A combined kinetic and thermodynamic approach for the interpretation of continuous-flow heterogeneous catalytic processes

Article abstract of DOI:10.1002/chem.201300181

The heterogeneous proline-catalyzed aldol reaction was investigated under continuous-flow conditions by means of a packed-bed microreactor. Reaction-progress kinetic analysis (RPKA) was used in combination with nonlinear chromatography for the interpretat

Full text of DOI:10.1002/chem.201300181

FULL PAPER
DOI: 10.1002/chem.201300181
A Combined Kinetic and Thermodynamic Approach for the Interpretation of
Continuous-Flow Heterogeneous Catalytic Processes
Olga Bortolini,[a] Alberto Cavazzini,*[b] Pier Paolo Giovannini,[a] Roberto Greco,[b]
Nicola Marchetti,[b] Alessandro Massi,*[a] and Luisa Pasti[b]
Dedicated to Professor Alessandro Dondoni on the occasion of his retirement
Abstract: The heterogeneous proline-
catalyzed aldol reaction was investigat-
ed under continuous-flow conditions by
means of a packed-bed microreactor.
information gathered by RPKA and
nonlinear chromatography proved to
be highly complementary and allowed
for the assessment of optimal operating
variables. In particular, the determina-
tion of the rate-determining step was
pivotal for optimizing the feed compo-
sition. On the other hand, the competi-
tive product inhibition was responsible
for the unexpected decrease in the re-
action yield following an apparently
obvious variation in the feed composi-
tion. The study was facilitated by a
suitable 2D instrumental arrangement
for simultaneous flow reaction and
online flow-injection analysis.
Reaction-progress
kinetic
analysis
(RPKA) was used in combination with
nonlinear chromatography for the in-
terpretation, under synthetically rele-
vant conditions, of important mechanis-
tic aspects of the heterogeneous cata-
lytic process at a molecular level. The
Keywords: aldol reaction
· flow
chemistry · heterogeneous catalysis ·
nonlinear chromatography · orga-
nocatalysis
Introduction
hours) residence/reaction times are normally detected in the
flow regime to reach the same level of batch conversion. A
rationalization for these observations, however, is generally
not supported by a true understanding of the heterogeneous
catalytic process. Indeed, although the microreactor inlet
and outlet can be transparently examined during the course
of the reaction, the catalytic bed is an opaque medium,
which severely complicates the interpretation of the hetero-
geneous process. Therefore, despite some spectroscopic
methods having been developed for in situ analysis of the
active catalysts,[5] noninvasive and cost-effective measure-
ments for investigating mechanism, kinetics, and thermody-
namics of the process under the real working conditions are
still a challenge. Herein, we propose a practical method to
approach the above issues. This relies on the combination of
reaction progress kinetic analysis (RPKA), a powerful meth-
odology developed by Blackmond for the study of kinetic
and mechanistic properties under synthetically relevant con-
ditions,[6] and nonlinear chromatography tools (principally,
frontal analysis measurements[7]) for the thermodynamic in-
terpretation of the catalytic process in the flow regime. The
data described herein finally show that merging kinetic and
thermodynamic information with a deep understanding of
mechanistic constraints might result in the effective design
of productivity-enhancing improvements.
Currently, continuous-flow microreactors are emerging as
new synthetic platforms for the sustainable, safe, and inten-
sified production of fine chemicals and pharmaceuticals.[1] In
particular, heterogeneous catalysis under a flow regime pro-
vides a useful addition to microreactor technology and
allows for simple product/catalyst separation, high resistance
of supports to mechanical degradation, and long-term usage
of (often costly) catalytic packing materials.[2] Very recently,
organocatalytic packed-bed microreactors[3] have been dem-
onstrated to show additional and unusual benefits, such as
the absence of metal leaching and high levels of stereoselec-
tivity in continuous-flow syntheses of valuable chiral mole-
cules.[4] In those studies,[3,4] operative flow conditions (feed
composition and temperature) typically result from the
direct translation of batch-mode conditions with only minor
empirical adjustments. Furthermore, shorter (minutes versus
[a] O. Bortolini, P. P. Giovannini, Dr. A. Massi
Dipartimento di Scienze Chimiche e Farmaceutiche
Laboratorio di Chimica Organica
Universitꢀ di Ferrara, Via L. Borsari 46
44121 Ferrara (Italy)
Fax: (+39)0532-455183
E-mail: alessandro.massi@unife.it
[b] Dr. A. Cavazzini, R. Greco, N. Marchetti, L. Pasti
Dipartimento di Scienze Chimiche e Farmaceutiche
Laboratorio di Chimica Analitica
Universitꢀ di Ferrara
Results and Discussion
44100 Ferrara (Italy)
E-mail: alberto.cavazzini@unife.it
The previously investigated[4a,d] heterogeneous proline-cata-
lyzed continuous-flow aldol reaction of cyclohexanone (1)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300181.
