High-pressure effect on organic reactions in fluorophobic media

Article abstract of DOI:10.1002/poc.601

The kinetic effect of fluorophobic interactions was examined in Diels-Alder reactions and the conjugate addition of amines to acrylonitrile at different pressures. Its magnitude is lower than for other solvophobic media (water, ethylene glycol). Activatio

Full text of DOI:10.1002/poc.601

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2003; 16: 265–270
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/poc.601
High-pressure effect on organic reactions in ¯uorophobic
media
GeÂrard Jenner* and Badra Gacem
Laboratoire de PieÂzochimie Organique (UMR 7123), Faculte de Chimie, Universite Louis Pasteur, 67008 Strasbourg, France
Received 28 October 2002; revised 10 December 2002; accepted 16 December 2002
ABSTRACT: The kinetic effect of fluorophobic interactions was examined in Diels–Alder reactions and the
conjugate addition of amines to acrylonitrile at different pressures. Its magnitude is lower than for other solvophobic
media (water, ethylene glycol). Activation volumes determined in perfluorohexane are less negative for Diels–Alder
cycloadditions owing to reduced fluorophobic interactions under pressure, in line with a former study. At variance, the
conjugate addition is more pressure sensitive in the fluorous medium owing to the combination of solvophobic
acceleration and enhanced electrostriction. Some synthetic applications of the multiactivation method (pressure
‡ fluorophobic activation) are presented with emphasis on the beneficial solvophobic properties of the fluorous
medium. Copyright  2003 John Wiley & Sons, Ltd.
KEYWORDS: fluorophobic effects; pressure; activation volume; Diels–Alder reaction; conjugate addition; Passerini
reaction
INTRODUCTION
medium effect in order to interpret DV* correctly,
particularly when mechanistic details are deduced.3
The occurrence of DVm* must be envisaged when rate
constants are solvent dependent. For example, in
ionogenic reactions or simply when the transition state
is more polar than the initial and final states, the polarity
of the medium influences reaction rate constants. This is
also the case when the reaction system is subjected to
solvophobic effects.4 Such effects were shown to result
from a concentration effect increasing the number of
intermolecular collisions and also from stabilization of
the activated complex by increased hydrogen bond
interactions if the formation of these bonds is possible.5
Solvophobic media for organic molecules are essentially
water or water-like media (formamide, glycols) and
fluorous hydrocarbons.
Perfluorohydrocarbons are unique as they show poor
miscibility and solvating power toward most organic
compounds. These properties have been exploited in
organic synthesis: fluorous biphase chemistry6 (a remark-
able recent application includes hydroformylation reac-
tions;7 in addition, it should be pointed out that
fluorophobic interactions may be observed only in non-
amphiphilic fluorous media; for reactions carried out in
the amphiphilic fluorous F-626 solvent, see Ref. 7d) and
use as a surfactant-like system in supercritical carbon
dioxide.8 A case of fluorophobic acceleration in the
Diels–Alder reaction of 9-hydroxymethylanthracene with
N-ethylmaleimide has recently been reported.9 It has also
been shown that perfluorous organic solvents accelerate
Michael reactions in solid-phase chemistry on resins.10
Solvophobic interactions result from the associative
The pressure dependence of rate constants ultimately
yields the activation volume DV*, the magnitude of
which describes the volume profile. However, DV* is
seldom a one-component expression. In fact, it is known
to be a composite quantity as it must accommodate two
main effects, the structural volume variation DVS* when
the reaction variable migrates from ground to transition
state and the environmental volume term DVm* resulting
from volume variations in solute–solvent interactions
when the molecules enter the transition state:1
Ã
Ã
ÁVà ˆ ÁVS ‡ ÁVm
ꢀ1†
This view seemed reasonably accepted until recently.
However, during the last decade, additional activation
volume components were reported, mostly connected
with DVm*.2 The idea is to consider not only electrostatic
interactions DVe*, but also to take into account
solvophobic interactions DVf* as
Ã
Ã
Ã
ÁVm ˆ ÁV" ‡ ÁVꢀ
ꢀ2†
It is therefore necessary to examine carefully the possible
*Correspondence to: G.-r. Jenner, Laboratoire de Pie´zochimie
Organique (UMR 7123), Faculte´ de Chimie, Universite´ Louis Pasteur,
67008 Strasbourg, France.
E-mail: jenner@chimie.u-strasbg.fr
Copyright  2003 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2003; 16: 265–270

