Concerning the Regiochemical Course of the Diels-Alder Reaction in Supercritical Carbon Dioxide

Full text of DOI:10.1021/jo9704523

4530
J . Org. Chem. 1997, 62, 4530-4533
Sch em e 1
Con cer n in g th e Regioch em ica l Cou r se of
th e Diels-Ald er Rea ction in Su p er cr itica l
Ca r bon Dioxid e
Adam R. Renslo,† Randy D. Weinstein,‡
J efferson W. Tester,‡ and Rick L. Danheiser*,†
Departments of Chemistry and Chemical Engineering,
Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
solvation effects near the critical point can result in
dramatic changes in reaction selectivities. Notable prior
reports of selectivity effects in scCO2 include the subtle
effect on Diels-Alder stereoselectivity observed by Kim
and J ohnston7 and the somewhat more pronounced
effects on the stereo- and regiochemical course of the
photochemical dimerization of isophorone reported by
Hrnjez et al.4b More recently, Weedon and co-workers
have investigated the photo-Fries rearrangement of
Received March 12, 1997
The application of supercritical carbon dioxide as a
reaction medium for chemical synthesis has received
considerable attention recently.1,2 This interest has been
fueled largely by environmental and health consider-
ations, as CO2 is inexpensive, relatively nontoxic and
nonflammable, and poses minimal problems with regard
to waste disposal.3 Another potential advantage of
supercritical carbon dioxide (scCO2) as a reaction solvent
derives from the much greater compressibility of super-
critical fluids relative to liquids. In principle, important
solvent properties such as density, viscosity, and dielec-
tric can be dramatically varied simply through small
changes in pressure and temperature near the critical
point. Especially intriguing are the remarkable solvation
effects on rate and selectivity that have been observed
in scCO2 near the critical point;4 these effects have been
attributed to greater clustering of solvent molecules
around the solute in the near-critical region. The obser-
vation of such effects is not general, however, and likely
requires a reaction which occurs on a time scale in accord
with the lifetime of the integrity of the solvent cluster.5
The overall goal of our research in this area has been
to investigate the rate and selectivity of organic reactions
in supercritical CO2 with the aim of thereby laying the
groundwork for the wider application of scCO2 as a
solvent for organic synthesis. In earlier studies, we
demonstrated a direct correlation between reaction rates
and solution density in the Diels-Alder reaction of ethyl
acrylate and cyclopentadiene in scCO2.6 Recently we
have turned our attention to the question of whether
4e
naphthyl acetate in scCO2 and observed a significant
increase in the ratio of rearrangement to cage-escape
products (i.e. 1-naphthol) near the supercritical density
of the solution.
Perhaps the most striking report of unusual selectivity
effects in scCO2 is that of Ikushima and co-workers, in
which a reversal of the normal regiochemical course of
the Diels-Alder reaction was observed near the critical
pressure of CO2 at 50 °C (Scheme 1).8,9
The ability to alter the normal regiochemical outcome
of cycloadditions simply by varying reaction conditions
in scCO2 would certainly represent a significant develop-
ment for organic synthesis. We have consequently
undertaken a systematic investigation of the effect of
changes in scCO2 pressure and density on selectivity in
several important classes of organic reactions, and we
report herein the results of our study of the regiochemical
course of the Diels-Alder reaction in supercritical carbon
dioxide.
Resu lts a n d Discu ssion
Reactor Design an d Exper im en tal P r otocol. From
the outset of our studies it was recognized that the design
of the reaction vessel and related equipment would be
crucial in obtaining meaningful and reproducible results.
In particular, the ability to monitor phase behavior was
considered to be vitally important. Although the critical
point and phase behavior of pure CO2 is well known, the
phase behavior of mixtures is not well characterized.
Indeed, the addition of even small amounts of solute can
greatly alter phase behavior and the critical locus of the
solution.10 The design of our reactor therefore includes
a sapphire window which permits visual access to the
entire reactor interior and thereby allows for verification
of phase behavior. A more comprehensive description of
this reactor is provided in the Experimental Section.
