An unexpected and significantly lower hydrogen-bond-donating capacity of fluorohydrins compared to nonfluorinated alcohols

Article abstract of DOI:10.1002/anie.201202059

Rewriting the rules as fluorination does not always increase hydrogen-bond acidity: while the strongly electron-withdrawing fluorine significantly enhances alcohol H-bond acidity in anti-vicinal fluorohydrins, an intramolecular F...HO interaction overrule

Full text of DOI:10.1002/anie.201202059

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Angewandte
Communications
DOI: 10.1002/anie.201202059
Hydrogen Bonding
An Unexpected and Significantly Lower Hydrogen-Bond-Donating
Capacity of Fluorohydrins Compared to Nonfluorinated Alcohols**
Jꢀrꢁme Graton,* Zhong Wang, Anne-Marie Brossard, Daniela GonÅalves Monteiro, Jean-
Yves Le Questel, and Bruno Linclau*
The success of fluorination in improving molecular properties
over a wide range of applications (including pharmaceuti-
cals,[1] agrochemicals,[2] materials,[3] and crystal engineering[4])
has been remarkable. Up to 20% of the pharmaceuticals
prescribed or administered in the clinic, and a third of the
leading 30 blockbuster drugs, contain at least one fluorine
atom[1a] and 30–40% of currently marketed agrochemicals
contain fluorine.[5]
fluorine atom is expected to significantly modify the H-bond
properties of an adjacent FG. It is therefore surprising that
despite H-bond acidity of alcohols has been previously
studied,[12] a thorough investigation of the influence of
fluorination on H-bond acidity appears limited to that of
polyfluorinated solvents such as trifluoroethanol (TFE) and
hexafluoroisopropyl alcohol (HFIP),[13] and to certain supra-
molecular receptor systems.[14] TFE and HFIP are very strong
H-bond donors (and very poor acceptors), which has been
exploited, when they were used as solvents, to influence the
reactivity of certain reagents.[13a,15] The H-bond properties of
TFE and HFIP are generally considered to originate from the
strong inductive effect of fluorine, leading to statements in the
literature such as “the ability of fluorine … as an inductive
activator of a H-bond donor group”[16] and “fluorination
always increases H-bond acidity”.[17]
Herein, we show that this is incorrect as a general rule.
Indeed, experimental determination of H-bond acidities of
a range of fluorohydrins shows that fluorination can lead to an
attenuation, in some cases very pronounced, of H-bond
acidity. In order to exclude conformational complications
(e.g., the fluorohydrin gauche effect),[18,19] this study was
carried out using conformationally restricted model com-
pounds 1–8 (Scheme 1), which adopt only chair conforma-
tions as confirmed by computational analysis (see below). The
obtained values have been compared to the H-bond acidities
of the corresponding nonfluorinated alcohols 9 and 10.
In many cases, fluorine is introduced following a particular
rationale.[6] Examples include enhancement of metabolic
stability, functional-group (FG) reactivity or acid/base-prop-
erty modification, and conformational stabilization. Impor-
tantly, these alterations cannot be considered individually as
usually a number of properties are influenced simultane-
ously.[7] For example, fluorination of amines in order to
decrease their pKa value also leads to an increase in their
lipophilicity and may induce significant conformational
changes. Furthermore, this decrease in pKa can be attenuated
if intramolecular NH+···F electrostatic interactions can
occur.[8] Hence, a comprehensive understanding of the effects
of fluorination is a prerequisite for successful planning and
rationalization of fluorine introduction, and research that
increases our knowledge in that respect is highly relevant.
The hydrogen bond (H-bond) is an important specific
interaction between a molecule and its local environment.[9]
Crucial functional roles include the binding of ligands to
protein receptors and the promotion of enzyme catalysis. In
the design of bioactive compounds, H-bonding impacts on
a wide range of molecular properties such as potency,
selectivity, permeability, and solubility.[10] Given the strong
electrostatic contribution to the overall energy of an H-
bond,[11] introduction of the small and highly electronegative
[*] Z. Wang, D. GonÅalves Monteiro, Dr. B. Linclau
Chemistry, University of Southampton
Highfield, Southampton SO17 1BJ (UK)
E-mail: bruno.linclau@soton.ac.uk
Scheme 1. Fluorohydrin model compounds and nonfluorinated refer-
ence alcohols.
