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Sulfonyl group
Sulfonyl group
Sulfonyl group
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A sulfone. It consists of a sulfonyl group bonded with two organic substituents.

In organosulfur chemistry, a sulfonyl group is either a functional group found primarily in sulfones, or a substituent obtained from a sulfonic acid by the removal of the hydroxyl group, similarly to acyl groups.[1]: 1470–1476 

Group

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Sulfonyl groups can be written as having the general formula R−S(=O)2−R′, where there are two double bonds between the sulfur and oxygen.[1]: 53 [2]

Sulfonyl groups can be reduced to the sulfide with diisobutylaluminium hydride (DIBALH). Lithium aluminium hydride (LiAlH4) reduces some but not all sulfones to sulfides.[1]: 1851 

In inorganic chemistry, when the group −S(=O)2− is not connected to any carbon atoms, it is referred to as sulfuryl.[3]

Examples of sulfonyl group substituents

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The names of sulfonyl groups typically end in -syl, such as:[1]: 497 

Group name Full name Pseudoelement symbol Example
Tosyl p-toluenesulfonyl Ts Tosyl chloride (p-toluenesulfonyl chloride)
CH3C6H4SO2Cl
Brosyl p-bromobenzenesulfonyl Bs
Nosyl o- or p-nitrobenzenesulfonyl Ns
Mesyl methanesulfonyl Ms Mesyl chloride (methanesulfonyl chloride)
CH3SO2Cl
Triflyl trifluoromethanesulfonyl Tf
Tresyl 2,2,2-trifluoroethyl-1-sulfonyl
Dansyl 5-(dimethylamino)naphthalene-1-sulfonyl Ds Dansyl chloride

See also

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References

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Sulfonyl group

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The sulfonyl group, denoted as -SO₂-, is a fundamental in consisting of a central atom double-bonded to two oxygen atoms and typically single-bonded to two carbon atoms or other substituents, as seen in with the structure R–SO₂–R'. This group imparts significant polarity and stability to molecules due to the strong S=O bonds, rendering it resistant to mild oxidation or reduction conditions. As an electron-withdrawing moiety, the sulfonyl group enhances the acidity of adjacent hydrogens and stabilizes carbanions, making it valuable for directing reactivity in synthetic transformations, such as generating α-anions with bases like butyllithium or facilitating coupling reactions in complex molecule assembly. Derivatives of the sulfonyl group, such as sulfonyl chlorides (R–SO₂–Cl), exhibit electrophilicity at the atom and undergo reactions with amines to form sulfonamides (R–SO₂–NR₂). The sulfonyl group plays a pivotal role in , serving as a core element in sulfonamide-based antibiotics that inhibit bacterial synthesis, and in for applications like polar aprotic solvents (e.g., ) and polymer initiators. Advances as of 2025 include photoinduced C–H sulfination for direct installation into complex scaffolds (2021) and sulfonyl exchange chemistry for developing targeted covalent inhibitors, underscoring its versatility in and late-stage functionalization.

Structure and Nomenclature

Definition

The sulfonyl group is a divalent functional group in organic chemistry characterized by a central sulfur atom double-bonded to two oxygen atoms, with the general formula R–SO₂–R', where R and R' represent organic substituents, such as alkyl or aryl groups, or other moieties bonded to the sulfur. This group is most commonly encountered in sulfones, where the sulfur is flanked by two carbon atoms, but it also appears as a substituent in derivatives like sulfonyl chlorides (R–SO₂–Cl) and sulfonamides (R–SO₂–NR₂). The sulfonyl moiety imparts distinctive reactivity due to the electron-withdrawing nature of the SO₂ unit, influencing the properties of the attached groups. The recognition of the sulfonyl group emerged in the amid investigations into organosulfur compounds, particularly through the synthesis and study of sulfonic acids and their derivatives. Early work on sulfonation reactions, such as the preparation of and diphenyl from and fuming by Eilhard Mitscherlich in 1834, laid the groundwork for understanding sulfur-oxygen functionalities, including the sulfonyl unit in oxidized sulfur compounds. By the late , oxidation of thioethers provided an additional route to sulfones, solidifying the sulfonyl group's identity as a key structural element in . It is important to distinguish the sulfonyl group from related sulfur-containing functionalities. The sulfinyl group, found in sulfoxides, features sulfur double-bonded to only one oxygen atom (R–SO–R'), resulting in lower and different reactivity compared to the fully oxidized sulfonyl. Similarly, the sulfate group in organic esters (RO–SO₂–OR') involves bonded to two oxygen-linked substituents rather than carbon, as in sulfonyl compounds, and is typically associated with inorganic or esterified derivatives. These distinctions highlight the sulfonyl group's unique role in carbon-based frameworks.

