Testing the validity of microwave-interfaced, in situ Raman spectroscopy as a tool for kinetic studies

Article abstract of DOI:10.1021/ol802594s

(Chemical Equation Presented) (Graph Presented) Raman spectroscopy in conjunction with microwave heating is a convenient and robust tool for monitoring organic reactions from a qualitative perspective. Its validity as a method for obtaining quantitative d

Full text of DOI:10.1021/ol802594s

ORGANIC
LETTERS
2009
Vol. 11, No. 2
365-368
Testing the Validity of
Microwave-Interfaced, in Situ Raman
Spectroscopy as a Tool for Kinetic
Studies
Jason R. Schmink, Jennifer L. Holcomb, and Nicholas E. Leadbeater*
Department of Chemistry, UniVersity of Connecticut, 55 North EagleVille Road, Storrs,
Connecticut 06269-3060
nicholas.leadbeater@uconn.edu
Received November 10, 2008
ABSTRACT
Raman spectroscopy in conjunction with microwave heating is a convenient and robust tool for monitoring organic reactions from a qualitative
perspective. Its validity as a method for obtaining quantitative data is shown. Activation enthalpies for the synthesis of a range of substituted
chalcones are determined and the results compared with well-established previous data and reactivity trends for this aldol condensation. The
methodology is used for obtaining previously unreported pKa data for substituted acetophenones.
Using microwave heating as a tool in organic chemistry
has many advantages. Reactions are often complete in a
matter of minutes and product yields can, in many cases, be
improved.1 A significant issue with performing reactions with
microwave apparatus is that monitoring its progress generally
requires stopping it, allowing the reaction mixture to cool
and then using standard analysis techniques such as IR and
NMR spectroscopy. Building on initial reports by Myrick
et al.2 and Pivonka and Empfield,3 there has been a dedicated
focus within our group to explore the scope and limitations
of employing Raman spectroscopy to monitor microwave-
promoted organic reactions from a qualitative perspective.4,5
There are many aspects of Raman spectroscopy that make
it well-suited to be an effective reaction monitoring tool.
First, it relies on light scattering so there is no physical or
mechanical interaction with the reaction sample. Next,
although Raman signal strength is proportional to a number
of variables including temperature, path length of the sample,
laser intensity, and concentration, through the course of a
reaction, all remain constant except concentration. This
(2) Stellman, C. M.; Aust, J. F.; Myrick, M. L. Appl. Spectrosc. 1995,
3, 392
.
(1) (a) Kappe, C. O.; Stadler, A. MicrowaVes in Organic and Medicinal
Chemistry; Wiley-VCH: Weinheim, Germany, 2005. (b) Loupy, A., Ed.
MicrowaVes in Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2006.
(c) Lidstro¨m, P.; Tierney, J. P., Eds. MicrowaVe-Assisted Organic Synthesis;
Blackwell: Oxford, UK, 2005.
(3) Pivonka, D. E.; Empfield, J. R. Appl. Spectrosc. 2004, 58, 41
(4) Leadbeater, N. E.; Schmink, J. R. Nat. Prot. 2008, 3, 1
(5) (a) Leadbeater, N. E.; Smith, R. J. Org. Biomol. Chem. 2007, 2770.
(b) Leadbeater, N. E.; Smith, R. J. Org. Lett. 2006, 8, 4589. (c) Barnard,
T. M.; Leadbeater, N. E. Chem. Commun. 2006, 3615
.
.
.
10.1021/ol802594s CCC: $40.75
Published on Web 12/12/2008
2009 American Chemical Society

