Difluoromethyl bioisostere: Examining the lipophilic hydrogen bond donor concept

Article abstract of DOI:10.1021/acs.jmedchem.6b01691

There is a growing interest in organic compounds containing the difluoromethyl group, as it is considered a lipophilic hydrogen bond donor that may act as a bioisostere of hydroxyl, thiol, or amine groups. A series of difluoromethyl anisoles and thioanisoles was prepared and their druglike properties, hydrogen bonding, and lipophilicity were studied. The hydrogen bond acidity parameters A (0.085-0.126) were determined using Abraham's solute ¹H NMR analysis. It was found that the difluoromethyl group acts as a hydrogen bond donor on a scale similar to that of thiophenol, aniline, and amine groups but not as that of hydroxyl. Although difluoromethyl is considered a lipophilicity enhancing group, the range of the experimental Δlog P(water-octanol) values (log P(XCF₂H) - log P(XCH₃)) spanned from -0.1 to +0.4. For both parameters, a linear correlation was found between the measured values and Hammett σ constants. These results may aid in the rational design of drugs containing the difluoromethyl moiety.

Full text of DOI:10.1021/acs.jmedchem.6b01691

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Article
The Difluoromethyl Bioisoster: Examining the
“Lipophilic Hydrogen Bond Donor” Concept
Yossi Zafrani, Dina Yeffet, Gali Sod-Moriah, Anat Berliner, Dafna
Amir, Daniele Marciano, Eytan Gershonov, and Sigal Saphier
J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.6b01691 • Publication Date (Web): 04 Jan 2017
Downloaded from http://pubs.acs.org on January 4, 2017
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Journal of Medicinal Chemistry is published by the American Chemical Society.
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The Difluoromethyl Bioisostere: Examining the “Lipophilic
Hydrogen Bond Donor” Concept
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Yossi Zafrani,* Dina Yeffet, Gali Sod-Moriah, Anat Berliner, Dafna Amir,
Daniele Marciano, Eytan Gershonov,* and Sigal Saphier*
The Department of Organic Chemistry, Israel Institute for Biological Research, Ness-Ziona 74100, Israel
ABSTRACT: There is a growing interest in organic compounds containing the difluoromethyl
group, as it is considered a lipophilic hydrogen bond donor which may act as a bioisostere of
hydroxyl, thiol or amine groups. A series of difluoromethyl anisoles and thioanisoles was
prepared and their drug-like properties; hydrogen bonding and lipophilicity were studied., The
hydrogen bond acidity parameters A (0.085-0.126) were determined using Abraham's solute
1H NMR analysis. It was found that the difluoromethyl group acts as a hydrogen bond donor
on a scale similar to that of thiophenol, aniline and amine groups, but not as that of hydroxyl.
Although difluoromethyl is considered a lipophilicity enhancing group, the range of the
experimental ∆logP(water-octanol) values (logP(XCF2H)-logP(XCH3)) spanned from -0.1 to +0.4.
For both parameters, a linear correlation was found between the measured values and Hammett
σ constants. These results may aid in the rational design of drugs containing the difluoromethyl
moiety.
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INTRODUCTION
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Introducing fluorine atom(s) into bioactive organic compounds has become a leading strategy
for drug design and lead optimization.1 Due to its unique properties fluorine is frequently
employed to modify biologically relevant properties such as metabolic stability, basicity,
lipophilicity and bioavailability.2 In addition, the binding affinity of compounds to biological
targets may also improve upon fluorination, and therefore, fluorine is considered an excellent
candidate to serve as a bioisostere for hydrogen.3 Most fluorine compounds in marketed drugs
consist of either alkyl or aryl groups holding a single fluorine atom, or a trifluoromethyl
moiety.4 As the interest in fluorination of candidate drugs increases, special interest in the
difluoromethyl group (CF2H) is also growing,5,6 since it may hold some distinct advantages
arising from its unique chemical and physical properties. In particular, replacing a methyl with
the difluoromethyl group may lead to a smaller lipophilicity increase relative to
trifluoromethyl7,8 and provides new hydrogen bonding ability9 (Figure 1A). There are many
examples exhibiting involvement of hydrogen bond donating interactions of this group at the
active site.10-12 Therefore, it is regarded as a possible “lipophilic hydrogen bond donor” moiety
or in other words, as a "lipophilic bioisostere" of hydroxyl (OH) and thiol (SH) functional
groups.13-16 It should be noted though, that the hydrogen bonding of this group has not been
studied systematically yet and is estimated to be relatively weak. For example, in a CH…O
interaction, it has been estimated by calculations that each fluorine adds about 1 kcal/mol to
the binding energy.17
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The term “lipophilic bioisostere” relates to the fact that when replacing a hydrogen with a
fluorine atom an increase in lipophilicity is usually expected.18,19 This however, does not
always occur, for example, when the CF2H is positioned at a primary carbon in aliphatic
compounds, a reduction in the lipophilicity of the molecule compared to its CH3 counterpart is
observed.5,8,20 Therefore, the terms "lipophilic hydrogen bond donor" or “lipophilic
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bioisostere” warrants a more systematic and quantitative study. How significant is the tendency
of CF2H to donate its -hydrogen and is it sensitive to other functions in the molecule?
