Use of Raman spectroscopy as an in situ tool to obtain kinetic data for organic transformations

Article abstract of DOI:10.1002/chem.200801158

Raman spectroscopy has been used as an in situ tool to obtain kinetic data for an organic transformation. The model reaction studied was the synthesis of 3-acetylcoumarin from the condensation between salicylaldehyde and ethyl acetoacetate with piperidine as a catalyst. The study shows that precise kinetic data can be obtained quickly and reproducibly, allowing for the facile determination of both overall reaction order and reaction order with respect to each component of the reaction. Additionally, Arrhenius parameters such as activation energy for a reaction can be readily obtained. In conjunction with computational modeling, this data-rich analysis technique also allows for in-depth probing of mechanistic aspects of reactions. Microwave heating proves to be an ideal tool for aiding in kinetic studies. It offers reproducible noncontact heating as well as precise temperature monitoring and data recording.

Full text of DOI:10.1002/chem.200801158

FULL PAPER
DOI: 10.1002/chem.200801158
Use of Raman spectroscopy as an In Situ Tool to Obtain Kinetic Data for
Organic Transformations
Jason R. Schmink, Jennifer L. Holcomb, and Nicholas E. Leadbeater*[a]
Abstract: Raman spectroscopy has
been used as an in situ tool to obtain
kinetic data for an organic transforma-
tion. The model reaction studied was
the synthesis of 3-acetylcoumarin from
the condensation between salicylalde-
hyde and ethyl acetoacetate with piper-
idine as a catalyst. The study shows
that precise kinetic data can be ob-
tained quickly and reproducibly, allow-
ing for the facile determination of both
overall reaction order and reaction
order with respect to each component
of the reaction. Additionally, Arrhenius
parameters such as activation energy
for a reaction can be readily obtained.
In conjunction with computational
modeling, this data-rich analysis tech-
nique also allows for in-depth probing
of mechanistic aspects of reactions. Mi-
crowave heating proves to be an ideal
tool for aiding in kinetic studies. It
offers reproducible noncontact heating
as well as precise temperature monitor-
ing and data recording.
Keywords: activation parameters ·
kinetics · microwave heating · Ram-
an spectroscopy · reaction mecha-
nisms
Introduction
of reactions by using this apparatus and we have applied it
to a range of synthetic transformations.[6–8]
Microwave heating offers a fast, clean approach to synthe-
sis.[1] It is often possible to perform reactions in minutes in-
stead of hours and, in many cases, product yields can be im-
proved. Also, as the field progresses, new chemistry is being
discovered and developed. An issue with performing a reac-
tion with microwave apparatus is that monitoring its prog-
ress generally requires stopping it, allowing the reaction
mixture to cool and then using standard analysis techniques
such as IR and NMR spectroscopy. As a result, optimization
of reaction conditions such as time and temperature is often
a matter of trial and error. In the case of inorganic materials
chemistry, neutron and X-ray scattering have been used as
in situ monitoring tools.[2,3] These techniques are less appli-
cable to preparative organic chemistry. We have built on the
initial work of Pivonka and Empfield[4] and developed an
apparatus for in situ reaction monitoring using Raman spec-
troscopy.[5] It has been possible to determine the end-point
While quantitative in situ infrared spectroscopy (e.g., Re-
actIRTM) has seen significant use for determination of reac-
tion kinetics,[9,10] there are very few reports of analogous
studies with Raman spectroscopy.[11] In their seminal publi-
cation in 2004, Pivonka and Empfield used Raman spectros-
copy for the study of a microwave-mediated imine forma-
tion reaction and a Knoevenagel condensation.[4] For the
latter reaction, they probed the kinetics of the reaction and
also elucidated a reactive intermediate they believed to be
formed along the path of the reaction. Having used our in
situ Raman apparatus in synthetic chemistry applications,
we also wanted to explore the potential for using our experi-
mental set-up for real-time kinetic studies.
