Intramolecular HB Interactions Evidenced in Dibenzoyl Oxalamide

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The Intramolecular HB Interactions Evidenced in Dibenzoyl Oxalamide Derivatives : NMR, QTAIM, NCI Studies Dhanishta Poshetti, Sandeep Kumar Mishra, and Nagarajarao Suryaprakash J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.7b10598 • Publication Date (Web): 08 Dec 2017 Downloaded from http://pubs.acs.org on December 12, 2017

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The Journal of Physical Chemistry

The Intramolecular HB Interactions Evidenced in Dibenzoyl Oxalamide Derivatives: NMR, QTAIM, NCI Studies P. Dhanishta, Sandeep Kumar Mishra and N. Suryaprakash* NMR Research Centre, Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560012, India. E-mail: [email protected]; Fax: +91 8023601550; Tel: +91 8022933300 Abstract Extensive NMR spectroscopic studies revealed information on the occurrence of bifurcated intramolecular hydrogen bond in the dibenzoyl oxalamide derivatives. One dimensional NMR experiments, viz., solvent dilution, temperature perturbation and two dimensional experimental techniques, such as,

15

N-1H HSQC and

19

F-1H HOESY have been exploited to derive the

unambiguous confirmation for the participation of organic fluorine in the hydrogen bonding interaction. The experimental NMR findings have been ratified by Density Functional Theory (DFT) based calculations, viz, NCI (Non-Covalent Interaction) and QTAIM (Quantum Theory of Atoms in Molecules) Introduction A hydrogen bond (HB) is defined as “an attractive interaction between a hydrogen atom of a molecular fragment X–H in which X is more electronegative than H, and an atom or a group of 1 ACS Paragon Plus Environment

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atoms in the same or a different molecule, in which there is an evidence of bond formation” 1. The HB could be intra- or intermolecular depending on whether the acceptor and donor atoms belong to the same or different molecule(s). Most of the times the HBs govern physical properties of organic compounds and the molecular aggregation

2-4

. The three centered or

bifurcated HBs can be classified into two types. One, where the participation of an acceptor and two donor groups takes place (H···A···H type), and other wherein one donor interacts with two acceptor groups (A···H···A)

5-8

. The increase in the electronegativity of an acceptor atom

increases the strength of HB 2, which has been established in the case of oxygen and nitrogen atoms. Although the electronegativity of the F atom is highest among all the elements in the periodic table, it has been reported several years ago the ‘‘Organic fluorine hardly ever accepts hydrogen bonds’’ 9-12. Nonetheless, numerous studies have been reported where such interactions are detected both in the solid and solution states, and has also been theoretically established 13-21. Recent reviews discussed several examples of HB where organic fluorine is involved 22-24. In biological systems, the HB is most important

5,25,26

as it plays a dominant role in the three-

dimensional structures of bio-macromolecules, viz. proteins and nucleic acids

26,27

. In natural

forms of biomolecules, the moieties such as, amides, oxalamates and oxalamide HBs are not present. Nevertheless, they have been deployed as pseudopeptide templates in bioorganic and medicinal chemistry 28,29. The presence of specific HB interactions in many biochemical systems and small molecules have been well documented 30. For understanding the peptide bonding, viz., HB interactions or molecular recognition process, oxalamides have been demonstrated to be an appropriate model example 4. In addition, oxalamides have diverse applications, viz., artificial receptors for biological recognition

31

, in crystal engineering and design

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32-34

and formation of

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organogels

35,36

. Oxalamides and their derivatives have been used as ligands in coordination

chemistry and identified as HIV-I inhibitors 37-39. In the present work we have synthesized the ortho substituted dibenzoyl oxalamide derivatives and characterized them by extensive NMR studies. These derivatives of dibenzoyl oxalamide are the building blocks of foldamers, whose rigid structures are stabilized by the three centered HB of the type C=O···H(N)···X–C, two centered HB of the type X-H···O(C) and C=O···H(N) (where X = F, Cl, OMe and OH). The molecular structures and the possible mechanism of the formation of three-cantered HB are depicted in scheme 1.

