Lewis acid catalysis of a Diels-Alder reaction in water

Article abstract of DOI:10.1021/ja960318k

Here we report the first detailed study of a Diels-Alder (DA) reaction that is catalyzed by Lewis acids in water. The effect of Co²⁺, Ni²⁺, Cu²⁺ and Zn²⁺ ions as Lewis acid catalysts on the rate and endo-exo selectivity of the DA reaction between the bidentate dienophiles 3-phenyl-1-(2-pyridyl)-2-propen-1-ones (1a-e) and cyclopentadiene (2) in water has been studied. Relative to the uncatalyzed reaction in acetonitrile, catalysis by 0.010 M Cu(NO₃)₂ in water accelerates the reaction by a factor of 79300. The kinetics of the catalyzed reaction were analyzed in terms of equilibrium constants for complexation of the Lewis acid with 1a-e and rate constants for the reaction of the resulting complexes with 2. The rate enhancement imposed upon the uncatalyzed DA reaction of substrates 1 with 2 by water is much more pronounced than that for the catalyzed reaction. The increase of the endo-exo selectivity induced by water in the uncatalyzed process is completely absent for the Lewis acid catalyzed reaction. The modest solvent and substituent effects observed for the catalyzed reaction indicate that the change in charge separation during the activation process is not larger than the corresponding change for the uncatalyzed reaction.

Full text of DOI:10.1021/ja960318k

7702
J. Am. Chem. Soc. 1996, 118, 7702-7707
Lewis Acid Catalysis of a Diels-Alder Reaction in Water
Sijbren Otto, Federica Bertoncin, and Jan B. F. N. Engberts*
Contribution from the Department of Organic and Molecular Inorganic Chemistry,
UniVersity of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
ReceiVed January 30, 1996X
Abstract: Here we report the first detailed study of a Diels-Alder (DA) reaction that is catalyzed by Lewis acids
in water. The effect of Co2+, Ni2+, Cu2+ and Zn2+ ions as Lewis acid catalysts on the rate and endo-exo selectivity
of the DA reaction between the bidentate dienophiles 3-phenyl-1-(2-pyridyl)-2-propen-1-ones (1a-e) and cyclo-
pentadiene (2) in water has been studied. Relative to the uncatalyzed reaction in acetonitrile, catalysis by 0.010 M
Cu(NO3)2 in water accelerates the reaction by a factor of 79 300. The kinetics of the catalyzed reaction were analyzed
in terms of equilibrium constants for complexation of the Lewis acid with 1a-e and rate constants for the reaction
of the resulting complexes with 2. The rate enhancement imposed upon the uncatalyzed DA reaction of substrates
1 with 2 by water is much more pronounced than that for the catalyzed reaction. The increase of the endo-exo
selectivity induced by water in the uncatalyzed process is completely absent for the Lewis acid catalyzed reaction.
The modest solvent and substituent effects observed for the catalyzed reaction indicate that the change in charge
separation during the activation process is not larger than the corresponding change for the uncatalyzed reaction.
Introduction
attained much attention ever since its discovery in 1980.9 An
extensive discussion of the origin of the remarkable acceleration
induced by water has already been given in previous papers.8
Evidence has been presented8 that there are two effects causing
this aqueous rate enhancement: enforced hydrophobic interac-
tions and hydrogen bonding to the activating group of the
dienophile. The way one can envisage these two effects to
operate will be briefly summarized.
The reaction partners in a typical DA reaction are usually
poorly soluble in water. As a result the water molecules
surrounding these reagents arrange themselves in hydrophobic
hydration shells. The DA reaction forces the reaction partners
into close contact in the activated complex, leading to a
reduction of the molecular surface area exposed to water. This
causes the transition state to be less destabilized than the initial
state, resulting in a faster reaction in water as compared to
nonaqueous solvents.
The second effect involves hydrogen bonding of the water
molecules to the activating group in the dienophile (for normal
electron-demand DA reactions). The role of this activating
group is to withdraw electron density from the double bond,
thereby lowering the LUMO energy of the dienophile and
facilitating the interaction with the diene HOMO. When a
hydrogen bond is formed to such an activating group, its electron
withdrawing capacity is enhanced, which results in a further
lowering of the LUMO energy, a smaller HOMO-LUMO gap,
and thus a faster reaction. The importance of hydrogen bonding
is also apparent from ab-initio studies by Jorgensen et al.10
Water also influences the selectivity of the DA reaction.
Studies of the effects of solvents on the regio-11 and diastereo-
facial12 selectivity of DA reactions have provided evidence that
these parameters are mainly influenced by the hydrogen-bond
The Diels-Alder (DA) reaction is of great synthetic value
and is often an important step in the (stereoselective) synthesis
of six-membered rings. The factors governing the reactivity
and selectivity of this cycloaddition reaction have been studied
in detail.1 Generally, the process of bond breaking and bond
formation in the DA reaction is considered to be concerted2
but not necessarily synchronous.3 In extreme cases the DA
reaction can even become a two-step process with a zwitterionic4
or biradical5 intermediate.
The concertedness implies that there is only a small change
in charge separation on going from the initial state to the
activated complex. As a result the rates of many DA reactions
remain almost unaffected by the solvent.1,6 The rate of some
DA reactions, however, can be strongly influenced by the
medium.7 This is especially true for aqueous media, where
accelerations up to 13 000 times (when compared to organic
solvents) can be achieved.8 This special effect of water has
X Abstract published in AdVance ACS Abstracts, August 1, 1996.
(1) Review: Sauer, J.; Sustmann, R. Angew. Chem., Int. Ed. Engl. 1980,
19, 779.
