Formaldehyde Encapsulated in Zeolite: A Long-Lived, Highly Activated One-Carbon Electrophile to Carbonyl-Ene Reactions

Article abstract of DOI:10.1021/ja039737p

Gaseous formaldehyde is extremely unstable and readily undergoes self-polymerization to a solid paraformaldehyde or disproportionation to methanol and formic acid in the presence of moisture. We disclose a simple method to stably store such a labile formaldehyde as a monomer in a nanoporous faujasite zeolite at 5 °C for at least 50 days without self-polymerization or disproportionation. The greater stability of formaldehyde encapsulated in zeolite was confirmed by ¹³C MAS NMR spectroscopy. Formaldehyde was not only stabilized within the zeolite cages but functioned as a powerful electrophile toward various olefins. Zeolite-encapsulated formaldehyde was proved to be a stable but highly reactive C1 reagent. Copyright

Full text of DOI:10.1021/ja039737p

Published on Web 02/10/2004
Formaldehyde Encapsulated in Zeolite: A Long-Lived, Highly Activated
One-Carbon Electrophile to Carbonyl-Ene Reactions
Takahiro Okachi and Makoto Onaka*
Department of Chemistry, Graduate School of Arts and Sciences, The UniVersity of Tokyo,
Komaba, Meguro, Tokyo 153-8902, Japan
Received November 22, 2003; E-mail: conaka@mail.ecc.u-tokyo.ac.jp
Traces of formaldehyde are found everywhere in nature; they
can be in the air, rain, streamwater, coal, or even wood smoke.
However, when formaldehyde is present in the atmosphere at ppm
levels, it can cause serious side effects such as sore throat, headache,
nausea, dizziness, atopic dermatitis, and other sick-house syndromes.
From the viewpoint of organic synthesis, formaldehyde is a
versatile one-carbon electrophile.1-3 However, its synthetic utility
is often limited by its intractableness because of a low boiling point
of -19.5 °C as well as its intrinsic instability because of a tendency
to rapidly polymerize to a solid paraformaldehyde. Therefore, for-
maldehyde is generally obtained by the depolymerization of parafor-
maldehyde or trioxane with thermal or Lewis acid treatment, just
prior to use.
Figure 1. 13C MAS NMR spectra acquired at 25 °C after the adsorption
of formaldehyde-13C on NaX and NaY: (a) HCHO-13C@ NaX, (b) HCHO-
13C@ NaX after storage in a refrigerator at 5 °C for 50 days, (c) HCHO-
13C@ NaY, (d) HCHO-13C@ NaY after storage in a refrigerator at 5 °C
for 50 days.
In 1990, Yamamoto et al. reported the generation of a stable
formaldehyde-bulky organoaluminum complex.3 The complex
enabled not only the carbonyl-ene reaction4 with olefins but the
addition of various nucleophiles in high yields. However, the
complex was not stable for a long time at 0 °C.3a Thus, it was
recognized that formaldehyde is difficult to preserve in a pure
monomer form under ambient conditions.
Here, we report the successful storage of formaldehyde using
zeolite, which suppresses self-polymerization and decomposition
without losing the reactivity of formaldehyde toward nucleophiles.
The zeolite-encapsulated formaldehyde (HCHO@zeolite) can now
be used as a highly reactive C1-electrophile in carbonyl-ene
reactions.
We selected commercially available X- and Y-type faujasite
zeolites (abbreviated as NaX and NaY, respectively) out of various
types of zeolites as a vessel for formaldehyde. NaX (Si/Al ) 1.5)
and NaY (Si/Al ) 2.7) zeolites, which have the same crystalline
structure and only differ in their ratio of Si and Al atoms, have the
following features: (i) they have interconnected supercages of 1.3
nm in diameter with pore windows of 0.74 nm in diameter, which
are large enough to let in various organic compounds; (ii) they
enable accelerated organic reactions due to the intrinsic acidity and
basicity of NaX and NaY, which are dependent on the ratio of Si
and Al atoms in the zeolite framework;5 and (iii) they specifically
react with reactants and products of select shape or select transition
states due to the uniform, three-dimensional structure of the zeolite
supercage in which the organic reactions proceed.6
At first, we investigated 13C-labeled formaldehyde encapsulated
in NaX and NaY by 13C MAS NMR (75 MHz) at 25 °C. In the 13
C
MAS NMR spectra of HCHO-13C@NaX (Figure 1a), we observed
a sharp single peak at 207 ppm which was identified as that of a
formyl carbon.8a Two small broad peaks at 91 and 81 ppm were
observed and assigned as those of a paraformaldehyde and
formaldehyde hydrate (CH2(OH)2) moiety, respectively.8 The
chemical shift (207 ppm) of formaldehyde adsorbed on NaX, which
was previously reported,8a was that of formaldehyde in the presence
of excess paraformaldehyde, but that shown in Figure 1a demon-
strates the example of formaldehyde exclusively adsorbed to NaX.
