Reaction Acceleration in Thin Films with Continuous Product Deposition for Organic Synthesis

Article abstract of DOI:10.1002/anie.201704520

Thin film formats are used to study the Claisen–Schmidt base-catalyzed condensation of 6-hydroxy-1-indanone with substituted benzaldehydes and to compare the reaction acceleration relative to the bulk. Relative acceleration factors initially exceeded 10

Full text of DOI:10.1002/anie.201704520

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Accepted Article
Title: Reaction Acceleration in Thin Films with Continuous Product
Deposition for Organic Synthesis
Authors: Zhenwei Wei, Michael Wleklinski, Christina Ferreira, and R
Graham Cooks
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201704520
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10.1002/anie.201704520
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Reaction Acceleration in Thin Films with Continuous Product
Deposition for Organic Synthesis
Zhenwei Wei, Michael Wleklinski, Christina Ferreira and R. Graham Cooks*
Abstract: Thin film formats are used to study the Claisen-Schmidt
base-catalyzed condensation of 6-hydroxy-1-indanone with
substituted benzaldehydes and to compare reaction acceleration
relative to bulk. Acceleration factors relative exceeded 103 initially and
were on the order of 102 at steady state, in spite of the fact that the
confined volume reaction was not electrostatically driven. Substituent
effects were muted compared to those in the corresponding bulk and
microdroplet reactions and it is concluded that the rate-limiting step at
steady state is reagent transport to the interface. Conditions were
found that allowed product deposition from the thin film to occur
continuously as reaction mixture was added and as solvent
evaporated. Yields of 74% and production rates of 98 mg/hour were
reached in a very simple experimental system which could be
multiplexed to greater scales.
meaningful use in chemical synthesis. The low milligram scale
suffices for chemical and biological screening and these amounts
14]
are available from simple droplet collection experiments.[2,
Samples on the order of 100 mg are needed for early stage
pharmaceutical testing; because electrospray-based microdroplet
reactions occur in the charged aerosol phase, it is difficult to
collect products on this scale. Moreover, the lifetimes of
microdroplets restrict reaction times[15] and limit yields for
reactions which are not very highly accelerated. The need to
evaporate large volumes of solvent represents an additional
concern in designing scaled-up experiments. Thin films of
reagents might be a better choice for further scale up given the
longer reaction times in thin film compared to microdroplets
although the lower surface area has the opposite effect.
Here, we introduce a thin film deposition method to achieve
reaction acceleration and scale up. A homemade flow injection
sprayer was used with pneumatic nebulization to generate an
electrically neutral sonic spray of reaction solution which was
continuously deposited onto a substrate at a fixed flow rate. The
arriving droplets generate a thin film on the substrate surface on
which products can precipitate before being washed off after
reaction. When the deposition rate and solution evaporation rate
are balanced, the thin film is expected to reach its maximum
thickness and to move upwards at constant thickness as reagent
spray continues to be added and reaction products are
precipitated. The novelty and advantages of this method are as
follows. Firstly, significant and unusual reaction acceleration is
observed using uncharged sonic spray generated droplets.
Secondly, the film lifetime should be indefinitely extendable, in
contrast to previously reported thin film acceleration methods.
Thirdly, the thin film is renewed continuously by addition of fresh
reaction solution, giving steady state conditions in which reaction
acceleration is independent of the scale of the synthesis.
Chemical reactions in confined volumes are often much faster
than those in bulk.[1] Confined volumes can take the form of
sprays, generated by nebulization using electric and or magnetic
fields, or thin films, generated for example by drop casting. For
instance, the Hantzsch reaction proceeds in 90% yield in charged
microdroplets generated by electrospray.[2] Base-catalyzed
Claisen-Schmidt condensation is accelerated in electrosprayed
droplets,[3] in levitated Leidenfrost droplets[4] and in the paper
spray experiment which combines a thin film format with charged
droplet emission [5]. Many other reactions involving C-H,[6] C-C,[2-
5, 7] C-N [2, 8] and C-O[9] bond formation have been reported to be
accelerated by factors of 10 ~ 106 in confined volumes.[10] The
underlying reasons for acceleration are increased reagent
reactivity, due to partial desolvation at the interface,[11] pH value
change,[12] and increased reagent concentration associated with
solvent evaporation.[13] Hours’ long reactions can be performed in
minutes in these mass spectrometry-informed syntheses.
