The Knoevenagel reaction: Analysis and recycling of the ionic liquid medium

Article abstract of DOI:10.1016/j.tetlet.2006.01.059

A study involving the scope of substrate in the Knoevenagel reaction in an IL medium has been conducted. Reactivity trends favor formation of the condensation product using electron deficient aryl aldehydes. Use of electron rich aldehydes and ketones lead

Full text of DOI:10.1016/j.tetlet.2006.01.059

Tetrahedron Letters 47 (2006) 1699–1703
The Knoevenagel reaction: analysis and recycling of the ionic
liquid medium
*
David C. Forbes, Amanda M. Law and Doug W. Morrison
University of South Alabama, Department of Chemistry, Mobile, AL 36688, USA
Received 8 August 2005; revised 12 January 2006; accepted 13 January 2006
Abstract—A study involving the scope of substrate in the Knoevenagel reaction in an IL medium has been conducted. Reactivity
trends favor formation of the condensation product using electron deficient aryl aldehydes. Use of electron rich aldehydes and
ketones lead to lower levels of conversion and no measurable amounts of condensation products, respectively. A recycling study
confirmed that the reaction medium could be used multiple times affording, with each run, the desired condensation product 1a
in excess of 90% conversion. Post-run analyses of the IL documented that the IL medium was unaltered upon reuse.
ꢀ
2006 Elsevier Ltd. All rights reserved.
1
. Introduction
communication focused on condensation processes, spe-
cifically, the Knoevenagel reaction and Robinson annu-
lation and for the first time the use and reuse of IL
technology in these two well established base-promoted
transformations were documented. The Knoevenagel
reaction was of particular interest because of its applica-
tion in industry. The preparation of several anti-fouling
agents, herbicides, and insecticides not only rely on this
condensation process but use as their choice of activated
Alternative technologies which circumvent the need to
use VOCs (volatile organic compounds) exist. One
such technology involves the use of ionic liquids. Ionic
liquid (IL) technology when used in place of classical
organic solvents offers a new and environmentally benign
approach toward organic synthesis. IL technology has
been successfully applied in several classical organic pro-
cesses. The implementation of task specific ionic liquids
1
,2
2
,3
4
5
12
methylene, malononitrile. Furthermore, these pro-
(
TSILs) further enhances the versatility of classical ionic
cesses are dependent upon the use of solvents in the con-
version of carbonyl derivative to ylidenemalononitrile
derivative. The two most commonly used solvents, eth-
anol and toluene, are part of the TRI hazardous air pol-
lutants inventory and thus do contribute to what is
6
liquids where both reagent and medium are coupled.
The union of reagent with medium is a viable alternative
approach toward modern synthetic chemistry especially
when considering the growing environmental demands
7
,8
13
being placed on chemical processes.
released into the environment.
Previous reports from these laboratories have docu-
mented the application and reuse of IL technology in
classical organic processes. One study focused on the
Research activities focusing on the development and use
of inert and recyclable ILs and TSILs are extremely
active. Our interests only compliment the research efforts
of others which, in part, addresses the need to develop
innovative technologies to conduct synthetic transfor-
9
,10
use of Brønsted acid TSILs.
An earlier communica-
tion reported on the viability of base-promoted reac-
1
1
14
tions in ILs. The reactions surveyed in the latter
mations void of VOCs. Not surprisingly, as new tech-
nologies and applications emerge, limitations become
evident. Accordingly, we wish to follow-up on some of
our initial findings and report on (1) scope of substrate
with respect to the aldehyde in Knoevenagel reactions
supported by an IL medium and (2) the structural integ-
rity of the IL medium having performed ten iterations of
condensation reactions using the same IL medium.
Keywords: Alternative technologies; Ionic liquid technologies; Reuse;
Knoevenagel reaction; Condensation reaction; Organic synthesis;
Scope of substrate; Pollution prevention; Clean technology.
