Influence of Alcohol β-Fluorination on Hydrogen-Bond Acidity of Conformationally Flexible Substrates

Article abstract of DOI:10.1002/chem.201604940

Rational modulations of molecular interactions are of significant importance in compound properties optimization. We have previously shown that fluorination of conformationally rigid cyclohexanols leads to attenuation of their hydrogen-bond (H-bond) donat

Full text of DOI:10.1002/chem.201604940

A Journal of
Accepted Article
Title: Influence of Alcohol β-Fluorination on Hydrogen-Bond Acidity of
Conformationally Flexible Substrates
Authors: Jerome Graton, Guillaume Compain, François Besseau,
Elena Bogdan, Joe Watts, Lewis Mtashobya, Zhong Wang,
Alex Weymouth-Wilson, Nicolas Galland, Jean-Yves Le
Questel, and Bruno Linclau
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To be cited as: Chem. Eur. J. 10.1002/chem.201604940
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10.1002/chem.201604940
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FULL PAPER
Influence of Alcohol β-Fluorination on Hydrogen-Bond Acidity of
Conformationally Flexible Substrates
J. Graton,*(a) G. Compain,(b) F. Besseau,(a) E. Bogdan,(a) J. M. Watts,(b) L. Mtashobya,(b) Z. Wang,(b) A.
Weymouth-Wilson,(c) N. Galland,(a) J.-Y. Le Questel,*(a) B. Linclau,*(b)
Abstract: Rational modulations of molecular interactions are of
significant importance in compound properties optimization. We
have previously shown that fluorination of conformationally rigid
cyclohexanols leads to attenuation of their hydrogen-bond (H-bond)
donating capacity (pKAHY) when OH•••F intramolecular hydrogen-
bond (IMHB) interactions occur, as opposed to an increase in pKAHY
due to the fluorine electronegativity. This work has now been
extended to a wider range of aliphatic β-fluorohydrins with increasing
degrees of conformational flexibility. We show that the –sometimes
unexpected– observed differences in pKAHY between closely related
diastereomers can be fully rationalized by subtle variations in
populations of conformers able to engage in OH•••F IMHB, as well
as by the strength of these IMHBs. We also show that the Kenny
theoretical Vα(r) descriptor of H-bond acidity accurately reflects the
effects, which have been amply exploited in many fields,
especially in the biosciences.[1, 4]
The impact of fluorination on Brønsted acid/base properties
is well-understood: in general, fluorine introduction increases
Brønsted acidity, and decreases Brønsted basicity, even if
subtle effects may occur.[5] On the other hand, the fluorine
influence on H-bond properties of adjacent functional groups has
been shown to be less chemically intuitive. While the strong
increase in H-bond donating capacity (H-bond acidity) of
polyfluorinated alcohols such as hexafluoroisopropanol (HFIP)
and trifluoroethanol (TFE) has been well-documented,[6] our
work involving stereochemically defined, conformationally rigid
fluorohydrins[7] (Figure 1) shows that monofluorination can lead
to a decreased OH H-bond acidity on the pKAHY scale,[6c] and
that β,β-difluorination only leads to a modest increase. The H-
bond acidities were measured in CCl4 at 25°C by FTIR
spectroscopy.[6c] Computationally obtained predictions of H-bond
properties, such as the Kenny Vα(r) parameter for H-bond
acidities[8] showed an excellent correlation with the experimental
values.[6c, 7]
observed variations and
a calibration equation extended to
fluorohydrins is proposed. This work clearly underlines the
importance of the weak OH•••F IMHB in the modulation of alcohol H-
bond donating capacity.
Introduction
Me
Me
N
K
O
O
N
ROH
+
R
H •••
Fluorination of organic compounds is well known to affect
chemical properties of adjacent functional groups, as well as
physicochemical properties at the molecular level.[1] In addition,
a C–F bond itself offers opportunities for weak attractive
intermolecular interactions with protein residues,[2] for example
as weak hydrogen bond (H-bond) acceptor.[3] The large fluorine
electronegativity, resulting in a highly polarized C–F bond and
weakly-polarizable fluorine lone pairs, is at the origin of these
KAHY
O
pKAHY = -log10 KAHY = +log10
K
OH
pKAHY
tBu
1.25
1.00
0.75
0.50
1.30
2b
2d
F
F
F
OH
F
OH
tBu
1.03
tBu
1e
0.93
0.85
OH
tBu
F
F
OH
1d
F
0.71
0.43
0.71
tBu
tBu
OH
OH
Dr. Jérôme Graton, Prof. Dr. Jean-Yves. Le Questel, Dr Elena
Bogdan, Dr Nicolas Galland, Mr François Besseau
CEISAM UMR CNRS 6230, Faculté des Sciences et des
Techniques, Université de Nantes
2, rue de la Houssinière – BP 92208,44322 NANTES Cedex 3 (F)
Fax: (+3) 2 51 12 54 02, E-mail: jerome.graton@univ-nantes.fr,
jean-yves.le-questel@univ-nantes.fr
tBu
tBu
2a
2c
1a
1c
0.56
0.51
OH
F
OH
tBu
1b
F
0.25
0.00
Prof. Dr. Bruno Linclau, Dr Guillaume Compain, Mr Joseph M.
