19.6 Nucleophilic Addition of HCN: Cyanohydrin Formation
3 min read•may 7, 2024
Cyanohydrins form when HCN adds to carbonyl compounds. This reaction showcases how nucleophiles attack electrophilic carbons, creating new C-C bonds. It's a prime example of how carbonyl groups react, setting the stage for understanding more complex organic reactions.
The resulting cyanohydrins are versatile intermediates in organic synthesis. They can be converted into amines or carboxylic acids, making them valuable building blocks for creating more complex molecules like pharmaceuticals and natural products.
Nucleophilic Addition of HCN: Cyanohydrin Formation
Mechanism of cyanohydrin formation
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- involves the addition of HCN () to a (aldehydes or ketones)
- Carbonyl carbon acts as an due to the polarization of the bond
- Cyanide anion () acts as a , attacking the electrophilic carbonyl carbon (, )
- Base catalysis often employed to generate the reactive cyanide anion from HCN
- Common bases used include , , or
- Base deprotonates HCN to form the cyanide anion ()
- pathway proceeds as follows:
- Cyanide anion attacks the carbonyl carbon, forming a
- Protonation of the alkoxide intermediate by water or another protic solvent yields the product (, )
- Protonation step regenerates the base catalyst ()
- This reaction is reversible, with the equilibrium favoring the cyanohydrin product under acidic conditions
Favorability of cyanohydrin reactions
- Favored due to the stability of the cyanide anion and the formation of a strong bond
- Cyanide anion is a strong nucleophile due to the high electronegativity of nitrogen and the linear geometry of the anion
- Resulting bond formed between the carbonyl carbon and the cyanide carbon is strong and stable
- In comparison, other protic acid additions are less favored due to:
- Weaker nucleophilicity of the corresponding anions ( or ) compared to cyanide (HCl, H2O)
- Formation of less stable or bonds compared to the bond in cyanohydrins
Lewis Acid-Base Interactions in Cyanohydrin Formation
- The carbonyl group acts as a , donating electrons to form a bond
- (HCN) acts as a , accepting electrons to form a bond
- This -base interaction is crucial for the formation of the cyanohydrin
- The resulting cyanohydrin often contains a , making this reaction useful in asymmetric synthesis
Synthetic applications of cyanohydrins
- Versatile synthetic intermediates that can be converted into various functional groups (primary amines, carboxylic acids)
- Conversion of cyanohydrins to primary amines:
- Reduction of the nitrile group in a cyanohydrin using or catalytic hydrogenation yields a
- Useful for synthesizing β-hydroxy amines, which are important in pharmaceutical chemistry (, )
- Conversion of cyanohydrins to carboxylic acids:
- Hydrolysis of the nitrile group in a cyanohydrin under acidic or basic conditions yields a
- Acidic conditions: Heat the cyanohydrin with a strong acid like or
- Basic conditions: Heat the cyanohydrin with a strong base like followed by acidification
- Useful for synthesizing α-hydroxy acids, which are important in natural product synthesis and biochemistry (, )
- Hydrolysis of the nitrile group in a cyanohydrin under acidic or basic conditions yields a
Key Terms to Review (34)
2-hydroxy-2-phenylpropanenitrile: 2-hydroxy-2-phenylpropanenitrile is a compound formed through the nucleophilic addition of hydrogen cyanide (HCN) to a ketone, resulting in the creation of a cyanohydrin. This reaction is covered in the context of the topic 19.6 Nucleophilic Addition of HCN: Cyanohydrin Formation.
Acetophenone: Acetophenone is an aromatic ketone compound with the chemical formula C6H5COCH3. It is a colorless liquid with a characteristic floral odor and is widely used in the production of various organic compounds and as a fragrance in personal care products.
Aldehyde: An aldehyde is a class of organic compounds containing a carbonyl group (C=O) where the carbon atom is bonded to one hydrogen atom and one alkyl or aryl group. Aldehydes are important functional groups in organic chemistry and are involved in various reactions and synthesis pathways.
Benzaldehyde: Benzaldehyde is an aromatic aldehyde compound with the chemical formula C6H5CHO. It is a colorless liquid with a characteristic almond-like odor and is widely used in the production of various organic compounds, including pharmaceuticals, flavors, and fragrances.