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1992, 48, 1667.
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Soc. 1991, 113, 4241. (b) Otto, S.; Blokzijl, W.; Engberts, J. B. F. N. J.
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Soc., Faraday Trans. 1994, 90, 1727. (c) Blake, J. F.; Dongchul, L.;
Jorgensen, W. L. J. Org. Chem. 1994, 59, 803.
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Soc., Perkin Trans. 2 1994, 847.
S0002-7863(96)00318-6 CCC: $12.00 © 1996 American Chemical Society

Lewis Acid Catalysis of a Diels-Alder Reaction in Water
J. Am. Chem. Soc., Vol. 118, No. 33, 1996 7703
donating ability of the solvent which affects the orbital
coefficients of the dienophile. Computer simulations suggest
that hydrogen bonds affect the diastereofacial selectivity by
influencing the s-cis/s-trans conformational equilibrium.13 It
has also been suggested that hydrogen bonding, by increasing
the orbital coefficients, leads to a tighter transition state in which
the asymmetric center already present has more interaction with
the stereocenter that is being formed.14 With regard to the regio-
and diastereofacial selectivity, water behaves as anticipated on
the basis of its hydrogen-bond donating capability.
Scheme 1
With respect to the endo-exo selectivity, water is an
outstanding solvent for the DA reaction since endo-exo ratios
are almost invariably higher in water than in organic solvents.15
The general preference for endo product is often rationalized
in terms of secondary orbital interactions.16,17 For explaining
the special effect of water on the endo-exo selectivity three
factors appear to be important. First of all water is a polar
solvent and polar solvents are known to favor the more polar
endo activated complex.18 Furthermore, the charge transfer
resulting from secondary orbital overlap in the endo activated
complex is more favored in polar media.15b Secondly, the endo
activated complex is usually the most compact with the smallest
surface area in contact with water and is thus favored over the
exo activated complex. This is underlined by the correlation
of endo-exo ratios with the Sp parameter.15c,19 Finally,
hydrogen bonding to the activating group is of importance as
is shown by linear free energy relationships in which the
hydrogen-bond donating capacity of the solvent (quantified by
the R-parameter) contributes to a significant extent.11,20 Since
a good hydrogen-bond donating solvent is often also a structured
solvent, we note that an intrinsic correlation between the Sp
and R-parameter can exist.12d
Rates and selectivities of DA reactions can also benefit
markedly from the use of Lewis acids as catalysts in organic
solvents.21 The mechanism by which Lewis acids affect the
DA reaction is analogous to the effects of hydrogen bonding
as delineated above.14,17a In the present study we address the
question whether the beneficial effects of water and Lewis acids
on the rate and endo-exo selectivity of the DA reaction can be
combined. Two important questions arise immediately. Is the
Lewis acid catalyzed reaction still accelerated by water?
Secondly, what is the effect of water on the selectivity of the
catalyzed reaction? In order to provide answers to these
questions, the first step was to design a diene/dienophile pair
which is subject to Lewis acid catalysis in water. This was by
no means trivial, since most Lewis acids used for the catalysis
of DA reactions in organic solvents are decomposed in water.
Although some examples of water-tolerant Lewis acids that
retain their activity when a small amount of water is present in
the solution have been reported,22 Lewis acid catalysis of DA
reactions in pure water was (to our knowledge) unprecedented
at the time we started our study. There are examples in the
literature of other organic reactions that are catalyzed by Lewis
acids in water. As early as 1951 it was shown that simple
transition metal ions catalyze the decarboxylation of dimethyl-
oxaloacetic acid.23 There are also many studies on the metal-
ion catalyzed hydrolysis of esters, amides, and phosphates.24
However, it should be noted that in these hydrolysis reactions
the metal ion does not only act as a Lewis acid, but also
coordinates the hydroxide nucleophile. In all cases the sub-
strates contain two sites for interaction with the metal ion.
Coordination of a monodentate substrate to a Lewis acid in water
is apparently not feasible. Displacement of a water molecule
from the coordination sphere of the Lewis acid by the substrate
is not likely to lead to a significant gain in Gibbs energy since
water is an appreciable Lewis base and present in a large excess.
We therefore restricted our search for a Lewis acid catalyzed
DA reaction in water to potentially bidentate dienophiles.
3-Phenyl-1-(2-pyridyl)-2-propen-1-one, 1 (Scheme 1), which
offers apart from a carbonyl oxygen also a pyridyl nitrogen atom
to the Lewis acid, turned out to be very successful.25 Herein
we present the first detailed study of Lewis acid catalysis of a
DA reaction in water.
(12) (a) Lubineau, A.; Queneau, Y. J. Org. Chem. 1987, 52, 1001. (b)
Waldmann, H.; Dra¨ger, M. Liebigs Ann. Chem. 1990, 681. (c) Lubineau,
A.; Auge´, J.; Lubin, N. J. Chem. Soc., Perkin Trans. 1 1990, 3011. (d)
Cativiela, C.; Garc´ıa, J. I.; Mayoral, J. A.; Royo, A. J.; Salvatella, L.;
Assfeld, X.; Ruiz-Lopez, M. F. J. Phys Org. Chem. 1992, 5, 230.
(13) Ruiz-Lo´pez, M. F.; Assfeld, X.; Garc´ıa, J. I.; Mayoral, J. A.;
Salvatellar, L. J. Am. Chem. Soc. 1993, 115, 8780.
(14) Houk, K. N.; Strozier, R. W. J. Am. Chem. Soc. 1973, 95, 4094.