Similarly, how is the lipophilicity induced by this group, affected by the molecular structure of
specific compounds?
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To answer these questions, we began by focusing on one of the most common moieties in
medicinal chemistry, the anisole. The importance of this functional group has been highlighted
by Xing et al7 who studied hundreds of molecular pairs from the Pfizer compound collection
of anisoles, difluoroanisoles and trifluoroanisoles, concluding that difluoroanisoles may be
superior to trifluoroanisoles in terms of metabolic stability and permeability. In these studies,
the hydrogen bond acidity of these groups, which may lead to even more favorable traits, was
not discussed and the lipophilicity was discussed on a statistical basis. This prompted us to
prepare a series of ArOCF2H compounds and to study their hydrogen bond acidity and
lipophilicity. In addition, a series of compounds with growing importance, ArSCF2H21,
exhibiting higher lipophilicity was also prepared in order to evaluate the effect of O versus S
on these properties (Figure 1B).
Figure 1. Physicochemical properties of CF2H group
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Specifically, systematic structure properties relationships of the above-mentioned series is
reported, regarding the hydrogen bond acidity parameter A (HB Acidity, the ability of a
molecule to act as a hydrogen-bond donor) of the functions XCF2H and the experimental ∆logP
values (logP(XCF2H)-logP(XCH3)). The sensitivity of these values to various functional groups,
enabled us to learn about the potential range of these properties and understand the structural
rules that govern them.
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RESULTS AND DISCUSSION
Synthesis. Difluoroanisoles 1a-j and difluorothioanisoles 3a-h were synthesized in good to
excellent yields according to the procedure previously reported by us,22 using O-
diethyl(bromodifluoromethyl) phosphonate as a difluorocarbene precursor (Figure 2). Both
series contain aryl moieties having various electron withdrawing or electron donating groups
(EWG or EDG, respectively) in order to inspect a possible correlation between the substituents
and the physicochemical properties. The OCF2H group of the anisoles is characterized by 1H
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NMR in CDCl3 as a triplet at around 6.5 ppm and by F NMR as a doublet at ca. -5 ppm.
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Similarly, the SCF2H group of the thioanisoles is characterized by H NMR as a triplet at
around 6.8 ppm and by 19F NMR as a doublet at ca. -16 ppm. Anisoles 2a-j, thioanisoles 4a-
h, as well as toluene derivatives 5 and 6 (Figure 5) are commercially available.
HB Acidity properties. A decade ago, a very convenient and simple method for the
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determination of a solute HB acidity, A, using H NMR was reported by Abraham et al.23,24
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Using a wide range of solutes, these authors have shown that the difference in the H NMR
chemical shifts (ppm) of a hydrogen in CDCl3 and DMSO-d6 solvents is directly related to
its A value. The latter can be simply calculated from the equation A = 0.0065 + 0.133 with
 =  (DMSO) –  (CDCl3). In addition to being a very convenient method, and contrary to
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other methods, this technique enables the determination of A values for a specific hydrogen in
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the molecule. Therefore, it is most appropriate for the present study in which case we set to
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Figure 2. Synthesis of difluoromethyl anisoles 1a-j and thioanisoles 3a-h
determine the A values of the CF2H group in various structures and compare them to their CH3
counterparts. The 1H NMR chemical shifts of the relevant hydrogen of 1a-j vs 2a-j solutes in
CDCl3 and DMSO as well as the  and the calculated A values are presented in Table 1.
Inspection of the data reveals that, indeed, relatively large positive  values (0.66-0.90 ppm)
were found for the hydrogen of the CF2H moiety of 1a-j, while very small negative  values
(-0.01 to -0.09 ppm) were found for the hydrogen of the CH3 moiety in their 2a-j counterparts.
