CF2H, a Hydrogen Bond Donor

Article abstract of DOI:10.1021/jacs.7b04457

The CF₂H group, a potential surrogate for the OH group, can act as an unusual hydrogen bond donor, as confirmed by crystallographic, spectroscopic, and computational methods. Here, we demonstrate the bioisosterism of the OH and CF₂H

Full text of DOI:10.1021/jacs.7b04457

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Article
2
CFH, a Hydrogen Bond Donor
Chanan D. Sessler, Martin Rahm, Sabine Becker, Jacob M. Goldberg, Fang Wang, and Stephen J. Lippard
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CF2H, a Hydrogen Bond Donor
Chanan D. Sessler,† Martin Rahm,‡ Sabine Becker,† Jacob M. Goldberg,† Fang Wang,† and Ste-
phen J. Lippard*†
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†Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA
02139, United States
‡Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, NY 14853, United
States
ABSTRACT: The CF2H group, a potential surrogate for the OH group, can act as an unusual hydrogen bond donor, as
confirmed by crystallographic, spectroscopic, and computational methods. Here, we demonstrate the bioisosterism of the
OH and CF2H groups and the important roles of CF2–H…O hydrogen bonds in influencing intermolecular interactions and
conformational preferences. Experimental evidence, corroborated by theory, reveals the distinctive nature of CF2H hydro-
gen bonding interactions relative to their normal OH hydrogen bonding counterparts.
oisostere of the OH group,17 despite its greater steric
INTRODUCTION
bulk23 and much weaker resonance effect (Table 1).22
Hydrogen bonding interactions play a crucial role in di-
The hydrogen bond donating ability of the CF2H group
verse chemical and biological processes, including cataly-
has been proposed since the 1990s. Studies of simple
sis,1 protein folding, and maintaining the structure of the
CF2H-containing molecules in the gas phase and in an
DNA double helix.2-3 Strong hydrogen bond donors, such
argon matrix at 15 K support this claim,9, 24-25 as do studies
as O−H, N−H, and S−H functional groups, have been
of hydrogen bonding interactions between CH2F2 and the
4
studied extensively.2, In contrast, the ability of C−H
extremely strong hydrogen bond acceptor F−.26 In addi-
bonds to act as hydrogen bond donors did not receive
tion, Erickson and McLoughlin investigated intramolecu-
much attention until relatively recently.5-8 Although the
lar hydrogen bonding between CF2H and amide groups.10
difluoromethyl group (CF2H) has long been proposed to
The hydrogen bonding ability of the CF2H group was indi-
act as a hydrogen bond donor and thus a surrogate for
rectly inferred from the red shifted carbonyl stretching
hydroxyl or thiol moieties, only a few experimental inves-
frequency in solid state IR spectra, evidence that was cor-
tigations have explored hydrogen bonding interactions of
roborated by solution NMR spectroscopy and theoretical
the CF2H group in the condensed phase.9-11 Here, we de-
calculations. Smith and Scheiner studied the contribution
of the intramolecular CF2–H…O interaction to the con-
scribe a thorough investigation of CF2H hydrogen bond-
ing interactions as revealed by NMR and IR spectroscopy,
formational preference of an α,α-difluoroamide by X-ray
X-ray crystallography, and theoretical calculations.
crystallography and quantum mechanical calculations.11
Short intramolecular CF2–H…O/N distances have been
Incorporation of fluorine can alter the properties of a
compound, such as volatility,12-14 conformational prefer-
observed in some X-ray structures and described as hy-
ence,15-16 metabolic stability,17-18 and acidity.12 Difluorina-
drogen bonding interactions.27-28 We conducted a com-
tion of the methyl group leads to a significant increase in
prehensive survey of structures deposited in the Cam-
the acidity of the C−H bond,19-21 presumably rendering the
bridge Crystal Structural Database and identified short
CF2–H…O distances (<2.7 Å) that may allow for hydrogen
CF2H group a better hydrogen bond donor than its non-
fluorinated counterpart. Electrostatic potential surfaces
bonding interactions in 59 structures (See SI §6.1).
reveal the high polarity of the CF2H group (Table 1) com-
pared to that of the methyl group and the possibility that
Table 1. Comparison of OH, CF2H, and CH3 Group
Properties
CF2H group is a hydrogen bond donor. As suggested by
their σI values,22 the CF2H and OH groups have similar
inductive properties. Based on its electronic characteris-
tics and putative ability to act as a hydrogen bond donor,
the CF2H motif is considered a metabolically stable bi-
b
Ph-X,
Dipole
moment
(Debye)
Electrostat-
ic potential
surfacea
Char-
ton
steric
param-
Acidity
(pKa in
DMSO)
σR
σIb
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ing distance and C−H…O angle are 2.42(3) Å and 157(2)°,
respectively, well in range of the sum of the van der Waals
eter
(v)c
1
2
3
4
5
6
7
8
9
radii (~2.7 Å). In comparison, the corresponding
O−H…O2N distance and O−H…O angle in the 1-OH dimer
are 2.65(2) Å and 133(2)°.
