Investigating the influence of fluorination on hydrogen bonding properties of functional groups
Lead Research Organisation:
University of Southampton
Department Name: Sch of Chemistry
Abstract
Fluorination of organic molecules is a widespread tactic to improve molecular properties in many areas, and hydrogen bonding is the most important non-covalent intermolecular interaction. This project aims to undertake a thorough investigation of the effects of fluorination on hydrogen-bonding properties of alcohol and amine (ammonium) functional groups, with as ultimate aim the provision of predictive tools in which these properties can be calculated for functional groups as part of a multifunctional substrate. This is important as the influence of fluorination on hydrogen bonding properties of functional groups is not straightforward: our first results have shown that fluorine introduction next to alcohols can lead to an increase as well as a decrease of the alcohol hydrogen bond donating capacity, clearly demonstrating a crucial importance of the relative configuration and position.
For each functional group, a set of specifically designed model compounds is proposed that allows the investigation of particular effects of fluorination on the hydrogen bonding properties. For this purpose, conformationally constrained compounds that allow for singling out a particular effect will be investigated first. In a second stage, conformationally flexible model compounds containing different relative stereochemistries will be evaluated as well. These compounds will be synthesised, followed by experimental determination of hydrogen bonding properties.
The prediction of H-bond properties of functional groups will be achieved by theoretical calculation of a suitable molecular descriptor, which will then be correlated with the experimentally obtained values to create a set of Linear Free Energy Relationships (one for each hydrogen bond property). Part of the model compounds aim to evaluate subtle substituent effects, which, if successfully predicted, will be viewed as important test cases for the accuracy of our predictive tool for polyfunctional substrates.
Thorough conformational, NBO and AIM analyses will be employed to aid the rationalisation of the observed effects. This will lead to the establishment of a set of rules or guidelines describing how fluorination influences H-bond properties of the abovementioned functional groups, which will further increase our understanding of the effects of fluorination.
Where feasible, the hydrogen bonding characteristics will be compared with experimental lipophilicity and pKa (pKa(H)) values, both of which are important molecular properties.
For each functional group, a set of specifically designed model compounds is proposed that allows the investigation of particular effects of fluorination on the hydrogen bonding properties. For this purpose, conformationally constrained compounds that allow for singling out a particular effect will be investigated first. In a second stage, conformationally flexible model compounds containing different relative stereochemistries will be evaluated as well. These compounds will be synthesised, followed by experimental determination of hydrogen bonding properties.
The prediction of H-bond properties of functional groups will be achieved by theoretical calculation of a suitable molecular descriptor, which will then be correlated with the experimentally obtained values to create a set of Linear Free Energy Relationships (one for each hydrogen bond property). Part of the model compounds aim to evaluate subtle substituent effects, which, if successfully predicted, will be viewed as important test cases for the accuracy of our predictive tool for polyfunctional substrates.
Thorough conformational, NBO and AIM analyses will be employed to aid the rationalisation of the observed effects. This will lead to the establishment of a set of rules or guidelines describing how fluorination influences H-bond properties of the abovementioned functional groups, which will further increase our understanding of the effects of fluorination.
Where feasible, the hydrogen bonding characteristics will be compared with experimental lipophilicity and pKa (pKa(H)) values, both of which are important molecular properties.
Planned Impact
The introduction of the small and electronegative fluorine atom in organic compounds can lead to significant alterations in a wide range of properties, including acid-base strength, conformation, lipophilicity, and chemical stabilisation. This has perhaps been most expensively exploited by the pharma and agro industries. Some statistics are very impressive: up to 20% of the pharmaceuticals prescribed or administered in the clinic and a third of the leading 30 blockbuster drugs contain at least one fluorine atom, and 30-40% of currently marketed agrochemicals contain fluorine. More recent applications involve investigating fluorination in materials chemistry (especially liquid crystals), crystal engineering and organocatalysis.