The calculated A values for the former compounds ranged from 0.094 to 0.126, namely, a gap
of 25% between the compound with the highest tendency to donate a hydrogen from the CF2H
moiety (1a) to that of the lowest one (1j). On the other hand there is essentially no tendency to
donate a hydrogen from the OCH3 groups of the matching pairs 2a-j (A ~ 0). These results
confirm that the two adjacent fluorines on the OCF2H are responsible for the effect of HB
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acidity of this group, owing to their high electronegativity. This property is clearly affected by
the aryl substituents with EWGs increasing the HB acidity of the OCF2H, and vice versa. The
calculated A values (standard deviations < 1%) were found to nicely correlate with the
Hammett  constants for the difluoro anisole derivatives 1a-j as shown in Figure 3. However,
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the relatively small  value (0.03) suggests that the main effect resulted from the geminal
fluorines and not by the substituent groups on the aromatic ring (Y).
Interestingly, a very similar behavior was observed for the series 3a-h and 4a-h. The 1H NMR
chemical shifts of the SCF2H group of 3a-h vs the SCH3 group of 4a-h in CDCl3 and DMSO
as well as the  and the calculated A (standard deviations < 1%) values are presented in Table
2. As in the case of their anisole counterparts, significant positive values (0.66-0.90 ppm)
were found for the hydrogen of the SCF2H moiety of 3a-h, while very small  values (-0.05-
0.03 ppm) were found for the hydrogen of the matched pairs 4a-h (SCH3). The calculated A
values for the difluoromethylated thioanisoles were found to be somewhat smaller (0.085-
0.116) than those of the difluoromethylated anisoles (0.094 - 0.126). Nevertheless, the same
gap of ca. 25% between the compound with the highest tendency to donate a hydrogen (EWG,
3a) to that of the lowest one (EDG, 3h, the similar A value of 3f is somewhat deviating from
this trend) was found. As was observed with the anisoles, the SCH3 group has no tendency to
form H-bonds (4a-h; A ~ 0, Table 2). Here also, the measured A paramters (measured standard
deviations < 1%) were found to correlate with the Hammett  constants for the difluoromethyl
thioanisole derivatives 3a-h (Figure 4). Interestingly, exactly the same relatively small  value
(0.03) was observed for both difluoromethyl- anisoles and thioanisoles, which again, suggests
that the main hydrogen bonding effect resulted from the geminal fluorines and not by the
aromatic substituent groups on the aromatic ring (Y).
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Table 1. 1H NMR chemical shifts of ArOCF2H vs ArOCH3, , and A values of the anisoles 1a-j and
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2a-j
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CDCl3 DMSO


CDCl3 DMSO


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0.126
0.117
0.117
0.114
0.112
0.104
0.104
0.098
0.100
0.094
0.005
0.004
0.004
0.003
0.001
0.000
-0.003
-0.004
-0.005
-0.004
6.63
6.57
6.55
6.62
6.52
6.45
6.51
6.51
6.46
6.42
7.53
7.40
7.38
7.43
7.31
7.18
7.24
7.20
7.16
7.08
0.90
0.83
0.83
0.81
0.79
0.73
0.73
0.69
0.70
0.66
3.91
3.85
3.85
3.89
3.80
3.78
3.81
3.80
3.79
3.77
3.90
3.83
3.83
3.86
3.76
3.73
3.74
3.72
3.70
3.69
-0.01
-0.02
-0.02
-0.03
-0.04
-0.05
-0.07
-0.08
-0.09
-0.08
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
1g
1h
1i
2g
2h
2i
1j
2j

0.13
p-NO2
ρ = 0.03
R² = 0.978
0.12
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0.1
m-CF3
p-CF3
p-C(O)Ph
m-F
H
p-F
m-CH3
p-CH3
p-OCH3
0.09
0.08
-0.4
-0.2
0
0.2
0.4
0.6
0.8
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Hammett σ values
Figure 3. Correlation between A (OCF2H) values of 1a-j and the Hammett  values of the substituents
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Table 2. 1H NMR shifts of ArSCF2H vs ArSCH3, , and A values of the thioanisoles 3a-h and 4a-h
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
CDCl3 DMSO


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6.94
6.80
6.81
6.79
6.83
6.77
6.79
6.75
7.76
7.50
7.55
7.46
7.52
6.36
7.41
7.35
0.82
0.70
0.74
0.67
0.69
0.59
0.62
0.60
0.116
0.100
0.105
0.096
0.098
0.085
0.089
0.086
2.55
2.48
2.47
2.47
2.50
2.46
2.47
2.47
2.58
2.47
2.47
2.46
2.46
2.41
2.43
2.43
0.03
0.011
0.005
0.007
0.005
0.001
0.000
0.001
0.001
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
-0.01
0.00
-0.01
-0.04
-0.05
-0.04
-0.04

3g
3h
4g
4h
0.12
p-NO2
 = 0.03
R² = 0.8434
0.11
0.1
p-Br
p-Cl
H
p-F
0.09
0.08
p-CH3
p-NHCOCH3
p-OCH3
-0.4 -0.2
0
0.2
0.4
0.6
0.8
1
Hammett  values
Figure 4. Correlation between A values of 3a-h and the Hammett  values of the substituents.
