiol-Ene Coupling (TEC):
thiol (1 equiv.); ene (3 equiv.)
Thermal: AIBN (1 equiv.), Toluene, 90 °C, 16 h
Photoinduced: DMAP (1 equiv.), MeOH, RT, hν 356 nm, 5 h
Scheme 1. Synthesis of silica-immobilized thiazolium salts S1-37a and S1-37b.
As far as the catalyst structure is concerned, both types of heterogeneous species S7 and M9 were
designed to display the active thiazolium moiety covalently linked to the matrix through a quite
flexible spacer. Earlier studies, in fact, demonstrated the low catalytic activity of analogous,
ionically bound derivatives prepared by N-alkylation of the thiazole ring with chloromethyl
polystyrene;8,17 a decreased activity was also observed for covalent polymeric thiazolium salts with
shorter spacers.2i
Therefore, the intermediate 3 was readily obtained from the commercially available 5-(2-
hydroxyethyl)-4-methylthiazole 1 and 4-vinylbenzyl chloride 2 (75% yield), and quantitatively
converted into the thiazolium salts 4a and 4b by standard chemistry. In analogy with our previous
works on silica-supported organocatalysts,10 the synthesis of heterogeneous S7a,b was addressed
using the photoinduced thiol-ene coupling (TEC) as the covalent immobilization strategy.18 Main
advantage of this approach is the utilization of mild reaction conditions (RT, hν),19 which may
3

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prevent sensitive substrates from side-reactions occurring on the solid matrix and thus of difficult
interpretation. Surprisingly, the photoinduced TEC (λmax = 365 nm) of thiol-silica S510b with either
4a or 4b in the presence of the sensitizer 2,2-dimethoxy-2-phenyl-acetophenone (DMAP) resulted
in no formation of target S7a,b, as confirmed by FT-IR and elemental analyses of the solid matrix.
A similar, unsatisfactory outcome was also detected under standard thermal conditions (AIBN, 90
°C), thus confirming an inhibition effect of the thiazolium salt unit towards the free-radical
coupling.20 Fortunately, the photoinduced TEC of the styryl thiazole 3 with thiol-silica S5
proceeded in a straightforward manner furnishing the thiazole silica S6 with a satisfactory level of
functionalization (f: 1.07 mmol g-1; Scheme 1).
Since the catalyst loading (i.e. the degree of thiazole N-alkylation) have been reported to strongly
influence the catalytic activity of supported NHCs because of unfavorable carbene dimers
formation,2j,21 quaternization of S6 (acetonitrile, 70 °C) was modulated by varying the equivalents
of the alkylating agents BnBr and EtBr. By this procedure, two triads of functionalized silica S1-37a
and S1-37b were obtained with a different loading of thiazolium units (f: 0.44-1.05 mmol g-1) as
determined by elemental analysis (Scheme 1).
The synthesis of the polystyrene monolithic counterparts of S7 was next addressed by an extensive
polymerization study (Scheme 2). Notably, as the ultimate goal of this work was the execution of
continuous-flow processes, monolithic materials were molded into both glass and stainless-steel
columns (10 cm length, 4.6 mm internal diameter) in parallel experiments. This approach allowed
to estimate the influence of the polymerization parameters on the flow-through behavior of the
monolithic reactors (“wall effect” and very high backpressure had to be avoided) and, at the same
time, to evaluate the mechanical and morphological properties of the prepared materials.
Technically, the new polymers obtained within the glass tube were first triturated for loading
determination and then tested in the form of powder in batch experiments.
4

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Me
O
N
S
2
3
+
DVB
(8% w/w)
STY
AIBN (1% w/w)
1-dodecanol (50% w/w)
toluene (10% w/w)
70 °C, 24 h
-
-
Br
S
Br
Me
N
Et
Bn
Me
O
Me
O
+
N
+
N
S
2
S
2
2
BnBr
EtBr
O
CH3CN,
70 °C, on
CH3CN,
70 °C, on
M19b (f: 0.91 mmol g-1
M29b (f: 0.57 mmol g-1
M39b (f: 0.18 mmol g-1
)
)
)
M19a (f: 0.90 mmol g-1
M29a (f: 0.57 mmol g-1
M39a (f: 0.21 mmol g-1
)
)
)
M18 (f: 0.92 mmol g-1
M28 (f: 0.57 mmol g-1
M38 (f: 0.22 mmol g-1
)
)
)
Scheme 2. Synthesis of polystyrene monolithic thiazolium salts M1-39a and M1-39b.
As expected, the free-radical polymerization (AIBN, 70 °C, 24 h) of the styryl thiazolium salts 4a
or 4b, styrene (STY), and divinylbenzene (DVB), in the presence of toluene/1-dodecanol as the
porogenic mixture, did not produce any polymeric product. Hence, after some experimentation with
the suitable thiazole monomer 3, the composition of the polymerization mixture was optimized as it
follows: 1-dodecanol (50% w/w), toluene (10% w/w), styrene (23% w/w), DVB (8% w/w), 3 (8%
w/w), and AIBN (1% w/w). Under these conditions, the polymerization was quantitative allowing a
complete incorporation of monomers into the polymeric monolith.22 Elemental analysis of the
resulting monolith M18 indicated a satisfactory loading of thiazole units (f: 0.92 mmol g-1).
Nonetheless, following the previous reasoning on carbene activity on supports, monoliths M28 and
M38 were also prepared with a lower degree of functionalization (f: 0.57 and 0.22 mmol g-1,
respectively) by diminishing the amount of 3 while keeping constant the sum of STY and 3 in the
polymerization mixture. Afterwards, each triturated M8 resin was quantitatively alkylated to afford
the two sets of polymeric thiazolium salts M1-39a and M1-39b (Scheme 2; see below for the N-
alkylation step under flow conditions).
At this stage of the study, preliminary batch experiments were performed with S7 and M9 for
establishing the influence of the support, the level of functionalization, and also of the N-substituent
on the activity and recyclability of the prepared heterogeneous thiazolium salt pre-catalysts.
Accordingly, the classical benzoin condensation, and our recently developed acyloin-type
5

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homocoupling of biacetyl 12a12c and Stetter reaction of 12a with chalcone12b were selected as the
benchmarks (Table 1).
