How does aqueous solubility of organic reactant affect a water-promoted reaction?

Article abstract of DOI:10.1021/jo500733v

It was widely reported that under the "on water" condition, various water-promoted organic reactions can proceed with very high speed. Thus, it is considered that the aqueous solubility of reactant is not an important issue in these reactions. Three types of water-promoted organic reactions were investigated in the current study to distinguish whether the reaction rate of an aqueous reaction was affected by the aqueous solubilities of the reactants. The results showed that, for a Diels-Alder reaction which was fast under the neat conditions, the aqueous solubilities of reactants had little influence on the reaction. However, for the reactions which proceeded slowly under the neat conditions, such as [2σ+2σ+2π] cycloaddition reactions and epoxide aminolysis reactions, the reactants with good aqueous solubilities proceeded fast in water. Poorly aqueous soluble reactants reacted slowly or did not react under the "on water" condition, and an appropriate amount of organic cosolvent was needed to make the reaction become efficient. This evidence suggested that for these two types of reactions, the dissolution of the reactants in water was required.

Full text of DOI:10.1021/jo500733v

Article
pubs.acs.org/joc
How Does Aqueous Solubility of Organic Reactant Affect a Water-
Promoted Reaction?
Yi-Jie Zuo and Jin Qu*
State Key Laboratory of Elemento-organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering
(Tianjin), Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: It was widely reported that under the “on
water” condition, various water-promoted organic reactions
can proceed with very high speed. Thus, it is considered that
the aqueous solubility of reactant is not an important issue in
these reactions. Three types of water-promoted organic
reactions were investigated in the current study to distinguish
whether the reaction rate of an aqueous reaction was affected
by the aqueous solubilities of the reactants. The results showed
that, for a Diels−Alder reaction which was fast under the neat
conditions, the aqueous solubilities of reactants had little
influence on the reaction. However, for the reactions which
proceeded slowly under the neat conditions, such as [2σ+2σ+2π] cycloaddition reactions and epoxide aminolysis reactions, the
reactants with good aqueous solubilities proceeded fast in water. Poorly aqueous soluble reactants reacted slowly or did not react
under the “on water” condition, and an appropriate amount of organic cosolvent was needed to make the reaction become
efficient. This evidence suggested that for these two types of reactions, the dissolution of the reactants in water was required.
The origin of the great rate-enhancing effect observed under
the “on water” condition has drawn great interest in recent
years.2−12 In 2007, Marcus’s group applied the model of
organic−aqueous interface to explain the “on water” phenom-
enon.2 They suggested that there are more free OH groups
dangling at the organic−aqueous interface than that in bulk
water; thus, the observed highest reaction speed under the “on-
water” condition is attributed to the elevated hydrogen-bond
activation. In recent years, many reports applied the “on water”
catalysis to explain the accelerating effect observed when using
water as the reaction medium.13
The interfacial catalytic mechanism aroused controversial
opinions in 2010. Jørgensen’s group reported the quantum and
molecular mechanics calculations of the water-promoted Diels−
Alder reactions at the vacuum−water interface or in the gas
phase.3 They found the model of two isolated reactants on the
water surface leads to a lower degree of catalysis than the fully
hydrated reactants, and they concluded that Diels−Alder
reactions are accelerated less on the surface of water than in
bulk water. Butler and Coyne noticed that reactants with
different aqueous solubilities present different reactivities in the
aqueous media.14 Recently, they measured the endo/exo products
ratio for Huisgen cycloadditions to investigate the “in water” and
“on water” border.15 Our previous studies on water-promoted
organic reactions also observed strong dependence of reaction
rate on the aqueous solubilities of organic reactants.16
INTRODUCTION
■
In 2005, Sharpless and co-workers reported that several organic
reactions, including [2σ+2σ+2π] cycloadditions, ene reactions,
Diels−Alder reactions, Claisen rearrangement reactions, and
epoxide aminolysis reactions, are much faster in aqueous medium
than in organic solvents.1 The detailed study of the aqueous
phase [2σ+2σ+2π] cycloaddition reaction between quadricy-
clane and dimethyl azodicarboxylate (DMAD) showed that the
reaction proceeds fast in heterogeneous suspension (in pure
water or in mixed solvents of CH3OH and H2O, v:v = 1:3 or 1:1),
but slows down considerably in the 3:1 CH3OH and H2O mixed
solvent in which the reaction system becomes homogeneous
(Figure 1). Thus, it is considered that aqueous solubility of
organic reactant is not essential to “on water” reactions.
Figure 1. [2σ+2σ+2π] cycloaddition reaction between quadricyclane
and dimethyl azodicarboxylate (DMAD) in water and in mixed solvent
of water and methanol.
Received: March 30, 2014
Published: July 7, 2014
© 2014 American Chemical Society
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Few numbers of organic reactants can totally dissolve in water;
thus, for the majority of water-promoted organic reactions, the
reactions proceed in a heterogeneous emulsion formed by
organic reactants and water. For a heterogeneous aqueous
reaction, it might proceed through three possible fashions: (1)
“In water” process, that is a small amount of reactants dissolve in
water and the reaction occurs; the formed products then
dissociate from water. The reaction is a microscopic “in water”
process although the reaction appears to be a macroscopic
heterogeneous reaction from the beginning to the end. (2) “On
water” process, the reaction mainly occurs at the oil−water
interface and the heterogeneity of the reaction system is essential
to achieving substantial accelerating effect. The heterogeneous
emulsion of reactants is gradually transformed to the
heterogeneous emulsion of products. (3) “In water” and “on
water” reaction pathways present simultaneously, and the
contribution of each pathway depends on the reaction type
and factors like the aqueous solubilities of the reactants, the
concentration of reactants, or the stirring method.
