Intramolecular OH×××FC hydrogen bonding in fluorinated carbohydrates: CHF is a better hydrogen bond acceptor than CF2

Article abstract of DOI:10.1002/anie.201303766

An intramolecular bifurcated H-bond from the axial HO-2 group to the axial F-4 atom and to the O5 atom of α-D-hexopyranosides in apolar solvents is evidenced in ¹H NMR spectra. The H-accepting properties of the F atom are modulated by the orien

Full text of DOI:10.1002/anie.201303766

.
Angewandte
Communications
DOI: 10.1002/anie.201303766
Hydrogen Bonding
Intramolecular OH···FC Hydrogen Bonding in Fluorinated
Carbohydrates: CHF is a Better Hydrogen Bond Acceptor than CF2**
Guy T. Giuffredi, Vꢀronique Gouverneur,* and Bruno Bernet*
Hydrogen bonds (H-bonds) are well-appreciated key inter-
actions, playing a major role in stabilizing tertiary structures
of peptides and nucleic acids, and being involved in molecular
recognition. Still, an official definition of the hydrogen bond
was only recently published by the IUPAC.[1] Fluoroorganic
compounds are widely used in materials, pharmaceuticals, and
agrochemicals, but the extent to which organofluorines can
act as hydrogen bond acceptor and how the proximal
substituents affect this interaction is still actively researched
and debated. A recent review of Schneider summarizes the
observation reflecting the high importance of H-bonding in
protein–ligand interactions. The two classes of compounds
À
À
that form X H···F C H-bonds in the solid state are fluori-
nated sterically crowded tertiary alcohols and fluorinated
polyols. The bulky substituents of the former class prevent the
formation of co-operative intermolecular OH···OH H-bonds
À
À
and favor the formation of dimers through O H···F C H-
bonds[11] or of monomers possessing an isolated intramolec-
[12]
À
À
ular O H···F C H-bond.
Fluorinated polyols have the
capacity to form both co-operative intermolecular OH···OH
H-bonds and bifurcated or tetravalent H-bonds with O- and
F-substituents as H-bond acceptors.[13]
À
À
current knowledge about X H···F C H-bonds (X = O, N, S,
and C) and describes the methods used to experimentally
identify factors influencing this weak interactions.[2] X H···F
C H-bonds are best assigned by X-ray diffraction in the solid
state, by computational methods in the gas phase, and by IR
and NMR spectroscopy in the liquid phase. They prefer to be
linear, with the bending of intramolecular H-bonds leading to
a decrease of the stabilization (e.g. 14 kJmolÀ1 for a linear[3]
Understanding the structure and properties of the
increasing number of newly designed fluorinated agents
requests a detailed investigation of the intra- and intermo-
lecular interactions of organofluoro compounds. In solution,
À
À
À
À
X H···F C H-bonds are formed in apolar environments in
the absence of stronger competing H-bond acceptors. Intra-
and 5 kJmolÀ1 for a bent O H···F H-bond in a five-membered
molecular X H···F H-bonds are observed in apolar solvents
À
À
ring[4]). The strong interest on XH···F H-bonds is evidenced
by a recent IR investigation of the intramolecular OH···F H-
bonding in fluorinated anancomeric cyclohexanols[5] and by
the detection of intermolecular XH···F (X = O or N) H-bonds
by 19F NMR spectroscopy in complexes of fluorinated agents
with enzymes.[6]
(like CDCl3 and C6D6) and are replaced in polar solvents by
intermolecular H-bonds to the solvent.[14,15]
Scalar coupling between XH and F (1hJ(XH,F[16]) in the
1
À
À
H NMR spectra is useful for the detection of X H···F C H-
bonds. The size of this coupling roughly reflects the strength
of the H···F H-bond. It decreases from 530 Hz for gaseous HF
À
À
Dunitz and Taylor with their paper titled “Organic
Fluorine Hardly Ever Makes Hydrogen Bonds” initiated an
to < 4 Hz for C H···F C H-bonds and close contacts between
[14]
À
C H and F as observed for example in 2-fluorotoluene.