Scheme 1: The molecular structures for the derivatives of N,N-dibenzoyloxalamide. The type of substituents (X) and the numbering of the molecule are given in the table adjacent to the structure. Experimental Section The close spatial proximity between hydrogen and HB acceptor is an essential requirement for the occurrence of HB. The information on the spatial proximity between two NMR active nuclei can be qualitatively derived by nuclear Overhauser effect. Hence as a first step, the 2D

19

F-1H

HOESY (hetero NOE spectroscopy) 40-43 experiment was carried out for the molecule 2 in which F atoms are substituted at the ortho positions of both the phenyl rings. The corresponding 3 ACS Paragon Plus Environment


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HOESY spectrum is reported in Fig.1. The strong cross peak between the F atom and NH proton, observed due to heteronuclear dipolar interaction between these two atoms, confirms their close spatial proximity.

Fig.1: 400 MHz 2D 19F -1H Heteronuclear Nuclear Overhauser (HOESY) spectrum of molecule 2. The solvent used is CDCl3. The detection of strong correlated peak between F and NH proton establishes their close spatial proximity.

For unequivocally establishing the presence of HB, many different NMR experiments are required to be carried out. The chemical shift of proton involved in HB is widely used as an NMR parameter to probe the presence or absence of HB. The dilution studies can be employed to infer whether the interaction is inter- or intramolecular. It was observed that irrespective of the extent of dilution by the solvent CDCl3 44-47, the δNH for all the molecules remained unaltered, ascertaining the absence of intermolecular interactions or molecular aggregation. The change in δNH as a function of incremental addition of CDCl3 was monitored and is reported in Fig. 2a. The chemical shift of the residual monomeric water in the solvent CDCl3 was 1.57 ppm and it remained unaltered, except for a small deviation of 0.03 ppm during CDCl3 titration indicating that the residual water has no effect on HBs in the investigated molecules 4 ACS Paragon Plus Environment

48

. The NH proton

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involved in HB gets deshielded on reducing the temperature consequent to its displacement towards the HB acceptor as a result of strengthening of the HB 49,50. This chemical shift change in the NH proton cannot be attributed to the equilibrium between the intra- and intermolecular hydrogen bonded species, since the absence of intermolecular HB has been established by dilution studies. The temperature dependent change in chemical shift of hydrogen bonded proton can be exploited to derive the evidence for the presence of intra-molecular HB

49,50

. Thus, the

temperature dependent change in the NH protons chemical shifts was monitored for the molecules 1–5, and is reported in Fig. 2b. From the figure it is very clearly obvious that, on lowering the temperature the NH proton chemical shifts are shifting towards the downfield region due to strengthening of HB. Such a phenomenon is also visualized for the molecule 1 where there is no substitution on the phenyl ring, indicating the participation of NH proton in the HB with the oxygen of neighboring CO group.

Fig. 2: Variation in the δNH for the molecules 1-5; (a) as a function of incremental addition of solvent CDCl3 to an initial volume of 450 µl at 298 K; (b) as a function of temperature over the range 300-230 K. The molecules are identified by the symbols given in the inset. The initial concentration taken was approximately 20 mM in the solvent CDCl3. 5 ACS Paragon Plus Environment


Consequent to the presence of symmetry, the molecules 2-5 yielded four types of distinct peaks for eight aromatic protons and the molecule 1 gave three different chemical shifts for the protons of phenyl rings. Further due to very close resonating frequencies, some of the protons peaks were overlapped in the 1H spectra of molecules 3 and 5. The corresponding 1H NMR spectra are reported in the supporting information. The experimentally observed δNH of molecules, 1-5, and their differential values with reference to δNH of molecule 1 are assimilated in Table 1. The significant downfield shift of δNH for the molecules, 2-5, are compared with the molecule 1, predicts the presence of bifurcated HB in all these molecules. Between the molecules 2 and 3 the molecule 2 showed more deshielding due to comparatively high electronegativity and as a consequence the strong HB interaction. When one compares the NH proton chemical shift of molecules 3 and 4 the molecule 4 exhibits high downfield shift due to strong HB accepting tendency of methoxy group. Interestingly the molecule 5 shows low field shift compared to the molecules 2, 3, 4, which is a strange behavior when compared to the electronegativities and HB accepting tendencies of the substituents. This unusual observation in the hydroxy substituted molecule is attributed to the HB of OH group with CO, and non-involvement of NH proton in the HB with oxygen of OH group, rendering it a different type of structure compared to other molecules, which is discussed in detail at the later part of the manuscript. It is well known that the chemical shift of the proton participated in the HB experiences a significant downfield shift. An empirical relationship between the HB energy (EHB) and the chemical shift has been reported as EHB = ∆δ + (0.4 ± 0.2) (Kcal/mol) 51-53, where ∆δ is the difference in chemical shifts of proton involved in hydrogen bond and free proton in the non-hydrogen bonded molecule. The ∆δ in the present work is derived by substracting the δNH of molecule 1 from the δNH of molecules 2-5, and the calculated EHB values using the above relationship are reported in the Table 1. The EHB values 6 ACS Paragon Plus Environment