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of the process and its long timescale. A suitable instrumen-
tal setup facilitated the experimental work because it al-
lowed online monitoring by HPLC analysis with a high den-
sity of data collection. For the sake of validation, correlation
between the measured reactant/product concentrations and
reaction progress was also confirmed by discontinuous sam-
pling and NMR spectroscopic analysis of the eluate.
Figure 1 describes the whole 2D equipment for simultaneous
flow-reaction and flow-injection analysis. Concisely (for a
more detailed description, see the Supporting Information),
in direction-1, the microreactor R (stainless-steel packed
column, 100ꢂ2.1 mm) is connected to pump-1 through a
mixer chamber. Channels A and B are used to deliver the
solutions of 1 and 2 in toluene, respectively. The effluent
from the microreactor is redirected to a 6-port 2-position
switching valve. In direction-2, the binary pump-2 delivers a
hexane/iPrOH solution into a hydrophilic interaction liquid
chromatography (HILIC) column by passing through the
switching valve. This is controlled by software and allows
for the switching from the “load” position (Figure 1, lower
left), in which the sampling loop (2–5) is filled with the ef-
fluent from the microreactor, to the “inject” position
(Figure 1, lower right), for flushing the content of the loop
into the HILIC column for fraction conversion determina-
tion.
Scheme 1. Continuous-flow model aldol reaction.
with p-nitrobenzaldehyde (2) was considered as the bench-
mark for this proof-of-concept study. The generally accepted
mechanism for the reaction in Scheme 1 involves the nucleo-
philic attack of silica-supported proline (3) on carbonyl
compound 1 to form enamine 5, followed by its attack on
electrophile 2 to yield product 4 with release of catalyst 3.
The proposal of Scheme 1 simplifies the whole mechanistic
picture as it omits the intrinsic effect of water within the cat-
alytic cycle.[8] Accordingly, the possible kinetic role of added
water, for which a negative order dependence was ascer-
tained by Blackmond and co-
The main features of the packed-bed microreactor R
(hold-up volume V0, total porosity, and loading of silica 3)
were determined by pycnometry and elemental analysis (see
the Supporting Information). They are summarized in
Table 1.
According to RPKA, the concentration dependencies and
the stability of the catalytic system can be probed using the
workers in a similar process
under homogeneous catalysis,[9]
is not considered in the present
study.
Hence, the overall sequence
of Scheme 1 appears reminis-
cent of the Michaelis–Menten
enzymatic reaction for which
the applicable rate expression
might be written in power-law
form as in Equation (1), in
which the constant proline 3
concentration (i.e., the loaded
amount of catalyst) has been
grouped into the constant k*.
x
y
x
y
*
Rate ¼ k½1ꢀ ½2ꢀ ½3ꢀ ¼ k ½1ꢀ ½2ꢀ
ð1Þ
The determination of the re-
action order and interpretation
of the reaction mechanism by
RPKA are, however, complicat-
Figure 1. Scheme of the 2D instrumental setup for flow-reaction and flow-injection analysis. Top: Block dia-
gram (R: microreactor; 6p2p valve: 6-port, 2-position switching valve). Bottom: Magnification on the 6-port 2-
ed by the heterogeneous nature position valve to show the “load” (left) and the “inject” (right) position.
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Heterogeneous Catalytic Processes
Table 1. Main features of microreactor R.
