Understanding the Role of Hydrophobic Terminal in the Hydrogen

Subscriber access provided by University of Massachusetts Amherst Libraries

B: Liquids, Chemical and Dynamical Processes in Solution, Spectroscopy in Solution

Understanding the Role of Hydrophobic Terminal in the Hydrogen Bond Network of the Aqueous Mixture of 2,2,2-Trifluoroethanol: IR, Molecular Dynamics, Quantum Chemical as Well as Atoms in Molecules Studies Saptarsi Mondal, Biswajit Biswas, Tonima Nandy, and Prashant Chandra Singh J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.8b04365 • Publication Date (Web): 30 May 2018 Downloaded from http://pubs.acs.org on May 30, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Physical Chemistry

Understanding the Role of Hydrophobic Terminal in the Hydrogen Bond Network of the Aqueous Mixture of 2,2,2-Trifluoroethanol: IR, Molecular Dynamics, Quantum Chemical as well as Atoms in Molecules Studies Saptarsi Mondal, Biswajit Biswas, Tonima Nandy, Prashant Chandra Singh* Department of Spectroscopy, Indian Association for the Cultivation of Science, Kolkata. Email id: [email protected]

Abstract: The aqueous mixture of 2,2,2-Trifluoroethanol (TFE) is one of the important alcoholic solvents which has been extensively used for understanding the stability of proteins as well as several chemical reactions. In this paper, the deconvolution of the IR lines in the OH stretching region has been applied to understand the local structure of water-water, alcohol-water and alcoholalcohol interactions in the water mixture of TFE and ethanol (ETH). Further, MD simulation, quantum chemical and atoms in molecules calculations have been performed to encode the local structure information obtained from the experimental data. Addition of small amount of alcohol in the pure aqueous medium enhances the aggregation of water molecules for the case of ETH whereas, the hydrogen bond between TFE and water is dominant contributor for TFE. The –CF3 substitution changes the orientation and hydrogen bonding site of water molecules from the hydrophilic OH terminal to the hydrophobic –CF3 terminal of TFE which decreases the clustering of water molecules as well as enhances the hydrogen bonding between TFE and water . In the TFE rich region of the water mixture of TFE, fluorine of TFE molecules interacts with themselves through weak fluorous interaction which reduces the hydrogen bonding between the –CF3 of TFE and water molecules. These findings about the hydrogen bond network of the water mixture of TFE induced by the hydrophobic –CF3 group provide a stepwise explanation of the unique hydrophobic properties of the trifluoromethyl group containing pharmaceutical molecules.

1 ACS Paragon Plus Environment

The Journal of Physical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 27

Introduction 2,2,2-Trifluoroethanol (TFE) is one of the most important fluorinated alcohol which has diverse applications such as reaction medium1-3, catalysis4-6, medicinal chemistry7-8, polymer synthesis910

, separation technique11,12-16. Presence of the –CF3 group in TFE provides them useful

physicochemical properties as compared to non-fluorinated analogs. The bond length as well as dipole moment of the C-F bond is higher than C-H and the direction of dipole is opposite to C-H group. In addition, the high electronegativity and smaller size of fluorine make C-F group less polarizable than C-H. Hence, by the virtue of the distinct properties of C-F group, fluorinated molecules are extremely hydrophobic, inert as well as prefer to self-aggregate through weak fluorous (F···F) interaction.17-21 Indeed, it has been found that the aqueous mixture of TFE stabilizes the secondary structure of protein more as compared to non-fluorinated alcohols and water.15 Based on several simulations and experimental studies, it has been proposed that TFE displaces water near to proteins more as compared to non-fluorinated alcohols which enhances the probability of hydrogen bond formation between protein molecules, causing stabilization of the secondary structure of proteins.15, 22 In another study, it has been shown that molecules containing C-F group get more stabilized in TFE due to the weak fluorous interaction between C-F group of probe and TFE molecule.23-24 It has also been observed that the selectivity and yield of several reactions are increased when the reactions are performed in the aqueous mixture of TFE than non-fluorinated alcohols.4, 25 Due to these unique and important properties of the aqueous mixture of TFE, numerous theoretical and experimental studies have been performed to realize its different physical and biological properties.12,

