Improved aqueous Cannizzaro reaction in presence of cyclodextrin

Article abstract of DOI:10.1007/s10847-010-9747-y

An aqueous hydroxypropyl-β-cyclodextrin solution has been used to increase the conversion of 4-biphenylcarboxaldehyde into the corresponding alcoholic and carboxylic substrates, by means of a Cannizzaro reaction. The observed enhancement has been ascribed to a partial solubilization of 4-biphenylcarboxaldehyde. In addition, as the main part of the organic substrates still remains insoluble, synthesized products are easily recovered by filtration. As a consequence, the basic cyclodextrin solution might also be reused for a new synthetic cycle, without significant loss of conversion. Aqueous solid-liquid biphasic reaction in presence of cyclodextrins thus seems to be a promising tool in the green chemistry field.

Full text of DOI:10.1007/s10847-010-9747-y

J Incl Phenom Macrocycl Chem (2011) 69:349–353
DOI 10.1007/s10847-010-9747-y
ORIGINAL ARTICLE
Improved aqueous Cannizzaro reaction in presence
of cyclodextrin
•
M. Canipelle D. Landy S. Fourmentin
•
Received: 30 October 2009 / Accepted: 25 January 2010 / Published online: 9 February 2010
Ó Springer Science+Business Media B.V. 2010
Abstract An aqueous hydroxypropyl-b-cyclodextrin
solution has been used to increase the conversion of 4-
biphenylcarboxaldehyde into the corresponding alcoholic
and carboxylic substrates, by means of a Cannizzaro
reaction. The observed enhancement has been ascribed to a
partial solubilization of 4-biphenylcarboxaldehyde. In
addition, as the main part of the organic substrates still
remains insoluble, synthesized products are easily recov-
ered by filtration. As a consequence, the basic cyclodextrin
solution might also be reused for a new synthetic cycle,
without significant loss of conversion. Aqueous solid–
liquid biphasic reaction in presence of cyclodextrins thus
seems to be a promising tool in the green chemistry field.
cyclodextrins generally improve aqueous solubility [1–3],
these macrocycles may be used to increase feasibility of
organic reaction in presence of water. For instance, this
concept has been widely applied in liquid–liquid biphasic
catalysis [4–9]. Cyclodextrins then act as a phase transfer
agent, between the two liquid phases. As cyclodextrins
could also act as a solid–liquid phase transfer agent, we
have decided to demonstrate in this study that they could be
used to extend known reactivity in pure water to solid
hydrophobic substrates. The concept of solid–liquid reac-
tions assisted by cyclodextrins is described in Fig. 1.
If an adequate amount of cyclodextrin is used, only a
part of the reactant might be solubilized. Thus, while an
enhanced reactivity could be observed as a consequence of
a greater reactant aqueous concentration, most of the
organic compound still remains in solid state. This means
that organic reactions might be carried out until comple-
tion, while purification may be then realized by simple
filtrations. As a consequence, the desired product could be
separated from the aqueous cyclodextrin solution, which
could be then reused for a new cycle of conversion.
Keywords Cyclodextrin ꢀ Phase transfer agent ꢀ
Solid–liquid reaction ꢀ Cannizzaro Reaction
Abbreviation
HPBCD Hydroxypropyl-b-cyclodextrin
In order to validate such a concept, we have applied
this principle to a Cannizzaro reaction, using insoluble
4-biphenylcarboxaldehyde in presence of hydroxypropyl-
b-cyclodextrin (HPBCD). If Cannizzaro reactions have
been widely used in water, they have been restricted to low
molecular weight organic compounds [10–13], or achieved
in presence of cosolvent [14, 15], under supercritical con-
ditions [16] or under microwave irradiation [17]. The
Cannizzaro conversion of large hydrophobic compounds in
‘‘pure’’ water is thus a challenging task. Within this scope,
the present work presents the influence of aqueous HPBCD
solution on the Cannizzaro conversion of 4-biphenylcar-
boxaldehyde, but also the characterization of the corre-
sponding complex by molecular modeling and solubility
Introduction
One of the main limitations in carrying organic reactions in
water is the limited solubility of most organic reactant. As
M. Canipelle ꢀ D. Landy (&) ꢀ S. Fourmentin
Univ Lille Nord de France, 59000 Lille, France
e-mail: landy@univ-littoral.fr
M. Canipelle ꢀ D. Landy ꢀ S. Fourmentin
ULCO, LSOE, 59140 Dunkerque, France
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J Incl Phenom Macrocycl Chem (2011) 69:349–353
Fig. 1 Recyclable solid/liquid
reaction assisted by
cyclodextrins
Solubility study
studies, as well as the recyclability of the basic cyclodex-
trin solution.
