Zwitterion from a cyclopropane with geminal donor and acceptor groups

Article abstract of DOI:10.1021/ol063021s

2,2-Dimethoxy-3,3-dicyanospiro[cyclopropane-1,9′-[9H]fluorene] reacted fast with methanol to afford 9-trimethoxymethyl-9-dicyanomethyl-9H- fluorene. Reaction with benzaldehydes also gave products of cyclopropane ring opening. Strong electron-donor p-subst

Full text of DOI:10.1021/ol063021s

ORGANIC
LETTERS
2007
Vol. 9, No. 4
695-698
Zwitterion from a Cyclopropane with
Geminal Donor and Acceptor Groups
Anna Sliwinska, Wojciech Czardybon, and John Warkentin*
Department of Chemistry, McMaster UniVersity, Hamilton, Ontario L8S 4M1, Canada
warkent@mcmaster.ca
Received December 14, 2006
ABSTRACT
2,2-Dimethoxy-3,3-dicyanospiro[cyclopropane-1,9′-[9H]fluorene] reacted fast with methanol to afford 9-trimethoxymethyl-9-dicyanomethyl-9H-
fluorene. Reaction with benzaldehydes also gave products of cyclopropane ring opening. Strong electron-donor p-substituents or a strong
attractor enhanced the rate. Ring opening of the cyclopropane to a zwitterion that recloses or reacts with an aryl aldehyde, to form either a
CO or a CC bond first, can explain the result. The former mode of closure is sensitive to p-substituents because they are directly conjugated
to the positive charge at the benzylic carbon of the former aldehyde. The latter mode is sensitive to the ground-state electrophilicity of the
carbonyl carbon of the former aldehyde. Thus, reaction of the cyclopropane with p-substituted aldehydes is accelerated by either electron-
donor or -acceptor substituents.
Dimethoxycarbene (DMC) is nucleophilic,1,2 and it reacts with
electrophilic alkenes bearing four electron-withdrawing groups3
by an unknown mechanism (Scheme 1). A stepwise cycload-
In any case, the cyclopropane expected from such a
cycloaddition has never been isolated, raising the question
as to whether such cyclopropanes are inherently unstable,
possibly because they undergo reversible ring opening to a
zwitterion, even in relatively nonpolar solvents (Scheme 2).
Scheme 1
Scheme 2
dition mechanism has been proposed,3 but electron transfer
followed by bond formation are among other possibilities.
Zwitterions are postulated intermediates in some of the
well-known synthetic applications of donor-acceptor cy-
clopropanes.4,5 We now report the isolation and properties
of two cyclopropanes that might be disposed toward such
ring openings.
(1) Hoffmann, R. W. Angew. Chem. 1971, 83, 595; Angew. Chem., Int.
Ed. 1971, 10, 529.
(2) Moss, R. A.; Wlostowski, M.; Shen, S.; Krogh-Jespersen, K.; Matro,
A. J. Am. Chem. Soc. 1988, 110, 4443.
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Dicyanomethylene compounds 3 and 7 were synthesized
by means of the reaction of fluorenone and adamantanone,
respectively, with malononitrile,6 and dimethoxycarbene (2)
was generated by thermolysis of the 5-methyl-5-[p-methox-
yphenyl] oxadiazoline precursor 1.3 Compound 3 reacted
with DMC (2) in benzene at 50 °C to afford cyclopropane
4 (Scheme 3) as indicated by means of NMR spectroscopy
and X-ray crystallography.
Scheme 5
Cyclopropane 8 also reacted with methanol but at a much
slower rate. After 72 h at 50 °C, there was 90% conversion
of the substrate to ester 10 (Scheme 6).
Scheme 3
Scheme 6
Reaction of 4 with CD3OH and CD3OD (1:1) did not
afford a meaningful kinetic isotope effect because the
dicyanomethine proton of 9 exchanged in the medium.
Dicyanomethane also exchanged its protons for deuterons
under the same conditions.
It was difficult to obtain good crystals of 4. Attempts to
purify it by chromatography on silica or by crystallization
of crude 4 from hot toluene led to its conversion to 6 (Scheme
3). Nearly pure 4 was obtained by washing the crude material
with hexane, thereby removing most of the p-methoxyac-
etophenone that comes from the oxadiazoline. Crystallization
of 4 from hot, dry hexane was ultimately achieved.
Dicyanomethylenadamantane (7) added 2 to form the more
hindered 8 that could be purified by chromatography on silica
and recrystallized from hexane without any appreciable
reaction (Scheme 4).
Scheme 4
Figure 1. X-ray structure of the unit cell of 4.
An X-ray crystal structure of 4 (Figure 1) showed that
the unit cell contains two molecules. In molecule A, the C1-
C2, C1-C3, and C2-C3 bond lengths are 1.544(3), 1.494-
(3), and 1.600(2) Å, and in molecule B, they are 1.542(3),
1.492(2), and 1.608(2) Å (Scheme 3).
Bond lengths in the cyclopropyl group of 8 were very
similar to those of the corresponding bonds in 4. The
structures suggest that, in the solid state, the species are not
at all zwitterionic and that unhindered cyclopropanes such
as 4 may form zwitterions only if the polar groups can be
The high reactivity of 4 could mean that it is equilibrated
in solution with the corresponding zwitterion 5. In fact, 4
reacted very rapidly with anhydrous methanol, at room
temperature, to afford 9, and the reaction was over before
an NMR scan could be made (Scheme 5).
(3) Zhou, H.; Mloston, G.; Warkentin, J. Org. Lett. 2005, 7, 487.
(4) Reissig, H.-U.; Zimmer, R. Chem. ReV. 2003, 103, 1151.
(5) Graziano, M. L.; Cimminiello, G. J. Chem. Res. (S) 1989, 42.
(6) Mirek, J.; Adamczyk, M.; Mokrosz, M. Synthesis 1980, 296.
696
Org. Lett., Vol. 9, No. 4, 2007