Bonding and Geometry

The sulfonyl group is characterized by a central sulfur atom in the +6 , forming two double bonds to oxygen atoms and two single bonds to groups (denoted as R). This bonding arrangement reflects the hypervalent nature of sulfur, where the octet is expanded through involvement of d-orbitals or hyperconjugative interactions. Crystallographic studies of simple sulfones, such as dimethyl sulfone, reveal typical S=O bond lengths of approximately 1.44 and S–C bond lengths of 1.78 , with slight variations depending on the substituents. The O–S–O bond angle is around 118°, approaching the ideal 120° for sp² in the SO₂ unit. These dimensions indicate strong, polarized S=O bonds and relatively longer S–R bonds due to the electron-withdrawing effect of the oxygens. The sulfur atom in the sulfonyl group is described with sp² hybridization for the SO₂ moiety, leading to a trigonal planar of the two oxygen atoms and one attached R group, while the second R group occupies a position consistent with overall tetrahedral coordination around sulfur. This hybridization model accounts for the planarity of the SO₂ unit and the observed bond angles. Resonance structures further describe the electronic distribution, where charge separation (e.g., S⁶⁺(O⁻)₂R₂ forms) and hyperconjugative donations from oxygen lone pairs to S–R antibonding orbitals impart partial double-bond character to the S–R linkages, enhancing their strength and influencing reactivity. These contributions avoid formal octet violations on and align with computational analyses of polarized bonding.

Nomenclature Conventions

The sulfonyl group (–SO₂–) is designated as a substituent prefix in substitutive , where it is cited as "sulfonyl" preceded by the name of the attached radical, such as "methanesulfonyl" for CH₃SO₂–. This convention applies to derivatives like sulfonyl halides, where (CH₃SO₂Cl) exemplifies the naming for R–SO₂–X (X = ). Similarly, sulfonyl groups attached to other functional groups follow this prefix, ensuring the sulfonyl is treated as a subordinate feature when higher-priority groups are present. Sulfones, characterized by the core structure R–SO₂–R', are primarily named using functional class , in which the names of the R and R' groups are listed in alphabetical order followed by the term "sulfone". For example, CH₃–SO₂–CH₃ is named dimethyl sulfone, a retained acceptable as a (PIN) for simple cases. In substitutive , particularly for unsymmetrical or more complex sulfones, the structure is expressed as (R-sulfonyl)R', with the senior group serving as the parent ; thus, C₆H₅–SO₂–CH₃ becomes (methylsulfonyl) as the PIN, contrasting with the older functional class name methyl phenyl sulfone. s like "methyl sulfone" persist in general usage for symmetrical dialkyl sulfones but are not extended to polysubstituted derivatives, where systematic substitutive names predominate to avoid ambiguity. Sulfonamides, with the general formula R–SO₂–NR'₂, are named substitutively by replacing the "ic acid" ending of the corresponding with the suffix "sulfonamide", yielding parent names like methanesulfonamide for CH₃–SO₂–NH₂. Substituents on the nitrogen atom are prefixed with italicized "N-" locants, as in N,N-dimethylmethanesulfonamide for CH₃–SO₂–N(CH₃)₂; this approach aligns with amide nomenclature priorities, where the function takes precedence over amines. While some sulfonamides retain trivial names (e.g., for 4-aminobenzenesulfonamide in medicinal contexts), IUPAC favors systematic names for consistency, especially in N-substituted cases, to clearly delineate the sulfonyl attachment.

