Halogenation process of chemical process industries

This presentation is about nitration process of industries, unit processes of chemical engineering.

1. Halogenation

2. Learning objectives After completion of this section, you will be able to: Understand the application and importance of halogenation Describe what is florination and applications Discuss various types of florination Describe what is chlorination and its applications Understand the thermodynamics of halogenation 2

3. Introduction 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 organo -halogens 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 iodo -organic forms, the iodine atom is easily removed. Thus the electronegativity of the halogen atom is a driving force for halogenation reactions. 3 https://www.mt.com/in/en/home/applications/L1_AutoChem_Applications/L2_ReactionAnalysis/Halogenations.html

4. Introduction 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 .   4 https://www.mt.com/in/en/home/applications/L1_AutoChem_Applications/L2_ReactionAnalysis/Halogenations.html

5. Why are Halogenation Reactions Important? 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 , agro-products , etc. Halogenated compounds constitute ca. 20% of the repertory of active pharmaceutical ingredients (APIs), and 30% of current agrochemicals. Halogenated compounds also find applications as dyes, flame retardants, imaging agents in medical diagnosis, and in materials science. The significance of halogenated compounds is increasing rapidly. Thus, ca. 80% of newly developed agrochemicals during the first decade of the 21 st century contained one or more halogen atoms. 5 Halogenation of organic compounds using continuous flow and microreactor technology

6. Why are Halogenation Reactions Important? Notably, 7 out of the top-10 best-selling drugs in the US in 2014 were halogenated compound Almost 5000 naturally occurring organic halogenated compounds have been identified so far. The beneficial effects of a carbon–halogen bonds within the structure of organic compounds, such as increased durability, stability towards biodegradation and oxidation, and higher biological activity and membrane permeability, are shared by synthetic APIs and natural compound. 6 Halogenation of organic compounds using continuous flow and microreactor technology

7. A notable difference is the relative distribution of the halogen elements among synthetic and naturally occurring organic compounds (Fig. 1). 7 https://www.mt.com/in/en/home/applications/L1_AutoChem_Applications/L2_ReactionAnalysis/Halogenations.html Fig. 1 Distribution of halogens within the structure of naturally occurring compounds (a) and synthetic APIs and agrochemicals (b).

8. 8 While chlorinated and brominated derivatives predominate in natural metabolites, with a relatively small number of compounds containing fluorine and iodine, synthetic APIs and agro-chemicals with fluorine and chlorine are more abundant. Despite the high incidence of chlorine and fluorine atoms in the final structure of APIs, brominations and iodinations are very often carried out for the generation of synthetic intermediates. Halogenated building blocks have seen increased relevance owing to the development of cross-coupling chemistry* over the past four decades * A cross-coupling reaction in organic synthesis occurs when two fragments are joined together with the aid of a metal catalyst. Cross-coupling has been an essential reaction in catalytic chemistry for the past 30 years starting with the pioneering work by Heck, Negishi , and Suzuki, who were awarded the Nobel Prize in Chemistry in 2010 for palladium-catalyzed cross-coupling. https://www.sigmaaldrich.com/PK/en/applications/chemistry-and-synthesis/synthetic-methods/cross-coupling

9. Bioavailability: When a medicine is given orally, only part of the administered dose appears in the plasma. (Example: if 100 mg of a medicine are administered orally and 70 mg of this medicine are absorbed unchanged, the bioavailability is 0.7 or seventy percent).* Bioavailability** Medicines contain an active substance, also referred to as Active Pharmaceutical Ingredient ( API ) and  they are used in order to cure, treat or prevent illness in human beings or in animals. But they can also be used for other purposes, such as diagnosis of certain diseases. In all these use cases, the API must be able to enter the body. But in order to have a therapeutic effect, the API is also needed in the correct dose at the specific site in the body where it has to work. This specific site is referred to as the target site. In addition, the API needs to reach the target within a certain time and to stay there for a defined period. 9

10. Bioavailability The rate and degree to which the API is available at the target site is known as bioavailability. This comes closest to defining a “true” or “ideal” bioavailability for a medicine. It is mirrored in the definition by a regulatory authority, the United States FDA. They define bioavailability as "the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of drug action", whereas the European EMA simply defines it as “The extent to which an active ingredient is absorbed from a medicine and becomes available in the body”. The latter, while less precise, is however closer to what is measured in reality. Lipophilicity refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. 10

11. Fluorination Organo -fluorine compounds have become one of the most important and common class of substances among pharmaceuticals and agrochemicals Decoration of an organic compound with fluorine atoms typically results in a significant enhancement of its biological properties. Increased bioavailability, lipophilicity , and metabolic stability otherwise difficult to obtain are typically acquired by the compounds after the introduction of one or more fluorine groups. The growing interest in this area has motivated intense research efforts for the development of novel catalytic methods and greener and more selective fluorinating agents. Elemental fluorine (F2) and hydrogen fluoride HF are among the most difficult to handle reagents in organic synthesis. 11

