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The carbonyl bond is one of the most synthetically important functional groups in the whole of organic chemistry, and is present in aldehydes, ketones, esters, amides and many other carboxylic acid derivatives. Consisting of a carbon atom joined to an oxygen atom by a double bond, the carbonyl group is key to the versatile chemistry these compounds can undergo.
It’s all about the carbonyl bond. The more electronegative oxygen atom draws electron density from the carbon, increasing the polarity of the bond. As a result, the carbon atom is a good electrophile and is more vulnerable to attack by marauding nucleophiles such as negatively charged ions or molecules with a lone pair of electrons. This electrophilic nature means carbonyl groups can be involved in a range of transformations, including simple addition reactions (where the double bond is broken) and addition–elimination reactions (where the double bond is retained at the end of the reaction).
The polar nature of the carbonyl bond also means that the alpha hydrogens (those present on the first carbon atom adjacent to the carbonyl group) are considerably more acidic than those of typical alkyl chain C–H bonds. This strong acidity results from the fact that the carbonyl bond is in tautomeric resonance with an enol, allowing the negative charge on the deprotonated species to be spread over a greater number of atoms. Now that’s what we call sharing the load!
Given this extensive chemistry, carbonyl groups play a key role in a wide range of synthetically important reactions and biological processes. Here, we look at a handful of key transformations involving carbonyl compounds. How many have you encountered – or rather, what’s your carbonyl footprint?
Amongst the most synthetically useful (and best known) reactions of aldehydes and ketones is the Grignard reaction. Named after French chemist Victor Grignard, who first reported it in 1900, the reaction enables the synthesis of secondary and tertiary alcohols from aldehydes and ketones, respectively, using organomagnesium halides (more commonly known as Grignard reagents).
Grignard reagents can be prepared by reacting alkyl, aryl or vinyl halides with magnesium metal in aprotic nucleophilic solvents such as ethers. Because the carbon–magnesium bond is highly polar, Grignard reagents are excellent carbon nucleophiles (making the carbon–carbon bond-forming step in the Grignard reaction relatively straightforward).
Another noteworthy reaction involving aldehydes and ketones is the Knoevenagel condensation. First reported in 1894 by German chemist Emil Knoevenagel, the reaction involves the nucleophilic addition of an active methylene compound to the carbonyl group of an aldehyde or ketone in the presence of a weak base to generate alpha, beta-unsaturated dicarbonyl compounds.
To facilitate the reaction, the active methylene groups require two electron withdrawing groups. Examples include malonic esters, acetoacetic esters, malonodinitrile or acetylacetone. As water is generated as a by-product of the reaction, removing it by adding molecular sieves or by azeotropic distillation helps to push the equilibrium to favor the product.
Named after the German chemist Carl Mannich, the Mannich reaction is another synthetically useful transformation involving the carbonyl group. Discovered in 1917, the reaction results in the generation of aminoalkylated derivatives by the condensation of a CH-activated compound (such as an aldehyde or ketone) with a primary or secondary amine or ammonia and a non-enolizable aldehyde or ketone. Perhaps the best-known application of the Mannich reaction today is its use in heterocycle synthesis, where it is commonly used in conjunction with an aza-Cope rearrangement.
The product of the Mannich reaction is a ‘Mannich base’, a substituted beta-amino carbonyl compound. Mannich bases have proven to be useful synthetic intermediates, and can undergo a wide range of transformations, including beta-elimination to produce alpha, beta-unsaturated carbonyl compounds, reaction with organolithium or Grignard reagents to generate beta-amino alcohols, or substitution of the dialkylamino group with nucleophiles to form functionalized carbonyl compounds.
The Reformatsky reaction is the zinc-activated reaction between an alpha-halo ester and an aldehyde or ketone. First reported in 1887 by Russian chemist Sergey Reformatsky, the transformation is now used in the synthesis of many natural products, including macrocyclic cytochalasins – fungal metabolites with wide-ranging biological activities.
The reaction involves two synthetic steps. First, the zinc metal inserts into the carbon–halogen bond to form a zinc enolate known as a Reformatsky reagent. This reagent subsequently reacts with the carbonyl compound in an aldol reaction. Activation of the zinc prior to use by removing the deactivating zinc oxide layer (using reagents such as iodine or 1,2-dibromoethane) or by reducing zinc halides in solution has since widened the scope of the Reformatsky reaction.
Now a widely used synthetic technique, the Wittig reaction is named after the German chemist Georg Wittig, who discovered and investigated the process in the early 1950s. Wittig, having his wits about him (not just in his name), recognized that the reaction between carbonyl compounds and phosphoranes could be used to generate carbon–carbon double bonds, a process which is now commonly used in the formation of alkenes.
There are several variants of the Wittig reaction, one of the most notable being the Horner–Wittig reaction, which involves phosphorus ylides based on phosphine oxides rather than triarylphosphines. The Horner–Wittig reaction between a biaryl aldehyde and a metalated carbamate was utilized in the total synthesis of the natural product buflavin.
Carbonyl compounds can undergo a wide range of chemical transformations – the reactions named here are just the start! Other well-known transformations featuring carbonyl compounds include the Bayliss–Hillman reaction, Corey–Fuchs alkyne synthesis, Evans aldol reaction, Hantzsch dihydropyridine synthesis, Pictet–Spengler tetrahydroisoquinoline synthesis and Stetter reaction. To learn more about carbonyl chemistry, visit our dedicated named reactions page.