*
Corresponding author. Tel.: +1 251 460 7423; fax: +1 251 460
359; e-mail: dforbes@jaguar1.usouthal.edu
7
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.059

1700
D. C. Forbes et al. / Tetrahedron Letters 47 (2006) 1699–1703
2. Results
Table 1. Condensation reactions of aldehydes with malononitrile in an
IL medium
The Knoevenagel reaction has been extensively studied
CH3
1
5
since its initial report in 1894. There has been a tre-
mendous amount of research focusing on all aspects of
this condensation process. Our initial report on the
Knoevenagel reaction established proof of principle
H C
3
N
0
N
CN
CN
PF6
CN
CN
a-f
R
O
+
R
.2 equiv glycine
1
1
(
Scheme 1). Reaction of benzaldehyde with malono-
o
4
5-55 C
22 h
1
nitrile resulted in 77% isolated yield of the desired
product using as reaction medium 1-hexyl-3-methyl
a
Entry
Carbonyl derivative
1 (%)
imidazolium hexafluorophosphate ([hmim][PF ]) and
6
Cl
glycine as promoter. We were successful in recycling this
process with the same IL medium which resulted in 39%
isolated yield of the desired condensation product.
1, a
86
O
Cl
All reactions reported here and in our initial communi-
cation were clean as judged by GC and NMR analysis of
the crude reaction mixture. That is, although incomplete
reactions were observed, analysis of the crude reaction
mixtures revealed no by-products other than the desired
product and unreacted starting material. Albeit low in
yield especially when considering the recycling experi-
ment, the unoptimized reaction conditions using equi-
molar quantities of aldehyde and activated methylene
would serve as our benchmark from which studies
focusing on scope of substrate with respect to the alde-
hyde would begin. For each system examined, toluene
was used to extract the products from the reaction
O
2, b
3, c
4, d
5, e
6, f
7
8
74
77
62
52
32
O N
2
O
O
H CO
3
O
(
ca. 2:1)
O
1
6
medium.
CH3
O
Since a host of carbonyl derivatives which ranged from
electron deficient aryl aldehydes to comparatively less
reactive electron rich carbonyl systems were examined
and we observed a notable difference in overall conver-
b
—
O
b
—
1
1
sion during the recycling experiment, a decision was
made to offset systems of lesser reactivity with warmer
reaction conditions. The reactions were run not at room
temperature but a warmer setting of 50 ꢁC (± 5 ꢁC). Our
focus was on the scope of the substrate using IL technol-
ogies, reuse of the IL medium and examination of the IL
medium, but not conversion. Except for this single mod-
ification, all other reaction conditions were kept the
same. A total of eight carbonyl derivatives were sur-
veyed. The data from the study are presented below.
a
Yields reported are unoptimized.
Desired condensation product not observed, recovery of carbonyl
derivative >95%.
b
products (entries 7 and 8). Several attempts with varying
reaction conditions with these carbonyl derivatives were
made which resulted in either very low yields or levels of
nondetection as determined by GC analysis. Isolation of
the starting carbonyl derivatives in >95% recovery con-
firmed poor efficiency of methylene transfer under these
Table 1 reveals some interesting trends. Overall, aryl
aldehydes (entries 1–4) were superior to aliphatic and
conjugated aryl aldehydes (entries 5 and 6). Electron
rich anisaldehyde (entry 4) yielded the desired product
in good yield but not as high when compared to the
more reactive systems benzaldehyde (entry 3) and
electron deficient aryl aldehydes (entries 1 and 2). Use
of ketones did not yield any of the desired condensation
1
7
reaction conditions.
Results from the scope of the substrate study were next
used as a basis for exploring the inherent stability of the
IL medium while performing recycling experiments. Our
aim was to recycle the IL medium, and using indicators
such as mass balance and percent conversion in conjunc-
tion with NMR spectroscopy, examine the IL medium
after each run in an effort to learn more about the appli-
cation of this technology in modern synthetic transfor-
mations. For this study, reaction of malononitrile with
2,6-dichlorobenzaldehyde in the presence of catalytic
quantities of glycine was selected (Scheme 2).1
CH3
H C
3
N
0
N
CN
CN
CN
CN
PF6
+
O
8
.2 equiv glycine
room temperature
2 h
77%)
2
Analysis of the crude reaction mixture for each run
in the recycling study revealed no less than 90% conver-
sion of aldehyde to dinitrile. Mass balance and NMR
(
Scheme 1.

D. C. Forbes et al. / Tetrahedron Letters 47 (2006) 1699–1703
1701
CH3
after having completed 10-cycles of the Knoevenagel
reaction using 2,6-dichlorobenzaldehyde and malono-
nitrile in the presence of catalytic quantities of glycine.