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varied from 2 to 5 Kcal/mol for different molecules indicating the presence of weak HB type of interactions. Table 1: The δNH for molecules 2-5 and their differential values with respect to molecule 1. The EHB are calculated using the experimentally measured chemical shift values in ppm.

Molecule number

δNH in the solvent Difference in δNH with Energy of HB (EHB) CDCl3 (in ppm) respect to molecule 1 (kcal mol-1) (in ppm)

1

8.04

0.00

---

2

10.68

2.64

3.0

3

10.41

2.37

2.8

4

12.28

4.24

4.6

5

10.08

2.04

2.4

Couplings Mediated Through HB Many a times the strong coupling between two NMR active nuclei are detected, even though they are separated by several covalent bonds. Such coupling arises because of through space transfer of spin magnetization mediated by HB

54-57

. The peak corresponding to NH proton of

molecule 2 gave a doublet with a frequency difference of 11.6 Hz (Fig. 3a). Further this doublet collapses into a singlet in the Fluorine decoupled 1H (1H{19F}) 58,59 spectrum (Fig. 3b) affirming the presence of the coupling between F and NH proton. Such a large interaction strength mediated through covalent bond (5JFH) is unusual. Hence it can be reasoned out to be the through space coupling mediated through HB

59,60

. This coupling also vanishes in a more polar solvent

DMSO-d6 (Fig. 3c) resulting in a singlet, due to the rupturing of HB at the cost of strong 7 ACS Paragon Plus Environment


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interaction between DMSO and NH proton, further confirming the existence of HB interaction between F and NH proton.

Fig. 3: 400 MHz 1H NMR spectra of molecule 2; (a) in the solvent CDCl3; (b) 1H{19F} in the solvent CDCl3 and (c) in the solvent DMSO-d6. Excessive broadening of NH peak due to the directly bonded quadrupolar 14N nucleus precludes the accurate measurement of couplings strengths of smaller magnitudes, if any, that are hidden within this broad signal. Furthermore, the 1D spectrum also does not permit the extraction of couplings between two passive NMR active nuclei. On the other hand, the 2D (NH coupled) experiment From the 2D

15

couplings, 1JNH,

7,40,59

15

N−1H HSQC

yielded relatively sharp signals for natural abundant

15

N nuclei.

N−1H HSQC spectrum of molecule 2 (Fig. 4A) it is possible to extract three 2h

JFN and

1h

JFH. As reported in our earlier studies58-60, the relative signs of the

scalar couplings were obtained from the direction of tilt of the cross sections of the HSQC spectrum. The magnitudes of the measured couplings from both 1H and

15

N dimensions of

HSQC spectrum are reported in Fig. 4B along with the chemical structure of the molecule. The 15

N-1H HSQC (NH coupled) spectrum in the highly polar solvent DMSO is also reported in Fig.