FULL PAPER
Loading
of 3
Amount
of 3
V0
VG
Vbed
t
A
Total
0.67
[mL][b] [mL][b,c] [mL][b,d]
[min][e] porosity[f]
[a]
[mmolgꢁ1
]
[mg][b]
0.81
190
230
346
110
46
[a] Determined by elemental analysis. [b] See the Supporting Informa-
tion. [c] Geometric volume. [d] Vbed =VGꢁV0. [e] Residence time calculat-
ed at 5 mLminꢁ1. [f] Total porosity etot =V0/VG.
“different excess” and “same excess” protocols, respective-
ly.[6] In the context of RPKA, the term “excess” [e] defines
the difference in initial concentrations of two reactants (i.e.,
[e]=[1]0ꢁ[2]0).[6] In the case of heterogeneous reactions, the
excess must refer to the system taken as a whole.[10] Howev-
er, as long as mass transfer and adsorption–desorption proc-
esses are so rapid that a constant equilibrium state can be
assumed between the bulk and the solid phase,[11] RPKA
can be properly employed.[10] Table 2 reports the initial con-
Figure 2. Kinetic profile for the model aldol reaction carried out under
conditions shown in Table 2 (entry 1). Diamonds: 2 (left y axis); circles:
*
percentage fraction conversion (right y axis) estimated by HPLC ( ) and
*
NMR spectroscopy ( ).
Table 2. Experimental conditions for reaction-progress kinetic analysis of
continuous-flow proline 3-catalyzed aldol reaction of cyclohexanone 1
with aldehyde 2 at 258C in toluene.[a]
Entry
[1]0 [m]
[2]0 [m]
Excess [m]
1
2
3
4
2.40
2.35
1.80
1.20
0.10
0.05
0.10
0.10
2.30
2.30
1.70
1.10
[a] See the Supporting Information for experimental procedures.
centrations of substrates 1 and 2 and the excess value for
each of the four kinetic runs in this study.
Reaction results for the illustrative first experiment are
plotted in Figure 2 as conversion of 2 relative to residence
time. Indeed, to the best of our knowledge, this study repre-
sents the first example of application of RPKA under heter-
ogeneous flow conditions.[12] Thus, the curve of Figure 2 was
obtained by measuring the steady-state conversion of differ-
ent experiments performed with the same reactor and feed
composition but at different flow rates.[13]
Figure 3. Rate versus [2] for “same excess” experiments as given in
*
*
Table 1 ( : entry 1; : entry 2).
The more informative rate versus [2] plot (Figure 3) was
then generated by differentiation of the concentration pro-
file of Figure 2; the same plot was also produced for run 2,
which was performed at the half-life of run 1. The overlay in
Figure 3 of these “same excess” experiments confirmed that
the total concentration of active catalyst 3 remained con-
stant during the continuous-flow process, and that the rate is
not significantly influenced by product inhibition (at least
under conditions of runs 1 and 2).[14]
Reaction orders of reactants 1 and 2 were next deter-
mined by the “different excess” protocol. Accordingly, ki-
netic profiles were obtained for runs 3 and 4 and plotted as
in Figure 4 (“normalized” rate versus concentration). While
the overlay between the two curves showed first-order ki-
netics in the “normalized” substrate [1] (x=1), the found
Figure 4. Rate/[1] versus 2 for “different excess” experiments as given in
*
*
Table 2 ( : entry 3; : entry 4).
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A. Cavazzini, A. Massi et al.
linear correlation reflected first-order kinetics in [2] (y=
1).[6]
The catalytic network of Scheme 1 is suitably described
by the full steady-state rate Equation (2), which is written in
terms of the elementary-step rate constants.
If one assumes that, in the denominator of Equation (6),
a[1] outweighs the other two product terms (which means
the absence of competitive adsorption) and, simultaneously,
that a[1]!1 (that is, [1] belongs to the linear range of the
adsorption isotherm), [1ads] would be linearly proportional
to the bulk concentration of cyclohexanone 1 ([1ads]=
qsa[1]), and the rate Equation (5) would reduce to Equa-
tion (7) [k’2 =k2qsa], which is consistent with our experimen-
tal finding (first-order dependence in either reactants).
