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ciation constant for PhCHF2 we have used the con-
centration of the molecule. If the concentration of
fluorine is used then the association constant KA
becomes smaller, 0.32mꢀ1 (or logKA =ꢀ0.50).
Shielded fluorine atoms such as primary and secon-
dary fluorine atoms are rare in fluorinated drugs
and ligands as recently shown in an analysis of the
PDB and integrity databases.[15] It is evident, ac-
cording to the findings reported in this work, that
the replacement of a proton with this type of fluo-
rine in a molecule could result in an improvement
in affinity to the receptor through intermolecular
hydrogen bonds or dipolar interactions involving
Table 1. Hydrogen-bond complex formation with p-fluorophenol measured with
19F NMR titration experiments at ꢀ28C in CCl4. KAPhCOMe/KA is the ratio of the association
constant of acetophenone with respect to the KA of the fluorinated molecules. DDG is
the difference in free energy with respect to acetophenone.
Molecule
KD
[mm]
KA
[mꢀ1
LogKA Ddmax(19F) KPAhCOMe/KA DDG
]
[ppm]
[kcalmolꢀ1
]
acetophenone
1-fluoroheptane
(fluoromethyl)benzene
(27.8ꢂ0.8)
36.0
1.56
0.16
0.13
1.99
1.09
1.38
0.55
1
0
(690.7ꢂ28.9) 1.45
(733.7ꢂ42.2) 1.36
25
26
56
1.73
1.76
2.17
(difluoromethyl)benzene (1566.4ꢂ56.1) 0.64 ꢀ0.19
(trifluoromethyl)benzene
too weak
At this point in time we do not have an explanation for the
mechanism responsible for this behavior.
the fluorine atom. In addition these primary and secondary
fluorine atoms should be well represented in the fluorine
library used for 19F NMR screening in order to increase the
diversity of the local environment of fluorine.[16]
It is evident from Table 1 that the fluorinated molecules are
weaker hydrogen-bond acceptors when compared to aceto-
phenone. This can be inferred from the smaller KA and smaller
Ddmax values. This can also be appreciated by comparing the
19F 2D DOSY experiments recorded for acetophenone and fluo-
romethyl benzene as shown in Figure 2c. The MW values of
acetophenone and fluoromethyl benzene are very similar, 110
versus 120 Dalton, respectively. Therefore, the diffusion coeffi-
cient D for both complexes with p-fluorophenol would be very
similar. The change of the diffusion coefficient (DD) for p-fluo-
rophenol is significantly larger in the presence of acetophe-
none than in the presence of fluoromethyl benzene. This de-
spite the nearly three-fold higher concentration used for fluo-
romethyl benzene with respect to acetophenone for recording
the spectra of Figure 2c.
Additional experimental evidence for the ranking order of
the molecules is obtained with the 2D 19F DOSY experiments
reported in Figure 3.
Two-dimensional 19F DOSY experiments with the optimized
pulse sequence for covering a large bandwidth recently report-
ed[15] were recorded for a 1 mm mixture of mono-, di-, and tri-
fluoromethyl benzenes in CCl4 at 258C in the absence and
presence of 1.1m phenol. In the absence of phenol the three
molecules can be ranked according to their MW values in the
diffusion coefficient dimension (vertical axis of Figure 3). The
2D spectrum in the presence of phenol was normalized in the
vertical axis with respect to the diffusion coefficient of the tri-
fluoromethyl benzene in the absence of phenol. This normaliz-
ing factor is very similar for trifluoromethoxy benzene (data
not shown). The change in the diffusion coefficient defined as
DD=D+ꢀDꢀ (shown with dashed line in Figure 3) with the +
and ꢀ symbols indicating the presence and absence of
phenol, respectively, is different for the three molecules and it
follows the order: PhCH2F>PhCHF2 >PhCF3. In the presence of
1.1m phenol the ranking of the diffusion coefficient D+ is now
different with PhCHF2 >PhCF3 >PhCH2F. This is due to the dif-
ferent hydrogen-bond association constants for the three fluo-
rinated acceptors, which at 1.1m concentration of phenol
result in different percentages of complex formation, in agree-
ment with the results reported in Table 1. The different percen-
tages of complex formation determine the observed ranking
order of D+.
The two primary fluorine atoms of 1-fluoroheptane and fluo-
romethyl benzene have almost the same association constant,
indicating that the presence or absence of the aromatic ring
does not play an important role in the interaction. According
to Table 1 the hydrogen-bond association constant for aceto-
phenone is 25 and 26 times larger when compared to 1-fluoro-
heptane and to fluoromethyl benzene, respectively. This corre-
sponds to a hydrogen-bonded complex formed with the CH2F
moiety, which is 1.7 kcalmolꢀ1 weaker with respect to the hy-
drogen-bonded complex formed with acetophenone. It was
argued by Taft and coworkers[13] that Ddmax(19F) for complete
proton transfer corresponds to 14 ppm, that is, the difference
in the chemical shift between p-fluorophenol in CCl4 and p-flu-
orophenoxide in DMSO. Therefore, the apparent percentage of
proton transfer in an hydrogen-bond complex can be approxi-
mated by Equation (2).
An important point worth noting is the downfield shift for
the 19F signals of the three fluorinated molecules in the pres-
ence of phenol. This downfield shift (Dd(19F)= jd+ꢀdꢀ j with
the + and ꢀ symbols indicating the presence and absence of
1.1m phenol) for PhCF3, PhCHF2, and PhCH2F was 0.06, 0.30,
and 2.21 ppm, respectively. These chemical shift differences
cannot be used to rank the three molecules according to their
association constants due to the different chemical shift sensi-
tivity on the chemical environment of the three fluorinated
groups. However, these Dd values of the 19F signals have im-
portant implications for 19F NMR screening as discussed below.
It is interesting to remark the similarity of the d(19F) values for
PhCH2F in the presence of 1.1m phenol and when dissolved in
19
ð2Þ
ffi 100 Â Ddmaxð FÞ=14
For acetophenone this value corresponds to 14%, whereas
for PhCH2F and 1-fluoroheptane is only 8 and 10%, respect-
ively.
The data in Table 1 indicate that the strength of hydrogen-
bond formation for the fluorinated molecules has the following
ranking order: 1-fluoroheptaneꢃPhCH2F>PhCHF2 >PhCF3,
which is in agreement with the rule of shielding. It should be
pointed out that in the evaluation of the hydrogen-bond asso-
Chem. Eur. J. 2014, 20, 11058 – 11068
11061
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