Heck reactions in hydrothermal, sub-critical water: Water density as an important reaction variable

Article abstract of DOI:10.1016/S0040-4039(01)01860-3

Heck coupling reactions of iodobenzene and cyclohexene in sub-critical water illustrate the importance of water density as a reaction variable. Altering the water density from 0.03 to 0.84 g/mL and the reaction pressure from 30 to greater than 213 bar at 225°C changed both product and isomer yields. The multiple physical effects of water density were also explored by the addition of ionic salts. Changing the isothermal state of the liquid water, measurably altered coupling reaction pathways suggesting that changes in solvent-solute interactions can influence transition states favoring some configurations and disfavoring others.

Full text of DOI:10.1016/S0040-4039(01)01860-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8555–8557
Heck reactions in hydrothermal, sub-critical water: water density
as an important reaction variable
Liz U. Gron,* Jeanna E. LaCroix, Cortney J. Higgins, Karen L. Steelman and Amanda S. Tinsley
Department of Chemistry, Hendrix College, Conway, AR 72032, USA
Received 10 July 2001; revised 27 September 2001; accepted 1 October 2001
Abstract—Heck coupling reactions of iodobenzene and cyclohexene in sub-critical water illustrate the importance of water density
as a reaction variable. Altering the water density from 0.03 to 0.84 g/mL and the reaction pressure from 30 to greater than 213
bar at 225°C changed both product and isomer yields. The multiple physical effects of water density were also explored by the
addition of ionic salts. Changing the isothermal state of the liquid water, measurably altered coupling reaction pathways
suggesting that changes in solvent–solute interactions can influence transition states favoring some configurations and disfavoring
others. © 2001 Elsevier Science Ltd. All rights reserved.
The last decade has seen significant growth in the
development of water-based synthetic chemistry, reflect-
ing a new appreciation for the unique characteristics of
Characterizing hydrothermal water reactions, below the
critical point (100<T<373°C) requires careful selection
of temperature, pressure, and effective water density to
control the aqueous phase behavior and insure the
solubility of organics. Correlation between water den-
sity and physical properties, including pressure and
1
water as a solvent. These important traits include low
cost, improved safety, and environmental compatibil-
2
ity. Recently, synthetic chemists have begun to move
5
beyond traditional low-temperature, aqueous reactions
dielectric constant, are documented in standard tables.
(
T <100°C) to exploit the physical changes that occur in
In supercritical water, the reaction rates and product
distribution of cyclohexanol dehydration have been
water at higher temperatures and pressures. Although
only a few groups are working directly in this area, a
3
7
demonstrated to be very sensitive to water density.
variety of organic reactions have been demonstrated in
sub-critical water including rearrangements, dehydra-
However, water density has not previously been linked
to synthetic results at sub-critical conditions. This paper
examines the affect of altering water properties through
changes in the water density, at 225°C, on Heck cou-
pling reactions of iodobenzene and cyclohexene. In all
the cases studied, only a single fluid phase was present
so the effective water density corresponds exactly to the
mass of water in grams charged internally to the reactor
divided by the reactor volume in mL.
4
tions, and carbonꢀcarbon coupling reactions.
At high temperatures and pressures, the physical prop-
erties of water change dramatically from those found
under ambient conditions. For example, the dielectric
constant of water decreases from m=80 at STP, to
m=31 at 225°C, P=100 bar, and finally to m=6 at the
5
critical point, T =374.15°C, P =221.2 bar, due to the
c
c
steady decrease in the effectiveness of hydrogen bonds
6
with increasing temperature. This makes sub-critical
water a realistic alternative to traditional organic sol-
vents by removing important solubility barriers.
Returning the system to ambient conditions restores the
insolubility of organics, obviating the need for solvent-
intensive extractions.
In a typical reaction, 12 mL 316 stainless steel reactors
were loaded with 1 mmol of iodobenzene, 3 or 5 mmol
of cyclohexene, 3 mmol of NaOAc, 0.06 mol of
Pd(OAc) , and 0.36–10.1 g of water. In some experi-
2
ments, either 55 (±0.5) bar N at room temperature, or
2
0
.1 m of n-Bu NBr was also added. At 225°C, creation
4
of a homogeneous, compressed aqueous phase required
8
*
0
Corresponding author. fax: (501) 450-3829; e-mail: gron@
hendrix.edu
a minimum water density of 0.84 g/mL. The water
density was varied from 0.03 to 0.84 (±0.01) g/mL by
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01860-3

