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Halohydrin

A halohydrin, also known as a haloalcohol or β-halo alcohol, is a type of organic compound featuring a halogen atom (typically chlorine, bromine, or iodine) and a hydroxyl group (-OH) bonded to adjacent (vicinal) saturated carbon atoms.^[1] These molecules generally follow the structure R-CH(OH)-CHX-R' or similar variants, where the carbons bear only hydrogen or hydrocarbyl groups otherwise, and common examples include 2-bromoethanol (ethylene bromohydrin) and 2-chloro-1-phenylethanol (styrene chlorohydrin).^[1] Halohydrins are primarily synthesized through the electrophilic addition of a halogen (X₂, where X = Cl or Br) to an alkene in the presence of water, or equivalently using hypohalous acid (HOX).^[2] This reaction proceeds via a three-membered cyclic halonium ion intermediate, first proposed in the context of alkene halogenation by Roberts and Kimball in 1937, where the alkene's π electrons attack the halogen to form the bridged ion.^[3] Water then acts as a nucleophile, attacking the more substituted carbon of the halonium ion in a stereospecific anti-addition manner, followed by deprotonation to yield the neutral product.^[2] In unsymmetrical alkenes, the addition is regioselective, with the hydroxyl group attaching to the more substituted carbon (Markovnikov orientation) and the halogen to the less substituted one, due to the partial positive charge development on the more stable carbocation-like position during nucleophilic attack.^[2] These compounds play a crucial role in organic synthesis as versatile intermediates, notably for the preparation of epoxides through base-promoted intramolecular cyclization.^[4] Treatment of a halohydrin with a strong base (e.g., NaOH) displaces the halide ion via an S_N2 mechanism, forming a three-membered oxirane ring while preserving the anti stereochemistry from the initial addition.^[4] This route is particularly valuable for regioselective epoxide synthesis from alkenes and has applications in producing pharmaceuticals, agrochemicals, and other fine chemicals, often as an alternative to peracid epoxidation methods.^[5] Halohydrins also exhibit reactivity in further transformations, highlighting their utility in stereocontrolled synthesis.

Definition and Nomenclature

Chemical Structure

A halohydrin features a core molecular framework consisting of a halogen atom (X, where X = F, Cl, Br, or I) and a hydroxyl group (-OH) bonded to adjacent (vicinal) carbon atoms, defining its characteristic functionality. This refers to vicinal halohydrins, where the groups are on adjacent carbons, as opposed to geminal halohydrins on the same carbon. The general formula is often expressed as R¹R²C(OH)–CR³R⁴X, with R¹–R⁴ representing hydrogen or alkyl/aryl substituents, allowing for a wide range of structural diversity. For chlorohydrins, a typical representation is R–CH(OH)–CH(Cl)–R', while analogous formulas apply to other halohydrins by replacing Cl with Br, I, or F.^[2]^[6] This vicinal positioning imparts distinct bonding characteristics, with the halogen-carbon bond typically polar covalent and the carbon-hydroxyl bond enabling hydrogen bonding interactions. Halohydrins can exist in acyclic forms, such as linear chains in simple alkyl derivatives, or cyclic configurations, exemplified by six-membered rings like trans-2-chlorocyclohexanol, where the halogen and hydroxyl occupy adjacent positions across the ring. They also appear in complex molecules like carbohydrates, where the motif integrates into polyhydroxy frameworks with the halogen substituting a hydroxyl-bearing carbon adjacent to another -OH group.^[7]

Naming Conventions

Halohydrins are named systematically under IUPAC recommendations as substituted alcohols, with the hydroxy group serving as the principal functional group that determines the suffix "-ol" for the parent chain. The carbon chain is selected and numbered to give the carbon atom bearing the hydroxy group the lowest possible locant, and halogen atoms are cited as prefixes (fluoro-, chloro-, bromo-, or iodo-) with their positions indicated. For instance, the compound with the formula HOCH₂CHClCH₃ is designated as 2-chloropropan-1-ol, prioritizing the hydroxy group's position at carbon 1./Alcohols/Nomenclature_of_Alcohols) In addition to IUPAC nomenclature, trivial or common names persist for certain halohydrins, particularly those derived from simple alkenes or featuring vicinal halogen and hydroxy groups. The term "chlorohydrin" specifically denotes compounds where chlorine is the halogen substituent, while "bromohydrin," "fluorohydrin," and "iodohydrin" apply analogously for the other halogens. These names, such as ethylene chlorohydrin for HOCH₂CH₂Cl, emphasize the functional group combination rather than the full structural detail and are widely used in synthetic contexts.^[2]^[8] Special naming conventions apply when halohydrins occur within complex molecules, such as carbohydrates. In sugar chemistry, these are typically designated as halo-deoxy derivatives, where the halogen replaces a hydroxy group at a specific position, as in 3-chloro-3-deoxy-D-glucose. The nomenclature follows carbohydrate-specific IUPAC rules, incorporating stereochemical descriptors (e.g., D or L) and locants that align with the standard numbering of the sugar ring or chain. The evolution of halohydrin nomenclature traces back to 19th-century organic chemistry, when early discoveries of compounds like ethylene chlorohydrin in 1859 prompted the adoption of descriptive trivial names to reflect their hybrid nature. By the late 1800s, terms like "chlorohydrin" entered chemical literature around 1885, facilitating communication amid rapid advancements in alkene reactivity studies. The shift to systematic IUPAC naming in the early 20th century standardized these conventions, integrating halohydrins into broader rules for alcohols and substituents while retaining trivial names for brevity in specialized applications.^[9]^[10]

