Supramolecular assemblies in ionic liquid catalysis for aza-michael reaction

Article abstract of DOI:10.1021/ol101557t

Supramolecular assemblies formed by a relay of cooperative hydrogen bonds and charge-charge interactions have been identified/characterized by (+ve) ESI and MALDI-TOF-TOF MS and MS-MS studies during the aza-Michael reaction of amines with α,β-unsaturated

Full text of DOI:10.1021/ol101557t

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3866-3869
Supramolecular Assemblies in Ionic
Liquid Catalysis for Aza-Michael
Reaction
Sudipta Raha Roy and Asit K. Chakraborti*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education
and Research (NIPER), Sector 67, S. A. S. Nagar 160 062, Punjab, India
akchakraborti@niper.ac.in; akchakraborti@rediffmail.com
Received July 7, 2010
ABSTRACT
Supramolecular assemblies formed by a relay of cooperative hydrogen bonds and charge-charge interactions have been identified/characterized
by (+ve) ESI and MALDI-TOF-TOF MS and MS-MS studies during the aza-Michael reaction of amines with r,ꢀ-unsaturated carbonyl compounds
in the presence of ionic liquids (ILs) digging out the role of catalysis by ILs, forming the basis of rational design/selection as organocatalysts,
and offering a diagnostic model to predict/rationalize the selectivity of the aza-Michael reaction in a competitive environment.
Weak intermolecular forces, particularly hydrogen bonds
(H-Bs), are harnessed by Nature to construct supramolecular
structures that are essential in the life process. In utilizing
weak intermolecular forces, efforts are made to visualize/
generate hydrogen-bonded self-assembly as the active species
in organocatalysis.1 However, organocatalysis mediated through
supramolecular assembly of small molecules formed by a
network of H-Bs and charge-charge interaction remains
underexplored.2 Identification and characterization of such
discrete entities that would provide a molecular level under-
standing of the mechanism of organocatalysis and form the basis
of rational design of organocatalyst is a challenging task.
and to assess their utility as aza-Michael adducts, which are
versatile synthetic intermediates.4 The catalytic potential of
a panel of 1-butyl-3-methylimidazolium (bmim)-based room-
temperature ionic liquids (RTILs) was tested for the reaction
of 1,3-diphenyl-2-propenone 1a with aniline 2a.5 The RTIL
[bmim][MeSO4] was found to be most effective and afforded
the desired aza-Michael adduct 1,3-diphenyl-3-(phenylami-
no)propanone 3a in high yield (Table 1). The catalytic power
of the ILs is markedly influenced by the counteranion,
and a drastic decrease in the catalytic efficiency was
observed when the C-2 hydrogen of the bmim cation was
substituted with a methyl group (compare entries 7 and
19, Table 1).
Toward this directive, we set forth to assess the organo-
catalytic efficiency of ionic liquids (ILs) for aza-Michael
addition due to its biochemical and synthetic importance as
the key step in the synthesis of bioactive natural products3
The molecular level interaction of the ILs with the
substrates is envisaged through the formation of the su-
pramolecular assembly A (Scheme 1) involving a relay of
(1) (a) Uraguchi, D.; Ueki, Y.; Ooi, T. Science 2009, 326, 120–123. (b)
Clarke, M. L.; Fuentes, J. A. Angew. Chem., Int. Ed. 2007, 46, 930–933.
(2) (a) Chakraborti, A. K.; Raha Roy, S. J. Am. Chem. Soc. 2009, 131,
6902–6903. (b) Chakraborti, A. K.; Raha Roy, S.; Kumar, D.; Chopra, P.
Green Chem. 2008, 10, 1111–1118.
(4) (a) Cardillo, G.; Tomasini, C. Chem. Soc. ReV. 1996, 117–128. (b)
Yamada, M.; Nagashima, N.; Hasegawa, J.; Takahashi, S. Tetrahedron Lett.
1998, 39, 9019–9022. (c) Juarisiti, E.; Lopez-Ruitz, H. Curr. Med. Chem.
1999, 6, 983–1004.