means that Raman spectroscopy is in theory an effective
means to measure concentration changes in a dynamic
system. Additionally, in terms of practicality, borosilicate
glass is essentially transparent to a Raman spectrometer and
this allows the use of standard laboratory glassware. Despite
these advantages, while quantitative in situ infrared spec-
troscopy (e.g., ReactIR) has seen significant use for deter-
mination of reaction kinetics,6 there are very few reports of
analogous studies with Raman spectroscopy.7 Recent ad-
vances in Raman spectroscopy now allow for data acquisition
at such a rate that quantitative data can be extracted. In
addition, microwave heating is also an ideal tool for
performing kinetic studies since it offers reproducible,
noncontact heating as well as precise temperature monitoring
and data recording.8 As a result we have become interested
in using microwave-interfaced, in situ Raman spectroscopy
for quantitative studies and have recently described a robust
method to derive precise kinetic data for organic transforma-
tions.9 In this letter we show further the validity of our
methods for determing kinetic data by using established pKa
data as a standard to which to compare our results.
work we use an open-vessel arrangement. Although this
limits the temperature range to that from room temperature
to the boiling points of solvents, the open-vessel format
allows for a quantitative reaction start time as the catalyst is
injected into the sample.
Starting with benzaldehyde and acetophenone as test
substrates yielding trans-chalcone as product, our initial
objective was to determine a calibration curve to transform
units of Raman signal intensity to the standard kinetic
parameters of concentration.10 Since Raman signal strength
when measuring only the Stokes shift is inversely propor-
tional to temperature, it was necessary to derive calibration
curves at each temperature the reaction would be monitored.
This process was repeated for each chalcone product that
would form part of our study.
We next turned our attention to monitoring the reactions.
To ensure accurate and reproducible results, a stock solution
of the appropriate benzaldehyde and acetophenone in ethanol
was prepared from which 20 trials were performed. We ran
four trials at each of five temperatures.11 Raw spectral data
were converted from units of Raman intensity·s-1 to standard
units of rate (mol·L-1·min-1). With this kinetic data in hand,
the Arrhenius plot of ln k vs 1/T was plotted for each reaction
studied from which activation energies were calculated (m
) -Ea/R, R ) 8.314 J·M-1·K-1). Additionally, the Eyring
plot of ln (k/T) vs 1/T was constructed for each reaction,
from which the activation enthalpy, ∆Hq, could be deter-
mined.12 As an example, the condensation between ac-
etophenone and benzaldehyde to yield chalcone was calcu-
lated to have an activation enthalpy of 49.0 kJ/mol (Figure
2), which is in good agreement for the previously reported
value of 11.6 kcal/mol (48.5 kJ/mol).13
Scheme 1. Claisen-Schmidt Condensation
We chose to examine the Claisen-Schmidt condensation
between an aromatic aldehyde and enolizable acetophenones
(Scheme 1). The polarizable R,ꢀ-unsaturated ketone moiety of
the chalcone system is highly Raman active and gives a
characteristic signal at approximately 1600 cm-1, thus allowing
us to follow the reaction easily in real time (Figure 1).
We calculated activation enthalpies for a wide range of
substituted chalcones. After a few initial studies, we observed
that the substitution on the acetophenone played a larger role
in dictating the activation enthalpies than that on the aldehyde
component. This is not unexpected since the rate-determining
step of the reaction is proportional to the concentration of
(7) (a) Waal, D. D.; Heynes, A. M. J. Solid State Chem. 1989, 80, 170.
(b) Ehly, M. E.; Gemperline, P. J.; Nordon, A.; Littlejohn, D.; Basford,
J. K.; De Cecco, M. Anal. Chim. Acta 2007, 595, 80.
(8) For a recent kinetic study of a microwave-promoted reaction not
involving in situ spectroscopy see: Gilday, J. P.; Lenden, P.; Moseley, J. D.;
Cox, B. G. J. Org. Chem. 2008, 73, 3130.
(9) Schmink, J. R.; Holcomb, J. L.; Leadbeater, N. E. Chem. Eur. J.
2008, 14, 9943.
(10) To achieve this, solutions of known concentrations of trans-chalcone
in ethanol were prepared. They were placed sequentially inside a round-
bottomed flask inside the microwave cavity and brought to reflux by using
microwave heating and then the Raman spectrum was collected. After
subtraction of signals due to the solvent, a plot of signal intensity at 1598
cm-1 vs concentration was constructed.
Figure 1. Typical three-dimensional Raman spectrum in the
“fingerprint” region from 250 to 2250 cm-1 generated during the
first 140 s of the Claisen-Schmidt condensation.
(11) Stock solution (25 mL) was placed in a standard 50 mL capacity
round-bottomed flask with a Teflon-coated stir bar, and this was placed
into the microwave cavity. It was then heated to the desired temperature at
which point a dark scan was taken. Next, the appropriate amount of sodium
hydroxide catalyst in a small volume of water was injected and Raman
spectra collected automatically at ∼7 s intervals. The initial rate of reaction
was determined by using the first few scans; generally under 1 min is all
that is needed. As such, all 20 data points for a pair of substrates could be
generated in a time period of less than 2 h.
(12) Bernasconi, C. F., Ed. InVestigations of Rates and Mechanisms of
Reactions, Part 1; John Wiley and Sons: New York, 1986.
(13) Noyce, D. S.; Pryor, W. A. J. Am. Chem. Soc. 1955, 77, 1397.
(14) Coombs, E.; Evans, D. P. J. Chem. Soc. 1940, 1295.
While the majority of microwave-promoted reactions are
performed with use of sealed tubes, to perform quantitative
(6) For selected recent examples see: (a) Denmark, S. E.; Pham, S. M.;
Stavenger, R. A.; Su, X. P.; Wong, K. T.; Nishigaichi, Y. J. Org. Chem.
2006, 71, 3904. (b) Grabarnick, M.; Zamir, S. Org. Proc. Res. DeV. 2003,
7, 237. (c) Almeida, A. R.; Moulijn, J. A.; Mul, G. J. Phys. Chem. C 2008,
112, 1552. (d) Tibiletti, D.; Meunier, F. C.; Goguet, A.; Reid, D.; Burch,
R.; Boaro, M.; Vicario, M.; Trovarelli, A. J. Catal. 2006, 244, 183.
366
Org. Lett., Vol. 11, No. 2, 2009

