Rate acceleration and subsequent retardation of Diels-Alder reactions in LiClO4-diethyl ether: An experimental investigation

Article abstract of DOI:10.1021/jo010459r

The experimental kinetic data for several Diels - Alder reactions why a 5 M LiClO₄-diethyl ether (LPDE) solution offers maximum enhancement of reaction rates, endo/exo ratios, and yields. These reactions, if carried out in LPDE solutions of concentrations higher than 5 M, show a substantial decrease in thse kinetic parameters. This decrease is attributed to the very high viscosity of LPDE solutions near saturation, though this interpretation is not consistent when considered in terms of sizes of the diene and dienophile. The monoetherates, dietherates, and higher other clusters in LPDE solutions and their relationship with the Lewis acid catalysis by Li⁺ offer a more plausible explanation of both enhancement and the decrease of the rate of Diels-Alder reactions in this medium.

Full text of DOI:10.1021/jo010459r

7646
J . Org. Chem. 2001, 66, 7646-7652
Ra te Acceler a tion a n d Su bsequ en t Reta r d a tion of Diels-Ald er
Rea ction s in LiClO4-Dieth yl Eth er : An Exp er im en ta l
In vestiga tion
Anil Kumar* and S. S. Pawar
Physical Chemistry Division, National Chemical Laboratory, Pune 411 008, India
akumar@ems.ncl.res.in
Received May 7, 2001
The experimental kinetic data for several Diels-Alder reactions show why a 5 M LiClO4-diethyl
ether (LPDE) solution offers maximum enhancement of reaction rates, endo/exo ratios, and yields.
These reactions, if carried out in LPDE solutions of concentrations higher than 5 M, show a
substantial decrease in these kinetic parameters. This decrease is attributed to the very high
viscosity of LPDE solutions near saturation, though this interpretation is not consistent when
considered in terms of sizes of the diene and dienophile. The monoetherates, dietherates, and higher
other clusters in LPDE solutions and their relationship with the Lewis acid catalysis by Li+ offer
a more plausible explanation of both the enhancement and the decrease of the rate of Diels-Alder
reactions in this medium.
In tr od u ction
Obviation of high pressure requirements and huge rate
enhancements of slow Diels-Alder reactions in 5 M
LPDE have led to its use for several other organic
reactions.7 The spectacular rate variations in Diels-Alder
reactions carried out in such solvent media have been
ascribed to solvent polarity, hydrophobic packing, en-
forced hydrophobic hydration, Lewis acid catalysis, etc.8-14
A careful literature search reveals that several Diels-
Alder reactions have been carried out in a specific 5 M
LPDE solution only for achieving maximum rate en-
hancement and not in solutions of LPDE of other
concentrations. However, no quantitative support for the
use of a 5 M LPDE solution only for achieving maximum
rate acceleration has been offered in the literature to
date.
Diels-Alder chemistry offers a powerful strategy for
synthesizing six-membered ring systems with excellent
stereochemical control.1 In principle, Diels-Alder reac-
tions should not be influenced by different solvents, as
these reactions involve isopolar-activated complexes.2
Contrary to this, however, Rideout and Breslow3 dem-
onstrated a remarkable rate enhancement of Diels-Alder
reactions in water. Later, Breslow and co-workers4
studied the kinetics of these reactions in aqueous salt
solutions and concluded that LiCl enhanced the reaction
rates, while LiClO4 and guanidinium chloride (GnCl)
retarded them. Later, Grieco, Nunes, and Gaul5 found a
dramatic rate acceleration of several sluggish Diels-
Alder reactions by employing a 5 M LiClO4-diethyl ether
solution, popularly known as LPDE. The conventional
synthesis6 of cantharidin under high external pressure
(≈15 kbar) was achieved under normal temperature and
pressure with an improved yield when 5 M LPDE was
used as a solvent medium for carrying out the reaction.5
The main objectives of this work are to address the
following three questions. (1) Is the concentration of 5
M LPDE critical for maximizing the rate enhancement
of Diels-Alder reactions? (2) What will happen if other
(7) (a) For
a recent review on LPDE, see: Sankararaman, S.;
Nesakumar, J . E. Eur. J . Org. Chem. 2000, 2001. (b) Waldmann, H.
In Organic Synthesis Highlights III; Mulzer, J ., Waldmann, H., Eds.;
Wiley-VCH: Weinheim, Germany, 1998; p 205. For earlier uses of
LPDE in organic synthesis, see: (c) Weinstein, S.; Smith, S.; Darwish,
D. J . Am. Chem. Soc. 1959, 81, 5511. (d) Pocker, Y.; Buchholz, R. F. J .
Am. Chem. Soc. 1970, 92, 2075, and several subsequent papers by
Pocker.
(8) Polarity: Braun, R.; Sauer, J . Chem. Ber. 1986, 119, 1269.
(9) Hydrophobic packing. See ref 4.
(10) Hydrogen bonding: Blake, J . F.; J orgensen, W. L. J . Am. Chem.
Soc. 1991, 113, 7430.