Physical and Chemical Properties

General Properties

Halohydrins, particularly simple examples such as those derived from small alkenes, are typically colorless liquids or low-melting solids at room temperature.^[11] For instance, 2-chloroethanol exists as a colorless liquid with an ether-like odor.^[11] The presence of the hydroxyl group imparts high water solubility to halohydrins, often making them miscible with water, while the halogen substituent enhances overall molecular polarity.^[12] This solubility is exemplified by 2-chloroethanol, which is fully miscible in water.^[11] The vicinal arrangement of the halogen and hydroxyl groups contributes to this polarity in a single sentence. Boiling and melting points vary with molecular size and halogen type, but simple halohydrins generally have moderate boiling points due to hydrogen bonding from the OH group. 2-Chloroethanol, for example, boils at 128–130 °C and melts at –67 °C.^[12] In infrared (IR) spectroscopy, halohydrins display characteristic absorption bands, including a broad O–H stretching vibration around 3400 cm⁻¹ indicative of hydrogen bonding in alcohols, and C–X stretching in the 850–515 cm⁻¹ range for the halogen (e.g., 850–550 cm⁻¹ for C–Cl).^[13] Nuclear magnetic resonance (NMR) spectroscopy reveals deshielded protons alpha to the halogen, typically appearing at 3.5–4.0 ppm; in 2-chloroethanol, the CH₂Cl protons resonate at approximately 3.87 ppm and the CH₂OH protons at 3.67 ppm in CDCl₃.^[14]

Stability and Reactivity

Halohydrins generally exhibit good thermal stability under ambient conditions but decompose at elevated temperatures, typically above 400°C for simple aliphatic examples. For instance, 2-chloroethanol undergoes thermal decomposition in the gas phase between 430–496°C, primarily yielding acetaldehyde and hydrogen chloride via a first-order process with an activation energy of approximately 230 kJ/mol.^[15] This decomposition pathway highlights the tendency of halohydrins to form carbonyl compounds under high heat, though more complex halohydrins may show lower onset temperatures depending on substituents and molecular structure.^[16] The hydroxyl group in halohydrins displays moderate acidity, with pKa values typically in the range of 14–15, slightly lower than those of analogous simple alcohols (pKa ≈ 15.9–18). For 2-chloroethanol, the pKa of the OH group is reported as 14.02, reflecting the electron-withdrawing inductive effect of the adjacent halogen, which stabilizes the conjugate base by dispersing negative charge.^[17] This inductive withdrawal increases acidity compared to unsubstituted alcohols, with the effect strengthening as the halogen's electronegativity rises (F > Cl > Br > I).^[18] Halohydrins show enhanced reactivity in acidic media, where protonation of the hydroxyl group converts it into a more labile water leaving group, facilitating subsequent transformations.^[19] This protonation is a key step in alcohol reactivity but is amplified in halohydrins due to the neighboring halogen's potential to influence the transition state through inductive or participation effects. In basic conditions, halohydrins are comparatively more stable, though the OH group remains deprotonatable. The nature of the halogen significantly influences overall stability, with bond strength playing a dominant role: fluorohydrins are the most stable due to the robust C–F bond (dissociation energy ≈ 485 kJ/mol), followed by chlorohydrins (≈ 328 kJ/mol), bromohydrins (≈ 276 kJ/mol), and iodohydrins (≈ 238 kJ/mol), which are the least stable and prone to C–I bond cleavage.^[20] In specific polycyclic systems, the stability order mirrors this trend: chlorohydrin > bromohydrin > iodohydrin, underscoring the impact of weaker C–X bonds on thermal and chemical endurance.^[21]

Synthesis

From Alkenes

Halohydrins are commonly synthesized from alkenes through the electrophilic addition of a halogen in the presence of water. This method involves treating an alkene with a dihalogen molecule such as chlorine (Cl₂) or bromine (Br₂) in an aqueous medium, leading to the formation of a halonium ion intermediate that is subsequently attacked by water as a nucleophile.^[22]^[23] The mechanism proceeds in two key steps. First, the alkene's π electrons attack one end of the polarized X–X bond, forming a three-membered halonium ion ring (chloronium or bromonium ion) and releasing the halide ion (X⁻). This cyclic intermediate shields one face of the alkene, preventing syn addition. Second, water acts as the nucleophile, attacking the more substituted carbon of the halonium ion from the opposite face in an anti fashion, followed by proton loss to yield the halohydrin product. The partial positive charge in the transition state is stabilized at the more substituted carbon, dictating the regioselectivity.^[22]^[24]^[23] This addition follows Markovnikov's rule, where the hydroxyl group (OH) attaches to the more substituted carbon and the halogen to the less substituted one. For example, the reaction of propene with Br₂ in water yields 1-bromopropan-2-ol as the major product. The general equation for a terminal alkene is:

