Community Hub0 Subscribers
Community hub
Cyanohydrin
View on Wikipediafrom Wikipedia
In organic chemistry, a cyanohydrin or hydroxynitrile is a functional group found in organic compounds in which a cyano and a hydroxy group are attached to the same carbon atom. The general formula is R2C(OH)CN, where R is H, alkyl, or aryl. Cyanohydrins are industrially important precursors to carboxylic acids and some amino acids. Cyanohydrins can be formed by the cyanohydrin reaction, which involves treating a ketone or an aldehyde with hydrogen cyanide (HCN) in the presence of excess amounts of sodium cyanide (NaCN) as a catalyst:[1]
- RR’C=O + HCN → RR’C(OH)CN
In this reaction, the nucleophilic CN− ion attacks the electrophilic carbonyl carbon in the ketone, followed by protonation by HCN, thereby regenerating the cyanide anion. Cyanohydrins are also prepared by displacement of sulfite by cyanide salts:[2]
Cyanohydrins are intermediates in the Strecker amino acid synthesis. In aqueous acid, they are hydrolyzed to the α-hydroxy acid.
Preparative methods
[edit]Cyanohydrins are traditionally prepared by the addition of HCN to the corresponding carbonyl. The reaction is typically catalyzed by base or an enzyme.[3][4] Because of the hazards with HCN, other less dangerous cyanation reagents are often used.[5]
- Trimethylsilyl cyanide, affording the silyl ether derivative of the cyanohydrin
- Diethylaluminium cyanide, especially for less reactive carbonyls
- Diethyl phosphorocyanidate (DEPC) and lithium cyanide
- Acyl cyanides (RC(O)CN)
Transhydrocyanation
[edit]Acetone cyanohydrin, (CH3)2C(OH)CN is the cyanohydrin of acetone. It is generated as an intermediate in the industrial production of methyl methacrylate.[6] In the laboratory, this liquid serves as a source of HCN. The process is called transhydrocyanation, where acetone cyanohydrin, is used as a source of HCN.[3][4][7] Thus, acetone cyanohydrin can be used for the preparation of other cyanohydrins, for the transformation of HCN to Michael acceptors, and for the formylation of arenes. Treatment of this cyanohydrin with lithium hydride affords anhydrous lithium cyanide:
Asymmetric cyanohydrin formation
[edit]Formation of cyanohydrins introduces a chiral center for aldehydes and for unsymmetrical ketones. The enantioselective hydrocyanation has attracted some attention for the preparation of 2-chloromandelic acid, a drug precursor.[3]
- Some Prominent Cyanohydrins
-
![Glycolonitrile, also called hydroxyacetonitrile or formaldehyde cyanohydrin, is the simplest cyanohydrin.[8]](//upload.wikimedia.org/wikipedia/commons/thumb/4/49/Glyconitrile_Structural_FormulaV1.svg/120px-Glyconitrile_Structural_FormulaV1.svg.png)
Glycolonitrile, also called hydroxyacetonitrile or formaldehyde cyanohydrin, is the simplest cyanohydrin.[8] -
-
![Mandelonitrile, occurs in small amounts in the pits of some fruits.[2]](//upload.wikimedia.org/wikipedia/commons/thumb/d/d2/Mandelonitrile-2D-skeletal.svg/120px-Mandelonitrile-2D-skeletal.svg.png)
Mandelonitrile, occurs in small amounts in the pits of some fruits.[2] -
Amygdalin, a naturally occurring cyanogenic glycoside
![Glycolonitrile, also called hydroxyacetonitrile or formaldehyde cyanohydrin, is the simplest cyanohydrin.[8]](https://en.wikipedia.org/wiki/File:Glyconitrile_Structural_FormulaV1.svg)
![Mandelonitrile, occurs in small amounts in the pits of some fruits.[2]](https://en.wikipedia.org/wiki/File:Mandelonitrile-2D-skeletal.svg)
See also
[edit]References
[edit]- ^ David T. Mowry (1948). "The Preparation of Nitriles". Chem. Rev. 42 (2): 189–283. doi:10.1021/cr60132a001. PMID 18914000.