H C
3
N
N
PF6
Cl
+
Analysis of the reaction mixture prior to completion of
reaction was found to be informative when considering
the presence (or absence) of isolable reaction intermedi-
HO
O
NH2
Cl
O
(
0.2 equiv)
Cl
CN
CN
+
1
ates. The H NMR spectrum revealed the presence of
CN
Cl
10 cycles performed
without dropping below
0% conversion
[
hmim][PF ], 2,6-dichlorobenzaldehyde, malononitrile,
6
CN
and small quantities of the condensation product. This
observation further supports our position that under
these reaction conditions, the reaction medium remains
intact. Throughout this study, aside from the retention
of the catalyst glycine and trace amounts of malononit-
rile, the condensation product 1a and trace amounts
of 2,6-dichlorobenzaldehyde were successfully extracted
from the IL medium leaving it intact and ready for reuse.
9
Scheme 2.
analyses of the crude reaction mixtures confirmed the
high level of conversion. Perhaps more interesting were
the post-run analyses. The IL medium, [hmim][PF6],
remained intact throughout the entire 10-cycling study
and thus, for the first time, an analysis of the IL medium
itself upon recycling the medium multiple times is
reported. While we cannot confirm changes in situ, we
can definitively state that the NMR spectra of the IL
medium prior to and post reaction were identical. The
3. Discussion
Based upon control reactions, glycine serves as
promoter for these reactions. We have no evidence that
glycine is extracted from the IL when washed with
1
H NMR spectrum presented in Figure 1 was taken
1
Figure 1. H NMR spectrum of [hmim][PF
6
] after 10 cycles.

1702
D. C. Forbes et al. / Tetrahedron Letters 47 (2006) 1699–1703
toluene. We do believe that glycine was part of the IL
medium throughout the recycling study. Glycine is solu-
ble in water and slightly soluble in alcohols and ether
and thus the absence of glycine in the NMR spectra.
Removing glycine from the IL could be accomplished
funding of this research. D.C.F. would also like to thank
Professor James H. Davis, Jr., for helpful discussions
regarding ionic liquid technologies.
1
9
by washing the IL with water.
References and notes
Imidazolium cations should not be considered spectator
1
. (a) Clean Technology for the Manufacture of Specialty
Chemicals; Hoyle, W., Lancaster, M., Eds.; Royal Society
of Chemistry: London, 2001; (b) Sheldon, R. J. Chem.
Tech. Biotechnol. 1997, 68, 381; (c) Clift, R. J. Chem. Tech.
Biotechnol. 1997, 68, 347.
2
0,21
ions.
The intermolecular properties of these salts
have been an active area of research. One area of research
has focused on the unique hydrogen bond donor proper-
2
2
ties at C-2. Welton and co-workers have reported on
the role of the hydrogen bond at C-2 in a Diels–Alder
2. Alternative technologies utilizing ionic liquid (IL) tech-
nologies, see: (a) Earle, M.; Forestier, A.; Olivier-Bourbi-
gou, H.; Wasserschied, P. In Ionic Liquids in Synthesis;
Wasserscheid, P., Welton, T., Eds.; Wiley-VCH: Wein-
heim, 2003; Use of supercritical carbon dioxide (sc-CO2),
see: (b) Beckman, E. Chem. Commun. 2004, 1885; For
alternative approaches utilizing water, see: (c) Andrade, C.
K. Z.; Alves, L. M. Cur. Org. Chem. 2005, 9, 195.
2
3
reaction. Rationale for endo-selectivity was because of
favorable participation of the hydrogen at C-2 of the imi-
dazolium cation with the carbonyl oxygen of the dieno-
phile. While we cannot confirm participation of the
imidazolium cation with the carbonyl oxygen in our
study, control studies support that these reactions are
facilitated by the presence of a general catalyst. The addi-
tion of the methylene compound to the carbonyl deriva-
tive is probably assisted by a number of possible
coordination events. Coordination of the carbonyl oxy-
gen with a proton source creates a more electrophilic car-
bon. It is not unreasonable to assume that the source of
the proton donor may come from either the ammonium
salt of glycine or the hydrogen at C-2 of the imidazolium
salt. However, if competition of hydrogen bonding with
the carbonyl oxygen exists, participation would favor
the ammonium salt of glycine and not the C-2 hydrogen
of the imidazolium cation. Because glycine is a stronger
acid and amino acids have been shown to be effective cat-
alysts in the condensation reaction of carbonyl deriva-
tives and active methylene compounds, we do believe
that glycine is acting as the acid promoter in these con-
3
. Holbrey, J. D.; Seddon, K. R. Clean Products and
Processes 1999, 1, 223.
