A novel intramolecular through-space interaction between F and CN: a strategy for the conformational control of an acyclic system.

Article abstract of DOI:10.1039/b107213g

X-Ray crystallographic analyses of fluorocyanides anti-1 and 2 revealed a novel intramolecular through-space interaction between F and CN in an acyclic system, which was applied to a stereoselective protonation of acyclic fluorocyanides 2 having flexible

Full text of DOI:10.1039/b107213g

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A novel intramolecular through-space interaction between F and CN:
a strategy for the conformational control of an acyclic system†
Kiyoharu Nishide,*a Yuri Hagimoto,a Hiroaki Hasegawa,a Motoo Shiro‡b and Manabu Node*a
a Department of Pharmaceutical Manufacturing Chemistry, Kyoto Pharmaceutical University, Misasagi,
Yamashina, Kyoto 607-8414, Japan. E-mail: node@mb.kyoto-phu.ac.jp; Fax: +81-75-595-4775;
Tel: +81-75-595-4639
b Rigaku Corporation, 3-9-12 Matsubara, Akishima, Tokyo 196-0003, Japan
Received (in Cambridge, UK) 8th August 2001, Accepted 11th October 2001
First published as an Advance Article on the web 2nd November 2001
X-Ray crystallographic analyses of fluorocyanides anti-1
and 2 revealed a novel intramolecular through-space inter-
action between F and CN in an acyclic system, which was
applied to a stereoselective protonation of acyclic fluoro-
cyanides 2 having flexible conformation.
The discovery of interactions between functional groups, such
as hydrogen-bonding, p–p stacking, and CH–p interactions, is
a pivotal area of investigation in organic and bioorganic
chemistry. In organic synthesis, these interactions have con-
trolled the stereochemistry in Diels–Alder and ene reactions.1
Based on theoretical studies of the ‘Bürgi–Dunitz trajectory’ in
nucleophilic additions to carbonyl groups,2 Dunitz et al.,
discovered in 1978 the interaction between the ethereal oxygen
and the carbonyl group in 8-methoxy-1-naphthyl methyl
ketones.3a The newly coined ‘nucleophilic–electrophilic inter-
action’ was also found between the nitrogen and the carbonyl
carbon and between the oxygen and the cyanide carbon.3
Recently, intramolecular nonbonded interactions between oxy-
gen and sulfur or selenium in heterocycles have also been
observed.4 Because of their unique characteristics of metabolic
inhibition and high lipophilicity, organofluorine compounds are
widely used in pharmaco- and agrochemistry. However despite
their extensive use, the interaction of fluoride with organofunc-
tional groups has remained virtually unexplored,5 whereas
interactions between fluoride and metals6 and hydrogen-
bonding interactions with fluoride7 are often observed. We
report herein the discovery of a novel through-space interaction
between F and CN, which serves as a conformational regulation
of a flexible acyclic carbon chain.
Fig. 1 Novel through-space nF ? p*CN interaction to freeze the
conformation in an acyclic system.
shorter than the sum (3.17 Å) of their van der Waals radii. The
angle between these atoms when projected in the C2–C4 plane
was 8.6°. These two functional groups formed an envelope-
shaped pseudo five-membered ring which includes the three
carbons C2–C4. The F moiety of the pseudo five-membered
ring was distorted toward the CN group. Among the angles
concerned with the pseudo ring, q1 and q2 were shorter than a
right angle, and q4 was found to be less than 180°, unlike the
usual cyanide having the linear sp configuration. These data
suggest that the lone pair of the fluorine (nF) is being donated to
the p* orbital on the cyanide carbon (p*CN).
