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

Abstract

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 [double bond splayed left]C=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.

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Introduction

The hydrogen bond (HB) plays a key role in stabilizing the three-dimensional structures of many organic and biomolecules and has tremendous influence 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 introduction 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 fluorine atom(s) which alter their physical properties 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 fluorine in the HB has been extensively debated. Earlier it was believed that organic fluorine hardly participates in the intramolecular HB.^18–22 Nonetheless, a number of recent reports established the existence of intramolecular HB with the participation of fluorine attached to the carbon atom. The recent report also states that, “it is now difficult to doubt the existence of hydrogen bonds involving organic fluorine”.¹⁹

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 shift 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 fluorine in the HB is also evidenced by the detection of ^1hJ_FH, mediated through non-covalent bond.²⁵ It has been reported that the couplings between F and H separated by 5 covalent bonds (⁵J_FH) is always less than 1 Hz. The detection of the significantly 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 J_HF, J_FF J_PF, and J_PP, 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 J_FH 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 substitution at the benzoyl ring where one H, one donor (N) and two H acceptors (O and X = F, OMe) are present which satisfies the requirement of bifurcated (three-centered) intramolecular HB (Scheme 1). All these molecules were characterized and subjected 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.

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.

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 significant downfield shift. 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 ([double bond splayed left]C=O) of amide group. The 2D ¹H–¹H NOESY establishes the spatial proximity between two spins and aids in arriving at the favorable 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.

Fig. 1 800 MHz 2D ¹H–¹H NOESY spectrum of molecule 1 in the solvent CDCl₃ at 298 K.

In molecule 2, the fluorine atom is presumed to be involved in an additional intramolecular HB with NH¹, rendering the bifurcation. 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 shift of protons when the interactions are of intermolecular type. However, the chemical shift remains invariant when the interaction is intramolecular. The plot of NH¹ chemical shifts 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 shifts of NH¹ proton when diluted to half its value, safely discards the possibility of any intermolecular interactions and confirming the existence of intramolecular HBs. However, the NH² and NH³ protons exhibited a slight shift towards the shielded region on dilution. The negligible change in the chemical shift of residual water peak (1.54 ppm) ascertains the trifling effect of monomeric water^8,23,42 on the intramolecular HB.

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.

Relative strengths of HB

The relative strengths of intramolecular HB interactions can be estimated by the titration study with a highly polar solvent 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 shift 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 shift of NH¹ proton was shifted 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 shift is inversely proportional to the strength of intramolecular HB in such systems^44,46 because the intramolecular HB minimizes the accessibility of sites for DMSO around the acidic proton. The small change in chemical shifts 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 shifts for molecules 1–3 on addition of 0.65 mole fraction of DMSO are reported in Table 1.

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.

Table 1 The difference in NH¹ chemical shifts of the molecules 1–3 with the addition of DMSO in mole fractions

Molecule	Substituent (X)	δNH^1 (ppm)		Difference in chemical shift δNH^1 (ppm)
		DMSO-d6 (in mole fraction = 0)	DMSO-d6 (in mole fraction = 0.65)
1	H	12.22	12.99	0.77
2	F	11.84	12.43	0.59
3	OMe	11.83	12.14	0.31

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Effect of temperature

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 shift of the NH¹ proton moved towards the higher resonance frequency as a consequence of the strengthening of the intramolecular HB (Fig. 4). However, in the case of NH² and NH³ protons, the shift 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 shifts also point towards the existence of HB. However, from the close inspection of the chemical structures, these deshielding can be attributed to intermolecular 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 confirmed. The calculated amide temperature coefficient values (Δδ_NH¹/ΔT) also reveal the small variation in the chemical shift of NH¹ protons with temperature, viz., from −0.3 to −1.3 ppb K⁻¹ and are assimilated in Table S1.† These values, which is more positive than −0.4 ppb K⁻¹, the HB predictivity is more than 85%.⁴⁷

Fig. 4 Effect of temperature on the chemical shifts of NH protons (δ_NH) of molecules 1–3. The temperature was varied from 300 K to 230 K. The solution concentration in CDCl₃, was maintained at 10 mM.

Detection of ^1hJ_XH

The interaction of NH¹ proton with the acceptor atom X can be reflected 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. The 1D ¹H{¹⁹F} NMR experiment on molecule 2 confirmed the interaction between ¹H and ¹⁹F, where NH¹ proton appeared as a singlet (Fig. 5b). In the present study, the observed ^1hJ_FH 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 ([double bond splayed left]C=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 ^1hJ_FH of 7.68 Hz, which implied that the observed doublet of 6.1 Hz for NH¹ proton in Fig. 5a, also had the contribution from the unresolved ¹J_¹⁴N–¹H and the additional broadening arose due to the ¹⁴N quadrupole relaxation.

Fig. 5 400 MHz ¹H spectrum corresponding to proton NH¹ of molecule 2 in the solvents CDCl₃; (a) ¹⁹F coupled spectrum and (b) ¹⁹F decoupled spectrum.