(15) (a) Breslow, R.; Maitra, U.; Rideout, D. Tetrahedron Lett. 1983,
24, 1901. (b) Breslow, R.; Maitra, U. Tetrahedron Lett. 1984, 25, 1239. (c)
Schneider, H.; Sangwan, N. K. Angew. Chem., Int. Ed. Engl. 1987, 26,
896.
(22) (a) Oldenkirk, W.; Rheingold, A. L.; Bosnich, B. J. Am. Chem. Soc.
1992, 114, 6392. (b) Hollis, T. K.; Robinson, N. P.; Bosnich, B. J. Am.
Chem. Soc. 1992, 114, 5464. (c) Kobayashi, S.; Hachiya, I.; Araki, M.;
Ishitani, H. Tetrahedron Lett. 1993, 34, 3755. (d) Kobayashi, S. Synlett
1994, 689. (e) Ishihara, K.; Hanaki, N.; Funahashi, M.; Miyata, M.;
Yamamoto, H. Bull. Chem. Soc. Jpn. 1995, 68, 1721. (f) Inanaga, J.;
Sugimoto, Y.; Hanamoto, T. New J. Chem. 1995, 19, 707. (g) Kobayashi,
S.; Nagayama, S. J. Org. Chem. 1996, 61, 2256.
(16) (a) Houk, K. N. Tetrahedron Lett. 1970, 30, 2621. (b) Gleiter, R.;
Bo¨hm, M. C. Pure Appl. Chem. 1983, 55, 237.
(17) Steric arguments and dipole-dipole interactions can often equally
well explain the observed endo selectivity: (a) Birney, D. M.; Houk, K. N.
J. Am. Chem. Soc. 1990, 114, 4127. (b) Karcher, T.; Sicking, W.; Sauer,
J.; Sustmann, R. Tetrahedron Lett. 1992, 33, 8027.
(18) Berson, J.A.; Hamlet, Z.; Mueller, W.A. J. Am. Chem. Soc. 1962,
84, 297.
(19) Cativiela, C.; Mayoral, J. A.; Avenoza, A.; Peregrina, J. M.; Roy,
M. A. J. Phys. Org. Chem. 1990, 3, 414.
(23) (a) Steinberger, R.; Westheimer, F. H. J. Am. Chem. Soc. 1951, 73,
429. (b) Prue, J. E. J. Chem. Soc. 1952, 2331. (c) Gelles, E.; Hay, R. W.
J. Chem. Soc. 1958, 3673. (d) Gelles, E.; Salama, A. J. Chem. Soc. 1958,
3683. (e) Gelles, E.; Salama, A. J. Chem. Soc. 1958, 3689. (f) Rund, J. V.;
Plane, R. A. J. Am. Chem. Soc. 1964, 86, 367. (g) Rund, J. V.; Claus, K.
G. J. Am. Chem. Soc. 1967, 89, 2256. (h) Hay, R. W.; Leong, K. N. Chem.
Commun. 1967, 800. (i) Rund, J. V.; Claus, K. G. Inorg. Chem. 1968, 7,
860. (j) Claus, K. G.; Rund, J. V. Inorg. Chem. 1969, 8, 59.
(24) Hay, R. W. In ComprehensiVe Coordination Chemistry; Wilkinson,
G., Gillard, R. D., McCleverty, J. A., Eds.; Pergamon Press: Oxford, 1987;
pp 411-485.
(20) Gajewski, J. J. J. Org. Chem. 1992, 57, 5500.
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7704 J. Am. Chem. Soc., Vol. 118, No. 33, 1996
Otto et al.
Table 3. Solvent Effect on the Hammett F-Values for the DA
Table 1. Second-Order Rate Constants k2 for the Uncatalyzed DA
Reaction of 1a with 2 in Different Solvents at 25 °C
Reaction of 1 with 2 Catalyzed by Cu(NO3)2 at 25 °C
solvent
acetonitrile
ethanol
water
2,2,2-trifluoroethanol
k2 (M-1 s-1
)
krel
solvent
[Cu2+] (mM)
F
r
1.40 × 10-5
3.83 × 10-5
4.02 × 10-3
6.75 × 10-3
1
2.7
287
482
acetonitrile
10
10
10
0.10
0.96
1.00
0.69
0.90
0.997
0.999
0.997
0.990
ethanola
water
2,2,2-trifluoroethanol
a For unknown reasons the point for 1a in the Hammett plot for
ethanol strongly deviates from the otherwise good correlation. The
data for 1a in ethanol have therefore not been used in the calculation
of F. Instead a new compound 1 with X ) CO2CH3 was used in the
correlation.
rationalized as follows. For the Lewis acid catalyzed reactions
the hydrogen bonding part of the acceleration will be largely
taken over by the Lewis acid, so it is likely that only the
hydrophobic effect will remain. This contribution will not be
unaffected by the Lewis acid either, since the catalyst will partly
destroy the hydrophobic hydration shell of the activated complex
and of the dienophile in the initial state. This will result in a
much smaller aqueous solvent effect on the catalyzed reaction.
The highest catalytic activity is observed in TFE. One might
envisage this to be a result of the poor interaction between TFE
and the copper(II) cation, so that the cation will retain a large
part of its Lewis acidity. In the other solvents the interaction
between their electron-rich heteroatoms and the cation is likely
to be stronger, thus diminishing the efficiency of the Lewis acid
catalysis. The observation that Cu(NO3)2 is only poorly soluble
in TFE and much better in the other solvents used is in accord
with this reasoning.
Figure 1. pH dependence of the rate of the DA reaction between 1a
and 2 in water at 25 °C.