It is very difficult to find a tool to directly study which of the
above modes dominates in a certain water-promoted reaction.
One possible way to get some information is to detect the
relationship between the reaction rates and the aqueous
solubilities of the organic reactants. If the reactions proceed as
“in water” fashion or the “in water” pathway is predominant, the
reaction rates should be exclusively related to the aqueous
solubilities of the reactants, i.e. reactants with good aqueous
solubilities should react much faster than those having poor
aqueous solubilities. If the reaction proceeds as “on water”
fashion or the “on water” pathway is predominant, reactants with
different aqueous solubilities should have roughly the same
reaction rates, or even less aqueous soluble reactants exhibit
slightly better reactivity sometimes.
The lack of knowledge about the place where the water-
promoted reactions occur makes the full understanding of the
catalytic function of water impossible and this also hinders the
correct application of water-promoted organic reactions. In the
current study, we chose three types of organic reactions which
exhibit accelerating effect when the reactions are carried out in
water. We prepared a series of reactants that have similar
reactivities but varying aqueous solubilities. The conversions of
the reactants were recorded to distinguish whether the reaction
rates are related to the aqueous solubilities of the reactants. For
each type of the above reactions, we also detected the changing of
reaction rates when varying the ratio of the binary mixed solvent
composed of water and water-miscible organic solvent. The
results of the experiments showed that for [2σ+2σ+2π]
cycloadditions and epoxide aminolysis reactions, the reaction
rates were apparently dependent on the aqueous solubilities of
the reactants, but the reactants with different aqueous solubilities
proceeded equally fast in Diels−Alder reactions.
time intervals, we added acetone (50 or 150 mL) to make the
reaction system homogeneous and the conversion of quad-
ricyclane of each reaction was analyzed by GC. By using the same
method, we conducted the kinetic studies of 2b and 2c in water.
For the epoxide-aminolysis reactions, 1,2-epoxyalkane (0.5
mmol) and morpholine (1.0 mmol) were reacted at 85 °C in
water (12 mL). For the Diels−Alder reactions, cyclopentadiene
(0.6 mmol) and fumarates (0.5 mmol) were reacted at 25 °C in
water (12 mL).
The above method was applied to carry out the kinetic studies
of reactions in water−organic binary solvent systems. For the
[2σ+2σ+2π] cycloadditions of 2a and 1, six reactions under the
same conditions were carried out separately using 2a (0.6 mmol)
and quadricyclane (1, 0.5 mmol) in mixed solvent (12 mL) at
different ratios at 25 °C. After 10 min, acetone (50 mL) was
added to make the reaction system homogeneous, and the
conversion of quadricyclane was measured by GC analysis. The
cycloaddition reactions of compounds 2b and 2c with 1 were
carried out under reaction conditions identical to those for 2a,
but the conversions were measured after 1.5 and 3 h, respectively.
For the epoxide-aminolysis reaction of 5a in water/1,4-
dioxane binary system, six reactions under the same conditions
were carried out separately using morpholine (4, 1 mmol) and 5a
(0.5 mmol) in mixed solvent (12 mL) with different ratios at 85
°C. After 1 h, acetone (50 mL) was added to make the reaction
system homogeneous, and the conversion of 5a was measured by
GC analysis. The reactions of 5b, 5c, or 5d with 4 were carried
out under reaction conditions identical to those for 5a, and the
conversions were measured after 2.5, 3.5, and 7 h, respectively.
For the Diels−Alder reaction of 8a and 7 in the water/THF
binary system, six reactions under the same conditions were
carried out separately using fumarates (0.5 mmol) and
cyclopentadiene (7, 0.6 mmol) in mixed solvent (12 mL) with
different ratios at 25 °C. After 30 min, the reaction was extracted
with ethyl acetate (100 mL) and washed with brine, and the
solvents were evaporated in vacuo. The conversion of fumarates
was measured by 1H NMR spectroscopy. The reactions of 8b, 8c,
or 8d with 7 were carried out under reaction conditions identical
to those for 8a, and the conversions were measured after 30 min,
40 min, and 1 h, respectively.
Reaction Rates of Reactants with Different Aqueous
Solubilities. The [2σ+2σ+2π] cycloaddition reaction of
quadricyclane with azodicarboxylate was first studied in aqueous
medium by Sharpless’s group.1 By prolonging the alkyl chain
which is far away from the azo functional group (note: DEAD but
not DMAD was chosen as the first reactant due to its better
stability in water), two DEAD analogues, dibutyl azodicarbox-
ylate (DBAD, 2b) and dihexyl azodicarboxylate (DHAD, 2c)
having lower aqueous solubilities were synthesized, respec-
tively.17 The cycloaddition reactions of 2a, 2b, 2c with
quadricyclane gave 1,2-diazetidines as the only product. The
pseudo-first-order constants of the reactions of 2a, 2b, and 2c
with quadricyclane in methanol were k′2a = 0.68, k′2b = 0.46, k′2c
= 0.42 respectively, which indicated that these analogues had
similar reactivities in homogeneous reaction system. Prolonging
the length of the alkyl substitutes has little effect on the
compounds’ inherent reactivity.
RESULTS AND DISCUSSION
■
Kinetic Study of Aqueous Heterogeneous Reactions.
We set a series of reactions under the identical reaction
conditions (same amount of reactants and solvent, same reaction
temperature, flasks of same size, stir bars of same size, same
stirring machine, and same stirring rate) and conducted these
identical reactions at different time intervals. The conversion of
reactants was subsequently analyzed by GC or NMR technique.
