Theoretical and experimental study on the in-plane SN2-type substitution reaction of haloalkenes with inversion of configuration at the sp2 carbon

Article abstract of DOI:10.1021/ol049119t

(Equation Presented) The intramolecular in-plane S_N2 type reaction of haloalkene E-8a was predicted to be a facile process for the first time by DFT calculations (B3LYP/6-31+G(d),SCRF(dipole, solvent = DMF)) (ΔG = 14.4 kcal/mol). The prediction was confirmed experimentally. When E-8a was treated with NaH in DMF, benzofuran was obtained in 95% yield. On the other hand, Z-8a was recovered quantitatively even after heating at 110 °C.

Full text of DOI:10.1021/ol049119t

ORGANIC
LETTERS
2004
Vol. 6, No. 14
2461-2463
Theoretical and Experimental Study on
the In-Plane SN2-Type Substitution
Reaction of Haloalkenes with Inversion
of Configuration at the sp2 Carbon†
,‡
,§
Kaori Ando,* Mitsuru Kitamura,§ Kasei Miura,§ and Koichi Narasaka*
College of Education, UniVersity of the Ryukyus, Nishihara-cho,
Okinawa 903-0213, Japan, and Department of Chemistry, Graduate School of Science,
The UniVersity of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
ando@edu.u-ryukyu.ac.jp
Received May 14, 2004
ABSTRACT
The intramolecular in-plane SN2 type reaction of haloalkene E-8a was predicted to be a facile process for the first time by DFT calculations
(B3LYP/6-31+G(d),SCRF(dipole, solvent ) DMF)) (∆G ) 14.4 kcal/mol). The prediction was confirmed experimentally. When E-8a was treated
with NaH in DMF, benzofuran was obtained in 95% yield. On the other hand, Z-8a was recovered quantitatively even after heating at 110 °C.
The bimolecular nucleophilic substitution (SN2) reaction is
one of the most fundamental reactions in organic chemistry.
The SN2 reaction at the sp3 carbon takes place in a single
step without intermediates when the entering nucleophile
attacks the substrate from a position 180° away from the
leaving group. On the other hand, there are a wide variety
of possible mechanisms for the corresponding SN2 reaction
at the sp2 carbon.1 The most common route is an addition-
elimination pathway, which is initiated by nucleophilic attack
at the π-bond. The in-plane SN2 route, in which the backside
attack of the nucleophile occurs concertedly with leaving
group expulsion within the molecular plane, has long been
rejected as a feasible pathway. Recently, the in-plane SN2
route has been predicted to be feasible on the Cl- + CH2d
CHCl reaction by ab initio calculations.2 Following this
discovery, the in-plane SN2 process received considerable
attention.3 However, the reported activation energies of the
theoretically calculated in-plane vinylic SN2 reactions of
haloalkenes are high (more than 30 kcal/mol) and no
experimental support has been provided.2,3c Only the reaction
of vinyl iodonium salts with halide ions1b,4 and the reactions
with charged three-membered rings are known.5
During the course of our study on the nucleophilic
cyclization of haloalkenes,6,7 one of us found that the
cyclization of fluoroalkene E-1a occurs via the in-plane SN2
(2) Glukhovtsev, M. N.; Pross, A.; Radom, L. J. Am. Chem. Soc. 1994,
116, 5961-5962.
(3) (a) Lucchini, V.; Modena, G.; Pasquato, L. J. Am. Chem. Soc. 1995,
117, 2297-2300. (b) Kim, C. K.; Hyun, K. H.; Kim, C. K.; Lee, I. J. Am.
Chem. Soc. 2000, 122, 2294-2299. (c) Bach, R. D.; Baboul, A. G.; Schlegel
H. B. J. Am. Chem. Soc. 2001, 123, 5787-5793.
(4) (a) Ochiai, M.; Oshima. K.; Masaki, Y. J. Am. Chem. Soc. 1991,
113, 7059-7061. (b) Okuyama, T.; Takino, T.; Sato, K. Ochiai, M. J. Am.
Chem. Soc. 1998, 120, 2275-2282. (c) Okuyama, T.; Yamataka, H. Can.
J. Chem. 1999, 77, 577-583.
(5) (a) Lucchini, V.; Modena, G.; Pasquato, L. J. Am. Chem. Soc. 1993,
115, 4527-4531. (b) Rappoport, Z. Tetrahedron Lett. 1978, 1073-1076.
† This paper is dedicated to Professor K. N. Houk on the occasion of his
60th birthday.
‡ University of the Ryukyus.
§ The University of Tokyo.
(1) For reviews, see: (a) Rappoport, Z. Acc. Chem. Res. 1992, 25, 474-
479. (b) Okuyama, T.; Lodder, G. In AdVances in Physical Organic
Chemistry; Tidwell, T. T., Richard, J. P., Eds.; Academic Press: New York,
2002; Vol. 37, pp 1-56.
10.1021/ol049119t CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/10/2004

