Nucleophilic addition carbonyl compounds

But the best El eliminations of all are with tertiary alcohols. The alcohols can be made using the methods of Chapter 9 nucleophilic attack by an organometallic on a carbonyl compound. Nucleophilic addition, followed by El elimination, is the best way of making this substituted cyclohexene, for example. Note that the the proton required in the first step is recovered in the last—the reaction requires only catalytic amounts of acid. 

Evidence, chiefly from kinetics and experiments with isotopically labeled compounds, indicates that even this seemingly different reaction follows the familiar pattern for carbonyl compounds nucleophilic addition. Two successive additions... 

The position of the equilibrium depends on the structure of the carbonyl compound. Nucleophilic addition is favoured by small alkyl groups attached to the carbonyl group and also by electron-withdrawing groups (e.g. CC13), which increase the 8+ character of the carbonyl carbon atom (see Section 8.3.1). 

III. FROM CARBONYL COMPOUNDS NUCLEOPHILIC ADDITION TO THE CARBONYL GROUP... 

The second fundamental reaction of carbonyl compounds, nucleophilic acyl substitution, is related to the nucleophilic addition reaction just discussed but occurs only with carboxylic acid derivatives rather than with aldehydes and ketones. When the carbonyl group of a carboxylic acid derivative reacts with a nucleophile, addition occurs in the usual way, but the initially formed tetra-... 

We have intentionally selected example reactions (Figs. 29-33) that would not usually be immediately obvious to a chemist. The examples chosen have all been concerned with rearrangements of various types, since their courses are frequently difficult to predict. It remains to emphasize that the reactivity functions contained in EROS perform perfectly well with other types of reaction. This is true, for example, with reactions that a chemist could derive directly from an analysis of the functional groups in a molecule. Thus, EROS predicts addition reactions to carbonyl compounds, nucleophilic substitutions, and condensation reactions, to name just a few examples. In all these reaction types, the possibility of assigning a quantitative estimate to the reactivity at the various sites via the reactivity functions is of particular merit. It... 

H20 or alcohols as nucleophiles give low molecular weight compounds when they add to the C=0 double bond of carbonyl compounds. These addition products are called aldehyde or ketone hydrates (Section 9.1.1) and hemiacetals or hemiketals (Section 9.1.2), respectively, depending on whether they result from the addition to an aldehyde or a ketone. Today, one no longer distinguishes systematically between hemiacetals and hemiketals, but the expression hemiacetal is frequently used to cover both. 

Two different approaches are commonly used for the synthesis of alkynes. In the first, an appropriate electrophile undergoes nucleophilic attack by an acetylide ion. The electrophile may be an unhindered primary alkyl halide (undergoes Sn2), or it may be a carbonyl compound (undergoes addition to give an alcohol). Either reaction joins two fragments and gives a product with a lengthened carbon skeleton. This approach is used in many laboratory syntheses of alkynes. 

Most organic free radicals are nucleophilic and will react with electrophilic centers. Lewis acids have been used to activate aj3-unsaturated carbonyl compounds towards addition of free radicals and also to stabilize a-keto radicals [67]. The first report of the use of a chiral Lewis acid to effect an asymmetric free-radical reaction was that of Urabe, Yamashita, Suzuki, Kobayashi, and Sato in 1995 [68]. They found that if the BINOL aluminum catalyst 313 is stoichiometrically complexed with lactone 323 and then treated with butyl iodide and tributylstannane in the presence of triethylborane the alkylated lactone 324 can be isolated in 47 % yield with 23 % ee (Sch. 40). 

Problem 3.14 a. This is another example of the reaction of an amine with a carbonyl compound in the presence of an acid catalyst. The first steps are protonation of the carbonyl group, nucleophilic addition of the amine, and deprotonation of the nitrogen to give intermediate 3-49. 

Formal E (E = S or Se) insertion, sulfurization of organic carbonyls, and nucleophilic addition to coordinated organosulfur and organoselenium compounds are reviewed in this section. Reactions of HjS, HE , and in which the chalcogen atoms exhibit nucleophilic character, as well as new contributions to CEj chemistry, especially reactions with coordinated car-banions and dimerizations, also receive attention. 

Alcohols can be obtained from many other classes of compounds such as alkyl halides, amines, al-kenes, epoxides and carbonyl compounds. The addition of nucleophiles to carbonyl compounds is a versatile and convenient methc for the the preparation of alcohols. Regioselective oxirane ring opening of epoxides by nucleophiles is another important route for the synthesis of alcohols. However, stereospe-cific oxirane ring formation is prerequisite to the use of epoxides in organic synthesis. The chemistry of epoxides has been extensively studied in this decade and the development of the diastereoselective oxidations of alkenic alcohols makes epoxy alcohols with definite configurations readily available. Recently developed asymmetric epoxidation of prochiral allylic alcohols allows the enantioselective synthesis of 2,3-epoxy alcohols. 

At this point we consider some general relationships concerning the reactivity of carbonyl compounds toward addition of nucleophiles. Several factors influence the overall rate of a reaction under various conditions. Among the cmcial factors are (1) structural features of the carbonyl compound (2) the role of protons or other Lewis acids in activating the carbonyl group toward nucleophilic attack (3) the reactivity of the nucleophilic species and its influence on subsequent steps and (4) the stability of the tetrahedral intermediate and the extent to which it proceeds to product rather than reverting to starting material. 

The formation of C—N bonds is an important transformation in organic synthesis, as the amine functionality is found in numerous natural products and plays a key role in many biologically active compounds [1]. Standard catalytic methods to produce C—N bonds involve functional group manipulations, such as reductive amination of carbonyl compounds [2], addition of nucleophiles to imines [3], hydrogenation of enamides [4—8], hydroamination of olefins [9] or a C—N coupling reaction [10, 11]. Recently, the direct and selective introduction of a nitrogen atom into a C—H bond via a metal nitrene intermediate has appeared as an attractive alternative approach for the formation of C—N bonds [12-24]. 

FIGURE 19.84 The two possible reactions of a nucleophile (Nu ) with an a,P-unsaturated carbonyl compound. Michael addition preserves the carbonyl group and is usually favored thermodynamically. 

The selective intermolecular addition of two different ketones or aldehydes can sometimes be achieved without protection of the enol, because different carbonyl compounds behave differently. For example, attempts to condense acetaldehyde with benzophenone fail. Only self-condensation of acetaldehyde is observed, because the carbonyl group of benzophenone is not sufficiently electrophilic. With acetone instead of benzophenone only fi-hydroxyketones are formed in good yield, if the aldehyde is slowly added to the basic ketone solution. Aldols are not produced. This result can be generalized in the following way aldehydes have more reactive carbonyl groups than ketones, but enolates from ketones have a more nucleophilic carbon atom than enolates from aldehydes (G. Wittig, 1968). 

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