For [2σ+2σ+2π] cycloaddition reaction, a series of aqueous
reactions containing 2a (0.6 mmol) and quadricyclane (1, 0.5
mmol) in water (12 or 100 mL) were run at 25 °C. At different
The reaction rates of the [2σ+2σ+2π] cycloadditions of
quadricyclane with DEAD (2a), DBAD (2b), or DHAD (2c) in
water were then separately monitored (Figure 2). The reaction of
DEAD which has the best aqueous solubility was very fast, and
the reaction completed in 20 min. Nevertheless, in the reaction of
DBAD which has relatively poor aqueous solubility, it took 24 h
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Figure 3. Conversion of 1,2-epoxyalkanes 5a−5d in the reactions with
morpholine in water (12 mL) at 85 °C.
Figure 2. Conversions of quadricyclane (1) at different time intervals in
the cycloaddition reactions with azodicarboxylates 2a, 2b, and 2c in
water (12 or 100 mL) at 25 °C. Concentration of quadricyclane is 0.042
M (in 12 mL water) and 0.005 M (in 100 mL water), concentration of
diazocarboxylate is 0.05 M (in 12 mL water) and 0.006 M (in 100 mL
water).
to reach 85% conversion of quadricyclane. As for DHAD, the
reaction proceeded considerably more slowly in water. The
conversion of quadricyclane was 30% after 24 h. It was found that
all three reactions were much faster in 100 mL of water than in 12
mL of water. Nevertheless, the reaction rates in 100 mL of water
also had strong dependence upon the aqueous solubilities of the
azodicarboxylates.
Aqueous phase epoxide aminolysis reactions were also
reported many times in the literature.16a,c,18−21 We carried out
a kinetic study of the reactions of morpholine (4) with 1,2-
epoxyalkane 5a, 5b, 5c, and 5d with increasing lengths of alkyl
chain.22 The pseudo-first-order constants of 5a, 5b, 5c and 5d in
methanol were k′5a = 1.37, k′5b = 1.22, k′5c = 1.14, k′5d = 1.02
respectively, which indicated that they had similar reactivities in
homogeneous solution. The rates of epoxide-opening reactions
of morpholine with 1,2-epoxyalkanes in water were separately
monitored. As illustrated in Figure 3, epoxide 5a bearing the
shortest alkyl chain reacted very fast in water, and reaction of
epoxide 5b exhibited a slightly slower rate. As for epoxide 5c, in a
fixed time of 4 h, we observed that the conversion of 5c was 13%.
The aminolysis of epoxide 5d bearing the longest alkyl chain
barely occurred in pure water within 4 h.
There have been many literatures reporting that Diels−Alder
reactions can be remarkably accelerated in aqueous medium and
the mechanistic of function of water was also explored.23−29 We
carried out a kinetic study of Diels−Alder reactions of
cyclopentadiene with four dialkylfumarates with decreasing
aqueous solubilities.30 The pseudo-first-order constants of the
Diels−Alder reactions in THF are k′8a = 1.26, k′8b = 1.21, k′8c =
1.12, k′8d = 1.09 respectively, which indicated that they had
similar reactivities in homogeneous reaction system. The
reactivities of dialkylfumarates 8a−8d in water are shown in
Figure 4. The reactions of dialkylfumarate 8a and 8b proceeded
almost equally fast while 8c reacted slightly slower. The reaction
rate of dialkylfumarate 8d which has the longest alkyl chain was
noticeably lower than 8a, 8b, and 8c. But if taking account the
Figure 4. Conversion of dialkylfumarates 8a−8d in the Diels−Alder
reactions with cyclopentadiene in water (12 mL) at 25 °C. Measured by
1H NMR in a fixed time.
fact that dialkylfumarate 8d is a solid and therefore have a
relatively slower rate when it disperse in water, the reaction rate
of dialkylfumarate 8d should be higher than it appears.
It appears that the dependence of reaction rate on aqueous
solubilities of reactants varied in the above three reaction types.
We think this may be related to the catalytic function of water in
each reaction. We investigated the relationship between the
reaction rate and the amount of water to understand whether the
above reactions only proceed in a large volume of water or if
these reactions can proceed smoothly in the presence of a very
small amount of water. As shown in Figure 5, under the solvent-
free conditions, the reaction of thoroughly dried DEAD and
quadricyclane was very slow since the conversion of quad-
ricyclane was 6% in 12 min. Adding 1 equiv of water to the
reaction system, the conversion of quadricyclane increased to
11%. The reaction rate exhibited substantial increase in 9 mL of
water, and the conversion of quadricyclane reached 50%. This
experiment indicated that the reaction could take place under the
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Figure 5. Conversion of reactants in three reactions with increasing
amounts of water. The amount of water is relative to the amount of
compounds 1, 5b, or 8a respectively.
neat conditions or in the presence of a small amount of water.
However, only in a large amount of water can the accelerating
effect of water be observed. The aminolysis of epoxide 5b
proceeded very slowly under neat conditions. With the addition
of a small amount of water (1−10 equiv), the reaction rates
increased considerably to 90%. In a large volume of water, the
aminolysis of 5b proceeded at a lower but reasonable rate. The
Diels−Alder reaction of diethyl fumarate 8a and cyclopentadiene
under neat conditions is so fast that the conversion of diethyl
fumarate reached 92% in 15 min. Adding water to the reaction
system has no apparent influence on the reaction rate. The
observation that some Diels−Alder reactions can work smoothly
under the neat conditions is consistent with previous studies.1,31
For the reactions that only proceed fast in large volume of
water, like the [2σ+2σ+2π] cycloaddition reaction, the aqueous
solubilities of the reactants strongly affect the rate of the aqueous
reaction. The reactants with short alkyl chains reacted much
faster than those having longer alkyl chains. Besides, the
concentration of the reactants also has obvious influence on
the reaction. Due to the limited solubility of organic compounds,
the aqueous system is always saturated, increasing the amount of
water can help the reactants disperse and then dissolve in water
thus the reaction was much faster. For the reactions which
already proceed with a high speeds under the neat condition, like
the Diels−Alder reaction, the reaction proceeded almost equally
fast under neat condition, with small amount of water, or with
large amount of water. Only carefully planned kinetic studies
choosing short reaction time can distinguish the rate differences
of the above three conditions. Thus, in this type of aqueous
reaction, the aqueous solubilities of the reactants did not affect
the rate of the aqueous reaction.
