HFIP Molecules Research Articles

Trp-cage-1,1,1,3,3,3-Hexafluoro-2-propanol-Water Interactions in a Nanosphere at 298 K.

MD simulations of the peptide Trp-cage dissolved in a solvent composed of 28% 1,1,1,3,3,3-hexafluoroisopropanol-water and contained within a nanosphere of 4.2 nm radius are described. To provide a thermal buffer, the nanosphere is submerged in a collection of liquid neopentane molecules, modeled as united atoms. It was found that the HFIP-water mixture demixes when confined under these conditions, with most of the fluoroalcohol becoming strongly associated with the walls of the nanosphere. The remaining HFIP interacts with the peptide and itself in the interior of the nanoshell. Diffusion of HFIP molecules near the surface of the nanoshell is limited, taking place over a small volume, while diffusion of the fluoroalcohol in the center of the nanoshell is more wide-ranging. By contrast, diffusion of the water in the solvent mixture appears to take place equivalently throughout the shell. The conformation of the peptide, distribution of solvent components around it, and the number and duration of the contacts with solvent molecules are calculated and contrasted to results previously reported for the bulk (non-nanocontained) system.

Examination of Interactions of Hexafluoro-2-propanol with Trp-Cage in Hexafluoro-2-propanol-Water by MD Simulations and Intermolecular Nuclear Overhauser Effects.

All-atom molecular dynamic simulations of the peptide Trp-cage in 30% hexafluoro-2-propanol- water (V/V) at 278 K have been carried out with the goal of exploring peptide hydrogen-solvent fluorine nuclear spin cross relaxation. Force field parameters for HFIP reported by Fioroni et al. along with the fluorine parameters of the TFE5 model reported by this lab were used. Water was represented by the TIP5P-Ew model. Peptide modeling used the AMBER99SB-ILDN force field. Translational diffusion coefficients of solution components at 278 K were predicted to within 35% of experimental values using these parameter sets. The simulations indicate that the solvent mixture is not homogeneous, with HFIP molecules clustered into aggregates as large as 53 fluoroalcohol molecules. The solvent environment of surface atoms of Trp-cage fluctuates between being HFIP-rich and more water-rich about every 10 ns. In accord with previous studies by other groups, the average concentration of HFIP near the surface of the peptide is significantly enhanced over the concentration of HFIP in the bulk solvent. In the simulations, ∼7% of the initial contacts between HFIP molecules and Trp-cage develop into peptide-fluoroalcohol interactions that persist for times as long as 8 ns. Most of the available experimental nuclear spin cross-relaxation rates (ΣHF) for hydrogens of the Trp-cage in 30% HFIP-water are reproduced from the MD trajectories to within uncertainties of the experimental data and the simulations. However, a few calculated ΣHF values for hydrogens of the Trp-cage do not agree with experiment. These tend to be situations where long-lived peptide-HFIP interactions are predicted. The disagreements between observed and calculated ΣHF in these instances signal defects in the modeling parameters and procedures that are presently unrecognized.

Conformational change of L-phenylalanine in fluorinated alcohol-water mixed solvents studied by IR, NMR, and MD simulations

To clarify the unique solvation properties of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) on a biomolecule of L-phenylalanine (Phe), the solvation structure of Phe in HFIP-water mixed solvents at 70 mmol dm−3 has been observed over the entire range of HFIP mole fraction xHFIP using infrared (IR), 1H and 13C NMR techniques with a help of molecular dynamics (MD) simulation. The solvation structure of Phe in the HFIP solvents has been compared with that in 2-propanol (2-PrOH)-water mixed solvents and the structure of L-leucine (Leu) in both alcohol-water mixed solvents previously reported. The results from IR, NMR, and MD simulations showed that water molecules hydrogen-bonded with the Phe carboxylate group are gradually replaced by HFIP with increasing xHFIP. In contrast, the replacement of water molecules by HFIP on the Phe aminium group does not easily take place. These findings arise from the high electron acceptability and the very low electron donicity of the HFIP hydroxyl group due to the electron drawing of the six fluorine atoms. In the 2-PrOH solutions, the replacement of water on the carboxylate group by 2-PrOH less easily occurs with increasing x2-PrOH compared to HFIP because of the lower electron acceptability of 2-PrOH. The solvation for the Phe hydrophilic parts is similar to that of Leu. The most significant difference between HFIP and 2-PrOH was observed for the solvation of the Phe phenyl group. The hydrophobic hydration shell around the phenyl group is collapsed with increasing alcohol content in both alcohol solutions. Instead of water, the HFIP fluorine atoms significantly interact with the phenyl hydrogen atoms, whereas 2-PrOH molecules do not markedly approach the hydrogen atoms. The conformational change of Phe molecule against the dihedral angle of Cγ-Cβ–Cα-COO− takes place with increasing HFIP content, but does not with the increase in 2-PrOH. This is attributed to the steric hindrance between the large phenyl group and the carboxylate group remarkably solvated by HFIP molecules.