4. Sheldon, R. Chem. Commun. 2001, 2399.
5. For a thematic issue focusing on the application of IL
technology in synthetic processes, see: issue 1 of J. Mol.
Catal. A: Chem. 2004, 214.
6
7
. Davis, J. H., Jr. Chem. Lett. 2004, 33, 1072.
. Ionic Liquids IIIA: Fundamentals, Progress, Challenges,
and Opportunities—Properties and Structure; Rogers, R.
D., Seddon, K. R., Eds.; ACS Symposium Series No. 901;
American Chemical Society: Washington, DC, 2005.
. Ionic Liquids IIIA: Fundamentals, Progress, Challenges,
and Opportunities—Transformations and Processes; Rog-
ers, R. D., Seddon, K. R., Eds.; ACS Symposium Series
No. 902; American Chemical Society: Washington, DC,
2005.
8
9
. Cole, A. C.; Jensen, J. L.; Ntai, I.; Tran, K. L. T.; Weaver,
K. J.; Forbes, D. C.; Davis, J. H., Jr. J. Am. Chem. Soc.
1
2,24
densation reactions.
Studies which include an exam-
2
002, 124, 5962.
ination of the role of the catalyst and the scope of the
substrate of activated methylene compounds using opti-
mized reaction conditions are currently being investi-
gated and will be reported in due course.
1
1
1
0. Forbes, D. C.; Weaver, K. J. J. Molecular Catalysis A:
Chemical 2004, 214, 129.
1. Morrison, D. W.; Forbes, D. C.; Davis, J. H., Jr.
Tetrahedron Lett. 2001, 42, 6053.
2. For an extensive review on the application of malono-
nitrile in the Knoevenagel reaction, see: (a) Fatiadi, A. J.
Synthesis 1978, 165; (b) Fatiadi, A. J. Synthesis 1978, 241;
4. Conclusions
(
c) Freeman, F. Chem. Rev. 1980, 80, 329; (d) Freeman, F.
Chem. Rev. 1969, 69, 591; For general reviews on the
Knoevenagel reaction, see: (e) Jones, G. Org. React. 1967,
A study involving the scope of the substrate in the
Knoevenagel reaction supported in an IL medium has
been conducted. Reactivity trends favor formation of
the condensation product using electron deficient aryl
aldehydes. A recycling study confirmed that the reaction
medium could be used multiple times affording, with
each run, the desired condensation product in excess
of 90% conversion. Post-run analyses documented for
the first time that the IL medium was unaltered upon
reuse. Our continued research in this area will explore
1
5, 204; (f) Tietze, L. F.; Beifuss, U. In Comprehensive
Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
New York, 1991; Vol. 2, Chapter 1.11, p 341.
1
3. Data from the US Environmental Protection Agency
Toxics Release Inventory for 2002 (www.epa.gov/tri).
4. (a) Fan, X.; Hu, X.; Zhang, X.; Wang, J. Aust. J. Chem.
2004, 57, 1067; (b) Xu, X.-M.; Li, Y.-Q.; Zhou, M.-Y.;
Tan, Y.-H. Chin. J. Org. Chem. 2004, 24, 284; (c) Su, C.;
Chen, Z.-C.; Zheng, Q.-G. Synthesis 2003, 555; (d) Bao,
W.; Wang, Z.; Li, Y. J. Chem. Res. (S) 2003, 294; (e) Hu,
Y.; Chen, J.; Le, Z.-G.; Zheng, Q.-G. Synth. Commun.
1
(
1) the function of the promoter, (2) the role of the IL
medium and (3) the scope of the substrate with activated
methylene donors.
2
005, 35, 739.
