Nitrogen Containing Organic Compounds - Ambident nucleophile

  • Ambident nucleophiles are molecules or ions that possess more than one nucleophilic center.
  • The nucleophilic centers can have different reactivities.
  • Nitrogen-containing organic compounds can act as ambident nucleophiles.

Amino Group (-NH₂)

  • Amino group (-NH₂) is a common nitrogen-containing functional group found in organic compounds.
  • It can act as an ambident nucleophile due to the presence of lone pair of electrons on nitrogen atom.
  • The lone pair of electrons can attack either through nitrogen or through one of the attached hydrogen atoms.
  • Example: Ammonia (NH₃), primary amines (R-NH₂), secondary amines (R₂NH), tertiary amines (R₃N).

Cyanide ion (-CN)

  • Cyanide ion (-CN) is a common ambident nucleophile containing nitrogen.
  • It can act as a nucleophile by attacking through nitrogen or carbon.
  • The carbon atom is more electronegative than the nitrogen atom, making the carbon-nitrogen bond stronger.
  • Example: Sodium cyanide (NaCN), potassium cyanide (KCN).

Thiocyanate ion (-SCN)

  • Thiocyanate ion (-SCN) is another example of an ambident nucleophile containing nitrogen.
  • It can act as a nucleophile by attacking through nitrogen or sulfur.
  • The sulfur atom is more electronegative than the nitrogen atom, making the sulfur-nitrogen bond stronger.
  • Example: Potassium thiocyanate (KSCN), ammonium thiocyanate (NH₄SCN).

Nitrogen Attack (Nitrogen as Nucleophile)

  • When the lone pair of electrons on nitrogen attacks an electrophile, it results in the formation of a new bond with the electrophile.
  • This can be represented using a reaction equation.
  • Example: R-X + NH₃ → R-NH₂ + HX

Hydrogen Attack (Hydrogen as Nucleophile)

  • When one of the hydrogen atoms attached to nitrogen attacks an electrophile, it results in the formation of a new bond with the electrophile.
  • The nitrogen atom donates its electron pair to the attached hydrogen atom, making it nucleophilic.
  • Example: R-X + NH₃ → R-NH₃⁺X⁻

Nitrogen Attack vs Hydrogen Attack

  • Nitrogen attack is favored when the electrophile has a positive charge or a partial positive charge.
  • Hydrogen attack is favored when the electrophile has a partial negative charge or an electron-withdrawing group.
  • The reactivity of the nucleophile depends on the strength of the bond being formed.

Example: Reactivity of Ammonia and Ammonium Ion

  • Ammonia (NH₃) and ammonium ion (NH₄⁺) can act as ambident nucleophiles.
  • Ammonia reacts with alkyl halides to form amines through nitrogen attack.
  • Ammonium ion reacts with alkyl halides to form ammonium salts through hydrogen attack.

Example Reaction Equations

  1. Nitrogen attack: R-X + NH₃ → R-NH₂ + HX
  1. Hydrogen attack: R-X + NH₃ → R-NH₃⁺X⁻

Applications of Ambident Nucleophiles

  • Ambident nucleophiles are commonly used in various organic reactions.
  • They provide different nucleophilic centers, allowing synthesis of different products.
  • Examples: Hofmann degradation, Gabriel synthesis, nucleophilic substitutions, etc.

Nucleophilic Substitution Reactions

  • Nucleophilic substitution reactions involve the replacement of a nucleophile with a leaving group in an organic compound.
  • Nitrogen-containing organic compounds can undergo nucleophilic substitution reactions as ambident nucleophiles.
  • The attacking nucleophile can either be the lone pair of electrons on nitrogen or one of the hydrogen atoms attached to nitrogen.
  • The leaving group is typically a halogen atom or a functional group that can easily be displaced.

Hofmann Degradation

  • Hofmann degradation is a reaction that involves the conversion of primary amides into primary amines.
  • The reaction is conducted using chloroform, sodium hypochlorite, and a strong base such as potassium hydroxide.
  • The primary amide acts as an ambident nucleophile, attacking the chloroform through nitrogen.
  • The reaction results in the replacement of the carbonyl group with an amino group, producing an amine.

