Intramolecular Hydrogen Bonding Appetency for Conformational

Article Cite This: J. Phys. Chem. A XXXX, XXX, XXX−XXX

pubs.acs.org/JPCA

Intramolecular Hydrogen Bonding Appetency for Conformational Penchants in Oxalohydrazide Fluoro Derivatives: NMR, MD, QTAIM, and NCI Studies A. Lakshmipriya,†,‡,⊥ Madhusudan Chaudhary,†,⊥ Santosh Mogurampelly,§ Michael L. Klein,§ and N. Suryaprakash*,†,‡ †

NMR Research Centre, Indian Institute of Science, Bangalore, Karnataka 560012, India Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore, Karnataka 560012, India § Institute for Computational Molecular Science, Temple University, Philadelphia, Pennsylvania 19122, United States ‡

S Supporting Information *

ABSTRACT: The conformational stability of synthesized diphenyloxalohydrazide and dibenzoyloxalohydrazide fluoro derivatives has been investigated by extensive NMR studies that are ascertained by various levels of theoretical calculations. Two-dimensional 1H−19F HOESY NMR experiments revealed the close spatial proximity between two NMR-active nuclei, confirming the hydrogen bond (HB)-mediated interaction between them, further aiding in establishing the probable stable conformations of these molecules. The relaxed potential energy scan disclosed the energy-minimized most stable structure among the several possible multiple conformations, which is in concurrence with NMR interpretations. Atomistic molecular dynamics simulations have been employed to unequivocally establish the conformational stability and the nature of HB formation at varied temperatures. With the possibility of occurrence of a number of probable conformations, the percentage of occurrences of different types of HBs in them was determined by MD simulations. Their population analysis was carried out using a Boltzmann distribution, in addition to deriving their Gibbs free energies. The molecular interactions governing the stable conformations have not only been ascertained by experimental NMR interpretations but also corroborated by other theoretical computations, viz., quantum theory of atoms in molecules (QTAIM) and noncovalent interaction (NCI).

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INTRODUCTION The hydrogen bond (HB) is an extremely important weak molecular interaction that is inherently present in many biological systems and plays a pivotal role in a number of chemical reactions.1,2 HBs dictate the double-helix structure of DNA3 and also play a key role in sustaining water molecules in the liquid state.4 The nature of HB formation and the underlying interactions are important in understanding numerous phenomena, such as molecular conformation, enzymatic catalysis, molecular recognition, folding of proteins, drug receptors, etc.1−5 The importance of the HB can be gauged by the statement of G. A. Jeffrey: “Without them, all wooden structures would collapse, cement would crumble, oceans would vaporize, and all living things would disintegrate into inanimate matter”.6,7 Although it was a common belief that organic fluorine rarely participates in hydrogen bonding,8−10 there are several recent experimental findings contradicting this general understanding.11−13 Organic molecules involving fluorine atoms require in-depth understanding because of several considerations: First, organic fluorine has tweaked the properties of drugs14−16 and tuned the engineering of crystals17,18 and biomaterials.19,20 © XXXX American Chemical Society

Second, as a consequence of the synthetic origin of organic fluorine compounds, their existence and roles in animals/plants are yet to be explored.21,22 As a result, there is a growing interest in exploring different compounds containing organic fluorine and understanding the chemistry of their conformational penchants. Oxalohydrazide derivatives are an indispensable group of compounds that have fostered their elevated impact because of their utility in synthetic organic chemistry.23−26 The derivatives of oxalohydrazide have been widely utilized in catalysis. The ligand N′,N′-bis{(1H-indol-3-yl)methylene}oxalohydrazide has been explored for N-2-aryl-substituted-1,2,3-triazoles synthesis.27 In polymer chemistry, self-polycondensation of oxalohydrazide has been carried out to obtain an open-chain polymer.28 Therefore, understanding of conformational penchants and the nature of molecular interactions in oxalohydrazide derivatives is essential in designing supramolecular structures with desirable structure and function. Received: January 31, 2018 Revised: February 27, 2018 Published: February 28, 2018 A

