One of the most common reactions of carboxylic acids and related compounds is nucleophilic acyl substitution. Figure 1 depicts this transformation in general terms.
Nucleophilic Acyl Substitution
When Y represents the nitrogen atom of an amine, the transformation converts a carboxylic acid or a derivative of a carboxylic acid into an amide. Equation 1 provides a simple example.
As we have seen, extension of reaction 1 to a bifunctional acid chloride and a bifunctional amine may be used to prepare polyamides such as nylon:
An alternative method of making polyamides is available when an acyl and an amino group are part of the same molecule:
The latter approach is the one involved in the formation of polyamides known as polypeptides or proteins. This topic looks briefly at the chemistry of these biopolymers. Before we consider that chemistry, you should familiarize yourself with the chemistry of the bifunctional molecules from which these polymers are made, amino acids.
Peptides are amides formed by the reaction of the a-amino group of one amino acid with the carboxylate group of another amino acid. Peptides which contain two amino acids are called dipeptides. Figure 2 shows the structure of a dipeptide formed from glycine and alanine.
Peptides made from three amino acids are called tripeptides, etc. Peptides containing from 2-10 amino acids are arbitrarily called oligopeptides. Compounds containing more amino acids are called polypeptides or proteins.
In order to simplify the representation of peptides, chemists assigned a 3-letter code to each amino acid. By this convention the dipeptide in Figure 6 would be Gly-Ala; the N-terminal amino acid is written first. Bradykinin, a nonapeptide which is involved in regulating blood pressure, has the structure Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg.
Peptides are structurally complex. However, two aspects of peptide structure make it easier to understand this complexity.
- The H-N-C=O fragment of each peptide unit is planar.
- The stereochemistry at each chiral a-carbon is the same, i.e. the R group always projects in the same direction.
Exercise 1 According to VSEPR theory, the geometry around the nitrogen atom of an amide should be approximately
trigonal planar pyramidal which means that the hybridization of the nitrogen atom should be approximately
Exercise 2 Resonance theory rationalizes the planarity of the amide group by suggesting that the lone pair of electrons on the nitrogen atom interacts with the pi system of the carbonyl group. Use curved arrows to depict this interaction. Draw the structure of the resonance contributor that is produced when the lone pair is fully delocalized onto the oxygen atom of the carbonyl group. Indicate all formal charges. What is it about this resonance contributor that is consistent with a planar fragment?
The structural features of proteins have been broken down into 4 categories, primary, secondary, tertiary, and quaternary structure.
This is simple. The primary structure of a peptide is the sequence in which the amino acids are connected, starting with the N-terminal amino acid. In the case of bradykinin mentioned above, the primary structure is Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg. A Lewis structure of bradykinin is shown in Figure 3. Bradykinin is a nonapeptide. The 8 peptide bonds that connect the 9 amino acids are shown in red in Figure 3.
Bradykinin: A Nonapeptide
The presence of the substituents attached to the a-carbon can obscure the primary structure of even a simple peptide like bradykinin. Figure 4 shows the "backbone" of a nonapeptide stripped of its Ca substituents.
A Peptide Backbone
There are several features about this representation that are noteworthy. First, it represents an idealized conformation in which all the "backbone" atoms lie in the same plane. (The substituents attached to each a-carbon project in front of and behind that plane.) Second, if you "read" the structure from left-to-right, the carbonyl group of the each amide unit points in the opposite direction of the N-H bond of that unit. This is called the "all-trans" conformation. It's a fantasy. Doesn't happen. Third, since the bond between the carbonyl carbon and the nitrogen atom of each amide unit has significant double bond character, rotation about that bond is restricted. However, "free" rotation about the N-Ca bond as well as the C-Ca bond of the O=C-Ca group is possible.
Rotation around single bonds in alkanes is described in terms of a dihedral angle. In the case of peptides, this parameter is called the torsional angle. There are two torsional angles of interest in peptides. The first, designated F, defines the angle of rotation about the N-Ca bond, while the second, which is labeled Y, is the angle of rotation about the C-Ca bond. Figure 5 defines these angles for an "all-trans" segment of polypeptide.
Note that F and Y are the rotational angles around the two main-chain bonds to Ca. Rotation around these bonds gives rise to the secondary structure of proteins.
The primary structure of a peptide doesn't convey any information about the 3-dimensional shape of the peptide. The secondary structure does. In talking about secondary structure, we are actually referring to the topology of regions within the peptide. Such localized structure is a reflection of the conformations about a sequence of peptide bonds. These conformations are determined in large part by the nature of the R groups attached to the a carbon. Biochemists have identified three common topologies, helices, pleated sheets, and turns. Figure 7 presents an interactive model of Gly-Gly-Gly-Gly-Gly-Gly-Gly-Gly-Gly which clearly indicates the helical nature of this synthetic nonapeptide.
The tertiary structure of a polypeptide describes the way in which the chain loops and twists and bends. While the primary structure usually depicts the backbone of a polypeptide as an extended chain in which the N-terminal amino acid is far away from the C-terminus, the fact is that the chain is not extended, and it is possible for the 5th amino acid to be spatially quite close to the 45th or the 450th, for example. Figure 6 shows the structure of one polypeptide chain from human insulin. This chain contains 51 amino acids.
Tertiary Strucutre in a Simple Protein
One of the roles that proteins play is that of reaction catalyst. In this role proteins are more commonly referred to as enzymes. Most enzymes are comprised of two or more polypeptide chains that are held together by non-covalent forces. The individual polypeptide chains are called sub-units. Hemoglobin, for example, contains four sub-units, each of which is organized around a central iron atom. Human insulin is a hexamer, i.e. it contains 6 sub-units. (Note-When you click on the Human insulin link, you will open a file. Before viewing the file enter 1 into the text field that asks you how many models you want to display. Click OK. Click OK on the next window that appears. You should now see a wireframe model of human insulin.) The spatial relationship of one sub-unit to another is called the quaternary structure of a protein.
Proteins serve two main functions, structural and catalytic. Structural proteins are generally fibrous in nature. Hair and smooth muscle are examples of structural proteins. Catalytic proteins generally have a globular quaternary structure that is more or less spherical. The catalytic site is buried in the interior of the structure.