A chiral organocatalytic polymer-based monolithic reactor

Article abstract of DOI:10.1039/c4gc00031e

Radical copolymerisation of divinylbenzene and a properly modified enantiomerically pure imidazolidinone inside a stainless steel column in the presence of dodecanol and toluene as porogens afforded the first example of a chiral organocatalyst immobilized

Full text of DOI:10.1039/c4gc00031e

Green Chemistry
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A chiral organocatalytic polymer-based monolithic
reactor†
Cite this: Green Chem., 2014, 16,
2798
Valerio Chiroli,a Maurizio Benaglia,*a,c Alessandra Puglisi,a,c Riccardo Porta,a
Ravindra P. Jumdeb,c and Alessandro Mandoli*b,c
Radical copolymerisation of divinylbenzene and a properly modified enantiomerically pure imidazoli-
dinone inside a stainless steel column in the presence of dodecanol and toluene as porogens afforded
the first example of a chiral organocatalyst immobilized onto a monolithic reactor. Organocatalyzed
cycloadditions between cyclopentadiene and cinnamic aldehyde were performed under continuous-flow
conditions; by optimizing the experimental set up, excellent enantioselectivities (90% ee at 25 °C) and high
productivities (higher than 330) were obtained, thus showing that a catalytic reactor may work efficiently
to continuously produce enantiomerically enriched compounds. The same catalytic reactor was also
employed to carry out three different stereoselective transformations in continuo, sequentially, inside the
chiral column (Diels–Alder, 1,3-dipolar nitrone-olefin cycloaddition, and Friedel–Crafts alkylation); excel-
lent results were obtained in the case of the former two reactions (up to 99% yield, 93% ee and 71% yield,
90% ee, at 25 °C, respectively). In addition to simplify the product recovery, the monolithic reactor
performed better than the same supported organocatalyst in a stirred flask and could be kept working
continuously for more than 8 days.
Received 8th January 2014,
Accepted 3rd March 2014
DOI: 10.1039/c4gc00031e
www.rsc.org/greenchem
The synthesis of fine chemicals in flow presents new and excit- grated into microflow systems, the inline analysis of the trans-
ing challenges and opportunities for both homogeneous and formations performed in micro (or mini) reactors can provide
heterogeneous transformations;1 in this context great opportu- reaction information more efficiently than flask reactors.
nities are offered by the use of immobilized chiral catalysts
When the use of a chiral catalyst under continuous-flow
under flow conditions.2 For decades petrochemical and com- conditions is envisaged, the heterogenization of the enantio-
modity chemical industries have exploited heterogeneous merically pure catalytic species plays a crucial point in the
catalytic processes, performing in flow many important trans- development of efficient systems.6 The retention of the catalyst
formations.3 However, the application of continuous-flow inside the reaction vessel can be achieved by different tech-
methodologies to the stereoselective synthesis of chiral multi- niques ranging from ultrafiltration through a MW-selective
functional molecules is much less developed.4 Although in the membrane to immobilization on an organic polymer or an in-
fine chemical industry production relies at the present on organic material like silica gel. According to the method used
batch or semi-batch processes, where flexibility and versatility to incorporate an immobilized catalyst into the microfluidic
are guaranteed, the possibility in the future to design a multi- device, catalytic (micro)reactors7 can be divided into three
purpose plant based on a continuous process is very attractive main typologies: packed-bed, monolithic and inner wall-func-
and full of promise.5 Further opportunities are offered if tionalized. The application of the last mentioned approach is
microreactor-based technologies are taken into consideration. almost unknown for chiral catalysts;8 on the other hand the
Since HPLC, GC-MS or LC-MS technologies can be easily inte- first one has been widely investigated, with both organic and
organometallic systems. Indeed most of the continuous-flow
processes utilize reactors with randomly packed catalytic beds;
this approach, however, does not withstand requirements from
a process and chemical engineering point of view. Major draw-
backs of these systems are uncontrolled fluid dynamics, stag-
nation zones and hot-spot formation, broad residence time
distribution, low selectivity and possibly low process efficiency.
