Real time HR-MAS NMR: Application in reaction optimization, mechanism elucidation and kinetic analysis for heterogeneous reagent catalyzed small molecule chemistry

Article abstract of DOI:10.1002/mrc.2321

A novel application of in situ ¹H high-resolution magic angle spinning (HR-MAS) NMR technique for real-time monitoring of H₂SO ₄-silica promoted formation of 2, 2-disubstituted quinozolin-4(3H)-ones is reported. The detailed NMR spectroscopic data led to elucidation of the mechanism, reaction optimization, kinetics and quantitative analysis of the product accurately and efficiently. The translation of the optimized parameters obtained by ¹H HR-MAS NMR in the wet laboratory provided similar results. It is proposed that ¹H HR-MAS has a potential utility for optimization of various organic transformations in solid supported catalyzed reactions. Copyright

Full text of DOI:10.1002/mrc.2321

Research Article
Received: 22 December 2007
Revised: 19 July 2008
Accepted: 29 July 2008
Published online in Wiley Interscience: 13 October 2008
(www.interscience.com) DOI 10.1002/mrc.2321
Real time HR–MAS NMR: application in
reaction optimization, mechanism elucidation
and kinetic analysis for heterogeneous reagent
catalyzed small molecule chemistry†
Abhijeet Deb Roy,a K. Jayalakshmi,c Somnath Dasgupta,b Raja Roya,c∗ and
Balaram Mukhopadhyayb
A novel application of in situ 1H high-resolution magic angle spinning (HR–MAS) NMR technique for real-time monitoring
of H2SO4-silica promoted formation of 2, 2-disubstituted quinozolin-4(3H)-ones is reported. The detailed NMR spectroscopic
data led to elucidation of the mechanism, reaction optimization, kinetics and quantitative analysis of the product accurately
and efficiently. The translation of the optimized parameters obtained by 1H HR–MAS NMR in the wet laboratory provided
similar results. It is proposed that 1H HR-MAS has a potential utility for optimization of various organic transformations in solid
c
supported catalyzed reactions. Copyright ꢀ 2008 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: HR-MAS NMR; heterogenous catalyst; kinetics; disubstituted quinazolinones
Introduction
quantum of information that HR–MAS NMR provides, it has now
become one of the most widely used and recognized techniques
in the fields of both chemistry and biology.[7]
Magic angle sample spinning (MAS) is one of the cornerstones
in high-resolution NMR of solid and semisolid materials.[1]
High-resolution magic angle spinning (HR–MAS) NMR, initially
developed in the late 1990s, has been used to characterize various
biological samples and for the study of gene mutation and drug
treatment in mammalian cells.[2] HR–MAS NMR spectroscopy
evolved from solid-state NMR techniques is also being used
as a method to analyze 1H spectra of molecules attached to
solid-phase synthetic resins.[3] It allows the analysis of materials
that swell, become partially soluble, or form true solutions in a
solvent even when some solids are still present.[4]In an HR–MAS
experiment, a heterogeneous or multiphase sample is spun at
a high speed (typically 3–5 kHz) around an axis oriented at
an angle of 54.7◦ (the so-called magic angle) with respect to
the direction of the static magnetic field. MAS averages out all
the anisotropic magnetic interactions (including residual dipolar
couplings, anisotropic chemical shifts, and bulk susceptibility
effects) that are responsible for additional line broadening in
heterogeneous samples and prevent the acquisition of well-
resolved spectra under conventional liquid conditions. As a result,
the MAS technique allows NMR spectra of heterogeneous systems
characterizedbylinewidthscomparabletothoseofclassicsolution
state NMR spectra. In recent years the application of HR–MAS
NMR has not only gained unparallel importance in the field of
metabolomics[5] but has also become the single most significant,
sensitive and nondestructive analytical method for obtaining
detailedstructureinformationofacompoundcovalentlyboundto
a resin support.[6] It has also been used to monitor the progress of
the solid-phase reaction and to determine the chemical structure
of a compound bound on a single bead. Owing to the unmatched
The application of 1H HR–MAS NMR in synthetic organic
chemistry has mainly been restricted so far only to the area
of solid phase organic synthesis (SPOS) for the quantification
and step-by-step analysis of supported organic reactions. The
growing interest for the use of solid supported catalyst for various
organic transformations in a greener and safer environment
encouraged us to evaluate the application of the above technique
to unveil the real-time mechanistic insight of these reactions.[8]
The major problem associated with the use of solution phase
NMR technique for real-time heterogeneous reactions is the peak
broadening because of the presence of solids and chemical
shift anisotropy created by the catalyst during the experiment
followed by loss of time because of manual off-axis shimming
for the suppression of spinning side bands. In nonspinning
mode the solid catalyst settles down quickly, slows down the
∗
Correspondence to: Raja Roy, Sopisticated Analytical Instrument Facility,
Central Drug Research Institute, Chattar Manzil Palace, Lucknow, India 226
001, India. E-mail: rajaroy cdri@yahoo.com
†
a
CDRI Communication No. 6956.
