Semicarbazide, reaction with aldehydes ketones

Semicarbazide reacts with aldehydes and ketones to produce a derivative that is called a semicarbazone (Eq. 25.23), a reaction that is discussed in Chapter 13. Because semicarbazide is unstable as the free base, it is usually stored in the form of its hydrochloric acid salt. In the procedure that follows, the free base is liberated from the salt by addition of sodium acetate. 

Reaction CXXXl. Formation of Semioxamazones.—Semioxamazide, NH2.CO.CO.NH.NH2, possesses similar properties to semicarbazide, and reacts well with aldehydes, but with ketones the reaction does not seem to be generally applicable. 

Ketones and aldehydes also condense with other ammonia derivatives, such as hydroxyl amine and substituted hydrazines, to give imine derivatives. The equilibrium constants for these reactions are usually more favorable than for reactions with simple amines. Hydroxylamine reacts with ketones and aldehydes to form oximes hydrazine and its derivatives react to form hydrazones and semicarbazide reacts to form semicarbazones. The mechanisms of these reactions are similar to the mechanism of imine formation. 

A compound containing the C=N—NH — CONH2 group, formed by the reaction of a ketone or aldehyde with semicarbazide. (p. 853)... 

In the reaction of guanidine derivatives 11 with base, the aminocarbodiimides 12 are generated, which undergo dimerization to form triaminotriazoles (R = H), or are intercepted with aldehydes or ketones to give the corresponding semicarbazides 13. ... 

A number of reactions of nitrogen-containing nucleophiles with aldehydes and ketones involve addition of the nitrogen to the carbon of the carbonyl group, followed by elimination of water to produce a double bond. Common examples are reactions of primary amines to produce substituted imines, reactions of secondary amines to produce enamines, reactions of hydrazine or substituted hydrazines to produce hydrazones, reactions of semicarbazides to give semicarbazones, and reactions of hydroxylamine to produce oximes. Usually these reactions are run with an acid catalyst. 

C=N- Reaction with ammonia, primary amines, hydrazine, hydroxyl-amine, semicarbazide, Girard D reagent Ketones [206], aldehydes [206] irreducible under given conditions better developed waves with some reducible compounds simultaneous determination of pyridoxal and pyridoxal-5-phosphate [193], 17-ketosteroids [238],... 

The heights of waves of semicarbazones are dependent on the equilibrium constant of the condensation reaction. This enables the analysis of some mixtures to be made. Generally speaking, the equilibrium is shifted in favour of semicarbazones more with aldehydes than ketones, and this permits the determination of aldehydes in the presence of smaller excesses of ketones. Thus butyraldehyde can be determined in the presence of a fourfold excess of acetone and a twofold excess of acetophenone, by recording the curves in OT M HCl with 0-02 m semicarbazide. 

SEMICARBAZONES. The products of the reaction between an aldehyde or a ketone with semicarbazide are termed semicarbazones. 

A mortar was charged with the aldehyde or ketone (1 mmol), hydrazine derivative or semicarbazide (1 mmol), sodium hydroxide (0.04 g, 1 mmol) and silica gel (0.1 g). The reaction mixture was ground with a pestle in the mortar. When TLC showed no remaining aldehyde or ketone, the reaction mixture was poured into a mixture of dichlorometliane (20 mL) and 5% HC1 (10 mL). The ethereal layer was washed with saturated NaHC03, dried (MgS04), and evaporated by rotary evaporation to give the pure product. 

Dissolve 1 g of semicarbazide hydrochloride and 1.5 g of crystallised sodium acetate in 8-10 ml of water, add 0.5 g of the aldehyde or ketone and shake. If the mixture is turbid, add alcohol (acetone-free) or water until a clear solution is obtained shake the mixture for a few minutes and allow to stand. Usually the semicarbazone crystallises from the cold solution on standing, the time varying from a few minutes to several hours. The reaction may be accelerated, if necessary, by warming the mixture on a water bath for a few minutes and then cooling in ice-water. Filter off the crystals, wash with a little cold water and recrystallise from water or from methanol or ethanol either alone or diluted with water. 

Difference in reactivity of aldehydes and ketones was used for selective protection of aldehydes in the presence of a ketone functional group. Chemoselectivity is demonstrated by two competitive reactions. When a 1 1 mixture of p-hydroxy- or p-nitrobenzaldehyde and p-hydroxy- or p-nitroacetophenone was allowed to react with 1.0 equiv. of semicarbazide hydrochloride for 45 min, the aldehydes were transformed quantitatively to their corresponding semicarbazones 59, whereas the ketones remain unreacted (Scheme 3.14). 

The maximum rates of the reactions of most aldehydes and ketones with semi-carbazide occur in the pH range of 4.5-5.0. For the purpose of making derivatives of carbonyl compounds (Sec. 25.7), semicarbazide is best used in an acetate buffer (CH3CO2H/CH3CO2 ) solution, which maintains a pH in the maximum rate range of 4.5-5.0. However, to demonstrate the principle of kinetic and thermodynamic control of reactions, buffers that maintain higher pHs, and thus produce lower rates, are more desirable. Parts A-C of the experimental procedure involve a phosphate buffer system, whereas the bicarbonate system is used in Part D. It is then possible to compare how the difference in rates in the two buffer systems affects the product ratio. Analysis of the products from the various parts of these experiments provides strong clues as to which of the semicarbazones is the product of kinetic control and which is the product of thermodynamic control. 

---