Table 1. Observed Activation Enthalpies (∆Hq) for the
Formaton of Substituted Chalcones
entry
R1
R2
-H
-H
-H
4-Cl
2-Cl
-H
-H
4-OCH3
-H
∆Hq (kJ/mol)
1
2
3
4
5
6
7
8
-H
4-Cl
2-Cl
-H
49.0
39.8
33.6
48.3
61.2
46.6
59.6
59.2
49.9
51.5
54.5
54.2
46.2
40.2
-H
4-Ph
4-OCH3
4-OCH3
4-F
Figure 2. Typical Erying plot of ln(k/T) vs 1/T yielding a straight
line, y ) mx + b, m ) -∆Hq/R, ∆Hq ) 49.0 kJ/mol, here for the
formation of trans-chalcone. Each data point is the average of at
least three trials agreeing to within 5%.
9
10
11
12
13
14
4-CH3
-H
-H
-H
-H
3,4-(OCH3)2
3-Br-4-OCH3
3-Cl-5-OCH3-2,4-(CH3)2
2-acetylpyridine
the enolate anion,14 which in turn should be dependent upon
the acidity of the R-proton of the substituted acetopheone.
Since our kinetic data are extracted from the first few seconds
of the reaction, three assumptions can be made: (1) [alde-
hyde] . [enolate], (2) δ[aldehyde] ≈ 0, and (3) [chalcone]
≈ 0. This last point is especially important, as the retro-
aldol reaction (regenerating starting materials) is in equilib-
rium with the forward reaction. Previous studies in which
kinetic data were aquired over longer periods of time state
that the substitution of the acetophenone has no impact on
the activation energies for the reaction.14 In stark contrast,
we hypothesized that holding the aldehyde component
constant in the reaction while varying the ketone substrate
would show a strong correlation between activation enthal-
pies and pKa values for the various acetophenones.
-H
etophenone and benzaldehyde was investigated. Figure 4
shows an overlay of the first 5 scans of the reaction and the
inset depicts the first 15 scans in the region of 1500-1700
cm-1. Two aspects are immediately apparent. First, the large
negative peaks at 882, 1001, 1049, 1094, and 1453 cm-1
are due to loss of the signal of the solvent, ethanol. In none
of the other reported chalcone syntheses did we observe this
phenomenon. Second, the Raman signal growing in at 1602
cm-1 is much less intense than had been observed for other
chalcones (Figure 4, inset). We believe that the rapid drop
in intensity of the solvent signal as well as the low Raman
signal intensity for the R,ꢀ-unsaturated ketone upon catalyst
injection arises from the slight insolubility of an intermediate
A plot of known pKa values15 for seven acetophenones (Table
1, entries 1, 2, 6, 7, 9, 10, and 14) vs our calculated activation
enthalpies for their respective condensations with benzaldehyde
(Figure 3) shows a strong correlation (R2 ) 0.985). We reasoned
that we should be able to calculate, with reasonable certainty,
pKa data for additional acetophenones. For this study, we used
both electron-rich and -poor ring systems as well as either
mono-, di-, or tetrasubstituted acetophenones to explore more
esoteric substitution patterns. We have determined for the first
time the pKa data for 2′-chloroacetophenone (23.0), 3′,4′-
dimethoxyacetophenone (25.2), 3′-bromo-4′-methoxyacetophe-
none (25.1), and the highly substituted 3′-chloro-5′-methoxy-
2′,4′-dimethylacetophenone (24.3). These few examples show
the power of our approach in allowing pKa data to be obtained
rapidly and easily.
A limiting factor when using the in situ Raman monitoring
methodology is that the reaction mixture must remain
homogeneous throughout the course of the reaction as well
as at all temperatures investigated. If a precipitate begins to
form, the path length of the laser is no longer a constant
and converting units of Raman intensity to concentration will
no longer be reliable. The reaction between 3′-chloroac-
Figure 3. Plot of known pKa values of acetophenones (O) versus
calculated activation enthalpies for the aldol condensation with
benzaldehde. Extrapolated pKa values (9) for 2′-chloroacetophenone
(23.0), 3′,4′-dimethoxyacetophenone (25.2), 3′-bromo-4′-methoxy-
acetophenone (26.0), and 3′-chloro-5′-methoxy-2′,4′-dimethylac-
etophenone (25.1) based upon the best-fit line, y ) mx + b; m )
0.104, b ) 19.51; R2 ) 0.985.
(15) Bordwell, F. G.; Conforth, F. J. J. Org. Chem. 1978, 43, 1763.
Org. Lett., Vol. 11, No. 2, 2009
367

