A mechanistic study of carbonyl activation under solvent-free conditions: Evidence drawn from the synthesis of imidazoles

Article abstract of DOI:10.1039/c5ra16386b

Syntheses of various imidazoles and their derivatives, imidazole N-oxides and 1-hydroxyimidazole 3-oxides, from sterically different dicarbonyl moieties provided insights into the self-catalytic effect of the condensed phase reactions of carbonyl compounds. The self-catalytic activity in solvent-free multi-component syntheses was investigated using a combination of methods viz., reactivity, spectroscopy and theory. While IR spectroscopic studies revealed that reacting molecules were polarised in bulk, quantum mechanical calculations of associated HCHO monomers suggest an increase in the average dipole moment of each monomer and provide evidence for the presence of cooperative effects. A comparative study of the kinetics of un-catalysed and catalysed reactions with the help of HPLC provided insights into the mechanism.

Full text of DOI:10.1039/c5ra16386b

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A mechanistic study of carbonyl activation under
solvent-free conditions: evidence drawn from the
synthesis of imidazoles†
Cite this: RSC Adv., 2016, 6, 10743
Kiran Pradhan,a Bipransh Kumar Tiwary,b Mossaraf Hossain,a Ranadhir Chakrabortyb
a
*
and Ashis Kumar Nanda
Syntheses of various imidazoles and their derivatives, imidazole N-oxides and 1-hydroxyimidazole 3-oxides,
from sterically different dicarbonyl moieties provided insights into the self-catalytic effect of the condensed
phase reactions of carbonyl compounds. The self-catalytic activity in solvent-free multi-component
syntheses was investigated using a combination of methods viz., reactivity, spectroscopy and theory.
While IR spectroscopic studies revealed that reacting molecules were polarised in bulk, quantum
mechanical calculations of associated HCHO monomers suggest an increase in the average dipole
moment of each monomer and provide evidence for the presence of cooperative effects. A comparative
study of the kinetics of un-catalysed and catalysed reactions with the help of HPLC provided insights
into the mechanism.
Received 14th August 2015
Accepted 18th January 2016
DOI: 10.1039/c5ra16386b
www.rsc.org/advances
Lewis acids and organocatalysts have been shown to be
excellent catalysts for C–C bond forming reactions, and through
1 Introduction
carbonyl activation provide effective avenues for upgrading
classical MCRs. In particular, close attention has to be paid to
condensation reaction mechanisms that involve the activation
of carbonyl-containing electrophiles. The vast number of
investigations related to chemical transformation mediated by
organocatalysts22 or by Lewis acids in anhydrous organic
media,23 aqueous media24 and in the absence of any media25 has
provided a basic understanding of the intricate dynamics of
adduct formation between the acid and the carbonyl moieties
and has shed light on the role that these adducts have in
accelerating catalytic transformations. A noteworthy example is
the dramatic increase in reaction rates for the Radziwenski
synthesis attained by the activation of a carbonyl group by
a Lewis acid center25 or by a Lewis base center26 through the
formation of adducts.
The application of a solvent-free synthetic methodology for
organic compounds that were conventionally synthesized in
a solvent medium has become more common in recent years.1
Thus, well-known organic reactions such as the aldol,2 Claisen,3
Stobbe4 and Knoevenagel condensations,5 the Thorpe,6
Tischenko,7 Reformatsky and Luche reactions,8 the Baeyer–Vil-
liger oxidation,9 the pinacol rearrangement10 and the oxidative
coupling of phenols,11 just to name a few, have been found not
only to occur under solvent-free conditions but are more effi-
cient than reactions in solution. In addition to the simplicity
and cleanness of the procedure, the absence of any media has
been found to lead to uncommon reactivities. Apart from these
efforts, over the past two decades organic synthesis has been
devoted to extending the scope of solvent free reactions, notably
for newer multi-component reaction (MCR) strategies.12
Solvent-free protocols have already been developed for almost
all the classical multi-component reactions namely the
Strecker,13 Hantzsch,14 Biginelli,15 Mannich,16 Passerini,17 Ugi,18
Gewald,19 Petasis,20 Radziwenski synthesis,21 and so on. And to
impart greater reactivity to the substrates and the reagents,
these synthetic protocols have constructively exploited the use
of transition metal catalysts and the very recent organocatalysts.
In the present study we have attempted to explore in some
details the mechanistic insight for better reaction under
solvent-free condition compared to reactions in solution. Here
we have chosen a well-studied method for imidazole synthesis.
