1,3-Dipolar cycloadditions of benzonitrile oxide with various dipolarophiles in aqueous solutions. A kinetic study

Article abstract of DOI:10.1021/jo980900m

The second-order rate constants for the 1,3-dipolar cycloaddition of benzonitrile oxide (1) with various dipolarophiles (2a-e) were determined in aqueous media and in organic solvents to gain more insight into the influence of an aqueous medium on pericyclic reactions. 1,3-Dipolar cycloadditions with electron-poor dipolarophiles are accelerated in water and protic solvents, whereas an aqueous medium has no special effect when electron-poor dipolarophiles are involved. These observations can be explained using frontier molecular orbital theory. In all cases, enforced hydrophobic interactions promote the reaction. These results are supported by kinetic experiments in waterethanol mixtures. Sodium dodecyl sulfate micelles accelerate the cycloaddition of 1 with both electron-rich and electron-poor dipolarophiles. More than for other systems, the present results show that hydrogen bonding and hydrophobic interactions can either cooperate or counteract each other in determining the kinetic medium effects in aqueous solutions.

Full text of DOI:10.1021/jo980900m

J . Org. Chem. 1998, 63, 8801-8805
8801
1
,3-Dip ola r Cycloa d d ition s of Ben zon itr ile Oxid e w ith Va r iou s
Dip ola r op h iles in Aqu eou s Solu tion s. A Kin etic Stu d y
Dick van Mersbergen, J an W. Wijnen, and J an B. F. N. Engberts*
Department of Organic and Molecular Inorganic Chemistry, University of Groningen,
Nijenborgh 4, 9747 AG Groningen, The Netherlands
Received May 11, 1998
The second-order rate constants for the 1,3-dipolar cycloaddition of benzonitrile oxide (1) with various
dipolarophiles (2a -e) were determined in aqueous media and in organic solvents to gain more
insight into the influence of an aqueous medium on pericyclic reactions. 1,3-Dipolar cycloadditions
with electron-poor dipolarophiles are accelerated in water and protic solvents, whereas an aqueous
medium has no special effect when electron-poor dipolarophiles are involved. These observations
can be explained using frontier molecular orbital theory. In all cases, enforced hydrophobic
interactions promote the reaction. These results are supported by kinetic experiments in water-
ethanol mixtures. Sodium dodecyl sulfate micelles accelerate the cycloaddition of 1 with both
electron-rich and electron-poor dipolarophiles. More than for other systems, the present results
show that hydrogen bonding and hydrophobic interactions can either cooperate or counteract each
other in determining the kinetic medium effects in aqueous solutions.
5
6
7
In tr od u ction
of olefins, Mannich reactions, halogenations, and po-
lymerizations.8 Two reactions of the class of pericyclic
Water has never been a popular medium in organic
chemistry. Chemists who use water as a solvent are
often confronted with practical problems such as limited
solubility of the reactants or the “aggressive” nature of
water toward organic compounds. However, since the
eighties, the use of water as a solvent in organic
chemistry has become an active field of research.1
One of the reasons for this rediscovery of water as a
reaction medium is the search for new synthetic proce-
dures in organic chemistry which are more environmen-
tally friendly or can lower the cost of industrial processes.
Furthermore, water is in several respects a unique
solvent and can affect a chemical reaction in various
ways. For example, organic reactions can be accelerated
or the endo/exo ratio of the products of cycloadditions can
be changed when a reaction is performed in water instead
9
reactions, the Claisen rearrangement and particularly
the Diels-Alder reaction,
reactions that take advantage of an aqueous reaction
medium.
10-14
are the best examples of
In general, the rate of a Diels-Alder reaction is quite
solvent insensitive, but in 1980, Breslow10 discovered a
striking rate enhancement of this reaction in water. He
attributed this acceleration to hydrophobic effects. Ever
since this publication, the Diels-Alder reaction has been
extensively studied in aqueous solutions3 and at present
it is widely accepted that two factors contribute to these
,11
(4) (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl.
971, 10, 496. (b) Lubineau, A.; Aug e´ , J . Tetrahedron Lett. 1992, 33,
073. (c) Larpent, C.; Patin, H. Tetrahedron 1988, 44, 6107. (d)
1
8
Larpent, C.; Meignan, G.; Patin, H. Tetrahedron 1990, 46, 6381. (e)
Larpent, C.; Meignan, G. Tetrahedron Lett. 1993, 34, 4331. (f) Keller,
E.; Feringa, B. L. Tetrahedron Lett. 1996, 37, 1879.