1
5. Knoevenagel, E. Chem. Ber. 1894, 27, 2345.
1
6. Representative procedure in the preparation of benzylidene
malononitrile derivatives: To a 5 mL reaction conical vial
containing a magnetic spin vane were added, in the
Acknowledgements
6
following order, 0.5 mL [hmim][PF ] (1.2 M), 0.61 mmol
malononitrile (1.0 equiv), 0.61 mmol aldehyde (1.0 equiv)
and 0.12 mmol glycine (0.2 equiv). The reaction mixture
D.C.F. would like to thank Research Corporation
(
CC5227) and N.S.F. (CHE 0514004) for partial

D. C. Forbes et al. / Tetrahedron Letters 47 (2006) 1699–1703
1703
was allowed to stir at 50 ꢁC (± 5 ꢁC) for a period ranging
from approximately 18–24 h at which time the reaction
mixture was extracted with toluene (3 · 2.0 mL). Temper-
atures did gradually fluctuate, ± 5 ꢁC, and were recorded
externally. Analysis of the crude reaction mixture revealed
that aside from glycine, >95% (wt) of the organic residues
introduced to the [hmim][PF6] were removed after
combined and analyzed for percent conversion by GC
analysis. The reaction conical vial was then carefully
placed in a 50 mL round bottom flask (24/40) equipped
with sufficient tissue paper which served to center and keep
the reaction conical vial upright and thus avoid any loss of
the IL medium due to spilling. The modified round bottom
flask containing the reaction conical vial was next attached
to a rotary evaporator. While under reduced pressure
(water aspirator) the flask was allowed to spin for
approximately 1 h at which time the system was allowed
to return to atmospheric pressure. The reaction conical
vial was then carefully removed from the round bottom
flask and returned to the stirrer hot plate for the next
cycling experiment. Prior to reaction, a 10 lL sample was
removed for NMR analysis. This workup procedure was
repeated a total of nine times. NMR analysis of the IL
1
performing three 2.0 mL washes with toluene ( H NMR
of IL and mass balance of materials extracted). The
organic extracts were then combined and concentrated in
vacuo. The resulting viscous oil was immediately purified
via silica gel chromatography [hexane/EtOAc, 1/1,
1
2
0 · 30 mm SiO , 3 mL fractions] to afford the title
compound. Spectral data obtained on each system were
in agreement with previous reports.
1
7. Reaction of acetophenone and malononitrile in the
presence of a AlPO
4
–AlO
3
solid support resulted in trace
6
revealed the presence of [hmim][PF ] and trace amounts of
quantities of product formation, see: Cabello, J. A.;
Campelo, J. M.; Garcia, A.; Luna, D.; Marinas, J. M. J.
Org. Chem. 1984, 49, 5195.
unreacted malononitrile. The spectral data of the recycling
experiments were in agreement with the data obtained
during the scope of substrate survey.
1
8. Recycling of [hmim][PF ] medium: The recycling exper-
19. For work on the use of amino acids in an IL medium, see
Vallette, H.; Ferron, L.; Coquerel, G.; Gaumont, A.-C.;
Plaquevent, J.-C. Tetrahedron Lett. 2004, 45, 1617.
20. Aggarwal, V. K.; Emme, I.; Mereu, A. Chem. Commun.
2002, 1612, and references cited therein.
21. Forment ´ı n, P.; Garc ´ı a, H.; Leyva, A. J. Mol. Catal. A:
Chem. 2004, 124, 137.
22. Poole, C. F. J. Chromatogr. A 2004, 1037, 49.
23. Aggarwal, A.; Lancaster, N. L.; Sethi, A. R.; Welton, T.
Green Chem. 2002, 4, 517.
6
iments were performed using a 5 mL reaction conical vial
equipped with a magnetic spin vane. The reaction conical
vial was charged with 1.0 mL [hmim][PF ] followed by the
6
addition of 18 mg glycine (0.24 mmol, 0.2 equiv). Upon
the addition of 2,6-dichlorobenzaldehyde (212 mg,
1
1
.21 mmol) and malononitrile (80 mg, 1.21 mmol,
.0 equiv), the reaction was warmed to 50 ꢁC and allowed
to react for a period of 22 h at which time the reaction
mixture was cooled to room temperature and extracted
with toluene (3 · 2.0 mL). The organic extracts were then
24. Prout, F. S. J. Org. Chem. 1953, 18, 928.