† Department of Chemistry.
‡ Department of Chemical Engineering.
(1) Reviews: (a) Savage, P. E.; Gopalan, S.; Mizan, T. I.; Martino,
C. J .; Brock, E. E. AIChE J . 1995, 47, 1723. (b) Subramaniam, B.;
McHugh, M. A. Ind. Eng. Chem. Process Des. Dev. 1986, 25, 1. (c)
Morgenstern, D. A.; LeLacheur, R. M.; Morita, D. K.; Borkowsky, S.
L.; Feng, S.; Brown, G. H.; Luan, L.; Gross, M. F.; Burk, M. J .; Tumas,
W. ACS Symp. Ser. 1996, 626, 132.
(2) For recent examples, see (a) DeSimone, J . M.; Guan, Z.; Elsbernd,
C. S. Science 1992, 257, 945. (b) Reetz, M. T.; Ko¨nen, W.; Strack, T.
Chimia 1993, 47, 493. (c) Tanko, J . M.; Blackert, J . F. Science 1994,
263, 203. (d) J essop, P. G.; Ikariya, T.; Noyori, R. Nature 1994, 368,
231. (e) Burk, M. J .; Feng, S.; Gross, M. F.; Tumas, W. J . Am. Chem.
Soc. 1995, 117, 8277. (f) J essop, P. G.; Ikariya, T.; Noyori, R. Science
1995, 269, 1065. (g) J essop, P. G.; Hsiao, Y.; Ikariya, T.; Noyori, R. J .
Am. Chem. Soc. 1996, 118, 344.
(3) For discussions of the advantages of scCO2, see (a) Clifford, T.;
Bartle, K. Chem. Ind. 1996, 449. (b) Poliakoff, M.; Howdle, S. Chem.
Br. 1995, 31, 118. (c) Black, H. Environ. Sci. Technol. 1996, 30, 124A.
(4) (a) Debenedetti, D. G. Chem. Eng. Sci. 1987, 42, 2203. (b) Hrnjez,
B. J .; Mehta, A. J .; Fox, M. A.; J ohnston, K. P. J . Am. Chem. Soc. 1989,
111, 2662. (c) Roberts, C. B.; Chateauneuf, J . E.; Brennecke, J . F. J .
Am. Chem. Soc. 1992, 114, 8455. (d) Phillips, D. J .; Brennecke, J . F.
Ind. Eng. Chem. Res. 1993, 32, 943. (e) Andrew, D.; Des Islet, B. T.;
Margaritis, A.; Weedon, A. C. J . Am. Chem. Soc. 1995, 117, 6132.
(5) Roberts, C. B.; Zhang, J .; Brennecke, J . F.; Chateauneuf, J . E.
J . Phys. Chem. 1993, 97, 5618.
(7) Kim, S.; J ohnston, K. P. Chem. Eng. Commun. 1988, 63, 49.
(8) (a) Ikushima, Y.; Ito, S.; Asano, T.; Yokoyama, T.; Saito, N.;
Hatakeda, K.; Goto, T. J . Chem. Eng. J pn. 1990, 23, 96. (b) Ikushima,
Y.; Saito, N.; Arai, M. J . Phys. Chem. 1992, 96, 2293.
(9) The critical constants for carbon dioxide are Tc ) 31 °C, Pc ) 74
bar, Fc ) 0.46 g/cm3.
(10) (a) McHugh, M. A.; Krukonis, V. J . Supercritical Fluid Extrac-
tion, 2nd ed.; Butterworth-Heinemann: Boston, MA, 1994; Chapters
3 and 5. (b) Adrian, T.; Hasse, H.; Maurer, G. J . Supercrit. Fluids 1996,
9, 19. (c) Wendland, M., Hasse, H.; Maurer, G. J . Supercrit. Fluids
1994, 7, 245.