The formyl carbon of HCHO-13C@NaY appeared at 202 ppm,
and other related compounds such as paraformaldehyde, formal-
dehyde hydrate, methanol, and formic acid were scarcely detected
on NaY (Figure 1c).
Surprisingly, the signal patterns of HCHO@NaX and
HCHO@NaY remained unchanged after storage in a refrigerator
at 5 °C for 50 days (Figure 1b and d). This result demonstrates the
high stability of formaldehyde in the supercages of NaX and NaY
and the tendency not to polymerize or disproportionate.
Formaldehyde incorporated in NaX and NaY shows slightly
different chemical shifts at 207 and 202 ppm, respectively, which
presages a difference in their reactivity to nucleophiles. We
examined the carbonyl-ene reactions of various olefins with
HCHO@zeolite to evaluate its reactivity (eq 1 and Table 1).
HCHO@NaX and HCHO@NaY were easily prepared. Powdery
NaX or NaY zeolite was placed in a flask, and gaseous formalde-
hyde generated by the thermal depolymerization of paraformalde-
hyde (or 99% 13C-enriched paraformaldehyde, Cambridge Isotopes)
was passed over the zeolite at 0 °C. Maximum adsorption of HCHO
was observed with equivalent units of HCHO one-half that of
sodium cations in the zeolite (about 72 mg of HCHO per g of NaX
or NaY). This corresponded to three to four HCHO molecules per
supercage.7
The carbonyl-ene reaction of R-methylstyrenes using HCHO@NaY
proceeded smoothly and in excellent yields (entries 1 and 5), which
9
2306
J. AM. CHEM. SOC. 2004, 126, 2306-2307
10.1021/ja039737p CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Carbonyl-Ene Reactions Using HCHO@NaYa
Zr(Ot-Bu)4/diisopropyl tartrate/cumene hydroperoxide/molecular
sieves, which was a key intermeditate for the synthesis of
Tachykinin receptor antagonists (8).11
In summary, we demonstrated that ubiquitous faujasite zeolite,
NaY, which forms uniform supercages of nanosize, can preserve
labile formaldehyde in a monomeric form for a long period of time
at ambient temperatures and can also activate the formaldehyde
sufficiently enough to react with various olefins. The application
of HCHO@zeolite to other nonionic nucleophiles is underway.12
Acknowledgment. We are grateful to Dr. K. Fujimoto (Process
Development Laboratories, Sankyo Co., Ltd.) for helpful discussions
and encouragement throughout this work.
a HCHO@NaY (HCHO content 2.4 mmol/g). b Solvent: cyclohexane.
c Solvent: cyclohexane/hexane
)
9/1. d Solvent: hexane. e Use of
HCHO@NaY stored at room temperature for 30 days. f Use of HCHO@NaX
(HCHO content 2.4 mmol/g). g Reacted with gaseous HCHO without zeolite.
h See ref 3b.
Supporting Information Available: Experimental procedures and
spectroscopic data (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
had been difficult to achieve efficiently by using typical Lewis
acids.2 More interestingly, the reaction with HCHO@NaY, which
had been kept at room temperature for 30 days, afforded a
comparable yield (entry 2). This proves that active HCHO can
survive in NaY even at room temperature for at least 30 days
without any loss of reactivity. In contrast, HCHO@NaX was much
less reactive in the same reaction even though monomeric form-
aldehyde was similarly incorporated in supercages of NaX (entry
3).9 We suppose that this is due to the lower acidity of NaX as
compared to that of NaY. It was also confirmed that a simple
treatment of olefin with gaseous formaldehyde without NaY gave
no ene adducts (entry 4). This result strongly supports the fact that
formaldehyde in HCHO@NaY is stabilized and simultaneously
activated inside the zeolite supercages, which increases its elec-
trophilicity.