Example: Hofmann Degradation

  • Reaction equation: RCONH₂ + CHCl₃ + KOH + NaOCl → RNH₂ + HCOONa + KCl + H₂O
  • In this example, the primary amide (RCONH₂) reacts with chloroform (CHCl₃) in the presence of a strong base (KOH) and sodium hypochlorite (NaOCl).
  • The reaction forms the primary amine (RNH₂) as the product, along with sodium formate (HCOONa), potassium chloride (KCl), and water (H₂O).

Gabriel Synthesis

  • Gabriel synthesis is a reaction used to prepare primary amines from alkyl halides through nucleophilic substitution.
  • The reaction is conducted using phthalimide, potassium hydroxide, and an alkyl halide.
  • The phthalimide acts as an ambident nucleophile, attacking the alkyl halide through nitrogen.
  • The reaction results in the replacement of the halogen atom with an amino group, producing a primary amine.

Example: Gabriel Synthesis

  • Reaction equation: Phthalimide + KOH + R-X → R-NH₂ + Potassium phthalimide
  • In this example, phthalimide reacts with potassium hydroxide (KOH) and an alkyl halide (R-X).
  • The reaction forms the primary amine (R-NH₂) as the product, along with potassium phthalimide as a byproduct.

Nitrogen Attacks in Nucleophilic Substitutions

  • In nucleophilic substitution reactions involving nitrogen-containing ambident nucleophiles:
    • Nitrogen attack (through the lone pair of electrons on nitrogen) often leads to the formation of primary amines.
    • Hydrogen attack (through one of the hydrogen atoms attached to nitrogen) often leads to the formation of ammonium salts.

Hydrogen Attacks in Nucleophilic Substitutions

  • Hydrogen attacks (through one of the hydrogen atoms attached to nitrogen) in nucleophilic substitution reactions involving nitrogen-containing ambident nucleophiles:
    • Give rise to ammonium salts, where the nitrogen atom bears a positive charge and is surrounded by either three alkyl or aryl groups or by at least two aryl groups.
    • Lead to the formation of quaternary ammonium salts, which are important intermediates in organic synthesis.

Quaternary Ammonium Salts

  • Quaternary ammonium salts are compounds where the nitrogen atom is bonded to four different groups.
  • They have a positive charge on the nitrogen atom.
  • These salts are widely used as catalysts, surfactants, and phase-transfer agents in organic synthesis.
  • They can be prepared by nucleophilic substitution reactions involving ambident nucleophiles such as amines and alkyl halides.

Example: Formation of a Quaternary Ammonium Salt

  • Reaction equation: R₄N⁺X⁻ + Y → (R₄N⁺)Y⁻ + X⁻
  • In this example, a quaternary ammonium salt (R₄N⁺X⁻) reacts with a nucleophile Y.
  • The reaction forms a new quaternary ammonium salt ((R₄N⁺)Y⁻) as the product, along with the original anion (X⁻) of the quaternary ammonium salt.

Summary

  • Nitrogen-containing organic compounds can act as ambident nucleophiles.
  • They can attack electrophiles either through the lone pair of electrons on nitrogen or through one of the hydrogen atoms attached to nitrogen.
  • Nitrogen attacks lead to the formation of primary amines.
  • Hydrogen attacks lead to the formation of ammonium salts and quaternary ammonium salts.
  • These reactions have wide applications in organic synthesis and are important in various fields of chemistry.

Nucleophilic Substitution Reactions in Nitrogen-Containing Organic Compounds

  • Nucleophilic substitution reactions involving nitrogen-containing organic compounds are important in organic chemistry.
  • These reactions involve the replacement of a nucleophile with a leaving group.
  • Nitrogen-containing organic compounds can act as ambident nucleophiles, attacking the electrophile through nitrogen or hydrogen atoms.
  • The reactivity of the nucleophile depends on the electrophile’s charge and the strength of the bond being formed.
  • Nucleophilic substitutions play a significant role in the synthesis and modification of organic compounds.

