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Hydrohalogenation
Hydrohalogenation
Hydrohalogenation
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A hydrohalogenation reaction is the electrophilic addition of hydrogen halides like hydrogen chloride or hydrogen bromide to alkenes to yield the corresponding haloalkanes.[1][2][3]

Hydrogen bromide addition to an alkene

If the two carbon atoms at the double bond are linked to a different number of hydrogen atoms, the halogen is found preferentially at the carbon with fewer hydrogen substituents, an observation known as Markovnikov's rule. This is due to the abstraction of a hydrogen atom by the alkene from the hydrogen halide (HX) to form the most stable carbocation (relative stability: 3°>2°>1°>methyl), as well as generating a halogen anion.

A simple example of a hydrochlorination is that of indene with hydrogen chloride gas (no solvent):[4]

hydrochlorination of indene

Alkynes also undergo hydrohalogenation reactions. Depending on the exact substrate, alkyne hydrohalogenation can proceed though a concerted protonation/nucleophilic attack (AdE3) or stepwise by first protonating the alkyne to form a vinyl cation, followed by attack of HX/X− to give the product (AdE2) (see electrophile for arrow pushing).[5] As in the case of alkenes, the regioselectivity is determined by the relative ability of the carbon atoms to stabilize positive charge (either a partial charge in the case of a concerted transition state or a full formal charge for a discrete vinyl cation). Depending on reaction conditions, the main product could be this initially formed alkenyl halide, or the product of twice hydrohalogenation to form a dihaloalkane. In most cases, the main regioisomer formed is the gem-dihaloalkane.[6] This regioselectivity is rationalized by the resonance stabilization of a neighboring carbocation by a lone pair on the initially installed halogen. Depending on relative rates of the two steps, it may be difficult to stop at the first stage, and often, mixtures of the mono and bis hydrohalogenation products are obtained.

Hydrohalogenation of alkynes

Anti-Markovnikov addition

[edit]
See also: Free-radical addition

In the presence of peroxides, HBr adds to a given alkene in an anti-Markovnikov addition fashion. Regiochemistry follows from the reaction mechanism, which exhibits halogen attack on the least-hindered unsaturated carbon. The mechanism for this chain reaction resembles free radical halogenation, in which the peroxide promotes formation of the bromine radical. However, this process is restricted to addition of HBr. Of the other hydrogen halides (HF, HCl, and HI), only HCl reacts similarly, and the process is too slow for synthetic use. (With HF and HI, the energy released in the halogen-carbon addition does not suffice to cleave another hydrogen-halogen bond. Consequently the chain cannot propagate.)[7][8]

The resulting 1-bromoalkanes are versatile alkylating agents. By reaction with dimethyl amine, they are precursors to fatty tertiary amines. By reaction with tertiary amines, long-chain alkyl bromides such as 1-bromododecane, give quaternary ammonium salts, which are used as phase transfer catalysts.[9]

With Michael acceptors the addition is also anti-Markovnikov because now a nucleophilic X− reacts in a nucleophilic conjugate addition for example in the reaction of HCl with acrolein.[10]

Addition of HCl to acrolein
Addition of HCl to acrolein

Scope

[edit]

Recent research has found that adding silica gel or alumina to H-Cl (or H-Br) in dichloromethane increases the rate of reaction making it an easy one to carry out.[citation needed]

References

[edit]
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Hydrohalogenation

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Hydrohalogenation is the of a (HX, where X is a such as , , or iodine) across a carbon-carbon double or in alkenes or alkynes, yielding the corresponding alkyl halide or products. This process is a cornerstone of , enabling the conversion of unsaturated hydrocarbons into functionalized saturated compounds. The reaction typically follows an mechanism, in which the π electrons of the or attack the electrophilic hydrogen of HX, generating a intermediate that is subsequently trapped by the nucleophilic halide ion. For unsymmetrical , the regiochemistry adheres to , dictating that the hydrogen adds to the less substituted carbon of the , thereby forming the more stable on the more substituted carbon. This ionic pathway is observed with HCl, HBr, and HI under standard conditions, often conducted in inert solvents without catalysts. A notable exception occurs with HBr in the presence of s, where the reaction shifts to a free radical chain mechanism, resulting in anti-Markovnikov addition—the attaches to the less substituted carbon. This peroxide effect, unique to HBr due to the favorable bond dissociation energies involved, provides synthetic control over and is widely exploited in for preparing primary alkyl bromides from terminal alkenes. Hydrohalogenation reactions are versatile and regioselective, playing a pivotal role in building carbon-halogen bonds for further transformations in pharmaceuticals, agrochemicals, and .