10 mL of HPBCD solutions (prepared by adequate
amounts of solid HPBCD added to pure distilled water)
were added at various concentrations: 0, 0.8, 1.7, 3.3 and
6.7 mM. 4-Biphenylcarboxaldehyde absorption in CD
solution was then analyzed by UV–Vis spectrometer, and
was used to evaluate the apparent solubility of 4-biphen-
ylcarboxaldehyde, which is defined as the amount of
4-biphenylcarboxaldehyde in solution in presence of
HPBCD. For each HPBCD concentration, three runs were
realized. The absorbance was used to evaluate soluble
4-biphenylcarboxaldehyde concentrations, which were
then plotted against HPBCD concentrations. The straight
lines thus obtained allowed the determination of formation
constant K, by means of their corresponding slopes S and
of 4-biphenylcarboxaldehyde solubility [4-biphenylcar-
boxaldehyde]0 in absence of HPBCD [2]:
Experimental details
Materials
All chemicals were purchased from Aldrich, except
HPBCD (mean molecular weight equal to 1500 g/mol)
`
which was kindly donated from Roquette Freres (Lestrem,
1
France). H (250 MHz) and 13C (60 MHz) NMR spectra
were recorded with a Bru¨ker ASPECT 3000 spectrometer,
in DMSO-d6. UV–Vis spectrometry was performed with a
UV–Vis PERKIN ELMER Lambda 2S spectrometer
(temperature kept constant to 25 °C by a thermostated
bath).
Synthesis
S
K ¼
½4-biphenylcarboxaldehydeꢁ0ꢂð1 ꢃ SÞ
200 mg of 4-biphenylcarboxaldehyde were added to
30 mL of a 20% potassium hydroxide aqueous solution, in
absence or in presence of 200 mg HPBCD. The suspension
was heated at 50 °C during 24 h. The reaction mixture was
then filtered, potassium hydroxide and HPBCD being
inside filtrate (which may be reused for a new conversion)
while products being precipitated. Products were then
washed with cold 1 M HCl solution in order to convert
4-biphenylcarboxylate into its acidic form. 4-Biphenyl-
methanol and 4-biphenylcarboxylic acid are then submitted
to separation by column chromatography (silica gel, ethyl
acetate 100%), and then dried. The products were com-
mercially available and the structures were confirmed by
Molecular modeling
Simulations were realized by means of Macromodel [18]
with MMFF force field and GB/SA simulation of water [19].
A symmetric CD structure was used to construct HPBCD.
HPBCD was simulated by an isomer which was hydroxy-
propylated two times on primary hydroxyls and four times on
secondary hydroxyls. This structure only represents one of
the multiple products of the HPBCD mixture, but it should be
representative of the steric contribution of hydroxypropyla-
tion. Hydroxypropyl arms were submitted to a Monte Carlo
conformational search prior to host–guest docking. The
docking of 4-biphenylcarboxaldehyde inside HPBCD
comparison of their H and 13C NMR spectra.