2 Experimental
The compounds 1a–1i, 2a–2l, 3a–3g, 4a–4g and 5a–5e were all
prepared under solvent-free conditions. All other reagents are
commercially available and were used as purchased from the
supplier. Grinding experiments were performed with an agate
mortar and pestle, which was acetone rinsed and dried prior to
use. The yield of the reaction was determined by the product
peak area count in HPLC analysis with respect to the puried
aDepartment of Chemistry, University of North Bengal, Darjeeling, India, 734013.
E-mail: ashis_nanda@hotmail.com; Tel: +91-9474329191
bDepartment of Biotechnologyy, University of North Bengal, Darjeeling, India, 734013
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c5ra16386b
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product. NMR spectra were recorded on Bruker Avance 300 precipitate formed. To the black precipitate was then added
spectrometer chemical shis (d in ppm) were referenced to a small volume of diethyl ether when a brown precipitate
external SiMe4. IR spectra were recorded on a FTIR-8300 SHI- separated. The precipitate was then thoroughly washed with
MADZU spectrophotometer. Analytical thin-layer chromatog- ethyl acetate, dissolved in ethanol and crystallized by addition
raphy was performed using silica gel aluminium sheets (Merck, of water to yield pure products.
TLC silica gel 60 F254). HPLC was performed on a Waters-2487
Dual Lambda absorber with a RP-18 (Symmetry Shield) column.
The solvent used was methanol with a ow rate of 0.5 ml minꢀ1
2.5 General procedure for the synthesis of N-substituted
imidazole-1-oxide (4a–4g)
.
In all experiments the same column and same ow rate was
maintained. The electrospray mass spectra were recorded on
a MICROMASS QUATTRO II triple quadruple mass spectrom-
eter. The ESI capillary was set at 3.5 kV and cone voltage was 40
V. X-Ray diffraction data was collected on a Bruker APEX CCD-II
diffractometer at 293 K. The structure was solved by a direct
method using the program SHELXS-97.27
1 mmol of the monoxime, 1 mmol of the aldehyde and 1.5
mmol of the amine was ground for 2 minutes and subsequently
heated in an oil bath at 115–120 C, when a melt was formed.
Aer a further 8 minutes of heating, the completion of the
reaction was indicated by TLC. On cooling the melt slowly
solidied and to the product so formed was added a little
amount of ether whereby a precipitate was obtained. The
precipitate was further washed with hot ethyl acetate. Recrys-
tallization from ethanol gave products with the same melting
points.
ꢁ
2.1 Computational details
The optimized geometry and the energy of each monomer were
calculated using the CBS-QB3 model chemistry. The CBS-QB3
model chemistry28 was employed for the calculation of the
molecular structures since this method is known to predict
thermochemical parameters with high accuracy.29 Molecular
geometry was fully optimized and harmonic vibrational
frequencies were calculated using the analytic second deriva-
tives to conrm the convergence to minima on the potential
surface. All the calculations were carried out using the Gaussian
98 suite of programs.30
2.6 General procedure for the synthesis of 1-hydroxy
imidazole-3-oxide (5a–5e)
2 mmol each of the monoxime and the aldehyde was thoroughly
ground with 695 mg (10 mmol) of hydroxylamine hydrochloride
in an agate mortar and pestle for a period of ca. 3 minutes
during which it melts and then gets hardened slowly. The
mixture was then transferred to a test tube and heated in an oil
bath maintained at 110–120 ꢁC when it started to melt.
Constant shaking for another 7 minutes gave the product which
remained in the melt form even at room temperature. On
completion of the reaction, checked by TLC, addition of 5 ml of
diethyl ether or 5 ml of ethyl acetate precipitated the product.
The water insoluble products were then washed with water and
ethyl acetate to get the pure products.
2.2 General procedure for the synthesis of 2,4,5-
trisubstituted imidazoles (1a–1i)
210 mg (1 mmol) of benzil, 1 mmol of the corresponding
aldehyde and 770 mg (10 mmol) of ammonium acetate was
taken in an agate mortar and thoroughly ground. The contents
ꢁ
were transferred to a test tube and heated to 150–160 C for 4
minutes. The contents were cooled and water was added to the 3 Results and discussion
test tube and ltered. The product was recrystallised from
ethanol. Completion of the reaction was checked by TLC.