(5) The reaction of an aryl amine with 1,3-diarylpropenone is difficult
to perform: Yang, L.; Xu, L.-W.; Zhou, W.; Li, L.; Xia, C.-G. Tetrahedron
Lett. 2006, 47, 7723–7726. That difficulty makes this reaction a model study
to assess the catalytic efficiency of ILs.
(3) (a) Ihara, M. Chem. Pharm. Bull. 2006, 54, 765–774. (b) Chan-
drasekhar, S.; Reddy, N. R.; Rao, Y. S. Tetrahedron 2006, 62, 12098–
12107.
10.1021/ol101557t  2010 American Chemical Society
Published on Web 08/06/2010

interaction of the nitrogen electron lone pair of 2a with the
quaternary nitrogen atom of the bmim cation that influences
the N-H hydrogen of 2a for H-B formation with the oxygen
Table 1. Aza-Michael Reaction of 1a with 2a to form 3a in the
Presence of Various ILsa
8
-
atom (H-B acceptor) of one of the SdO groups in MeSO4
(nucleophilic activation) through a six-membered chairlike
cyclic structure and nestles the nitrogen of 2a in a position/
orientation suitable for nucleophilic attack at the ꢀ carbon
of 1a and forms A. Nucleophilic attack followed by transfer
of hydrogen from the NH2 group of 2a through the hydrogen
bridge (that might provide rigidity to the noncovalently
constructed supramolecular framework) in the hydrogen-
bonded cluster A to the carbonyl oxygen of 1a forms the
enolate of the aza-Michael adduct 3a and brings the IL back
to the catalytic cycle. The decrease in the yield of 3a in using
[bdmim][MeSO4] (entry 19, Table 1) that is devoid of the
C-2 hydrogen at the imidazolium moiety supports electro-
philic activation of 1a through H-B formation with the C-2
hydrogen of the bmim cation. However, while the “electro-
philic activation” of 1a mediated by H-B formation with
the C-2 hydrogen atom of the IL is a contributing factor in
imparting the catalytic property to the IL, the counteranion
also plays a crucial role (in the form of H-B acceptor of
the NH2 hydrogen) during the catalysis as the relative
catalytic efficiency of the various ILs cannot be rationalized
solely on the basis of H-B donor ability of the C-2
hydrogen.9
entry
IL
equivb
temp (°C)
yieldc, d (%)
1
2
3
4
5
6
7
8
none
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.0
1.1
1.1
1.2
1.5
1.1
1.1
1.1
1.1
1.1
1.1
80
80
80
80
80
80
80
80
60
40
80
80
80
80
80
80
80
80
nile
45e
64e
40e
30e
32e
75
[bmim][Br]
[bmim][Cl]
[bmim][BF4]
[bmim][ClO4]
[bmim][PF6]
[bmim][MeSO4]
[bmim][MeSO4]
[bmim][MeSO4]
[bmim][MeSO4]
[bmim][MeSO4]
[bmim][MeSO4]
[bmim][MeSO3]
[bmim][OAc]
[bmim][HCOO]
[bmim][NTf2]
[bmim][HSO4]
[bdmim ][MeSO4]
73
9
40e
nile
77
10
11
12
13
14
15
17
18
19
79
31e
42e
63
40e
65
35e
For a direct proof of concept, we planned to identify and
characterize the supramolecular structure A (Scheme 1). The
electrospray ionization mass spectrometry (ESI MS)10 is the
frontline analytical technique for the study of noncovalent
complexes due its ability to generate efficiently the ions of
noncovalent adducts in the gas phase, but its applications in
identifying noncovalent cluster are restricted to large bio-
molecules (mass range 19000-34000 Da).11
a 1a (0.208 g, 1 mmol) was reacted with 2a in the presence of the IL
(10 mol %) for 1.5 h. b Molar equiv of 2a used with respect to 1a. c Isolated
yield of 3a. d The product was characterized by IR, NMR, and MS. e The
unreacted starting material was recovered.
cooperative H-Bs6 and charge-charge interactions wherein
the IL exhibits an “electrophile nucleophile dual activation”
role.