DOI: 10.1021/acs.jpca.8b00913 J. Phys. Chem. A XXXX, XXX, XXX−XXX

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The Journal of Physical Chemistry A

acetonitrile-d3. A Bruker Avance 400 MHz spectrometer was used to record all of the NMR spectra reported in this work. Two-dimensional 1H−19F HOESY33 and 15N−1H HSQC34 experiments were recorded using standard pulse programs available with the system. Computational Method. MD simulations at the atomistic level were carried out to understand the conformational stability and HB formation in oxalohydrazide derivatives in acetonitrile solvent at different temperatures. The general AMBER force field (GAFF)35 along with torsion parameters and partial charges obtained from quantum calculations in vacuum were employed. Langevin dynamics was used to perform MD simulations in an NPT ensemble at a specified target temperature and pressure of 1 atm36 using NAMD 2.11 software.37 A damping coefficient of 1 ps−1 was used to couple the simulation box with a Langevin thermostat. A decay period of 0.2 ps and a damping time of 0.1 ps were used for the barostat. A multiple time step algorithm was employed with a time step of 1 fs in which short- and long-range forces were calculated every alternative time steps, respectively.38 The longrange electrostatic interactions were calculated with the particle mesh Ewald (PME) method39 with a real space cutoff of 10 Å and a grid size of 1 Å. The van der Waals interactions were gradually switched between 8.5 and 10 Å. During the equilibration stage of NPT over a 10 ns long trajectory, according to the experimental conditions, the density of the solvent was optimized. Periodic boundary conditions were used in all three directions during the simulation. All of the results of conformational stability and the formation of HB analyses presented in this work are based on simulation trajectories of 50 ns long at each temperature. For DFT40-based theoretical calculations for all of the molecules, Gaussian0941 with a B3LYP/6-311G+g(d,p) basis set and acetonitrile as the default solvent medium was used.

Among the number of tools available for conformational analysis and the study of HB interactions, NMR spectroscopy has proven to be the most powerful. The 1H−19F HOESY NMR experiment29,30 provides through-space correlation information between two NMR-active nuclei, thereby aiding conformational analysis. The chemical shifts of protons that are influenced by HBs are affected by temperature, concentration, and the solvent, enabling tactical utility of NMR for the recognition and characterization of HBs. Because many chemical understandings can be construed into structure−energy relationships, it is advantageous to obtain relevant molecular properties, such as the geometry and electron distribution. Density functional theory (DFT)-based calculations are widely practiced to determine the optimal geometry, free energy, and chemical shifts for a particular conformer of a molecule. Besides, molecular dynamics (MD) simulations have evolved as a full-fledged deterministic technique to provide information on system dynamics at the atomic scale. In Quantum Theory of Atoms in Molecules (QTAIM),31 topological analysis of the electron density of chemical bonds is carried out. In such an analysis, the bonding between two atoms is indicated by the presence of a bond critical point (BCP) and an atomic interaction line (AIL) intersecting the BCP. As an extension of QTAIM analysis, the noncovalent interaction (NCI)32 index is employed to detect NCIs in real space. A typical indicator for NCIs is a spike in the low electron density and low reduced density gradient (RDG) region. The main focus of the present work is to gain insight into the stable conformations of diphenyloxalohydrazide and dibenzoyloxalohydrazide fluoro derivatives and thereby understand the weak molecular interactions that stabilize the conformations using NMR experiments and theoretical calculations, viz., QTAIM, NCI, and MD simulations. The chemical structures of the investigated molecules are given in Scheme 1. Each molecule might exhibit several possible conformations [denoted as (a), (b), and (c)], which are pictorially depicted in Scheme 2.

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RESULTS AND DISCUSSION The study was initiated by recording the two-dimensional 1 H−19F HOESY spectrum, which yielded the cross peak between fluorine and the proton (Ha) (Figure 1), establishing their close spatial proximity. The information derived from 1 H−19F HOESY reveals that all of the investigated molecules adapted the conformations denoted as (a) in Scheme 2 and also awakened the genesis of intramolecular HB-mediated interaction between the fluorine atom and NHa proton. Relaxed Potential Energy Scan. It is the inherent tendency of a molecule to adopt the structure with its minimum potential energy. In order to derive the information about the energy associated with the internal rotation of the phenyl rings through a single bond, the molecules of interest were investigated by DFT-based relaxed potential energy scans for internal rotation through a single bond in the solvent CD3CN.11 They are reported in Figure 2. For such a purpose, the B3LYP/6-311G** level of theory at ambient temperature, in 36 steps with 10° dihedral angle increments (0−360°), was employed. The relaxed potential energy scans reveal that conformation (a) (Scheme 2) has minimum energy and is most stable. Thus, the relaxed potential energy scan results support the NMR spectroscopic findings in proposing the stable conformation of all of the investigated molecules. Molecular Dynamics Simulations. After investigating the stable conformation of the molecules by NMR spectroscopy and DFT-based relaxed potential energy scans, MD simulations

