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Isothiocyanate

Isothiocyanates are a class of organosulfur compounds distinguished by the presence of the isothiocyanate functional group (–N=C=S), in which a nitrogen atom attached to an organic substituent (R) forms a cumulative double bond with a carbon-sulfur moiety, yielding the general formula R–N=C=S.^[1] This functional group renders isothiocyanates highly reactive electrophiles, with the central carbon atom serving as the primary site for nucleophilic attack by biological nucleophiles such as thiols and amines.^[2] They occur widely in nature as secondary metabolites, particularly in plants of the order Brassicales, where they are generated via the myrosinase-catalyzed hydrolysis of glucosinolates upon tissue damage, acting as chemical defenses against herbivores and pathogens.^[3] Prominent examples include allyl isothiocyanate, responsible for the pungent flavor of mustard and horseradish, and sulforaphane, found in broccoli sprouts.^[4]^[5] These compounds are not only key contributors to the sensory qualities of cruciferous vegetables like cabbage, kale, and radish but also exhibit significant bioactivity in human health contexts.^[3] Isothiocyanates have been extensively studied for their pharmacological properties, including antimicrobial effects against bacteria such as Escherichia coli and Pseudomonas aeruginosa, anti-inflammatory mechanisms via modulation of NF-κB pathways, and chemopreventive potential through induction of phase II detoxification enzymes and apoptosis in cancer cells.^[3]^[6] In addition to their natural roles, isothiocyanates find applications in organic synthesis and industry; for instance, phenyl isothiocyanate is employed in the Edman degradation for protein sequencing by selectively reacting with N-terminal amino groups to form phenylthiohydantoin derivatives.^[7] Certain derivatives, such as methyl isothiocyanate, serve as soil fumigants and nematicides in agriculture due to their biocidal properties.^[8] Despite these benefits, some isothiocyanates are toxic at high exposures, causing irritation to skin, eyes, and respiratory tracts, and they are regulated accordingly in occupational settings.^[9] Ongoing research continues to explore their therapeutic potential, particularly in cancer prevention and treatment, leveraging their ability to conjugate with glutathione and influence cellular redox balance.^[10]

Chemical Fundamentals

Definition and Nomenclature

Isothiocyanates are a class of organosulfur compounds characterized by the functional group –N=C=S, with the general molecular formula R–N=C=S, where R represents an organic substituent such as an alkyl, aryl, or other hydrocarbon group.^[11] These compounds are sulfur analogs of isocyanates (R–N=C=O), differing by the replacement of oxygen with sulfur, while they are structural isomers of thiocyanates (R–S–C≡N), in which the sulfur atom is singly bonded to the carbon in a linear –S–C≡N arrangement.^[11] According to IUPAC nomenclature, isothiocyanates are systematically named using the prefix "isothiocyanato-" attached to the parent hydrocarbon chain, such as alkyl isothiocyanates for simple cases (e.g., methyl isothiocyanate for CH₃–N=C=S) or more complex substitutive names for unsaturated or aromatic derivatives. For instance, phenyl isothiocyanate (C₆H₅–N=C=S) is named isothiocyanatobenzene, reflecting the direct attachment of the functional group to the benzene ring. Historical or common names persist for certain compounds, such as "mustard oil" for allyl isothiocyanate (CH₂=CH–CH₂–N=C=S), which is systematically 3-isothiocyanatoprop-1-ene.^[12] The term "isothiocyanate" derives from the prefix "iso-," indicating its isomeric relationship to thiocyanates, highlighting the rearranged connectivity of the –NCS unit where nitrogen links to the organic group and sulfur forms the double bond with carbon.^[13] Key examples include benzyl isothiocyanate (C₆H₅CH₂–N=C=S, IUPAC name: isothiocyanatomethylbenzene), often studied for its biological activity, and phenethyl isothiocyanate (PEITC, C₆H₅CH₂CH₂–N=C=S, IUPAC name: (2-isothiocyanatoethyl)benzene), a prominent natural derivative.

Molecular Structure and Bonding

The isothiocyanate functional group, -N=C=S, exhibits a nearly linear geometry around the central carbon atom, characteristic of cumulene systems. In representative compounds such as methyl isothiocyanate, X-ray crystallographic and electron diffraction analyses reveal bond lengths of approximately 119.6 pm for the N=C double bond and 157.9 pm for the C=S double bond, with the C-N single bond measuring 143.9 pm. These dimensions reflect partial multiple-bond character due to resonance delocalization. In aryl derivatives like phenyl isothiocyanate, the C-N=C bond angle is approximately 165°, deviating from ideality due to conjugation with the aromatic ring, as observed in crystal structures of coordinated species.^[14]^[15] The electronic structure of isothiocyanates arises from cumulene-like resonance involving major contributing forms R–N=C=S ↔ R–N⁺≡C–S⁻, which impart partial double-bond character to the C-N linkage and enhance the polarity of the C=S bond. This delocalization stabilizes the linear N=C=S arrangement and influences the group's reactivity, with the nitrogen atom bearing partial positive charge in the dominant resonance hybrid. Computational studies at the MP2 and CCSD(T) levels confirm these bond orders, showing the N=C bond order intermediate between double and triple (around 2.2-2.5) and the C=S bond order slightly less than double.^[16]^[17] Isothiocyanates (R-N=C=S) predominate over their thiocyanate (R-S-C≡N) or cyanate isomers due to greater thermodynamic stability, driven by stronger C-N bonds compared to C-S bonds in the alkylated forms. Isomerization from thiocyanates to isothiocyanates occurs under heating or basic conditions, as the energy difference favors the N-linked form by 10-20 kJ/mol in aliphatic cases. Thiocyanate tautomers are rare and typically unstable, appearing only transiently in synthetic pathways.^[18]^[19] Spectroscopically, isothiocyanates display a characteristic strong infrared absorption band at 2100-2200 cm⁻¹, attributed to the asymmetric stretching vibration of the N=C=S moiety, which is intense due to the change in dipole moment along the linear axis. In ¹³C NMR spectra, the central carbon resonance appears around 130-140 ppm, often broadened or low-intensity owing to quadrupolar relaxation from the adjacent nitrogen and dynamic averaging of conformers, as exemplified by allyl isothiocyanate at approximately 142 ppm. These features aid in structural identification without interference from other functional groups.^[20]^[21]

