Competing HB acceptors: An extensive NMR investigations corroborated by single crystal XRD and DFT calculations

Article abstract of DOI:10.1039/d1ra02538d

A series of N-benzoylanthranilamide derivatives have been synthesized with the substitution of competitive HB acceptors and investigated by NMR spectroscopy and single crystal XRD. The interesting rivalry for HB acceptance between CO and X (F or OMe) is observed in the investigated molecules which leads to an unusual increase in the electron density at the site of one of the NH protons, reflecting in the high field resonance in the 1H NMR spectrum. The NMR experimental findings and single crystal XRD are further reinforced by the DFT studies.

Full text of DOI:10.1039/d1ra02538d

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Competing HB acceptors: an extensive NMR
investigations corroborated by single crystal XRD
Cite this: RSC Adv., 2021, 11, 15195
and DFT calculations†
a
Surbhi Tiwari,a Neeru Arya,a Sandeep Kumar Mishrab and N. Suryaprakash
*
A series of N-benzoylanthranilamide derivatives have been synthesized with the substitution of competitive
HB acceptors and investigated by NMR spectroscopy and single crystal XRD. The interesting rivalry for HB
acceptance between pC]O and X (F or OMe) is observed in the investigated molecules which leads to an
unusual increase in the electron density at the site of one of the NH protons, reflecting in the high field
resonance in the 1H NMR spectrum. The NMR experimental findings and single crystal XRD are further
reinforced by the DFT studies.
Received 31st March 2021
Accepted 11th April 2021
DOI: 10.1039/d1ra02538d
rsc.li/rsc-advances
extensively debated. Earlier it was believed that organic uorine
hardly participates in the intramolecular HB.18–22 Nonetheless,
Introduction
a number of recent reports established the existence of intra-
molecular HB with the participation of uorine attached to the
carbon atom. The recent report also states that, “it is now
difficult to doubt the existence of hydrogen bonds involving
organic uorine”.19
The hydrogen bond (HB) plays a key role in stabilizing the three-
dimensional structures of many organic and biomolecules and
has tremendous inuence in chemistry, biology, drug design,
etc.1–3 The HB can exist between an H atom covalently bonded to
a donor atom (D) and acceptor atom(s) (A), where both D and A
should be more electronegative than H.4 Based on the number
of acceptor atoms the HB could be two-centered, or three-
centered (bifurcated). The bifurcated HB can either be of (A/
H/A) or (H/A/H) type.5–9 These HBs can be inter- or intra-
molecular or a mixture of both types. The existence of inter-
and/or intra-molecular HB may administer the architecture of
various natural and synthetic compounds. The selective intro-
duction of HBs may lead to the desired conformation of
a molecule.10 The strength of any HB is directly related to the
electronegativity of acceptor atom(s)10 and also depends on
geometrical parameters, such as, the angle and the distance
between H and acceptor atom. Owing to the electronegativity
of N and O atoms, the strong HBs of N–H/O, O–H/O, and
O–H/N motifs are usually encountered.11 The substantial
fraction of the commercially available pharmaceutical drugs
possess the uorine atom(s) which alter their physical proper-
ties and improves the binding affinity with the target molecules
through HB(s).12–16 Despite being the most electronegative
atom,17 the participation of organic uorine in the HB has been
Among many available analytical techniques, the NMR
spectroscopy has been proved to be the most valuable one in the
study of HB. The change in chemical shi upon dilution with
the solvents of different polarities, variable temperature
studies, 2D HOESY and 2D HSQC experiments, clearly ascertain
the presence or the absence of HB.23,24 The participation of
1h
uorine in the HB is also evidenced by the detection of
J ,
FH
mediated through non-covalent bond.25 It has been reported
that the couplings between F and H separated by 5 covalent
bonds (5JFH) is always less than 1 Hz. The detection of the
signicantly large coupling strength between 19F and 1H has
been attributed to be HB mediated.26–28 There are several
examples of detection of direct through space couplings
between many homo- and hetero-nuclear spins, such as JHF, JFF
JPF, and JPP, and between many other NMR active nuclei, and