(11) Enforced hydrophobic hydration: (a) Blokzijl, W.; Blandamer,
M. J .; Engberts, J . B. F. N. J . Am. Chem. Soc. 1991, 113, 4241. (b)
Blokzijl, W.; Engberts, J . B. F. N. J . Am. Chem. Soc. 1992, 114, 5440.
(12) Lewis acid effect: (a) Forman, M. A.; Dailey, W. P. J . Am. Chem.
Soc. 1991, 113, 2761. (b) Desimoni, G.; Faita, G.; Righetti, P. P.
Tetrahedron, 1991, 47, 8399. (c) Pagni, R. M.; Kabalka, G. W.; Bains,
S.; Plesco, M.; Wilson, J .; Bartmess, J . J . Org. Chem. 1993, 58, 3130.
(13) Internal pressure: Kumar A. J . Org. Chem. 1994, 59, 230.
(14) (a) Kumar, A.; Phalgune, U.; Pawar, S. S. J . Phys. Org. Chem.
2001, 14, 577. (b) Kumar, A.; Phalgune, U.; Pawar, S. S. J . Phys. Org.
Chem. 2000, 13, 555. (c) Pawar, S. S.; Phalgune, U.; Kumar, A. J . Org.
Chem. 1999, 64, 7055. (d) Kumar A. Pure Appl. Chem. 1998, 70, 615.
(e) Kumar, A. J . Phys. Org. Chem. 1996, 9, 287. (f) Kumar, A. J . Org.
Chem. 1994, 59, 4612; see also refs 1a and 13.
* To whom correspondence should be addressed. Fax: +91 20 589
3044.
(1) (a) Kumar, A. Chem. Rev. 2001, 101, 1. Several reviews and
monographs are available in the literature and are cited in this article;
other relevant refs are: (b) Organic Synthesis in Water; Grieco, P. A.,
Ed.; Blackie: Glassgow, 1998. (c) Breslow, R. Water as Solvent for
Chemical Reactions; Anastas, P. T., Williamson, T. C., Ed.; Oxford
University Press: Oxford, 1998. (d) Li, C.-J .; Chan, T.-H. Organic
Reaction in Aqueous Media; Wiley: New York, 1997. (e) Togni, A.;
Vernanzi, L. M. Angew. Chem., Int. Ed. Engl. 1994, 33, 497. (f) Pindur,
U.; Lutz, G.; Otto, C. Chem. Rev. 1993, 93, 741. (g) Kagan, H. B.; Riant,
O. Chem. Rev. 1992, 92, 1007. (h) Reissig, H.-U. In Organic Synthesis
Highlights; VCH: Weinheim, Germany, 1991; p 71.
(2) Sauer, J .; Sustmann, R. Angew. Chem., Int. Ed. Engl. 1980, 19,
779.
(3) Rideout, D. C.; Breslow, R. J . Am. Chem. Soc. 1980, 102, 7816.
(4) (a) Breslow, R.; Maitra, U.; Rideout, D. C. Tetrahedron Lett. 1983,
24, 1901. (b) Breslow, R.; Rizzo, C. J . J . Am. Chem. Soc. 1991, 113,
4340. (c) Rizzo, C. J . J . Org. Chem. 1992, 57, 6382. (d) For a summary,
see: Breslow, R. Acc. Chem. Res. 1991, 24, 159.
(5) Grieco, P. A.; Nunes, J . J .; Gaul, M. D. J . Am. Chem. Soc. 1990,
112, 4595.
(6) Dauben, W. G.; Kessal, C. R.; Takemura, K. H. J . Am. Chem.
Soc. 1980, 102, 6893.
10.1021/jo010459r CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/17/2001

Diels-Alder Reactions in LiClO4-Diethyl Ether
J . Org. Chem., Vol. 66, No. 23, 2001 7647
F igu r e 2. krel (9) and % yield (0) as a function of [LiClO4] in
LPDE for the reaction of 4 with 5.
Sch em e 2
F igu r e 1. krel (b) and endo/exo (0) ratios as a function of
[LiClO4] in LPDE for the reaction of 1 with 2.
Sch em e 1
rate increase of 26 times is witnessed in 5 M LPDE when
compared to that in pure diethyl ether. It is important
to note that a sharp increase in rate constants can be
marked in LPDE solutions with concentrations above 4
M LPDE. The krel value, which was about 9 in 4 M LPDE,
more than doubles in 4.5 M LPDE and triples in 5 M
LPDE. The reaction rate begins to fall if the reaction is
carried out in 5.5 M LPDE. The increase in krel between
4.5 and 5 M LPDE is quite strong suggesting that LPDE
offers a spectacular advantage around concentrations
between 4.5 and 5 M. The slow decrease in krel observed
between 5 and 5.3 M LPDE indicates that a maximiza-
tion of reaction rate has already been achieved in 5 M
LPDE. Furthermore, kinetic measurements in nearly
saturated 6 M LPDE reveal that the reaction rate falls
to krel ) 16 from its value of 26 in 5 M LPDE. The rate
retardation effect in Diels-Alder reactions carried out
in very concentrated LPDE solutions has been recorded
for the first time and is an important point of this
investigation.