\text{R-CH=CH}_2 + \text{X}_2 + \text{H}_2\text{O} \rightarrow \text{R-CH(OH)-CH}_2\text{X}

Yields are typically high under mild conditions, often at room temperature, with water serving both as solvent and reactant.^[22]^[23] The stereochemistry results in trans addition, producing a racemic mixture from achiral alkenes or meso compounds from symmetric ones like cyclohexene. This anti stereospecificity arises from the backside nucleophilic attack on the halonium ion.^[24]^[22] This synthesis method was first applied industrially in 1914 for the production of ethylene chlorohydrin as a precursor to ethylene oxide.^[25]

From Epoxides

Halohydrins are synthesized from epoxides through nucleophilic ring-opening reactions, primarily under acidic conditions using hydrogen halides (HX, where X = Cl, Br, or I) in aqueous or alcoholic media.^[26] The reaction proceeds via an acid-catalyzed mechanism, where the epoxide oxygen is protonated by H⁺ from HX, forming a protonated epoxide intermediate that enhances the electrophilicity of the adjacent carbons.^[27] This protonation weakens the C-O bonds, allowing the halide ion (X⁻) to attack as the nucleophile.^[28] In the acid-catalyzed pathway, the regioselectivity is such that the halide attacks the more substituted carbon of the protonated epoxide, as this position better stabilizes the partial positive charge in the transition state, akin to an SN1-like mechanism for unsymmetrical epoxides.^[27] For symmetrical epoxides, such as cyclohexene oxide, the reaction with HBr yields trans-2-bromocyclohexanol, where the bromine attaches to one of the equivalent carbons and the hydroxyl group to the adjacent carbon.^[26] Under basic conditions, epoxide ring opening with a halide nucleophile (e.g., from NaX) inverts the regioselectivity, with the nucleophile attacking the less hindered, less substituted carbon via an SN2 mechanism.^[28] This approach is less common for halohydrin formation compared to the acidic method but provides complementary selectivity for regioselective synthesis.^[29] The stereochemistry of epoxide ring opening is consistently anti, resulting in trans halohydrins due to backside attack by the nucleophile, which inverts the configuration at the attacked carbon.^[27] Epoxides employed in these reactions are frequently prepared upstream from alkenes via epoxidation.^[26]

From Other Precursors

Halohydrins can be synthesized from alpha-halo carbonyl compounds through reduction of the carbonyl group, yielding vicinal halo-alcohols. For example, alpha-halo ketones or aldehydes are reduced using hydride reagents such as sodium borohydride, preserving the alpha-halogen while converting the carbonyl to a hydroxyl group. This method is particularly useful for preparing non-carbonyl halohydrins and is detailed in comprehensive reviews of alpha-halo carbonyl chemistry.^[30] Another route involves allylic halogenation of alkenes to form allyl halides, followed by enzymatic hydration or addition processes that incorporate the hydroxyl group adjacent to the halogen. In biological systems, halohydrin dehalogenases or related enzymes facilitate the conversion of allyl halides to halohydrins via intramolecular participation of the allylic halogen during double bond functionalization. For instance, the reaction pathway can involve propene undergoing allylic halogenation to 3-bromoprop-1-ene (CH₂=CH-CH₂Br), followed by enzyme-mediated incorporation of the hydroxyl group to yield a vicinal halohydrin such as 1-bromopropan-2-ol through neighboring group migration.^[31] Electrochemical methods provide a clean alternative for halohydrin formation, particularly through anodic oxidation in halide media. In this approach, alkenes are oxidized at the anode in the presence of iodide sources like ammonium iodide and water or alcohol nucleophiles, generating iodohydrins without external oxidants or metal catalysts. Yields range from 19% to 90% depending on the alkene substrate, with the process involving in situ generation of electrophilic iodine species. This technique is highlighted in recent advancements for sustainable synthesis.^[32] Less common chemical routes include selective substitution of vicinal dihalides, where one halogen is displaced by a hydroxyl group under controlled hydrolytic conditions. Enzymatic catalysis using halohydrin dehalogenases enables regioselective hydrolysis of compounds like 1,2-dibromoethane to 2-bromoethanol, offering high specificity in biological or biocatalytic contexts. Chemical analogs may employ mild aqueous conditions or silver-assisted displacement for similar transformations, though yields and selectivity vary.^[33] Recent biocatalytic advances include the enantiodivergent synthesis of halohydrins via engineered cytochrome P450 enzymes, which perform stereoselective C–H hydroxylation on alkyl halides to introduce the hydroxyl group adjacent to the halogen (reported as of 2023). This method enables access to both enantiomers and complements traditional routes.^[34]

