Engagement of CF3 Group in NâHÂ·Â·Â·FâC Hydrogen Bond in the

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Engagement of CF Group in N-H F-C Hydrogen Bond in the Solution State: NMR Spectroscopy, DFT and MD Simulation Studies Sachin Rama Chaudhari, Santosh Mogurampelly, and Nagarajarao Suryaprakash J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/jp310798d • Publication Date (Web): 04 Jan 2013 Downloaded from http://pubs.acs.org on January 5, 2013

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The Journal of Physical Chemistry

Engagement of CF3 Group in N-H…F-C Hydrogen Bond in the Solution State: NMR Spectroscopy, DFT and MD Simulation Studies Sachin Rama Chaudhari a,b, Santosh Mogurampellyc and N. Suryaprakasha,b,* a

NMR Research Center and bSolid State and Structural Chemistry Unit, cDepartment of Physics Indian Institute of Science, Bangalore 560012, India Tel: ++91 80 22933300, Fax: ++91 80 23601550. e-mail: [email protected]

KEYWORDS: Organic fluorine, Hindered rotation of CF3 group, N-H…F-C Hydrogen bond, NMR Spectroscopy, MD simulations, Geometry optimization, DFT calculations.

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Abstract

Unambiguous evidence for the engagement of CF3 group in N-H…F-C hydrogen bond in a low polarity solvent, the first observation of its kind, is reported. The presence of such weak molecular interactions in the solution state is convincingly established by one and two dimensional 1H, 19F and natural abundant 15N NMR spectroscopic studies. The strong and direct evidence is derived by the observation of through space couplings, such as, 1hJFH, 1hJFN and 2hJFF, where the spin polarization is transmitted through hydrogen bond. In an interesting example of a molecule containing two CF3 groups getting simultaneously involved in hydrogen bond, where hydrogen bond mediated couplings are not reflected in the NMR spectrum,

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F-19F NOESY

experiment yielded confirmatory evidence. Significant deviations in the strengths of 1JNH, variable temperature and the solvent induced perturbations yielded additional support. The NMR results are corroborated by both DFT calculations and MD simulations, where the quantitative information on different ways of involvement of fluorine in two and three centered hydrogen bonds, their percentage of occurrences and geometries have been obtained. The hydrogen bond interaction energies have also been calculated.

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Introduction

Organic fluorine has gained enormous importance in crystal engineering [1], the design of functional materials [2], and also in numerous applications, such as drug design, agro chemicals, molecular imaging and biomaterials [3]. In medicinal and bio-inorganic chemistry, the formation of intermolecular H-bonds with organic fluorine, viz., X-H…F-C (X= O, N and C) is extremely important, especially in the binding of fluorinated compounds to enzyme active sites [4], although the role of organic fluorine as an H-bond acceptor is highly debated [5]. A report on the statistical analysis of the Cambridge Structural Database System (CSDS) [5] has concluded that “organic fluorine hardly ever accepts the H-bond”. Nevertheless, the importance of such types of interactions in crystal packing considerations has been discussed [2]. As far as the Hbond between fluorine atom and different hybridized carbons is concerned, it has been reported that C(Sp3)-F fluorine is a better acceptor than C(Sp2)-F and C(Sp)-F fluorine [6].

The

participation of CF3 group in H-bond is, however, rarely encountered owing to the fact that the strength of interaction should be strong enough to hinder the free rotation of CF3 group. There are very few examples giving evidence for weak molecular interactions of the type C-F…H-C [7] and C-F…H-O in covalently bound organofluorine compounds containing CF3 group [8], although the detection of C-F…H-O in the solution state is a debatable point [9]. Till date, to the best of our knowledge, there is no example of C-F…H-N H-bond formation in the solution state with the participation of CF3 group. To get deeper insight into the role of CF3 group in H-bond and in structural chemistry, we have carried out in depth studies on trifluoromethyl substituted derivatives of benzanilides and reporting the first example of the engagement of CF3 group in 3



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intramolecular C-F…H-N H-bond. Interestingly the same investigated molecules in the solid state favour the formation of strong intermolecular interactions, such as, N-H…O, C-H…O over the F…H-N [10].