Inspection of the A values of OH, SH and NH, which were reported by Abraham et al23, and
are presented in Figure 5, reveals that the solute HB acidity of the above described fluorinated
functional groups OCF2H and SCF2H is less significant than that of the hydroxylic groups, but
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similar to those of amines, anilines and thiophenols (marked in blue). By definition, the
electronegativity values of atoms D and A in the hydrogen bond D-H….A regulate its strength,
i.e. the higher the electronegativity, the greater the attractive interaction. The C-H group is
considered a very weak hydrogen bond donor unless it holds electronegative groups. For
example, the A values of pentane (Me), dichloromethane and trichloromethane are 0.00, 0.10
and 0.15, respectively.23 In our difluoro- anisole and thioanisole series we show that in addition
to the electronegative fluorine atoms which make the main contribution to the observed A
values, the third group, i.e. the phenolic and thiophenolic groups respectively, also contribute
to the HB acidity to a small extent. It is therefore reasonable that electron withdrawing groups
on the aromatic ring increases the A values of both series and vice versa (as was shown by the
Hammett correlation obtained). The somewhat higher A values of difluoroanisoles relative to
their difluorothioanisoles counterparts may also be due to the higher electronegativity of the
phenolic group versus the thiophenolic one.
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Figure 5. Reported A values of the functions OH, NH2 and SH, and those of CF2H group
In order to perform a preliminarily evaluation of the effect of this third phenolic/thiophenolic
group versus phenylic groups, we measured the A values of the difluorotoluenic compounds 5
and 6 (Figure 5). In the latter compounds the CF2H is directly bound to the aromatic ring,
analogously to phenol, aniline and thiophenol. As expected, the p-nitro group increases the A
value of difluorotoluene (from 0.057 to 0.070), yet both values were found to be smaller than
those of the corresponding difluoro- anisoles 1a/1g and thioanisoles 3a/3e (Tables 1 and 2).
All the observed solute HB acidities of the aromatic compounds holding the CF2H moiety were
of a similar order of magnitude, resembling anilines, amines and thiophenols. Therefore, this
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group may be considered as a bioisostere of NH2 and ArSH from the hydrogen bonding point
of view. To address the “lipophilic” part of the bioisostere definition, we now turn to examine
the lipophilicity
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Lipophilicity properties: Lipophilicity is commonly expressed as logP, the logarithm of the
partition coefficient, i.e., the distribution of a compound between an aqueous phase and an
organic phase, with octanol being considered the most relevant to biological membranes. Due
to the fact that octanol and water have similar hydrogen bond accepting ability, this property
does not have much effect on the phase distribution. 25-27 Moreover, the A value measured
refers to a single hydrogen and not to the molecule in total. We therefore proceeded to measure
and compare the partition coefficients (logPoct) of the anisoles and thioanisoles matched pairs.
As mentioned in the introduction, Xing et al7 have shown that statistically, replacing anisole
with difluoroanisole, was superior to trifluoroanisoles, in terms of metabolic stability and
permeability on a Pfizer collections of molecular pairs. For more than four hundred
OCH3/OCF3 molecular pairs, there was no contribution to metabolic stability, possibly because
blocking of site-specific metabolism was offset by the overall increase in lipophilicity, which
enhances binding to CYP metabolizing enzymes. The increase in lipophilicity for the OCH3-
OCF3 exchange in anisoles was found to be anywhere between 0.3 to 1.3 log units7 and in
another report, an average of ∆logP ~ 1.0 was reported 8. However, for OCF2H a much smaller
increase of ∆log P~0.38 with a range of 0.2-0.67 was found. Since these analyses were
performed based on matched molecular pairs of existing databases, the differences within the
variety of OCF2H containing molecules in terms of lipophilicity increase could not be analyzed
for structure-lipophilicity relationship.
The logP of ten pairs of anisoles and difluoroanisoles (Table 3) and eight pairs of thioanisoles
and difluorothioanisoles (Table 4) was measured under identical conditions for each pair. The
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compounds examined were lipophilic with a logP range from around 2 to 3. For the thiol
counterparts, as expected, higher lipophilicities were measured, usually, around 0.5 logP units
higher for the same substituents and up to logP of 3.4. The ∆log P for each pair was calculated
and in contrast to simple calculations using ClogP (from chemdraw ∆logP = 0.446) or
molinspiration milog P28 (∆log P = 0.56) values, which gave a constant ∆logP for all these
pairs, in reality, our experimental measurements of ∆logP showed differences spanning from -
0.11 to + 0.45 (Tables 3 and 4).