In the solvent DMSO-d₆, the observed ^1hJ_FH was only 3.8 Hz in both 1D ¹H and 1D ¹H{¹⁴N} spectra (Fig. 6(b) and S13†). However, in many earlier reports, this coupling completely vanished^45,46,48,49 in DMSO except in molecules where the structural restraint resists the complete breaking of HB by DMSO.^26,44 The retention of the ^1hJ_FH for molecule 2 in the 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 fluorine atom increases, leading to the decrease in ^1hJ_FH. However, in the earlier reports, the cis form of the structure stabilizes in a non-polar solvent by the influence of intramolecular HB and the molecules attain the lowest energy structure by rupturing the HB in DMSO which is different from the cis form, resulting in a complete nullification of ^1hJ_FH.

Fig. 6 400 MHz of ¹H NMR spectrum of molecule 2, at 298 K, corresponding to NH¹ proton; (a) in CDCl₃ solvent; (b) in DMSO-d₆ solvent.

Variation in ^1hJ_FH

On lowering the temperature from 300 K to 230 K, the value of ^1hJ_FH in molecule 2 changed from 6.1 Hz to 8.9 Hz (Fig. 7). The 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 significant variation in the ^1hJ_FH for molecule 2, is attributed to the coupling mediated through HB.

Fig. 7 The temperature dependent variation in the ^1hJ_FH in molecule 2, in the range 300 K to 230 K. The solute concentration was taken 10 mM in the solvent CDCl₃.

Unusual chemical shift 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 [double bond splayed left]C=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 [double bond splayed left]C=O⋯H HB during the competition with another HB acceptor.

Fig. 8 400 MHz ¹H NMR spectra in CDCl₃ solvent at 298 K, corresponding to the NH¹ proton region of; (a) molecule 1; (b) molecule 2; and (c) molecule 3.

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 shift 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 shift 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 reported molecules.^{45,46,48–52}

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.

All these in-depth NMR studies leads to the conclusion that the N–H⋯X interactions are influenced by strong [double bond splayed left]C=O⋯H HB, which is also reflected in the shielding of NH¹ proton and reduced value of ^1hJ_FH in the molecule 2. These narrations suggest that the competitive equilibrium between N–H⋯X and [double bond splayed left]C=O⋯H–N type HBs debilitate with each other and is the possible reason for the shielding of NH¹ proton in the molecules 2 and 3 compared to 1. The aforesaid facts are also corroborated by findings from the single crystal XRD and theoretical calculations discussed in the forthcoming part of this manuscript. A good single crystal for molecule 2 was obtained, and unfortunately, we failed in our efforts to crystallize other molecules, and thus XRD study is restricted only to molecule 2.

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 180° and closer to this value validates the presence of stronger HB.^53,54 The distance between the H and the acceptor atom between 1.2–1.5 Å also indicates a strong HB, whereas the distance of 1.5–2.2 Å suggests the HB of moderate strength and the value > 2.2 Å establishes a relatively weak HB.⁵³ The XRD structure of the molecule 2 is reported in Fig. 10.

Fig. 10 Single-crystal XRD structure of molecule 2 at 298 K with ORTEP view with 50% probability level (CCDC number: 2049223†).

The NH¹⋯F distance and the N–H¹⋯F angle were determined as 2.310 Å and 110° respectively, which corresponds to a weak HB in the solid state. The results derived from the single crystal XRD are assimilated in Table 2 and the experimental details are provided in ESI (Table S2†).

Table 2 The DFT computed structural parameters and single crystal XRD studies. All the bond distances (d) are expressed in Å; bond angles (φ) and torsion angles (Φ) are in degrees

Parameter	DFT							XRD
	Molecule							Molecule
	1	2	3	4	5	6	7	2
dN–H^1	1.018	1.019	1.018	1.019	1.018	1.009	1.018	0.965
dO⋯^1HN	1.821	1.847	2.013	1.798	1.808	—	1.829	1.974
dNH^1⋯F/OMe	—	2.310	1.938	—	—	1.895	—	2.322
φNH^1O	139.2	138.3	130.1	139.94	139.71	—	138.60	139.2
φNH^1F/NH^1OMe	—	110.0	128.4	—	—	137.34	—	109.3
Φ^1N1C5C4C7	−2.41	−6.30	−0.68	−2.41	−2.60	—	−2.43	−2.4(3)
Φ^2N1C8C9C10	−22.82	38.24	−15.025	21.86	18.31	2.24	−26.96	39.8(3)
Energy of HB (EHB) (kcal mol^−1)	—	−2.823	1.283	—	—	2.902	—	—

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DFT computations

The DFT based computations carried out also reinforces the NMR and XRD findings. 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 optimized structure of molecule 2 is reported in Fig. 11 and of molecules 1 and 3 in Fig. S40 and S41† respectively, and the computed structural parameters are provided in Table 2. The formation of three-center HB usually increases the D–H bond lengths with decrease in the H⋯X distance and D–H⋯A bond angle⁴ tending towards the planar geometry. Thus, the theoretical computations highlight the following aspects:

Fig. 11 The DFT optimized spatial structure of molecule 2; (a) and (b) are two different projections.

