Hydrophobic acceleration in the Diels—Alder reaction of 9-hydroxymethylanthracene with N-phenylmaleimide

Article abstract of DOI:10.1007/s11172-016-1568-8

The Diels—Alder reaction rates of 9-hydroxymethylanthracene with N-phenylmaleimide and N-ethylmaleimide in water, butan-1-ol, ethylene glycol, acetonitrile, chloroform, and 1,4-dioxane have been compared.

Full text of DOI:10.1007/s11172-016-1568-8

Russian Chemical Bulletin, International Edition, Vol. 65, No. 9, pp. 2202—2205, September, 2016
2202
Hydrophobic acceleration in the Diels—Alder reaction of
9ꢀhydroxymethylanthracene with Nꢀphenylmaleimide
V. D. Kiselev,а H. A. Kashaeva,а L. N. Potapova,а D. A. Kornilov,а L. I. Latypova,а and A. I. Konovalovb
aA. M. Butlerov Institute of Chemistry of Kazan Federal University,
18 ul. Kremlyovskaya, 420008 Kazan, Russian Federation.
Fax: +7 (843) 292 7278. Eꢀmail: vkiselev.ksu@gmail.com
bA. E. Arbuzov Institute of Organic and Physical Chemistry of Kazan Scientific Center of Russian Academy of Sciences,
8 ul. Arbuzova, 420008 Kazan, Russian Federation.
Fax: +7 (843) 273 1872
The Diels—Alder reaction rates of 9ꢀhydroxymethylanthracene with Nꢀphenylmaleimide
and Nꢀethylmaleimide in water, butanꢀ1ꢀol, ethylene glycol, acetonitrile, chloroform, and
1,4ꢀdioxane have been compared.
Key words: the Diels—Alder reaction, hydrophobic acceleration, Nꢀphenylmaleimide.
Scheme 1
Several ways to increase the Diels—Alder reaction
(DAR) rate are known.1,2 Formation of strong n,vꢀcomꢀ
plexes (donorꢀacceptor complexes) between the substituꢀ
ent heteroatoms in a dienophile, conjugated with a reacꢀ
tion center, and Lewis acids increases the reaction rate by
up to six orders of magnitude without changing the equiꢀ
librium constants.1,2 Performing the ring formation reacꢀ
tions under high hydrostatic pressure condition results in
an increase in both the rate and equilibrium constants.1—3
Carrying out the DAR in water4,5 did not attract much
attention until the kinetic measurements have not been
performed. Unexpected acceleration of the nonꢀpolar
DAR in water heightened interest both in the possibility of
applying water as a virtually safe ("green") and available
solvent and in studying the mechanism of the acceleration
effect.6—15 Currently, a lot of reaction types are known,
which are considerably accelerated in water.15 There is
described a novel approach to accelerate and modify
the reaction selectivity in a selfꢀassembled coordination
cage wherein the reagents were "pressed" due to the hydroꢀ
phobic effect14 as well as an application of a Vortex fluꢀ
idic device to remove molecules from the crystal surface
in water, which creates a pseudohomogeneous mediꢀ
um.16,17 Surprisingly high acceleration effects for cycloꢀ
pentadiene dimerization in water has been described.12
However, this acceleration probably comprises both the
reaction of cyclopentadiene molecules accumulated in
microdrops with a local concentration and the reaction in
the pure reagent.18
2, 3: R = Et (a), Ph (b)
The choice of diene 1 for studying the hydrophobic
effect is defined by its poor solubility in water (about
10–4 mol L–1), however due to the high adsorption coeffiꢀ
cient of diene 1 (lgε = 3.97, λ = 366 nm) this is sufficient
for the spectrophotometric control of the reaction. Higher
solubility of Nꢀethylmaleimide (2a) in water allows kinetꢀ
The rate of the DAR between 9ꢀhydroxymethylanꢀ
thracene 1 and Nꢀethylmaleimide 2а (Scheme 1) was thorꢀ
oughly studied in water, aqueous salt solutions, and in
conventional organic solvents.6—13
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 2202—2205, September, 2016.
1066ꢀ5285/16/6509ꢀ2202 © 2016 Springer Science+Business Media, Inc.