A large research effort has been devoted, especially in the last 20 years, to the understanding of the effects of fluorination.
Hydrogen bonding (H-bonding) is the most important specific non-covalent intermolecular interaction, and is at the heart of many different disciplines including pharmaceuticals, agrochemicals, materials and catalyst design, and underpins research in biological sciences. Crucial functional roles include the binding of ligands to protein receptors, and the promotion of enzyme catalysis. In the design of bioactive compounds, H-bonding impacts on a wide range of molecular properties such as potency, selectivity, permeability and solubility. Despite this, the influence of fluorination on H-bonding properties has not been studied yet in detail, except for some polyfluorinated solvents. So far it has been assumed that, due to the fluorine electronegativity effect, fluorination always increases H-bond donating capacity of H-bond donors (and vice versa for acceptors).
Our first results involving fluorinated alcohols show that this is not the case, with the H-bond donating capacity of some F-alcohols decreased compared to the parent alcohol. We also have shown significant effects can be achieved by introducing a single fluorine (in both directions). Furthermore, we found that there is an excellent correlation between a (calculated) molecular descriptor, and the experimental H-bond donating capacity, which can be used in H-bond property prediction.
Given the importance of both fluorination and H-bonding, increased understanding of how fluorination influences H-bond properties of functional groups (FG) will be of great relevance to the abovementioned fields and industries. The knowledge from the proposed research will allow scientists to better understand the consequences of fluorine introduction (leading to improved accuracy in data-interpretation, and also provide a new strategy to increase or attenuate H-bond properties of the molecule in question, not by changing a particular FG, but by judicious fluorination.
In addition, the proposed research involving a wider range of model compounds and FGs will validate the correlation between molecular descriptor and experimental H-bond properties, with as ultimate aim to provide a predictive tool for the calculation of H-bond properties of polyfunctional molecules.
Clearly, this work will accelerate drug discovery through improved compound design, and open new avenues in supramolecular chemistry, materials and organocatalysis, through the ability for finetuning of H-bond properties. This will lead to improved healthcare, improved agrochemicals, better catalysts, higher performing liquid crystals etc, all of which will directly impact upon our lives.
Hence, there will be an impact in several research areas within the EPSRC portfolio, such as Synthetic Supramolecular Chemistry, Catalysis, Chemical Biology and Biological Chemistry, Computational and Theoretical Chemistry and Chemical Structure. Also, there is a potential impact in the "Systems Chemistry:understanding interactions" EPSRC Grand Challenge, especially in Theme 3: "Controlling molecular self-assembly in biological and biomimetic systems".
A large research effort has been devoted, especially in the last 20 years, to the understanding of the effects of fluorination.
Hydrogen bonding (H-bonding) is the most important specific non-covalent intermolecular interaction, and is at the heart of many different disciplines including pharmaceuticals, agrochemicals, materials and catalyst design, and underpins research in biological sciences. Crucial functional roles include the binding of ligands to protein receptors, and the promotion of enzyme catalysis. In the design of bioactive compounds, H-bonding impacts on a wide range of molecular properties such as potency, selectivity, permeability and solubility. Despite this, the influence of fluorination on H-bonding properties has not been studied yet in detail, except for some polyfluorinated solvents. So far it has been assumed that, due to the fluorine electronegativity effect, fluorination always increases H-bond donating capacity of H-bond donors (and vice versa for acceptors).
Our first results involving fluorinated alcohols show that this is not the case, with the H-bond donating capacity of some F-alcohols decreased compared to the parent alcohol. We also have shown significant effects can be achieved by introducing a single fluorine (in both directions). Furthermore, we found that there is an excellent correlation between a (calculated) molecular descriptor, and the experimental H-bond donating capacity, which can be used in H-bond property prediction.