Reactions and Transformations

Epoxide Formation

The formation of epoxides from halohydrins proceeds via a base-promoted intramolecular cyclization, where the hydroxyl group of the halohydrin acts as a nucleophile to displace the adjacent halide, forming a three-membered oxirane ring.^[35] This reaction is a classic example of an intramolecular Williamson ether synthesis adapted for ring closure.^[36] The mechanism begins with deprotonation of the hydroxyl group by a base, generating an alkoxide ion. This alkoxide then performs a backside nucleophilic attack on the carbon atom bearing the halide in an S_N2 fashion, displacing the halide ion and closing the epoxide ring.^[36]^[35] The general equation for this transformation is:

\ce{R-CH(OH)-CH2Cl + OH^- ->[base] R-CH\ -CH2 (epoxide) + Cl^- + H2O}

where R represents an alkyl substituent, and the epoxide is depicted in its ring form.^[35] Typical conditions involve treatment with aqueous sodium hydroxide (NaOH) or potassium hydroxide (KOH), often at mild temperatures, leading to high yields.^[36] For instance, the chlorohydrin derived from propylene (1-chloro-2-propanol) cyclizes to propylene oxide, while the chlorohydrin from allyl alcohol yields glycidol (2,3-epoxy-1-propanol) in good efficiency.^[37] The stereochemistry of the cyclization features inversion of configuration at the carbon bearing the halogen due to the S_N2 mechanism, which preserves the overall trans geometry of the starting halohydrin in the resulting epoxide.^[38] This cyclization serves as a key step in the industrial chlorohydrin process for propylene oxide production, where propylene chlorohydrin is treated with bases like calcium hydroxide (Ca(OH)₂) or NaOH to generate the epoxide on a large scale.^[39]

Substitution and Elimination

Halohydrins serve as substrates for nucleophilic substitution reactions primarily at the carbon atom bearing the halogen, as the halide functions as a good leaving group in SN2 pathways, particularly when the carbon is primary or unhindered secondary. For instance, primary chlorohydrins can undergo halide exchange via the Finkelstein reaction with sodium iodide in acetone, converting the chloride to iodide to facilitate subsequent transformations, as the iodide ion acts as a strong nucleophile displacing the chloride in an SN2 mechanism. The general reaction for nucleophilic substitution is represented as:

\ce{R-CH(OH)-CH2Br + Nu^- -> R-CH(OH)-CH2Nu + Br^-}

where \ce{Nu^-} is a nucleophile such as azide or cyanide, proceeding via backside attack with inversion of configuration at the substituted carbon. Leaving group ability influences the rate, with iodide being the best (I > Br > Cl) due to weaker C–I bond strength and better stabilization of the negative charge on the departing anion. Solvent effects are critical: polar aprotic solvents like acetone or DMF favor SN2 by solvating the nucleophile poorly, enhancing its reactivity, while polar protic solvents such as water or alcohols promote SN1 pathways for secondary or tertiary halohydrins through carbocation intermediates, potentially leading to rearrangements.^[40]^[41] The hydroxyl group in halohydrins can also undergo displacement under acidic conditions, where protonation converts –OH to –OH₂⁺, a excellent leaving group (water), allowing substitution typically with hydrogen halides like HBr or HI to form dihalides. This SN1 or SN2 process (depending on the carbon substitution) follows the reactivity order HI > HBr > HCl, with primary halohydrins favoring SN2 and secondary favoring SN1 via carbocation formation. For example, treatment of a secondary chlorohydrin with HBr in acetic acid yields the corresponding vicinal chlorobromo compound with bromide replacing the hydroxyl.^[42] Elimination reactions of halohydrins are base-induced and proceed via E2 mechanisms, yielding alkenes when a β-hydrogen trans to the halogen is available. The E2 pathway requires anti-periplanar alignment of the β-hydrogen and leaving group in the transition state for efficient orbital overlap, leading to stereospecific anti elimination and favoring trans alkenes when applicable. Epoxide formation can compete as an intramolecular pathway, but elimination predominates with bulky bases or in non-cyclizing geometries.^[43]^[44]

Other Key Reactions

Halohydrins can undergo oxidation of the hydroxyl group to yield α-halo ketones, a transformation that preserves the halogen substituent while converting the secondary alcohol to a carbonyl. This reaction is typically achieved using mild oxidizing agents such as pyridinium chlorochromate (PCC) in dichloromethane or manganese dioxide (MnO₂) in neutral conditions, which selectively target the alcohol without displacing the adjacent halogen. For example, the oxidation of a chlorohydrin proceeds as follows:

\ce{R-CH(OH)-CH2Cl ->[PCC or MnO2] R-C(O)-CH2Cl}

This method is particularly useful for preparing α-halo carbonyl compounds, which serve as versatile intermediates in organic synthesis due to their reactivity in nucleophilic substitutions and enolate formations.^[45] In polymer chemistry, halohydrins are employed in coupling reactions to introduce vicinal functionalities into polymer chains, often through ring-opening of epoxide precursors followed by halogenation or direct incorporation via nucleophilic substitution. This approach allows for the synthesis of halohydrin-containing polymers with tailored properties, such as enhanced reactivity for further cross-linking or functionalization. For instance, polymer-bound epoxides can be converted to halohydrins using halide sources, enabling subsequent coupling steps that build complex macromolecular structures.^[46] Halohydrins also participate in C-C bond formation via organometallic routes, where the halide acts as a leaving group in cross-coupling reactions with organozinc or organoboron reagents under palladium catalysis. These transformations extend the carbon skeleton while retaining stereochemical control from the original halohydrin, facilitating the construction of chiral building blocks. Such methods are valuable in total synthesis, where the hydroxyl group can be protected or leveraged for directing selectivity.^[47] Under ultraviolet (UV) irradiation, halohydrins can exhibit photochemical halogen migration, involving 1,2-shifts facilitated by homolytic cleavage of the C-halogen bond and radical intermediates. This process is particularly observed in iodohydrins or under conditions promoting hypo-halite formation, leading to rearranged products with potential applications in stereoselective ether synthesis. The migration is influenced by solvent and light wavelength, with visible or UV light inducing rearrangements in hypoiodite derivatives of halohydrins. Recent developments since 2020 have advanced the use of halohydrins in asymmetric synthesis through chiral catalysts, particularly biocatalysts like halohydrin dehalogenases (HHDHs) and transition metal complexes. For example, evolved HHDHs enable stereoselective ring-opening of aziridines or epoxides with azide nucleophiles, yielding enantioenriched halohydrins for triazole synthesis compatible with Cu(I) catalysis. Additionally, Ir-catalyzed asymmetric hydrogenation of α-halo enones using dynamic kinetic resolution with chiral f-phamidol ligands produces vicinal halohydrins with high enantioselectivity (up to 99% ee), addressing limitations in scalable chiral pool access. In 2023, engineered cytochrome P450 enzymes (P450DA) enabled enantiodivergent synthesis of γ-halohydrins and β-haloallyl alcohols as building blocks for pharmaceuticals.^[34] In 2025, electrochemical deprotonation of halohydrins was shown to enable cascading reactions for CO2 capture and formation of cyclic carbonates, offering sustainable routes to value-added chemicals.^[48] These methods highlight the growing role of halohydrins in enantiopure compound production.^[49]^[50]^[51]

Derivatives and Examples

Polyhalogenated Halohydrins

Polyhalogenated halohydrins are a class of halohydrins featuring multiple halogen atoms attached to the carbon chain, typically adjacent to or on the same carbon as the hydroxyl group, exemplified by 1,2-dichloroethanol (ClCH₂CH(OH)Cl).^[52] These compounds differ from monohalohydrins by incorporating additional halogens, which can be vicinal, geminal, or distributed along the chain, leading to distinct structural and reactive profiles. Synthesis of polyhalogenated halohydrins often involves the addition of halogenating agents in aqueous media to polyhalogenated alkenes, analogous to standard halohydrin formation but adapted for substrates with pre-existing halogens. For instance, vinyl chloride undergoes reaction with chlorine in water to produce 1,2-dichloroethanol:

\ce{CH2=CHCl + Cl2 + H2O -> ClCH2CH(OH)Cl + HCl}

This process proceeds via a chloronium ion intermediate, with the hydroxyl group adding to the more substituted carbon influenced by the existing chlorine substituent. Alternatively, ring-opening of halogenated epoxides with hydrogen halides can yield these structures, where the epoxide's inherent strain facilitates nucleophilic attack by the halide, incorporating additional halogens during the process. The presence of multiple halogens imparts unique properties to polyhalogenated halohydrins, notably increased acidity of the hydroxyl group due to the inductive electron-withdrawing effects of the halogens, which stabilize the conjugate base and lower the pKa compared to unsubstituted alcohols.^[53] This enhanced acidity facilitates deprotonation under milder conditions, promoting further reactivity. Additionally, these compounds exhibit heightened instability and reactivity relative to monohalohydrins, often undergoing spontaneous elimination of hydrogen halide to form carbonyl derivatives, such as aldehydes or ketones, driven by the geminal or vicinal arrangement of the functional groups.^[53] Physical properties, such as boiling point (approximately 166.5°C for 1,2-dichloroethanol) and density (1.398 g/cm³), reflect the polar nature augmented by the halogens.^[54] Polyhalogenated halohydrins demonstrate elevated toxicity compared to their monohalogenated counterparts, with the additional halogens exacerbating cellular damage through increased oxidative stress and reactivity toward biomolecules.^[55] In environmental contexts, they arise as disinfection byproducts during chlorination of water containing organic precursors, contributing to the overall health risks associated with halogenated disinfection byproducts, including potential carcinogenicity and cytotoxicity.^[56]