In many regards Raman spectroscopy in conjunction with
microwave heating is, in principle, an ideal tool for perform-
ing kinetic studies. The microwave offers reproducible non-
contact heating as well as precise temperature monitoring
and data recording. The Raman spectrometer is able to ac-
quire data at such a rate that quantitative data can be ex-
tracted for even the most rapid of reactions.[12] Furthermore,
since most spectroscopic techniques require a dark environ-
ment for accurate signal measurement, the fact that the mi-
crowave cavity is free of significant ambient light is an
added advantage. Finally, Raman spectroscopy is in theory
an effective means to measure concentration changes in a
dynamic system. To probe this and show the potential for
[a] J. R. Schmink, J. L. Holcomb, Dr. N. E. Leadbeater
Department of Chemistry, University of Connecticut
55 North Eagleville Road, Storrs, CT 06269-3060 (USA)
Fax: ( +1)8606173518
E-mail: nicholas.leadbeater@uconn.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801158.
Chem. Eur. J. 2008, 14, 9943 – 9950
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9943

using Raman spectroscopy as a tool for real-time kinetic
analysis, we chose as a sharpening stone the synthesis of 3-
acetylcoumarin, formed from the base-catalyzed reaction of
salicylaldehyde with ethyl acetoacetate. We have previously
shown that this reaction can be monitored qualitatively
from a synthetic chemistry perspective[5] and Pivonka and
Empfield used an analogous reaction for their kinetic stud-
ies[4] (reaction of salicylaldehyde with benzyl acetoacetate).
We wanted to use these foundations to build upon. Our re-
sults are presented here. We demonstrate how, using this ap-
paratus, it is possible to quickly and easily obtain valuable
kinetic data as well as begin to probe reaction intermediates.
We show how we have built on previous work and deter-
mined orders of reaction for each reagent in units of con-
centration as well as1 Arrhenius parameters for the reac-
tion. In addition, by using our apparatus in conjunction with
calculations, we propose a mechanistic pathway for the reac-
tion that differs from that originally proposed.
Figure 1. Raman spectrum of 3-acetylcoumarin (0.35m in ethyl acetate)
with signals due to solvent subtracted
after application of the appropriate scaling factor,[20] corre-
lated to a stretching frequency of 1602 cmꢀ1, fitting well
with our observed value of 1608 cmꢀ1. The complexstretch-
ing mode is shown in Figure 2.
Results and Discussion
Coumarins have been found to have multibiological activi-
ties.[13] They can be prepared by using a number of synthetic
routes[14] and microwave heating has been used as a tool.[15]
In our model reaction shown in Scheme 1 (synthesis of 3-
Scheme 1. Reaction of salicylaldehyde with ethyl acetoacetate to yield 3-
acetylcoumarin.
acetylcoumarin from salicylaldehyde with ethyl acetoace-
tate), we used piperidine as the catalyst and ethyl acetate as
the solvent. While this reaction on the outset looks simple,
the precise mechanism is still a matter of debate and small
changes in the system may result in very different reaction
pathways.[16] This added to our motivation to probe the reac-
tion in detail. Upon inspection of the Raman spectra of sali-
cylaldehyde, ethyl acetoacetate, and 3-acetylcoumarin we
found that there are two clearly defined signals in the prod-
uct (1563 cmꢀ1, 1608 cmꢀ1) that are not present in the start-
ing materials, so it is one of these (1608 cmꢀ1) that we decid-
ed to follow in our reaction. The spectrum of 3-acetylcou-
marin taken in ethyl acetate with signals due to solvent sub-
tracted is shown in Figure 1.
