"On water": Unique reactivity of organic compounds in aqueous suspension

Article abstract of DOI:10.1002/anie.200462883

(Chemical Equation Presented) Water, the medium of choice: Many reactions, such as Claisen rearrangements (see scheme), are dramatically accelerated when performed in aqueous suspension ("on water") relative to organic (Table Presented) solvents or even neat conditions. Low miscibility of organic compounds with water is not detrimental: in fact, it facilitates the isolation of products.

Full text of DOI:10.1002/anie.200462883

Angewandte
Chemie
Organic Chemistry
“On Water”: Unique Reactivity of Organic
Compounds in Aqueous Suspension**
Sridhar Narayan, John Muldoon, M. G. Finn,
Valery V. Fokin, Hartmuth C. Kolb, and
K. Barry Sharpless*
Water is a desirable solvent for chemical reactions for reasons
of cost, safety, and environmental concerns, and the study of
organic reactions in aqueous solvents has an intriguing
history.[1] Most notably, certain pericyclic reactions such as
[*] Dr. S. Narayan, Dr. J. Muldoon, Prof. M. G. Finn, Prof. V. V. Fokin,
Prof. H. C. Kolb, Prof. K. B. Sharpless
Department of Chemistry and
the Skaggs Institute of Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road
La Jolla, CA 92037 (USA)
Fax: (+1)619-554-6738
E-mail: sharples@scripps.edu
[**] We thank Dr. Vladislav Litosh for carrying out preliminary work.
Support from the National Institutes of Health, National Institute of
General Medical Sciences (GM 28384), the National Science
Foundation (CHE9985553), the Skaggs Institute for Chemical
Biology, and the W. M. Keck Foundation is gratefully acknowledged.
S.N. thanks the Skaggs Institute for a postdoctoral fellowship. We
also thank Dr. Suresh Suri, Edwards Air Force Base, California, for a
generous gift of quadricyclane. We urge our fellow chemists to float
their problematic reactions on water and to send observations of
success or failure to us at onwater@scripps.edu for public
dissemination with attribution.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2005, 44, 3275 –3279
DOI: 10.1002/anie.200462883
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Diels–Alder cycloadditions[2] and Claisen rearrangements[3]
stirring the reactant(s) with water to generate an aqueous
suspension. Nonpolar liquids that separate from water into a
clear organic phase are ideal candidates for these reactions.
Solid reactants can also be utilized, provided one reaction
partner is a liquid and adequate mixing is ensured. Vigorous
stirring promotes the reaction, most likely by increasing the
area of surface contact between the organic and aqueous
phases. The observed rate acceleration does not depend on
the amount of water used, as long as sufficient water is present
for clear phase separation to occur.[10] The product is isolated
simply by phase separation or filtration. In cases where clear
phase separation does not occur, such as in small-scale
reactions, liquid–liquid extraction may be necessary.
of hydrophobic compounds have been found to be acceler-
ated in dilute aqueous solution. Yet, either organic co-
solvents and/or substrate modifications are almost always
employed in preparative-scale reactions performed in
water,[1] as it is assumed that solubility is required for efficient
reaction. Not only do these strategies detract from the
simplicity and advantages sought from the use of water in
the first place, but, as we report here, the venerable
assumption “corpora non agunt nisi soluta” (substances do
not interact unless dissolved) can be distinctly counterpro-
ductive.
In recent years, we have focused on modular synthetic
techniques that rely on a few nearly perfect reaction types.[4]
In the course of this work, we have noticed that many such
reactions often proceed optimally in pure water,[5] and
particularly when the organic reactants are insoluble in the
aqueous phase.[6] We present here several examples that
illustrate a remarkable phenomenon: substantial rate accel-
eration when insoluble reactants are stirred in aqueous
suspension, denoted here as “on water” conditions. Even
when the rate acceleration is negligible, the use of water as the
only supporting medium has other advantages including ease
of product isolation and above all, safety, thanks to its high
heat capacity[7] and unique redox stability.
