Hydrophobicity and mixing effects on select heterogeneous, water-accelerated synthetic reactions

Article abstract of DOI:10.1021/jo801134r

(Chemical Equation Presented) The influence of aqueous reaction media on organic reactions is a topic of long-standing interest, particularly as it affects the rate or selectivity of synthetic reactions. Sometimes such reactions appear homogeneous, typica

Full text of DOI:10.1021/jo801134r

Hydrophobicity and Mixing Effects on Select Heterogeneous,
Water-Accelerated Synthetic Reactions
Michael C. Pirrung,* Koushik Das Sarma,† and Jianmei Wang
Department of Chemistry, UniVersity of California, RiVerside, CA 92521-0403
michael.pirrung@ucr.edu
ReceiVed May 27, 2008
The influence of aqueous reaction media on organic reactions is a topic of long-standing interest, par-
ticularly as it affects the rate or selectivity of synthetic reactions. Sometimes such reactions appear
homogeneous, typically in dilute solution, whereas others are obviously heterogeneous, typically in
concentrated solution that is more characteristic of a preparative synthetic reaction. The latter situation
has been termed “on water.” Here, it is demonstrated that the rates of heterogeneous ene reactions, Passerini
reactions, and Ugi reactions in pure water and in aqueous solutions are dependent on the mixing method
and reactant polarity, consistent with the involvement of hydrophobic interactions in their acceleration.
Introduction
must be accelerated in water as it is under pressure”.5 The ∆Vq
term (volume of activation) in this paradigm is a quantity less
recognized or used than others affecting reaction rates, such as
∆Gq. The volume of activation is simply the volume of the
transition state minus the volume of the reactant(s).6 The molar
volume of reactants is easily obtained from the ratio of molecular
mass (Mr) to density (F). The molar volume of the transition
state is more obscure, but in general highly ordered transition
states are more compact than reactants. The ∆Vq can be
determined by the pressure dependence of the reaction rate, and
it contributes to the ∆Sq term of ∆Gq. The acceleration of
reactions by pressure was first recognized in the 1930s, and
The effects of aqueous solvent on the rates of reactions of
organic compounds is a topic of recent research.1 Cycloaddition
reactions, primarily of quadricyclane with azo compounds,1b
have been examined as well as ene reactions of alkenes like
pinene with azo compounds,2 with a key feature being the
insolubility of the reactants in water. Several publications have
exploited these findings3 and offered speculations4 on the basis
for the rate acceleration of such reactions.
The origin of this field can be traced at least as far back as
Lubineau, who stated in 1986: “a reaction under kinetic control
between two non-polar molecules for which ∆Vq is negative
† Department of Chemistry, Duke University, Durham, NC; Current address:
Advinus Therapeutics Pvt. Ltd., International BioTech Park, Hinjewadi, Pune -
411057, India.
(1) (a) Dickerson, T. J.; Lovell, T.; Meijler, M. M.; Noodleman, L.; Janda,
K. D. J. Org. Chem. 2004, 69, 6603–9. (b) Narayan, S.; Muldoon, J.; Finn,
M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B. Angew. Chem., Int. Ed. 2005,
44, 3275–9. (c) Jung, Y.; Marcus, R. A. J. Am. Chem. Soc. 2007, 129, 5492–
502.
(2) (a) Kolb, H. C.; Sharpless, K. B. Drug DiscoVery Today 2003, 8, 1128–
37. (b) Rouhi, A. M. Chem. Eng. News 2004, 82 (7), 63–65. (c) Narayan, S.;
Fokin, V. V.; Sharpless, K. B. Abstr. Pap. Am. Chem. Soc. 2004, 228, U126-
U126 554-ORGN. (d) Narayan, S.; Fokin, V. V.; Sharpless, K. B. Abstr. Pap.
Am. Chem. Soc. 2005, 230, U3087-U3088 140-ORGN. (e) Narayan, S.; Fokin,
V. V.; Sharpless, K. B. In Organic Reactions in Water: Principles, Strategies
and Applications; Lindstro¨m, U. M., Ed.; Blackwell Pub.: Ames, IA, 2007; pp
350-364.
10.1021/jo801134r CCC: $40.75
Published on Web 10/28/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8723–8730 8723

Pirrung et al.
many reactions with significant pressure acceleration are
known.7 Bimolecular reactions that give single molecule
products often fall into this category, as do those with highly
ordered transition states. Application of external pressure lowers
the ∆Gq for reactions with a large negative ∆Vq, accelerating
them. This occurs because the energy of the more compact
transition state is lowered by pressure more than that of the
ground state. A variety of cycloaddition and other pericyclic
reactions, such as the Claisen rearrangement, have significant
negative ∆Vq and also exhibit pressure acceleration.8 While its
relationship to pressure acceleration is one view of the accelera-
tion of reactions in aqueous media, there are others.
force that gives liquids their cohesion, and is expressed in eq
1, which is simply the molar energy of vaporization divided by
the molar volume. The ced values for many pure liquids have
been determined and are available from tabulations.16 The ced
of water is one of the highest known, and when expressed in
units of pressure is ca. 23 kbar.
∆Hvap - RT
c.e.d. )
(1)
Mr ⁄ F
The cohesive pressure concept enables consideration of the
energetics of the hydrophobic effect, though there are opposing
contemporary views on this matter.17 As the ced is inversely
related to molar volume, water has one of the largest ceds
because of its small molar volume (18 cm3/mol), the smallest
of any liquid commonly used as a reaction solvent. When water-
immiscible organic compounds are dissolved in water, a void
is created and the capsule of water molecules formed around
the hydrophobic compound can be described as a clathrate. The
energetic cost of displacing/releasing water to form this void
within bulk water relates to the ced. The cohesive energy density
has proved useful to understand solvent effects on both sol-
volysis reactions and the Claisen rearrangement, particularly
those involving aqueous solvent and the hydrophobic effect.18
The ced of the solvent is even correlated with the rates of some
Diels-Alder reactions.19
A large body of work, coming initially from Breslow,9 con-
cerns the acceleration of the Diels-Alder reaction in aqueous
media. This reaction is pertinent here because of its acceleration
under pressure and therefore its relation to Lubineau’s hypoth-
esis. Interestingly, a very early report by Diels and Alder of
the reaction of furan and maleic anhydride was performed in
water.10 Breslow describes the reaction mixtures as suspensions
when aqueous Diels-Alder reactions of cyclopentadiene are
performed at 0.45 M,11 which he called the formal concentration
because of the presence of two phases. Narayan et al.1b conduct
their reactions at higher formal concentrations (up to 4.5 M!).