In understanding the existence of such weak molecular interactions we have carried out extensive use of NMR experimental techniques, supported by Molecular Dynamics (MD) simulations, since these techniques are very useful for the study of H-bond involving organic fluorine [6,11]. The studies focused on trifluoromethyl derivatives of benzanilides, whose chemical structures are reported in scheme 1, were carried out by diverse one and two dimensional NMR experiments. The unambiguous conclusions have been drawn on the weak molecular interactions, and the MD simulations threw light on the various possibilities of Hbonds of fluorine atoms of CF3 with NH proton and the percentage of their occurrence.

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Scheme 1: Chemical structure of benzanilide (1) and its trifluoromethyl derivatives (2-5).

Results and Discussion The H-bond can be investigated by utilizing various NMR experiments, such as, the temperature perturbations, concentration variation, change in the polarity of the solution (titrations experiments), two dimensional correlation experiments, and also by the detection of through space couplings between nuclei directly involved in hydrogen bonding.

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Figure 1. a)Temperature dependent variation of chemical shift of NH proton in molecules 2, 3 and 5 in the solvent CDCl3 (10 mM concentration); b) Variation of chemical shifts of NH proton with the incremental addition of DMSO-d6 in the solution containing 200 µl of CDCl3 (10 mM) at 298 K for the molecules 2, 3 and 5 (black- molecule 2, red- molecule 3, blue - molecule 5). The lowering of temperature results in the strengthening of the H-bond, causes excessive deshielding of proton as a result of its displacement towards the acceptor atom, and shortens the H-bond length. The deshielding of NH chemical shift on lowering the temperature, reported in Fig. 1a, gives evidence for H-bond.

Usefulness of solvent titration in understanding such

interactions has also been reported [12]. For such a purpose the high polarity solvent DMSO-d6 was chosen, which is well known as an H-bond acceptor and results in more pronounced shifts in resonances of protons that participate in H-bond. The incremental addition of DMSO-d6 to the solution disrupts the H-bond of the investigated molecules and forms H-bond with itself resulting in the deshielding of NH chemical shift. The solvent titration was therefore carried out and the DMSO-d6 induced perturbation of δNH for the molecules 2, 3 and 5, are reported in Fig. 1b. We have also investigated the concentration dependence of NH chemical shift for the molecules 1, 2 and 3. It is observed that for molecule 1 where no hydrogen bond is expected, the NH chemical 6


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shift is strongly dependent on the concentration of the molecule in the solvent, while in the case of molecules 2 and 3 the chemical shifts of NH proton are independent of concentration. All the related 1H-NMR spectra are reported [Figs. S5-S7 in SI]. Another important NMR observable that provides direct evidence for the formation of H-bond is the through space coupling between the two NMR active nuclei involved in H-bond [13-15]. For the molecule 2, the 1H NMR spectrum displayed a doublet of separation 16.7 Hz for NH proton [Fig. S1 and S6 in SI]. It has earlier been established that such a large coupling mediated through covalent bonds is quite unlikely and is a result of transmission of spin polarization through Hbond [14, 15]. This is attributed to 1hJFH between NH proton and the fluorine of ring “a”. This is further confirmed by 1H{19F} experiment and also the disappearance of doublet in a high polarity solvent, such as, DMSO-d6. However, the excessive broadening of NH signal due to 14N quadrupole relaxation prevents the precise measurement of small couplings, if any, that are hidden within the line width. In circumventing such problems we have carried out 2D 15N-1H HSQC experiment where 15N is present in its natural abundance. The 15N-1H HSQC spectrum in the solvent CDCl3 and the measured scalar couplings are reported in Fig. 2. The spectrum yielded two types of couplings for 1hJFH and 2hJFN. Assuming 1hJFH to be negative as reported in earlier studies for similar type of molecules [14,15], relative slopes of the displacement vectors indicate that signs of

1h

JFH and

significant strengths, such as,

2h

1h

JFN are same. The observation of through space couplings of

JFH and

2h

JFN gives another direct evidence for involvement of

CF3 group in H-bond. The similar information has been derived for all the remaining molecules, whose HSQC spectra along with the measured couplings are reported [Figs. S12-S14 in SI]. 7



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Figure 2: 400 MHz 2D 15N- 1H-HSQC spectrum of molecule 2 in the solvent CDCl3, depicting the through-space couplings. The measured couplings are identified by alphabets a-d.