1
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351
was realized by means of Monte Carlo searches, with gen-
eration of 10000 conformations (Polak-Ribiere Conjugate
Gradient minimization, convergence fixed to 0.05 kJ/
with, as a consequence, an important stabilization in term of
enthalpy (up to 16.7 kcal/mol). Even if the well known
enthalpy/entropy compensation is not evaluated in these
simulations, such energetic values of stabilization suggest
that HPBCD cavity is well suited to 4-biphenylcarboxalde-
hyde, and that a stable complex should be observed between
the two species. More specifically, the aldehyde part of
4-biphenylcarboxaldehyde might be exposed to both pri-
mary and secondary rims of cyclodextrin. Even if the sec-
ondary rim is more open and gives rise to a better exposition
of aldehyde to external hydroxide, the accessibility of such
aldehyde also appears to be sufficient when it is exposed to
primary rim. Thus, we may reasonably think that Cannizzaro
reactions might occur not only for the free soluble part of
4-biphenylcarboxaldehyde but also inside the inclusion
compound, whatever conformation is considered.
˚
A mol). 4-Biphenylcarboxaldehyde was freely modified
while HPBCD was kept rigid. The most stable conformation
for each inclusion compound was then completely relaxed
˚
(convergence fixed to 0.05 kJ/A mol).
Results and discussion
Heating (50 °C) of a 4-biphenylcarboxaldehyde suspension
in an aqueous potassium hydroxide solution leads to the
formation of the corresponding alcoholic and carboxylated
substrates, with conversion yields depending on the
absence or presence of HPBCD (Fig. 2).
While only 30% of the initial reactant is converted in
24 h in absence of cyclodextrin, the organic reaction takes
place in a quantitative way (99%) in presence of HPBCD.
The solution is then easily filtered, leading to the recovery
of 90% of synthesized products. Moreover, no cyclodextrin
is observed in the precipitated products after filtration, as
evidenced by 1H NMR. It has also to be mentioned that the
use of smaller concentrations of HPBCD or potassium
hydroxide leads to weaker reaction yields. On the contrary,
high reaction yields are still obtained when increasing
concentrations of these reactants, but it induces a decrease
of the recovery yields. This is especially true for high
potassium hydroxide quantities, which lead to an increase
of viscosity and which prevent efficient filtrations. The
proposed experimental conditions thus represent optimized
ones.
As a consequence, it is not surprising that an enhanced
reactivity is observed in presence of cyclodextrins, if, in
addition, the formation of an inclusion complex between
the insoluble 4-biphenylcarboxaldehyde and the highly
soluble HPBCD leads to a greater concentration of
4-biphenylcarboxaldehyde in solution. We have thus tried
to demonstrate the influence of cyclodextrin on the aqueous
4-biphenylcarboxaldehyde solubility, by means of UV–Vis
spectroscopic measurements. A linear relationship between
the apparent solubility of 4-biphenylcarboxaldehyde versus
CD concentrations (from 0 to 6.7 mM) is indeed observed
with a high correlation factor, as seen in a typical set of
results (Fig. 4).
The 4-biphenylcarboxaldehyde solubility is rapidly
increasing with HPBCD concentration, 1 mM of cyclo-
dextrin being sufficient to solubilize 0.5 mM of 4-biphen-
ylcarboxaldehyde. A 28 times improved solubility is even
obtained for a 7 mM HPBCD solution (4-biphenylcar-
boxaldehyde solubility then equal to 3 mM). Moreover, the
fact that a straight line is obtained allows the evaluation
of the binding stability for HPBCD/4-biphenylcarbox-
aldehyde inclusion compound. A formation constant of
7800 1200 M-1 is calculated, thus confirming a good
complementarity between the two species, as previously
underlined by our modeling study.
When a substrate reactivity is enhanced in presence of
cyclodextrins, it is generally ascribed to the formation of an
inclusion compound between the two species. As a con-
sequence, we have studied the steric complementarity
between 4-biphenylcarboxaldehyde and HPBCD by means
of molecular modeling. 4-Biphenylcarboxaldehyde has
been submitted to Monte Carlo searches (MMFF force
field), with an implicit representation of water (GB/SA).