Much mechanistic work discussed in the literature following
was performed at low concentrations that are not useful pre-
paratively, some as low as 0.1 mM.
The phenomena underlying the acceleration of organic
reactions “on water” has been considered by Marcus.1c He notes
the unique environment of water molecules located directly at
an organic-aqueous phase boundary and the special availability
of ‘dangling’ hydrogen bonds, that is, hydrogen bonding cap-
acity that is unfulfilled by other water molecules, unlike the
situation in bulk water. He distinguishes clathrates, where water
encapsulates an organic droplet, from the situation at an organic/
water emulsion interface, and proposes that hydrogen bonding
of dangling water to organic molecules/intermediates at such
an interface exerts a rate-accelerating effect on biradical for-
mation in the cycloaddition of quadricyclane to dimethyl azo-
dicarboxylate.1b However, it seems that nonaqueous, hydrogen-
bonding solvents could also exert this effect, begging the
question of what makes water unique as a solvent for this
reaction. This idea is reminiscent of Jorgensen’s explanation
for aqueous acceleration of quinone Diels-Alder reactions,
enhanced hydrogen bonding in the transition state.13 While
hydrogen bonding to water may be involved in promoting
cycloadditions of some reactants, other reactants whose hydro-
gen bonding capacity is nil (diphenylacetylene) also experience
rate accelerations in water,4b showing that hydrogen bonding
cannot account for all of these effects. Marcus discounts the
value of concentrating the reactants into an organic droplet by
hydrophobic interactions, reasoning that the concentration inside
a clathrate must be similar to that of neat reactants (wherein
the reaction is slower). This view does not take into account
the vastly different polarities of aqueous media and the neat
organic reactants, an effect Breslow believes is important.10 This
theory also does not consider the known pressure acceleration
of quadricyclane-azo compound cycloadditions.20 In sum, there
are many perspectives on the factors that influence the rates of
Acceleration of Diels-Alder reactions of nonpolar reactants
in water compared to organic solvents has been attributed to
many factors, including the hydrophobic effect,12 enforced
hydrophobic interactions in the transition state,13 enhanced
hydrogen bonding in the transition state,14 and the high cohesive
energy density (ced) of water (550.2 cal•mL-1 at 25 °C).15 While
hydrogen bonding and the hydrophobic effect are familiar to
many chemists, cohesive energy density is not. Cohesive energy
density (also called cohesive pressure) is the energy of the
interaction among molecules of a liquid. It is the intermolecular
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Tellado, F. Chem. Commun. 2006, 2798–2800. (c) Suzuki, I.; Suzumura, Y.;
Takeda, K. Tetrahedron Lett. 2006, 47, 7861–7864. (d) Bose, A. K.; Manhas,
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8724 J. Org. Chem. Vol. 73, No. 22, 2008

Heterogeneous, Water-Accelerated Synthetic Reactions
reactions of nonpolar compounds in aqueous media, but no
unified theory has been developed that accounts for all observa-
tions and has been accepted as valid.
pressure-accelerated24 and observed no reaction. We hypothesize
that polar reactants that are miscible with water, as these are,
will not experience unique reaction environments (such as
clathrates) or the hydrophobic/ cohesive pressure effect. That
reactions of such compounds would not benefit from rate
acceleration in water is consistent with Lubineau’s hypothesis,
which specifies its application to nonpolar compounds. That
these reactions are homogeneous is a hindrance rather than a
help.
Many reactions of organic compounds in aqueous media are
heterogeneous. Chemists typically avoid heterogeneous reactions
if possible because they can be difficult to scale up. One basis
of this problem may be a rate-limiting mass-transport step
between phases, rather than a chemical step as in a homogeneous
reaction. In such circumstances, the efficiency of mixing can
strongly influence the rate of reactant movement across the
phase boundary and therefore the reaction rate. The inability
to ensure efficient mixing on all reaction scales translates to
scalability issues. One natural response to this concern is to
use organic cosolvents in an attempt to render the reaction
mixture homogeneous. Because the unique properties of water
(such as its high surface tension and high cohesive pressure)
may contribute significantly to the rate acceleration, creating
homogeneous reaction media using organic cosolvents that
lack these traits may compromise the potential benefits of
water on reaction rate.
Work in our laboratory concerning the acceleration of re-
actions in water has focused on multicomponent reactions such
as the Ugi and Passerini reactions,21 a class also known to be
pressure-accelerated. The reactions described are far faster in
water than in organic solvents that are more polar than water
(formamide) or are less polar but offer similar hydrogen bonding
capability (methanol). These two solvents have c.e.d.s much
smaller than water. These reactions are heterogeneous at the
beginning and become more so as they proceed because the
products are typically much less soluble in aqueous media than
the reactants. A follow-on study examined the scope of the
water-accelerated Passerini reaction, and found that reactants
that include alcohols and tertiary basic nitrogen gave poor
results.22 As will be described following, such polar functionality
likely decreases the hydrophobicity of the reactants and therefore
hydrophobic interactions and cohesive pressure effects that we
propose play an important role in rate acceleration.
We aimed here to further study the rates of some organic
reactions in water to better understand the effects of hydrophobic
interactions and mixing on rates.