many reports have discussed the mechanism and strengths of
such through-space interactions.29 The detection of JFH has also
been extensively debated as, whether it arises because of
hydrogen bond or due to the overlap of electronic clouds.29–33
Some studies also attributed the term “through-space” and
evidenced that the spin polarization could be transferred
between the two nuclei, H and F, via hydrogen bonds.34,35
The anthranilamide derivatives are pharmacologically
important and known for their applications as antibacterial,36,37
antiviral,38 anticoagulants agents39 and also serve as a potent
inhibitor of human factor Xa.40,41 Consequently, a series of N-
benzoylanthranilamide were synthesized with ortho substitu-
tion at the benzoyl ring where one H, one donor (N) and two H
aNMR Research Centre and Solid State and Structural Chemistry Unit, Indian Institute
of Science, Bangalore 560012, India. E-mail: nsp@iisc.ac.in; suryaprakash1703@
gmail.com; Fax: +91 80 23601550; Tel: +91 80 23607344; +91 80 22933300; +91 98
45124802
bDepartment of Physics and NMR Research Centre, Indian Institute of Science
Education and Research, Pune 411008, India
† Electronic supplementary information (ESI) available. CCDC 2049223. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/d1ra02538d
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conformation of the molecule. The detection of correlation peak
in the NOESY spectrum of molecule 1 (Fig. 1), corroborates the
spatial proximity between the proton of NH1 and H17.
In molecule 2, the uorine atom is presumed to be involved in
an additional intramolecular HB with NH1, rendering the bifur-
cation. This assumption is strengthened by the detection of
strong correlation peak between 19F and NH1 proton (Fig. S14†)
in the 2D 19F–1H HOESY (Heteronuclear Overhauser Effect
SpectroscopY) spectrum. Hence these results direct towards the
existence of bifurcated HB in the investigated systems.
Differentiating inter- and intra-molecular HB
To validate the intermolecular or intramolecular HB and to
ascertain the effect of monomeric water on HB42 if any, the
dilution study23 using a non-polar solvent CDCl3 was carried
out. The dilution results in the dispersion of the molecules and
consequently a substantial change in the chemical shi of
protons when the interactions are of intermolecular type.
However, the chemical shi remains invariant when the inter-
action is intramolecular. The plot of NH1 chemical shis as
a function of dilution with solvent CDCl3, for all the molecules,
is given in Fig. 2. Although the solute concentration was not
diluted to a large extent, the invariance of chemical shis of
NH1 proton when diluted to half its value, safely discards the
possibility of any intermolecular interactions and conrming
the existence of intramolecular HBs. However, the NH2 and NH3
protons exhibited a slight shi towards the shielded region on
dilution. The negligible change in the chemical shi of residual
water peak (1.54 ppm) ascertains the triing effect of mono-
meric water8,23,42 on the intramolecular HB.
Scheme 1 (a) The structural frameworks of N-benzoylanthranilamide
and its derivatives along with the numbering of H atoms involved in
HB; (b) illustration of the possible formation of a bifurcated HB.
acceptors (O and X ¼ F, OMe) are present which satises the
requirement of bifurcated (three-centered) intramolecular HB
(Scheme 1). All these molecules were characterized and sub-
jected to investigations by the utility of NMR experiments to
ascertain the presence or absence of HBs. The basic structural
frameworks of the molecules are reported in Scheme 1.
Results and discussions
Generally, the amide protons resonate between 5–9 ppm in the
1H NMR spectrum, and the formation of hydrogen bond leads to
signicant downeld shi. In the present study, the NH1 proton
of molecule 1, resonated at 12.22 ppm. The extensive deshielding
of this proton may be attributed to the intramolecular HB
between NH1 proton and the carbonyl oxygen (pC]O) of amide
Relative strengths of HB
group. The 2D H–1H NOESY establishes the spatial proximity The relative strengths of intramolecular HB interactions can be
1
between two spins and aids in arriving at the favorable estimated by the titration study with a highly polar solvent
1
Fig. 1 800 MHz 2D H–1H NOESY spectrum of molecule 1 in the solvent CDCl3 at 298 K.
