The role of fluorocarbon group in the hydrogen bond network, photophysical and solvation dynamics of fluorinated molecules

https://doi.org/10.1016/j.jfluchem.2019.109414Get rights and content

Abstract

Fluorinated molecules have been used extensively in pharmaceutical, chemical and polymer industries. Indeed, the presence of fluorine provides unique but important physicochemical properties to the fluorinated molecules. In this review, we have discussed the effects of fluorine on the hydrogen bond network, photophysical and solvation behavior of the fluorinated molecules which have been obtained by the state of art spectroscopic and molecular dynamics simulation techniques. The substitution of fluorine in alcohols reorganizes the hydrogen bond network in its aqueous mixture by changing the orientation of water from its hydrophilic to the hydrophobic terminal. The fluorous (F···F) interaction has been found to affect photophysical and solvation properties of the fluorinated molecules significantly. The solvation time scale of the fluorinated molecules gets slower due to the fluorous interaction between probe and solvent molecules. The understanding of the role of fluorine on the hydrogen bond network, photophysical and solvation properties can be useful for the stepwise justification of the unique physicochemical properties of fluorinated molecules.

Introduction

Molecules containing fluorine possess unique but important physicochemical properties due to its small size and most electronegative nature [[1], [2], [3], [4], [5]]. The bond length of Csingle bondF group (1.35 Å) is longer as compared to Csingle bondH group (1.09 Å). The dipole moment of Csingle bondF group is higher (1.85 Debye) than its Csingle bondH analogue (0.3 Debye) due to the high electronegativity of fluorine. The direction of the dipole moment of Csingle bondF group is opposite to Csingle bondH group [6]. The strength of Csingle bondF group is 14 kcal/ mol higher than Csingle bondH group [2,6].

The unique properties of fluorine containing molecules have been utilized extensively in the development of medicines [7,8] and agrochemicals [[9], [10], [11]]. Fluorine containing drug molecules are regularly being used in the treatment of central nervous system and oncology [[12], [13], [14], [15], [16], [17], [18], [19], [20], [21]]. Indeed, it has been shown that fluorinated solvents can serve as artificial blood substitutes for the patients having cancer-induced anemia and hypoxia [[22], [23], [24], [25], [26]]. Extensive research has been devoted for the development of fluorine containing drug molecules as it enhances the biological activity, metabolic, and binding affinity to protein [21]. The substitution of fluorine alters the physicochemical properties by affecting the chemical reactivity, stability of neighboring functional groups, pKa and dipole moment. Fluorination of drug molecules modulates the lipophilicity, acidity and decreases the conformational bias causing increase in the drug penetration inside the nucleus and thereby improving their pharmacological properties [[27], [28], [29]]. Importance of fluorine substituted drug molecules can be noticed with the monotonic increase in the number of fluorinated molecules used either for clinical trials or approved for the cure of several diseases. Indeed, the best selling drug molecules in the market mostly contain fluorine [30,31]. Moreover, fluorinated molecules have also been used for the 19F based contrasting agents for magnetic resonance imaging which is a very useful technique for the medical intervention [[32], [33], [34], [35], [36]].

Apart from the drug development, fluorinated molecules have been used extensively as polymers [37,38], reaction media [[39], [40], [41], [42], [43], [44], [45]], catalyst [4,[46], [47], [48], [49]] and in separation techniques [50]. Fluorinated polymers depict spectacular thermal and chemical resistance, low friction coefficients which makes them useful for several applications such as biomedicines, artificial muscle actuators, microfluidics and in tissue engineering [[51], [52], [53], [54], [55], [56], [57], [58], [59], [60]]. Fluorinated solvents have been used vigorously in organic reactions to increase the selectivity and yield of the product [[61], [62], [63]]. Fluorocarbon substituted amino acids have been used in protein engineering to understand the increased stability of protein induced by fluorocarbon group [[64], [65], [66], [67], [68], [69]].