Rate ¼ k1k2½1ꢀ½2ꢀ½3totꢀ=ðkꢁ1 þ k1½1ꢀ þ k2½2ꢀÞ ½3totꢀ ¼ ½3ꢀ þ ½5ꢀ
ð2Þ
Rate ¼ k02½1ꢀ½2ꢀ
ð7Þ
It becomes evident from the presence of the denominator
term in Equation (2) that simple first-order dependence in
the concentration of reactants cannot be assumed as a gen-
eral result, and that the intrinsic kinetic role of both sub-
strates can be quite complicated. Hence, following the ap-
proach described by Blackmond and co-workers in their
batch study on a homogeneous proline-catalyzed aldol reac-
tion,[9] a possible correlation between the theoretical steady-
state and experimentally found power-law rate equations
was considered in the two limiting cases in which: 1) the re-
action that consumes enamine 5 is the slow step [in this
case, Eq. (2) is reduced to Eq. (3)]; 2) the rate-determining
step is the formation of enamine 5, and the unactivated cat-
Thus, the validity of the assumptions that lead to simpli-
fied rate Equation (7) has been examined for the experi-
mental conditions of Table 2 by a chromatographic study.
Essentially, our scope is to test that competitive adsorption
can be neglected and that the isotherm is linear. To this end,
both linear measurements (namely, the retention factors of
1, 2, and 4 on the silica-supported proline 3 using toluene as
eluent) and nonlinear measurements (i.e., the adsorption
isotherm of cyclohexanone 1 from toluene on silica-support-
ed proline 3)[18] were performed (details in the Supporting
Information). Since, under the assumption of the same satu-
ration factor, the ratio of the retention factors of two sub-
strates corresponds to the ratio of their adsorption equilibri-
um constants,[19] the chromatographic study allows us to es-
tablish that the adsorption constant of 2 [b in Eq. (6)] is
roughly twice that of 1 [a in Eq. (6)], and that c (the adsorp-
tion constant of product 4) is about four times larger than a.
Accordingly, the denominator of Equation (6) can be rewrit-
ten as Equation (8), which has the advantage of permitting
an easier comparison of the relative magnitude of the terms
in brackets.
alyst
3 represents the “resting state” of the catalyst
[Eq. (4)].
Rate ¼ k2½5ꢀ½2ꢀ
Rate ¼ k1½1ꢀ½3ꢀ
ð3Þ
ð4Þ
We shall see that the observed first-order dependence of
rate on [1] and [2] is consistent only with Equation (3).
Indeed, since for each molecule of cyclohexanone adsorbed
on the immobilized proline (1ads), one molecule of enamine
5 is formed, Equation (3) can be recast in the form of Equa-
tion (5), provided that mass-transfer effects are negligible.[11]
1 þ að½1ꢀ þ 2½2ꢀ þ 4½4ꢀÞ
ð8Þ
Since the concentration ratio of feed components [1]0/[2]0
was 18:1 and 12:1, respectively, for entries 3 and 4 of
Table 2, the assumption that p-nitrobenzaldehyde 2 does not
compete for the adsorption with cyclohexanone 1 (i.e.,
2[2]![1]) appears to be entirely reasonable. As for the com-
petitive adsorption by product 4, the situation is complicated
by the fact that 4 is generated inside the reactor. RPKA,
however, comes to our aid, as the “same excess” experi-
ments excluded product inhibition (Figure 3). Inasmuch as
the competitive adsorption by the product would reasonably
be a source of catalyst deactivation, the conclusion that
product 4 does not compete for the adsorption under the
conditions of Table 2 would seem to be sound. Translated
into a mathematical form, this means 4[4]![1]. A deeper
examination of this last inequality is central to our subse-
quent rationalization, and it requires knowledge of fraction
conversions. Under the conditions of Table 2, entry 3, a
52% conversion is achieved with a residence time of
45 min.[20] Accordingly, [4] at the microreactor outlet is
about 0.05m, and the term 4[4], which we might refer to as
the competition factor of product 4, results in roughly 10%
Rate ¼ k2 ½1adsꢀ½2ꢀ
ð5Þ
The importance of this formulation is that it establishes a
connection between the measurable quantity [1ads] and the
reaction rate. In fact, [1ads] can be measured through the