[7]
[17,18]
ongoing debate about X H···F C H-bonds. This statement
is correct for the solid state where alcohols prefer to form
bands of co-operative intermolecular OH···OH H-bonds.[8]
Examination of the Cambridge Structural Database revealed
that only 0.6% of all CF groups are engaged as H-bond
Most X H···F C H-bonds (X = O,
N,[19,20] or S[18a]) show
À
À
À
À
1hJ(XH,F) couplings of 5–12 Hz. The precise orientation of
À
X H of primary and secondary XH groups may be deduced
from the vicinal J(H,XH) couplings. Cyclic carbohydrates,
especially rigid pyranosides, are ideal for the investigation of
O H···F H-bonds; they allow access to epimers with the
3
[7,9]
À
À
acceptors of X H (X = N or O).
A Protein Database
search, however, suggests that approximately 10% of all CF
desired orientation of the F and the secondary OH substitu-
ents. Since OH groups of carbohydrates show maximal
3J(H,OH) couplings to antiperiplanar CH of 12–12.5 Hz,[15a]
the Karplus equation of Fraser et al.[21] (J180 = 12.1 Hz) is
considered in preference to the more recent equation of
Serianni and co-workers[22] (J180 = 14.6 Hz). Vasella, Bernet,
and co-workers investigated the intramolecular O H···F C
H-bonds of fluorinated myo-inositols (1[23] and 2[24]) and
levoglucosans (3–6)[14] in CDCl3 (Figure 1). The combined
analysis of the 1hJ(OH,F) and 3J(H,OH) couplings evidenced
divalent H-bonds in 1, 2, and 6 and trivalent (so-called
bifurcated) H-bonds in 3–5. Bifurcated H-bonds were also
observed in a-l-talopyranoside 7 (R = daunomycinon-7-yl)[25]
and in b-l-ribopyranoside 8.[26]
groups may be involved in intermolecular H-bonding,[10] an
[*] Dr. B. Bernet
Laboratorium fꢀr Organische Chemie, ETH Zꢀrich
Wolfgang Pauli Strasse 10, 8093 Zꢀrich (Switzerland)
E-mail: bernet@org.chem.ethz.ch
À
À
Dr. G. T. Giuffredi, Prof. V. Gouverneur
Chemistry Research Laboratory, University of Oxford
12 Mansfield Road OX1 3TA Oxford (UK)
E-mail: veronique.gouverneur@chem.ox.ac.uk
[**] We thank Prof. B. Jaun, Dr. B. W. Schweizer (both ETH Zꢀrich), Dr.
T. D. W. Claridge, Dr. B. Odell, and Dr. A. L. Thompson (all
University of Oxford) for helpful advices concerning NMR spec-
troscopy and X-ray crystallography, and the Berrow Foundation for
a scholarship to G.T.G.
Herein, we investigate the intramolecular H-bonding of
pyranosides possessing 1,3-diaxial fluoro and hydroxy sub-
stituents and evaluate the influence of the nature and the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303766.
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couplings unambiguously (Table 1). The large 3J(2,OH)
values of all compounds (> 10.8 Hz for 9–13; 9.2–10.5 Hz
for 14 and d/l-15–16 in [D8]toluene and CDCl3 evidence
intramolecular H-bonds of HO-2. In [D6]DMSO, the intra-
molecular H-bond is mostly replaced by an intermolecular H-
3
bond to the solvent as evidenced by J(2,OH) = 4.5–5.6 Hz
(typical for a completely solvated OH group[15]) and 1hJ-
3
(OH,F) ꢀ 1.1 Hz. Intermediate J(2,OH) values in CD3CN,
À
À
Figure 1. Intramolecular O H···F C H-bonds of carbohydrates in
CDCl3 solution.
