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than the number of examples for PhOCH3 and PhOCF3. Further
examination of these X-ray structures shows there is no prefer-
ence for the other torsion angle that is, C(ar)-O-C-F. In all of
the observed C(ar)-C(ar)-O-C torsions, existence of either both
or one CÀF bond is observed in an anomeric orientation that
is, C(ar)-O-C-F torsion ~608. This is nicely borne out by the
PhOCF2H CSD structures that is, ZIJFAB and SOTBAE (Fig-
ure S2). Both have an approximate orthogonal conformation
(81 and 898) with respect to the C(ar)-C(ar)-O-C torsion. Howev-
er, the SOTBAE entry has both CÀF bonds in an anomeric ori-
entation (endo-endo conformation), while only one anomeric
CÀF bond is observed for ZIJFAB (endo-exo conformation). No
examples of crystal structures were found for PhOCFH2.
ertheless nonlinear. The first and second fluorine add 0.17 and
0.27 log units each, while the last fluorination dramatically in-
creases ClogP by 0.66 in value. As a result, the OCH3 to OCF3
conversion is associated with an increase of 54 in molecular
weight and 1.1 log units in ClogP (Figure S3).
Matched molecular pair analysis using the Pfizer compound
collection yielded 700PhOCH3 and PhOCF3 pairs, 217PhOCF2H
and PhOCH3 pairs, and 213PhOCF2H and PhOCF3 pairs. For
each pair, we mined experimental data for differences in physi-
cochemical and ADME properties, with a goal to develop
a better understanding for the generality of the observed
trends. Such knowledge could help us make more rational
choices in compound design with respect to introducing fluo-
rine atoms.
This is a case where strong steric and electronic effects of
fluorine substitution fundamentally shift the conformational
preference. In anisole, the stabilizing mesomeric interaction be-
tween the phenyl electrons and the oxygen lone pair is pre-
dominant, which is maximized at the coplanar conformation.
On the other hand, the high electronegativity of fluorine re-
sults in a highly polarized CÀF bond, and a vacant low-energy
s* orbital of the OÀCF3 bond that can interact with the adja-
cent s bonds or nonbonding electron pairs. A comparison be-
tween anisole and trifluoroanisole illustrates the interplay be-
tween the resonance and inductive effect. The orientation of
the methyl group relative to the benzene plane results from
the balance of the two opposing effects: 1) resonance effects
that favor the coplanar conformation to maximize the electron-
ic conjugation between the oxygen lone pairs and the aromat-
ic p system; 2) counteracting steric effects that favor the or-
thogonal conformation due to steric repulsion with the ortho
hydrogen atoms on the phenyl ring. Because of the strong
electron-withdrawing property of the trifluoromethyl group,
the resonance donor capacity is attenuated and in part bal-
anced by the overlap between the phenyl p-orbital and the s*
orbital, resulting in reduced conjugation with the aromatic
ring. Furthermore, the additional steric bulk of the trifluorome-
thoxy group increases the effects of sterics on conformation. In
combination, the decrease in the resonance effect and the in-
crease in the steric effect both contribute to the orthogonal
conformation observed for PhOCF3. Quantum mechanics calcu-
lations have produced the corresponding energy minima for
PhOCH3 and PhOCF3. Using theories and basis sets of different
levels and complexities, the rotational barrier was reported to
range from ~1.5 to ~3.0 kcalmolÀ1 for the co-planar PhOCH3
and from ~0.5 to ~1.4 kcalmolÀ1 for the orthogonal
PhOCF3.[1a,9] Results from experimental studies of anisole dis-
agreed on the exact magnitude of the barrier height in gas
To better illustrate trends for the relatively large number of
data points in the HLM and RRCK data sets, we applied classifi-
cation guidelines recommended by Pfizer PDM (Pharmacoki-
netics, Dynamics and Metabolism) scientists for characterizing
compounds. Based on studies of standards with known in vivo
hepatic extraction and back calculation from 0.3 and 0.7 in
vivo extraction ratios, an HLM clearance of <9.2 mLminÀ1 mgÀ1
is considered low, and >48 mLminÀ1 mgÀ1 is deemed high
clearance. Clearance values in between are regarded moderate.
Similarly, three classification ranges were recommended to pro-
vide guidance for project teams on absorption potential of
compounds: low, moderate, and high absorption using 2.5 and
1010À6 cmsÀ1 of RRCK values. These thresholds are derived
based on studies of standards with known in vivo absorption
values and transport mechanisms, and taking into account the
experimental variations.[10]
Comparison of anisoles and trifluoroanisoles
Lipophilicity: logD
Lipophilicity has been shown to significantly impact binding
affinity, pharmacokinetics and toxicity.[11] Highly lipophilic com-
pounds tend to afford low solubility and poor metabolic stabil-
ity, leading to low oral bioavailability.[12] High lipophilicity is
also frequently associated with increased promiscuity, giving
rise to higher risk of adverse events.[13] Over the years, lipophi-
licity has been recognized as a key drug-like physicochemical
property that determines the overall quality of a clinical candi-
date.[11b,14] A recent report has revealed a marked increase in
the lipophilicity of compounds being synthesized in leading
pharmaceutical companies.[11b] Efforts to reverse this trend are
needed to decrease attrition in drug discovery and develop-
ment due to lack of selectivity and compound-related toxico-
logical events.
phase, but they generally estimated it as <3.1 kcalmolÀ1 [9b]
.
Overall, the dramatic effects of fluorine on ligand conforma-
tional bias could clearly influence ligand binding affinities and
should be an important consideration when exploring fluoroa-
nisoles as potential anisole bioisosteres.
ClogP calculation is the most widely used assessment for lip-
ophilicity of a compound.[15] However, for molecules that con-
tain charged moieties it does not take into account the proper
ionic states and their influence on partitioning into aqueous
and hydrophobic (e.g., octanol) phases. The distribution coeffi-
cient (logD) addresses this by taking into account the extent
of ionization at a certain pH and the distribution between the
two immiscible solutions at equilibrium.
Comparison of properties
Each replacement of hydrogen with fluorine results in an in-
crease of 18 in molecular weight. The ClogP increment is nev-
ChemMedChem 2015, 10, 715 – 726
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