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When evaluating the lipophilicity effect a certain substituent has on a particular arylic system,
the Fujita and Hansch hydrophobic parameter π may be used.29 It is defined as πX = log (PX/PH),
the result of subtracting log P in an aromatic system containing substituent X from the same
aromatic system without substituent X. The πX value varies from one aromatic system to
another. Calculating ∆π = πX(Ar)- πX(Bz) for a specific aromatic systems (Ar) by subtracting from
the benzene system may show a good correlation to Hammett constants of the substituents (for
example with phenols, aniline and benzyl alcohols), while other systems, may not show such
a correlation requiring more elaborate analysis (for example benzoic acids and
nitrobenzenes).30,31 As with these examples, and in contrast with anisoles, we found no
correlation when subtracting πX of thedifluoro systems fromthat of benzene. Therefore, in order
to gain understanding of the expected lipophilicity, the analysis of the lipophilicities observed
were performed by comparing the logP values obtained to that of the parent anisole or
thioanisole which was also more relevant to the bioisostere concept.
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Table 3: log P for anisoles and difluoromethyl anisoles and their ∆log P
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6
Functional
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8
9
Comp
log P
Comp
log P
∆log P
Group
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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29
30
31
32
33
34
35
36
37
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p-NO2
1.98 ± 0.06
2.76 ± 0.10
2.69 ± 0.09
2.85 ± 0.09
2.59 ±0.05
2.47 ± 0.10
2.29 ± 0.09
2.87 ± 0.02
2.88 ±0.05
2.35 ± 0.11
2.04 ± 0.06
2.87 ± 0.01
2.79 ± 0.13
2.69 ± 0.07
2.43 ±0.02
2.14 ± 0.05
1.99 ± 0.03
2.58 ± 0.01
2.56 ± 0.10
1.92 ± 0.07
-0.06
-0.11
-0.10
0.16
0.16
0.33
0.29
0.29
0.32
0.43
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
p-CF3
m-CF3
p-COPh
m-F
p-F
H
1g
1h
1i
2g
2h
2i
m-CH3
p-CH3
p-OCH3
1j
2j
0.5
0.4
0.3
0.2
0.1
0.0
-0.1
-0.2
 = -0.40
R² = 0.939
p-OCH3
p-F
H
p-CH3
m-CH3
p-C(O)Ph
m-F
p-NO2
m-CF3
p-CF3
0.6
-0.4
-0.2
0.0
0.2
0.4
0.8
1.0
Hammett σ values
Figure 6. Correlation between ∆logP (OCF2H-OCH3) values of 1a-1j vs. 2a-2j and the corresponding
Hammett  constants of the substituents
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Examining the correlation between ∆logP and electronic properties of the substituents, it is
clear that the more electron withdrawing the substituent, the less lipophilicity is added to the
molecule upon insertion of the fluorine atoms. Using the Hammett equation we obtained for
anisoles a linear correlation between ∆logP and Hammett σ constants with a ρ value of -0.40
(Figure 6). Two compounds comprising CF3 substituents in para and meta positions, fell even
further from the curve, giving rise to a higher reduction of lipophilicity than expected. Both
pairs showed nearly identical ∆logP, indicating that other factors may also affect the
lipophilicity change resulting from the CF3 group. Treating these highly lipophilic compounds
as outliers gave a good correlation.
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Although in general thioanisole and difluorothioanisoles show higher values of logP than the
anisoles and difluoroanisoles, respectively, the same trend was observed, with a similar ρ value
of -0.54 (Table 4 and Figure 7). This observation validates our findings and the role that the
electronic character of the substituents have on the lipophilicity of the molecules. Also here, a
good correlation between ∆log P and hammett σ value was obtained.
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Table 4. log P for thioanisoles and difluoromethyl thioanisoles and their ∆log P
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6
7
Functional
Comp
log P
Comp
log P
∆log P
8
Group
p-NO2
p-Cl
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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30
31
32
33
34
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60
2.54 ± 0.04
3.24 ± 0.13
2.96 ± 0.05
2.92 ± 0.05
2.89 ± 0.06
2.42 ± 0.05
3.41 ± 0.15
3.11 ± 0.04
2.64 ± 0.04
3.01 ± 0.03
2.78 ± 0.22
2.77 ± 0.01
2.60 ± 0.02
1.96 ± 0.02
3.01 ± 0.03
2.66 ± 0.05
-0.10
0.23
0.18
0.15
0.29
0.46
0.40
0.45
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
p-Br
p-F
H
p-NHCOMe
p-CH3
4-OCH3
3g
3h
4g
4h
p-OCH3
0.5
0.4
0.3
0.2
0.1
0.0
-0.1
-0.2
p-NHCOCH3
 = -0.54
R² = 0.831
p-CH3
H
p-Cl
p-Br
p-F
p-NO2
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
Hammett σ values
Figure 7. Correlation between ∆log P (SCF2H-SCH3) values of 3a-3h vs 4a-4h and the corresponding
hammett σ constants of the substituents.