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accessibility of sites for DMSO around the acidic proton. The
small change in chemical shis upon DMSO-d6 addition could
possibly be attributed to the favorable near planar geometry of
these molecules which also limits the accessibility of the sites
for the association of DMSO by creating hindrance. The change
in the NH1 chemical shis for molecules 1–3 on addition of 0.65
mole fraction of DMSO are reported in Table 1.
Effect of temperature
Fig. 2 Variation in the chemical shifts of NH proton as a function of
the concentration of solvent CDCl3, for the molecules 1–3. The initial
concentration was taken as 10 mM in 450 ml of solvent at 298 K. The
NH protons and the molecules are identified by numbers and different
colour codes given in the inset.
The lowering of temperature leads to the strengthening of HB,
which results in the deshielding of the proton involved in the
HB. On systematically varying the temperature from 300 K to
230 K the chemical shi of the NH1 proton moved towards the
higher resonance frequency as a consequence of the strength-
ening of the intramolecular HB (Fig. 4). However, in the case of
NH2 and NH3 protons, the shi towards the deshielded region
(Fig. 4) is attributed to the decrease in the electron density on
amide (>CO–NH2) group. Additionally, the deshielding in NH2
and NH3 proton chemical shis also point towards the exis-
tence of HB. However, from the close inspection of the chemical
structures, these deshielding can be attributed to intermolec-
ular HBs between carbonyl oxygen and these protons at low
temperature (Fig. 4), rather than intramolecular HB. This
possibility was also inferred from the dilution studies with
CDCl3 solvent (Fig. 2), which is now conrmed. The calculated
Fig. 3 Change in the chemical shift of NH1 protons for the molecules
1–3 on addition of 0.65 mole fraction of DMSO-d6 at 298 K. The initial
concentration taken was 10 mM in 450 ml of CDCl3 and DMSO-d6 was
systematically added to it.
1
amide temperature coefficient values (DdNH /DT) also reveal the
small variation in the chemical shi of NH1 protons with
temperature, viz., from ꢀ0.3 to ꢀ1.3 ppb Kꢀ1 and are assimi-
lated in Table S1.† These values, which is more positive than
ꢀ0.4 ppb Kꢀ1, the HB predictivity is more than 85%.47
dimethyl sulfoxide (DMSO).43 Due to the high affinity towards
HB acceptance, the solvent DMSO is capable of rupturing
a variety of inter- or intra-molecular HBs. Hence the titration
with systematic addition of DMSO-d6 to the 10 mM solutions of
the molecules 1–3 in CDCl3 were carried out and the variation in
chemical shi of NH1 peak was monitored (Fig. 3). The severe
overlap of the NH2 and NH3 resonances with the aromatic
protons hindered the determination of the effect of DMSO on
these peaks. On incremental addition of DMSO-d6, the chemical
shi of NH1 proton was shied to higher frequency region for
all the molecules, which is attributed to the engagement of NH1
proton in the intermolecular HB with DMSO (Fig. 3).8,44,46 The
deshielding in the NH1 proton chemical shi is inversely
proportional to the strength of intramolecular HB in such
Fig. 4 Effect of temperature on the chemical shifts of NH protons
(dNH) of molecules 1–3. The temperature was varied from 300 K to 230
systems44,46 because the intramolecular HB minimizes the K. The solution concentration in CDCl3, was maintained at 10 mM.
Table 1 The difference in NH1 chemical shifts of the molecules 1–3 with the addition of DMSO in mole fractions
1
dNH (ppm)
Substituent
(X)
DMSO-d6 (in mole
fraction ¼ 0)
DMSO-d6 (in
mole fraction ¼ 0.65)
1
Molecule
Difference in chemical shi dNH (ppm)
1
2
3
H
F
OMe
12.22
11.84
11.83
12.99
12.43
12.14
0.77
0.59
0.31
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Fig.
5
400 MHz 1H spectrum corresponding to proton NH1 of Fig. 7 The temperature dependent variation in the 1hJFH in molecule 2,
molecule 2 in the solvents CDCl3; (a) 19F coupled spectrum and (b) 19
F
in the range 300 K to 230 K. The solute concentration was taken
10 mM in the solvent CDCl3.
decoupled spectrum.
