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University of Groningen
Cycloadditions in aqueous mediaWijnen, Jan Willem
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Cycloadditions in aqueous media. s.n.
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107
Chapter 6
1,3-Dipolar Cycloadditions in Aqueous Solutions1
This chapter reports kinetic results describing 1,3-dipolar
cycloadditions in aqueous media. On the
basis of mechanistic considerations it is expected that this
type of cycloaddition should benefit from
an aqueous medium, in a manner similar to that observed for
Diels-Alder reactions. Three
representatives of this class of reactions have been studied :
(inter- and intramolecular) additions to
aromatic azides, nitrile oxides and nitrones. The intrinsic
differences of these reactions enables
formulation of a complete description of the influence of water
on Diels-Alder and 1,3-dipolar
cycloadditions. FMO theory is used to rationalise the observed
solvent effects.
6.1 Introduction
Diels-Alder (DA) reactions have attained a principle position as
an example of a water-promoted
organic reaction and the previous chapters have illustrated that
a wide variety of these cycloadditions
benefit from an aqueous reaction medium. The aqueous DA
reactions are not just a kinetic peculiarity.
Many synthetic applications are known2. Usually yields and
selectivities are upgraded and some
reactions are only successful when water is used as solvent.
Therefore it is worthwhile exploring the
influence of water on other organic reactions as well, because
similar advantageous results may appear.
DA reactions are classified as pericyclic reactions3 and another
representative of pericyclic
C
B
AR
C
B
AR2
CB
AR
+_
_+
BAR2
C
Scheme 6.1
-
Chapter 6
108
reactions, the Claisen rearrangement, also greatly benefits from
aqueous reaction media4. Therefore it is
conceivable that a third pericyclic reaction, 1,3-dipolar
cycloadditions (DC reactions), would be also
promoted in water. Some examples of DC reactions are given in
Scheme 6.1. DC reactions share many
mechanistic features with DA reactions, so water could possibly
accelerate these reactions. This
possibility seems even more likely when we take into account the
fact that the dienophiles in DA
reactions act as dipolarophiles in 1,3-dipolar cycloadditions.
Perhaps in this case water also promotes
the cycloaddition by reducing the energy of the MOs of the
dipolarophile.
6.2 1,3-Dipolar Cycloadditions : Mechanism, Solvent Effects and
Applications5
Addition of unsaturated compounds to 1,3-dipoles yields a
five-membered (hetero) ring and is known as
1,3-dipolar cycloaddition (DC reaction) (Scheme 6.1). These
cycloadditions are reversible6. The 2π-
species are known as dipolarophiles and they are the same
compounds that act as dienophiles in DA
reactions. Also in the case of DC reactions both electron-rich
and -poor dipolarophiles can be employed.
Dipoles are rather unusual compounds, which contain four
electrons in three parallel molecular π
orbitals. These dipoles contain formally a positive charge,
which is compensated by a negative charge.
However, dipoles bear a small net charge and have a surprisingly
small dipole moment. Usually dipoles
are generated in situ. Dipoles are generally divided in two
classes : the propargyl-allenyl type and the
allyl type (Scheme 6.2).
A synopsis of the mechanistic characteristics of DC reactions
has a strong déjà-vu flavour :
practically all features are analogous to those mentioned in
Chapter 1 for DA reactions. Similarly to DA
reactions, little dispute exists about the mechanism of DC
reactions and the conclusions have been
reviewed5. Generally, DC reactions are concerted, nearly
synchronous processes with an early transition
state. Sometimes radical or stepwise mechanisms are thought to
play a role7. A strong argument in
favour of the concerted mechanism is the retention of
configuration of the dipolarophile in the product8.
The negative volume of activation9 and strongly negative entropy
of activation10,11 are typical for
concerted bimolecular cycloadditions. The modest Hammett
ρ-values for DC reactions point to a small
change in polarity of the reacting system during the activation
process5.
Many aspects of DC reactions are accounted for by Frontier
Molecular Orbital (FMO)
theory12,13. This theory is summarised in Chapter 1. The
reactivity of dipoles towards dipolarophiles is
determined by the energy of the MOs of the reactants. The Gibbs
energy of activation is determined by
the energy gap between the two dominantly interacting HOMO and
LUMO of the reactants. The energy
of the MOs of the reactants can be experimentally assessed
(ionisation potentials (HOMO) or electron
affinities (LUMO)) or theoretically estimated. Houk14 has
calculated the energy for MOs of a number of
-
1,3-Dipolar Cycloadditions in Aqueous Media
109
common DC reactants and the outcome is reasonably in accord with
experimental studies. Also the
reactivity of the dipolarophiles follows approximately the same
order for all DC reactions. For most DC
reactions a good correlation is observed between the ∆≠Gθ and
the ionisation potential of the
dipolarophile, signifying the quantitative correlation with the
MO energy13. Also the stereoselectivity
and regioselectivity is accounted for by FMO theory : reactions
take place in the direction of maximal
HOMO-LUMO overlap15.
The solvent effects on DC reactions are even smaller than those
for the DA reaction11,16. A
remarkable difference is the fact that many DC reactions have an
inverted solvent effect i.e. the reaction
is (slightly) retarded by polar solvents. Therefore, the
activated complex of DC reactions has a smaller
dipole moment than the reactants16. It has been noticed that
protic solvents have an unusual effect on
DC reactions (in terms of reaction rate). The small solvent
effect has been generally explained as a
logical consequence of the early transition state.
Kadaba17reported the beneficial effect of either dipolar
aprotic or protic solvents (including aqueous mixtures) on a
number of DC reactions, in particular when
diazo or azide compounds are used.
