Why Fluoroalkanes are the Least Reactive Haloalkanes

Fluoroalkanes - one group of haloalkanes that have carbon-fluorine (C-F) bonding - are the chemically least reactive of all the haloalkanes. That's supported by some intrinsic molecular attributes such as bond strength, electronegativity, steric effects, and electronic shielding. All of these interact to affect fluoroalkane reactivity in both nucleophilic and electrophilic reactions that differentiate fluoroalkanes from the other haloalkanes (choloroalkanes, bromoalkanes, iodoalkanes).

Exceptional Bond Strength of Carbon-Fluorine Bonds

One of fluoroalkanes' hallmarks is the C-F bond - it's the strongest bond dissociation energy of all carbon-halogen bonds. This energy - greater than 480 kJ/mol - makes the bond extremely indestructible to break, even in ordinary chemical reactions. On the other hand, the bond dissociation energies of C-Cl, C-Br, and C-I bonds are far less than that, so these bonds are more vulnerable to chemical changes.

This strong bond strength is because of the high orbital overlap between the small fluorine atom and the carbon atom, and also because of the powerful electrostatic attraction of fluorine's high electronegativity. Fluoroalkanesare thus not as responsive to reactions that require the dissociation of the carbon-halogen chain (eg, nucleophilic substitution, elimination reactions).

Halogen	C-X Bond Dissociation Energy	Reactivity
Fluorine	485 kJ/mol	Lowest
Chlorine	340 kJ/mol	Moderate
Bromine	280 kJ/mol	High
Iodine	240 kJ/mol	Highest

Fluorine Shielding Effects in Electrophilic Substitution Reactions

The electronic effect of fluorine significantly affects the behavior of fluoranes in chemical reactions. The high electronegativity of fluorine attracts electron density toward itself, thereby reducing the electron density of neighboring carbon atoms and weakening their ability to participate in nucleophilic or electrophilic substitution reactions. The electron-absorbing effect also increases the activation energy of many reactions, which further inhibits reaction rates, resulting in slower reaction rates than for other haloalkanes.

In addition, fluorine has a shielding effect that limits the access to reaction centers. This spatial and electronic hindrance is particularly evident in electrophilic substitution reactions, where fluoroalkanes resist attack due to the high bond energies and interference of the fluorine atoms in the reaction pathways.

Interestingly, in some specialized reactions, such as photocatalytic transformations, the effect of fluorine alters the reaction pathways to produce unique results. For example, density-functional theory (DFT) studies have shown that the π→σ*CF hyperconjugation effect can invert the polarity of the carbon-carbon (C=C) double bond in fluoro olefin derivatives, thereby facilitating specific cyclization reactions^[1].

Fig.1 Regio- and diastereoselective syntheses of quaternary carbonyl fluoroalkyl cyclobutanes were achieved via photocatalytic 4-exo-trig cyclization of cascade thioalkynes or trifluoromethylalkenes^[1].

The High Electronegativity of Fluorine

Electronegativity is a function of atoms' ionization energy and electron affinity that tells us how well an atom attracts electrons in a chemical compound. The highest electronegativity of any element is found in fluorine (3.38). That extremely high electronegativity draws the electrons from other atoms in the system towards fluorine and creates polar bonds.

The polarity of C-F bonds stems from the difference in electronegativity between carbon and fluorine, which further complicates their breaking. The electronegativity of fluorine creates a large partial positive charge on the carbon atom, which increases the polarity of the bond and also stabilizes it. While this polarity theoretically enhances the electrophilicity of the carbon atom, the energy barrier to breaking the bond usually outweighs this effect, resulting in lower overall reactivity.

Comparison of Reactivity with Other Haloalkanes

A large body of experimental data supports the low reactivity of fluoroalkanes. In aliphatic nucleophilic substitution reactions, the ability of halogens to dissociate groups follows the order I^- > Br^- > Cl^- > F^-, indicating that fluoride is the least effective dissociating group. This order is consistent with the observation that the reaction rate of halothane is significantly lower compared to chloroalkanes, bromoalkanes and iodoalkanes under the same conditions.

Despite their low reactivity, halothane exhibits significant selectivity in certain complex molecular environments where their chemical inertness can be exploited to target specific reaction sites.

Industrial Implications

Fluoroalkanes' low reactivity means that they aren't ideal for ordinary organic synthesis, but because they are so special, they are useful in special applications. The chemical inertness of fluoroalkanes is then harnessed to produce chemically stable substances like fluoropolymers, or in pharmaceuticals for which selective fluorination provides the stability of metabolism. Further, fluoroalkanes under certain controlled conditions are subject to certain reactions, including formylation and reductive addition reactions, which are critical for the synthesis of fluorinated organic molecules.

Reference

1. Zhou Y., et al. (2024). "Fluorine-Effect-Enabled Photocatalytic 4-Exo-Trig Cyclization Cascade to Access Fluoroalkylated Cyclobutanes." Angew Chem Int Ed Engl, 63(30), e202405678.