1h
However, in many earlier reports, this coupling completely
vanished45,46,48,49 in DMSO except in molecules where the
Detection of
J
XH
The interaction of NH1 proton with the acceptor atom X can be
reected as J coupling in the 1D 1H NMR spectrum, if X is also
an NMR active nucleus. The NH1 proton in the molecule 2
appeared as a doublet with the frequency separation of 6.1 Hz.
structural restraint resists the complete breaking of HB by
1h
DMSO.26,44 The retention of the
J
for molecule 2 in the
FH
DMSO-d6 is due to the favorable cis geometry (Fig. 1), which
prevents the complete solvation of HB. The molecules tend to
surround the NH1 proton causing the steric hindrance whereby
the distance between NH1 proton and uorine atom increases,
leading to the decrease in 1hJFH. However, in the earlier reports,
the cis form of the structure stabilizes in a non-polar solvent by
the inuence of intramolecular HB and the molecules attain the
lowest energy structure by rupturing the HB in DMSO which is
The 1D H{19F} NMR experiment on molecule 2 conrmed the
1
interaction between 1H and 19F, where NH1 proton appeared as
a singlet (Fig. 5b). In the present study, the observed 1hJFH value
of 6.1 Hz (Fig. 5a) is small compared to the previous
reports,8,44,45 and can be attributed to the presence of another
strong HB acceptor (pC]O group of amide) which pulls the
NH1 proton far from the F atom, which resulted in the
decreased F/HN strength. To extract the hidden couplings, if
any, the 1D 1H{14N} and 2D 15N–1H coupled HSQC experiments
at the natural abundance of 15N were carried out for molecule 2,
and the spectra are reported in Fig. S10 and S17 respectively in
the ESI.† These spectra yielded 1hJFH of 7.68 Hz, which implied
different from the cis form, resulting in a complete nullication
1h
of
J
.
FH
1h
Variation in
J
FH
that the observed doublet of 6.1 Hz for NH1 proton in Fig. 5a,
On lowering the temperature from 300 K to 230 K, the value of
1
1h
14
1
also had the contribution from the unresolved J
and the
J
in molecule 2 changed from 6.1 Hz to 8.9 Hz (Fig. 7). The
N– H
FH
additional broadening arose due to the 14N quadrupole
covalent bond mediated scalar coupling remains practically
invariant, while the HB mediated coupling varies with changing
the distance between H and acceptor atom.23 Therefore, this
relaxation.
1h
In the solvent DMSO-d6, the observed
J
was only 3.8 Hz
FH
in both 1D 1H and 1D 1H{14N} spectra (Fig. 6(b) and S13†).
1
Fig. 6 400 MHz of H NMR spectrum of molecule 2, at 298 K, cor- Fig. 8 400 MHz 1H NMR spectra in CDCl3 solvent at 298 K, corre-
responding to NH1 proton; (a) in CDCl3 solvent; (b) in DMSO-d6 sponding to the NH1 proton region of; (a) molecule 1; (b) molecule 2;
solvent.
and (c) molecule 3.
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Fig. 9 The chemical structures of; (a) molecule 4, and (b) molecule 6; (c and d) the corresponding 400 MHz 1H NMR spectra in the CDCl3 solvent
recorded at 298 K.
signicant variation in the 1hJFH for molecule 2, is attributed to HB, which is also reected in the shielding of NH1 proton and
1h
the coupling mediated through HB.
reduced value of
J
in the molecule 2. These narrations
FH
suggest that the competitive equilibrium between N–H/X and
pC]O/H–N type HBs debilitate with each other and is the
possible reason for the shielding of NH1 proton in the mole-
cules 2 and 3 compared to 1. The aforesaid facts are also
corroborated by ndings from the single crystal XRD and
theoretical calculations discussed in the forthcoming part of
this manuscript. A good single crystal for molecule 2 was ob-
tained, and unfortunately, we failed in our efforts to crystallize
other molecules, and thus XRD study is restricted only to
molecule 2.
Unusual chemical shi value of NH1 proton
Conventionally, the presence of HB or the introduction of
additional HB(s) results in the deshielding of proton in the 1H-
NMR spectrum. Contrary to the expectation, the NH1 proton is
observed to be more shielded (Fig. 8(b) and (c)) on substitution
of X at the ortho position of benzoyl ring (in molecules 2 and 3).