We performed (+ve) ESI MS studies12 on aliquots of
samples withdrawn after 30 min from the [bmim][MeSO4]-
catalyzed reaction of 1a with 2a using variable power at the
source/cone (30, 40, and 50 V) and capillary (37, 47, and
57 V). The optimum results were obtained in using the
source/cone and capillary voltages of 50 and 47 V, respec-
tively. The total ion chromatogram (TIC) revealed the
presence of ions at m/z 591.59 (m1), 551.27 (m2), 513.11
(m3), 495.21, 479.53 (m4), 459.5, 446.39, 441.45 (m5), 423.49
(m6), 416.88, and 403.45 corresponding to [A + K+], [A+],
[A + K+-Ph], [A+ - Bu], [A+ - Bu-Me], [A+ - Ph-Me],
[A+ - Ph-CO], [A + H+-HMeSO4], [m1 - MeSO4-Bu], [A+
- Bu-Ph,] and [A+ - Ph-Me-(MeNHCHCH)], respectively
(Figure 1), which are diagnostics of A. Further support of A
was obtained from the tandem mass (MS-MS) studies on a
few selected ions observed in the TIC.12
Scheme 1
.
Role of [bmim][MeSO4] in the Aza-Michael
Reaction
(8) Lungwitz, R.; Spange, S. New J. Chem. 2008, 32, 392–394.
(9) The 1H NMR chemical shift values (δ in ppm in DMSO-d6 at 40 °C)
of the C-2 hydrogen of the ILs are as follows: [bmim][BF4], 9.05; [bmim][ClO4],
9.05; [bmim][PF6], 9.06; [bmim][NTf2], 9.08; [bmim][MeSO4], 9.10; [bmim]-
[HSO4], 9.19; [bmim][MeSO3], 9.22; [bmim][N(CN)2], 9.28; [bmim][HCO2],
9.30; [bmim][MeCO2], 9.33; [bmim][Cl], 9.58.
The carbonyl oxygen of 1a forms H-B (electrophilic
activation) with the C-2 hydrogen of the bmim cation due
to its H-B donor ability.7 This is followed by electrostatic
(10) Fenn, J. B.; Mann, M.; Meng, C. K.; Wong, S. F.; Whitehouse,
C. M. Science 1989, 246, 64–71.
(6) Steiner, T. Angew. Chem., Int. Ed. 2002, 41, 48–76.
(7) Lungwitz, R.; Friedrich, M.; Linert, W.; Spange, S. New J. Chem.
2008, 32, 1493–1499.
(11) Pramanik, B. N.; Bartner, P. L.; Mirza, U. A.; Liu, Y.-H.; Ganguly,
A. K. J. Mass Spectrom. 1998, 33, 911–920.
(12) See the Supporting Information.
Org. Lett., Vol. 12, No. 17, 2010
3867

corresponding intermediate supramolecular asemblies were
identified in the (+ve) ESI MS.12 The sample of the
[bdmim][MeSO4]-catalyzed reaction of 1a with 2a did not
exhibit the supramolecular structure akin to A in the (+ve)
ESI MS and justifies that the inferior catalytic activity is
due to the lack of the C-2 hydrogen.
To prove that A or B is not simply the most stable
noncovalent adduct generated by aggregation of the mixture
components in the dissolved state, the mixtures of [bmim]-
[MeSO4] and the aza-Michael adducts 3a and 3b were
separately subjected to (+ve) ESI MS and MALDI-TOF-
TOF MS, and no ion peak characteristics of the correspond-
ing noncovalent adduct were observed.
The implication of the mechanistic model is that the
catalytic power of the IL should be governed by its ability
to form supramolecular structures akin to A/B and a measure
of the catalytic efficiency of an IL may be obtained by
identification and estimation of the abundance/concentration
of the supramolecular assemblies corresponding to A/B
during the course of the reaction using mass spectrometric
techniques.13
Figure 1. TIC of (+ve) ESI MS of sample withdrawn after 30
min for the reaction of 1a with 2a catalyzed by [bmim][MeSO4].