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METHODS Experimental Method. All of the molecules discussed in this work were synthesized using the procedure reported in the Supporting Information (SI). The samples for NMR study were prepared by dissolving the molecule of interest in the solvent Scheme 1. Chemical Structures of Investigated Molecules: (A) Diphenyloxalohydrazide Derivatives; (B) Dibenzoyloxalohydrazide Derivativesa

a

In MD simulations, the distance between the sites X present on the two phenyl rings as well as the angles involving X−C−Na atoms was utilized to examine the conformational stability of the molecules. B


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Scheme 2. Possible Conformations [Denoted as (a), (b), and (c)] of (A) Diphenyloxalohydrazide Derivatives and (B) Dibenzoyloxalohydrazide Derivatives

Figure 1. 400 MHz 1H−19F HOESY spectra of the molecules 1, 2, 3, and 4 in the solvent CD3CN, labeled as A, B, C, and D, respectively. The mixing time used in the experiment was 450 ms.

Conformational Stability. Depending on the governing molecular interactions, the oxalohydrazide derivatives attain a specific conformation in thermodynamic equilibrium, which is expected to eventually lead to different self-assembled structures. However, it is to be resolved whether the molecular orientations of the phenyl rings with respect to the nearest N−

were carried out for conformational analysis and to ascertain the presence of a HB. The simulations were carried out at varied temperatures between 248 and 398 K in the solution state using acetonitrile as the solvent medium. The results discussed here for different properties pertain to room temperature unless otherwise mentioned. C


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Figure 2. Relaxed potential energy surface scans for the internal rotations of phenyl rings through a single bond in acetonitrile-d3 solvent, for the all investigated molecules. The selected dihedral angles chosen for carrying out the potential energy scans are highlighted with cyan color in the corresponding molecular structure given on the left side. The four atoms that are used to describe the dihedral angle for molecule 1 are N8−N7− C5−C6, for molecule 2, they are N8−N7−C5−C4, for molecule 3, they are N8−C7−C5−C6, and for molecule 4, they are N8−C7−C5−C6.

Ha amide would preferentially be in-phase or out-of-phase. In particular, it would be interesting to investigate the proximity of the terminus site X with respect to the amide N−H groups. In realizing the above objective, we have analyzed two different parameters, viz., (i) the separation r between the sites

located at positions X as indicated in Scheme 1 and (ii) the angle θ defined by the atomic positions XCNa at both termini. The equilibrium values of r and θ and their associated fluctuations determine the conformational stability of different oxalohydrazide derivatives in the solution state. D


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The Journal of Physical Chemistry A Conformational Analysis of Molecules 1 and 2. The results of the probability distribution of separation P(r) between the X atoms of the phenyl rings obtained from MD simulations at 298 K are reported in Figure 3a. It is seen that

observe any conformational possibility, such as the one schematically depicted in Figure 3d, wherein each C−X vector oriented opposite to the direction of its nearest N−H bond vector simultaneously. Conformations of Molecules 3 and 4. We observed that the peak position of P(r) is slightly shifted left for molecules 3 and 4 when compared to molecules 1 and 2, respectively. Interestingly, the P(r) values for molecules 3 and 4 display a much broader width, indicating that there may be more than one probable conformation. However, the P(r) alone may not be sufficient to derive conclusive evidence. Therefore, the analysis was also focused on the angle involving X−C−Na atoms, which is further expected to reveal the existence of different conformations attained by molecules 3 and 4. The results displayed in Figure 4 reveal that molecules 3 and 4 indeed exhibit multiple conformations. The conformational stability of molecule 3 is seen to be very similar to those observed for molecules 1 and 2 wherein the C−X and its nearest N−H bond vectors tend to align in the same direction (please see the snapshots presented in Figure 4a). However, surprisingly, molecule 4 appears to behave differently from the other three molecules. Explicitly, molecule 4 is characterized by a most stable conformation in which the C−X and its nearest N−H bond vectors align in the opposite directions, as depicted in the snapshot reported in Figure 4b. The above results are indicative of a distinct mechanism of HB formation in molecule 4, which will be discussed in a later part. Effect of Temperature on the Conformations. The features of conformational stability at elevated temperatures are very interesting. Explicitly, the occurrence of rare conformations is seen to be promoted at elevated temperatures compared to low-temperature conformations. The results of temperature dependency on P(r) reported in Figure 5 (more clarity is in the inset of Figure 5a) clearly demonstrate such an enhanced proportion of rare conformations in the investigated molecules. Large thermal fluctuations help to overcome the potential barrier (which is approximately 3.5 kcal/mol for molecule 1 calculated using F(r) = −kBT log(4πr2P(r)) and reported in Figure S1) for flipping of the phenyl ring from being in-phase with the nearest N−H bond vector to the outof-phase orientation. Broadening of distribution functions P(r) and P(θ) for molecules 3 and 4 (cf. Figures 5 and 4, respectively) indicates that the presence of an additional CO linker between the