To determine the nature of the stretching mode observed
at 1608 cmꢀ1 we used a computational approach. The
stretching modes for 3-acetylcoumarin were calculated using
Gaussian 03,[17] applying the Becke exchange functional[18]
(B) coupled with the correlation functional developed by
Lee, Yang, and Parr[19] (LYP) at the 6-31G(d) basis set. The
calculations yielded an intense signal at 1666 cmꢀ1 which,
Figure 2. Stretching mode giving rise to the observed Raman peak at
1602 cmꢀ1 as calculated at the B3LYP-6/31G(d) theory level (observed
1608 cmꢀ1
)
Experimental considerations: The majority of microwave-
promoted reactions are performed using sealed tubes. To
ensure precise reaction monitoring conditions, for our kinet-
ic studies here we opted for an open-vessel configuration.
First, the salicylaldehyde, ethyl acetoacetate, and the ethyl
acetate solvent were brought to refluxat which point a
background scan was taken. Having the reaction at the de-
sired temperature before the catalyst was added alleviated
any peak intensity variation due to temperature effects
during a specific experiment. Second, this set-up allowed for
a quantitative t=0 spectrum to be obtained. The formation
of the coumarin can be effected at room temperature, so ad-
dition of piperidine to the reaction mixture prior to heating
(e.g., under sealed-vessel conditions) would initiate the reac-
tion before the introduction into the microwave cavity. Fi-
nally, to determine kinetic parameters accurately, it was es-
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Raman Spectroscopy
FULL PAPER
sential to have the reaction at the desired reaction tempera-
ture before adding the catalyst. Adding piperidine prior to
heating leads to dynamic, and consequently imprecise, kinet-
ic data being obtained during the ramp to the desired tem-
perature. While these issues are not crucial when monitoring
reactions in a qualitative manner, our desire to develop the
Raman spectrometer/microwave interface as a quantitative
tool demanded this precise control of reaction parameters.
peratures with confidence.[21] This was achieved by measur-
ing the intensity of the 1608 cmꢀ1 signal of known concentra-
tions of 3-acetylcoumarin at temperatures within our range
of interest. The average of ten scans at five temperatures
ranging from 35–758C and at four different concentrations
gave a total of 20 data points (Figure 4). From this, a scaling
factor was determined.
Obtaining a calibration curve: To be able to measure prod-
uct concentration accurately and ultimately derive rate laws,
a calibration curve was required to translate signal strength
of the peak forming at 1608 cmꢀ1 into units of concentration
in standard terms. To achieve this, solutions of known con-
centrations of 3-acetylcoumarin in ethyl acetate were pre-
pared. They were sequentially placed inside a round-bot-
tomed flask inside the microwave cavity, brought to reflux
(83–848C) using microwave irradiation and the Raman spec-
trum collected. After subtraction of signals due to the sol-
vent, a plot of signal intensity at 1608 cmꢀ1 versus concentra-
tion was made (Figure 3) which yielded a straight line (R2 =
0.9986).
Figure 4. Plot of Raman signal intensity vs. temperature at constant con-
centrations. A second-order polynomial proved the best fit line over the
temperature range: f(T)=(ꢀ2.259”10ꢀ5 T2ꢀ1.558”10ꢀ3 T+1.244)ꢀ1; T in
8C, R2 =0.9934
Determination of reaction orders: With the appropriate cali-
bration curve and scaling factor in hand, we wanted to use
the apparatus to determine the order of the reaction with
respect to each reagent. We postulated that precise reaction
rates could be determined by running a series of experi-
ments by varying concentrations of reagents and monitoring
the appearance of the signal at 1608 cmꢀ1 due to product
formation followed by conversion of units of Raman intensi-
ty to units of molarity. To achieve this we set up a series of
reactions based around the kinetic method of initial rates
(varying the concentration of one reagent at a time and
measuring the rate of reaction at t=0) in conjunction with
the isolation method (performing experiments in which the
concentration of one or more reagents is kept constant to
determine rate dependence as a function of the reagent
being probed). We decided to focus attention initially on the
order of the reaction with respect to the piperidine catalyst.