Reaction Fundamentals

Definition and General Equation

Hydrohalogenation is the reaction in which a (HX, where X is a such as chlorine, bromine, or iodine) adds across a carbon-carbon double or triple bond in unsaturated hydrocarbons, primarily alkenes and alkynes. The general equation for the reaction with alkenes is represented as: \ceR−CH=CH2+HX−>R−CHX−CH3\ce{R-CH=CH2 + HX -> R-CHX-CH3} This equation depicts the Markovnikov addition product, in which the halogen attaches to the more substituted carbon; the anti-Markovnikov product (\ceR−CH2−CH2X\ce{R-CH2-CH2X}) forms under specific conditions such as the presence of peroxides with HBr, but is not the focus here. The hydrogen halides typically employed are HCl, HBr, and HI, as HF exhibits low reactivity due to the strength of its H-F bond, making it rarely used in such additions. While alkenes are the primary substrates, the reaction also applies to alkynes, yielding vinyl halides or geminal dihalides depending on the equivalents of HX added. Hydrohalogenation is thermodynamically favorable, as the reaction is exothermic, arising from the formation of new, stronger σ bonds (C-H and C-X) compared to the broken π bond of the alkene and the H-X bond.

Markovnikov's Rule

Markovnikov's rule is an empirical guideline in organic chemistry that predicts the regioselectivity of electrophilic addition reactions involving hydrogen halides (HX, where X is a halogen such as Cl, Br, or I) to unsymmetrical alkenes. According to the rule, the hydrogen atom from HX adds to the carbon atom of the double bond that already has the greater number of hydrogen substituents, while the halogen adds to the carbon with fewer hydrogen substituents. This results in the formation of the more substituted alkyl halide product. The rule was formulated by Russian chemist Vladimir Vasilyevich Markovnikov in 1869, based on his experimental observations of the addition of hydrogen halides to various s during his doctoral research at the University of Kazan. In his seminal paper, Markovnikov analyzed the products from reactions such as the addition of HI to and noted a consistent pattern favoring the more branched, halogen-bearing product over the linear alternative. This empirical observation laid the foundation for understanding in alkene additions long before the underlying ionic mechanisms were fully elucidated. The preference described by stems from the relative stability of the intermediates formed during the process, where the more substituted is thermodynamically favored (though the full mechanistic details are covered elsewhere). A classic example is the reaction of propene (CH₃-CH=CH₂) with HBr, which yields (CH₃-CHBr-CH₃) as the major product rather than (CH₃-CH₂-CH₂Br). This outcome aligns with the rule, as the hydrogen adds to the terminal carbon (with two hydrogens), forming a secondary that leads to the internal attachment. An important exception to Markovnikov's rule occurs in the addition of HBr to alkenes in the presence of peroxides, where the reaction proceeds via a free radical mechanism, resulting in anti-Markovnikov regioselectivity (the bromine adds to the less substituted carbon). This peroxide effect was first reported by Morris S. Kharasch and F. R. Mayo in 1933.

Electrophilic Addition Mechanism

Protonation Step

In the protonation step of the electrophilic addition mechanism for hydrohalogenation, the π electrons of the alkene double bond act as a nucleophile, attacking the electrophilic proton (H⁺) from the hydrogen halide (HX), where X is a halogen such as Cl, Br, or I. This initial acid-base reaction generates a carbocation intermediate by breaking the π bond and forming a new σ bond between the proton and one of the alkene carbons. The regioselectivity of this step follows Markovnikov's rule, favoring the more stable carbocation. The general reaction for this protonation can be represented as follows for a like R₂C=CH₂: R2C=CH2+H+→R2C+−CH3\mathrm{R_2C=CH_2 + H^+ \rightarrow R_2C^+-CH_3} For unsymmetrical alkenes, occurs such that the forms on the carbon that yields the greater stability, such as a secondary or tertiary (e.g., CH₃-CH⁺-CH₃ from propene, CH₃-CH=CH₂ + H⁺ → CH₃-CH⁺-CH₃). For a tertiary example, consider 2-methylpropene: (CH₃)₂C=CH₂ + H⁺ → (CH₃)₃C⁺. Secondary and tertiary s are preferred over primary ones because of enhanced stabilization. Carbocation stability increases in the order tertiary > secondary > primary, primarily due to —where adjacent C-H σ bonds donate to the empty p orbital of the —and inductive effects from alkyl groups that push toward the positive charge. Tertiary , with three alkyl substituents, exhibit the most hyperconjugative structures (up to nine from methyl groups), making them approximately 10⁵ times more stable than primary based on relative formation rates in solvolysis reactions. Carbocations formed may rearrange if a more stable is accessible, such as a 1,2-hydride shift. For example, in 3-methyl-1-butene (CH₂=CH-CH(CH₃)₂ + H⁺), the initial secondary carbocation rearranges to a tertiary one ((CH₃)₂CH-CH⁺-CH₃), leading to rearranged alkyl products. This is the rate-determining step of the overall reaction, as it involves the highest barrier due to the endothermic formation of the intermediate; the subsequent nucleophilic attack by the is rapid and exothermic. The is influenced by the of HX, with the order HI > HBr > HCl reflecting the ease of proton dissociation and paralleling their pKa values (HI: -9.3; HBr: -8.7; HCl: -6.3).

