AOT-based microemulsions accelerate the 1,3-cycloaddition of benzonitrile oxide to N-ethylmaleimide

Article abstract of DOI:10.1021/jo060809f

We studied the 1,3-dipolar cycloaddition of benzonitrile oxide to N-ethylmaleimide in AOT/isooctane/water microemulsions at 25.0 °C and found the reaction rate to be roughly 150 and 35 times greater than that in isooctane and pure water, respectively. The

Full text of DOI:10.1021/jo060809f

AOT-Based Microemulsions Accelerate the 1,3-Cycloaddition of
Benzonitrile Oxide to N-Ethylmaleimide
J. B. F. N. Engberts,† E. Ferna´ndez,‡ L. Garc´ıa-R´ıo,*,‡ and J. R. Leis‡
Physical Organic Chemistry Unit, Stratingh Institute, UniVersity of Groningen, Nijenborgh 4,
9747 AG Groningen, The Netherlands, and Departamento de Qu´ımica F´ısica, Facultad de Qu´ımica,
UniVersidad de Santiago, 15782 Santiago, Spain
qflgr3cn@usc.es
ReceiVed April 17, 2006
We studied the 1,3-dipolar cycloaddition of benzonitrile oxide to N-ethylmaleimide in AOT/isooctane/
water microemulsions at 25.0 °C and found the reaction rate to be roughly 150 and 35 times greater than
that in isooctane and pure water, respectively. The accelerating effect of the microemulsion is the combined
result of an increase in the local concentrations of the reactants through incorporation into the interface
and of the intrinsic rate of the process through electrostatic interactions with the headgroups in the
surfactant.
Introduction
cycloadditions increases or decreases with increasing polarity
depending on the particular medium or is even completely
independent of the medium composition in some cases.4
Microemulsions are thermodynamically stable dispersions of
either water in oil (w/o) or oil in water (o/w). Their stability is
a result of the presence of an appropriate surfactant. The solutes
in microemulsions can partition between three different com-
partments, namely, (a) the internal aqueous core or water pool,
(b) the micellar interface formed by a monolayer of surfactant
molecules with their polar groups oriented toward the water
pool, and (c) the external organic phase.5 Microemulsions have
grown substantially as reaction media in recent years. Among
other applications, they have been used to prepare nanomaterials
1,3-Dipolar cycloaddition reactions involve an unsaturated
compound and a 1,3-dipole and result in the formation of a five-
membered ring.1 These reactions, which have been extensively
studied both experimentally2 and computationally,3 share many
of the characteristics of the well-known Diels-Alder reactions.
One major difference between the two has to do with the effect
of the reaction medium; thus, the rate constant of 1,3-dipolar
† University of Groningen.
‡ Universidad de Santiago.
(1) Eastman, C. J. AdVances in Heterocyclic Chemistry; Academic
Press: San Diego, CA, 1994; Vol. 60.
(2) (a) Gholami, M. R.; Yangheh, A. H. Int. J. Chem. Kinet. 2001, 33,
118-123. (b) Elender, K.; Riebel, P.; Weber, A.; Sauer, J. Tetrahedron
2000, 56, 4261-4265.
(3) (a) Pekasky, M. P.; Jorgensen, W. L. Faraday Discuss. 1998, 110,
379-389. (b) Hu, Y.; Houk, K. N. Tetrahedron 2000, 56, 8239-8243. (c)
Me´ndez, F.; Tamariz, J.; Geerlings, P. J. Phys. Chem. A 1998, 102, 6292-
6296. (d) Rastelli, A.; Gandolfi, R.; Amade´, M. S. J. Org. Chem. 1998, 63,
7425-7436.
(4) Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; Wiley: New York,
1984.
(5) (a) Pileni, M. P. Structure and ReactiVity in ReVerse Micelles;
Elsevier: Amsterdam, 1989. (b) Luisi, P. L., Straub, B. E., Eds. ReVerse
Micelles; Plenum Press: New York, 1984. (c) Degiorgio, V. Physics of
Amphiphiles: Micelles, Vesicles and Microemulsions; North-Holland:
Amsterdam, 1985.