Seeking insight into the origin of rate acceleration in the
DMAD–quadricyclane cycloaddition, the reaction between 1
and 2 was carried out under a variety of conditions and the
time to completion was monitored (Table 2). Under homo-
Table 2: Reaction of quadricyclane (1) with dimethyl azodicarboxylate in
various solvents.[a]
Solvent
Conc. [m][b] Time to completion
In connection with our studies on the reactivity of strained
olefins, we explored the preparation of 1,2-diazetidines from
quadricyclane (1) by the 2s + 2s + 2p cycloaddition with
azodicarboxylates, discovered by Lemal and co-workers.[8]
The typical reaction conditions involve heating 1 with
dimethyl azodicarboxylate (DMAD, 2) in toluene or benzene
at 808C for 24 h or longer.[8,9] In contrast, when a mixture of
DMAD and quadricyclane is vigorously stirred “on water”,
the reaction is complete within a few minutes at ambient
temperature. The corresponding neat (solvent-free) reaction
of these two liquids takes nearly two days to reach comple-
tion, which shows that the rate acceleration is not the sole
consequence of an increase in the effective concentration of
reagents (Table 1).
toluene
EtOAc
CH3CN
CH2Cl2
DMSO
MeOH
neat
on D2O
2
2
2
2
2
2
4.53
4.53
4.53
4.53
2
>120 h
>120 h
84 h
72 h
36 h
18 h
48 h
45 min
36 h
10 min
4 h
10 min
10 min
on C6F14
on H2O
MeOH/H2O (3:1, homogeneous)
MeOH/H2O (1:1, heterogeneous)
MeOH/H2O (1:3, heterogeneous)
4.53
4.53
[a] Compound 3 was the only product observed in each case. [b] Con-
centrations of the neat and heterogeneous reactions are calculated from
the measured density of a 1:1 mixture of 1 and 2. DMSO=dimethyl-
sulfoxide.
As the cycloaddition of DMAD with quadricyclane
demonstrates, the “on water” method consists simply of
genous conditions, polar protic solvents accelerate the
reaction, with observed reaction rates in the following
order: MeOH/H2O (3:1) > MeOH > DMSO > CH3CN ꢀ
CH2Cl2 > EtOAc ꢀ toluene.[11] This trend suggests that hydro-
gen bonding, charge stabilization, and dipolar effects may
each be important for rate acceleration.[12] While water
contributes to such properties in homogeneous mixtures,
heterogeneity was crucial for observing large rate accelera-
tions. Thus, the presence or absence of methanol in a
heterogeneous reaction made little difference, but the rate
slowed considerably when enough methanol was used to
make the reaction homogeneous. However, heterogeneity in
itself is not responsible for rate acceleration as the reaction
“on” perfluorohexane was only slightly faster than the neat
reaction. Interestingly, a significant solvent isotope effect was
also observed: the reaction slowed noticeably when D2O was
used in place of water.
Table 1: Reaction of quadricyclane (1) with dimethyl azodicarboxylate
(2).
Solvent
Conc. [m]
T [8C]
t
Yield [%][a]
neat
neat
toluene
on H2O
on H2O
4.53[b]
4.53[b]
1
0
23
80
0
2 h
48 h
24 h
1.5 h
10 min
0[c]
85
74
93
4.53[d]
4.53[d]
23
82
[a] Yields are of isolated pure products. [b] Calculated from the measured
density of a 1:1 mixture of 1 and 2. [c] No product discernible after 2 h.
[d] The maximum effective concentration “on water” is assumed to be
the same as that of the neat reaction.
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Acceleration of reactions “on water” is evident even when
a nonpolar solvent comprises a part or most of the organic
phase as shown in Table 3. Thus, the reaction of quadricyclane
(1) with diethyl azodicarboxylate (DEAD, 4), carried out
simply by stirring a toluene solution of DEAD with 1 “on
water”, proceeds at a considerably higher rate than when the
reaction is carried out in toluene alone.
product as a white precipitate. In practical terms, reactions of
solid components in aqueous suspension are more reprodu-
cible and convenient than in the absence of solvent, as water
provides for efficient “mixing” of the reactants without the
dilution cost of a true solvent. Furthermore, the effective
melting point of solid reaction mixtures is noticeably lowered
in the presence of water, such that a fused organic phase is
often formed.
