Oxygen bases, nucleophilic addition

Oxygen-based nucleophiles 1.03.3.2.2(1) Intermolecular addition reactions... 

Despite the synthetic value of p-hydroxy-carbonyl derivatives, few reports have been published on the organocatalytic addition of oxygen-based nucleophiles to a, 3-unsaturated compounds. Some of the difficulties found in the addition of... 

Obviously, the trifluoromethylation of highly acidic oxygen-based nucleophiles (sulfonic or phosphonic acids) occurs even without the addition of acid, as the substrate itself acts as activating agent in these cases (see Sect. 5.1) [19, 20]. 

The Michael addition of oxygen-based nucleophiles to electron-deficient olefins has proven a challenging problem in organic synthesis. The relative weakness of O-nucleophiles, coupled with problems associated with reaction reversibility, has hampered the development of general methods for this transformation. ... 

It was pointed out earlier that the low nucleophilicity of fluoride ion and its low concentration in HF solutions can create circumstances not commonly observed with the other halogen acids. Under such conditions rearrangement reactions either of a concerted nature or via a true carbonium ion may compete with nucleophilic attack by fluoride ion. To favor the latter the addition of oxygen bases, e.g., tetrahydrofuran, to the medium in the proper concentration can provide the required increase in fluoride ion concentration without harmful reduction in the acidity of the medium. 

A Grignard reaction begins with an acid-base complexation of Vfg2+ to the carbonyl oxygen atom of the aldehyde or ketone, thereby making the carbonyl group a better electrophile. Nucleophilic addition of R then produces a tetrahedral magnesium alkoxide intermediate, and protonation by addition of water... 

Conversion of Amides into Carboxylic Acids Hydrolysis Amides undergo hydrolysis to yield carboxylic acids plus ammonia or an amine on heating in either aqueous acid or aqueous base. The conditions required for amide hydrolysis are more severe than those required for the hydrolysis of add chlorides or esters but the mechanisms are similar. Acidic hydrolysis reaction occurs by nucleophilic addition of water to the protonated amide, followed by transfer of a proton from oxygen to nitrogen to make the nitrogen a better leaving group and subsequent elimination. The steps are reversible, with the equilibrium shifted toward product by protonation of NH3 in the final step. 

A mechanistic interpretation is based on the ring-opening principle deduced in the next chapter the very unusual electrophilic attack of bromine at carbonyl oxygen is followed by nucleophilic addition of bromide ion at elevated temperature and ring-opening by transfer of bromine to CljC2. 

Base catalysis of ligand substitutional processes of metal carbonyl complexes in the presence of oxygen donor bases may be apportioned into two distinct classifications. The first category of reactions involves nucleophilic addition of oxygen bases at the carbon center in metal carbonyls with subsequent oxidation of CO to C02, eqns. 1 and 2 (l, 2). Secondly, there are... 

This is a further example of a carbonyl-electrophile complex, and equivalent to the conjugate acid, so that the subsequent nucleophilic addition reaction parallels that in hemiacetal formation. Loss of the leaving group occurs first in an SNl-like process with the cation stabilized by the neighbouring oxygen an SN2-like process would be inhibited sterically. It is also possible to rationalize why base catalysis does not work. Base would simply remove a proton from the hydroxyl to initiate hemiacetal decomposition back to the aldehyde - what is needed is to transform the hydroxyl into a leaving group (see Section 6.1.4), hence the requirement for protonation. 

Application of an organocatalytic domino Michael addition/intramolecular aldol condensation to the preparation of a series of important heterocycles has recently received much attention [158] with methods being disclosed for the preparation of benzopyrans [159-161], thiochromenes [162-164] and dihydroquinolidines [165, 166]. The reports all use similar conditions and the independent discovery of each of these reactions shows the robust nature of the central concept. A generalised catalytic cycle which defines the principles of these reports is outlined in Fig. 10. Formation of iminium ion 102 is followed by an intermolecular Michael addition of an oxygen, sulfur or nitrogen based nucleophile (103) to give an intermediate... 

Most probably, the last stage in the synthesis of 2-amino-4H-pyrans involves base-catalyzed nucleophilic addition of the enolic oxygen to a C=N group, which can be regarded as a hetero-Thorpe-Ziegler reaction (Scheme 21). 

It is appropriate at this point to summarize the tendency of various nucleophiles to add to the carbonyl group. In general, the strong bases (organometallics, hydrides, negative ions) are most effective among the neutral nucleophiles, the soft ones, for example the sulfur bases, tend to be more effective in addition than the hard ones, for example the oxygen bases. 

Enolate ions, which are usually strong nucleophiles, are more important in preparative applications than are the enols. In additions to carbonyl groups, the carbon end, rather than the oxygen end, attacks but in SA,2 substitutions on alkyl halides, significant amounts of O-alkylation occur. The more acidic compounds, such as those with the j3-dicarbonyl structure, yield enolates with the greater tendency toward O-alkylation. Protic solvents and small cations favor C-alkylation, because the harder oxygen base of the enolate coordinates more strongly than does the carbon with these hard Lewis acids.147... 

With 1,3,5-trinitrobenzene no diversity of attack is possible, though for substituted derivatives such as 2,4,6-trinitroanisole or 2,4,6-trinitro-aniline the mode of interaction may vary on changing the nucleophile. Thus structural measurements show that the thermodynamically stable adducts of 2,4,6-trinitroanisole with OMe-, Ns- or NEt2 result from addition at Cl while the apparently stable adducts with S03 or CHg CO CH2 are formed at C3. The failure to detect addition of these latter nucleophiles at Cl may be ascribed to steric strain. This may occur either in the Cl adducts themselves, so that they are no longer thermodynamically preferred to the C3 adducts, or alternatively in the transition states for their formation, so that their formation is very slow. Again the mode of ionization of 2,4,6-trinitroaniline and its N-substituted derivatives depends on the relative affinities for carbon or hydrogen of the particular nucleophile used. Thus sulphur bases such as SEt- and SPh will preferentially add at the 3-position, while with oxygen bases abstraction of an amino proton also occurs. 

Although these additions to CO double bonds have some superficial similarities to the electrophilic additions to CC double bonds that were presented in Chapter 11, there are many differences. The acidic conditions mechanism here resembles the mechanism for addition to carbon-carbon double bonds in that the electrophile (the proton) adds first, followed by addition of the nucleophile. However, in this case the first step is fast because it is a proton transfer involving oxygen, a simple acid-base reaction. The second step, the attack of the nucleophile, is the rate-determining step. (Recall that it is the first step, the addition of the electrophile, that is slow in the additions to CC double bonds.) Furthermore, in the case of additions to simple alkenes there is no mechanism comparable to the one that operates here under basic conditions, in which the nucleophile adds first. Because the nucleophile adds in the slow step, the reactions presented in this chapter are termed nucleophilic additions, even if the protonation occurs first. In... 

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