Dr. J. Graton, A.-M. Brossard, Prof. Dr. J.-Y. Le Questel
CEISAM UMR CNRS 6230, Facultꢀ des Sciences et des Techniques
Universitꢀ de Nantes
2, rue de la Houssiniꢁre – BP 92208
44322 NANTES Cedex 3 (France)
The synthesis of fluorohydrins 1–8 is detailed in the
Supporting Information. Of note is the diastereoselectivity
observed in the reductions of 2-fluoroketones 11 and 12
(Scheme 2). The reduction of 11 with L-selectride gave only
equatorial attack, as observed with (nonfluorinated) 4-tert-
butylcyclohexanone,[20] but a complete reversal in diastereo-
selectivity was found for the reduction of 12 using the same
reagent. This is the first report of a fully diastereoselective
reduction of each of the diastereomeric 2-fluorocyclohexa-
nones.[18c,21]
E-mail: jerome.graton@univ-nantes.fr
[**] D.G.M. thanks Chemistry, University of Southampton for support.
We thank for access to the HPC resources of [CCRT/CINES/IDRIS]
under the allocation c2012085117 made by GENCI (Grand Equi-
pement National de Calcul Intensif) and the CCIPL (Centre de
Calcul Intensif des Pays de la Loire) for grants of computer time.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202059.
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Chemie
Scheme 2. Stereoselective reduction of 2-fluorocyclohexanone diaste-
reomers.
The relative H-bond acidities pKAHY of 1–10 (Table 1,
Figure 1) were determined by adapting an established proce-
dure using FTIR spectroscopy.[22] The decrease in absorbance
of the nOH stretching band of the hydroxy group upon
complexation with N-methylpyrrolidinone (NMP) was moni-
tored in dilute CCl4 solution.
Table 1: Determination of fluorohydrin H-bond acidity in CCl4 at 258C.
Figure 1. Visualization of the H-bond acidity range of 1–10, with
selected energetic differences between mono- and difluorinated alco-
hols.
Compound
K[a]
5.10
pKAHY
DG8[b]
dDG8[b,c]
9
10
1
2
3
4
5
6
7
0.71
0.70
1.30
0.43
0.51
0.56
ꢀ0.15
0.93
1.03
0.85
ꢀ9.8
ꢀ9.8
–
–
ing the magnitude of the acidity. Apart from the reduced H-
bond acidities of 2–4 compared to 9 and 10, the most
surprising observations are the reduced H-bond acidity of the
difluorohydrins compared to certain monofluorohydrins (e.g.,
7 and 1, and even 8 and 6, which is though a 1,3-fluorohydrin),
and the dramatically reduced H-bond acidity of 5 compared
to 9.
Quantum chemical calculations strongly support these
experimental trends. Conformation analysis (MPWB1K/6-
31 + G(d,p) level in vacuum) of all cyclohexanols, which only
5.06
19.94
2.70
3.26
3.63
0.71
8.45
10.8
7.00
ꢀ13.2
ꢀ8.2
ꢀ3.4
+1.6
+1.1
+0.8
+4.9
ꢀ1.3
ꢀ1.9
ꢀ0.8
ꢀ8.7
ꢀ9.0
ꢀ4.9
ꢀ11.1
ꢀ11.7
ꢀ10.6
8
[a] In dm3 molꢀ1. [b] DG8[kJmolꢀ1]=ꢀ5.708pKAHYꢀ5.781. [c] Defined as
DG8(fluorohydrin)ꢀDG8(corresponding nonfluorinated alcohol).