Given these established capabilities, a significant question is
whether accelerated reactions can be scaled up to allow
[a]
Dr. Zhenwei Wei, Dr. Michael Wleklinski, Dr. Christina Ferreira and
Prof. R. Graham Cooks
Department of Chemistry
Purdue University
West Lafayette, IN 47907
E-mail: cooks@purdue.edu
Supporting information for this article is given via a link at the end of
the document.
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Figure 1. a) Claisen-Schmidt reaction of 6-hydroxy-1-indanone 1 with substituted benzaldehydes 2a ~ 2f b) Four reaction formats explored in this study, each of
them using KOH as base
Fig. 1 illustrates the chemical reaction studied, the Claisen-
Schmidt reaction of 6-hydroxy-1-indanone 1 with substituted
benzaldehydes 2a ~ 2f of different reactivity. It also shows the four
methods used to examine this set of reactions. The 6-hydroxy
derivative was chosen to generate strong negative ion signals and
bulk phase reaction was chosen as the reference method while
the other three feature different thin film reaction formats. The
reaction products were characterized by nanoelectrospray mass
spectrometry (nESI-MS) using conventional non-accelerating
conditions (see ref. 1 for a discussion on accelerating and non-
accelerating reaction conditions). All reactions were evaluated by
two parameters, the conversion ratio (CR) and the acceleration
factor (AF). Conversion ratios were measured in negative ion
mode nESI-MS as the intensity of product 4 relative to the sum of
intensities of product 4 and reagent 1. (Reagents 2a ~ 2f give very
weak signals which were ignored.) Because the reaction
acceleration was found to be deposition time dependent (see
discussion of mechanism, below), AF’s was measured as the
average conversion ratio vs. that for the bulk in a 3-minute
reaction time.
Table 1. Conversion ratio (CR) and Acceleration Factor (AF) for Claisen-Schmidt Reactions of 1 and 2 using Different Methods
Non-premixed Thin Film
Bulk Phase Reaction
Thick Film Reaction
Thin Film Reactionǂ
Reactionǂ
Aldehyde
CR
0.7%
3.6%
1.1%
4.0%
0.3%
10.6%
AF
1
CR
AF
22
3
CR
AF
100
8
CR
AF
262
48
2a
2b
2c
2d
2e
2f
14.9%
10.7%
22.6%
14.0%
2.5%
33.4%
15.8%
23.1%
9.1%
88.0%
86.0%
73.6%
95.6%
20.7%
98.2%
1
1
21
4
42
4
138
48
1
1
8
6.4%
38
6
126
18
1
83.8%
8
27.4%
ǂ AF multiplied by two in these cases to correct roughly for slow addition of reaction solution to substrate over time
by off-line nESI measurements made under non-accelerating
Table 1 show the conversion ratios and acceleration factors
for reactions of 1 and 2a ~ f in bulk reaction, thick film reaction,
non-premixed thin film and premixed thin film formats. All three
film reactions showed acceleration relative to the bulk as judged
conditions. Among these three methods, the thin film format
showed notably greater acceleration factors than the other two
methods, with an acceleration factor as high as 262 in reaction of
2a. The highest acceleration factors in the corresponding thick
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film and non-premixed thin film reaction formats were only 22 and
100, respectively. More features of these methods can be seen in
the mass spectra shown in Fig. 2 and Table S1. Take reaction of
2a as an example (Fig. 2): in the bulk phase the conversion to
product 4a and intermediate 3a both occurred to less than 5%. In
the thick film reaction, the conversion ratio to product 4a was 15%,
which is much higher than in the bulk phase (less than 5%).
However, the conversion to the intermediate was 39%, the
highest ratio in all four methods. A possible explanation is based
on the key role of interfacial reactions in producing acceleration.
The thick film method significantly increased the surface area to
volume ratio of the reaction solution relative to the bulk phase
reaction, but it was still smaller than in the thin film method.
Moreover, the presence of excess solvent might be expected to
hinder the loss of water needed to convert the intermediate to the
final product 4a. Therefore, limited reaction acceleration and large
amounts of intermediate were observed in the thick film reaction.
