Atomic motions and protonation stereochemistry in nucleophilic additions to bicyclobutanes

Article abstract of DOI:10.1021/ja960370g

Several nucleophilic reactions on bicyclobutanes activated at the gehead carbon by electron withdrawing groups (SO₂Ph, CO₂Me, COPh, and CN) were performed in MeOH. In all cases, the less stable 1,3-disubstituted cyclobutanes isomer was preferentially obtained (compared to the equilibrium ratio). The results for the two charge localizing groups CN and SO₂Ph oppose the existing knowledge regarding the protonation stereochemistry of such carbanions. Ab initio calculations (6-31G*) have shown that as the nucleophile approaches the bicyclobutane, the bridgehead activating group moves inward toward an axial position. With a charge localizing group (CN and S(H)SO₂) the carbanion remains pyramidal, whereas with C(H)=O as an activating group, the carbanion is nearly planar. It is suggested therefore that under conditions where the carbanion undergoes rapid protonation, it is trapped in its initial pyramidal geometry. Whereas, in cases where the lifetime of the carbamon is long enough to allow appreciable equilibration, protonation may result in a different product distribution. This hypothesis was tested by slowing down the protonation rates. As a result, the more stable isomer was indeed preferentially obtained.

Full text of DOI:10.1021/ja960370g

5456
J. Am. Chem. Soc. 1996, 118, 5456-5461
Atomic Motions and Protonation Stereochemistry in
Nucleophilic Additions to Bicyclobutanes1
Shmaryahu Hoz,* Carmela Azran, and Ariel Sella
Contribution from the Department of Chemistry, Bar-Ilan UniVersity, Ramat-Gan, Israel 52900
ReceiVed February 5, 1996X
Abstract: Several nucleophilic reactions on bicyclobutanes activated at the bridgehead carbon by electron withdrawing
groups (SO2Ph, CO2Me, COPh, and CN) were performed in MeOH. In all cases, the less stable 1,3-disubstituted
cyclobutanes isomer was preferentially obtained (compared to the equilibrium ratio). The results for the two charge
localizing groups CN and SO2Ph oppose the existing knowledge regarding the protonation stereochemistry of such
carbanions. Ab initio calculations (6-31G*) have shown that as the nucleophile approaches the bicyclobutane, the
bridgehead activating group moves inward toward an axial position. With a charge localizing group (CN and S(H)-
SO2) the carbanion remains pyramidal, whereas with C(H)dO as an activating group, the carbanion is nearly planar.
It is suggested therefore that under conditions where the carbanion undergoes rapid protonation, it is trapped in its
initial pyramidal geometry. Whereas, in cases where the lifetime of the carbanion is long enough to allow appreciable
equilibration, protonation may result in a different product distribution. This hypothesis was tested by slowing
down the protonation rates. As a result, the more stable isomer was indeed preferentially obtained.
As early as 1954, Zimmerman had shown that protonation
Therefore, protonation will take place preferentially from the
axial direction, leading to the formation of the more stable
isomer. In the case of a transition state with a nearly planar
carbanion (EWG ) NO2, RCdO, etc.), 1,3-diaxial interactions
with the EWG are absent. Hence, the proton donor will
approach the carbanion from the less hindered equatorial side,
pushing the EWG to the axial position and ultimately leading
to the preferential formation of the less stable isomer.
of enolates in cyclic systems, such as 1-benzoyl-2-phenylcy-
clohexane (eq 1) and the corresponding nitronate, takes place
from the least hindered equatorial side to give preferentially
the thermodynamically less stable isomer.2
In contradistinction to the behavior of the sulfonyl group in
the system studied by Zimmerman, in the cyclobutyl carbanion
generated by nucleophilic attack on bicyclobutane, CN, which
is also a localizing EWG,5 induces mainly equatorial protonation
to give preferentially the less stable isomer (eq 3).6,7
Since then, this phenomenon has been demonstrated many
times in similar systems.3 On the other hand, in the case of
the analogous sulfone activated system, the more stable isomer
is preferentially obtained (eq 2).4
In the present work it was established that CN is not unique
in this sense and that the sulfonyl group also exhibits, in the
cyclobutane system, a behavior similar to that of delocalizing
EWGs. Thus, both the cyano and the sulfone groups in
cyclobutane show preference for equatorial protonation from
the less hindered (equatorial) side in an apparent violation of
Based on the above discrepancy, Zimmerman suggested that
differentiation should be made between electron withdrawing
groups (EWG), which delocalize the charge away from the
carbon (e.g., carbonyl and nitro groups) and groups which
stabilize the negative charge by exerting mainly an inductive
effect (e.g., sulfone).3 When the EWG is a charge delocalizing
one, the carbanion will be nearly planar at the transition state.