Physical and Chemical Properties

Physical Characteristics

The sulfonyl group confers high polarity to organic compounds due to the electronegative oxygen atoms in the SO₂ moiety, resulting in stronger intermolecular dipole-dipole interactions compared to analogous carbonyl compounds. This leads to substantially higher s for sulfonyl-containing molecules; for example, dimethyl (CH₃SO₂CH₃) has a boiling point of 238 °C, over 180 °C higher than that of acetone (CH₃COCH₃) at 56 °C, despite structural similarities. In larger systems, diphenyl boils at 379 °C, approximately 73 °C higher than at 306 °C. The polarity of sulfonyl compounds is reflected in their dipole moments, which typically range from 4 to 5 D; sulfolane, a cyclic , exhibits a dipole moment of 4.7 D. This contributes to their profile, where polar sulfones dissolve readily in both and common organic solvents. For instance, is fully miscible with and most organic liquids, while dimethyl sulfone shows a of 187 g/L at 30 °C and good in polar organics like and acetone. In (IR) , the sulfonyl group displays characteristic strong absorption bands for S=O stretching vibrations at 1300–1350 cm⁻¹ (asymmetric) and 1150–1200 cm⁻¹ (symmetric), which are diagnostic for identifying sulfones and related derivatives. ¹³C (NMR) spectroscopy reveals deshielding of carbons alpha to the sulfonyl group, with chemical shifts typically in the 50–70 ppm range for -CH₂-SO₂- moieties, as seen in aliphatic sulfones where the β-effect from the electron-withdrawing SO₂ influences nearby carbons.

Electronic Properties

The sulfonyl group acts as a strong (EWG) in organic molecules, primarily due to its ability to stabilize negative charges and destabilize positive ones through electron withdrawal. This is quantified by the Hammett substituent constant σ_p = 0.73 for the -SO₂CH₃ group, which is nearly as strong as the nitro group (σ_p = 0.78), making it one of the most powerful meta-directing groups in . The electron-withdrawing effect of the sulfonyl group is predominantly inductive, transmitted through sigma bonds owing to the high electronegativity of the atom ( ≈ 2.58) and the two oxygen atoms, which pull from adjacent atoms or groups. While effects also contribute to withdrawal—particularly in stabilizing carbanions or delocalizing lone pairs—any potential donation from sulfur d-orbitals is minimal, as computational studies indicate limited d-orbital participation in bonding, favoring octet-rule compliant structures over hypervalent representations. This electronic profile enhances the acidity of alpha-hydrogens in sulfones, where the pK_a is approximately 29 in DMSO (e.g., for PhSO₂CH₃), compared to around 50 for alkanes, enabling with strong bases to form stabilized carbanions via inductive stabilization of the negative charge. In molecular orbital terms, the sulfonyl group's low-lying lowest unoccupied (LUMO) arises from the antibonding π* orbitals of the SO₂ unit, which facilitate electron acceptance and contribute to its overall EWG character in conjugated systems.

Stability and Reactivity

The sulfonyl group imparts significant thermal stability to compounds containing it, particularly in sulfones, which often withstand temperatures up to 300°C or higher without . For instance, diphenyl sulfone remains resistant to thermal breakdown even at 550°C, as demonstrated by analysis of heated samples showing no significant degradation products. This stability arises from the robust S=O bonds and the overall electronic configuration of the group, making sulfonyl-containing polymers suitable for high-temperature applications. In contrast to esters, which are prone to hydrolytic cleavage under aqueous conditions, sulfones exhibit strong resistance to due to their chemical inertness, maintaining structural integrity in both acidic and basic environments. Reactivity patterns of the sulfonyl group vary markedly depending on the substituents attached to the sulfur atom. Sulfonyl halides, such as sulfonyl chlorides, are highly susceptible to nucleophilic attack at the sulfur center, undergoing rapid substitution reactions with nucleophiles like amines or alcohols to form sulfonamides or sulfonate esters, respectively. This electrophilic nature stems from the electron-withdrawing oxygen atoms, facilitating displacement of the halide. In contrast, dialkyl or diaryl sulfones (R-SO₂-R) are generally inert to such nucleophilic assaults under mild conditions, owing to the absence of a good leaving group and the stabilized tetrahedral geometry around sulfur. The chemistry of the sulfonyl group allows for controlled reduction under specific conditions. Sulfones can be reduced to the corresponding sulfides (R-S-R) using , a process that cleaves both S=O bonds through stepwise , as established in early studies on aromatic and aliphatic systems. Partial reduction to sulfinates is less common for symmetric sulfones but can occur in unsymmetric cases or via alternative reagents targeting one oxygen atom. Additionally, activated sulfones bearing α-hydrogens or α-leaving groups show sensitivity to strong bases, undergoing α-elimination to form alkenes or other unsaturated products, as seen in rearrangements involving sulfonyl-stabilized carbanions. These reactivity profiles highlight the sulfonyl group's versatility while underscoring its stability in non-activated forms.