Some of these problems may find a solution by the develop-
ment of monolithic materials, functionalized with a chiral
promoter. A monolith is defined as “a block of structured
aDipartimento di Chimica, Università degli Studi di Milano, via Golgi 19, 20133
Milano, Italy. E-mail: maurizio.benaglia@unimi.it; Fax: +390250314159;
Tel: +390250314171
bDipartimento di Chimica e Chimica Industriale, Università di Pisa,
via Risorgimento, 35, 56126 Pisa, Italy
cISTM-CNR, via Golgi 19, 20133 Milano, Italy
†Electronic supplementary information (ESI) available: Synthetic procedures
and 1H NMR, 13C NMR, and IR spectra of new compounds. Preparation, analysis
and characterization of polymer-supported chiral catalysts. NMR and HPLC
traces of the stereoselective reaction products. See DOI: 10.1039/c4gc00031e
2798 | Green Chem., 2014, 16, 2798–2806
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material which consists of continuous substructures of regular Wennemers22 have reported stereoselective Michael additions
or irregular channels”.9 Since monoliths are characterized by a promoted in continuo by polymer-supported tripeptides. Very
high void volume and a large geometric surface area, the recently, Pericas and coworkers reported the synthesis of a
passage of a gas or a fluid occurs without significant pressure polystyrene-supported pyrrolidine-based catalyst23 and a 1,1′-
drop, and a large contact area of the catalyst with the fluid is bi-2-naphthol-derived phosphoric acid24 to be used under con-
guaranteed.10 Monolithic materials may be prepared by copoly- tinuous flow conditions. It should be noted that all these
merisation of different monomers in the presence of poro- works were almost exclusively limited to the use of packed-bed
gens,11 or by polymerisation of a monolithic polymeric phase reactors filled with catalyst supported onto inorganic or gel-
wedged inside the microchannel pore system of an inert type organic materials, with substrate activation via enamine
support such as glass.12
intermediates.
While numerous examples of achiral catalytic monoliths
We wish to report here the preparation of the first mono-
are known,13 only very few examples of effective chiral catalysts lithic material loaded with a chiral imidazolidinone organo-
immobilized onto monoliths have been reported. After early catalyst25 and its use to promote stereoselective reactions via
studies on TADDOL derivatives,14 in 2007 Luis, Mayoral and substrate-iminium activation.
coworkers reported the synthesis of a heterogenized chiral
An ad hoc designed MacMillan type catalyst was easily syn-
pyridyl bisoxazoline (Pybox) by polymerization of 4-vinyl-pybox thesized starting from (S)-tyrosine methyl ester 1, to give after
in the presence of styrene and divinylbenzene to generate a a single chromatographic purification the imidazolidinone 2
macroporous monolithic miniflow reactor.15 The corres- bearing a carbon–carbon triple bond (Scheme 1 and ESI†). The
ponding ruthenium/pybox complex was evaluated in the cyclo- modified MacMillan catalyst 2 was reacted with 4-(azido-
propanation reaction between styrene and ethyldiazoacetate methyl)styrene in the presence of CuCl and tris[(1-benzyl-1H-
under flow conditions. A slightly modified monolithic mini- 1,2,3-triazol-4-yl)methyl]amine (TBTA), to afford the corres-
flow reactor containing a supported bisoxazoline-Cu(OTf)2 ponding styrene monomer 3.
complex was then prepared and used in the same cyclopropa-
The monolithic organocatalyst was prepared inside a stan-
nation reaction.16 Recently the same group described the con- dard HPLC column (0.46 cm i.d. ×15 cm, 2.49 mL total
tinuous-flow cyclopropanation reaction promoted by a new volume) under Frechét-type conditions for polystyrene
supported catalyst with improved efficiency, a pyridineox- materials.11 The AIBN initiated copolymerization of 3 and
azoline (pyox)-copper complex.17
divinylbenzene (DVB) was carried out at 70 °C in the presence
As far as we know, however, chiral organocatalysts immobi- of 1-dodecanol and toluene as the porogenic solvents (3 : 1 v/v,
lized onto a monolithic support are completely unknown; approx. 60 vol% of the feed mixture). Exhaustive washing of
moreover, only a few examples of chiral organocatalysts the column with THF and analysis of the eluate indicated a
employed under continuous-flow conditions were reported. complete incorporation of the monomers into the monolith.26
After the pioneering work by Lectka with polystyrene-immobi- Based on these results, the loading of MacMillan organocata-
lized cinchona alkaloid derivatives,18 Pericas and Massi lyst onto the polymeric support (0.51 mmol g−1 or 25 wt%),
have studied the use of polymer-supported proline19 and the absolute amount of the chiral derivative immobilized
prolinol20 derivatives in mini flow reactors. Lately Fulop21 and inside the flow device (0.48 mmol) and the void volume in the
Scheme 1 Preparation of the monolithic reactor containing the chiral imidazolidinone catalyst Supp-3.