Example: Nucleophilic Substitution in Ammonia

  • Ammonia (NH₃) is a versatile ambident nucleophile.
  • It can undergo nucleophilic substitution reactions with alkyl halides to form amines.
  • A reaction example: CH₃Cl + NH₃ → CH₃NH₂ + HCl
  • In this reaction, ammonia attacks the electrophilic carbon, replacing the chlorine atom.
  • The product is methylamine (CH₃NH₂) and hydrochloric acid (HCl) as a byproduct.

Example: Nucleophilic Substitution in Ammonium Ion

  • Ammonium ion (NH₄⁺) can also participate in nucleophilic substitution reactions.
  • It reacts with alkyl halides, forming quaternary ammonium salts.
  • A reaction example: CH₃Cl + NH₄⁺ → [CH₃₄N⁺]Cl⁻
  • In this reaction, the hydrogen atom attached to nitrogen acts as a nucleophile, replacing the chlorine atom.
  • The product is a quaternary ammonium salt, [CH₃₄N⁺]Cl⁻.

Example: Nucleophilic Substitution in Cyanide Ion

  • Cyanide ion (-CN) is another nitrogen-containing ambident nucleophile.
  • It can attack electrophiles through either nitrogen or carbon.
  • A reaction example: RX + NaCN → RCN + NaX
  • In this reaction, the nitrogen atom of the cyanide ion attacks the electrophilic carbon, producing the nitrile (RCN) and sodium halide (NaX) as a byproduct.

Example: Nucleophilic Substitution in Thiocyanate Ion

  • Thiocyanate ion (-SCN) is an ambident nucleophile that can attack through nitrogen or sulfur.
  • The sulfur atom is more electronegative than the nitrogen atom, making the sulfur-nitrogen bond stronger.
  • A reaction example: RX + KSCN → RSCN + KX
  • In this reaction, the nitrogen atom or sulfur atom of the thiocyanate ion attacks the electrophilic carbon, producing the thiocyanate ester (RSCN) and potassium halide (KX) as a byproduct.

Comparison of Ambident Nucleophiles

  • Different nitrogen-containing ambident nucleophiles can be compared based on their reactivity in nucleophilic substitution reactions.
  • Factors affecting reactivity include electronegativity, bond strength, and charge distribution.
  • Amines tend to prefer nitrogen attack, while ammonium ions prefer hydrogen attack.
  • Cyanide ion and thiocyanate ion can attack through nitrogen or sulfur, but sulfur attack is generally more favorable due to stronger bonds.

Application of Nucleophilic Substitution Reactions

  • Nucleophilic substitution reactions have numerous applications in organic synthesis:
    1. Preparation of amines and ammonium salts
    2. Synthesis of pharmaceuticals and agrochemicals
    3. Modification of organic compounds
    4. Formation of quaternary ammonium salts for use as catalysts and surfactants
    5. Hofmann degradation and Gabriel synthesis for amine preparation

Summary

  • Nitrogen-containing organic compounds act as ambident nucleophiles in nucleophilic substitution reactions.
  • Ammonia, ammonium ions, cyanide ions, and thiocyanate ions are examples of nitrogen-containing ambident nucleophiles.
  • Nitrogen or hydrogen attacks in these reactions lead to the formation of amines or ammonium salts.
  • Cyanide and thiocyanate ions can attack through nitrogen or sulfur, but sulfur attack is generally preferred.
  • Nucleophilic substitution reactions involving nitrogen-containing organic compounds have various applications in organic synthesis.

Practice Questions

  1. Which of the following can act as an ambident nucleophile? a. Ammonia b. Cyanide ion c. Thiocyanate ion d. All of the above
  1. What is the main difference between nitrogen attack and hydrogen attack in nucleophilic substitution reactions?
  1. Explain the Hofmann degradation and Gabriel synthesis reactions briefly.
  1. How are quaternary ammonium salts formed? Provide an example reaction.
  1. How are nucleophilic substitution reactions involving nitrogen-containing organic compounds useful in organic synthesis? Give examples.

References

  1. Solomons, T. W. G., & Fryhle, C. B. (2010). Organic Chemistry (10th ed.).
  1. Morrison, R. L., & Boyd, R. N. (1992). Organic Chemistry (6th ed.).
  1. Clayden, J., Greeves, N., Warren, S., & Wothers, P. (2012). Organic Chemistry (2nd ed.).