Figure 3. Probability distribution of (a) the distance between atomic sites X of the terminal phenyl rings for all molecules studied at room temperature, 298 K. The position of fluorine atom in the functional group X was treated as the representative of site X for the analysis, and the arrows given in the molecular structure indicate the direction of N−H as well as the C−X bond vectors. The representative conformation shown in (b) was observed to be the most probable, while the one displayed in (c) was observed to be very rare. On the other hand, the conformation shown in (d) is not observed in the case of molecules 1 and 2. Note the flipping of the nearest N−H bond vector at the right phenyl ring for the rare conformation at a separation distance of r = 8.5 Å.

P(r) is characterized by a dominant peak corresponding to the most probable conformation. The most natural conformation represents the bond vector C−X of each phenyl ring, and its adjacent amide N−H bond vector exists in a cis configuration in molecules 1 and 2. A snapshot of such a conformation for molecule 2 is reported in Figure 3b. On the other hand, P(r) also revealed the possibility of occurrence of rare conformations that are characterized by one of the C−X vectors orienting opposite to the direction of the nearest N−H bond vector (like in the trans configuration) as reported in Figure 3c. However, the stability of such a rare conformation was observed to be very weak for all of the molecules. Interestingly, we do not

Figure 4. Probability distribution of the angle involving atoms X−C−Na at both termini for (a) molecule 3 and (b) molecule 4 at different temperatures. Snapshots representing the most natural and rare conformations (corresponding to the largest and smallest peaks, respectively) for each molecule are given in the insets of each figure. E


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Figure 5. Effect of temperature on the conformational stability of molecules 1−4 (a−d, respectively). The symbols represent different temperatures, as indicated in the legend.

phenyl rings and the amide N−H groups in dibenzoyloxalohydrazide derivatives increases the flexibility of molecules 3 and 4 to a large extent. Therefore, the phenyl rings in molecules 3 and 4 undergo more flexible rotations compared to molecules 1 and 2. Additionally, the phenyl rings are functionalized with CF3 groups in molecule 4, which further increases the rotations of phenyl rings with respect to the linker connecting two phenyl rings. Enhancement in the rotational degrees of freedom of the phenyl rings due to the presence of an additional CO linker as well as a CF3 functional group is therefore responsible for the unusual conformations observed for molecule 4. Percentage of HB Occurrences. The possibility of HB formation with different N−H groups and their percentage of formation were calculated using a widely used geometry-based HB criterion. Explicitly, we quantified the HBs D−H···A (where D, H, and A denote the donor, hydrogen, and acceptor atoms) in which a cutoff of 120° for the DHA angle and a cutoff of 3.5 Å for the distance between D and A were considered. The results of the percentages of occurrence of different types of HBs are presented in Figures 6 and 7 for all of the molecules. Consistent with the behavior of the respective distance and angle distribution functions (please see the Supporting Information, Figure S2), it is found that the HBs of type Na−Ha···F are more likely to prevail than HBs of the type Nb−Hb···F in all of the molecules investigated. The above result can be understood as a consequence of the close proximity of amide Na−Ha to the donor atom compared to that of Nb−Hb. However, the fluorine atoms present on both phenyl rings have equal probability of forming HBs with Na− Ha groups for a given molecule (please see the Supporting Information, Figure S3). No HBs of any type were observed in molecule 1. Interestingly, among all of the investigated molecules, only molecule 2 is seen to exhibit HBs of the type

Figure 6. Representative snapshots of all molecules exhibiting different types of HBs and their percentage of occurrences at 298 K. No HBs of any type were observed in molecule 1. Among all possible types of HBs, the Na−Ha···F type of HB is more prominent and only molecule 2 displays HBs of the type Nb−Hb···F. Three centered HBs of the type F···Na−Ha···O are possible only in molecule 2 in the presence of acetonitrile solvent.