Cosolvent Impurities in SWCNT Nanochannel Confinement: Length Dependence of Water Dynamics Investigated with Atomistic Simulations.

The advent of nanotechnology has seen a growing interest in the nature of fluid flow and transport under nanoconfinement. The present study leverages fully atomistic molecular dynamics (MD) simulations to study the effect of nanochannel length and intrusion of molecules of the organic solvent, hexafluoro-2-propanol (HFIP), on the dynamical characteristics of water within it. Favorable interactions of HFIP with the nanochannels comprised of single-walled carbon nanotubes traps them over time scales greater than 100 ns, and confinement confers small but distinguishable spatial redistribution between neighboring HFIP pairs. Water molecules within the nanochannels show clear signatures of dynamical slowdown relative to bulk water even for pure systems.The presence of HFIP causes further rotational and translational slowdown in waters when the nanochannel dimension falls below a critical length of 30 Å. The enhanced slowdown in the presence of HFIP is quantified from characteristic relaxation parameters and diffusion coefficients in the absence and presence of HFIP. It is finally seen that the net flow of water between the ends of the nanochannel shows a decreasing dependence with nanochannel length only when the number of HFIP molecules is small. These results lend insights into devising ways of modulating solvent properties within nanochannels with cosolvent impurities.

Solvation power of HFIP for the hydrophilic and the hydrophobic moieties of l-leucine studied by MD, IR, and NMR techniques

Abstract The solvation properties of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) in its aqueous binary solvents have been evaluated using l -leucine (Leu) as a probe molecule by both theoretical and experimental approaches. Thus, molecular dynamics (MD) simulations, infrared (IR) and 1 H and 13 C NMR spectroscopic experiments have been conducted on Leu-HFIP-water solutions with varying the HFIP mole fraction from x HFIP = 0 to 1. Spatial distribution functions (SDFs) obtained from the MD simulations showed that the Leu carboxylate group is gradually solvated by HFIP molecules with increasing x HFIP , instead of water molecules. Thus, the replacement of water by HFIP for the carboxylate group progresses as the x HFIP rises. This was proved by the C O stretching vibrations and the 13 C chemical shift of the carboxylate group. On the contrary, the Leu aminium group is preferentially solvated by water below x HFIP = 0.7. However, HFIP molecules begin to solvate the aminium group above this mole fraction. The trifluoromethyl groups of HFIP significantly enclose the alkyl group of Leu even at the low x HFIP . By surrounding the Leu alkyl group with the HFIP trifluoromethyl groups, the C H stretching vibrations of Leu blueshift with increasing x HFIP . Simultaneously, the hydrogen and carbon atoms of the Leu alkyl group are electronically shielded as the x HFIP rises. The MD pair correlation function g ( r ) HCLeu-FHFIP showed the H F interactions between the Leu alkyl hydrogen and the HFIP fluorine atoms with the distance of 2.75 A. Consequently, the present results proved that the HFIP trifluoromethyl groups may interact with the Leu alkyl group through the blueshift hydrogen bonds of C H ⋯ F C.

A Study of the Solvation Structure of L-Leucine in Alcohol-Water Binary Solvents through Molecular Dynamics Simulations and FTIR and NMR Spectroscopy.

The solvation structures of l-leucine (Leu) in aliphatic-alcohol-water and fluorinated-alcohol-water solvents are elucidated for various alcohol contents by using molecular dynamics (MD) simulations and IR, and (1) H and (13) C NMR spectroscopy. The aliphatic alcohols included methanol, ethanol, and 2-propanol, whereas the fluorinated alcohols were 2,2,2-trifluoroethanol and 1,1,1,3,3,3-hexafluoro-2-propanol. The MD results show that the hydrophobic alkyl moiety of Leu is surrounded by the alkyl or fluoroalkyl groups of the alcohol molecules. In particular, TFE and HFIP significantly solvate the alkyl group of Leu. IR spectra reveal that the Leu C-H stretching vibration blueshifts in fluorinated alcohol solutions with increasing alcohol content, whereas the vibration redshifts in aliphatic alcohol solutions. When the C-H stretching vibration blueshifts in the fluorinated alcohol solutions, the hydrogen and carbon atoms of the Leu alkyl group are magnetically shielded. Consequently, TFE and HFIP molecules may solvate the Leu alkyl group through the blue-shifting hydrogen bonds.

