Protonated nucleophiles

The neutral 1,4- and 1,2-quinone methides react as Michael acceptors. However, the reactivity of these quinone methides is substantially different from that of simple Michael acceptors. The 1,6-addition of protonated nucleophiles NuH to simple Michael acceptors results in a small decrease in the stabilization of product by the two conjugated 7T-orbitals, compared to the more extended three conjugated 7T-orbitals of reactant. However, the favorable ketonization of the initial enol product (Scheme 1) confers a substantial thermodynamic driving force to nucleophile addition. By comparison, the 1,6-addition of NuH to a 1,4-quinone methide results in a large increase in the -stabilization energy due to the formation of a fully aromatic ring (Scheme 2A). This aromatic stabilization is present to a smaller extent at the reactant quinone methide, where it is represented as the contributing zwitterionic valence bond structure for the 4-0 -substituted benzyl carbocation (Scheme 1). The ketonization of the product phenol (Scheme 2B) is unfavorable by ca. 19 kcal/mol.1,2... 

We might be tempted to say that methoxide is a much better nucleophile because it is much more basic. This would be a mistake because basicity and nucleophilicity are different properties. Basicity is defined by the equilibrium constant for abstracting a proton. Nucleophilicity is defined by the rate of attack on an electrophilic carbon atom. In both cases, the nucleophile (or base) forms a new bond. If the new bond is to a proton, it has reacted as a base if the new bond is to carbon, it has reacted as a nucleophile. Predicting which way a species will react may be difficult most (but not all) good nucleophiles are also strong bases, and vice versa. 

Bases attack protons. Nucleophiles attack other electron-deficient atoms (usually carbons). 

The reaction follows the general mechanism for the acetalization of a ketone but yields the hemiacetal elimination product 18. After activation of the secondary ketone 17 by protonation, nucleophilic attack of methanol yields the protonated hemiacetal 30. Deprotonation and protonation of the alcohol moiety provides species 32, which eliminates water to give the carboxenium ion 33. 

Barros, R.J., Wehtje, E., and Adlercreutz, P. (1999) Enhancement of immobilized protease catalyzed dipeptide synthesis by the presence of insoluble protonated nucleophile. Enzyme Microb. Technol., 24 (8-9), 480-488. 

Basicity is a measure of how well a compound shares its lone pair with a proton. Nucleophilicity is a measure of how readily a compound is able to attack an electron-deficient atom. In comparing molecules with the same attacking atom or with attacking atoms of the same size, the stronger base is a better nucleophile. If the attacking atoms are very different in size, the relationship between basicity and nucleophilicity depends on the solvent. In protic solvents, stronger bases are poorer nucleophiles because of ion-dipole interactions between the ion and the solvent. 

Scheme 9.35. A representation of base catalysis of nucieophiiic addition to the carbonyl of an aldehyde or ketone in which the oxygen is not lost. Nu-H is a protonated nucleophile B is a generalized (Brpnsted or Lewis) base.

Basicity is a measure of how well a compound shares its lone pair with a proton nucleophilicity is a measure of how readily a species with a lone pair is able to attack an electron-deficient atom. 

On the other hand, is grossly proportional to the value of the protonated nucleophile ... 

In this reaction, the strongest nucleophile present in solution is the unprotonated starting alcohol. As soon as one alcohol molecule has been protonated, nucleophilic attack begins, the ultimate products being an ether and water. 

We have seen that a molecule or an ion having a lone pair of electrons can act as an electron pair donor in a reaction with either a proton or an electrophilic carbon atom. In both cases, a new bond is formed. When the bond is to a proton, the electron pair donor has reacted as a base. When the bond is to a carbon atom, the electron pair donor has reacted as a nucleophile. Chemists use the terms basicity and nucleophilicity when referring to the tendency of an electron pair donor to act as a base or a nucleophile in a reaction. Basicity is a measure of the tendency of an electron pair donor to react with a proton. Nucleophilicity is a measure of how readily (how fast) a nucleophile attacks an electrophilic carbon atom. We use equihbrium constants (fCb) when comparing molecules or ions in terms of their basicity, and thus basicity is an equilibrium (thermodynamic) property. When comparing molecules or ions in terms of their nucleophilicity, we are comparing them in terms of the rates at which they attack an electrophilic carbon, and thus nucleophihdty is a kinetic property. 

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