This is due to the fact that the NH1 proton is involved in a strong
HB with the pC]O oxygen of amide group. Furthermore, the
substitution of F or OMe increases the electron density on the
NH1 proton by stabilizing an equilibrium between two hydrogen
acceptors resulting in the shielding of proton.49 Another
possible reason could be the weakening of strong two-center
pC]O/H HB during the competition with another HB
acceptor.
Single crystal X-ray diffraction (XRD) studies
The XRD is another powerful technique for the investigation of
HB, where the linearity in the bond angle i.e. D–H/A of 180ꢁ
and closer to this value validates the presence of stronger
To derive more insight, additionally the molecules 4–7 were
synthesized (Fig. 9a, S31, 9b and S36). When the F in the
molecule 4 was displaced from ortho to meta position on the
benzoyl ring with respect to NH1, the value of chemical shi of
NH1 was observed to be similar to that of molecule 1 (Fig. 9c).
Also considering the electronic effect, when the F was displaced
to para position in molecule 5 (ESI, Fig. S31†), the observed
chemical shi value was similar to those detected in molecules
1 and 4. Subsequently, when the amide group of the molecule 2
was displaced from ortho to meta position (molecule 6), the NH1
proton exhibited a doublet with a separation of 16.25 Hz
(Fig. 9d), whose value is similar to those observed for other re-
ported molecules.45,46,48–52
All these in-depth NMR studies leads to the conclusion that
Fig. 10 Single-crystal XRD structure of molecule 2 at 298 K with
the N–H/X interactions are inuenced by strong pC]O/H ORTEP view with 50% probability level (CCDC number: 2049223†).
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Table 2 The DFT computed structural parameters and single crystal XRD studies. All the bond distances (d) are expressed in A˚; bond angles (4)
and torsion angles (F) are in degrees
XRD
DFT
Molecule
Molecule
Parameter
1
2
3
4
5
6
7
2
1
dN–H
1.018
1.821
—
139.2
—
ꢀ2.41
ꢀ22.82
—
1.019
1.847
2.310
138.3
110.0
ꢀ6.30
38.24
ꢀ2.823
1.018
2.013
1.938
1.019
1.798
1.018
1.808
1.009
1.895
1.018
1.829
0.965
1.974
2.322
139.2
109.3
ꢀ2.4(3)
39.8(3)
—
1
dO/ HN
—
—
1
dNH /F/OMe
1
4NH O
1
4NH F/NH OMe
—
—
—
130.1
139.94
—
ꢀ2.41
21.86
—
139.71
—
ꢀ2.60
18.31
—
138.60
1
128.4
ꢀ0.68
ꢀ15.025
1.283
137.34
—
2.24
2.902
—
F1
F2
ꢀ2.43
ꢀ26.96
—
N1C5C4C7
N1C8C9C10
Energy of HB (EHB) (kcal molꢀ1
)
HB.53,54 The distance between the H and the acceptor atom optimized structure of molecule 2 is reported in Fig. 11 and of
˚
between 1.2–1.5 A also indicates a strong HB, whereas the molecules 1 and 3 in Fig. S40 and S41† respectively, and the
˚
distance of 1.5–2.2 A suggests the HB of moderate strength and computed structural parameters are provided in Table 2. The
53
˚
the value > 2.2 A establishes a relatively weak HB. The XRD formation of three-center HB usually increases the D–H bond
structure of the molecule 2 is reported in Fig. 10.
lengths with decrease in the H/X distance and D–H/A bond
The NH1/F distance and the N–H1/F angle were deter- angle4 tending towards the planar geometry. Thus, the theo-
ꢁ
˚
mined as 2.310 A and 110 respectively, which corresponds to retical computations highlight the following aspects:
˚
1
a weak HB in the solid state. The results derived from the single
ꢂ The bond length (dN–H ) of molecule 2 (1.019 A) is observed
˚
crystal XRD are assimilated in Table 2 and the experimental to be longer than the molecule 1 (1.018 A) whereas the molecule
˚
details are provided in ESI (Table S2†).
3 showed no signicant change (1.018 A).
ꢂ The distance between H and the X (X ¼ F or OMe) was
˚
˚
observed 2.310 A and 1.938 A in the molecules 2 and 3 respec-
tively, suggesting the presence of a weak HB.