Table 2. Second-Order Rate Constants k2 for the Cu2+-Ion
Catalyzed Reaction of 1c with 2 in Different Solvents at 25 °C
solvent
acetonitrile
ethanol
[Cu2+] (mM)
k2 (M-1 s-1
)
10
10
10
0.472
0.309
1.11
It is interesting to examine the influence of substituents on
the Lewis acid catalyzed DA reaction, since there are indications
for a relatively large charge separation in the activated complex
of the catalyzed reaction compared to the uncatalyzed one in
organic solvents.17a This might induce a larger effect of
substituents on the rate of the catalyzed reaction. Therefore,
we have measured the rate of the Cu2+-catalyzed DA reaction
between 1a-e and 2 in four solvents, resulting in excellent
Hammett correlations with σ+ (Table 3). The fact that good
correlations are observed with σ+ rather than with σ is indicative
of a strong interaction of the substituent through direct resonance
with a positive charge in the reacting system. However, the
F-values do not exceed unity and are not significantly different
from those values reported in the literature for the uncatalyzed
reaction.1 The tempting conclusion that the charge separation
in the activated complex of the catalyzed reactions is also not
significantly different from that in the uncatalyzed reaction is,
however, not valid. Since it is reasonable to assume that the
initial state of the catalyzed reaction (the dienophile/Lewis acid
complex) is more polarized than the initial state of the
uncatalyzed reaction, it is not justified to make a direct
comparison between the activated complexes of the rate-limiting
step for the uncatalyzed and catalyzed reactions just on the basis
of F-values. Among the different solvents water occupies a
special position with a relatively small F-value (Table 3). This
is anticipated, since water is the solvent with the strongest
interactions with the partial charges of the reacting system and
the substituents. Substituent effects are usually larger in solvents
that only weakly interact with these partial charges26 and, hence,
have maximal values in vacuum.27 It is important to note here
that we have no detailed knowledge about the exact structure
of the catalytically active species in the organic solvents.
water
2,2,2-trifluoroethanol
0.10
3.22
Results and Discussion
The dienophiles 1a-e are readily prepared32 from an aldol
condensation between (substituted) benzaldehyde and 2-acetyl-
pyridine. The compounds are poor dienophiles and, as far as
we know, no DA reactions have been reported previously.
Herein we describe an extensive study of the DA reaction of 1
with 2 putting particular emphasis on rates and selectivity by
systematic variation of the solvent, the substituent X, and the
Lewis acid.
Effect of Solvent on the Rate of the Uncatalyzed Reaction.
Rates of the DA reaction of 1a with 2 in water and three organic
solvents are shown in Table 1. The solvents were chosen to
cover as broad a range in solvent properties as possible. In
fact hexane was initially also among them, but unfortunately
the rate of the reaction in this solvent is extremely low. It is
clear that the DA reaction is accelerated markedly by water.
Striking is the observation that the reaction is fastest in 2,2,2-
trifluoroethanol (TFE). This might well be a result of the high
Brønsted acidity of this solvent. Indirect evidence comes from
the pH-dependence of the rate of the reaction in water (Figure
1). Protonation of the pyridyl nitrogen obviously accelerates
the reaction.
Solvent and Substituent Effects on the Cu2+-Catalyzed
Reaction. The rate of the uncatalyzed reaction is in all four
solvents rather slow. (The half-life at [2] ) 1.00 mM is at least
28 h). We find that complexation of Cu2+ ion to 1a-e
dramatically increases the rate of the DA reaction between these
compounds and 2. Table 2 shows the rate constants for the
Cu2+-catalyzed DA reaction between 1c and 2 in different
solvents. It is obvious that the relatively large solvent effect
of water observed in the uncatalyzed reaction (Table 1) is
strongly diminished for the catalyzed reaction. This can be
(26) (a) Jaworski, J. S.; Malik, M.; Kalinowski, M. K. J. Phys. Org.
Chem. 1992, 5, 590. (b) Bartnicka, H.; Bojanowska, I.; Kalinowski, M. K.
Aust. J. Chem. 1993, 46, 31.
(27) Headley, A. D.; McMurry, M. E.; Starnes, S. D. J. Org. Chem.
1994, 59, 1863.

Lewis Acid Catalysis of a Diels-Alder Reaction in Water
J. Am. Chem. Soc., Vol. 118, No. 33, 1996 7705
Table 5. Hammett F-Values for Complexation of 1a-e to
Different Lewis Acids and for the DA Reaction of 1a-e with 2
Catalyzed by Different Lewis Acids in Water at 2.00 M Ionic
Strength at 25 °C
Scheme 2
complexation
rate constants
Lewis acid
F
r
F
r
Co2+
Ni2+
Cu2+
Zn2+
-0.19
-0.44
-0.51
-0.42
0.981
0.999
0.997
0.991
0.72
0.94
0.85
0.84
0.999
0.999
0.999
0.998
complexation of 1a-e to the four different transition-metal ions
were determined. Good to excellent Hammett plots were
obtained using σ+ substituent constants.29 As anticipated the
data in Table 5 show that the complexation is characterized by
negative F-values, indicating that the binding process is favored
by electron donating substituents. The order of the F-values
for complexation of the different Lewis acids again follows the
Irving-Williams series.