4C. It is evident from Fig. 4C that except 1JNH, the remaining disappeared. This establishes that

1h

JFH, and

2h

2h

JFN and

1h

JFH, couplings

JFN determined in the solvent CDCl3 are HB

mediated and provides direct and strong support for the intramolecular HB involving organic fluorine. The measured

15

N chemical shifts of molecules 2-5 are significantly different from 8 ACS Paragon Plus Environment

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molecule 1. For the molecules 2-4, the NH proton is involved in the HB with the substituents. However, in the molecule 5, unlike other molecules, there are two types of hydrogen bonds, viz., OH···OC and NH···OC. The comparative study of experimentally measured and theoretically calculated 1hJFH and 2hJFN in 2-fluorobenzamide have been reported 44 where the authors systematically correlated the N-H...F geometries with 1hJFH and 2hJFN values. The 1hJFH and 2hJFN of 2-fluorobenzamide were -11.5 Hz and -7.0 Hz respectively. The theoretically obtained F···H, N-H distances were 1.987 Å, 1.006 Å respectively and N-H...F bond angle was 127.9o. Since the geometry of molecule 2 in the present study is similar to that of 2-fluorobenzamide we have compared the experimentally obtained 1h

JFH and

2h

JFN with N-H...F geometry of both the molecules. For the molecule 2 the

experimentally measured 1hJFH and 2hJFN are -15.8 Hz and -9.5 Hz respectively, and theoretically calculated bond distances and bond angle were, F···H (1.849 Å), N-H (1.000 Å) and N-H...F (132.5o). The 1hJFH and

2h

JFN for the molecule 2 compared to 2-fluorobenzamide are higher due

to the shorter F···H and N-H distances and larger N-H...F bond angle.



Fig. 4: 800 MHz (A) 15N-1H coupled HSQC spectrum of molecule 2 in the solvent CDCl3; (B) The chemical structure and the magnitudes of scalar and through space couplings are indicated by double headed arrows. The relative slopes of cross sections yielded relative signs of the couplings; (C) NH coupled 15N-1H HSQC spectrum in the solvent DMSO-d6. Since the magnetic moment of 15N is negative 1JNH is negative. The Strength of 1JNH and the Nature of HB The value of 1JNH has an important significance in the determination of the nature of HB. The NH coupling strength increases for electrostatic type and decreases for covalent type of hydrogen bond61,62. The increase in 1JNH indicates a gradual displacement of the proton towards nitrogen atom resulting in the weakening of NH···F HB (electrostatic type of HB). On the other hand, the decrease in 1JNH indicates a gradual displacement of NH proton towards the Fluorine atom resulting in strong NH···F HB (covalent type of HB). To ascertain whether HB interaction is electrostatic type or covalent type, the NH couplings were measured for all the investigated molecules in the solvent CDCl3 using NH coupled

15

N-1H HSQC spectra and are compiled in

Table 2. Comparing the magnitudes of 1JNH with an unsubstituted molecule 1 (-89.0 Hz) the 10 ACS Paragon Plus Environment

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increase in the 1JNH values was observed for all other substituted molecules, providing the evidence for the ionic nature of HB. The

15

N-1H HSQC spectra of remaining molecules are

reported in the supporting information. Table 2: The change in the chemical shift of the NH proton measured on varying the temperature from 298 K to 230 K, on solvent dilution and titration with DMSO, for the molecules 1–5. The 1JNH and 15N Chemical Shifts (δN) were measured in the solvent CDCl3. 1

Molecule Number

HB Type (X···HN)

∆δNH (ppm)

1

(H···HN)

JNH in δN in the solvent solvent Upon Upon On varying CDCl3 CDCl3 addition addition the (Hz) (in ppm) of 500 µL of 250 µL temperature CDCl3 DMSO from 298 K to 230 K - 0.02 2.65 0.28 - 89.0 132.15

2

(F···HN)

- 0.01

0.76

0.42

- 92.1

146.85

3

(Cl···HN)

- 0.01

1.58

0.38

- 90.2

152.53

4

(OCH3···HN) + 0.01

- 0.36

0.28

- 89.5

148.8

5

(OH···OC)

2.01

0.47

- 90.1

143.3

- 0.01

After unequivocally establishing the presence of intramolecular HB, for comparing their relative strengths the titration experiments using highly polar solvent DMSO-d6 have been carried out for all the molecules. The observed change in δNH as a function of incremental addition of DMSO is reported in Fig. 5. It is well known that the collapse of intramolecular HB due to strong interaction58-60 with the solvent DMSO results in the deshielding of NH proton. On the contrary, for the molecule 4 the high field shift in δNH was observed. This is attributed to the fact that in this molecule OMe group is involved in HB and this interaction is stronger compared to the interaction by DMSO and the competitive process results in a stable equilibrium between inter11 ACS Paragon Plus Environment


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and intra-molecular HB species, which increases the electron density around the NH protons, causing shielding.