Holding the concentrations of salicylaldehyde and ethyl ace-
toacetate constant at 1.00m, an initial range of piperidine
concentrations were screened, ranging from 0.0200m to
0.400m, the data being shown in Figure 5. At low catalyst
loadings (0.0200–0.0800m) the reaction appears to be first-
order with respect to the piperidine concentration. Howev-
er, at increasing catalyst loading, it becomes apparent that
the piperidine is implicated in numerous reversible steps in
the reaction mechanism and is of a complexorder, since
there is significant deviation from linearity. At these higher
catalyst concentrations, the reaction rate is approximately
proportional to the square root of the concentration of pi-
Figure 3. Plot of Raman signal intensity of the peak arising at 1608 cmꢀ1
versus [3-acetylcoumarin] yielding a line, f(x)=mx+b; x=[3-acetylcou-
marin] in molLꢀ1, m=47,393; R2 =0.9986
Temperature scaling factor: When monitoring reactions
using Raman spectroscopy at different temperatures it is im-
portant to take into account that fact that the Stokes
Raman band (which is being monitored) is inversely propor-
tional to temperature. This relationship is due to the funda-
mental manner in which Raman spectroscopy probes a mol-
ecule; that is it excites it in the lowest energy electronic
state. As temperature increases, there is a smaller popula-
tion of molecules in that ground state to be excited, and so
the signal intensity drops. This being said, over small tem-
perature ranges the change in the Stokes shift is fairly negli-
gible, but, for analytical accuracy, we deemed it important in
our study to determine an appropriate scaling factor that
would allow us to compare peak intensities at different tem-
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N. E. Leadbeater et al.
tions of 0.125, 0.250, and 0.500m, the reaction rate was
linear for approximately the first 60 s or six scans before be-
ginning to deviate from linearity. Data obtained in the
linear region is gathered in Table 1 and shown graphically in
Table 1. Data for the signal growing in at 1608 cmꢀ1 [intensitysꢀ1] and
conversion to units of rate [mminꢀ1] in the linear region at various con-
centrations of salicylaldehyde.
A
[intensitysꢀ1
]
rateobs [mminꢀ1
]
2.00
1.00
0.50
0.25
0.125
0.063
0.031
314
167
0.398
0.211
0.103
0.056
0.031
0.022
0.012
81.7
44.4
24.3
17.1
9.41
Figure 5. Plot of rate of formation of 3-acetylcoumarin as monitored by
the peak forming at 1608 cmꢀ1 versus piperidine concentration. Increas-
ing concentrations above 0.0800m show loss of linear dependence on cat-
alyst loading. Note: a linear approximation can be made at low catalyst
loadings.
Figure 6. At concentrations of 0.0625m and lower, the detec-
tion limit of the Raman spectrometer set to 10 s integrations
became a factor. At concentrations of 1.00m linearity is
peridine used. The general rate law is given in Equation (1)
in which f([piperidine])ꢁ[piperidine]1 for concentrations
below 0.080m, and f([piperidine])ꢁ[piperidine]1/2 for con-
centrations from 0.100–0.400m
a
rate ¼ k ½salicylaldehydeŠ ½ethyl acetoacetateŠb fð½piperidineŠÞ
ð1Þ
The complexnature of the rate dependence upon the cat-
alyst concentration is not totally unexpected. The pipiridine
could be imagined to be involved in a range of equilibrium
processes. The pKa values in dimethyl sulfoxide (DMSO) for
the piperdinium cation, the phenolic proton of the salicylal-
dehyde, and the acidic proton of ethyl acetoacetate are 10.9,
14.8, and 14.1, respectively.[22]
Figure 6. Plot of Raman signal intensity due to the peak growing in at
1608 cmꢀ1 versus time in the linear region at various concentrations of
salicylaldehyde, holding [ethyl acetoacetate] at 1.0m.