ꢀ
involves rotation around the C O bond (Table 2), shows that
there is only one predominant conformer (two in 8) for those
structures in which the hydroxy proton can be located close to
the fluorine atom. When the modeling of bulk-solvent effects
is included (in this case CCl4), through the polarizable
continuum model (PCM),[24] the relative population of the
solvated conformers is distributed similarly to that of the
isolated structures (see the Supporting Information). For 2–4,
The equilibrium constant K was first determined for the
reference compounds, cis- and trans-4-tert-butylcyclohexanol,
9 and 10, respectively. Interestingly, there was no difference
between these two alcohols (axial and equatorial), which to
the best of our knowledge has not previously been estab-
lished.[23] Of the monosubstituted 1,2-fluorohydrins, only
trans diaxial 1 showed the expected increase in H-bond
acidity, with an almost four-fold higher K value. In contrast,
fluorohydrins 2–4 showed a decreased H-bond acidity, with
equilibrium constants amounting to 53–72% of the value of
the nonfluorinated alcohols. For 1,3-fluorohydrins, the
cis isomer 5 had a dramatically decreased H-bond acidity,
with the hydroxy group virtually losing its ability to act as a H-
bond donor. In contrast, the trans isomer 6 shows a significant
increase of the H-bond donating capacity. Both 2,2-difluor-
oalcohols, 7 and 8, have a greater H-bond acidity than the
nonfluorinated alcohols, with a stronger enhancement for the
axial hydroxy group in 7.
ꢀ
7, and 8, the energy barrier DGTS to rotation of the O H bond
is calculated to be in the range of 11–13 kJmolꢀ1, whereas it is
only 3–5 kJmolꢀ1 for 1, 6, 9, and 10. With the 1,3-coaxial
fluorohydrin 5, this energy barrier is raised to 18 kJmolꢀ1 [25]
.
This significant variation is attributed to the occurrence of an
F···HO interaction, which is particularly favorable in the case
of a 1,3-coaxial fluorohydrin, as illustrated by NMR spec-
troscopy (h1JF-HO ꢁ 12 Hz),[26] and by the significantly shorter
calculated dF···H distance in 5 (2.033 ꢀ) than found in the 1,2-
fluorohydrins (2.3–2.4 ꢀ).
The topic of fluorine-mediated H-bonding has been
subject to extensive debates,[9c,27] but the stabilizing nature
of 1,3-syn F···HX interactions has been invoked to explain
conformational effects in fluorinated amines and amides,[7] as
well as pKa modulations in the former.[7,8] Interestingly, NBO
(natural bond orbital) and AIM (atoms in molecules)
These results demonstrate the importance of the relative
fluorohydrin configuration on H-bond acidity, and that the
fluorine inductive effect cannot be the only factor determin-
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ꢀ
Table 2: Relative Gibbs energies (DG) and populations (pi) of 1–10, with characteristics of the O H
bond.
substituent into 2 (to also give 7)
leads to a strong H-bond acidity
increase. The reduction of H-bond
acidity due to intramolecular H-
bonding had been reported previ-
ously for a series of phenols, and the
energy of the intramolecular H-
bond was shown to be unrelated to
the overall H-bond acidity of the
studied structures.[34]
Another important conclusion
is that the electronegativity of
a gauche fluorine substituent is
only partially translated to the hy-
droxy group: for compounds 2–4
(all containing F···HO), the increase
in H-bond acidity resulting from
introduction of an anti fluorine
substituent is about twice the
increase in H-bond acidity resulting
from introduction of a gauche fluo-
rine substituent (Figure 1: compare
[a,c]
[a,d]
[e,f]
[g]
ꢀ
VaðrÞ
Entry
trans
gꢀ
g+
DGTS
E(2)
dH···F
n!s*
DG[a] pi[b]
DG[a] pi[b]
DG[a] pi[b]
[h]
[h]
[h]
9
10
1
2
3
4
5
6
7
1.0
0.8
3.6
14.9
0.0
12.2
0.0
24.9
26.8
12.5
0.2 10.7
97.5 11.7
0.7 10.8
99.7 14.7
0.0
0.0
0.0
75.1[h]
4.0
4.6
3.1
–
–
–
4.1
4.1
3
17.1
–
2.2
4.2
0.3184
0.3177
0.3315
0.3127
0.3108
0.3133
0.2915
0.3227
0.3262
0.3193
–
–
–
[h]
73.2[h]
54.4
1.3
1.2
0.0
10.1
33.0
98.4 12.2
1.6 10.9
98.1 11.7
2.287 (g+)
2.291 (trans)
2.372 (g+)
2.033 (trans)
–
2.332 (g+)
2.275 (trans)
2.364 (g+)
0.9
1.2
0.3
0.0
[i]
[i]
17.9
3.6
97.8 11.3
56.1 12.9
14.8
0.6
0.2
43.4 11.9
9.7
2.0
0.5
0.0
0.0
8
[a] In kJmolꢀ1. [b] Boltzmann population in %. [c] Barrier height for O H rotation. [d] Interaction energy
from F lone pair to s*OꢀH charge transfer. [e] Kenny electrostatic potential, weighted by the conformer’s
Boltzmann population. [f] In a.u. [g] F···HO distance, in ꢂ. [h] Degenerated conformation. [i] No local
minima found.