Similarly to DA reactions, Lewis acids can catalyse DC
reactions18. However, several examples
of Lewis-acid inhibition of DC reactions are also known. For
example, both yield and reaction rate of
the addition of acrylates to aromatic nitrones18 or aliphatic
nitrile oxides19 decrease in the presence of
several Lewis acids. These particular DC reactions are
LUMO(dipolarophile)-HOMO(dipole)
controlled and complexation of Lewis acids should promote the
cycloaddition. However, dipoles are
better Lewis bases than the dipolarophiles and consequently the
catalysts interact with the dipoles which
increases the MO-energy gap. Other methods that promote DC
reactions include the use of ultrasound
radiation20 and biocatalysts21.
CB
A A CB
+ +_ _
CB
A CB
A
+ +__
propargyl-allenyl type
allyl type
Scheme 6.2
-
Chapter 6
110
6.3 Aqueous 1,3-Dipolar Cycloadditions : An Overview
Compared to Diels-Alder reactions, DC reactions in aqueous
solutions have been studied far less. Again
the low solubility of the reactants plays a discouraging role,
but an additional problem is the instability
of most of the compounds that can participate as a dipole in
this reaction and their tendency to dimerise
(also by means of 1,3-dipolar cycloaddition). In fact, even in
inert organic solvents it is common
practise to generate the reactive species in situ in the
presence of an excess of dipolarophile to ensure an
efficient reaction.
In the literature several examples can be found of 1,3-dipolar
cycloadditions in biphasic
aqueous/organic mixtures22. No attempts were made to elucidate
in which phase the cycloaddition takes
place. Synthetically, homogeneous aqueous solutions have only
been sparsely used as medium for DC
reactions. Mixed aqueous media are advantageous for a number of
DC reactions17. Grigg and
coworkers23 generated ylides in the presence of strong
dipolarophiles, but the use of an aqueous solution
seems to be inspired by reagent-solubility, rather than reaction
rate.
In 1978, Hegarty24 demonstrated that water can play a useful
role in the generation of dipoles
and simultaneously serve as reaction medium for a consecutive
1,3-dipolar cycloaddition with numerous
dipolarophiles. Nitrile oxides were generated in situ by
dehydrohalogenation of hydroxamoyl chlorides,
in which case water acts as a base. The nitrile oxides readily
hydrolyse in alkaline water25, but in neutral
water this hydrolysis is slow enough to enable cycloaddition of
the dipole to dipolarophiles. Using ethyl
acrylate and dimethyl maleate as dipolarophiles, Hegarty24 noted
no special beneficial effect of pure
water on the rate of the cycloaddition
[k2(water)/k2(water-dioxane (1:1)) ≈ 1.8]. In pure water the
Hammett ρ-value of the addition of acrylonitrile to substituted
benzonitrile oxides is small (+0.36),
indicating the absence of any significant charge build-up during
the activation process24. This particular
study did not divulge anything ‘special’ about the aqueous
reaction medium and therefore it took
another thirteen years before the next paper in this subject
appeared. Shiraishi and coworkers26
announced an unusual solvent effect on the cycloaddition of
2,6-dichlorobenzonitrile oxide with 2,5-
dimethyl-p-benzoquinone in ethanol-water solutions. In organic
solvents this reaction exhibits the
common insensitivity towards a change of solvents, but in an
ethanol-water mixture (6:4, v:v) a
fourteen-fold increase of the rate constant relative to the rate
of reaction in chloroform was observed.
Although this rate enhancement may seem rather modest, it is
rather large compared to the usual solvent
effects observed in DC reactions. The authors applied
UV/VIS-spectroscopic methods to gain insight
into the origins of the rate enhancement, but they could not
discover a relationship between the
spectroscopic data of all compounds involved and the rate
constants. Their conclusion that “other
reasons, such as cage effect of the solvent or solvophobic
effect of the substrates may play a role” is
somewhat uninspired. The authors furthermore point out that the
aqueous reaction medium has an
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1,3-Dipolar Cycloadditions in Aqueous Media
111
attractive synthetic application : the product can be easily
isolated, because it precipitates during the
reaction. No recrystallisation is required and yields are higher
compared to those in organic media.
Rohloff reported another elegant application of water as a
medium for DC reactions27. His
method was actually a modified procedure of the previously
mentioned two-phase media.
Dibromoformaldoxime is decomposed in alkaline water after which
it smoothly and in high yield adds to
dipolarophiles. Again, the ease of this synthetic procedure is
emphasised by the authors.
Following Grigg23, Lubineau and coworkers28 generated azomethine
ylides in aqueous solutions
and studied their reactivity in detail. These dipoles add to
N-ethylmaleimide but a mixture of products
from a Michael addition and DC reaction is obtained. Curiously,
water promotes the Michael addition
and organic cosolvents are required to direct the reaction to
the desired cycloaddition pathway.
6.4 Results and Discussion
6.4.1 Intermolecular Cycloaddition of Electron-rich
Dipolarophiles to Aromatic Azides in Organic
Solvents and in Water
We have undertaken a kinetic study of the addition of phenyl
azide (6.1) to norbornene (6.2) in organic
solvents. Azides are versatile and relatively stable
1,3-dipoles29. Addition of dipolarophiles yields 1,2,3-
triazolines or -triazoles, regularly followed by decomposition
to aziridines or imines30. DC reactions
with azides proceed via a highly ordered transition state as
revealed by a negative and large in
magnitude entropy of activation10. The cycloadditions are
stereospecific and concerted, but the extent to
which both bonds are completed is not equal in the transition
state as indicated by the Hammett reaction
constant of +0.84 for the addition of 6.2 to substituted phenyl
azides10. On the basis of a rather limited
set of solvents, the addition of 6.1 with 6.2 was classified as
very solvent insensitive10. Azides add to
both electron-poor and -rich dipolarophiles. The cycloadditions
that are discussed in this section are
dominated by HOMO(dipolarophile)-LUMO(azide) interactions (See
Chapter 1).