Given the importance of both fluorination and H-bonding, increased understanding of how fluorination influences H-bond properties of functional groups (FG) will be of great relevance to the abovementioned fields and industries. The knowledge from the proposed research will allow scientists to better understand the consequences of fluorine introduction (leading to improved accuracy in data-interpretation, and also provide a new strategy to increase or attenuate H-bond properties of the molecule in question, not by changing a particular FG, but by judicious fluorination.
In addition, the proposed research involving a wider range of model compounds and FGs will validate the correlation between molecular descriptor and experimental H-bond properties, with as ultimate aim to provide a predictive tool for the calculation of H-bond properties of polyfunctional molecules.
Clearly, this work will accelerate drug discovery through improved compound design, and open new avenues in supramolecular chemistry, materials and organocatalysis, through the ability for finetuning of H-bond properties. This will lead to improved healthcare, improved agrochemicals, better catalysts, higher performing liquid crystals etc, all of which will directly impact upon our lives.
Hence, there will be an impact in several research areas within the EPSRC portfolio, such as Synthetic Supramolecular Chemistry, Catalysis, Chemical Biology and Biological Chemistry, Computational and Theoretical Chemistry and Chemical Structure. Also, there is a potential impact in the "Systems Chemistry:understanding interactions" EPSRC Grand Challenge, especially in Theme 3: "Controlling molecular self-assembly in biological and biomimetic systems".
Publications
Bogdan E
(2016)
a-Fluoro-o-cresols: The Key Role of Intramolecular Hydrogen Bonding in Conformational Preference and Hydrogen-Bond Acidity.
in Chemphyschem : a European journal of chemical physics and physical chemistry
Bogdan E
(2015)
Influence of Fluorination on the Conformational Properties and Hydrogen-Bond Acidity of Benzyl Alcohol Derivatives.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Graton J
(2017)
Influence of Alcohol ß-Fluorination on Hydrogen-Bond Acidity of Conformationally Flexible Substrates.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Linclau B
(2019)
A New Straightforward Method for Lipophilicity (log<em>P</em>) Measurement using <sup>19</sup>F NMR Spectroscopy
in Journal of Visualized Experiments
Linclau B
(2015)
Intramolecular OH···Fluorine Hydrogen Bonding in Saturated, Acyclic Fluorohydrins: The ?-Fluoropropanol Motif.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Linclau B
(2016)
Investigating the Influence of (Deoxy)fluorination on the Lipophilicity of Non-UV-Active Fluorinated Alkanols and Carbohydrates by a New log P Determination Method.
in Angewandte Chemie (International ed. in English)
O'Hagan D
(2016)
Accurate Lipophilicity (log P) Measurements Inform on Subtle Stereoelectronic Effects in Fluorine Chemistry.
in Angewandte Chemie (International ed. in English)
Quiquempoix L
(2017)
A Study of Intramolecular Hydrogen Bonding in Levoglucosan Derivatives.