Solvation of the Amphiphilic Diol Molecule in Aliphatic Alcohol−Water and Fluorinated Alcohol−Water Solutions

We investigated the solvation properties of aqueous solutions of aliphatic alcohols and fluorinated alcohols. These included ethanol (EtOH), 2-propanol (2-PrOH), 2,2,2-trifluoroethanol (TFE), and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP). The amphiphilic diol, 1,4-pentanediol (1,4-PD), was used as the solute to probe solvation properties at the molecular level. Small-angle neutron scattering (SANS) experiments revealed that the inherent microheterogeneity of HFIP-water binary solutions was significantly enhanced by addition of 1,4-PD. In contrast, the addition of 1,4-PD to EtOH-, 2-PrOH-, and TFE-water solutions hardly changed the mixing state. Molecular dynamics simulations were used to obtain the spatial distribution functions for the oxygen atom of water molecules and the carbon and fluorine atoms of alcohol molecules around 1,4-PD. Of the alcohols studied, these spatial distributions illustrated that HFIP molecules formed the strongest hydrophobic solvation shell around the hydrocarbons of 1,4-PD. This preferential solvation of 1,4-PD by HFIP leads to enhancement of HFIP clusters in the solutions. (13)C NMR and infrared spectroscopic measurements on 1,4-PD in the different alcohol-water solutions suggested that the number of water molecules around the hydrocarbons of 1,4-PD decreased in aliphatic alcohol-water solutions. Additionally, HFIP molecules are thought to strongly interact with the hydrocarbons of 1,4-PD in HFIP-water solutions.

Structure of hexafluoroisopropanol–water mixture studied by FTIR-ATR spectra and selected chemometric methods

The FTIR spectra of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP)–water binary solutions have been obtained by means of attenuated total internal reflection (ATR) spectroscopy. The spectral properties of the system have been analyzed as a function of alcohol concentration by following methods: multivariate curve resolution based on alternating least-square procedure (MCR-ALS) preceded by evolving factor analysis (EFA), kernel analysis, and two-dimensional (2D) correlation spectroscopy. From all the information obtained by these methods the four-component model describing the aggregation of HFIP and water molecules in HFIP–water mixtures was proposed. In characterization of properties of the components not only changes in the aggregation process were taken into account but also variations in relative population of different HFIP conformations were considered. The case reported is a very good example to show how the MCR-ALS and 2D analysis could complement each other, leading to enhancement of the multicomponent data interpretation.

Peptide α/310-Helix Dimorphism in the Crystal State

The fully Cα-methylated homo-peptide Ac-[l-(αMe)Val]7-NHiPr is completely 310-helical when its crystals are grown from a methanol solution, whereas it is α-helical when crystallized from HFIP (1,1,1,3,3,3-hexafluoropropan-2-ol), thus providing an example of a solvent-driven α/310-helix dimorphism in the crystal state. The interactions of cocrystallized HFIP molecules with the peptide in the α-helical structure are reported.

Dramatic Acceleration of Olefin Epoxidation in Fluorinated Alcohols: Activation of Hydrogen Peroxide by Multiple H-Bond Networks

In 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as solvent, the epoxidation of olefins by hydrogen peroxide is accelerated up to ca. 100 000-fold (relative to that in 1,4-dioxane as solvent). The mechanistic basis of this effect was investigated kinetically and theoretically. The kinetics of the epoxidation of Z-cyclooctene provided evidence that higher-order solvent aggregates (rate order in HFIP ca. 3) are responsible for the rate acceleration. Activation parameters (DeltaS++ = -39 cal/mol.K) indicated a highly ordered transition state in the rate-determining step. In line with these findings, DFT simulations revealed a pronounced decrease of the activation barrier for oxygen transfer from H(2)O(2) to ethene with increasing number of (specifically) coordinated HFIP molecules. The oxygen transfer was unambiguously identified as a polar concerted process. Simulations (combined DFT and MP2) of the epoxidation of Z-butene were in excellent agreement with the experimental data obtained in the epoxidation of Z-cyclooctene (activation enthalpy, entropy, and kinetic rate order in HFIP of 3), supporting the validity of our mechanistic model.