[D8]THF, and [D6]acetone reveal the existence of intra- and
intermolecularly H-bonded species. Noteworthy is the strong
H-bond of HO-3 to HO-2 of the diols 9, 10, and d/l-15
orientation of the vicinal O-substituent. Replacement of the
CHF group by a CF2 group served to probe the different H-
accepting properties of these two moieties.
3
Table 1: 1H NMR 1hJ(2-OH,F), J(2,OH), and 3J(3,OH) coupling con-
stants [Hz] of 9–d/l-16. The pictures reflect the intramolecular H-bonds
The 4,4-difluoro-a-d/l-lyxo-hexopyranosides d/l-15 and
d/l-16[27] are well-suited to investigate OH···F H-bonds
(Figure 2). For studying the effect of the O-substituent at
C3, the 4-monofluorinated analogs, the 4-fluoro-a-d-talopyr-
anosides 9–12, and the 4-fluoro-a-d-idopyranosides 13 and 14
were prepared.[28] Here, we describe the results of the H-
in apolar solvents.
Structure
Solvent
1hJ(2-OH,F)[a]
3J(2,OH)
3J(3,OH)
[D8]toluene
CDCl3
CD3CN
[D8]THF
[D6]DMSO
8.4 (8.4)
8.1 (8.0)
4.3
4.6 (4.6)
1.0
12.2
12.0
8.0
8.6
4.8
11.3
10.8
9.2
10.0
7.8
1
bonding analysis of these fluorinated compounds by H and
19F NMR spectroscopy.
[D8]toluene
CDCl3
[D8]THF
[D6]acetone
[D6]DMSO
9.1 (9.2)
9.1 (8.7)
5.6 (5.8)
5.2 (5.0)
0.9 (0)
12.1
12.1
9.3
8.1
4.8
10.9
11.2
10.0
9.3
7.8
[D8]toluene
CDCl3
CD3CN
[D8]THF
[D6]DMSO
11.4 (11.4)
10.8 (10.8)
5.3 (5.1)
5.3 (5.5)
0 (0)
11.4
10.8
8.0
9.2
5.4
Figure 2. Intramolecular bifurcated H-bonds of HO-2 to F and O5 in 4-
fluoro- and 4,4-difluorohexopyranosides.
In apolar solvents, HO-2 of the monofluorinated 9–14 and
of the difluorinated d/l-15 and d/l-16 forms a bifurcated H-
bond to the axial F atom and to O5 (Figure 3). The torsion
angle H-C2-O-H may vary from 2108 (OH···F H-bond) to
1508 (OH···O5 H-bond). Whereas 1hJ(OH,F) decreases upon
decrease of torsion angle, 3J(H,OH) increases from both
extreme conformations and reaches the maximal value at H-
C2-O-H torsion angle of 1808 when a symmetric bifurcated H-
bond is formed.
[D8]toluene
CDCl3
CD3CN
[D8]THF
[D6]DMSO
10.0 (10.1)
10.5 (10.4)
3.1
3.3 (3.0)
<1.5 (br. s)
11.8
11.6
8.4
9.1
br. s
[D8]toluene
CDCl3
CD3CN
[D8]THF
[D6]DMSO
9.3 (8.1)
9.8 (9.6)
br.