We next turned attention to determining the order of the
reaction with respect to ethyl acetoacetate and salicylalde-
hyde. We decided to perform the kinetic measurements at a
piperidine concentration of 0.0800m. To simplify our future
calculations we reformulated Equation (1) to give us Equa-
tion (2), in which rateobs and kobs are the rate and rate con-
stant at 0.0800m piperidine catalyst loading.
maintained for only approximately the first 30 s (4 data
points) of the reaction. At the 2.00m concentration, the
signal intensityꢁs deviation from linearity was so rapid that
at most three points could be used to determine the initial
rate. As such, this data was deemed unusable. The experi-
ments were then repeated, holding the initial concentration
of ethyl acetoacetate at a constant 1.00m and similarly vary-
ing the concentrations of salicylaldehyde (Figure 7; Table 2).
For both ethyl acetoacetate and salicyladehyde, a plot of
rate of reaction versus initial concentration gives a straight
line showing that the reaction is first order in both of these
reagents. Thus the overall rate equation is given by Equa-
tion (3) in which rateobs and kobs are the rate and rate con-
stant at 0.08m piperidine catalyst loading or, more fully, by
Equation (4) in which f([piperidine]) ꢁ[piperidine]1 for
concentrations below 0.080m, and f([piperidine])ꢁ[piperi-
dine]1/2 for concentrations from 0.100–0.400m
a
b
ð2Þ
rateobs ¼ kobs ½salicylaldehydeŠ ½ethyl acetoacetateŠ
All subsequent calculations could then be performed in
terms of rateobs and kobs. In the first series of experiments, in-
itial rates were measured as a function of various concentra-
tions of ethyl acetoacetate (0.0312–2.00m) holding the sali-
cyladehyde concentration constant at 1.00m and the piperi-
dine concentration constant at 0.0800m. Again the appear-
ance of the signal at 1608 cmꢀ1 due to product formation
was monitored and the units of Raman intensity were con-
verted to molarity values. At ethyl acetoacetate concentra-
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Raman Spectroscopy
FULL PAPER
Table 3. Data for the signal growing in at 1608 cmꢀ1 for 3-acetylcoumarin
in units of Raman intensitysꢀ1, subsequent temperature-corrected (Tc)
values by using Equation (5), and conversion to units of kobs [mꢀ1 sꢀ1] at
various temperatures.
T
[K]
1/T
slope
[IUsꢀ1
scaled slope kobs
ꢂ
lnkobs
G
]
Tc [IUsꢀ1
]
[mꢀ1 minꢀ1
]
309.65 0.003229
320.3 0.003122
330.25 0.003028
340.8
350.15 0.002856 132
27.8
45.8
68.4
24
0.0304
0.0517
0.0801
0.1224
0.1690
0.0018 ꢀ3.4945
0.0063 ꢀ2.9620
0.0009 ꢀ2.5248
0.0048 ꢀ2.1002
0.0050 ꢀ1.7779
40.8
63.2
96.7
133.5
0.002934 100.2
Figure 7. Plot of Raman signal intensity due to the peak growing in at
1608 cmꢀ1 versus time in the linear region at various concentrations of
ethyl acetoacetate, holding [salicylaldehyde] at 1.0m.
Table 2. Data for the signal growing in at 1608 cmꢀ1 [intensitysꢀ1] and
conversion to units of rate [mminꢀ1] in the linear region at various con-
centrations of ethyl acetoacetate.
[ethyl acetoacetate]
[intensitysꢀ1
]
rateobs [mminꢀ1
]
2.00
1.00
0.50
0.25
0.125
0.063
0.031
304
167
0.385
0.211
0.108
0.058
0.032
0.019
0.014
85.1
46.1
25.1
15.2
10.8
Figure 8. Plot of ln kobs versus 1/T yielding a straight line, y=mx+b, m=
Ea/R=4602, b=11.407. R2 =0.9990, average of 2 trials at each tempera-
ture.
those we obtained for our qualitative studies previously
when using the Raman apparatus simply as a tool for moni-
toring how long the reaction took to reach completion.