In a study of the cycloaddition in aqueous media, the nature and
in particular the hydrophobicity
of the azide moiety needs to be considered carefully. The azide
group is an electron-withdrawing
moiety31 with a relatively small dipole moment (dipole moment of
phenyl azide = 1.55 D, less than
bromobenzene (µ = 1.70 D) and similar to aniline (µ = 1.53)). A
Hansch P-parameter, a conventional
hydrophobicity scale, is not known for the azide functionality,
but the limited solubility of 6.1 shows
that this compound is rather hydrophobic.
-
Chapter 6
112
On a synthetic scale this DC reaction proceeds smoothly in a
water-ethanol (1:1 v/v) solution,
which permits the isolation of 6.3 10,32. Reaction in ethanol
leads to the same exo adduct. No other
products were detected. Samples of the product were used to
determine the extinction coefficient of the
triazoline. The ‘initial-rate-kinetic’ method10,33 was used to
determine the second-order rate constants,
compiled in Table 6.1.
As usual for this type of reaction, a moderate response is
observed to a change of solvent. This
trend is largely in accord with a previously reported limited
data set10. Polar solvents appear to have a
slight rate-enhancing effect, and the observation that aprotic
dipolar solvents (DMSO and DMF) are the
best organic solvents suggests that hydrogen bonding by the
solvent is not favourable for this addition.
Considering the wide variety of organic solvents, acceleration
of the cycloaddition in aqueous media is
spectacular and unprecedented. On going from hexane to
water/1-cyclohexyl-2-pyrrolidinone (NCHP)
(99 : 1) the rate constant increases by a factor of 53. The
extent of this aqueous rate enhancement is in
the range observed for the aqueous DA reaction. For the aqueous
solutions, alkaline water (pH 12) was
used, in order to prevent the rearrangement of the product30,
which hampers the kinetic experiments.
Since norbornene is insoluble in pure water the cycloaddition
could not be studied in this solvent.
Another analogy with the aqueous DA reactions is the cosolvent
effect. Initial addition of water
Table 6.1 Second-order Rate Constants for the Intermolecular
1,3-Dipolar Cycloaddition of 6.1 with6.2 at 40.3°C in Organic
Solvents and in Water
Solvent k2 / 10-5 M-1 s-1 Solvent k2 / 10
-5 M-1 s-1
n-Hexane 4.7 EtOH 7.4THF 5.3 2-PrOH 8.2CHCl3 6.8 t-BuOH 8.0CCl4
5.5 H2O/MeOH (XW = 0.75)b 35CH3CN 7.7 H2O/EtOH (XW = 0.75)b 37DMSO
17.5 H2O/2-PrOH (XW = 0.92)b 83DMF 11.3 H2O/t-BuOH (XW = 0.94)b
72MeOH 7.3 H2O/NCHP
a (XW = 0.99)b 250a NCHP : 1-Cyclohexyl-2-pyrrolidinone. b XW =
mole fraction of water.
N N N+ _
+ N
NN
6.1 6.2 6.3
Scheme 6.3
-
1,3-Dipolar Cycloadditions in Aqueous Media
113
to hydrophobic cosolvents (e.g. t-BuOH) has no immediate effect
on the reaction rate (Figure 6.1).
Large mole fractions of water are necessary to produce
significant accelerations. In agreement with
aqueous DA reactions the mole fraction and the extent of the
additional accelerations correlate with the
hydrophobicity of the alcohols. Experimentally, measurement of
the second-order rate constants in
highly aqueous media is troublesome. The data points in Figure
6.1 are reproducible to within 4 %. In
solutions with still higher water contents, the reaction rate is
considerably reduced. However, the exact
second-order rate constants are irreproducible. In line with DA
reactions in water, a reduction of the
rate constants in (almost) pure water may be anticipated. The
exact extent remains unknown.
A notable experimental difference with the DA reactions
described in the previous chapters has
to be mentioned. The reported rate constants have been measured
under pseudo-first-order conditions,
with an excess of 6.2. Due to the modest reactivity of 6.1 and
6.2, the kinetic experiments were carried
out at the highest possible concentrations of 6.2. Certainly,
the properties of such solutions are no
longer ideal at these concentrations and microheterogeneities
possibly promote the intermolecular DC
reaction. So, aggregation of reactants could be excluded for DA
reactions in water, but not for the
present DC reaction.
0.0 0.2 0.4 0.6 0.8 1.00
20
40
60
80
k 2 /
10-5 M
-1.s-
1
Mole Fraction of Water
Figure 6.1 Second-order rate constants for the DC reaction of
6.1 with 6.2in water-alcohol mixtures versus the mole fraction of
water at 40.3 °C.MeOH (ˇ), EtOH (u), 2-PrOH (O), t-BuOH (t).
-
Chapter 6
114
Due to the low solubility of norbornene, the DC reaction of 6.1
with 6.2 could not be
investigated in pure water, which seriously hampers the quest
for a suitable explanation of the results.
Therefore, the addition of p-nitrophenyl azide (6.4) to
2,3-dihydrofuran (6.5) was examined (Scheme
6.4), because 6.5 is more hydrophilic than 6.2. This reaction
has been previously investigated by
Huisgen34. The second-order rate constant of this reaction in
organic solvents is 2.2 . 10-5 (CHCl3), 2.6 .