Notable Compounds

One of the earliest notable halohydrins is ethylene chlorohydrin, also known as 2-chloroethanol (HOCH₂CH₂Cl), first prepared in 1859 by Charles-Adolphe Wurtz via the reaction of ethylene glycol with hydrochloric acid.^[57] This compound, isolated by distillation under reduced pressure, served as a key precursor in the development of ethylene oxide production processes.^[58] Another significant example is 2-bromoethanol (HOCH₂CH₂Br), a simple bromohydrin prepared by the addition of bromine to ethylene in aqueous medium, followed by extraction with ether and distillation.^[59] Alternatively, it can be synthesized from ethylene oxide and hydrobromic acid, with isolation via fractional distillation to yield a colorless liquid boiling at 150–151°C.^[60] This compound is valued in organic synthesis for its reactivity as a bifunctional alkylating agent. Chloral hydrate (Cl₃CCH(OH)₂), discovered in 1832 by Justus von Liebig through chlorination of ethanol, is often regarded as a halohydrin analog despite being a geminal diol rather than a vicinal halohydrin.^[61] Its structure features three chlorine atoms adjacent to the hydrated carbonyl, and it was isolated as colorless crystals from aqueous solutions. Glycerol chlorohydrins, such as α-monochlorohydrin (HOCH₂CH(OH)CH₂Cl), are important derivatives obtained by controlled chlorination of glycerol with hydrochloric acid.^[62] These compounds, isolated by fractional distillation, find application in the manufacture of surfactants due to their amphiphilic properties.

Applications

In Organic Synthesis

Halohydrins serve as versatile intermediates in organic synthesis, particularly for constructing epoxides through base-mediated cyclization, which facilitates the introduction of oxygen functionality in complex molecules. This transformation is widely employed due to the ability of halohydrins to undergo regioselective ring closure, yielding epoxides that can be further functionalized via nucleophilic ring-opening reactions. In pharmaceutical synthesis, halohydrin-derived epoxides are crucial for producing chiral building blocks in antiviral drugs, such as the HIV protease inhibitor nelfinavir, where a chlorohydrin intermediate is generated via enzymatic reduction of an α-chloroketone and subsequently cyclized to form the epoxide core before incorporation into the final structure.^[63] Similarly, asymmetric organocatalytic methods have enabled the synthesis of epoxide intermediates for antiviral alkaloids like (+)-gliocladin C through kinetic resolution of spiro-epoxyindoles, achieving high enantiomeric excesses.^[64] Chiral halohydrins play a pivotal role in asymmetric induction during total synthesis, enabling the stereocontrolled assembly of natural products and pharmaceuticals by leveraging their dual functionality for subsequent displacements or cyclizations. For instance, iridium-catalyzed asymmetric hydrogenation of halogenated ketones produces enantioenriched halohydrins that serve as precursors for bioactive compounds, with selectivities up to 99% ee.^[65] In total synthesis applications, chiral epoxides derived from halohydrins have been utilized in routes to antibiotics like monocillin I and hypoglycemic agents such as (R)-methyl palmoxirate, where the halohydrin step ensures stereochemical control.^[66] Specific examples include the enantioselective preparation of halohydrin precursors for β-blockers like propranolol, achieved through yeast-catalyzed reduction of α-haloketones, yielding the (R)-enantiomer with 95% ee and 85% yield using Pichia mexicana.^[67] In carbohydrate chemistry, halohydrins derived from inositols undergo lithium hydride-mediated epoxide formation to access ring-modified derivatives, proceeding via an axial-rich conformation for efficient stereocontrol.^[68] The primary advantage of halohydrin formation lies in its regioselective functionalization of alkenes, where the reaction with X₂ in water generates a halonium ion intermediate that directs nucleophilic attack by water to the more substituted carbon, following Markovnikov's rule and yielding anti addition products with predictable regiochemistry.^[69] This regioselectivity contrasts with non-directed halogenation and enables precise control in polyfunctionalized systems. Modern organocatalytic methods have advanced this process, such as chiral ammonium salt-catalyzed asymmetric chlorocyclization of allylic alcohols, which proceeds through a chlorohydrin intermediate to afford chlorotetrahydrofurans with up to 99:1 dr and 95% ee, expanding access to enantioenriched motifs.^[70] Additionally, organocatalytic haloetherification of alkenes provides stereoselective halohydrins as synthetic equivalents for further elaboration in natural product synthesis.^[71] These approaches update traditional methods by incorporating mild conditions and high stereocontrol, making halohydrins indispensable for efficient synthetic routes.