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Scheme 2 Enantioselective Diels–Alder reactions with different substrates under continuous-flow conditions catalyzed by imidazolidinone sup-
ported catalyst Supp-3.
reactor (1.49 ml)27 could be calculated directly from the feed
composition.
Table 1 Diels–Alder reaction in continuo between 4 and cyclopenta-
diene, promoted by the TFA salt of polymer-supported catalyst Supp-3a
For comparative purposes, several monolithic reactors were
ee endo-5
prepared as described above. The filling polymeric material
from two of such columns was removed from the device,
crushed, thoroughly washed with MeCN and dried. By this pro-
cedure the powder form of the same supported organocatalyst
in the monolithic reactors could be obtained, which was used
for running batch heterogeneous catalysis reactions as well as
for preparing a packed-bed continuous-flow reactor (vide infra).
IR characterization of the material (ESI†)25e confirmed the
Running
Entry time [h]
ϕ
Yieldc
τb [h] [%]
(ee exo-5)e
[µL min−1
]
drd
[%]
1
2
3
4
5
6
7
0–2
2–4
4–6
6–18
18–20
20–48
48–120
5
5
5
5
5
2
1
—
—
5
20
47
54
58
61
77
91
46/54 n.d.
44/56 86 (85)
42/58 91 (93)
43/57 90 (92)
43/57 91 (90)
44/56 90 (88)
43/57 87 (86)
5
5
12.4
24.8
incorporation and integrity of the chiral units (νCvO
=
a Reactions conditions: 25 °C; HPLC column (0.46 cm i.d. × 15 cm,
containing 0.475 mmol of catalyst); cinnamaldehyde (0.195 M, 1 eq.)
1695 cm−1).28 N2 adsorption measurement provided a BET
specific surface area (485 m2 g−1) consistent with a texture and cyclopentadiene (1.365 M, 7 eq.) in 95/5 CH3CN–H2O mixture.
b Residence time calculated as void volume/flow rate. c Yields
comprising meso- and micropores.11 At the same time, pre-
determined by 1H NMR and confirmed on isolated products after
chromatographic purification. d Endo-5/exo-5 diastereoisomeric ratio,
liminary flow tests revealed the good fluid dynamic properties
associated with the occurrence of convective pores (P < 5 bar at determined by 1H NMR on the crude reaction mixture. e Enantiomeric
flow-rate ϕ = 300 μL min−1 of THF or MeCN).11 Among the
excess determined by HPLC on the alcohols obtained by NaBH4
reduction of adducts.
several stereoselective transformations catalyzed by chiral imid-
azolidinones,29 the Diels–Alder cycloaddition between trans-
cinnamaldehyde (4) and cyclopentadiene30 was selected as the
was further incremented to 91%, by operating at ϕ = 1 µL
min−1 (entries 6–7, Table 1).32
first model reaction to study the catalytic behavior.
The reaction (Scheme 2 and Table 1) was initially carried
out at 25 °C, by pumping a solution of the reagents at ϕ = 5 µL
min−1 through the monolithic reactor containing the imid-
azolidinone organocatalyst Supp-3 activated by treatment with
trifluoroacetic acid (TFA).31
After a conditioning time of 4–6 hours a steady-state regime
was reached, which allowed us to produce in continuo the
cycloadducts 5 in 54–61% yield. In agreement with the results
obtained with the non-supported catalyst,30 the product was
obtained as a rough 1 : 1 mixture of endo/exo isomers, both
with enantioselectivities higher than 90% ee (entries 3–5,
Table 1). In order to improve the chemical yield, the flow rate
was reduced so as to increase the residence time τ. Indeed
with ϕ = 2 µL min−1 the product was isolated in 77% yield that
In order to compare the behavior of the polymer-supported
catalyst under batch and continuous-flow conditions, the same
reaction between 4 and cyclopentadiene was performed in a
flask with polymeric powder Supp-3 and trifluoroacetic acid
(Table 2). By running the reaction at 25 °C, in the presence of
30% mol amount of the supported catalyst the product was
obtained in 60% yield after 24 hours and 85% yield after
48 hours (90% ee, entries 1 and 2, Table 2). The yield did not
further increase at longer reaction times, thus suggesting the
loss of catalytic activity in a relatively short time with respect
to the continuous-flow set-up described above: possibly, the
continuous flow efficiently removes trace impurities and mini-