10-5 (toluene) and 2.7 . 10-5 (acetonitrile) M-1 s-1. Similarly
to the DC reaction of 6.1 with 6.2, the
second-order rate constant in water-alcohol solutions increases
gradually with the water concentration.
Unfortunately, in highly aqueous media a side reaction
interferes and the accuracy of the rate constants
diminishes. A 1H NMR-spectrum of the products of this DC
reaction in pure water indicated the
presence of a complex reaction mixture in which p-nitroaniline
and butyrolactone were identified, the
products of a hydrolysis34. The hydrolysis only occurs in highly
aqueous solvents. Still, despite the large
experimental error, we conclude that the DC reaction is not
dramatically accelerated in pure water. In
fact, the second-order rate constant is probably slightly
reduced for reactions in pure water, similarly to
the pattern for most bimolecular DA cycloadditions.
N NNO2 NO
NN
NNO2
O
+
_
6.4 6.5 6.6
+
Scheme 6.4
-
1,3-Dipolar Cycloadditions in Aqueous Media
115
6.4.2 Intramolecular Cycloaddition of Electron-rich
Dipolarophiles to Aromatic Azides in Organic
Solvents and in Water
More information concerning the influence of aqueous solutions
on DC reactions comes from a
comparison of intermolecular and intramolecular 1,3-dipolar
cycloadditions (IMDC) to aromatic
azides35. The investigation of an IMDC reaction has several
advantages. No pseudo-first-order
conditions are required and therefore very low concentrations of
the reactant are possible. Most
importantly, aggregation phenomena in the IMDC reaction can be
excluded. This approach was proven
to be highly successful in the study of aqueous DA reactions36.
Like their intermolecular counterparts,
the ∆≠Gθ of the intramolecular DA reactions is reduced in
aqueous solutions, which elegantly hints at
the absence of hydrophobic aggregation as the factor responsible
for the aqueous rate effect of the
intermolecular DA reaction.
IMDC reactions have greatly extended the scope of DC
methodology, as they enable synthesis
with control over all stereocentres of complicated multi-ring
heterocyclic compounds35. In addition,
IMDC reactions proceed more smoothly than their intermolecular
counterparts and this allows synthesis
of heterocycles, that are otherwise difficult to prepare (for
example, the addition of nitriles to azides37).
0.0 0.2 0.4 0.6 0.8 1.0
3
4
5
6
7
8
9
10
11
12
k 2 /
10-5
M-1
.s-1
Mole Fraction of Water
Figure 6.2 Second-order rate constants for the DC reaction of
6.4 with 6.5 inwater-alcohol mixtures versus the mole fraction of
water at 40.0 °C. EtOH(ˇ), t-BuOH (u).
-
Chapter 6
116
The IMDC reaction of 6.7 (Scheme 6.5) has been previously
reported38. The final step in the
synthesis of 6.7 involves diazotation, followed by addition of
azide anions at 0 °C. At this low
temperature cyclisation does not take place, allowing
preparation and identification of 6.7. Dissolving
6.7 in warm solvent (40 °C) is sufficient to initiate the
cycloaddition and the reaction is readily
monitored using UV/VIS-spectroscopy. The first-order rate
constants are presented in Table 6.2.
The rate constants for the reaction in pure alcohols (Table 6.2)
are in excellent agreement with
results reported by Garanti et al.38. The data reveal a stunning
contrast between the kinetics of the intra-
and intermolecular DC reaction. Compared to a pure organic
medium, the IMDC reaction is retarded in
aqueous media and in pure water the rate constant is the lowest.
Water is a better hydrogen-bond
donating solvent than the alcohols and therefore this
observation shows that hydrogen bonding of the
solvent does not play a significant role in determining reaction
rates of DC reactions with azides.
Apparently the interaction of the solvent with both reacting
parts of 6.7 does not affect their energy,
because in that case a kinetic effect should have been observed.
Similarly, rate enhancement of the
intermolecular DC reaction of 6.1 and 6.2 cannot be attributed
to hydrogen-bond interactions. This
would leave hydrophobic interactions to be the prime
accelerating factor for the rate enhancement of the
addition of 6.1 to 6.2. For this particular reaction the
presence of microheterogeneities (due to the high
concentrations of 6.2) surely further promotes the DC
reaction.
6.4.3 1,3-Dipolar Cycloadditions of Electron-poor and -rich
Dipolarophiles to Aromatic Nitrile
Oxides in Organic Solvents and in Aqueous Media
A second representative of DC reactions involves cycloadditions
with nitrile oxides39. These dipoles are
among the most frequently used reagents in DC chemistry, adding
readily to many dipolarophiles
yielding isoxazolines or isoxazoles. Nitrile oxides have been
successfully utilised in stereoselective
reaction routes. Apart from a rare exception40, rapid
dimerisation prevents isolation of nitrile oxides, so
in general, nitrile oxides are generated in situ and many
procedures are available39. Basically, two
methods to generate nitrile oxides are used : (i) oxidation of
aldoximes (mostly in a halogenation-
N N N
O CH2 C CH
+ _
O
N
NN
6.7 6.8
Scheme 6.5
Table 6.2 First-order Rate Constants for the Intramolecular
Cycloadditionof 6.7 at 40.0 °C in Water-Alcohol Mixtures.
Mole Fraction of Water k1 (2-PrOH) / 10-5 s-1 k1 (t-BuOH) /
10
-5 s-1
0 1.69 1.740.75 1.61 1.630.90 1.54 1.610.95 1.32 1.461 1.08
1.08
-
1,3-Dipolar Cycloadditions in Aqueous Media
117
dehydrohalogenation sequence), and (ii) dehydration of nitro
compounds. In some cases an aqueous
two-phase system is used22. Nitrile oxides are dipoles of the
propargyl- allenyl type and they are better
Lewis bases than azides.