Natural Sources

Occurrence in Nature

Isothiocyanates are primarily found in plants belonging to the Brassicaceae family, commonly known as cruciferous vegetables, including broccoli, cabbage, and mustard, where they are released from glucosinolate precursors upon tissue damage such as chewing by herbivores or mechanical injury.^[2] These compounds contribute to the pungent flavors characteristic of these plants and serve as natural defenses against herbivores and pathogens by deterring feeding and inhibiting microbial growth.^[22] For instance, allyl isothiocyanate is a prominent component in mustard and horseradish, responsible for their sharp taste and aroma.^[12] Similarly, sulforaphane, derived from glucoraphanin, is abundant in broccoli sprouts, while sinigrin in black mustard seeds yields allyl isothiocyanate upon hydrolysis.^[23]^[24] In food sources, isothiocyanate concentrations vary, with mustard seeds typically containing 400–15,000 mg/kg of allyl isothiocyanate, though levels around 100–400 mg/kg are common in processed forms depending on extraction conditions.^[25] These quantities highlight their significant presence in dietary staples, where they play a role in plant protection by repelling insects and suppressing fungal and bacterial pathogens through toxicity and disruption of cellular processes.^[26] Beyond plants, trace amounts of isothiocyanates occur in other organisms, such as in the defense secretions of insects like sawfly larvae, which sequester glucosinolates from host plants to produce these compounds for protection against predators.^[27] Certain bacteria, including species of Burkholderia, can biosynthesize isothiocyanates naturally, contributing to their ecological roles in microbial communities.^[28] Additionally, isothiocyanates exhibit environmental persistence in soil, originating from the degradation of plant material, where they influence soil microbial dynamics and provide residual biofumigation effects against pathogens.^[29]

Biosynthesis Pathways

In plants, particularly those in the order Brassicales such as Brassicaceae family members, isothiocyanates are primarily biosynthesized through the hydrolysis of glucosinolate precursors by the enzyme myrosinase (β-thioglucosidase). Glucosinolates are sulfur-rich secondary metabolites derived from amino acids like methionine, phenylalanine, or tryptophan. The biosynthesis begins with amino acid chain elongation, where methionine, for example, undergoes transamination to an α-keto acid, followed by condensation with acetyl-CoA, isomerization, and oxidative decarboxylation to extend the chain by 1-4 methyl groups in most cases, regulated by genes like the MAM family in Arabidopsis thaliana.^[30] Subsequent core structure formation involves conversion of the elongated amino acid to an aldoxime by cytochrome P450 enzymes (CYP79 family), followed by formation of an S-(hydroxyalkyl)thiohydroximate intermediate via CYP83B1. This intermediate is then glycosylated by UDP-glucosyltransferases to form desulfoglucosinolates and sulfated using 3'-phosphoadenosine-5'-phosphosulfate by sulfotransferases to yield the final glucosinolate.^[30] Upon plant tissue disruption, such as from herbivore damage, myrosinase is released from myrosin cells and hydrolyzes glucosinolates in a reaction that produces isothiocyanates, glucose, and sulfate:

\text{Glucosinolate} + \text{H}_2\text{O} \xrightarrow{\text{myrosinase}} \text{Isothiocyanate} + \text{D-glucose} + \text{HSO}_4^-

This process serves as a defense mechanism, with the unstable aglycone rearranging via a Lossen-like mechanism to form the isothiocyanate.^[30]^[31] Variations in this pathway occur across species, influencing the specific isothiocyanates produced. In Moringa oleifera, glucomoringin—a glucosinolate derived from phenylalanine—undergoes myrosinase-catalyzed hydrolysis to yield 4-(α-L-rhamnopyranosyloxy)benzyl isothiocyanate, involving side-chain elongation by enzymes like BCAT4/BCAT3 and core formation by CYP79A2/CYP83B1, with the rhamnosyloxy group added during modification.^[32] A representative example is sulforaphane, formed from glucoraphanin in broccoli via this pathway, highlighting aliphatic isothiocyanate production. Recent 2024 research on engineered plants has enhanced yields; for instance, overexpression of AOP2 in Arabidopsis thaliana doubled aliphatic glucosinolate levels, increasing potential isothiocyanate output upon hydrolysis, while de novo pathway introduction in Nicotiana benthamiana produced precursors like 4-methylsulfinylbutyl glucosinolate.^[33] Beyond plants, minor isothiocyanate production occurs in bacteria through distinct enzymatic mechanisms. In certain bacterial species, rhodanese-like enzymes catalyze sulfur transfer from thiosulfate or persulfides onto isonitrile precursors, forming isothiocyanates as specialized metabolites, differing from the plant glucosinolate route and contributing to microbial chemical diversity.^[28] Insect-specific pathways are less characterized but involve oxidases in defense contexts, where some herbivores adapt by metabolizing plant-derived isothiocyanates rather than de novo synthesis.^[34]