Sopisticated Analytical Instrument Facility, Central Drug Research Institute,
Chattar Manzil Palace, Lucknow, India 226 001, India
b
c
Medicinal andProcessChemistry Division, andCentral Drug Research Institute,
Chattar Manzil Palace, Lucknow, India 226 001, India
Centre of Biomedical Magnetic Resonance, Sanjay Gandhi Post Graduate
Institute of Medical Sciences, Lucknow, India
c
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A. D. Roy et al.
Schiff base (Fig. 1(a)) as the emergence of the dimethyl signal
at 1.25 ppm in the beginning, which subsequently diminishes
during the course of the reaction. The completion of the reaction
was identified by the emergence of the dimethyl resonance at
1.45 ppm (Fig. 1(b)) and the signals of the product (Fig. 1(c)) with
nearly complete disappearance of the acetone signal(Fig. 1(d)),
which showed more than 95% of conversion of the starting
material as shown in the buildup curve of the reaction (Fig. 2).
For the synthesis of 2,2-di-substituted quinazolin-4(3H)-ones
using a heterogenous acid catalyst two plausible pathways can be
drawn(pathAandpathB, Fig. 3). Outof thesetwomechanismsthe
formerwasdiscardedsincefromthesecondspectrumonwardsthe
dimethyl signal of the acetone reactant showed a distinct splitting
that not only revealed the presence of two forms of acetone in the
system (Fig. 1(d)), protonated and the nonprotonated acetone,
but also indicated the initiation of the reaction by the acid
catalyst. The splitting of the acetone signal then disappeared
with time indicating complete protonation of the entire acetone
reactant. In another experiment, no change was observed in the
anthranilamide spectrum in the absence of the acid catalyst,
which indicated that the involvement of the acid source for the
protonation of the ketone was the initial step that drove the
reaction in the forward direction. This was further reinstated
by the initial splitting of the HOD (partially deuterated water
present in deuterated methanol) signal (Fig. 1(e)) in its protonated
and nonprotonated forms owing to involvement of the acid
catalyst. Concomitantly, appearance of reaction intermediates
signals followed by the equilibrium shift to the formation of
hydrazone with coherent appearance of the final product, 2,2-
disubstituted quinazolinone (2) was clearly visible from the initial
stage of monitoring. Whereas, the fully protonated HOD signal
appears as a singlet at the later time of the reaction, hence the
reaction proceeds via path B (Fig. 3).
Scheme 1. H2SO4-silica promoted reaction of anthranilamide with ace-
tone.
reaction and does not allow mimicking the reaction as carried
out in the wet laboratory. In both spinning and nonspinning
situations in solution state NMR, isotropic mixing of the reaction
mixture cannot be induced in a reaction having heterogeneous
catalyst. This unavoidable drawback as we experienced in our
endeavors has drawn our attention toward real-time HR–MAS
NMR involving a heterogeneous catalyzed reaction. To establish
the utility of the technique, we opted for an otherwise simple
reaction so that the clarity of the outcome enables us to
justify our exploration. Formation of the privileged class of 2,2-
di-substituted quinazolin-4(3H)-ones from anthranilamide and
various ketones is an important and well-reported reaction
using various Lewis/Bronsted acids.[9] We observed that H2SO4
immobilized on silica is also capable of doing this transformation
smartly leading to excellent yield of the target in a practical time
frame and a much greener way. Thus, this reaction was chosen for
our study of real-time HR–MAS experiment monitoring. Here,
we report a novel application of HR–MAS NMR in reaction
optimization, mechanism elucidation and kinetic analysis for
heterogeneous reagent catalyzed synthesis of 2,2-di-substituted
quinazolin-4(3H)-ones.
Results and Discussion
Identical experiments were then performed using the higher
alkyl ketone analogue of ethyl propyl ketone and identical
results were obtained at room temperature. In this case, the time
taken for the reaction to complete was longer than the previous
one and the reaction was rather slow which provided us the
better overview of the initial process. The entire changes initially
observed in this case were in the ketone resonances rather than
in the anthranilamide resonances, which were again due to the
protonation of the ketone moiety first, supporting the second
mechanistic pathway and the final product was found to be
2-ethyl-2-propyl-2,3-dihydro-1H-quinazolin-4-one (3) (Scheme 2).