DFT computations
ꢂ The N–H1/O bond angles in molecules 1, 2 and 3 were
determined to be, 139.2ꢁ, 138.3ꢁ and 130.1ꢁ respectively,
whereas the N–H1/X (X ¼ F or OMe) bond angles in molecules
2 and 3 were found to be 110ꢁ and 128.4ꢁ, respectively, sug-
gesting the comparatively strong N–H1/O]C HB than N–
H1/X.
The DFT based computations carried out also reinforces the
NMR and XRD ndings. The lowest energy structures were
optimized using Gaussian09 suite with B3LYP/6-311+g(d,p)
level of basis set using chloroform as the default solvent.55 The
ꢂ The molecules 1–3 lacks the planarity which is also noticed
on comparing the torsion angles (Table 2). In the molecule 2 the
torsion angle (F2
¼ 38.24ꢁ) was found to be higher
N1C8C9C10
than in the molecule 1 (F2
¼ ꢀ22.82ꢁ), whereas in the
N1C8C9C10
molecule 3 it was observed much close to the planarity
(F2
¼ ꢀ15.02ꢁ), which indicates the stronger interac-
N1C8C9C10
tion by methoxy group compared to the uorine substituent.
ꢂ The energies of HBs (EHB) were calculated as ꢀ2.823 and
ꢀ1.283 kcal molꢀ1 for molecules 2 and 3 respectively, showing
agreement with the presence of weak HBs.
ꢂ The substitution of X (F or OMe) in the molecules 2 and 3
leads to the increase in the O/H distance in O/1H–N (dO/H ).
1
All the O/H distances are reported in the Table 2.
The theoretically computed structural parameters of the
molecules 1–3 are also compared with those of molecules 4–7 in
the Table 2. The DFT optimized minimum energy structures of
molecules 4–7 are reported in Fig. S42–S45 of ESI.† The
displacement of X (F or OMe) from ortho to meta position in the
molecules 4 and 7 resulted in the decrease in the O/H
˚
˚
1
distances (dO/H ¼ 1.798 A and 1.829 A, respectively) compared
Fig. 11 The DFT optimized spatial structure of molecule 2; (a) and (b)
are two different projections.
˚
˚
1
1
to the molecules 2 and 3 (dO/H ¼ 1.847 A and dO/H ¼ 2.013 A,
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respectively), indicating the strong O/H HB in the molecules 4 formation of N-benzoylanthranilamide and its derivatives was
and 7. However, on shiing the amide group from ortho to meta characterized by electron spray ionization mass spectrometry
position in the molecule 6, the strength of observed H/F HB (ESI-HRMS) and using NMR techniques.
increases and displayed the planarity in the structure with
a torsion angle of 2.24ꢁ which is signicantly less compared to
Conflicts of interest
that of molecule 2 (F2
¼ 38.24ꢁ) (ESI, Fig. S44†). The
N1C8C9C10
chemical shi of NH1 (dNH ) computed from the DFT optimized Authors declare no conict of interest.
1
minimum energy structures and the experimently observed
chemical shis of molecules 1–7 are reported in Table S3.† The
results obtained from DFT and single crystal XRD for molecule 2
Acknowledgements
are compared in Table 2.
ST is grateful to CSIR for Senior Research Fellowship. NA is
grateful IISc for RA position. NS gratefully acknowledges the
generous nancial support by the Science and Engineering
Research Board (SERB), New Delhi (Grant Number: CRG/2018/
Conclusions
The presence of weak HB in the N-bezoylanthranilamide and its 002006).
derivatives is substantiated by one- and two-dimensional NMR
experimental investigations. The strong correlated peak in the
References
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doublet for NH1 proton provided clear evidence for the HB
between 19F and NH1 proton. The residual 1hJFH (ꢃ60%) in the
high polarity solvent DMSO-d6 and 2D 1H–1H NOESY experi-
ments conrmed the existence of favorable cis conformers for
the investigated molecules. The rivalry between N–H/X and
pC]O/H–N types of HBs is perceived as unusual shielding in
´
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tively small
J
coupling in the molecule 2. The NMR experi-
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