Results
While the effects of mixing on organic reactions such as
heterogeneous hydrogenations can be investigated through
variables such as stirring rate, we aimed to discover an optimum
mixing method for multicomponent reactions in water that
would offer significant rate acceleration over earlier work. An
initial qualitative study of the effect of the mixing method on
Passerini reactions in water (eq 2) was performed using
carboxylic acids 1-5 (Chart 1), tert-butylisonitrile, and isov-
CHART 1
The foregoing alludes to possible effects of reactant hydro-
phobicity on rate acceleration for organic reactions conducted
in water. While in some ways obvious, this factor has not been
given much past consideration.23 The hydrophobicity of an
organic compound may be viewed from many perspectives, but
one useful convention is the log of the octanol/water partition
coefficient, or log P. It is widely used in physicochemical
studies, tabulated for many organic compounds, and easily
calculated for compounds for which it has not been measured
(using chemical drawing programs, inter alia). For example, the
water-miscible acetone has a calculated log P (Clog P) of -0.2,
and more hydrophobic molecules have positive log Ps. To keep
this representative value for polarity/hydrophobicity in mind,
the Clog Ps are provided for all reactants in this paper. In
unpublished work, we examined in water solution several
reactions of acetone and nitromethane that are known to be
aleraldehyde. Isolated yields following the reaction times given
in Table 1 were determined for reactions performed under
magnetic stirring, wrist-action shaking, or in a laboratory
ultrasonic cleaning bath. Some reactions were also performed
without agitation. Yields were determined based on mass
recovered and comparison of starting material and product peak
areas by HPLC. All of these reactions were performed on a
0.1-0.3 mmol scale at a concentration of 0.1 M. This con-
centration is comparable to that used in almost all of Breslow’s
work; reaction mixtures were visibly heterogeneous at their
initiation. Because we have previously demonstrated that
(20) (a) Papadopoulos, M.; Jost, R.; Jenner, G. J. Chem. Soc. Chem. Commun.
1983, 221–222. (b) Papadopoulos, M.; Jenner, G. NouV. J. Chim. 1983, 7, 463–
464. (c) Jenner, G. Bull. Soc. Chim. Fr. 1984, 275–284. (d) Papadopoulos, M.;
Jenner, G. NouV. J. Chim. 1984, 8, 729–732. (e) Jenner, G. New J. Chem. 1991,
15, 897–899. (f) Pirrung, M. C. Chem.-Eur. J. 2006, 12, 1312.
(21) (a) Pirrung, M. C.; Sarma, K. D. J. Am. Chem. Soc. 2004, 126, 444. (b)
Pirrung, M. C.; Das Sarma, K. Synlett 2004, 1425–1427. (c) Pirrung, M. C.;
Sarma, K. D. Tetrahedron 2005, 61, 11456.
(24) (a) Musumi, Y.; Bulman, R.; Matsumoto, K. Heterocycles 2002, 56,
599. (b) Sekiguchi, Y.; Sasaoka, A.; Shimomoto, A.; Fujioka, S.; Kotsuki, H.
Synlett 2003, 1655. (c) Sera, A.; Takagi, K.; Katayama, H.; Yamada, H.;
Matsumoto, K. J. Org. Chem. 1988, 53, 1157.
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J. Org. Chem. Vol. 73, No. 22, 2008 8725

Pirrung et al.
TABLE 1. Effect of Mixing Method on the Product Yield for
Reactions 2 and 3a
metal pins to transmit sonic energy into each well of a 96-well
plate, permitting parallel sonication. When the Passerini reaction
of 1 was performed using this instrument, the ultrasound effects
were dramatic. A single 10 s pulse of ultrasound gave 40%
conversion to product, and six 10 s ultrasound pulses gave 60%
conversion. There was no background reaction without ultra-
sound. Because of the heating that is intrinsic to ultrasonication,
cooling of these reactions and short pulses of sonic irradiation
were essential, as we have previously shown that this reaction
exhibits an inverse temperature dependence (i.e., it is slower at
higher temperature).
acid Clog P time (min) stirring shaking ultrasound
still
1
2
3
4
5
6
1.279
2.015
1.235
2.384
1.622
30
30
60
30
15
NP
10
35
52
10
47
41
NP
32
54
NP
83
100
32
55
65
52
<5
NP
10-20
variable
NP
-2.834
360
NP
NP
a NP - not performed.
While the foregoing results support a strong effect of mixing
method on the rate of these multicomponent reactions in water,
we aimed to gain more quantitative data on the effect of mixing
on aqueous organic reactions. To obtain high-quality reaction
progress data on a heterogeneous process is tedious and lab-
orious (vide infra), but precise rate constants would be needed
to discern small rate differences dependent on the mixing
method. Because the Passerini reaction has a third-order rate
law,28 it was less desirable for initial studies, so we instead
sought a water-accelerated reaction with a second-order rate law.
We chose the ene reaction of azo compounds with ꢀ-pinene,
which was known in organic solvents29 and had been reported
by Narayan et al.2d,e to be water-accelerated (concentration not
specified). Our initial study showed a modest rate increase of
about 3-fold in water for the reaction between ꢀ-pinene and
DIAD (eq 4), similar to the initial report of Narayan et al. A
study reported later2e using DEAD as the azo compound gave
the ene reaction product in 82% yield in water in 3 h, while the
same reaction neat gave the product in 90% yield but in 36 h.
Passerini reactions in water can show an inverse temperature
dependence and the water in the ultrasonic bath warms over
time, ice was added periodically to maintain the bath temperature
at ambient, like the reactions performed with the other mixing
methods.
The Passerini reaction of acid 1 in water gives the product
in quantitative yield after 30 min under ultrasonication. We
earlier reported18 that this reaction gives the product in 95%
yield in 200 min; that trial was performed using wrist-action
shaking. As a control for ultrasound-specific effects, this reaction
was also performed for 30 min in CH2Cl2 with ultrasonic
irradiation, and the product was obtained in only 15% yield.
Passerini reaction of 1 in water without mixing gives less than
5% conversion to product. Ultrasonication also proved to be
the superior method of mixing in promoting Passerini reactions
of acids 2-5. Reactions without mixing were either very slow
or variable in their rates. The variance of the rate of Passerini
reactions in water with mixing method is consistent with
heterogeneous reaction media. A similar investigation of the
Ugi reaction of acid 6 to create a ꢀ-lactam (eq 3) was performed.