Successfulexecutionof thereal-timeHR–MAStechniqueforthe
reaction monitoring and evaluation of the mechanistic pathway
with alkyl ketones prompted us to investigate the reaction
involvinganaromaticketonealongwithitskineticanalysisinorder
toprovidequantitativeresultsforthereaction. Thusstoichiometric
amount of acetophenone was reacted with anthranilamide in
methanol using H2SO4 silica. The standardization of the reaction
was carried out in the HR–MAS rotor itself using in situ HR–MAS
experiments followed by the synthesis of the compound in the
wet lab. In the beginning, the reaction was performed at room
temperature using same amount of catalyst as used in the acetone
reaction but the reaction did not proceed for 3 h and only 20–25%
of the final product could be identified even after 8 h. Therefore,
in order to achieve the desired result while keeping same
amount of catalyst, the temperature of the reaction mixture was
standardizedwithanincrementof10 ◦Catatimeandtheoptimum
reaction temperature was found to be at 50 ◦C. In the next set
of experiments, the reaction was monitored at 50 ◦C and the
NMR analysis
The reaction was initially standardized using the commercially
available anthranilamide (1, 1 mmol) and acetone (1 ml) in the
presence of H2SO4 silica as the heterogeneous catalyst (10 mg)
in 10 ml of dry methanol. It showed complete conversion of
the starting material to a faster running component on TLC
within 10 min at room temperature (Scheme 1). The compound
was obtained in almost quantitative yield after filtration and
evaporation of the solvent and was confirmed to be the desired
2,2-di-methyl quinazolin-4(3H)-one (2) by NMR spectroscopy and
mass spectrometry. No traces of the starting material or any other
byproducts were detected. To get an insight into the mechanism
of this quinazolinone formation, the reaction was monitored by
real-time NMR measurements in HR–MAS probe using 50 µl of the
total reaction mixture under stoichiometric conditions (0.11 mmol
of anthranilamide, 10 µl of acetone and 1 mg of catalyst in 40 µl
of methanol-d4). The recording of the HR–MAS NMR spectra were
carried out as soon as the spinning speed was achieved (4.0 kHz)
without any further shimming. Hence, the time between sample
preparation and recording of the NMR spectra was approximately
between 1 and 2 min. Similar, real-time NMR measurements under
automation was also performed on 5-mm solution state probe
head in spinning as well as in nonspinning mode, but no mean-
ingful observation could be deciphered from the recorded data
because of initial inhomogeneity of the sample followed by the
nonisotropic mixing of the catalyst leading to incomplete reaction.
The NMR stack plots (Fig. 1) and their zoomed portions
(Fig. 1(a–e)) clearly indicate the formation of the intermediate
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Real time HR–MAS NMR in small molecule chemistry
(a)
Figure 1. Represents a stack plot of 27 NMR spectra out of 40 NMR data recorded at 4.0 kHz spinning rate under automation in 25 min time with eight
number of scans in each experiment. The first NMR spectrum represents anthranilamide and acetone resonances in the mixture prior to the addition of
the catalyst followed by real-time NMR spectra of the reaction with the catalyst until the completion of the reaction. The series of spectra provided the
snapshots of the mechanistic pathways of the reaction. The last spectrum represents the final product of the same sample after 25 min. (a) Expanded
region (1.30–1.20 ppm) of the stack plot of four NMR spectra of 0.0 , 2.0 , 25.0 and >25.0 min from Fig. 1. (b) Expanded region (1.60–1.40 ppm) of the
stack plot of four NMR spectra of 0.0 , 2.0, 25.0 and >25.0 min from Fig. 1. (c) Expanded region (8.50–5.50 ppm) of the stack plot of four NMR spectra of
0.0 , 2.0 , 25.0 and >25.0 min from Fig. 1. (d) Expanded region (2.20–2.00 ppm) of the stack plot of four NMR spectra of 0.0 , 2.0, 25.0 and >25.0 min from
Fig. 1. (e) Expanded region (5.10–4.65 ppm) of the stack plot of four NMR spectra of 0.0, 2.0 , 25.0 and >25.0 min from Fig. 1.
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A. D. Roy et al.
(b)
(c)
Figure 1. (Continued).
NMR spectra (Fig. 4) showed an immediate emergence of methyl
signal of the quinazolinone at 1.75 ppm, which subsequently
increased with time and was characterized as 2-methyl-2-phenyl-
2,3-dihydro-1H-quinazolin-4-one (4) (Scheme 3).