Synthesis Methods

Laboratory Preparation

One classic laboratory method for preparing isothiocyanates involves the thermal or catalyzed isomerization of the corresponding thiocyanates, where the sulfur atom migrates from the alkyl or aryl group to the nitrogen. For example, heating allyl thiocyanate leads to allyl isothiocyanate, as demonstrated in early studies on alkyl derivatives. The general reaction is represented as:

\text{R-SCN} \rightarrow \text{R-NCS}

This rearrangement typically requires temperatures around 100–200 °C and can be facilitated by Lewis acids like zinc chloride for certain substrates, yielding the isothiocyanate in moderate to good efficiency on a small scale.^[18] A widely used route starts from primary amines, which react with carbon disulfide (CS₂) in the presence of a base to form dithiocarbamate salts, followed by desulfurization to afford the isothiocyanate. The initial step proceeds as:

\text{RNH}_2 + \text{CS}_2 \rightarrow \text{RNHCS}_2\text{H}

Desulfurization can be achieved using reagents such as lead(II) nitrate for aryl derivatives, providing yields of 74% or higher after steam distillation, or tosyl chloride for both alkyl and aryl cases, enabling rapid conversion (<30 min) with yields starting from 34% and purification by column chromatography.^[35]^[36] A specific example is the preparation of phenyl isothiocyanate from aniline, where aniline reacts with CS₂ to form the dithiocarbamate intermediate, which is then treated with mercury(II) oxide (HgO) for desulfurization:

\text{C}_6\text{H}_5\text{NH}_2 + \text{CS}_2 + \text{HgO} \rightarrow \text{C}_6\text{H}_5\text{NCS}

This method is effective for bench-scale synthesis and has been employed in classical organic procedures.^[37] Recent advances in laboratory preparation emphasize metal-free protocols to enhance sustainability and compatibility with sensitive functional groups. Azide-based routes, such as those involving the Staudinger reaction followed by aza-Wittig with CS₂, provide access to isothiocyanates under mild conditions with yields of 77–92%. Additionally, oxime-derived methods, including reactions of chloroximes with thioureas followed by rearrangement, achieve yields of 71–94%. A 2024 review highlights green variants of these methods, including one-pot processes with high atom economy, achieving 80–95% yields for diverse substrates while minimizing waste.^[38]^[39]

Industrial Production

The primary industrial route for synthesizing isothiocyanates involves the reaction of primary amines with thiophosgene (Cl₂C=S) in the presence of a base, yielding the desired RNCS product along with HCl as a byproduct.^[40] This method is favored for its efficiency in large-scale operations, achieving yields of 72% or higher, and is applicable to both aromatic and aliphatic amines.^[40] An alternative variant employs phosgene in combination with thiols to generate intermediates that form isothiocyanates upon reaction with amines, though thiophosgene remains the dominant reagent due to its direct reactivity.^[41] These processes prioritize cost-effectiveness and high throughput, often conducted in continuous flow systems to enhance safety and scalability. A key example is the production of allyl isothiocyanate, a commercially significant compound used in the food industry. It is manufactured either through natural extraction via steam distillation of mustard seeds (Brassica juncea or Sinapis alba), where the enzyme myrosinase hydrolyzes glucosinolates to release the isothiocyanate, or synthetically by reacting allyl chloride with ammonium thiocyanate followed by thermal rearrangement. The synthetic route predominates for industrial volumes, supporting annual global production on the order of thousands of tons to meet demand for flavoring and preservatives.^[42] Safety considerations are paramount in these operations, as thiophosgene is highly toxic through inhalation, ingestion, and dermal contact, necessitating enclosed reactors and stringent ventilation protocols.^[40] Purification typically occurs via distillation under reduced pressure, exploiting boiling points in the 100–200 °C range for most isothiocyanates, ensuring high purity for commercial applications.^[40] Recent developments emphasize sustainability, including amine-catalyzed sulfurization of isocyanides with elemental sulfur.^[43] Additionally, biocatalytic approaches using myrosinase enzymes have advanced sulforaphane production from glucosinolate precursors in rapeseed meal, with applications in scalable bioprocessing.^[44]^[45]

Properties and Reactivity

Physical Properties

Isothiocyanates, particularly those with low molecular weights, typically exist as colorless to pale yellow liquids at room temperature, exhibiting a pungent odor due to their volatility.^[4] For instance, allyl isothiocyanate appears as a colorless to pale-yellow oily liquid, while phenyl isothiocyanate is a colorless liquid with a melting point of -21 °C and a boiling point of 218 °C.^[46] Certain isothiocyanates, such as methyl isothiocyanate (molecular weight 73 g/mol), form colorless low-melting solids with a melting point of 36 °C and a boiling point of 117–119 °C, despite its relatively low molecular weight.^[8] These compounds demonstrate good solubility in common organic solvents, including ethanol, diethyl ether, dichloromethane, and benzene, facilitating their use in various laboratory applications.^[8] In contrast, their solubility in water is limited; methyl isothiocyanate, for example, dissolves to about 0.76 g/100 mL at 20 °C, while allyl isothiocyanate shows solubility around 0.2 g/100 mL.^[8] This hydrophobicity, combined with moderate vapor pressures—such as 3.54 mmHg for methyl isothiocyanate at 25 °C—underpins their volatility and characteristic odors, relevant for environmental dispersion modeling.^[8] Densities of isothiocyanates generally fall in the range of 1.0–1.1 g/cm³, with specific values like 1.013 g/cm³ for allyl isothiocyanate and 1.07 g/cm³ for methyl isothiocyanate at ambient conditions.^[4]^[8] Refractive indices are typically between 1.5 and 1.53, as exemplified by 1.529 for allyl isothiocyanate at 20 °C.^[47] Isothiocyanates show a characteristic infrared absorption band at 2100-2200 cm⁻¹ due to the asymmetric stretch of the N=C=S group.^[1] Regarding stability, isothiocyanates exhibit thermal stability under dry conditions but can decompose at elevated temperatures; for example, allyl isothiocyanate shows significant loss above 80 °C.^[48] They undergo slow hydrolysis in moist air, emphasizing the need for careful storage to prevent degradation.^[49] The isothiocyanate functional group's structure contributes to this volatility without inducing reactivity under neutral, anhydrous environments.