26-31

NMR, X-ray, and neutron scattering studies have shown that the

aggregation of TFE is more than non-fluorinated alcohols in their water mixtures.32-35 Partial molar volume, density and other thermodynamic properties of the aqueous mixture of TFE show deviation from the ideal behavior. Chitra et al. performed the molecular dynamics (MD) simulation on the aqueous mixture of TFE and reproduced most of the experimental thermodynamic data and concluded that the aggregation of TFE causes deviation from the ideal behaviour.28, 36Jalili et al. studied the hydrogen bond structure of TFE-water mixture using the 2 ACS Paragon Plus Environment

Page 3 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


MD simulation and concluded that the hydrogen bond between TFE and water is broken when TFE is diluted with water.17 The aggregation of TFE in their aqueous mixture is well established, however, the extensive information about the role of hydrophobic fluorine terminal (-CF3) on the interaction with water and their effect on the hydrogen bond network is still not very clear. In this paper, we have studied the aqueous mixture of TFE and ETH using IR spectroscopy in the OH stretching region and MD simulation method to understand the role of different binding sites of alcohols in the evolution of their hydrogen bond network. The OH stretching frequency is extremely sensitive to the local hydrogen bond environment and has been used earlier to realize the hydrogen bond network of many complex liquids and their mixtures.37-40 The IR and MD studies combinedly reveal that the hydrophobic -CF3 group of TFE causes to switch of the hydrogen bonding site of water molecules from the OH to the -CF3 end of TFE which increases the O-HTFE···Ow hydrogen bond between TFE and water molecules as well as decreases the clustering of water molecules via O-Hw···Ow hydrogen bond, contrast to ETH-water mixture where clustering of water molecules dominate. The fluorous interaction between the fluorine of TFE molecules dominates in the TFE rich region which reduces the hydrogen bonding between the water and the fluorine of TFE. Methods The IR spectra of the aqueous mixtures of ETH and TFE in their OH stretching region were measured by the Fourier transformed infrared spectrometer (Nicolet iS10, ThermoFisher) working in the attenuated total reflection mode (ATR). N2 gas was flown to avoid the effect of the atmospheric vapors from the measurements. The resolution of the instrument was two cm-1. The measured IR spectra have been corrected for the ATR correction. All the experiments were performed at the room temperature (26 ± 4ºC). ETH (99.9%) and TFE (99.9%) were purchased from spectrochem (Mumbai, India) and dried using the molecular sieve prior to all measurements. In order to assure that the pure alcohols are not contaminated by moisture, we have measured the IR spectra of pure alcohols in the bending region of water. The aqueous mixtures of ETH and TFE were prepared by using the Milli-Q water (H2O, Millipore, 18.3 MΩ cm resistivity).



Page 4 of 27

MD simulation of the water mixtures of ETH and TFE were carried out using two different all atom simulation methods using GROMACS molecular dynamics simulation package.41 All atom OPLS and Amber99sb-ildn force field parameters for ETH were used as available in GROMACS topology. Water model has been described by TIP3P for OPLS force field whereas TIP5PE was used for Amber99sb-ildn force field. The OPLS force field parameters for TFE was adopted from Duffy et al. whereas Amber99sb-ildn force field was taken from Gerig et al.42 First, each trajectory was equilibrated in a NVT ensemble at 800 K for 500 ps to remove the biased dependencies on the initial configuration followed by an equilibration in NPT ensemble at 300 K temperature and 1 bar pressure for 1 ns. Further, the production run of equilibrated configuration was performed for another 5 ns in NPT ensemble at 300 K and 1 bar pressure. The temperature and pressure were kept constant using Berendsen thermostat43 with a time constant (τ) of 0.1 ps-1 and Parrinello-Rahman barostat44 with a τ of 1.0 ps-1, respectively. Particle Mesh Ewald (PME) method was used for the incorporation of the electrostatic interactions.45 Two fs time step with the periodic boundary condition was used for each MD run. Non-bonded force calculation with a grid and updated after 5 steps was used for the neighbor list generation. The neighbor list generation and van der Waal's interaction was calculated with a cut-off radius of 1.2nm. Performance of the force fields was checked by the calculation of volumetric properties (molar volume of neat liquids, partial molar volume, and excess volume of mixing), enthalpy of mixing and comparing them with the existing simulation as well as experimental results (Tables S1S15). The simulated value of density, molar volume and molar enthalpy of pure liquids using these two force fields are in well agreement with the experimental values. It can be seen that the density, partial molar volume, excess molar volume of the aqueous mixture of ETH and TFE estimated from the Amber99sb-ildn force field is closer to their respective experimental values than OPLS case. The dielectric constant of alcohol-water mixture estimated from the Amber99sb-ildn force field is in good agreement with experimental value in the water rich region of mixture whereas the OPLS force field estimates the correct dielectric constant value in the alcohol rich region of the mixture. Sign of the molar enthalpy of mixing of the ETH-water mixture has been estimated correctly by both the force fields, however, the minima has been correctly reproduced by the OPLS force field. The sign of the molar enthalpy of mixing of the TFE-water mixture has been correctly estimated by OPLS force field whereas the Amber99sb4 ACS Paragon Plus Environment