Scheme 1
pathway in an Onsager continuum model for dimethylfor-
mamide (DMF)8 (∆G ) 25.8 kcal/mol) and occurs via a
concerted π-addition-elimination pathway in the gas phase
[B3LYP/6-31+G(d)] (Scheme 1).6 This mechanistic change
inspired us to do further study on the in-plane SN2 reaction.
All calculations were performed using the Gaussian 98
program.9,10
The transition structure for the cyclization of E-1b was
located in the gas phase and in solution by the B3LYP hybrid
functional13 together with the 6-31+G(d) basis and the
Onsager continuum model14 for DMF (ꢀ ) 37.06) (Figure
1). The in-plane SN2 transition structure E-1b-ts was obtained
with the activation free energy of 14.4 kcal/mol in DMF (17.1
kcal/mol in the gas phase). Hydrogen bonding of the
oxyanion with the vinylic hydrogen makes E-1b a planar
molecule. The intrinsic reaction coordinate (IRC) calculations
showed that spontaneous dissociation of the C-Cl bond
occurs when the oxyanion approaches the sp2 carbon while
Figure 1. Transition structures for the nucleophilic cyclization of
chloroalkene anions 1b and 3a [B3LYP/6-31+G(d), SCRF (dipole,
solv ) DMF)]. The italic numbers are the values in the gas phase.
keeping this hydrogen bonding (the O-H distance is 2.00-
2.23 Å). The distances of the forming O-C and the breaking
C-Cl bonds are 2.22 and 2.23 Å in E-1b-ts, respectively,
while the distance of the CdC double bond was slightly
reduced. Even after many trials, we could not get any
π-addition transition structures. On the other hand, only
π-addition transition structures are obtained from both Z-1b
and the dichloro compound 3a.6 Due to both the steric
hindrance and electronic repulsion between the oxyanion and
the electronegative chlorine atom, both Z-1b and 3a are no
longer planar molecules and the oxyanion approaches to the
sp2 carbon to the double bond plane perpendicularly. The
activation energies of these are much higher than the one of
E-1b. The high activation energies for the π-addition are
mainly associated with large deformation energies required
to adjust the reactants to their TS geometry without interac-
tion with the nucleophile. The deformation energy might be
roughly estimated by the energy difference (38.6 kcal/mol)
between Z-1b and Z-1b-ts, in both of which the alkoxy anion
was replaced with a hydrogen. Since the deformation energy
destabilizes the π-addition TS and the intramolecular hy-
drogen bonding stabilizes the in-plane SN2 type reaction,
E-1b-ts becomes the only favorable pathway. The in-plane
SN2 type reaction is also the preferred pathway for the
corresponding bromoalkene E-1c.15
(6) Ando, K. J. Org. Chem. 2004, 69, 4203-4209.
(7) Yanagisawa, H.; Miura, K.; Kitamura, M.; Narasaka, K.; Ando, K.
Bull. Chem. Soc. Jpn. 2003, 76, 2009-2026.
(8) Since DMF is able to dissolve many salts and tends to surround metal
cations rather than nucleopfilic anions, the use of free anions as model
systems could be approved.
(9) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-
Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P.
M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.;
Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98, Revision A.9;
Gaussian, Inc., Pittsburgh, PA, 1998.
(10) Gibbs free energies are the values at 298.15 K and 1.00 atm. The
thermal energy corrections are not scaled.11 Vibrational frequency calcula-
tions gave only one imaginary frequency for all transition structures and
only harmonic frequencies for the reactants and products. The structures
of the reactants and products were obtained by the optimization of the last
structures on both sides of IRC calculations.12
(11) The scale factors for B3LYP are very close to 1.0; see: Bauschlicher,
C. W., Jr.; Partridge, H. J. Chem. Phys. 1995, 103, 1788-1791. Scott, A.
P.; Radom, L. J. Phys. Chem. 1996, 100, 16502-16513.
(12) (a) Gonzalez, C.; Schlegel, H. B. J. Chem. Phys. 1989, 90, 2154-
2161. (b) Gonzalez, C.; Schlegel, H. B. J. Phys. Chem. 1990, 94, 5523-
5527.
(13) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652. (b) Lee,
C.; Yang, W.: Parr, R. G. Phys. ReV. B 1988, 37, 785-789.
(14) (a) Onsager, L. J. Am. Chem. Soc. 1936, 58, 1486-1493. (b) Wong,
M. W.; Frisch, M. J.; Wiberg, K. B. J. Am. Chem. Soc. 1991, 113, 4776-
4782.
To see the effect of the benzene ring as a linker, the
cyclization reaction of the anion 4a was studied. The
transition structures for the cyclization of E-4a were located
(15) Full details will be soon presented.
2462
Org. Lett., Vol. 6, No. 14, 2004