The non-premixed thin film reaction was a special case of thin film
reaction in which one reagent was pre-deposited on the substrate
before the other reagent was deposited onto substrate by sonic
spray. The mass spectra showed fairly good conversion (33% to
product 4a) and less than 5% conversion to the intermediate. The
performance was better than that of the thick film reaction but not
as good as in the thin film (premixed) reaction. The latter format
achieved 88% conversion ratio of product 4a, the best of all the
methods. It was also notable that there was almost no observable
intermediate in this reaction. These features make the thin film
reaction the method of choice for reaction scale up.
similar conversion ratios in the thin film format. This is reflected in
the ρ value of 0.042 for the thin film reaction, demonstrating its
insensitivity to substituent effects. The differences in these plots
suggest that the intrinsic substituent effect in the Claisen-Schmidt
reaction is overwhelmed by another factor in the thin film reaction.
The greater than expected rates for electron donating groups
in the thin film reactions demands an inverse dependence of the
acceleration factors to compensate for the intrinsic increase with
substituent. That this is the case is shown by the AF data in Fig.
3. As detailed in the SI, the relationship between the acceleration
factor (AF) and the difference (Δρ) in the reaction constants for
the thin film and bulk reactions is given by Eq. (1) where ꢀ푌 is the
Hammett substituent constant.
푙표푔 퐴퐹 = ∆ꢁꢀ푌 + 푐표푛푠푡.
(1)
The plot of log AF vs. σY (Fig. 3) is indeed linear and has a slope
of -0.957. A reasonable explanation is that diffusion of the reagent
to the thin film interface (where reaction rates are highest)[17] has
replaced attack of the carbanion at the carbonyl group as the slow
step in the thin film Claisen Schmidt reaction. Therefore, rate in
the thin film reaction is determined by the collision frequency of
the aldehyde at the interface solution/air interface. The fact that
the AF decreases during stage 1 of the reaction (as shown in Fig.
4 and explained below) is consistent with this argument regarding
a slow diffusion step.
Figure 2. Mass spectra of product collected after 3 min of reaction of ketone 1
with 2-methoxybenzaldehyde (2a) using each of the four formats and recorded
by non-accelerating nESI.
Figure 3. Hammett relationship showing plot of log acceleration factor vs.
substituent constant, σY, for thin film reactions performed for 3 min.
Among the thin film reactions of 2a ~ f, acceleration factors
(integrated over 3 min of reaction) of 126 ~ 262 were observed for
reactions a, c and e, while a medium acceleration factor of 42 ~
48 was observed for reaction b and d and, a low acceleration
factor of 18 was observed for reaction f. Clearly, the acceleration
factor correlates inversely with the reactivity of substituted
benzaldehydes. The Hammett relationship[16] for the bulk Claisen-
Schmidt reaction, shown in Fig. S1, displays the expected
correlation of conversion ratio (representing reaction rate) vs.
substituent sigma constant with a ρ value of 0.99 and with reaction
being promoted by electron withdrawing substituents. In strong
contrast, all substituted benzaldehydes except for 2e showed
In addition to the acceleration factor, the influence of several
experimental variables on the conversion ratio in thin film
reactions must be considered before applying thin film reactions
to scaled up synthesis. Data on the effects of (a) sonic spray flow
rate, (b) choice of substrate and (c) distance between sprayer and
substrate are reproduced in Fig. S2. Increased flow rates from 30
µL/min to 250 µL/min caused a modest decrease in the
conversion ratio, from 88% to 80%. This drop of conversion ratio
is acceptable because high flow rates increase thin film thickness
and decrease the effective collision frequency at the interface.
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Because the drop of conversion ratio was small, high flow rates
are recommended in scaled up synthesis. The influence of
substrate choice on thin film reaction was also not strong: paper,
PTFE and aluminum foil each gave similar 90 ± 3% conversion
ratios. On the other hand, the distance of the sonic spray tip from
the surface influenced the reaction conversion ratio greatly. On
increasing the spray distance from 2 cm to 5 cm a drop in
conversion ratio from 88 % to 55 % was observed. Interestingly
this effect is the opposite to that seen for droplet reactions (e.g.