In contrast, in the case of a localizing EWG, the geometry
around the carbon carrying the negative charge will be
pyramidal, and the EWG may assume either an axial or an
equatorial position at the transition state. Due to the 1,3-diaxial
interactions the EWG will prefer an equatorial position.
(5) Bell, R. P. In The Proton In Chemistry; Chapman and Hall: London,
1973; Chapter 10. Bordwell, F. G.; Bares, J. E.; Bartmess, J. E.; Drucker,
G. E.; Gerhold, J.; McCollum, G. J.; Van Der Puy, M.; Vanier, N. R.;
Matthews, W. S. J. Org. Chem. 1977, 42, 326. Fujio, M.; McIver, R. T.,
Jr.; Taft, R. W. J. Am. Chem. Soc. 1981, 103, 4017. Hibbert, F. In The
Chemistry of Functional Groups, Supplement C; Patai, S., Ed.; Wiley: New
York, 1982; Chapter 17. Lien, M. H.; Hopkinson, A. C.; McKinney, M. A.
J. Mol. Struct. Theochem. 1983, 105, 37. Delbeck, F. J. Org. Chem. 1984,
49, 4838. Abbotto. A.; Bradamante, S.; Pagani, G. A. J. Org. Chem. 1993,
58, 444, 449.
X Abstract published in AdVance ACS Abstracts, May 1, 1996.
(1) Presented in part at the Swedish-Israeli Symposium on New Trends
in Organic Chemistry; Stockholm, August 14, 1994.
(2) Zimmerman, H. E. J. Am. Chem. Soc. 1957, 79, 6554. Zimmerman,
H. E.; Thomas, E. N. J. Am. Chem. Soc. 1957, 79, 6559.
(3) Zimmerman, H. E. Acc. Chem. Res. 1987, 20, 263.
(4) Zimmerman, H. E.; Thyagarajan, B. S. J. Am. Chem. Soc. 1958, 80,
3060.
(6) In nucleophilic attacks on bicyclobutane, the nucleophile always
approaches the molecule from the equatorial direction. For a review of the
chemistry of bicyclobutane, see: Hoz, S. In The Chemistry of the
Cyclopropyl Group; Rappoport, Z., Ed.; Wiley: New York, 1987; Chapter
19.
(7) In 1,3-disubstituted cyclobutane, cis substitution is more stable, since
the two bulky substituents can simultaneously adopt the cis diequatorial
geometry. Moriarty, R. M. Top. Stereochem. 1974, 8, 271.
S0002-7863(96)00370-8 CCC: $12.00 © 1996 American Chemical Society

Nucleophilic Reactions on Bicyclobutanes
J. Am. Chem. Soc., Vol. 118, No. 23, 1996 5457
the rule suggested by Zimmerman. Using a combination of
computational and experimental techniques, this paper will show
that the origin of the deviation of the cyclobutane system from
the general pattern outlined by Zimmerman stems from con-
certed atomic (or group) motions in the course of nucleophilic
attacks on bicyclobutane.
Chart 1a
Results (Experimental)
Reactions with MeO- in MeOH. The stereochemistry of
the addition of MeO- in MeOH to the first three substrates in
eq 4 was determined at several temperatures under kinetic and
thermodynamic control conditions.
a Energies in au and R in deg.
The reactions of the sulfone (1s) and the ketone (1k) gave a
quantitative yield of a mixture of cis and trans addition products.
The ester (1e) gave the two isomers of the addition product,
which, at high conversion percentages, were accompanied by
some unidentified compounds. Therefore, for the reaction of
1e, product distribution was determined from the first 30% of
the reaction, where no side products were observed.
The cis and trans isomers of the reaction adducts (3s′ and 3n
for the PhS adducts and 4s′ and 4n for the PhSe adducts) were
equilibrated in t-BuOH-t-BuO-. The equilibrium ratios were
1.24 for 3s′, 1.23 for 4s′, 1.65 for 3n, and 1.51 for 4n, in favor
of the cis isomer. For the new compounds, the structural (cis-
trans) assignment was based on the equilibrium ratio, as well
as on the NMR data.9
Throughout the course of the reaction of the sulfone derivative
1s, the ratio of cis/trans isomers in the product 2s remains
constant (0.13 ( 0.01) at 60 °C. Incubation of the product
mixture for 14 days with 0.675 M MeO- at 60 °C raised this
ratio to ca. 0.5. A stable equilibrium composition in which the
cis/trans ratio was found to be 1.29 ( 0.06 was achieved only
in t-BuO-/t-BuOH.