H
O
0.33
0.29
0.01
0.32
18.0d
−0.70
0.03
1.693
Kinetic
acidity
~104
H
F
F
0.68
0.52
higher
than
3.277
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PhMee
H
H
H
42f
−0.18
0.523
a
The electrostatic potential plotted on an isodensity sur-
face of the electron density set to 0.001 e/bohr3. Red = −25
kcal/mol, blue = +25 kcal/mol. b σR and σI are resonance and
inductive effect parameters, respectively. Reference 22. c Ref-
erence 23. d Reference 21. e Reference 19. f Reference 20.
Recently, Zafrani et al. determined the hydrogen bond
Figure 1. (a, b) Crystal structures of 1-OH and 1-CF2H; (c, d)
IR spectra of 100 mM of 1-OH, p-bromophenol (2-OH), 1-
CF2H, and p-bromo-α,α-difluorotoluene (2-CF2H) in CCl4.
Red and grey traces in panel (d) correspond to CF2H- and
CF2D-containing compounds, respectively. Peaks of interest
are identified with arrows. In panel d, the peak labeled with
the asterisk appears in the IR spectra of both 1-CF2H and 1-
CF2D, suggesting that it cannot be attributed to a CF2−H
stretching mode. The O−H stretching of 1-OH is red shifted
by −372 cm-1 relative to that of 2-OH. In contrast, the CF2−H
stretching of 1-CF2H is blue shifted by +44 cm-1 relative to
that of 2-CF2H.
1
acidity of the CF2H moiety based on H NMR chemical
shifts of the OCF2H and SCF2H protons.29 These results
suggest that CF2H ethers and thioethers can act as hydro-
gen bond donors, but the influence of the neighboring
oxygen or sulfur atoms on the hydrogen bonding ability
of the CF2H functional group may be considerable. Owing
to the presence of α-oxygen and sulfur atoms, this work is
presumably much more relevant to bioisosteres of the O–
OH and S–OH moieties, which are less common func-
tional groups than the C–OH group in medicinal chemis-
try and biology. Initial studies9-11, 24 of CF2H…X hydrogen
bonding interactions have routinely been used to justify
CF2H functionalization of small molecules.30-37 Several key
questions regarding CF2H hydrogen bonding interactions
remain, including those concerning the relation between
CF2H and OH hydrogen bonding interactions, the nature
of CF2H hydrogen bonding, and the influence of CF2H
hydrogen bonding on the conformational behavior of
molecules in solution. Studies of CF2–H…O interactions
have primarily been conducted in an intramolecular con-
text, even though the influence of conformational prefer-
ence can be better parsed intermolecularly. Surprisingly,
such interactions are largely unexplored in the condensed
phase.
X-ray structures indicate the presence of intramolecular
O/CF2−H…O2N interactions in both 1-OH and 1-CF2H. The
intramolecular O−H…O2N distance in 1-OH (1.78(2) Å) is
significantly shorter than the corresponding CF2−H…O2N
distance in 1-CF2H (2.45(2) Å). The shorter O−H…O2N
distance, as well as the co-planarity of the nitro and hy-
droxyl groups, is facilitated by the smaller size of the hy-
droxyl group. In contrast, this arrangement is disfavored
in 1-CF2H because of the greater steric bulk of the CF2H
group. The crystal packing of the 1-CF2H group requires
approximately 0.14 Å more space than that observed in
the 1-OH stucture, which is consistent with the Charton
parameters (see Table 1 and Figs. S44B and S45B).
Despite the structural similarity between 1-CF2H and 1-
OH in the crystalline state, IR spectroscopy reveals signif-
icant differences in the intramolecular OH and CF2H hy-
drogen bonding interactions. To investigate the effect of
hydrogen bonding on the O−H and CF2−H bond stretch-
ing modes, we examined the IR spectra of compounds
that cannot form intramolecular hydrogen bonds. We
chose p-bromophenol (2-OH) and p-bromo-α,α-
difluorotoluene (2-CF2H) as reference compounds for 1-
OH and 1-CF2H, respectively (Figs. 1c-1d). The O−H
stretching frequency of 1-OH is red-shifted by −372 cm-1
relative to that of p-bromophenol (Fig. 1c). In contrast,
the intramolecular CF2−H…O2N interaction in 1-CF2H
leads to a +44 cm-1 blue shift in the CF2−H stretch with
decreased intensity relative to that in 2-CF2H (Fig. 1d).