mizes catalyst deactivation due to product inhibition, which
helps in preserving the catalytic activity of the chiral species in
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Table 2 Diels–Alder reaction in batch between 4 and cyclopentadiene,
promoted by the TFA or HBF4 salt of polymer-supported catalyst
Supp-3a
Table 3 Diels–Alder reactions in continuo with different α,β-unsatu-
rated aldehydes, promoted by the HBF4 salt of polymer-supported cata-
lyst Supp-3a
ee endo-5
Running
time [h]
Yieldb
[%]
ee endo
Acid
additive
Yieldb
[%]
(ee exo-5)d Entry
Product
drc
(ee exo)d [%]
Entry
t [h]
drc
[%]
1
0–24
5
—
7
7
—
9
9
—
75
—
88
95
—
94
97
—
73
47/53
—
49/51
47/53
—
52/48
49/51
—
92 (91)
—
90 (91)
91 (90)
—
83 (75)
85 (75)
—
1
2
TFA
TFA
TFA
TFA
HBF4
HBF4
HBF4
24
48
72
48
24
48
72
60
85
88
25
77
97
70
46/54
44/56
47/53
42/58
45/55
43/57
44/56
90 (90)
90 (89)
89 (88)
71 (75)
90 (86)
90 (88)
85 (83)
2e
3
24–32
32–48
48–60
60–72
72–86
86–108
108–120
120–150
3
4
4e
5
5e
6
6
7
7e
8e
9
5
47/53
94 (89)
a Reactions run at 25 °C; for the other conditions, see the ESI. b Yields
determined by 1H NMR and confirmed on isolated products after a Flow rate ϕ = 2 µL min−1; residence time = 12.4 h. Reactions
chromatographic purification. c Endo-5/exo-5 diastereoisomeric ratio conditions: 25 °C; HPLC column (0.46 cm i.d. × 15 cm, containing
determined by 1H NMR on the crude reaction mixture. d Enantiomeric 0.475 mmol of catalyst); α,β-unsaturated aldehyde (0.195 M, 1 eq.) and
excess determined by HPLC on the alcohols obtained by NaBH4 cyclopentadiene (1.365 M, 7 eq.) in 95/5 CH3CN–H2O mixture. b Yields
reduction of adducts. e Recovered catalyst was employed.
determined by 1H NMR and confirmed on isolated products after
chromatographic purification. c Endo/exo diastereoisomeric ratio
determined by 1H NMR on the crude reaction mixture. d Enantiomeric
excess of the endo diastereoisomer, determined by HPLC (ESI); in
parentheses enantiomeric excess of the exo diastereoisomer. e Column
washing.
the flow reactor for longer operation times than in the batch
process.
In addition to facilitating the separation of the catalyst
from the reaction products, the immobilization on a polymer
should allow simple catalyst recovery and recycling. In this produced the cycloadduct 7 in up to 94% yield and 90–91% ee
case, the separation of the catalyst was obtained by concentrat- for both diastereoisomers (entries 3 and 4, Table 3).
ing the reaction mixture under vacuum and adding hexanes/
After 3 days of continuous operation the reactor was
diethyl ether. The polymer-supported catalyst was then iso- washed and used for carrying out the reaction between cyclo-
lated by centrifugation and filtration in yields ranging from 50 pentadiene and crotonic aldehyde (8). Gratifyingly, also in this
to 80% and the organic phase was worked-up to obtain the third run the expected cycloadduct (9) was obtained in yields
products. The recovered catalyst was then shortly dried under higher than 94% and enantioselectivities up to 85% ee (entries
vacuum to remove traces of solvent and recycled.33 However, 6 and 7, Table 3).
already after one cycle a marked decrease in the chemical and
Finally, in order to verify the activity of the system after a
stereochemical efficiency was observed (25% yield and 71–75% prolonged time on stream (TOS) the reactor was washed once
ee after 48 h; entry 4, Table 2). Better results were obtained more and used to promote again the initial reaction between
when the tetrafluoroborate salt of the immobilized MacMillan cyclopentadiene and cinnamic aldehyde. Indeed, after 150
catalyst was employed (entries 5–7, Table 2). In that case the working hours of the catalytic reactor, product 5 was isolated
product was isolated in an almost quantitative yield after in yields and stereoselectivities totally comparable with those
48 hours, and the recovered catalyst performed also somehow of the first 24 hours of activity (compare entry 9 with entry 1,
better than the corresponding TFA salt. Based on this obser- Table 3).
vation, further experiments were carried out by using HBF4 as
the acid additive.
