Addition to a Carbonyl

Model 1 Addition of a Lithium (Grignard or Hydride) Reagent to C=0 

Review from CA 16 Lithium, Grignard, and hydride delivery (eg., LiAlHt) reagents react quickly and irreversibly with a carbonyl to yield an alkoxide anion (the conjugate base of an alcohol). 

Draw a 5+ and a 5- on appropriate atoms of formaldehyde to show the polarity of the C=0 bond. 

Use curved arrows to show a mechanism for the reaction in Model 1. 

Draw the alcohol product that results when an aldehyde or ketone is... 

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Like a carbonyl group, a nitrile group is strongly polarized and has an electrophilic carbon atom. Nitriles therefore react with nucleophiles to yield 5p2-hybridized imine anions in a reaction analogous to the formation of an sp3-hybridized alkoxide ion by nucleophilic addition to a carbonyl group. 

The fundamental mechanisms of free radical reactions were considered in Chapter 11 of Part A. Several mechanistic issues are crucial in development of free radical reactions for synthetic applications.285 Free radical reactions are usually chain processes, and the lifetimes of the intermediate radicals are very short. To meet the synthetic requirements of high selectivity and efficiency, all steps in a desired sequence must be fast in comparison with competing reactions. Owing to the requirement that all the steps be fast, only steps that are exothermic or very slightly endothermic can participate in chain processes. Comparison between addition of a radical to a carbon-carbon double bond and addition to a carbonyl group can illustrate this point. 

This comparison suggests that of these two similar reactions, only alkene additions are likely to be a part of an efficient radical chain sequence. Radical additions to carbon-carbon double bonds can be further enhanced by radical stabilizing groups. Addition to a carbonyl group, in contrast, is endothermic. In fact, the reverse fragmentation reaction is commonly observed (see Section 10.3.6) A comparison can also be made between abstraction of hydrogen from carbon as opposed to oxygen. 

Typical reactions are amine or phosphine alkylation or addition to a carbonyl group (Scheme 3.3). In these examples, because of the development of dipoles in the TS, we are concerned with a polarity increase during the course of the reaction starting from the GS towards the TS. Favorable microwave effects are, consequently, expected. 

The most typical situation can be depicted for amine additions to a carbonyl group (Eq. 9)... 

A combination of a deprotonation with an intramolecular Michael addition/isomerization is found in the conversion of 187 to 188 [608] (Scheme 1.84). The analogous intramolecular addition to a carbonyl group leads to 190 [609] (Scheme 1.85). 

Until then, only heterogeneous catalyst had been successful. However, in the mid-1980s, the work of Ito et al. led to an outstanding discovery in a catalytic asymmetric aldol reaction. In this case, enantioselectivity was given by a chiral ferrocene diphosphine ligand, with a carbon nucleophile addition to a carbonyl... 

Like Cram s Rule, the Felkin-Cherest-Anh model, developed by Felkin and coworkers6, is an attempt to understand and predict the stereochemistry of addition to a carbonyl group. This model requires a "small 0" interpretation in which the largest group is oriented anti to the attacking nucleophile s trajectory. One should note that the Felkin-Cherest-Anh model neglects the interaction of the carbonyl oxygen. In this approach, the R/S or RJM interactions dominate. 

Example 3-Oxoacyl-CoA transferase (Y = —S—CoA) B. Addition to a carbonyl group aldol condensation... 

The 1,2-migration of a silicon moiety to the oxygen anion of a carbon-oxygen single bond produced by nucleophilic addition to a carbonyl group (Brook... 

We have already discussed in Chapter 2 that nucleophilic addition to a carbonyl group is controlled by stereoelectronic effects. Both X-ray data and theoretical calculations indicate a clearly defined path (cf. p.32) for the attack of a nucleophile on a carbonyl group. Baldwin (1) has also used a vector analysis approach to predict the stereochemistry of the addition products. 

The second group of cyclic compounds which illustrate the intramolecular carbanion addition to a carbonyl group, include 2-ethoxycarbonylcyclo-pentanone (23) and indane-l,3-dione (24). 

Although in the above paper MeS- was studied, MeO- was not, but the latter has now been investigated in detail. Lehn149 and co-workers computed the PE surface for the simplest nucleophilic addition to a carbonyl group, i.e. reaction (8). A... 

Studies of Felkin s model have shown that the transition state for nucleophilic addition to a carbonyl compound is strongly stabilized when the C2-X and Nu- Cj bonds are antiperiplanar.41 Let us apply this rule to a configurationally rigid cyclohexanone. 

Ammonium germanates gave the same 1,2-addition to a carbonyl group (equation 165)48.. 1. PhCOMe... 

These nucleophilic additions to a carbonyl group were also used to synthesize a germene by Peterson s reaction (equation 169)180. 

Nitration of an Arene Section 17.4 Figure 17.3 Nucleophilic Addition to a Carbonyl Group ... 

An acetylide ion can serve as the nucleophile in this addition to a carbonyl group. The acetylide ion adds to the carbonyl group to form an alkoxide ion. Addition of dilute acid (in a separate step) protonates the alkoxide to give the alcohol. 

If a synthesis requires both alkylation of an acetylide and addition to a carbonyl, add the less reactive group first alkylate, then add to a carbonyl. In general, you should add reactive functional groups late in a synthesis. 

In effect, the base-catalyzed addition to a carbonyl group results from nucleophilic attack of a strong nucleophile followed by protonation. Acid-catalyzed addition begins with protonation, followed by the attack of a weaker nucleophile. Many additions are reversible, with the position of the equilibrium depending on the relative stabilities of the reactants and products. 

The base-catalyzed hydration is a perfect example of base-catalyzed addition to a carbonyl group. The strong nucleophile adds, then protonation gives the hydrate. 

You met nucleophilic addition to a carbonyl group on p. 114 and 119, where we showed you how cyanide reacts with acetone to give an alcohol. As a reminder, here is the reaction again, with its mechanism. 

The product of nucleophilic addition to a carbonyl group is not always a stable compound... 

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