5) (a) Fringuelli, F.; Germani, R.; Pizzo, F.; Savelli, G. Tetrahedron
Lett. 1989, 30, 1427. (b) Fringuelli, F.; Pizzo, F.; Germani, R. Synlett
991, 475. (c) Fringuelli, F.; Germani, R.; Pizzo, F.; Santinelli, F.;
Savelli, G. J . Org. Chem. 1992, 57, 1198.
6) Tychopoulos, V.; Tyman, J . H. P. Synth. Commun. 1986, 16,
1401.
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O. J . Org. Chem. 1997, 62, 236.
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1993, 1119.
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4, 515. (b) Grieco, P. A.; Brandes, E. B.; McCann, S.; Clark, J . D. J .
Org. Chem. 1989, 54, 5489. (c) Severance, D. L.; J orgensen, W. L. J .
Am. Chem. Soc. 1992, 114, 10966. (d) Gao, J . J . Am. Chem. Soc. 1994,
2
,3
of in the usual organic solvents.
The special effects of water on chemical reactions are
due to several interaction mechanisms. In particular,
(
3
1
hydrophobic interactions, which largely stem from the
limited ability of water to dissolve apolar molecules, are
of importance. Also, the capacity of water to act as both
a hydrogen-bond donor and a hydrogen-bond acceptor can
have major effects on chemical transformations.
A growing group of organic reactions appears to benefit
from aqueous media. Among them are 1,2- and 1,4-
nucleophilic additions to carbonyl groups, epoxidations
(
(
2
(
5
4
1
16, 1563. (e) Gajewski, J . J .; Brichford, N. L. J . Am. Chem. Soc. 1994,
116, 3165.
(10) Rideout, D. C.; Breslow, R. J . Am. Chem. Soc. 1980, 102, 7816.
(
1) (a) Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie:
Glasgow, 1998. (b) Li, C.-J .; Chan, T.-H. Organic Reactions in Aqueous
Media; Wiley: New York, 1997. (c) Lubineau, A. Chim. Ind. 1996, 123.
d) Lubineau, A.; Aug e´ , J .; Queneau, Y. Synthesis 1994, 741. (e) Li, C.
(11) (a) Grieco, P. A.; Yoshida, K.; Garner, P. J . Org. Chem. 1983,
48, 3137. (b) Waldmann, H.; Braun, M. Liebigs Ann. Chem. 1991, 1045.
(c) Lubineau, A.; Aug e´ , J .; Grand, E.; Lubin, N. Tetrahedron 1994, 50,
10265.
(12) (a) Blake, J . F.; J orgensen, W. L. J . Am. Chem. Soc. 1991, 113,
7430 (b) Blake, J . F.; Lim, D.; J orgensen, W. L. J . Org. Chem. 1994,
59, 803.
(
Chem. Rev. 1993, 93, 2023. (f) Grieco, P. A. Aldrichimica Acta 1991,
2
4, 59. (g) Breslow, R. Acc. Chem. Res. 1991, 24, 159.
2) Blokzijl, W.; Engberts, J . B. F. N. Angew. Chem., Int. Ed. Engl.
993, 32, 1545.
3) (a) Blokzijl, W.; Blandamer, M. J .; Engberts, J . B. F. N. J . Am.
(
1
(
Chem. Soc. 1991, 113, 4241. (b) Blokzijl, W.; Engberts, J . B. F. N. J .
Am. Chem. Soc. 1992, 114, 5440. (c) Otto, S.; Blokzijl, W.; Engberts,
J . B. F. N. J . Org. Chem. 1994, 59, 5372. (d) Wijnen, J . W.; Zavarise,
S.; Engberts, J . B. F. N. J . Org. Chem. 1996, 61, 2001.
(13) Van der Wel, G. K.; Wijnen, J . W.; Engberts, J . B. F. N. J . Org.
Chem. 1996, 61, 9001.
(14) Wijnen, J . W.; Engberts, J . B. F. N. J . Org. Chem. 1997, 62,
2039.
1
0.1021/jo980900m CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/01/1998

8
802 J . Org. Chem., Vol. 63, No. 24, 1998
van Mersbergen et al.
accelerations in aqueous media. First, the enhanced
hydrogen bonding of water (in combination with the
polarity of water) often stabilizes the transition state
compared to the initial state, thereby increasing the rate
of the reaction. Second, enforced hydrophobic inter-
actions3 promote Diels-Alder reactions in water. This
phenomenon is related to the fact that the water-
accessible surface area of the activated complex is
reduced compared to that of the hydrated reactants.