But it still puzzled us why the aminolysis reaction of 5c and 5d
are much slower than that of 5a and 5b when evidence showed
that 1 equiv of water could make the reaction of 5b work
efficiently. We than compared the reactivities of 5b and 5c in
increasing amount of water (Figure 6). Under the neat condition,
both reactions of 5b and 5c proceeded slowly. With the addition
of 1 equiv of water, both reactions achieved the highest rates.
However, when increasing the amount of water continuously, the
aminolysis of 5b still proceeded at a reasonable rate, but the rate
of the reaction of 5c decreased significantly and the reaction did
not occur in 40 mL of water (100 equiv). This experiment
showed when the epoxide dissolved in morpholine containing 1
equiv of water (water is miscible with morpholine), the
intermolecular reaction proceed very fast due to the high
concentration of each reactant. When an increasing amount of
Figure 6. Conversion of epoxides in the aminolysis reaction in different
amount of water. The amount of water is relative to the amount of 5b
and 5c, respectively.
water was added to the reaction system, epoxide dissociated from
the aqueous solution of morpholine, and thus, the bimolecular
reaction slowed down. If the aqueous solubility of the epoxide is
very poor, the reaction could not proceed further in the diluted
aqueous solution.
Change of the Reaction Rates in Water/Organic Binary
Solvent Systems at Different Ratios. Water/organic binary
solvent systems have been employed as a mechanistic tool to
investigate water-promoted reactions.1,4,9,29,31−37 The cyclo-
additions of quadricyclane (1) and DMAD have been studied in
the water/methanol binary system by Sharpless’s group before;1
four ratios were studied (water/methanol = 1:0; 3:1; 1:1; and
1:3) therein, and they found that the heterogeneity of the
reaction system is essential to achieving a great accelerating
effect. We systematically measured the conversion of quad-
ricyclane in the [2σ+2σ+2π] cycloaddition reaction with
azodicarboxylates 2a, 2b, and 2c at six different ratios of mixture
solvent (Figure 7). The data determined were reproducible to
within 6%.
For the reaction of DEAD (87 mg, 94 uL, 0.6 mmol) and
quadricyclane (47 uL, 0.5 mmol) in 12 mL of pure water, the
conversion of quadricyclane was 69% at 10 min, and this value
increased to 93% in an aqueous solution containing 20 vol % of
methanol. When 40 vol % of methanol was present in the
aqueous solution, DEAD became totally soluble. The reaction
mixture finished as a clear solution, and the conversion of
quadricyclane at 10 min was 96%, representing the highest
reaction rate. When the vol % of methanol was increased to 60,
quadricyclane dissolved in the mixed solvent, but the conversion
of quadricyclane dropped sharply. The reaction rate decreased
further in the mixed solvent containing 80 vol % of methanol and
barely took place in pure methanol in 10 min.
Taking the same experimental procedure, the reaction of
quadricyclane with compounds 2b and 2c were carried out. For
reactions of both compounds, the conversion of quadricyclane
increased initially, reaching a maximum before decreasing with
further addition of methanol. These curves look similar to the
curve of DEAD, but it is worth noting that the vertexes of the
curves shifted to the right. The reaction rate of dibutyl
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Figure 7. Conversion of quadricyclane (1) in the cycloaddition reaction
with DEAD (2a), DBAD (2b), and DHAD (2c).
Figure 8. Conversion of epoxides 5a−5d in the aminolysis reactions
with morpholine in water/1,4-dioxane mixed solvent system.
azodicarboxylate 2b reached the highest point in the binary
solvent composed of 60 vol % of methanol (DBAD became
soluble in this mixed solvent). For dihexyl azodicarboxylate
(DHAD) with the longest alkyl chain, the reaction rate reached
the highest point in the binary solvent composed of 80 vol % of
methanol (DHAD became soluble in this mixed solvent).
As shown in Figure 7, compared with Sharpless’s experiment
which employed DMAD as the reactant, we also found the
reaction of DEAD bearing the short alkyl chain was fast in pure
water or mixed solvent containing a low vol % of methanol.
However, our study showed that pure water was not the optimal
medium for DEAD and also its two analogues. Besides, contrary
to their conclusion that a heterogeneous emulsion is essential to
achieving a great accelerating effect, we found that the reaction
rate reached the highest point in the binary solvent with 40 vol %
of methanol when DEAD became soluble at this point. The
reaction of 2b or 2c also reached the highest point where 2b and
2c became soluble in the mixed solvent. Thus, the great rate-
enhancing effect did not depend on the heterogeneity of the
reaction system. Even when the reaction system is heteroge-
neous, the increase of organic cosolvent also has influence on the
reaction rate.
maximum reaction rate were right-shifted with the elongation
of the alkyl substitutes.