Fig. 5: The variation in δNH as a function of mole fraction of DMSO-d6 for the molecules 1-5. The initial concentration taken was 20 mM in the solvent CDCl3. The DMSO- d6 was incrementally added to an initial volume of 450 µl in CDCl3, at 298 K. The molecules 1-5 are represented by individual symbols given in the inset.

Computational Details For authenticating the NMR experimental findings, the DFT

63,64

based theoretical calculations

have been performed, and details of parameters, software, etc. are discussed in the latter part of this manuscript. Theoretically computed δNH of all the molecules compiled in Table 3 are comparable to the experimental findings. For the molecule 5 (5a in Fig. 8), whose planar structure is similar to other molecules, 1-4, the theoretically calculated chemical shift of NH proton is not agreeing with the experimental observation. The molecule is presumed to be in different possible conformation, i.e. 5b, where proton of OH and CO groups are involved in HB, giving rise to a six-membered ring. In this conformation, the theoretical and experimental 12 ACS Paragon Plus Environment

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chemical shift values are in good agreement. This is further confirmed by deshielding in the chemical shift of OH proton on lowering the temperature reported in Fig. 6. As in the conformer 5b the proton of hydroxy group is interacting with the oxygen of carbonyl group through HB and on lowering the temperature this HB is getting strengthened and as a consequence of this the deshielding in the OH proton is observed. The Gibbs free energies obtained for the optimized conformers 5a and 5b are; -1177.984948 (Hartree), -1177.998858 (Hartree) respectively. It is found that the difference in the free energies between the conformers 5a and 5b is 8.71 kcal mol-1 which favors the presence of conformer 5b. In addition to this the relative population density for both the conformers of molecule 5 have also been calculated and conformer 5b is determined to be more than 99.99 %.

This is diagrammatically illustrated in Fig. 7. The experimentally and

theoretically computed chemical shift values differ by nearly 0.5 ppm with the conformer 5b. Based on the population difference, Gibbs free energy and the chemical shift values, 5b is established to be the major conformer. The HB mediated coupling constant between 1H and 19F obtained for the molecule 2 by theoretical calculations is -19.3 Hz. On the other hand, the experimentally obtained value is -15.8 Hz. This difference of 3.5 Hz may probably be attributed due to the rigid structure in the optimized model, while it is not true in solution state. The covalent bond mediated coupling will generally not be so large, and it can safely be assumed to be mediated through HB.



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Table 3: Electron density (ρ(r)) and Laplacian of electron density (∇2× ρ(r)) at different BCPs of type (3,-1) for (X···HN) HB. The chloroform has been used as a default solvation medium for theoretical calculations. The GIAO method of simulation is used to theoretically simulate chemical shifts (ppm) of NH protons. The reported NH chemical shifts (ppm) for all the molecules are in the solvent CDCl3. The chemical shift of NH proton for molecule 1 is 8.04 ppm. The molecule 1 does not exhibit hydrogen bond of the type X···NH and hence is not reported in the table.

Molecule

HB type Electron density (X…HN) (ρ(r)) (a.u.)

2

(F···HN)

3 4

Delocaliza Theoretical Experiment tion Index value of δNH al value of (ppm) δNH (ppm) (DI)

0.0246

Laplacian of electron density ( 2× ρ(r)) 0.1054

0.053

11.33

10.68

(Cl···HN)

0.0113

0.0438

------

10.01

10.41

(OCH3···H

0.0343

0.1355

0.077

12.69

12.28

N) 5a

(OH···HN)

0.0306

0.1273

0.070

12.30

10.08

5b

(OH···OC)

0.0486

0.1466

0.111

10.54

10.08

Fig. 6: Variation in the chemical shift of OH proton as a function of temperature for the molecule 5 in CDCl3. 14 ACS Paragon Plus Environment

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Fig. 7: The percentage of population densities for the two most probable conformers 5a and 5b of molecule 5. The calculations reveal the population of 5b is greater than 99.99%.