Computer simulations have confirmed that the accelera-
tion of aqueous Diels-Alder reactions is due to these two
factors.12 The magnitude of both effects depends on the
nature of the reactants. Recently, Diels-Alder reactions
have been examined for which either hydrogen-bond
interactions13 or enforced hydrophobic interactions can
be neglected. These studies revealed that enhanced
hydrogen bonding of water to the activated complex is
often the major factor for the aqueous accelerations of
Diels-Alder reactions.
After the success of the Claisen rearrangement and the
Diels-Alder reaction in aqueous solutions, it seems likely
that 1,3-dipolar cycloadditions, another representative of
the class of pericyclic reactions, could also benefit from
water as the reaction medium. This idea is supported
by the fact that 1,3-dipolar cycloadditions and Diels-
Alder reactions share many mechanistic features, in
particular the fact that both reactions are concerted,
nearly synchronous processes with an early transition
state.15 In fact, the dipolarophiles in 1,3-dipolar cycload-
ditions act as dienophiles in Diels-Alder reactions.
Sch em e 1
a
further attempts were made to investigate the origin of
this kinetic medium effect. The aqueous reaction me-
dium also had a synthetic advantage: the product
precipitates during the reaction, which facilitates isola-
tion of the product. Yields are higher than in organic
media, and recrystallization of the product is not neces-
sary.
14
Another application of water as a medium for 1,3-
dipolar cycloadditions was reported by Rohloff. Dibro-
20
moformaldoxime decomposes into nitrile oxide in alkaline
water, after which it smoothly and in high yields adds
to dipolarophiles. In this case, also, the synthetic ad-
vantages of an aqueous medium were emphasized.
Following Grigg,21 Lubineau22 has studied the reaction
between azomethine ylides and N-ethylmaleimide in
aqueous solutions. In this case, a mixture of products
arising from a Michael addition and a 1,3-dipolar cy-
cloaddition is obtained. Curiously, water promotes the
Michael addition and organic cosolvents are required to
direct the reaction toward the desired cycloaddition
pathway.
1
,3-Dipolar cycloadditions with nitrile oxides yield
-isoxazolines or isoxazoles, which are useful intermedi-
ates in organic synthesis, and still much research is
focused on extending the synthetic possibilities.16
2
The 1,3-dipolar cycloaddition of phenyl azide with
norbornene in aqueous solutions has also been studied.
A
2
3
common medium for 1,3-dipolar cycloadditions with
nitrile oxides is a biphasic aqueous/organic mixture.17 In
these mixtures, the 1,3-dipoles are generated in situ,
which is necessary because of the instability of the dipole.
In 1978, Hegarty18 was the first to demonstrate that
water could act both as a base for the generation of the
dipole from benzohydroxamoyl chloride and as a medium
for the consecutive 1,3-dipolar cycloaddition. He per-
formed the cycloadditions of p-nitrobenzonitrile oxide
with ethyl acrylate and dimethyl maleate in various
media. No unusual beneficial effect of pure water on the
rate of cycloaddition was observed (the rate constant in
water was roughly twice the rate constant in a 1:1
mixture of water and 1,4-dioxane). However, in 1991, a
Kinetic data revealed a remarkable rate acceleration in
water-rich solutions compared with conventional organic
solvents. Hydrophobic interactions were considered to
be the prime accelerating factor for the rate enhance-
ment. Herein we describe an extensive study of the
kinetics of 1,3-dipolar cycloadditions of benzonitrile oxide
with various dipolarophiles in several organic and aque-
ous media.
Resu lts a n d Discu ssion
1
,3-Dip ola r Cycloa d d it ion s of Nit r ile Oxid es in
Wa ter a n d in Or ga n ic Solven ts. Second-order rate
constants for the 1,3-dipolar cycloadditions of benzonitrile
oxide (1) with various dipolarophiles (Scheme 1) were
determined using UV spectroscopy. It is known that 1,3-
dipolar cycloadditions can be performed with both electron-
rich and electron-poor dipolarophiles.15 We chose cyclo-
pentene (2a ) and 2,3-dihydrofuran (2b) as electron-rich
dipolarophiles. In addition, we selected methyl vinyl
ketone (2c), acrylonitrile (2d ), and N-methylmaleimide
1
2
4-fold increase of the rate constant for the addition of
,6-dichlorobenzonitrile oxide to 2,5-dimethyl-p-benzo-
quinone in a mixture of ethanol and water (6:4, v/v)
relative to that in chloroform was reported by Shiraishi.19
Compared to the usual solvent effects observed for 1,3-
dipolar cycloadditions, this rate enhancement is rather
large. No relationship between spectroscopic data of the
reactants and the rate acceleration was found, and no
(
2e), which are dipolarophiles possessing electron-
(
15) 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley:
New York, 1984.