Unlike the anti-1, the crystallographic analysis11 (see ESI†)
of the other diastereomer syn-1 has revealed that the angle
between these atoms when projected in the C1–C3 plane is
2118.6°. Instead of a through-space interaction, an inter-
molecular hydrogen-bonding between phenolic hydrogen and
cyano nitrogen was observed in the packing structure. This
suggests that the observed through-space interaction between F
and CN is weaker than the hydrogen-bonding interaction. Since
the phenol moiety of the syn- and anti-1 had drastically affected
their conformation through the hydrogen-bonding interaction,
we next decided to investigate the conformation of their methyl
ethers syn- and anti-2.
A molecule having two functional groups with large dipole
moments in an acyclic system usually adopts a stable conformer
in which the dipole moments oppose each other. However, we
have observed the unusual phenomenon in which two functional
groups in an acyclic system align to give the maximum dipole
moment. Namely, during studies on ferroelectronic crystals,8 a
large spontaneous polarization was observed in liquid crystals
doped with optically active 3-fluorocyanide derivatives. It is
possible that in this case the two functional groups with large
dipole moments aligned in the same direction to make a large
spontaneous polarization; therefore, we postulated the existence
of a novel through-space interaction between F and CN, as
depicted in Fig. 1. In order to prove this hypothesis, we carried
out X-ray crystallographic analyses of the crystalline fluoro-
cyanides 1 and 2.
The crystallographic analysis12 (see ESI†) of anti-2 has
shown that the distance between F and C(9) is 2.872 Å, which
is 0.30 Å shorter than the sum of their van der Waals radii. The
conformation of anti-2 was found to be almost the same as that
of anti-1; therefore, the novel through-space interaction was
The crystallographic analysis9 (see ESI†) of optically active
anti-1, which was prepared from 4-methoxyphenylacetonitrile
and (R)-epoxyoctane,10 is shown in Fig. 2. The distance
between F and C(1) was found to be 2.890 Å, which is 0.28 Å
† Electronic supplementary information (ESI) available: experimental
procedure for the syntheses of syn- and anti-1 and 2, spectroscopic data for
all compounds, a procedure for the stereoselective protonation of 2, full
crystallographic data of syn- and anti-1 and anti-2. See http://www.rsc.org/
suppdata/cc/b1/b107213g/
Fig. 2 Crystal structure of anti-1.
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Chem. Commun., 2001, 2394–2395
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b107213g

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proved to be independent of the intermolecular hydrogen-
bonding of the phenol moiety. However, conformational data on
syn-2 in solid state could not be obtained because it is an oil.
Since the through-space interaction between F and CN had
been established in the crystal, we turned our attention to the
existence of this new interaction in solution. The 1H-NMR
signals of the methylene protons (ABXXA type) in syn-1 were
observed at 1.98 and 2.34 ppm in CDCl3, whereas those of anti-
1 were at 1.94–2.13 (2H). These chemical shift values and the
coupling patterns in syn- and anti-1 were very similar to those
of the corresponding cis-g-lactone (1.99 and 2.72) and the
trans-g-lactone (2.35 and 2.46), respectively.8a,b This observa-
tion suggests that the through-space interaction also occurs via
a pseudo five-membered ring in both the syn and anti-
fluorocyanides 1 in solution. To demonstrate the conforma-
tional control of an acyclic system utilizing this interaction, we
investigated the stereoselective protonation of the a-anion of
the cyanide derived from an equimolar mixture of syn- and anti-
2. Our working hypothesis is that the diastereoselective
protonation of the naked anion intermediate13 with a bulky
proton source would give syn-2 preferentially by 1,3-asym-
metric induction, based on a chiral carbon bearing a fluorine
atom, if the through-space interaction between F and CN existed
in the naked anionic molecule in solution. Our results are
summarized in Table 1. Bulky phenols as proton sources gave
products with higher diastereoselectivity than benzoic acid
derivatives. 2,5-Dichlorobenzoic acid gave a product with
lower selectivity than did benzoic acid, probably due to its
higher acidity. The major diastereomer obtained was syn-2, with
a very significant diastereoselectivity (5.3+1). We interpret this
result as follows: the 1,3-asymmetric induction would arise
from the pseudo five-membered ring intermediate formed by
the through-space interaction between a lone pair of F and an sp-
carbon of the naked a-anion of the cyanide, as in the control
experiment under the same reaction conditions using an
equimolar mixture of the corresponding cis- and trans-g-
lactones to give predominantly the cis-g-lactone (94% yield,
cis+trans = 10.6+1). From the above experiments, this through-
space interaction, even in a solution containing the carbanion, is
able to affect the conformational regulation of an acyclic carbon
chain, but the ring formed by the interaction is not completely
fixed as in the g-lactone. However, this novel conformational
regulation in an acyclic compound is valuable because of (1) the
diastereoselective reaction of the a-anion of the 3-fluoro-
cyanide and (2) the stereochemical prediction of the product,
both of which are usually difficult in acyclic systems.