along the reaction pathway. The resultant cloudy solution
shortens the path length of the laser, and results in inprecise
intensity data being recorded. Furthermore, as solubility is
dependent upon temperature, the intermediate is most likely
more soluble at high temperatures than at lower ones, leading
to a longer effective path length at elevated temperatures
and thus limiting our ability to extract quantitative kinetic
data.
Figure 5. Erying plot for the formation of 3′-chlorochalcone.
Calculated activation enthalpy (46.8 kJ/mol) deviates from the
expected value (34.8 kJ/mol) due to the heterogeneous reaction
conditions upon addition of the catalyst.
kinetic data for organic reactions. We were able to determine
the activation enthalpies for the formation of a number of
substituted chalcones and were able to show that our results
correlate well with known pKa data. This shows the vailidity
of our methods. A limiting factor, however, is that the
reaction mixture must remain homogeneous throughout the
course of the reaction to be able to obtain accurate data.
Current work is underway to exploit this technique further
and to examine other, less well-characterized, organic
reactions.
Figure 4. Overlay of the first five Raman spectra generated while
monitoring the condensation between 3′-chloroacetophenone and
benzaldehyde. The large negative peaks are due to signal loss of
the ethanol solvent and indicate loss of effective path length. Inset:
The first 15 scans of the reaction in the region of 1500-1700 cm-1
.
The low signal strength due to the formation of the chalcone also
indicates a shortened path length.
Acknowledgment. The authors thank Dr. Eric Wu of
Enwave Optronics for Raman equipment support and CEM
Corp. for microwave equipment support. The University of
Connecticut Research Foundation is acknowledged for fund-
ing.
Despite these problems, since the pKa data are known for
3′-acetophenone, we continued to probe the reaction using this
substrate to test our reasoning that insolubility would be a larger
factor at low temperatures, hence leading to a larger negative
slope in the derived Eyring plot. As predicted, the plot of ln(k/
T) vs 1/T (Figure 5) leads to a calculated activation enthalpy of
46.8 kJ/mol, significantly higher than the expected value of 34.8
kJ/mol determined from Figure 3 by using the known pKa value
of 23.2 for 3′-chloroacetophenone.
Supporting Information Available: Apparatus overview,
detailed experimental procedures, and copies of 1H and 13
C
NMR of all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
In summary, this work shows the scope and limitations
when using Raman spectroscopy as a method to determine
OL802594S
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Org. Lett., Vol. 11, No. 2, 2009