Halogenation Reactions

A Halogenation reaction occurs when one or more fluorine, chlorine, bromine or iodine atoms replace hydrogen atoms in organic compound. The order of reactivity is fluorine > chlorine > bromine > iodine. Fluorine is especially aggressive and can react violently with organic materials. It also tends to make the most stable of the organohalogens and it is difficult to remove a fluorine atom once added. Conversely, iodine is more difficult to add to an organic molecule but once an iodoorganic forms, the iodine atom is easily removed. Thus the electronegativity of the halogen atom is a driving force for halogenation reactions. The reactions also depend on the nature of the substrate molecule that is being halogenated.

Halogenations occur by several different processes depending on the substrate: saturated hydrocarbons halogenate via a free radical process; unsaturated organics halogenate via an addition reaction; aromatics halogenate via electrophilic substitution. 

Halogenation reactions are important in both bulk and fine chemical synthesis and the products and intermediates generated via halogenation are well represented in pharmaceuticals, polymers and plastics, refrigerants, fuel additives, fire retardants, agroproducts, etc.

As examples in pharmaceuticals, fluorine or chlorine atoms added to a molecule can increase the potential for its therapeutic activity. Furthermore, organobromides and organoiodines are very useful as intermediate compounds, providing a means to add functional groups to a substrate, as well as enabling the synthesis of more complex structures. As examples, a C-Cl or C-Br bonds can be hydrolyzed to alcohols which, in turn, can be oxidized to yield ketones, aldehydes and acids. Through elimination reactions, double bonds can be formed. Bromination of organic compounds is frequently an important step towards forming a Grignard reagent, offering a synthetic pathway to build C-C bonds. The alkylation of aromatic rings via the Friedel-Crafts reaction is broadly applicable and alkyl halides are critical reagents for this reaction

Some important commercial chemicals and products result from halogenation reactions. In a classic example, chloroform is fluorinated to form chlorodifluoromethane, which is then converted to fluoroethylene and polymerized to yield PTFE. Another example, is the addition halogenation of ethylene with chlorine to form dichloroethane, which then is polymerized to yield PVC. 

Halogenation reactions may require a catalyst to increase the electrophilicity of the halogen. As an example, electrophilic substitution reactions of aromatic compounds require a catalyst. Since, bromine and chlorine are not electrophilic enough by themselves to cause the substitution of the hydrogen, they require the presence of a Lewis acid. Thus, typical catalysts for halogenation of aromatic rings are as examples, AlCl3 or AlBr3. In the presence of the Lewis acid, the bonding of the halogen becomes more polarized and the enhanced positively charged halogen is a far stronger electrophile.

Fluorination of aromatics does not require a catalyst because fluorine is such a strong electrophile and this reaction can be very energetic. It is difficult to control the amount of fluorine substitution that occurs and more than one fluorine atom may halogenate the aromatic ring. For iodine to substitute on an aromatic ring, the metal halides are not effective catalysts, but an oxidizer such as nitric acid will convert iodine to HIO3 and enable the iodization of benzene.

Halogenations are exceptionally useful reactions and encompass a broad scope of use in synthetic chemistry. A few examples: Chlorination, bromination and iodization of aldehydes and ketones in the α-position is straightforward, though that reaction with fluorine is not possible. Halogenation of the α –hydrogen in carboxylic acids with bromine or chlorine can occur via the Zell-Volhard-Zelinsky reaction, however a catalyst such as P or PBr3 is necessary. The easier it is to enolize a substrate, the easier it is to halogenate it. For this reason, acyl halides, anhydrides, malonic esters all undergo α –halogenation without the need for a catalyst. The Hoffman rearrangement reaction uses bromine to convert amides to amines. Aromatic rings can be brominated or chlorinated but require a catalyst such as Fe (actually FeCl3) or AlCl3 or AlBr3. Fluorine itself is to aggressive for fluorinating aromatics, but there are reagents such as ClO3F that can be utilized to fluorinate certain substrates such as phenols. In general, bromine and chlorine readily halogenate compounds with double and triple bonds.

