The Reactions of Aldehydes and Ketones with Water

Librium was structurally modified in an attempt to find other tranquilizers (Section 11.9). One successful modification produced Valium, a tranquilizer almost 10 times more potent than Librium. Currently, there are 8 benzodiazepines in clinical use as tranquilizers in the United States and some 15 others abroad. Rohypnol is one of the so-called date-rape drugs. 

The addition of water to an aldehyde or a ketone forms a hydrate. A hydrate is a molecule with two OH groups bonded to the same carbon. Hydrates are also called gcm-diols (gem comes from geminus, Latin for twin ). 

The electrostatic potential maps show that the carbonyl carbon of the protonated aldehyde is more electrophilic (the blue is more intense) than the carbonyl carbon of the unprotonated aldehyde, 

Removal of a proton from the protonated tetrahedral intermediate forms the hydrate. 

Hydration of an aldehyde can also be catalyzed by hydroxide ion. Propose a mechanism for the reaction. 

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An example of the reaction of aldehydes and ketones with water to form addition products called hydrates is illustrated in the following equation for the case of acetaldehyde ... 

This section and Sections 17-7 and 17-8 introduce the reactions of aldehydes and ketones with water and alcohols. These compounds attack the carbonyl group through the mechanisms just outlined, utilizing either acid or base catalysis. 

Let us focus here on determining the various carbony compounds. Figure 4.46 shows a HPLC chromatogram for the separation and detection of the first six homologous series of aldehydes as their 2,4-dinitrophenylhydrazone derivatives accomplished in the author s laboratory. The reaction of aldehydes and ketones with 2,4-nitrophenylhydrazine under mildly acidic conditions in water to form stable hydrazones is a well-known reaction in organic chemistry. The homologous series with R representing Ci, C2, C3, C4, C5, and Cg react as follows ... 

The most versatile method for preparing enamines involves the condensation of aldehydes and ketones with secondary amines [Eq. (1)]. Mannich and Davidsen (/) discovered that the reaction of secondary amines with aldehydes in the presence of potassium carbonate and at temperatures near 0° gave enamines, while calcium oxide and elevated temperatures were required to cause a reaction between ketones and secondary amines, although usually in poor yield. The introduction by Herr and Heyl 2-4) of the removal of the water produced in the condensation by azeotropic distillation with benzene made possible the facile preparation of enamines from ketones and disubstituted aldehydes. 

Recently, Sarangi et al. (1995) discovered that the Barbier-type allylation of carbonyl compounds could be mediated by zero-valent copper. In the experimental procedure copper(ll) chloride in its hydrated form was mixed with magnesium powder. This reaction did not proceed with anhydrous CuCU, but addition of water to this anhydrous salt in the presence of magnesium allowed the allylation of aldehydes and ketones with allylic bromides. In the absence of halides, the hydrated reagent (CuCl2 2H20/Mg) turned out to be efficient in the reduction of aldehydes. However, the water of crystallization could not suffice and addition of water promoted the reduction process (Sarangi eta/., 1995). 

The condensation of aldehydes or ketones with secondary amines leads to "encunines via N-hemiacetals and immonium hydroxides, when the water is removed. In these conjugated systems electron density and nudeophilicity are largely transferred from the nitrogen to the a-carbon atom, and thus enamines are useful electroneutral d -reagents (G.A. Cook, 1969 S.F. Dyke, 1973). A bulky heterocyclic substituent supports regio- and stereoselective reactions. 

Besides direct reduction, a one-pot reductive amination of aldehydes and ketones with a-picoline-borane in methanol, in water, and in neat conditions gives the corresponding amine products (Scheme 8.2).40 The synthesis of primary amines can be performed via the reductive amination of the corresponding carbonyl compounds with aqueous ammonia with soluble Rh-catalyst (Eq. 8.17).41 Up to an 86% yield and a 97% selectivity for benzylamines were obtained for the reaction of various benzaldehydes. The use of a bimetallic catalyst based on Rh/Ir is preferable for aliphatic aldehydes. 

Later, Araki et al. found that the allylation of aldehydes and ketones can be carried out by using catalytic amounts of indium(III) chloride in combination with aluminum or zinc metal.109 This reaction was typically performed in a THF-water (5 2) mixture at room temperature, although the conversion was much slower compared to the same reaction mediated by use of a stoichiometric amount of indium and it required days to complete. When the reaction was carried out in anhydrous THF alone, the yield dropped considerably and side-reactions such as reduction to alcohol increased. The combinations of Al-InCL or Zn-InCl3 gave comparable results. 