The Radziwenski Imidazole (R-I) synthesis is a very useful
preparative method for imidazole and its derivatives. The
manifold utilizes a diketone, an aldehyde and ammonium
acetate as the ammonia source (Scheme 1). The pure products
have been synthesized in quantitative yields in 4 minutes at the
given temperature by heating in an oil bath under solvent-free
conditions. The temperature conditions and product yield
were optimised by HPLC studies (ESI†).
2.3 General procedure for the synthesis of 1,2,4,5-
tetrasubstituted imidazoles (2a–2l)
210 mg (1 mmol) of benzil, 1 mmol of aldehyde, 1 mmol of
primary amine and 385 mg (5 mmol) of ammonium acetate was
taken in an agate mortar and thoroughly ground. The contents
were transferred to a test tube and heated to 150–160 ꢁC for
4 minutes. The contents were cooled and water was added to the
test tube and ltered. The product was recrystallised from
ethanol. Completion of the reaction was checked by TLC.
Besides usual spectroscopic methods for determining the
structure, we have used single crystal X-ray diffraction (Sc-XRD)
2.4 General procedure for the synthesis of imidazole N-oxide
(3a–3g)
1 mmol of the monoxime, 1 mmol of the aldehyde and 385 mg
(5 mmol) of ammonium acetate was ground into an intimate
mixture in an agate mortar and pestle. The mixture was then
ꢁ
heated to 115–120 C in an oil bath with constant shaking. A
black solution resulted which was cooled when a black sticky Scheme 1 R-I synthesis of tri-substituted imidazoles (1a–1i).
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data of one of the representative compounds, 4,5-diphenyl-1H-
imidazole, 1i, to conrm the structure. The single crystals of the
compound suitable for Sc-XRD were obtained by the slow
evaporation from methanol/hexane mixture. The compound
crystallizes in a monoclinic crystal system with the space group
˚
˚
P21/c (Hall group ꢀP2ybc); a ¼ 11.0471(4) A, b ¼ 9.2483(3) A, c ¼
ꢁ
ꢁ
ꢁ
˚
11.5780(4) A, a ¼ 90 , b ¼ 93.921(3) , g ¼ 90 , Z ¼ 4, m ¼ 0.577
mmꢀ1, F000 ¼ 468.0 and Ka ¼ 1.54184 A. The ORTEP diagram is
˚
presented in Fig. 1. The heterocyclic ring is planar. One inter-
esting point in the diagram is the attachment of one proton in
each nitrogen atom which reects overall an excess of one
proton. The N7–C11 and N9–C10 bond distances are identical
Scheme 2 R-I synthesis of tetra-substituted imidazoles (2a–2l).
for 10 min also gave the corresponding imidazole N-oxides (3a–
3g), N-substituted imidazole N-oxides (4a–4g) and 1-hydroxy
imidazole 3-oxide derivatives (5a–5e) in quantitative yields
(Scheme 3). This is the rst report of a solvent-free condensed
phase protocol for the oxide and hydroxyl oxide derivatives of
imidazoles. Apart from the usual characterizations of the
compounds, further spectroscopic investigations, vibrational
assignments, HOMO–LUMO, NBO and MEP analysis of two of
the synthesized compounds 3a32 and 3c33 have already been
done and reported. The syntheses also proves that acetic acid,
generated in situ in the reaction, is not the only catalysing factor
for enhancing the reaction rates under solvent-free conditions.
In order to understand, at least partially, why these reactions
proceed so efficiently under solvent-free conditions, a combi-
nation of methods viz., reactivity, spectroscopy and theory have
been used.
˚
˚
(1.380 A and 1.3799 A respectively), similarly N7–C8 and N9–C8
˚
˚
bond distances are also close (1.3157 A and 1.3462 A respec-
tively); corresponding N7 and N9 centered bond angles are also
close (107.83ꢁ and 105.91ꢁ).
Intermolecular extra proton transfer rate in imidazole is re-
ported in the order of 0.3 ꢂ 10ꢀ12 second31 but there is no such
data for intramolecular N to N proton transfer due to the shi of
N–C double bond in imidazole; intuitively it is difficult to say
that the process could be faster than X-ray diffraction time
(10ꢀ18 second). However, the bond lengths are in between C–N
single bond (1.47 A) and double bond (1.25 A). Since both the
nitrogen atoms are identical, and on probability basis H atoms
might have added to both the atoms during computation. The
extra proton does not originate from the imidazolinium salt
because in such case the counter ion should be in the unit cell;
and non equivalence of the nitrogen atoms would have been
observed.