The reaction of trisubstituted and cyclic olefins with HCHO@NaY
afforded the corresponding ene products in good yields (entries
6-8), but unfortunately with low selectivity (entry 7). In the case
of limonene, there was a large difference in selectivity between
HCHO activated by Lewis acids and HCHO@NaY (entry 8).
Dimethylaluminum chloride and a much bulkier organoaluminum
reagent, MAPH (methylaluminum bis(2,6-diphenylphenoxide)),
induced the reaction preferentially at the olefinic site on the side
chain of limonene.3b On the other hand, the reaction of limonene
with HCHO@NaY predominantly gave ene adduct 4 with good
selectivity and in high yield. This selectivity seems to be derived
from the particular affinity of a NaY supercage to a cyclic
hydrocarbon over a linear one.10
References
(1) (a) Angelo, J.; Stork, G. J. Am. Chem. Soc. 1974, 96, 7114. (b) Hajos, Z.
G.; Parrish, D. R. J. Org. Chem. 1973, 38, 3244. (c) Lucast, D. H.;
Wemple, J. Synthesis 1976, 724. (d) Stork, G.; Isobe, M. J. Am. Chem.
Soc. 1975, 97, 4745.
(2) (a) Snider, B. B. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, pp 527-561.
(b) Okachi, T.; Fujimoto, K.; Onaka, M. Org. Lett. 2002, 4, 1667.
(3) (a) Maruoka, K.; Concepcion, A. B.; Hirayama, N.; Yamamoto, H. J.
Am. Chem. Soc. 1990, 112, 7422. (b) Maruoka, K.; Concepcion, A. B.;
Murase, N.; Oishi, M.; Hirayama, N.; Yamamoto, H. J. Am. Chem. Soc.
1993, 115, 3943.
(4) (a) Mikami, K.; Terada, M.; Shimizu, M.; Nakai, T. J. Synth. Org. Chem.,
Jpn. 1990, 48, 292. (b) Mikami, K.; Shimizu, M. Chem. ReV. 1992, 92,
1021.
(5) NaX containing more aluminum atoms is more basic than NaY; NaX has
a less acidic character than NaY.
(6) (a) Breck, W. Zeolite Molecular SieVes; John Wiley & Sons: New York,
1974. (b) Baerlocher, C.; Meier, W. M.; Olson, D. H. Atlas of Zeolite
Framework Types, 5th ed.; Elsevier: New York, 2001. (c) Izumi, Y.;
Urabe, K.; Onaka, M. Zeolite, Clay, and Heteropoly Acid in Organic
Reactions; Kodansha: Tokyo, 1992.
(7) Freeman, J. J.; Unland, M. L. J. Catal. 1978, 54, 183.
(8) (a) Sefcik, M. D. J. Am. Chem. Soc. 1979, 101, 2164. (b) Philippou, A.;
Anderson, M. W. J. Am. Chem. Soc. 1994, 116, 5774. (c) Hunger, M.;
Schenk, U.; Weitkamp, J. J. Mol. Catal. A: Chem. 1998, 134, 97. (d)
Hunger, M.; Schenk, U.; Weitkamp, J. J. Mol. Catal. A: Chem. 2000,
156, 153.
(9) By using HCHO@CaA and HCHO@Na-mordenite, no carbonyl-ene
adducts were obtained.
(10) (a) Eberly, P. E.; Baker, L. E. J. Appl. Chem. 1967, 17, 44. (b) Wu, P.;
Ma, Y. Zeolites 1983, 3, 118.
(11) (a) Okachi, T.; Murai, N.; Onaka, M. Org. Lett. 2003, 5, 85. (b) Nishi,
T.; Ishibashi, K.; Takemoto, T.; Nakajima, K.; Fukazawa, T.; Iio, K.;
Mukaiyama, O.; Yamaguchi, T. Bioorg. Med. Chem. Lett. 2000, 10, 1665.
(12) Ionic reagents such as RMgX are not proper as a nucleophile toward
HCHO@zeolite because the aluminosilicate framework of zeolites with
a high Al content such as NaX and NaY is fragile under such strongly
basic conditions.
Carbonyl-ene product 6 was able to be transformed to a chiral
epoxide 7 in 93% yield with 89% ee by a combination of
JA039737P
9
J. AM. CHEM. SOC. VOL. 126, NO. 8, 2004 2307