Table 4. Second-Order Rate Constants (kobs) for the Catalyzed DA
Reaction between 1c and 2, Equilibrium Constants for
Complexation of 1c to Different Lewis Acids (Ka), and
Second-Order Rate Constants for the Reaction of These Complexes
with 2 (k2) in Water at 2 M Ionic Strength at 25 °C
a
kobs (M-1 s-1
)
Ka (M-1
)
k2 (M-1 s-1
)
The effect of substituents on the rate of the reaction catalyzed
by different metal ions has also been studied. Correlation with
σ+ resulted in perfectly linear Hammett plots. Now the F-values
for the four Lewis acids do not follow the Irving-Williams
order. Note that the substituents have opposing effects on
complexation, which is favored by electron donating substitu-
ents, and reactivity, which is increased by electron withdrawing
substituents. The effect on the reactivity is clearly more
pronounced than the effect on the complexation equilibrium.
So far we have compared the four transition-metal ions with
respect to their effect on (1) the equilibrium constant for
complexation to 1c, (2) the rate constant of the DA reaction of
the complexes with 2, and (3) the substituent effect on processes
1 and 2. We have tried to correlate these data with some
physical parameters of the respective metal ions. The second
ionization potential of the metal should, in principle, reflect its
Lewis acidity. Furthermore the values for k2 might be strongly
influenced by the Lewis acidity of the metal. A quantitative
correlation between these two parameters is, however, not
observed. Alternatively, the acidity of the hexaaquo metal
cation can be taken as a measure of Lewis acidity but this
parameter did not exhibit a quantitative correlation with the
above data either.
Lewis acid
Co2+
Ni2+
Cu2+
Zn2+
4.53 × 10-2
8.26 × 10-2
2.36
1.17 × 102
6.86 × 102
1.16 × 103
7.28 × 101
8.40 × 10-2
9.46 × 10-2
2.56
4.29 × 10-2
1.18 × 10-1
a For [M2+] ) 10 mM.
Variation of the Catalyst. We contend that Lewis acids
affect the rate of a DA reaction in water by the mechanism
depicted in Scheme 2. The first step in the cycle comprises
rapid and reversible coordination of the Lewis acid to the
dienophile, leading to a complex in which the dienophile is
activated for reaction with the diene. After the irreversible DA
reaction the product has to dissociate from the Lewis acid in
order to make the catalyst available for another cycle. The
overall rate of the reaction is determined by Ka, k2, and Kd. In
our kinetic runs we always used a large excess of catalyst. Under
these conditions Kd will not influence the observed rate of the
DA reaction. Kinetic studies by UV-vis spectroscopy require
a low concentration of the dienophile (∼10-5 M). The use of
only a catalytic amount of Lewis acid will seriously hamper
complexation of the dienophile because of the very low
concentrations of both reaction partners under these conditions.
The contributions of Ka and k2 to the observed overall rate
constant have been determined by measuring kobs and Ka
separately (Experimental Section). The data obtained in this
way are in excellent agreement with the results of the Line-
weaver-Burke analysis of the rate constants at different catalyst
concentrations. The results for Co2+, Ni2+, Cu2+, and Zn2+
catalysis of the reaction of 1c with 2 in water at constant ionic
strength (2.00 M KNO3) are shown in Table 4. Cu2+ is the
best catalyst with respect to both complexation and rate of
reaction with 2. The trend observed in rate and equilibrium
constants follows the empirical Irving-Williams order28 Co2+
< Ni2+ < Cu2+ > Zn2+. This order is usually observed for
equilibrium constants of binding processes and catalytic activi-
ties of these metal ions.28 A quantitative correlation between
rate and equilibrium constants for the different metal ions is
absent. The observed rate enhancements are a result of catalysis
by the metal ions and are clearly not a result of protonation of
the pyridyl group, since the pH’s of all solutions were within
the region where the rate constant is independent of the pH
(Figure 1). Catalysis by the four transition-metal ions was also
compared with respect to their sensitivity toward substituents
in the dienophile. To this end the equilibrium constants for
Endo-Exo Selectivity. The reaction between 1 and 2 yields
four products: two enantiomeric endo products and two
enantiomeric exo products. We have examined the effect of
the solvent, the Lewis acid, and the substituents on the endo-
exo selectivity.
The endo and the exo isomer (Scheme 1) give rise to two
different NMR spectra with several peaks that are well separated.
From the integration of those signals the endo-exo ratio can
be determined. Measurement of the endo-exo ratio by GC was
not successful, most likely because the adducts are subject to a
retro-DA reaction at elevated temperatures. Assignment of the
signals to the different isomers was based on COSY and
NOESY spectra. Interpretation of the spectra starts with the
identification of the long-range coupling between H7s and H2,
characteristic for norbornene systems.30 The chemical shifts
of the other protons can now easily be deduced. The discrimi-
nation between endo and exo adduct is subsequently based upon
the following considerations. A NOE signal between H3 and
a proton on the phenyl ring and a long-range coupling between
H2 and a proton of the phenyl ring are both characteristic for
(29) Literature examples of good Hammett correlations of stability
constants are rare: May,W.R.; Jones, M.M. J. Inorg. Nucl. Chem. 1962,
24, 511.
(28) Irving, H.; Williams, R. J. P. J. Chem. Soc. 1953, 3192.
(30) Nicolas, L.; Beugelmans-Verrier, M. Tetrahedron 1981, 37, 3847.

7706 J. Am. Chem. Soc., Vol. 118, No. 33, 1996
Otto et al.