Addition of electron-poor dipolarophiles to nitrile oxides are
the only examples of DC reactions
for which detailed kinetic studies in aqueous media have been
carried out24,26. Only when very electron-
poor dipolarophiles are used, an aqueous medium appears
favourable26. According to one of these
studies nitrile oxides are slowly hydrolysed and this process is
catalysed by bases24.
Our initial experiments were carried out on a synthetic scale by
adapting a literature procedure
in which benzonitrile oxide was generated in a two-phase system
after which it was allowed to react
with styrene22c. We found that the organic phase is not required
for a successful synthesis. The reaction
can be simply accomplished by dissolving styrene (6.10a) and
benzaldoxime in a bleach solution which
leads to a swift precipitation of the product. Analysis revealed
the formation of 6.11a, in agreement with
results obtained by Huisgen41.
Cycloadditions with benzonitrile oxides proceed rapidly,
enabling facile determination of rate
Table 6.3 Second-order Rate Constant for the Intermolecular
1,3-Dipolar Cycloaddition of 6.9with 6.10b-f at 25.0 °C in Organic
Solvents and in Water
Dipolarophile
Solvent6.10bk2 / 10
-1 M-1 s-16.10ck2 / 10
-2 M-1 s-16.10dk2 / 10
-3 M-1 s-16.10ek2 / 10
-2 M-1 s-16.10fk2 / 10
-3 M-1 s-1
n-Hexane 4.8 1.5 3.6 2.6 2.71,4-Dioxane 1.8 1.3 1.2 1.7
3.7CH2Cl2 0.9 0.6 0.7 1.2 2.9DMSO 2.3 3.1 3.0 2.7 10.9EtOH 3.3 1.4
2.2 2.3 6.3TFE 0.6 0.2 0.6 3.3 8.3Water 3.0 1.1 2.6 8.5 30.0
C ON + ON
A B
+ _
BA
A B
a : -H -C6H5b : -H -COMec : -H -CNd : -CON(Me)CO-e :
-CH2CH2CH2-f : -CH2CH2O-
6.9 6.10 6.11
Scheme 6.6
-
Chapter 6
118
constants for the reactions in Scheme 6.6. Rate constants for DC
reactions of five dipolarophiles
(6.10b-f) with benzonitrile oxide (6.9) in organic solvents and
in water are given in Table 6.3. Some of
these reactions have been previously investigated and show a
high regioselectivity5,39. Interestingly, the
effect of the solvent depends on the nature of the
dipolarophile. Cycloadditions of 6.9 with electron-rich
dipolarophiles (cyclopentene (6.10e) and
2,3-dihydrofuran(6.10f)) are promoted in water, whereas water
has no special accelerating effect on the cycloaddition with the
three electron-deficient dipolarophiles
(methyl vinyl ketone (6.10b), acrylonitrile (6.10c) and
N-methylmaleimide (6.10d)). Clearly water only
promotes the DC reaction of 6.9 with electron-rich
dipolarophiles. We have not analysed whether the
regioselectivity of the DC reactions with 6.10b, 6.10c and 6.10f
is changed by the solvent. In view of
studies on DA reactions it is not unlikely that also these
aspects of the DC reaction are altered.
Qualitatively, the results are consistent with the two previous
kinetic studies, in which it was
shown that cycloadditions of 6.9 with ethyl acrylate and
dimethyl maleate are almost equally fast in
water and in water-dioxane (1:1)24 and that the DC reaction with
a very electron-deficient dipolarophile
(benzoquinone, comparable to 6.10d) is indeed considerably
faster in an aqueous medium compared to
chloroform26.
On several occasions we have carried out cycloadditions in
2,2,2-trifluoroethanol (TFE), a
solvent with hydrogen-bond donating properties similar to that
of water. Comparison of kinetic data for
DA reactions in this solvent and in water established that
hydrogen bonding (of water) is a major
contribution to the rate enhancements in water. Also in this
case the kinetic data for reaction in TFE
shed light on the exact influence of water on the DC reaction.
For electron-rich dipolarophiles, the
influence of TFE parallels that of water, but is less extreme.
This ‘super-protic’ solvent also promotes
these cycloadditions. The DC reaction with electron-poor
dipolarophiles is inhibited in TFE. This
pattern demonstrates that hydrogen bonding by the solvent is an
important factor for the reactivity of
DC reactions. We contend that part of the influence of water on
cycloadditions is governed by its
hydrogen-bond donating capacity.
-
1,3-Dipolar Cycloadditions in Aqueous Media
119
As in the case of the previously described cycloadditions, the
results can be partly explained
using FMO-theory12. This approach was used by Desimoni42 for
cycloadditions in organic solvents. For
a large number of cycloadditions a good correlation is observed
between rate constants and acceptor
numbers (AN) of the solvents. This latter parameter indicates
the capacity of a solvent to interact with
electron pairs. This analysis is also based on a relationship
between MO energies and ∆≠Gθ. Figure 6.2
schematically illustrates how hydrogen bonding of protic
solvents (e.g. water) affects the MOs of the
reactants. Nitrile oxides are good Lewis bases (as indicated by
the preferred complexation of Lewis
acids with nitrile oxides18,19) and consequently the MOs of
these dipoles are substantially stabilised.
Because 6.10e and 6.10f are weak hydrogen-bond acceptors, their
MOs are either not or only slightly
affected by hydrogen-bond interactions. Overall this interaction
leads to a smaller difference of energies
between the dominant MOs of the reacting partners and the ∆≠Gθ
is reduced in protic solvents, including
water. The electron-deficient dipolarophiles are relatively good
hydrogen-bond acceptors and
consequently their MOs are stabilised in protic solvents.