266
G. JENNER AND B. GACEM
effect forcing the organic molecules together in order to
minimize the solvent–hydrocarbon interfacial area (e.g.
to remove the solvent-accessible non-polar surface area
in the transition state). In hydrophobic media, the kinetic
acceleration is due to (i) enforced hydrophobic interac-
tions,11 (ii) hydrogen bonding12 and (iii) electrostatic
interactions.13 It is generally not easy to distinguish
which effect is the main determining parameter of the
kinetic alteration. As an example, in the cycloaddition of
methyl vinyl ketone to isoprene, all three effects take part
as shown by a pressure study.14 At variance with water
and water-like solvents, perfluorohydrocarbons are
simpler structured liquids and, accordingly, fluorophobic
interactions are expectedly easier to understand. Owing
to their very low dielectric constant and solubility
parameter, polarity effects are non-existent and hydrogen
bonding properties extremely weak. If fluorophobic
acceleration is observed, the kinetic effect must be
ascribed to solvophobicity alone. A further advantage of
using such media lies in the fact that they do not react
with the quasi totality of reagents, at variance with
alcohols and, a fortiori, with water which is usually not
tolerated in many reactions.
Scheme 1
examined under pressure in our laboratory.14,15 All these
reactions are characterized by fairly negative activation
volumes. We first studied the solvent effect at atmos-
pheric pressure. In a second step, we report the pressure
effect in these reactions according to the medium.
The aim of this paper is to report our recent results on
the effect of pressure on possible fluorophobic interac-
tions and to correlate the results with previous DV* data
determined in dissociating and/or solvophobic media.
The synthetic aspect will also be considered.
Effect of solvent at ambient pressure
We followed the kinetics of the [4 ‡ 2] cycloaddition of
toluquinone to isoprene (reaction A) and the conjugate
addition of tert-butylamine to acrylonitrile (reaction D) in
different solvents of various polarities defined by their ꢁ2
values (cohesion energy density) (Scheme 1, Table 1).
The lowest rate constants are found in chloroform for
both reactions. Interestingly, the relative k ratios (r
values) are around 3 and 11 for the respective reactions in
perfluorohexane, despite the lower polarity. Although the
rate increase in the fluorous medium is relatively modest
compared with the corresponding r values in water and
RESULTS
Solvophobic interactions are directly related to the
solubility of reactants. Partial solubility is required to
observe reaction. However, there is no solvophobic effect
in reactions where the substrates are fully dissolved. For
the fluorous hydrocarbon, we selected a prototypical
fluorous medium, perfluorohexane, and for reactions, we
investigated Diels–Alder reactions and the conjugate
addition of amines to acrylic compounds previously
Table 1. Solvent effect in the Diels±Alder reaction and conjugate additiona
Diel–Alder reaction (reaction A)
Conjugate addition (reaction D)
105 k
rb
106 k
rb
Solvent
ꢁ2
35
86
104
154
161
208
213
369
547
C6F14
CHCl3
CH2Cl2
CF3CH2OH (TFE)
C2H5OH
CH3OH
HOCH2CH2OH
HCONH2
H2O
2.62
0.87
—
28.7
2.23
—
45
71
1270
3.0
1.0
—
33
2.6
—
52
82
17.8
1.6
1.9
—
—
6.1
87
11.1
1.0
1.2
—
—
3.8
54
165
820
103
683
1460
a
Conditions: P = 0.1 MPa, reaction A 303.5 K, reaction D 300.7 or 317.2 K (see Ref. 14); k is given in dm3 molÀ1 sÀ1
.
Copyright  2003 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2003; 16: 265–270