Table 6. Solvent Effect on the Endo-Exo Selectivity (% endo -
% exo) of the Uncatalyzed and Cu2+-Ion Catalyzed DA Reaction
between 1c and 2 at 25 °C
Chart 1
solvent
acetonitrile
ethanol
water
2,2,2-trifluoroethanol
uncatalyzed
10 mM Cu2+
67-33
77-23
84-16
87-13
94-6
96-4
93-7
capability of forming a chelate with the Lewis acid, react with
2 in the presence of catalyst at rates at least three orders of
magnitude lower than those for 1. The scope of Lewis acid
catalysis of DA reactions in water appears to be limited to
bidentate reactants. Whether and how this restriction can be
circumvented is currently under investigation. Furthermore, a
study of Lewis acid catalyzed DA reactions in the presence of
micelles is in progress.31
Table 7. Effect of Different Catalysts on the Selectivity of the DA
Reaction between 1c and 2 in Water at 25 °C
catalyst
% endo - % exo
10 mM Co(NO3)2
10 mM Ni(NO3)2
10 mM Cu(NO3)2
10 mM Zn(NO3)2
10 mM HCl
87-13
86-14
93-7
86-14
94-6
Conclusions
Table 8. Substituent Effect on the Selectivity of the
Cu2+-Catalyzed Reaction of 1 and 2 in Water at 25°C
The DA reaction between 1 and 2 can be accelerated
dramatically by Lewis acid catalysis combined with the
beneficial aqueous solvent effect. The catalytic efficiency of
the Lewis acids studied followed the empirical Irving-Williams
order: Co2+ < Ni2+ < Cu2+ >> Zn2+. The rate enhancing
effect of water on the catalyzed reaction is less pronounced than
the corresponding effect on the uncatalyzed reaction between
1 and 2. In general, the solvent effect on the catalyzed reaction
is remarkably modest and the substituent effects observed are
similar to those normally obtained for uncatalyzed DA reactions.
This implies that the changes in charge separation during the
activation process of the catalyzed reaction are not significantly
larger than the corresponding changes for the uncatalyzed
reaction. The endo-exo selectivity of the catalyzed DA reaction
is also only moderately sensitive to the solvent and to substi-
tuents in the dienophile. Water does not induce an enhanced
endo-selectivity for this reaction.
dienophile
% endo - % exo
1a
1b
1c
1d
1e
88-12a
92-8a
93-7
93-7
93-7
a The dienophile was not completely dissolved.
the endo isomer. Furthermore, the downfield shift of H3 is
larger in the exo isomer, where it experiences the influence of
the nearby carbonylpyridyl group, than in the endo adduct,
where H3 is situated next to the phenyl group. Comparison of
the NMR data with literature data reported for the DA adducts
of cyclopentadiene and substituted cinnamic acids30 further
supports the assignments.
The effects of the solvent on the endo-exo selectivity of the
uncatalyzed and Cu2+-catalyzed reaction are shown in Table 6.
For the uncatalyzed reaction the endo isomer is preferred over
the exo isomer. This tendency becomes even more pronounced
in more polar solvents, which is in good agreement with
previous studies of the solvent effect on the selectivity of DA
reactions.15 For the Cu2+-catalyzed reaction the differences
between the selectivities in the four solvents are much smaller.
Obviously, water does not induce a higher selectivity in this
case and there appears to be no indication for an enforced
hydrophobic effect favoring the endo-activated complex. Pre-
sumably this is caused by the disturbing influence of the metal
cation on the hydrophobic hydration shells of the reacting
system.
Table 7 shows the endo-exo selectivities for the DA reaction
between 1c and 2 catalyzed by protons and four different metal
ions in water. Copper is clearly the most selective metal-ion
catalyst. Interestingly, proton catalysis also leads to high
selectivities. This is a strong indication that selectivity in this
DA reaction does not result from steric interactions. Table 8
shows the effect of substituents on the endo-exo ratio. Under
homogeneous conditions there is hardly any substituent effect
on the selectivity. Consequently the substituents must have
equal effects on the Gibbs energies of the endo and the exo
activated complex.
In summary, we have examined the effects of a number of
important parameters for the catalyzed DA reaction between 1
and 2 representing the first example of Lewis acid catalysis of
a DA reaction in water. Crucial for the success of Lewis acid
catalysis of this reaction is the bidentate character of 1. The
structurally related compounds 5 and 6 (Chart 1), lacking the
Experimental Section
Materials. trans-Chalcone (6) (mp 57.1-57.7 °C) was obtained
from Aldrich and recrystallized form ethanol. Cyclopentadiene was
prepared from its dimer (Merck-Schuchardt) immediately before use.
Dimineralized water was distilled twice in a quartz distillation unit.
Ethanol (Merck) was of the highest purity available. Acetonitrile
(Janssen) was run over basic aluminium oxide prior to use. 2,2,2-
Trifluoroethanol (Acros) was purified by distillation (bp 79°C).
Co(NO3)2‚6H2O, Ni(NO3)2‚6H2O, Cu(NO3)2‚3H2O, Zn(NO3)2‚4H2O,
and KNO3 were of the highest purity available. Compounds 1a-e and
5 were prepared by an aldol condensation of the corresponding
substituted benzaldehyde with 2- or 4-acetylpyridine, following either
of two modified literature procedures.32
1a and 1b. To a stirred solution of 0.5 ml of 10% aqueous sodium
hydroxide and 8.25 mmol of the appropriate aldehyde in 10 mL of
ethanol was added dropwise over 2-3 h 8.25 mmol of 2-acetylpyridine.
The temperature was kept at 0 °C. After being stirred for another 2 h
the reaction mixture was filtered, yielding almost pure solid 1a (7.26
mmol, 88%) or 1b (7.76 mmol, 94 %). After crystallization from
ethanol the melting points were recorded and the compounds were
1
1
characterized by H NMR. 1a: mp 158.2-158.5 °C; H NMR (200
MHz, CDCl3) δ 7.55 (m, 1H), 7.86 (d, 2H), 7.91 (m, 2H), 8.22 (m,
1H), 8.27 (d, 2H), 8.45 (d, 1H), 8.77 (d, 2H). 1b: mp 102.2-102.5
°C; 1H NMR (200 MHz, CDCl3) δ 7.39 (d, 2H), 7.50 (m, 1H), 7.67 (d,
2H), 7.88 (m, 2H), 8.19 (m, 1H), 8.29 (d, 1H), 8.75 (m, 1H).