Though halogenation with X2 or HX is used, these molecules are often toxic, corrosive and difficult to manage. As examples, Fluorine and HF are incredibly corrosive, reactive, cause unwanted side products and in general are difficult to work with and to control reaction exothermicity. For this reason, compounds have been developed that can provide a fluorine atom but are more stable and controllable. As an example, diethylaminosulfur trifluoride (DAST) is a stable solid that converts alcohols, aldehydes, and ketones to the corresponding organofluoride and is far safer and convenient to use then fluorine or sulfur tetrafluoride gases. Reagents such as SOCl2 and PCl5 are used for producing organochlorine compounds from the corresponding alcohols and, as in the case of fluorine, easier to use and control reactions than with elemental chlorine. As an alternative to bromine, N-bromosuccinimide (NBS) is widely used to brominate an alkene. 

Halogenations can be very energetic and are sensitive to moisture and air. Additionally, reaction yield and selectivity is a function of the substrate, halogenating reagent, reaction temperature, and other variables. This combination of requirements make the need for in situ analysis and precise control an important objective in halogenations.

Understanding the kinetics and thermodynamics of halogenations is important in order to achieve the product and safety objectives and this is especially true while scaling-up a reaction. Automated lab reactors such as EasyMax and RC1 have important roles in ensuring that reaction energetics are well understood and that the effect of variables on reaction performance are well modelled. ReactIR and ReactRaman in situ spectroscopic technologies are highly useful for tracking and monitoring key reaction species providing both kinetics and mechanistic information. Halogenations often generate intermediates and by-products and knowing the effect of reaction variables on the generation of these species aids in ensuring reaction performance and safety. Engineers and chemists use the combination of automated lab reactors in conjunction with in situ spectroscopic probes to ensure the performance and safety of halogenations.

Thomas Scattolin, Kristina Deckers, and Franziska Schoenebeck, “Direct Synthesis of Acyl Fluorides from Carboxylic Acids with the Bench-Stable Solid Reagent (Me₄N)SCF₃”,Org. Lett. 2017, 19, 5740−5743_.

The authors report preparing acyl fluorides from the reaction of alkyl and aromatic carboxylic acids with the reagent (Me₄N)SCF_3. This reagent is stable, solid and safe, enabling fluorination without the need for dangerous or toxic reagents such as cyanuric fluoride or HF. They went on to explore the scope of the reaction and prepared various acyl fluorides. One example was the corresponding acyl fluoride from to 1-adamantanecarboxylic acid. They also synthesized acyl fluorides from the corresponding Boc-, Fmoc-, and Cbz-N-protected amino acids .

In order to elucidate possible mechanism, ReactIR measurements were performed on three carboxylic acids that are electronically different. Based on the kinetic information gleaned and the observation that a gas, carbonyl sulfide is released, the authors proposed a mechanism that suggest key intermediates form prior to generation of the acyl fluoride.

The authors report the development of a continuous flow route to synthesize trifluoromethylated N-fused heterocycles. They state that the safety issues associated with the reaction were mitigated by using a plug flow reactor design to help control the exothermicity of the acid/base dosing. The use of this approach avoided the accumulation of unreacted reagent as well as other benefits. This resulted in reactions with reduced by-products, higher yields, better scalability and safety as compared to conventional batch reactions.

EasyMax equipped with calorimetry was used to assess critical temperature parameters for each step of the synthesis. The results showed that introduction of trifluoroacetic acid and propylphosphonic anhydride to the reaction solution caused an exotherm of 50 oC. The addition of triethylamine and trifluoroacetic anhydride caused a greater than 50 oC exotherm. As a result it was apparent that a batch method would be problematic, supporting the feasibility and use of the continuous flow approach.

Lara Amini-Rentsch, Ennio Vanoli, Sylvia Richard-Bildstein, Roger Marti, Gianvito Vilé, “A Novel and Efficient Continuous-Flow Route To Prepare Trifluoromethylated N-Fused Heterocycles for Drug Discovery and Pharmaceutical Manufacturing”, Ind. Eng. Chem. Res. 2019, 58, 24, 10164-10171.