Based on the data of Tables 1 and 3, it is evident that the
long residence time represents a major drawback of the
The general applicability of the chiral monolithic reactor present system, which hampers a really advantageous use of
was studied next (Scheme 2 and Table 3). With this aim an the monolithic reactor in an effective continuous process.
identical monolithic column, containing polymeric Supp-3 Therefore some optimization studies have been performed on
(activated by tetrafluoroboric acid), was used for performing the model Diels–Alder reaction in continuo of cinnamic alde-
the reaction in continuo between cyclopentadiene and three hyde with cyclopentadiene, carried out with the tetrafluoro-
different aldehydes.
borate salt of the monolithic imidazolidinone Supp-3
Expectedly, repetition of the reaction with cinnamic alde- (Table 4).
hyde afforded product 5 in 75% yield and 90% ee for both
After the first 24 hours of operation at ϕ = 2 µL min−1, the
isomers (entry 1, Table 3), thus confirming chemical and flow rate was progressively increased up to 18.8 µL min−1
stereochemical performances comparable to the TFA-activated (entries 2–5, Table 4). Much to our delight, under these con-
monolithic catalyst (see entry 6, Table 1).
ditions only a marginal decrease in the chemical yield was
Then, the column was washed and used in further cyclo- observed, but without any change in the enantioselection
addition runs with different aromatic aldehydes. By pumping extent. Indeed, at ϕ = 18.8 µL min−1 the catalytic reactor kept
a 95/5 CH3CN–H2O solution of 2-nitro-cinnamic aldehyde on producing the cycloadducts in 73% yield and 90% ee for
(6) and cyclopentadiene, the catalytic column continuously both isomers, with a remarkable productivity improvement
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Table 4 Optimization studies for the reaction between 4 and cyclo-
pentadiene, promoted in continuo by the monolithic reactor using
polymer-supported catalyst Supp-3/HBF4
Table 6 Batch vs. continuous-flow reactions, with different columns
Conditionsa
Salt
Time (h)
Productivityb
TONc
a
Entry
1
2
Batch
Batch
Batch
Monolithic flow
Monolithic flow
Monolithic flow
Packed bed flow
TFA
TFA
HBF4
TFA
HBF4
HBF4
HBF4
48
120
120
120
120
24
59
31
46
38
37
338
120
2.8
3.8
5.6
4.6
4.4
8.1
4.4
ee endo-5
Running
time [h]
ϕ
τb
[h]
Yieldc
[%]
(ee exo-5)e
Entry
[µL min−1
]
drd
[%]
3
4d
5d
6e
7f
1
2
3
4
5
0–4
4–24
24–44
44–55
55–70
2
2
7.7
18.8
18.8
12.4
12.4
3.2
1.3
1.3
n.d.
75
67
68
73
—
—
47/53
48/52
47/53
45/55
92 (91)
90 (90)
90 (86)
90 (88)
24
a Reactions run at 25 °C; data taken from Tables 1, 3, 4 and 5.
b Productivity is measured in mmol(product) h−1 mmol(catalyst)−1
103. c Turn over number is measured in mmol(product) mmol
×
a Reactions run at 25 °C; Reactions conditions: 25 °C; HPLC column
(0.46 cm i.d. 15 cm, containing 0.475 mmol of catalyst);
cinnamaldehyde (0.195 M, 1 eq.) and cyclopentadiene (1.365 M, 7 eq.)
in 95/5 CH3CN–H2O mixture. b Residence time. c Yields determined by
1H NMR and confirmed on isolated products after chromatographic
purification. d Endo-5/exo-5 diastereoisomeric ratio, determined by 1H
NMR on the crude reaction mixture. e Enantiomeric excess determined
by HPLC on the alcohols obtained by NaBH4 reduction of adducts.
(catalyst)−1 d Flow rate 2 µL min−1 (Table 1 entry 6 and Table 3 entry
.
×
1). e Flow rate 18.8 µL min−1 (Table 4 entry 5). f Flow rate 7.7 µL min−1
(Table 5 entry 3).
in continuo was performed at 18.8 µL min−1, when the packed-
bed reactor produced the cycloadducts in 21% yield only and
87–85% ee (entry 5, Table 5). Compared to 73% yield and
86–90% ee obtained with the monolithic reactor (see entries
2–5, Table 4), these results confirm the higher catalytic activity
of monolithic devices over the packed-bed ones, already dis-
cussed in the literature.34
Table 5 Diels–Alder reaction in continuo between 4 and cyclopenta-
diene, performed in a packed-bed reactor filled with polymeric non-
a
monolithic material Supp-3/HBF4
It is interesting to compare some results obtained in the
organocatalyzed cycloaddition performed with supported cata-
lysts in batch or under continuous-flow conditions, with two
different columns (packed-bed and monolithic reactors). The
data are collected in Table 6, where the total turnover number
(TON) and productivity of the different materials and reaction
conditions are reported.
ee endo-5
Running
Entry time [h]
ϕ
Yieldc
τb [h] [%]
(ee exo-5)e
[µL min−1
]
drd
[%]
1
2
3
4
5
0–4
4–24
24–44
44–50
55–70
2
2
7.7
7.7
18.8
10.8
10.8
2.8
n.d.