10.1021/jo060809f CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/06/2006
6118
J. Org. Chem. 2006, 71, 6118-6123

1,3-Cycloaddition of Benzonitrile Oxide to N-Ethylmaleimide
SCHEME 1
droplet size but also the physical properties of the entrapped
water. Variable AOT concentrations ranging from 0.10 to 0.60
were used at each W value; in this way, the number of
microdroplets increased with increasing surfactant concentration
at constant W. The kobs was determined for each microemulsion
composition studied. To avoid errors arising from potential
changes in the reactant concentrations, kobs values were obtained
at three different N-ethylmaleimide concentrations (5.60 × 10-4
,
7.00 × 10-4, and 1.05 × 10-3 M). The observed rate constants
always exhibited a linear correlation with the N-ethylmaleimide
(m) concentration in the AOT-based microemulsions. The slopes
of the corresponding plots were used to calculate the apparent
bimolecular rate constant, kapp, which was a function of the
microemulsion composition:
of controlled particle size adjusted via the microemulsion
composition.5 Also, because the microemulsion structure allows
the accommodation of compounds of widely variable polarity,
microemulsions can also be useful with a view to inducing
regiospecificity in some organic reactions.7 Finally, microemul-
sions have lately been used as an alternative to phase transfer
catalysts.8
In previous work, we studied the effect of microemulsions
on the Diels-Alder reaction between cyclopentadiene and
N-ethylmaleimide and found its rate at the microemulsion
interface to be smaller than that in the aqueous medium, but
greater than that in isooctane. This was a result of the micro-
emulsions exhibiting no enforced hydrophobic interactions due
to the reduced water content of the interface9 relative to the
aqueous medium. In this work, we extended the previous study
to the 1,3-dipolar cycloaddition of benzonitrile oxide to N-
ethylmaleimide (Scheme 1) in AOT/isooctane/water micro-
emulsions. The choice of this reaction, which had previously
been extensively studied in water and micellar media,10 was
justified by the small dependence of its rate on the particular
solvent, which distinguishes it from the Diels-Alder reaction.
kobs ) kapp[m]
(1)
Table 1 shows the kapp values obtained at variable surfactant
concentrations and W values. A strong catalytic effect is apparent
relative to the rate constant in pure hexane, k0 ) 2.6 × 10-3
M-1 s-1. In fact, the reaction was roughly 140 times faster in
the microemulsion, and the catalytic effect was virtually
unaffected by its composition. Also, the reaction was about 35
times faster than that in pure water (kw ) 8.5 × 10-3 M-1 s-1).
The data in Table 1 can be used to examine the influence of
the surfactant concentration on the apparent second-order rate
constant, kapp, at different W values. As can be seen, raising the
surfactant concentration in the microemulsion had virtually no
effect on kapp (Figure 1). This is a result of the reaction taking
place largely at the microemulsion interface, where it was much
faster than that in an organic solvent, even at low surfactant
concentrations. The slight decrease in kapp with an increase in
[AOT] results from the increase of the interfacial volume and
a decrease of the local reactant concentrations with increasing
surfactant concentration.
Experimental Section
AOT was obtained from Aldrich and vacuum-dried in a desic-
cator for 2 days prior to use without further purification. N-
Ethylmaleimide was purchased in the highest available purity from
Fluka and used as received. On the other hand, benzonitrile oxide
was prepared in situ by dissolving benzaldoxime (Aldrich) in a
bleach/1-propanol mixture in a test tube with shaking for a few
seconds.10 The addition of sodium chloride caused the formation
of two layers. A 0.5-1 µL aliquot of the organic layer was
transferred to a quartz cuvette containing the reaction medium plus
the other reactant (N-ethylmaleimide).