in Molecules (Basel, Switzerland)
Description | We have shown that fluorination does not always increase hydrogen bond donating (HBD) capacity of adjacent alcohol groups. There are two main effects: the fluorine inductive effect causes the HBD capacity to increase, but intramolecular OH...F hydrogen bonding causes a decrease. We have been able to show spectroscopic evidence of this OH...F hydrogen bond, even on acyclic substrates. Importantly, for conformationally flexible substrates, we have shown that the HBD capacity can be explained and predicted by a rigorous conformational analysis, followed by proportionally considering the properties of each conformer according to their conformation. |
Exploitation Route | Hydrogen bonding is the primary interaction between bioactive compounds and proteins. Hence, knowledge on how to modulate hydrogen bond properties will be useful in a drug development context. In addition, hydrogen bonds are also key interactions in catalysis and supramolecular chemistry. |
Sectors | Chemicals Healthcare Pharmaceuticals and Medical Biotechnology |
Description | The research outcomes of this award will have increased understanding of medicinal chemists of the influence of fluorination on properties relevant to the action of drugs. This is not a type of impact that would be made public. |
First Year Of Impact | 2012 |
Sector | Chemicals,Pharmaceuticals and Medical Biotechnology |
Impact Types | Economic |
Description | AstraZeneca internal CASE award scheme |
Amount | £33,000 (GBP) |
Organisation | AstraZeneca |
Sector | Private |
Country | United Kingdom |
Start | 09/2015 |
End | 09/2018 |
Description | EPSRC Responsive mode |
Amount | £387,478 (GBP) |
Funding ID | EP/P019943/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2017 |
End | 03/2020 |
Description | Aliphatic fluorination of alcohols and carbohydrates: influence on hydrogen bond/lipophilicity properties and protein binding (AZ Gothenburg) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Invited seminar at AstraZeneca Gothenburg (Sweden) |
Year(s) Of Engagement Activity | 2016 |
Description | An investigation on the effects of CF3/CH3 exchange in aliphatic and perfluoroalkylated alcohols on lipophilicity (poster RSC F) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Poster presentation of Benjamin Jeffries, 17th Annual RSC Fluorine Subject Group Postgraduate Meeting, 18-19th Sept, 2017, Leicester, 1st place award. |
Year(s) Of Engagement Activity | 2017 |
Description | BL Invited talk at Irish MedChem Symposium |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited Speaker at 2nd Irish Medicinal Chemistry Symposium, Dublin (Ireland)("The influence of fluorination on lipophilicity and hydrogen bonding properties of aliphatic alcohols") |
Year(s) Of Engagement Activity | 2018 |
Description | BL Talk SCI |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Invited talk at SCI "Organofluorine Chemistry: synthetic methods and application" conference, London, UK ("The Influence of Fluorination on Lipophilicity and Hydrogen Bond Properties of Alcohols") |
Year(s) Of Engagement Activity | 2018 |
Description | Influence of Fluorination on Alcohol Hydrogen Bonding and Lipophilicity Properties |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invites talk at the American Chemical Society Meeting, Fluorine Division |
Year(s) Of Engagement Activity | 2015 |
Description | Intramolecular OH•••F hydrogen bonding in fully saturated acyclic 3-fluorinated alkanols |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited speaker at the 21st International symposium of fluorine chemistry |
Year(s) Of Engagement Activity | 2015 |
Description | Investigating the Influence of (Deoxo)fluorination on the Lipophilicity of Non-UV-Active Fluorinated Alkanols and Carbohydrates by a New logP Determination Method (ANORCQ, Rouen) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Poster presentation at the 13th Anglo Norman Organic Chemistry Colloquium, Rouen, France 24-27 April 2016. |
Year(s) Of Engagement Activity | 2016 |
Description | Investigating the Influence of (Deoxo)fluorination on the Lipophilicity of Non-UV-Active Fluorinated Alkanols and Carbohydrates by a New logP Determination Method (RSC Analytical Research Forum) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Poster presentation at the RSC Analytical Research Forum, London, 8/07/2016 |
Year(s) Of Engagement Activity | 2016 |
Description | Investigating the effects of fluorination on physical properties of aliphatic alcohols and carbohydrates |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Plenary speaker at the International Conference on Heteroatom Chemistry (ICHAC-11) |
Year(s) Of Engagement Activity | 2015 |
Description | Presentation at IITB |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited presentation at Institute of Indian Technology Bombay (IITB), Mumbai (India), "The Influence of Fluorination on Aliphatic Lipophilicity" |