Synthesis Methods

Oxidation of Organosulfur Compounds

The oxidation of organosulfur compounds, particularly dialkyl or alkyl aryl sulfides (R-S-R'), represents a primary synthetic pathway to sulfones bearing the sulfonyl group (R-SO₂-R'). This method elevates the sulfur oxidation state from -2 to +4 through sequential oxygen transfer, typically proceeding in two distinct steps: initial formation of the sulfoxide intermediate (R-SO-R') followed by further oxidation to the sulfone. Common oxidants include peroxides such as hydrogen peroxide (H₂O₂) or meta-chloroperoxybenzoic acid (mCPBA), as well as potassium permanganate (KMnO₄), which enable efficient conversion under mild conditions. For instance, treatment of dialkyl sulfides with excess H₂O₂ in acetic acid at elevated temperatures yields the corresponding sulfone. The mechanism of sulfide oxidation involves nucleophilic attack by the lone pair on the electrophilic oxygen atom of the oxidant, facilitating direct oxygen transfer without radical intermediates in most peroxide-mediated cases. This first generates the , where the adopts a pyramidal with a , before a second equivalent of oxidant targets the less nucleophilic but still reactive to form the . Yields for aliphatic s often exceed 90%, attributed to the high reactivity of the center and minimal side reactions under controlled conditions. Aromatic s may require harsher conditions due to electronic deactivation. Historically, this transformation dates back to the mid-19th century, with early reports employing as an oxidant for converting sulfides to sulfones, marking one of the foundational developments in . Modern protocols emphasize selectivity to halt at the sulfone stage without over-oxidation to sulfonic acids, achieved by stoichiometric control, temperature modulation (e.g., for sulfoxides, 50-75°C for sulfones), or catalysts like tungsten oxides that enhance H₂O₂ efficiency while preventing decomposition. For example, niobium carbide-catalyzed H₂O₂ oxidation selectively delivers sulfones from dialkyl sulfides in 92-99% yields under solvent-free conditions, avoiding the sulfoxide buildup. The resulting sulfonyl group exhibits high stability toward further oxidation, supporting its utility in synthetic sequences.

Preparation of Sulfonyl Halides

Sulfonyl chlorides, key precursors in the synthesis of various sulfonyl compounds, are frequently prepared from s or their salts through chlorination reactions. A classical method involves treating the sulfonic acid with (PCl5), which replaces the hydroxyl group with chloride while generating and as byproducts. The reaction is represented as: \ceR−SO3H+PCl5−>R−SO2Cl+POCl3+HCl\ce{R-SO3H + PCl5 -> R-SO2Cl + POCl3 + HCl} This approach is efficient for both aliphatic and aromatic sulfonic acids and is often conducted under anhydrous conditions to prevent hydrolysis. Thionyl chloride (SOCl2) serves as an alternative chlorinating agent, particularly when milder conditions are desired, though it may require the addition of catalysts like dimethylformamide for optimal yields. For aromatic systems, direct chlorosulfonation using chlorosulfonic acid (ClSO3H) provides a streamlined route to arylsulfonyl chlorides via electrophilic aromatic substitution. This reagent acts as both a sulfonating and chlorinating agent, introducing the -SO2Cl group in a single step, with reaction conditions typically involving excess ClSO3H at controlled temperatures to favor the para or ortho positions depending on the arene's substituents. The method is versatile for electron-rich arenes and avoids intermediate isolation of the sulfonic acid. Purification of sulfonyl chlorides is challenging owing to their sensitivity to moisture, which causes rapid hydrolysis to the corresponding sulfonic acids and HCl. Consequently, these compounds are commonly purified by vacuum distillation under reduced pressure to minimize decomposition and ensure high purity for subsequent use as synthetic intermediates. In industrial applications, such as the large-scale production of saccharin, o-toluenesulfonyl chloride is generated via chlorosulfonation of toluene with chlorosulfonic acid; this intermediate is then ammonolyzed without extensive purification to form o-toluenesulfonamide, highlighting efficient scale-up strategies in pharmaceutical precursor synthesis.