The rate constant, kobs, for the process was determined from
spectroscopic measurements made on a Varian Cary 50 UV-vis
spectrophotometer. Thus, we monitored the decrease in the absor-
bance at 298 nm due to the disappearance of the dienophile from
the reaction medium at 25.0 ( 0.1 °C. The benzonitrile oxide
concentration used in all tests was markedly under-stoichiometric
relative to that of N-ethylmaleimide.
Figure 2 shows the influence of W on kapp at a constant
surfactant concentration. As can be seen, kapp is virtually
independent of W.
Discussion
Interpretation of our experimental results in quantitative terms
requires the determination the local reactant concentrations and
the intrinsic rate constants in the different microemulsion
pseudo-phases from the previously calculated apparent rate
constants. Our research group has developed a kinetic model
based on the pseudo-phase formalism that can be used to
quantify the effects of microemulsion composition on chemical
reactivity.11 To apply the pseudo-phase formalism to the 1,3-
dipolar cycloaddition of benzonitrile oxide to N-ethylmaleimide,
we assumed that the microemulsion comprised three pseudo-
phases depicted in Scheme 2, namely, an aqueous phase (w), a
continuous medium consisting essentially of isooctane (o), and
an interface formed mainly by the surfactant headgroups (i).
On the basis of previous results9,10 and on the solubility of our
substrates in water and various organic solvents, we assumed
N-ethylmaleimide to be present in the three microemulsion
Results
In the present study, we used widely different microemulsion
compositions ranging from W ) 2 to W ) 40, where W )
[H2O]/[AOT]. This allowed us to modify not only the micro-
(6) Khan-Lodhi, A.; Robinson, B. H.; Towey, T.; Herrmann, C.; Knoche,
W.; Thesing, U. The Structure, Dynamics and Equilibrium Properties of
Colloidal Systems; Bloor, D. M., Wyn-Jones, E., Eds.; Kluwer Academic
Publishers: Dordrecht, The Netherlands, 1990; p 373.
(7) Chatre, A. S.; Joshi, R. A.; Kulkarni, B. D. J. Colloid Interface Sci.
1993, 158, 183-187.
(8) Ha¨ger, M.; Holmberg, K. Tetrahedrom Lett. 2000, 41, 1245-1248.
(9) Engberts, J. B. F. N.; Ferna´ndez, E.; Garc´ıa-R´ıo, L.; Leis, J. R. J.
Org. Chem. 2006, 71, 4111.
(11) (a) Garc´ıa-R´ıo, L.; Iglesias, E.; Leis, J. R.; Pen˜a, M. E. J. Phys.
Chem. 1993, 97, 3437-3442. (b) Garc´ıa-R´ıo, L.; Leis, J. R.; Mejuto, J. C.
J. Phys. Chem. 1996, 100, 10981-10988. (c) Garc´ıa-R´ıo, L.; Herve´s, P.;
Mejuto, J. C.; Perez-Juste, J.; Rodr´ıguez-Dafonte, P. New J. Chem. 2003,
27, 372-380.
(10) (a) van Mersbergen, D.; Wijnen, J. W.; Engberts, J. B. F. N. J.
Org. Chem. 1998, 63, 8801-8805. (b) Rispens, T.; Engberts, J. B. F. N. J.
Org. Chem. 2003, 68, 8520-8528.
J. Org. Chem, Vol. 71, No. 16, 2006 6119

Engberts et al.