80
65
—
—
48/52 85 (80)
48/52 86 (87)
47/53 89 (86)
48/52 87 (85)
2.8
52
1.2
21
Considering the results obtained with the TFA salt of Supp-3,
in batch 1 gram of resin produced 1.4 mmol of the product
with 90% ee in 48 hours (85% yield, entry 2, Table 2). Accord-
a Reactions conditions: 25 °C; HPLC column (0.46 cm i.d. × 15 cm,
containing 0.32 mmol of catalyst); cinnamaldehyde (0.128 M, 1 eq.)
and cyclopentadiene (0.896 M, 7 eq.) in 95/5 CH3CN–H2O mixture.
b Residence time calculated as void volume/flow rate (void volume = ing to the data of Table 1, at ϕ = 2–5 µL min−1 the same
1.3 ml, determined by picnometry). c Yields determined by 1H NMR
amount of resin in the monolithic reactor produced 1.6 mmol
and confirmed on isolated products after chromatographic
purification. d Endo-5/exo-5 diastereoisomeric ratio, determined by 1H
of cycloadducts in an identical time-frame (48 hours). For
NMR on the crude reaction mixture. e Enantiomeric excess determined longer times, the process in flow offers clearly better perform-
by HPLC on the alcohols obtained by NaBH4 reduction of adducts.
ances: by recycling the catalyst, in 120 hours 1.8 mmol of pro-
ducts were obtained in batch (data not shown in Table 2),
while operating in flow 3.8 mmol of adducts were produced
with high enantioselectivity in the same time (Table 1).
With tetrafluoroborate salt that behaved better in batch, for
long operation times the following data were collected: in
120 hours 2.9 mmol of the product was produced in batch, to
be compared with the isolation of 4.0 mmol of cycloadducts
(90% ee) in the continuous-flow run at ϕ = 2 µL min−1 (con-
ditions of entries 1–4, Table 6).
Productivity and TON of the reactions performed under
continuous flow conditions are always better than those for
the corresponding reactions in batch, with an improvement of
both parameters by a factor 1.4–2.9 (entries 1–5, Table 6).
Nevertheless, due to the long residence time, productivity at
ϕ = 2 µL min−1 was still quite low (38). However, thanks to the
tolerance of the tetrafluoroborate chiral monolithic reactor to
flow rate increase, the very remarkable level of productivity of
338 h−1 could be reached at ϕ = 18.8 µL min−1 (entry 6,
over previous conditions (for comparative data, see Table 6
below). Although the reasons for the relatively small activity
variation on changing the flow-rate are not clear at present,
these findings evidence another significant advantage of using
HBF4 as the acid additive, instead of TFA of the initial
experiments.
For the sake of comparison the packed-bed reactor contain-
ing the polymeric catalyst Supp-3 in the powder form was
employed to carry out the same model cycloaddition reaction
between 4 and cyclopentadiene (Table 5). At 2 µL min−1 flow
rate and conditions otherwise identical to those of Table 4, the
packed-bed reactor (entries 1 and 2, Table 5) showed compar-
able results with the monolithic one; however, already when
the flow rate was increased to 7.7 µL min−1, the products were
formed in lower yield and enantioselectivity (entries 3 and 4,
Table 5). The largest difference was observed when the reaction
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Scheme 3 Enantioselective catalytic reactions under continuous-flow conditions with imidazolidinone supported catalyst Supp-3.
Table 6). Interestingly, this latter result is larger than attained
Table 7 Organocatalytic stereoselective reactions in continuo pro-
with powdered Supp-3, either in batch or in the packed-bed moted by the HBF4 salt of polymer-supported catalyst Supp-3a
reactor (entries 3 and 7, Table 6, respectively).
Running
time [h]
Yieldb
[%]
Finally, a new monolithic reactor containing Supp-3 was
prepared and employed in the tetrafluoroborate salt form to
sequentially promote three different stereoselective reactions
in continuo, with temperature and reaction solvent variations
(Scheme 3a–c and Table 7).