Watts, Mr Lewis Mtashobya, Dr Zhong Wang
Chemistry, University of Southampton, Highfield, Southampton
SO17 1BJ (UK)
OH
F
-0.15
tBu
2e
Fax: (+44) 23 8059 7574, E-mail: bruno.linclau@soton.ac.uk
Figure 1. Experimental H-bond acidities of conformationally restricted
Dr Alex Weymouth-Wilson
Dextra Laboratories Ltd, The Science and Technology Centre,
Earley Gate, Whiteknights Road, Reading RG6 6BZ, UK
fluorohydrins.[7]
The changes in pKAHY, shown in Figure 1, were explained as
the result of a combination of the fluorine electronegativity,
which increases H-bond acidity (e.g. 2b vs 2a), and of OH•••F
Supporting information for this article is given via a link at the end of
the document
1
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10.1002/chem.201604940
Chemistry - A European Journal
FULL PAPER
intramolecular hydrogen-bond (IMHB) interactions (e.g. 2c vs
2a), which have an attenuating effect. Indeed, after long
debates,[1, 9] the effective ability of fluorine to act as a H-bond
acceptor, through inter- and intramolecular OH•••F interactions,
is now clearly established.[3] We also noted that the effect of the
fluorine electronegativity depended on the fluorohydrin dihedral
angle.[10]
in the current experiments) were accounted for during geometry
optimization. The main conformers results for 3–5 are shown in
Table
1 (full data in the Supporting Information). Where
appropriate, F•••HO intramolecular distances are given.
For series 3, conformational nomenclature consists of
descriptors that indicate whether the OH group is axial or
equatorial, and that characterize the H–O–C–H dihedral angle.
The cis-fluorohydrin 3b is calculated to have a virtually equally
distributed population between the two chair conformations (in
CCl4, at 25 °C), with a strong preponderance for the Ax_g+
(50%) and Eq_t (45%) forms in which the O–H and C–F bonds
are oriented parallel. The F•••HO distances are just below 2.3 Å,
up to 10% shorter than the sum of the fluorine and hydrogen van
der Waals radii (2.57 Å).[13] However, using NMR spectroscopic
The conformational rigidity of the cyclohexane rings in the β-
fluorohydrins shown in Figure 1 results in a fully defined
fluorohydrin F–C–C–O dihedral angle, with the rotation around
the C–O bond being the only relevant conformational flexibility
feature. Following from this study, we have now investigated the
influence of fluorination on the H-bond acidities of β-fluorohydrin
families 3–6 (Figure 2), the results of which are reported herein.
These fluorinated compounds present various degrees of
conformational flexibility related to the β-fluorohydrin C–C bond:
cyclohexanols 3, with chair inversion leading to two possible β-
fluorohydrin conformations; and substrates 4, 5, 6, with full
fluorohydrin flexibility. However, in 4 and 5, the alcohol group
has a fixed equatorial or axial position. We report their synthesis,
the experimental determination of their H-bond acidities, and the
computational analyses of their conformational properties.
Natural Bond Orbital (NBO)[11] analyses, aimed to provide an
accurate description of the different IMHB interactions occurring
in the various fluorohydrins are included, as well as
computations of the electrostatic potential Vα(r) descriptor which
is correlated to the experimental H-bond acidity values.[3h, 6c, 7-8]
Finally, the relationship between the frequency shift, ΔνOH, of the
νOH stretching vibration and pKAHY is discussed.
analysis at -80°C, Basso et al. found
a conformational
preference significantly in favor of the equatorial form in
dichloromethane (73%), acetone (68%) and methanol (75%).[14]
These differences likely originate from a temperature and
solvent dependence. For the trans fluorohydrin 3c, the chair
conformation is strongly favored towards the gauche
fluorohydrin arrangement, that is with both substituents in
equatorial positions (total population: 93%, see Table S1), and
mainly as the Eq_g+ conformer (88%). This is in good agreement
with a previously published result (92% for the equatorial form)
derived from the coupling constants measured by NMR
spectroscopy in CCl4 solution.[15] In the same solvent,[16]
a
population of 98% for the equatorial form was evaluated after
deconvolution of the νOH stretching band at 3614 cm-1 with a
shoulder at 3633 cm-1. Similarly, the three major conformations
of difluorinated 3d, Ax_g+ (65%), Eq_g+ (18%) and Eq_t (12%),
corresponding to about 95% of the whole population, present
one fluorine atom close to the hydroxyl group. For the IMHB
conformers of both 3c and 3d, all OH•••F distances are larger
than 2.3 Å.
OH
X
CHnF3-n
OH
OH
CHnF3-n
OH
CHnF3-n
tBu
tBu
Y
4a: n=3
5a: n=3
6a: n=3
6b: n=2
6c: n=1
6d: n=0
3a: X=Y=H
4b: n=2
4c: n=1
4d: n=0
5b: n=2
5c: n=1
5d: n=0
3b: X=F, Y=H
3c: X=H, Y=F
3d: X=Y=F
For series 4 and 5, the two descriptors used for the
monofluorinated derivatives relate to the H–O–C–CH3 and F–
CH2–C–O dihedral angles, while for the difluoromethylated
compounds, the second descriptor now relates to the H–CF2–C–
O dihedral angle. In these compounds, the hydroxyl group is
mainly found as part of a gauche fluorohydrin conformation,
whatever the degree of fluorination. However, it is worth noting
that for the non-fluorinated 4a and 5a, this preference is partly
due to the higher degeneracy of the gauche form. Conversely,
for the mono-, di-, and trifluorinated derivatives, these G
conformers essentially benefit from the stabilizing IMHB
interactions, and it is interesting to note the significant difference
of the exocyclic CH2F conformations of 4a, 5a with the
equivalent compounds without the hydroxyl group, as recently
described in detail by Huchet et al.[17] Their populations indeed
reach at least 85% in CCl4, except for compound 5b (72% for
the G_g+ conformer). Interestingly, the OH•••F distances in 4c/d
are longer compared to those in 5c/d, and the proportion of
IMHB conformers increases from 5b to 5d, and to a lesser
extent from 4b to 4d.