It also shows a dependence of rate on the mixing method, with
wrist-action shaking being superior to conventional magnetic
stirring.
Ultrasound can exert profound effects on organic reactions.25
While many explanations have been offered for these observa-
tions, ultrasonication commonly speeds reactions with hetero-
geneous character, which can be attributed at least partially to
an increase in the rate of transfer between phases. Ultrasound
is regarded by some as the most efficient method of mixing.
There is also specific precedent for the acceleration of reactions
of organic compounds in water by ultrasonication,26 which may
also be attributed to enhanced phase transfer. The ultrasonication
literature makes clear that common laboratory ultrasonic clean-
ing baths can be poor sources of ultrasound for enhancing
chemical reactions. The observation of an ultrasound effect on
reaction 2 using such a source is thus encouraging. Superior
ultrasound effects are often observed using power ultrasound
from a sonic horn. We therefore aimed to investigate reaction
2 using power ultrasound. Because of our interest in high-
throughput synthesis using multicomponent reactions in water,18a
we sought an ultrasound source that could irradiate multiple,
small volumes. A 96-well format sonicator is available for
resuspension of compounds in chemical libraries following
storage in frozen DMSO.27 It uses a metal plate bearing multiple
The dependence of the rate of the reaction in eq 1 on mixing
method, the medium, and reactant hydrophobicity were next
investigated. It was followed by internal standard gas chroma-
tography, evaluating the amount of ꢀ-pinene remaining. Rep-
licate reactions were set up in the same number as the number
of time points and all were treated identically. The initial reactant
concentration was 0.25 M. These reactions were performed at
ambient without special efforts to control temperature, as the
inability to monitor the reaction continuously was viewed as a
far larger contribution to the variation in observed reaction
progress than temperature fluctuations. There is no assurance
that the effectiveness of each mixing method is equal to the
others, but the intensity of each method was maintained across
all experiments. These reactions are clearly heterogeneous at
their initiation, with organic liquid droplets on or under the
aqueous phase. At each time point, one replicate was extracted
with organic solvent to ensure that no reactants or products were
depleted or enriched by differential solubility in the medium.
The inverse of reactant concentration was plotted vs time, and
data were linear for more than 3 half-lives (Figure 1). The
mixing methods used included magnetic stirring, wrist-action
(25) Cravotto, G.; Cintas, P. Chem. Soc. ReV. 2006, 35, 180–196.
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149, 153. (b) Cravotto, G.; Demetri, A.; Nano, G. M.; Palmisano, G.; Penoni,
A.; Tagliapietra, S. Eur. J. Org. Chem. 2003, 4438. (c) Cravotto, G.; Palmisano,
G.; Tollari, S.; Nano, G. M.; Penoni, A. Ultrason. Sonochem. 2005, 12, 91. (d)
Li, J.-T.; Zhang, X.-H.; Lin, Z.-P. Beilstein J. Org. Chem. 2007, 3, 13.
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(28) Baker, R. H.; Stanonis, D. J. Am. Chem. Soc. 1951, 73, 699.
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8726 J. Org. Chem. Vol. 73, No. 22, 2008

Heterogeneous, Water-Accelerated Synthetic Reactions
CHART 2
TABLE 3. Effect of azo Reactant on the Rate of the ene Reaction
with Pinene
a
R
Clog P H2Oa CH2Cl2
k(H2O)/k(CH2Cl2)
SD
i-Propyl
tert-Butyl
Benzyl
2.33
2.76
4.48
4.47
18
1.1
16
83
2.8
0.38
21
1700
6.4
2.9
0.76
0.05
0.6
0.3
0.08
0.005
Trichloroethyl
a Rate constant × 105 (L·mol-1 ·s-1) average, n ) 3.
FIGURE 1. Kinetic plot for the ene reaction of ꢀ-pinene and 7 in water
with vortexing.
TABLE 2. Effect of Mixing Method and Solvent on the Rate of
Reaction 4
rate constant × 105
solvent
CH2Cl2
H2O
H2O
H2O
H2O
1 M aq LiCl
2 M aq glucose
1:9 CH3OH:H2O
mixing method
(L·mol-1 ·s-1
)
SD
stir
stir
2.8
8.3
9.4
17.6
6.7
8.1
0.3
0.8
0.9
1.8
0.7
0.8
0.9
1.4
shake
vortex
still
shake
shake
shake
9.1
13.7
shaking, vortexing, and no mixing. The effect of water-soluble
solutes was also examined. The results are summarized in
Table 2.
FIGURE 2. Kinetic plot for a single run of the Passerini reaction in
eq 3.
The rate constants measured in water and in methylene
chloride with stirring were consistent with the preliminary study.
The rate in water increased as this reaction was shaken or
vortexed. Interestingly, little decrement in rate was noted for
reactions that were not mixed at all. Some agitation must have
occurred through handling essential to the experimental proce-
dure, however. The effect of solutes on this reaction was
examined because of extensive earlier studies of the effect of
salting-in or salting-out agents on the hydrophobic effect and
reactions affected by it.8 For this reaction, there was no
significant effect of solutes. One of the faster reactions studied
included low proportions of an organic cosolvent. Overall, the
rate differences are modest, but their variation with mixing
method is as expected for the heterogeneous medium observed.
Considering the implication discussed earlier that the ability
of aqueous solvents to affect organic reaction rates should be
related to reactant hydrophobicity, we examined the dependence
of the rate of this ene reaction on the Clog P of the azo
compound. Rate constants were determined in triplicate. Four
available azo compounds 7-10 were studied using vortexing,
the most efficient mixing method found above, for these
reactions in water (Chart 2). Their rates in CH2Cl2 were also
determined to discern the solvent effect. The log Ps of each
azo reactant were also calculated, and all data are given in
Table 3.