RESULTS AND DISCUSSION
In the course of our research, we observed unusual 19F
NMR spin-spin coupling patterns in 2,2-difluoro-1-phenyl
ethyl triflate derivatives in various solvents, features in-
dicative of intramolecular CF2H hydrogen bonding inter-
actions. These observations prompted us to explore this
phenomenon in simpler model compounds. We investi-
gated intermolecular hydrogen bonding interactions in o-
nitrophenol (1-OH, Fig.
1a) and
o-nitro-α,α-
difluorotoluene (1-CF2H, Fig. 1b). Both 1-OH and 1-CF2H
crystallize in a similar manner as hydrogen-bonded di-
mers, suggesting bioisosterism of the CF2H and OH
groups (Figs. 1a-b). The intermolecular CF2−H…O2N bond-
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Decreased IR intensity is a characteristic of blue-shifting
hydrogen bonds.38 Our findings reveal that the
1
2
3
4
CF2−H…O2N interaction is an example of a blue-shifting
hydrogen bonding interaction, a known phenomenon.39
1H NMR spectroscopy provides additional evidence for
the presence of intramolecular O/CF2−H…O2N hydrogen
bonding interactions. The CF2H proton of 1-CF2H is sig-
nificantly deshielded compared to that of 2-CF2H (∆δ =
+0.78 ppm). This result is consistent with an electron
density analysis (quantum theory of atoms in molecules,
QTAIM) that showed the hydrogen bonded CF2H proton
of 1-CF2H to have +0.04 more positive charge than that of
2-CF2H. Moreover, deshielding of the CF2H proton in
deuterated chloroform is independent of 1-CF2H concen-
tration over the range of 1 to 500 mM, a finding that indi-
cates the presence of intramolecular hydrogen bonding
interactions in 1-CF2H under these conditions. The con-
centration-independent deshielding of the hydroxyl pro-
ton of 1-OH (∆δ = +5.81 ppm compared to that of 2-OH)
also suggests the presence of intramolecular hydrogen
bonding in 1-OH, corresponding to an increase in the
calculated atomic charge on the phenolic proton of 1-OH
by +0.07. Although the local diamagnetic contribution of
the electron density around a proton is an important fac-
tor that affects the chemical shift, the influence of mag-
netic anisotropic effects of the nitro group can be non-
negligible.40
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Figure 2. Selected conformations/dimers of o-
nitrophenol (a; 1-OH) and o-nitro-α,α-difluorotoluene (b;
1-CF2H) in the gas phase and calculated relative energies
(ΔE). H NMR spectroscopic studies showed 1-OH and 1-
CF2H to be predominantly monomeric in 100 mM CDCl3
1
solutions.
Intermolecular CF2−H…O2N interactions also lead to di-
merization of 1-CF2H-a to form (1-CF2H-a)2. The struc-
ture of the dimer observed in the crystalline state is simi-
lar to that predicted by DFT calculation in the gas phase
(Fig. 1b). The dimerization of 1-CF2H structurally and en-
ergetically resembles that of 1-OH. Both dimerization
processes provide ca 3.1 kcal/mol stabilization (Fig. 2, Ta-
ble 2). Our calculations predict the CF2−H stretching fre-
quency of 1-CF2H-a to be blue-shifted by ca. +72 cm-1 (un-
scaled) relative to that of 1-CF2H-b. Because the IR spec-
trum of 1-CF2H has contributions from both 1-CF2H-a and
1-CF2H-b, an experimental determination of the relative
IR shift is challenging. To better validate our theoretical
calculations, we compared the computed CF2−H stretch-
ing frequency in 1-CF2H-a to that in 2-CF2H. The former
is blue shifted by ca. +81 cm-1 (unscaled; Scheme S2). This
result is qualitatively consistent with the experimental
observation of a shift of +44 cm-1 between 1-CF2H and 2-
CF2H (Fig. 1d) and the blue-shifting nature of the CF2H
hydrogen bonding interaction. Dimerization of 1-CF2H-a
to form (1-CF2H-a)2 results in a further blue shift of +11
cm-1. In contrast, we calculated that 1-OH-a should be red
shifted by −287 cm-1 (unscaled) relative to 2-OH. This
result resembles the experimental value of −372 cm-1.