Nucleophilic Attack Step

In the nucleophilic attack step of the mechanism for hydrohalogenation, the halide ion (X⁻) serves as a and attacks the intermediate formed in the preceding step, proceeding in a manner analogous to an SN1 reaction. This step involves the formation of a new carbon-halogen bond, yielding the final alkyl halide product. The general reaction for this step can be represented as: \ceR2C+−CH3+X−−>R2C(X)−CH3\ce{R2C^+-CH3 + X^- -> R2C(X)-CH3} where the is typically secondary or tertiary for stability, and X represents Cl, Br, or I. This occurs rapidly following formation, as the energy barrier is low due to the high reactivity of the electrophilic and the availability of the nucleophilic . The resulting alkyl halide is the more stable Markovnikov product, with the halogen attached to the carbon that can best stabilize the positive charge. If the is planar and the product features a new chiral center, the nucleophilic attack from either face leads to a of enantiomers, as there is no in this ionic mechanism. Polar protic solvents, such as or alcohols, enhance the rate of this step by solvating and stabilizing the ionic species involved, including the and the developing , thereby facilitating the nucleophilic approach.

Free Radical Addition Mechanism

Initiation by Peroxides

The peroxide effect, discovered by Morris S. Kharasch and Frank R. Mayo in 1933, describes the of HBr to alkenes that yields anti-Markovnikov in the presence of peroxides. This phenomenon is observed exclusively with HBr and not with HCl or HI, due to the unique of the radical chain process for HBr. Initiation begins with the thermal homolysis of a , such as a dialkyl (ROOR), to form two alkoxy radicals: \ceROOR−>[Δ]2RO∙\ce{ROOR ->[\Delta] 2 RO^\bullet} The alkoxy radical then abstracts the atom from HBr, generating a radical and alcohol: \ceRO∙+HBr−>ROH+Br∙\ce{RO^\bullet + HBr -> ROH + Br^\bullet} This radical serves as the chain carrier for subsequent . The specificity to HBr stems from bond dissociation energies (BDEs) that make the overall radical chain viable only for this : H-Cl at 103.2 kcal/mol, H-Br at 87.5 kcal/mol, and H-I at 71.3 kcal/mol. For HCl, the carbon radical of hydrogen (alkyl• + HCl → alkyl-H + Cl•) is endothermic by approximately 5 kcal/mol, slowing ; for HI, the initial addition of I• to the is endothermic due to the weak C-I bond, preventing effective chain . Only trace amounts of s (typically 0.01–0.1 mol%) or light are required to trigger homolysis, contrasting with the peroxide-free ionic pathway that follows .

Propagation and Termination Steps

In the free radical mechanism of hydrohalogenation, the propagation steps form the core of the that efficiently produces the anti-Markovnikov product. The first propagation step involves the addition of a radical (Br•) to the , where the radical adds to the less substituted carbon of the , generating a carbon-centered radical intermediate. For a general R-CH=CH₂, this is represented as: Br∙+R-CH=CH2→R-CH∙-CH2Br\text{Br}^\bullet + \text{R-CH=CH}_2 \rightarrow \text{R-CH}^\bullet\text{-CH}_2\text{Br} This step favors the formation of the more stable radical (typically secondary over primary), ensuring attaches to the terminal carbon. The second step entails the abstraction of a from HBr by the carbon radical, yielding the alkyl bromide product and regenerating the radical to continue the chain. For the intermediate from the previous step: R-CH∙-CH2Br+HBr→R-CH2-CH2Br+Br∙\text{R-CH}^\bullet\text{-CH}_2\text{Br} + \text{HBr} \rightarrow \text{R-CH}_2\text{-CH}_2\text{Br} + \text{Br}^\bullet This produces the 1-bromoalkane (anti-Markovnikov orientation) and maintains the radical concentration, allowing a single initiating radical to propagate thousands of product molecules in a highly efficient . The arises from the stability of the radical intermediate in the first step: the radical adds preferentially to the less substituted carbon to form the more stable (more substituted) carbon radical, which then abstracts from HBr more readily than from the alternative pathway. This contrasts with the ionic mechanism and leads to attaching to the more substituted carbon overall. Termination steps occur when two radicals collide and combine, the chain without producing new radicals. Common examples include the recombination of two radicals: Br∙+Br∙→Br2\text{Br}^\bullet + \text{Br}^\bullet \rightarrow \text{Br}_2 or coupling of two carbon radicals: R∙+R∙→R-R\text{R}^\bullet + \text{R}^\bullet \rightarrow \text{R-R} These processes are minor compared to under typical conditions but become significant at high radical concentrations, effectively ending the reaction.