(competitive) adsorption isotherm, which relates the adsor-
bed amount to the bulk fluid phase concentrations of sub-
strates 1, 2, and even product 4, which is produced in the
microreactor during the process.[7] Equation (5) thus gives
an appropriate mathematical form to use in testing a pro-
posed reaction rate expression. The basis for most analyses
of this type is the Langmuir competitive isotherm [Eq. (6),
in which qs =monolayer saturation capacity [m], a, b, c=ad-
sorption equilibrium constants[15] for substrates 1, 2, and 4,
respectively [mꢁ1]]. This model assumes that both 2 and
product 4 might compete with 1 for the adsorption on the
(homogeneous) silica surface.[16] The product terms, b[2] and
c[4], quantify the competitive adsorption by 2 and 4.[17]
½1adsꢀ ¼ qsa½1ꢀ=ð1 þ a½1ꢀ þ b½2ꢀ þ c½4ꢀÞ
ð6Þ
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Heterogeneous Catalytic Processes
FULL PAPER
Table 3. Relationship between concentration of cyclohexanone 1 in the
feed ([1]0) and amount of adsorbed cyclohexanone (1ads), relative surface
coverage (q), and percentage fraction conversion (f). Process conditions:
residence time, 45 min; constant ratio of feed concentrations, [1]0/[2]0 =
24:1.
3.6), which indicates that saturation capacity has been
reached (fractional surface coverage is given in column 4 of
Table 3). Thus for [1]0 >1.8, the simple kinetic model given
by Equation (7) is not expected to hold any longer. Conse-
quently, a series of ad hoc experiments were conducted to
investigate the process outcome under these regimes (en-
tries 5–9 in Table 3) and eventually find a correlation be-
tween the estimated surface coverage (Table 3, column 4)
and fraction conversion (Table 3, column 5).
In the concentration interval 1.8<[1]0 <3.6, the steady-
state rate Equation (2) assumes the form given by Equa-
tion (9), since the competitive adsorption by both p-nitro-
benzaldehyde 2 and product 4 can be neglected under the
conditions of runs 4 and 5 of Table 3. The statement on [2] is
justified by the strongly unfavorable 24:1 feed ratio [1]0/[2]0,
whereas that on [4] comes from the consideration that the
product term 4[4] is smaller than 10% of [1]0, as it was in
the case in which RPKA excluded product inhibition.
Entry
[1]0 [m]
1ads [mmol][a]
q[b]
f [%]
1
2
3
4
5
6
7
8
9
0.2
0.6
1.2
1.8
2.4
3.6
4.0
4.4
5.0
12
40
77
106
119
142
143
144
146
0.08
0.26
0.50
0.68
0.77
0.92
0.93
0.94
0.95
8
20
40
56
64
85
83
84
82
[a] Per reactor. Calculated by frontal analysis. [b] Calculated as the ratio
between 1ads and the total amount of silica-supported proline 3 in the re-
actor (154 mmol). See the Supporting Information for details.
Rate ¼ k02½1ꢀ½2ꢀ=ð1 þ a½1ꢀÞ
ð9Þ
Since the first-order dependence of [1] in the numerator
is tempered by the concentration term in the denominator,
the fraction conversion is expected to increase more slowly
as [1]0 increases than in the linear range of the isotherm.
This is demonstrated by the change in the slope of the plot
of fraction conversion relative to [1]0 (dotted line in
Figure 5), which drops from about 30 when [1]0 <1.8
(Table 3, entries 1–4) to less than 15 if 1.8<[1]0 <3.6
(Table 3, entries 4–6). Finally, at the isotherm plateau (i.e.,
for [1]0 >3.6), the fraction conversion is found to be practi-
cally constant (Table 3, entries 7–9).
Under these conditions, all the available silica-supported
proline 3 is transformed to enamine 5 (Table 3, column 4),
and any further increase in concentration (keeping the ratio
[1]0/[2]0 and residence time constant) does not affect the
conversion efficiency (Table 3, column 5). These considera-
tions show that 3.6m is the optimal cyclohexanone feed con-
centration for the reactor R employed in this work. The
study was concluded with the evaluation of the optimal con-
centration of aldehyde 2 in the feed by performing different
experiments in which [1]0 was kept constant at the 3.6m
value. After some experimentation, it turned out that [2]0 =
0.1m furnished an almost quantitative conversion (f=98%).