Chemical Reactions

Isothiocyanates (RNCS) function as weak electrophiles, with the central carbon of the -N=C=S moiety being the primary site of reactivity due to its electron deficiency. Nucleophilic addition at this carbon is the dominant pathway, as attack at the sulfur or nitrogen atoms is disfavored owing to electronic and steric factors. This electrophilicity arises from the cumulative double bond structure, where the carbon bears a partial positive charge, facilitating interactions with nucleophiles such as water, amines, and thiols.^[1] Hydrolysis of isothiocyanates occurs slowly under neutral conditions, proceeding via nucleophilic attack by water on the central carbon to form an unstable thiocarbamic acid intermediate, which subsequently decomposes to the corresponding primary amine and carbonyl sulfide:

\text{RN=C=S} + \text{H}_2\text{O} \rightarrow \text{RNH-C(S)OH} \rightarrow \text{RNH}_2 + \text{COS}

The reaction is catalyzed by acids or bases, with acid catalysis accelerating the process through protonation of the nitrogen, enhancing the electrophilicity of the carbon. For instance, in aqueous perchloric acid, the first-order rate constant for phenyl isothiocyanate hydrolysis is approximately $1.3 \times 10^{-4} s^{-1} at 25°C and 0.5 M HClO_4, though rates at pH 7 are significantly slower, on the order of $10^{-5} to $10^{-4} s^{-1} depending on substituents. Electron-withdrawing groups on the R moiety, such as nitro or cyano, increase the rate by stabilizing the transition state, while electron-donating groups retard it.^[50] Isothiocyanates readily undergo nucleophilic addition with amines and thiols. Reaction with primary or secondary amines yields unsymmetrical thioureas through addition-elimination at the central carbon:

\text{RN=C=S} + \text{R'NH}_2 \rightarrow \text{RNH-C(S)-NHR'}

These reactions proceed efficiently in polar solvents like ethanol or acetone, often at room temperature, with high yields. In contrast, reactions with thiols are faster—up to 1000 times more rapid than with amines of comparable nucleophilicity—forming dithiocarbamates:

\text{RN=C=S} + \text{R'SH} \rightarrow \text{RNH-C(S)-SR'}

This enhanced rate for thiols is attributed to the higher nucleophilicity of sulfur compared to nitrogen, and the equilibrium is reversible under physiological conditions.^[51]^[52] Beyond simple additions, isothiocyanates participate in cycloaddition reactions, notably [3+2] dipolar cycloadditions that construct five-membered heterocycles. For example, aziridines react with isothiocyanates under Lewis acid catalysis, such as FeCl₃, to form 2-iminothiazolidines via attack of the aziridine nitrogen on the central carbon followed by ring closure involving the sulfur. These transformations are regioselective and complete rapidly, often in minutes at ambient temperature. Similarly, thiiranes undergo metal-free [3+2] cycloadditions with isothiocyanates to yield 1,3-dithiolanes.^[53]^[54] Reduction of isothiocyanates can selectively yield thioformamides, typically via chemoselective methods that add two electrons and two protons across the C=N bond. Electrochemical reduction achieves this transformation, proceeding through a two-electron process to form RNH-CH=S, though chemical reductants like the Schwartz reagent (zirconocene hydrochloride) provide mild alternatives with full control over the C=S bond integrity. These reductions are valuable for preserving the thioamide functionality without over-reduction to amines.^[55] Recent advancements include palladium-catalyzed couplings enabling C-C bond formation. For instance, Pd-catalyzed decarboxylative [3+2] cycloadditions of vinylethylene carbonates with isothiocyanates generate oxazolidine-2-thiones, incorporating a new C-C bond in the process. Such methods highlight the versatility of isothiocyanates in constructing complex carbon frameworks under mild conditions.^[56]