TABLE 1. Second-Order Apparent Rate Constant for the 1,3-Dipolar Cycloaddition of Benzonitrile Oxide to N-Ethylmaleimide in AOT/
Isooctane/Water Microemulsions at 25.0 °C
k
app/M-1 s-1
[AOT]/M
W ) 2
W ) 5
W ) 7
W ) 10
W ) 13
W ) 17
W ) 20
W ) 25
W ) 30
W ) 35
W ) 40
0.103
0.150
0.206
0.309
0.411
0.514
0.617
0.3699
0.3652
0.3725
0.3544
0.3393
0.2837
0.2832
0.3923
0.3775
0.4148
0.5467
0.4450
0.4055
0.3489
0.4016
0.3220
0.3577
0.4110
0.3566
0.3701
0.3619
0.3420
0.3698
0.3214
0.2198
0.5604
0.5429
0.4088
0.3137
0.4247
0.4626
0.3700
0.4020
0.3690
0.3430
0.3290
0.3020
0.2930
0.4571
0.3487
0.3843
0.3704
0.3437
0.4401
0.4305
0.5085
0.4316
0.2440
0.3819
0.4137
0.3799
0.2172
0.2350
0.3530
0.4146
0.4182
0.3980
0.3763
0.1390
0.2470
0.3719
0.4255
0.4355
0.3766
0.2029
0.2923
0.7025
0.3801
SCHEME 2
isooctane and AOT; Z ) [isooctane]/[AOT], and [m]w, [m]i,
and [m]o are the N-ethylmaleimide concentrations in the aqueous
phase, interface, and continuous medium, respectively, as
referred to the total microemulsion volume. The N-ethylmale-
imide concentrations in the different microemulsion pseudo-
phases can be estimated by assuming their total concentration
to be the sum of the concentrations in the three phases.9
Similarly, one can use the following expressions for the
benzonitrile oxide concentrations at the interface and aqueous
phase as referred to the total microemulsion volume:
FIGURE 1. Influence of the AOT concentration on kapp for the 1,3-
dipolar cycloaddition of benzonitrile oxide to N-ethylmaleimide at T
) 25.0 °C and (b) W ) 2, (2) W ) 17, and (9) W ) 40.
KmoiW[m]T
KmoiKmwi + KmwiZ + KomiW
[m]w )
[m]i )
(3)
(4)
(5)
(6)
KmoiKmwi[m]T
KmoiKmwi + KmwiZ + KomiW
ZKmwi[m]T
KmoiKmwi + KmwiZ + KomiW
FIGURE 2. Influence of W on kapp for the 1,3-dipolar cycloaddition
of benzonitrile oxide to N-ethylmaleimide at T ) 25.0 °C and an [AOT]
of (b) 0.103 M, (O) 0.309 M, and (9) 0.514 M.
[m]o )
pseudo-phases and benzonitrile oxide at the interface and
aqueous phase only.
KDwi
KDwi + W
W
[D]i )
[D]T [D]w )
[D]T
KDwi + W
The partitioning of N-ethylmaleimide between the micro-
emulsion pseudo-phases can be defined in terms of its partition
On the basis of the distribution of the reactants in the
microemulsion, the 1,3-dipolar cycloaddition can take place at
the interface and in the aqueous phase. Therefore, the reaction
rate for the process can be expressed as follows:
constant between the aqueous phase and the interface,9 Kwmi
)
133, and that between the continuous medium and the interface,9
Kmoi ) 16. On the other hand, benzonitrile oxide (D) will only
partition between the aqueous phase and the interface, with
KDwi. The previous partition constants are given by
rate ) k′[D]i + k′ [D]w
(7)
i
w
[m]
[m]
[D]
Kmwi
)
i W Kmoi )
iZ KDwi
[m]o
)
i W
[D]w
(2)
where ki′ and kw′ are the pseudo-first-order rate constants at the
interface and in the aqueous phase, respectively. To establish
the rate law as a function of the first-order rate constants, one
must use the N-ethylmaleimide concentration at the interface
[m]w
where parameter Z, by analogy with W, is the mole ratio between
6120 J. Org. Chem., Vol. 71, No. 16, 2006

1,3-Cycloaddition of Benzonitrile Oxide to N-Ethylmaleimide
w
k2 KmoiVh
k2 KmoiVhH O
+
AOTW
i
KmwiKDwi
2
1
)
(13)
slope
1
1 + D W
Kwi
Figure 4 illustrates the influence of parameter W on the
reciprocal slopes of Figure 3. As can be seen, they are all
independent of the water content of the microemulsion.