Analogous behavior of the concentration dependence
of endo/exo ratios and yields is observed for the above
reaction in different LPDE solutions. The endo/exo ratio
(8.1:1), which is the highest in 5 M LPDE, reduces to 5.2:1
in 6 M LPDE. Similarly, the yield of 3 increases to 91%
in 5 M LPDE before declining to 69% in 6 M LPDE (not
shown).
Another reaction studied is that of transpiperylene 4
with 2,6-dimethyl benzoquinone 5 (Scheme 2) in 5 M
LPDE, which affords an 80% yield after 15 min as
compared to <20% yield after 24 h in water.5 The krel
values and yields in LPDE solutions of different concen-
trations obtained in the current study are demonstrated
in Figure 2. The reaction becomes 125 times faster in 3
M LPDE as compared to 5 times faster in 1 M LPDE. A
4.5 M LPDE solution accelerates the reaction by about
500 times with a maximum enhancement of about 880
times occurring in 5 M LPDE as compared to that in
diethyl ether alone. In LPDE solutions above 5 M, the
krel value falls to about 400 times in 6.06 M LPDE as
compared to that in pure solvent. Again, a slow decrease
in reaction rates between 5 and 5.2 M LPDE is noted.
Analogous behavior can be seen in the case of yields of
cycloadduct 6 (Scheme 2). The yield, which is 38% in 3
salt concentrations are chosen for carrying out such a
reaction. (3) What is the comparative performance of
other solvent media in giving maximum rate enhance-
ment, and at which concentrations does this occur?
During the course of this study, some interesting experi-
mental results were obtained in this laboratory and are
reported in this paper and hoped to be of general use to
chemists. This work is a part of systematic investigations
being carried out in this laboratory on delineating the
origin of forces responsible for spectacular rate variations
of Diels-Alder reactions in different salt solutions.14
Resu lts a n d Discu ssion
To achieve the objectives cited above, several Diels-
Alder reactions were carried out in LiClO4 solutions
prepared in diethyl ether and other organic solvents.
Largely, the reactions are conducted in concentrated
LiClO4 solutions. As rate data for several reactions
studied here were obtained in solutions of low concentra-
tions of LiClO4 by earlier authors, the measurements
were extended up to solubility limits. The solubility data
suggest that it is possible to prepare LPDE solutions up
to 6.06 M at room temperature.15
The starting point of this investigation is the pioneer-
ing work of Grieco, Nunes, and Gaul,5 who first studied
the reaction of cyclopentadiene 1 with ethyl acrylate 2
in 5 M LPDE only to give a 93% isolated yield of
cycloadduct 3 with an endo/exo ratio of 8:1 (Scheme 1).
Their criteria for estimating the progress of this reaction
were yields and endo/exo products. No direct kinetic data
were collected to support their claim. To quantify the
effect of LPDE on the progress of this reaction, this
reaction was carried in LPDE solutions of different
concentrations. In Figure 1 are plotted the relative rate
constant, krel (rate constant in LiClO4 solution/rate
constant in pure solvent), and endo/exo ratios as a
function of concentration of LiClO4, [LiClO4], for the
reaction of 1 with 2. A 9-time increase in the reaction
rates is observed in 4 M LPDE. Surprisingly, a drastic
(15) Willard, H. H.; Smith, G. F. J . Am. Chem. Soc. 1923, 45, 286.

7648 J . Org. Chem., Vol. 66, No. 23, 2001
Kumar and Pawar
Sch em e 5
Sch em e 6
3a). A 2 M LPDE solution enhances the reaction rate by
300 times, reaching a maximum of about 400 times in 5
M LPDE, as seen from the plot drawn in Figure 3a. No
changes in reaction rates are noted in the concentration
range from 5 to 5.5 M, and therefore the krel vs salt
concentration curve becomes invariant in this concentra-
tion range. A slow retardation of reaction rates is
observed in 6 M LPDE.
It is interesting to find out whether the rate retarda-
tion in very highly concentrated LPDE exists for Diels-
Alder reactions with mild increases in reaction rates. An
example of mild rate enhancement for the reaction of 7
with 4-bromonitrosobenzene 13 (Scheme 5) is shown in
Figure 3b. This reaction proceeds about 2.5 times faster
in 2 M LPDE as compared to that in diethyl ether.16 The
present results show that if this reaction is carried out
in higher concentrations of LPDE, a maximum accelera-
tion of 5 times in ≈4.75 M LPDE with reference to that
in pure diethyl ether is observed. The reaction slows
down in LPDE of concentrations between 5 and 6 M
giving only an acceleration of 4 times.
F igu r e 3. Dependence of krel on [LiClO4] in LPDE for
reactions of (a) 7 with 8 (∆) and of 10 with 11 (b) and of (b) 7
with 13 (1).