PM3 calculation of anti-1, and by ab initio MP2 6-31G* and
density functional df 6-31G* calculations of the simplified
model compound of anti-1.14 We also demonstrated the utility
of the through-space interaction by a stereoselective protonation
of an anion in solution. Further studies on through-space
interactions between the functional groups are underway in our
laboratory.
We are grateful for a Grant-in-Aid (No. 11672126 to K. N.)
from the Ministry of Education, Science, Sports and Culture of
Japan, in partial financial support of this research. We are also
grateful to Professor Tamejiro Hiyama, Kyoto University, for
helpful discussions at Sagami Chemical Research Center. We
also thank the Japan Energy Corporation, Toda, Saitama, Japan,
for its kind gift of (R)-epoxyoctane.
Notes and references
‡ Responsible for an X-ray crystallographic analysis of a fine needle of syn-
1 on a Rigaku RAXIS-IV imaging plate area detector.
1 (a) R. Tripathy, P. J. Carroll and E. R. Thornton, J. Am. Chem. Soc.,
1990, 112, 6743; (b) D. A. Evans, K. T. Chapman and J. Bisaha, J. Am.
Chem. Soc., 1988, 110, 1238; (c) J. K. Whitesell, R. M. Lawrence and
H.-H. Chen, J. Org. Chem., 1986, 51, 4779.
2 (a) H. B. Bürgi, J. D. Dunitz and E. Shefter, J. Am. Chem. Soc., 1973,
95, 5065; (b) H. B. Bürgi, J. M. Lehn and G. Wipff, J. Am. Chem. Soc.,
1974, 96, 1956; (c) H. B. Bürgi, J. D. Dunitz, J. M. Lehn and G. Wipff,
Tetrahedron, 1974, 30, 1563.
3 (a) W. B. Schweizer, G. Procter, M. Kaftory and J. D. Dunitz, Helv.
Chim. Acta, 1978, 61, 2783; (b) G. Procter, D. Britton and J. D. Dunitz,
Helv. Chim. Acta, 1981, 64, 471.
4 (a) F. T. Burling and B. M. Goldstein, J. Am. Chem. Soc., 1992, 114,
2313; (b) D. H. R. Barton, M. B. Hall, Z. Lin, S. I. Parekh and J.
Reibenspies, J. Am. Chem. Soc., 1993, 115, 5056; (c) Y. Nagao, T.
Hirata, S. Goto, S. Sano, A. Kakehi, K. Iizuka and M. Shiro, J. Am.
Chem. Soc., 1998, 120, 3104 also see references cited therein.
5 A. Wilk, A. Grajkowski, L. R. Phillips and S. L. Beaucage, J. Am. Chem.
Soc., 2000, 122, 2149.
6 (CF–Li) (a) C.-P. Qian, T. Nakai, D. A. Dixon and B. E. Smart, J. Am.
Chem. Soc., 1990, 112, 4602; (b) U. Pieper, S. Walter, U. Klingebiel and
D. Stalke, Angew. Chem., Int. Ed. Engl., 1990, 29, 209; (Se–F) (c) M.
Iwaoka, H. Komatsu and S. Tomoda, Chem. Lett., 1998, 969;
Conformational fixation by Li–F: (d) T. Yamazaki, M. Ando, T.
