Structure-function relationship nucleophile

Protein chemical modification is a problem-solving technique in research and technology. Modifications also occur in natural deteriorations. Generally these modifications are with the most reactive side chains and are predominantly oxidations, reductions, and nucleophilic and electrophilic substitutions. Deteriorations include peptide bond scissions, racemizations, fi-eliminations, and formation of products by the reaction of proteins with added chemicals. Proteins are modified intentionally for structure-function relationship studies or for development of new and improved products. Although appearing quite varied, the techniques used in pharmacological, food and feed, or other industrial areas differ more operationally than from major differences in the levels of chemical sophistication that are used. 

Some of the earliest correlations between nucleophilicity and reactivity focused solely on the pKn of the conjugate acid of the nucleophile. If one keeps the electronic and steric properties of a series of nucleophiles similar, and uses the same solvent for the analyses, reactivity does nicely correlate with the basicity of the nucleophile Kt, see Chapter 5). An LFER as defined in Eq. 8.48 can be used to correlate the data. This structure-function relationship is called a Brensted relationship. 

I have been pursuing enzyme mimics, artificial enzymes that perform biomimetic chemistry, since starting my independent career in 1956. In the first work [52-59] my co-workers and I studied models for the function of thiamine pyrophosphate 1 as a coenzyme in enzymes such as carboxylase. We discovered the mechanism by which it acts, by forming an anion 2 that we also described as a stabilized carbene, one of its resonance forms. We examined the related anions from imidazolium cations and oxazolium cations, which produce anions 3 and 4 that can also be described as nucleophilic carbenes. We were able to explain the structure-activity relationships in this series, and the reasons why the thiazolium ring is best suited to act as a biological... 

The fundamental aspects of the structure and stability of carbanions were discussed in Chapter 6 of Part A. In the present chapter we relate the properties and reactivity of carbanions stabilized by carbonyl and other EWG substituents to their application as nucleophiles in synthesis. As discussed in Section 6.3 of Part A, there is a fundamental relationship between the stabilizing functional group and the acidity of the C-H groups, as illustrated by the pK data summarized in Table 6.7 in Part A. These pK data provide a basis for assessing the stability and reactivity of carbanions. The acidity of the reactant determines which bases can be used for generation of the anion. Another crucial factor is the distinction between kinetic or thermodynamic control of enolate formation by deprotonation (Part A, Section 6.3), which determines the enolate composition. Fundamental mechanisms of Sw2 alkylation reactions of carbanions are discussed in Section 6.5 of Part A. A review of this material may prove helpful. 

Remember that not all nucleophiles will successfully undergo Michael additions—you must bear this in mind when making a 1,3-disconnection of this type. Most reliable are those based on nitrogen, sulfur, and oxygen (Chapter 22). Our second example is an amine structurally similar to the deadly nightshade drug, atropine, which has the ability to calm involuntary muscle movements. There is a 1,3-relationship between the amine and ketone functional groups, and 1,3-disconnection takes us back to piperidine and an unsaturated ketone. 

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