the Hantzsch reaction), and we assume that the evaporation of
solvent (methanol is volatile solvent) with spray distance made
0.9946), which fits Eq. 3 very well. After 45s, all subsequent points
show another very good linear relationship, y = 0.0188x – 0.109
(R2 = 0.9751). The cross point of these two lines occurs at 101.68
= 47.9 s, which is the time at which the reaction becomes diffusion
controlled. From Eq. 2, with the increase of deposition time, the
term reflecting diffusion controlled reaction rate drops
exponentially. Therefore, the drop of reaction rate (AF) during
Stage 1 is consistent with the gradual replacement of intrinsic
reactivity by diffusion controlled reactivity which is complete at the
beginning of Stage 2. From Eq. 3, for different reactions, the slope
1-a should be constant. This interpretation is supported by the
data for 4-chloro-benzaldehyde. In Fig. S5, the intrinsic reaction
rate for 4-chloro-benzaldehyde is higher than that for 2-methoxy-
benzaldehyde and hence Stage 1 is shorter in time (37 s vs. 48
s). The slope of log/log curve of conversion ratio vs. deposition
time is constant (0.52 vs. 0.51)
the deposited thin film much drier and less reactive. The
[17a]
corresponding microdroplet reactions
do not show the slow
diffusion step, either, presumably because diffusion is fast over
the much smaller distances involved.
To investigate the mechanism of the thin film Claisen-Schmidt
reaction further we determined the conversion ratio of the reaction
of 1 with 2a as a function of deposition time. From Fig. 4a, the
conversion ratio initially increased very quickly, slowing down and
reaching a plateau after ca. 50 s at about 80%. Clearly, the curve
of conversion ratio vs. deposition time has two stages. In stage 1,
the values of the AF in the interval 5s ~ 10s, 10s ~20s, 20s ~ 30s,
30s ~ 45s and 45s ~ 60s are 1602, 672, 598, 560 and 140,
respectively (in each case referenced against the bulk phase
reaction rate). This behavior is associated with the decrease in
surface/volume ratio as reaction solution is added[18]. Between 45
s and 60 s, the AF drops from 560 to 140 as seen most clearly in
the log/ log plot (Fig. 4b). The system undergoes an abrupt
transition from stage 1 to stage 2 and in the latter stage the
conversion ratio remains essentially constant. This suggests that
the thin film reaches its maximum interfacial area at the transition
point (see illustrations in SI and Fig. S4) and thereafter the system
is at steady state. Steady state applies both to the solute in the
solution (product, unreacted reagents, salts and alkali). Solids
precipitate from the thin film as more solution is added. The
amount of precipitate (thickness of thin film) grows with deposition
time while evaporation and solvent addition remain in equilibrium.
As at the end of stage 1, the thin film has reached its maximum
thickness and we can evaluate the thickness from the
experimental data. From Fig. S6, the coloration of the product on
the paper substrate showed that the diameter of the interface was
about 10 mm. With a flow rate of 30 µL/min, the total amount of
KOH, reagents and products on paper after deposition for 47.9 s
was 1.02 mg. Assuming a density is 1 g/mL and a uniform
distribution, the estimated thin film thickness is about 6.5 µm.
Figure 4. Conversion ratio vs. thin film reaction solution deposition time with
analysis of products by nESI MS at the time points indicated by the data symbols
(three replicates). a) Conventional plot and b) log/log plot.
We suggest that the reaction is controlled by collision
frequency of the aldehyde at the solution/air and
solution/substrate interface. These ideas can be tested using a
model to describe the behavior in stage 1 and stage 2 (see
additional discussion of two stages of thin film reaction in SI and
Fig. S4). Briefly, during stage 1, the reaction rate r vs. deposition
time t follows equation (2):
These mechanistic considerations indicate that thin film
reactions run under these conditions are well suited to scale up.
Staying with the example of reaction of 1 with 2a, we performed a
scaled up synthesis using a flow rate of 250 µL/min for 60 min.
The theoretical rate of product formation is 132.5 mg/hr. Fig. S7
shows the mass spectrum for the product. From Fig. S7a, the
conversion ratio is 74 %, which is somewhat decreased over ca.
88% for the short time and low flow rate experiment of Fig. 4.
However, this is acceptable in scaled up synthesis since high flow
rates significantly enhance throughput but only slightly decrease
reaction conversion. Therefore, the actual synthesis rate of
product 4a was about 98 mg/hr in the scaled up synthesis.
퐸
푎
푟 = 퐴2퐶1푡−푎 × 푒−
.
(2)
푅푇
To integrate Eq. 2, the function of CR vs. deposition time t is:
퐸
푎
(
)
푙표푔 퐶푅 = 1 − 푎 푙표푔 푡 −
+ 푐표푛푠푡.