1.0
0 (0)
11.4
11.7
6.2
6.2
5.0
9.7
10.0
[b]
5.1
5.0
Solutions (about 0.025m) of the monofluoro com-
pounds 9–14 and the difluoro compounds d/l-15 and d/l-16
in a range of polar and apolar solvents were analyzed by
[D8]toluene
CDCl3
CD3CN
[D8]THF
[D6]DMSO
4.7 (4.7)
5.7 (5.6)
0 (0)
0.8
0 (0)
10.2
10.5
6.2
6.9
5.6
1
measuring F-coupled and F-decoupled H NMR spectra and
19F NMR spectra to assign 1hJ(OH,F), 3J(2,OH), and 3J(3,OH)
[D8]toluene
CDCl3
[D8]THF
<1.5 (0)
<1.5 (0)
0 (0)
9.2
9.7
6.2
4.7
10.4
10.4
9.2
[D6]DMSO
0 (0)
7.9
[D8]toluene
CDCl3
CD3CN
[D8]THF
[D6]acetone
[D6]DMSO
3.2
4.2
0 (0)
0 (0)
0 (0)
0 (0)
9.6
10.2
6.7
6.7
6.3
5.5
Figure 3. The range of bifurcated H-bond of HO-2 to F and O5 in 4-
fluoro- and 4,4-difluorohexopyranosides.
[a] Values from 19F NMR spectra in parenthesis. [b] Not assigned.
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persisting to about 50% even in [D6]DMSO (3J(3,OH) = 7.8–
7.9 Hz) and revealing co-operative intra- and intermolecular
weaker H-acceptor of the bifurcated H-bond. However,
3J(2,OH) of 10.3 and 10.5 Hz corresponds to a torsion angle
qH-C2-O-H ꢁ 1578 suggesting a H-bond exclusively to O5; this
highlights the limits of the Karplus equation of Fraser et al.[21]
Recently, a significant shielding of 19F of organofluoro
compounds engaged in intermolecular H-bonding interac-
tions with enzymes has been postulated.[6] However, we could
not detect any influence on the chemical shift of 19F of the
talopyranosides 9–12 and the lyxo-hexopyranosides d/l-15
and d/l-16 upon replacement of the bifurcated intramolecular
H-bond observed in [D8]toluene and CDCl3 by an intermo-
lecular H-bond to the solvent in [D6]DMSO (Dd ꢀ 1.4 ppm).
The larger Dd values (2.2–3.9 ppm) for the idopyranosides 13
and 14 are attributed to the change of the conformation from
4C1 in the apolar solvents to OS2 in [D6]DMSO.
À
À
O(3) H···O(2) H···O = SMe2 H-bonds.
All three coupling constants of 10 in CDCl3 are slightly
larger than those of the parent compound 8 (D3J(H,OH) =
0.6–0.7 Hz, D1hJ(OH,F) = 1.6 Hz) probably because of the
stabilization of the 4C1 conformation imposed by the trityloxy-
methyl substituent. The data assembled for 9 and 10 indicate
that the protecting group of HO-6 has no influence on
3J(2,OH) and very little impact on 1hJ(OH,F) (ca. 0.8 Hz
reduction with the more polar pivaloyl group). The large
3J(2,OH) values (12.0–12.2 Hz) of 9 and 10 in [D8]toluene and
CDCl3 are consistent with an antiperiplanar arrangement of
À
À
the C2 H and O H bonds and therefore with a symmetric
bifurcated H-bond (qH-C2-O-H ꢁ 1808). Protection of HO-3 by
an acetyl (11) or a triflyl group (12) led to a slight reduction of
3J(2,OH) (10.8–11.8 Hz) and an increase of 1hJ(OH,F) (10.0–
11.4 Hz, DJ = 0.9–2.3 Hz). This reveals an asymmetric bifur-
cated H-bond with a shorter OH···F distance (qH-C2-O-H = 190–
2008). As anticipated, the different protection of HO-3 has
a negligible influence on the H-accepting capacity of F-4,
since RO-3 and F-4 are synclinal causing a poor overlap of the
sC-O and s*C-F orbitals. The difference in the intramolecular H-
bonding of the diols 9 and 10 and the monoalcohols 11 and 12
in aprotic solvents is rationalized by the formation of a co-
A comparison of the 4,4-difluorohexosides d/l-15 and d/l-
16 with the corresponding 4-fluorotalosides 10 and 12 in
[D8]toluene and CDCl3 shows a significant decrease of
3J(2,OH) (9.2–10.2 Hz, DJ = 1.4–2.9 Hz) and
a strong
decrease of 1hJ(OH,F) (< 1.5 for d/l-15 and 3.2–4.2 of d/l-
16, DJ ꢂ 6.3 Hz). The values of d/l-15 and d/l-16 are
consistent with an asymmetric bifurcated H-bond of HO-2
with O5 as the dominant H-bond acceptor. These results
provide experimental evidences that CF2 is a weaker H-bond
acceptor than CHF as already postulated by calculation
(CH2F2 is a 0.8 kJmolÀ1 weaker H-bond acceptor than
CH3F[2]).