QTAIM Calculations The magnitudes of the Laplacian of electron density ( 2×ρ(r)), electron density (ρ(r)), potential energy density (V(r)) and the critical points (rcp) where the gradients of the electron density (ρ(r)) are getting vanished at corresponding (3, -1) BCPs

65-69

, have been derived using QTAIM

62-66

calculations. The sign of Laplacian of electron density ( 2×ρ(r)) and the value of electron density (ρ(r)) determines respectively the bonding type and bonding strength. The molecular model containing bond paths including (3, -1) BCPs for all the investigated molecules are given in Fig. 8. The theoretically obtained electron density values are in the expected range of 0.01 to 0.05 a.u. which are for HBs. The sign of ( 2×ρ(r)) at BCP is having significance in discerning the closedshell (van der Waals interaction, ionic interactions and HB (+ve)) and shared-shell (covalent bond (-ve)). From Table 3 it is evident that the Laplacian of electron density (

2

ρ(r)) values for

all the investigated molecules are positive. This is the signature for the HB interactions. 15 ACS Paragon Plus Environment


Delocalization indices (DI) serves as a measure of the electron-pair sharing between two atoms forming a bond. As DIs are related to the polarity of the bond, they can be employed to classify the HB strengths. The values of delocalization indices, viz., (δ(A, B), DI) provide information on the electronic nature of the HB. Fradera et al.

70

have also demonstrated that DIs are powerful

tool to describe the electron-pair structure of molecules, and provides a deeper insight for bond definition. The DI between the two atoms is related to the polarity of the bond and yields the value 1 for a perfectly shared electron-pair. For a totally ionic bond DI is close to zero. Poater et al.71 have utilized DI for the study of nature of HB. From the DI values reported in Table 3 the ionic nature of HB is clearly evident. The calculated DI values along with the structures for all the investigated molecules are reported in Supporting Information. NCI Analysis One can visualize non-covalent interactions, viz, Van der Waals, HB, steric repulsion, etc. by employing electron density based non-covalent interaction (NCI) 72. Using Multiwfn 73 program, the NCI based grid points have been plotted for a defined function of real space, sign (λ2(r))ρ(r), as function 1 and reduced density gradient (RDG) as function 2. The VMD 74 program was used to plot the colour filled isosurface graphs using these grid points. This is reported in Fig. 9 for all the molecules. For the molecules 1 and 3, there are two spikes on the left-hand side of the Fig. 9(A), which denotes two HBs of expected C-H···O=C and N-H···O=C types. Another expected spike for N-H···Cl in the molecule 3 is not distinguishable as it might be overlapped with one of these two spikes. On the other hand, for the molecules 2, 4 and 5a there are four spikes on the left-hand side, for the C-H···O=C, N-H···X, N-H···O=C and C=O···O=C type interactions are observed. As discuss earlier, for the molecule 5 there are two possible conformers, viz. 5a and 5b. 16 ACS Paragon Plus Environment

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Fig. 8: The visualization of BCPs and bond paths of HB for the molecules 1-5. multiwfn software has been used to arrive at these plots. Dots imply the CPs and thin bars imply the path between two interacting atoms passing through BCP of HB interactions.

On the other hand, for the 5b conformer, one would expect 3 spikes for attractive interactions, corresponding to O-H···O=C, O-C···O=C and N-H···O=C types. But four spikes are visible on the left hand side of the Fig. 9(A). This fourth spike represents the C-H···H-N type of interaction. Interestingly the C=O···O=C interaction is also detected in the investigated molecules. These interactions (O···O and H···H) can be identified as van der Waals type, because the density of electrons in this region is low. The regions in the center of rings show strong steric effect and are represented by red colour. For the molecule 4 there are two spikes in the middle of the graph representing Van der Waals interactions between OCH3 group with ortho proton of phenyl rings 17 ACS Paragon Plus Environment


and one of the oxygen of CO group. These interactions can be clearly visualized in the coloured isosurface plots of the molecules 1-5 reported in Fig. 9B.


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Fig. 9: (A) The plot of sign(λ2(r))*ρ(r) as function 1 v/s the RDG as function 2, and (B) colour filled isosurface plot for the molecules 1-5. The green colour denotes weak HB, dark green colour denotes strong HB and red colour stands for steric effect.