Nb−Hb···F. However, the HBs of type Nb−Hb···F are found to be very rare, with a percentage of occurrence of only 0.31 for forming one HB and 0.02 for forming two HBs. The above result is due to a sharp peak for the Na−Ha−F angle distribution at 50° (please see the Supporting Information, Figure S2). Consistent with the above observations, molecule 2 contains the most number of HBs of any type compared to molecule 4 due to the wide range of angle distributions in F


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Table 2. Gibbs Free Energy (in units of Hartree) Values of Three Possible Conformations of the Investigated Molecules

molecule 4 (please see the Supporting Information, Figures S3 and S4). The simulations reveal that, although molecule 2 can indulge in several types of HBs, only molecule 3 can get involved in at least one HB at any given time. The HBs of the type Na−Ha···O are very rare compared to those of the type Na−Ha···F, as demonstrated by the distributions of respective distances and angles presented in the Supporting Information, Figure S4. Therefore, we expect that three centered HBs of the type X···Na−Ha···O are extremely rare to occur. However, to improve the statistics in the simulations on the occurrence of three centered HBs, we chose the angle cutoff for Na−Ha···O to be 110°. Even with such a widened cutoff angle, we could still find that the three centered HBs are rare to occur. Specifically, for 50000 configurations saved at an interval of 1 ps, we found only 21 HBs of the type F···Na−Ha···O in molecule 2, and no such bonds are observed for any other molecule. Interestingly, the F···Na−Ha···O type HBs increase to 45 at 348 K and 132 at 398 K. Gibbs Free Energies of Conformers. Gibbs free energy values for three different conformations of molecules 1−4 are assimilated in Table 1. The more negative value of the Gibbs free energy indicates the stability of the corresponding conformation.42 Table 1. Two Most Stable Conformations of Molecules 1−4 and Their Percentage of Populations

molecule

first most stable conformation

second most stable conformation

population of second most stable conformation (%)

1 2 3 4

A(a) A(a) B(a) B(a)

96.5 99.95 98.7 69.0

A(c) A(c) B(c) B(b)

3.5 0.05 1.3 31.0

(a)

(b)

(c)