Table 1. Evaluation of catalysts S7 and M9 performance under batch conditions.a
O
O
S7 or M9 (20 mol %)
H
(a)
(b)
(c)
OH
11a
phosphate buffer (pH = 8), 35 °C
10a
Et3N (100 mol%)
O
S7 or M9 (20 mol %)
Me
Me
O
Me
O
O
O
OH
Me
Me
Me
Me
O
EtOH, 25 °C
HO
Me
O
12a
13a
14 d.r. 9:1
Et3N (100 mol%)
Me
Ph
O
O
O
O
S7 or M9 (20 mol %)
Me
+
Me
Ph
Ph
Ph
EtOH, 50 °C
O
16a
15a
12a
Entry
1
2
3
4
5
6
7
Reaction
Catalyst
S27a
S27a
Product
11a
13a
16a
11a
13a
16a
11a
11a
11a
13a
16a
Yield [%]b
15 (-)c
a
b
42e (-)c e
38 (-)c
cd
a
S27a
M29a
M29a
M29a
M19a
M39a
M29b
M29b
M29b
>95 (-)c
>95e (5)c,e
>95 (-)c
85 (-)c
b
cd
a
8
9
a
61 (-)c
a
84 (12)c
88e (44)c,e
81 (15)c
10
11
b
cd
aReaction performed with 0.125 mmol of acyl anion donor and
b
c
equimolar acceptor (reaction time: 24 h). Isolated yield. Isolated
yield at 2nd cycle. dReaction performed with 0.125 mmol of 15a
and 3 equiv. of 12a. Yield determined by 1H NMR analysis of the
e
crude reaction mixture using bromoform as internal standard.
As anticipated, a prerequisite of the present study was the utilization of water or ethanol solvent for
the next development of green applications of the newly prepared materials. Thus, under these
solvent conditions, it found that polystyrene monoliths M9 outperformed the silica analogues S7 in
all the model reactions investigated (entries 1-3 vs. entries 4-6; only selected experiments are
reported in Table 1).23 In general, this result might be explained by the occurrence of favorable
hydrophobic interactions between the catalytic sites and the polymeric support in polar media.24 To
this end, it is important to remember that the umpolung of α-diketone 12a strictly requires the use
of amphiprotic solvents;12b,c therefore, this mechanistic constraint prevented us to evaluate a
plausible positive effect of the polar silica support on the activity of thiazolium salts S7 in acyloin-
type and Stetter reactions performed in apolar solvents.25 Additionally, the utilization of biacetyl
12a was precluded in aqueous basic medium because of the preferential formation of the lactone 14
through an aldol/cyclization sequence (see the Experimental Section). Biacetyl, however, works
nicely in EtOH/Et3N and it may be preferred to acetaldehyde as acetyl anion equivalent in virtue of
6

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its higher boiling point (88 vs. 21 °C) and, consequently, of its safer handling in thermal flow
processes. Overall, the results of the batch study indicated monolith M29a as the most active
catalyst among the materials tested. Indeed, this polymer furnished complete conversions (>95%)
within 24 hours in the benzoin condensation (phosphate buffer pH = 8, RT), acetyl acetoin 13a
formation (Et3N, EtOH, RT), and in the synthesis of γ-diketone 16a (Et3N, EtOH, 50 °C; entries 4-
6). Remarkably, monolith M29a displayed the same activity of its homogeneous counterpart, that is
the 3-benzyl-5-(2- hydroxyethyl)-4-methylthiazolium chloride, in all the model reactions
investigated in terms of both reaction rate and productivity. A direct comparison was, in fact,
possible thanks to our previous studies on acyloin-type and Stetter reactions,12b,c and through a
dedicated experiment with the above unsupported thiazolium salt utilized catalytically (20 mol%) in
the aqueous benzoin condensation of 10a (isolated yield of 11a: 95% in 24 hours reaction time).
Monoliths M19a and M39a with higher and lower levels, respectively, of thiazolium
functionalization resulted less active than M29a (entries 7-8), thus confirming the requirement of a
suitable balance between the catalyst loading and catalyst site isolation for the good activity of
polystyrene-supported NHC species.2j Additionally, it was observed that the presence of the ethyl
instead of the benzyl N-thiazolium group determined a slight decrease (ca. 10%) in the catalytic
activity of monoliths M29. Nevertheless, M29b was the sole monolith that, after the first recycling,
only very partially retained its catalytic activity in all the reactions examined (entries 9-11).26 Taken
as a whole, the recycling experiments showed the complete deactivation of catalysts M9a within 24
hours27 and, at the same time, indicated the improved stability of monoliths M9b when reacted at
room temperature with the EtOH/Et3N system. The highest turnover number value (TON = 6.4) was
in fact observed for the catalyst M29b in the model acyloin-type condensation.
With this information in hand, we next tested the performance of the monolith M29b as column
microreactor with the hope that the continuous removal of trace impurities and exclusion of air
could improve catalyst stability for longer-term utilizations of flow reactors. Accordingly, a micro-
HPLC was suitably adapted for this study with minimized extra-column volumes. For the
preparation of the monolithic microreactor (hereafter designed as MM), the optimized
polymerization mixture containing monomer 3 was transferred into the stainless-steel column,
which was subsequently sealed at both ends and heated at 70 °C for 24 h in a standard convection
oven (Scheme 3). After cooling, the resulting monolithic microreactor MM28 was connected to the
HPLC instrument and then washed with THF (50 ꢀL/min; HPLC oven: 50 °C; 5 h) to remove the
porogen and residual non-polymeric material.
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3 (5% w/w)
STY (26% w/w)
DVB (8% w/w)
1-dodecanol (50% w/w)
toluene (10% w/w)
AIBN (1% w/w)
-
Br
Me
O
Et
Me
O
+
N
N
S
2
S
2
THF:
50ꢀL/min
1. EtBr stop-flow
60 °C, 12 h
50 °C, 5 h
2. THF: 50ꢀL/min
RT, 2 h
MM28
(f: 0.57 mmol g-1
MM29b
(f: 0.55 mmol g-1
)
)
70 °C, 24 h
Scheme 3. Fabrication of monolithic microreactor MM29b.
The thiazolium-functionalized monolithic microreactor MM29b was then prepared by means of the
stop-flow reaction technique. Hence, an input stream of pure EtBr was pumped inside the
microreactor to completely fill the monolith; subsequently, the column was tightly sealed and
warmed at 60 °C for 12 h. Finally, the column was washed with THF (50 ꢀL/min; RT; 2 h) to
eliminate the excess alkylating agent. The hold-up (dead) volume V0 and the total porosity εtot of
MM8 and MM29b were determined by pycnometry. The main features of these microreactors
including the loaded amount of catalyst, residence time, and the observed backpressure are
summarized in Table 2.