adequately solvated. The lower reactivity of 8 toward
methanol might be attributed to steric hindrance to rotation
and solvation in the corresponding zwitterion, which would
affect heterolytic bond scission of 8.
Attempts to cis/trans equilibrate unsymmetrically substi-
tuted cyclopropanes 12a-c in solution in the manner of
Chmurny and Cram7 failed. Treatment of 11a with ethoxy-
(methoxy)carbene at 50 °C did not afford 12a but only the
five-membered ring 13 (Scheme 7). Equilibration of 12b-c
handling by means of glove bag techniques, was effective.
Excellent pseudo first-order plots, with aldehyde in 20-fold
excess over the cyclopropane, were obtained with benz-
aldehyde 14a as well as with p-F, p-Cl, p-Me, and p-OMe
benzaldehydes in benzene-d6 at room temperature, by means
1
of H NMR spectroscopy at 600 MHz. p-Me2NC6H4CHO
reacted much too quickly, and p-O2NC6H4CHO was too
insoluble in benzene at 20-fold excess. The second-order rate
constants were determined (equal concentrations of 4 and
aldehyde), and the pseudo first-order rate constants at a 20-
fold excess of aldehyde were estimated by multiplying the
experimental second-order rate constants by 20. Figure 2 is
Scheme 7
Figure 2. Plot of log (k/k0) vs σ+.
could not be attempted because ethoxy(methoxy)carbene
failed to add to 11b or 11c.
Advantage was then taken of the reaction of 4 with
benzaldehydes to afford 14 (Scheme 8). We thought that
a Hammett plot of log (k/k0) against the σ+ constants of the
substituents, where k and k0 are the pseudo first-order rate
constants for reaction of a substituted benzaldehyde and
benzaldehyde.
It is clear at once, whether σ or σ+ is chosen, that there is
a change of mechanism with substituent. The two electron-
donor and the p-nitro substituents accelerate the rate of
cycloaddition compared to the others. What could it mean?
A simple explanation would have p-nitrobenzaldehyde
react with the zwitterion to make a CC bond first, and p-MeO
and p-Me2N aldehydes make a CO bond first. Electron
transfer (ET) as the rate-limiting step is excluded because
the p-nitro compound, one of the faster reactants, should be
the poorest at transferring from its HOMO to the LUMO of
the cyclopropane.
Scheme 8
In view of the earlier postulates of zwitterionic intermedi-
ates from cyclopropanes with fewer than two donor groups
at one carbon and electron-withdrawing groups at another
and in view of the literature on zwitterionic intermediates,4,5,8-16
not neccessarily from cyclopropanes, we calculated the
barrier to bond heterolysis in 4. At the b3pw91/6-31g* level
there might be a substantial p-substituent effect that could
betray the mechanism by which 4 reacts with an aryl
aldehyde. The p-substituents chosen were H, F, Cl, Me, MeO,
Me2N, and NO2.
Stringent purification of the aldehydes was required
because any hydroxylic impurities, such as acids or H2O,
were known to react fast with the cyclopropane. Washing
of the aldehydes with dilute aqueous sodium carbonate was
not effective, presumably because of the Cannizzaro reaction.
In the end, vacuum distillation of the liquids under N2, and
(8) Nair, V.; Deepthi, A.; Poonoth, M.; Santhamma, B.; Vellalath, S.;
Babu, B. P.; Mohan, R.; Suresh, E. J. Org. Chem. 2006, 71, 2313.
(9) Nair, V.; Menon, R. S.; Sreekanth, A. R.; Abhilash, N.; Bijou, A. T.
Acc. Chem. Res. 2006, 39, 520.
(10) Nair, V.; Deepthi, A. Tetrahedron Lett. 2006, 47, 2037.
(11) Itoh, K.; Iwata, S.; Kishimoto, S. Heterocycles 2006, 68, 395.
(12) Cermola, F.; Di Gioia, L.; Graziano, M. L.; Iesce, M. R. J. Chem.
Res. 2005, 677.
(13) Esmaeili, A. A.; Zendegani, H. Tetrahedron 2005, 61, 4031.
(14) Young, I. S.; Kerr, M. A. Angew. Chem., Int. Ed. 2003, 42, 3023.
(15) Saigo, K.; Shimada, S.; Hashimoto, Y.; Hasegawa, M. Chem. Lett.
1989, 1293.
(7) Chmurny, A. B.; Cram, D. J. J. Am. Chem. Soc. 1973, 95, 4327.
Org. Lett., Vol. 9, No. 4, 2007
(16) Abdallah, H.; Gree, R.; Carrie, R. Tetrahedron 1985, 41, 4339.
697