Table 1. Intramolecular Nucleophilic Substitution Reaction
entry substrate(R, XY) conditions yieldb (%) recoveryc (%)
1
2
3
4
5
6
7
8
E-8a (Me, HCl) rt, 13 h
Z-8a (Me, HCl) rt to 110 °Ca
E-8b (Me, HBr) rt, 3 h
95
0
73
6
100
87
Z-8b (Me, HBr) rt, 6 days
E-9
Z-9
80 °C, 10h
80 °C, 10 h
60 °C, 2h
82
Figure 2. Transition structures for the nucleophilic cyclization of
chloroalkene anions 4a and 6a [B3LYP/6-31+G(d), SCRF (dipole,
solv ) DMF)]. The italic numbers are the values in the gas phase.
0d
0e
8c (Bu, Cl2)
E-8d (Bu, HF)
80 °C, 43 h
17e
a rt, 13 h; 50 °C, 1 h; 80 °C, 1 h; 110 °C, 1 h. b Isolated yield. c The
recovery of the substrate. d A complex mixture. e Ref. 16.
(Figure 2). The in-plane SN2 type transition structure E-4a-
ts1 is more stable than the π-addition transition structure
E-4a-ts2 (not shown) by 11.9 kcal/mol (DMF) (∆G). Only
π-addition transition structures are obtained from both Z-4a
and the dichloro compound 6a. The activation energies are
much higher than the one associated with E-4a-ts1. It should
be noted that the activation energies in DMF are higher than
the ones in the gas phase by 4 kcal/mol for E-4a-ts1 and
7-11 kcal/mol for the π-additions. These differences seem
to arise from a large stabilization of the unstable oxyanions
4a and 6a in a polar solvent compared with their corre-
sponding transition structures.
treated with NaH in DMF at room temperature. E-9 gave
the SN2 product 11 in 82% yield, while 11 was not obtained
from Z-9.
In summary, we showed the first in-plane SN2 type reaction
of haloalkenes by both DFT calculations and experiments.
The in-plane SN2 pathway opens up many possibilities for
mainly intramolecular reactions, from which useful meth-
odologies in organic synthesis can be developed. Further
investigation on this type of reaction is currently in progress
in our laboratories.
The theoretical predictions were confirmed experimentally,
by preparing haloalkenes 8 and 9. The E- and Z-isomers were
separated by column chromatography and the geometry of
the olefin moiety was determined by NOE experiments. The
stereochemistry of E-9 was determined by X-ray analysis.
When E-8a was treated with NaH in DMF at room
temperature, benzofuran 10 was obtained in 95% yield (entry
1 in Table 1). On the other hand, Z-8a was recovered
quantitatively even after heating at 110 °C. In a similar way,
the bromoalkene E-8b reacted smoothly to give 10 in 73%
yield at room temperature. Z-8b gave 10 in only 6% yield
after a prolonged reaction time (rt, 6 days) along with 87%
of Z-8b. These experimental results including the previous
data from the fluoroalkene E-8d (E-8a is more reactive than
E-8d) and 8c16 consist of the DFT calculations and support
the in-plane SN2 mechanism for E-8. Furthermore, 9 was
Acknowledgment. K.A. thanks MEXT.KAKENHI
(15590014) for partial financial support and the Computer
Center of the Institute for Molecular Science for the use of
the Fujitsu VPP5000 computer. We also thank Dr. Naokazu
Kano, The University of Tokyo, for the X-ray analysis of
E-9.
Supporting Information Available: Typical experimen-
tal procedure, spectral data for new compounds, and X-ray
crystallographic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL049119T
(16) Ichikawa, J.; Wada, Y.; Fujiwara, M.; Sakoda, K. Synthesis 2002,
1917-1936.
Org. Lett., Vol. 6, No. 14, 2004
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