However, these reactions are not very efficient in solution,
and the yield of product is not very high. Existing literature
reveals that the Debus–Radziszewski imidazole synthesis in
solution state takes around 24 h to achieve moderate to good
yield.25 By contrast, solvent-free reactions proceed efficiently
under much simpler conditions to give products in quantitative
yield (Scheme 2).
˚
˚
3.1 Kinetic studies
Firstly, the reaction kinetics of imidazoles 1b and 1c were
studied through HPLC monitoring of benzil and aldehyde
(reactants) consumption along with product (imidazoles)
formation. A good linearity was observed in each case with the
plots of natural logarithm values (ꢀve for the reactants and +ve
for the products) of peak area against time. From the slope of
Interestingly, very similar solvent-free reactions of various
ammonia derivatives and alkyl/aryl monoximes at 115–120 C
these curves the rst order rate constants and half lives (t1/2
were determined. The observed dependence of reactants'
concentrations (logarithm) and product formation with the
)
ꢁ
Scheme 3 Analogous R-I synthesis of imidazole N-oxides (3a–3g), N-
substituted imidazole N-oxides (4a–4g) and 1-hydroxy imidazole 3-
oxides (5a–5e).
Fig. 1 ORTEP diagram of 1i derived from single crystal data.
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ꢁ
variation of time (at reaction temperature 125 C, temperature increase in the rate of benzil consumption and vefold increase
optimised for maximum conversion) is shown in Fig. 2. The in imidazole formation as against the catalyst free reaction was
product peak in HPLC was not much prominent within the rst observed. Considering that in a reaction, catalysts in general,
10 minutes. This information helps to understand more about are used in very small proportions. Therefore only a small mole-
the sequences of reactions which manifest together as a multi- fraction of the substrate would have the chance to be associated
component reaction.
with the catalyst and thus the probability of the substrate taking
The catalytic effect of some metal salts (5 mol%) at the same part in adduct formation would be further reduced. Hence with
reaction temperature (125 ꢁC) was also compared. The corre- only traces of a catalyst (5 mol% in the present case) added to
sponding rate constant and half life values are shown in Table 1. a reaction, its rate should have hardly been affected as only
The general catalytic process at the molecular level maybe a few molecules would engage in the activated complex in
represented as in Scheme 4.
comparison to the vast number of un-associated molecules in
The compiled results indicate that the catalysts acted at the reaction media. We also studied the reactions at different
different stages of the reaction sequences of the MCR reaction. elevated temperatures and found that at the temperature range
To cite a representative case of ytterbium triate, a threefold 150–160 ꢁC, almost quantitative products formed in a very short
time of 4 minutes; and that too without using any catalyst. This
is a landmark record in imidazole synthesis (ESI†).
3.2 Infrared studies
In order to contemplate the cause behind the efficacy in solvent-
free procedure; we studied the IR-spectra of pure benzil in thin
lm as well as that with catalyst. The carbonyl region of a benzil
thin lm and that with 5 mmol% of ytterbium triate has been
presented in Fig. 3. It was observed that the free carbonyl band
(with catalyst) at 1676 cmꢀ1 has apparently increased in inten-
sity with concomitant shi to lower frequency compared to the
corresponding band for benzil. It was earlier reported34 that
C]O stretching band of benzil appears at 1676 cmꢀ1 in the
Fig. 2 (ꢀve)/(+ve) ln(I) vs. time (mins) of [i] benzil during formation of
crystalline state and at 1685 cmꢀ1 in solution.
imidazoles (1b) and (1c); [ii] rate curve of the product imidazoles (1b)
and (1c) formation; I ¼ peak area.
As the catalyst caused a red-shi and brought about
enhancement in intensity, we have considered this phenom-
enon as a marker of catalytic effect. Similar shi of carbonyl
stretching frequency for benzophenone in TiO2 surface has also
been reported.35 The difference in stretching frequency (9 cmꢀ1
red-shi) indicates a greater degree of single bond character in
the C]O bond (polarisation enhancement) in the solid state
compared to that in the solution state for benzil. The red-shi of
carbonyl stretching provides an indication of bulk polarization
of benzil in the solid state and similar effect is also observed
with catalysts in the solid state.