To gain more insight we have carried out two-dimensional heteronuclear correlation experiment of 1H and

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F (HOESY), where the correlation is established through-space, since such an

experiment has been demonstrated to be powerful in identifying the presence of H-bond [16]. The 2D

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F-1H HOESY spectra of the molecules 2-5 are reported [Figs. S8-S11 in SI]. The

observation of a cross peak between 1H and 19F is an indicator of the involvement of fluorine in weak molecular interaction.

The scalar coupling 1JNH has also been demonstrated to be a powerful indicator of an H-bond, especially in the study of DNA base pairs and chemical systems [17], where it is established that more downfield of NH resonance associated with stronger 1hJFH and 2hJFN couplings but weaker 8


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scalar coupling 1JNH is an indicator of H-bond. The increase in 1JNH indicates a gradual shift of the proton from donor to the acceptor atom by increasing in the covalent character of N-H bond and decreasing of the donor and acceptor atomic distance. For ascertaining the utilization of this parameter, 1JNH was measured for all the molecules using 15N-1H HSQC. The determined values showed the deviation of nearly 2-3 Hz compared to the molecule which is not involved in Hbond [S23 in SI]. These observations imply that in the solution state the fluorine participates in the H-bond, although no such interactions are detected in the solid state [10]. Thus the nature of interactions in the solution and solid states are completely different. To ascertain this weak molecular interaction, the experimental results are compared with DFT calculations. All DFT method calculations were performed by using Gaussian09 and B3LYP/6-311+g (d,p) level of theory [18] was used for full geometry optimizations of molecules 2-5. The optimized molecular geometries for all these molecules are reported in Fig. 3. The comparison of H-bond geometric parameters obtained with the literature values [19] indicates that fluorine is involved in weak interactions.

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Figure 3: DFT Optimized structures of fluorinated benzanilide molecules 2-5.

There are various possible mechanisms of weak interactions because of three fluorine atoms of the CF3 group, such as, two-centered, three centered or even four centered H-bonds. Although the NMR spectroscopy confirmed the existence of H-bond involving the CF3 group, it is difficult to extract the quantitative information on the contribution of all these possible H-bonds because of their dynamic nature. To obtain such quantitative information we have carried out both quantum chemical calculations and MD simulations. For the calculation of H-bond, we used the geometry measurement criteria in which H-bond is represented as N-H… F, where N is the donor atom and F is the acceptor atom which is bonded to N through the H atom. If the distance, r between N and F atom is less than 3.5 Å and the angle ∠NHF (θ) is greater than 120º, then there 10


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exists an H-bond between the atoms N and F. The probability of their distance, P(r), and probability of the angle, P(θ), are calculated for all the fluorine atoms in each of these four molecules.

For the detailed study initially the molecule 3, where only CF3 group is present in ring “b” was investigated. There are two possible types of H-bonds with CF3 group in this molecule, viz., any one of the fluorine atoms of CF3 group might participate giving rise to two centered or any two fluorine’s might get involved giving rise to three-centered H-bond i.e. a bifurcated H-bond. MD simulations also confirmed the same and we are able to calculate the % of occurrence of various types of H-bonds (Fig. 4). It is observed that the situation when there is no H-bond is 56.27 %, whereas the occurrence of two centered H-bond is 42.60 % (Fig. 4a) and the occurrence of bifurcated H-bond is very less and is 1.13 % (Fig. 4b). The H-bond geometrical parameters obtained by MD simulations are reported in Fig. 4c and 4d. It is interesting to note that all three F atoms in CF3 group have equal probability of forming H-bonds, as P(r) and P(θ) are same for three F atoms (Figs. 4c and 4d). Since the percentage of two centered H-bond formation is very high, there is an equal probability of all the three fluorines participating to form an H-bond with an angle of 120◦. The probability of the distance between N and any F atom, i.e. P(r) has two strong peaks, one at 2.9 Å corresponding to H-bond (for θ > 120◦) and 4.25 Å corresponding to the absence of H-bond formation. This implies that the H-bonds are transient. This is also confirmed by the detection of quartet for NH proton in the 15N- 1H HSQC spectrum [Fig. S12 in SI].