(6) Weinstein, R. D.; Renslo, A. R.; Danheiser, R. L.; Harris, J . G.;
Tester, J . W. J . Phys. Chem. 1996, 100, 12337. See also, Paulaitis, M.
E.; Alexander, G. C. Pure Appl. Chem. 1987, 59, 61.
S0022-3263(97)00452-0 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 13, 1997 4531
Ta ble 1. Regioselectivity of Diels-Ald er Rea ction s in
Ca r bon Dioxid e a n d Con ven tion a l Solven ts
(Table 1, entries 3, 4, 6) examined in the previous study.
Entry 4 represents the conditions under which the
dramatic reversal of regiochemistry had been reported
previously (74.5 bar, 50 °C). Significantly, under these
conditions we observed a two-phase mixture through the
reactor window. Analysis of the total reaction mixture
after four days revealed the formation of cycloadducts 1
and 2 in a ratio very similar to that obtained in
conventional media such as toluene (entries 1, 2); i.e.,
no dramatic reversal in Diels-Alder regioselectivity was
observed. Similarly, no deviation from the normal Diels-
Alder regioselectivity was found when the reaction was
conducted at 50 °C and 95.2 bar, the pressure at which
we first observed the formation of a single supercritical
phase (entry 5). Indeed, under all conditions examined,
the dramatic selectivity effects reported by Ikushima and
co-workers were not observed, and in addition, conversion
to products was consistently very low.
We believe that these results highlight the importance
of verifying phase-behavior when sampling a CO2 reaction
mixture. Ikushima and co-workers sampled aliquots of
reaction mixtures in which the phase behavior was
apparently not known with certainty (no visual access).
Although in pure CO2 a pressure of 74.5 bar at 50 °C
results in a homogeneous supercritical phase, a two-
phase mixture may be obtained when solutes (reactants
and/or products) are present. In light of our results with
the view-cell reactor, it is possible that the previously
reported experiments8 may have been conducted in a two-
phase region below the critical point of the mixture.
We next designed a series of experiments to probe
whether unusual selectivity effects might emerge in
reactions involving more electronically and more steri-
cally biased pairs of dienes and dienophiles. Ikushima
et al. had rationalized their regiochemical results on the
basis of steric effects, arguing that the clustering of
solvent molecules around the activated complex in the
near supercritical region in some fashion disfavors the
“more sterically stable” para isomer, resulting in the
preferential formation of the abnormal meta cycloadduct.
Theoretical chemists, on the other hand, have generally
employed electronic arguments based on molecular or-
bital methods to account for the stereo- and regiochemical
outcome of Diels-Alder reactions. The most popular
model, based on frontier molecular orbital theory,11 has
recently been the subject of criticism,12 and this has
encouraged consideration of alternative electronic models
for predicting selectivities in cycloadditions. In particu-
lar, the regiochemical course of the Diels-Alder reaction
has been discussed in terms of a non-synchronous cy-
cloaddition proceeding via an unsymmetrical biradicaloid
transition state,13 and other arguments have been ad-
vanced based on the matching of complementary reactiv-
ity surfaces14 and several variants of perturbational
molecular orbital theory.15 The modeling of solvent
effects on selectivity in Diels-Alder reactions has also
been the subject of much theoretical attention. In a classic
1962 paper, Berson et al. discussed solvent effects on
a
b
Isolated yield or yield estimated by 1H NMR analysis. Ratio
of isomers determined by H NMR and (GC-FID) analysis. c Two-
1
d
phase reaction mixture observed. Ratio could not be determined.
e Approximate ratio due to low conversion.
In our experiments we chose to sample the entire
reaction volume to ensure reproducible results. This was
accomplished by slow bubbling of the entire contents of
the reactor through diethyl ether and by thorough rinsing
of the reactor and sampling lines. Sampling a small
portion of a supercritical reaction mixture is reliable only
if the phase behavior of the mixture is known with
certainty (e.g., if it can be monitored visually), and if
control experiments verify that the sampling is repre-
sentative of the entire mixture.