Figure 2. Structures of the β-fluorohydrins under study, with decreasing levels
of conformational [fluorohydrin bond] restriction: cyclohexanols (series 3), t-
butyl cyclohexanols (series 4 and 5), and pentan-2-ols (series 6).
Experimental and Computational Results
Fluorohydrin synthesis
The synthesis of compounds 3–5, and 6d was achieved
according to the literature, and the synthesis of the novel
compounds 6b and 6c was achieved using standard fluorination
methodology. All synthesis and characterization details are
provided in the Supporting Information.
Theoretical conformational analysis
A full description of the H-bond properties of functional groups is
innately connected with their thorough conformational
analysis,[3h, 12] which was undertaken for the compounds under
study by density functional theory (DFT) calculations. For a
proper description of their structural features and the relative
populations of the various conformers, the solvent effects (CCl4
Without any structural constraint, the conformational
landscape of the pentan-2-ol derivatives 6a-d is very diverse,
with a large number of conformers (15 for 6a, 23 for 6b, 20 for
2
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10.1002/chem.201604940
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FULL PAPER
Table 1. Calculated parameters related to the conformers of 3–5 in CCl4 medium at the IEFPCM-MPWB1K/6-31+G(d,p) level of theory.
E(2)
ΔG°
ΔG°
dOH-
[b]
→σ
[b]
[c]
n
*
Compound
Conf.
Ax_g+
Eq_t
Compound
Conf.
Eq_g+
Ax_g-
dOH-F
V (r)
E(2)
V (r)
[c]
(pi)[a]
(pi)[a]
α
→σ
α
n
*
F
0.0
(88.2
)
H
0.0
(49.8)
O
O
2.293
2.298
-
4.3
4.3
-
2.370
-
3.2
-
H
F
H
0.3126
0.3153
F
O
3b
3c
H
F
0.2
(45.1)
8.2
(3.2)
O
F
1.9
(12.0×2
)
0.0
(64.8
)
Ax_g+
Eq_g+
Eq_t
2.353
3.0
H
Ax_g
Eq_g
Eq_t
H
O
O
F
F
0.0
(25.5×2
)
3.1
(18.3
)
0.3179
0.3256
F
F
3a
-
-
3d
2.381
2.8
O
O
H
H
F
H
O
H
O
4.3
(11.6
)
0.5
(21.0)
F
-
-
2.323
3.6
0.0
(33.7×2
)
0.0
(42.1
×2)
H
CH3
O
O
G
T
-
-
G
T
-
-
H
O
CH3
tBu
tBu
tBu
tBu
0.3153
0.3170
4a
5a
CH3
H
2.4
(15.8
)
O
0.1
(32.6)
-
-
4.5
-
-
-
CH3
H
H
F
0.0
(43.0×2
)
0.0
(36.1
×2)
H
H
H
F
G_g+
T_g
G_t
2.292
G_g+
T_g
G_t
2.311
3.6
O
H
O
tBu
tBu
tBu
tBu
H
H
F
H
F
H
10.5
(0.5×
2)
O
O
H
F
6.2
(3.6×2)
O
H
-
-
-
-
H
0.3125
0.3176
H
H
4b
5b
H
H
3.2
(10.0
×2)
8.9
(1.2×2)
H
H
O
-
-
-
-
tBu
tBu
tBu
F
H
O
H
H
5.0
(4.8)
T_t
-
F
0.0
(24.7×2
)
4.4
(6.3×
2)
F
F
H
H
F
F
O
O
G_t
G_g-
T_g
2.317
2.8
4.2
-
G_t
2.401
1.9
3.6
-
F
F
H
H
O
tBu
tBu
tBu
tBu
tBu
H
H
F
H
0.5
(20.3×2
)
0.0
(37.3
×2)
H
F
2.284
G_g-
T_g
G_g+
2.326
O
F
F
0.3227
0.3278
0.3350
3
4c
5c
F
H
H
O
O
8.5
(1.2×
2)
F
H
4.8
(3.5×2)
-
-
-
-
O
H
tBu
H
F
H
F
F
H
5.0
(5.0×
2)
10.8
(0.3×2)
G_g+
-
-
H
t-Bu
O
F
tBu
0.0
(45.0×2
)
0.0
(49.5
×2)
H
CF3
O
H
G
T
2.363
-
1.9
-
G
T
2.456
-
1.3
-
O
CF3
tBu
tBu
tBu
tBu
0.3326
4d
5d
CF3
H
O
O
H
3.7
(10.0)
9.4
(1.1)
CF3
[a] in kJ mol-1 (%). [b] in Å. [c] in kJ mol-1. [d] in a.u. [e] calculated from eq. (2).
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10.1002/chem.201604940
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FULL PAPER
6c, and 9 for 6d) found within an energetic range of 10 kJ mol-1
(see Table S4). Nevertheless, the following trends can be
drawn: the proportion of IMHB conformers steadily increases
from 6b to 6d (80%, 92%, and 99.7%), despite a concomitant
lengthening of the OH•••F distances (the weighted values are
2.326, 2.350 and 2.450 Å, respectively).
acidity observed upon the first fluorination according to the
chemical structure of the fluorinated derivatives. Whereas
compounds 3b and 4b are significantly less acidic than their
non-fluorinated analogues 3a and 4a, 3c shows a H-bond acidity
almost equivalent to 3a. Moreover, an increase in pKAHY value is
measured for compounds 5b and 6b, by comparison with 5a and
6a. The difference between closely related stereoisomers such
as 3b/3c, and 4b/5b is unexpected.