Scope and Applications

Substrates and Regioselectivity

Hydrohalogenation reactions primarily involve the of halides (HX, where X = Cl, Br, or I) to unsaturated carbon-carbon bonds in alkenes and alkynes, with governed by the stability of the resulting intermediates under ionic conditions. Terminal alkenes, such as propene (CH₃CH=CH₂), undergo regioselective following , yielding 2-halopropane as the major product, where the attaches to the more substituted carbon. Internal symmetrical alkenes, like trans-2-butene ((CH₃CH=CHCH₃)), produce a single racemic product without concerns, as both carbons of the are equivalently substituted. Conjugated dienes exhibit dual addition modes due to resonance-stabilized allylic carbocations, resulting in 1,2-addition products where HX adds across one and 1,4-addition products where the ends up at the distant carbon. For example, 1,3-butadiene (CH₂=CH-CH=CH₂) reacts with HBr to form 3-bromo-1-butene (1,2-addition, kinetic product at low temperatures) and 1-bromo-2-butene (1,4-addition, thermodynamic product at higher temperatures). Alkynes also serve as substrates, with terminal alkynes (RC≡CH) undergoing stepwise addition to first form vinyl halides and then dihalides upon excess HX. The initial addition follows Markovnikov , producing (E)- and (Z)-1-halo-1-alkenes such as RCX=CH₂; a second equivalent of HX then adds to yield dihalides like RCX₂CH₃. For instance, 1-hexyne (CH₃(CH₂)₃C≡CH) reacts with two equivalents of HBr to give 2,2-dibromohexane as the major product. Regioselectivity in hydrohalogenation is influenced by electronic effects, where stability dictates halogen placement on the carbon best able to bear positive charge, and steric hindrance, which can disfavor highly substituted transition states. Electron-withdrawing groups adjacent to the double bond slightly favor anti-Markovnikov orientation by destabilizing the more substituted , though Markovnikov products predominate in most cases. rearrangements, such as shifts, further affect ; for example, 3-methyl-1-butene ((CH₃)₂CHCH₂CH=CH₂) with HCl forms primarily 2-chloro-2-methylbutane via a 1,2- shift from the initial secondary to a tertiary one. Representative examples highlight these patterns: styrene (PhCH=CH₂) adds HBr to give 1-bromo-1-phenylethane (PhCHBrCH₃) as the major Markovnikov product, stabilized by the benzylic .

Reaction Conditions and Variations

Hydrohalogenation reactions typically proceed under mild conditions, often at , using neat (HX, where X = Cl, Br, or I) or aqueous solutions for alkenes, with no additional catalysts required for HCl or HBr additions. These conditions facilitate the mechanism, yielding alkyl halides efficiently for most terminal and internal alkenes. Solvents are generally non-nucleophilic to avoid competing reactions, though polar protic solvents like acetic acid can be employed for specific studies. For anti-Markovnikov regioselectivity in HBr additions, a free radical mechanism is induced by adding 1-5% organic peroxides, such as benzoyl peroxide or tert-butyl peroxide, under an inert atmosphere to prevent oxygen inhibition and ensure clean propagation. This variation requires mild heating to cleave the peroxide O-O bond (bond energy ≈35 kcal/mol), typically around 60-80°C, and is unique to HBr due to favorable thermodynamics in the propagation steps; HCl and HI do not respond similarly because their respective bond strengths lead to endothermic or inefficient radical processes. Temperature plays a key role in the ionic pathway as well: low temperatures (e.g., 0°C) favor kinetic control and minimize carbocation rearrangements, while higher temperatures (above 50°C) can promote equilibration or side reactions in sensitive substrates. Variations extend to conjugated dienes and alkynes, where controlled equivalents of HX (e.g., one for monoaddition to alkynes yielding vinyl halides) allow selective 1,2- or 1,4-addition in dienes under similar conditions, often favoring kinetic 1,2-products at low temperatures. Industrially, HBr hydrohalogenation is applied in synthesis, such as producing brominated intermediates for flame-retardant additives. HI exhibits high reactivity in hydrohalogenation but is limited by proneness to side reactions, including over-addition to diiodides or reduction pathways due to its weak C-I bond, while HF is generally avoided owing to its extreme corrosiveness, fuming nature, and safety hazards despite following the same Markovnikov pathway.

References

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