Other Synthetic Routes

The Friedel-Crafts sulfonylation provides a classical route to aryl sulfones by reacting aromatic substrates, such as or , with sulfonyl chlorides or anhydrides in the presence of Lewis acids like AlCl₃. This generates a sulfonium-like that attacks the arene, typically proceeding in high yields for activated systems under solvent-free or low-temperature conditions. Arylsulfonyl chlorides can also be synthesized from aryldiazonium salts via a Sandmeyer-type reaction involving SO₂ and CuCl₂ as the mediator. Originally developed by Meerwein and colleagues, this radical-mediated converts anilines to sulfonyl chlorides through diazotization followed by sulfur dioxide insertion and chlorination, offering good yields (50–95%) across electron-rich and electron-poor substrates while tolerating halides and other functional groups. A contemporary approach utilizes palladium-catalyzed three-component couplings of aryl or alkyl halides with the SO₂ surrogate DABSO and organometallic nucleophiles, such as Grignard or organolithium reagents, to directly assemble sulfones. Performed in a one-pot sequence at low temperatures followed by heating, this method accommodates diverse electrophiles like benzyl halides and epoxides, delivering sulfones in 50–90% yields with broad compatibility. Stereoselective routes to chiral sulfones often employ chiral auxiliaries to control asymmetry. For instance, enantiopure sulfinic acids derived from (R)- or (S)-methylbenzylamine are condensed with β-keto esters to form chiral β-keto sulfones, which are then reduced with DIBAL-H or LiAlH₄ to afford β-hydroxy sulfones with diastereoselectivities exceeding 90:10, depending on the . Camphor-derived chiral sulfones, prepared via of camphor-10-sulfinate with allylic or benzylic halides, function as auxiliaries in base-promoted cyclizations, yielding tricyclic β-hydroxy sulfones with complete stereocontrol through Wagner–Meerwein rearrangements.

Common Sulfonyl Derivatives

Sulfones

Sulfones are organosulfur compounds featuring a sulfonyl functional group bonded to two carbon atoms, with the general formula R–SO2–R′R\text{–}SO_2\text{–}R', where RR and R′R' represent alkyl, aryl, or other organic substituents. These compounds exhibit high thermal stability and polarity due to the electron-withdrawing nature of the SO2SO_2 moiety, making them useful in various synthetic contexts. A classic example is dimethyl sulfone (\ceCH3SO2CH3\ce{CH3SO2CH3}), a white crystalline solid with a melting point of 109 °C, which serves as an effective high-temperature solvent for inorganic and organic substances owing to its boiling point of approximately 238 °C. Sulfones play a pivotal role in key carbon-carbon bond-forming reactions, notably the . In this process, a stabilized by an aryl or heteroaryl group is deprotonated at the alpha position to generate a , which undergoes to an , yielding a β\beta-hydroxy intermediate. This intermediate is then subjected to , typically using or other reducing agents, to afford the corresponding with control over . The reaction, originally reported by Julia and Paris in 1973, is particularly valuable for constructing EE-selective alkenes in complex molecule synthesis. Another signature transformation is the Ramberg–Bäcklund reaction, where α\alpha-halo sulfones are treated with a base to induce rearrangement into alkenes via an episulfone (thiirane dioxide) intermediate, accompanied by extrusion of . The mechanism proceeds through deprotonation of the α\alpha-carbon, intramolecular displacement to form the three-membered ring, and subsequent decomposition to the olefin. First described by Ramberg and Bäcklund in 1940, this method enables the preparation of alkenes from non-terminal sulfones and is especially useful for generating strained or cyclic olefins. In modern synthetic strategies, sulfones function as directing groups for selective C–H bond activation. For instance, the (2-pyridyl)sulfonyl moiety coordinates to catalysts, facilitating ortho-selective C–H functionalization of aryl rings, such as arylation or , followed by deprotection if needed. This approach leverages the chelating ability of the pyridine-sulfone hybrid to achieve high in late-stage modifications.