Sch em e 3
Sch em e 4
Forman and Dailey12a were the first to demonstrate
that the rate acceleration of Diels-Alder reactions car-
ried out by Grieco and co-workers5 in 5 M LPDE was due
to Lewis acid catalysis. They showed Li+ acting as a
Lewis acid by demonstrating a linear dependence of the
second-order rate constant on the concentration of LiClO4
for the reaction of acrylonitrile 15 with 9,10-dimethyl-
anthracene 16 (Scheme 6) in LPDE solutions up to a
maximum concentration of 4.55 M. These authors did not
carry out the reaction in LPDE solutions above the
concentration of 4.55 M. Their explanation that Lewis
acid catalysis is responsible for the dramatic rate en-
hancement of Diels-Alder reactions in LPDE-type media
has been widely accepted.1,7 Their experiments were
extended further in this laboratory beyond 4.55 M LPDE.
The temperature-dependent rate data from 28 to 43 °C
obtained in the present study, together with the rate
constant obtained in 4.55 M LPDE at 28 °C from Forman
and Dailey,12 are plotted in Figure 4 in the form of krel
vs [LiClO4]. The krel still increases in 5 M LPDE before
declining by 17% in 6 M LPDE. An examination of Figure
4 suggests that the degree of rate retardation in the
LPDE solutions of concentrations between 5 and 6 M
becomes weak with an increase in temperature (from 28
to 43 °C).
M LPDE, doubles in 4.5 M LPDE before reaching a
maximum of 83% in 5 M LPDE. In 6.06 M LPDE, where
the reaction rate falls dramatically as compared to that
noted in 5 M LPDE, a substantial decrease in the yield
from 83 to 43% is witnessed.
The reaction of 2,3-dimethylbutadiene 7 with 1,4-
naphthoquinone 8 (Scheme 3) is accelerated about 1300
times in 2 M LPDE solution as compared to that in
diethyl ether alone.16 The kinetic data obtained in this
study, when plotted in Figure 3a for this reaction, show
a huge acceleration in the rates by about 2600 times in
5 M LPDE. When the same reaction is carried out in 5.5
and 6 M LPDE, the reaction rate declines to 2500 and
2200 times, respectively, from 2600 times noted in 5 M
LPDE.
The reaction of 1-phenyl-4-benzylidene-5-pyrazolone 10
with ethyl vinyl ether 11 (Scheme 4) is greatly influenced
by the concentration of LiClO4 in diethyl ether16 (Figure
An attempt was also made to examine whether this
effect also exists in solutions of LiClO4 in other solvents.
The reaction of 1 with 2 was examined in high concentra-
(16) Faita, G.; Righetti, P. P. Tetrahedron Lett. 1995, 51, 9091.

Diels-Alder Reactions in LiClO4-Diethyl Ether
J . Org. Chem., Vol. 66, No. 23, 2001 7649
LPDE and LPAC on the kinetic data for the reaction of
1 with 2. The krel values for this reaction in LPME shown
in Figure 5a reach a maximum of ∼7 in 4 M LPME. As
seen in the above reaction, no further rate enhancement
takes place above 4 M LPME.
Furthermore, the reaction of 7 and 8 was carried out
in LPAC (Figure 5b). A huge rate enhancement of about
800 times in 4 M LPAC as compared to that in acetone
alone was noted in earlier work.17 However, when this
reaction was carried out under identical conditions in
LPAC with concentration above 4 M, the interesting
results shown in Figure 5b were observed. A maximum
rate enhancement of about 1000 times is obtained in 4.5
M LPAC. A further increase in the concentration of LPAC
decreases the reaction rates. In short, a 1000-fold rate
enhancement at 4.5 M is reduced to 400 times at 5.25 M
LPAC. One should note that the concentration zone
between 4 and 4.5 M LPAC is very sensitive to the rate
enhancement, while the zone between 4.5 and 5 M is
sensitive to retardation of the rate of this reaction.
The reaction of 7 with 13 reaches a maximum rate
acceleration of about 6 times in 4 M LPAC solution before
declining to about 4 times in 5 M LPAC as compared to
that in acetone alone (Figure 5b).17
F igu r e 4. Second-order rate constant, k2, for the reaction of
15 with 16 in concentrated LPDE solutions at various tem-
peratures: (0) from ref 12a at 4.55 M at 28 °C, (9) 28 °C, (∆)
33 °C, (b) 38 °C, and (∇) 43 °C.
The reaction of 7 and 13 occurs about 3 times faster
in a 4 M solution of LiClO4 in methanol (LPME) (Figure
5b). No further noticeable change in krel is seen in the
LPME solutions of concentrations higher than 4 M.
It has been suggested that the tapering of the krel vs
salt concentration at high concentrations may be the
result of the solubility of salt in the solvent used to
prepare the solution in which the reaction is carried
out.4d,14e As the reaction rates for many Diels-Alder
reactions reach a maximum in 5 M LPDE and the
solubility of LiClO4 in diethyl ether is about 6.06 M, the
tapering effect may not be due to solubility factor alone.