1 2 3 4

−1109.920584 −1585.652345 −1336.672354 −1812.389201

−1109.915394 −1585.641077 −1336.661826 −1812.388448

−1109.917453 −1061.859277 −1336.668255 −1812.388223

respectively. In contrast, atomistic MD reveals that conformation B(b) is more stable for molecule 4 than conformation B(a) with approximately 2:1 occurrence possibly due to increased rotational degrees of freedom caused by an additional CO linker and CF3 functional group. Molecular Interactions. After establishing the stable conformation(s) of all of the molecules by NMR and MD simulations and obtaining their population distributions, we embarked on understanding the molecular interactions governing the conformation(s) within the molecule using experimental and computational approaches. In NMR spectroscopy, the chemical shift is one of the important parameters to probe weak molecular interactions.11−13 Exploring such interactions by monitoring the chemical shifts of a hydrogen-bonded proton in the NMR spectrum by adapting the strategy of temperature perturbation is well-known.11−13 The graphical representations of the systematic change in the chemical shifts of NHa and NHb protons for all of the molecules are reported in Figure 8. The measured temperature coefficient (ΔδNHa/ΔT) values for the NHa proton of molecules 1 and 2 are about 1.1 and 0.4 Hz K−1, respectively. This reveals that molecule 2 has a stronger N−H··· F HB in the investigated diphenyloxalohydrazide derivatives. The ΔδNHa/ΔT values for the NHa proton of molecules 3 and 4 are about 1.38 and 2.2 Hz K−1, respectively, which indicates that molecule 3 is involved in a stronger N−H···F HB in the dibenzoyloxalohydrazide derivatives. The NHb proton has a higher slope than the NHa proton in all of the molecules, which indicates that the fluorine atom interacts with the NHa proton (or) positioned toward the NHa proton side. The change in the frequency separation of the NH doublets (#a) at various temperatures and the collapse of the doublet of the proton spectrum (#a) into a single in the fluorine decoupled proton spectrum (#a*) at a particular temperature, reported in Figure 9, indicates the interaction of the fluorine atom with the labile proton (Ha). Another important NMR parameter to probe weak molecular interactions is the HB-mediated coupling interaction.43−47 The NHa proton of molecule 3 appeared as a doublet with a coupling constant of 6.2 Hz in the 1H spectrum, whereas it appeared as a singlet in the fluorine decoupled 1H spectrum, confirming that the observed doublet is due to JHF. This doublet disappeared in the solvent DMSO, indicating that the observed coupling is HB-mediated (1hJHF) and spin polarization transfer is not mediated through a covalent bond. The theoretically calculated chemical shifts for the protons Ha and Hb using the GIAO method48 with the B3LYP/6-311G** basis set and the experimental chemical shifts are assimilated in Table 3. Heteronuclear Single Quantum Correlation. 1H−15N HSQC (heteronuclear single quantum coherence) spectrum of molecule 2, reported in Figure 10, exhibited a quartet. The relaxed potential energy surface scan performed on this molecule revealed that the energy barrier relating to the

Figure 7. Bar chart representation of the percentage of occurrences of the number of HBs (reported in Figure 6) for molecules 1−4.

population of first most stable conformation (%)

molecule

Populations of Conformers. Population analysis has been performed using the Boltzmann distribution, and the values of the percentages (%) of population of the most stable conformation and the second most stable conformation have been calculated.42 The corresponding values are compiled in Table 2. From population analysis, it can be inferred that molecules 1−3 preferably exist in conformation (a), whereas molecule 4 exists in two conformations, (a):(b) in a ratio of 2:1, G


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Figure 8. Variation of the chemical shift of (A) NHa and (B) NHb protons with temperature. The molecules are represented by the symbols given in the inset.

Figure 9. Selected regions of the NMR spectra of molecules 1−3 represented as (1), (2), and (3), respectively. The different temperatures at which the experiment was carried out is represented by the color codes. #a and #a* refer to the fluorine coupled and fluorine decoupled proton spectra corresponding to the NHa proton.

temperature in 24 steps with 5° increment of dihedral angle (H24−C4−C32−F36). QTAIM Calculations. QTAIM analysis uses electron density and its topology as the source of information for characterizing the types of interactions. The presence of BCP and AIL between two atoms indicates that the two atoms are bonded. The shared shell [covalent (−ve)] and closed shell interactions [ionic, van der Waals, and HB (+ve)] are differentiated by the sign of the Laplacian of the electron density at the BCP. In the present study, QTAIM calculations were carried out to explore the weak molecular interactions in all of the investigated molecules. The BCPs, AIL, and ring critical points (RCPs) were obtained by the Multiwfn program49 for molecules 1−4 and are reported in Figure 11. The observation of a positive sign of the Laplacian of the

Table 3. Theoretically Calculated Chemical Shifts of Protons (Ha and Hb) for Molecules 1−4 experimental chemical shift values (ppm)

theoretically calculated chemical shift values (ppm)

molecule

Ha

Hb

Ha

Hb

1 2 3 4

6.58 6.72 8.77 8.72

9.34 9.41 9.47 9.45

6.2 6.61 10.18 9.21

8.69 8.67 10.67 10.44

internal rotation of the −CF3 functional group is about 2.55 kcal/mol (Figure 10C).11,12 This low-energy barrier can be attributed to the observation of a quartet in the 1H−15N HSQC spectrum. The relaxed potential energy scan was performed using the B3LYP/6-311G** level of theory at ambient

Figure 10. (A) 1H decoupled 1H−15N HSQC spectrum; (B) DFT optimized structure highlighting the selected dihedral angle (H24−C4−C32− F36) for the relaxed potential energy scan; (C) relaxed potential energy scan for molecule 2 in acetonitrile-d3. H


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Figure 11. QTAIM analysis of molecules 1−4 with their conformations given in brackets. The chemical bonds between the atoms are indicated by a red colored BCP, AIL is represented by a line intersecting the BCP, and a ring is indicated by yellow colored RCPs.