16) Eastman, C. J . in Advances in Heterocyclic Chemistry; Academic
Press: San Diego, 1994; Vol. 60.
17) (a) Grundmann, C.; Richter, R. J . Org. Chem. 1967, 32, 2308.
b) Grundmann, C.; Datta, S. K. J . Org. Chem. 1969, 34, 2016. (c) Lee,
G. A. Synthesis 1982, 508.
18) Dignam, K. J .; Hegarty, A. F.; Quain, P. L. J . Org. Chem. 1978,
3, 388.
(20) Rohloff, J . C.; Robinson, J ., IIII; Gardner, J . O. Tetrahedron
Lett. 1992, 33, 3113.
(
(21) (a) Grigg, R.; Aly, M. F.; Sridharan, V.; Thianpatanagul, S. J .
Chem. Soc., Chem. Commun. 1984, 182. (b) Grigg, R.; Mongkolaussa-
varatana, T.; Pounds, C. A.; Sivagnanam, S. Tetrahedron Lett. 1990,
31, 7215.
(22) Lubineau, A.; Bouchain, G.; Queneau, Y. J . Chem. Soc., Perkin
Trans. 1, 1995, 2433.
(
(
(
4
6
(
19) Inoue, Y.; Araki, K.; Shiraishi, S. Bull. Chem. Soc. J pn. 1991,
(23) Wijnen, J . W.; Steiner, R. A.; Engberts, J . B. F. N. Tetrahedron
Lett. 1995, 36, 5389.
4, 3079.

1
,3-Dipolar Cycloadditions of Benzonitrile Oxide
J . Org. Chem., Vol. 63, No. 24, 1998 8803
withdrawing groups and are classified as electron-poor
dipolarophiles.
The cycloadditions were studied in seven different
solvents. Among them were the apolar and aprotic
n-hexane and dichloromethane, which is used as the
organic layer in the biphasic system in which 1,3-dipolar
cycloadditions are generally performed. Furthermore,
some protic solvents were used because hydrogen-bond-
ing probably affects the reaction rate. We included 2,2,2-
trifluoroethanol (TFE) because this solvent shows a
F igu r e 1. Schematic drawing of the levels of the FMOs of an
electron-rich dipolarophile (2a ,b, left), benzonitrile oxide (1,
middle), and an electron-poor dipolarophile (2a -c, right). The
solid lines depict the FMOs in n-hexane, and the dashed lines
depict the FMOs in a protic solvent.
Ta ble 1. Secon d -Or d er Ra te Con sta n ts for th e
1
,3-Dip ola r Cycloa d d ition s of 1 w ith 2a -e in Va r iou s
“
protic behavior” similar to that of water.24 Low sub-
Or ga n ic Solven ts a n d in Wa ter a t 25.0 °C
strate concentrations were used in the experiments,
allowing the use of water as a solvent. The kinetic
results are collected in Table 1.
dipolarophile
2
a
2b
2c
2d
2e
2
3
2
1
0 k
2
10 k
2
10k
2
10 k
2
10k
2
Comparing the second-order rate constants for the
reactions in n-hexane and in water, it is interesting to
see that the cycloadditions with the electron-rich dipo-
larophiles 2a and 2b are accelerated in aqueous solutions,
whereas the aqueous medium has a small rate-retarding
effect on the rate constants for the cycloadditions with
the electron-poor dipolarophiles (2c-2e). Also of interest
are the cycloadditions performed in TFE. The results of
these measurements show a trend similar to that for
the reactions in water: cycloadditions of nitrile oxide with
electron-rich dipolarophiles 2a and 2b are accelerated,
and cycloadditions of nitrile oxide with electron-poor
dipolarophiles 2c-e are strongly retarded in TFE, using
n-hexane as the reference solvent. These results clearly
signal the influence of hydrogen bonding of the solvent
to the reactants (positive for electron-rich dipolarophiles,
negative for electron-poor dipolarophiles). We contend
that water affects these 1,3-dipolar cycloadditions through
this mechanism.