Diels—Alder reaction of Nꢀphenylmaleimide in water Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016 2203
(λ = 550 nm, 1,2ꢀdichloroethane). Residual absorption (30.5%)
corresponds to purity of compound 1 above 99%.
NꢀPhenylmaleimide (2b) (Aldrich) was used without further
purification.
ic measurements with a large access of the former relative
to a diene. Dienophile 2а proved to be rather stable to
hydrolysis in a neutral aqueous medium.19
Possible reasons of the hydrophobic acceleration of
the DARs have been considered. In most cases, DARs are
known to proceed faster in chloroform because of activaꢀ
tion of dienophiles due to the formation of Нꢀbonds.1,2,20—22
Trifluoroethanol was noted to form more strong Нꢀbonds
compared to water. However, the reaction rate in water is
nearly 60 times higher.12,13 In the reaction 1+2a, the rate
constant (L mol–1 s–1, 45 °C) decreases among the solꢀ
vents: isoꢀoctane (7.96•10–3), butanꢀ1ꢀol (6.66•10–3),
methanol (3.44•10–3), and acetonitrile (1.07•10–3).6,9,11
Therefore, a considerable acceleration of the reaction in
water can be explained neither by the elevated polarity of
solvent nor by the formation of hydrogen bonds beꢀ
tween the molecules of water and dienophile. The reason
for the acceleration of reactions in water is considered
to be an enhanced probability of association between
reacting nonꢀpolar species due to the hydrophobic
effect.6,11 Data on changing the solvation free energy
of the reactants and activated complex in the DAR
between cyclopentadiene and ethylvinylketone in a series
of solvents corresponds to the considerable increase in
the free energy of the reactants in aqueous solution
with a minor change in the free energy of the activated
complex.12
Stability of solutions of 1 and 2b in studied organic solvents
was examined recording their UV spectra (Hitachi Uꢀ2900) during
several days. Diene 1 is stable in water, while dienophile 2b
slowly hydrolyzes to give amino acid 4 (see Scheme 1).24
Kinetic measurements. All kinetic measurements were perꢀ
formed at 45 °C.
Preparation of the solution of diene 1 in water. Compound 1
(5—7 mg) was heated to reflux for 10—15 min with stirring in
50 mL of freshly distilled water, then cooled to 45 °C. Undisꢀ
solved crystals of 1 were removed by hot filtration. The solution
was heated to reflux under argon atmosphere to remove the
traces of carbon dioxide and recooled to 45 °C. Concentration of
the resulting solution of 1 was determined using the known data
on the absorption coefficient in water (ε = 9400, λ = 366 nm).25
In all measurements, the initial concentration of 1 in water was
(9—11)•10–5 mol L–1
.
Preparation of aqueous solutions of reactants 1 and 2b. Preꢀ
pared solution of the compound 1 in water (25 mL) was added
to the flask loaded with compound 2b (6.5 mg) at 45 °C and
stirred for 10 min at 45 °C until the complete dissolution of
compound 2b. Concentration of 2b in the reaction medium was
15 times higher than the concentration of diene 1 (Table 1),
therefore the rate constant for the formation of 3b was calculatꢀ
ed according Eq. (1)
k2•t•c2b,t = ln(D1,t=0/D1,t),
(1)
In the present study, we have investigated the reaction
between 1 and Nꢀphenylmaleimide (2b). Introduction of
the phenyl group can result in a change in the hydrophoꢀ
bic acceleration of the reaction in water relative to the well
characterized dienophile 2а. The rates of DAR 1+2b in
water, butanꢀ1ꢀol, ethylene glycol, acetonitrile, chloroꢀ
form, and 1,4ꢀdioxane were investigated.
wherein c2b,t is concentration of dienophile 2b at the time t,
D1,t=0 and D1,t are initial and current optical density of diene 1,
determined by subtracting the calculated absorption of dienoꢀ
phile 2b from the total absorption of the reactant solution.
Since there are two parallel reactions, namely, 2b + H2O → 4
and 2b + 1 → 3b, proceeding in an aqueous solution under given
conditions, it was necessary to determine the rate of the reaction
2b + H2O → 4.
These data were obtained from the change of absorption of
compound 2b in water at 45 °C at λ = 295 nm. The rate constant
for the formation of compound 4 was calculated from the relaꢀ
Experimental
9ꢀHydroxymethylanthracene (1) (97%, «Aldrich») was reꢀ
crystallized from benzene. M.p. 161—162 °C (cf. Ref. 23:
m.p. 159—161 °C). Purity of compound 1 was measured on
the final absorption of the solution in a fast reaction with 30%
molar excess of sublimated 4ꢀphenylꢀ1,2,4ꢀtriazolinꢀ3,5ꢀdione
tionship between ln(D2b) and t and was 1.2•10–6 L mol–1 s–1
.
This allowed calculation the current value c2b,t for Eq. (1) and
the constant rate for reaction 2b + 1 → 3b. It is known1,2 that the
rate of the DAR involving acyclic dienophiles is significantly
lower than that for the cyclic ones. Therefore, the contribution
Table 1. Initial concentrations of reactants 1 and 2b, wavelength for monitoring their absorbance, and
observed conversion of diene 1
Solvent
c1,t=0
c2b,t=0
λ/nm
Conversion
of diene 1 (%)
mol L–1
Acetonitrile
Ethylene glycol
Butanꢀ1ꢀol
Chloroform
1,4ꢀDioxane
Water
1.5•10–4
1.3•10–4
1.0•10–2
385.6
386.5
386.5
386.5
392—414
364.0
97
23
45
95
49
80
(8.0—10.0)•10–3
(7.6—8.0)•10–3
5.9•10–3
(1.3—1.5)•10–4
1.3•10–4
(7.0—13)•10–4
(9.0—11)•10–5
(1.05—2.16)•10–2
1.5•10–3