Industrial and Biological Roles

Halohydrins play a central role in industrial production, particularly through the chlorohydrin process for manufacturing propylene oxide (PO), a key precursor for polyurethanes, propylene glycols, and other chemicals. In this process, propylene reacts with hypochlorous acid to form propylene chlorohydrin, which is then converted to PO using lime. As of 2024, the chlorohydrin route accounted for approximately 46% of global PO production, with overall PO demand reaching 10.1 million tonnes.^[72]^[73] This method dominates in regions like Asia, where it supports large-scale facilities, though its share has been declining in some markets due to environmental concerns. As of 2025, the HPPO process continues to expand, with projections indicating it will capture a larger share of production due to its environmental benefits, potentially reducing the chlorohydrin dominance below 40% by 2030.^[74] Biologically, halohydrins are generated through enzymatic halogenation in marine organisms, serving roles in defense, signaling, and metabolite synthesis. Vanadium-dependent haloperoxidases in marine algae, such as those in red and brown seaweeds, catalyze the oxidation of halides (e.g., bromide or iodide) by hydrogen peroxide to form hypohalites, which can add to unsaturated substrates like terpenes to produce halohydrins.^[75]^[76] Similarly, flavin-dependent halogenases in bacteria facilitate regioselective chlorination or bromination, leading to halohydrin intermediates in the biosynthesis of natural products, including antibiotics and pigments.^[75] These enzymes enable mild, stereospecific halogen incorporation under aqueous conditions, contrasting with harsh chemical methods. In environmental contexts, halohydrins emerge as byproducts during seawater chlorination for desalination or disinfection, where chloride reacts with bromide ions (abundant at ~65 mg/L in seawater) to form hypobromite, which can react with organic matter containing double bonds to yield bromohydrins.^[77]^[78] Such brominated species contribute to the suite of disinfection byproducts (DBPs) like bromoform and bromoacetic acids, posing challenges in coastal water treatment systems.^[78] Related to industrial scales, precursors like epichlorohydrin—derived from allyl chloride via halohydrin intermediates—see global production of around 2 million tonnes per year, supporting epoxy resin and glycidol synthesis.^[79] Sustainability issues with the chlorohydrin process include high salt waste (e.g., calcium chloride) and chlorine consumption, prompting a shift to greener alternatives like the hydrogen peroxide-based PO (HPPO) process, which eliminates most inorganic byproducts and reduces water usage by up to 80%.^[80]^[81] Commercialized by Dow and BASF since 2009, HPPO now represents growing capacity, with projections for further expansion to address eco-efficiency gaps in traditional routes.^[82]^[83]

Safety and Hazards

Health and Environmental Risks

Halohydrins exhibit acute toxicity through multiple exposure routes, acting as potent irritants to skin and eyes, with contact causing burns and inflammation. Inhalation leads to respiratory tract irritation, coughing, and potential pulmonary edema, while ingestion or dermal absorption can result in systemic effects including nausea, headache, and central nervous system depression. For instance, 2-chloroethanol, a representative chlorohydrin, has an oral LD50 of approximately 71 mg/kg in rats, indicating high acute toxicity that may be fatal at low doses via inhalation, ingestion, or skin absorption.^[11]^[84]^[85] Chronic exposure to halohydrins raises concerns for carcinogenicity and reproductive toxicity. Certain compounds, such as epichlorohydrin, are classified by the International Agency for Research on Cancer (IARC) as probably carcinogenic to humans (Group 2A), based on sufficient evidence from animal studies showing tumors in multiple organs and limited human data linking occupational exposure to cancer risks. 2-Chloroethanol is suspected of causing cancer and damaging the unborn child (EU CLP Category 2), though animal studies show no clear evidence of carcinogenicity.^[86]^[87]^[88] In the environment, while some halogenated organic compounds persist, halohydrins often exhibit moderate persistence due to their reactivity, including hydrolysis or microbial degradation, with half-lives typically ranging from days to weeks in water (e.g., ~14 days for 2-chloroethanol under neutral conditions). However, they can contribute to contamination if not degraded quickly. Simple bromohydrins show low bioaccumulation potential in aquatic organisms due to low log Kow values (e.g., ~0.3 for 2-bromoethanol), though more lipophilic derivatives may pose higher risks.^[89]^[90]^[91]^[92] Human exposure to halohydrins occurs primarily through industrial accidents, where spills or leaks enable inhalation of vapors or dermal contact during manufacturing and handling. Additionally, halohydrins form as minor disinfection byproducts in chloraminated drinking water, leading to low-level ingestion via treated supplies.^[93]^[94] Regulatory frameworks address these risks through occupational and environmental limits. The Occupational Safety and Health Administration (OSHA) sets a permissible exposure limit (PEL) of 5 ppm (16 mg/m³) as an 8-hour time-weighted average for 2-chloroethanol, with skin notation due to absorption hazards. The U.S. Environmental Protection Agency (EPA) monitors disinfection byproducts, including halogenated species, under the Stage 1 and Stage 2 Disinfectants and Disinfection Byproducts Rules (as of November 2025).^[93]^[95]^[96]