The most stable conformations which have been simulated
are illustrated in Fig. 3.
These solubility and stability results highlight the
experimental conditions required by the concept of solid–
liquid reactions assisted by cyclodextrins. Indeed, when
One can observe that the whole 4-biphenylcarboxalde-
hyde structure might be encapsulated in HPBCD cavity,
Fig. 2 Cannizzaro conversion
of 4-biphenylcarboxaldehyde
into 4-biphenylmethanol and
4-biphenylcarboxylic acid
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J Incl Phenom Macrocycl Chem (2011) 69:349–353
Fig. 3 Most stable structures of
HPBCD/4-
biphenylcarboxaldehyde and
energetic stabilization, as
simulated by Monte Carlo
searches (MMFF-GB/SA)
100%
80%
60%
40%
20%
0%
3.0
2.5
2.0
1.5
1.0
0.5
0.0
R2 = 0.9996
1
2
3
4
5
Number of cycles
0
1
2
3
4
5
6
7
[HPBCD] T (mM)
Fig. 5 Conversion yields for five consecutive cycles of Cannizzaro
reaction on 4-biphenylcarboxaldehyde in presence of HPBCD
Fig. 4 4-Biphenylcarboxaldehyde solubility in function of HPBCD
concentration
added after each cycle. As could be seen from Fig. 5, these
consecutive reactions take place without significant loss of
conversion (with products recovery being stable and close to
90%).
1.10 mmol (200 mg) of 4-biphenylcarboxaldehyde is
mixed with 4.40 mmol (200 mg) of HPBCD, only
0.05 mmol of complex is formed, leading to the solubili-
zation of only 0.05 mmol of 4-biphenylcarboxaldehyde.
Nevertheless, it represents a quantity which is 16 times
superior to 4-biphenylcarboxaldehyde solubility in absence
of cyclodextrin, and it explains why a significant conver-
sion enhancement is observed in presence of HPBCD. It
also accounts for the good recovery of the synthesized
products by a simple filtration, since 95% of 4-biphenyl-
carboxaldehyde is still in solid form, while HBCD is
exclusively in solution. The fact that greater cyclodextrin
concentrations might induce weaker recovery yields is also
A slight diminution is observed however, but it might be
ascribed to the natural consumption of reactant, since 1
equivalent of potassium hydroxide is needed for the for-
mation of alcoholic and carboxylated substrates. Moreover,
a slight quantity of solution is lost upon each filtration, thus
decreasing the presence of both HPBCD and potassium
hydroxide. This could be easily compensated by adding the
little corresponding losses after each cycle.
In summary, this study has demonstrated that an aque-
ous HPBCD/potassium hydroxide could be used to enhance
the Cannizzaro conversion of 4-biphenylcarboxaldehyde
into the corresponding alcoholic and carboxylic substrates,
in a quantitative and recyclable way.
explained, since
a greater 4-biphenylcarboxaldehyde
quantity is then maintained in aqueous phase when reaction
mixture is filtered. As reaction yield is already close to
100% when 4.40 mmol of HPBCD is used, it is thus
unfavorable to increase the cyclodextrin amount.
Conclusions
Since desired products and phase transfer agents (HPBCD)
might be easily separated from each other, recyclability of the
HPBCD/potassium hydroxide aqueous solution could also be
allowed. As a consequence, five consecutive Cannizzaro
cycles have been achieved with the same initial solution, to
which 200 mg of 4-biphenylcarboxaldehyde were simply
In this work, the concept of solid–liquid reactions assisted
by cyclodextrins has been illustrated in the case of a
Cannizzaro reaction. It could be extended to any typical
reactivity which takes place in water, for any solid sub-
strate which would be insufficiently hydrosoluble and
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