Table 1 Rate constants and half lives of reactant consumption and
product formation at 125 ꢁC under solvent-free conditions
Rate of benzil Rate of aldehyde Rate of product
consumption
consumption
(t1/2
formation
(t1/2
a
Catalyst
(t1/2
)
)
)
Solvent-free
(no catalyst)
0.011 (63.01)
0.008 (86.64)
0.026 (26.66)
Sm(NO3)3$6H2O 0.012 (57.76)
0.008 (86.64)
0.009 (77.02)
0.017 (40.77)
0.024 (28.88)
0.021 (33.00)
0.023 (30.13)
0.115 (6.03)
0.034 (20.38)
0.112 (6.19)
0.041 (16.90)
The extent of the shi caused by the presence of trace
amounts of zirconyl nitrate and ytterbium triate on benzil
Yb(SO3CF3)3
ZrO(NO3)2
(NH4)2Ce(NO3)6
NiCl2$6H2O
0.033 (21.00)
0.058 (11.95)
0.035 (19.80)
0.032 (21.66)
a
Note: half-life (t1/2) in minutes.
Scheme 4 Mechanism of the R-I synthesis.
10746 | RSC Adv., 2016, 6, 10743–10749
Fig. 3 IR spectra of benzil thin film, with and without a catalyst.
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carbonyl stretching frequency in hexane solution was also
studied. The IR spectra in the carbonyl range have been pre-
sented in Fig. 4.
It was found that in the solution spectra, the free carbonyl
peak at 1685 cmꢀ1 and all other associated peaks showed a little
amount of red-shi in the presence of a catalyst. In addition to
this, there was concomitant diminishing of the intensity of the
free carbonyl peak with increasing intensities of some other
peaks at lower frequencies (particularly the peak at 1680 cmꢀ1
)
in the presence of traces of catalyst. It is also apparent that the
catalyst, zirconyl nitrate, caused a little bit more polarization
than that with ytterbium triate. Notably we have found that the
catalytic effect of zirconyl nitrate is a bit greater for benzil
consumption rate as well (Table 1). The conspicuous enhance-
ment of the band at 1680 cmꢀ1 in the presence of catalyst in
both solution state and in solid state is observed. The peak at
1680 cmꢀ1 has been described as another C]O stretching band
associated with the different symmetry of the molecule.36
Enhancement of the band near 1680 cmꢀ1 in presence of
catalyst suggests that the catalysts not only polarize the carbonyl
but also inuence the conformation of benzil. The IR spectro-
scopic investigation thus strongly provides evidences in favour
of bulk polarization in the condensed phase which conse-
quently leads to the enhancement of the electrophilicity of the
carbonyl carbon. The above observation suggests that catalysts
bind to the carbonyl oxygen and the weak interaction activates
the carbonyl group with the enhancement of polarization.
Fig. 5 Minimum energy models with partial charges.
Table 2 Mulliken atomic charges, dipole moment and C–O bond
distances in monomers and trimer from the CBS-QB3 modela
Parameter
Monomer
Trimer
Mulliken charge at C (au)[a]
Mulliken charge at O (au)[a]
Dipole moment (Debye)
C–O bond distance (A)
Symmetry
0.316740
ꢀ0.316740
2.8542
1.20001
C2v
0.372316
ꢀ0.372316
3.2133[b]
1.20259
C1
˚
Note: [a]atomic charges with hydrogens summed into heavy atoms;
a
[b]average value.
It is evident that the atomic charges in the associated
monomers are different to those in the isolated free monomer,
indicating a sizeable charge reorganisation due to the associa-
tion. These may be interpreted as atomic expressions of sizeable
cooperative effects. This charge reorganization in the carbonyls,
as a consequence, brings about enhanced polarization in the
carbonyl groups in their environment as the partial charges
increase in each atom. A seminal report has already established
the possibility of a dipole–dipole type of intermolecular inter-
action and the occurrence of little or no H-bond in formalde-
hyde itself.37
The theoretical ab initio calculation of conformationally
similar formaldehyde dimer was done by Smith et al.,38 whereby
they have shown that an excess electron can attach to the system
forming a dipole bound anion. This work indirectly supports
our proposition as well, to the cause of enhancement in elec-
trophilic behavior of the carbonyl group under solvent-free
condition. The theoretical results also suggest that, as a result
of the cooperative effect of very weak forces a bulk amount of
carbonyl groups get activated. Therefore, the activation can be
attributed to a unique spatial organization of the carbonyl
moieties. This would be best understood if we consider an
arbitrary molecular assembly where polarization transfer
through a non-covalent bond (weak bond interactions) could
well be conceived of as shown in Scheme 5.