Cycloa d d ition Stu d ies. Table 1 summarizes the
results of our systematic investigation of the regiochemi-
cal course of the Diels-Alder reaction in supercritical
carbon dioxide. We began our study by examining the
cycloaddition of methyl acrylate and isoprene, the reac-
tion for which a remarkable reversal of regioselectivity
had been reported by Ikushima and co-workers.8 Our
initial experiments were carried out under the same
conditions of pressure, temperature, and concentration
(11) (a) Fleming, I. Frontier Orbitals and Organic Chemical Reac-
tions; J ohn Wiley & Sons: London, 1976; pp 121-142.
(12) Dewar, M. J . S. J . Mol. Struct.: THEOCHEM 1989, 200, 301.
(13) Dewar, M. J . S.; Olivella, S.; Stewart, J . J . P. J . Am. Chem.
Soc. 1986, 108, 5771.
(14) Kahn, S. D.; Pau, C. F.; Overman, L. E.; Hehre, W. J . J . Am.
Chem. Soc. 1986, 108, 7381.
(15) (a) Bonati, L.; Moro, G.; Pitea, D.; Gatti, C. J . Mol. Struct.:
THEOCHEM 1990, 208, 235. (b) Craig, S. L.; Stone, A. J . J . Chem.
Soc., Faraday Trans. 1994, 90, 1663.

4532 J . Org. Chem., Vol. 62, No. 13, 1997
Notes
conducted in the near-supercritical region (entries 9, 13,
17), and for comparison, all cases were also evaluated at
117 bar and 50 °C (entries 10, 14, 18). In addition, higher
temperature runs were used to determine regioselectivity
under conditions that provide cycloadducts in syntheti-
cally useful yields (entries 11, 15).
The reaction of acrylate with 2-tert-butyl-1,3-butadi-
ene18 was examined first. We reasoned that the ratio of
isomers produced in the reaction of this diene in CO2
would be more sensitive to reaction conditions as com-
pared to isoprene if steric interactions dominate in
determining Diels-Alder regioselectivity as suggested by
Ikushima et al. In the event, however, little variation in
regioselectivity was observed under a variety of condi-
tions, with only a small temperature effect on selectivity
being noted. In particular, no dramatic reversal in the
regiochemical course of the reaction was observed near
the critical point of CO2.
Similar results were obtained when we turned our
attention to varying the electronic character of the diene
and dienophile substituents. The reaction of 2-(trimeth-
ylsiloxy)butadiene with methyl acrylate has previously
been reported to produce 5 and 6 in a ratio of 98:2.19 In
our hands, under identical conditions (refluxing toluene,
45 h, entry 12), 5 and 6 were formed in an 87:13 ratio as
determined by 1H NMR analysis. In carbon dioxide this
reaction proved very sluggish, affording only traces of 5
and 6 after 3 days at 50 °C (entries 13, 14). At 150 °C,
higher conversions were obtained (entry 15) with selec-
tivity similar to that observed in toluene (entry 12). The
last system examined involved the reaction of nitroeth-
ylene with isoprene. Surprisingly, under standard condi-
tions (benzene, BHT, 60 °C, entry 16) the expected Diels-
Alder adducts 7 and 8 were obtained in a ratio of 81:19
in contrast to the ratio of 95:5 reported previously under
identical conditions.20,21 When the reaction was con-
ducted in scCO2, very similar regioselectivity (84:16) was
observed (entries 17, 18). In these reactions the low
yields obtained are most likely due to polymerization of
the dienophile, since the reactions in CO2 were performed
in the absence of a radical inhibitor such as BHT.
F igu r e 1. Illustration of the view-cell reactor incorporating
sapphire window.