This result can be explained in two different ways. First, the
numerator and denominator on the right-hand side of eq 13 may
m
oi
m
w
i
fulfill the following inequalities: k2 K VhH O , k2 K VhAOT
/
2
oi
KmwiKDwiW and 1 , 1/KwDiW. If these relations hold, then the
expression can be simplified to
FIGURE 3. Fitting of eq 12 to the experimental results obtained in
the 1,3-dipolar cycloaddition of N-ethylmaleimide to benzonitrile oxide
in AOT/isooctane/water microemulsions at 25.0 °C; (b) W ) 2, (O)
W ) 17.
w
k2 KmoiVh
AOT ) 0.0160
(14)
1
)
Kmwi
slope
as referred to the interface volume, [m]ii, and that in the aqueous
where the reciprocal slope is clearly independent of W,
consistent with the experimental results. Equation 14 allows k2
w
w
phase as referred to its volume, [m]w
:
to be easily calculated since one knows Kmoi ) 16, Kwmi ) 133,
and VhAOT ) 0.34 M-1. This leads to k2w ) 0.39 M-1 s-1, which
is rather disparate from the reported value in bulk water (kw )
8.5 × 10-3 M-1 s-1).10a We can therefore rule out this
possibility. The other is that the numerator and denominator
on the right-hand side of eq 13 may fulfill these alternative
i
w
rate ) kobs[D]T ) k2 [m]ii[D]i + k2 [m]ww[D]w
(8)
In this equation, [m]ii and [m]w refer to the interface and
aqueous phase volume, respectively. For easier manipulation,
one must refer them to the total microemulsion volume:
w
m
m
w
inequalities: k2 K VhH O . k2 K VhAOT/Km KD W and 1 .
i
2
oi
oi
wi wi
1/KDwiW. If so, then
1
1
w
[m]ii )
[m]i [m]w
)
[m]w (9)
VhAOT[AOT]
VhH O[H2O]
2
1
i
) k2 KmoiVhH O ) 0.0160
(15)
2
slope
This allows the following expressions for the reaction rate to
be derived:
Consistent with the experimental results, eq 15 predicts that the
reciprocal slope is independent of W. If it holds, then one can
determine the rate constant at the microemulsion interface (k2
1
1
i
i
w
rate ) k
[m]i [D]i + k2
[m]w[D]w
2 VhAOT[AOT]
Vh [H2O]
H2O
) 0.055 M-1 s-1). The latter possibility is consistent with KDwi
g 400, so the inequality must be fulfilled at any W value,
including the highest (W ) 40). The equilibrium constant for
incorporation of benzonitrile oxide from the water microdroplets
to the interface can be extrapolated from the results for aqueous
micelles. Thus, SDS micelles have been found to fulfill the
following expression: KsD ) VmPD ) [D]m/[D]w[SDS], where
PD is the partition coefficient of D between the micelles and
the aqueous medium, and Vm the surfactant molar volume. On
the basis of previously reported values,10b KsD ) 24.5 M-1. This
value can be expressed in terms of the equilibrium constant for
incorporation from the water microdroplets to the microemulsion
interface, KDwi, simply by introducing the water concentration:
(10)
By substituting eq 6 and the expressions for [m]w and [m]i into
the rate equation, one obtains the following relation between
the apparent rate constant and parameter Z:
KmoiKmwiKDwi
2 VhAOT[AOT]
KmoiW
i
W
k
+ k2
VhH O[AOT]
2
1
kapp
)
(11)
KmoiKmwi + KmwiZ + KomiW
(KDwi + W)
(KDwi + W)[KomiKmwi + KmoiW]
k2 KomiKwmiKDwiVh + k2 KmoiVhAOTW
1
KDwi ) KsD[H2O] ) [D]m/[D]w [H2O]/[SDS]. This yielded KD
)
+
i
w
wi
kapp[AOT]Vh VhAOT
) 1360, which clearly obeys the inequality 1 . 1/KDwiW.