We used density functional theory (DFT) to calculate the
CF2−H…O2N and O−H…O2N hydrogen bonding interac-
tions in these systems. All structures and thermal correc-
tions were evaluated at the M06-2X/6-31+G(d,p) level of
theory in the gas phase (see SI §5.5.1). Final energies were
obtained from M06-2X/aug-cc-pVTZ single-point calcula-
tions. Similar results were also obtained from calculations
at
the
PCM(CHCl3)-M06-2X/6-
311++G(2d,2p)//PCM(CHCl3)-B3LYP/6-31+G(d,p) level of
theory (see SI §5.1.3.4—5.1.3.8). Monomeric 1-OH has two
conformers, 1-OH-a and 1-OH-b (Fig. 2a). Conformer 1-
OH-a has an intramolecular hydrogen bonding interac-
tion and is predicted to be 9.9 kcal/mol lower in energy
than the non-hydrogen bonding counterpart. In keeping
with our observations in the crystalline state, the dimeri-
zation of 1-OH is facilitated by two identical intermolecu-
lar hydrogen bonding interactions, adding up to 3.5
kcal/mol. In contrast, three conformers were identified
for monomeric 1-CF2H (Figs. 2b and S38). In 1-CF2H-a,
intramolecular hydrogen bonding interactions appear to
be present and this conformer is 4.3 kcal/mol lower in
energy compared to the non-hydrogen bonding 1-CF2H-b.
Steric effects are a significant driving force behind this
energy difference and, as discussed below, the stabiliza-
tion of 1-CF2H-a cannot be solely attributed to a bonding
interaction.
Scheme 1. Synthesis of 2,2-difluoro-1-phenyl ethyl
triflate derivatives (4-X) from 2,2-difluoro-1-phenyl
ethan-1-ol (3-X).
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2
2
3
ppm, dddq, JFb-Fa = 285.7 Hz, JFb-H1 = 53.7 Hz, JFb-H2 = 5.6
Hz, JFb-CF3, through space = 4.1 Hz , Figs. 3c-d). These quartets of
4.1 Hz, most likely the consequence of through-space 19F-
19F coupling with the CF3 group of the triflate, suggest that
4-NO2 adopts a conformation in which Fb is spatially close
to the CF3 group.43 Moreover, the through-space 19F-19F
coupling constant is essentially independent of solvents
and concentration, indicating the high conformational
rigidity of 4-NO2 (Figs. S2 and S3). The 1H NMR spectrum
of 4-NO2 in CDCl3 shows a vicinal coupling constant 3JH1-H2
of 1.7 Hz. According to a modified Karplus equation that
accounts for substituent effects,44 this value corresponds
to an H1-C1-C2-H2 dihedral angle of 68° or 43°. In addi-
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1
tion to 1D NMR studies, the H-19F 2D heteronuclear
With these results in hand, we explored by NMR spec-
troscopy the influence of CF2H hydrogen bonding interac-
tions on the properties and conformational behavior of a
NOESY (HOESY) spectrum of 4-NO2 displays a strong
NOE between H1 and the CF3 group but a weak H6-Fa
interaction. From these results we conclude that the
CF2−H bond of 4-NO2 points toward the NO2 moiety, pos-
sibly facilitating an intramolecular hydrogen bonding
interaction (Fig. 3a).
more
complicated
molecule,
2,2-difluoro-1-(2-
nitrophenyl)ethyl triflate (4-NO2). This compound has
more rotational freedom than 1-CF2H. As shown in
Scheme 1, we prepared 3-NO2 by treating the correspond-
41-42
We also prepared 2,2-difluoro-1-(4-bromophenyl)ethyl
ing aldehyde with TMSCF2H.
Triflation of 3-NO2 af-
triflate
(4-Br,
Fig.
3f)
and
2,2-difluoro-1-(2-
forded 4-NO2.
fluorophenyl)ethyl triflate (4-F, Fig. 3k), neither of which
should exhibit significant intramolecular hydrogen bond-
ing interactions. As in 1-CF2H, we found that the CF2H
proton of 4-NO2 shifts downfield by 0.27 ppm and 0.13
ppm relative to those of 4-Br and 4-F, respectively, a re-
sult suggesting the presence of intramolecular hydrogen
bonding interactions in 4-NO2.
As depicted in Figs. 3a-b, 4-NO2 exhibits unusual NMR
features. The trifluoromethyl (CF3) group, generally a sin-
glet in the 19F NMR spectrum, unexpectedly appears as a
doublet (δ = −74.3 ppm, J = 4.1 Hz) in the spectrum of 4-
NO2 in CDCl3 (Fig. 3b-e). Fa exhibits the expected doublet
of doublets of doublets (δ = −133.7 ppm, ddd, 2JFa-Fb = 285.5
2
3
Hz, JFa-H1 = 53.8 Hz, JFa-H2 = 15.6 Hz, Fig. 3e), but Fb is a
doublet of doublets of doublets of quartets (δ = −124.5
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Figure 3. NMR conformational analysis of 4-NO2 (a), 4-Br (f), and 4-F (k) in CDCl3 at a concentration of 50 mM. Strong (s) and
1
weak (w) NOE interactions observed in H-19F HOESY are depicted with solid and dashed double-headed arrows, respectively.