ꢀ
ꢁ
2.303
b0(a0 − x)
a0(b0 − x)
κA =
log10
dm3 mol−1 s−1
t(a0 − b0)
wherea0 andb0 aretheinitialconcentrationsoftheacetophenone
and anthranilamide, respectively and x is the amount of the
product formed at time t.
a0 − x and b0 − x are the concentration of acetophenone and
Kinetic and analysis
anthranilamide at time t.
The rate constant of the reaction between anthranilamide and
acetophenone was then determined using second-order rate
equation, a = b and [A] = [B].[10]
Becauseoftheabsenceofanystandardreferenceinthereaction,
change in concentration of the reactants and the product with
respect to time was calculated using the integral values of all
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Real time HR–MAS NMR in small molecule chemistry
(d)
(e)
Figure 1. (Continued).
the experiments by integrating the anthranilamide resonance at
6.72 ppm, acetophenone signal at 2.41 ppm, and the product
signal at 1.75 ppm. In this reaction almost 85% conversion was
clearly observed by simple visualization of the real-time HR–MAS
spectrum after 5 h. The percentage of the product formed was
found to be 83.99% by theoretical calculations and the results
were found to be similar when the reaction was carried out in the
wet lab in which the reaction provided 87% crude product in 4 h
time.
Subsequently the rate constant for the same reaction was
calculated by plotting[10] log[b0(a0 − x)/a0(b0 − x)] versus time
(t) in seconds. Though the plotted curve is discontinuous, the
reaction mainly follows second-order reaction mechanism with
the rate constant of 109 × 10−6 dm3 mol−1 s−1 as shown in Fig. 5.
Similarly, calculation of the rate constant at t−he1 middle of the
reaction showed it to be 108 × 10−6 dm3 mol s−1 which was
similar for the whole reaction. This indicates that the reaction
mainly follows second-order kinetics.
Figure 2. Buildup curve of the product 2,2-dimethyl-2,3-dihydro-1H-
quinazolin-4-one along with the decay curve of the reactant, acetone.
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A. D. Roy et al.
Figure 3. Plausible mechanisms of the acid-catalyzed quinazolinone formation.
1H/13C HR–MAS dual probehead equipped with magic angle
gradient in CD3OD in a two-dimensional format. Chemical shifts
are given on the ppm scale and are referenced to the TMS
at 0.00 ppm for proton and for 13C NMR spectra. In the one-
dimensional measurements (1H, 13C and DEPT) 32 K data points
were used for the FID. The pulse programs of the following 2D
experiments were taken from the Bruker software library and the
parameters were as follows.
Scheme 2. H2SO4-silica promoted reaction of anthranilamide with ethyl
propyl ketone.
300/75 MHz gradient HSQC spectra: relaxation delay d1 = 2 s;
evolution delay d2 = 3.44 ms; 90◦ pulse, 6.85 µs for 1H, 10 µs for
13C hard pulses at −3.0 dB and 60 µs for 13C Globally optimized
Alternating phases of Rectangular Pulses (GARP) decoupling with
gradient ratio GPZ1 : GPZ2 : GPZ3 = 50 : 30 : 40.1; 1024 data points
in t2; spectral width 9.0 ppm in F2 and 160 ppm in F1; number
of scans 32; 256 experiments in t1; linear prediction to 512; zero
filling up to 1 K and apodization with sine bell in both dimensions
prior to double Fourier transformation.
Moreover, the reaction of anthranilamide with acetophenone
wasalsocarriedoutatroomtemperatureusingdoubletheamount
of catalyst, which expectedly showed the protonation of the
ketone along with the emergence of Schiff base methyl signal, but
the reaction did not proceed further at this temperature. Thus, on
the basis of these results it was concluded that for the reaction to
move in forward direction from the Schiff base intermediate to the
final cyclized product a much higher temperature is required.
300/75 MHz gradient HMBC spectra: relaxation delay d1 = 2 s;
delay of the low-pass J-filter d2 = 3.44 ms; delay for evolution
of long-range coupling d6 = 71 ms with gradient ratio same as
HSQC; 2048 data points in t2; spectral width 11.0 ppm in F2 and
240 ppm in F1; number of scans 52; 256 experiments in t1; linear
prediction to 512; zero filling up to 2 K and apodization with
90◦ shifted square sine bell in F1 dimension and sine bell in F2
dimension prior to double Fourier transformation.
Conclusion
In summary, we have shown that the progress of a heterogeneous
reagent catalyzed reaction could be monitored using real-time
HR–MAS NMR spectroscopy. These observations open a new
avenue of 1H HR–MAS real-time monitoring of the reaction. The
results not only provided information about the completion of
the reaction but it also afforded the product yield, which could
be quantified using this technique. In addition, the monitoring
provided us an insight into the reaction, allowing a simple
evaluation of the reaction mechanism. This information is also
valuable when trying to optimize reaction conditions.