However, this value should be considered with caution as it
was obtained on the assumption that the micelle association
constants for SDS and AOT are similar. However, the extrapo-
lated value of KDwi was large enough to rule out the first
assumption, 1 , 1/KwDiW, as it would require KwDi e 0.2, which
is about 104 times lower than the value extrapolated from that
for SDS micelles.
H2O
H2O
(KDwi + W)Kmwi
Z (12)
i
w
k2 KmoiKmwiKDwiVhH O + k2 KmoiVhAOTW
2
Figure 3 is consistent with the linear correlation predicted by
eq 12.
To determine the rate constant at the interface, ki, we shall
focus on the slopes of the fitting of eq 12 to the experimental
results as these can be more accurately determined than the
intercepts. The reciprocal slopes of Figure 3 can be expressed
as
Table 2 shows the rate constants for the reaction into various
solvents. As can be seen, the values are similar in all solvents
except water, which reveals a slight accelerating effect. Note,
however, that the rate constant at the microemulsion interface
J. Org. Chem, Vol. 71, No. 16, 2006 6121

Engberts et al.
thermore, one should take into consideration that the levels of
the FMOs can be affected by (de)stabilizing factors. For
example, electron-withdrawing substituents stabilize the FMOs,
whereas electron-donating substituents raise the FMO energy.
Similarly, complexation of Lewis acids leads to a drop in FMO
energy.16 Hydrogen bonding is another factor that can promote
cycloadditions by reducing the energies of the FMOs.17 Hydrogen-
bond interactions can stabilize the FMOs of the reactants, and
the magnitude depends on the susceptibility of the reactants
toward such interactions. The preferred complexation of Lewis
acids with nitrile oxides18 indicates that nitrile oxides are good
Lewis bases. Therefore, the FMOs of these dipoles are
substantially stabilized in protic solvents. For the reaction of
nitrile oxides with electron-poor dipolarophiles, the dominating
interaction is that between the HOMO of the 1,3-dipole and
the LUMO of the dipolarophile. The electron-poor dipolaro-
philes are relatively good hydrogen-bond acceptors, leading to
a reduction of the levels of the FMOs in protic solvents.
However, this interaction is less efficient than that between the
nitrile oxide and protic solvents. This means that the Gibbs
energy of activation is increased for this reaction, leading to a
retardation of the cycloadditions of the nitrile oxide with
electron-poor dipolarophiles in protic solvents.
FIGURE 4. Fitting of eq 13 to the experimental results obtained in
the 1,3-dipolar cycloaddition of benzonitrile oxide to N-ethylmaleimide
in AOT/isooctane/water microemulsions at 25.0 °C.
TABLE 2. Rate Constant of the 1,3-Dipolar Cycloaddition of
Benzonitrile Oxide to N-Ethylmaleimide at 25.0 °C
solvent
k/M-1 s-1
hexanea
2.6 × 10-3
1.7 × 10-3
1.2 × 10-3
2.7 × 10-3
3.3 × 10-3
2.3 × 10-3
8.5 × 10-3
5.5 × 10-2
1,4-dioxanea
dichloromethanea
DMSOa
Hydrogen bonding would provoke the reaction rate of
benzonitrile oxide cycloaddition to N-ethylmaleimide to diminish
on increasing the water content of the microemulsion. Previous
studies in our laboratory have allowed us to obtain the values
of the solvent ionizing power of the interface depending on the
water content of AOT-based microemulsions.19 The ionizing
power and nucleophilicity of the interface of AOT-based
microemulsions are influenced by the water content of the
system. When W decreases so does the ionizing power because
2,2,2-trifluoroethanola
ethanola
watera
interface or AOT-based
microemulsionb
a From ref 10b. b In AOT/isooctane/water microemulsions.
is roughly 20 times higher than that in the organic solvents and
approximately 5 times higher than that in water; this is rather
surprising as the reaction is weakly sensitive to the polarity of
the medium.