As seen above, the reaction rates for several Diels-Alder
reactions decline in LPDE solutions above 5 M only.
Does the viscosity of concentrated LPDE solutions play
any role in reducing the reaction rates, endo/exo products,
and yields? The literature data show that the viscosity
of a saturated LPDE solution is about 800% higher than
that of pure diethyl ether at 25 °C.15 The viscosity of 5
M LPDE increases by about 15 times as compared to that
of pure DE. There is, however, a very sharp exponential
increase in viscosity between 5 and 6.07 M solutions. A
42-fold rise in viscosity is seen in 5.3 M LPDE and
becomes 250-fold in 5.8 M LPDE solution. A 500-fold
increase in the viscosity of a 5.95 M LPDE solution is
enhanced to about 800-fold in 6.07 M LPDE, a saturated
solution of LiClO4 in diethyl ether. Two zones showing
the changes in viscosity of LPDE solutions are demon-
strated in Figure 6. Remarkable differences between the
viscosities of LPDE solutions below and above the
concentrations of 5 M LPDE are noticeable.
F igu r e 5. krel - [LiClO4] plots for the reactions of (a) 1 with
2 in LPAC (b), LPEA (O), and LPME (4), and (b) for the
reactions of 7 with 8 in LPAC (O) and 7 with 13 in LPAC (9)
and in LPME (4).
tions of LiClO4 in ethyl acetate (LPEA) and acetone
(LPAC) (see Figure 5a). In LPEA, the reaction was fastest
in 4.25 M solution. This rate was accelerated by about
24 times as compared to that in pure ethyl acetate. It
may be noted that a 26-time acceleration in the rate was
achieved in 5 M LPDE. If this reaction is carried out in
5 M LPAC, the rate is 21 times faster than that in
acetone alone before krel falls to a value of ≈13 in 6 M
LPAC. A decrease in the rates of reactions carried out in
very highly concentrated acetone and ethyl acetate
solutions of LiClO4 is observed. In both LPEA and LPAC,
the reaction becomes slow in highly concentrated salt
solutions, i.e., 4.5 and 4 M, respectively, as compared to
5 M LPDE. The concentration dependence of the endo/
exo ratios and yields in LPEA and LPAC show trends
comparable to those noted using LPDE. LiClO4 is soluble
in methanol up to about 6.7 M at room temperature.15
The effect of LPME is less pronounced than those of
A significant development in the effect of viscosity on
the rates of Diels-Alder reactions was made by Firestone
and co-workers.19 Swiss and Firestone19a reported the
rate enhancement of dimerization of cyclopentadiene
with viscosity of several hydrocarbon solvents up to 1 cP
with a subsequent drop in the solvents with viscosities
>1 cP. A similar observation was made for the 1,3-dipolar
(17) Casaschi, A.; Desimoni, G.; Faita, G.; Invernizzi, A. G.; Lanati,
S.; Righetti, P. P. J . Am. Chem. Soc. 1993, 115, 8002.
(18) Ekelin, K.; Sillen, L. G. Acta Chem. Scand. 1953, 7, 987.

7650 J . Org. Chem., Vol. 66, No. 23, 2001
Kumar and Pawar
F igu r e 6. Concentration dependence of the relative viscosity,
η
rel, for LPDE solutions; the break on the y-axis is shown to
cover the huge viscosity enhancement (data from ref 15).
F igu r e 8. ln krel vs ln ηrel for the reaction of 15 with 16 at (9)
28 °C, (4) 33 °C, (]) 38 °C, and (3) 43 °C.
discussed by many authors, more notably by Hynes.20 The
rate reduction of the reaction of 15 with 16 in LPDE
solutions with concentrations above 5 M can also be
explained in a similar fashion. A similar effect was also
noted in LPAC, LPEA, and LPME, though the viscosity
enhancement of these solutions near their saturation
limits is not as high as that of LPDE.
If viscosity plays an important role in retarding the
reaction rates, it should be supported by the temperature-
dependent rate and viscosity data. In Figure 4 are shown
the second-order rate constants as a function of concen-
tration of LiClO4 from 4.5 M to near saturation at 28,
33, 38, and 43 °C. The viscosity of LPDE solutions
decreases with increases in temperature, thereby allow-
ing lesser dense reaction media to be used for the
reaction.21 The curve of ln krel vs ln ηrel at different
temperatures is plotted in Figure 8. An examination of
Figures 4 and 8 suggests that the portions of plots that
were highly curved in very high LPDE concentrations at
the lowest temperature (28 °C) tend to become straight
with increases in the temperature of the reaction em-
phasizing the role of viscosity.