NBO and AIM analyses
For conformations showing an OH•••F IMHB, the charge transfer,
Irrespective of the series under study, difluorination and
trifluorination lead to significant and similar enhancements of H-
bond acidity. At equivalent fluorination state, the H-bond acidity
estimated with E(2) *, from the fluorine lone pair to the hydroxyl
→σ
n
antibonding orbital was calculated through NBO analyses (Table
1). This electronic descriptor is found to be well-correlated to the
structural parameter dOH F, with the strongest charge transfers

Table 2. Experimental spectroscopic features, νOH, εOH, and ΔνOH, and H-bond
acidity properties, pKAHY, ΔGAHY, of β-fluorohydrins under study.
corresponding to the shortest distances. Furthermore, in general,
the charge transfer decreases from the monofluorinated to the
trifluorinated derivatives (typically from 4 to 3, and to 2 kJ mol-1),
in line with their decreasing H-bond accepting character.[3u]
AIM analysis[18] may lead to the localization of a bond critical
point (BCP) between the fluorine and the hydroxyl hydrogen
atoms. From the potential energy densities Vb computed at the
[b]
[a]
[a]
[a]
[c]
Entry
εOH
pKAHY
νOH
νOH…B
ΔνOH
ΔGAHY
3a [d]
3b
3c
3d
4a
4b
4c
4d
5a
5b
5c
5d
6a
6b
6c
6d
3623
3608
3615
3617
3616
3603
3602
3602
3612
3606
3605
3604
3628
3617
3619
3620
64
103
127
129
61
3449
3414
3416
3382
3452
3417
3378
3345
3443
3412
3378
3344
3452
3414
3367
3335
174
194
199
235
164
186
224
257
169
194
227
260
176
202
252
285
0.67
0.47
0.66
0.98
0.63
0.51
0.85
1.28
0.55
0.76
1.06
1.48
0.72
0.81
1.24
1.67
-3.8
-2.7
-3.8
-5.6
-3.6
-2.9
-4.9
-7.3
-3.1
-4.3
-6.0
-8.4
-4.1
-4.6
-7.1
-9.5
BCP, the energy (EHB) of the corresponding IMHB interaction
3i, 12]
can be estimated.[3h,
Unfortunately, these analyses
systematically failed to find any BCP in the β-fluorohydrin series,
which is in agreement with literature reports of similar 5-
membered IMHB motifs.[19]
120
136
139
79
Theoretical H-bond acidity estimation
The H-bond acidity is a property that can be estimated from
the calculation of the electrostatic potential parameter Vα(r).[6c, 7]
For a given compound, the individual values are first computed
for each conformer detected on the potential energy surface
(see Supporting Information), a weighted Vα(r) value being then
derived from the Boltzmann distribution (Table 1). Regardless
the series, the highest Vα(r) values are computed for the
trifluorinated alcohols, followed systematically by the
difluorinated ones, and finally the monofluorinated derivatives.
As already depicted and rationalized for other fluorohydrin
derivatives,[3j, 7] it is worth noting that the values calculated for
non-fluorinated compounds are located between the mono- and
the difluoroalcohols (except in series 5, see Table S7).
111
119
140
54
60
92
93
H-bond acidity measurements
[a] cm-1, [b] L mol-1 cm-1, [c] kJ mol-1, [d] ref [6c]
.
The H-bond donating capacity, pKAHY
, of the alcohols is
determined by IR spectroscopy through complexation with a
standard H-bond acceptor, N-methylpyrrolidinone (NMP), in CCl4
at 25 °C as shown in Figure 1.[6c] The decrease in intensity of the
νOH band with increasing amounts of NMP is measured, as well
as the frequency shifts, ΔνOH, of the OH band observed upon
complexation. The measured ΔνOH, εOH, pKAHY values, and the
is roughly found to be stronger when the β-fluorohydrin C–C
bond presents an increasing degree of conformational flexibility.
Discussion: influence of fluorination on pKAHY
corresponding free energies of complexation, ΔGAHY
, are
gathered in Table 2. The intensity of the νOH stretching vibration
significantly increases upon fluorination. The molar absorption
coefficient, εOH, in difluorinated derivatives reaches twice the
unfluorinated values, while a limited increase is finally measured
with a third fluorination.
To facilitate discussion of the various trends, the pKAHY
values of 3–6 are also presented on an experimental scale in
Figure 3. A striking result is the opposite variation of H-bond
The experimental observations are explained through a careful
analysis of the conformational profile of the compounds. For 3b,
each chair conformer allows for OH•••F IMHB (95% of the total
population), while the trans isomer 3c exhibits only one
conformation featuring an OH•••F IMHB (88% of the total
population), next to conformations featuring a trans-diaxial
fluorohydrin motif, or a trans-diequatorial fluorohydrin motif with
the OH bond rotated away from the fluorine (no OH•••F IMHB).
4
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pKAHY
(1.67)
6d
OH
R
OH
OH
1.6
(R = CF3)
R
OH
tBu
H,F
tBu
R
1.5
1.4
1.3
1.2
1.1
1.0
0.9
0.8
0.7
0.6
0.5
H,F
(1.48)
5d (R = CF3)
+0.43
(1.28)
4d (R = CF3)
+0.42
(1.24)
6c (R = CHF2)
+0.43
(1.06)
5c (R = CHF2)
+0.44
(0.98)
3d
+0.30
(0.85)
4c (R = CHF2)
+0.32
(0.80)
+0.51
(0.76)
6b (R = CH2F)
+0.08
5b (R = CH2F)
(0.72)
6a (R = CH3)
+0.34
(0.67)
3a
(0.66)
(0.63)
+0.21
-0.01
3c
(trans)
4a
(R = CH3)
-0.12
(0.55)
5a (R = CH3)
-0.20
(0.51)
4b (R = CH2F)
(0.47)
3b (cis)
Figure 3. Experimental H-bond acidity variations observed for series 3-6 upon an increasing degree of fluorination.