The studies of the Diels−Alder reactions of cyclopentadiene
with dialkylfumarates 8a−8d in water/THF mixtures at 293 K
(Figure 9) showed that reactions of 8a, 8b, and 8c proceeded
We endeavored to provide further insight into the other water-
promoted reactions in order to check if the phenomenon present
above is limited to the [2σ+2σ+2π] cycloaddition reactions. The
binary mixtures of water/1,4-dioxane were used to study the
change of the reaction rate of epoxide aminolysis reaction from a
heterogeneous emulsion to a homogeneous solution. Since the
boiling point of water/1,4-dioxane system at different ratios
ranges from 87 to 101 °C,38 we controlled the reaction
temperature at 85 °C in order to prevent the experimental
results from being disturbed by the different refluxing temper-
atures. As illustrated in Figure 8, the curves can be divided into
two different types. Epoxide 5a, which has the shortest alkyl chain
among the four selected epoxides, reacted fast when the volume
percentage of 1,4-dioxane was between 0%−60%. Then the
reaction rates decreased sharply with further decrease of the ratio
of water. Nevertheless, the reaction rates of 5b, 5c, and 5d first
increased with the addition of 1,4-dioxane, reaching a maximum
before decreasing with further addition of 1,4-dioxane. The
solvent compositions in which the reaction reached the
Figure 9. Conversion of dialkylfumarates 8a−8d in the Diels−Alder
reactions with cyclopentadiene in mixed water/THF solvent system.
optimally in pure water. Upon the increase of the volume
percentage of THF, the conversion of dialkylfumarates decreased
gradually. When it came to didodecylfumarate 8d, in pure water,
the conversion of 8d was 69% in the fixed time of 1.5 h, and the
conversion slightly increased to 83% in the mixed solvent of 20%
THF. However, further addition of THF decreased the reaction
rate like the trend for dialkylfumarates 8a−8c.
For [2σ+2σ+2π] cycloaddition reactions and epoxide
aminolysis reactions, the reaction rates in water strongly depend
on the aqueous solubilities of reactants, the conversion of the
reactants in the binary solvent system recorded after a fixed time
showed two types of curves, the first one is the “ever-decreasing”
type represented by the reaction of 5a. This is because epoxide 5a
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with the shortest alkyl chain can partially dissolve in water and
react smoothly (the aqueous solubility of 5a at room temperature
is 3.1 g/L).The second type of curve is the “up and down” type
represented by the reactions of 2a−2c and 5b−5d. Apparently,
the reactions of these reactants do not proceed optimally in pure
water. Actually, organic cosolvent was needed to dissolve the
reactants, and the reaction rate increased with the addition of
organic cosolvents. The best volume percent of organic cosolvent
for getting the highest reaction rate was related to the aqueous
solubilities of reactants; reactant with poor aqueous solubility
needed an increasing amount of organic cosolvent.
When it comes to the reason why the reaction rate of 5a
decreased upon the addition of organic cosolvent, and also the
reaction rates of 2a−2c and 5b−5d decreased after excess
amount of organic cosolvent was added, the rate-enhancing effect
in water mainly derives from hydrogen-bonding activation,
beneficial hydrophobic effect, high polarity of water, or a mix of
the three effects.2−11 The decrease of the reaction rate upon the
addition of organic cosolvent is likely due to the diminution of
hydrogen-bonding activation, the reduction of hydrophobic
effect, or a lower polarity of the resulted reaction medium. In
order to verify our assumption, three organic cosolvents, 1,4-
dioxane, acetone, and methanol which have different hydrogen
bond formation ability and apparent dielectric constants (2.21,
20.56, 32.66 respectively),39 were used in further investigation of
the [2σ+2σ+2π] cycloaddition reaction between quadricyclane
and DEAD. As shown in Figure 10, in the reaction using 1,4-
the epoxide-aminolysis reactions. The reactions of cyclo-
pentadiene with 8a, 8b, and 8c all proceeded optimally in pure
water. Because all the reactants have poor solubilities in water,
tiny oil droplets are formed when stirring the two reactants in
water. The reaction might actually proceed in the tiny oil droplets
containing both of the reactants since the reaction exhibited a
high reaction rate under neat conditions. Adding organic solvent
results in a low concentration of each reactant and thereby
decreased the reaction rate. The reason for a slightly higher
reaction rate of 8d in the mixed solvent containing 20% of THF
might be due to the solid 8d mixing better with cyclopentadiene
in the presence of a small amount of organic solvent.
CONCLUSION
■
In summary, we prepared a series of reactants with different
aqueous solubilities and compared their reaction rates in pure
water and in mixed aqueous−organic binary solvents at various
ratios. It was found that for reactions which could proceed very
fast under the neat conditions, like the Diels−Alder reactions
between cyclopentadiene and fumarates, the aqueous solubilities
of reactants had very little influence on the rate of the aqueous
reaction. However, for reactions which proceeded very slowly
under the neat reaction conditions, the addition of water could
remarkably promote the reaction, such as [2σ+2σ+2π] cyclo-
addition reactions and the epoxide aminolysis reactions;
reactants with different aqueous solubilities reacted at apparently
different rates. The reactants with good aqueous solubilities
reacted fast in water and reactants with poor aqueous solubilities
reacted slowly or not at all. In addition, appropriate dilution of
the aqueous system could sometimes make the reaction proceed
more efficiently. This evidence suggested that, when conducting
these two types of reactions in aqueous solution, the dissolution
of the reactants in water was crucial for the efficient progress of
the reactions. Reactants with poor aqueous solubilities always
needed organic cosolvents to help them dissolve or disperse in
water. The required amount of organic cosolvent depended on
the aqueous solubility of the reactant. However, an excess
amount of organic cosolvent would diminish the accelerating
effect of water.
From the experimental results observed in this study, the fact
that some reactants react faster in heterogeneous aqueous
solution (with no or a small amount of organic cosolvent) than in
homogeneous mixed aqueous−organic binary solvent do not
exclusively point to an interfacial catalysis mechanism. The “on
water” phenomenon could also be attributed to the following:
(1) The reactions can proceed efficiently under neat condition,
adding an increasing amount of organic solvent decreases the
concentration of reactants, and thus the reaction becomes
slower. (2) The reactants have reasonable aqueous solubilities,
and the reaction rate is the fastest in pure water. Adding water-
miscible organic solvent decreases the degree of hydrogen-bond
activation, the hydrophobic effect, or the polarity of the reaction
medium, and thus, the reaction is slower in the homogeneously
aqueous−organic binary solvents. However, for other reactants
with poor aqueous solubilities, the pure water reaction medium
no longer delivers the fastest reaction rate; adding an appropriate
amount of organic cosolvent can make the reaction more
efficient, and sometimes the highest reaction rates are achieved in
a homogeneous aqueous−organic solvent system.