ꢀ
analyses reveal, for fluorohydrin 5, a significant charge
transfer (17.1 kJmolꢀ1) from the fluorine lone pair to the
antibonding s*OH orbital and a bond critical point (BCP)
between the F and H atoms (1 = 0.0192 e), a weak value
typical of an H-bond interaction.[28] Much weaker charge
transfer (between 2.2 and 4.2 kJmolꢀ1, Table 2) and no BCP
are found for the vicinal fluorohydrins, suggesting that in
these cases, this intramolecular OH···F interaction probably
represents more a weak electrostatic stabilization than
a typical H-bond.[29] Interestingly, no BCP was found between
the Fand H atoms in 2-fluorophenol,[30] and in glucopyranose,
AIM analysis detected intramolecular H-bonding between
1,3-diol groups, but not for vicinal diols.[31]
Because of the electrostatic character of H-bond inter-
actions, various theoretical descriptors based on the electro-
Figure 2. Correlation between the H-bond acidity of 1–10 and the
Kenny electrostatic potential descriptor Va(r).
static potential have been extensively used.[32] The Va(r)
descriptor,[33] which is calculated at a distance of 0.55 ꢀ from
ꢀ
the hydrogen atom along the O H bond, was calculated (in
vacuum) for all fluorohydrin conformers, and weighted by
their relative populations. Pleasingly, an excellent correlation
was found between Va(r) and the experimentally determined
H-bond acidity (r2 = 0.978, s = 0.06, Figure 2). Hence, this
descriptor accurately predicts the H-bond acidity for alcohols
that are predominantly in a conformation with F···HO
contact.
2!7 with 3,4!8). These observations are corroborated by
Bols et al., in the context of amine basicity and glycoside
hydrolysis, who concluded that the electronegativity of a polar
substituent (e.g., OH, F) is greater in an antiperiplanar
arrangement, compared to a gauche,[8,35] which may originate
from a stereochemical dependence of hyperconjugation
donor/acceptor abilities of s bonds involved.[36]
The above analysis allows rationalization of the exper-
imental trends: whereas the fluorine inductive effect is
responsible for the four-fold increase in H-bond acidity of
1 (compared to 9), any decrease in H-bond acidity is
attributed to the unavailability of the OH group owing to
an intramolecular F···HO interaction. It also explains
(Figure 1) why the introduction of a second fluorine atom
into 1 (to give 7) leads to a decrease in H-bond acidity (this
new fluorine atom can engage in an intramolecular F···HO
interaction), and why the introduction of an anti fluorine
Given the weak nature of an F···HO interaction, its ability
to overturn the influence of the fluorine electronegativity is
most surprising, even if the incomplete translation of electro-
negativity due to a gauche dihedral angle is taken into
account. Consideration of the Va(r) values of the unchelated
conformers of 2–5, 7, and 8 allows estimation of a putative H-
bond acidity, the difference with the experimental value then
being an estimate of the loss in H-bond acidity caused by the
F···HO interaction. This amounts to around 2–4 kJmolꢀ1 for
the 2-, and 6 kJmolꢀ1 for the 3-fluorocyclohexanols (see the
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Brameld, J. Graton, J.-Y. Le Questel, E. Renault, J. Med.
Chem. 2009, 52, 4073 – 4086.
Supporting Information). In this context, it is interesting to
observe that the F···HN+ interaction is not overriding the
effect of fluorine electronegativity on the pKa of ammonium
ions, but only attenuates the decrease in pKa.[8]
[10] a) C. Bissantz, B. Kuhn, M. Stahl, J. Med. Chem. 2010, 53, 5061 –
5084; b) M. H. Abraham, A. Ibrahim, A. M. Zissimos, Y. H.