Additional proof of A was obtained from (+ve) MALDI-
TOF-TOF MS studies wherein the TIC exhibited the
′
diagnostic peaks at m/z 597.34 (m1 : A + 2Na+-H+), 487.06
To substantiate this, the reaction of 1a with 2a was
separately carried out in the presence of mixtures (10 mol
% each) of [bmim][MeSO4] and [bmim][Cl], [bmim][Me-
SO4] and [bmim][OAc], [bmim][MeSO4] and [bmim][Br],
[bmim][MeSO4] and [bmim][BF4], and [bmim][MeSO4] and
[bmim][MeSO3]. The aliquots of sample withdrawn after 30
min from each of these reaction mixtures were subjected to
(+ve) ESI MS, and the ion currents of the ions at m/z 551.71
and 475.24, 551.71 and 499.28, 551.71 and 519.19, 551.71
and 527.27, and 551.71 and 535.25 were measured.12 In all
of these cases, the area of the ion at m/z 551.71 corresponding
to the hydrogen-bonded cluster of [bmim][MeSO4] was found
to have a higher value than those derived from the other ILs
and justified the superior catalytic activity of [bmim]-
[MeSO4].12 A good correlation was observed for the ion
current ratio of the cluster corresponding to A derived from
a set/pair of ILs and the ratio of the product (aza-Michael
adduct 3a) yields obtained from the reaction catalyzed
separately by the individual IL (Table 2).
[A + H+ + Na+-Bu+-OMe], 439.12 [A+ - H-HMeSO4],
423.10 [A + K+-Bu+-MeSO4], respectively, and the MS-MS
of a few selected ions provided further structural support.12
The generality of the mechanistic proposal was established
by demonstrating the involvement of the corresponding
supramolecular structure B through the (+ve) ESI MS
experiments on the [bmim][MeSO4]-catalyzed reaction of
1-(4-benzyloxyphenyl)-3-phenylprop-2-en-1-one 1b (1 equiv)
with 2a (1.1 equiv). The TIC (+ve) ESI MS (Figure 2) of
Table 2. Assessment of Relative Catalytic Power of a Pair of
ILs
Figure 2
.
TIC of (+ve) ESI MS of sample withdrawn after 30
min for the reaction of 1b with 2a catalyzed by [bmim][MeSO4].
ion
ratio yielda (%)
(x:y) (IL1:IL2)
entry
1
IL
m/z (A+)
current
[bmim][MeSO4](IL1) 551.71 53415 (x)
an aliquot of sample withdrawn after 30 min exhibited ions
at m/z 647.5 (m7: B + Li+-H2O), 638.86 (B + K+-H-Bu),
624.99 (m8: B + Na+-MeNCHdCH), 610.99 (m8: H-Bu),
605.43 (B + K+-Ph-CH3), 513.13 (B+K+-C6H4-OBn),
441.52 (m8: C6H4-OBn) and proved involvement of B during
the mechanistic course of the reaction. Further support was
obtained by the MS-MS of a few selected ions observed in
the TIC.12 Additional support for B was derived from the
(+ve) MALDI-TOF-TOF MS.12
[bmim][MeSO3](IL2) 535.25 26964 (y) 1.98
[bmim][MeSO4](IL1) 551.71 125423 (x)
2.41
1.88
1.7
2
3
4
5
[bmim][BF4] (IL2)
[bmim][MeSO4](IL1) 551.71 404000 (x)
[bmim][OAc] (IL2) 499.28 285977 (y) 1.41
[bmim][MeSO4](IL1) 551.71 236027 (x)
[bmim][Br] (IL2) 519.19 177276 (y) 1.33
[bmim][MeSO4](IL1) 551.71 179230 (x)
[bmim][Cl] (IL2) 475.24 155851 (y) 1.15
527.27 80816 (y) 1.55
1.67
1.17
a The ratio of the yield (Table 1) of 3a obtained by the reaction of 1a
with 2a catalyzed separately by the individual IL1/IL2.