Computational Results and Discussion
All calculations were performed at the 6-31G* level using
Gaussian 92.10 Although, in the experimental studies, MeO-,
PhS- and PhSe- were employed as nucleophiles, for obvious
reasons, F- was used as the nucleophile in the computational
work.
Equilibration of the product stereoisomers was fast, compared
to the addition rate for the two carbonyl derivatives 1e and 1k.
In both cases, the kinetic controlled ratio was determined by
an extrapolation to t ) 0. For 2e, the cis/trans ratio at t ) 0 at
60 °C was 0.85 ( 0.1, and the ratio leveled off at a value of
2.2 ( 0.1. For 2k, the ratios at t ) 0 were 1.5 and 2.0 ((0.1)
at 0 °C and 25 °C, respectively. The final equilibrium ratios
were 3.55 and 2.9 ((0.05) at 0 °C and 25 °C, respectively.
Depicted in Table 1 are some of these results, along with the
previously reported data for the cyano activated system 1n.8
The data show that in all cases there is a preference to produce
more of the less stable isomer, compared to the thermodynamic
ratio. This is much more pronounced for the localizing groups
(CN and SO2Ph) than for the carbonyl derivative (COPh and
COOMe).
Since the stereochemistry of the products is determined by
protonation of the carbanion, the first step was to compute the
optimal geometry of the CN, SO2H, and CHO activated
fluorocyclobutyl carbanions.
Puckered 3-fluorocyclobutyl rings with a pyramidal carbanion
can exist as four possible isomers (with F and EWG being
axial-axial, equatorial-equatorial; axial-equatorial, and equa-
torial-axial). However, attempts to optimize structures with
F at an axial position ended in a ring flip, which relocated the
F atom at an equatorial position.
At the optimized geometry, the CHO activated carbanion was
found to be essentially planar. For the CN and SO2H activated
systems, two stationary structures were obtained, and in both
cases the more stable geometry was the one in which the
activating group assumed an equatorial position.
The reactions of bicyclobutyl phenylsulfone (1s′) and 1n with
PhS- and PhSe- as nucleophiles were studied at room temper-
ature in DME (dimethoxyethane) solutions. To these solutions,
variable amounts of MeOH or trifluoroethanol (TFE) were
added. The reactions went to completion in a matter of seconds
(or less) in pure DME. The presence of alcohol slowed the
reaction rates with both nucleophiles. For example, in pure
MeOH with PhS- as the nucleophile, a 90% conversion were
obtained only after 10 min. The percent of the trans isomer
(i.e., equatorial protonation) was determined as a function of
the alcohol concentration. As can be seen from the data in Table
2, the addition of alcohol induced an increase in the fraction of
the trans isomer.
Chart 1 shows the calculated pyramidality (R) of the
corresponding model compounds (the pyramidality is defined
as the angle formed between the C1-C2-C4 plane and the
C1-EWG bond vector).
Examination of the data in Table 1 shows that the essentially
planar carbonyl activated systems, 1e and 1k, have shown, in
(9) The hydrogens on the 1 and 3 carbons are shifted to lower fields
when they are cis to an electronegative groups. Hoz, S.; Livneh, M.; Cohen,
D. J. Org. Chem. 1986, 51, 4537 (see also ref 16 below and references
cited therein).
(10) Gaussian 92, Revision C.; Frisch, M. J.; Trucks, G. W.; Head-
Gordon, M.; Gill, P. M. W.; Wong, M. W.; Foresman, J. B.; Johnson, B.
G.; Schlegel, H. B.; Robb, M. A.; Replogle, E. S.; Gomperts, R.; Andres,
J. L.; Raghavachari, K.; Binkley, J. S.; Gonzalez, C.; Martin, R. L.; Fox,
D. J.; Defrees, D. J.; Baker, J.; Stewart, J. J. P.; Pople, J. A. Gassian, Inc.:
Pittsburgh, PA, 1992.
(8) Hoz, S.; Aurbach, D. J. Am. Chem. Soc. 1980, 102, 2340.

5458 J. Am. Chem. Soc., Vol. 118, No. 23, 1996
Hoz et al.