Performing the reaction at 1308C we found that it took
approximately 8 min to reach completion. Extrapolating our
1
1
ð3Þ
rateobs ¼ kobs ½salicylaldehydeŠ ½ethyl acetoacetateŠ
rate ¼ k ½salicylaldehydeŠ ½ethyl acetoacetateŠ1 fð½piperidineŠÞ
1
quantitative rate data to 1308C we found that kobs
=
ð4Þ
0.972mꢀ1 minꢀ1 or 0.0162mꢀ1 sꢀ1. Using the half-life equation
for a second-order reaction (t1/2 =1/kobs), we calculated the
half-life for the reaction at 1308C to be 62 seconds. After six
half-lives (ꢁ6 min) the projected yield would be ꢁ98.4%;
this corresponded with the observed product yields in the
reaction and fits well with our previous qualitative results.
Determination of activation energy: Having obtained kinetic
data to ascertain the orders of the reagents our next objec-
tive was to determine the activation energy (Ea) for the re-
action. This was achieved by running the reaction at a range
of temperatures between 25 and 808C. The reactions were
performed using 1m concentrations of ethyl acetoacetate
and salicyladehyde and 0.08m piperidine and the product
signal at 1608 cmꢀ1 was monitored. After translating Raman
signal intensity to units of concentration using our calibra-
tion curve and then compensating for temperature effects
using our temperature scaling factor, we obtained rate con-
stant data (kobs) in units of mꢀ1 minꢀ1 (Table 3). Plotting
lnkobs versus 1/T (Figure 8) gave a straight line, the slope of
which corresponds to ꢀEa/R, (R=8.314 JKꢀ1 molꢀ1). From
this, the activation energy for the reaction was calculated to
be 38.3 kJmolꢀ1.
Mechanistic insight: Our next objective was to probe the
mechanism of the reaction knowing the first-order depend-
ence on both the concentrations of ethyl acetoacetate and
salicylaldehyde. In their study Pivonka and Empfield saw
evidence for the formation of a transient intermediate in the
reaction of salicylaldehyde and benzyl acetoacetate.[4] They
proposed that the intermediate,
1, was the result of a Knoeve-
nagel
condensation.
This
seemed surprising to us given
that the restricted rotation
about the C=C double bond
would limit product formation
to a 50% theoretical yield, but
The quantitative data obtained was then used to extrapo-
late and calculate a rate constant (kobs) for other reaction
temperatures. We wanted to compare our results here with
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N. E. Leadbeater et al.
obtained product yields for the reaction are high, generally
greater than 90%. The two key reactions taking place in
their reaction and also ours are the Knoevenagel condensa-
tion and a transesterification. We decided to perform series
of experiments using model substrates with the aim of deter-
mining in which order these reactions occur. To address the
Knoevenagel condensation component we used o-anisalde-
hyde as a test substrate (Scheme 2). With this, while a Kno-
viation from planarity and the energy taken for the conden-
sation step and concomitant formation of the carbon–carbon
double bond could be imagined to be quite high. Analysis of
a product mixture from the reaction with o-anisaldehyde
showed the expected E and Z isomers of the condensation
product.
There are four plausible mechanistic pathways that would
exhibit first-order dependence upon both salicylaldehyde as
well as ethyl acetoacetate, denoted as 1, 2, 3 and 4 in
Scheme 3. Path 1 is the complete Knovenagel-type reaction
followed by ring closure proposed by Pivonka and Empfield.
We know that the activation energy for our model substrate
o-anisaldehyde was significantly higher than that observed
in the reaction with salicylaldehyde. Moreover, the relative
energy for intermediate 1c was calculated to 74.3 kJmolꢀ1,
much higher than the observed activation energy for the re-
action. Based on these results, as well as the issues of re-
stricted rotation about the C=C double bond, we believe
that this is not the mechanism for the reaction. Path 4 in-
volves full transesterification followed by lactone formation
with loss of ethanol and then dehydration to form the prod-
uct. Calculation of the relative energy of intermediate 4b
along this pathway shows that the formation of the initial
transesterified compound requires more energy than the cal-
culated activation energy thereby ruling out this pathway.