A full explanation of this result is not a trivial task, as it re-
quires the modeling of the spatial and temporal distribution
of the concentration profiles of all compounds (1, 2, and 4)
between the bulk and the adsorbed phase inside the micro-
reactor. This study is currently underway in our laboratories
and will be the subject of a forthcoming publication.
Figure 5. Adsorption isotherm of cyclohexanone from toluene on silica-
*
supported proline 3 ( , left y axis) and percentage fraction conversion
*
(
, right y axis) versus cyclohexanone concentration [1]0. Adsorbed con-
centration of cyclohexanone 1 ([1ads]) in micromole per microliter of
packing (Vbed). Process conditions as in Table 3.
of the cyclohexanone concentration in the feed ([4]/[1]0 =
0.2:1.8). Thus, this simple reasoning will be employed as an
indication for estimating the presence of competitive ad-
sorption by the product (see below).
The adsorption isotherm of cyclohexanone 1 (columns 2
and 3 in Table 3 and Figure 5) allowed us to evaluate the
meaning of the last approximation introduced to obtain
Equation (7) with regard to the linearity of the adsorption
isotherm (or, a[1]!1). As the isotherm exhibits a substan-
tially linear behavior until [1]0 =1.8m, the condition holds in
the concentration ranges of entries 3 and 4 of Table 2.
Hence, it is possible to conclude that under these conditions,
the full steady-state rate Equation (2) simplifies to Equa-
tion (7), and that enamine addition to aldehyde is the rate-
determining step, which is in agreement with the homogene-
ous case.[9]
Conclusion
By increasing the concentration of 1 in the feed above
1.8m, however, the adsorption isotherm exhibits at first a
curvature (for 1.8<[1]0 <3.6), and then it flattens out ([1]0 >
In this proof-of-concept study, we have proposed an innova-
tive approach for the characterization of heterogeneous cat-
alytic reactions in flow mode. In particular, we have focused
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A. Cavazzini, A. Massi et al.
Angew. Chem. 2010, 122, 2530–2537; Angew. Chem. Int. Ed. 2010,
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on the proline-catalyzed aldol reaction, which has been ex-
tensively investigated under homogeneous batch conditions.
Essentially, we have coupled the kinetic information that
comes from the application of reaction-progress kinetic
analysis (RPKA) with the thermodynamic information that
results from nonlinear chromatographic measurements. Sig-
nificantly, the two methodologies turned out to be strongly
complementary and allowed for a clear understanding of im-
portant features of the heterogeneous continuous-flow proc-
ess, such as the dependence of the reaction order on feed
composition and saturation capacity of the catalytic bed.
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Experimental Section
Microreactor packing: Microreactor R was fabricated by using a 100ꢂ
2.1 mm stainless-steel column, which was filled with silica 3 by slurry-
packing. Slurry-packing was performed under constant pressure (300 bar,
30 min, toluene as solvent) by using an air-driven liquid pump. The slurry
was prepared by suspending an excess in weight of functionalized silica
in toluene.
Kinetic analysis: For the determination of reaction profiles at constant
flow rate (reaction isotherm curve; Figure S2 in the Supporting Informa-
tion), microreactor R was fed with a solution of 1 (2.40m) and 2 (0.10m)
in toluene and operated at 258C for about 4 h at 2 mLminꢁ1. Fraction
conversion was determined by online HPLC analysis (see Figure 1) and
by 1H NMR spectroscopic analysis (a sample of the eluate was taken
every 40 min). The collected solution at the steady-state regime was final-
ly concentrated and eluted from a column of silica gel with 5:1 toluene/
AcOEt to give the corresponding mixture of anti/syn adducts 4. This ki-
netic study was repeated with the same feed composition but at different
flow rates to determine the kinetic profile depicted in Figure 2. To com-
plete the RPKA of the model reaction, the above approach was then ap-
plied to all the experiments of Table 2.
[5] For a recent review, see: W. Zhang, S. Xu, X. Han, X. Bao, Chem.