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In cases where fluorine addition does not lead to higher lipophilicity as expected, it is assumed
that polarity effects of the polar C-F bonds become more dominant and offset the effect of the
added hydrophobicity from the volume increase introduced by the fluorine atoms.8 It is known
that in anisoles, the methoxy group usually occupies a planar conformation relative to the
aromatic ring owing to conjugation between the oxygen lone pairs and the π electrons of the
aromatic ring. In contrast, when all hydrogen atoms of the methoxy are replaced with fluorine
atoms, anomeric interactions of the C-F σ* orbitals with the oxygen lone pair orbitals weaken
the π conjugation and lead the OCF3 group into an orthogonal position.8 For difluoro anisoles,
conformational analysis of different structures, did not show one distinct orientational
preference, and it was found that in all structures one or two of the C-F bonds were in anomeric
orientation.7,1c Vector analysis of the possible conformations for ArOCF2H has been used
previously to explain the relatively modest addition of polarity compared to ArOCF3.8 It was
shown that there are two possible conformations, i.e endo-endo and exo-endo (Figure 8A). The
endo-exo conformer displays increased polarity and is probably predominant. Just how
predominant this conformation may be was not determined and this probably changes as a
function of other substituents. At the endo-endo conformation, both C-F bonds have anomeric
interaction with the O lone pair orbital. Therefore, in our case, it is conceivable that with EDGs,
this conformation may be more favorable and lead to lower polarity, thereby leading to the
expected 0.3-0.4 increase in lipophilicity which we observed. With EWGs, little electron
density may remain for anomeric interaction and thus the endo-exo conformer may be more
dominant, leading to higher vector polarity and decreased lipophilicity. However, despite the
fact that anomeric effects are considered to be only weakly sustained by sulfur compounds,32
the same lipophilicity difference trend was observed for both the anisoles 1a-j, 2a-j and
thioanisole 3a-h, 4a-h series. Therefore, regardless of the possible structural analysis, for both
series, EWG lead to more polar structures compared to EDG. With the most EWGs, i.e. nitro
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and trifluoromethyl, the polarity increased to the extent of rendering the molecule more polar
than the parent anisole or thioansiole structure.
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The fact that the hydrogen donating property of the XCF2H also increased with increasing
electron withdrawing substituents on the aromatic ring, implies that the carbon center has
become more positive, because of the third electron withdrawing phenolic or thiophenolic
group (Figure 8B). This simple depiction of dipole with a positive carbon and electronegative
substituents also suggests a more polar molecule compared to structures with electron donating
groups, leading to a smaller increase in lipophilicity. Thus, regardless of the exact structural
analysis, we can conclude that the term “lipophilic bioisostere” is strongly dependent on the
nature of the different substituents that are included in the molecular structure of the drug
candidate, with electron withdrawing groups eliminating this lipophilicity.
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Figure 8. Proposed explanations for the substituents effect on the lipophilicity. A. Two
possible conformations of the OCF2H group showing possible conformations and their effect.
B. EWGs leading to a stronger dipole with a more positive carbon center.
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CONCLUSIONS
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Aiming at understanding the scope of the properties which make CF2H group a possible
lipophilic hydrogen bonding isoster, we have investigated in detail the properties of a series of
difluoroanisoles and difluorothioanisoles. The hydrogen bond acidity of XCF2H is of the scale
of aniline / amine or thiophenol but not of phenol / alcohol. The lipophilicity of both series
compared to the anisole or thioanisole parent compounds may increase or decrease, depending
on the type of substituents on the aromatic rings. These findings will enable the rational design
of, for example, fluorinated drug candidates with added metabolic stability or binding affinity
without undesired increase in lipophilicity. More precise design rules may be set for fine tuning
of the replacement of OCH3 with OCF2H according to the needed change in the molecule.