-1
-1) (M-1
-1) (M-1
-1) (M-1
-1) (M-1
s
-1)
(
M
s
s
s
s
n-hexane
2.6
1.7
1.2
2.7
3.7
2.9
4.8
1.8
0.9
1.5
1.3
0.6
3.6
1.2
0.7
1
,4-dioxane
dichloro-
methane
dimethyl
sulfoxide
2.7
3.3
10.9
8.3
2.3
0.6
3.1
0.2
3.0
0.6
2,2,2-trifluoro-
ethanol
ethanol
water
2.3
8.5
6.3
30.0
3.3
3.0
1.4
1.1
2.2
2.6
The relative levels of the HOMO and LUMO of both
reactants determine whether the HOMO(dipole)-LUMO-
(dipolarophile) interactions or the LUMO(dipole)-HO-
MO(dipolarophile) interactions are dominant. Further-
more, 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
We suggest an explanation for these results in terms
of the frontier molecular orbital (FMO) theory, which has
been used extensively to explain and predict reactivity
29
leads to a drop in FMO energy. Hydrogen bonding is
another factor that can promote cycloadditions by reduc-
30
ing the energies of the FMOs.
2
5
in 1,3-dipolar cycloadditions. This theory states that
the Gibbs energy of activation is related to the energy
gap between the (dominant) interacting HOMO and
LUMO. The energies of HOMO and LUMO can be
experimentally assessed (ionization potential and elec-
tron affinity, respectively) or theoretically estimated. For
a number of common reactants in 1,3-dipolar cycloaddi-
tions, Houk26 has calculated the energy of the FMOs. The
results of these calculations are in reasonable accord with
experimental studies. For most 1,3-dipolar cycloaddi-
tions, a good correlation is observed between the Gibbs
energy of activation and the ionization potential of the
Figure 1 shows a schematic presentation of the levels
of the FMOs of an electron-rich dipolarophile (left),
benzonitrile oxide (1) (center), and an electron-poor
dipolarophile (right). The solid lines represent the FMOs
in hexane, and the dashed lines represent the FMOs in
a protic solvent. Hydrogen-bond interactions can stabi-
lize the FMOs of the reactants, and the magnitude
depends on the susceptibility of the reactants toward
such interactions. The preferred complexation of Lewis
31
acids with nitrile oxides indicates that nitrile oxides are
good Lewis bases. Therefore, the FMOs of these dipoles
are substantially stabilized in protic solvents. The
2
7
dipolarophile, in accordance with FMO theory. FMO
theory also accounts for stereoselectivity and regioselec-
(29) Laszlo, P.; Lucche, J . Actual. Chim. 1984, 42.
tivity: reactions take place in the direction of maximum
(30) (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.
HOMO-LUMO overlap.28
2
1989, 437. (c) Burdisso, M.; Desimoni, G.; Faita, G.; Righetti, P.;
(
24) Wijnen, J . W. Ph.D. Thesis, University of Groningen, 1997.
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. Desimoni, G.; Faita, G.; Pasini, D.;
Righetti, P. P. Tetrahedron 1992, 48, 1667.
(31) (a) Seerden, J .-P. G. Ph.D. Thesis, Catholic University of
Nijmegen, 1995. (b) Curran, D. P.; Kim, B. H.; Piyasena, H. P.;
Loncharich, R. J .; Houk, K. N. J . Org. Chem. 1987, 52, 2137.
(25) (a) Sauer, J .; Sustmann, R. Angew. Chem., Int. Ed. Engl. 1980,
1
9, 779. (b) Huisgen, R. Pure Appl. Chem. 1980, 52, 2283.
26) Houk, K. N.; Sims, J .; Duke, R. E.; Strozier, R. W.; Geroge, J .
(
K. J . Am. Chem. Soc. 1973, 95, 7287. (b) Houk, K. N.; Sims, J .; Watts,
C. R.; Luskus, L. J . J . Am. Chem. Soc. 1973, 95, 7301. (c) Houk, K. N.;
Chang, Y.-M.; Strozier, R. W.; Caramella, P. Heterocycles 1977, 7, 793.
(
(
27) Sustmann, R. Pure Appl. Chem. 1974, 40, 569.