Alyssa M. Hua, Duy N. Mai, Ramon Martinez, and Ryan D. Baxter, “Radical C−H Fluorination Using Unprotected Amino Acids as Radical Precursors”, Org. Lett. 2017, 19, 11, 2949-2952.

The authors report the fluorination of benzylic C-H using unprotected amino acids in a radical-generating process. Using a silver catalyst and Selectafluor [1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)] oxidative decarboxylation of unprotected amino acids produce α-aminoalkyl radicals. The Selectafluor provides the source of electrophilic fluorine.

ReactIR measurements provided evidence for the mechanism of the radical fluorination. No change in the Selectfluor concentration was observed when silver nitrate was added, however when glycine was added, the Selectfluor concentration quickly decreased. As a result, it appeared that the glycine is critical to the reaction between Ag(I) and Selectafluor, and this led the researchers to postulate a Ag(I)/Ag(II) catalyst cycle for decarboxylation of unprotected amino acids with Selectfluor. They state that that coordination of the unprotected amino acid lowers the oxidation potential of Ag(I) enabling oxidation to occur under mild conditions.

Lara Amini-Rentsch, Ennio Vanoli, Sylvia Richard-Bildstein, Roger Marti, Gianvito Vilé, “A Novel and Efficient Continuous-Flow Route To Prepare Trifluoromethylated N-Fused Heterocycles for Drug Discovery and Pharmaceutical Manufacturing”, Ind. Eng. Chem. Res. 2019, 58, 24, 10164-10171.

The authors report the development of a continuous flow route to synthesize trifluoromethylated N-fused heterocycles. They state that the safety issues associated with the reaction were mitigated by using a plug flow reactor design to help control the exothermicity of the acid/base dosing. The use of this approach avoided the accumulation of unreacted reagent as well as other benefits. This resulted in reactions with reduced by-products, higher yields, better scalability and safety as compared to conventional batch reactions.

EasyMax equipped with calorimetry was used to assess critical temperature parameters for each step of the synthesis. The results showed that introduction of trifluoroacetic acid and propylphosphonic anhydride to the reaction solution caused an exotherm of 50 ^oC. The addition of triethylamine and trifluoroacetic anhydride caused a greater than 50 ^oC exotherm. As a result it was apparent that a batch method would be problematic, supporting the feasibility and use of the continuous flow approach.

• Masafumi Sugiyama, Midori Akiyama, Kohei Nishiyama, Takashi Okazoe, Kyoko Nozaki, “Synthesis of Fluorinated Dialkyl Carbonates from Carbon Dioxide as a Carbonyl Source”, ChemSusChem, 17 February 2020.
• Lara Amini-Rentsch, Ennio Vanoli, Sylvia Richard-Bildstein, Roger Marti, Gianvito Vilé, “A Novel and Efficient Continuous-Flow Route To Prepare Trifluoromethylated N-Fused Heterocycles for Drug Discovery and Pharmaceutical Manufacturing”, Ind. Eng. Chem. Res. 2019, 58, 24, 10164-10171.
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• Alyssa M. Hua, Duy N. Mai, Ramon Martinez, and Ryan D. Baxter, “Radical C−H Fluorination Using Unprotected Amino Acids as Radical Precursors”, Org. Lett. 2017, 19, 11, 2949-2952.
• Thomas Scattolin, Kristina Deckers, and Franziska Schoenebeck, “Direct Synthesis of Acyl Fluorides from Carboxylic Acids with the Bench-Stable Solid Reagent (Me4N)SCF3”, Org. Lett. 2017, 19, 5740−5743.
• Eloah P. Ávila, Isabella F. de Souza, Alline V. B. Oliveira, Vinicius Kartnaller, João Cajaiba, Rodrigo O. M. A. de Souza, Charlane C. Corrêa, Giovanni W. Amarante, “Catalyst free decarboxylative trichloromethylation of aldimines”, RSC Adv., 2016,6, 108530-108537.
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• Antal Harsanyi and Graham Sandford, “Fluorine gas for life science syntheses: green metrics to assess selective direct fluorination for the synthesis of 2-fluoromalonate esters”, Green Chem., 2015, 17, 3000–3009.