The notion of the special nature of water as a solvent for
organic reactions began with examples of Diels–Alder
reactions more than fifty years ago.[14] The first quantitative
data were reported by Rideout and Breslow, who showed that
Diels–Alder reactions between nonpolar compounds pro-
ceeded at much higher rates in water (dilute homogeneous
solution) than in organic solvents.[15] Rate accelerations as
high as 200-fold were noted in certain cases. Breslow et al.
also noted the high endo selectivity of certain Diels–Alder
reactions carried out in water, under both homogeneous and
heterogeneous conditions.[16] Although rate acceleration and
selectivity were ascribed primarily to hydrophobic effects, it
has since been appreciated that hydrogen bonding plays an
important role.[17] Ironically, much of the careful quantitative
work on the process does not directly apply to synthetic
chemistry, as the experiments reported by Breslow, Engberts,
and others were conducted at low concentrations (mm or less)
to maintain homogeneity in water, while preparative reac-
tions usually require much higher concentrations. In a rare
example of a heterogeneous process, Grieco et al. reported
the Diels–Alder reaction of an acyclic diene bearing a
carboxylic acid group to occur in aqueous suspension faster
than in organic solution.[18] The best results were obtained in
the reactions of diene carboxylate salts with various dien-
ophiles in water, and the rate accelerations due to water were
ascribed to micellar catalysis.[19] As some of these reactions
were carried out under conditions similar to ours, we
evaluated the effectiveness of the “on water” protocol for
Diels–Alder reactions.
Table 3: Cycloaddition of quadricyclane (1) performed with DEAD
(commercial reagent in toluene) “on water”.[a]
t [h]
Conversion [%][b]
toluene on H2O[d]
toluene[c]
3
6
17
4
8
18
42
56
69
[a] Isolated yield after 24 h at 238C: toluene, 24%; toluene “on water”,
1
72%. [b] Determined by H NMR spectroscopy using acetophenone as
internal standard. [c] Commercial DEAD in toluene used (49%, 2.86m).
[d] As [c], except for the presence of an equal volume of water to toluene.
We have found that the high reactivity of azodicarbox-
ylates “on water” is not limited to their cycloaddition
reactions: the ene reactions of these compounds respond
similarly to conditions of aqueous suspension relative to
organic solution. Leblanc et al. have used the ene reaction of
bis(trichloroethyl) azodicarboxylate (7) to achieve the allylic
amination of olefins under thermal conditions.[13] In nonpolar
solvents such as benzene, prolonged heating at 808C was
reportedly required to attain useful levels of reactivity with
simple olefins such as cyclohexene (6). In the absence of
solvent, the reaction of liquid 6 and solid 7 was found to
proceed at 508C, but still required 36 h for completion as well
as the presence of excess cyclohexene. In contrast, the
reaction performed “on water” was complete within eight
hours at 508C and afforded the product in 91% yield (see
Table 4). The neat reaction between 6 and 7 not only
appeared to be slower, but the reaction mixture was also
considerably harder to mix uniformly. In contrast, when
heated to 508C “on water” the reaction mixture initially
formed a molten organic phase, which gave way to the
We performed the cycloaddition of the water-insoluble
trans,trans-2,4-hexadienyl acetate (9) and N-propylmaleimide
(10) under various conditions (Table 5). As before, a protic
solvent (methanol) was better than nonprotic solvents, and
Table 5: Comparison of water versus organic solvents for a typical Diels–
Alder reaction.
Table 4: Ene reaction of cyclohexene (6) with bis(trichloroethyl) azodi-
carboxylate (7) “on water”.