Hence, the dependence of the measured pKAHY values for the
monofluorinated cyclohexanols on their relative stereochemistry
can be explained as follows: in 3b, the OH•••F IMHB in both
conformers leads to a decrease of the H-bond acidity.
2c and 1b are observed, with OH•••F distances shorter than 2.3
Å. Moreover, the charge transfer from the fluorine lone pair to
the O–H antibonding orbital is in each case slightly larger than 4
kJ mol-1. Similarly, the decrease of H-bond donating ability
observed for 3b (0.20 pK units) from the non-fluorinated
counterpart 3a is very similar to that observed from 2a to 2c, and
from 1a to 1b (Figure 1). Interestingly, the H-bond acidity of the
cis fluorohydrin 3b is very nicely estimated from the
experimental pKAHY values of 1c and 2b weighted by the
corresponding computed equatorial and axial populations of 3b
(Scheme 1(a) and Table S1). For the IMHB conformer of 3c, the
OH•••F distance is longer (2.370 Å) and the charge transfer is
weaker (3.20 kJ mol-1) than found in 3b, but exactly as found in
the equivalent derivative 1c. Again, the pKAHY value for 3c can
be derived from the corresponding weighted values of 1c and 2b
(Scheme 1(a)).
Difluorination (3d) significantly enhances the H-bond acidity
despite the possibility to form OH•••F IMHBs irrespective of the
hydroxyl position (axial/equatorial). In these systems, the
fluorine electron withdrawing effect prevails over the IMHB effect,
a behavior previously observed with the rigid substrates 1d and
2d (Figure 1). As shown in Scheme 1(b), there is again an
excellent equivalence between the experimental H-bond acidity
Conversely for 3c, conformations leading to its increase are
significantly populated (12%), enough to compensate for the
attenuating effect of the OH•••F IMHB, leading to an overall
negligible change in pKAHY compared to 3a. It is interesting to
compare how the different conformations without any IMHB
contribute to the overall pKAHY value. For the trans-diaxial Ax_g-,
an increase of pKAHY of +0.72 is calculated from the individual
electrostatic potential values (see Section 3 in SI), which is in
line with the +0.59 increase experimentally observed between
compounds 2a and 2b. In contrast, a weaker increase (+0.41) is
calculated for the non IMHB trans-diequatorial forms, which is
consistent with the aforementioned dependence of the fluorine
inductive effect on the dihedral angle.[7]
There is an internal consistency between the H-bond
properties of 3b/3c and those of the corresponding
conformationally rigid fluorohydrins 1b/1c and 2c/2b. The
hydroxyl surroundings of the axial and equatorial conformations
of 3b are equivalent to that of compounds 2c and 1b,
respectively. Hence, similar OH•••F IMHBs to that of compounds
5
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10.1002/chem.201604940
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of the flexible difluorinated alcohol 3d and the value estimated
from the combination of the rigid compounds 1d and 2d.
Then, the behaviors within these two series are different
upon fluorination of the methyl group. A decrease in pKAHY
indeed occurs upon monofluorination for 4b, while there is an
increase for 5b. This trend can also be rationalized by the
conformational features of these derivatives. For 4b, 86% of the
population is that of the G_g+ conformation, which presents an
IMHB motif, while the corresponding conformer for 5b has a
notably lower population (72%). Also, the IMHB in 4b is shorter
compared to that in 5b, resulting in a larger nF→σ*O-H charge
Substrates 4 and 5, which feature full conformational
flexibility around the C(OH)–C(HnF3-n) bond, are distinguished by
the fixed equatorial and axial orientation of the alcohol group.
For the two nonfluorinated alcohols 4a and 5a, a slight decrease
in H-bond acidity is observed compared with the non-methylated
analogues 1a and 2a (Figure 1).[7] In addition, in contrast to 1a
vs 2a, the axial alcohol 5a has a lower pKAHY value compared to
transfer. Furthermore, 4b has
a negligible population of
(a)
conformers where the C–F and C–OH bonds are antiperiplanar
(3%), while 5b features two such conformers totaling 25% in
population.
pKAHY(3b)exp = 0.47
OH
F
For both 4 and 5 series, a similar increase is observed upon
di- (+0.30 pK units) and trifluorination (+0.42 pK units), with the
H-bond donating ability of 5b-d thus being systematically higher
than that of 4b-d. Hence, 4c has a lower pKAHY value (0.85) than
5c (1.06), despite both have a similar population of IMHB
conformations (90% vs 88%). However, for equivalent
conformers the OH•••F distance is larger in the latter, resulting in
a smaller charge transfer. Hence, their IMHB is weaker, resulting
in a larger H-bond acidity. In addition, 5c exhibits a larger
population where the C–F and C–OH bonds are antiperiplanar
(87%) compared to 4c (49%). The same explanation is invoked
for the lower pKAHY value for 4d compared to 5d: despite the
IMHB conformation for the former is less populated (90%) than
that of 5d (99%), the weaker IMHB for 5d compared to that of 4d
is again taken as origin for the measured H-bond acidity
difference.