Within each solvent series, the intrinsic reactivity of these
azo compounds can be discerned. The azo compound 10 with
the electron-withdrawing trichloroethyl ester is most reactive,
and the azo compound 8 with the bulky tert-butyl ester is least
reactive. For azo reactants 7 and 8 of intermediate hydrophobic-
ity, reactions were modestly faster in water. For azo reactants
9 and 10 of high hydrophobicity, reactions were faster in the
organic solvent.
While the foregoing studies were instructive, the rate ac-
celeration by the solvent water was small by comparison to some
of the more interesting reactions that have been earlier studied.
We therefore undertook a kinetics study of a Passerini reaction
that experiences a substantial rate acceleration in water. Fol-
lowing some initial scouting, reaction 5 was chosen because it
does not proceed at all in methanol, analysis of the ketone
reactant by internal standard gas chromatography is reliable,
and the reaction in water has a reasonable rate. The same
protocols as described for reaction 4 were observed. Reaction
progress data were plotted according to the integrated form of
the third-order rate equation. Plots of the inverse of the square
of the reactant concentration vs time were linear (Figure 2).
Rate constants were determined in triplicate.
The rate of reaction 5 varies with the mixing method as
expected for this heterogeneous medium (Table 4). Surprisingly,
J. Org. Chem. Vol. 73, No. 22, 2008 8727

Pirrung et al.
TABLE 4. Effect of Mixing Method and Solvent on the Rate of
Reaction 5
conditions
rate constanta
SD
H2O, stir
H2O, vortex
H2O, shake
2.5 M aq LiCl, shake
15
1.5
1.8
0.89
1.5
8.8
7.4
12
a Rate constant × 107 (L2 ·mol-2 ·s-1), average, n ) 3.
FIGURE 3. Proposed reaction progress plot for an idealized organic
reaction with a large negative ∆Vq in organic solvent (blue), in organic
solvent under pressure (green), or in water (red). External static pressure
lowers the transition state energy from b to c. In water, the ground-
state energy is raised to d, but the transition state e is not raised as
much owing to the favorable effect of cohesive pressure. Salting-out
solutes (like LiCl) raise the ground-state energy from d to f.
magnetic stirring proved to be the most effective method of
mixing for this reaction. The addition of LiCl with shaking
caused nearly a doubling of the reaction rate, clearly a significant
effect, but smaller than some observed earlier.18
these reactions. For the Passerini reaction, addition of the
carboxylic acid to the nitrilium ion to form an imidate, or its
rearrangment to give the product, are thought to be rate-
determining.25 For the Ugi reaction, the rate-determining step
is unknown; a rate law has not been reported. While it is also
possible that the rate-determining step for the reaction might
change with solvent, we have observed no evidence of such
behavior.
Discussion
The observations reported here that mixing affects the rates
of several organic reactions in water were certainly foreshad-
owed in the work of Breslow. His original work on the
Diels-Alder reaction in water noted an increase of reaction rate
with vigorous stirring,8 certainly an expectation in a heteroge-
neous reaction.
For reactions best accelerated by ultrasonication, it is tempting
to consider that the extreme conditions of temperature and
pressure associated with the formation and collapse of bubbles
in solution, the so-called sonochemical hot spot,30 plays a role.
However, the effects of this spectroscopically determined hot
spot do not appear to be available to accelerate most solution-
phase reactions; if they were, ultrasonication could be much
more broadly used to promote reactions. Ultrasonication is
undoubtedly a very effective method to facilitate phase transfer
in heterogeneous organic reactions, and most of the circum-
stances in which significant rate/efficiency effects of ultrasoni-
cation have been demonstrated involve some aspect of hetero-
geneity. While ultrasonication of water can generate hydroxyl
radical, it is difficult to see how this could affect the reactions
studied here. The hot spot also seems to be comparable in
organic and aqueous media,30 so the differential effects of ul-
trasound on these reactions in different solvents cannot be ex-
plained by variations in the effects of ultrasound.
One potentially puzzling aspect of our results is the accelera-
tion in water of the ꢀ-lactam-forming Ugi reaction. The amino
acid reactant is surely fully soluble in water, and therefore it is
not expected to form a clathrate. However, the initial step in
the Ugi reaction is condensation of the amino acid with the
aldehyde to form imine 11, and its hydrophobicity is similar to
reactants in other water-accelerated reactions. It is also interest-
ing that the Ugi reaction is successful in water even though
this initial imine-forming reaction produces a molecule of water,
and the 55 M concentration of water as solvent creates as
disfavorable an equilibrium as can be imagined. This fact
requires that imine formation make no contribution to the rate
limitation of the Ugi reaction in water. Indeed, knowing the
rate-determining step is key to considering the acceleration of
One hypothesis stimulated by the results in Table 3 is that
reactants that are too nonpolar and therefore totally insoluble
will react poorly when water is used as solvent because they
are in the wrong phase. Likewise, the ability of 10% (v/v)
methanol to provide a rate enhancement in reaction 4 compared
to pure water could be explained by its ability to increase the
mixing of the reactants. While one might expect 10% methanol
to reduce the ced of the solution, just as it reduces its surface
tension (observed when volatile alcohols or ketones are used
to rinse water droplets from glassware), the effect of organic
cosolvents on the ced itself is unknown. Small amounts of
organic cosolvents can significantly change the course of sol-
volysis reactions, which might be partly attributed to changes
in the c.e.d.
The observation that reaction 5 is fastest when stirred rather
than mixed by other methods, when aggregated with our other
observations, suggests that the most effective mixing method
for organic reactions in water may need to be determined
empirically for each reaction in question. While this is less
convenient than knowing in advance that the best outcome
should be obtained with a specific method, awareness of this
phenomenon at least permits the chemist to undertake appropri-
ate studies to ensure that optimum reaction procedures are
reached. It was perplexing, however, that some reactions of
pinene with azodicarboxylates were not slowed without mixing.
Formation of clathrates is less likely in the absence of agitation,
so such reactions might be good candidates for explanation by
the ‘surface waters’ hypothesis.