Solvent
Conc. [m]
Time to completion [h]
Yield [%]
toluene
CH3CN
MeOH
neat
1
1
1
144
>144
48
79
43[a]
82
Solvent
T [8C]
t [h]
Yield [%]
3.69[b]
3.69[b]
10
8
82
81
benzene
neat
on H2O
80
50
50
24
36[b]
8
70[a]
62
91
H2O
[a] Yield after chromatographic purification. Other yields are of crude
products, which were >95% pure by H NMR spectroscopy. [b] Calcu-
1
[a] Data from Ref. [13]. [b] Additional 6 added after 24 h.
lated from the measured density of a 1:1 mixture of 9 and 10.
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the reaction in aqueous suspension showed substantial rate
cult to control under neat conditions. Instead, protic solvents
such as alcohols and especially alcohol/water mixtures
provide good homogeneous media for these transforma-
tions.[4] Here too, we find that water alone is the medium of
choice. The reactions are completed in shorter times than in
other protic solvents, and the pure product often precipitates,
to be isolated by simple filtration.
acceleration over homogeneous solution. Consistent with the
results of Grieco et al.[18] and in contrast to the reaction of 1 +
2 described above, the neat Diels–Alder addition of 9 to 10
(both liquids) was approximately as fast as in water suspen-
sion.[20]
Claisen rearrangements are another significant class of
reactions for which the accelerating effect of water is well-
recognized.[21] The initial discovery appears to have been
made during mechanistic studies of the chorismate–prephen-
ate rearrangement, a key step in the biosynthesis of shikimic
acid.[22] Brandes, Grieco, and Gajewski then performed a
kinetic study on the rearrangement of an allyl vinyl ether
substrate with an attached carboxylate functionality.[23] The
rate of rearrangement of the carboxylate salt in water was
found to be about two orders of magnitude higher than that of
the methyl ester in nonpolar solvents.[24] These findings were
exploited further by Grieco et al., who used the accelerating
influence of water to promote difficult rearrangements.[25]
In contrast to the aliphatic Claisen rearrangements, the
effect of water on the analogous aromatic Claisen rearrange-
ment is little known.[26] We have made preliminary measure-
ments on naphthyl ether 12, which undergoes rearrangement
at an appreciable rate even at room temperature. Table 6
The reaction of cyclohexadiene monoepoxide (14) with N-
(3-chlorophenyl)piperazine (15) is illustrative (Table 7).
Table 7: Application of the “on water” method to the nucleophilic
opening of an epoxide.
Solvent
Conc. [m]
t [h]
Yield [%]
toluene
neat
EtOH
on H2O
1
120
72
60
<10[a]
76
89
3.88[b]
1
3.88[b]
12
88
[a] Determined by 1H NMR spectroscopic analysis of the crude reaction
mixture. [b] Calculated from the measured density of a 1:1 mixture of 14
and 15.
Table 6: Comparison of solvents for an aromatic Claisen rearrangement
(0.28–0.46m), performed at room temperature.[a]
When heated at 508C, the reaction “on water” was completed
overnight, while the reactions in solution in ethanol or
without solvent required approximately three days to reach
completion. In toluene, less than 10% conversion occurred
after five days at the same temperature. Thus, taking into
account the concentrations of the reagents, the rates of
reactions “on water” and in ethanol appeared to be approx-
imately the same, and greater than that for the reaction
performed in the absence of solvent.
Solvent
Yield [%][b]
toluene
DMF
16
21
Thus, a variety of reactions can be efficiently carried out in
aqueous suspension, with the most dramatic effects observed
for the addition of azodicarboxylates to unsaturated hydro-
carbons. To the best of our knowledge, these examples
represent some of the largest rate accelerations due to water
observed under preparative conditions, that is, at molar
concentrations. A central theme in the field of aqueous
organic chemistry has been the need to promote solubility in
these reactions. Clearly, solubility is not essential.
CH3CN
MeOH
neat
27
56[c]
73
on H2O
100
[a] Conversion was monitored by 1H NMR analysis of aliquots. [b] Except
in the case of MeOH, no other products were detected by 1H NMR
spectroscopy. [c] 14% of 4-chloro-1-naphthol was also observed.
shows the effect of various solvents on this process. After five
days at 238C, the sample of 12 in aqueous suspension had
completely rearranged to 13, while the rearrangement was
considerably slower in organic solvents. The neat reaction was
again closest in rate to water and required one further day to
reach completion. As with Diels–Alder reactions, the “on
water” protocol provides the best set of conditions in terms of
efficiency, convenience, and safety, even when rate acceler-
ations are not large.