Table 1. Kinetic and Thermodynamic Cis/Trans Ratio for the
Reaction of 1 with MeO- in MeOH
on the two faces of the carbanion. The differences between
the two faces in the sp3 hybridized carbanions are more
pronounced than in the case of sp2 carbanions. Therefore, an
equatorial approach will be even more preferred over the axial
one than in the nearly planar CdO activated carbanion. This
explanation can, however, be ruled out because first, as was
pointed out by Zimmerman, placing the large bulk of the
sulfonyl group in the transition state at the axial position and
the proton donor at an equatorial one is energetically less
favored. Second, since the sulfonyl group is much bigger than
the cyano group, one would have expected much more equatorial
protonation in the case of the cyano derivative. Yet, as can be
seen from Table 1, the fraction of the equatorial protonation
(trans isomer) is much larger for the sulfonyl group.
The most plausible explanation is that the nucleophilic attack
on the cyano and sulfone activated bicyclobutanes produces the
carbanions in a pyramidal geometry which places the EWG at
the axial position. Protonation by the solvent (MeOH), to a
large extent, traps the carbanions before they undergo complete
equilibration by pyramidal inversion.
cis/trans ratio
reactant
kinetic
thermodynamic
rel ratio
1s
1e
1k
0.13 ( 0.01a
0.85 ( 0.1c
1.5 ( 0.1d
2.0 ( 0.1e
0.28
1.3 ( 0.06b
2.2 ( 0.1c
3.55 ( 0.05d
2.9 ( 0.05e
2.1
10.0
2.6
2.4
1.5
7.2
1nf
b
a In the range of 60 °C. In t-BuOH. c At 60 °C. d At 0 °C. e At 25
°C. f Data from ref 8.
agreement with the data obtained by Zimmerman, a small
preference to give more of the less stable isomer compared with
the thermodynamic distribution. The cyano and sulfone deriva-
tives, which are much more pyramidal, display a much higher
preference in the same direction.
The results of the latter systems cannot be predicted on the
basis of Zimmerman’s rules. In the cyclohexyl system, the
average ratio was ca. 3, in favor of the thermodynamically more
stable isomer, whereas, in the reactions in MeOH (this study),
the less stable isomer was preferentially obtained in ratios
ranging from 8 to 3.5 (Tables 1 and 2).
In order to determine that, indeed, the initial geometry in
which the carbanions are formed is such that the EWG is in an
axial position, F- was located at various distances along the
line of attack, and the motion of the central atom in the activating
groups was followed as a function of the F- approach. In order
to avoid ion-dipole complexes, where the nucleophile is
One could have argued that for the CN and SO2 cyclobutane
derivatives, product distribution is determined, as in the case
of enolate (and nitronate), by the differential ease of protonation
Table 2. Percents of 2-Trans (Equatorial Protonation) as a Function of [ROH] in the Reaction of 1s and 1n
percent of the trans isomer
substrate
nucleophile
ROH
1s′
1n
PhSe
PhS
PhSe
PhS
MeOH
TFE
32.5
MeOH
TFE
30.9
MeOH
48.7
TFE
MeOH
[ROH], M
0.01
[ROH], M
0.01
32.5
32.4
32.6
33.3
34.5
35.8
30.9
30.8
31
31.6
32.2
32.9
48.7
48.8
48.8
49.0
47.0
0.035
0.084
0.134
0.158
0.257
0.288
0.405
0.504
0.566
0.844
0.998
1.492
1.678
1.986
2.79
0.045
0.097
0.149
0.164
0.184
0.219
0.257
0.319
0.319
0.358
0.412
0.504
0.628
0.69
0.705
0.936
1.226
1.245
2.171
2.443
4.333
4.354
7.111
7.42
8.176
10.435
10.508
10.816
12.694
13.595
14.511
16.991
18.525
20.696
23.166
24.71
48.8
49.7
50.3
37.7
39.2
37.7
38.5
34.1
35.1
48.9
49.0
42.6
45.5
43.5
45.5
47.2
47.3
51.4
41.7
48.8
39.2
43.5
48.9
49.7
50.5
50.5
53.5
65.5
53.5
46.5
54.5
57.4
2.79
60.8
70.6
81.5
3.962
4.736
5.938
6.96
57.4
62.3
54.5
60.8
64.9
73.8
84.7
51.7
53.1
50.7
55.1
58.9
61.1
67.1
7.914
8.902
9.462
11.866
12.242
12.36
14.83
16.312
18.157
19.77
21.252
23.228
24.71
57.0
68.3
92.5
95.4
89.9
95.1
71
60.0
78.9
86.1
73.3
78.3
81.1
83.8
74.4
77.5
81.1
82.9
62.4
64.0
91.3
65.5
68.6
72.3
74.8
67.0
71.0
74.8

Nucleophilic Reactions on Bicyclobutanes
J. Am. Chem. Soc., Vol. 118, No. 23, 1996 5459
Table 3. Energies and Structural Parameters as a Function of F-
which the degree of pyramidality reaches a maximum. The
activating group then oscillates back, relaxing to the stable
carbanion geometry, which is pyramidal for CN and SO2 and
nearly planar for the CHO derivative.