Understanding of all of the effects that may impinge on
organic reactions that are accelerated in water compared to
organic solvents is certainly incomplete. We propose here a
simplified reaction coordinate diagram given in Figure 3 for
several different reaction conditions. Ground state reactants in
(30) (a) Suslick, K. S.; Hammerton, D. A.; Cline, R. E., Jr. J. Am. Chem.
Soc. 1986, 108, 5641–5642. (b) Didenko, Y. T.; McNamara, W. B., III.; Suslick,
K. S. J. Am. Chem. Soc. 1999, 121, 5817–5818.
8728 J. Org. Chem. Vol. 73, No. 22, 2008

Heterogeneous, Water-Accelerated Synthetic Reactions
organic solvent are state a, and under normal conditions the
reaction proceeds via the blue pathway through transition state
b, which has a smaller volume than the reactants. If this reaction
is pressurized, the relative energy of the transition state is
reduced to state c and the reaction is accelerated, proceeding
through the green pathway. If this reaction is performed in
aqueous solution, the energy of the ground-state reactants is
now d [ground-state destabilization in water is well-known for
tert-butyl chloride solvolysis,16 for example], and the reaction
proceeds through transition state e via the red pathway. For this
reaction to be accelerated, the increase of the transition state
energy owing to the performance of the reaction in water must
be less than the increase in the ground-state energy. This
phenomenon has been demonstrated for a limited set of Diels-
Alder reactions.31 Reactions that should meet this requirement
include those with large negative ∆Vqs, forming the basis of
Lubineau’s rule. When the water also contains a “salting-out”
solute, the energy of the ground-state reactants in water is
increased, just as saturating the aqueous phase of a solvent-
partitioning extraction with salt sends water-soluble organics
to the organic phase. The energy of ground-state reactants is
then state f and, proVided that the transition state for the reaction
is not also salted out, this raising of the ground-state energy
should lower ∆Gq and further speed the reaction.
One question posed in recent discussions of organic reactions
in water is whether a ‘concentrated organic phase’ might be
involved, and whether in such instances the reaction is properly
identified as occurring in water.32 If a clathrate, which is intrinsic
to the hydrophobic effect, is identified as such a phase, then
any reaction that owes its effectiveness in water to the hy-
drophobic effect does involve a concentrated organic phase.
Reactions that are accelerated in water, are fully homogeneous,
and do not involve clathrates must exploit phenomena other
than the hydrophobic effect. Many organic reactions have been
reported in “aqueous” reaction media,33 which could mean as
little as 10% water in an organic solvent. While such solvents
clearly offer far fewer concerns about reaction heterogeneity,
the hydrophobic effect or cohesive pressure should play no role
in the effectiveness of such reactions.
concentrations to react in aqueous media and their reactions
should be poor candidates for aqueous acceleration. However,
ene reactions of pinene (Clog P 4.70) with azo compounds of
the appropriate polarity are accelerated in water, whereas
reactions with very nonpolar azo compounds are not. One
reactant of the correct Clog P may be enough. Even for reactions
with a large negative ∆Vq, a parabolic dependence of aqueous
reaction rate is expected as reactant polarity varies from polar
and water-miscible to nonpolar and water-immiscible. However,
water-soluble reactants or intermediates that are not involved
in the rate-determining step may still permit the observation of
aqueous reaction acceleration, as for the Ugi reaction studied
in this work.
It is worthwhile to emphasize the reaction conditions under
which the unique characteristics of water can accelerate organic
reactions through the hydrophobic effect. Pure water or water
including salting-out solutes should work best. A balance must
be struck in the addition of organic cosolvents, because even
though reaction homogeneity may be improved, the hydrophobic/
cohesive pressure effect could be compromised. While there is
no direct evidence concerning the ced of organic/water solvent
mixtures, they have significantly lower surface tension than
water and are therefore expected to have reduced hydrophobic
effects. Dramatic, nonlinear effects of organic cosolvents on
the rates of some dipolar cycloaddition reactions in aqueous
media provide strong support for this caution.34 Similar effects
are known for Diels-Alder reactions when alcoholic cosolvents
reach critical proportions at a mole fraction of ca. 0.3.35 Re-
actions conducted at high temperatures are not likely to benefit
from hydrophobic/cohesive pressure acceleration, simply be-
cause it is an entropic phenomenon and is less favorable toward
∆Gq at higher temperature. The ced also diminishes with
temperature. We and others have observed inverse temperature
dependence for reactions in water promoted by solvophobic
interactions.30a To gain the benefit of hydrophobic/cohesive
pressure effects, reactants should not be water-miscible, and
therefore reactions will all be heterogeneous, if not at the
macroscopic level, at the microscopic, and mixing effects on
reaction efficiency are to be expected.
This topic is clearly one that is drawing a great deal of
attention, and controversy. As stated by one reviewer: “Whether
such reactions occur at the water-organic interface or in droplets
or in clathrate ‘cages’ is not clear (and all of these can, in
principle, be operational).” This work does not present a
definitive view on the subject but aims to provide further data
to inform the development of a better understanding of these
phenomena.
Many reactions in water studied here that have reactants with
Clog Ps in the range of 1-2 exhibit the larger rate accelerations.
We suggest that among reactions that fit Lubineau’s criterion
of a large negative ∆Vq, those with reactants of about this
polarity will prove the best candidates for acceleration in water.
This measurement of hydrophobicity refines Lubineau’s rule
for rate acceleration, which only specified nonpolar compounds
generally. Earlier correlations of rate acceleration in aqueous
media with hydrophobicity have shown definite effects, but used
the free energy of transfer of a compound from organic solvent
to water to represent hydrophobicity.31 While rigorous, the free
energy of transfer is not nearly so available or intuitive as Clog
P as a measure of the hydrophobicity of reactants that would
commonly be used in synthetic reactions. As mentioned earlier,
since water-miscible organic compounds do not experience the
hydrophobic effect, reactions of compounds that are too polar
should not benefit from aqueous acceleration. Likewise, com-
pounds that are too nonpolar may be unable to achieve adequate
Experimental Section
Well Plate Ultrasonication of the Passerini Reaction of 1. This
reaction has been previously described in water with mixing by
shaking.18a Ultrasonication was performed on a 0.05 mmol scale
at 0.10 M. A suspension of the acid and aldehyde in water was
introduced into each well of a deep-well 96-well plate and frozen
at -80 °C overnight. The tert-butyl isocyanide was then added and
the plate was again kept at -80 °C for 4 h before transfer to the
SonicMan well plate sonicator. Blank reactions were not sonicated.