Table 2. Main features of microreactors MM28 and MM29b.a
Reactor
Loading
[mmol/g]b
0.52
V0
Total
Porosityd
0.80
Time
[min]e
132
Pressure
[bar]f
[mL]c
1.32
1.16
MM28
5
5
MM29b
0.48g
0.77
116
aGeometric volume (VG) of the stainless-steel column: 1.66 L. bDetermined
by elemental analysis of reference monolithic columns and expressed as mmol
c
of thiazole units per gram of functionalized resin. Determined by pycnometry
e
(see the Experimental Section). dTotal porosity εtot = V0/VG. Residence time
f
calculated at 10 ꢀLmin-1. Backpressure measured at 10 ꢀLmin-1 (RT, THF).
gAmount of active thiazolium salt.
A SEM image of monolith MM29b fracture surface shows the macroporous nature of this material
(Figure 1). Monolith MM29b is mechanically stable and displays nearly no swelling in aqueous
buffer and ethanol solvents.24
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Figure 1. SEM picture of the macroporous polymer MM29b.
Continuous-flow experiments were performed by first considering the benzoin condensation of
benzaldehyde 10a. It turn out that the preparation of a fully homogeneous 0.10 M solution of 10a in
the reaction phosphate buffer (pH = 8) required the addition of DMSO (10% v/v). Then, the above
reaction mixture was continuously degassed with argon using the purge system of the HPLC
instrument and pumped at different flow rates through the microreactor MM29b for establishing the
influence of the residence time on conversion efficiency. Accordingly, portions of the outlet stream
were taken at regular time intervals (60 min) and analyzed (NMR spectroscopy) to determine the
11a/10a ratio. While good levels of conversion (> 50%) were detected at 35 °C with flow rates up
to 50 ꢀL/min, complete conversion of benzaldehyde into benzoin was obtained with a flow rate of
10 ꢀL/min (residence time: 116 min; Table 3, entry 1). Actually, driving the reaction to completion
is an important goal in continuous process optimization for the easier purification of target
molecules; indeed, under the above operative conditions, isolation of pure 11a was simply achieved
by extraction of the collected eluate with organic solvent. The long-term stability of monolithic
microreactor MM29b was next examined to determine the effect of the flow regime on catalyst
deactivation rate. The analysis of the conversion versus process time plot (model benzoin reaction,
Figure 2a) shows that the steady-state conversion22 is reached after ca. 6 h at 35 °C and it is
maintained at elevated values (≥95%) for 36 h. A progressive loss of catalytic activity is observed
after that time with monolith MM29b fully deactivated after ca. 95 h on stream. The turnover
number after 36 h for the process presented in Figure 2a is 7.4, a value close to that found in the
corresponding batch process (TONbatch = 4.8). Taken together, these results indicate the poor
stability of catalysts of type M9b in aqueous basic medium as well as the modest effect of the
continuous set-up on the productivity of benzoin condensation.23
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Figure 2. Conversion of the model reactions as a function of time in microreactor MM29b. Figure
2a: benzoin condensation of 1a in phosphate buffer (pH = 8) at 35 °C (plain line). Figure 2b:
acyloin-type condensation of 12a in EtOH/Et3N at room temperature (dashed line). Figure 2c:
Stetter reaction of 12a with 15a in EtOH/Et3N at 50 °C (dotted line).
The transition of acyloin-type and Stetter reactions from batch to flow conditions was next
addressed following the thread of the previous study on benzoin reaction.29 Accordingly, a solution
of biacetyl 12a and Et3N in absolute EtOH ([12a] = 0.10 M; [Et3N] = 0.10 M) was continuously
degassed and injected into microreactor MM29b with a flow rate of 10 ꢀL/min to give acetyl
acetoin 13a with almost complete conversion, as detected by GC analysis (entry 2). Isolation of the
valuable α-hydroxyketone 13a was achieved by fractional distillation of the collected eluate, that
permitted the removal of the EtOH solvent and triethyl ammonium salt by-product.31 Outstandingly,
the efficiency of the continuous-flow process was maintained unaltered for ca. 180 h (Figure 2b).
This result corresponds to a turnover number of 37.5 and demonstrates that the productivity of the
model acyloin condensation can be maximized under flow conditions with a 5-fold increase relative
to the batch process (TONbatch = 6.4). A beneficial, but less marked effect of the flow regime on
process productivity was also detected for the Stetter reaction of biacetyl 12a with chalcone 15a
(entry 3). This process was optimized at 50 °C with a flow rate of 10 ꢀL/min and using an excess of
biacetyl in analogy to the batch study (feed composition: [12a] = 0.15 M; [Et3N] = 0.15 M; [15a] =
0.05 M).29 High conversions into the γ-diketone 16a (≥ 90%) were maintained for 90 h (TONflow
=
9.3; TONbatch = 4.8); after that period, however, catalytic MM29b quickly degraded (Figure 2c), this
being a further evidence of the detrimental effect of the temperature on the stability of the prepared
monolithic carbene catalysts.
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Table 3. Optimization of continuous-flow model reactions in monolithic microreactor MM29b and
short substrate scope study.a
-
Br
Et
Me
O
+
N
S
2
HPLC
pump
flow rate
solvent
donor + acceptor
product
MM29b
Temperature
residence time
Flow Rate
[ꢀL/min]
Donor
(c [M])
Acceptor
(c [M])
Temp.
[°C]b
Time
Product
Entry
1
Solvent
Productivitye
207
[min]c
(Conversion [%])d
O
O
buffer
H
f
35
25
10
10
116
(pH 8)g
OH
10a (0.10)
11a (>95)
O
O
O
Me
f
2
3
4
5
EtOHh
EtOHi
116
232
77
207
104
310
207
Me
Me
Me
O
HO
Me
O
13a (>95)
Me
12a (0.10)
O
O
O
Me
Ph
Me
Ph
50
35
50
10
15
10
O
12a (0.15)
15a (0.05)
16a (>95)
O
O
O
O
buffer
f
O
(pH 8)g
H
O
OH
O
10b (0.10)
11b (>95)
F
H
buffer
f
116
(pH 8)g
OH
F
F
10c (0.10)
11c (95)
O
O
O
Et
f
6
7
EtOHh
EtOHh
25
25
10
10
116
116
186
54
Et
Et
Et
HO
Et
O
13b (90)
12b (0.10)
O
O
O
O
Me
OEt
Me
Me
Me
HO
OEt
O
Me
O
O
18 (52)
12a (0.05)
17 (0.15)
Me
O
O
O
Me
Ph
EtOHi
EtOHi
50
50
10
5
232
232
78
36
Me
Ph
8
9
O
Br
Br
12a (0.15)
15b (0.05)
16b (75)
Me
O
O
O
O
Me
Ph
Me
Ph
O
Me
Me
12a (0.15)
15c (0.05)
16c (69)
aSee the Experimental Section for a description of the experimental setup. bAll temperatures were measured by a thermometer placed inside the
thermostated unit containing the microreactor. Calculated residence time. dInstant conversion in steady-state regime as established by 1H NMR or GC
c
analysis. eProductivities are measured in mmol(product) h-1 mmol(catalyst)-1× 103. fHomo-coupling reaction. hReaction performed with DMSO (10% v/v).
hReaction performed with [Et3N] = 0.10 M. iReaction performed with [Et3N] = 0.15 M.