Path 2 involves partial Knoevenagel reaction followed by
cyclization, concomitant loss of ethanol, and finally dehydra-
tion to yield the product. Path 3 involves partial transesteri-
fication reaction followed by cyclization, carbon–carbon
bond formation, loss of ethanol, and then dehydration to
yield the product. One of these two mechanisms seems the
most likely and fit our recorded kinetic data.
Scheme 2. Reaction of o-anisaldehyde with ethyl acetoacetate to yield
ethyl-(E/Z)-2-acetyl-3-(2-methoxyphenyl)-acrylate.
venagel condensation with ethyl acetoacetate can take
place, there is no potential for cyclization. We performed a
range of kinetic measurements holding the reagents at
1.00m in ethyl acetate, and again using 0.08m piperidine as
the catalyst and monitored formation of the carbon–carbon
double bond (Raman signal at 1601 cmꢀ1). From the outset
it was clear that the reaction with o-anisaldehyde was much
slower than that using salicylaldehyde and that no observa-
ble reaction took place below 358C within 10 min of moni-
toring. Plotting the observed rate constants we obtained at
higher temperatures versus 1/T gave a straight line, from
which the activation energy for the reaction was calculated
to be 51.3 kJmolꢀ1, significantly higher than for the conden-
sation to form 3-acetylcoumarin (38.3 kJmolꢀ1). The fact
that the activation energy is higher when using o-anisalde-
hyde is not too surprising. The product shows significant de-
Observation of transient intermediates: In an attempt to
probe the mechanism further, we plotted in three dimen-
Scheme 3. The 4 most plausible reaction pathways for formation 3-acetylcoumarin from salicylaldehyde and ethyl acetoacetate.
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Raman Spectroscopy
FULL PAPER
sions the formation of the 3-acetylcoumarin product as a
function of time and Raman intensity. Careful analysis of
the 3D profile in the region between 1500–1680 cmꢀ1 shows
evidence for the formation and subsequent consumption of
a transient intermediate (Figure 9). A peak with a local
rise to no new peaks in this region. The same can be said for
the addition of piperidine to a solution of ethyl acetoace-
tate; no new peaks arise within the Raman spectrum. There-
fore, the observable intermediate must be a new adduct be-
tween the salicylaldehyde and ethyl acetoacetate with a low
enough energy so as to build a sufficient population as to be
observable by Raman spectroscopy under these conditions,
thus implicating intermediate 2b/3b. However, even with a
putative characterization of the intermediate formed during
the reaction, it is still not possible to differentiate between
mechanisms 2 and 3.
Conclusion
We have built on previous work showing that Raman spec-
troscopy can employed as an in situ tool to obtain kinetic
data for organic transformations. The model reaction stud-
ied shows that precise kinetic data can be obtained quickly
and reproducibly, allowing for the facile determination of
both overall reaction order and reaction order with respect
to each component of the reaction. Additionally, Arrhenius
parameters such as activation energy for a reaction can be
readily obtained. This data-rich analysis technique also
allows for in-depth probing of mechanistic aspects of reac-
tions, especially when used in conjunction with results from
computational chemistry. Furthermore, microwave heating
proves to be an ideal tool for aiding in kinetic studies, offer-
ing reproducible noncontact heating as well as precise tem-
perature monitoring and data recording. Investigations are
currently underway to exploit further the full potential of
this combination of microwave heating and in situ Raman
spectroscopy with regard to kinetic studies of other reac-
tions.