However, one notes certain contradictions when at-
tempting to describe the rate variations in terms of
viscosity.22 The reaction of 4 with 5 slows down by about
54% between 5 and 6 M LPDE. An about 38% fall in the
rates is noted in the case of reaction of 1 and 2. On the
other hand, a 17% fall in the rates is observed for the
reaction of 15 and 16 with an approximately equal fall
in the rates for the reaction of 7 with 8. The rate drop
for the reaction of 10 with 11 is less than 10%. If the
higher viscosity were the primary source of hindrance to
the diffusion of the diene and dienophile, one would
expect that the reaction with the larger molecule would
exhibit a larger drop as compared to that of the smaller
ones. Larger molecules will offer larger molecular surface
areas interacting with the solvent medium. Accordingly,
the reaction of 10 with 11 should have shown a larger
drop in the rates than that of 1 with 2 as compound 10
is larger in size than 1. In connection with such contra-
dictions, it is important to recall the contribution of Swiss
and Firestone,19a who critically examined the roles of both
macroviscosity and microviscosity23 on the reaction rates.
While macroviscosity is a bulk property, microviscosity
F igu r e 7. Correlation of ln krel with ln ηrel for the reactions
of 1 with 2 (b), 4 with 5 (O), 7 with 8 (0), and 15 with 16 (∆)
in LPDE solutions.
cycloaddition of diphenyldiazomethane with ethylphenyl-
propiolate. The viscosity-induced rate enhancement and
subsequent decrease in these two reactions cannot be
explained in terms of current kinetic theory. Variation
of ln krel on the ln ηrel (ηrel ) relative viscosity ) viscosity
of solution/viscosity of pure solvent) for the reactions of
1 with 2, of 4 with 5, and of 7 with 8 in LPDE solutions
is shown in Figure 7. The reaction rates, in general, rise
up to a value of viscosity of 3.5 cP corresponding to 5 M
LPDE. Then, the reaction rates level off in the viscosity
range from 3.5 to 42 cP corresponding to concentrations
of 5 to 5.3 M LPDE. Retardation of the reaction in the
viscosity range from 42 to 190 cP is observed (near the
solubility range). As shown in Figure 6, the viscosity of
LPDE solution does not rise dramatically up to a con-
centration of 5 M. As the viscosity of nearly saturated
LPDE solution is too high (≈800 times with respect to
that of diethyl ether), the reactants cannot find each
other (because of diffusional problems) in such a highly
viscous syrup, which leads to reduction of reaction
rates.19,20 The observed rate in a highly viscous solution
decreases as the rate of diffusion is inversely proportional
to the viscosity of a medium. Such models have been
(19) (a) Swiss, K. A.; Firestone, R. A. J . Phys. Chem. A 1999, 103,
5369. (b) Firestone, R. A.; Swiss, K. A. J . Phys. Chem. A, 2001, 105,
3430. (c) Firestone, R. A.; Vitale, M. A. J . Org. Chem. 1981, 46, 2160.
(d) Firestone, R. A.; Christensen, B. G. Tetrahedron Lett. 1973, 389.
For other supporting references, see, for example: (e) Sternbach, D.
D.; Rossana, D. M. Tetrahedron Lett. 1982, 23, 303. (f) Dunams, T.;
Hoekstra, M.; Pentaleri, M.; Liotta, D. Tetrahedron Lett. 1988, 29,
3745.
(20) There are several models to describe the viscosity-dependent
reaction rates. For examples, see: (a) Truhlar, D. G.; Hase, W. L.;
Hynes, J . T. J . Phys. Chem. 1983, 87, 2664. (b) Van der Zwan, G.;
Hynes, J . T. Chem. Phys. Lett. 1983, 101, 367. (c) Grote, R. F.; Hynes,
J . T. J . Chem. Phys. 1982, 77, 3736. Bagchi, B.; Biswas, R. In Advances
in Chemical Physics Prigogine, I., Rice, S. A.; J ohn Wiley: New York,
1999; Vol. 109 and refs cited therein.
(21) Temperature-dependent viscosity data show a 25% decrease in
ln η near saturation per 5 °C increase in temperature. The viscosities
of LPDE solutions at 25 °C are taken from ref 18.
(22) An anonymous reviewer is thanked for pointing this out to the
authors.
(23) For microviscosity, see: Sun, Y.-P.; Saltiel, J . J . Phys. Chem.
1989, 93, 8310.

Diels-Alder Reactions in LiClO4-Diethyl Ether
J . Org. Chem., Vol. 66, No. 23, 2001 7651
is defined as the viscosity experienced by the diene and
dienophile in a given solvent medium. The sizes of the
diene and dienophile and properties of solvent (salt
solution in this case) determine whether the macro- and
microviscosity can be alike or not.24 How the microscopic
viscosity can be estimated in the current situation
involving salts is presently not clear to the authors.25 Its
estimation, however, can help in delineating the viscosity
effect on the kinetics of Diels-Alder reactions. The ion-
solvent and ion-ion interactions in relation to their
impact on the microviscosity in changing ionic concentra-
tions are subjects of future study. As the dienes and
dienophiles employed in this study were not selected on
the basis of their sizes, it is difficult to compare the effect
of individual reactants in terms of microviscosity. Our
proposal that the viscosity of the medium (not the
microviscosity) plays role is a preliminary and tentative
explanation and is not consistent when considered in
conjunction with microviscosity.
