LETTER
The Studies of the Intramolecular C–F---H–N Hydrogen Bonding
1757
The spectra were taken in solution in identical concentra-
tions (0.05 mmol/mL) at room temperature. The low field
shift for the amine protons of 1a containing o-fluorophe-
nol as compared to nonfluorinated 1b was observed
(
= 0.148 ppm). Similar low field shift was also ob-
tained in the case of 2a as compared to 2b ( = 0.104
ppm). Since the compounds 1 and 2 were insoluble in
CDCl3, we next examined the 1H NMR data of more sim-
ple compounds 3–5 in both CDCl3 and DMSO-d6. In all
cases, the chemical shifts of the fluorinated compounds
3a–5a were also shifted to downfield as compared to the
reference nonfluorinated compounds 3b–5b independent
of the solvents ( = 0.078–0.243 ppm) (Table 1).
Figure 4 X-ray crystal structure of 1a
Table 1 1H NMR Chemical Shifts of the Amine Protons of 1–5.
thesis of base pair model compounds 1–5 is worth noting
because the compounds are structurally similar to Flosul-
fide,16,20 selective cyclooxygenase-2 inhibitor, and other
biologically interesting compounds.15,21
1–5
NH2/ppma,c
/ppm
NH2/ppmb,c
/ppm
( =
–
)
( =
–
)
(b)
(a)
(b)
(a)
1a
1b
2a
2b
3a
3b
4a
4b
5a
5b
5.078
4.930
4.797
4.693
4.911
4.833
5.986
5.852
4.884
4.776
0.148
0.104
0.078
0.134
0.108
Acknowledgement
This work was partially supported by a Grant-in-Aid from the Mi-
nistry of Education, Science, Sports and Culture, Japan. N. S. wis-
hes to thank the Kato Memorial Bioscience Foundation, for support.
3.795
3.552
4.873
4.778
3.408
3.319
0.243
0.095
0.089
References and Notes
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a In DMSO-d6.
b In CDCl3.
c Each amine protons (NH2) signal was observed as a broad singlet.
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However, the downfield shift values seemed to be insig-
nificant to provide information for the existence of even
weaker N–H---F–C hydrogen bonding. The H NMR
1
chemical shifts in lower temperature or different concen-
trations did not give any additional information. The cor-
responding amine protons were observed as broad singlet
and were not split into doublet and eventually no hydro-
gen bonding was observed. We finally investigated the X-
ray structure of 1a.19 X-ray crystallographic analysis re-
veals that fluorine atom of 1a does not participate in any
intramolecular hydrogen bonding. The plane of the benz-
imidazole group is orthogonal to the plane of the fluo-
robenzene ring (Figure 4).
(8) Howarth, J. A. K.; Hoy, V. J.; O’Hagan, D.; Smith, G. T.
Tetrahedron 1996, 52, 12613.
(9) Yamazaki, Y.; Kitazume, T. Enantiocontrolled Synthesis of
Fluoro-organic Compounds: Stereochemical Challenges
and Biomedicinal Targets; Wiley: Chichester, 1999, 575.
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Kishi, Y. Angew. Chem. Int. Ed. 2001, 40, 1471.
In summary, we have first time studied the hydrogen
bonding using covalently linked F–A base pair models
and concluded that no F–A hydrogen bonding is existed
even in the covalently linked base pair models in both so-
lution state (1H NMR studies of 1–5) and the solid-state
structure of 1a. These studies support the Kool’s state-
ment stronger than by the studies of intermolecular F/A
base pair or molecular calculations. Incidentally, the syn-
Synlett 2001, No. 11, 1755–1758 ISSN 0936-5214 © Thieme Stuttgart · New York