28) Fukui, K. Acc. Chem. Res. 1971, 4, 57.

8
804 J . Org. Chem., Vol. 63, No. 24, 1998
van Mersbergen et al.
electron-rich dipolarophiles 2a and 2b are weak hydrogen-
bond acceptors, which means that their FMOs are only
slightly affected by hydrogen-bond interactions. Overall,
both effects lead to a reduction of the energy gap between
the interacting FMOs (in this case, the HOMO of the
dipolarophile and the LUMO of the 1,3-dipole). Conse-
quently, the Gibbs energy of activation of the reaction is
reduced, and the reaction is accelerated in protic solvents,
including water. For the reaction with the electron-poor
dipolarophile, the dominating interaction is that between
the HOMO of the 1,3-dipole and the LUMO of the
dipolarophile. The electron-poor dipolarophiles are rela-
tively good hydrogen-bond acceptors, leading to a reduc-
tion of the levels of the FMOs in protic solvents. How-
ever, we assume that this interaction is less efficient than
that between the nitrile oxide and protic solvents, in view
of the known examples of Lewis acid inhibition of the
F igu r e 2. Second-order rate constants of the 1,3-dipolar
cycloaddition of 1 with 2a (9), 2b (1), 2c (0), 2d (4) and 2e
(O) in various ethanol-water mixtures at 25.0 °C, relative to
the second-order rate constants in pure ethanol.
1
,3-dipolar cycloadditions of acrylates with aromatic
3
1a
31b
nitrones or aliphatic nitrile oxides.
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.
However, we cannot account for all the results in Table
1
; in particular, the differences in rate constants for the
reactions in TFE and water (despite similar “protic”
2
4
character ) are not accounted for. We have to consider
the fact that the (de)stablizing influence on the FMOs is
the sole solvent effect that is included in the FMO theory.
Another contributor to aqueous accelerations of pericyclic
3
a
reactions are enforced hydrophobic interactions. En-
forced hydrophobic interactions are a result of the reduc-
tion of the water-accessible surface area of the reactants
during the activation process. For all cycloadditions in
this study, this effect will exert a favorable influence on
the rate of the reaction. We propose that the enforced
hydrophobic interactions account for the larger rate
constants in water compared to those for TFE. It is
interesting to note that for cycloadditions in aqueous
media hydrogen-bond interactions and enforced hydro-
phobic interactions can actually counteract each other.
Because Diels-Alder reactions are controlled by the same
mechanism, it is likely that these interactions also
counteract in the case of specific Diels-Alder reactions
in water. Indeed, the reaction of p-nitrostyrene with di-
F igu r e 3. Second-order rate constants of the 1,3-dipolar
cycloaddition of 1 with 2b (9) and 2c (1) in micellar solutions
of SDS at 25.0 °C, relative to the second-order rate constants
in pure water.
beyond a certain concentration (about 10 mol % for
ethanol) the hydrophobic hydration shells of the cosolvent
molecules start to overlap significantly, which leads to
the formation of cosolvent-rich domains and preferential
solvation by ethanol of the reactants. Consequently, the
reacting molecules no longer experience the unique
34
driving force of hydrophobic acceleration. This leads
to a decrease of the reaction rate.
1
,3-Dip ola r Cycloa d d it ion s of Nit r ile Oxid es in
Micella r Solu tion s. Finally, we have studied the effect
of anionic micelles on the cycloaddition of 1 with 2b and
(2-pyridyl)-1,2,4,5-tetrazine is retarded by hydrogen-bond
interactions (slow reaction in TFE), whereas this reaction
2
c. Sodium dodecyl sulfate (SDS) with a critical micelle
is promoted by enforced hydrophobic interactions.32
concentration (CMC) of 8.2 mM was used as surfactant.
The results are depicted in Figure 3.