12. Fluorination F2 is the most powerful oxidant known, and both HF and F2 are highly corrosive and toxic compounds. Even some N- fluoro derivatives that are generally easier to handle are highly reactive, hazardous compounds. Fluorination reactions, especially those using F2 directly as fluorine source, are very exothermic and difficult to control. Lack of reaction selectivity* is a common drawback. Not surprisingly, many research groups have studied the fluorination of organic materials using microreactor technology. * The selectivity of a reaction is the ratio of the desired product formed (in moles) to the undesired product formed (in moles) . 12

13. Fluorination Direct Fluorination: Direct vapor-phase fluorination using elemental fluorine is accomplished by using large volumes of an inert gaseous fluorine and hydrocarbon carrier, such as nitrogen, a mixing system that rapidly and intimately brings the two reactants into contact, and a reactor design that effectively removes the heat of reaction. Under these conditions, hydrocarbons can be fluorinated to their corresponding fluorides: CH4 +4F2 CF4 + 4HF 13

14. Fluorination Dilute fluorine reacts with metal carbides such as UC2, ThC2, and CaC2, producing fluorocarbons and metal fluorides. All these direct fluorination reactions are accompanied with high-energy type of condensation reactions where fluorocarbons of higher carbon chain length are formed. HF as a Fluorinating Agent Hydrogen fluoride adds in vapor phase by means of catalysts to acetylene 14

15. Fluorination Hydrogen fluoride may also replace chlorine in aliphatic chlorofluoro -carbons, liberating hydrogen chloride: Hydrogen fluoride in a liquid-phase reaction readily replaces chlorine in many organic compounds: 15

16. Chlorination The importance of chlorinated organic compounds in the field of agrochemicals and pharmaceuticals is comparable to that for organofluorines regarding improved pharmacological properties. In addition, chlorinated compounds are useful building blocks for the generation of more complex structures, as well as for the preparation of plastic materials or dyes. One of the most widely utilized procedures for the generation of organochlorines is the transformation of alcohols into the corresponding chlorides by substitution of the OH group. Chlorinating reagents such as SOCl2 or PCl5 are often used for this reaction. The greenest alternative for these chloro-dehydroxylation reactions is the use of HCl as reagent. 16

17. Chlorination Using directly anhydrous HCl gas, the neat alcohols were converted into the corresponding chlorides at 120 °C and 10 bar pressure Special precautions had to be taken to keep the HCl dosing part of the system anhydrous, as moisture in the HCl produced significant damage of metal parts such as the mass flow controller. Elemental chlorine (Cl2) is a powerful and atom-economic* chlorinating agent for organic compounds, as well as one of the cheapest oxidizing agents available. *Atom economy is the conversion efficiency of a chemical process in terms of all atoms involved and the desired products produced. The simplest definition was introduced by Barry Trost in 1991 and is equal to the ratio between the mass of desired product to the total mass of products, expressed as a percentage. 17

18. Chlorination Despite the importance of Cl2 as an oxidizing and chlorinating agent in organic synthesis, its extremely high reactivity limits its use in many instances, as undesired overreactions and exotherms typically occur. The efficient mixing and enhanced mass transfer achieved under continuous flow conditions minimize these problems. Apart from the problems associated with the high reactivity of Cl2 towards organic compounds, handling and storage of Cl2 gas cylinders in organic synthesis labs and production facilities is an important safety issue on his own. Use, handling, and transportation regulations for this substance are strictly regulated. 18

19. Chlorination Sites where Cl2 gas is used normally need to be isolated, and the personnel specifically equipped and trained for the handling of chlorine. 19

20. Thermodynamics of Halogenation Reactions 20

21. Many reactions of halogens with organic compounds are recorded in the literature, and many of them are utilized in commercial processes. In the consideration of both equilibrium and reaction rates, reference to the "bond energies" of the chemical bonds involved is frequently helpful; some pertinent bond energies are given in Table 1 21

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23. The heat of a reaction is given approximately by the sum of the energies of the bonds formed minus the sum of the energies of the bonds broken. The ∆ H of reaction is the negative of this. Thermodynamics of Halogenation Reactions Substitution Halogenation A survey of the thermodynamics of substitution halogenation reactions shows that All ∆ H (change in heat content) is extremely exothermic in the case of fluorine, highly exothermic for chlorine, moderately exothermic for bromine, and endothermic for iodine and that ∆ S is very small in all cases. The equilibrium is in favor of the right-hand side of the reaction at all temperatures for fluorine, chlorine, and bromine but in favor of the left-hand side at all temperatures for iodine. 23

24. Thermodynamics of Halogenation Reactions Substitution Halogenation These deductions are illustrated by data on the following reactions at 25°C, in which all reactants and products are in the gaseous state at 1 atm. 24

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26. The ∆ H of chlorination of aliphatic compounds tends to increase ,with the chain length and the possibility of substitution in other than the primary position. Addition Halogenation A survey of the thermodynamics of the addition of halogens to double bonds shows that ∆ H is highly exothermic for all the halogens and ∆ S o is of the order of -20 cal per mole deg , since there is a change of negative one in the number of molecules. ∆ F o is therefore negative, and equilibrium is in favor of the right-hand side of the reaction at all temperatures up to about 1000°C for Cl, up to about 700°C for Br, and up to about 50°C for I. These conclusions are illustrated by the accompanying reactions, in which the data are for the same conditions as given above. 26

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