Sulfonyl Halides

Sulfonyl halides are organosulfur compounds with the general RSO₂X, where R represents an and X is a , most commonly or . These compounds serve as versatile electrophiles in owing to the electron-deficient atom, which facilitates nucleophilic attack and displacement of the . Unlike typical alkyl halides, the reactivity centers on the sulfur rather than carbon, enabling selective transformations under mild conditions. The preparation of sulfonyl halides commonly involves the chlorination of sulfonic acids or their salts using reagents such as (SOCl₂) or (PCl₅), yielding the corresponding sulfonyl chlorides in high efficiency. This method allows access to a wide range of derivatives, with sulfonyl fluorides often obtained via halide exchange from chlorides using silver fluoride. Sulfonyl halides undergo reactions at sulfur, analogous to acyl substitutions, where nucleophiles displace the to form new S–Nu bonds. A representative example is the reaction with alcohols to produce esters: \ceRSO2Cl+R′OH−>[base]RSO2OR′+HCl\ce{RSO2Cl + R'OH ->[base] RSO2OR' + HCl} This process exhibits second-order kinetics, with rates influenced by the nucleophile's basicity and the leaving group's nature, as demonstrated in studies probing addition-elimination mechanisms. Sulfonyl fluorides display tempered reactivity compared to chlorides, making them suitable for selective bioconjugation due to slower hydrolysis rates. A key application involves p-toluenesulfonyl chloride (TsCl), widely employed for protecting primary and secondary alcohols as tosylates, which enhance ability in SN2 displacements or eliminations. The tosylation typically proceeds in with , affording tosylates in yields exceeding 90% while suppressing side reactions like elimination. These protected intermediates enable regioselective functionalization in complex syntheses. Sulfonyl halides are highly reactive and hazardous, exhibiting lachrymatory properties that cause tearing and upon exposure to vapors. They are corrosive to skin, eyes, and respiratory tissues, potentially leading to severe burns or ; handling requires inert atmospheres, fume hoods, and full protective gear to minimize risks.

Sulfonamides

Sulfonamides represent a key class of sulfonyl derivatives with the general structure R-SO₂NR₂, where R and R' denote organic groups, and are widely recognized for their roles in and . The most common synthetic route involves the nucleophilic acyl substitution reaction between sulfonyl chlorides and , typically conducted in the presence of a base to neutralize the generated HCl. For instance, the reaction of a sulfonyl (R-SO₂Cl) with a primary amine (R'NH₂) yields the secondary R-SO₂NHR, along with HCl, and this method accommodates a broad range of substituents due to the high reactivity of the sulfonyl . This approach is versatile, allowing for the preparation of both primary (R-SO₂NH₂) and substituted sulfonamides under mild conditions, often in solvents like or . Primary sulfonamides (R-SO₂NH₂) exhibit tautomerism, equilibrating between the sulfonamide form and the sulfonimide (or N-sulfonyl ) tautomer R-S(=O)(OH)=NH, though the energy barrier is low and the sulfonamide structure predominates in non-polar environments. In the gas phase, the energy difference between these tautomers is small, typically less than 6 kcal mol⁻¹, favoring the sulfonamide; however, increasing polarity shifts the equilibrium toward the sulfonimide form due to enhanced stabilization of the polar tautomer through hydrogen bonding and effects. This tautomerism influences the compounds' spectroscopic properties and reactivity, as confirmed by calculations and on N-heterocyclic examples. The biological significance of sulfonamides emerged prominently in the 1930s with the discovery of sulfa drugs, marking the advent of synthetic antibiotics; , isolated as the of in 1935, inhibits in bacteria, blocking biosynthesis essential for production—a pathway absent in humans who obtain from diet. This mechanism revolutionized treatment of bacterial infections like and before the penicillin era. In contemporary applications, sulfonamides feature in diuretics such as , a that inhibits the Na-K-2Cl in the thick ascending limb of the , promoting excretion of sodium, chloride, and water to manage and . Furthermore, sulfonamide groups are integral to HIV protease inhibitors, exemplified by , a second-generation nonpeptidic inhibitor that binds tightly to the , preventing viral polyprotein cleavage and replication even against resistant strains.