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Figure 4: a) and b) The snapshot of H-bonds formation in the molecule 3, along with their percentage of occurences, obtained from MD simulations. Blue coloured dashed lines show Hbonds. c) and d) the probability distributions of angles and distances, respectively.

The similar study on the molecule 5, where CF3 group is situated on the ring “a” reveals that the situation is entirely different in the molecule.

Even in this molecule, 5, similar to that of

molecule 3, there are two possibilities of H-bonds, viz., two centered and bifurcated types. However, the probability of the absence of H-bond is very small, which might be due to the highly flexible torsion angle between F-C-C-C. The three centered H-bond is more favourable 12


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(67.23%) compared to two centered H-bond (32.7%) and their probability of distribution, and percentage of occurrence are reported [Figs. S25-S32 in SI]. In the case of molecule 2, containing a single fluorine in the ring “a” and CF3 group in the ring “b” there are five different possibilities of fluorine getting involved in the H-bond formation and also a possibility when there is no H-bond. All such possibilities with their percentage of occurrence obtained by MD simulations are reported in Fig. 5.

It is clearly evident from the

figure that the first case (Fig. 5a) is more favorable because of more stable conformers. It is also interesting to note that

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F{1H} NMR spectrum of this molecule exhibited doublet and quartet

patterns for CF3 and CF groups respectively and the corresponding spectrum is reported in Fig. 6. However, the two fluorine’s in molecule 2, is separated by eight covalent bonds and the scalar couplings between them mediated through covalent bonds is quite unlikely. Consequent to the bifurcated character of the H-bond, one can expect the possible interaction and the transferring of spin polarization between two fluorine atoms are mediated through H-bond. Furthermore the detection of

2h

JFF of 5.7 Hz yields a very strong evidence for the observation of conformation

shown in Fig. 5c. The detection of 2hJFF was also further established by 2D-19F-19F COSY and Jresolved experiments [Figs. S15-S17 in SI]. Additional evidence is obtained from the spectrum, where the multiplet pattern disappeared in the solvent DMSO-d6. Detection of this coupling gives additional and strong evidence for the engagement of CF3 and CF groups in the formation of bifurcated H-bond. MD simulations on the other hand revealed the percentage of occurrence of H-bond as nearly 36.91 % [Fig. 5c].

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Figure 5: Various possibilities of H-bond formation for the molecule 2, with their % of occurrence obtained from the MD simulations (H-bond is shown by blue line)

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Figure 6: 376.7 MHz coupling

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F{1H}-NMR spectrum of molecule 2 showing

2h

JFF through space

In the case of molecule 4, there are six F atoms with two CF3 groups situated on both the rings “a” and “b” and MD simulations revealed various possibilities of H-bonds [Figs. S29 and S30 in SI]. In this situation the probabilities of occurrences of H-bond resembles that of molecules 3 for the CF3 group situated on the ring “b”, and resembles the observation made for molecule 5 for other CF3 group present in ring “a”. It is also interesting to note that in this molecule there is always a probability of fluorine forming H-bond in any one of the conformations. All the related information for this molecule is reported [Figs. S29 and S30 in SI]. For the molecule 5 NMR did not give through-space couplings such as 2hJFF [Figs. S4 and S14, in SI]. This may be attributed to weak interaction consequent to CF3 groups forming a six and seven member rings with NH proton. For establishing this fact the two dimensional 1H-19F HOESY and

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F-19F NOESY

experiments were carried out and the corresponding spectra are reported [Figs. S10 and S33 in SI]. The observation of cross-peaks between two CF3 groups gives evidence for their close spatial proximity and established the participation of CF3 in H-bond. On the other hand in the 15