Zhao, J. Comer, D. P. Reynolds, Drug Discovery Today 2002, 7,
1056 – 1063.
[11] E. Arunan, G. R. Desiraju, R. A. Klein, J. Sadlej, S. Scheiner, I.
Alkorta, D. C. Clary, R. H. Crabtree, J. J. Dannenberg, P. Hobza,
H. G. Kjaergaard, A. C. Legon, B. Mennucci, D. J. Nesbitt, Pure
Appl. Chem. 2011, 83, 1619 – 1636, and references therein.
[12] a) M. H. Abraham, P. P. Duce, D. V. Prior, D. G. Barratt, J. J.
Morris, P. J. Taylor, J. Chem. Soc. Perkin Trans. 2 1989, 1355 –
1375; b) M. H. Abraham, P. L. Grellier, D. V. Prior, P. P. Duce,
J. J. Morris, P. J. Taylor, J. Chem. Soc. Perkin Trans. 2 1989, 699 –
711.
In summary, we reported alcohol H-bond acidity meas-
urements of a range of conformationally restricted fluorohy-
drins. The results force the conclusion that contrary to current
assumptions, fluorination can lead to a significant attenuation
of alcohol H-bond acidity compared to the corresponding
nonfluorinated alcohols. DFT calculations indicate that intra-
molecular F···HO interactions are responsible for the H-bond
acidity attenuation, and it is most remarkable that these weak
interactions outcompete the fluorine electron-withdrawing
effect. However, the obtained data also indicate that the
effect of fluorine electronegativity strongly depends on the
fluorohydrin dihedral angle, with a 1808 dihedral angle
required for maximum effect, and with an estimated halving
of the fluorine electron-withdrawing power for a 608 (gauche)
dihedral angle. These insights open up new opportunities for
compound-property modification through fluorination in
a wide range of applications where H-bonding is important.
Research on a wider range of substrates is currently ongoing
in our groups.
[13] a) D. Vuluga, J. Legros, B. Crousse, A. M. Z. Slawin, C.
Laurence, P. Nicolet, D. Bonnet-Delpon, J. Org. Chem. 2011,
ˇ ´
76, 1126 – 1133; b) B. Jursic, M. Ladika, D. E. Sunko, Tetrahe-
dron Lett. 1985, 26, 5323 – 5324; c) T. Ganguly, S. Mal, S.
Mukherjee, Spectrochim. Acta Part A 1983, 39, 657 – 660.
[14] a) P. Anzenbacher, Jr., A. C. Try, H. Miyaji, K. Jursꢄkovꢅ, V. M.
Lynch, M. Marquez, J. L. Sessler, J. Am. Chem. Soc. 2000, 122,
10268 – 10272; b) P. A. Gale, C. C. Tong, C. J. E. Haynes, O.
Adeosun, D. E. Gross, E. Karnas, E. M. Sedenberg, R. Quesada,
J. L. Sessler, J. Am. Chem. Soc. 2010, 132, 3240 – 3241.
[15] a) A. Berkessel, J. A. Adrio, D. Hꢃttenhain, J. M. Neudçrfl, J.
Am. Chem. Soc. 2006, 128, 8421 – 8426; b) Review: J.-P. Bꢂguꢂ,
D. Bonnet-Delpon, B. Crousse, Synlett 2004, 18 – 29.
[16] P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis, Reac-
tivity, Applications, Wiley-VCH, Weinheim, 2004, p. 16.
[17] B. E. Smart, J. Fluorine Chem. 2001, 109, 3 – 11.
[18] a) D. A. Dixon, B. E. Smart, J. Phys. Chem. 1991, 95, 1609 – 1612;
b) R. J. Abraham, E. J. Chambers, W. A. Thomas, J. Chem. Soc.
Perkin Trans. 2 1994, 949 – 955; c) J. M. Bakke, L. H. Bjerkeseth,
T. E. C. L. Rfnnow, K. Steinsvoll, J. Mol. Struct. 1994, 321, 205 –
214; d) C. R. S. Briggs, M. J. Allen, D. OꢁHagan, D. J. Tozer,
A. M. Z. Slawin, A. E. Goeta, J. A. K. Howard, Org. Biomol.
Chem. 2004, 2, 732 – 740.
