Investigating the influence of fluorination on hydrogen bonding properties of functional groups

Lead Research Organisation: University of Southampton
Department Name: School 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.

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".

Publications

10 25 50
 
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 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 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 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 (Laval University, Quebec City, 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 (University of Sherbrooke, Sherbrooke, Canada
Year(s) Of Engagement Activity 2015