First the Diels–Alder cycloaddition between 4 and cyclo-
pentadiene was performed under the new set of conditions
(Table 7, entries 1–4). As expected on the basis of the results in
batch, the catalytic reactor promoted very efficiently the trans-
formation, affording 93% yield and 90% ee for both isomers
after only 4 hours (Table 7, entry 1). Cooling to −5 °C seems
not to have a decisive effect on the catalytic activity and
enantioselectivity (Table 7, entry 2), while at room temperature
the monolithic reactor was able to continuously process the
reagents and to produce the cycloadducts in essentially quanti-
tative yield and 90% ee for both stereoisomers, even after 80 h
time on stream (Table 7, entries 3 and 4).
Entry
T [°C]
Product
drc
eed
1
2
3
0–4
4–28
28–32
32–80
80–100
100–130
130–180
180–200
200–248
248–260
260–310
25/−5
−5
−5/25
25
25/−15
−15
25
25
25
25/−15
−15
5
5
5
5
—
11
11
—
13
—
13
93
90
97
99
—
45
71
—
55
—
21
47/53
48/52
45/55
47/53
—
94/6
91/9
—
90 (90)
91 (90)
91 (93)
90 (90)
—
90 (n.d.)
90 (n.d.)
—
4
5e
6
7
8e
9
—
—
—
15
—
35
10e
11
a Flow rate ϕ = 2 µL min−1, residence time = 12.4 h; same reaction
conditions as in Table 1. b Yields determined by 1H NMR and
confirmed on isolated products after chromatographic purification.
c Endo/exo diastereoisomeric ratio determined by 1H NMR on the crude
reaction mixture. d Enantiomeric excess of the endo diastereoisomer,
determined by HPLC (ESI); in parentheses enantiomeric excess of the
exo diastereoisomer. e Column washing.
At this time the column was washed and used in a second
reaction, the 1,3 dipolar cycloaddition of N-benzyl-C-phenyl
nitrone (10) with crotonic aldehyde.35 By performing the reac-
tion at −15 °C the yield of the transformation was only 45%
(Table 3, entry 6), but at 25 °C (Table 3, entry 7) the isooxazo-
line 11 was isolated in good yield (71%), high diastereo-
selectivity
(91 : 9)
and
without
compromising
the
enantioselectivity (90% ee for the major endo-9 isomer).
After 180 hours of continuous operation the column was
washed and further used in a third different reaction, the
Friedel–Crafts alkylation of N-methyl pyrrole (12) with
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cinnamaldehyde.36 In this case the results were less satisfac-
tory: the process carried out at 25 °C (Table 3, entry 9) afforded
Acknowledgements
the product 13 in fair yield (55%) and low enantioselectivity Financial support by Cariplo Foundation (Milano) within the
(15% ee), whereas at −15 °C (Table 3, entry 11) the stereo- project 2011-0293 “Novel chiral recyclable catalysts for one-pot,
selectivity could be only marginally improved (35% ee) at the multi-step synthesis of structurally complex molecules”, FIRB
cost, however, of a significant drop of the yield (21%).
project RBFR10BF5 V “Multifunctional hybrid materials for
Although these findings clearly indicate the need for the development of sustainable catalytic processes” is grate-
further optimization studies, it is worth mentioning that the fully acknowledged. M. B. thanks COST action CM9505
same reaction performed at 25 °C in batch in the presence of “ORCA” Organocatalysis.
30% mol amount of powdered Supp-3 and HBF4 afforded the
product 13 in equally low enantioselectivity (15% ee) and even
lower yield (40%) than in the continuous-flow run (Table 3,
Notes and references
entry 9).37 Hence, the worse performance of the monolithic
reactor with respect to the soluble MacMillan catalyst38 can be
traced back to a negative influence of the macromolecular
architecture39 and not to any major degradation of the cata-
lytic material after extended use. However, it is worth mention-
ing that, also in this case, the reaction performed under
continuous-flow conditions led to a cleaner reaction mixture
than that obtained in batch, thus greatly simplifying the
product isolation procedure.
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In conclusion the first example of an enantiomerically pure
organocatalyst immobilized into a monolithic reactor was rea-
lized: inside the chiral column Diels–Alder reactions were per-
formed under continuous-flow conditions, leading to the
products in high yield and excellent enantioselectivity (up to
93% ee at 25 °C).40 The general applicability of the catalytic
system was verified, by carrying out Diels–Alder reactions
in continuo with three different aldehydes. The versatility of the
system was also proven by sequentially performing with the
same column, three different reactions in continuo, for a total
of more than 300 hours on stream. For the first time stereo-
selective organocatalyzed Diels–Alder reactions, 1,3-dipolar
cycloadditions and Friedel–Crafts alkylations were performed
in a monolithic reactor under continuous-flow conditions.