Fluorinated amino acid analogues have been successfully engineered into proteins in order to understand the water–protein interaction which controls many processes such as enzyme catalysis, unfolding and interaction with other molecules [[70], [71], [72], [73]]. Zewail and co-workers had studied the effect of side chain volume and fluorination on solvation dynamics by the incorporation of 5, 5, 5- trifluroroleucine in place of leucine in a protein. It was concluded that fluorination of amino acid causes to generate electrostatic force on proximal water molecules which in turn slow down the motion of water on the protein surface resulting in slower solvation dynamics [74]. In other studies, the tryptophan of monellin was replaced by 5-fluoro tryptophan to understand the contribution of the pseudo-time dependent fluorescence Stokes shift in the solvation time scale [75]. It was found that the higher electron affinity of 5-fluoro tryptophan suppresses the electron transfer quenching significantly as compared to the tryptophan due to which the solvation time scale of 5-fluorotryptophan is dominated by relaxation rather than pseudo-time dependent fluorescence Stokes shift. Krishnamoorthy and co-workers have shown that the replacement of tryptophan with 5-fluorotryptophan decreases the lifetime heterogeneity in proteins [76]. In another study, the activity of bovine pancreatic trypsin inhibitor was investigated by replacing the noncanonical amino acids of inhibitor with fluorinated ones [[77], [78], [79]]. It was found that fluorine of the trypsin inhibitor combines with water molecules and restores the inhibitory activity to a mutant having corresponding hydrocarbon chain at the same site. Meech and coworkers investigated the spectroscopic properties of fluorine substituted chromophore of the green fluorescent protein and found that the substitution of fluorine causes barrier less proton transfer in the excited state of the chromophore of green fluorescent protein [80,81]. It is apparent that the substitution of fluorine enables to understand several complex biological phenomena such as water-protein interaction, enzymatic activity and excited state properties of proteins.

Hydrocarbon and fluorocarbon, both are hydrophobic in nature, however, the physicochemical properties fluorocarbon is distinctly different. Hence, it is plausible that fluorine affects the surrounding (solute or solvents) differently from the hydrocarbon. However, not much information is available on the role of fluorocarbon on the effect of surroundings such as modification of the hydrogen bond network, photophysical properties and solvation time scale of the fluorinated molecules which can lead them to show the unusual but important physicochemical properties. The change in the hydrogen bond network [[82], [83], [84]], photophysical properties and solvation time is directly correlated with the physicochemical properties of the fluorinated molecules [85,86]. In this review, we have discussed the role of Csingle bondF group of fluorinated molecules in the modification of the hydrogen bond network, photophysical properties and solvation time scale of fluorine containing molecules.

Section snippets

Methods

Alcoholic solvents namely, ethanol (ETH), 2-fluoroethanol (monofluoroethanol, MFE), 2,2-difluoroethanol (DFE) and 2,2,2,-trifluoroethanol (TFE) were procured from spectrochem. The probe molecules, coumarin 6H (C6H), coumarin 480 (C480) and coumarin 153 (C153) were purchased form Sigma Aldrich. Milli-Q water (H2O, Millipore, 18.3 MΩ cm resistivity) was used for the preparation of the aqueous mixture of alcohols.

Thermo Fisher Scientific (Evolution 201) UV-Vis spectrometer was used for the

Role of fluorocarbon group in the hydrogen bond network of the bulk fluorinated alcohols

The IR spectrum of ETH shows a single peak feature centered at ∼3300 cm-1 (Fig. 1a) which become broader and blue shifted on the fluorination as evident from the IR peak of MFE and TFE (Fig. 1 b and c). Interestingly, MFE shows an additional feature at 3580 cm-1, whereas, it appears for TFE at 3620 cm-1. The appearance of broad feature and blue shift in the central peak position of the IR spectra of fluorinated alcohols suggest that the presence of inhomogeneous hydrogen-bond network weakened

Role of fluorocarbon group in the hydrogen bond network of the aqueous mixture of bulk fluorinated alcohols

Fig. 4 shows the IR spectra of different mole fraction of the aqueous mixture of ETH and MFE in their OH stretching region. The spectral feature of the aqueous mixture of alcohols have been divided in three different regions (1) water rich (0.97 ≥ χw ≥ 0.83) (2) intermediate (0.70 ≥ χw ≥ 0.25) (3) alcohol rich (χw ≤ 0.25). The IR spectrum of water is broad with double peak feature in the OH stretching region covering the range of 3000−3800 cm-1. The IR feature of water were deconvoluted into