Applications and Uses

In Organic Synthesis

The sulfonyl group plays a versatile role in organic synthesis as a protecting group, particularly the tosyl (Ts) derivative for amines. The N-tosylation of amines using p-toluenesulfonyl chloride in the presence of a base forms stable sulfonamides that protect the nitrogen from unwanted reactivity during multi-step syntheses, such as in peptide coupling or alkylation reactions. This protection is orthogonal to many other functional groups like esters or ketones. Deprotection is achieved through reductive cleavage, commonly with sodium in liquid ammonia, which selectively breaks the N-S bond to regenerate the free amine without affecting other functionalities. Alternative mild reductive methods, such as using Raney nickel or mischmetal with TiCl₄, have also been developed for sensitive substrates, yielding the deprotected amine in high efficiency. Sulfones, bearing the sulfonyl moiety, function as electron-withdrawing activators in cycloaddition reactions, notably as dienophiles in Diels-Alder cycloadditions. Vinyl sulfones, such as phenyl vinyl sulfone, react with conjugated dienes like cyclopentadiene or butadiene under thermal conditions to afford cyclohexene adducts with the sulfone group positioned at the 4-location, enabling further synthetic elaboration. The electron-deficient alkene in vinyl sulfones enhances reactivity compared to unactivated olefins, often proceeding with high regioselectivity due to the endo preference dictated by secondary orbital interactions. These adducts serve as precursors for natural product synthesis or material intermediates, with the sulfone later removable via desulfonylation under reductive conditions. Seminal studies have demonstrated intramolecular variants using sulfone-substituted sulfolenes, where SO₂ extrusion generates the diene in situ, facilitating complex ring formations. The sulfonyl group (SO₂R) acts as a traceless directing element in selective C-H functionalizations, particularly palladium-catalyzed meta-arylation of arenes. In this strategy, the SO₂R installs on the arene and coordinates to the Pd catalyst, guiding activation to the meta position via a mechanism involving norbornene-mediated migratory insertion, bypassing traditional ortho-directing limitations. Subsequent C-S bond cleavage removes the directing group, yielding the meta-arylated product without residual sulfonyl functionality. This approach has been applied to electron-rich and -poor arenes, achieving high site selectivity and broad substrate scope, as exemplified in syntheses requiring precise remote functionalization. A key application of sulfonyl derivatives is the Mislow-Evans rearrangement, which enables stereocontrolled synthesis of allylic alcohols from allylic sulfoxides. Allylic sulfides are oxidized to sulfoxides, which then undergo [2,3]-sigmatropic rearrangement to allylic sulfenates. The sulfenates are subsequently trapped or hydrolyzed to provide allylic alcohols with inversion of configuration at the allylic center. This method provides high enantioselectivity when using chiral sulfoxides and offers a mild route for allylic transposition with excellent stereocontrol, as demonstrated in syntheses of prostaglandins.