À
À
operative intramolecular O(3) H···O(2) H···F-4/O-5 H-bond
(3J(3,OH) = 11.0–11.3 Hz, qH-C3-O-H = 160–1658) in the diols.
À
This O(3) H···O(2) H-bond entails a restriction of the
The H-bonding of 10–d/l-16 was investigated by DFT
calculations (B3LYP function, and 6-31-G* basis set) using
the program Spartan 08 on Macintosh.[31] These calculations
were carried out on the parent gt-configured O6-benzyl ethers
10B, 11B, 12B, 13B, and 14B, and on d-15 and d-16. Energy
profiles were calculated by varying the torsion angle qH-C2-O-H
from 150 to 2108 in 108 steps (Figure 4). As anticipated, the
different protection of the acetate 11B (minimum at 1908)
and the triflate 12B (minimum at 1888; graph not shown in
Figure 4) only had a negligible influence upon the energy
profile. To determine the limiting torsion angle qH-C2-O-H, the
rotational freedom of HO-2. Modeling of
9 suggests
À
a highly unlikely H···O2 H bond angle of 648 with F acting
as the sole H-bond acceptor, and a more likely bond angle of
948 correlating well with the experimentally preferred sym-
metric bifurcated H-bond.
In their H-bond analysis of levoglucosans 3–5, Bernet and
Vasella observed that the electron-withdrawing nature of an
antiperiplanar OR substituent affects the H-accepting prop-
erties of the F atom.[14] Thus, the antiperiplanar orientation of
À
À
the C F and C3 OR bonds in the a-d-idopyranosides 13 and
14 should allow an optimal overlap of the sC-O and s*CÀ
F
bonds; hence, F of these idopyranosides, especially of diol 13
with an electron-rich O-substituent (partial deprotonation
because of the intramolecular H-bond to the methoxy group),
should be a good H-bond acceptor.[29]
The intramolecular H-bonds of 13 and 14 in [D8]toluene
and CDCl3 are mostly replaced in CD3CN and [D8]THF by
intermolecular H-bonds to the solvent and completely so in
[D6]DMSO. In the absence of intramolecular H-bonds, 13 and
14 adopt an OS2 skew boat conformation which is character-
istic for protected idopyranosides.[30] The intramolecular H-
4
bond is responsible for the C1 conformation of 13 and 14 in
apolar solvents. The 3J(2,OH) values of 13 in [D8]toluene and
CDCl3 (11.4 and 11.7 Hz) correspond to a torsion angle qH-C2-
O-H ꢁÆ 1678. The slightly larger 1hJ(OH,F) of 13 versus epimer
10 (DJ = 0.2–0.7 Hz) reveals that F of 13 is a stronger H-bond
acceptor than O5 (qH-C2-OH. ꢁ 1938). The 3J(3,OH) values of 13
(9.7 and 10.0 Hz) correspond to a torsion angle qH-C3-O-H
=
À
1508 evidencing an intramolecular O(3) H···OMe H-bond.
The strongly reduced 1hJ(OH,F) values of the acetate 14 in
[D8]toluene and CDCl3 (4.9 and 5.7 Hz) inform that F is the
Figure 4. DFT calculated energy profiles for the intramolecular H-
bonding of HO-2 of 4-fluoro- and 4,4-difluoro-a-d-hexopyranosides.