Applications

Food and Flavor Chemistry

Isothiocyanates contribute significantly to the sensory profile of foods derived from Brassica vegetables, imparting a characteristic pungent, mustard-like taste and aroma. Allyl isothiocyanate (AITC), predominant in mustard and wasabi, and phenethyl isothiocyanate (PEITC), more prominent in horseradish, are key volatile compounds responsible for this sharpness in plants of the Brassicales order. ^[4] ^[57] The human odor detection threshold for AITC ranges from 0.008 to 0.42 ppm, enabling its potent sensory impact even at low concentrations. ^[4] These compounds form primarily through enzymatic hydrolysis during food processing. The enzyme myrosinase, compartmentalized in plant cells, activates upon mechanical disruption such as chewing or crushing, converting glucosinolate precursors into isothiocyanates. ^[58] Heat from cooking inactivates myrosinase, thereby reducing isothiocyanate yield and pungency; for instance, boiling or steaming broccoli diminishes sulforaphane levels by up to threefold compared to raw consumption. ^[59] Recent research from 2023–2025 has explored isothiocyanates for flavor enhancement in functional foods, such as incorporating AITC into rice-based products to boost sensory appeal without overpowering bitterness at optimized doses. ^[60] Analytical techniques like gas chromatography-mass spectrometry (GC-MS) enable precise profiling of isothiocyanates in food matrices, facilitating quality control and formulation. ^[61] Additionally, their antibacterial properties support food preservation, with natural concentrations of 3–17 ppm in cabbage demonstrating inhibition of pathogens like Escherichia coli and Listeria monocytogenes. ^[62] AITC serves as a synthetic essence replicating mustard flavor in condiments and sauces, offering a stable alternative to natural extracts. ^[63] In the EU, AITC is authorized as a flavoring with an acceptable daily intake of 0.02 mg/kg body weight and maximum use levels up to 5 mg/kg in foods; in the US, it holds Generally Recognized as Safe (GRAS) status for direct addition as a flavoring agent without specified numerical limits beyond good manufacturing practices. ^[64]

Biological and Medicinal Uses

Isothiocyanates exhibit significant health benefits, primarily through their antioxidant properties mediated by activation of the Nrf2 pathway, which upregulates cellular defense against oxidative stress. This mechanism enhances the expression of phase II detoxification enzymes, such as glutathione S-transferases and NAD(P)H:quinone oxidoreductase 1, while inhibiting certain phase I enzymes that activate procarcinogens. Sulforaphane, a prominent isothiocyanate derived from broccoli, exemplifies these effects by potently inducing phase II enzymes and elevating glutathione levels to mitigate reactive oxygen species (ROS) damage. In anticancer applications, isothiocyanates like phenethyl isothiocyanate (PEITC) induce apoptosis in various cancer cell lines, including prostate and leukemia cells, through ROS-dependent signaling and activation of caspases-9 and -3. These actions contribute to tumor growth inhibition without broadly affecting normal cells. Specific applications highlight the therapeutic potential of individual isothiocyanates. Allyl isothiocyanate (AITC) demonstrates anti-inflammatory effects in preclinical models, including suppression of NF-κB signaling and reduction of pro-inflammatory cytokines in inflammatory conditions. Moringin, an isothiocyanate from Moringa oleifera, provides neuroprotection by attenuating oxidative stress and neuroinflammation in neurodegenerative models, as evidenced in recent reviews and rat studies showing preserved neuronal integrity post-pretreatment. Additionally, isothiocyanates such as sulforaphane and indole-3-carbinol-derived compounds offer antidiabetic benefits by improving glucose tolerance and reducing insulin resistance, alongside cardioprotective effects through lowered lipid peroxidation and enhanced endothelial function. As of 2025, sulforaphane supplements are in phase II clinical trials for autism spectrum disorder, demonstrating improvements in social responsiveness and behavioral symptoms in randomized controlled studies. For cancer prevention, phase II trials of sulforaphane in former smokers have shown reduced proliferative markers like Ki-67 in bronchial biopsies, supporting its role in lung cancer chemoprevention. However, high doses pose toxicity risks; for instance, methyl isothiocyanate has an oral LD50 of approximately 175 mg/kg in rats, leading to gastrointestinal irritation and systemic effects. Key mechanisms underlying these benefits include histone deacetylase (HDAC) inhibition, which promotes chromatin remodeling and gene expression favoring apoptosis and detoxification, as seen with PEITC and benzyl isothiocyanate targeting HDAC1 and HDAC3. Isothiocyanates also scavenge ROS directly and indirectly via Nrf2, balancing intracellular redox homeostasis. Bioavailability remains a challenge due to poor aqueous solubility, but liposomal formulations of PEITC enhance gastrointestinal absorption and systemic delivery, improving therapeutic efficacy in preclinical models.