Page 5 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


ildn force field overestimates the values of molar enthalpy of mixing and provides the opposite sign. It is evident from the calculation that the volumetric properties are better estimated by the amber99sb-ildn whereas OPLS force field estimates more accurately to molar enthalpy of mixing. Nevertheless, the radial distribution function of the different interacting groups providing the information about the hydrogen bond network of the water mixtures of ETH and TFE obtained from these two force fields show the similar trend except that the aggregation of water in the alcohol rich region is higher for OPLS as compared to Amber99sb-ildn force field. B3LYP method and 6-311+G(d,p) basis set were used for the optimization of the different types of clusters of ETH-water and TFE-water in their respective bulk media. The polarizable continuum model (PCM) has been used to realize the solvent effect in the calculation. Frequency calculations of each optimized structures were performed to ensure that the optimized structures are minimum energy structure. Standard convergence criteria and frozen core approximation were used for the optimization. G09 suites of the program were used for all the calculation.46 In order to understand the nature of interaction between two groups, AIM calculations were performed.



Page 6 of 27

Results and Discussion (a) IR study and the deconvolution of the bands

Figure 1: IR spectra in the OH stretching region for different compositions of the water mixture of ETH (a) and TFE (b). The offset has been provided for the clarity. In order to find the difference in the band shape, the normalized IR spectra of ETH-water and TFE-water mixture for two different compositions in the OH stretching region with respect to the pure water have been shown (c) and (d), respectively. The change in the band shape has also been shown in the inset of (c) and (d) for the clarity of visualization.


Page 7 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


The IR spectral feature of the water mixtures of alcohol in their OH stretching region covering the range of 3000-3800 cm-1 is depicted in Figure 1. The IR spectrum of bulk water shows two peak feature centered at 3260 and 3370 cm-1 (Figure 1 a and b, red line). The origin of double peak features of water has been controversial. Some groups believe that the spectral feature ~3200 cm-1 belong to water molecules in the symmetrical tetrahedral hydrogen bond network and the peak at 3370 cm-1 is assigned to the asymmetric tetrahedral hydrogen bonded network.36 In contrast, other groups believe that the double peak feature of water originates due to the Fermi resonance between the stretching and bending modes of the water molecules.38,

40

Bulk ETH

shows broad single IR peak at 3330 cm-1 (Figure 1 a, dark yellow) which depicts the absence of Fermi resonance in bulk ETH. Bulk TFE shows a broad IR peak centered ~3341 cm-1 along with a comparatively narrow band feature ~3634 cm-1 (Figure 1 b, brown line). In our previous study, the broad IR feature below 3600 cm-1 has been assigned to the different size of OHTFE···OTFE hydrogen bonded clusters of TFE and the narrow feature at the high frequency region of OH spectrum (~3634 cm-1) has been attributed to the O-HTFE···FTFE interaction mainly originating from the dimer and trimer of TFE clusters.47 The IR feature of bulk TFE ~3634 cm-1 is relatively broad as well as slightly red shifted than the IR spectrum of TFE in the isolated gas phase (~3651cm-1) which also justify the assignment of this band to the weakly hydrogen bonded O-HTFE···FTFE species (Figure S1).48 The IR spectrum of TFE is broad and blue shifted than ETH suggesting that the average hydrogen bond strength of bulk TFE is less than bulk ETH. In fact, the significant number of O-HTFE···FTFE interaction appears at the cost of O-HTFE···OTFE in the bulk TFE which decreases the average hydrogen bond strength of bulk TFE. The hydrogen bond among different species of alcohol-water mixture competes throughout different compositions which determine the shape of IR spectra in the OH stretching region. To discuss the role of all contributors in the IR spectra, the aqueous mixture of alcohols have been divided into three regions: a) water rich region (Xw > 0.80), b) intermediate region (0.80 ≥ Xw ≥ 0.20), c) alcohol rich region (Xw

Understanding the Role of Hydrophobic Terminal in the Hydrogen

Recommend Documents