Carbonyl compounds reactions with nucleophiles

Treatment of a, -unsaturated carbonyl compounds 18 with nucleophilic selenium species affords -seleno carbonyl compounds 19 in good yields via Michael addition (Scheme 27) [46]. This reaction has been applied to protect a, -unsa-turated lactones [47], in natural product synthesis [48], and in asymmetric Michael additions in the presence of an alkaloid [49]. Michael addition also proceeds with selenolates that are prepared from diphenyl diselenide by cathodic reduction [22], reduction with the Sm-Me3SiCl-H20 system [19], and reduction with tributyl phosphine [25]. 

Class I carbonyl compounds undergo nucleophilic acyl substitution reactions. These reactions are discussed in Chapter 17, where you will see that all Class I carbonyl compounds react with nucleophiles in the same way— they form an unstable tetrahedral intermediate that collapses by eliminating the weakest base. So all you need to know to determine the product of a reaction—or even whether a reaction will occur—is the relative basicity of the groups in the tetrahedral intermediate. 

Although the reaction of ketones and other carbonyl compounds with electrophiles such as bromine leads to substitution rather than addition, the mechanism of the reaction is closely related to electrophilic additions to alkenes. An enol, enolate, or enolate equivalent derived from the carbonyl compound is the nucleophile, and the electrophilic attack by the halogen is analogous to that on alkenes. The reaction is completed by restoration of the carbonyl bond, rather than by addition of a nucleophile. The acid- and base-catalyzed halogenation of ketones, which is discussed briefly in Section 6.4 of Part A, provide the most-studied examples of the reaction from a mechanistic perspective. 

The compounds referred to as azolides are heterocyclic amides in which the amide nitrogen is part of an azole ring, such as imidazole, pyrazole, triazole, tetrazole, benzimidazole, benzotriazole, and their substituted derivatives. In contrast to normal amides, most of which show particularly low reactivities in such nucleophilic reactions as hydrolysis, alcoholysis, aminolysis, etc., the azolides are characterized by high reactivities in reactions with nucleophiles within the carbonyl group placing these compounds at about the same reactivity level as the corresponding acid chlorides or anhydrides. 11... 

The enantioselective addition of a nucleophile to a carbonyl group is one of the most versatile methods for C C bond formation, and this reaction is discussed in Chapter 2. Trifluoromethylation of aldehyde or achiral ketone via addition of fluorinated reagents is another means of access to fluorinated compounds. Trifluoromethyl trimethylsilane [(CF SiCFs] has been used by Pra-kash et al.87 as an efficient reagent for the trifluoromethylation of carbonyl compounds. Reaction of aldehydes or ketones with trifluoromethyltrime-thylsilane can be facilitated by tetrabutyl ammonium fluoride (TBAF). In 1994, Iseki et al.88 found that chiral quaternary ammonium fluoride 117a or 117b facilitated the above reaction in an asymmetric manner (Scheme 8-42). 

Today reactions of etiolates are usually carried out much differently by utilizing very strong, nonnucleophilic bases for generating the enolate nucleophile. Instead of having only small equilibrium concentrations of an enolate produced in solution, the use of strong, nonnucleophilic bases like LDA, KHMDS, and KH that have pAYs >35 permits carbonyl compounds, whose a protons have pA"a s of 20-25, to be converted completely to enolate anions. Doing so completely converts the carbonyl compound into a nucleophile which cannot condense with itself and is stable in solution. This enolate can then be reacted with a second carbonyl compound in a subsequent step to give product ... 

Up to now, the discussion of carbonyl compounds has centered on their reactions with nucleophiles at the electrophilic carbonyl carbon. Two general reactions are observed, depending on the structure of the carbonyl starting material. 

Carbonyl compounds reacting with organometallic nucleophiles ch9 Carbonyl compounds taking part In nucleophilic substitution reactions chl2 chl4... 

Reactions with carbonyl compounds as both nucleophile and electrophile... 