However, this interaction is less efficient
(compared to 6.9) and explains why these cycloadditions are
retarded in protic solvents.
As explained previously (Chapter 1), this FMO approach only
delineates the interaction
between the two reactants. The influence of the solvent is
merely limited to the (de)stabilising influence
on the MOs of the reactants. FMO theory analyses the reaction as
if only one or two solvent molecules
are present. The results in Table 6.3 clearly demonstrate that
the FMO approach cannot completely
explain the effect of water on DC reactions, because in all
cases the reaction in water is faster than in
the other protic solvents, despite the fact that water is the
superior hydrogen-bond donor. The reason is
MO energy
HOMO
LUMO
HOMO
HOMO
LUMO
LUMO
Figure 6.3 Schematic representation of the MO energies of
anelectron-rich dipolarophile (left), 6.9 (middle) and an
electron-poor dipolarophile (right). The solid lines represent the
MOs inhexane and the dashed lines those in a protic solvent
-
Chapter 6
120
that FMO theory does not take into account hydrophobic effects.
Similarly to DA reactions, the rate
accelerating effect in water is due to the reduction of the
water-accessible surface area during the
activation process which is always a favourable process in
water, irrespective of the effect of water on
the MOs of the reacting species.
More than our previous results, this system enables separation
of the two factors that influence
organic reactions in water : hydrogen bonding by water and
hydrophobic interactions. The nature of the
reactants determines whether these two mechanisms operate
collaboratively or counteractively.
Roughly, this pattern can be predicted using FMO theory.
However, hydrophobic interactions are
always favourable for cycloadditions in water.
6.4.4 1,3-Dipolar Cycloadditions of Electron-poor and -rich
Dipolarophiles to Aromatic Nitrones in
Organic Solvents and in Aqueous Media
Addition of dipolarophiles to nitrones yields isoxazolidines and
this procedure is especially attractive for
the synthesis of alkaloids and natural products39a. These DC
reactions have been extensively studied and
all mechanistic and kinetic data are in accord with common DC
characteristics43. This type of DC
reaction has a so-called inverted solvent effect44 (see Section
6.2). Addition of electron-poor
dipolarophiles generally proceeds efficiently, but when
electron-rich dipolarophiles are used, more
drastic reaction conditions are required. Often the addition of
dipolarophiles to nitrones is reversible45.
Second-order rate constants are presented in Table 6.4 for the
DC reaction of 3,4-
dihydroisoquinoline-N-oxide (6.12) with an electron-poor
(dimethyl acetylenedicarboxylate, 6.13)46 and
-rich dipolarophile (norbornadiene, 6.15)47 (Scheme 6.7). In
aqueous solutions the DC reaction of 6.12
with 6.13 is severely hindered by a side reaction. This reaction
was identified as a previously reported
complicated rearrangement of 6.14 which eventually leads to a
diketone46. To ascertain that the
spectroscopically observed reaction involves the DC reaction,
this cycloaddition was followed in a D2O-
CD3OD mixture. 1H NMR spectra were analysed on the basis of the
literature48 and revealed the
presence of 6.14, without significant quantities of side
products. Therefore, rearrangement of 6.14 is not
rate determining and the measured rate constants represent the
cycloaddition.
-
1,3-Dipolar Cycloadditions in Aqueous Media
121
Both cycloadditions proceed most rapidly in apolar aprotic
solvents, whereas protic solvents
such as TFE considerably retard the reaction. The results of the
kinetic study with the nitrone are
comparable to those for the DC reaction of electron-poor
dipolarophiles with benzonitrile oxide (6.9).
Also the DC reactions with 6.12 can be partly rationalised on
the basis of FMO theory (Figure 6.4).
The effect of protic solvents on the MO energies of the
reactants is most dramatic for nitrone 6.12,
because this nitrone is a good Lewis base. As a result ∆≠Gθ
increases in protic solvents, including water.
The observation that the second-order rate constants of both
reactions are still relatively high in water is
a result of enforced hydrophobic interactions. Because
norbornadiene is insoluble in pure water, 5 mol%
of t-BuOH was added to water. For DA reactions in aqueous media
this concentration of t-BuOH may
induce a modest additional rate acceleration and therefore it
seems probable that this second-order rate
constant overestimates the reactivity in pure water.
The previous chapters disclosed that aqueous rate enhancements
of DA reactions are the result
of two cooperative mechanisms of water, hydrogen bonding and
enforced hydrophobic effects. In many
cases comparison of reaction rates in fluorinated alcohols might
prompt the conclusion that water is just
a good protic solvent which is very effective as a result of its
small size. However, this chapter
demonstrates unambiguously how the two mechanisms can actually
counteract each other and
establishes the operation of hydrophobic effects. Addition of
several dipolarophiles to 6.9 and 6.12 is
inhibited in TFE, resulting from strong Lewis acid-Lewis base
interactions. If this factor was decisive
for the ∆≠Gθ of cycloadditions, water would be the worst
solvent. But in aqueous solutions, part of the
water-accessible surface area of the reacting substrates is
reduced by the formation of the activated
complex which promotes the reaction in water. This mechanism
does not depend on the effect that
NO
++ _N
O
CO2CH3CH3OCO
CH3O2C CO2CH3
+O
N
6.12 6.13 6.14
6.15 6.16
Scheme 6.7
-
Chapter 6
122
hydrogen-bond interactions have on the energy of the MOs of the
reactants. The two mechanisms may
either operate cooperatively or counteract each other. Due to
the large Lewis basicity of some dipoles,
the separate operation of the two mechanisms becomes clearly
manifested for DC reactions.
