After the carbonyl is attacked by the nucleophile, the negatively charged oxygen has the capacity to act as a nucleophile. However, most commonly the oxygen acts instead as a base, abstracting a proton from a nearby acid group in the solvent or enzyme active site.
This very common type of reaction is called a nucleophilic addition. In many biologically relevant examples of nucleophilic addition to carbonyls, the nucleophile is an alcohol oxygen or an amine nitrogen, or occasionally a thiol sulfur. In one very important reaction type known as an aldol reaction (which we will learn about in section 13.3) the nucleophile attacking the carbonyl is a resonance-stabilized carbanion. In this chapter, we will concentrate on reactions where the nucleophile is an oxygen or nitrogen.
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Ionic Addition to Carbonyl Group
As a result of the dipole shown in the resonance structures, polar reagents such as LiAlH4 and NaBH4 (hydride reagents) or R’MgX (Grignard reagent) will reduce the carbonyl groups, and ultimately convert unsaturated aldehydes and ketones into unsaturated alcohols. Since these reagents are extremely basic, their addition reactions are irreversible.
There are, however, addition reactions with less basic nucleophiles such as water, thiols, and amines that are capable of establishing equilibria or reversible reactions. These less basic reagents can react with the carbonyl group via two pathways: nucleophilic addition-protonation and electrophilic addition-protonation.
Addition of strong nucleophiles: Nucleophilic addition-protonation
With strong nucleophiles, direct nucleophilic attack of the electrophilic carbon takes place. As the nucleophile approaches the electrophilic carbon, two valence electrons from the nucleophile form a covalent bond to the carbon. As this occurs, the electron pair from the pi bond transfers completely over to the oxygen which produces the intermediate alkoxide ion. This alkoxide ion, with a negative charge on oxygen is susceptible to protonation from a protic solvent like water or alcohol, giving the final addition reaction.
Acid-catalyzed nucleophilic addition of weak nucleophiles.
Under acidic conditions, protonation of the carbonyl oxygen takes place. Then nucleophilic attack by the nucleophile finishes the addition reaction. This type of reaction works best when the reagent being used is a very mildly basic nucleophile.
- Vollhardt, K. P.C. & Shore, N. (2007). Organic Chemistry (5th Ed.). New York: W. H. Freeman. p. 775-777
- Otera, Junzo, ed. Modern Carbonyl Chemistry. Weinheim; Chichester: Wiley-VCH, 2000.
Relative Reactivity of Carbonyl Compounds to Nucleophilic Addition
In general aldehydes are more reactive than ketones because of the lack of stabilizing alkyl groups. The primary carbocation formed in the in the polarizing resonance structure of an aldehyde (discussed above) is less stable and therefore more reactive than the secondary carbocation formed by a ketone.
- Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
- Prof. Steven Farmer (Sonoma State University)
If the reaction is catalyzed by an enzyme, the stereochemistry of addition is tightly controlled, and leads to one specific stereoisomer – this is because the nucleophilic and electrophilic substrates are bound in a specific positions within the active site, so that attack must occur specifically from one side. If, however, the reaction occurs uncatalyzed in solution, then either side of the carbonyl is equally likely to be attacked, and the result will be a 50:50 racemic mixture.