• The bond length (d_N–H¹) of molecule 2 (1.019 Å) is observed to be longer than the molecule 1 (1.018 Å) whereas the molecule 3 showed no significant change (1.018 Å).

• The distance between H and the X (X = F or OMe) was observed 2.310 Å and 1.938 Å in the molecules 2 and 3 respectively, suggesting the presence of a weak HB.

• The N–H¹⋯O bond angles in molecules 1, 2 and 3 were determined to be, 139.2°, 138.3° and 130.1° respectively, whereas the N–H¹⋯X (X = F or OMe) bond angles in molecules 2 and 3 were found to be 110° and 128.4°, respectively, suggesting the comparatively strong N–H¹⋯O=C[double bond splayed right] HB than N–H¹⋯X.

• 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 (Φ²_N1C8C9C10 = 38.24°) was found to be higher than in the molecule 1 (Φ²_N1C8C9C10 = −22.82°), whereas in the molecule 3 it was observed much close to the planarity (Φ²_N1C8C9C10 = −15.02°), which indicates the stronger interaction by methoxy group compared to the fluorine substituent.

• The energies of HBs (E_HB) were calculated as −2.823 and −1.283 kcal mol⁻¹ for molecules 2 and 3 respectively, showing agreement with the presence of weak HBs.

• 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 (d_O⋯H¹). 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 distances (d_O⋯H¹ = 1.798 Å and 1.829 Å, respectively) compared to the molecules 2 and 3 (d_O⋯H¹ = 1.847 Å and d_O⋯H¹ = 2.013 Å, respectively), indicating the strong O⋯H HB in the molecules 4 and 7. However, on shifting the amide group from ortho to meta position in the molecule 6, the strength of observed H⋯F HB increases and displayed the planarity in the structure with a torsion angle of 2.24° which is significantly less compared to that of molecule 2 (Φ²_N1C8C9C10 = 38.24°) (ESI, Fig. S44†). The chemical shift of NH¹ (δ_NH¹) computed from the DFT optimized minimum energy structures and the experimently observed chemical shifts of molecules 1–7 are reported in Table S3.† The results obtained from DFT and single crystal XRD for molecule 2 are compared in Table 2.

Conclusions

The presence of weak HB in the N-bezoylanthranilamide and its derivatives is substantiated by one- and two-dimensional NMR experimental investigations. The strong correlated peak in the 2D NOESY (molecule 1) and 2D HOESY (molecule 2) spectra ascertain the spatial propinquity between NH¹ and X (F or methoxy), leading to the existence of bifurcated HB. The doublet for NH¹ proton provided clear evidence for the HB between ¹⁹F and NH¹ proton. The residual ^1hJ_FH (∼60%) in the high polarity solvent DMSO-d₆ and 2D ¹H–¹H NOESY experiments confirmed the existence of favorable cis conformers for the investigated molecules. The rivalry between N–H⋯X and [double bond splayed left]C=O⋯H–N types of HBs is perceived as unusual shielding in NH¹ resonance frequency of molecules 2 and 3 and comparatively small ^1hJ_FH coupling in the molecule 2. The NMR experimental findings are strongly supported by the single crystal XRD and DFT computational studies.

Experimental

All the NMR spectra were recorded using 400 MHz and 800 MHz spectrometers at 298 K, except for the variable temperature studies. The TMS was used as an internal reference to measure the proton chemical shifts. The synthesized molecules were characterized by electron spray ionization mass spectrometry (ESI-HRMS) and various one- and two-dimensional NMR techniques. The commercially available chemicals, including deuterated solvents, were purchased and used as received. The XRD data was collected on a diffractometer with Mo K_α radiation. The structure was solved by direct methods using SHELXS97 (ref. 56) and refined in the spherical atom approximation (based on F²) by SHELXL97 (ref. 56) using the WinGX suite (ref. 57).

General synthesis of molecules 1 to 7

The 1 equivalent of benzoyl chloride (500 mg, 3.67 mmol) of interest and pyridine (290.29 mg, 3.67 mmol) was added dropwise to the 1.09 equivalent of amino benzamide (4.003 mmol) of interest solution in 15 ml of chloroform at 0 °C. After that, the ice bath is removed, and the reaction mixture was stirred at room temperature for 1 hour. A precipitate obtained was filtered and washed with a copious amount of water. The trace of pyridine was evaporated by adding toluene solvent. The formation of N-benzoylanthranilamide and its derivatives was characterized by electron spray ionization mass spectrometry (ESI-HRMS) and using NMR techniques.

Conflicts of interest

Authors declare no conflict of interest.

Acknowledgements

ST is grateful to CSIR for Senior Research Fellowship. NA is grateful IISc for RA position. NS gratefully acknowledges the generous financial support by the Science and Engineering Research Board (SERB), New Delhi (Grant Number: CRG/2018/002006).

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Footnote

† 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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