Amongst these, sustained catalytic performances were demon-
strated for more than 150 hours. Optimization studies allowed
to significantly increase the productivity of the monolithic
reactor, up to 338. Although the turnover number and reaction
rates need to be further improved, it was already demonstrated
that the process in continuo may positively compete with the
reaction in batch, affording, in the same time, larger amounts
of product, in a user-friendly experimental procedure that
leads to cleaner crude reaction mixtures and greatly simplified
isolation procedures.
For the asymmetric transformations examined in the
present study the use of a catalytic monolithic reactor led to
less waste materials and better use of a valuable chiral catalyst
in comparison with alternative batch and continuous-flow
process intensification schemes. Because the advantages dis-
closed in the present study are expected to be rather general,
hopefully the approach described herein will prove a general
tool for improving the greenness of many other enantio-
selective organocatalytic transformations and for addressing
the issues that currently hamper their use above the bench-
scale.
5 For a review discussing the merits of batch and micro flow
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K. F. Jensen, Angew. Chem., Int. Ed., 2011, 50, 7502–7519;
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2804 | Green Chem., 2014, 16, 2798–2806
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genic mixture in the polymerization feed (about 60%), pro-
vided that (a) the porogen is completely removed from the
reactor after polymerization (as confirmed by the weight of
the porogen recovered after column washing); (b) the
monolith swelling is negligible. Both conditions are satis-
fied in the present work.
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28 According to our previous experience (ref. 25a–c) the reac- 36 N. A. Paras and D. W. C. MacMillan, J. Am. Chem. Soc.,
tion conditions used to perform catalyst immobilization do 2001, 123, 4370–4371.
not affect the stereogenic center. Moreover, the integrity of 37 The reaction performed under continuous-flow conditions
1
amidic bond (as demonstrated by IR) guarantees the integ-
rity of the imidazolidinone ring.
29 G. Lelais and D. W. C. MacMillan, Aldrichimica Acta, 2006,
39, 79–92.
30 K. A. Ahrendt, C. J. Borths and D. W. C. MacMillan, J. Am.
Chem. Soc., 2000, 122, 4243–4244.
31 For detailed experimental procedures see the ESI.†
32 No traces of imidazolidinone or its degradation was found
in the products or after column washing, proving that no
leaching of the catalyst occurs.
led to a reaction mixture much cleaner (TLC and H NMR)
than that obtained in batch, thus greatly simplifying the
product isolation procedure. This observation can partially
explain the better yield of the product 13 obtained in the
continuous-flow device.
38 It must be mentioned that in our hands the alkylation of
12 with 8 catalyzed by commercial MacMillan catalyst
under similar experimental conditions, at 25 °C, led to the
product 13 in 50% yield and 65% ee.
39 The modification of the phenyl ring of the MacMillan cata-
lysts can have a profound influence on the catalytic per-
formance. See: M. C. Holland, S. Paul, W. B. Schweizer,
K. Bergander, C. Mück-Lichtenfeld, S. Lakhdar, H. Mayr
and R. Gilmour, Angew. Chem., Int. Ed., 2013, 52, 7967–
7971.
33 Several procedures of recovery and recycle of the catalyst
were attempted, including thoroughly washing and drying
under high vacuum; no appreciable improvements were
obtained.
34 See for example: (a) K. A. El, R. Chimenton, A. Sachse,
F. Fajula, A. Galarneau and B. Coq, Angew. Chem., Int. Ed., 40 For a recent contribution on stereoselective organocata-
2009, 48, 4969–4972; (b) A. Sachse, A. Galarneau, F. Di Renzo,
F. Fajula and B. Coq, Chem. Mater., 2010, 22, 4123–4125.
35 W. S. Jen, J. J. M. Wiener and D. W. C. MacMillan, J. Am.
Chem. Soc., 2000, 122, 9874–9875.
lyzed reactions performed under continuous-flow con-
ditions in packed-bed reactors see: V. Chiroli, M. Benaglia,
F. Cozzi, A. Puglisi, R. Annunziata and G. Celentano, Org.
Lett., 2013, 15, 3590–3593.
2806 | Green Chem., 2014, 16, 2798–2806
This journal is © The Royal Society of Chemistry 2014