F
OH
pKAHY (3b) = pi . pKAHY(1b)
= 0.49 . 0.51
+
+
(1-pi) . pKAHY(2c)
0.51 . 0.43
pKAHY (3b) = 0.47
pKAHY(3c)exp = 0.66
OH
OH
F
F
pKAHY (3c) = pi . pKAHY(2b)
= 0.93 . 0.56
+
+
(1-pi) . pKAHY(1c)
0.07 . 1.30
pKAHY (3c) = 0.61
(b)
pKAHY(3d)exp = 0.98
In the acyclic series 6, conformational analysis of 6b (Table
S4) reveals that the features of the IMHB conformers, a
population of 84% with a mean distance (2.326 Å) and a mean
charge transfer (3.8 kJ mol-1), are intermediate between 4b and
5b. This is in good agreement with the rather small increase
upon monofluorination (ΔpKAHY = +0.08) from 6a to 6b, that can
be compared to the significant decrease observed in series 4
and to the important increase found in series 5. Much stronger
enhancements are measured with the introduction of a second
(ΔpKAHY = +0.44 from 6b to 6c) and a third fluorine atom (ΔpKAHY
= +0.43 from 6c to 6d). Again, the mean intramolecular distance
(2.350 Å) and charge transfer (2.3 kJ mol-1) found in 6c (Table
S5) are less favorable than in 4c and 5c, and in line with the
greater increase of pKAHY observed from 4b/5b to 4c/5c.
All these data clearly illustrate the influence of fluorine on the
hydroxyl H-bond acidity. On the one hand, the major role is
obviously played by the increased electron withdrawing effect
with higher degree of fluorination yielding to H-bond acidity
increase. On the other hand, the occurrence of IMHB
conformations acts against this increase, with a greater extent
for monofluorinated compounds than for di- and trifluorinated
derivatives, given to the reduced H-bond accepting ability of the
latter.[3q] Moreover, it is shown that, for a given degree of
fluorination, very subtle differences, either in populations or
OH
F
F
OH
F
F
pKAHY (3d) = pi . pKAHY(1d)
= 0.30 . 0.85
+
+
(1-pi) . pKAHY(2d)
0.70 . 1.03
pKAHY (3d) = 0.98
Scheme 1. Correlation between the experimental pKAHY values of 3b, 3c and
3d, and the values estimated by combination of the computed conformer
distribution and the experimental pKAHY values of series 1 and 2.
the equatorial alcohol 4a. The overall decrease can be explained
by the electron-donating inductive effect of the methyl
substituent on the hydroxyl group, possibly augmented by steric
effects that can occur in these tertiary alcohols. The lower pKAHY
value for the axial alcohol could be due to the electron donating
σC-H→σ*C-O hyperconjugation. Indeed, the NBO analysis for
isomer 5a shows that three σC-H bonding orbitals exhibit charge
transfer to the σ*C-O antibonding orbital amounting from 20 to 25
kJ mol-1. In contrast, only one σC-H bonding orbital is involved in
isomer 4a, with a charge transfer of 18 to 21 kJ mol-1 (in addition
to weaker ones due to σC-C→σ*C-O hyperconjugation, from 12 to
14 kJ mol-1). As a result, calculated partial charges from the
Natural Population Analysis, are slightly more negative on the
oxygen and slightly less positive on the hydrogen atom of 5a, in
line with its experimental weaker H-bond acidity.
strengths of such IMHB conformers, have
observable impact on their H-bond acidity.
a
direct and
6
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FULL PAPER
Frequency shifts upon complexation (ΔνOH
During the experimental determination of the H-bond acidity
by IR spectroscopy, a systematic frequency shift of the hydroxyl
)
deviation of this calibration line (0.13 units). This behaviour is
attributed to the occurrence of OH•••F IMHB interactions. In
series 4, the higher deviations from the pKAHY-ΔνOH correlation,
at equivalent fluorination states than in series 5, are caused by
stronger IMHBs as highlighted by our conformational analysis.
With equivalent fluorination states, 3b and 3c show
equivalent ΔνOH values but the deviation from the regression line
is much less pronounced for 3c. This is rationalized by the
occurrence of an OH•••F IMHB interaction only in the equatorial
conformer of 3c, whereas both axial and equatorial forms can
exhibit such an IMHB in 3b. The deviation observed for 3d is
also less important than for 3b. It can be attributed to the
compensation of the fluorine electron-withdrawing effect that
increases the frequency shift, towards the occurrence of IMHBs,
weakened for a CF2 group in comparison with a CF one.[3u] The
same behavior is apparent for the trifluorinated derivatives 4d,
5d and 6d, where the H-bond accepting ability of CF3 is even
worse.[3u]
stretching vibration, ΔνOH
, towards lower wavenumbers is
consistently observed upon complexation with NMP. We have
previously shown that ΔνOH is correlated to pKAHY for
homogeneous families of compounds (Figure 4A).[3h,
6c]
Accordingly, for 1–6, ΔνOH is dependent on the number of
fluorine atoms. The following frequency shift ranges are
measured: 170±10 cm-1 for the unfluorinated, 190±10 cm-1 for
the monofluorinated, 230±10 cm-1 for the difluorinated, and
finally 260±10 cm-1 for the trifluorinated cyclohexanols.
We have also shown that deviations from the pKAHY – ΔνOH
correlation can reveal peculiar behaviors, such as IMHBs.[3h, 6c]
This is consistent with the significant downward deviation that
can be found for fluorohydrins 1–4 (Figure 4B), the compounds
belonging to series 5 and 6 being situated within the standard
The two experimental parameters pKAHY and ΔνOH measure two
different features of the hydrogen-bond. The logarithm of the
equilibrium constant, pKAHY, is a thermodynamic parameter and
takes into account the intrinsic properties of both the fluorohydrin
monomer and of its H-bond complex with NMP. As
a
consequence, when an IMHB involving the H-bond donor moiety
of the monomer can occur, it partially prevents the
intermolecular H-bond to be established with NMP. This results
in a significant lowering of the equilibrium constant. Conversely,
the frequency shift, ΔνOH, is a spectroscopic probe comparing
the stretching frequencies before and after H-bond complexation
without considering any equilibrium aspects. It is mainly
dependent of the intermolecular H-bond complex because, as
can be seen in Table 2, the monomeric νOH stretching mode is
just slightly disturbed by the weak OH•••F IMHB. As
a
consequence, ΔνOH is much less influenced by IMHB than pKAHY
,
and this results in downward deviations from the pKAHY - ΔνOH
correlation. As an example, by considering 3c and the
corresponding experimental ΔνOH of 199 cm-1, it can be seen
from the correlation of Figure 4B that such ΔνOH should lead to a
pKAHY value close to 0.95, whereas the observed pK value is
0.66, illustrating the direction (downward) of the observed
deviations.
