Question
In the ____ step of Strecker synthesis, strong acid in water
protonates the nitrile group, turning it back into its carboxylic acid form.
Answer
In the third step of Strecker synthesis, strong acid in water
protonates the nitrile group, turning it back into its carboxylic acid form.
Note: Pay attention to Steps 1 thru 4, to see conversion of nitrile group to allow the Alcohol (-OH) first, then another water molecule nucleophilic-ally substituting itself, overall (because technically it is a nucleophilic addition followed by elimination), with NH3 to finally become a carboxylic acid group at the end, to fully form all structural components of an amino acid.
Strecker First Half Pathways:
#1 - If ammonia is added first, you get an imine as intermediate which then reacts with cyanide, thru nucleophilic addition, to form α-amino nitrile.
#2 - If cyanide is added first, you get a cyanohydrin (aka hydroxynitrile) as the intermediate which then reacts with ammonia, thru nucleophilic substitution, to form α-amino nitrile.
Fun Fact: Hydroxynitrile used to know cyanohydrin. For purposes of the MCAT, we are mainly exposed to 'cyanohydrin' but you never know when knowing this fact can help you net one extra question.
Full Excerpt from EK: In the Strecker synthesis, not seen in Figure 3.52 because here it is Ammonia + Hydrogen Cyanide, an aldehyde is mixed with
potassium cyanide and ammonium chloride, which is seen in the Kaplan Figures and other Figures listed way below. In the first step, the cyanide anion
acts as a nucleophile toward the carbonyl. This initially results in a hydroxynitrile molecule. However, nitrogen(referring to the ammonium present) is a better nucleophile than oxygen, and acid
is present to protonate the alcohol group. This leads to the second step, in which nucleophilic substitution occurs and an aminonitrile is formed, thanks to presence of the ammonia. The nitrile group
behaves as a carboxylic acid derivative. In the third step, strong acid(H+) in water
protonates the nitrile group(–C≡N), turning it back into its carboxylic acid form. The
molecule is now an amino acid.
Point of Confusion:
- Nucleophilic cyanide ion normally adds to an aldehyde to give a cyanohydrin, an α-hydroxy nitrile. (As EK tries to explain!)
- However, in the presence of ammonium chloride, the analogous α-amino nitrile is obtained. (How it is illustrated in the images down below!)
Question Asked on Organic Chem. Tutor Site:
- Hi, great explanation! I am just wondering why the ammonia is added to the Aldehyde and not the Cyanide directly? because I learned that Cyanide is more nucleophilic than ammonia?
Response: The ammonia is added to the aldehyde because an imine needs to be formed first before the cyanide attacks. If the ammonia is added after addition of cyanide, the product will be a cyanohydrin. Not what we want in this case : – )
Note: In Strecker synthesis, first an aminonitrile is generate from an aldehyde or ketone. Secondly, hydrolysis of the aminonitrile results in formation of an amino acid.
Note: The starting material for the Strecker synthesis is a planar carbonyl-containing compound; therefore, the product of this pathway is a racemic mixture. The incoming nucleophiles are equally able to attack from either side of the carbonyl; thus, both L- and D-amino acids can be generated through this process.
Mechanism: In the Strecker synthesis, one starts with an aldehyde, ammonium chloride (NH4Cl), and potassium cyanide (KCN), as shown in Figure 10.6. The carbonyl oxygen is protonated, increasing the electrophilicity of the carbonyl carbon. Then ammonia can attack the carbonyl carbon, forming an imine. The imine carbon is also susceptible to nucleophilic addition reactions; thus, the CN– anion from KCN attacks, forming a nitrile group (–C≡N). The final molecule at the end of Step 1 is an aminonitrile—a compound containing an amino group (–NH2) and a nitrile group.
Mechanism Con'td: In Step 2, the nitrile nitrogen is protonated, increasing the electrophilicity of the nitrile carbon. This is similar to protonating the oxygen of a carbonyl. A water molecule attacks, leading to the creation of a molecule with both imine and hydroxyl moieties on the same carbon. This imine is attacked by another equivalent of water. A carbonyl is formed, kicking off ammonia and creating the carboxylic acid functionality. This step, shown in Figure 10.7, is performed in aqueous acid and can be accelerated by the use of heat.
Note: See how the only difference between cyanohydrin and α-amino nitrile is the presence of OH vs. NH2. Nitrogen is a better nucleophile than Oxygen. Substitution takes place at the Cyanohydrin, to form the α-amino nitrile by using the ammonia provided to us.
Note: As seen below, the final product has the classic amino acid groups. Amino acid is generated from phthalimide (nucleophile) and diethyl bromomalonate, using two SN2 reactions, hydrolysis, and decarboxylation.
Question: What are the two ways we can organically synthesize amino acids?
1. Strecker Synthesis (Strecker uses Cyanide)
2. Gabriel Synthesis (Gabriel uses Rings)
Extra Note: The product of both the Strecker and the Gabriel synthesis pathways is a racemic mixture; both L- and D- amino acids are generated.
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