Carbonyl group: A carbonyl group is a functional group characterized by a carbon atom double-bonded to an oxygen atom, represented as C=O. This group is pivotal in organic chemistry as it forms the backbone of various important classes of compounds, influencing their chemical properties and reactivity.
Carboxylic Acid: Carboxylic acids are organic compounds characterized by the presence of a carboxyl functional group (-COOH), which consists of a carbonyl (C=O) and a hydroxyl (-OH) group. They are widely found in nature and play a crucial role in various organic chemistry topics.
Carboxylic acid derivative: Carboxylic acid derivatives are compounds that contain a functional group which is a modified form of the carboxylic acid group (–COOH), where the hydroxyl part (-OH) is replaced by another atom or group of atoms. These derivatives undergo nucleophilic acyl substitution reactions, where an electron-rich nucleophile attacks the carbonyl carbon, leading to the substitution of the leaving group.
Chiral Center: A chiral center is a carbon atom with four different substituents attached, resulting in a non-superimposable mirror image. This structural feature is crucial in understanding the concepts of enantiomers, Pasteur's discovery of enantiomers, the sequence rules for specifying configuration, and the nucleophilic addition of HCN to form cyanohydrins.
Cyanide Ion: The cyanide ion, represented as CN-, is a polyatomic ion consisting of a carbon atom triple-bonded to a nitrogen atom. It is an important reactive species in organic chemistry, particularly in the context of nucleophilic addition reactions and the formation of cyanohydrins.
Cyanohydrin: A cyanohydrin is a compound formed by the addition of hydrogen cyanide (HCN) to the carbonyl group of an aldehyde or ketone, resulting in the formation of a new carbon-carbon bond and a hydroxyl group. This reaction is a type of nucleophilic addition and is an important tool in organic synthesis.
Electrophile: An electrophile is a species that is attracted to electron-rich regions and seeks to form new bonds by accepting electron density. Electrophiles play a crucial role in many organic reactions, including polar reactions, electrophilic aromatic substitution, and nucleophilic acyl substitution, among others.
Ephedrine: Ephedrine is a naturally occurring alkaloid compound found in various plant species, particularly the Ephedra plant. It is a stimulant drug that acts on the sympathetic nervous system, producing effects similar to those of adrenaline. Ephedrine is commonly used in the context of organic chemistry reactions, particularly in the ring-opening of epoxides and the nucleophilic addition of HCN to form cyanohydrins.
Hydrocyanic Acid: Hydrocyanic acid, also known as hydrogen cyanide, is a highly toxic chemical compound with the formula HCN. It is a colorless, volatile liquid that is used in various industrial processes and can be produced through the nucleophilic addition of hydrogen cyanide to carbonyl compounds, a reaction known as cyanohydrin formation.
Hydrogen Cyanide: Hydrogen cyanide, also known as hydrocyanic acid or prussic acid, is a highly toxic chemical compound composed of hydrogen and cyanide. It is a colorless, volatile liquid with a distinctive almond-like odor. Hydrogen cyanide is particularly relevant in the context of nucleophilic addition reactions and the formation of cyanohydrins.
Ketone: A ketone is a functional group in organic chemistry that consists of a carbonyl group (a carbon-oxygen double bond) bonded to two alkyl or aryl groups. Ketones are widely encountered in various organic chemistry topics, including the hydration of alkynes, oxidative cleavage of alkynes, organic synthesis, oxidation and reduction reactions, and the chemistry of aldehydes and ketones.
Lactic Acid: Lactic acid is a chemical compound produced in the body during anaerobic respiration, where glucose is broken down without the use of oxygen. It is a key player in various biochemical processes, including the reason for handedness in molecules, spin-spin splitting in 1H NMR spectra, cyanohydrin formation, and the regulation of biological acids through the Henderson-Hasselbalch equation.
Lewis acid: A Lewis acid is a chemical species that accepts an electron pair from another molecule during the formation of a covalent bond. Unlike the traditional concept of acids and bases, which focuses on proton donors and acceptors, the Lewis definition emphasizes the role of electron pair donors and acceptors.
Lewis Acid: A Lewis acid is an electron pair acceptor that can form a coordinate covalent bond with a Lewis base, which is an electron pair donor. Lewis acids play a crucial role in various organic chemistry reactions, including electrophilic aromatic substitution, the Friedel-Crafts reaction, and cyanohydrin formation.