Finally, the scope and the applicability of the disclosed flow processes were briefly investigated.
Gratifyingly, the benzoin condensation of both furfural 10b and 4-fluorobenzaldehyde 10c
11

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proceeded with high conversion efficiencies (≥ 95%) by suitably adjusting the flow rate of the
optimized feed solutions as reported in Table 3 (entries 4-5). The homocoupling of 3,4-hexanedione
12b and the cross-coupling of 12a with ethyl pyruvate 17 also proved to be compatible with the
continuous-flow set-up, thus offering further operational simplicity and practicability to the
synthesis of the challenging tertiary alcohols 13b and 18 (entries 6-7). Satisfactory conversion
efficiencies were lastly detected in the Stetter reactions of biacetyl with chalcone 15b and 15c
having, respectively, an electron-withdrawing and electron-donating substituent on the aromatic
ring (entries 8-9). Notably, the high selectivity of the disclosed continuous-flow processes was
confirmed by the unique formation of the target products and, in the case of incomplete
conversions, by the recovery of unmodified starting materials.
Conclusions
In summary, we have prepared unprecedented thiazolium-functionalized monolithic microreactors
and demonstrated their synthetic potential in continuous-flow umpolung transformations such as
benzoin, acyloin-type, and Stetter reactions. The utilization of environmentally benign reaction
media (aqueous buffer or ethanol), the easy of product/catalyst separation, and the continuous-flow
operation synergistically contributed to the development of effective and green umpolung
processes. In this endeavor, the observed increase of carbene stability moving from batch to flow
conditions was an additional and fundamental benefit, which permitted productivity enhancements
up to fivefold as in the case of the acyloin-type reaction. While small-scale monolithic reactors have
been presented in this work, an easy scale-up of the disclosed flow procedures may be envisaged by
the use of multiple columns (numbering up) and the design of monoliths with larger diameters. On
the other hand, monolithic microreactors can be fabricated a low cost without the need of specialist
equipment, as demonstrated in this study. Therefore, we believe that the methodology herein
described may represent an attractive strategy for the development of efficient continuous-flow
processes based on thiazolium carbene catalysis.
Experimental Section
Liquid aldehydes were freshly distilled before their utilization. All moisture-sensitive reactions
were performed under a nitrogen atmosphere using oven-dried glassware. Solvents were dried over
standard drying agent and freshly distilled prior to use. Flash column chromatograph was performed
on silica gel 60 (230-400 mesh). Reactions were monitored by TLC on silica gel 60 F254 with
detection by charring with sulfuric acid and/or ninhydrin. Flash column chromatography was
12

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1
performed on silica gel 60 (230-400 mesh). H (300 MHz) and 13C (75 MHz) NMR spectra were
recorded for CDCl3 solutions at room temperature unless otherwise specified. Peaks assignments
were aided by 1H-1H COSY and gradient-HMQC experiments. ESI MS (LTQ-XL Linear Trap from
Thermo Scientific) analyses were performed in positive ion mode with samples dissolved in 10mM
solution of HCO2NH4 in 1:1 MeCN/H2O. FT-IR analyses were performed with the Bruker
Instrument Vertex 70. Elemental analyses were performed with FLASH 2000 Series CHNS/O
analyzer (ThermoFisher Scientific). SEM analyses were performed with a Zeiss Gemini 1530
scanning electron microscope. Vertical agitation was performed with the FirstMateTM synthesizer,
Argonaut Technology. The household UVA lamp apparatus was equipped with four 15 W tubes
(1.5 × 27 cm each). Photoinduced reactions were carried out in a glass vial (diameter: 1 cm; wall
thickness: 0.65 mm), sealed with a natural rubber septum, located 2.5 cm away from the UVA lamp
(irradiation on sample: 365 nm, 1.04 W/m2). The system used for continuous-flow reactions was
composed of an HPLC pump (Agilent 1100 micro series), an in-line pressure transducer, a
thermostated microreactor holder (Peltier unit), a system to collect fractions, and a data acquisition
system (Agilent ChemStation). The units were connected by peek tubing (internal diameter 0.01
inch from Upchurch Scientific). The system hold-up volume was smaller than 80 µL. The
temperature was controlled by inserting a thermometer inside the Peltier unit (temperature
measurement error: 0.5 ºC). Silica gel (grade 9385, pore size 60 Å, particle size ~50 ꢀm,
superficial area 500 m2/g) and 5-(2-hydroxyethyl)-4-methylthiazole 1 were purchased from Sigma-
Aldrich. The level of functionalization f of solid supports is expressed as mmol of ligand per gram
of bare support; f is utilized to evaluate the conversion of solid-phase reactions by elemental
analysis and it is determined using nitrogen as the reference atom [N(%) = (f × 14 × 100 /1 + f ×
(MWligand)) 103]. The loading value is expressed as mmol of ligand per gram of functionalized
support. To preserve support particles from mechanical degradation, the derivatization steps on
solid-phase were carried out with the FirstMateTM synthesizer. Continuous-flow benzoin, acyloin-
type, and Stetter reactions were performed with continuous degassing of the input stream with Ar
using the purge system of the HPLC instrument. Spectroscopic data of compounds 11a-c,32
13a,b,12c 18,12c and 16a-c12b were identical to those reported in the literature.
4-Methyl-5-(2-((4-vinylbenzyl)oxy)ethyl)thiazole (3)
To a cooled (0 °C), stirred mixture of NaH (134 mg, 3.36 mmol of a 60% dispersion in oil), 4-
vinylbenzyl chloride (592 ꢀL, 4.20 mmol), and anhydrous DMF (4 mL) a solution of 2-(4-
methylthiazol-5-yl)ethanol (335 ꢀL, 2.80 mmol) in anhydrous DMF (1 mL) was added dropwise.