Figure 10. Conversion of quadricyclane in different organic cosolvents.
dioxane as the organic cosolvent, the maximum of the reaction
rate was at 20 vol % of 1,4-dioxane. When using acetone as the
organic cosolvent, the reaction rate reached the maximum at 30
vol % of acetone. The best ratio for using methanol as the
cosolvent was 40 vol %. The reason for the right shift of the vertex
of the curve from 1,4-dioxane to methanol might be related to the
different solubility of quadricyclane in these three solvents. The
nonpolar 1,4-dioxane can dissolve hydrophobic quadricyclane
better; thus, with the addition of relatively small amount of 1,4-
dioxane, the reaction could reach the highest reaction speed.
However, a larger amount of methanol was required for the
optimal reaction rate, but the reaction was less affected in an
excessive amount of methanol compared with 1,4-dioxane and
acetone. This may due to the hydrogen bond formation ability
and high dielectric constant of methanol.
In this respect, a newly reported water-promoted reaction
should not be classified into the “on water” catalysis simply
because the reaction is faster in water than in organic solvent.
More research should be done to distinguish the role that water
The experimental results of the Diels−Alder reaction are far
different from that of [2σ+2σ+2π] cycloaddition reactions and
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The Journal of Organic Chemistry
Article
C21H34N2O4: m/z 401.2416 ([M + Na]+), found: m/z 401.2408 ([M +
Na]+).
plays in those aqueous reactions. Also, the aqueous solubilities of
the reactants should be placed with high value while conducting a
water-promoted reaction. The mechanistic function of water in
promoting organic reactions might be complicated and deserve
more research efforts.
l-(4-Morpholino)-2-hexanol (6a).41 Prepared according to the
1
kinetic study procedure; 89 mg, yield:95%; colorless liquid; H NMR
(400 MHz, CDCl3) δ 3.76−3.64 (m, 5H), 3.39 (br s, 1H), 2.68−2.63
(m, 2H), 2.40−2.23 (m, 2H), 2.35 (dd, J = 3.2, 12.4 Hz, 1H), 2.28−2.22
(m, 1H), 1.47−1.41 (m, 2H), 1.40−1.32 (m, 4H), 0.91 (t, J = 6.8 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ 67.0, 65.9, 64.8, 53.6, 34.5, 27.7,
22.8, 14.0.
EXPERIMENTAL SECTION
■
General Methods. Water was purchased from Watson’s or from
Milli-Q Ultrapure Water Purification System. Flash column chromatog-
raphy was performed using the indicated solvent system on Qingdao-
Haiyang silica gel (200−300 mesh). All of the compounds were
characterized by 1H NMR and 13C NMR. Peaks recorded are relative to
the internal standards: TMS (δ = 0.00) for 1H NMR and CDCl3 (δ =
77.00) for 13C NMR spectra. High-resolution mass spectral analyses
(HRMS) were performed on a high-resolution MALDI-FT-ICR mass
spectrometer.
l-(4-Morpholino)-2-octanol (6b).42 Prepared according to the
kinetic study procedure; 100 mg, yield: 93%; colorless liquid; 1H
NMR (400 MHz, CDCl3) δ 3.75−3.68 (m, 5H), 3.39 (br s 1H), 2.69−
2.63 (m, 2H), 2.39−2.36 (m, 2H), 2.35 (dd, J = 2.8, 12.4 Hz, 1H), 2.28−
2.22 (m, 1H), 1.52−1.45 (m, 2H), 1.45−1.20 (m, 8H), 0.88 (t, J = 6.4
Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 67.0, 65.9, 64.7, 53.6, 34.8,
31.8, 29.4, 25.5, 22.6, 14.0.
l-(4-Morpholino)-2-dodecanol (6c).16c Prepared according to the
kinetic study procedure; 129 mg, yield: 95%; colorless liquid; 1H NMR
(400 MHz, CDCl3) δ 3.76−3.65 (m, 5H), 3.41 (br s, 1H), 2.68−2.63
(m, 2H), 2.39−2.22 (m, 4H), 1.47−1.26 (m, 18H), 0.88 (t, J = 6.4 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ 66.9, 65.8, 64.7, 53.5, 34.7, 31.8,
29.6, 29.5, 29.2, 25.5, 22.5, 14.0.
Compound 1 was prepared according to the literature reports.40
Compound 4 was freshly distilled prior to its use. Cyclopentadiene was
freshly cracked from its dimer. Morpholine was purified according to the
standard method to ensure its purity. All reactions were carried out in
aerial atmosphere. Reaction temperatures reported in the schemes were
the temperatures of the oil bath or the water bath.
l-(4-Morpholino)-2-hexadecanol (6d).43 Prepared according to the
kinetic study procedure; 155 mg, yield: 95%; white solid, mp: 36−38 °C;
1H NMR (400 MHz, CDCl3) δ 3.76−3.65 (m, 5H), 2.69−2.64 (m, 2H),
Preparation of Dialkyl Azodicarboxylate 2b−2c. Dibutyl Azodi-
carboxylate (2b). To the solution of hydrazine hydrate (1.25 g, 25
mmol), water (10 mL) and methanol (10 mL) was added n-butyl
chloroformate (6.83 g, 50 mmol) under ice bath and stirring, the
reaction mixture was stirred for 1.5 h, and then, the reaction was
extracted with EtOAc, washed with brine, and dried over anhydrous
Mg2SO4, and the solvent was evaporated in vacuo to give dibutyl
hydrazine-1,2-dicarboxylate. The crude product was used without
further purification. To a solution of dibutyl hydrazine-1,2-dicarboxylate
was added NBS (4.45 g, 25 mmol); the reaction was monitored by TLC.