Role of fluorous interaction in the photophysical and solvation properties of fluorinated molecules

In the above sections, the role of the fluorocarbon group in the reorganization of the hydrogen bond network of solvents (fluorinated alcohols) and its aqueous mixtures was discussed. The role of fluorocarbon group in the photophysical and solvation properties of probe molecules is equally important as it facilitates them unique properties. To understand the role of fluorocarbon group in the photophysical properties of fluoro group containing molecules, three prototypical coumarin dye molecules

Role of fluorous interaction in the solvation properties of fluorinated molecules

In order to realize the role of fluorocarbon group in the solvation properties, the solvent correlation time C (t) of C6H and C153 was measured in ETH, MFE and TFE solvents. The C (t) of both the dyes in all solvents shows three components (as shown in Table 1) of which first two fast components originate due to the inertial nature of solvent (liberation and hindered motion), whereas, the slow component arises due to the diffusive motion (viscosity of the solvent and solute–solvent interaction)

Conclusion

The presence of Osingle bondH⋯F hydrogen bond in fluorinated alcohols decreases the average hydrogen bond strength than nonfluorinated alcohol, hence, the IR spectra of the bulk alcohol gets blue shifted with the substitution of fluorine. The experimental and simulation studies reveal that the substitution of a single fluorine on the alcohol decreases the clustering of water molecules via Osingle bondHMFE⋯Ow in their aqueous mixture by moving some of water molecules from the hydrophilic OH site to the hydrophobic

Acknowledgements

This work is supported partially by the research grants provided by the Council of Scientific and Industrial Research (CSIR) [Grant No. 01(2803)/14/EMR-II] and Department of Science and Technology (DST-SERB) [Grant No. EMR/2015/001605] India. Thanks are also acknowledged to the CRAY facility of IACS for the MD simulations and CSIR-India for the fellowship to BB.

References (119)

  • N. Johari et al.

    The effect of fluorine content on the mechanical properties of poly (ε-caprolactone)/nano-fluoridated hydroxyapatite scaffold for bone-tissue engineering

    Ceram. Int.

    (2011)
  • J.A. Brydson

    Chapter 13 - Fluorine-containing polymers

  • J.G. Drobny

    Chapter 14 - Fluorine-containing polymers

  • L.W. McKeen

    Chapter 11 - Fluoropolymers

  • A. Meskini et al.

    Dielectric behaviour of copolymers based on 2,2,2-trifluoroethyl methacrylate and cyano co-monomers

    Eur. Polym. J.

    (2009)
  • W. Yao et al.

    Fluorinated poly(meth)acrylate: synthesis and properties

    Polymer

    (2014)
  • S. Khaksar

    Fluorinated alcohols: a magic medium for the synthesis of heterocyclic compounds

    J. Fluorine Chem.

    (2015)
  • R. Pongdee et al.

    Elucidation of enzyme mechanisms using fluorinated substrate analogues

    Bioorg. Chem.

    (2004)
  • S.P. Laptenok et al.

    Photoacid behaviour in a fluorinated green fluorescent protein chromophore: ultrafast formation of anion and zwitterion states

    Chem. Sci.

    (2016)
  • S. Mondal et al.

    A combined molecular dynamics simulation, atoms in molecule analysis and IR study on the biologically important bulk fluorinated ethanols to understand the role of weak interactions in their cluster formation and hydrogen bond network

    J. Mol. Liq.

    (2017)
  • R.S. Fee et al.

    Estimating the time-zero spectrum in time-resolved emmsion measurements of solvation dynamics

    Chem. Phys.

    (1994)
  • D. Frenkel et al.

    Chapter 8 - the gibbs ensemble

  • B. Biswas et al.

    Combined molecular dynamics, atoms in molecules, and IR studies of the bulk monofluoroethanol and bulk ethanol to understand the role of organic fluorine in the Hydrogen bond network

    J. Phys. Chem. A

    (2017)
  • E. Clot et al.

    Csingle bondF and Csingle bondH bond activation of fluorobenzenes and fluoropyridines at transition metal centers: how fluorine tips the scales

    Acc. Chem. Res.

    (2011)
  • R.A. Cormanich et al.