HIGH-PRESSURE EFFECT ON ORGANIC REACTIONS IN FLUOROPHOBIC MEDIA
267
prene ‡ methyl acrylate) (reaction B) and one inverse
electron demand reaction (hexachlorocyclopentadiene
‡ styrene) (reaction C) (Scheme 1).
According to Fig. 1, there is a minimum for r (in
CHCl3). The kinetic behavior of the four reactions
resembles the results reported for the Diels–Alder
cycloaddition between N-ethylmaleimide and 9-hydro-
xymethylanthracene.9 For the latter reaction, the mini-
mum is even more pronounced owing to the extremely
low solubility of both reactants in perfluorohexane, hence
resulting in enforced fluorophobic interactions.
Dependence of DV* on solvent
Figure 1. Semi-logarithmic plot of r against solubility
parameter ꢁ for four solvents [C6F14, CHCl3, (CH2OH)2,
H2O]. The r value for the styrene reaction in C6F14 is 2.41
As outlined in the Introduction, solvophobic interactions
affect DV*. In a previous study, we showed how DVm*
followed Eqn. (2).14 The situation can be rather complex
if the medium is water or a water-like solvent. Different
activation volume terms are possibly involved which act
in divergent ways during the progression of the reaction
towards the transition state. In these media DVf* itself
must acknowledge the volume expansion due to the
decrease of hydrophobic interactions and the volume
shrinkage ascribed to the promotion of hydrogen bonding
by pressure. It is expected that the activation volumes
determined for reactions carried out in fluorophobic
media would be simpler to interpret as DVf* should be
exclusively ascribed to solvophobic interactions. Accord-
ingly, we followed the kinetics of the reactions described
in the first part of the paper in the 0–100 MPa pressure
range (Table 2) using perfluorohexane as the medium.
The DV* values were compared with those previously
reported for the same reactions in other media14,15 (Table
3). The results are instructive. Overall, one can
distinguish three trends (within uncertainty limits):
water-like media, it is perceptible. In fact, according to
Hildebrand’s theory, in the absence of solvophobic
interactions the ratios should be less than unity. The k
ratios determined in C6F14 are indicative of the existence
of fluorophobic interactions. The rate increase with
increasing polarity of the medium must be interpreted
differently according to the reaction. The conjugate
addition is an ionogenic reaction with formation of
zwitterions, obviously promoted in a more polar medium.
Fluorophobic effects also intervene, as testified by the
higher k values in C6F14. On the other hand, the rate
increase in the Diels–Alder reaction is only partly due to
increased electrostatic interactions. This is highlighted by
comparison of the r values in ethanol and TFE, which
have similar ꢁ2 values. The r value is 2.6 in ethanol, but
about 33 in TFE. The latter alcohol is known to develop a
strong hydrogen-bonding network with carbonyl
groups.16 This is also the case for ethylene glycol,
formamide and water. Solvophobic interactions take also
much importance in these media, particularly in water
(ꢂ = 1460).
1. The conjugate addition of tert-butylamine (reaction D)
conforming to the expected electrostriction shows a
regular trend, e.g. a strong increase in DV* with
increasing polarity of the medium. DV* =
À65 cm3molÀ1 in C6F14, which is the least polar
medium (for a thorough description of electrostriction
In order to extend these results, we investigated the
kinetics of two other Diels–Alder cycloadditions, con-
sisting of one normal electron demand reaction (iso-
Table 2. Kinetic pressure effect on reactions A±D in per¯uorohexanea
Pressure (MPa)
A (303.5 K)
B (335.2 K)
C (323.3 K)
D (317.2 K)
0.1
2.62 Â 10À5
2.80 Â 10À6
2.32 Â 10À5
1.78 Â 10À5
25
2.95
3.85
3.11
3.38
35
3.74
4.35
3.41
3.85
50
4.10
5.15
4.27
5.23
60
—
—
—
6.28
75
4.22
6.62
4.85
8.33
100
—
8.65
6.47
—
(DV*)T (cm3molÀ1
)
À27
À36
À32
À65
k (in dm3 molÀ1 À1).
s
a
Precision of DV* values is estimated to be Æ 1.5 cm3molÀ1 for Diels–Alder cycloadditions and 10% in reaction D.
b
Copyright  2003 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2003; 16: 265–270

