PREPARATORY PROBLEM 31 (PRACTICAL) Formation of double carbon-nitrogen bond Imines (nitrogen analogu — Organic Chemistry Chemistry Question
Formation of double carbon-nitrogen bond
PREPARATORY PROBLEM 31 (PRACTICAL)
Formation of double carbon-nitrogen bond
Imines (nitrogen analogues of carbonyl compounds) are formed when any primary amine reacts with aldehyde or ketone under appropriate conditions. Mechanically, the amine first attacks the aldehyde with formation of an intermediate. Its subsequent dehydration gives the imine.
Imine formation is like a biological reaction: it is fastest near neutrality. Many biological processes involve imine formation. Three outstanding examples are: synthesis of amino acids from oxoacids, transamination of α-amino acids and mechanism of vision. The former two processes include formation of an imino intermediate between an amino acid and vitamin B6 derivative (pyridoxal). The transformation of light energy into electric signal in our eyes includes the cis-trans-photoisomerization of a polyene retinal (an aldehyde), which is covalently linked to the protein (an amine) by the imine bond. Imines are also very important in organic synthesis as intermediates in the so-called “reductive amination” reaction allowing direct transformation of carbonyl compounds into amines.
In this task you will prepare aniline derivative of benzaldehyde (I).
Chemicals and Reagents
• Aniline
• Benzaldehyde
• 96% aqueous ethanol
Equipment and Glassware
• Magnetic stirrer with heating
• Magnetic bar
• Glass beaker, 25 cm3
• Round-bottom two necked flask, 50 cm3
• Reflux condenser
• Laboratory stand with metal rings and clamps
• Adding funnel
• Separating funnel
• Filter flask
• Porous Shott’s glass filter
• Water- or vacuum pump
• Analytical balance (± 0.001 g)
• Capillary for melting point determination (2 - 3 ea.)
• Glass tube for capillary filling
• Melting point apparatus
• Glass rod
• Ice bath
Procedure
N-[(E-Phenylmethylene]aniline
0.42 g of freshly distilled benzaldehyde is placed in a round bottom two necked flask equipped with a reflux condenser and an addition funnel. The reaction vessel is mounted on the magnetic stirrer with a heating mantle. 0.37 g of freshly distilled aniline is poured in the funnel. The aniline is added dropwise to the flask with intensive stirring. Almost immediately the yellow precipitate starts to form and the reaction mixture warms up. After the addition of aniline is finished, the reaction mixture is stirred for 15 minutes. To the end of this process prepare a 25 cm3 glass with 3 cm3 of 96% ethanol. Transfer the reaction mixture from the flask to the glass, wash the flask with 1 cm3 of ethanol and add this to the glass. Then place the glass in an ice-bath for 10 minutes. Knead the content of the glass and transfer it on the glass Shott’s filter. Turn on the water-pump, connect it to the filtration flask and filter the precipitate off. To provide for effective drying, keep the precipitate pressing with the glass rod from time to time until the mother liquor stops to drop down. Keep drying the product under vacuum for at least 10 min. Weigh the product and calculate the yield. Pick out a few crystals of the product for further determination of its melting point.
Determination of melting point
Use a glass capillary sealed from one side. Place the non-sealed end of the capillary into a product crystals, then turn it sealed end down and throw several times down through a glass tube. Check that the sealed side of the capillary is filled with the product. Apply the ready capillary to a melting point apparatus and record the melting point of the product.
Draw the mechanism of imine formation. How can you name the intermediate? What are the rate-limiting steps at low and high pH conditions?
Model Answer
Hemiaminal.
Mechanism:
[VISUAL]
(Or represented as: R-CHO + R'-NH2 → R-CH(OH-NH-R' (hemiaminal) → R-CH=N-R' + H2O)
The rate-limiting steps are:
- The amine attack at the carbonyl carbon atom at low pH, since most of the amine molecules are protonated;
- Dehydration of the tetrahedral hemiaminal intermediate at high pH, since this requires protons.
What is similar and different in mechanisms of imine and acetal formation?
Model Answer
Both reactions proceed through the positively charged intermediates, iminium and oxonium ions, respectively. While the former just loses the proton to form the final product, the later acts as an electrophile adding another molecule of alcohol to become the full acetal.
Draw the mechanism of vitamin B6 derivative catalyzed transformation of pyruvic acid into alanine.
[VISUAL]
Model Answer
Mechanism of transamination:
[VISUAL]
Reaction steps:
pyridoxamine phosphate + pyruvic acid ⇌ ketimine intermediate ⇌ aldimine intermediate ⇌ pyridoxal phosphate + alanine.
The reaction involves condensation of pyridoxamine phosphate and pyruvic acid to form an imine, followed by a prototropic shift (isomerization of the double bond) to form a new imine, which is then hydrolyzed to yield alanine and pyridoxal phosphate.
Draw the mechanism of reductive amination of cycohexanone into N,N-dimethyl cyclohexylamine using sodium cyanoborohydride and dimethylamine.
Model Answer
Mechanism of reductive amination:
[VISUAL]
Reaction steps:
1. Protonation of cyclohexanone increases electrophilicity of carbonyl carbon.
2. Dimethylamine attacks the carbonyl carbon to form a hemiaminal intermediate.
3. Proton transfer and loss of a water molecule yields a highly electrophilic iminium cation intermediate.
4. Sodium cyanoborohydride acts as a mild reducing agent, transferring a hydride ion (H⁻) to the iminium carbon, yielding the final tertiary amine, N,N-dimethylcyclohexylamine.
Suggest mechanisms for the two hereunder reactions. Draw the correct stereochemistry for the product of the second reaction.
[VISUAL]
Model Answer
Mechanism 1:
Reaction of secondary amine with formaldehyde under acid catalysis to form a bicyclic methylene-bridged product:
[VISUAL]
Mechanism 2:
Reaction of a di-secondary amine with formaldehyde in the presence of H⁺ to yield a cis-fused dimethyl-substituted bicyclic imidazolidine derivative:
[VISUAL]