Received: March 15, 2012
Published online: May 10, 2012
Keywords: computational chemistry · conformation analysis ·
.
fluorine · fluorohydrins · hydrogen bonding
[1] a) D. OꢁHagan, J. Fluorine Chem. 2010, 131, 1071 – 1081; b) J.-P.
Bꢂguꢂ, D. Bonnet-Delpon, J. Fluorine Chem. 2006, 127, 992 –
1012; c) K. L. Kirk, J. Fluorine Chem. 2006, 127, 1013 – 1029;
d) F. M. D. Ismail, J. Fluorine Chem. 2002, 118, 27 – 33.
[2] a) P. Jeschke, ChemBioChem 2004, 5, 570 – 589; b) P. Jeschke,
Pest Manage. Sci. 2010, 66, 10 – 27.
[3] R. Berger, G. Resnati, P. Metrangelo, E. Weber, J. Hulliger,
Chem. Soc. Rev. 2011, 40, 3496 – 3508.
[4] D. Chopra, T. N. Guru Row, CrystEngComm 2011, 13, 2175 –
2186.
[19] Conformation analysis of 2-fluorocyclohexanols: a) R. J. Abra-
ham, T. A. D. Smith, W. A. Thomas, J. Chem. Soc. Perkin Trans.
2 1996, 1949 – 1955; b) E. A. Basso, L. A. Abiko, G. F. Gauze,
R. M. Pontes, J. Org. Chem. 2011, 76, 145 – 153.
[20] a) H. C. Brown, S. Krishnamurthy, J. Am. Chem. Soc. 1972, 94,
7159 – 7161; b) M. Spiniello, J. M. White, Org. Biomol. Chem.
2003, 1, 3094 – 3101.
[5] A. M. Thayer, Chem. Eng. News 2006, 84(23), 15 – 24.
[6] a) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc.
Rev. 2008, 37, 320 – 330; b) W. K. Hagmann, J. Med. Chem. 2006,
51, 4359 – 4369; c) K. L. Kirk, Curr. Top. Med. Chem. 2006, 6,
1447 – 1456; d) H.-J. Bçhm, D. Banner, S. Bendels, M. Kansy, B.
Kuhn, K. Mꢃller, U. Obst-Sander, M. Stahl, ChemBioChem
2004, 5, 637 – 643; e) P. Kirsch, Modern Fluoroorganic Chemis-
try: Synthesis Reactivity, Applications, Wiley-VCH, Weinheim,
2004.
[7] a) D. OꢁHagan, Chem. Soc. Rev. 2008, 37, 308 – 319; b) L.
Hunter, Beilstein J. Org. Chem. 2010, 6, 38; c) L. E. Zimmer,
C. Sparr, R. Gilmour, Angew. Chem. 2011, 123, 12062 – 12074;
Angew. Chem. Int. Ed. 2011, 50, 11860 – 11871.
[21] a) P. Moreau, A. Casadevall, E. Casadevall, Bull. Chem. Soc. Fr.
1969, 2013 – 2020; b) R. E. Rosenberg, R. L. Abel, M. D. Drake,
D. J. Fox, A. K. Ignatz, D. M. Kwiat, K. M. Schaal, P. R. Virkler,
J. Org. Chem. 2001, 66, 1694 – 1700; c) P. R. Anizelli, D. C.
Favaro, R. H. Contreras, C. F. Tormena, J. Phys. Chem. A 2011,
115, 5684 – 5692; reductions on related unbiased rigid cyclo-
hexanones: d) L. Mion, A. Casadevall, E. Casadevall, Bull.
Chem. Soc. Fr. 1968, 2950 – 2957; e) L. Mion, A. Casadevall, E.
Casadevall, Bull. Chem. Soc. Fr. 1969, 3199 – 3208.
[22] C. Ouvrard, M. Berthelot, C. Laurence, J. Chem. Soc. Perkin
Trans. 2 1999, 1357 – 1362.
[23] The obtained value is close to that of cyclohexanol (0.67): J.
Graton, A. Deroche, E. Charpentier, A. M. Brossard, F.
Besseau, J. Y. Le Questel, in preparation.