Experimental vs theoretical H-bond acidity.
The comparison between the experimental pKAHY values and the
theoretical Vα(r) descriptor of H-bond acidity is very instructive.
On the whole, there is an excellent correlation between the
experimentally determined and the calculated pKAHY values,
even for closely related stereoisomers with significantly different
H-bond acidities.
For series 3, a clear decrease in H-bond acidity is indeed
predicted upon cis-monofluorination, and
a
much lower
decrease upon trans-monofluorination (Table 1). The significant
increase upon addition of a second fluorine atom (3d) was
correctly predicted. In series 4, we observe at first a decrease of
Vα(r) upon fluorination (Table 1), and then an increase with di-
and trifluorination. The regular increase of Vα(r) calculated for
series 5 is in agreement with the experimental trend. The
Figure 4. Plot of pKAHY versus ΔνOH frequency shift for a series of alcohols and
phenols (A) and extension (B) to emphasize the downward deviations
[7]
observed for fluorohydrins (ref.
CCl4.
and this work) with IMHB conformations in
7
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10.1002/chem.201604940
Chemistry - A European Journal
FULL PAPER
systematic higher H-bond acidity properties of 5b, 5c and 5d, in
comparison with 4b, 4c and 4d, is also well reproduced.
quantum chemical calculations. It was found that the H-bond
acidity (pKAHY) of β-monofluorinated alcohols was either lower,
similar, or higher compared to the nonfluorinated parent, Beyond
these general observations, with unexpected differences
between closely related diastereomers, either within a series (eg
3), or between series (4 and 5). In contrast, geminal di- and
trifluorination always led to successive pKAHY increases.
Within series 6, the electrostatic potential descriptor fails
describing the increase of the H-bond acidity due to the first
fluorination. The contribution of the IMHB seems to be
overestimated, resulting in a too strong attenuation of the
predicted pKAHY value. However, the computed values for the di-
and trifluoropentanols are in good agreement with the
The observations were rationalized through considering two
main effects: the fluorine electronegativity (leading to an
increase in H-bond acidity), and intramolecular hydrogen
bonding between the fluorine and the alcohol group (leading to a
decrease). The extent of intramolecular hydrogen bonding for
flexible fluorohydrins was determined by conformational analysis.
Between diastereomeric substrates, it was found that the relative
population of IMHB conformers, as well as the calculated OH•••F
distance (which was correlated with the charge transfer
occurring within the IMHB) could explain differences in H-bond
donating capacity. For example, 2-cis-fluorocyclohexanol 3b has
a lower H-bond acidity, and 2-trans-fluorocyclohexanol 3c a
similar H-bond acidity as cyclohexanol. Indeed, in the former,
the two chair conformations of the cyclohexyl ring can lead to
the formation of an OH•••F IMHB, whereas only one chair
conformation can give an OH•••F interaction in 3c, while its other
chair conformation has a vicinal trans fluorohydrin motif, which is
known to increase the pKAHY. Hence, in 3c, these opposite
effects cancel each other, resulting in 3c having a similar H-
bond acidity compared to cyclohexanol. It was also evidenced
that there is an internal consistency between the pKAHY values of
conformationally rigid, fluorinated cyclohexanols, and the
experimental data, corroborating that with
conformational flexibility, the fluorine inductive effect overrides
the IMHB contribution.
a
higher
Hence, with one exception, this clearly demonstrates the
validity of the Kenny electrostatic descriptor Vα(r) in probing the
hydrogen bond donating capacity of fluorohydrins, the effects of
fluorination being well-reflected. An excellent correlation
between pKAHY and Vα(r) for all hydroxyl H-bond donors studied
so far (78 compounds),[3h, 3j, 6c, 7] including the current series of
15 alcohols, is shown in Figure 5. The resulting sample yields a
robust correlation equation, Eq.(1), which updates the previously
reported calibration line.[6c] The corresponding predicted values
for the current series are given in Table S7, for comparison with
experimental data.
pKAHY = 50.14 Vα(r) – 15.26
(1)
n = 78, r2 = 0.9731, s = 0.116, F = 2749
individual
2-fluoro
and
2,2-difluorocyclohexanol
chair
conformations.
The examination of the relation between the two
experimental parameters, pKAHY and ΔνOH, provides useful
complementary information. Since the two parameters measure
different features of the H-bond interaction, deviations from the
relation reveals peculiar behaviors. Indeed, the significant
downward deviations observed in the pKAHY vs ΔνOH are
attributed to the occurrence of IMHB with subtle differences,
these experimental findings being well corroborated by the
results of the theoretical conformational analysis.
It was confirmed that the Kenny theoretical Vα(r) descriptor of
H-bond acidity accurately reflects these effects (one exception).
An updated correlation between the experimental pKAHY and
Vα(r) descriptor values of 78 fluorinated and nonfluorinated
alcohol H-bond donors is presented.
Hence, apart from the fluorine electron withdrawing effect,
our results clearly show that OH•••F IMHB is a determining
factor in the H-bond donating capacity of fluorohydrins.