A flat plate bearing metal pins was inserted into the 96-well plate,
(31) Meijer, A.; Otto, S.; Engberts, J. B. F. N. J. Org. Chem. 1998, 63, 8989–
8994.
(32) Brogan, A. P.; Dickerson, T. J.; Janda, K. D. Angew. Chem., Int. Ed.
2006, 45, 8100–8102.
(33) (a) Kobayashi, S. AdV. Synth. Catal. 2002, 344, 219. (b) Li, C. J. Chem.
ReV. 2005, 105, 3095–3165.
(34) (a) Butler, R. N.; Cunningham, W. J.; Coyne, A. G.; Burke, L. A. J. Am.
Chem. Soc. 2004, 126, 11923–9. (b) Gholami, M. R.; Yangjeh, A. H. J. Phys.
Org. Chem. 2000, 13, 468–472.
(35) Blokzijl, W.; Blandamer, M. J.; Engberts, J. B. F. N. J. Am. Chem.
Soc. 1991, 113, 4241–4246.
J. Org. Chem. Vol. 73, No. 22, 2008 8729

Pirrung et al.
which was cooled to ca. 5 °C before sonication. Sonication of these
plates was performed on the SonicMan in two ways, one at full
power for 10 s and one at full power in six 10 s pulses. In each
case, four pins were removed to give negative control wells which
experienced the same temperature fluctuations but not sonication.
The increase in temperature with each pulse was 6-9 °C. Cooling
time between pulses was up to 25 min. No more than two ten-
second bursts were performed without a cool-down period of 30-45
min in an ice bath to remove the heat produced by the sonication.
Kinetic Studies of ene Reactions. ꢀ-Pinene (39 µL, 0.25 mmol)
and a disubstituted azodicarboxylate (0.28 mmol) were added to a
glass vial (15 × 45 mm). Solvent (CH2Cl2 or H2O) (1 mL) was
added. 1-Nitro-2-propyl benzene (30 µL) was added as the internal
standard. The reaction in CH2Cl2 was mixed by magnetic stirring.
Reactions in H2O were mixed by magnetic stirring, shaking, or
vortexing, and also conducted still, without mixing. Reaction progress
was monitored by GC under standard-1 or standard-2 conditions.
Dibenzyl azodicarboxylate (9) and bis(2,2,2-trichloroethyl) azodicar-
boxylate (10) did not show GC peaks under either temperature
program. The concentration of ꢀ-pinene was calculated by comparison
of GC peak areas with the internal standard. These data were used for
determination of rate constants using KaleidaGraph (version 3.5)
software to fit the linear equation by least-squares.
2H), 2.33 (m, 1H), 2.22 (d, J ) 8.1 Hz, 2H), 2.07 (m, 2H), 1.23 (s,
3H), 1.09 (d, J ) 8.7 Hz, 1H), 0.79 (s, 3H). 13C NMR (CDCl3): δ
156.5, 155.9, 142.8, 136.0, 135.8, 128.7, 128.6, 128.4, 128.3, 128.0
(2C), 121.8, 121.2, 68.2, 67.7, 55.1, 54.4, 43.7, 40.8, 38.2, 31.6,
31.3, 26.2, 21.2. IR (neat): 3293, 3033, 2916, 2832, 1709, 1498,
1455, 1408, 1341, 1305, 1261, 1207, 1120, 1046, 1029, 1002, 910,
887, 734, 695 cm-1. HRMS (ESI): calcd for C26H30N2O4Na [M +
Na]+ 457.2103, found 457.2094.
Bis(2,2,2-trichloroethyl) 1-((6,6-Dimethylbicyclo[3.1.1]hept-2-en-
2-yl)methyl)hydrazine-1,2-dicarboxylate (18). This compound was
prepared as in the previous procedure starting with bis(2,2,2-
trichloroethyl) azodicarboxylate (10). Colorless liquid (129 mg, 100%).
Rf ) 0.52 (ethyl acetate/hexanes 1:5). 1H NMR (CDCl3): δ 5.49 (brs,
1H), 4.78 (m, 4H), 4.14 (m, 2H), 2.37-2.45 (m, 1H), 2.28 (m, 2H),
2.13 (m, 2H), 1.28 (s, 3H), 1.17 (d, J ) 9 Hz, 1H), 0.85 (s, 3H). 13
C
NMR (CDCl3): δ 154.9, 154.5, 153.9, 153.4, 142.0, 122.7, 122.2, 94.9,
75.9, 75.7, 75.1, 55.4, 54.7, 43.6, 40.8, 38.3, 31.6, 31.4, 26.2, 21.2. IR
(neat): 3298, 2919, 2833, 1725, 1494, 1439, 1408, 1306, 1254, 1198,
1136, 1105, 1047, 972, 908, 862, 807, 719 cm-1. HRMS (ESI): calcd
for C16H21Cl6N2O4 [M + H]+ 514.9632, found 514.9609.
Kinetic Studies of Passerini Reactions. Cyclohexyl methyl
ketone (28 µL, 0.20 mmol), p-toluic acid (27 mg, 0.20 mmol), and
tert-butyl isocyanide (23 µL, 0.20 mmol) were added to a glass
vial (15 × 45 mm). Solvent (H2O, 1 mL) was added. 1,4-Dimethoxy
benzene (40 µL of a 5 M solution in CHCl3, 0.20 mmol) was added
as the internal standard. Reactions in H2O were mixed by magnetic
stirring, shaking and vortexing. The reaction in 2.5 M aq. LiCl
solution was mixed by shaking. Reaction progress was monitored
by GC under standard-1 conditions. The concentration of cyclohexyl
methyl ketone was calculated by comparison of GC peak areas with
the internal standard. These data were used for determination of
the rate constant using KaleidaGraph (version 3.5) software to fit
the linear equation by least-squares.