3.3 Computational studies
As further proof of concept, the CBS-QB3 model chemistry
calculations of a HCHO monomer and trimer were performed.
Geometry optimization for a linear arrangement of the trimer
was done as shown in Fig. 5. In molecular association a number
of minimum energy conformations with different geometries
are feasible, we searched for minimum energy in linear
arrangement and our calculation terminated on convergence to
such minima.
The partial charges on the carbon and the oxygen atom and
the dipole moment of the associated monomer are found to be
enhanced as we move from the monomer to the trimer
(Table 2).
This pseudo-conjugated pi-system in the proposed supra-
molecular assembly makes the system more chemically so
(more polarizable) compared to a free carbonyl which is also
responsible for better reactivity in solvent free reaction media.
Hence, considerable catalytic action became viable in
condensed phase. Since, in such an assembly a set of reacting
Fig. 4 Solution IR spectra in the carbonyl range of benzil in hexane.
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catalytic effect. This phenomenon can be well utilized to
generate a self-catalytic effect without using any catalytic
substance.
Acknowledgements
The author gratefully acknowledges IISER, Kolkata for the
Single crystal X-ray studies and CDRI, Lucknow for elemental
analysis and mass spectra. The authors are also thankful to Dr
Anirban Misra, Professor and Mr Tamal Goswami, Reseach
Associate, Department of Chemistry, N.B.U for the computa-
tional calculations.
References
Scheme 5 Polarization transfer through a non-covalent bond without
1 K. Tanaka and F. Toda, Chem. Rev., 2000, 100, 1025; F. Toda,
CrystEngComm, 2002, 4, 215; G. W. V. Cave, C. L. Raston and
J. L. Scott, Chem. Commun., 2001, 2159; G. Rothenberg,
A. P. Downie, C. L. Raston and J. L. Scott, J. Am. Chem.
Soc., 2001, 123, 8701; G. W. V. Cave and C. L. Raston,
Chem. Commun., 2000, 2199; V. P. Balema, J. W. Wiench,
M. Pruski and V. K. Pecharsky, Chem. Commun., 2002, 724.
2 F. Toda, K. Tanaka and K. Hamai, J. Chem. Soc., Perkin Trans.
1, 1990, 3207.
3 K. Yoshizawa, S. Toyota and F. Toda, Tetrahedron Lett., 2001,
42, 7983.
4 K. Tanaka, T. Sugino and F. Toda, Green Chem., 2000, 2, 303.
5 G. Kaupp, M. R. Naimi-Jamal and J. Schmeyers, Tetrahedron,
2003, 59, 375.
6 K. Yoshizawa, S. Toyota and F. Toda, Green Chem., 2002, 4,
68.
7 D. C. Waddell and J. Mack, Green Chem., 2009, 11, 79.
8 K. Tanaka, S. Kishigami and F. Toda, J. Org. Chem., 1991, 56,
4333.
9 F. Toda, M. Yagi and K. Kiyoshige, J. Chem. Soc., Chem.
Commun., 1988, 958.
10 F. Toda and T. Shigemasa, J. Chem. Soc., Perkin Trans. 1,
1989, 209.
and with a catalyst.
molecules participates in a cycle, the process undoubtedly
becomes faster. In addition to this self-activating effect, if some
oxyphilic substance were present in catalytic amount it bonded
to the terminal carbonyl oxygen affecting further activation of
the trail of carbonyls and thereby resulting in further
enhancement of the catalytic effect (Scheme 5). The present
work emphasizes on meeting this challenge of using weak
forces as a design tool for imparting new properties and
performance in molecules and materials.
The present work incorporates the concept of constitutional
dynamic chemistry to resolve the existing paradox in the
process of catalysis (involving carbonyl activation). According to
Prof. Lehn, supramolecular entities are assembled entities of
discrete number of molecular sub-units held together reversibly
through weak interactions (non-covalent interactions).39 When
extended to the carbonyl system, one could conceive the
carbonyl molecular sub-units to be held together through
similar type of weak interactions, by virtue of it being polar. In
our opinion this hypothesis unequivocally embraces all the
catalytic effects on carbonyls in solution state as well as in
solvent-free molten state. As a proof of concept, we have re-
ported herein the un-catalyzed Radziwenski synthesis of imid-
azole and its derivatives under solvent-free conditions
employing a multicomponent protocol.