After reacting for 30 min, the solution was diluted by CH2Cl2 (100 mL).
The resulting mixture was washed by pure water and brine and dried
over anhydrous Mg2SO4; the solvent was evaporated in vacuo to give the
crude product; the residue was purified by silica gel chromatography
(0−2% EtOAc/P.E. as an eluent); and the desired product 2b was
obtained as a yellow liquid (4.14 g, 72%); 1H NMR (400 MHz, CDCl3)
δ 4.45 (t, J = 6.8 Hz, 4H), 1.82−1.75 (m, 4H), 1.48−1.41 (m, 4H), 0.97
(t, J = 7.6 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ 160.4, 69.2, 30.4,
18.8, 13.5.
2.39−2.22 (m, 4H), 1.47−1.25 (m, 26H), 0.88 (t, J = 6.8 Hz, 3H); 13
C
NMR (CDCl3, 100 MHz) δ 67.0, 65.9, 64.7, 53.6, 34.8, 31.9, 29.7, 29.6,
29.6, 29.6, 29.6, 29.3, 25.6, 22.7, 14.1.
Diethyl Bicyclo[2.2.1]hept-5-ene-(2-endo,3-exo)-dicarboxylate
(9a).44 Prepared according to the kinetic study procedure; 117 mg,
yield: 98%; colorless liquid; 1H NMR (400 MHz, CDCl3) δ 6.28 (dd,
1H, J = 3.2, 5.6 Hz), 6.07 (dd, 1H, J = 2.8, 5.6 Hz), 4.17 (q, 2H, J = 7.2
Hz), 4.12−4.07 (m, 2H), 3.38 (t, 1H, J = 4.0 Hz), 3.27 (br s, 1H), 3.12
(br s, 1H), 2.68 (dd, 1H, J = 1.6, 4.8 Hz), 1.61 (d, 1H, J = 8.8 Hz), 1.47−
1.44 (m, 1H), 1.30−1.22 (m, 3H); 13C NMR (100 MHz, CDCl3) δ
174.4, 173.2, 137.5, 135.0, 60.8, 60.5, 47.8, 47.7, 47.2, 47.1, 45.7, 14.2,
14.2.
Dibutyl Bicyclo[2.2.1]hept-5-ene-(2-endo,3-exo)-dicarboxylate
(9b).45 Prepared according to the kinetic study procedure; 138 mg,
yield: 94%; colorless liquid; 1H NMR (400 MHz, CDCl3) δ 6.28 (dd, J =
3.2, 5.6 Hz, 1H), 6.07 (dd, J = 2.8, 5.6 Hz, 1H), 4.11 (t, J = 6.4 Hz, 2H),
4.07−4.02 (m, 2H), 3.38 (t, J = 4.0 Hz, 1H), 3.26 (br s, 1H), 3.11 (br s,
1H), 2.68 (dd, J = 1.2, 4.4 Hz, 1H), 1.67−1.56 (m, 5H), 1.47−1.35 (m,
5H), 0.96−0.91 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ 174.5, 173.3,
137.5, 135.1, 64.7, 64.4, 47.9, 47.7, 47.2, 47.2, 45.6, 30.6, 30.6, 19.1, 13.7,
13.7.
Dioctyl Bicyclo[2.2.1]hept-5-ene-(2-endo,3-exo)-dicarboxylate
(9c).46 Prepared according to the kinetic study procedure; 191 mg,
yield: 94%; colorless liquid; 1H NMR (400 MHz, CDCl3) δ 6.29 (dd, J =
3.2, 5.2 Hz, 1H), 6.07 (dd, J = 2.8, 5.6 Hz, 1H), 4.10 (t, J = 6.4 Hz, 2H),
4.01−4.00 (m, 2H), 3.38 (t, J = 4.0 Hz, 1H), 3.26 (br s, 1H), 3.11 (br s,
1H), 2.68 (dd, J = 1.2, 4.0 Hz, 1H), 1.67−1.56 (m, 5H), 1.45 (dd, J = 1.6,
8.8 Hz, 1H), 1.37−1.23 (m, 20H), 0.88 (t, J = 6.4 Hz, 6H); 13C NMR
(CDCl3, 100 MHz) δ 174.4, 173.2, 137.5, 135.0, 64.9, 64.6, 47.8, 47.6,
47.2, 47.1, 45.6, 31.7, 29.1, 28.5, 25.8, 22.6, 14.0.
Didodecyl Bicyclo[2.2.1]hept-5-ene-(2-endo,3-exo)-dicarboxylate
(9d). Prepared according to the kinetic study procedure; 238 mg, yield:
92%; colorless liquid; 1H NMR (400 MHz, CDCl3) δ 6.28 (dd, J = 3.2,
5.6 Hz, 1H), 6.06 (dd, J = 2.8, 5.6 Hz, 1H), 3.37 (t, J = 4.0 Hz, 1H), 3.26
(br s, 1H), 3.11 (br s, 1H), 2.68 (dd, J = 1.2, 4.4 Hz, 1H), 1.67−1.56 (m,
5H), 1.45 (dd, J = 1.6, 8.8 Hz, 1H), 1.19−1.40 (m, 40H), 0.88 (t, J = 6.8
Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ 174.3, 173.1, 137.4, 135.0,
64.8, 64.5, 47.8, 47.6, 47.1, 47.1, 45.6, 31.8, 29.5, 29.5, 29.3, 25.8, 22.6,
14.0.