Soc. Rev. 2012, 41, 192–210.
[6] a) D. G. Blackmond, Angew. Chem. 2005, 117, 4374–4393; Angew.
Chem. Int. Ed. 2005, 44, 4302–4320; b) J. S. Mathew, M. Klussmann,
H. Iwamura, F. Valera, A. Futran, E. A. C. Emanuelsson, D. G.
Blackmond, J. Org. Chem. 2006, 71, 4711–4722.
[7] a) G. Guiochon, A. Felinger, D. G. Shirazi, A. M. Katti, Fundamen-
tals of Preparative and Nonlinear Chromatography, 2nd ed., Aca-
demic Press, Amsterdam, 2006; b) A. Cavazzini, L. Pasti, F. Dondi,
M. Finessi, V. Costa, F. Gasparrini, A. Ciogli, F. Bedani, Anal.
Chem. 2009, 81, 6735–6743; c) A. Cavazzini, F. Dondi, S. Marmai,
E. Minghini, A. Massi, C. Villani, R. Rompietti, F. Gasparrini, Anal.
Chem. 2005, 77, 3113–3122.
[8] The occurrence of the postulated oxazolidinone–enamine conversion
process has not been considered in this study: a) M. B. Schmid, K.
Zeitler, R. M. Gschwind, Angew. Chem. 2010, 122, 5117–5123;
Angew. Chem. Int. Ed. 2010, 49, 4997–5003; b) A. K. Sharma, R. B.
Sunoj, Angew. Chem. 2010, 122, 6517–6521; Angew. Chem. Int. Ed.
2010, 49, 6373–6377.
Chromatographic measurements: The binary pump-2 delivered a hex-
anes/iPrOH 99.7:0.3 (v/v) solution into a 150ꢂ4.6 mm 5 mm-particle-di-
ameter HILIC column by passing through the switching valve (see
Figure 1). The flow rate along direction-2 was 1 mLminꢁ1. Under these
conditions, the retention times of 2, syn-, and anti-aldol product were 2.3,
6.4, and 11.2 min, respectively. The detector was calibrated at 290 nm for
both 2 and 4 (different calibration curves were employed depending on
the concentration of cyclohexanone 1 in the feed).
In separate experiments, microreactor R was used as a chromatographic
column for determining the retention factors of 1, 2, and 4. The mobile
phase was pure toluene. The adsorption isotherm of 1 on silica 3 was
measured from toluene by frontal analysis (see the Supporting Informa-
tion for details).
[9] N. Zotova, L. J. Broadbelt, A. Armstrong, D. G. Blackmond, Bioorg.
Med. Chem. Lett. 2009, 19, 3934–3937.
[10] For application of RPKA to liquid–liquid biphasic media, see: a) M.
Colladon, A. Scarso, P. Sgarbossa, R. A. Michelin, G. Strukul, J.
Am. Chem. Soc. 2007, 129, 7680–7689; b) S. Xu, Z. Wang, Y. Li, X.
Zhang, H. Wang, K. Ding, Chem. Eur. J. 2010, 16, 3021–3035.
[11] A criterion of whether a molecule, after being displaced a certain
distance dp (dp: diameter of a packing particle), was moved primari-
ly by diffusion or by flow is given by the dimensionless quantity
Peclet number (in chromatography more often referred to as re-
duced velocity), dpv/Dm, in which v and Dm are the linear velocity of
flow and the diffusion coefficient, respectively. When this quantity is
less than one, the diffusion time is less than the flow time, which in-
dicates that the displacement by diffusion is the more rapid of the
two. The opposite conclusion is reached for a ratio greater than one.
See, for example: J. C. Giddings, Dynamics of Chromatography,
Part I, Marcel Dekker, New York, 1965. By considering the geomet-
rical characteristics of microreactor R (10 cm length by 0.21 cm
inner diameter) and those of the packing (dp =5 mm), in the range of
Acknowledgements
We gratefully acknowledge the Italian Ministry of University and Scien-
tific Research (Progetto PRIN grant nos. 2009ZSC5K2 004 and
20098SJX4F 004) for financial support. Thanks are also given to Mr.