11 F. Toda, K. Tanaka and S. Iwata, J. Org. Chem., 1989, 54, 13.
12 N. Elders, D. van der Born, L. J. D. Hendrickx, B. J. J. Timmer,
A. Krause, E. Janssen, F. J. J. de Kanter, E. Ruijter and
R. V. A. Orru, Angew. Chem., Int. Ed., 2009, 48, 5856.
13 B. Karimi and D. Zareyee, J. Mater. Chem., 2009, 19, 8665;
H. Wang, X. Zhao, Y. Li and L. Lu, Org. Lett., 2006, 8(7),
1379; P. Galletti, M. Pori and D. Giacomini, Eur. J. Org.
Chem., 2011, 3896.
4 Conclusions
The polarizability of organized carbonyl functionalities in 14 M. A. Zolgol, E. Kolvari, A. Abdoli and M. Shiri, Mol.
condensed phase contributes for the observed self-catalysis.
High yields of many different imidazoles were obtained from
the simply mechanical grinding and heating of MCR starting
materials, even in the absence of Lewis acid catalysts. The very
Diversity, 2010, 14(4), 809; V. Sivamurugan, R. S. Kumar,
M. Palanichamy and V. Murugesan, J. Heterocycl. Chem.,
2005, 42(5), 969; G. V. M. Sharma, K. L. Reddy,
P. S. Lakshmi and P. R. Krishna, Synthesis, 2006, 55.
weak dipole of carbonyls can induce polarization in bulk 15 F. Bigi, S. Carloni, B. Frullanti, R. Maggi and G. Sartori,
because the carbonyl bonds are very much polarisable and the
net result is the enhancement of electrophilicity of carbonyls. In
polar solvents, the weak but favorable conformation of the
Tetrahedron Lett., 1999, 40(17), 3465; J. Peng and Y. Deng,
Tetrahedron Lett., 2001, 42(34), 5917; R. Wang and Z. Liu, J.
Org. Chem., 2012, 77(8), 3952.
carbonyl cluster expectedly breaks due to stronger solute– 16 L. el Kaim, L. Gautier, L. Grimaud, L. M. Harwood and
solvent interactions. Thus solvents act adversely to the self-
V. Michaut, Green Chem., 2003, 5, 477; Y. Hayashi,
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RSC Advances
T. Urushima, S. Aratake, T. Okano and K. Obi, Org. Lett., 25 S. D. Sharma, P. Hazarika and D. Konwar, Tetrahedron Lett.,
2008, 10(1), 21. 2008, 49, 2216.
17 D. Koszelewski, W. Szymanski, J. Krysiak and 26 S. Samai, G. C. Nandi, P. Singh and M. S. Singh, Tetrahedron,
R. Ostaszewski, Synth. Commun., 2008, 38(7), 1120; 2009, 65, 10155.
T. Bousquet, M. Jida, M. Soueidan, R. Deprez-Poulain, 27 G. M. Sheldrick, SHELXS-97, University of Gottingen, 1997.
F. Agbossou-Niedercorn and L. Pelinski, Tetrahedron Lett., 28 J. A. Montgomery, M. J. Frisch, J. W. Ochterski and
2012, 53(3), 306.
18 N. Liu, S. Cao, J. Wu, J. Yu, L. Shen, X. Feng and X. Qian,
Tetrahedron, 2008, 64, 3966; L. El Kaim, L. Grimaud and
G. A. Petersson Jr, J. Chem. Phys., 2000, 112, 6532;
J. A. Montgomery, M. J. Frisch, J. W. Ochterski and
G. A. Petersson Jr, J. Chem. Phys., 1999, 110, 2822.
S. Hadrot, Tetrahedron Lett., 2006, 47(23), 3945; M. Jida, 29 L. A. Curtiss, K. Raghavachari, G. W. Trucks and J. A. Pople, J.
S. Malaquin, R. Deprez-Poulain, G. Laconde and B. Deprez,
Tetrahedron Lett., 2010, 51(39), 5109.