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Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016
Kiselev et al.
Table 2. Rate constants (k45/L mol–1 sec–1) for reactions 1 + 2a and 1 + 2b and ratio of the
reaction rate constants in water and an organic solvent (S) (kwater/kS)
Solvent
1 + 2aa
kwater/kS
1 + 2bb
k45
k45
kwater/kS
Water
0.226,
111
211
—
0.170, 0.184, 0.173, 0.170,
0.173 [0.174 0.004]
111
0.212c
Acetonitrile
Ethylene glycol
Butanꢀ1ꢀol
1.07•10–3
1.50•10–3, 1.56•10–3
114
178
124
[(1.53 0.03)•10–3
]
11—
2.30•10–3, 2.17•10–3
[(2. 24 0.06)•10–3
]
6.66•10–3
6.77•10–3 c
11—
,
134
7.24•10–3, 7.30•10–3
,
7.27•10–3 [(7.27 0.03)•10–3
3.41•10–3
]
Chloroform
1,4ꢀDioxane
—
—
151
109
11—
1.57•10–3, 1.62•10–3
[(1.59 0.03)•10–3
]
a Data of the study.6
b Data of the present study. There are mean values indicated in the square brackets.
c Data of the study.18
of reaction 1 + 4 might be neglected. Reaction 2b + 1 → 3b
proceeds in organic solvents without side processes.
tates the release of a part of the solvent molecules and
subsequent formation of weak intermolecular S—S interꢀ
actions. In the first case, removal of a part of the solvent
molecules from the solvation shell of the reactants is acꢀ
companied with more favorable water—water interaction.
In the solution of alkanes and particularly perfluoroalꢀ
kanes, the intermolecular diene—dienophile interaction
is usually stronger (more favorable) compared to S—S inꢀ
teraction.26 Therefore, in both cases one should expect an
increase in the DAR, this effect is to be more pronounced
in water. In 1,4ꢀdioxane at 25 °C, the rate constants
(L mol–1 s–1) for the reaction between compound 2b and
anthracene (7.2•10–6), 9ꢀmethylantracene (5.1•10–4) and
9,10ꢀdimethylantracene (3.0•10–2) differ significantly.1,2
Interestingly, in 1,4ꢀdioxane at 45 °C the rate constants
k45 (L mol–1 s–1) of the reaction between compound 2b
and 9ꢀhydroxymethylantracene (1.59•10–3, see Table 2)
and 9ꢀmethylanthracene (2.60•10–3) are rather close. This
means that the effect of the hydroxy group on the reaction
center through the methylene linker in diene 1 is low.
Since 9,10ꢀdimethylanthracene is nearly two orders of
magnitude more active than 9ꢀmethylanthracene,1,2 it
might be expected that more active 9,10ꢀdihydroxymethylꢀ
anthracene will allow obtaining kinetic data for the DAR
in water using a wide range of less active dienophiles.
In conclusion, it can be noted that in homogeneous
reaction 2b + 1 → 3b as well as in reaction 2a + 1 → 3a no
increase in a reaction rate on going to protonꢀdonating
solvents (alcohols) or more polar ones (acetonitrile, see
Table 2) is observed. Even more strong acceleration is obꢀ
served for the heterophase DARs in water on vigorous stirꢀ
ring: a jump in the rate in this case is accounted for the
reactants activation on the water—organic reactant phase
boundary.27—29
Results and Discussion
The kinetic data obtained are summarized in Table 2.
Dienophiles 2a and 2b have rather close reactivity
in the DAR towards 9ꢀhydroxymethylanthracene 1 (see
Table 2). It should be noted that no increase in the reacꢀ
tion rate in chloroform is observed, probably due to the
formation of the Нꢀbonds between the molecules of chloroꢀ
form and those of both reactants.
It is always necessary to remove a part of the solvent (S)
molecules surrounding the reaction centers of a diene and
a dienophile to produce an activated compex in the DAR
(Diene)•Sn + (Dienophile)•Sm
→
→ (Activated compex)•Sp +S(n + m – p).
In the case of an increased energy of interaction beꢀ
tween the reactants and a solvent compared to that for
solvent—solvent (hereinafter designated as "S—S"), the
achievement of the transition state will be hampered and
the reaction rate will decrease.20,21 Decreased interaction
energy for the reactants and a solvent, e.g., water, alkanes
or perfluoroalkanes, may result in an increased rate of the
DAR.26 Two extreme groups of solvents in terms of their
influence on the DAR rate can be distinguished: (1) a weak
bond between the molecules of reactants and water on
achieving the activated complex facilitates the release of
a part of the solvent molecules and subsequent formation
of strong intermolecular S—S interactions; (2) a weak bond
between the molecules of reactants and alkanes and perꢀ
fluoroalkanes on achieving the activated complex faciliꢀ

Diels—Alder reaction of Nꢀphenylmaleimide in water Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016 2205
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The present study was financially supported by the
Foundatition of the Governement of the Russian Federaꢀ
tion as part of the competitive development of the Kazan
Federal University.
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Received November 5, 2015;
in revised form April 15, 2016