Paolo Formaglio for NMR spectroscopic experiments and to Mrs. Ercoli-
na Bianchini for elemental analyses.
[1] a) J. Wegner, S. Ceylan, A. Kirschning, Adv. Synth. Catal. 2012, 354,
17–57; b) I. R. Baxendale, J. J. Hayward, S. Lanners, S. V. Ley, C. D.
Smith, Microreactors in Organic Synthesis and Catalysis (Ed.: T.
Wirth), Wiley, New York, 2008; c) F. E. Valera, M. Quaranta, A.
Moran, J. Blacker, A. Armstrong, J. T. Cabral, D. G. Blackmond,
employed flow rates (1–30 mLminꢁ1
)
reduced velocities smaller
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Heterogeneous Catalytic Processes
FULL PAPER
than one were obtained in confirmation that mass-transfer effects
can be neglected.
series of dedicated HPLC experiments using toluene as the eluent.
See the Supporting Information for details.
[17] Incidentally, we want to remark here that, also in steady-state condi-
tions, [1] and [2] in Equation (6) do not correspond to the feed con-
centrations [1]0 and [2]0 since the system is reactive.
[12] For reaction-progress kinetic analysis of the continuous-flow aldol
reaction in a liquid–liquid microfluidic device, see reference [1c].
[13] 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 (see the reaction iso-
therm curve in the Supporting Information).
[14] Progressive loss of catalytic activity of the packing material 3 was
observed at 258C after approximately 24 h on stream. For the uti-
lization of the more stable 5-pyrrolidin-2-yl)tetrazole-functionalized
silica in the same aldol process, see reference [4a].
[15] Adsorption constants can be determined by chromatographic ex-
periments. The chromatographic retention factor, kchrom, traditionally
defined as the ratio between the correct retention time and the
hold-up time, in fact, also corresponds to the product between the
so-called Henry constant of adsorption (H) and the phase ratio, F
[18] This is a necessary simplification. Equation (6) is in fact a competi-
tive adsorption isotherm. Accordingly, the amount of adsorbed cy-
clohexanone should not be a function of only its bulk concentration
(as we are assuming here) but also of the concentration of 2 and 4.
Nevertheless, as the system is reactive, the competitive isotherm of 1
cannot be experimentally measured. In light of the excess amount of
1 with respect to 2 and 4, however, this appears a physically sound
approximation at this stage of the study.
[19] By assuming the same saturation capacity for 1, 2, and 4 (which is
reasonable in light of their similar molecular dimensions), the ratio
of retention factors correspond to the ratio of the adsorption equili-
brium constants, the phase ratio F being the same in all the cases
(see also ref. [15]). The retention factors for 1, 2, and 4, using tol-
uene as eluent, were 0.52, 1.10, and 2.10, respectively (see the Sup-
porting Information).
(i.e., the ratio between the stationary and the mobile phase): kchrom
=
HF. In turn, H is the product between the saturation constant (ach-
ievable by the adsorption isotherm) and the equilibrium adsorption
constant a (i.e., H=qsa).
[20] Since the reaction studied in this work is quite slow, a residence
time of 45 min was taken for these experiments as a reasonable
compromise between fraction conversion and analysis time.
[16] The assumption that only one type of adsorption site (namely, the
catalytic sites) is present on the surface was verified by considering
the retention behavior of cyclohexanone 1 on an alkylated silica gel
(by TEC of mercaptopropyl thiol silica and 1-heptene) through a
Received: January 17, 2013
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
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A. Cavazzini, A. Massi et al.
Heterogeneous Catalysis
O. Bortolini, A. Cavazzini,*
P. P. Giovannini, R. Greco,
N. Marchetti, A. Massi,*
L. Pasti ......................... &&&& — &&&&
A Combined Kinetic and Thermody-
namic Approach for the Interpretation
of Continuous-Flow Heterogeneous
Catalytic Processes
A good synergy: Reaction-progress
kinetic analysis and nonlinear chroma-
tography are useful tools for investi-
gating a model aldol reaction per-
formed in continuous-flow microreac-
tors packed with proline-functionalized
silica gel (see figure). The study was
facilitated by a suitable instrumental
arrangement for online monitoring; it
also assessed optimal operating and
feed variables.
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ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!