The resulting mixture was then warmed to room temperature, stirred overnight, diluted with AcOEt
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(45 mL), and washed with saturated aqueous NH4Cl (2 × 10 mL), brine (2 × 10 mL), and H2O (2 ×
5 mL). Then, the organic phase was dried (Na2SO4), concentrated, and eluted from a column of
silica gel with 3.5 : 1 cyclohexane-AcOEt to give 3 (545 mg, 75%) as a pale yellow oil. 1H NMR: δ
8.30 (s, 1 H, H-2), 7.42-7.38 (m, 2 H, Ar), 7.35-7.24 (m, 2 H, Ar), 6.70 (dd, 1 H, J = 10.9 Hz, J =
17.6 Hz, H-1”), 5.74 (dd, 1 H, J = 0.9 Hz, J = 17.6, Hz, H-2”a), 5.23 (dd, 1 H, J = 0.9 Hz, J = 10.9
Hz, H-2”b), 4.51 (s, 2 H, CH2Ph), 3.64 (t, 2 H, J = 6.5 Hz, 2 H-2’), 3.04 (t, 2 H, J = 6.5 Hz, 2 H-
1’), 2.39 (s, 3 H, CH3). 13C NMR: δ 149.8, 149.2, 137.6, 137.0, 136.4, 128.0, 127.8 (2 C), 126.3 (2
C), 113.9, 72.8, 70.0, 27.0, 14.9. ESI-MS (259.4): 260.9 (M + H+). HRMS (ESI/Q-TOF): calcd m/z
for C15H18NOS [M + H]+: 260.1109; found: 260.1135. Found: C, 69.46; H, 6.61; N, 5.40; S, 12.36.
C15H17NOS requires C, 69.61; H, 6.85; N, 5.32; S, 12.53%.
3-Benzyl-4-methyl-5-(2-((4-vinylbenzyl)oxy)ethyl)thiazol-3-ium bromide (4a)
A screw-capped vial, containing a magnetic bar, was charged with a solution of 3 (100 mg, 0.39
mmol) in acetonitrile (0.5 mL); then, benzyl bromide (70 ꢀL, 0.59 mmol) was added in one portion.
The mixture was warmed to 70 °C, stirred at that temperature for 16 h, and then cooled to room
temperature and concentrated. The excess benzyl bromide was removed by repeatedly adding
pentane to the residue and pipetting away the upper portions of the liquid to give 4a (167 mg,
>95%) at least 95 % pure as determined by 1H NMR analysis. 1H NMR: δ 11.27 (s, 1 H, H-2), 7.32-
7.14 (m, 9 H, Ar), 6.61 (dd, 1 H, J = 10.9 Hz, J = 17.6 Hz, H-1”), 6.01 (s, 2 H, NCH2Ph), 5.69 (dd,
1 H, J = 0.9 Hz, J = 17.6, Hz, H-2”a), 5.20 (dd, 1 H, J = 0.9 Hz, J = 10.9 Hz, H-2”b), 4.43 (s, 2 H,
CH2Ph), 3.61 (t, 2 H, J = 6.5 Hz, 2 H-2’), 3.00 (t, 2 H, J = 6.5 Hz, 2 H-1’), 2.34 (s, 3 H, CH3).13C
NMR: δ 157.7, 142.0, 137.4, 136.5, 136.3, 135.5, 131.9, 129.4 (2 C), 129.3 (2 C), 128.3 (2 C),
128.2 (2 C), 126.4, 114.3, 73.1, 67.7, 56.9, 27.8, 12.6. ESI-MS (430.4): 430.9 (M+).
3-Ethyl-4-methyl-5-(2-((4-vinylbenzyl)oxy)ethyl)thiazol-3-ium bromide (4b)
A screw-capped vial, containing a magnetic bar, was charged with a solution of 3 (100 mg, 0.39
mmol) in acetonitrile (0.5 mL); then, ethyl bromide (146 ꢀL, 1.95 mmol) was added in one portion.
The mixture was warmed to 70 °C, stirred at that temperature for 16 h, and then cooled to room
temperature and concentrated. The resulting residue was co-evaporated three times with toluene to
1
give 4b (141 mg, >95%), at least 95 % pure as determined by 1H NMR analysis. H NMR: δ 11.3
(s, 1 H, H-2), 7.42-7.38 (m, 2 H, Ar), 7.25-7.20 (m, 2 H, Ar), 6.70 (dd, 1 H, J = 10.9 Hz, J = 17.6,
Hz, H-1”), 5.74 (dd, 1 H, J = 0.9 Hz, J = 17.6 Hz, H-2”a), 5.23 (dd, 1 H, J = 0.9 Hz, J = 10.9 Hz,
H-2”a), 4.76 (q, 2 H, J = 8.0 Hz, NCH2), 4.51 (s, 2 H, CH2Ph), 3.64 (t, 2 H, J = 6.5 Hz, 2 H-2’),
3.04 (t, 2 H, J = 6.5 Hz, 2 H-1’), 2.39 (s, 3 H, CH3), 1.60 (t, 3 H, J = 8.0 Hz, CH3). 13C NMR: δ
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157.3, 141.1, 137.3, 136.5, 136.2, 135.5, 127.9 (2 C), 126.3 (2 C), 114.2, 73.1, 67.8, 49.2, 27.8,
15.6, 12.1. ESI-MS (368.3): 368.8 (M+).
Preparation of 3-mercaptopropyl silica gel (S5)
To preserve silica particles from mechanical degradation, this derivatization step was carried out in
a standard rotary evaporator in which a two-necked flask was fitted with solvent condenser, solvent
collector, and nitrogen inlet for syringe addition of reactant solutions under an inert atmosphere.
Mixing was obtained by spinning the flask around its axis and warming by means of a standard oil-
bath. Silica gel (grade 9385, pore size 60 Å, particle size ~50 ꢀm, superficial area 500 m2/g) was
dried before its use (0.1 mbar, T= 110 °C, 2 h). To a stirred slurry of silica gel (5.00 g), anhydrous
toluene (60 mL), and freshly distilled triethylamine (0.25 mL) was slowly added a solution of (3-
mercaptopropyl)-trimethoxysilane (2.5 mL) in anhydrous toluene (10 mL). The resulting mixture
was then warmed to 60 °C and stirred for 20 h. Subsequently, the mixture was refluxed until ca. 15
mL of solvent were collected (eventually by the aid of a nitrogen stream). The mixture was then
refluxed for an additional 1 h, cooled to room temperature, and centrifuged with 20-mL portions of
toluene, MeOH, EtOH, and cyclohexane. The resulting thiol-functionalized silica gel S510b was
finally dried at reduced pressure (0.1 mbar, 60 °C, 6 h). FT-IR (KBr): ν 2577(SH) cm-1. Elemental
analysis (%) found: S 3.36 (f = 1.29 mmolg-1; loading = 1.05 mmolg-1).