1
,3-Dip ola r Cycloa d d it ion s of Nit r ile Oxid es in
Wa ter -Eth a n ol Mixtu r es. We have also examined the
cycloadditions of nitrile oxide with the five dipolarophiles
in various ethanol-water mixtures. In Figure 2, the rate
constants for these reactions are given relative to rate
constants for the reaction in pure ethanol. All reactions
show a maximum of the rate constant at a mole fraction
of water of roughly 0.9. This observation is in line with
similar results for Diels-Alder reactions, and for the
latter reactions, this phenomenon has been attributed to
hydrophobic effects.33 Small amounts of hydrophobic
cosolvent increase hydrophobic interactions in water,
further promoting bimolecular cycloadditions. However,
In both cases, an increase of the second-order rate
constant is observed above the CMC. This is probably
due to the fact that the hydrophobic dipolarophile is
bound to the micellar surface. However, at higher
concentrations of SDS, the rate is still increasing. Usu-
ally, the rate decreases at higher micelle concentrations
because the reactants are “diluted” over an increasing
number of micelles. This indicates that the binding of 1
to the micelles is relatively weak and that a high
concentration of micelles is necessary for complete bind-
ing of 1. Also, the fact that the wavelength at which
maximum absorption of 1 takes place hardly shifts in the
presence of micelles is indicative for the weak interac-
tions between 1 and the micelles.
(
32) Wijnen, J . W.; Zavarise, S.; Engberts, J . B. F. N.; Charton, M.
J . Org. Chem. 1996, 61, 2001.
33) Cargill, R. W.; MacPhee, D. E.; J . Chem. Soc., Faraday Trans.
1989, 85, 2665.
(
1
(34) Blokzijl, W. Ph.D. Thesis, University of Groningen, 1991.

1
,3-Dipolar Cycloadditions of Benzonitrile Oxide
J . Org. Chem., Vol. 63, No. 24, 1998 8805
Con clu d in g Rem a r k s
under vigorous stirring to a solution of 1.6 g of styrene in a 50
mL household-bleach solution. The reaction mixture became
warm, and a cream-colored solid spontaneously precipitated
1
,3-Dipolar cycloadditions of nitrile oxides in water
1
7c
illustrate how water affects bimolecular cycloadditions
in general: (1) enforced hydrophobic interactions acceler-
ate these bimolecular processes, because these interac-
tions promote the transformation of two hydrophobically
hydrated molecules into a less hydrophobic activated
complex, and (2) the effect of hydrogen-bond interactions
depends critically on the dominant HOMO-LUMO in-
teraction for the reaction. Only if hydrogen bonding
predominantly reduces the LUMO energy is the cycload-
dition further accelerated. Consequently, an additional
rate acceleration is only observed when the electron-poor
reactant (usually the 2π species) is more susceptible to
such interactions. Kinetic results for the 1,3-dipolar
cycloaddition with nitrones in aqueous media are in line
with this hypothesis.2
(3,5-diphenyl-2-isoxazoline; mp: 72-73 °C (lit. 73-75 °C);
1
H NMR (CDCl
.39 (m, 8H), 7.70 (m, 2H).
For all kinetic experiments, the following procedure was
3
): δ 3.34 (dd, 1H), 3.79 (dd, 1H), 5.75 (dd, 1H),
36
7
applied. Preparation of 1 was performed in a test tube by
dissolving benzaldoxime in a bleach/dichloromethane two-
phase system and shaking this tube for a few seconds. Several
microliters of the organic phase were transferred into a quartz
UV cell (1 cm) which contained the dipolarophile solution
(dipolarophile in excess) and which was placed in a thermo-
stated cell compartment of a Perkin-Elmer λ2 spectrophotom-
eter. The reactions were monitored at 273 nm at 25.0 °C, and
pseudo-first-order rate constants were calculated using a PC
fitting procedure (absorbance versus time). Starting concentra-
tions were ca. 0.1 mM of benzonitrile oxide and 5-40 mM of
dipolarophile. In all cases, isosbestic points were observed
throughout the spectral change. In the absence of dipolaro-
phile, the UV spectrum of 1 in water remained unchanged,
which indicates that side reactions such as hydrolysis, isomer-
ization, or dimerization are negligible. Each experiment was
carried out at least three times. Rate constants were repro-
ducible to within 4%.
4,35
Exp er im en ta l Section
All compounds were purchased from Aldrich. Dipolaro-
philes 2a -d were distilled before use. Solvents were either
of the best quality available or distilled before use.
One 1,3-dipolar cycloaddition was performed on a synthetic
scale. Thus, 1.6 g of pure benzaldoxime was added dropwise
J O980900M
(
36) (a) Sustmann, R.; Huisgen, R.; Huber, H. Chem. Ber. 1967, 100,
(35) Van Rietschoten, E. M.; Wijnen, J . W.; Engberts, J . B. F. N., to
1802. (b) Bast, K.; Christl, M.; Huisgen, R.; Mack, W.; Sustmann, R.
be published.
Chem. Ber. 1973, 106, 3258.