Coordination and Materials Science

Isothiocyanates (RNCS) serve as ambidentate ligands in coordination chemistry, capable of binding to metal centers through either the nitrogen or sulfur atom, similar to their inorganic analog thiocyanate (SCN⁻), though the latter is more commonly employed. In mononuclear complexes, organic isothiocyanates form stable structures analogous to octahedral [M(NCS)₆]⁴⁻ species, where coordination typically occurs via the nitrogen lone pair, as observed in transition metal complexes like those of copper(II) with L-arginine and isothiocyanate ions.^[65] For instance, organotin(IV) isothiocyanates, such as Ph₂Sn(NCS)₂, exhibit trigonal-bipyramidal geometries with N-bound ligands, demonstrating the versatility of RNCS in forming five-coordinate species.^[66] In coordination polymers, isothiocyanates act as bridging linkers, enabling the construction of extended frameworks with potential catalytic applications. Phenyl isothiocyanate (PhNCS), for example, participates in reactions with N-heterocyclic carbene-supported nickel complexes to form nickelacycles, which can facilitate insertions of E-H bonds (E = C, N, P, S) into heterocumulenes, highlighting its role in catalytic processes.^[67] Although specific Pd or Rh systems with PhNCS for catalysis are less documented, related thiocyanate-based polymers with palladium have shown promise in cross-coupling reactions, suggesting analogous utility for RNCS derivatives.^[68] Recent efforts have explored luminescent metal-organic frameworks (MOFs) incorporating isothiocyanate linkers, where the -N=C=S group contributes to tunable emission properties through metal-ligand charge transfer, as seen in cadmium-based MOFs with aminopyridine and isothiocyanate ligands that exhibit fluorescence suitable for sensing applications.^[69] Beyond coordination compounds, isothiocyanates find applications in materials science as precursors for advanced carbon-based materials. Pyrolysis of isothiocyanate-containing ionic liquids, such as 1-ethyl-3-methylimidazolium thiocyanate (Emim-SCN), yields nitrogen-sulfur co-doped porous carbons with tunable heteroatom content (up to 10 at% S and 15 at% N), enhancing electrocatalytic performance in oxygen reduction reactions due to improved active site density.^[70] These materials exhibit high surface areas (over 1000 m²/g) and are synthesized in a one-pot process, making them viable for energy storage devices. Additionally, isothiocyanate-functionalized thin films, often in polymer dot hybrids, enable sensitive detection of nucleophiles like amines through intramolecular charge transfer mechanisms, with detection limits as low as 0.1 μM for tyramine, leveraging the electrophilic central carbon for selective reactivity.^[71] In agrochemical materials, methyl isothiocyanate (MITC) remains a key soil fumigant, volatilizing to penetrate soil pores and suppress pathogens, nematodes, and weeds. Studies from 2022–2023 have shown that post-application practices like tarping can extend its persistence up to 168 hours while aiding emission control.^[72] MITC, generated from metam sodium, is subject to regulatory monitoring in California for environmental risks, including groundwater protection, with ongoing shifts toward alternatives like biofumigation in some practices.^[73] The bonding in isothiocyanate ligands involves σ-donation primarily from the nitrogen lone pair to the metal, complemented by π-acceptance through the cumulene π* orbitals, which stabilizes low-valent metals and influences redox properties.^[74] Upon coordination, the infrared spectrum shows a characteristic shift in the ν(CNS) stretching frequency to 2050–2100 cm⁻¹ for N-bound modes, distinguishing them from S-bound (around 780–860 cm⁻¹) and free ligand vibrations (2100–2140 cm⁻¹), as confirmed in complexes like iron(II isothiocyanates with pyrazines.^[75]^[76] This spectroscopic marker aids in determining binding modes and has been pivotal in structural analyses of thiocyanato and isothiocyanato derivatives.^[77]