Approach to Activated Bicyclobutanesa
C-F
distance,
Å
pyramidality,
bridge bond
length, Å
energy,
au
R
The oscillation phenomenon, that is, an inward motion
followed by an outward one as the bridge bond is further
stretched, was previously suggested based on X-ray data and
observed by STO-3G computations.11 It was found computa-
tionally also for the radical cation of bicyclobutane.12 The
present finding, being the third example of the oscillation
phenomenon, seems to suggest that stretching of the central bond
of bicyclobutane, regardless of the charge or multiplicity, results
in the oscillation phenomenon. For obvious reasons, it is
expected that the amplitude of the inward motion will be much
smaller for the carbonyl substituent than for the two charge
“localizing” substituents, CN and S(H)O2, and that its maximum
will be reached earlier. These expectations are fully born out,
as can be seen from Figure 1.
The above computational results show that the carbanion is
initially formed in the geometry which will yield the less stable
trans isomer by equatorial protonation. Thus, the obserVed
product distribution may result from a partially successful
trapping of the carbanions in their pyramidal geometry,
reflecting the fact that in the initially formed carbanion, the
EWG, due to the inward motion, assumes an axial position.
The proposed model can be experimentally tested in the
following way. If, indeed, the carbanion is trapped in the
reactions in MeOH in its initial conformation, then slowing
down the protonation rate will enable equilibration by inversion
of the carbanion. The proton donor will then trap the
equilibrated carbanion, giving a product mixture in which the
percent of the product derived from the equatorial protonation
will decrease with the protonation rate. The results will thus
resemble those obtained by Zimmerman for the cyclohexylsul-
fone system in the sense that the more stable product will be
preferentially obtained. This was achieved by carrying out the
reactions in an inert solvent (DME). Because of the insolubility
of MeO- in this medium, PhS- and PhSe- were used as
nucleophiles. As in the Zimmerman study, the more stable
isomer was indeed obtained in (a ca. two - fold) excess over
the less stable one. The protonating agent in this case is
probably the solvent itself, because adding large excess of
MeOD after 1 min. did not result in deuterium incorporation
into the product.
EWGdSO2H
10.0
14.0
22.0
33.0
41.5
43.1
43.8
41.3
1.47
-702.27121
-801.46691
-801.46692
-801.46628
-801.47186
-801.47726
-801.48271
-801.51403
2.5
2.2
2
1.8
1.7
1.6
1.394
1.517
1.606
1.742
1.914
1.985
2.041
2.112
EWGdCN
9.7
12.2
17.2
25.3
42.6
44.9
45.6
41.4
1.478
1.522
1.581
1.703
1.886
1.962
2.022
2.104
-246.61423
-346.05158
-346.04836
-346.04481
-346.04622
-346.04958
-346.05323
-346.08228
2.5
2.2
2
1.8
1.7
1.6
1.401
EWGdCHO
14.7
20.8
25.4
29.4
27.0
21.3
14.4
8.0
1.494
1.565
1.637
1.703
1.89
1.96
2.013
2.075
-267.61045
-367.04337
-367.04195
-367.04123
-367.04564
-367.05059
-367.05579
-367.08674
2.5
2.2
2
1.8
1.7
1.6
1.397
a The data for C-F distance ) relates to the unpreturbed substrate.
In the next step, increasing amounts of the proton donor-
MeOH or trifluoroethanol (TFE) were added to the reaction
mixture. According to Scheme 1 (using PhSe- as a nucleophile
and the CN derivative as an example), it is clear that as the
protonation rate is enhanced, more of the trans isomer will be
obtained. The results given in Table 2 and Figures 2-4 show
that, indeed, when protonation rate is enhanced, either by
increasing the concentration of the proton donor or by using a
stronger acid (TFE), the fraction of the equatorial protonation
is increased and then levels off. As expected, a sharper rise is
obtained for the stronger acid TFE (Table 2 and Figures 2-4).
Figure 1. Pyramidality as a function of the C-F distance.
attached to the bridgehead hydrogen, the fluoride ion approach
was restricted to a line forming the same F-C3-H angle which
is formed at the transition state for the nucleophilic attack (80o).