Figure 9. Formation of 3-acetylcoumarin as
a function of time and
Raman intensity in the region from 1500 to 1680 cmꢀ1 during the first
10 min of the reaction.
maximum at 1630 cmꢀ1 grows in rapidly and then disappears
over the course of the reaction. This is clearly seen when
normalized Raman signal intensities for the intermediate
and the product are plotted versus time (Figure 10). We be-
lieve that the intermediate formed is most likely 2b/3b. The
optimized structure is calculated to have a very low every
(DG=+1.3 kJmolꢀ1 vs. starting materials) and a calculated
Raman frequency slightly higher than the acetylcoumarin
product (1605 vs. 1602 cmꢀ1). Though computational model-
ing predicts a slightly higher Raman active vibrational fre-
quency for intermediate 2c/3c as well, the relative energy
calculated is such that we believe there would not be a suffi-
cient population to be observable by Raman spectroscopy
under these conditions. No other intermediates modeled are
calculated to have a Raman active frequency between 1600
and 1650 cmꢀ1. Moreover, the addition of piperidine catalyst
to a 1.00m solution of salicylaldehyde in ethyl acetate gives
Experimental Section
General experimental: All reagents were obtained from commercial sup-
1
pliers (Sigma-Aldrich or Fisher) and used without further purification. H
and 13C NMR spectra were recorded at 293 K on a 300 MHz spectrome-
ter.
Apparatus: Reactions were conducted using a monomode microwave
unit (CEM Discoverꢂ S-Class) interfaced with a Raman spectrometer
(Enwave Optronics) and is described in detail elsewhere and in the Sup-
porting Information.
Typical procedure for monitoring the formation of 3-acetylcoumarin: Sal-
icyaldehyde (6.106 g, 50.00 mmol) and ethyl acetoacetate (6.507 g,
50.00 mmol) were placed in a 50.00 mL volumetric flask. The reagents
were diluted with ethyl acetate (final volume 50.00 mL). This solution
was transferred to a 50 mL long-necked round-bottomed flask equipped
with a Teflon-coated stirbar. The flask was placed into the microwave
cavity, making sure that any company glassware markings were orthogo-
nal to the Raman laser path. The microwave attenuator was then locked
in place. A 5 cm adapter was connected to the round-bottomed flask to
allow a Claisen adapter with septum inlet to be placed atop the reaction
flask. A refluxcondenser was placed on the Claisen adapter. The septum
inlet was capped with a rubber stopper with a 22-gauge syringe needle in-
serted through. The Raman probe was inserted into the microwave cavity
until the quartz light pipe just made contact with the side of the reaction
Figure 10. Plot of normalized signal intensity versus time for the Raman
signals at 1630 and 1608 cmꢀ1
.
Chem. Eur. J. 2008, 14, 9943 – 9950
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9949

N. E. Leadbeater et al.
flask. The reaction mixture was brought to reflux (83–848C), at which
point a background scan of the reaction that would be subtracted from
all subsequent scans was taken. The Raman spectrometer was set to take
a scan every 10 s. and continuous scans commenced. After the first scan
(t=0), the piperidine catalyst (436 mg, 4.0 mmol, 8 mol%) was rapidly
injected into the reaction mixture through the septum in the Claisen
adaptor. After running the reaction for the requisite period of time, the
Raman data acquisition and the microwave heating were halted. The re-
action mixture was allowed to cool to room temperature and the product
isolated was stopped. Upon cooling, the product was collected by
vacuum filtration and recrystallized from ethanol. 1H NMR (300 MHz,
CDCl3): d=8.51 (s, 1H), 7.67 (m, 2H), 7.40 (m, 2H), 2.73 ppm (s, 3H).
13C NMR (300 MHz, CDCl3): d=195.4, 159.2, 155.3, 147.4, 134.4, 130.2,
125.0, 124.5, 118.2, 116.7, 30.5 ppm.
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The University of Connecticut Research Foundation is thanked for fund-
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Received: June 12, 2008
Published online: October 1, 2008
9950
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 9943 – 9950