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solid state, the two CF3 groups of the molecule are in trans configuration and their spatial distance has been reported to be 5.9 Å, [10], and did not reveal any such H-bond. If this is the situation in the solution state the NOESY spectrum would not give rise to any cross peaks [20]. Therefore the present study gives strong evidence of the existence of H-bonds in all the fluorinated molecules investigated. The various H-bond possibilities with their probabilities of occurrence are obtained by MD simulations. Finally, we have also calculated the strengths of H-bond for each fluorine atom present in all the molecules using atomistic molecular dynamics. From the 50 ns molecular dynamics simulation trajectory, we have calculated the combined histogram of the H-bond formation; H(r,θ) i.e., as a function of the distance, r between donor and acceptor atoms and θ the angle between donorhydrogen-acceptor atoms. This histogram is then utilized to estimate the free energy landscape, F(r,θ), of each atom involved in H-bond formation as; F(r,θ) = -kBT ln(2πr2sinθH(r, θ))

……… (1)

where kB is the Boltzmann constant and T is the temperature. We have kept T=300K. F(r,θ) is shown in Fig. 7 for N-H…F1-C (F1 could be any of the fluorine atoms) configuration that occurred in molecule 4. For any F atom (in all the investigated molecules) which has a possibility of H-bond formation with N atom, F(r,θ) will have two minima as shown in Fig.7. These minima correspond to two states, one with H-bond and other with no H-bond. In case of N-H…F1-C in molecule 4 shown in Fig. 7, the minima on the left hand side is a state with H-bond (for which r and θ satisfy for H-bond conditions) and the other minima is for no H-bond. The strength of H-bond is calculated as; 16


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Ehb = Fhbmin (r, θ) -Fno-hbmax (r, θ)

…… (2)

where Fhbmin (r, θ) is the minima of H-bonded state and Fno-hbmax (r, θ) is the maxima for no Hbonded state. We note that Ehb calculated from the above formula is independent of the H-bond criteria.

Figure 7: F(r,θ) for N-H… F1-C Hydrogen bond occurred in molecule 4.

The hydrogen bond energy for all the molecules is reported in the Table 1. From the table it is observed that the Ehb is less than 4 kcal/mol, indicating that the fluorine atom is involved in weak hydrogen bond in accordance with the literature [19].

Table 1: Hydrogen bond energy Ehb for each “F" atom in molecules, 2-5.

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Molecule

Atom

Ehb k cal/mol

2

3

4

5

F1

2.50 ± 0.04

F2

2.39 ± 0.04

F3

2.32 ± 0.03

F4

2.78 ± 0.03

F1

2.40 ± 0.04

F2

2.40 ± 0.04

F3

2.50 ± 0.04

F1

2.36 ± 0.01

F2

2.42 ± 0.00

F3

2.47 ± 0.03

F4

1.54 ± 0.02

F5

2.25 ± 0.03

F6

2.31 ± 0.03

F1

2.31 ± 0.03

F2

2.32 ± 0.02

F3

-----No HB bond -------

Conclusions The extensive studies have been carried out by one and two dimensional NMR spectroscopy to understand the weak molecular interactions in trifluoromethyl derivatives of benzanilides where 18


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CF3 group is participating. The strongest evidence for F...H-N H-bond is observed by the detection of through space couplings such as, 1hJFH,

2h

JFN and

2h

JFF. In addition the solvent and

temperature induced perturbations also provide the convincing evidence for the participation of CF3 group in the H-bond. In conjunction with NMR studies, the quantum calculations and classical MD simulations have supported the various possible ways of H-bond formation with fluorine atom. All fluorine atoms of CF3 group (in ring “b”) have equal probability of forming an H-bond in all the four molecules, whereas, all the CF3 group in ring “a” have biased chances. The strengths of hydrogen bonds of various fluorine atoms range from 1.5 to 2.8 kcal/mol. These studies therefore lead to better understanding of biological importance of H-bond and open up opportunities in architectural design of the foldamers and supramolecular chemistry.