Can Lewis acid catalysis explain the retardation of
reactions in LPDE solutions of concentrations above
5 M? The spectacular rate enhancement in 5 M LPDE
has already been attributed to the Lewis acid catal-
ysis.12a It is established that LPDE solution exists as a
dietherate, Li+(OC2H5)2ClO4-, below the concentration of
4.25 M.7d The rate enhancement in this concentration
range can be understood in terms of decreasing ether
coordination of Li+, thus rendering a “partly naked” ion
Con clu sion
The kinetic results obtained on several Diels-Alder
reactions carried out in different LiClO4-containing sol-
vent media quantitatively suggest the concentrations of
such media that can be employed for maximizing the
reaction rates and yields. This study is expected to offer
valuable guidelines to synthetic organic chemists for
achieving the optimum reaction conditions required in
their synthetic work, as the limiting conditions of LPDE
are quite clear from this investigation. It is hoped that
these studies will provide further insight into the origin
of forces responsible for the salt effects on Diels-Alder
reaction kinetics. A quantitative estimation of the micro-
viscosity in a salt solution and its correlation with the
reaction rates will be a step forward in this direction.
Exp er im en ta l Section
The kinetic data were collected by the methods employed
in the original papers. Therefore, their details are not repro-
duced here. LiClO4 was recrystallized twice from distilled
water in the form of LiClO4‚3H2O and then dried at 140 °C
for 8h before LiClO4 solutions were prepared in UV-grade
solvents that were procured commercially. The salt was stored
in a sealed bottle in a desiccator until used since it was neces-
sary to keep it in a completely anhydrous state (CAUTION:
LiClO4 is potentially explosive and must be handled with
care).27 The dienes and dienophiles used in this work were
procured from M/S Aldrich or Merk, unless otherwise indi-
cated. Cyclopentadiene (1) was freshly cracked from its dimer,
while 1-phenyl-4-benzylidene-5-pyrazolone (10) and 4-bromo-
nitrosobenzene (13) were prepared according to the procedure
described elsewhere.28 2,6-Dimethyl benzoquinone (5), 1,4-
naphthoquinone (8), and 9,10-dimethylanthracene (16) were
commercially recrystallized products. Other dienes and dieno-
philes were freshly distilled prior to their use.
The rates of the reaction of 1 with 2 were determined by
the procedure outlined elsewhere.3 This study was performed
under pseudo-first-order conditions with 4 mmol of 1 and 39.5
mmol of 2. A volumetric pipet was used to measure accurately
2 mL of 2 in the salt solution, which was then transferred to
a cuvette. A 15 µL volume of 1 was added, and the cuvette
was capped and mixed. The progress of the reaction was
followed at 250 nm, in which a first-order disappearance of 1
was observed over two half-lives. The pseudo-first-order rate
constant was recorded to be first-order in 2. The endo/exo
ratios were determined using NMR as described in an earlier
work.14c
as a more powerful Lewis acid. Above 4.25 M, a mix-
-
ture of dietherate and monoetherate, Li(OC2H5)ClO4
,
becomes gradually richer in monoetherate with an in-
crease in concentration. As LiClO4 can be solvated by a
smaller mole fraction of ether than of water, the effect
begins at a lower concentration and contributes to the
large rate accelerations. Higher clusters have also been
reported in LPDE solutions.7d In very highly concen-
trated LPDE solutions, the clusters come together to
grow almost to a lattice driven by the lack of solvent.18
This cluster formation at these concentrations adversely
affects the degree to which Li+ would be available at
these concentrations as a Lewis acid catalyst. As less
active Li+ is expected to be available in the clusters, a
fall in the rates is noticed.22
Does this situation exist in Diels-Alder reactions
carried out in aqueous salt solutions? Recent work14c
from this laboratory on the reaction of cyclopentadiene
with methyl acrylate showed that the endo/exo ratios
increased with increases in the concentrations of LiCl,
NaCl, NaBr, and CaCl2 up to a concentration of about
4 M. The log(endo/exo) vs [salt] plots leveled off in
solutions with concentrations higher than 4 M. The
solutions of LiCl, NaCl, and NaBr are less viscous than
those of CaCl2 in the full concentration range extending
up to solubility.26 Thus, it seems that a decrease of qjthe
endo/exo ratios is not clearly seen in aqueous LiCl,
NaCl, and NaBr solutions of the above concentrations.
The log(endo/exo) - [salt] plot in aqueous CaCl2 is not
steep throughout the concentration range, possibly due
to increases in viscosity by 3.6 and 8.3 times in 4 and
5 M solutions, respectively.
The reaction of 4 (0.6 M) with 5 (2 × 10-4 M) was inves-
tigated under pseudo-first-order conditions. A 3.5 mL volume
of 4 (in a definite amount of salt solution) was measured using
a volumetric pipet and transferred to a cuvette. Then, 25 µL
of 5 dissolved in salt solution was added. The cuvette was
capped. After vigorous shaking, the disappearance of 5 was
monitored at 250 nm.29
The progress of the reaction of 7 with 8 was examined by a
procedure taken from the literature.16 Quantities of 12 mmol
of 7 and 48 mmol of 8 were used in this reaction. A definite
amount of 8 was added to 10 mL of salt solution. Then, the
solution was prepared by adding 7 to a weighed 5 mL
volumetric flask. After the flask was reweighed, it was filled
with the salt solution. Three samples of 8 were placed in a
thermostat, in which definite amounts of 7 ranging from 0.25
(27) Schumacher, J . C. Perchlorates-Their Properties, Manufacture
and Uses, ACS Monograph Series; American Chemical Society: Wash-
ington, DC, 1960.
