Organic Chemistry: Concepts and Applications - Headley Allan D. 2020
Synthetic Polymers and Biopolymers
20.11 Reactions of α-Amino Acids
Amino acids are bifunctional molecules in that they have both an amine functionality and a carboxylic acid functionality. As we have discussed in Chapter 15, carboxylic acids will undergo substitution reactions at acyl carbon, but the OH is a poor leaving group, so these types of substitution reactions are typically acid catalyzed; nonetheless, a carboxylic acid functionality is a reactive functionality. The amine functionality is basic and hence will undergo an acid—base reaction in addition to a nucleophilic substitution reaction. As we have seen for the reactions that involve polyfunctional molecules, protection of functionalities typically has to take place to prevent unwanted reactions. This strategy is used for most of the reactions of amino acids. Consider the reaction given in Reaction (20-22), in which it is desired to have the nucleophilic Grignard reagent react with the ester functionality of proline ester to produce the tertiary alcohol shown in the box.
(20-22)
For Reaction (20-22), it is expected that there will be a substitution reaction at the acyl group in which the nucleophilic Grignard substitutes the methoxy (—OCH3) group to produce the target molecule. The challenge is that another reaction can take place in which the anime nitrogen acts as the nucleophile to give a different molecule as shown. Thus, in order to achieve the goal of the synthesis of the target molecule, the use of a protecting group must be considered to protect the amine functionality.
20.11.1 Protection—Deprotection of the Amino Functionality
The reaction that is typically used to protect the amino functionality is shown in Reaction (20-23).
(20-23)
In the first step of the reaction mechanism, the nucleophilic amine attacks the electrophilic carbonyl carbon of di-tert-butyldicarbonate as shown in Reaction (20-24).
(20-24)
A driving force for this reaction to occur as you can imagine is the release of carbon dioxide gas. In addition, tert-butanol readily loses water to form isobutene, as shown in Reaction (20-25).
(20-25)
With the protected amino acid ester in hand, the desired reaction can be carried out as shown in Reaction (20-26) to obtain the salt of the desired product.
(20-26)
Deprotection of the amine functionality to give the target molecule can be accomplished as shown in Reaction (20-27).
(20-27)
Since the last step in which the removal of the protecting boc group requires an aqueous acidic solution, it is not necessary to introduce an additional step to convert the Grignard salt to a protected alcohol before removal of the protecting group.
20.11.2 Reactions of the Carboxylic Acid Functionality
Sometimes it will be necessary to protect the carboxylic acid functionality in order to carry out a reaction at the amine functionality of an amino acid. Typical protection includes converting the carboxylic acid group to an ester. Reagents such as thionyl chloride and methanol or trimethylchlorosilane (TMSCl) with methanol have been successfully used and are shown in Reactions (20-28) and (20-29).
(20-28)
(20-29)
Deprotection of the ester functionality can take place in the presence of acid hydrolysis of the ester group as shown in Reaction (20-30)
(20-30)
Problem 20.10
Show how to carry out the following transformation.
20.11.3 Reaction of α-Amino Acids to Form Dipeptides
Amino acids are bonded together by a special bond, the peptide bond, to form peptides and proteins. The general representation of the peptide bond is shown below.
If the desire is to synthesize a specific dipeptide by mixing two amino acids, no reaction will occur. Amino acids do not automatically react with each other to form peptides. Furthermore, if two amino acids were to react to form a dipeptide, there are two possible dipeptides, as shown in Reaction (20-31).
(20-31)
Thus, there are a number of considerations that must be kept in mind when synthesizing peptides from amino acids. First, how to get the desired amino and carboxylic acid functionalities to react with each other to get the desired peptide. Another consideration is the type of reactions that should be considered to achieve the target peptide. As we have seen from the previous section, protecting groups must be employed in order to achieve desired reactions. Let us look at a strategy for the synthesis of dipeptide 1 in Reaction (20-32). First, the protection of the amino functionality of amino acid 1 must be accomplished. For amino acid 2, protection of the carboxylic acid functionality must also occur as illustrated in Reaction (20-32) where the circles indicate desired protection of the functional groups shown.
(20-32)
Once the coupling of both protected amino acids occurs to form a new peptide bond and the protected dipeptide is formed, the protections can be removed to liberate the desired dipeptide.
Let us first concentrate on the protection of the amino functionality and the protection group that is typically used is the boc protection, and this reaction is shown Reaction (20-33).
(20-33)
Next, the protection of the carboxylic acid functionality of the other amino acid is required, as shown in Reaction (20-34).
(20-34)
The next step in the sequence of reactions for peptide synthesis is the coupling of the two protected amino acids. For the coupling of the protected amino acids, a special compound dicyclohexylcarbodimide (DCC) is used to assist with the coupling and the formation of the peptide bond. First, the boc-protected amino acid is mixed with DCC to form a complex as shown in Reaction (20-35).
(20-35)
In the next step of the reaction sequence, the protected amino acid 2 is added, which reacts with the complex formed in the reaction above as shown in Reaction (20-36).
(20-36)
In the next step of the reaction, the protected dipeptide is liberated, along with 1,3-dicyclohexylurea as shown in Reaction (20-37)
(20-37)
The last step in this sequence of reactions is the deprotection of the amine and carboxylic acid functionalities, which is shown in Reaction (20-38).
(20-38)
Note that in order to synthesize peptide 2 as shown in Reaction (20-31), the protection of the starting amino acids would have to be the reverse.
Problem 20.11
Show how to synthesize the dipeptide shown below.
20.11.4 Reaction of α-Amino Acids With Ninhydrin
If an unknown substance is mixed with ninhydrin and a violet color appears, which is also known as Ruhemann's purple, this observation is a strong indication that the unknown substance could be an amino acid owing to the reaction of amino acids with ninhydrin, which is shown in Reaction (20-39).
(20-39)
This reaction is typically used to detect the presence of amino acids and is sometimes used in the detection of fingerprints since traces of amino acids are typically present with fingerprints. The first step in the mechanism for the reaction of ninhydrin and an α-amino acid is shown Reaction (20-40).
(20-40)
In an aqueous solution, ninhydrin exists as shown in Reaction (20-40) as an equilibrium. Even though the equilibrium lies to the left, a minute amount of the keto form reacts with the nucleophilic amine functionality of amino acids. In the next step of the mechanism, the elimination of water occurs to form the imine, as shown in Reaction (20-41).
(20-41)
In the next step, carbon dioxide is lost and an equilibrium is established as shown in Reaction (20-42)
(20-42)
In the next step of the reaction, water adds to the electrophilic carbon that is bonded to the nitrogen, followed by the loss of RCHO (an aldehyde) as shown in Reaction (20-43).
(20-43)
In the next step of the reaction mechanism, the nucleophilic nitrogen attacks another mole of ninhydrin as shown in Reaction (20-44).
(20-44)