Lewis Base: A Lewis base is a chemical species that can donate an electron pair to form a covalent bond with a Lewis acid. It is a key concept in understanding nucleophilic addition reactions, such as the formation of cyanohydrins through the nucleophilic addition of hydrogen cyanide (HCN).
Mandelic Acid: Mandelic acid is an organic compound with the chemical formula C6H5CH(OH)COOH. It is a chiral molecule and exists as two enantiomers, (R)-mandelic acid and (S)-mandelic acid. Mandelic acid is commonly used in the context of nucleophilic addition of HCN, specifically in the formation of cyanohydrins.
Mandelonitrile: Mandelonitrile is a cyanohydrin, a type of organic compound formed by the addition of hydrogen cyanide (HCN) to an aldehyde or ketone. It is specifically the cyanohydrin derived from benzaldehyde, and is an important intermediate in organic synthesis.
Nucleophile: A nucleophile is a species that donates a pair of electrons to form a covalent bond with another atom or molecule. Nucleophiles are central to understanding many organic reactions, including polar reactions, electrophilic addition reactions, and nucleophilic substitution reactions.
Nucleophilic Addition: Nucleophilic addition is a fundamental organic reaction in which a nucleophile, a species that donates electrons, adds to an electrophilic carbon center, typically a carbonyl carbon, to form a new product. This reaction is central to understanding many important topics in organic chemistry, including functional groups, polar reactions, carbocation stability, reaction stereochemistry, and the chemistry of aldehydes, ketones, alcohols, and other carbonyl-containing compounds.
Nucleophilic addition reaction: A nucleophilic addition reaction is a chemical process where a nucleophile forms a bond with an electrophilic carbon atom of a compound, typically found in aldehydes and ketones. This reaction results in the conversion of the carbonyl group into a more complex, often larger, molecule.
Potassium Cyanide: Potassium cyanide is a highly toxic chemical compound consisting of the cyanide anion (CN-) and the potassium cation (K+). It is a white, crystalline solid that is commonly used in various industrial processes, including metal extraction and electroplating. However, potassium cyanide's toxicity makes it a dangerous substance that requires strict handling and safety protocols.
Primary Amine: A primary amine is a nitrogen-containing organic compound where the nitrogen atom is bonded to one alkyl or aryl group and two hydrogen atoms. These amines are important functional groups that participate in various organic reactions.
Primary amine (RNH2): A primary amine is an organic compound that contains a nitrogen atom attached to one alkyl or aryl group and two hydrogen atoms. It represents the simplest class of amines in organic chemistry.
Pseudoephedrine: Pseudoephedrine is a sympathomimetic amine that acts as a decongestant and stimulant. It is commonly used in the treatment of nasal and sinus congestion, and is also a precursor chemical in the illicit manufacture of methamphetamine.
Reversible Reaction: A reversible reaction is a chemical reaction in which the products can react to form the original reactants. This means the reaction can occur in both the forward and reverse directions, depending on the conditions.
Sodium Cyanide: Sodium cyanide is a highly toxic chemical compound that consists of a sodium cation and a cyanide anion. It is commonly used in various industrial processes, including gold mining and chemical synthesis, and is an important precursor in the preparation of carboxylic acids.
Tetrahedral Alkoxide Intermediate: The tetrahedral alkoxide intermediate is a key species that arises during the nucleophilic addition of hydrogen cyanide (HCN) to a carbonyl compound, leading to the formation of a cyanohydrin. This intermediate is characterized by a central carbon atom with four attached substituents, adopting a tetrahedral geometry.
α-Hydroxy Acid: An α-hydroxy acid is an organic compound that contains a hydroxyl (-OH) group attached to the carbon atom adjacent to the carboxyl (-COOH) group. These compounds are important in various chemical reactions, including the formation of cyanohydrins in the context of nucleophilic addition of HCN.
β Diketone: A β-diketone is an organic compound containing two ketone groups separated by a carbon atom, which is the beta (β) position relative to each ketone group. These molecules are characterized by the presence of hydrogen atoms on the carbon between the two carbonyl (C=O) groups, making them acidic and prone to enolate ion formation.
β-hydroxy amine: A β-hydroxy amine is a type of organic compound containing both a hydroxyl (-OH) group and an amine (-NH2) group, where the hydroxyl group is positioned on the carbon atom that is β (beta) to the amine group. These compounds are important intermediates in various organic reactions, particularly in the context of nucleophilic addition reactions involving hydrogen cyanide (HCN).