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energy profiles of 5-carba-13B and 4-epi-10B, which exclu-
sively form an intramolecular 2-OH···F-4 (qH-C2-O-H = 2068)
and 2-OH···O-5 H-bond (qH-C2-O-H = 1588), were also calcu-
lated. The energy profiles corroborate with the experimental
results: firstly, F of the monofluorinated 10B, 11B, and 12B is
a better H-acceptor than F of the difluorinated d-15 and d-16,
respectively; secondly, F of the 3-O-protected and d-talo-
configured 11B, 12B, and d-16 is a better H-acceptor than F
of the corresponding diols 10B and d-15, respectively; finally,
F of the d-ido-configured diol 13B is a better H-acceptor than
F of the corresponding acetate 14B.
Figure 5. Intramolecular bifurcated H-bonds of HO-3 to two F in 4-
fluoro-, 4,4-difluorohexopyranosides, and in 2,2,6,6-tetrafluorocyclohex-
anol.
different F atoms have been assigned by scalar 1hJ(NH,F)
couplings of 17.7 and 3.7 Hz[34] and by X-ray crystallogra-
phy.[35]
The lowest-energy structures of the above energy profiles
were further optimized and the calculated torsion angles qH-C2-
The large 3J(3,OH) values of 11.5–12.2 Hz for 17 and d/l-
18 in [D8]toluene and CDCl3 reveal symmetric bifurcated H-
bonds, although F-2 of d/l-18 should be a better H-acceptor
than Fax-4 (Table 3). These H-bonds persist to about 70% in
determined from the resulting minimum structures and
O-H
compared with the corresponding experimental torsion angles
calculated from 3J(2,OH) in CDCl3 solutions using the
Karplus equation of Fraser et al.[21] (Table 2). The experi-
3
Table 3: 1H NMR 1hJ(OH,4-F), 1hJ(OH,2-F), and J(3,OH) coupling con-
stants [Hz] of 17 and d/l-18. The pictures reflect the intramolecular H-
bonds in apolar solvents.
Table 2: Comparison of the experimental qH-C2-O-H values from CDCl3
solution with the calculated ones from modeling.
Structure
Solvent
1hJ(OH,4-F)[a] 1hJ(OH,2-F)[a] 3J(3,OH)
Structure
10
11
13
14
d/l-15
d/l-16
[D8]toluene
CDCl3
[D8]THF
<1.5 (0)
<1.5 (0)
<1.5 (0)
0
<1.5 (0)
<1.5 (0)
<1.5 (0)
0
12.2
12.1
10.2
7.0
3J(2,OH) [Hz]
Exp. qH-C2-O-H [8]
Corr. qH-C2-O-H [8][a]
Structure
12.1
180
10.8
200
189
11.7
191
10.5
158
193
14B
184
10.6
159
168
d-15
173
10.1
205
180
d-16
183
[D6]DMSO
10B
178
11B
13B
190
Calc. qH-C2-O-H [8]
190[b]
[D8]toluene
CDCl3
[D8]THF
CD3CN
1.8 (2.0)
2.3 (2.5)
<1.5 (0)
0
0
1.6 (2.0)
2.3 (2.5)
<1.5 (0)
0
0
11.8
11.5
10.0
7.9
[a] Assuming a reduction of 3J(2,OH) by 1.0 Hz for each additional polar
substituent. [b] 1888 for 12B.
[D6]DMSO
7.5
mental and calculated data coincide well for diols 10 and 13.