A mixture of 1,4-dioxane and water is often used as the solvent for the conversion of aldehydes and ketones by H2Se03 to a-dicarbonyl compounds in one step (Eq. 8.117).331 Dehydrogenation of carbonyl compounds with selenium dioxide generates the a, (i-unsaturated carbonyl compounds in aqueous acetic acid.332 Using water as the reaction medium, ketones can be transformed into a-iodo ketones upon treatment with sodium iodide, hydrogen peroxide, and an acid.333 Interestingly, a-iodo ketones can be also obtained from secondary alcohol through a metal-free tandem oxidation-iodination approach. 

The hydroxylamine reaction was used to estimate ketone and aldehyde groups. The method used was similar to one described by Kaverzneva and Salova (6). A 25-ml. solution of 5% aqueous hydroxylamine hydrochloride (previously adjusted to a pH 7.5-8 with sodium hydroxide) was added to 1.5 grams of sample and allowed to react for 18-24 hours at room temperature. The mixture was filtered, washed with water, and dried. The residue was analyzed for nitrogen, and the amount of aldehyde and ketone structure was calculated from the nitrogen increase. 

Attempts were made to reduce any aldehyde and ketone function with sodium borohydride. A 1.5-gram sample was weighed into a 100-ml. reaction flask and suspended in 10 ml. of methanol. A solution of 0.3 gram of sodium borohydride in 25 ml. of 0.1 IV sodium hydroxide was added to the sample over a period of 15 minutes. The mixture was refluxed under nitrogen for 6 hours, filtered, and washed thoroughly with water. The amount of aldehyde and ketone was estimated by the decrease in the 5.8 micron peak in the infrared spectrum of the treated sample as compared with the untreated sample. 

Condensation of aldehydes and ketones with secondary amines in the presence of dehydrating agents (often potassium carbonate69-71) represents a general method of enamine preparation. By this procedure ketones afford the enamines directly, whereas aldehydes are converted in the first step into diamino derivatives which decompose on distillation to give the enamine and a molecule of the secondary amine. In the case of ketones and disubstituted acetaldehydes, the water formed by the reaction can be removed by azeotropic distillation with benzene, toluene, or xylene.27,31,72-75 In the case of derivatives of aromatic aldehydes, the formation of intermediary carbinolamines 76 is sometimes observed. 

The achiral allylation of aldehydes has also been achieved in recyclable ionic liquids" and in water." Greener still is the corresponding Barbier allylation" of aldehydes and ketones with allylic bromides in water mediated by tin metal. The atom efficiency of this reaction is actually less than the corresponding tetraallyltin allylation of (say) benzaldehyde (65% and 83%, respectively) because of the loss of the heavy bromine atom, but this neglects the synthesis of tetraallyltin, which is prepared from allyl bromide or chloride. A particularly intriguing recent advance with this thoroughly studied reaction is the use of nano-tin " (Scheme 5.8.17). 

Recently, nanometer tin-mediated allylation of aldehydes or ketones in distilled or tap water gave rise to homoallyl alcohols in high yield without any other assistance such as heat or supersonic or acidic media (Eq. 8.41). Allylation of P-keto aldehydes and functionalized imines by diallyltin dibromide was carried out to generate skipped and conjugated dienes. Aldehydes are allylated with CH2=CHCH2SnBu3 using Sn catalysts in acidic aqueous media. Exclusive aldehyde selectivity was observed for competitive reactions of aldehydes and ketones in the presence of 5 mol% of (CH2=CHCH2)4Sn or SnCU in a mixture of aqueous HCl and THE (Eq. 8.42). ... 

The different reactivities of aldehydes and ketones with hydroxylamine hydrochloride were used as a method for protecting aldehydes by oximation in the presence of a ketone functional group. The competitive reactions with 1 1 mixtures of o-nitro- or p-nitrobenzaldehyde and o-nitro- or p-nitroacetophenone when milled with 1 equiv. of NH20H flCl for 60 min at 25°C afforded only the transformation of aldehydes to their corresponding oximes, whereas the ketones did not react. In a similar manner the difference in temperatures needed for the conversion of ketones into the 2,4-dinitrophenyIhydrazones was used for chemoselective reaction of aldehydes. As an example, milling of 1 1 mixture of p-nitrobenzaldehyde and p-nitroace-tophenone with 2,4-dinitrophenylhydrazine and water at 70°C for 50 min produced quantitative transformation of aldehyde to its 2,4-dinitrophenylhydrazone, whereas the ketone remained unaffected. 

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