The C-F distance was gradually varied from 2.5 Å to the final
geometry of the adduct (ca. 1.4 Å), and the rest of the molecule
was fully optimized at each point. The results given in Table
3 and Figure 1 show the bridge bond length and the pyramidality
as a function of the C-F distance for the three substituents.
The results show that, as the fluoride ion approaches the
molecule, the central bond is lengthened and the activating group
moves inward, increasing the pyramidality. This motion
produces an intermediate structure (at a C-F distance of ca.
1.75 Å for CN and SO2H and 2 Å for the CHO derivative) at
Summary and Conclusions
A carbanion in a cyclic system may have either a planar or
a pyramidal geometry at the transition state of a protonation
reaction. Zimmerman has shown that, in the case of a planar
geometry, the proton donor will prefer to approach the molecule
(11) Paddon-Row, M. N.; Houk, K. N.; Dowd, P.; Garner, P.; Schappert,
R. Tetrahedron Lett. 1981, 22, 4799. Irngartinger, H.; Lukas, K. L. Angew.
Chem., Int. Ed. Engl. 1979, 18, 694.
(12) Hoz, S.; Basch, H.; Goldberg, M.; J. Am. Chem. Soc. 1992, 114,
4364.

5460 J. Am. Chem. Soc., Vol. 118, No. 23, 1996
Hoz et al.
the elongation of the central bond in the course of the
nucleophilic attack, and an inward motion of the bridgehead
substituents. When protonation is fast enough, the majority of
the carbanions are trapped in their incipient geometry before
an appreciable inversion can take place, giving the less stable
isomer preferentially. For obvious reasons, this phenomenon
should be more pronounced with the pyramidal (CN and SO2R
stabilized) carbanions than with the planar (RCdO stabilized)
ones. Slowing down the protonation rate, by using only small
amounts of proton donor in DME, brought back the adherence
to the Zimmerman rule.
Figure 2. The % of the trans isomer in the reaction of 1n with PhS-
b, PhSe- 9 in MeOH, and PhSe- in TFE 2.
Experimental Section
General Methods. NMR spectra were recorded on a Bruker AM-
300 spectrometer and measured in CDCl3 solution. Mass spectra were
taken with a Finnigan 4021 mass spectrometer. For analytical purposes,
a Packard Model 878 (FI detector) gas chromatograph was used,
whereas for preparative separations a Varian 920 gas chromatograph
(TC detector) was used.
Reactants and Products. 1s and 1s′ were obtained from Prof. Y.
Gaoni and are known in the literature.14 Methylbicyclobutanecarboxy-
late (1e) was prepared according to a literature procedure,15 with the
difference that the two-step hydrolysis of the nitrile function and
esterification of the resulting acid derivative were combined into a single
step, according to the following procedure: a heterogeneous mixture
of 2.8 g (0.024 mol) of 3-chlorobicyclobutanecarbonitrile and 21 mL
of conccentrated HCl were vigorously stirred under gentle reflux for 1
h. MeOH (40 mL) was added, and the solution was refluxed for 22 h.
The reaction mixture was treated with methylene chloride and aqueous
NaHCO3. The organic phase was dried over MgSO4, filtered, and
evaporated, yielding 3.53 g (95% yield) of yellow liquid composed
mainly of the two isomers of methyl 3-chlorocyclobutanecarboxylate.
The mixture was then subjected to elimination, and the product, methyl
bicyclobutanecarboxylate, was kept in ethereal solution at -25 °C.
Before each experiment, the product was separated and purified by
preparative gas chromatography (5% XE 60 on Chromosorb W, 50
°C). Bicyclobutyl phenylketone (1k) was prepared according to
literature procedure16 and purified by preparative GC (0.5% XE 60 on
Chromosorb W, nonacid washed, 95 °C).
Figure 3. The % of the trans isomer in the reaction of 1s with PhS-
in MeOH b, and in TFE 9.
The methoxy adducts of the three substrates were prepared according
to published procedures. The two isomers of 3-methoxycyclobutyl
p-tolylsulfone (2s)14 were separated on a GC column (0.5% XE 60 on
Chromosorb W, nonacid washed, 170°). The two isomers of methyl
3-methoxycyclobutylcarboxylate (2e) were separated, and their geom-
etry was assigned by Razin et. al.17 The two isomers of 3-methoxy-
cyclobutyl phenylketone (2k)16 were obtained as a mixture after column
chromatography with methylenechloride.