Synthesis of silica-supported thiazole S6 via photoinduced TEC
A vertically-agitated mixture of thiol-silica S5 (1.00 g, 1.05 mmol; loading = 1.05 mmolg-1),
thiazole derivative 3 (816 mg, 3.15 mmol), 2,2-dimethoxy-2-phenyl-acetophenone (DMAP, 267
mg, 1.05 mmol), and MeOH (6 mL) was irradiated at room temperature for 5 h, and then
centrifuged with 5-mL portions of MeOH (4 ×). The resulting silica-supported thiazole S6 was
finally dried at reduced pressure (0.1 mbar, 40 °C, 6 h). Elemental analysis (%) found: N 1.02 (f =
1.07 mmolg-1; loading = 0.73 mmolg-1). Excess intermediate 3 can be easily recycled by column
chromatography of the centrifugate.
Synthesis of silica-supported N-benzyl thiazolium salts (S1-37a)
A mixture of thiazole-silica S6 (500 mg, 0.37 mmol; loading = 0.73 mmolg-1), benzyl bromide (131
ꢀL, 1.11 mmol), and acetonitrile (4 mL) was vertically-agitated at 70 °C for 12h, and then cooled to
room temperature and centrifuged with 5-mL portions of acetonitrile (4 ×). The resulting silica-
supported N-benzyl thiazolium salt S17a was finally dried at reduced pressure (0.1 mbar, 40 °C, 6
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h). Elemental analysis (%) found: N 0.89 (f = 1.05 mmolg-1; loading = 0.64 mmolg-1). FT-IR (KBr):
ν 2947, 1496, 1455 cm-1.
Silica S27a was obtained by the same procedure using 2.0 equiv. of benzyl bromide. Elemental
analysis (%) found: N 0.73 (f = 0.78 mmolg-1; loading = 0.52 mmolg-1).
Silica S37a was obtained by the same procedure using 1.0 equiv. of benzyl bromide. Elemental
analysis (%) found: N 0.51 (f = 0.47 mmolg-1; loading = 0.36 mmolg-1).
Synthesis of silica-supported N-ethyl thiazolium salts (S1-37b)
A mixture of thiazole-silica S6 (500 mg, 0.37 mmol; loading = 0.73 mmolg-1), ethyl bromide (138
ꢀL, 1.85 mmol), and acetonitrile (4 mL) was vertically-agitated at 70 °C for 12h, and then cooled to
room temperature and centrifuged with 5-mL portions of acetonitrile (4 ×). The resulting silica-
supported N-ethyl thiazolium salt S17b was finally dried at reduced pressure (0.1 mbar, 40 °C, 6 h).
Elemental analysis (%) found: N 0.89 (f = 1.00 mmolg-1; loading = 0.64 mmolg-1). FT-IR (KBr): ν
2860, 1607, 1514, 1416 cm-1.
Silica S27b was obtained by the same procedure using 3.0 equiv. of ethyl bromide. Elemental
analysis (%) found: N 0.74 (f = 0.75 mmolg-1; loading = 0.53 mmolg-1).
Silica S37b was obtained by the same procedure using 2.0 equiv. of ethyl bromide. Elemental
analysis (%) found: N 0.49 (f = 0.44 mmolg-1; loading = 0.35 mmolg-1).
Synthesis of thiazole-functionalized monoliths (M1-38)
A homogeneous mixture of thiazole derivative 3 (130 mg, 0.50 mmol), styrene (400 ꢀL, 3.46
mmol), divinylbenzene (technical grade, 80%; 140 ꢀL, 1.00 mmol), toluene (180 ꢀL, 1.74 mmol),
1-dodecanol (940 ꢀL, 4.18 mmol), and AIBN (6 mg, 0.04 mmol) was degassed under vacuum, and
saturated with argon (by an Ar-filled balloon) three times. The mixture was then poured in a glass
column (length: 10 cm, 0.46 cm internal diameter) sealed at both ends, and placed in a vertical
position in a standard convection oven. The polymerization was allowed to proceed for 24 h at 70
°C, then the column was cooled to room temperature, the glass broken, and the resulting monolith
M18 triturated to obtain a yellow powder. This powder was suspended in THF (5 mL) and
centrifuged with 5-mL portions of THF (2 ×). The collected supernatants were analyzed (1H NMR
analysis) to verify the complete incorporation of monomer 3 into the polymer. The triturated M18
resin was utilized for elemental and FT-IR analyses and subsequent derivatization steps. Elemental
analysis (%) found: N 1.12 (f = 0.92 mmolg-1; loading = 0.80 mmolg-1).
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Monolith M28 was obtained by the same procedure but varying the amounts of styrene (508 ꢀL,
4.42 mmol) and 3 (80 mg, 0.31 mmol). Elemental analysis (%) found: N 0.73 (f = 0.57 mmolg-1;
loading = 0.52 mmolg-1).
Monolith M38 was obtained by the same procedure but varying the amounts of styrene (419 ꢀL,
3.65 mmol) and 3 (30 mg, 0.12 mmol). Elemental analysis (%) found: N 0.30 (f = 0.22 mmolg-1;
loading = 0.21 mmolg-1).
Synthesis of N-benzyl thiazolium salt-functionalized monoliths (M1-39a)
A mixture of triturated M18 (100 mg, 0.40 mmol; loading = 0.80 mmolg-1), benzyl bromide (143
ꢀL, 1.20 mmol), and acetonitrile (2 mL) was vertically-agitated at 70 °C for 12h, and then cooled to
room temperature and filtered. The resulting N-benzyl thiazolium salt-functionalized monolith
M19a was finally dried at reduced pressure (0.1 mbar, 40 °C, 6 h). Elemental analysis (%) found: N
0.97 (f = 0.90 mmolg-1; loading = 0.69 mmolg-1). FT-IR (KBr): ν 3025, 2922, 1601, 1510, 1493,
1452 cm-1.