- ^ a b Corson, B. B.; Dodge, R. A.; Harris, S. A.; Yeaw, J. S. (1941). "Mandelic Acid". Organic Syntheses; Collected Volumes, vol. 1, p. 336.
- ^ a b c North, Michael; Usanov, Dmitry L.; Young, Carl (2008). "Lewis Acid Catalyzed Asymmetric Cyanohydrin Synthesis". Chemical Reviews. 108 (12): 5146–5226. doi:10.1021/cr800255k. PMID 19067648.
- ^ a b Gregory, Robert J. H. (1999). "Cyanohydrins in Nature and the Laboratory: Biology, Preparations, and Synthetic Applications". Chemical Reviews. 99 (12): 3649–3682. doi:10.1021/cr9902906. PMID 11849033.
- ^ Juhl, Martin; Petersen, Allan R.; Lee, Ji-Woong (2021). "CO2-Enabled Cyanohydrin Synthesis and Facile Iterative Homologation Reactions*". Chemistry – A European Journal. 27: 228–232. doi:10.1002/chem.202003623.
- ^ William Bauer, Jr. "Methacrylic Acid and Derivatives" in Ullmann's Encyclopedia of Industrial Chemistry 2002, Wiley-VCH, Weinheim. doi:10.1002/14356007.a16_441. Article Online Posting Date: June 15, 2000
- ^ Haroutounian, S. A. "Acetone Cyanohydrin" Encyclopedia of Reagents for Organic Synthesis 2001, John Wiley & Sons. doi:10.1002/047084289X.ra014
- ^ Gaudry, R. (1955). "Glycolonitrile". Organic Syntheses; Collected Volumes, vol. 3, p. 436.
External links
[edit]Cyanohydrin
View on Grokipediafrom Grokipedia
Definition and Structure
Functional Group
A cyanohydrin is an organic compound containing both a hydroxy group (-OH) and a cyano group (-CN) attached to the same carbon atom, with the general formula R₁R₂C(OH)CN, where R₁ and R₂ can be hydrogen atoms, alkyl groups, or aryl groups. This functional group arises from the addition of hydrogen cyanide (HCN) across the carbon-oxygen double bond of a carbonyl compound, such as an aldehyde (where one R is H) or a ketone (where both R groups are non-hydrogen). The structural origin of cyanohydrins lies in the nucleophilic addition reaction of cyanide ion (CN⁻) to the electrophilic carbonyl carbon, forming a tetrahedral intermediate that protonates to yield the α-hydroxy nitrile. In this structure, the central carbon atom is tetrahedral, bonded to the hydroxyl group, the cyano group, and the two R substituents, which imparts specific stereochemical possibilities if the R groups differ. The general structural formula can be represented as:
where the tetrahedral carbon center features the -OH and -CN groups in close proximity, influencing the compound's polarity and reactivity.
The cyanohydrin reaction was first reported in 1832 by Justus von Liebig and Friedrich Wöhler during their investigations of benzaldehyde.