Dihexyl Azodicarboxylate (2c). Prepared according to the general
1
procedure; 4.93 g, yield: 69%; yellow liquid; H NMR (400 MHz,
CDCl3) δ 4.44 (t, J = 6.4 Hz, 4H), 1.83−1.76 (m, 4H), 1.45−1.38 (m,
4H), 1.34−1.32 (m, 8H), 0.90 (t, J = 6.8 Hz, 6H); 13C NMR (CDCl3,
100 MHz) δ 160.4, 69.5, 31.2, 28.4, 25.2, 22.4, 13.9.
Diethyl-3,4-diazatricyclo[4.2.1.02,5]non-7-ene-3,4-dicarboxylate
(3a).1 Prepared according to the kinetic study procedure; 122 mg, yield:
92%; colorless liquid; 1H NMR (400 MHz, CDCl3) δ 5.99 (s, 2H), 4.18
(q, J = 6.8 Hz, 4H), 4.12 (s, 2H), 3.24 (s, 2H), 1.83 and 1.64 (AB system,
JAB = 10.0 Hz, 2H), 1.24 (t, J = 6.8 Hz, 6H); 13C NMR (CDCl3, 100
MHz) δ 159.3, 135.5, 64.8, 62.4, 43.8, 40.5, 14.5.
Dibutyl-3,4-diazatricyclo[4.2.1.2,5]non-7-ene-3,4-dicarboxylate
(3b). Prepared according to the kinetic study procedure; 143 mg, yield:
1
89%; colorless liquid; H NMR (400 MHz, CDCl3) δ 6.06 (s, 2H),
4.23−4.14 (m, 4H), 4.19 (s, 2H), 3.30 (s, 2H), 1.89 and 1.70 (AB
system, JAB = 10.0 Hz, 2H), 1.67−1.62 (m, 4H), 1.45−1.35 (m, 4H),
0.94 (t, J = 7.6 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ 159.3, 135.4,
66.1, 64.7, 43.7, 40.4, 30.8, 18.8, 13.6; HRMS (MALDI-FT-ICR) exact
mass calcd for C17H26N2O4: m/z 345.1790 ([M + Na]+), found: m/z
345.1788 ([M + Na]+).
Dihexyl-3,4-diazatricyclo[4.2.1.2,5]non-7-ene-3,4-dicarboxylate
(3c). Prepared according to the kinetic study procedure; 166 mg, yield:
1
88%; colorless liquid; H NMR (400 MHz, CDCl3) δ 6.06 (s, 2H),
4.22−4.12 (m, 4H), 4.19 (s, 2H), 3.30 (s, 2H), 1.89 (d, J = 10 Hz, 1H),
1.71−1.63 (m, 5H), 1.40−1.26 (m, 12H), 0.89 (t, J = 6.8 Hz, 6H); 13C
NMR (CDCl3, 100 MHz) 159.5, 135.6, 66.6, 64.8, 43.8, 40.6, 31.4, 28.8,
25.4, 22.5, 14.0; HRMS (MALDI-FT-ICR) exact mass calcd for
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Article
(18) Vilotijevic, I.; Jamison, T. F. Science 2007, 317, 1189−1192.
ASSOCIATED CONTENT
■
(19) Byers, J. A.; Jamison, T. F. J. Am. Chem. Soc. 2009, 131, 6383−
S
* Supporting Information
6385.
Typical GC and NMR analysis, 1H NMR, 13C NMR spectra of
substrates and products. This material is available free of charge
via the Internet at http://pubs.acs.org.
(20) Morten, C. J.; Jamison, T. F. J. Am. Chem. Soc. 2009, 131, 6678−
6679.
(21) Azizi, N.; Saidi, M. R. Org. Lett. 2005, 7, 3649−3651.
(22) Scifinder provided that the aqueous solubilities of 5a, 5b, 5c, and
5d at room temperature were 0.031 mol/L, 5.2 × 10−3 mol/L, 1.7 × 10−4
mol/L and 7.0 × 10−6 mol/L respectively.
AUTHOR INFORMATION
Corresponding Author
*E-mail: qujin@nankai.edu.cn
■
(23) Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102, 7816−
7817.
Notes
(24) Breslow, R. Acc. Chem. Res. 1991, 24, 159−164.
(25) Otto, S.; Blokzijl, W.; Engberts, J. B. F. N. J. Org. Chem. 1994, 59,
5372−5376.
The authors declare no competing financial interest.
(26) Engberts, J. B. F. N. Pure Appl. Chem. 1995, 67, 823−828.
(27) Meijer, A.; Otto, S.; Engberts, J. B. F. N. J. Org. Chem. 1998, 63,
8989−8994.
ACKNOWLEDGMENTS
■
This work was financially supported by the NSFC (21072098,
21372119), the National Natural Science Foundation of China
Innovation Group (21121002), and the Tianjin Natural Science
Foundation (14JCYBJC20200). We thank Professor Chi Zhang
at Nankai University for helpful discussions.
(28) Otto, S.; Engberts, J. B. F. N. Pure Appl. Chem. 2000, 72, 1365−
1372.
(29) Blokzijl, W.; Blandamer, M. J.; Engberts, J. B. F. N. J. Am. Chem.
Soc. 1991, 113, 4241−4246.
(30) Scifinder provided that the aqueous solubilities of 8a, 8b, 8c, and
8d were 0.054 mol/L, 1.9 × 10−3 mol/L, 3.9 × 10−6 mol/L and 1.7 ×
10−8 mol/L respectively.
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(17) Note: we did not measure the exact aqueous solubilities of three
azodicarboxylates. The chemical search engine Scifinder can provide
water solubility data (determined by computational methods) of organic
reactants and these valuable data are widely used in pharmaceutical
applications. The aqueous solubility of 2a, 2b, and 2c was calculated to
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6839
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