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[15]
Crystal structure of chlorido(η2-phenyl isothiocyanate-κ2 C,S)
Upon complexation to the iridium cation in the title compound, the N—C bond in phenyl isothiocyanate lengthens to 1.256 (7) Å, the C—S bond lengthens to 1.757 ...
[16]
The structures of the azido-, isocyanato- and isothiocyanato ...
The MP2 and CCSD(T) results correlate strongly for a series of these molecules; thus the CCSD(T) bond lengths are larger by about 1.9%. ... N N, C O or C S.
[17]
[PDF] Near-Silence of Isothiocyanate Carbon in 13C NMR Spectra
Jan 12, 2015 · atoms of the ITC functional group (10−33 ppm). The accessible range of the bond angle γ is largely determined by the superposition of the γ ...
[18]
The Isomerization of Alkyl Thiocyanates to Isothiocyanates
Experimental and theoretical studies on the isomerization of allyl thiocyanate to allyl isothiocyanate. Heteroatom Chemistry 1997, 8 (1) , 35-43. https ...
[19]
Ambident Reactivity of the Thiocyanate Anion Revisited
Aug 6, 2025 · Though alkyl isothiocyanates are more stable than their thiocyanate counterparts in thermodynamic terms, the alkylation of SCN − usually leads ...<|separator|>
[20]
The infrared spectra of alkyl isothiocyanates - ScienceDirect
The Cα N stretching vibration is assigned to absorption bands at about 640 cm−1 on the basis of a “splitting” observed in this region in n-propyl isothiocyanate ...
[21]
Near-Silence of Isothiocyanate Carbon in 13C NMR Spectra
The analysis provides a general explanation for the near-silence of the ITC carbon in 13 C NMR spectra of organic isothiocyanates.Missing: central | Show results with:central
[22]
Functional Ingredients From Brassicaceae Species - NIH
Mar 15, 2020 · Isothiocyanates (ITC) are the most characteristic compounds, considered responsible for their pungent taste. Besides ITC, these vegetables are ...
[23]
Sulforaphane Bioavailability from Glucoraphanin-Rich Broccoli - NIH
Nov 2, 2015 · Glucoraphanin from broccoli and its sprouts and seeds is a water soluble and relatively inert precursor of sulforaphane, the reactive isothiocyanate.
[24]
Biologically Active Compounds in Mustard Seeds: A Toxicological ...
Sinigrin is the major glucosinolate in the seeds of black mustard and can be hydrolysed to allyl-isothiocyanate (AITC) giving the characteristic of a pungent ...
[25]
[PDF] Allyl Isothiocyanate - Agricultural Marketing Service
Oct 3, 2014 · AITC concentration (mg/kg). Brussels sprouts. 0.10. Cabbage. 3.00. Cauliflower. 0.08. Horseradish. 1,350. Mustard. 400–15,000. Baked goods. 25– ...
[26]
Isothiocyanates from cruciferous plants as geroprotectors
Isothiocyanates (ITCs) are plant secondary metabolites predominantly found in the Brassicaceae family, responsible for their characteristic pungent taste ...
[27]
Sequestration of Host Plant Glucosinolates in the Defensive ...
The chemical diversity and distribution of glucosinolates and isothiocyanates ... Eucalyptus oil in the defensive oral discharge of Australian sawfly larvae ( ...
[28]
Bacterial Isothiocyanate Biosynthesis by Rhodanese‐Catalyzed ...
Nov 2, 2023 · We have recently discovered an unusual isothiocyanate, sinapigladioside (9), which is produced by Gram-negative bacteria, Burkholderia gladioli.
[29]
Degradation of Biofumigant Isothiocyanates and Allyl Glucosinolate ...
Jul 17, 2015 · Glucosinolates can have a greater effect on soil bacterial community composition than their hydrolysis products.
[30]
[PDF] Glucosinolates, isothiocyanates and indoles - IARC Publications
Biosynthesis of these glucosino- lates and their resultant isothio- cyanates or indole derivatives can be separated into four parts: amino acid chain elongation ...<|control11|><|separator|>
[31]
Myrosinase-dependent and –independent formation and control of ...
Brassicales contain a myrosinase enzyme that hydrolyzes glucosinolates to form toxic isothiocyanates (ITC), as a defense against bacteria, fungi, insects and ...
[32]
Functional activities and biosynthesis of isothiocyanates in Moringa ...
Nov 29, 2024 · This review comprehensively examines the bioactivity, bioavailability, and biosynthetic pathways of M. oleifera Lam. isothiocyanates, alongside ...
[33]
Advancements in balancing glucosinolate production in plants to ...
The GSL-myrosinase system can be induced to release multiple bioactive products when plants are subjected to mechanical damage, environmental stress, or ...
[34]
β-Cyanoalanine synthase protects mites against Arabidopsis defenses
Brassicaceae-specialized herbivores have evolved various strategies to avoid isothiocyanate toxicity and develop glucosinolate resistance. For example ...
[35]
https://doi.org/10.1021/jo070246n
[36]
https://doi.org/10.1055/s-0037-1612303
[37]
[PDF] Synthesis of Isothiocyanates: A Review - Chemistry & Biology Interface
Apr 30, 2020 · Initialy, the method begins with aniline to prepare phenyl isothiocyanate(Scheme 15) via N-phenyl dithiocarbamate followed by desulphurylation.
[38]
Recent advancement in the synthesis of isothiocyanates
Consequently, they have attracted the attention of biologists and chemists. This review summarizes recent advancements in the synthesis of isothiocyanates.
[39]
[PDF] Recent Advancement in Synthesis of Isothiocyanates - ChemRxiv
Generally, thermodynamically controlled conditions are required to selectively obtain isothiocyanates that are more stable than thiocyanates.
[40]
Synthesis of Isothiocyanates: An Update - PMC - NIH
One of the most common synthetic methods is to form a dithiocarbamate salt, either as the first step or in situ, and then treat the salt with a desulfurization ...
[41]
Isothiocyanate synthesis - Organic Chemistry Portal
A facile and efficient synthesis of isothiocyanates involves the reaction of amines with phenyl chlorothionoformate in the presence of solid sodium hydroxide by ...
[42]
Allyl Isothiocyanate Market 2025 Forecast to 2032
Rating 4.9 (3,567) Jul 10, 2025 · Global Allyl Isothiocyanate market was valued at USD 39.4M in 2024 and is projected to reach USD 49.4M by 2032, at a 3.4% CAGR.
[43]
RSC - 404 Error - Page not found
**Summary:**
[44]
Error (ACS Publications)
**Summary:**
[45]
sustainable bioconversion of rapeseed meal-derived glucosinolates ...
Sep 18, 2025 · 70 % conversion from RSM-derived glucosinolates (GLs) into isothiocyanates (ITCs) was achieved.
[46]
103-72-0(Phenyl isothiocyanate) Product Description - ChemicalBook
Phenyl isothiocyanate Property. Melting point: −21 °C(lit.) Boiling point: 218 °C(lit.) Density, 1.132 g/mL at 20 °C(lit.) vapor pressure, 10 hPa (20 °C).
[47]
https://www.sigmaaldrich.com/US/en/product/aldrich/377430
[48]
Isothiocyanates – A Review of their Health Benefits and Potential ...