Variations in population of IMHB conformers and subtle
differences in IMHB strengths were shown to correlate with the
pKAHY value. The demonstration that our updated correlation
equation accurately predicts fluorohydrin H-bond donating
capacity from the calculated Kenny Vα(r) descriptor for both
conformationally rigid and flexible fluorohydrins, will be of
general interest in the many research fields for which
intermolecular hydrogen bonding and its modulation by
fluorination is of interest. A significant consequence of this work
Figure 5. Plot of pKAHY versus the V (r) electrostatic potential descriptor. The
α
fluorohydrins studied in the current work (in green squares, see numerical
values in Table S7) obey to the correlation previously established. The rigid
fluorohydrins[7] are also highlighted in pink triangles, alcohols and phenols[6c]
are shown in blue diamond and benzyl alcohols[3h] in orange circles. The
calibration equation is hence updated with this dataset of 78 compounds.
Conclusion
The H-bond donating capacities of four series of aliphatic β-
fluorohydrins, characterized by increasing conformational
flexibility, have been investigated by FTIR measurements and
8
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10.1002/chem.201604940
Chemistry - A European Journal
FULL PAPER
theory. The NBO analyses were applied at the IEF-PCM/MPWB1K/6-
31+G(d,p) level of theory using the NBO6.0 program.[23]
regards the possibility to obtain accurate H-bond donating
capacity data for fluorohydrins that are part of more complex,
polyfunctional substrates, as experimental determination would
not be possible for such substrates.
The H-bond acidity of the compounds under study were evaluated as
recommended previously[6c] through the calculation of the Kenny Vα(r)
descriptor.[8] It consists in calculating in vacuo the electrostatic potential
value along the OH bond at a distance r = 0.55 Å from the hydroxyl
hydrogen atom, at the MPWB1K/6-31+G(d,p) level of theory. Indeed, the
initial data sets[6c, 7] were considered in the gas phase at the MPWB1K/6-
31+G(d,p) level of theory. The Vα(r) value is determined for each
conformation, taking into account the solvated geometry and a weighted
value calculated from their respective Boltzmann populations.
Experimental Section
Fluorohydrins synthesis. The details of the synthesis of substrates 3b-
d, 4a-d, 5a-d, 6b-d (Figure 1) is given in the Supporting Information (SI).
Chemicals. Carbon tetrachloride solvent, of spectroscopic grade, was
kept for several days over freshly activated 4 Å molecular sieves before
use. Commercial N-methylpyrrolidinone, 99.5+% of purity, was also
stored over molecular sieves and in darkness to prevent its deterioration.
All cyclohexanol derivatives prepared for this study were solids, and
therefore their ultimate purification and drying was carried out by
sublimation in presence of P2O5. After control of its GC purity, the 1,1,1-
trifluoropentan-2-ol derivative, which is a liquid compound, was dried
over freshly activated 4 Å molecular sieves before use. Residual amount
of Et2O and CH2Cl2 solvent have been detected for 1-fluoropentan-2-ol
and 1,1-difluoropentan-2-ol and a transfer under high vacuum has been
carried out prior to their drying.
Acknowledgements
The EPSRC (grants EP/K016938/1 and EP/K039466/1 (core
capability)), and the ANR (JCJC “ProOFE” grant (ANR-13-JS08-
0007-01), are gratefully acknowledged for their financial support.
The current work was granted access to the HPC resources of
(CCRT/CINES/IDRIS) under the allocation c2015085117 made
by GENCI, and HPC resources from ArronaxPlus, grant ANR-
11-EQPX-0004 funded by the ANR. We thank the CCIPL for
grants of computer time. Apollo Scientific is gratefully
acknowledged for the donation of chemicals.
FTIR Spectrometry measurements. The handling of all chemicals and
their CCl4 solutions, and the filling of the cells for IR measurements were
performed in the dry atmosphere of a glove box at room temperature. IR
spectra were recorded in carbon tetrachloride solutions with a Fourier-
transform spectrometer Bruker Vertex 70 at a resolution of 1 cm-1. An
Infrasil quartz cell, of  = 1 cm path length and thermostatted at 25.0 ±
0.2 °C by a Peltier effect regulation, was used for the studies of H-bond
complexation. The H-bond acidity, pKAHY, of the alcohols under study
Keywords: H-bond acidity • Alcohols • Fluorination • FTIR
spectroscopy • Quantum chemistry calculations
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Computational procedure
All DFT calculations were performed using the D.01 version of the
Gaussian 09 program.[20] The conformational analysis of compounds
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weighted according to these populations.
e−ΔG / RT
i
pi =
(2)
n
−ΔG / RT
i
e
∑
i=1
The charge transfer between the acceptor lone pair(s) of electrons and
the σ* donor antibonding orbital was estimated through NBO analyses[11]
to characterize the IMHB conformers. The corresponding interaction
energies (E(2) *) were evaluated from the second-order perturbation
→σ
n
9
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10.1002/chem.201604940
Chemistry - A European Journal
FULL PAPER
Entry for the Table of Contents
pKAHY
pKAHY
J. Graton,* G. Compain, F. Besseau,
E. Bogdan, J. M. Watts, L.
Mtashobya, Z. Wang, A. Weymouth-
Wilson, N. Galland, J.-Y. Le
Questel,* B. Linclau,*
Variations in hydrogen-bond (H-
bond) donating capacity of closely
related conformationally flexible
fluorohydrin diastereomers can be
explained by subtle differences in
conformational profile and in
strengths of OH•••F intramolecular
OH
F
0.8
0.7
0.6
0.5
0.4
tBu
OH
OH
OH
tBu
Page No. – Page No.
F
Influence of Alcohol β-Fluorination
on Hydrogen-Bond Acidity of
Conformationally Flexible
Substrates
H-bonding.
correlation
An
(updated)
enabling
equation
OH
F
tBu
accurate H-bond donating capacity
prediction from theoretical
descriptor is presented.
a
OH
tBu
OH
F
11
This article is protected by copyright. All rights reserved.