4-Methyl-benzoic Acid 1-Tert-butylcarbamoyl-1-cyclohexyl-
ethyl Ester (19). Cyclohexyl methyl ketone (28 µL, 0.20 mmol),
p-toluic acid (27 mg, 0.20 mmol), and tert-butyl isocyanide (23
µL, 0.20 mmol) were placed in a glass vial (15 × 45 mm). Solvent
(H2O, 1 mL) was added and the reaction mixture was mixed by
shaking at room temperature for 4-6 d. The reaction mixture was
extracted with CH2Cl2 (1 mL × 2). The organic layer was washed
with brine and dried over anhydrous Na2SO4. The solvent was removed
in vacuo and the product was purified by flash chromatography (ethyl
acetate/hexanes 1:5) to give the product as a white solid (17 mg, 25%).
Rf ) 0.40 (ethyl acetate/hexanes 1:5). 1H NMR (CDCl3): δ 7.88 (d, J
) 8.0 Hz, 2H), 7.24 (d, J ) 7.6 Hz, 2H), 5.66 (s, 1H), 2.40 (s, 3H),
1.70-1.95 (m, 6H), 1.65 (s, 3H), 1.32 (s, 9H), 1.10-1.30 (m, 5H).
13C NMR (CDCl3): δ 170.8, 164.8, 143.8, 129.5, 129.1, 128.0, 86.5,
46.3, 28.6, 27.4, 27.0, 26.5, 26.4, 26.4. IR (neat): 3402, 2932, 2853,
1701, 1648, 1609, 1517, 1456, 1365, 1285, 1219, 1177, 1101, 1074,
1016, 834, 762, 696 cm-1. HRMS (ESI), calcd for C21H32NO3 [M +
H]+ 346.2382, found 346.2382. mp: 124 °C.
Diisopropyl 1-((6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-yl)methyl)-
hydrazine-1,2-dicarboxylate (15). ꢀ-Pinene (39 µL, 0.25 mmol) and
7 (53 µL, 0.28 mmol) were added to a glass vial (15 × 45 mm).
Solvent (CH2Cl2 or H2O) (1.0 mL) was then added. The reaction
mixture was mixed by different mixing methods at room temper-
ature for 7-24 h. Reactions were monitored by GC under standard-1
conditions. For reaction in CH2Cl2: The reaction mixture was
concentrated in vacuo and the product was purified by flash
chromatography (ethyl acetate/hexanes 1:5) to give the product as
a colorless liquid (75 mg, 89%). For reaction in H2O: The reaction
mixture was extracted with CH2Cl2 (1 mL × 2). The organic layer
was washed with brine and dried over anhydrous Na2SO4. The
solvent was removed in vacuo and the product was purified by flash
chromatography (ethyl acetate/hexanes 1:5) to give the product as
a colorless liquid (67 mg, 80%). Rf ) 0.34 (ethyl acetate/hexanes
1
1:5). H NMR (CDCl3): δ 5.40 (s, 1H), 4.95 (m, 2H), 4.10 (brs,
2H), 2.38 (m, 1H), 2.26 (d, J ) 9.3 Hz, 2H), 2.10 (m, 2H),
1.21-1.28 (m, 15H), 1.15 (d, J ) 8.7 Hz, 1H), 0.84 (s, 3H). 13C
NMR (CDCl3): δ 156.1, 155.6, 143.1, 120.9, 120.2, 69.9, 69.5,
54.4, 43.5, 40.7, 38.0, 31.4, 31.1, 26.1, 22.0, 21.9, 21.0. IR (neat):
3298, 2982, 2917, 1698, 1468, 1406, 1385, 1375, 1261, 1218, 1180,
1106, 1037, 918, 764, 731 cm-1. HRMS (ESI): calcd for
C18H31N2O4 [M + H]+ 339.2283, found 339.2280.
Ditert-butyl 1-((6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-yl)meth-
yl)hydrazine-1,2-dicarboxylate (16). This compound was prepared
as in the previous procedure starting with di-tert-butyl azodicarboxylate
(8). Colorless liquid (62 mg, 68%). Rf ) 0.49 (ethyl acetate/hexanes
1:5). 1H NMR (CDCl3): δ 5.38 (brs, 1H), 3.96 (brs, 2H), 2.37-2.41
(m, 1H), 2.26 (d, J ) 9.9 Hz, 2H), 2.10 (m, 2H), 1.46 (s, 18H), 1.26
(s, 3H), 1.15 (d, J ) 8.7 Hz, 1H), 0.84 (s, 3H). 13C NMR (CDCl3): δ
155.7 (2C), 143.7, 120.8, 81.2 (2C), 54.1, 43.8, 40.9, 38.2, 31.6, 31.4,
28.3 (2C), 26.3, 21.2. IR (neat): 3321, 2979, 2916, 2834, 1705, 1478,
1456, 1392, 1366, 1345, 1253, 1153, 1049, 1021, 910, 861, 780, 761,
733 cm-1. HRMS (ESI): calcd for C20H34N2O4Na [M + Na]+
389.2416, found 389.2403.
Dibenzyl 1-((6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-yl)meth-
yl)hydrazine-1,2-dicarboxylate (17). This compound was prepared
as in the previous procedure starting with dibenzyl azodicarboxylate
(9). Colorless liquid (97 mg, 89%). Rf ) 0.32 (ethyl acetate/hexanes
1:5). 1H NMR (CDCl3) δ 5.37 (brs, 1H), 5.15 (brs, 4H), 4.07 (brs,
Acknowledgment. We are grateful to Kevin Oldenburg and
Kurt M. Scudder for providing access to their SonicMan well
plate sonicator and for performing irradiations.
Supporting Information Available: General experimental
conditions, characterization of 12-14 and the Passerini
1
products of the acids in Chart 1, and H NMR spectra for
12-19. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO801134R
8730 J. Org. Chem. Vol. 73, No. 22, 2008