Coupling constant analyses of Fb and Fa are shown for each molecule (b-e, g-j, and l-o). Panels l-o are from the 19F{1H} NMR spec-
trum of 4-F.
Conformational analysis suggests that 4-Br and 4-F be-
have differently than 4-NO2. Unlike that of 4-NO2, the 19
trum the through-space coupling constants of Fd with Fa
and Fb are identical (Jthrough-space = 3.0 Hz), indicating pos-
sibly similar Fd…Fa and Fd…Fb distances (Fig. 3m). This
analysis suggests a dominant “anti” arrangement of the
CF2−H bond with respect to the C8−Fd bond, which is
consistent with the rather weak through-space coupling
between Fd and H1 (0.8 Hz) observed in the 1H NMR spec-
trum (Fig. S100). This conformational analysis demon-
strates that 4-F has a 3D geometry similar to that of 4-Br.
Taken together, these results indicate that the presence of
a relatively strong hydrogen bond acceptor, such as a ni-
tro group, can alter the conformational preference of the
CF2−H bond. By comparison, very weak hydrogen bond
acceptors, such as the C−F motif,45 have little influence on
the orientation of CF2−H bonds. Moreover, the proton of
the CF2H group is deshielded in 4-NO2 (δ = 6.25 ppm)
compared to those in 4-F (δ = 6.12 ppm) and 4-Br (δ =
5.98 ppm), a trend indicating the presence of a relatively
strong hydrogen bonding interaction in 4-NO2. As dis-
cussed in the supporting information (§8), a similar trend
F
NMR signal of the CF3 group of 4-Br is a pseudo triplet
owing to through-space coupling with Fa and Fb of 2.4 Hz
and 1.1 Hz, respectively (Fig. 3g). Presumably, the slightly
stronger coupling of the CF3 group with Fa indicates that
Fa is closer than Fb is to the CF3 group (Fig. 3f). Analysis of
the coupling constants of H2 further supports this hy-
3
pothesis. The JH1-H2 of 4.1 Hz indicates a nearly antiparal-
lel geometry for the H1-C1-C2-H2 unit (147°) based on a
3
3
modified Karplus equation.44 The values of JH2-Fa and JH2-
Fb (ca. 10 Hz) suggest similar Fa-C1-C2-H2 and Fb-C1-C2-H2
dihedral angles, an observation that supports the pro-
posed H1-C1-C2-H2 arrangement (Figs. 3h-j). Taken to-
gether, these results suggest that the orientation of the
CF2H group of 4-Br differs from that of 4-NO2, most likely
due to CF2−H…O2N hydrogen bonding.
The CF3 group of 4-F is spatially close to both Fa and Fb, as
indicated by the through-space coupling of 1.8 Hz with Fa
and Fb (Fig. 3l). The multiplicity of the benzylic proton of
3
can be seen in
a series of ortho- substituted α-
4-F is similar to that of 4-Br, particularly the JH1-H2 of 4.2
difluoromethylbenzyl alcohols (ArCH(OH)CF2H) in
which greater deshielding of the CF2H proton is associat-
ed with stronger hydrogen bond acceptors in the ortho
position.
Hz, and corresponds to that of a nearly identical H1-C1-
C2-H2 dihedral angle. A through-space coupling analysis
of the aromatic fluorine atom, Fd, provides additional
structural information. As shown in the 19F{1H} NMR spec-
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We also investigated the vibrational properties of the
within 12 cm-1 (scaled) of the experimental values, con-
firming the blue-shifting nature of the CF2−H…O2N inter-
actions. Our analysis of 4-NO2 and 4-Br indicates that the
CF2−H…O2N hydrogen bonding interaction is sufficiently
strong to alter the conformational preference of more
complicated molecules in solution.
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3
4
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7
8
CF2H group in the three model compounds, 4-NO2, 4-Br,
and 4-F. As discussed above, 4-Br and 4-F are reference
compounds that do not exhibit significant hydrogen
bonding interactions. We identified the CF2−H bond
stretching frequencies of 4-NO2 and 4-Br by comparing
their IR spectra to those of the corresponding CF2D-
containing analogues, 4-NO2-D and 4-Br-D. The stretch-
ing frequency of the 4-Br CF2−H bond occurs at 2972 cm-1
(Figs. S8C-D). Even though 4-F allows for the Fd atom to
be in close proximity to the H1 atom in several populated
conformations, the 4-F CF2−H bond stretching frequency
is almost identical (2971 cm-1; Fig. S10). The CF2−H region
of the IR spectrum of 4-NO2 is complicated, but we tenta-
tively assigned the peak at 3008 cm-1 to the CF2−H stretch,
corresponding to a blue shift of +36 cm-1 relative to 4-Br
(Fig. S6). This result is consistent with the blue-shifting
nature of the CF2H…O2N interaction in 1-CF2H, which is
blue shifted by +44 cm-1 relative to that of 2-CF2H.