-
the strong interaction between the SO3 anionic headgroup of
the surfactant and the water molecules decreases the electrophilic
character of water. Nevertheless, the results obtained in the
present work show that the reaction rate is W-independent and
approximately 5 times higher than that in bulk water. Recent
studies20 on the cycloaddition of nitrones to nitriles have shown
that the interaction of Lewis acids with the nitrile in the course
of the reaction facilitates the cycloaddition by stabilizing
transition states, intermediate, and product rather than by
activating the nitrile. When the reaction takes place at the
interface of AOT-based microemulsions, the possibility of
interaction with Lewis acids must be discarded since the
interface of the microemulsion presents an increase of the basic
character in comparison with bulk water due to the interactions
with the SO3- anionic headgroup of the surfactant and the water
molecules.
Experimental results for the 1,3-dipolar cycloaddition of
benzonitrile oxide to N-ethylmaleimide10a were explained in
terms of the frontier molecular orbital (FMO) theory, which
has been used extensively to explain and predict reactivity in
1,3-dipolar cycloadditions.12 This theory states that the Gibbs
energy of activation is related to the energy gap between
the interacting HOMO and LUMO. The energies of HOMO
and LUMO can be experimentally assessed (ionization poten-
tial and electron affinity, respectively) or theoretically esti-
mated. For a number of common reactants in 1,3-dipolar
cycloadditions, Houk13 has calculated the energy of the FMOs.
For most 1,3-dipolar cycloadditions, a good correlation is ob-
served between the Gibbs energy of activation and the ionization
potential of the dipolarophile, in accordance with the FMO
theory.14 FMO theory also accounts for stereoselectivity and
regioselectivity: reactions take place in the direction of
maximum HOMO-LUMO overlap.15 The relative levels of
the HOMO and LUMO of both reactants determine whether
the HOMO(dipole)-LUMO(dipolarophile) interactions or the
LUMO(dipole)-HOMO(dipolarophile) interactions are dominant. Fur-
To justify the behavior observed in AOT/isooctane/water
microemulsions, one must consider the specific region of the
(16) Laszlo, P.; Lucche, J. Act. Chim. 1984, 42.
(17) (a) Corsico Coda, A.; Desimoni, G.; Ferrari, E.; Righetti, P. P.;
Tacconi, G. Tetrahedron 1984, 40, 1611. (b) Desimoni, G.; Faita, G.;
Righetti, P.; Tornaletti, N.; Visigalli, M. J. Chem. Soc., Perkin Trans. 2
1989, 437. (c) Burdisso, M.; Desimoni, G.; Faita, G.; Righetti, P.; Tacconi,
G. J. Chem. Soc., Perkin Trans. 2 1989, 845. (d) Corsico Coda, A.;
Desimoni, G.; Faita, G.; Righetti, P.; Tacconi, G. Tetrahedron 1989, 45,
775. (e) Desimoni, G.; Faita, G.; Righetti, P. P.; Toma, L. Tetrahedron
1990, 46, 7951. (f) Desimoni, G.; Faita, G.; Righetti, P. P. Tetrahedron
1991, 47, 5857. (g) Desimoni, G.; Faita, G.; Pasini, D.; Righetti, P. P.
Tetrahedron 1992, 48, 1667.
(18) Curran, D. P.; Kim, B. H.; Piyasena, H. P.; Loncharich, R. J.; Houk,
K. N. J. Org. Chem. 1987, 52, 2137.
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6122 J. Org. Chem., Vol. 71, No. 16, 2006

1,3-Cycloaddition of Benzonitrile Oxide to N-Ethylmaleimide
SCHEME 3
SCHEME 5
by the presence of a negatively charged environment (Scheme
4); this destabilizes benzonitrile oxide, the initial state of the
reaction, and favors the 1,3-dipolar addition. This is supposed
to be the decisive factor accounting for the acceleration of the
1,3-dipolar addition reaction in AOT/isooctane/water micro-
emulsions in relation to organic solvents and water.