(24) Akesson, E.; Hakkarainen, A.; Laitinen, E.; Helenius, V.;
Gillbro, T.; Korppi-Tommola, J .; Sundstrom, V. J . Chem. Phys. 1991,
95, 6508.
(25) The microviscosity determination in pure organic liquid though
is relatively simple. See ref 19a.
(28) (a) Desimoni, G.; Gamba, A.; Righetti, P. P.; Tacconi, G. Gazz.
Chim. Ital. 1971, 101, 2635. (b) Desimoni, G.; Astolfi, L.; Cambieri,
M.; Gamba, A.; Tacconi, G. Tetrahedron 1973, 29, 2627. (c) Desimoni,
G.; Faita, G.; Righetti, P. P.; Toma, L. Tetrahedron 1990, 46, 7951.
(29) Flaig, W.; Salfeld, J .-C.; Baume, M. E. Annalen der Chemie
1958, 117.
(26) Isono, T. J . Chem. Eng. Data 1984, 29, 45.

7652 J . Org. Chem., Vol. 66, No. 23, 2001
Kumar and Pawar
to 0.75 mL were added. In the beginning and at definite
intervals (after quenching of samples), the absorbance of 8 was
monitored at 350 nm. An agreement of ( <5% was noted in
the rate constants collected in this work and those reported
in dilute salt solutions.16
measuring the absorbance at 398 nm to follow the disappear-
ance of 16. The procedure is analogous to that given for the
reaction of 1 with 2. The details are provided by Forman and
Dailey.12a Agreement of the rate constant obtained in 4.55 M
LPDE in the current work was noted to be better than 1.5%
when compared with rate data collected in lower salt
solutions.12a
An average of three readings were treated as a final rate
data recorded in tables and shown in figures. A J ulabo
constant-temperature bath was used for maintaining the
temperature of the reaction mixtures.
Quantities of 0.01 mmol of 10 and 5.5 mmol of 11 were used
for the measurement of kinetic data. To 10 mL of salt solution
was added 10. The solution of 11 was prepared in an accurately
weighed 5 mL volumetric flask containing 3 mL of the required
salt solution. The concentration of 11 was accurately calculated
by reweighing the flask. Then, the flask was filled with the
salt solution. Using a pipet, we placed 2 mL of the salt solution
of 10 in three cuvettes, into which constant amounts from 0.25
to 0.75 mL of 11 were added. After the flask was vigorously
shaken, the absorbance of 10 was measured at 410 nm to
examine the progress of the reaction of 10 with 11. The
reaction rates in the lower salt concentrations collected in the
present work agreed to (2% with the reported values.16
Quantities of 5 mmol of 7 and 0.15 mmol of 13 were
employed in the reaction of 7 with 13. To 10 mL of salt solution
was added a definite amount of 13. The solution of 7 was
prepared by addition into an accurately weighed 5 mL volu-
metric flask containing 3 mL of the required salt solution. The
concentration of 7 was accurately calculated by reweighing the
flask. Then, the flask was filled with the salt solution. Using
a pipet, we placed 2 mL of the salt solution of 13 in three
cuvettes, into which constant amounts from 0.25 to 0.75 mL
of 7 were added. After the flask was vigorously shaken, the
absorbance of 13 was measured at 740 nm to examine the
progress of the reaction of 7 with 13.16 The experimental rate
constants obtained in this study agreed to (2.5% with the
reported data in lower salt solutions.16
Ack n ow led gm en t . This work was supported by
the Department of Science and Technology, New
Delhi, in the form of a Grant-in-aid (SP/S1/G-19/99).
Thanks are due to Prof. Biman Bagchi, Indian Institute
of Science, Bangalore, India, for correspondence on the
viscosity-dependent reaction rates. The anonymous
reviewers are acknowledged for their constructive
suggestions, which improved the quality of this paper.
The authors also thank Dr. Raymond A. Firestone
of Boehringer Ingelheim Pharmaceuticals, Inc., USA,
for attracting their attention to macroviscosity and
microviscosity in connection with Diels-Alder reactions.
Su p p or tin g In for m a tion Ava ila ble: Experimental ki-
netic data for different reactions and viscosity data of LPDE
solutions at 28, 33, 38, and 43 °C. This material is available
free of charge via the Internet at http://pubs.acs.org.
The reaction of 15 (0.7 M) with 16 (2 × 10-4 M) was carried
out under pseudo-first-order conditions and was monitored by
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