In Pharmaceuticals and Materials

Sulfonamide antibiotics represent one of the earliest and most impactful applications of sulfonyl groups in pharmaceuticals, revolutionizing treatment for bacterial infections. The discovery of , the first sulfonamide drug, occurred in 1935 when demonstrated its efficacy against streptococcal infections in mice, marking the advent of for bacterial diseases. These compounds exert their antibacterial action by mimicking para-aminobenzoic acid (PABA), a substrate essential for biosynthesis in bacteria. Specifically, sulfonamides competitively inhibit , the enzyme that incorporates PABA into dihydropteroic acid, thereby disrupting and protein synthesis in susceptible pathogens. This mechanism, elucidated in 1940 by , established sulfonamides as PABA antimetabolites and paved the way for their widespread clinical use against , though resistance has since limited their role. Sulfonylureas, another key class of sulfonyl-containing pharmaceuticals, are widely employed as oral antidiabetic agents for managing . These compounds stimulate insulin secretion from pancreatic beta cells by binding to the receptor 1 (SUR1) subunit of ATP-sensitive potassium (KATP) channels. This binding induces channel closure, leading to beta-cell membrane depolarization, calcium influx, and subsequent insulin release. Glipizide, a second-generation introduced in the 1980s, exemplifies this class with its potent hypoglycemic effects at low doses, improving glycemic control in non-insulin-dependent diabetes. The hypoglycemic potential of sulfonylureas was first noted in 1942 by Auguste Loubatières, who observed insulinotropic effects from sulfonamide derivatives in animal models, laying the foundation for their therapeutic development. In , sulfonyl groups contribute to the structure of , high-performance thermoplastics valued for their exceptional thermal and mechanical properties. , synthesized via of dihalodiphenyl sulfones with , exhibit a glass transition temperature (Tg) of approximately 190°C, enabling sustained performance at elevated temperatures up to 150–180°C without significant degradation. This thermal stability, combined with inherent flame retardancy and chemical resistance, makes ideal for demanding applications such as medical devices, membranes, and components. Recent advances have incorporated sulfonyl groups into proteolysis-targeting chimeras (PROTACs), bifunctional molecules designed for targeted protein degradation in cancer therapy. Post-2010 developments revealed that certain sulfonamides hijack the E3 ubiquitin ligase DCAF15 to induce degradation of RNA-binding motif protein 39 (RBM39), a splicing factor overexpressed in various malignancies. By binding to a residue in RBM39's RNA recognition motif, these sulfonyl-based PROTACs promote ubiquitination and proteasomal degradation, disrupting oncogenic splicing without requiring traditional active-site inhibition. This approach, highlighted in seminal work from 2017, exemplifies how sulfonyl moieties enable selective protein knockdown, offering a novel paradigm for precision medicine beyond conventional small-molecule inhibitors. Recent advances include sulfur-fluoride exchange (SuFEx) chemistry utilizing sulfonyl fluorides for developing targeted covalent inhibitors, enhancing selectivity in as of 2025.

Biological and Environmental Roles

The sulfonyl group, characteristic of sulfones (R-SO₂-R'), occurs naturally in biological systems as part of metabolites involved in cycling and nutrient provision. Dimethyl sulfone (MSM, (CH₃)₂SO₂), an oxidative product of (DMSO), is a ubiquitous sulfone found in bloodstream and , as well as in animal tissues, where it acts as a bioavailable source for biosynthesis and cellular functions. This compound originates from the marine , with DMSO derived from the cleavage and oxidation of (DMSP) produced by marine algae and ; MSM itself serves as an alternative sulfur source for under sulfur-limited conditions, supporting microbial survival and . In bacterial biochemistry, sulfonyl-containing lipids, such as sulfonolipids, are present in the outer membranes of Gram-negative bacteria from the Bacteroidetes phylum, including human gut commensals like Alistipes species; these lipids contribute to membrane integrity and have been linked to immunoregulatory effects in the host microbiome, potentially influencing inflammatory responses in conditions like inflammatory bowel disease. Sulfonolipids also play a role in bacterial signaling, such as triggering multicellular development and gliding motility in environmental microbes. Although structurally related sulfonates like taurine (H₂N-CH₂-CH₂-SO₃H) and the sulfonate moiety in coenzyme M (HS-CH₂-CH₂-SO₃⁻) dominate sulfur biochemistry—serving in osmoregulation and methanogenesis, respectively—the sulfonyl group in sulfones like MSM provides a distinct, reduced oxidation state for sulfur transfer in aerobic metabolic pathways. In environmental contexts, sulfonyl-containing compounds exhibit persistence that impacts ecosystems. Sulfonamides (R-SO₂-NH-R), widely used antibiotics, are detected in at concentrations up to several micrograms per liter and resist complete in treatment plants, leading to their accumulation in surface waters and alteration of aquatic microbial community structures and diversity. Sulfonylurea herbicides, such as (a sulfonyl-containing compound), demonstrate moderate environmental persistence in , with an average of 30 days under aerobic conditions, during which they inhibit acetolactate synthase in target plants but also exert ecotoxic effects on non-target microbes, reducing microbial activity and diversity. This persistence contributes to long-term ecological disruptions in agricultural settings, though degradation accelerates under neutral to alkaline pH and higher temperatures.

References

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