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EXPERIMENTAL SECTION
General. Commercially available high-grade reagents and solvents were used without further
purification. NMR spectra were recorded on 500 MHz spectrometer (1H NMR: 500.2 MHz,
19F NMR: 470.7 MHz). Chemical shifts are reported in parts per million (δ ppm). 1H NMR
chemical shifts were referenced to the residual CDCl3 (δ=7.26 ppm) and d6-DMSO (δ=2.50
ppm). 19F NMR chemical shifts are reported downfield from external trifluoroacetic acid in
D2O. Solutions of 10 mg/mL were prepared in CDCl3 and d6-DMSO for the determination of
HB acidity properties23 with standard deviations in the calculation of A from repeated
measurements less than 1%. Column chromatography was performed with silica gel 60 (230-
400 mesh). UV Absorbance for logP calculations were recorded on a UV-Vis
Spectrophotometer from Amersham biosciences, Ultrospec 2100-pro model.
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General Procedure for difluoro anisoles and thioanisoles.
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All compounds were synthesized according to the procedure previously reported by us.22 All
reactions were placed in a sealed tube or vial, equipped with a magnetic stirrer. To a cooled
(0oC or -78oC) mixture of phenol or thiophenol (1 mmol), KOH (20 mmol) in CH3CN-H2O (10
mL, 1:1) was added in one portion diethyl bromodifluoromethylphosphonate (2 mmol). The
reaction was allowed to warm to 25oC and stirred for 20 min, after which time the reaction
mixture was diluted with ether (10 mL) and the organic phase was separated. The water phase
was washed with a further amount of ether (10 mL), and the combined organic fractions were
dried over anhydrous Na2SO4 and the solvent was evaporated. The crude product was purified
by column chromatography, by passing a solution of the crude product through a short column
of silica gel (specific solvents are reported in the compounds synthetic procedure). Compounds
1a,d,g,j and 3a-c,e,g-h were prepared, characterized and reported by us previously.22
Experimental data for compounds, 1b,33 1c,e,34 1f,35 1h,36 1i,35 3d,37 3f38 were reported
previously and were prepared according to the procedure described above.
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4-Trifluoro difluoromethyl anisole (1b). Known product, according to the general procedure.
The reaction was stirred for 2h at 25oC, the residue was purified with hexane over silica gel, as
colorless oil (35% yield). 1H NMR (500 MHz, CDCl3) δ 7.65 (d, J = 8.3 Hz, 2H), 7.23 (d, J =
8.3 Hz, 2H), 6.57 (t, JHF = 71.7 Hz, 1H); 19F NMR (470.6 MHz, CDCl3) δ 13.62 (s, 3F), -5.88
(d, JFH = 71.7 Hz, 2F).
3-Trifluoro difluoromethyl anisole (1c). Known product, according to the general procedure.
The reaction was stirred for 2h at 25oC, the residue was purified with hexane over silica gel, as
1
colorless oil (42% yield). H NMR (500 MHz, CDCl3) δ 7.50-7.53 (m, 2H), 7.39 (brs, 1H),
7.32-7.34 (m, 1H), 6.55 (t, JHF = 74.1 Hz, 1H); 19F NMR (470.6 MHz, CDCl3) δ 13.05 (s, 3F),
-5.60 (d, JFH = 74.1 Hz, 2F).
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3-Fluoro difluoromethyl anisole (1e). Known product, according to the general procedure.
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The reaction was stirred for 2h at 25oC, the residue was purified with hexane over silica gel, as
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colorless oil (31% yield). H NMR (500 MHz, CDCl3) δ 7.31 (q, J = 7.7 Hz, 1H), 6.86-6.95
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(m, 3H), 6.52 (t, JHF = 72.0 Hz, 1H); 19F NMR (470.6 MHz, CDCl3) δ -34.30 (dd, JFH = 14.1
Hz, 8.0 Hz, 2F), -5.55 (d, JFH = 72.0 Hz, 1F).
4-Fluoro difluoromethyl anisole (1f). Known product, according to the general procedure,
the residue was purified with hexane over silica gel, as colorless oil (31% yield). 1H NMR (500
MHz, CDCl3) δ 7.03-7.12 (m, 4H), 6.45 (t, JHF = 74.5 Hz, 1H); 19F NMR (470.6 MHz, CDCl3)
δ -5.12 (d, JFH = 74.5 Hz, 2F), -41.24 (s, 1F).
3-Methyl difluoromethyl anisole (1h). Known product, according to the general procedure.
The reaction was stirred for 2h at 25oC, the residue was purified with hexane over silica gel, as
colorless oil (76% yield). 1H NMR (500 MHz, CDCl3) δ 7.26 (t, J = 8.5 Hz, 1H), 7.04 (d, J =
19
7.4 Hz, 1H), 6.93-6.96 (m, 2H), 6.51 (t, JHF = 72.4 Hz, 1H), 2.38 (s, 3H); F NMR (470.6
MHz, CDCl3) δ -4.54 (d, JFH = 72.4 Hz, 2F).