268
G. JENNER AND B. GACEM
Table 3. Dependence of the activation volume DVT* on solubility parameter ꢁ of the medium (cm3 molÀ1
)
Medium
ꢁ (cal cm3)À1/2
A (303.5 K)
B (335.2 K)
C (323.3 K)
D (317.2 K)
C6F14
5.9
9.27
12.7
14.4
14.6
23.39
À27
À39
À36
nd
À36
À39
nd
À32
À35
nd
À65
À55
nd
À35
À23
À25
CHCl3
C2H5OH
CH3OH
HCONH2
H2O
À38
À33
À33
nd
nd
nd
À37
À28
phenomena, see Ref. 17). However, considering also
the results detailed in Table 1, DV* should contain a
volume term due to fluorophobic interactions. This
volume is probably low, masked by the very negative
value for DV*.
reactions could be a means to overcome difficult
syntheses. Considering the results detailed above, the
kinetics of the multiactivation process (pressure
‡ solvophobic activation) should be regarded as a
compromise between (i) enhanced rate constant in
perfluorohexane vs organic solvents at ambient pressure,
and (ii) reduced sensitivity to pressure for isopolar
reactions making DVT* less negative in C6F14 than in
other solvents of low polarity.
We examined several types of reactions which occur
sluggishly or not at all under normal conditions (Diels–
Alder, Michael-like and Passerini reactions) (Scheme 2).
Table 4 reports the results. It should be pointed out that
the yields reported may change on varying the reagent
concentrations, owing to the heterogeneous, even bi-
phasic system, obtained by mixing the reagents with the
fluorous medium.
2. The Diels–Alder reaction between isoprene and
methyl acrylate (reaction B) is characterized by a
quasi insensitivity of DV* towards medium polarity.
This is in line with an earlier observation explained by
equally matched volume effects along the reaction
coordinate.14
3. Two Diels–Alder reactions (reactions A and C) exhibit
a maximum in the DV* diagram. For both reactions
fluorophobic interactions should be relatively impor-
tant leading to DVf* > 0, thereby increasing DV*. The
maximum is observed in weakly polar solvents such as
CHCl3.
According to Table 4, for each reaction, operation in
perfluorohexane improves the yield, although modestly
when compared with a solubilizing organic medium. The
improvement can certainly be ascribed fully or partly to
fluorophobic interactions. An interesting result is dis-
played in entry 1 (R = CH3). The addition of methyl vinyl
Application to high-pressure organic synthesis
Remembering the beneficial kinetic effect of hydro-
phobic interactions, fluorophobic activation of organic
a
Table 4. High-pressure (300 MPa) synthesis in C6F14
Entry
Medium
Type
Yield (%) Ref.
18
1 (R = H)b
CHCl3
C6F14
Diels–Alder
d° (idem)
17
40
17,19,20
1 (R = CH3)c CHCl3
C6F14
2
3
4
Michael-like
Diels–Alder
Diels–Alderd
d° (idem)
16
32
21
Acetone
C6F14
8e
13e
22
Propanol
C6F14
Michael-likef
d° (idem)
13
30
23
Pinacolone Passerinig
13
C6F14
d° (idem)
40
a
Total volume 2.5 ml. No reaction in the non-fluorous medium at 0.1 MPa
under the conditions used.
b
Furan 1.37 mmol, vinyl ketone 1.2 mmol, 30°C, 16 h.
c
Methylfuran 1.0 mmol, vinyl ketone 0.9 mmol, 30°C, 16 h.
d
Isoprene 0.75 mmol, 2,6-dimethylbenzoquinone 0.30 mmol, 20°C, 24 h.
The ratio of the two regioisomers (about 1:1) does not change with the
e
medium.
f
Cinnamonitrile 1.8 mmol, propanol 2.0 mmol, P(C4H9)3 0.3 mmol, 50°C,
24 h.
g
Benzoic acid 0.45 mmol, ketone 0.40 mmol, tert-butyl isocyanide
0.50 mmol, 25°C, 16.5 h.
Scheme 2.
Copyright  2003 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2003; 16: 265–270