In principle the same effect can be observed for bimolecular DA
reactions, but most common
dienes are poor hydrogen-bond acceptors and therefore this
pattern is rare. However, there is one
example. The DA reaction of p-nitrostyrene with
di-(2-pyridyl)-1,2,4,5-tetrazine (Chapter 2) is slowest
in TFE and this trend points to the unfavourable effect of
hydrogen-bonding on the reaction rate. But
also in that case the reaction still proceeds by far the fastest
in water, because of enforced hydrophobic
interactions. Also the hetero retro DA reaction (Chapter 4)
serves as an example how hydrogen bonding
(of water) can have an unfavourable influence on pericyclic
reactions.
At first sight it is surprising that the DC reaction with an
electron-rich dipolarophile such as
6.15 is still hindered by hydrogen bonding of the solvent. This
pattern seems inconsistent with the
kinetic results with benzonitrile oxide, in which case the
addition to electron-rich dipolarophiles is
promoted. However, a careful analysis of Figure 6.4 resolves
this apparent anomaly. The numbers in
this figure are rough estimates, based on calculations by
Houk14, who estimated the MOs of nitrones
and a number of dipolarophiles. We have adapted these estimates
by taking into account the specific
influence of substituents on the MOs of the reactants. For
example, the HOMO and LUMO of the
nitrone moiety are close in energy due to the aromatic
substitution. When the MO energy of the
dipolarophile is gradually decreased the dominant
HOMO(dipolarophile)-LUMO(dipole) interaction is
eventually replaced by the HOMO(dipole)-LUMO(dipolarophile)
interaction (Figure 6.3). This shift
explains why hydrogen-bond interactions are sometimes favourable
and sometimes unfavourable for the
reaction, as exemplified by DC reactions with benzonitrile
oxide. Generally, 6.15 acts as an electron-
Table 6.4 Second-order Rate Constants for the DC reaction of
6.12with 6.13 (at 25.0 °C) or 6.15 (at 40.0 °C) in Organic Solvents
and inAqueous Media.
DipolarophileSolvent 6.13
k2 / 10-2 M-1 s-1
6.15k2 / 10
-5 M-1 s-1
n-Hexane 131 53.8Toluene 61.7 --1,4-Dioxane -- 14.4Chloroform
9.22 --Acetonitrile 24.0 3.12EtOH 6.87 2.56TFEa 0.6 0.53Water 8.45
2.77ba TFE : 2,2,2-trifluoroethanol. b Containing 5 mol %
t-BuOH.
-
1,3-Dipolar Cycloadditions in Aqueous Media
123
rich species, but due to the relatively high energy of the HOMO
of nitrone 6.12, the former HOMO-
LUMO interaction dominates. Consequently, protic solvents have
an unfavourable effect on
cycloadditions with both 6.13 and 6.15.
6.5 Conclusions
In this chapter we have seen a dramatic contrast in the effect
of water on DC reactions. Some reactions
are accelerated in water, whereas others are retarded or do not
experience a special effect of this solvent.
The rate effects in water are related to those in other protic
solvents. In all cases combination of FMO
theory and enforced hydrophobic interactions accounts for the
kinetic results. Water interacts with good
Lewis bases (in particular nitrile oxides and nitrones) and this
affects the MOs of the reactants. The
overall influence of this interaction on the rate of the DC
reaction depends on the dipolarophile and may
be either favourable or unfavourable. Irrespective of this
mechanism, constant enforced hydrophobic
interactions in water always favours the formation of the
activated complex (and product). These
hydrophobic interactions are solely responsible for the
acceleration of the DC reaction with aromatic
azides. Microheterogeneities further accelerate these
cycloadditions.
6.6 Experimental Section
Intermolecular DC Reactions with Aromatic Azides
MO energy (eV)
HOMO
LUMO
HOMO
HOMO
LUMO
LUMO
-11
0
1
-9
-7.5
0.5
Figure 6.4 Schematic representation of the MOs of 6.13
(left),6.12 (centre) and 6.15 (right).
-
Chapter 6
124
Synthesis and Product Analysis
Phenyl azide (6.1) and p-nitrophenyl azide (6.4) were prepared
according to a literature procedure49.
Norbornene (6.2) was purchased from Aldrich and used as
received. 2,3-Dihydrofuran (6.5) was
purchased from Aldrich and distilled before use. All solvents
were of the highest purity available or
freshly distilled. Water was distilled twice. The cycloadduct
6.3 was prepared by dissolving 0.1 g of 6.1
and 0.12 g of 6.2 in 10 ml of water-ethanol (1:1 v/v) and
stirring the solution for 24 hours at 40-50 °C,
during which time a white solid precipitated. After cooling, the
reaction mixture was filtered and the
solid was recrystallised from n-hexane. M.p. 101-102 °C (lit.10
101-102 °C). The cycloadduct 6.6 was
prepared and identified on a synthetic scale as follows : 0.215
g of p-nitrophenyl azide and 0.5 ml of
2,3-dihydrofuran were dissolved in 2.5 ml of water-ethanol (91:9
v/v) and stirred at room temperature.
After 2 hours a solid had formed and the solution was filtered.
The white solid was washed with water,
dried and crystallised from CH2Cl2-MeOH (1:1). M.p 157 °C (lit.
: 156 °C34). 1H NMR (DMSO) : δ
2.28 (m, 2H), 3.01 (m, 1H), 3.92(t, 1H), 5.37 (t, 1H), 6.14 (d,
1H), 7.54 (d, 2H), 8.27 (d, 2H).