The experimental qH-C2-O-H values suggest the F atom as the
only H-acceptor for the acetate 11 and the triflate d-16, and
O5 for the acetate 14 and the difluoride d-15. In contrast, the
calculated qH-C2-O-H values hint at bifurcated H-bonds in the q
range of 173–1908. Proximal polar substituents lead to the
reduction of geminal and vicinal coupling constants.[32] The
reduction due to OH groups is already included in Fraserꢀs
Karplus equation, but the electron-withdrawing AcO and
TfO, and the additional equatorial fluoro substituent of the
above compounds should lead to an additional reduction of
3J(2,OH). This prevents the applicability of Fraserꢀs Karplus
equation to 11, 14, d-15, and d-16; an analogous general-
[a] Values from 19F NMR spectra in parenthesis.
[D8]THF and to 35–40% in [D6]DMSO. These data evidence
for 17 and d/l-18 in polar solvents a tetravalent H-bond with
two F as intra- and a solvent molecule as intermolecular H-
bond acceptor. Such a tetravalent H-bond is also present in
the solid state of d/l-19[27] (see X-ray structure in the
Supporting Information). Despite the strong persistence of
the bifurcated H-bond, the 1hJ(OH,F) couplings of 17 (only
line broadening) and d/l-18 are small (ꢀ 2.5 Hz), probably
because of a strong reduction by the two axial F atoms. The
1hJ(OH,F) couplings of the pivaloylate 17 are about 0.8 Hz
smaller than those of the benzyl ether d/l-18 as already stated
for the pivaloylate 9 as compared to the trityl ether 10. The
1H NMR spectrum of the 2,2,6,6-tetrafluorocyclohexanol 20
was published without discussion of the H-bonding.[36] The
data however inform that the two equatorial F atoms lead to
reduction of 3J(1,OH) to 6.6 Hz and to the complete
disappearance of the 1hJ(OH,F) coupling.
ization as done in Altonaꢀs generalized Karplus equation for
[33]
3JHCCH
would be required. Corrected qH-C2-O-H values
(Table 2) were obtained by assuming a bona fide reduction
of 1 Hz for each additional polar substituent (one in 11, 14
and d/l-15; two in d/l-16). These corrected values fit well with
the calculated values suggesting that the DFT calculations
correctly predict the H-accepting properties of these 4-
fluorinated hexopyranosides.
In conclusion, the 1H and 19F NMR studies and DFT
calculations reported here confirm that intramolecular
OH···FC H-bonding is an important interaction of fluorinated
carbohydrates in apolar solvents. Our data provide further
evidence that 1) the F atom competes favorably as H-acceptor
with the endocyclic O5 of hexopyranosides; 2) the bifurcated
H-bond to F and O5 is remarkably persistent in acetone,
acetonitrile, and THF, and almost completely disrupted in
DMSO; 3) the strength of the OH…FC bond is modulated by
the nature of a vicinal O-substituent disposed antiperiplanar
The 2,4-difluoro-a-d-talopyranoside 17[28] and the 2,4,4-
trifluoro-a-d/l-lyxo-hexopyranoside d/l-18[27] are interesting
as HO-3 of these 2,4-difluorohexosides should form a bifur-
cated H-bond to two F atoms (Figure 5). Analogous bifur-
cated H-bonds of an equatorial OH to two vicinal axial O-
substituents have been described, for example, for HO-2 of
myo-inositols 1 and 2 in CDCl3 and were evidenced by large
3J(H,OH) couplings of 11.8–12 Hz.[23,24] Furthermore, asym-
metric bifurcated H-bonds of NH of benzanilides to two
Angew. Chem. Int. Ed. 2013, 52, 10524 –10528
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 10527

.
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3
(OH,F) and J(H,OH) couplings by polar substituents is an
additional important output in this study; this observation
suggests that caution is necessary in the qualitative and
quantitative interpretation of the size of these couplings.
These advances are of fundamental interest and may help
with the design of high-performance materials or pharma-
ceuticals.
Received: May 2, 2013
Revised: July 11, 2013
Published online: August 19, 2013
Keywords: carbohydrates · density functional calculations ·
.
fluorinated alcohols · hydrogen bonds · scalar couplings
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