Non-pericyclic reactions such as the opening of epoxides
and aziridines with heteroatom nucleophiles also derive
unique benefits from the “on water” environment. Hydrogen
bonding is crucial for the activation of such electrophiles,
making these ring-opening processes autocatalytic and diffi-
Although the reactivity phenomenon described here has
immediate practical implications, its origins are presently
unclear; nevertheless, a few preliminary remarks are in order.
For example, it is possible that reactions “on water” actually
proceed through small amounts of dissolved solutes. Rate
acceleration in homogeneous aqueous solution has been
attributed to a variety of effects such as hydrophobic
aggregation,[2,15] cohesive energy density,[27] or ground-state
destabilization.[28,29] Breslow et al. have invoked solution-
phase hydrophobic effects to explain the high endo selectivity
of certain Diels–Alder reactions in aqueous suspension and
solution.[2a,16] Engberts and co-workers made a fundamental
point by providing evidence that, in cycloaddition reactions,
hydrophobic destabilization will have a considerably greater
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impact on the ground state than on the transition state.[29,30]
The importance of hydrogen bonding in the acceleration of
Diels–Alder reactions in aqueous solution is supported by
both experimental[31] and theoretical[32] studies.
ylates at À608C, see: M. A. Brimble, C. H. Heathcock, J. Org.
Chem. 1993, 58, 5261.
[14] R. B. Woodward, H. Baer, J. Am. Chem. Soc. 1948, 70, 1161; H.
Hopff, C. W. Rautenstrauch, US 2262002, 1939 [Chem. Abstr.
1942, 36, 10469].
However, it seems that many of the reactions described
above are simply too fast for the acceleration to be solely due
to solution-phase phenomena. In this regard, the observed
requirement for heterogeneity and the finding that the rates
of reactions “on water” often exceed those of the same
reactions performed in the absence of solvent demand
attention. Perhaps the unique properties of molecules at the
macroscopic phase boundary between water and insoluble
hydrophobic oils play a role.[33] The same principles that
contribute to solution-phase effects may be amplified at such
phase boundaries, but other factors, such as the redistribution
of surface species driven by surface-tension energetics,[34] may
also be relevant. We plan to keep exploring the “on water”
phenomenon both for practical applications and mechanistic
understanding.
[15] D. C. Rideout, R. Breslow, J. Am. Chem. Soc. 1980, 102, 7816.
[16] R. Breslow, U. Maitra, D. Rideout, Tetrahedron Lett. 1983, 24,
1901.
[17] For an excellent recent review of the role of hydrophobic effects
on reactivity, see: S. Otto, J. B. F. N. Engberts, Org. Biomol.
Chem. 2003, 1, 2809.
[18] P. A. Grieco, P. Garner, Z. He, Tetrahedron Lett. 1983, 24, 1897.
[19] P. A. Grieco, K. Yoshida, P. Garner, J. Org. Chem. 1983, 48, 3137;
However, see: R. Breslow, U. Maitra, Tetrahedron Lett. 1984, 25,
1239, and Ref. [28b].
[20] As both starting materials and the product are oils, the neat
reaction is not prone to physical “mixing” issues, which can arise
when one of the reactants is a solid. Even when mixing is not an
issue, we have encountered a few cases where the reactions “on
water” are two- to threefold faster than the corresponding neat
reaction, although the example shown here is typical.
[21] J. J. Gajewski in Organic Synthesis in Water (Ed.: P. A. Grieco),
Blackie, London, 1998, p. 82.
Received: December 10, 2004
Published online: April 21, 2005
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D. P. Curran, J. Am. Chem. Soc. 1987, 109, 1160; c) J. J. Gajewski,
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[24] Grieco subsequently reported that the rearrangement of the
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Keywords: click chemistry · cycloaddition · interfaces ·
.
rearrangement · water chemistry
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