Recent Advances in the Synthesis of Fluorinated Alkynes

Fluorinated alkynes are one such highly reactive, multifunctional type of chemical, being electrophilic and nucleophilic due to the fluorine atom. They are useful intermediaries in organic synthesis, most useful for creating fluorinated heterocyclic compounds through Diels-Alder reactions or 1,3-dipolar cycloadditions. Fluorinated alkynes have thus been increasingly employed in the synthesis of biologically active intermediates and fluorinated drugs. In recent decades, techniques to make fluorinated alkynes have branched out and made it possible to produce them in ever more efficient and selective ways for industrial and medical purposes. These are the main synthetic techniques that are developed here.

Fluorine Groups Addition to Alkynes

Fluorinated alkynes can often be made by adding fluorine groups to the existing alkynes. In a reaction of propargyl bromide, for example, with organometallic reagents and fluorine carbonyls, 1-fluoroalkyl substituted propargyl alcohols are obtained. Also, phenylethyne's reaction with hexafluoroisopropyl imidazolidine-1,3-dione was reported to produce fluorinated alkynes. Such processes provide simple access to fluorinated alkynes, which can be used as intermediaries in the production of more complex organic compounds.

Fig.1 Phenylacetylene reacts with hexafluoroisopropylimidazolidine-1,3-dione to form fluorinated acetylene.

Reaction of Perfluoroalkyl Iodides with Grignard Reagents

With an excess of alkyl or aryl magnesium halides, perfluoroalkyl iodides are single-pot converted into perfluoroalkyl magnesium halides. These intermediates can then be mixed with different reagents, such as Grignard reagents, to give fluorinated alkynes. It is a robust path to the synthesis of these very reactive molecules without having to subject them to intense reaction conditions.

Fig.2 Reaction of perfluoroalkyl iodides with grignard reagents.

Introduction of Triple Bonds to Fluorinated Aromatic Groups

Fluorinated aromatics can also be good precursors for introducing C≡C triple bonds for making fluorinated alkynes. For instance, using 1,1-dichloro-2,2-difluoroethylene as an acetylene precursor was found to yield fluorinated aryl alkynes in 50-80 % yield. This approach is especially suitable for making fluorinated aromatic alkynes, which can be further functionalised for various purposes in materials science and medicinal chemistry.

Fig.3 Fluorinated aryl alkynes can be efficiently produced using 1,1-dichloro-2,2-difluoroethylene as an acetylene precursor.

Intramolecular Wittig Reaction

This Wittig reaction, normally used for the creation of carbon-carbon double bonds, was also modified to make fluorinated alkynes by intramolecular cyclisation. Here, phosphonium ylides with fluorine substituents are thermally broken down into functionalised fluorinated alkynes. It's a winning strategy because this approach lets us directly introduce functional groups into the alkyne chain such as esters, nitriles, ketones, perfluoroketones, aldehydes, and aromatic moieties. The reaction is generally highly yield- and purity-assured when the right conditions are provided, and so can be used to produce fluorinated alkynes in research as well as industrial settings.

Fluorinated Phosphonates and Aldehydes Reaction.

Another method for producing fluorinated alkynes is to react fluorinated phosphonates with aldehydes, via a reaction with hexamethyldisiloxane or tetrabutylammonium fluoride (TBAF). It generates fluorinated alkynols in sufficient quantities and could introduce a range of functional groups into the alkyne moiety. However the reaction with ketones yields less as a result of steric inhibition and reduced carbonyl reactivity. This is a limitation, but the process is still a useful path to fluorinated alkynes for making complex molecules.

Fig.4 Reaction of fluorinated phosphonates with aldehydes^[1].

Electrochemical Methods for Fluorinated Alkynes

Electrochemical synthesis provides a more sustainable way of making fluorinated alkynes, especially those with long carbon chains. Fluorinated alkynes can be electrolyzed at a carbon fiber cathode by starting with perfluoroalkyl iodides. It's also more convenient as it doesn't require organic solvents and leaves minimal residue. The reaction proceeds very efficiently (80-90%) and unlocks a series of fluorinated alkynes that conventional chemical processes could not access.

Summary of Synthesis Methods for Fluorinated Alkynes

Synthesis Method	Key Features	Examples of Compounds
Introduction of Fluorine Groups into Alkynes	Use of organometallic reagents and fluorine carbonyls	1-fluoroalkyl-propargyl alcohols, phenylethyne derivatives
Perfluoroalkyl Iodides with Grignard Reagents	One-pot conversion to fluorinated alkynes	Fluorinated alkynes derived from perfluoroalkyl iodides
Triple Bond Introduction in Fluorinated Aromatics	Synthesis of aryl alkynes via fluorinated aromatic precursors	Fluorinated aryl alkynes, e.g., difluoroethyl phenylacetylene
Functionalization of Simple Fluorinated Alkynes	Addition of functional groups (e.g., esters, hydroxyls)	Functionalized fluorinated alkynes for organic synthesis
Intramolecular Wittig Reaction	Formation of functionalized alkynes via phosphonium ylides	Fluorinated alkynes with esters, nitriles, or aromatic groups
Reaction of Fluorinated Phosphonates with Aldehydes	Synthesis of alkynols with functional groups	Fluorinated alkynols, e.g., fluorinated alkynyl alcohols
Electrochemical Methods	Environmentally friendly synthesis via electrolysis	Long-chain fluorinated alkynes from perfluoroalkyl iodides

These approaches have multiple benefits in selectivity, reaction conditions and functional group compatibility, and they can be widely used for fluorinated alkynes in organic synthesis, materials science and pharmaceutical development. Increasing demand for fluorinated materials - particularly in drug discovery and electronic components - will make it even more important to develop a way to produce fluorinated materials effectively and selectively.

Reference

1. Ishihara, T., et al. (1986). "An efficient synthesis of α-G-alkynylated alcohols by new siloxane-fluoride ion catalyzed reaction of 1H-F-1-alkenephosphonates with aldehydes." Tetrahedron Letters., 27(3), 357-360.