1c, 1d, 1e, and 5. Seventeen millimoles of the appropriate
acetylpyridine and 16.5 mmol of the appropriate benzaldehyde were
introduced in 100 mL of water at temperatures below 5 °C. The mixture
(31) In the presence of copper dodecylsulfate micelles rate enhancements
in the order of 106 can be achieved.
(32) (a) Engler, C.; Engler, A. Chem. Ber. 1902, 35, 4061. (b) Marvel,
C.S.; Coleman, L.E., Jr.; Scott, G.P. J. Org. Chem. 1955, 20, 4061.

Lewis Acid Catalysis of a Diels-Alder Reaction in Water
J. Am. Chem. Soc., Vol. 118, No. 33, 1996 7707
was shaken thoroughly in order to obtain a finely dispersed emulsion.
Ten milliliters of a 10% sodium hydroxide solution was added. The
mixture was again shaken and left overnight undisturbed at 4 °C. The
solution should not be stirred since this results in a phase separation
and lower yields. The product separated as an oil that solidified upon
shaking. Filtration and washing with water gives the almost pure
product in satisfactory yields: 1c, 95%; 1d, 84%; 1e, 96%; 5, 76%.
After crystallization from ethanol the melting points were recorded and
difference between the extinction coefficients of uncomplexed and
complexed dienophile. The metal-ion concentrations were chosen so
as to cover the largest possible change in ꢀobs with the smallest possible
change in [M2+]. Solutions of different [M2+] with total ionic strength
of 2.00 M were prepared. KNO3 was used as the background
electrolyte. Extinction coefficients were determined by filling the cuvet
with an accurately known volume of this solution and measuring the
absorption after injection of 3-10 µL of a stock solution of the
dienophile in 1-propanol. Typical concentration ranges were [dieno-
phile] ) (6 × 10-6)-(2 × 10-5) M and [M2+] ) (5 × 10-3)-(2 ×
10-5) M.
Product Analysis. Endo-exo product mixtures were isolated using
the following procedure. A solution of cyclopentadiene (concentration
2 × 10-3 M in water and 0.4 M in organic solvents) and the dienophile
(concentration 1-5 mM) in the appropriate solvent, eventually contain-
ing a 0.01 M concentration of catalyst, was stirred at 25 °C until the
UV-absorption of the dienophile had disappeared. The reaction mixture
(diluted with water in the case of the organic solvents) was extracted
with ether. The ether layer was washed with water and dried over
sodium sulfate. After the evaporation of the ether the adducts were
obtained in quantitative yields and almost invariably as oils. Only the
reaction of 1c and 2 in water with 10 mM HCl gave a white precipitate.
The product mixtures were analyzed with respect to their endo-exo
ratio by 1H NMR. By repeating the extraction-drying procedure it was
checked that the work-up procedure did not influence to endo-exo
ratio of the isolated product mixture.
We have been able to purify only the products of 1a and 1c by
crystallization from 1-propanol and ethanol, respectively. The purified
products were still a mixture of endo and exo isomers. Elemental
analyses of these compounds are given below. The DA adducts of
1b, 1d, and 1e were characterized by comparison of their NMR spectra
with those of 1a and 1c. We will report here only the NMR data for
the endo isomer, since the signals of the minor (7-12%) exo isomer
partly coincide with the larger signals of the endo isomer and no
attempts were made to separate the two. 3a: Anal. Calcd for
C19H16N2O3: C, 71.22; H, 5.04; N, 8.75. Found C, 70.82; H, 4.93; N,
8.66. 1H NMR (300 MHz, CDCl3) δ 1.65 (dd, 1H), 1.99 (d, 1H), 3.11
(d, 1H), 3.52 (d, 1H), 3.59 (s, 1H), 4.46 (dd, 1H), 5.85 (dd, 1H), 6.47
(dd, 1H), 7.21 (m, 3H), 8.0 (m,5H), 8.6 (d, 1H). 3b: 1H NMR (300
MHz, CDCl3) δ 1.61 (dd, 1H), 2.00 (d, 1H), 3.04 (d, 1H), 3.40 (dd,
1H), 3.54 (s, 1H), 4.45 (dd, 1H), 5.82 (dd, 1H), 6.47 (dd, 1H), 7.21
(m,5H), 7.45 (m, 1H), 7.82 (m, 1H), 7.99 (d, 1H), 8.66 (d, 1H). 3c:
Anal. Calcd for C19H17NO: C, 82.87; H, 6.23; N, 5.09. Found: C,
82.28; H, 6.24; N, 5.21. 1H NMR (300 MHz, CDCl3) δ 1.61 (dd, 1H),
2.05 (d, 1H), 3.07 (d, 1h), 3.43 (dd, 1H), 3.53 (s, 1H), 4.51 (dd, 1H),
5.81 (dd, 1H), 6.47 (dd, 1H), 7.21 (m,5H), 7.41 (m, 1H), 7.80 (m, 1H),
7.99 (m, 1H), 8.65 (m, 1H). 3d: 1H NMR (300 MHz, CDCl3) δ 1.60
(dd, 1H), 2.07 (d, 1H), 3.06 (d, 1H), 3.42 (d, 1H), 3.54 (s, 1H), 4.53
(dd, 1H), 5.83 (dd, 1H), 6.49 (dd, 1H), 7.09 (d, 2H), 7.22 (d, 2H), 7.43
(m, 1H), 7.80 (m, 1H), 8.00 (d, 1H), 8.67 (d, 1H). 3e: 1H NMR (300
MHz, CDCl3) δ 1.59 (dd, 1H), 2.05 (d, 1H), 3.02 (d, 1H), 3.39 (d,
1H), 3.52 (s, 1H), 4.49 (dd, 1H), 5.81 (dd, 1H), 6.48 (dd, 1H), 6.82 (d,
2H), 7.23 (d, 2H), 7.43 (m, 1H), 7.79 (m, 1H), 7.99 (d, 1H), 8.67 (d,
1H).