Figure 12. NCI plot defining sin(λ2)ρ as function 1 and RDG as function 2. The numbering represents molecules 1−4.

Figure 13. RDG isosurfaces of molecules 1−4. The numbering represents the molecules, and their conformations are given within brackets.

electron density at N−H···F reveals the presence of an N−H··· F type HB in the stable conformations of molecules 2−4. NCI Analysis. NCI analysis helps in the detection of NCIs in real space using the electron density and its derivatives. In

the present study, NCI analyses were performed on the stable conformations of all investigated molecules using the Multiwfn program, which generated high-quality grid data for two real space functions in the same spatial scope. We employed the I


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The Journal of Physical Chemistry A usual definitions sin(λ2)ρ as function 1 and RDG50 as function 2 in the present study, which provided the NCI plots (Figure 12). In all cases, two sets of spikes were observed. The spike with negative density values indicates the stabilized interactions depicting the presence of HB, whereas the spike with positive density values indicates repulsive steric clash. For such a purpose, Visual Molecular Dynamics (VMD) software was utilized to plot the color-filled isosurface graphs from the grid points (Figure 13). During NCI analysis, the extension distance of the grid range in all directions was set to 0 Bohr for all of the molecules except for molecule 3 because the weak interaction regions appear only in the internal region of the system, thus not leaving a buffer region at the system boundary. For molecule 3, it was set to 1 Bohr because with the grid data generated at a 1 Bohr extension distance RDG isosurfaces were well observed in VMD. The evolution of the RDG isosurfaces with an extension distance from 0.1 to 0.9 Bohr, with an increment of 0.1 Bohr, is reported in the Supporting Information along with respective NCI indexes, as (Supporting Inforamtion, Figure S5) for molecule 3. Like QTAIM and MD simulations, NCI plots and the color-filled isosurface graphs of molecules 2 and 4 reveal the presence of an N−H···F HB. However, for molecule 1, NCI study reveals the presence of an N−H···F HB, in contrast to the QTAIM and MD simulation results.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Fax: +91 8023601550. Tel: +91 8022933300. ORCID

N. Suryaprakash: 0000-0002-9954-5195 Author Contributions ⊥

A.L.P. and M.C. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS A.L.P. thanks CSIR for a Senior Research Fellowship and Subbarao Kanchi and P. Dhanishta for their help in theoretical calculations. N.S. gratefully acknowledges financial support from the Science and Engineering Research Board (SERB), New Delhi (Grant Number: EMR/2015/002263). The computational part of this research was supported in part by the National Science Foundation (NSF) through major research instrumentation Grant Number 1625061.

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CONCLUSIONS Extensive utility of NMR spectroscopy and various levels of theoretical calculations revealed information on the stable conformations of synthesized diphenyloxalohydrazide and dibenzoyloxalohydrazide fluoro derivatives. The DFT-based relaxed potential energy scans unravelled the single and most stable conformation with minimum energy, supporting the NMR observations. In molecules 1 and 2, the conformations represent the bond vector C−X of the phenyl rings and the nearby amide N−H bond vector existing in cis configurations, although the possibility of occurrence of rare conformations that are characterized by one of the X sites orienting opposite to the direction of the nearest N−H bond was detected by MD simulations. No conformational possibility with two C−X bond vectors existing in trans configurations to the nearest N−H bond vectors was discovered. On the other hand, molecule 4 was observed to exist in multiple conformations, where the mechanism of the HB is distinct and the stable conformation is established to be the one where C−X and the nearest N−H bond vectors tend to align in opposite directions. However, in contrast, the conformational stability of molecule 3 is similar to that of molecules 1 and 2. The Gibbs free energies of different conformations were also calculated, and their population analysis was carried out using a Boltzmann distribution. Weak molecular interactions in the identified stable conformations have been further corroborated by QTAIM and NCI analysis. We believe that the results presented in the article may provide strategic guidelines in designing various supramolecular structures with desired properties and highlight the importance of different functional groups in influencing the weak molecular interactions.

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Two-dimensional HSQC spectra of molecules, MD simulation data, DFT optimized structure coordinates, and synthesis procedure (PDF)

REFERENCES

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Intramolecular Hydrogen Bonding Appetency for Conformational

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