This reaction has previously been studied in SDS and CTAB
micellar media;10b the rate constants in both cases were lower
than those obtained in pure water (kSDS/kwater ) 0.23 and kCTAB
/
kwater ) 0.44) as a result of the effect of the polar headgroups
in the surfactant being smaller than those in the microemulsions
and the micelles, therefore not influencing the stability of
benzonitrile oxide. This different behavior of aqueous micelles
and microemulsions has previously been observed for solvolytic
reactions. Thus, the solvolysis of anisoyl chloride was found to
always be faster in cationic microemulsions (TTABr/hexanol/
isooctane/water), TTABr being tetradecyltrimethylammonium
bromide, than in the case of anionic ones (SDS/hexanol/
isooctane/water); also, the k+/k- ratio increased with decreasing
water content in the microemulsion.21 This effect can be ascribed
to the release of the leaving group, Cl-, being more favorable
in the presence of cationic TTABr headgroups than in that of
anionic SDS headgroups. By contrast, Bunton et al.22 found the
k+/k- ratio in aqueous micelles to be only 0.1. The difference
between the behavior observed in w/o microemulsions and
aqueous micelles may be the result of a difference in the relative
ease of stabilization of the acylium ion and leaving group. In
aqueous micelles, where abundant water is available, solvation
of the chloride leaving group is fast and easy, so the reaction is
faster with anionic surfactants than with cationic ones because
the former help stabilize the acylium ion. Conversely, in w/o
microemulsions, the contribution of the surfactant headgroups
to solvation of the leaving group outweighs its contribution to
stabilization of the acylium ion. This interpretation is consistent
with the result that the k+/k- ratio increases with decreasing
W. The decreased ability of the microemulsion to solvate the
negative charge in the cycloaddition of benzonitrile oxide
relative to SDS and CTAB micelles destabilizes the oxide and
consequently increases its reactivity.
SCHEME 4
interface where the 1,3-dipolar cycloaddition takes place and
also the reaction mechanism. Because of the dipolar nature of
benzonitrile oxide, its 1,3-dipolar addition will take place in
the innermost region of the microemulsion interface (Scheme
3), so that the oxide can be in direct contact with the polar
headgroups in the surfactant and their solvating water molecules.
The interface region where the reaction is to occur will possess
some negative charge by virtue of the presence of the polar
headgroups in the surfactant and will destabilize the negative
charge of benzonitrile oxide (Scheme 4). No such instability
will occur in water or an organic solvent. If the 1,3-dipolar
cycloaddition took place in a positively charged environment,
then the oxide will not be so markedly destabilized, and its
positive charge would be efficiently stabilized by the resonance
in the benzene ring.
1,3-Dipolar cycloaddition reactions proceed via a concerted
mechanism (Scheme 5). If the reaction medium destabilizes the
reactants, the process will be favored. In water or an organic
solvent (Table 1), the stability of benzonitrile oxide is not
affected; hence the absence of substantial differences in rate
constant in these media. However, when the reaction takes place
at the interface of an AOT/isooctane/water microemulsion, the
negative charge in benzonitrile oxide is strongly destabilized
Acknowledgment. Financial support from the Ministerio de
Ciencia y Tecnolog´ıa (Project CTQ2005-04779BQU) and Xunta
de Galicia (PGIDT03-PXIC20905PN and PGIDIT04TMT-
209003PR) is gratefully acknowledged.
JO060809F
(21) Garc´ıa-R´ıo, L.; Leis, J. R.; Reigosa, C. J. Phys. Chem. B 1997,
101, 5514-5520.
(22) Bunton, C. A.; Savelli, G. AdV. Phys. Org. Chem. 1986, 22, 213-
309.
J. Org. Chem, Vol. 71, No. 16, 2006 6123