Some carbonyl-based compounds (imines, carboxylic acids) are better electrophiles under acidic conditions than they are under basic conditions. Reactions using these compounds as electrophiles are usually executed under acidic conditions. On the other hand, enolates are always better nucleophiles than enols when carbonyl compounds are required to react with electrophiles that are not particularly reactive, such as esters or alkyl bromides, basic conditions are usually used. Carbonyl compounds that are particularly low in energy (esters, amides) have such a small proportion of enol at equilibrium that they cannot act as nucleophiles at the a-carbon under acidic conditions. Nevertheless, no matter whether acidic or basic conditions are used, carbonyl compounds are always nucleophilic at the a-carbon and electrophilic at the carbonyl carbon. 

Reactions of chiral allylic boranes with carbonyl compounds Reactions of chiral allyl boranes with imines Asymmetric Addition of Carbon Nucleophiles to Ketones Addition of alkyl lithiums to ketones Asymmetric epoxidation with chiral sulfur ylids Asymmetric Nucleophilic Attack by Chiral Alcohols Deracemisation of arylpropionic acids Deracemisation of a-halo acids Asymmetric Conjugate Addition of Nitrogen Nucleophiles An asymmetric synthesis of thienamycin Asymmetric Protonation... 

Carbonyl-carbonyl condensation reactions. These reactions involve both a nucleophilic addition step and an a-substitution step. They can occur when two carbonyl compounds react with one another. For example, reaction of two molecules of ethanal. 

Lithium salts of t-butylhydrazones of aldehydes have been shown to be useful acyl anion equiv-alents. Treatment of an aldehyde r-butylhydrazone with an alkyllithium reagent or LDA gives the am-bident nucleophile (95), which reacts with both aldehydes and ketones to give carbon-substituted products as shown in equation (35). The condensation works best with nonenolizable carbonyl derivatives. Extension of this chemistry to the reaction of (95) with a,3-unsaturated carbonyl compounds met with mixed success. While good yields of Michael products were seen in the addition of (95) to methyl crotonate, other a,p-unsaturated electrophiles such as methyl acrylate, acrylonitrile and methyl P,p-di-methylacrylate gave negligible yields of carbon-substituted products. 

There are two major reactions of enolates (1) displacement reactions with alkyl halides or other suitable electrophiles and (2) nucleophilic addition to carbonyl compounds. Reaction of 58 with butanal to give 59 and reaction of 61 with bromopentane to give 62 are simple examples of each process. Enolate anions function as carbon nucleophiles and their reactions are fundamentally the same as those discussed in Section 8.3.C for acetylides. Although there are interesting differences, treating an enolate anion as a carbon nucleophile is very reasonable. 

Condensation reactions with the carbonyl compounds essentially involve nucleophilic addition. It is, however, pertinent to mention here that since the active hydrogen component is not itself sufficiently nucleophilic to add to the carbonyl group, base removal of a proton from the a-position with respect to the active hydrogen component (i.c., the most acidic position) is required. 

Enols have an OH group and are alcohols of a sort. Normal alcohols form stable ethers that are difficult to convert back to the alcohol. Powerful reagents such as HI or BBra are required and these reactions were discussed in Chapter IS. The reaction with HI is an 5 2 attack on the methyl group of the protonated ether and that is why a good nucleophile for saturated carbon, such as iodide or bromide, is needed for the reaction. Enol ethers, by contrast, are relatively unstable compounds that are hydrolysed back to the carbonyl compound simply with aqueous acid—dilute HCl or H2SO4, for example. 

A general method for the synthesis of dialdoses and nucleoside 5 -aldehydes has been described, and their asymmetric reaction with nucleophiles discussed. The reversible interconversion of GDP-D-mannose and -L-galactose which is brought about by a Chorella enzyme system was proposed to occur as shown in Scheme 2 following the observation that tritium incorporation from the solvent occurred equally at C-3 and C-5. Epimerizations at positions a to the carbonyl groups can also be photoinduced, and compound (1) has now been isolated in... 

Although the dominant reactivity pattern for carbonyl compounds in reactions with nucleophiles is the direct nucleophilic attack at the carbonyl k, eliminations promoted by assistance from the lone pair of oxygen are also possible in those rare cases when X is a strong acceptor with a low energy o (Figure 7.38). There is no stereoelectronic bias in this system the lone pair of oxygen is positioned well to overlap well with both carbonyl substituents and subsequent reactivity is determined by the leaving ability of X vs. R. 

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