A variety of explanations for blue-shifting hydrogen
46-50
bonds have been suggested in the literature.38,
One
rationalization for blue-shifting hydrogen bonding inter-
actions invokes electronegativity equalization as embod-
ied in Bent’s rule.48, 51 In this model, the approaching hy-
drogen bond acceptor induces a polarization of the donor
bond (Xᵟ-−Hᵟ+…Aᵟ-). The increased negative charge on the
donor atom (X) corresponds to an increased electronega-
tivity, which in turn is made possible by an increased s-
character of X. Increased s-character leads to a shorter
bond and a blue shift of the X−H stretching vibration.
This blue-shifting effect can also be expressed in terms of
electron donation from the hydrogen bond acceptor into
the hydrogen bond donor (X−H bond), which is strength-
ened.9, 38 The bond lengthening and red shifting of ‘nor-
mal’ hydrogen bonding interactions can, in contrast, be
explained by the more predominant effect of electron
donation into the C−H σ* orbital, through hyperconjuga-
tion.38, 48
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We used DFT calculations to explore the conformational
distribution of 4-NO2, 4-Br, and 4-F (Fig. S18, S20, and
S22). Our theoretical calculations suggest that the H1-C1-
C2-H2 unit of the preferred 4-NO2 conformer adopts a
gauche arrangement due to intramolecular CF2−H…O2N
interactions, as shown in Fig. 3a. The CF2−H…O2N dis-
tances are ~2.5 Å. In contrast, the non-hydrogen bonding
model compounds 4-Br and 4-F prefer an anti H1-C1-C2-
H2 geometry, as shown in Figs. 3f and 3k. These theoreti-
cal results are in good agreement with the results of our
NMR conformational analysis. To verify the calculated
conformational distributions for each molecule, we pre-
The existence of these two competing processes allows for
charge transfer to the hydrogen bond acceptor, in differ-
ent manners. We performed topological analyses of the
calculated electron densities before and after hydrogen
bonding in our examples of red- and blue-shifting hydro-
gen bonding interactions. These results indicate that be-
tween 0.01 and 0.08 electrons are transferred to the hy-
drogen bond donor in either case (see Table S2).
1
13
dicted the H, 19F, and C NMR chemical shifts of the ma-
jor conformers of 4-NO2, 4-Br, and 4-F at the GIAO-PCM-
B3LYP/aug-cc-pVTZ level. The population-weighted pre-
dicted chemical shifts agree well with the experimental
values, suggesting that the conformational distribution is
well described by the theoretical model (SI §5.2). The cal-
culated IR stretching frequencies of the CF2−H bond are
Table 2. Energy partitioning analysis of selected interactions.
ΔEa
Δχ
̅
ΔVNN/n
Δ(VNN+ ω)/n
Qb
X−H shiftc
(cm-1)
(kcal/mol)
(kcal/mol)
(kcal/mol)
(kcal/mol)
Intramolecular:
1-OH-b → 1-OH-a
15.4
3.55
0.95
53
−9.9
−4.3
−3.69
−0.99
−250 (red)
1-CF2H-b → 1-CF2H-a
Intermolecular:
40
+72 (blue)
−37.0
2 1-OH-a → (1-OH-a)2
2 1-CF2H-a → (1-CF2H-a)2
2 CH2F2 → (CH2F2)2
2.99
3.64
<|0.5|
4.93
1.42
1967.1
2328.7
~54
+70 (blue)
+11 (blue)
−3.5
−3.1
−3.02
−3.66
<|0.5|
−4.97
−1.51
−250
−420
N/Ae
−250
−32
−1.7
+30 (blue) d
+36 (blue)
−350 (red)
−64 (red)d
−273 (red)d
2-CF2H + DMF → [2-CF2H…DMF]
2-OH + DMF → [2-OH…DMF]
2 H2O → (H2O)2
−5.5
−11.2
−5.2
−27.7
1424.5
1546.6
577.5
0.69
3.42
−0.95
−3.63
−6.3
−35
G + C → GC base pair
2021.8
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a
From left to right: bond energy, ΔE, change in the average binding energy (= electronegativity equalization), Δχ̅ , nuclear-
1
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3
4
5
6
7
8
repulsion, ΔVNN/n, and multielectron-contribution per electron summed with nuclear repulsion, Δ(VNN+ ω)/n, for selected intra-
and intermolecular interactions. All energies in kcal/mol. Two decimal places are given for Δχ and Δ(VNN + ω)/n so that Q can
be calculated.