19 J. S. B. Forero, E. M. de Carvalho, J. J. Junior and F. M. da
Silva, Heterocycl. Lett., 2011, 1(1), 61; K. Wang, D. Kim and
A. Domling, J. Comb. Chem., 2010, 12, 111.
Chem. Phys., 1991, 94, 7221; L. A. Curtiss, K. Raghavachari,
P. C. Redfern, V. Rassolov and J. A. Pople, J. Chem. Phys.,
1998, 109, 7764; J. W. Ochterski, G. A. Petersson and
J. A. Montgomery, J. Chem. Phys., 1996, 104, 2598;
G. A. Petersson, D. K. Malick, W. G. Wilson,
J. W. Ochterski, J. A. Montgomery and M. J. Frisch, J.
Chem. Phys., 1998, 109, 10570.
20 P. Nun, J. Martinez and F. Lamaty, Synthesis, 2010, 12, 2063.
21 B. Jiang, X. Wang, F. Shi, S.-J. Tu, T. Ai, A. Ballew and G. Li, J.
Org. Chem., 2009, 74, 9486; G. Bratulescu, Synthesis, 2009, 30 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria and
2319; X. Diao, Y. Wang, Y. Jiang and D. Ma, J. Org. Chem.,
2009, 74, 7974; T. Horneff, S. Chuprakov, N. Chernyak,
M. A. Robb, et al., Gaussian 09, Revision A.11.4, Gaussian,
Inc., Pittsburg PA, 2002.
V. Gevorgyan and V. V. Fokin, J. Am. Chem. Soc., 2008, 130, 31 W. Munch, et al., Solid State Ionics, 2001, 145, 437.
14972; P. Saha, T. Ramana, N. Purkait, M. A. Ali, R. Paul 32 K. B. Benzon, H. T. Varghese, C. Y. Panicker, K. Pradhan,
and T. Punniyamurthy, J. Org. Chem., 2009, 74, 8719;
M. M. Heravia, M. Zakeria, N. Karimia, M. Saeedia,
B. K. Tiwary, A. K. Nanda and C. V. Alsenoy, Spectrochim.
Acta, Part A, 2015, 151, 965.
H. A. Oskooiea and N. T. Hosienib, Synth. Commun., 2010, 33 K. B. Benzon, H. T. Varghese, C. Y. Panicker, K. Pradhan,
40, 1998; K. Hirano, S. Urban, C. Wang and F. Glorius, Org.
Lett., 2009, 11, 1019.
B. K. Tiwary, A. K. Nanda and C. V. Alsenoy, Spectrochim.
Acta, Part A, 2015, 146, 307.
22 P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2004, 43, 34 E. C. Lee, D. Kim, P. Jurecka, P. Tarakeshwar, P. Hobza and
5138; D. Basavaiah, A. J. Rao and T. Satyanarayana, Chem. K. S. Kim, J. Phys. Chem. A, 2007, 111, 3446.
Rev., 2003, 103, 811; P. Langer, Angew. Chem., Int. Ed., 35 L. Colombo, D. Kirin, V. Volovsek, N. E. Lindsay,
2000, 39, 3049–3052; H. Groger and J. Wilken, Angew. J. F. Sullivan and J. R. Durig, J. Phys. Chem., 1989, 93, 6290.
Chem., Int. Ed., 2001, 40, 529; J. W. J. Kennedy and 36 L. M. Babkov, T. V. Bezrodnaya, G. A. Puchkovskaya,
D. G. Hall, Angew. Chem., Int. Ed., 2003, 42, 4732; B. List,
Tetrahedron, 2002, 58, 5573.
K. E. Uspenskii and V. V. Shimanovaskaya, J. Struct. Chem.,
2008, 49, 517.
23 M.-O. Simon and C.-J. Li, Chem. Soc. Rev., 2012, 41, 1415.
24 C.-J. Li, Chem. Rev., 2005, 105, 3095; Y. R. Leshkov and
37 T. Bercovici, J. King and R. S. Becker, J. Chem. Phys., 1972, 56,
3956; J. E. D. Bene, J. Chem. Phys., 1971, 60, 3812.
M. E. Davis, ACS Catal., 2011, 1, 1566; F. Cruz-Acosta, 38 M. A. Dayle, J. S. Smith, Y. Elkadi and L. Adanokicz, Chem.
A. Santos-Exposito, P. de Armas and F. Garcia-Tellado, Phys. Lett., 1999, 305, 169.
Chem. Commun., 2009, 6839; R. N. Butler and A. G. Coyne, 39 J. M. Lehn, Angew. Chem., Int. Ed., 1990, 29, 1304.
Chem. Rev., 2010, 110, 6302.
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