Nomenclature
Cyanohydrins are systematically named as hydroxy nitriles in accordance with IUPAC recommendations, where the principal chain includes the carbon of the nitrile group (–C≡N) and is numbered starting from that carbon atom, with the hydroxy group denoted by the "hydroxy-" prefix and its locant.[6] This approach ensures a consistent structure-based naming convention for these compounds, which feature both a hydroxyl (–OH) and a cyano (–CN) group attached to the same carbon.[6] For example, the cyanohydrin from formaldehyde, commonly known as glycolonitrile or hydroxyacetonitrile, has the IUPAC name 2-hydroxyacetonitrile. Similarly, the cyanohydrin from acetone is named 2-hydroxy-2-methylpropanenitrile, reflecting the branched chain at the alpha carbon. The cyanohydrin from benzaldehyde is designated 2-hydroxy-2-phenylacetonitrile. Common names for cyanohydrins are frequently derived from the parent aldehyde or ketone by appending "cyanohydrin," providing a straightforward reference to their origin; for instance, formaldehyde cyanohydrin for glycolonitrile, acetone cyanohydrin for the compound from acetone, and benzaldehyde cyanohydrin or mandelonitrile for the one from benzaldehyde.[6] These retained names are widely used in chemical literature and industry despite the preference for systematic IUPAC nomenclature in formal contexts.[6] In cases of substitution on the carbon chain or alpha carbon, the IUPAC name incorporates additional prefixes and locants to describe the substituents, such as 3-hydroxy-2-methylbutanenitrile for a branched variant. For chiral cyanohydrins, which arise when the alpha carbon bears four different substituents (typically from aldehydes), stereochemical descriptors "(R)-" or "(S)-" are prefixed to the systematic name, as in (R)-2-hydroxy-2-phenylacetonitrile for one enantiomer of mandelonitrile. This follows the Cahn-Ingold-Prelog priority rules for specifying absolute configuration.Physical and Chemical Properties
Stability and Solubility
Cyanohydrins are highly soluble in water and polar organic solvents such as alcohols and ethers, owing to the polar nature of their hydroxyl (OH) and cyano (CN) groups, which facilitate hydrogen bonding and dipole-dipole interactions.[7] For instance, acetone cyanohydrin is miscible with water in all proportions at 20 °C.[8] These compounds exhibit thermal and hydrolytic instability, characterized by reversible decomposition back to the parent carbonyl compound and hydrogen cyanide (HCN) via an equilibrium process.[9] This decomposition is promoted at elevated temperatures or in acidic/basic aqueous conditions, with the equilibrium generally favoring the cyanohydrin for aldehydes and less sterically hindered ketones.[9] The hydroxyl group in cyanohydrins is more acidic than in simple alcohols (pKa ~15–16) due to the electron-withdrawing effect of the adjacent cyano group; this acidity enhances solubility in aqueous media, particularly under basic conditions where deprotonation to the alkoxide ion occurs.[7] In acetone cyanohydrin, the pKa is approximately 12.8.[10] Acetone cyanohydrin serves as a representative example, with a density of 0.932 g/mL at 25 °C and a boiling point of 82 °C at reduced pressure (23 mmHg), beyond which thermal decomposition predominates.[11]Reactivity Characteristics
Cyanohydrins possess an amphoteric nature arising from the hydroxyl group, which can undergo deprotonation under basic conditions to form an alkoxide ion, and the cyano group, which serves as a leaving group in the reverse reaction, facilitating reversion to the parent carbonyl compound. This dual reactivity allows cyanohydrins to participate in both acid-base equilibria and nucleophilic displacement processes.[12] The formation of cyanohydrins involves the reversible addition of hydrogen cyanide to aldehydes or ketones, establishing an equilibrium between the cyanohydrin, the carbonyl compound, and HCN. This equilibrium is governed by Le Chatelier's principle, where increasing the concentration of HCN or removing water can shift the balance toward cyanohydrin formation, while excess carbonyl or acidic conditions favor dissociation.[9][13] Cyanohydrins demonstrate sensitivity to acidic and basic environments, which catalyze their decomposition into the original carbonyl and cyanide components. Strong acids or bases accelerate this breakdown by protonating or deprotonating key functional groups, leading to rapid reversal of the addition reaction.[14] Spectroscopically, cyanohydrins are characterized by a sharp, intense infrared absorption band near 2250 cm⁻¹ attributed to the C≡N stretching vibration of the cyano group. In ¹³C NMR spectroscopy, the alpha carbon (the quaternary carbon bearing both the OH and CN substituents) typically resonates in the 50-70 ppm range, reflecting the electron-withdrawing effects of the adjacent groups, while the cyano carbon appears around 115-120 ppm.[15]Natural Occurrence