̅
b
Q descriptor (unitless) separates interactions governed by orbital stabilization (Q>0) from interactions governed by charge
transfer (Q<0).
c Frequency shift of hydrogen bond donor X−H bond stretch calculated at the M06-2X/6-31+G(d,p) level (cm-1, unscaled).
d Average shift of symmetric and asymmetric X−H bond stretches in hydrogen bond acceptor.
e Δχ
̅ for (CH2F2)2 –formation is small and its sign depends on the geometry, in turn sensitive to the level of theory. Q cannot
be safely assigned.
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An appealing justification for blue shifting, as discussed
above, invokes electronegativity, or more precicely, the
change in electronegativity upon bond formation. To
quantify the degree of ‘electronegativity equalization’
associated with the processes of forming hydrogen
bonding interactions, we employed an energy partition-
ing analysis that defines electronegativity as the average
being driven by both the release of steric crowding in
addition to a favorable orbital interaction.
These two intramolecular transformations exemplify a
fundamental challenge with analyzing such processes,
namely, our inability to uniquely separate the reaction
energy into parts attributable to local bonding interac-
tions and all other aspects of the structural rearrange-
ment in question. In order to parse out the underlying
cause-and-effect in hydrogen bonding we also consid-
ered intermolecular interactions. In energetically favor-
able dimerization processes, the net structural change is
always due to favorable intermolecular bonding interac-
tions.
binding energy, χ .52-53 In this framework, the reaction or
̅
bond energy, ΔE, can be expressed as the sum of three
terms,
ΔE/n = Δχ + Δ(VNN+ ω)/n,
(Eq 1)
̅
where n is the number of electrons, ΔVNN is the change
in nuclear-nuclear repulsion due to structural transfor-
mation over a reaction, and Δω encompasses all ways
that electrons, on average, change their interactions
All intermolecular hydrogen bonding processes shown
in Table 2 are characterized by increases in χ (Δχ >0).
̅
̅
On average, these bonds are all disfavored by the desta-
bilization of orbitals. Alternatively, they are all charac-
terized by an overall net decrease in electronegativity as
the bond forms. This somewhat counterintuitive bond-
ing situation is, in fact, common and characteristic of
polar, ionic, and metallogenic bonds, and of charge
over the course of a reaction. The quantity χ is a meas-
̅
ure of how strongly the average electron is bound to a
system. Similarly, Δχ captures the change in overall
̅
electronegativity over a given transformation, i.e., it
expresses electronegativity equalization. Another way of
interpreting Δχ is as the average orbital stabilization,
̅
transfer processes.53 For bonding processes where Δχ >0,
which in turn is related to the degree of covalency.53
̅
the energy lowering associated with bond formation
arises solely from the introduction of multielectron in-
teractions, Δω (Eq 1). As already discussed, a degree of
charge transfer is an expected prerequisite of both red-
and blue-shifting hydrogen bonding interactions (Table
S2).
As we attempt to rationalize and analyze these bonding
processes it is important to keep in mind that a) the
interactions are weak, <4 kcal/mol, and b) a shift of a
vibrational frequency of ca. 40 cm-1 corresponds to a
change in energy of only ~0.1 kcal/mol—a small value in
comparison to the classical Pauling unit (PU) of electro-
negativity, which can be translated into energy as 1 PU ≈
140 kcal/mol (see SI §5.5.1).
To differentiate red- from blue-shifting intermolecular
hydrogen bonding interactions we turn to a bonding
descriptor that is reflective of the energy partitioning
shown as Eq 1, and that has also shown property-
predictive promise,53
The data in Table 2 illustrate that the rotation of a hy-
drogen bond donating group in both 1-OH and 1-CF2H,
which leads to red and blue shifts of the O−H and C−H
stretching vibrations, respectively, corresponds to a de-
Q = (Δχ – Δ(V + ω)/n)/ΔE = 2nΔχ /ΔE – 1 (Eq 2)
̅
̅
NN
crease in χ . When Δχ <0, both processes are favored by
̅
̅
Q quantifies the balance between the Δχ (electronega-
̅
orbital stabilization, indicating that a degree of covalen-
cy is at play. One marked difference between the two
intramolecular processes becomes apparent when con-
sidering ΔVNN/n. This term is in a sense an overall
measure of the change in steric crowding during a struc-
tivity equalization and orbital stabilization) term and
the Δ(VNN+ ω)/n term, which quantifies charge-drift due
to bonding interactions. On the positive side of the
scale, Q ranges from Q=1, attributed to ‘perfect covalen-
cy,’ to Q>1, where disfavoring electron-electron interac-
tions become more significant, to Q>>1, where disper-
sion and strong electrostatic interactions fall. On the
negative side, Q=–1 is associated with ‘perfect ionicity’
and Q<–1 corresponds to polar, ionic and metallogenic
bonds, where electron-electron interactions play an in-
creasingly important role. Examples of Q for a repre-
→
tural change. The blue-shifting 1-CF2H-b
1-CF2H-a
process corresponds to an overall relaxation of nuclear-
→
nuclear repulsion, whereas, in the red-shifting 1-OH-b
1-OH-a event, nuclei move on average closer together.