1
the compounds were characterized by H NMR. 1c: mp 74.5-75.3
1
°C, H NMR (200 MHz, CDCl3) δ 7.46 (m, 4H), 7.74 (m, 2H), 7.86
(m, 1H), 7.95 (d, 1H), 8.20 (m, 1H), 8.32 (d, 1H), 8.75 (m, 1H). 1d:
1
mp 84.8-85.3 °C, H NMR (200 MHz, CDCl3) δ 2.40 (s, 3H), 7.23
(d, 2H), 7.49 (m, 1H), 7.64 (d, 2H), 7.87 (m, 1H), 7.93 (d, 1H), 8.19
(m, 1H), 8.27 (d, 1H), 8.74 (m, 1H). 1e: mp 84.6-85.2 °C, 1H NMR
(200 MHz, CDCl3) δ 3.85 (s, 3H), 6.93 (d, 2H), 7.47 (m, 1H), 7.69 (d,
2H), 7.86 (m, 1H), 7.92 (d, 1H), 8.19 (d, 1H), 8.19 (m, 1H), 8.73 (m,
1
1H). 5: mp 89.0-89.2 °C, H NMR (200 MHz, CDCl3) δ 7.44 (d,
1H), 7.45 (m, 3H), 7.65 (m, 2H), 7.77 (m, 2H), 7.85 (d, 1H), 8.84 (m,
2H).
Kinetic Measurements. All kinetic measurements were performed
using UV-vis spectroscopy (Perkin Elmer λ2, 5 or 12) monitoring
the disappearance of the absorption of the dienophile at 25 ( 0.1 °C.
Two methods were used to determine the reported second-order rate
constants. The rates of the faster reactions (half-lives not more than a
few hours) were determined following procedures described earlier.8a
The rate constants of the slower reactions in organic solvents and the
reactions with cyclopentadiene in water with half-lives of more than
15 minutes were determined using initial rate kinetics.33 Using a known
excess of cyclopentadiene, the following expression was used to
calculate the second-order rate constants:
k2 ) d[Adienophile]/dt‚((ꢀdienophile - ꢀproduct)‚
[dienophile]0‚[cyclopentadiene]0)-1
Where d[Adienophile]/dt is the slope of the plot of the absorption of the
dienophile vs time during the first 5% of the reaction. The extinction
coefficients of the dienophile and the product were determined
separately under the same conditions as used in the kinetic runs. This
method has been successfully tested by comparing the results with rate
constants obtained by traditional pseudo-first-order kinetics. Typical
concentrations were [dienophile] ) 1 × 10-5 M, [cyclopentadiene] )
1 × 10-3 M, and [catalyst] ) 1 × 10-2 M. All rate constants were
measured at least three times. Those obtained by the traditional method
were reproducible to within 3%, whereas the initial rate method gave
a reproducibility of 5%.
Equilibrium Constants. Measurements were performed employing
a Perkin Elmer λ2, 5 or 12 UV-vis, spectrophotometer at 25 ( 0.1
°C. Equilibrium constants were determined by measuring the extinction
coefficient at a suitable wavelength of the partially complexed
dienophile (ꢀobs) as a function of the concentration of metal ion. The
following expression can be derived:34
[M2+]/(ꢀdienophile - ꢀobs) ) Ka/(ꢀdienophile - ꢀcomplex) +
[M2+]/(ꢀdienophile - ꢀcomplex
)
Supporting Information Available: A listing of second-
order rate constants of the Cu2+-catalyzed reaction of 1a, 1b,
1d, and 1e with 2 in acetonitrile, ethanol, water and 2,2,2-
trifluoroethanol as well as second-order rate constants and
After determining the extinction coefficient of the uncomplexed
dienophile (ꢀdienophile), [M2+]/(ꢀdienophile - ꢀobs) was plotted versus [M2+
]
yielding a straight line. The equilibrium constant now equals the ratio
intercept/slope of this line. Very accurate measurements of the
extinction coefficients are a prerequisite for obtaining reliable equi-
librium constants. Crucial in this respect were the choice of the
wavelength and the choice of the appropriate metal-ion concentrations.
The most accurate results were obtained at the wavelength of maximal
equilibrium constants for the Co2+-, Ni2+-, Cu2+-, and Zn2+
-
catalyzed reaction of 1a, 1b, 1d, and 1e with 2 in water at 2.00
M ionic strength (1 page). See any current masthead page for
ordering information and Internet access instructions.
Acknowledgment. We gratefully acknowledge financial
support from the Research School “Netherlands Institute for
Catalysis Research”.
(33) Frost, A. A.; Pearson, R. G. Kinetics and Mechanism; Wiley: New
York, 1961; p 45.
(34) Hartley, F.R.; Burgess, C.; Alcock, R. Solution Equilibria; Wiley:
New York, 1980.
JA960318K