Year(s) Of Engagement Activity | 2019 |
Description | Synthesis and properties of fluorinated carbohydrates |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Talk at the American Chemical Society meeting, Carbohydrate division |
Year(s) Of Engagement Activity | 2015 |
Description | Synthesis and properties of fluorinated carbohydrates (CARBO Delhi) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Plenary Speaker at International Conference on New Frontiers in carbohydrate Chemistry and Biology, Delhi (India), 14-16/11/2016 |
Year(s) Of Engagement Activity | 2016 |
Description | Synthesis and properties of polyfluorinated carbohydrates |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Invited Seminar at UCL (London) |
Year(s) Of Engagement Activity | 2015 |
Description | Synthesis and properties of polyfluorinated carbohydrates |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Invited seminar at the University of York |
Year(s) Of Engagement Activity | 2014 |
Description | Synthesis of polyfluorinated carbohydrates (IIT Bombay) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited seminar at the Indian Institute of Technology Bombay, Mumbai, India, 19/11/2016 |
Year(s) Of Engagement Activity | 2016 |
Description | Synthesis of stereochemically defined fluorohydrins and polyfluorinated carbohydrates, and investigations on the impact of fluorination on hydrogen bond/lipophilicity and protein binding properties (Leeds Uni) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Invited seminar in Leeds, 10/05/2016 |
Year(s) Of Engagement Activity | 2016 |
Description | The Influence of Aliphatic Fluorination on Lipophilicity and Hydrogen Bond Properties of Alcohols (Syngenta Jealott's Hill) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | Invited seminar at Syngenta (13/10/2017) |
Year(s) Of Engagement Activity | 2017 |
Description | The Influence of Aliphatic Fluorination on Lipophilicity and Hydrogen Bond Properties of Alcohols and carbohydrates (Maynooth) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited Seminar at Maynooth University (06/06/2017) |
Year(s) Of Engagement Activity | 2017 |
Description | The Influence of Aliphatic Fluorination on Lipophilicity and Hydrogen Bond Properties of Alcohols: Application in Carbohydrates (Basel) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited Seminar at the Basler Chemische Gesellshaft |
Year(s) Of Engagement Activity | 2017 |
Description | The hydrogen bond donating capacity of conformationally flexible fluorohydrins (RSC Carbohydrate Warwick) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Poster presentation at teh RSC Carbohydrate Symposium, warwick, 29-30/10/2016 |
Year(s) Of Engagement Activity | 2016 |
Description | The hydrogen bond donating capacity of conformationally flexible fluorohydrins (RSC Fluorine meeting Oxford) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Poster presentation at the annual RSC Fluorine Postgraduate Symposium, Oxford, 22-23/09/2016 |
Year(s) Of Engagement Activity | 2016 |
Description | The influence of aliphatic fluorination on lipophilicity and alcohol hydrogen bond properties (Sydney) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited Seminar, University of Sydney, 26/4/2017 |
Year(s) Of Engagement Activity | 2017 |
Description | The influence of aliphatic fluorination on lipophilicity and alcohol hydrogen bond properties (UNSW) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited seminar at The University of New South Wales, 02/05/2017 |
Year(s) Of Engagement Activity | 2017 |
Description | The influence of fluorination on molecular properties: lipohilicity, hydrogen bonding and fluorinated carbohydrates |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Invited seminar at a company (Janssen Pharmaceutica), Beerse, Belgium |
Year(s) Of Engagement Activity | 2014 |
Description | The influence of fluorination on molecular properties: lipohilicity, hydrogen bonding and fluorinated carbohydrates |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited seminar, University of Poitiers, Poitiers, France. |
Year(s) Of Engagement Activity | 2013 |
Description | The influence of fluorination on molecular properties: lipohilicity, hydrogen bonding and fluorinated carbohydrates |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited seminar (University of Ghent, Belgium) |
Year(s) Of Engagement Activity | 2014 |
Description | The interplay between organofluorine and alcohol groups: hydrogen bonding, lipophilicity and protein-ligand binding |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited seminar (University of Sherbrooke, Sherbrooke, Canada |
Year(s) Of Engagement Activity | 2015 |
Description | The interplay between organofluorine and alcohol groups: hydrogen bonding, lipophilicity and protein-ligand binding |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited seminar (Laval University, Quebec City, Canada) |
Year(s) Of Engagement Activity | 2015 |