(3)
2.303푅푇
The synthetic method described here is not limited to the
Claisen-Schmidt reaction as illustrated by its applicability to the
Katritzky reaction. This base-catalysed reaction is known to show
reaction acceleration in paper spray[8a] and in Leidenfrost
droplets[4] Fig. S8 shows the result observed in neutral thin films
In the above equations, Ea is activation energy, R is the gas
constant, T is temperature, a is an index between 0 and 1
reflecting the reactants diffusion activity. Fig. 4b shows the
relationship between log CR and log t. The first five time points
show a very good linear relationship y = 0.511x - 0.938 (R2
=
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[3]
[4]
[5]
[6]
[7]
[8]
T. Muller, A. Badu-Tawiah, R. G. Cooks, Angew. Chem. Int. Ed. 2012,
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compared with the bulk solution phase reaction (both without base
catalyst). The conversion ratio in a 3-minute bulk reaction was
only 9 % but it was boosted to 67 % in a 3-minute thin film reaction
in which the acceleration factor was 14.
R. M. Bain, C. J. Pulliam, F. Thery, R. G. Cooks, Angew. Chem. Int. Ed.
2016, 55, 10478-10482.
Y. F. Li, X. Yan, R. G. Cooks, Angew. Chem. Int. Ed. 2016, 55, 3433-
3437.
C. Geng, J. L. Li, T. Weiske, M. Schlangen, S. Shaik, H. Schwarz, J. Am.
Chem. Soc. 2017, 139, 1684-1689.
Experimental Section
S. Banerjee, C. Basheer, R. N. Zare, Angew. Chem. Int. Ed. 2016, 55,
12807-12811.
All chemicals were purchased from Sigma Aldrich. For the Claisen-
Schmidt reaction the reagent concentrations were 0.03 M (1:1) for the
ketone and aldehyde and 0.6 M for KOH. Methanol was used as solvent.
For the Katritzky reaction, the concentration was 0.05 M (1:1) for both
reactants and acetonitrile was solvent. In the thick film reaction, 90 µL
reaction solution was cast onto a triangle film paper (1 cm2) to react for 3
min. In the non-premixed thin film reaction, 45 µL aldehyde solution was
cast onto paper and dried (sample spot diameter was ca. 2 cm) and then
ketone was deposited by sonic spray for reaction. A homemade electrically
neutral sonic sprayer (using pneumatic nebulization) was used to deposit
reaction solution on the substrate. The pressure of nebulization gas (N2)
was 100 psi. Unless otherwise noted, the solution flow rate was 30 µL/min
and the distance from sprayer to substrate was 2 cm. After the film reaction,
the products on the paper were washed using 1 mL methanol for nESI
analysis. The nESI analysis was carried out using a Thermo Fisher LTQ
mass spectrometer (Thermo Scientific Inc., San Jose, CA). The capillary
temperature was 200 °C. The spray voltage was 2.0 kV for positive mode
and -2.0 kV for negative mode.
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1142-1148; b) R. M. Bain, C. J. Pulliam, S. T. Ayrton, K. Bain, R. G.
Cooks, Rapid Commun. Mass Spectrom. 2016, 30, 1875-1878; c) S.
Banerjee, R. N. Zare, Angew. Chem. Int. Ed. 2015, 54, 14795-14799.
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Acknowledgements
[13] A. K. Badu-Tawiah, D. I. Campbell, R. G. Cooks, J. Am. Soc. Mass
Spectrom. 2012, 23, 1461-1468.
The authors thank Caitlin Falcone for helpful discussions. Financial
Support is acknowledged from the Department of Defense: Defense
Advanced Research Projects Agency (award no. W911NF- 16-2-0020).
This material is also based in part upon work supported by the U.S.
Department of Energy, Office of Science, Office of Basic Energy Sciences,
Separations and Analysis Program, under Award Number DE-FG02-
06ER15807.
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Keywords: Ambient Ionization • Spray-based Ionization • Preparative Mass
Spectrometry • Mechanism of Acceleration • Confined Volume Reactions
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Layout 1:
COMMUNICATION
Thin films with continuous reactants
deposition and product precipitation
are used for accelerated, scaled-up
organic synthesis. Mechanistic study
shows two stages of thin film reaction.
Constant acceleration factor of 102 and
conversion ratio of 70 ~ 98% in the
diffusion controlled stage 2 enable us
to synthesize the Claisen-Schmidt
product at a rate of ca. 100 mg/hr
Zhenwei Wei, Michael Wleklinski,
Christina Ferreira and R. Graham Cooks
*
Page No. – Page No.
Reaction Acceleration in Thin Films
with Continuous Product Deposition
for Organic Synthesis
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