O-nucleophiles

In this section, we will focus our attention on oxygen nucleophiles. Let s begin by exploring what happens when an alcohol functions as a nucleophile and attacks a ketone or aldehyde. 

Be warned the mechanism we are about to see is one of the longer mechanisms that you will encounter in this course. But it is incredibly important because it lays the foundation for so many other mechanisms. If you can master this mechanism, then you will be in really good shape to move on. And to be honest, there is no other option you MUST master this mechanism. So, be prepared to read through the next several pages slowly, and then be prepared to reread those pages as many times as necessary until you know this mechanism intimately. 

Alcohols are nucleophilic because the oxygen atom has lone pairs that can attack an electrophile  

When an alcohol attacks a carbonyl group, an intermediate is generated that should remind us of the intermediate that was formed in the previous section  

Notice how similar this is to the hydride attack we explored in the previous section  

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O Nucleophilic attack on the ketone or aldehyde by the lone-pair electrons of an amine leads to a dipolar tetrahedral intermediate. 

O Nucleophilic addition of a secondary amine to the ketone or aldehyde, followed by proton transfer from nitrogen to oxygen, yields an intermediate carbinolamine in the normal way. 

O Nucleophilic addition of hydroxide ion to the CN triple bond gives an imine anion addition product. 

O Nucleophilic addition of thiamin diphosphate (TPP) ylide to pyruvate gives an alcohol addition product. 

Benzyl carbamates have been used to form both five- and six-membered nitrogen-containing rings. The selectivity for N over O nucleophilicity in these cases is the result of the nitrogen being able to form a better ring size (5 or 6 versus 7 or 8) than the carbonyl oxygen. 

A series of hydroxy-, alkoxy-, and phenoxyfurazans and difurazanyl ether derivatives 184 were synthesized by reactions of mono- and dinitrofurazans 183 with O-nucleophiles. The effect of the furazan nature and reactant ratio on the structure of products has been discussed <1999RJ01525>. In this way, the nitro group has been replaced by alkoxy derivatives (Equation 33) <2000BMC1727>. 

Fig. 23 Entropy effects on intramolecular reactions of polymethylene chains. Plot of 9AS (e.u.) against number of single bonds for (O) nucleophilic substitutions at saturated carbon ( ) electron-exchange reactions (A) quenching of benzophenone phosphorescence. The straight line has intercept +30 e.u. and slope —4.0 e.u. per rotor. The right-hand ordinate reports the purely entropic EM s calculated as exp(0AS /J )...

Rearrangements of nitrones due to migration of the A-oxide oxygen can be induced both, photochemically and by various reagents, but in specific conditions it can proceed spontaneously. On one hand, such transformations are caused by the O-nucleophilic character of nitrones able to react easily with acid anhydrides, their halo anhydrides, sulfonyl chloride and other agents on the other hand, by a significant CH-acidity of a-alkyl groups. 

Structure B is of most interest. It is responsible for the activity of nitronates as 1,3-dipoles in [3+ 2]-cycloaddition reactions. This is the most important aspect of the reactivity of nitronates determining the significance of these compounds in organic synthesis (see e.g., Ref. 267). In addition, this structure suggests that nitronates can show both, O -nucleophilic properties, that is, react at the oxygen atom with electrophiles, and a-C-electrophilic properties, that is, add nucleophiles at the a-carbon atom. 

N-diazeniumdiolates are an interesting class of compounds, presently under development, which can deliver NO specifically to a target site. Diazeniumdiolates are N O nucleophile complexes capable of releasing NO in an aqueous environment or in... 

C-nucleophile (X = active H-borate, boronate) N-nucleophile (amine, NaN3, tosyl amide, amide, lactam, imine, carbamate, urea) O-nucleophile (alcohol, acid, carbonate) S-nucleophile (PhS02Na)... 

The symmetrical anhydride is less reactive and consequently more selective in its reactions than the O-acylisourea. Although the latter can acylate both N- and O-nucleophiles, the symmetrical anhydride will only acylate V-nuclcophilcs. This means that the hydroxyl groups of the side chains of serine, threonine, and tyrosine that have not been deprotonated are not acceptors of the acyl group of the symmetrical anhydride. An additional feature of this approach to carbodiimide-mediated reactions is that it avoids a possible side reaction between the carbodiimide and the iV-nucleophilc, which gives a trisubstituted guanidine [(C6HuN)2C=N-CHR5CO-... 

Hydroxylamine can act as either a N-nucleophile or O-nucleophile, depending on which of the reactive centers is protected. For all reactions Ph-Pybox has been used as ligand, and moderate to high levels of selectivity have been achieved. Hydroxamic acid derivatives and oximes have also been probed as O-nucleophiles [63]. 

Further examples of acylphosphates are found in fatty acyl-AMPs (see Section 15.4.1) and aminacyl-AMPs (see Section 13.5), activated intermediates in the metabolism of fatty acids and formation of peptides respectively. Each of these is attacked on the C=0 by an appropriate S or O nucleophile, displacing the phosphate derivative AMP. 

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