In summary, we have investigated the regiochemical
course of several Diels-Alder reactions in supercritical
carbon dioxide and conventional media. 1H NMR and
GC analyses of reactions carried out in CO2 have failed
to confirm the previously reported dramatic effect of
varying reaction conditions on Diels-Alder regiochem-
istry. We have described the design of a view-cell reactor,
features of which are crucial for the meaningful analysis
of reactions in supercritical media. In particular, the
ability to directly monitor phase behavior is vital when
studying reactions in scCO2 and we strongly recommend
incorporation of this feature into reactors designed for
such research. It seems possible that a combination of
unknown phase behavior and partial sampling of reaction
mixtures may have led to erroneous results in the earlier
F igu r e 2. Flow diagram of view-cell reactor and related
apparatus. For reactor peripherals see Figure 1.
endo/exo selectivity in terms of the relative solvation of
transition states with differing dipolar character.16 More
recently, several different versions of molecular orbital
theory have been applied to the problem of rationalizing
solvent effects on Diels-Alder selectivities.17
Table 1 presents the results of our study of steric and
electronic substituent effects on the regiochemical course
of the Diels-Alder reaction in scCO2. All experiments
were carried out under single-phase supercritical condi-
tions as determined by visual monitoring of reaction
mixtures. For each case, at least one experiment was
(18) Kugatova-Shemyakina, G. P.; Berzin, V. B. Zh. Org. Khim.
1971, 7, 290.
(19) J ung, M. E.; McCombs, C. A.; Takeda, Y.; Pan, Y.-G. J . Am.
Chem. Soc. 1981, 103, 6677.
(20) Ono, N.; Miyake, H.; Kamimura, A.; Kaji, A. J . Chem. Soc.,
Perkin Trans. 1 1987, 1929.
(21) Nitro alkenes are generally regarded to exert
a powerful
(16) Berson, J . A.; Hamlet, Z.; Mueller, W. A. J . Am. Chem. Soc.
1962, 84, 297.
(17) For a review, see Cativiela, C.; Garcia, J . I.; Mayoral. J . A.;
Salvatella, L. Chem. Soc. Rev. 1996, 25, 209.
directing effect on the regiochemical course of Diels-Alder reactions,
although exceptions have been noted in the reaction of certain nitro
olefins with isoprene: Roma´n, E.; Ban˜os, M.; Gutie´rrez, J . I.; Serrano,
J . A. J . Carbohydr. Chem. 1995, 14, 703.

Notes
J . Org. Chem., Vol. 62, No. 13, 1997 4533
study8 of the regiochemical course of the Diels-Alder
Rep r esen ta tive P r oced u r e (Am p ou les Meth od ). This
procedure was used for entries 9, 10, 13, 14, 17, and 18 (Table
1). Methyl acrylate (0.344 g, 4.0 mmol) and 2-tert-butyl-1,3-
butadiene (0.440 g, 4.0 mmol) were placed in separate oven-dried
ampoules and sealed under argon. The ampoules were placed
in the reactor (predried at 120 °C under positive argon pressure)
along with a magnetic stirbar. The reactor was sealed, placed
on a stirplate, and wrapped with heating tape. Low pressure
CO2 was passed through the system while the temperature was
raised to 50 °C over 8 min. The reactor was then pressurized
causing the ampoules to burst. After 3 days at 50 °C and 117
bar, the pressure in the reactor was slowly released through a
long narrow tube, the end of which was immersed in ca. 70 mL
of diethyl ether. Additional ether (ca. 30 mL) was used to rinse
the inside of the reactor and the sampling tube. The combined
ether solutions were dried over MgSO4, filtered, and concen-
trated at ca. 20 mmHg to provide 0.031 g (4%) of a colorless oil.
1H NMR and GC analyses revealed 3 and 4 in ratios of 69:31
and 68:32, respectively.
Rep r esen ta tive P r oced u r e (Dir ect F eed Meth od ). This
procedure was used for large scale reactions (entries 3-6).