When the reaction of 1a was performed with 4-chloroa-
niline, 2-methylaniline, and methyl 4-aminobenzoate, the
3868
Org. Lett., Vol. 12, No. 17, 2010

We next hypothesized that the importance of H-B
formation involving the NH2 hydrogen of the amine in the
mechanistic course of the reaction should direct a selective
aza-Michael reaction of a common Michael acceptor during
competition involving amines with varying H-B formation
ability. Thus, 1a was separately treated with mixtures of 2a
and cyclohexylamine, 2a and 2-phenethylamine, 2a and
piperidine, and 2a and N-methylaniline in the presence of
10 mol % of [bmim][MeSO4] that resulted in the formation
of 3a as the only product in 75, 74, 77, and 72% yields,
respectively (Scheme 2).12
30 min, was subjected to (+ve) ESI MS, no ions of the
supramolecular assembly analogous to A was observed as
the poor H-B donor ability of the aliphatic/alicyclic amines
was not conducive to the formation of the cluster akin to A.
In case of N-methylaniline, the absence of the supramolecular
structure similar to A could be due to the lack of involvement
of the hydrogen bridge that is expected to provide rigidity/
stability to the noncovalent cluster. Thus, no aza-Michael
adduct formation takes place for the reaction of 1a with
N-methylaniline although the latter is more nucleophilic than
2a. When aliquots of samples withdrawn after 30 min
from each of the reaction mixtures of the [bmim][MeSO4]
catalyzed reaction of 2a and cyclohexylamine, 2a and
2-phenethylamine, 2a and piperidine, and 2a and N-methy-
laniline were subjected to (+ve) ESI MS experiments, only
the ion at m/z 551.71 corresponding to the cluster A derived
from 1a, 2a, and [bmim][MeSO4] was detected and provides
rationale for the selectivity. Although the nitrogen atom in
cyclohexylamine, 2-phenethylamine, and piperidine is more
nucleophilic compared to that in 2a, no significant amount
of formation of the aza-Michael adduct of these amines was
observed due to the poor H-B donor ability of these amines
because of which these amines could not effectively form
the supramolecular assembly akin to A.
Scheme 2. Reverse Selectivity for Aza-Michael Reaction
Catalyzed by [bmim][MeSO4] in Intermolecular Competition
The supramolecular assemblies of small molecules formed
by a relay of cooperative H-Bs and charge-charge interac-
tions have been identified and characterized by (+ve) ESI
and MALDI-TOF-TOF MS and MS-MS to reveal the
molecular level role of ILs in promoting an aza-Michael
reaction. The mechanistic model provides a conceptual
advancement for a qualitative and quantitative assessment
of catalytic power of ILs for an aza-Michael reaction through
mass spectrometric identification of the supramolecular
assemblies and is diagnostic for predicting the selectivity
through determination of the concentration (ion current) of
the relevant supramolecular assemblies and should promote
rational development of sustainable chemistries using ILs.
The supramolecular structures A/B reveal a new type of
cooperative H-Bs herein classified under “charge-charge-
cooperativity” and designated as “charge-charge-assisted
hydrogen bond” (CCAHB), relinking the fields of crystal
engineering and ionic liquids.14
The reverse selectivity compared to the reported aza-
Michael addition wherein aliphatic amines are observed to
react in preference to aromatic amines provides the attractive
feature of the IL-catalyzed reaction. The selective aza-
Michael reaction with the aromatic amine (weak nucleophile)
in preference to the aliphatic amine (stronger nucleophile)
suggests that the nucleophilicity is not the only decisive
factor. The outcome of selectivity can be rationalized by the
mechanistic model (Scheme 1) that takes into account the
H-B and charge-charge interactions in addition to amine
nucleophilicity. Hence, the selectivity/reactivity of different
amines should be governed by the ease of formation of the
relevant noncovalent adducts.
Acknowledgment. S.R.R. thanks CSIR, New Delhi, India,
for a Senior Research Fellowship.
Supporting Information Available: Typical procedure,
spectral data, and scanned spectra of unknown compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
When the reaction of 1a was carried out individually with
cyclohexylamine, 2-phenethylamine, piperidine, and N-
methylaniline in the presence of [bmim][MeSO4] (10 mol
%) and an aliquot of these reaction mixtures, withdrawn after
OL101557T
(13) Alfassi, Z. B.; Hui, R. E.; Milman, B. L.; Neta, P. Anal. Bioanal.
Chem. 2003, 377, 150–164.
(14) Rogers, R. D. Aust. J. Chem. 2010, 63, 533–534.
Org. Lett., Vol. 12, No. 17, 2010
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