Figure 4. The % of the trans isomer in the reaction of 1s with PhSe-
in MeOH b, and in TFE 9.
Scheme 1
Bicyclobutanecarbonitrile (1n) was prepared according to published
procedure.17
The thiophenoxide adducts (3s and 3n) and the phenylselenolate
adducts (4s and 4n) were prepared in the following procedure, which
was used also for the studies of the effect of added alcohols to the
DME solution. The substrate (3-4) mg was dissolved in 0.35-0.75
mL of DME or DME-alcohol mixture. To this, 50-150 µL of a
nucleophile stock solution were injected to give a reaction mixture with
(13) A referee had suggested an alternative explanation for the observed
stereochemistry at high proton donor concentration. According to this
explanation, at high MeOH concentration, the reaction is concerted, and
no free carbanion is formed under these conditions. We believe that this
suggestion can be safely ruled out on the basis of microscopic reversibility
since all the 1,3-elimination reactions in the cyclobutane bicyclobutane
system are known to be stepwise (see ref 6 above). Moreover, to the best
of our knowledge, there is no single reported case of a concerted
1,3-elimination reaction. The reversal must therefore also be a stepwise
reaction.
(14) Gaoni, Y.; Tomazic, A. J. Org. Chem. 1985, 109, 2948.
(15) Hall, H. K., Jr.; Smith, C. D.; Blanchard, E. P., Jr.; Cherkofsky, C.
S.; Sieja, J. B. J. Am. Chem. Soc. 1971, 93, 121.
(16) Azran, C.; Hoz, S. Tetrahedron 1995, 51, 11421.
(17) Razin, V. V.; Eremenko, M. V.; Ogloblin, K. A.; Z. Org. Khim.
1977, 13, 1003.
from the less hindered equatorial direction, whereas, in the
pyramidal geometry case, the favored approach will be from
the axial one. In contradistinction to these rules, pyramidal
carbanions obtained via the route shown in eq 4 all show
disposition toward equatorial protonation. Moreover, this
preference is, by far, more pronounced than that for the planar
carbanions. We have shown that this behavior is unique to the
bicyclobutane-cyclobutane system in fast protonating media.
This uniqueness stems from the coupling between two motions,

Nucleophilic Reactions on Bicyclobutanes
J. Am. Chem. Soc., Vol. 118, No. 23, 1996 5461
a total volume of 0.5-0.8 mL, with substrate and nucleophile
concentrations in the ranges of 0.03-0.05 M and 0.06-0.1 M,
respectively. The reaction mixtures were allowed to stand at room
temperature for periods of minutes to 2 h (In general, the reactions
were slower with PhS- as nucleophile and in the presence of large
concentrations of alcohol.) The reaction mixtures were quenched with
2 mL of CH2Cl2, followed by 2 mL of water. The aqueous phase was
washed with three portions of 3 mL of CH2Cl2. The combined organic
phase was dried over MgSO4 and evaporated. In all cases, the isolated
yield (based on weighing and NMR determination against internal
standard (CHBr3)) was between 90 and 100%.
(tt, 1H, HC-CN), 3.85 (tt, 1H, HC-SePh), 7.3 (m, 3H), 7.48 (m, 2H).
m/e (DCI-NH3) 255.1, 253.1, 251.1, 250.1, 248.1, 237.0, 184.0.
4n trans: 1H NMR, δ 2.49 (m, 2H, CH2), 2.83 (m, 2H, CH2), 3.25
(dtt, 1H, HC-CN), 4.12 (dtt, 1H, HC-SePh), 7.3 (m, 3H), 7.48 (m, 2H).
m/e (DCI-NH3) 255.1, 253.1, 251.1, 250.1, 248.1, 237.0, 184.0.
Satisfactory C, H, N analyses were obtained for the two isomers.
Equilibration of 3 and 4. The adducts (10-17 mg) were dissolved
in 1 mL of t-BuOH. Added to this were 23 mg of tert-butoxide to
give a solution with a base concentration of 0.2 M and a substrate
concentration in the range 0.03-0.075 M. The reaction mixtures of
the CN derivatives were examined after 80 and 160 min, and those of
the sulfone derivatives were examined after 24 and 48 h. In both cases,
the ratio remained constant for the two reaction times.
General Procedure for the Reaction of MeO- with 1. Solutions
of MeONa in MeOH were prepared from Na and MeOH under nitrogen.