Monolith M29a was obtained by the same procedure starting from M28. Elemental analysis (%)
found: N 0.67 (f = 0.57 mmolg-1; loading = 0.48 mmolg-1).
Monolith M39a was obtained by the same procedure starting from M38. Elemental analysis (%)
found: N 0.28 (f = 0.21 mmolg-1; loading = 0.20 mmolg-1).
Synthesis of N-ethyl thiazolium salt-functionalized monoliths (M1-39b)
A mixture of triturated M18 (100 mg, 0.40 mmol; loading = 0.80 mmolg-1), ethyl bromide (149 ꢀL,
2.00 mmol), and acetonitrile (2 mL) was vertically-agitated at 70 °C for 12h, and then cooled to
room temperature and filtered. The resulting N-ethyl thiazolium salt-functionalized monolith M19b
was finally dried at reduced pressure (0.1 mbar, 40 °C, 6 h). Elemental analysis (%) found: N 1.02
(f = 0.91 mmolg-1; loading = 0.73 mmolg-1). FT-IR (KBr): ν 3024, 2920, 1601, 1492, 1425 cm-1.
Monolith M29b was obtained by the same procedure starting from M28. Elemental analysis (%)
found: N 0.70 (f = 0.57 mmolg-1; loading = 0.50 mmolg-1).
Monolith M39b was obtained by the same procedure starting from M38. Elemental analysis (%)
found: N 0.24 (f = 0.18 mmolg-1; loading = 0.17 mmolg-1).
Procedure for the model benzoin reaction under batch conditions (Table 1, entry 9)
A mixture of benzaldehyde 11a (25 ꢀL, 0.25 mmol), monolith M29b (0.025 mmol, 50 mg; 20
mol%), and phosphate buffer pH = 8 (1 mL) was vertically-stirred for 24 h at 35 °C, and then
filtered. The filtrate was analyzed by 1H NMR to determine the reaction conversion. Subsequently,
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the residue was eluted form a column of silica gel with 4: 1 cyclohexane - AcOEt to give benzoin
11a32 (23 mg, 84%). The recycled catalyst M29b was subjected to the same reaction furnishing 11a
in 12% isolated yield. Catalyst M29b was inactive at the third run. This result corresponds to a
turnover number of 4.8 for M29b in the model benzoin reaction.
Procedure for the model acyloin-type reaction under batch conditions (Table 1, entry 10)
A mixture of biacetyl 12a (22 ꢀL, 0.25 mmol), monolith M29b (0.025 mmol, 50 mg; 20 mol%),
Et3N (34 ꢀL, 0.25 mmol), and EtOH (1 mL) was vertically-stirred for 24 h at room temperature, and
1
then filtered. The filtrate was analyzed by H NMR to evaluate the yield of acetyl acetoin 13a12c
(88%) using bromoform as the internal standard. The recycled catalyst M29b was subjected to the
same reaction furnishing 13a in 44% isolated yield. Catalyst M29b was inactive at the third run.
This result corresponds to a turnover number of 6.4 for M29b in the model acyloin-type reaction.
Procedure for the model Stetter reaction under batch conditions (Table 1, entry 11)
A mixture of trans-chalcone 15a (26 mg, 0.125 mmol), biacetyl 12a (33 ꢀL, 0.38 mmol), monolith
M29b (0.025 mmol, 50 mg; 20 mol%), Et3N (52 ꢀL, 0.38 mmol), and EtOH (1 mL) was vertically-
stirred for 24 h at 50 °C, and then cooled to room temperature and filtered. The filtrate was
1
analyzed by H NMR to determine the reaction conversion. Subsequently, the residue was eluted
form a column of silica gel with 12: 1 cyclohexane - AcOEt to give the γ-diketone 16a12b (26 mg,
81%). The recycled catalyst M29b was subjected to the same reaction furnishing 16a in 15%
isolated yield. Catalyst M29b was inactive at the third run. This result corresponds to a turnover
number of 4.8 for M29b in the model Stetter reaction.
Preparation of monolithic microreactor (MM29b)
A homogeneous mixture of thiazole derivative 3 (80 mg, 0.31 mmol), styrene (508 ꢀL, 4.42 mmol),
divinylbenzene (technical grade, 80%; 140 ꢀL, 1.00 mmol), toluene (180 ꢀL, 1.74 mmol), 1-
dodecanol (940 ꢀL, 4.18 mmol), and AIBN (6 mg, 0.04 mmol) was degassed under vacuum, and
saturated with argon (by an Ar-filled balloon) three times. The mixture was then poured in a
stainless-steel columns (length: 10 cm, 0.46 cm internal diameter) sealed at both ends, and placed in
a vertical position in a standard convection oven. The polymerization was allowed to proceed for 24
h at 70 °C, then the column MM28 was cooled to room temperature and the seals removed. The
column was provided with fittings, connected to the HPLC pump, and warmed to 50 °C. Then, THF
was pumped through the warmed column at a flow rate of 50 ꢀL min-1 for 5 h to remove the
porogenic solvents and residual non-polymeric materials. The column MM28 was cooled to room
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temperature and then an input stream of pure EtBr (2 mL) was pumped at 50 ꢀL min-1 inside the
column to completely fill the microreactor (V0 = 1.07 mL). The pump was then stopped, the column
sealed at both ends, and placed in a vertical position in a standard convection oven. The N-
alkylation step was allowed to proceed for 12 h at 60 °C, then the column MM29b was cooled to
room temperature and the seals removed. The column was provided with fittings, connected to the
HPLC pump, and washed at room temperature with THF at a flow rate of 50 ꢀL min-1 for 2 h to
remove the excess BnBr. The whole procedure was performed with a reference microreactor in a
parallel experiment with the aim to establish the level of N-alkylation and the weight of dried
polymer inside the stainless-steel column (604 mg). Elemental analysis (%) found: N 0.67 (f = 0.55
mmolg-1; loading = 0.48 mmolg-1).
Determination of microreactor void-volume
Microreactor void volume (V0) was determined by pycnometry.33 This method consists in filling the
microreactor successively with two distinct solvents (solvent 1: water; solvent 2: n-hexane) and
weighing the filled microreactors accurately. Simple math shows that:34
w − w2
δ1 −δ2
1
V0 =
where
w δ
and w2 are the weights of the microreactor filled with solvents 1 and 2 and 1 and δ2 the
1
densities of the solvents.