Jun 14, 2022 · Isothiocyanates are the highly reactive organo-sulphur phytochemicals and are product of hydrolysis of glucosinolates which are present mainly ...Missing: definition | Show results with:definition
[49]
Hydrolysis of aryl and alkyl isothiocyanates in aqueous perchloric acid
The slow hydrolysis of aromatic and aliphatic isothiocyanates in water is promoted by added perchloric acid. The hydrolysis leads first to the thiocarbamic ...
[50]
https://pubs.rsc.org/en/content/articlelanding/1992/p2/p29920000339
[51]
https://www.sciencedirect.com/science/article/pii/B0080447058002284
[52]
and stereo-selective [3 + 2] dipolar cycloaddition of aziridines with ...
A FeCl 3 -catalyzed [3 + 2] cycloaddition reaction of aziridine with isothiocyanate was developed. The cycloaddition reaction was completed in two minutes.
[53]
Metal-Free [3+2]-Cycloaddition of Thiiranes with Isothiocyanates ...
PDF | Metal‐free regioselective [3+2]‐cycloaddition of 2‐aryl/alkylthiiranes with isothiocyanates, isoselenocyanates and carbodiimides is developed.
[54]
Chemoselective reduction of isothiocyanates to thioformamides ...
Thioformamides are easily prepared – under full chemocontrol – through the partial reduction of isothiocyanates with the in situ generated Schwartz reagent.
[55]
Pd-Catalyzed Decarboxylative Cycloaddition of Vinylethylene ...
Jun 17, 2020 · In summary, we have developed a formal [3 + 2] cycloaddition reaction between vinylethylene carbonates and isothiocyanates to efficiently ...Missing: cycloadditions | Show results with:cycloadditions
[56]
Investigation of isothiocyanate yield from flowering and non ...
The characteristic odour and taste of wasabi is due to isothiocyanate formation following the action of myrosinase on glucosinolate when plant tissues are ...<|separator|>
[57]
Total isothiocyanate yield from raw cruciferous vegetables ...
1.1). Upon vegetable cutting or chewing, myrosinase is released from the damaged plant cells to hydrolyze glucosinolates.
[58]
Disposition of glucosinolates and sulforaphane in humans ... - PubMed
Results of this study indicate that the bioavailability of ITCs from fresh broccoli is approximately three times greater than that from cooked broccoli.
[59]
Impact of Allyl Isothiocyanate Addition on Consumers' Sensory ...
Jun 16, 2025 · However, the addition of AITC led to increased bitterness and sourness as well as a metallic flavor. To continue this work, the presented study ...
[60]
Gas chromatography-mass spectrometric determination of total ...
A gas chromatography-mass spectrometric (GC-MS) method for the determination of total isothiocyanates (ITCs) has been developed based on the quantification ...
[61]
Antimicrobial properties of isothiocyanates in food preservation
Aug 6, 2025 · Plants containing AITC include horseradish, cabbage, wasabi, Brussels sprouts, watercress, broccoli, and cauliflower.
[62]
allyl isothiocyanate, 57-06-7 - The Good Scents Company
Food Additive: Functional use(s) - flavoring agents. Has a sulfurous type odor and an mustard type flavor.
[63]
Scientific Opinion on the safety of allyl isothiocyanate for the proposed uses as a food additive
### Summary of Allyl Isothiocyanate (AITC) as a Food Flavoring in the EU
[64]
Isothiocyanate - Wikipedia
Isothiocyanate is a functional group as found in compounds with the formula R−N=C=S. Isothiocyanates are the more common isomers of thiocyanates.Methyl isothiocyanate · Phenyl isothiocyanate · Allyl isothiocyanate
[65]
Isothiocyanate controlled architecture, spectroscopic and magnetic ...
We synthesized an l–arginine complex, containing Cu(II) and isothiocyanate ions, with the formula [Cu(l–Arg)2(NCS)]·(NCS)·H2O (1) (l–Arg = l–arginine).
[66]
Organotin isothiocyanate complexes: the interaction of alkyltin ...
Trimethyltin isothiocyanate Me3Sn(NCS) forms 1 : 1 adducts with monodentate ligands, the five-co-ordinate compounds having trigonal-bipyramidal structures with ...Missing: coordination | Show results with:coordination
[67]
Reaction of Phenyl Iso(thio)cyanate with N‑Heterocyclic Carbene ...
Aug 8, 2016 · Reaction of Phenyl Iso(thio)cyanate with N‑Heterocyclic Carbene-Supported Nickel Complexes: Formation of Nickelacycles.
[68]
[PDF] Design and characterization of metal-thiocyanate coordination ...
This thesis focuses on exploring the synthesis and chemical reactivity of thiocyanate- based building blocks of the type [M(SCN)x]y- for the synthesis of ...<|separator|>
[69]
Synthesis, characterization, and Hirshfeld surface analysis of ...
In this article, we describe the successful synthesis of three coordination compounds formed by the ligands 3-aminopyridine, 4-aminopyridine, and isothiocyanate ...
[70]
One-pot synthesis of nitrogen–sulfur-co-doped carbons with tunable ...
The commercially available ionic liquid (IL) 1-ethyl-3-methyl imidazolium thiocyanate (Emim-scn) is used as a highly efficient precursor for the synthesis ...
[71]
Hybrid polymer dots with isothiocyanate functional groups for rapid ...
Two novel fluorescent sensors were designed for tyramine detection. The isothiocyanate amination between sensors and tyramine triggered the ICT.Missing: thin nucleophiles
[72]
[PDF] Methyl Isothiocyanate Concentration, Distribution, and Persistence ...
Feb 12, 2025 · This study analyzes how post-dazomet practices like tilling, rolling, irrigation, tarping, and water-seal affect MITC concentration, ...
[73]
[PDF] Fumigant Use in California and an Assessment of Available ...
Jan 27, 2025 · This report assesses fumigant use in California, focusing on 1,3-D and chloropicrin, and available alternatives.
[74]
[PDF] Multidecadal Change in Pesticide Concentrations Relative to ...
This assessment of decadal groundwater pesticide concentrations provides a characterization of changes in water availability because of pesticide contamination ...
[75]
Buy Tetraisothiocyanatosilane | 6544-02-1 - Smolecule
Rating 4.5 (5) The isothiocyanate group possesses both sigma-donating and pi-accepting capabilities, which influence the overall electronic structure of the complex [5] [17].
[76]
Iron (II) isothiocyanate complexes with substituted pyrazines
Feb 17, 2015 · Complex 5 demonstrates insignificant shifts for carbonyl stretching vibration bands in the FT-IR spectrum and a characteristic strong single ...
[77]
COORDINATION COMPLEXES OF GROUP (IV) HALIDES
According to Lieber (7) the infrared spectra of isothiocyanates exhibit a strong band in the region of 2 100 cm-I due to the isothiocyanate group. This band ...
[78]
[PDF] On the Infrared Spectra of Thiocyanic Acid and some Thiocyanato ...
The frequency and the integrated absorption of the C-N stretching vibration of HNCS as compared to that of NCS have been maesured to see if more information can ...