Methyl acrylate (1.26 g, 14.6 mmol) and isoprene (1.99 g, 29.2
mmol) were placed in the predried reactor along with a stirbar.
The system was sealed, briefly flushed with CO2, and then
heated to 50 °C. The reactor was then pressurized, the reaction
was carried out for the required time, and the products were
then isolated and analyzed as described above.
Rep r esen ta tive P r oced u r e (F eed Lin e Meth od ). This
method was used (entries 11, 15) when significant polymeriza-
tion or degradation of the reactants took place during the reactor
heat up period. Methyl acrylate (0.344 g, 4.0 mmol) and 2-tert-
butyl-1,3-butadiene (0.440 g, 4.0 mmol) were placed in a feed
line connected to the predried reactor (see Figure 2). Low
pressure CO2 was flushed through the system via the feed line
bypass, while the temperature was raised to 150 °C. The reactor
was then pressurized by directing the CO2 through the feed line.
The reaction was carried out for the desired time, and the
products were then isolated and analyzed as described above.
reaction in supercritical CO2.
Exp er im en ta l Section
Ma ter ia ls. Isoprene and methyl acrylate were purchased
from Aldrich Chemical Company and purified by distillation.
Nitroethylene22 and 2-(trimethylsiloxy)butadiene19 were pre-
pared according to literature procedures. 2-tert-Butyl-1,3-buta-
diene was prepared as described by Korotkov and Roguleva23
except that dehydration was effected according to the general
method of Traynelis et al.24 Research Grade 5 carbon dioxide
was purchased from BOC gases.
In str u m en ta tion . 1H NMR spectra were recorded on Varian
XL-300 and Unity 300 spectrometers using a delay time of 10 s.
Gas chromatographic analyses were performed on a Hewlett-
Packard 6890 gas chromatograph with FID detector and DB wax
column. All reported GC ratios are the result of averaging three
measurements.
Rea ctor Design . The reactor (see Figure 1) has a working
volume of 25 mL and is constructed of 316 stainless steel with
a
design similar to that in use at Los Alamos National
Laboratory.1c The temperature limits of our reactor have been
increased by substituting copper gaskets for polymeric ones in
the window seals and using taper seals (High Pressure Equip-
ment Company) in the body of the reactor. These improvements
have allowed for reaction temperatures up to 250 °C and
pressures to 250 bar (or as high as 350 bar at ambient
temperature).
Sa m p le In tr od u ction . The methods for sample introduction
and sampling are important for obtaining reliable and reproduc-
ible results. A flow diagram for our system is shown in Figure
2. Reactants are sealed in oven-dried glass ampoules and placed
in the reactor along with a magnetic stirbar. After heating to
the desired temperature, pressurization of the vessel with CO2
causes the ampoules to rupture while the stirbar ensures
efficient mixing of the reactants. Alternatively, reactants may
be placed directly in the reactor or in feed lines, isolated from
the system. Upon pressurization, CO2 passes though the feed
lines and into the reactor. All three feed methods were shown
to give reliable results. Representative procedures for the three
methods used are given below.
Ack n ow led gm en t. We thank Clean Harbors Inc. of
Braintree, MA, and the Emission Reduction Research
Center for partial support of this work. We gratefully
acknowledge Dr. W. Tumas and S. Buelow (Los Alamos
National Laboratory) for advice on apparatus design
and Dr. J onathan Harris for contributions in the early
phases of this project.
(22) Ranganathan, D.; Rao, C. B.; Ranganathan, S.; Mehrotra, A.
K.; Iyengar, R. J . Org. Chem. 1980, 45, 1185.
(23) Korotkov, A. A.; Roguleva, L. F. Zh. Org. Khim. 1965, 1, 1180.
(24) Traynelis, V. J .; Hergenrother, W. L.; Livingston, J . R.; Vali-
centi, J . A. J . Org. Chem. 1962, 27, 2377.
J O9704523