Minggu, 11 Oktober 2009

Host-Guest Chemistry


Most people are familiar with the "lock-and-key" theory of enzyme activity. According to this theory, the catalytic activity of enzymes stems from the fact that the substrate, i.e. the compound undergoing reaction, fits tightly into a "pocket" in the surface of the enzyme much like a key fits into a lock. Once inside this "pocket", the substrate is held in close proximity to a reactant which converts it to product. The activity of enzymes has served as a source of inspiration for the research efforts of many organic chemists. The enzyme chymotrypsin has played a central role in the research of Nobel laureate Donald J. Cram, who, for over 40 years, has been trying to answer the question "What makes enzymes such good catalysts?" Professor Cram's attempts to answer this question have led to the development of an entire field of chemistry known as host-guest chemistry. This topic provides an overview of that field and serves as our introduction to chemical reaction. We'll start with a brief survey of one class of reactions, nucleophilic substitutions.

Chemical Reactions

Equation 1 describes a reaction that everyone is familiar with, the neutralization of hydrochloric acid with sodium hydroxide.

To an organic chemist, reaction 1 is an example of a substitution reaction- the chlorine atom of the hydrogen chloride is replaced by the OH group from the NaOH. The color coding is included to make this reaction theme apparent in Equations 2-5.

Equation 2 depicts a process called a nucleophilic aliphatic substitution reaction. In this case the OH group replaces a Br from the methyl carbon atom. We will consider this reaction is detail when we examine its mechanism.

Our next example illustrates a process known as saponification. Here the OH group substitutes for an OR group of an ester. This reaction is called a nucleophilic acyl substitution.

Equation 4 provides another example of a nucleophilic acyl substitution reaction. In this case the functional group involved is an amide instead of an ester.

Here's one more for you to digest before we move on:

Reaction 5 describes the hydrolysis of a protein, a polymeric form of an amide. This is precisely the type of reaction that chymotrypsin catalyses.


Chymotrypsin is a member of a class of enzymes known as serine proteases. This type of enzyme catalyses the hydrolysis of proteins, i.e. digestion.

The "active site" of all serine proteases contain four common elements:

  1. a binding site
  2. an OH group that is part of a serine residue in the polypeptide chain
  3. an imidazole ring that is part of a histidine residue
  4. an aspartate group that is part of an aspartic acid residue

As you can see from the model of chymotrypsin, there is a lot of the polypeptide that is remote from the active site. This fact led Professor Cram to ask a more specific question, namely, "What are the minimum structural features required to observe "chymotrypsin-like" catalytic activity?" In order to answer this question Cram and his colleagues "spent hundreds of hours building CPK models of potential complexes and grading them for desirability as research targets." The final target they selected as a "host" is shown in Figure 1. It contains all four of the elements found in serine proteases. That portion of the structure shown in purple is the binding site. The ArCH2OH group shown in red is an analog of the serine residue. The imidazole ring shown in blue corresponds to the histidine residue, and the -CO2- group in orange fills the role of the aspartate group.

Figure 1

A Bare-Bones "Enzyme"

The compound they selected as a "guest" and the reaction they expected it to undergo are illustrated in Equation 6.

In Equation 6, the HOCH2Ar represents that portion of the "host" designed as a serine analog. In fact, Cram's group was not successful in their attempts to synthsize the "host" target. They did manage to prepare a related structure, however, and to demonstrate that it displayed remarkable catalytic activity. Figure 2 shows the structure of the product of reaction 6 when HOCH2Ar represents the alternative "host".

Figure 2

Not Quite an Enzyme

Note how the -NH3+ group is complexed to the binding site of this modified "host". Presumably the Coulombic attractions between the positive charge on the nitrogen atom and the lone pairs of electrons on the oxygen atoms holds the "guest" in place so that reaction 6 may occur more readily. The rate of reaction 6 when HOCH2Ar represents the alternative "host" is 1011 times faster than when HOCH2Ar represents the model compound compound shown in Equation 7.

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