Kinetic Studies of Olefin Epoxidation with Hydrogen Peroxide in 1,1,1,3,3,3‐Hexafluoro‐2‐propanol Reveal a Crucial Catalytic Role for Solvent Clusters

AbstractThe epoxidation of cyclooctene and 1‐octene with hydrogen peroxide was studied kinetically in HFIP (1,1,1,3,3,3‐hexafluoro‐2‐propanol)/1,4‐dioxane mixtures. In the case of cyclooctene, no additional catalyst was applied, whereas the epoxidation of 1‐octene was run in the presence of phenylarsonic acid as catalyst. For both reaction types, two kinetic regimes can be distinguished: at low HFIP concentration (nHFIP/ntotal≤0.15), both the catalyzed and the uncatalyzed reaction show first order dependence on the HFIP concentration. This result is interpreted by the HFIP “charge template” for the uncatalyzed epoxidation (as postulated by Shaik and Neumann) and by the formation of an arsonic acid mono‐HFIP ester for the catalyzed reaction. At high HFIP concentration (nHFIP/ntotal≥0.5), both reaction types are up to ca. 5 orders of magnitude faster and show ca. 12th order dependence on the HFIP concentration. We propose that the dramatic accelerations observed at high HFIP concentrations are brought about by HFIP clusters. Based on literature data (Fioroni, Roccatano, Hong, Suhm), it is concluded that the epoxidation reactions studied here take place in a HFIP coordination sphere comprising ca. 12 HFIP molecules, and that this coordination sphere effects the enormous increases in epoxidation rates. This mechanistic model bears resemblance to enzymatic reactions taking place in and being catalyzed by a protein matrix.

Structure and dynamics of hexafluoroisopropanol-water mixtures by x-ray diffraction, small-angle neutron scattering, NMR spectroscopy, and mass spectrometry

The structure and dynamic properties of aqueous mixtures of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) have been investigated over the whole range of HFIP mole fraction (xHFIP) by large-angle x-ray scattering (LAXS), small-angle reutron scattering (SANS), F19-, C13-, and O-NMR17 chemical shifts, O-NMR17 relaxation, and mass spectrometry. The LAXS data have shown that structural transition of solvent clusters takes place at xHFIP∼0.1 from the tetrahedral-like hydrogen bonded network of water at xHFIP⩽∼0.1 to the structure of neat HFIP gradually formed with increasing HFIP concentration in the range of xHFIP⩾0.15. The Ornstein–Zernike plots of the SANS data have revealed a mesoscopic structural feature that the concentration fluctuations become largest at xHFIP∼0.06 with a correlation length of ∼9 Å, i.e., maximum in clustering and microhetrogeneities. The F19 and C13 chemical shifts of both CF3 and CH groups of HFIP against xHFIP have shown an inflection point at xHFIP∼0.08, implying that the environment of HFIP molecules changes due to the structural transition of HFIP clusters. The O17 relaxation data of water have shown that the rotational motion of water molecules is retarded rapidly upon addition of HFIP into water up to xHFIP∼0.1, moderately in the range of ∼0.1<xHFIP≲0.3, and almost constant at xHFIP≳0.3, reflecting the structural change in the solvent clusters at xHFIP∼0.1. The mass spectra of cluster fragments generated in vacuum from HFIP-water mixtures have shown that the predominant clusters are A1Wn (n<12, A=HFIP, W=water) and water clusters Wn (n=5–8) at xHFIP=0.09 and 0.20 and only HFIP oligomers in a water-rich region of xHFIP=0.005∼0.01. From all the information obtained in the present study, the models are proposed for the aggregation of HFIP and water molecules in HFIP-water mixtures.

Clustering of Fluorine-Substituted Alcohols as a Factor Responsible for Their Marked Effects on Proteins and Peptides

Among various alcohols, those substituted with fluorine, such as 2,2,2-trifluoroethanol (TFE) or 3,3,3,3‘,3‘,3‘-hexafluoro-2-propanol (HFIP), have a marked potential to induce the formation of α-helical structures in peptides and to denature the native structures of proteins. However, the mechanism by which these alcohols exert their effects is unknown. Melittin, a bee venom peptide, is unfolded in the absence of alcohol, but is transformed to an α-helical structure upon addition of alcohols. On the other hand, addition of alcohols to β-lactoglobulin, a predominantly β-sheet protein, denatures the molecule and transforms it to an α-helical structure. We examined the role of several factors in these alcohol-induced transitions, i.e., relative dielectric constant, strength of hydrogen bond estimated by the pH titration of salicylic acid, and clustering of alcohol molecules measured by solution X-ray scattering. Although relative dielectric constant and hydrogen bond strength were confirmed to be important, they did not explain the marked effects of TFE and HFIP. X-ray scattering detected clusters of TFE or HFIP molecules in alcohol/water mixtures with a maximum at around 30% (v/v) of each alcohol. When the conformational transitions induced by TFE and HFIP were plotted against the extent of cluster formation by the corresponding alcohol/water mixtures, the TFE and HFIP-induced transition curves agreed with each other for both melittin and β-lactoglobulin. This suggests that clustering of alcohol molecules is an important factor that enhances the effects of alcohols on proteins and peptides.