Continuous-flow benzoin reactions (Table 3, entries 1, 4, and 5)
Microreactor MM29b was fed with a continuously degassed solution of the aromatic aldehyde 10 in
phosphate buffer (pH 8) and DMSO (10% v/v; see Table 3 for molarity concentrations), and
operated at the stated temperature for 5 h (under steady-state conditions) at the stated flow rate.
Instant conversion was determined (1H NMR analysis) every 60 min by taking a sample of the
eluate. The collected solution was finally extracted with Et2O (3 × 25 mL), and the resulting organic
phase concentrated to give the corresponding adduct 1125 (yield: > 95%), at least 95% pure as
established by 1H NMR analysis.
The long-term stability experiment was performed using benzaldehyde 10a (0.10 M) as the
substrate; microreactor MM29b was operated at 35 °C with a flow rate of 10 ꢀ
L min-1 for ca. 100 h.
After the achievement of the steady-state regime (ca. 6 h), full conversion of 10a was maintained
for 36 h, while a progressive loss of catalytic activity was observed after that time (TONflow = 7.4).
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Continuous-flow acyloin-type reactions (Table 3, entries 2, 6, and 7
)
Microreactor MM29b was fed with a continuously degassed solution of donor 12a or 12b, acceptor
12a 12b, or 17, and Et3N in absolute EtOH (see Table 3 for molarity concentrations), and operated
,
at 25 °C for 5 h (under steady-state conditions) at the stated flow rate. Instant conversion was
determined (1H NMR or GC analysis) every 60 min by taking a sample of the eluate. The collected
solution containing the adduct 13a or 13b was bulb-to bulb distilled (13a: 50 °C, 5 mmHg; 13b: 84
°C, 5 mmHg) to give the corresponding product 1312c (yield: > 90%), at least 95% pure as
established by 1H NMR analysis. In the case of product 18, the collected solution was concentrated
and eluted from a column of silica gel with 3: 1 cyclohexane-AcOEt to give 1812c (yield: 52%).
The long-term stability experiment was performed using biacetyl 12a (0.10 M) as the substrate;
microreactor MM29b was operated at 25 °C with a flow rate of 10 ꢀ
L min-1 for ca. 250 h. After the
achievement of the steady-state regime (ca. 4 h), full conversion of 12a was maintained for ca. 180
h, while a progressive loss of catalytic activity was observed after that time (TONflow = 37.2).
Continuous-flow Stetter reactions (Table 3, entries 3, 8, and 9
)
Microreactor MM29b was fed with a continuously degassed solution of biacetyl 12a, chalcone 15
,
and Et3N in absolute EtOH (see Table 3 for molarity concentrations), and operated at 50 °C for 5 h
(under steady-state conditions) at the stated flow rate. Instant conversion was determined (1H NMR
analysis) every 60 min by taking a sample of the eluate. The collected solution was concentrated
and eluted from a column of silica gel with the suitable elution system to give the γ-diketone 1612b
(yield: 69-95%).
The long-term stability experiment was performed using biacetyl 12a (0.15 M) and trans-chalcone
15a (0.05 M) as the substrates; microreactor MM29b was operated at 25 °C with a flow rate of 10
ꢀ
L min-1 for ca. 130 h. After the achievement of the steady-state regime (ca. 5 h), full conversion of
15a was maintained for ca. 90 h, while a progressive loss of catalytic activity was observed after
that time (TONflow = 9.3).
Acknowledgements. We gratefully acknowledge the University of Ferrara (Progetto FAR 2011)
and the Italian Ministry of University and Scientific Research (Progetto PRIN Grants 2009ZSC5K2
004 and 20098SJX4F 004) for financial supports. Thanks are also given to Mr. Paolo Formaglio for
NMR experiments, to Mrs. Tatiana Bernardi for HRMS analyses, and to Mrs. Ercolina Bianchini
for elemental analyses.
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It is likely that the thiazolium salt acts as a radical sponge. For ESR evidences of the
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21.
22.
The complete incorporation of thiazole-functionalized monomers into the corresponding
1
monoliths was checked by H NMR analysis of the THF solution used to wash the solid
material. FT-IR and UV analyses proved to be less effective in this determination because of
the complexity of the washing solution.
23.
24.
A negative effect of silica acidity on the lower activity of catalysts S7 can be reasonably
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Very poor results were detected when the benzoin condensation was performed with
catalysts S7 and M9 in the low-polarity solvents toluene and diisopropyl ether under the
conditions of Table 1 (isolated yields of 11a: 5-10%).
25.
26.
27.
28.
At this stage of the study we cannot firmly suggest the mechanism of degradation of
monoliths M9. Dedicated FT-IR and MAS-NMR analyses are currently underway in our
laboratories.
Regeneration of catalytic activity of monoliths M9 by washing the polymeric material with
dilute methanolic HCl as previously reported (see Ref. 8) did not produce any satisfactory
result.
Dedicated experiments showed a linear relationship between backpressure and flow rate for
aqueous buffer and ethanol solvents; this clearly demonstrates that the monolith MM29b is
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mechanically stable and that no swelling occurs (Y. Li, H. D. Tolley, and M. L. Lee, Anal.
Chem. 2009, 81, 9416-9424).
29.
Achievement of the steady-state regime was assumed when constant reactants/product outlet
concentrations accompanied by complete inlet mass recovery in the eluate were detected. It
is important to note that steady-state conditions have been optimized in this study by finding
the best compromise between conversion efficiency and catalyst stability. To this aim, a
limited number of experiments were performed with different feed compositions, flow rates,
and reaction temperatures. Of course, this cannot exclude that an in depth study on process
productivity might result in improved process conditions.
30.
31.
32.
The premature deactivation of NHC catalysts was also observed in benzoin condensations
promoted by poly-(NHC-CO2) adducts (see Ref. 3b).
The asymmetric version of the continuous-flow acyloin-type condensation of 1,2-diones
using an enzymatic packed-bed reactor will be the object of a forthcoming publication.
I. Chiarotto, M. Feroci, M. Orsini, M. M. M. Feeney and A. Inesia, Adv. Synth. Catal., 2010,
352, 3287-3292.
33.
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R.M. McCormick and B.L. Karger, Anal. Chem., 1980, 52, 2249-2257.
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1
Electronic supplementary information (ESI) available: copies of H and 13C NMR spectra for new
compounds, FT-IR spectra of thiazolium salt-functionalized supports S7a,b and M9a,b
.
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A polystyrene monolithic microreactor functionalized with N-ethyl thiazolium salt effectively
produces valuable compounds under continuous-flow conditions via umpolung catalysis.