Handling Precautions

When handling halohydrins in laboratory or industrial settings, appropriate personal protective equipment (PPE) is essential to minimize exposure risks. Workers should wear chemical-resistant gloves such as those made from Viton or chloroprene rubber, safety goggles or face shields, and flame-retardant antistatic clothing to protect against skin contact, eye irritation, and potential ignition sources.^[97] Respiratory protection, including filters rated for organic vapors (e.g., A-P3 type), is recommended when working in areas with inadequate ventilation or during procedures that may generate mists or vapors.^[97] All manipulations should occur in a well-ventilated fume hood to prevent inhalation of volatile compounds.^[97] For storage, halohydrins must be kept in a cool, dry, well-ventilated area away from incompatible materials, particularly strong bases, which can induce decomposition to epoxides via intramolecular cyclization.^[98] Containers should be corrosion-resistant, tightly sealed, and stored under inert gas if prone to oxidation; access should be restricted to authorized personnel to prevent accidental exposure.^[97] Avoid proximity to heat sources, open flames, or ignition points due to the flammability of many halohydrins, such as 2-chloroethanol.^[97] In the event of a spill, immediately evacuate non-essential personnel and ensure adequate ventilation to disperse vapors. Cover nearby drains to prevent environmental release, then absorb the liquid with inert materials like vermiculite or commercial absorbents (e.g., Chemizorb), collecting the waste for proper disposal as hazardous material.^[97] Use non-sparking tools during cleanup to avoid ignition risks.^[97] For emergency exposure, first aid measures prioritize rapid decontamination. In cases of skin contact, immediately remove contaminated clothing and rinse the affected area with copious amounts of water for at least 15 minutes, then seek medical attention.^[97] For eye exposure, flush with water or saline for 15 minutes while holding eyelids open, removing contact lenses if present, and consult an ophthalmologist promptly.^[97] If inhaled, move the individual to fresh air and provide oxygen if breathing is difficult; call emergency services immediately.^[97] For ingestion, do not induce vomiting; rinse the mouth with water and seek urgent medical advice.^[97] Halohydrins exhibit general toxicity profiles similar to alkyl halides and alcohols, with potential for severe irritation and systemic effects.^[97] Best practices include conducting operations in closed or contained systems, especially for volatile halohydrins, to limit airborne exposure and reduce fire hazards. Always label containers clearly, maintain an inventory of stored materials, and train personnel on emergency procedures; work should never be performed alone when handling these compounds.^[97] Wash hands and exposed skin thoroughly after use, and prohibit eating, drinking, or smoking in handling areas.^[97]

Nomenclature Issues

Common Misnomers

One common misnomer in the nomenclature of halohydrins arises with epichlorohydrin, a compound whose name suggests it is a chlorohydrin featuring a chlorine and hydroxyl group on adjacent carbons; however, it is actually an epoxide, specifically 2-(chloromethyl)oxirane, with a three-membered ring oxygen structure rather than a vicinal halo alcohol.^[99] Another frequent source of confusion is the term sulfuric chlorohydrin, which is an alternative name for chlorosulfonic acid (ClSO₃H), an inorganic oxoacid used in sulfonation reactions but lacking the characteristic C-C bonded halogen and hydroxyl groups of organic halohydrins. Halohydrins are also sometimes conflated with alpha-halo ethers, such as chloromethyl methyl ether (ClCH₂OCH₃), where a halogen is attached to a carbon adjacent to an ether oxygen rather than a hydroxyl group, leading to misinterpretation of reactivity patterns in synthetic contexts.^[100] In addition, vicinal diols like ethylene glycol (HOCH₂CH₂OH) can be mistakenly grouped with halohydrins due to structural similarity, though they lack the halogen substituent entirely.^[101] A classic example of proper versus informal naming is ethylene chlorohydrin, commonly used but systematically designated as 2-chloroethanol to distinguish it from other chlorinated derivatives and avoid implying a direct relation to hypochlorous acid (HOCl), which is an inorganic species not equivalent to organic chlorohydrins. These misnomers, including outdated historical designations like "oxychloride" for certain halo alcohols in early 19th-century literature, can propagate errors in chemical databases and patent documentation by misclassifying compounds and complicating literature searches. Early 19th-century literature often used terms like "oxychloride" for halo alcohols, stemming from incomplete understanding of structures before organic analysis advanced. Modern IUPAC nomenclature standardizes halohydrins as haloalcohols, e.g., 2-chloroethanol, to avoid confusion.^[1] As of 2025, no major nomenclature controversies persist, but green synthesis innovations highlight need for precise terminology in patents.

Historical Context

The direct formation of halohydrins through the addition of hypochlorous acid (generated from halogens in aqueous media) to alkenes was first reported in 1863 by the German chemist Georg Ludwig Carius, yielding ethylene chlorohydrin from ethylene.^[102] This discovery laid the foundation for understanding electrophilic addition to double bonds, as the compound was subsequently used by Charles-Adolphe Wurtz in 1859 to synthesize ethylene oxide via base treatment.^[57] Industrial development of halohydrin chemistry accelerated in the early 20th century, particularly with the chlorohydrin process for producing epoxides. Commercial production of propylene oxide via propylene chlorohydrin began in the early 1900s.^[37] Advances in the mid-20th century focused on mechanistic insights, with the stereochemistry of halohydrin formation—characterized by anti addition through a halonium ion intermediate—elucidated through experimental studies in the 1950s, confirming trans product geometry via kinetic and product analyses.^[103] In the 2020s, environmental concerns over the traditional chlorohydrin route's salt-heavy wastewater have driven innovations in green synthesis, including biocatalytic resolutions using halohydrin dehalogenases for enantioselective production and electrochemical cascades that minimize reagents and byproducts.^[49]^[48] As of November 2025, these approaches address wastewater issues in traditional routes. Influential 19th-century chemists like Viktor Meyer contributed indirectly through foundational work on halogenated organics, including vapor density measurements aiding structural studies of haloforms, which share mechanistic parallels with halohydrin pathways.

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