In Plants and Organisms
Cyanohydrins occur naturally in plants primarily as components of cyanogenic glycosides, which are β-glucosides of α-hydroxynitriles derived from various aldehydes and hydrogen cyanide.[16] These compounds are sequestered in plant vacuoles and released upon tissue damage to deter herbivores and pathogens. Notable examples include amygdalin, found in bitter almonds (Prunus dulcis), and dhurrin, present in sorghum (Sorghum bicolor), both serving as defense mechanisms through cyanide release.[17][18] The biosynthesis of cyanogenic glycosides in plants begins with amino acids such as L-phenylalanine (precursor to amygdalin) or L-tyrosine (precursor to dhurrin), which are converted to aldoximes by cytochrome P450 enzymes (CYP79 family). The aldoximes are then converted to nitriles and hydroxylated to cyanohydrins by cytochrome P450 enzymes, such as those in the CYP71 family, followed by glycosylation to form the stable glycosides. This pathway is conserved across cyanogenic species and ensures compartmentalized storage to prevent autotoxicity.[19] Cyanogenic glycosides are distributed in over 2,500 plant species spanning more than 100 families, including Poaceae (e.g., sorghum), Rosaceae (e.g., almonds), and Fabaceae, with the highest diversity in tropical and subtropical regions.[16] This widespread occurrence underscores their evolutionary role in chemical defense against biotic stresses.[20] In microorganisms, free cyanohydrins are less common but have been identified in certain fungi, such as the glyoxylic acid cyanohydrin produced by the basidiomycete Marasmius oreades (fairy ring mushroom), where it functions in antimicrobial defense and is biosynthesized from glycine.[21] This compound contributes to the fungus's ability to inhibit competing bacteria and other microbes in soil environments.Biological Role
Cyanohydrins play a crucial defensive role in plants through cyanogenesis, a process where hydrogen cyanide (HCN) is released upon tissue damage to deter herbivores and pathogens.[22] This mechanism acts as a rapid chemical deterrent, inhibiting feeding and microbial growth by exploiting the toxicity of cyanide to cytochrome c oxidase in mitochondrial respiration.[23] In cyanogenic plants, cyanohydrins are typically stored as stable glycosides, which decompose only when plant cells are disrupted, preventing self-toxicity while enabling targeted defense.[24] The release of HCN from cyanohydrins occurs via enzymatic hydrolysis catalyzed by β-glucosidases, which cleave the glycosidic bond in cyanogenic glycosides to form the unstable cyanohydrin intermediate, followed by spontaneous or enzymatic breakdown to HCN and a carbonyl compound.[25] This two-step process—first by β-glucosidase to yield the cyanohydrin, then by α-hydroxynitrile lyase—ensures efficient HCN production at sites of injury, such as herbivore bites or pathogen invasion.[26] In species like sorghum and cassava, these enzymes are compartmentalized separately from substrates, maintaining stability until activation is needed.[27] Cyanohydrins may also contribute to allelopathic effects, where released HCN or related compounds inhibit the growth of competing plants by interfering with seed germination and root development in nearby soil.[28] Studies on cyanogenic glycosides like dhurrin demonstrate their potential to persist in soil and disrupt microbial activity and nutrient cycling, thereby influencing plant competition in ecosystems.[29] In human health contexts, cyanohydrins and their precursors pose significant toxicity risks, leading to cyanide poisoning through inhibition of cellular respiration and resulting in symptoms such as headache, vertigo, respiratory failure, and potentially death.[30] The median oral LD50 for key cyanogenic glycosides like linamarin and amygdalin ranges from 450 to 880 mg/kg body weight in animal models, while the lethal dose for HCN in humans is approximately 0.5–3.5 mg/kg body weight, highlighting the acute danger from consumption of cyanogenic plant materials.[31] Chronic low-level exposure can cause goitrogenic effects, such as thyroid enlargement, due to cyanide's interference with iodine uptake.[32]Synthesis
Hydrocyanation with HCN
The classical laboratory synthesis of cyanohydrins involves the direct addition of hydrogen cyanide (HCN) to the carbonyl group of aldehydes or ketones, forming a hydroxy nitrile through nucleophilic addition.[33] This reaction, known as hydrocyanation, proceeds under mild conditions and serves as a foundational method in organic synthesis, particularly for extending carbon chains in carbohydrates via the Kiliani-Fischer synthesis.[34] The general reaction is represented as:
where can be hydrogen, alkyl, or aryl groups.[35]
The mechanism is base-catalyzed and catalytic in cyanide, involving the generation of the nucleophilic cyanide anion (CN⁻) from HCN, which has a low acidity (pKa ≈ 9.2). A base such as potassium cyanide (KCN) or sodium cyanide (NaCN) is added to initiate the process, deprotonating HCN to form CN⁻ in equilibrium. The CN⁻ then attacks the electrophilic carbonyl carbon, forming a tetrahedral alkoxide intermediate. This intermediate is subsequently protonated by another molecule of HCN, yielding the neutral cyanohydrin and regenerating CN⁻ for catalysis.[36][35] The reaction is reversible, with equilibrium favoring the cyanohydrin under controlled conditions, but pure HCN alone reacts slowly due to insufficient CN⁻ concentration.[33]
Typical conditions employ aqueous solutions at room temperature (20–25°C), often generating HCN in situ from KCN or NaCN and a mild acid such as acetic acid, sulfuric acid, or HCl to maintain a pH of 4–5, which optimizes the balance between CN⁻ availability and carbonyl reactivity.[35][37] This approach avoids handling pure HCN gas directly, which is highly toxic, volatile (boiling point 25.6°C), odorless in low concentrations but detectable as bitter almonds, and prone to explosive polymerization in air or light.[33] Reaction times vary from minutes to hours, depending on the substrate, with yields typically exceeding 80% for reactive carbonyls when pH is properly controlled.[35]
This method is most effective for aldehydes, which exhibit higher electrophilicity and lower steric hindrance at the carbonyl carbon compared to ketones, leading to faster reaction rates and higher equilibrium constants (e.g., K_eq ≈ 10–300 for aldehydes vs. 0.1–10 for ketones).[33] Ketones, particularly those with bulky substituents, react more sluggishly and often require excess HCN or longer reaction times. A representative example is the synthesis of glycolonitrile from formaldehyde, where aqueous formaldehyde reacts with HCN (generated from KCN and acid) at neutral to slightly acidic pH to afford HOCH₂CN in high yield (up to 95%), serving as a key intermediate for glycolic acid production.[38]
Recent developments include CO₂-enabled hydrocyanation, where carbon dioxide promotes the addition of cyanide from insoluble sources like KCN under neutral conditions, avoiding HCN generation and enabling iterative homologation reactions with broad substrate scope for aldehydes and ketones as of 2021.[39]
Transhydrocyanation
Transhydrocyanation is a synthetic method for preparing cyanohydrins that involves the transfer of a cyanide group from a donor cyanohydrin, typically acetone cyanohydrin, to a carbonyl compound such as an aldehyde or ketone. The reaction proceeds as a reversible equilibrium, represented by the equation:
This process generates the desired cyanohydrin and acetone as a byproduct, with the equilibrium often driven forward by the distillation of acetone due to its low boiling point.[40][41]
The mechanism relies on the dissociation of the donor cyanohydrin into hydrogen cyanide and the corresponding carbonyl, followed by nucleophilic addition of the cyanide to the acceptor carbonyl; however, the reaction avoids the need for free gaseous HCN by maintaining low concentrations through the equilibrium. This exchange is facilitated by catalysts that accelerate both the dissociation and addition steps without promoting side reactions.[42][40]
A key advantage of transhydrocyanation over direct hydrocyanation with HCN is enhanced safety, as acetone cyanohydrin is a stable, liquid cyanide source that is less volatile and toxic than HCN gas, reducing handling risks in laboratory and industrial settings. Additionally, it often provides higher yields for less reactive ketones, where direct HCN addition may suffer from unfavorable equilibria.[41][43]
Various catalysts promote transhydrocyanation, including basic cyanide sources like potassium cyanide for efficient transfer to aldehydes such as crotonaldehyde, achieving near-quantitative yields under mild conditions. Lewis acidic metal salts, notably lanthanoid(III) alkoxides such as those derived from ytterbium or samarium, enable rapid reactions with both aldehydes and ketones at room temperature, often completing in minutes with high efficiency. Biocatalysts like oxynitrilase enzymes also mediate the process, offering selectivity in aqueous media while utilizing acetone cyanohydrin as the cyanide donor.[40][43][42]
Industrial applications have advanced with continuous flow processes, such as the cyanation of glycosides using trimethylsilyl cyanide (TMSCN) for the synthesis of the antiviral drug remdesivir, providing safe, scalable handling of cyanide reagents and high yields as of 2020.[44]