    The seeming lack of CFtriple bondHO intramolecular hydrogen bonds in linear aliphatic fluoroalcohols in solution

    Phys. Chem. Chem. Phys.

    (2014)
  • M. Heger et al.

    From hydrogen bond donor to acceptor: the effect of ethanol fluorination on the first solvating water molecule

    Phys. Chem. Chem. Phys.

    (2013)
  • R.E. Rosenberg

    Microsolvation of fluoromethane

    J. Phys. Chem. A

    (2016)
  • M.E. Evans et al.

    Energetics of Csingle bondH bond activation of fluorinated aromatic hydrocarbons using a [Tp′Rh(CNneopentyl)] complex

    J. Am. Chem. Soc.

    (2009)
  • H.-J. Böhm et al.

    Fluorine in medicinal chemistry

    ChemBioChem

    (2004)
  • K. Müller et al.

    Fluorine in pharmaceuticals: looking beyond intuition

    Science

    (2007)
  • D. Cartwright

    Recent developments in fluorine-containing agrochemicals

  • F. Menaa et al.

    Importance of fluorine and fluorocarbons in medicinal chemistry and oncology

    J. Mol. Pharm. Org. Process Res.

    (2013)
  • P. Flamen et al.

    Additional value of whole-body positron emission tomography with fluorine-18-2-fluoro-2-deoxy-d-glucose in recurrent colorectal cancer

    J. Clin. Oncol.

    (1999)
  • G. Antoch et al.

    Accuracy of whole-body dual-modality Fluorine-18–2-Fluoro-2-Deoxy-d-Glucose positron emission tomography and computed tomography (FDG-PET/CT) for tumor staging in solid tumors: comparison with CT and PET

    J. Clin. Oncol.

    (2004)
  • K. Spaepen et al.

    Prognostic value of positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose ([18F]FDG) after first-line chemotherapy in non-Hodgkin’s lymphoma: is [18F]FDG-PET a valid alternative to conventional diagnostic methods?

    J. Clin. Oncol.

    (2001)
  • E.P. Gillis et al.

    Applications of fluorine in medicinal chemistry

    J. Med. Chem.

    (2015)
  • R.J. Boohaker et al.

    The use of therapeutic peptides to target and to kill cancer cells

    Curr. Med. Chem.

    (2012)
  • P. Shah et al.

    The role of fluorine in medicinal chemistry

    J. Enzyme Inhib. Med. Chem.

    (2007)
  • J. Bauer et al.

    Perfluorocarbon-filled poly(lactide-co-gylcolide) nano- and microcapsules as artificial oxygen carriers for blood substitutes: a physico-chemical assessment

    J. Microencapsul.

    (2010)
  • F. Menaa et al.

    Development of carbon-fluorine spectroscopy for pharmaceutical and biomedical applications

    Faraday Discuss.

    (2011)
  • K.C. Lowe

    Engineering blood: synthetic substitutes from fluorinated compounds

    Tissue Eng.

    (2003)
  • C. Heidelberger et al.

    Fluorinated pyrimidines, a new class of tumour-inhibitory compounds

    Nature

    (1957)
  • R.J. Kaufman

    Perfluorochemical emulsions as blood substitutes

  • Y. Zhou et al.

    Next generation of fluorine-containing pharmaceuticals, compounds currently in phase II–III clinical trials of major pharmaceutical companies: new structural trends and therapeutic areas

    Chem. Rev.

    (2016)
  • M. Salwiczek et al.

    Fluorinated amino acids: compatibility with native protein structures and effects on protein–protein interactions

    Chem. Soc. Rev.

    (2012)
  • S. Purser et al.

    Fluorine in medicinal chemistry

    Chem. Soc. Rev.

    (2008)
  • J. Wang et al.

    Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001–2011)

    Chem. Rev.

    (2014)
  • I. Ojima

    Exploration of fluorine chemistry at the multidisciplinary interface of chemistry and biology

    J. Org. Chem.

    (2013)
  • M.S. Fox et al.

    Fluorine-19 MRI contrast agents for cell tracking and lung imaging

    Magn. Reson. Insights

    (2016)
  • C. Fu et al.

    Enhanced performance of polymeric 19F MRI contrast agents through incorporation of highly water-soluble monomer MSEA

    Macromolecules

    (2018)
  • View full text