Generalprocedureforthesynthesisof2,2disubstitutedquinazolinone
To a solution of anthranilamide (200 mg, 1.5 mmol) and ketone
(1.5 mmol) in dry methanol (10 ml) was added H2SO4 silica (20 mg)
and the mixture was stirred at the required temperature until TLC
(1 : 1 n-hexane-ethyl acetate) showed complete conversion of the
starting material. The mixture was filtered through Celite and the
solvents were evaporated under reduced pressure. Compounds
thus obtained were analyzed by NMR spectroscopy and mass
spectrometry.
Experimental Section
General consideration
All the products were characterized by 1H, 13C, DEPT90,
DEPT135, two-dimensional heteronuclear single quantum coher-
ence (HSQC), heteronuclear multiple bond correlation (HMBC)
spectroscopy, Fast Atom Bombardment Mass Spectrometry (FAB-
MS). All the chemicals used in the study were purchased from
Sigma Aldrich.
The NMR spectra were recorded at 303 K using a Bruker
Avance 400 MHz and Avance DRX 300 MHz FT–NMR spectrometer
equipped with a 5-mm multinuclear inverse probe head with z-
shielded gradient. Time dependent HR–MAS 1H NMR experiments
were recorded with 400 MHz FT–NMR spectrometer using 4 mm
General procedure for the 1H HR–MAS NMR analysis
To a solution of anthranilamide (10 mg, 0.11 mmol) and ketone
(1.5 mmol, 10 µl in case of acetone) in deuterated methanol (40 µl)
was added H2SO4 silica (1 mg) in a 50 µl 4 mm HR–MAS rotor
and the rotor was sealed by spacer and screw cap. The HR–MAS
rotor was then directly inserted in the prior shimmed and tuned
4 mm 1H/13C HR–MAS dual probe. As soon as the spinning speed
(4.0 kHz) was achieved, recording of the NMR data was carried out
without further shimming of the probe for given time.
c
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Real time HR–MAS NMR in small molecule chemistry
Figure 4. One-dimensional stack plot of in situ 1H NMR experiments with anthranilamide and acetophenone in methanol-d4 in the presence of
stoichiometric amount of H2SO4 immobilized on silica. (a) Full spectrum; (b) and (c) expanded region.
c
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A. D. Roy et al.
Supporting information
Supporting information may be found in the online version of this
article.
Scheme 3. H2SO4-silica promoted reaction of anthranilamide with ace-
tophenone.
Acknowledgements
ADR and SD are thankful to CSIR and JK is thankful to DST, New
Delhi for providing fellowship.
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2-Ethyl-2-propyl-2,3-dihydro-1H-quinazolin-4-one (3)
311 mg (97% yield), 1H NMR (CDCl3, 300 MHz) δ = 0.89 (t(o),
J = 7.5 Hz, 3H, –CH3), 0.95 (t(o), J = 7.2 Hz, 3H, –CH3), 1.43 (m, 2H,
–CH2), 1.75 (m, 4H, 2x-CH2), 4.24 (s, 1H, –ArNH), 6.59 (d, J = 8.1 Hz,
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128.1, 133.8, 146.4, 164.6. HRMS calcd. For C13H18N2NaO (M + Na):
241.1317; found: m/z 241.1318.
2-Methyl-2-phenyl-2,3-dihydro-1H-quinazolin-4-one (4)
325 mg (93%yield), 1HNMR(CDCl3 +DMSO-d6, 300 MHz)δ = 1.80
(s,3H, –CH3),5.48(brs,1H,ArNH),6.65–6.71(m,2H,ArH),7.18–7.27
(m, 5H, ArH), 7.48 (d, J = 7.5 Hz, 2H, ArH), 7.74 (d, J = 7.5 Hz, 1H,
ArH) : 13C NMR (CDCl3 + DMSO-d6, 75 MHz) δ = 30.2, 70.7, 114.6,
115.2, 118.5, 125.2, 127.8, 128.1, 128.3, 133.7, 145.5, 146.1, 164.6.
HRMS calcd. For C15H14N2NaO (M + Na): 261.1004; found: m/z
261.1001.
[10] K. J. Laidler, Chemical Kinetics (3rd edn), Pearson Education:
Singapore, 2004, p 22.
c
www.interscience.wiley.com/journal/mrc
Copyright ꢀ 2008 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2008, 46, 1119–1126