[8] M. Morgenthaler, E. Schweizer, A. Hoffmann-Rçder, F. Benini,
R. E. Martin, G. Jaeschke, B. Wagner, H. Fischer, S. Bendels, D.
Zimmerli, J. Schneider, F. Diederich, M. Kansy, K. Mꢃller,
ChemMedChem 2007, 2, 1100 – 1115.
[24] J. Tomasi, B. Menucci, R. Cammi, Chem. Rev. 2005, 105, 2999 –
3094.
[25] This large energy barrier could also originate from a destabiliza-
tion caused by lone-pair repulsion, see Ref. [18c].
[26] a) B. Bernet, A. Vasella, Helv. Chim. Acta 2007, 90, 1874 – 1888;
b) M. A. Biamonte, A. Vasella, Helv. Chim. Acta 1998, 81, 695 –
717.
[9] a) S. J. Grabowski, Chem. Rev. 2011, 111, 2597 – 2625; b) T.
Steiner, Angew. Chem. 2002, 114, 50 – 80; Angew. Chem. Int. Ed.
2002, 41, 48 – 76; c) G. R. Desiraju, T. Steiner, The Weak
Hydrogen Bond in Structural Chemistry and Biology, Oxford
University Press, New York, 1999; d) C. Laurence, K. A.
Angew. Chem. Int. Ed. 2012, 51, 6176 –6180
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
6179

.
Angewandte
Communications
[27] a) H.-J. Schneider, Chem. Sci. 2012, 3, 1381 – 1394; b) J. D.
Dunitz, R. Taylor, Chem. Eur. J. 1997, 3, 89 – 98; c) J. A. K.
Howard, V. J. Hoy, D. OꢁHagan, G. T. Smith, Tetrahedron 1996,
52, 12613 – 12622.
[28] R. F. W. Bader, H. Essꢂn, J. Chem. Phys. 1984, 80, 1943 – 1960.
[29] Minimization of the lone-pair–lone-pair F···OH repulsion
cannot be excluded; see Ref. [18c].
[30] R. A. Cormanich, M. A. Moreira, M. P. Freitas, T. C. Ramalho,
C. P. A. Anconi, R. Rittner, R. H. Contreras, C. F. Tormena,
Magn. Reson. Chem. 2011, 49, 763 – 767.
[31] R. A. Klein, J. Am. Chem. Soc. 2002, 124, 13931 – 13937.
[32] a) M. Devereux, P. L. A. Popelier, I. M. McLay, Phys. Chem.
Chem. Phys. 2009, 11, 1595 – 1603; b) J. Schwçbel, R.-U. Ebert,
R. Kꢃhne, G. Schꢃꢃrmann, J. Phys. Chem. A 2009, 113, 10104 –
10112; c) O. Lamarche, J. A. Platts, Phys. Chem. Chem. Phys.
2003, 5, 677 – 684; d) P. Politzer, J. S. Murray, Z. Peralta-Inga, Int.
J. Quantum Chem. 2001, 85, 676 – 684.
[33] P. W. Kenny, J. Chem. Inf. Model. 2009, 49, 1234 – 1244.
[34] F. T. T. Huque, J. A. Platts, Org. Biomol. Chem. 2003, 1, 1419 –
1424.
[35] a) M. Bols, X. Liang, H. H. Jensen, J. Org. Chem. 2002, 67, 8970 –
8974; b) H. H. Jensen, L. Lyngbye, M. Bols, Angew. Chem. 2001,
113, 3555 – 3557; Angew. Chem. Int. Ed. 2001, 40, 3447 – 3449;
c) C. M. Pedersen, J. Olsen, A. B. Brka, M. Bols, Chem. Eur. J.
2011, 17, 7080 – 7086; for an example where fluorine stereo-
chemistry had minimal effects on solvolysis rate contants, see:
S. S. Lee, I. R. Greig, D. J. Vocadlo, J. D. McCarter, B. O. Patrick,
S. G. Withers, J. Am. Chem. Soc. 2011, 133, 15826 – 15829.
[36] I. V. Alabugin, T. A. Zeidan, J. Am. Chem. Soc. 2002, 124, 3175 –
3185.
6180 www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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