Solutions at the appropriate concentration were incubated in a tem-
perature bath. These were either added to the substrate (1s) placed in
the temperature bath, or a 5 µL methylenechloride solution of the
substrate (1k) was injected into 2 mL of the methoxide solution at the
appropriate concentration. In some cases (1e), a weighed amount of
the substrate was directly injected into the methoxide solution. In
several runs, fluorene or naphthalene were added to the reaction mixture
as an internal standard. Aliquots of 0.2 -0.25 mL were periodically
removed. The reactions of 1s and 1k were quenched by aqueous NaCl
solution and extracted with ether. The total volume of the ether and
the water was 1.5 mL. In the case of 1e, quenching was done with
AcOH. Care was taken to assure that the quenched solutions were
neutral, since under either basic or acidic conditions the composition
of the samples did not remain constant over several days. A 2% XE-
60 on Chromosorb W column was used for the GC analysis of the
reactions of 1e, whereas a 0.5% XE-60 on Chromosorb W (non-acid
washed) column was used for the GC analysis of the reactions of 1s
and 1k. A similar procedure was used in the isomerization experiments.
3s cis: 1H NMR, δ 2.6 (t, 4H, CH2), 3.67 (tt, 1H, HC-SPh), 3.68
(tt, 1H, HC-SO2Ph), 7.2-7.35 (m, 5H), 7.45-7.7 (m, 3H), 7.84 (m,
2H). m/e (CI-NH3) 322.1, 278.1, 256.1.
3s trans: 1H NMR, δ 2.29 (m, 2H, CH2), 3.03 (m, 2H, CH2), 3.93
(dtt, 1H, HC-SO2Ph), 4.05 (dtt, 1H, HC-SPh), 7.2-7.35 (m, 5H), 7.5-
7.7 (m, 3H), 7.88 (m, 2H). m/e (CI-NH3) 322.1, 278.1, 256.1.
Satisfactory C, H, S analyses were obtained for the two isomers.
4s cis: 1H NMR, δ 2.52-2.75 (m, 4H, CH2), 3.69 (tt, 1H, HC-
SO2Ph), 3.73 (tt, 1H, HC-SePh), 7.22-7.38 (m, 5H), 7.5-7.67 (m,
3H), 7.8 (m, 2H). m/e (CI-NH3) 372.1, 370.1, 368.1, 367.1, 366.1,
364.1, 223.1, 206.1, 204.5.
4s trans: 1H NMR, δ 2.35 (m, 2H, CH2), 3.07 (m, 2H, CH2), 3.88
(dtt, 1H, HC-SO2Ph), 4.1 (dtt, 1H, HC-SePh), 7.22-7.38 (m, 5H), 7.5-
7.67 (m, 3H), 7.85 (m, 2H). m/e (CI-NH3) 372.1, 370.1, 368.1, 367.1,
366.1, 364.1, 223.1, 206.1, 204.5.
Satisfactory C, H, S, Se analyses were obtained for the two isomers.
3n cis: 1H NMR, δ 2.44 (m, 2H, CH2), 2.82 (m, 2H, CH2), 3.01
(tt, 1H, HC-CN), 3.77 (tt, 1H, HC-SPh), 7.21-7.35 (m, 5H). m/e (CI-
NH3) 207.0, 204.5, 189.0, 136.0, 134.0.
3n trans: 1H NMR, δ 2.44 (m, 2H, CH2), 2.82 (m, 2H, CH2), 3.29
(dtt, 1H, HC-CN), 4.07 (dtt, 1H, HC-SPh), 7.21-7.35 (m, 5H). m/e
(CI-NH3) 207.0, 204.5, 189.0, 136.0, 134.0.
Satisfactory C, H, N analysis was obtained for the two isomers.
4n cis: 1H NMR, δ 2.49 (m, 2H, CH2), 2.83 (m, 2H, CH2), 3.01
Supporting Information Available: Gaussian archive records
for the geometry optimized molecules, their fluoride adducts,
and transition states for inversion of the carbanions. (4 pages).
See any current masthead page for ordering information.
(18) Blanchard E. P.; Cairncross, A. J. Am. Chem. Soc. 1966, 88, 487.
Hall, H. K., Jr.; Blanchard, E. P. Jr.; Cherkofsky, C. S.; Sieja, J. B. J. Am.
Chem. Soc. 1971, 93, 110. Dietz, P.; Szeimies, G. Chem. Ber. 1980, 113,
398. Hall, H. K., Jr.; Smith, C. D.; Blanchard, E. P., Jr.; Cherkofsky, C. S.;
Sieja, J. B. J. Am. Chem. Soc. 1971, 93, 121.
JA960370G