4-Methyl difluoromethyl anisole (1i). Known product, according to the general procedure.
The reaction was stirred for 2h at 25oC, the residue was purified with hexane over silica gel, as
1
colorless oil (40% yield). H NMR (500 MHz, CDCl3) δ 2.34 (s, 3H), 6.46 (t, JHF = 74.8 Hz,
1H), 7.01 (d, J = 8.2 Hz, 2H), 7.16 (t, J = 8.1 Hz, 2H); 19F NMR (470.6 MHz, CDCl3) δ -4.54
(d, JFH = 74.8 Hz, 2F).
4-Fluoro difluoromethyl thioanisole (3d). Known product, according to the general
procedure. The reaction was stirred for 3h at 25oC, after which time the reaction mixture was
diluted with pentane and the organic phase was separated. The organic phase without
1
evaporation, was purified by two columns of silica gel. Colorless oil (35% yield). H NMR
(500 MHz, CDCl3) δ 7.58 (dd, J = 10.0 Hz, 5.3 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 6.79 (t, JHF
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= 54.3 Hz, 1H); 19F NMR (470.6 MHz, CDCl3) δ -16.22 (d, JFH = 54.3 Hz, 2F), -34.55-(-34.49)
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(m, 1F).
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4-Acetamido difluoromethyl thioanisole (3f). Known product, according to the general
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procedure. The reaction was stirred for 5h at 25oC, the residue was purified with hexane/EA
1
(0%-30% Hex) silica gel, as colorless solid (25% yield). H NMR (500 MHz, CDCl3) δ 2.19
19
(s, 3H), 6.77 (t, JHF = 59.1 Hz, 1H), 7.39 (brs, 1H), 7.54 (dd, J = 11.3 Hz, 8.7 Hz, 4H); F
NMR (470.6 MHz, CDCl3) δ -16.00 (d, JFH = 59.1 Hz, 2F).
Determination of Octanol-Water Partition Coefficients (LogP)
The partition coefficients were calculated as the logarithm of the ratio of the compound
concentration in the octanol phase to its concentration in the aqueous phase. The "shake-flask"
method was used for the determination of logP values.29 Both octanol and water were pre
saturated with each other for at least 24 hours prior to the experiment. The different anisoles
were dissolved in water saturated octanol to obtain a concentration of 10 mM. The maximum
wavelength (λmax) for each compound was determined and the absorbance recorded using UV
Spectroscopy. Measurements of the compounds concentration were performed on dilute
solutions giving absorbance in the range of 0.2-1. Following preliminary experiments
identifying an optimal water/octanol ratio39, to 45 mL of octanol saturated water, 0.3 mL of the
water saturated octanol solution with the dissolved compound was added and the mixture was
shaken for 5 minutes. The solutions were then centrifuged at 3000 rpm for 5 min. An aliquot
of the octanolic phase was diluted and absorbance was measured. The experiment was repeated
at least three times for each sample under identical conditions and each result is presented as
an average with the standard deviation of these measurements. The extraction ratio was
obtained by difference and logP was calculated taking into account the volume ratio between
the water and octanol.
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AUTHOR INFORMAION
Corresponding Authors
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Y.Z: e-mail, yossiz@iibr.gov.il; telephone, 972-8-9385884
E.G: e-mail, eytang@iibr.gov.il; telephone, 972-8-9381577
S.S: e-mail, sigals@iibr.gov.il; telephone, 972-8-9385884
Notes:
The authors declare no competing financial interest
ACKNOWLEDGMENTS
This work was internally funded by the Israeli prime minister’s office
ABBREVIATIONS USED
HB, hydrogen bond; EWG, electron withdrawing Group; EDG, electron donating group
REFERENCES
(1) Selected papers on the topic: a. Gillis E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.;
Meanwell, N. A. Applications of fluorine in medicinal chemistry. J. Med. Chem. 2015, 58,
8315-835. b. Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Acena, J. L.; Soloshonok, V. A.;
Izawa, K.; Liu, H. Next generation of fluorine-Containing pharmaceuticals, compounds
currently in phase II-III clinical trials of major pharmaceutical companies: new structural trends
and therapeutic areas. Chem. Rev. 2016, 116, 422-518. c. Műller, K.; Faeh, C.; Diederich, F.
Fluorine in pharmaceuticals: looking beyond intuition. Science 2007, 317, 1881-1886.
(2) Böhm, H-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.;
Stahl, M. Fluorine in medicinal chemistry. ChemBioChem 2004, 5, 637-643.
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