The latter is a clear indication of bonding in a delocal-
ized sense, whereas the former may be interpreted as
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sentative range of bonding interactions are Xe2 (~60 cient stabilization to facilitate the dimerization as well
1
2
3
4
5
6
7
8
“dispersion, highly correlated”), F2 (16, “covalent, highly
correlated”), CO (4, “covalent”), HF (−2, “polar”), NaH
(−7, “ionic”), Na2 (−35, “metallogenic”) and CsI (−100,
“ionic, highly correlated”). The bond energy represents a
natural second dimension of what is a veritable map of
bonding interactions.53
as to influence the conformational preference of CF2H-
containing molecules. The moderate strength of CF2H
interactions can, in principle, be exploited to design
molecules that disrupt other hydrogen bonding interac-
tions encountered in chemical biology and pharmaceu-
tical science. These findings validate the use of the CF2H
group as a functional OH surrogate in chemical and
medicinal applications and offer insight into the nature
of CF2H hydrogen bonding interactions.
All intramolecular hydrogen bonding interactions are
characterized by negative values of Q, a result support-
ing the interpretation of charge transfer as being con-
current with these processes. “Normal” red-shifting hy-
drogen bonding interactions, here exemplified by water
dimerization, 2-OH + DMF complexation, and guanine-
cytosine base pairing, correspond to more moderate Q
values of –6, −32 and –35, respectively. The blue-shifting
interactions considered are distinctly different, and as-
sociated with substantially negative Q values, <–200. A
very large absolute value of Q does not necessitate a
small ΔE. Rather it means that the two terms adding up
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ASSOCIATED CONTENT
Supporting Information
This material is available free of charge via the Internet at
http://pubs.acs.org.
Experimental and computational details and characteriza-
tion data (PDF)
Crystallographic data (CIF)
AUTHOR INFORMATION
to the bond energy in Eq 1, i.e. Δχ̅ and Δ(VNN+ ω)/n, are
of opposite sign but of nearly equal magnitude (Eq 2).
This unusual situation of near equal-opposite terms will
generate a Q value that is large and increasingly sensi-
tive to the level of theory (or the experimental accura-
cy). Regardless of the exact value of Q, intermolecular
blue-shifting hydrogen bonding interactions inhabit a
distinct region on this scale of chemical interactions.
The region of blue-shifting hydrogen bonding interac-
tions is, in a manner of speaking, the antithesis of at-
tractive electrostatic interactions. The strong formation
of the NaCl dimer from prepolarized Na+ and Cl– ions
corresponds to Q = +60 and +350 in the gas phase and in
aqueous solution, respectively.53 In recent work on blue-
shifting hydrogen bonds using a Block-Localized Wave-
function Energy Decomposition approach,46 the elec-
tron-electron electrostatic repulsion term is identified as
the dominant driving force behind the blue shifting
phenomenon. In our approach, changes to electron-
electron electrostatic repulsion are included in the Δω
term (Eq. 1). Assuming that exchange and correlation
effects, which are more short range, are less important,
for Δω>0, the electron-electron electrostatic repulsion
must decrease over the hydrogen bond forming reac-
tion.52-53
Corresponding Author
* Phone: 617-253-1892. E-mail: lippard@mit.edu.
ACKNOWLEDGMENT
This work was supported by funding from National Insti-
tutes of Health grant R01-GM065519 (to S.J.L.) and postdoc-
toral fellowship F32-GM109516 (to J.M.G.). This work was
partly supported by the German Academy of Sciences Leo-
poldina (Grant No. LPDS 2015-02 to S.B.). We thank Prof.
Roald Hoffmann for valuable comments and for sharing
computational resources. We are also grateful to Prof. Karl
O. Christe and Dr. Peter Müller for helpful discussions.
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In conclusion, our experimental and theoretical studies
support the long-proposed hydrogen bond donor ability
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Table of Contents Figure as .tiff file
22x6mm (600 x 600 DPI)
ACS Paragon Plus Environment