HIGH-PRESSURE EFFECT ON ORGANIC REACTIONS IN FLUOROPHOBIC MEDIA
Table 5. High-pressure (300 MPa) synthesis in solvophobic mediaa
269
Reaction
Medium
Yield (%)
Endo (%)
Selectivity (%)b
Entry 1 (R = H)
Water
87
97
86
40
72
60
70
32
2
61
60
61
76
—
53
47
48
100
100
100
100
0
Formamide
Ethylene glycol
Perfluorohexane
Water
Entry 1 (R = CH3)
Formamide
Ethylene glycol
Perfluorohexane
Water
Ethylene glycol
Perfluorohexane
80
35
95
Entry 4 (Passerini reaction)
0
30
a
Conditions as in Table 4.
b
Chemoselectivity with respect to cycloaddition.
ketone to 2-methylfuran can proceed according to two
different pathways: [4 ‡ 2] cycloaddition (pathway A)19
or/and Michael-like addition (pathway B)17,20 (Scheme
2). The reaction in water or water-like solvents occurs
mostly (65–100%) according to pathway B, whereas the
situation is reversed in the fluorous medium (see Table 5).
We compared the yields obtained in different solvo-
phobic media (Table 5). The furan Diels–Alder reaction
(entry 1, R = H) proceeds chemoselectively in all
solvophobic media affording endo and exo cycloadducts.
This is a difficult reaction which occurs at ambient
pressure only under adequate catalytic activation.21 At
300 MPa the yields range from modest to excellent. In this
reaction, water and water-like media are more appropriate
than perfluorohexane. The endo preference is higher in the
latter owing to two factors, low polarity and the
solvophobic effect.24 The methylfuran Diels–Alder reac-
tion (entry 1, R = CH3), however, is better performed in
the fluorous medium since the chemoselectivity regarding
the cycloaddition is highest whereas only pathway B is
followed in water. This is ascribed to the negative
electrostatic potential developed around the oxygen atom
in methylfuran which is enhanced in water.25 The
selectivity results in ethylene glycol and formamide may
be related to small quantities of water whereas the
perfluorous compound is a highly demixing system.
At variance, the Passerini multicomponent reaction
described in entry 4 is a highly sterically hindered
reaction.23 It does not proceed in water and ethylene
glycol at 300 MPa. Perfluorohexane is the medium of
choice, making the multiactivation method as a useful tool
for the synthesis of sterically congested Passerini products
which could be of real interest as bioactive substances.26
and acrylonitrile were distilled before use. Other reagents
were used as received. Solvents were dried. Kinetic
measurements were performed as follows. Weighed
reagents and internal standard (1,2,3-trimethoxybenzene
or bibenzyl, depending on the reaction) were introduced
in PTFE tubes of large volume (15 ml) for the runs in
perfluorohexane. In order to obtain homogeneous values
of rate constants, the concentration of substrates was
chosen low enough (about 2 Â 10À3 mol dmÀ3). For runs
in the other solvents, 2.5 ml tubes were used. After
completing the residual volume with the solvent, the tube
was closed and vigorously shaken for about 30 s before
introduction into a thermostated (Æ0.1°C) high-pressure
vessel. After reaction, the non-fluorous solvents were
removed in vacuo, whereas the fluorous medium was
easily separated from the biphasic system and re-used in
1
subsequent runs. The residue was then analyzed by H
NMR spectroscopy (300 MHz). The kinetic data were
reproducible to better than 5% (runs in the fluorous
medium) and 2–3% (runs in the other solvents).
Activation volumes were determined in two ways: (i)
from the initial slope of the plot of log k against pressure
and (ii) from derivatization of the polynomial log
k = a ‡ bP ‡ cP2.
Synthetic runs
The synthetic runs reported in Tables 4 and 5 were
carried out in the same way as those described in Refs
17–23.
CONCLUSION
Fluorophobic effects are demonstrated in Diels–Alder
reactions and conjugate additions of amines to acrylic
compounds. Their intensity is lower than for other
solvophobic media such as water and water-like solvents.
The pressure effect in these reactions carried out in
EXPERIMENTAL
Kinetic determinations
Isoprene, styrene, methyl acrylate, methyl vinyl ketone
Copyright  2003 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2003; 16: 265–270

270
G. JENNER AND B. GACEM
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J. Phys. Org. Chem. 2003; 16: 265–270