Kitazume, T. Kubota and M. Omura, Org. Lett., 1999, 1, 905.
7 For example: (F–HC) (a) W. B. Farnham, D. C. Roe, D. A. Dixon, J. C.
Calabrese and R. L. Harlow, J. Am. Chem. Soc., 1990, 112, 7707; (F–
HN) (b) J. P. Snyder, N. S. Chandrakumar, H. Sato and D. C. Lankin,
J. Am. Chem. Soc., 2000, 122, 544.
8 (a) T. Kusumoto, A. Nakayama, K. Sato, K. Nishide, T. Hiyama, S.
Takehara, T. Shoji, M. Osawa, T. Kuriyama, K. Nakamura and T.
Fujisawa, J. Chem. Soc., Chem. Commun., 1991, 311; (b) S. Takehara,
T. Kuriyama, K. Nakamura, T. Shoji, T. Fujisawa, M. Osawa, T.
Hiyama, T. Kusumoto, A. Nakayama and K. Nishide, Japan Kokai
Tokkyo Koho, 1990, H02-286673.
9 Crystal data of anti-1: C16H22FNO, M = 263.35, monoclinic, a =
7.855(2), b = 5.462(2), c = 17.607(1) Å, b = 100.90(1)°, V = 741.7(3)
Å3, T = 23 °C, space group P21 (#4), Z = 2, R = 0.055, Rw = 0.084.
CCDC 169361.
10 The syntheses of syn- and anti-1 and 2 from p-methoxyphenylacetoni-
trile and (R)-epoxyoctane (91% ee) are described in ESI.†
11 Crystal data of syn-1: C16H22FNO, M = 263.35, orthorhombic, a =
7.509(1), b = 35.774(4), c = 5.596(1) Å, V = 1503.3(4) Å3, T =
2130 °C, space group P212121 (#19), Z = 4, R = 0.043, Rw = 0.057.
CCDC 169362.
In conclusion, we have observed for the first time a novel
intramolecular through-space interaction between F and CN by
X-ray crystallographic analyses of the 1,3-fluorocyanides anti-1
and 2. Although this through-space interaction is weaker than
the hydrogen-bonding interaction, acyclic compounds having
flexible conformations were conformationally controlled by
this interaction to form the distorted pseudo five-membered
ring. However, it is particularly noteworthy that the existence of
this novel interaction can not be predicted by the semiemperical
Table 1 Stereoselective protonation of the naked a-anion of cyanidea
12 Crystal data of anti-2: C17H24FNO, M = 277.38, monoclinic, a =
7.696(4), b = 5.627(3), c = 18.628(2) Å, b = 95.02(2)°, V = 803.6(6)
Å3, T = 23 °C, space group P21 (#4), Z = 2, R = 0.081, Rw = 0.192.
CCDC 169360. See http://www.rsc.org/suppdata/cc/b1/b107213g/ for
crystallographic data in .cif or other electronic format.
Run
H+
syn+antib
Yield (%)c
13 The usual lithium anion is considered to have the known intra- and/or
1
2
3
4
Benzoic acid
3.5+1
1.9+1
4.4+1
5.3+1
100
90
87
intermolecular Li–F coordination.6
2,5-Dichlorobenzoic acid
2,6-Diphenylphenol
2,6-Di-tert-butyl-p-cresol
14 All three theoretical calculations showed that the most stable conformer
had the angle (ca. 120°) between CN and F when projected in the C1–C3
plane. The relative energy differences between the conformers having
the through-space interaction and the most stable conformers were 2.72
kcal mol21 (PM3), 1.34 kcal mol21 (MP2 6-31G*), and 2.12 kcal mol21
(df 6-31G*).
91
a syn+anti = 1.2+1. b Determined by 1H-NMR of the crude products.
c Isolated yield.
Chem. Commun., 2001, 2394–2395
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