Question

Write a mechanism for the reaction of glycine with N- carboethoxyphthalimide involving a sequence of carbony1 addition, ring opening, ring closure and elimination. Would you expect a similar reaction with L-phenylalanine to yield the \(L\), the \(D\), or the D,L-product?

Short answer

The reaction of glycine with N-carboethoxyphthalimide involves the following steps: 1. Carbonyl addition: The nitrogen atom from glycine's amino group attacks the carbonyl carbon, forming an alkoxide ion intermediate. 2. Ring opening: Carboxylate group attacks the oxygen atom from the middle of the five-membered ring, forming a linear ester intermediate. 3. Ring closure: Negative charged oxygen atom attacks the carboxylate carbon, forming a cyclic ester ring intermediate. 4. Elimination: Deprotonating the nitrogen atom with a base, collapsing the ester ring and restoring aromaticity in the phthalimide product, and forming N-carboxylate glycine. For L-phenylalanine, the stereochemistry should be retained, yielding the L-product, because there are no racemization or inversion steps in the mechanism.

Step-by-step solution

Carbonyl Addition

First, the nitrogen atom from the amino group of glycine will attack the carbonyl carbon from the N-carboethoxyphthalimide, forming a new bond and breaking one of the double bonds in the carbonyl group. This will result in an alkoxide ion intermediate and a positive charged nitrogen.

Ring Opening

After carbonyl addition, the negative charge on the oxygen will prompt the carboxylate group to attack the oxygen atom from the middle of the five-membered ring in N-carboethoxyphthalimide. This opens the ring and forms a linear ester intermediate.

Ring Closure

Now, a ring closure will occur when the negative charged oxygen atom that started as the carbonyl of N-carboethoxyphthalimide attacks the carboxylate carbon that was part of the glycine molecule. This step forms a cyclic ester ring intermediate.

Elimination

Finally, elimination will occur by deprotonating the nitrogen atom in the intermediate using a base, which will promote the collapse of the ester ring and restore aromaticity in the resulting phthalimide product. Alongside, it forms N-carboxylate glycine as the other product. Now, let's predict whether a similar reaction with L-phenylalanine would yield the L, the D, or the D, L-product.

Prediction

L-Phenylalanine is an enantiomerically pure compound, and the reaction mechanism would follow the same steps as described for glycine. Since no racemization or inversion of stereochemistry occurs at any step in the mechanism, the configuration of L-phenylalanine should be retained, yielding the L-product.

Key concepts

Carbonyl Addition

In organic chemistry, understanding how molecules react involves studying different types of addition reactions. Carbonyl addition is one such crucial reaction. It typically occurs when a nucleophile, like the nitrogen atom from the amino group in glycine, approaches and interacts with a carbonyl group, such as the one in N-carboethoxyphthalimide.

Here's how it happens:

• The nucleophile, which has a lone pair of electrons, attacks the electrophilic carbon atom in the carbonyl group.
• As a result of this attack, the double bond between the carbon and oxygen in the carbonyl group breaks, transforming the oxygen into an alkoxide ion with a negative charge.

This new structure, called an intermediate, is formed. It's important in understanding the step-by-step transformation leading to the final product. Remember, recognizing and identifying intermediates like these can help break down complex reactions into easier-to-understand parts.

Ring Opening

Ring opening involves breaking a single ring structure to form a linear chain. This step is crucial because it allows molecules to rearrange and eventually reform into new products. After the initial carbonyl addition with glycine and N-carboethoxyphthalimide, the alkoxide ion plays a pivotal role.

The oxygen atom (now bearing a negative charge) from the alkoxide ion can engage in nucleophilic attack on another part of the molecule. By attacking the ring, it prompts the ring to break open.

• In this specific context, the attack targets an oxygen that is part of the five-membered heterocyclic ring.
• Breaking the ring and creating a linear structure assists the molecule in proceeding to the next transformation, specifically ring closure.

Ring opening is a flexible process and highly significant because it offers pathways to form diverse molecular architectures.

Ring Closure

In the ring closure step, the molecule reforms into a cyclic structure from a previously linear or more complex form. This task is crucial as it helps stabilize the new molecular structure that was transformed during the earlier stages of the reaction.

In the case of the glycine and N-carboethoxyphthalimide reaction, the formerly opened linear ester wants to form a more stable cyclic ester. Here's how this happens:

• The negatively charged oxygen from the earlier formed alkoxide ion attacks the carbon from the carboxylate end of glycine.
• This interaction leads the ends of the molecule to join back together, forming a ring structure—essentially a cyclic ester.

Understanding ring closure is vital because it highlights how linear forms can turn into complex and stable cyclic forms naturally in organic chemistry.

Stereochemistry in Reactions

Stereochemistry explores how the spatial arrangement of atoms affects the physical and chemical properties of a molecule. In reactions like the one involving L-phenylalanine, it's crucial to consider stereochemistry because it influences the outcome of the reaction.

In the given mechanism, L-phenylalanine undergoes the same sequence of additions, openings, closings, and eliminations as glycine. However, what's unique is the preservation of the stereochemistry:

• Throughout all steps—carbonyl addition, ring opening, and closure—the configuration of L-phenylalanine is kept constant.
• This means no change in the spatial orientation of its atoms, ensuring the final product retains the initial configuration, the L-form.

Grasping stereochemistry in reactions is crucial, especially in biochemistry and pharmaceuticals, where the efficacy and safety of compounds can depend heavily on their three-dimensional arrangements.