8
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L. U. Gron et al. / Tetrahedron Letters 42 (2001) 8555–8557
changing the amount of loaded water. The reactors
were sealed with a 1 mm titanium gasket, torqued to
a yield of 22% phenylcyclohexenes (entry 5). However,
the benefit of added pressure was lost in the homoge-
neous compressed aqueous systems, d=0.84 g/mL,
where the reaction yield decreased from 22% (entry 5)
1
2
40 ft/lb, attached to a shaker system, and heated to
25 (±1)°C for 20 min in a fluidized sandbath. Reac-
9
tions were quenched in an ice/water bath. Organics
were extracted with toluene and identified by capillary
GC–MS. Quantitation was performed by GC with
naphthalene, added after reaction work-up as an inter-
nal standard. An optically transparent cell, fitted with a
pressure transducer (±3 bar), was used to confirm the
to 15% (entry 4). The addition of N restored the yield
2
of phenylcyclohexenes by compensating for the pres-
sure lost by reducing the water density. Very high
pressures, 8 kbar, have been reported to improve Heck
1
1
reaction yields in organic solvent systems, T 5100°C.
The increased yields were attributed to decreased cata-
lyst precipitation due to catalyst stabilization by coordi-
nation of the solvent molecules. In the present work,
1
0
phase behavior of the reaction mixtures.
At homogeneous, compressed aqueous phase condi-
tions, the yield of the desired coupling products,
phenylcyclohexenes, was 21% (entry 1). With a water
density of 0.84 g/mL, the isomers were generated in
reaction yields were improved with modest N pressures
2
but the effect was limited to two-phase aqueous sys-
tems. This result is consistent with water’s superior
coordinating ability compared to that of typical organic
solvents.
8:31:62 ratios (1-phenylcyclohexene, 1:3-phenyl-cyclo-
hexene, 2:4-phenylcyclohexene, 3). As the water density
was reduced from 0.84 g/mL to 0.71 g/mL, the reaction
pressure dropped from 114 to 45 bar and a two-phase
reaction system, gas and liquid, was created. The
product yield declined from 21 (entry 1) to 12% (entry
In a separate series of experiments, the effect of multi-
ple phases within the reactor was probed by examining
the coupling of iodobenzene and cyclohexene in the
presence of n-Bu NBr. In traditional Heck reactions in
4
2
). This yield remained constant for all the reactions
with reduced water, 0.03–0.63 g/mL, 29<P<41 bar
entry 3). The percentage of undesirable side-products
organic solvents, the presence of a quaternary ammo-
nium salt is known to both increase yield and improve
12
(
selectivity. Systems containing nonvolatile, ionic salts
should be particularly sensitive to the aqueous phase
behavior. In homogeneous, compressed, aqueous phase
increased concomitant with the decreased water density.
Benzene yields increased from 4 to 9% and biphenyl
increased from 3 to 8%. The isomer ratios were unaf-
fected by changes in the water density and the yields
were not improved by vigorous stirring. Overall results
are summarized in Table 1.
reactions, d=0.84 g/mL, the addition of n-Bu NBr
4
increased the yield of phenylcyclohexenes from 21
(entry 1) to 47% (entry 8) and changed the isomer
distribution of the products. Without the quaternary
ammonium salt, isomer 3 was preferred, 8:31:62 (1:2:3)
In the above experiment, altering the water density
affected both the pressure and the distribution of water,
between compressed liquid and gaseous phases. In
order to separately probe these physical factors, 55 bar
(entry 1), while, after the addition of n-Bu NBr isomer
4
1 was preferred, 55:16:28 (1:2:3) (entry 8). These results
at homogeneous, compressed aqueous conditions were
surprisingly similar to the synthesis results from same
9
of N was added to increase internal reaction pressure.
reaction in typical organic solvents.
2
In reactions with reduced water density, N increased
2
the yield phenylcyclohexenes by about 60% (entries 5
and 6). The beneficial effect of the added nitrogen was
optimized at a density of 0.75 g/mL, which resulted in
The coupling of iodobenzene to cyclohexene in the
presence of n-Bu NBr proved to be very sensitive to the
4
amount of water in the reaction vessel. A modest
Table 1. Effect of water density at 225°C on coupling reactions of iodobenzene and cyclohexene with added pressure or
ionic salts
Entry
Reactant ratios
Additives
Water densitya
Internal pressure
(bar)
% Yieldb
Isomer ratiosc
(1:2:3)
(iodobenzene:cyclohexene)
1
2
3
4
5
6
7
8
9
1:5
1:5
1:5
1:5
1:5
1:5
1:5
1:3
1:3
1:3
1:3
1:3
1:3
–
–
–
0.84
0.71
0.03–0.63
0.84
0.75
0.58
0.17–0.40
0.84
0.75
0.67
114
45
29–41
\213
200
136
120–123
130
21
12
12
15
22
20
14
47
21
18
28
25
24
8:31:62
3:32:65
5:27:68
3:35:63
12:30:58
6:32:62
14:29:57
55:16:28
8:29:63
8:30:62
11:29:60
14:28:58
22:22:56
55 bar N2
55 bar N2
55 bar N2
55 bar N2
1 m n-Bu NBr
1 m n-Bu NBr
1 m n-Bu NBr
1 m n-Bu NBr
1 m n-Bu NBr
1 m n-Bu NBr
4
39
38
34
32
4
10
11
12
13
4
0.50
0.33
0.17
4
4
30
4
a
b
c
Water density (d)=grams of water/mL of reactor volume.
Yield of phenylcyclohexenes.
-Phenylcyclohexene (1):3-phenylcyclohexene (2):4-phenylcyclohexene (3).
%
1