Kinetic Experiments
Second-order rate constant for both reactions were determined at
40.0 °C in a thermostatted cell holder,
using a Perkin-Elmer Lambda 2, 5 or 12. The ‘initial-rate
method’10,33 was employed. This method
requires estimation of the extinction coefficient of both
reactants and product. The slow reactions
prompted use of high concentrations of 6.2 (0.1-0.01 M) or 6.5
(0.1-0.5 M). The DC reaction of 6.1
with 6.2 was followed at 320 nm, the addition of 6.1 to 6.5 at
350 nm. Following this procedure, the
reproducibility of the rate constants was within 5 %.
Intramolecular DC Reaction with Aromatic Azides
Synthesis and Product Analysis
6.7 was synthesised following the method of Garanti and
coworkers38. The last step of this synthesis
involves diazotation of a substituted aniline. This reaction was
carried out at 0°C and 6.7 was kept as a
solution in ether. A small amount of this solution was
evaporated to dryness and the residue was
dissolved in CDCl3. The 1H NMR spectrum was in accord with that
reported for 6.738. A second portion
of the ether solution was evaporated to dryness and the residue
dissolved in a water-ethanol solution
(2:1 v/v)). This solution was stirred for several days at 40-50
°C after which 1H NMR analysis revealed
the formation of 6. 838.
Kinetic Experiments
First-order rate constants were determined at 40.0 °C by
monitoring the reaction at 293 nm.
Reproducibility was within 3 %.
-
1,3-Dipolar Cycloadditions in Aqueous Media
125
DC Reactions with Aromatic Benzonitrile Oxide
Synthesis and Product Analysis
All chemicals were purchased from Aldrich. Methyl vinyl ketone
(6.10b), acrylonitrile (6.10c),
cyclopentene (6.10e) and 2,3-dihydrofuran (6.10f) were distilled
before use. Solvents were either of the
best quality available or distilled before use. One DC reaction
was performed on a synthetic scale. 1.6 g
of pure benzaldoxime was added dropwise while stirring
vigorously to a solution of 1.6 g of styrene
(6.10a) in a 50 ml household-bleach solution. The reaction
mixture became warm and a cream-coloured
solid spontaneously precipitated. M.p. 72-73 °C (lit.22c
73-75°C) 1H NMR (CDCl3) : δ 3.34 (dd, 1H),
3.79 (dd, 1H), 5.75 (dd, 1H), 7.39 (m, 8H), 7.70 (m, 2H)41.
Kinetic Experiments
For kinetic experiments 6.9 was prepared in a test tube by
dissolving a small amount of benzaldoxime in
a bleach/dichloromethane two-phase system. Several microliters
of the organic phase were transferred to
a UV cuvette which contained the dipolarophile solution
(dipolarophile in excess). In all solvents no or a
very slow reaction was observed in the absence of dipolarophile.
Pseudo-first-order rate constants for
the DC reactions were monitored at 273 nm and 25.0 °C. Starting
concentrations were ~ 0.1 mM of 6.9
and 5-40 mM of dipolarophile. Reproducibility was within 4
%.
DC Reactions with Aromatic Nitrones
Synthesis and Product Analysis
6.12 was synthesised following a literature procedure50 and
purified by column chromatography (Al2O3
(neutral), CHCl3-Et3N (98:2)). It was not possible to obtain
completely anhydrous samples. The 1H
NMR spectrum was in accord with the literature50b. Dimethyl
acetylenedicarboxylate (6.13) and
norbornadiene (6.15) were purchased from Aldrich and distilled
before use. Adduct 6.14 was identified
through 1H NMR-analysis. 6.16 was prepared by following a
procedure of Boyle47.
Kinetic Experiments
Both reactions were monitored at 297 nm. The DC reaction of 6.12
with 6.13 was monitored at 25.0
°C, using conventional pseudo-first-order kinetics and an excess
of 6.13. Typical starting concentrations
were [6.12] = 4-8.10-5 M and [6.13] = 5-8.10-3 M.
Reproducibility was within 2%. The second-order
rate constants for the addition of 6.12 to 6.15 were determined
at 40.0 °C, by means of initial-rate
kinetics10,33. This requires determination of the extinction
coefficients of 6.12 in all solvents (typically in
the range 16000-17000). Both 6.15 and 6.16 have a negligible
extinction coefficient at 297 nm, thus
facilitating the procedure. Typical starting concentration was
[6.15] = 1-4.10-2 M. Reproducibilty was
4%.
-
Chapter 6
126
1H NMR-experiments
Addition of 6.12 to 6.13 was carried out in a D2O-CD3OD (1:2
v/v) mixture, with [6.13] = 0.02 M and
[6.12]=0.01 M. After 12 minutes, the 1H NMR spectrum showed
evidence of the (first) product at 7.38-
7.13 (4H, m), 5.87 (H, s), 3.85 (3H, s), 3.83 (3H, s), 3.35-2.60
(4H, m). Following Scheeren48 these
features were assigned to 6.14. Addition of 6.12 to 6.15 was
also carried out in a D2O-CD3OD (1:1 v/v)
mixture. The 1H NMR spectrum was in accord with the
literature47.
Acknowledgement
This chapter contains the work of several researchers, who
deserve admiration because kinetic
experiments with DC reactions in aqueous media turned out to be
experimentally difficult.
Roberto Steiner, Francesca Dal Santo and Simona Barison
initiated and carried out most of the work
with the azides. Evert van Rietschoten admirably persevered in
investigating the reactions with nitrones
and Dick van Mersbergen superbly controlled the DC reactions
with benzonitrile oxide.
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