Experimental Methods:

NMR Measurements The individual solutions of all the investigated molecules were prepared in the solvent CDCl3. All the 1H,

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C and

19

F NMR spectra were recorded using Bruker Avance 400 and 500

spectrometers. Temperatures were monitored by a Eurotherm Variable temperature unit to an accuracy of ±1.0 C. The 1H and 13C chemical shifts were referenced to TMS and 19F spectra were reference to trifluoroacetic acid. NMR titrations were carried out using a Bruker DRX 500 spectrometer. The

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F-19F NOESY and 1H-19F HOSEY experiments were carried out using the

well known pulse sequence reported in the literature. All coupling scalar couplings are measured

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using 1H-15N and homonuclear 2D J-resolved (1H,

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F) spectra. Other experimental details are

given in SI. Quantum and classical simulations Possibility of H-bond formation in various molecules has been investigated using combination of quantum calculations and classical molecular dynamics simulations. Torsion parameters and partial atomic charges on atoms were calculated from quantum density functional theory (DFT) method. Geometry optimization of all molecules is performed with B3LYP/6-311g (d,p) [19,21] basis set. For the optimized structures, we have calculated the electrostatic potential (ESP). Using ESP, we calculated partial atomic charges on all atoms with restrained electrostatic potential (RESP) least square fitting procedure [22] implemented in ‘antechamber’ [23, 24]. The C-N-C-O, C-C-N-H and C-C-C-N torsion parameters are also derived from quantum method using Gaussian09 [25]. The optimized structures are simulated using molecular dynamics (MD) at 300 K with intra and inter-atomic potentials in a solution of chloroform (CHCl3) to mimic experimental conditions. Chloroform is known to promote H-bond formation in organic molecules at room temperature. All the four systems are solvated with chloroform solvent numbering roughly 130 molecules resulting in a total system size to be 650-750 atoms depending on molecule. We use general AMBER force field (GAFF) along with torsion parameters and partial charges obtained from quantum calculations in vacuum. The long range electrostatic interactions were calculated with the Particle Mesh Ewald (PME) method [26] with a real space cut-off of 12 Å. We have used periodic boundary conditions in all three directions during the simulation. Constant pressure-temperature (NPT) simulation is performed for 1 ns followed by 20


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constant volume-temperature (NVT) simulation with 1fs time step. During NPT, the density of solvent is optimized corresponding to experimental condition. After NPT, the size of the simulation box is roughly 29.9 x 25.8x25.5 Å3 for all the four structures. For analysis of structures and H-bond formation studies, the systems are simulated for 50 ns of NVT production. All the MD simulations were performed using NAMD simulation package [27]. Simulation trajectories of 50 ns have been analyzed for H-bond formation and its statistics in all the four molecules. ASSOCIATED CONTENT Supporting Information: The schemes for syntheses procedure for fluorinated benzanilides. The detail results of NMR measurements (including 1H,19F, 1D and 2DNMR spectra and 1H-15NHSQC spectra and J couplings,), MD simulations (distributions of torsional angles and interatomic distances), QM calculations. This material is available free of charge via the Internet at http://pubs.acs.org. Acknowledgements SRC would like to thank UGC for SRF. NS gratefully acknowledges the generous financial support by the Science and Engineering Research Board, New Delhi (grant No. SR/S1/PC42/2011). Authors would like to thank Mr. Srinu for DFT calculations.

AUTHOR INFORMATION Corresponding Author 21



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* N. Suryaprakash NMR Research Center and Solid State and Structural Chemistry, Unit and Indian Institute of Science, Bangalore 560012, India Tel: ++91 80 22933300, Fax: ++91 80 23601550.e-mail: [email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ABBREVIATIONS TSC, Through space coupling; MD simulations, Molecular Dynamic Simulations; H-bond, Hydrogen bond; DMSO, Dimethyl sulphoxide; SI, supporting information.

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Graphical Abstract

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Engagement of CF3 Group in NâHÂ·Â·Â·FâC Hydrogen Bond in the

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