L. U. Gron et al. / Tetrahedron Letters 42 (2001) 8555–8557
8557
reduction in water density from 0.84 g/mL to 0.75
g/mL, led to a 50% decrease in product yield. Interest-
ingly, this reduction in water density caused the
product isomer ratios (entry 9) to revert to those gener-
ated in reactions where the quaternary ammonium salt
was absent (entries 2 and 3). Further reduction in water
density caused an increase in the scrambling of the
product isomers (entries 10–13). The preference for
isomer 1 in the homogeneous compressed aqueous sys-
tem was lost with lower water density, despite the
presence of the quaternary ammonium salt. Even vigor-
ous agitation failed to improve the conversion or iso-
mer ratios. Experiments are presently underway to
investigate the origin of this effect.
on Undergraduate Research for her Summer Under-
graduate Research Fellowship.
References
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Acknowledgements
8. The phase behavior of water is critically dependent upon
the temperature and water density. Calculations for
homogeneous compressed water systems are based on
data for pure water in Ref. 5.
The authors gratefully acknowledge support from the
National
Science
Foundation
(CHE-9709224),
9. CAUTION: High-temperature and high-pressure reac-
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Research Corporation Cottrell College Science Award,
Research Corporation Department Development
Award, and the Donors of the Petroleum Research
Fund, administered by the American Chemical Society.
Additionally, A. Tinsley thanks the SILO Advisory
Council Undergraduate Research Fellowship (SURF)
program for support and J. LaCroix thanks the Council
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