Synthesis of Molecules General procedure for the synthesis of oxalamides: Ortho substituted methoxybenzamide was synthesized using the ortho substituted methoxy benzoyl chloride and ammonia solution. The AR grade solvent chloroform (CHCl3), n-hexane (C6H14) and ethylacetate (C4H8O2) were used in the synthesis. All other benzamides and oxalyl chloride were purchased and used as received. To the best of our knowledge this method for synthesis of this type of oxalamides is not reported in the literature.

Synthesis of Dibenzoyl Oxalamide The corresponding benzamides (two eq) were taken in 50 ml round bottom flask and dissolved in the solvent chloroform. After complete dissolution, the dropwise addition of oxalyl chloride (one eq) to the solution was carried out. The reaction is stirred at room temperature until the formation of white precipitate. This white precipitate was washed with water and kept for recrystallization in the 99:1 solvent mixture of chloroform and ethanol respectively. The white compound was obtained after complete evaporation of solvents, which was examined and confirmed by several spectroscopic techniques. The similar synthesis procedure was opted for the all other compounds.



Page 20 of 30

NMR Parameters All the spectra were obtained using 800, 500 and 400 MHz NMR spectrometers. The standard references were used for

15

N and

19

F spectra. For both 1H and

13

C NMR spectra internal

reference used was Tetramethylsilane (TMS). Solvents CDCl3 and DMSO-d6 were purchased and used as received. The synthesized molecules were characterized by using various NMR experiments and ESI-MS technique. The two-dimensional NMR experiments, such as HSQC and HOESY, were acquired using the available pulse programs in the NMR spectrometers library. All the experiments were carried out at ambient temperature (298K) unless otherwise mentioned. Parameters for DFT Calculations For the DFT

63,64

based theoretical calculations of all the molecules, Gaussian09

75

with

B3LYP/6-311G+g(d,p) basis set and the solvent medium as default chloroform has been used. The optimized lowest energy structures were established by harmonic vibrational frequency. From these optimized minimum energy structures, the wave function files were generated using same Gaussian09 program for the Non Covalent Interaction (NCI) and Quantum Theory of Atoms in Molecule (QTAIM) calculations. For the simulation of 1H NMR chemical shifts by using GIAO 76 method the optimized coordinates with identical parameters were utilized. For the Gibbs free energy and population difference calculation between the confirmers 5a and 5b, the B3LYP-D3 in 6-311+g(d,p) basis set has been used. AIMALL software was used to determine the delocalization indices.77 Conclusions The blend of NMR experimental findings (one dimensional, two dimensional) and DFT based theoretical calculations confirmed the existence of intramolecular HBs in the derivatives of 20 ACS Paragon Plus Environment

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dibenzoyl oxalamide. The

19

F-1H HOESY experiment revealed the close spatial proximity.

Solvent dilution experiments discarded the possibility of any self or cross dimerization. Solvent titration studies and temperature variation revealed the information about HB, and their relative strengths. The through space couplings, in which the spin polarization is transmitted through HB between two NMR active nuclei has been detected in the fluorine containing molecule. The 2D 15

N-1H HSQC experiment permitted the measurement of coupling strengths and their relative

signs. The entanglement of organic fluorine in the formation of HB is convincingly established. The occurrence of HB in non-fluorinated molecules has also been established by numerous NMR experiments. The NMR observations have also been authenticated by DFT based theoretical calculations. QTAIM calculations yielded qualitative strengths of HBs. The sign of Laplacian of electron density is used as a signature of the identifying different HBs. NCI analysis provided the unambiguous evidence for the presence of bifurcated HBs and other type of interactions in the investigated molecules. Supporting Information: Supporting Information is available: One-dimensional 1H NMR spectra, Two-Dimensional HSQC spectra of molecules, and the general chemical structures for the derivatives of N,Ndibenzoyloxalamide. Acknowledgements PD and SKM would like to thank UGC, New Delhi for Senior Research Fellowship. PD would like to thank A. Lakshmipriya, Kiran and Naveen Dandu for their help. NS gratefully acknowledges the generous financial support by the Science and Engineering Research Board (SERB), New Delhi (Grant Number: EMR/2015/002263). 21 ACS Paragon Plus Environment


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Intramolecular HB Interactions Evidenced in Dibenzoyl Oxalamide

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