of theory, the barrier to formation of a zwitterion in benzene,
with the charge-bearing groups substantially turned, is about
24.4 kcal mol-1 (Figure 3). Onsager’s method, in which the
the same energy and geometry as that in the unrestricted
mode. The latter would have permitted a singlet diradical
species, if that were of lower energy. We were unable to
find a transition state for direct reaction of 4 with benzal-
dehyde.
In summary, the fast reaction of 4 with p-MeO, p-Me2N,
and p-O2N benzaldehydes in benzene seems to fit with
reversible heterolysis of 4 to a zwitterion. There is a
considerable body of literature in which the existence of
zwitterions from less favorably substituted cyclopropanes has
been postulated, but there is no previous proof that such
zwitterions can exist in a solvent of relatively low ionizing
power. Computation indicated that the barrier to CC het-
erolysis of 4 in benzene is about 24.4 kcal mol-1. For
benzaldehydes to compete with reclosure of the zwitterion,
the activation energy for the aldehyde reaction has to be low
also.
Acknowledgment. We are grateful to Professor Jim
Britten, Dr. Laura Harrington, Erika Bellhouse, and Craig
Robertson (all at McMaster) for the X-ray work. SHARC-
NET graciously provided computation facilities to W.C.
(University of Madeira). This work was supported by
NSERC of Canada.
Figure 3. Potential energy vs reaction coordinate for zwitterion
formation from 4.
dielectric constant of the solvent is entered into the calcula-
tion, was used.17 Moreover, the calculation (gas phase) in
the restricted mode (electrons paired in the same orbital) gave
Supporting Information Available: Experimental data
for the reported reactions. This material is available free of
charge via the Internet at http://pubs.acs.org.
(17) (a) Onsager, L. J. J. Am. Chem. Soc. 1936, 58, 1486. (b) Kirkwood,
J. G. J. Chem. Phys. 1939, 7, 911. (c) Tapia, O.; Goscinski, O. Mol. Phys.
1975, 29, 1653. (d) Wong, M. W.; Wiberg, K. B.; Frisch, M. J. J. Am.
Chem. Soc. 1992, 114, 1645.
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