1- Reaction at the carbonyl carbon (Nucleophilic addition reactions).

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1 Reactions of aldehydes and Ketones Aldehydes and Ketones undergo many reactions to give a wide variety of useful derivatives. There are two general kinds of reactions that aldehydes and ketones undergo: 1- Reaction at the carbonyl carbon (Nucleophilic addition reactions). 2-reaction at the α carbon. A second general reaction of aldehydes and ketones involves reaction at the α carbon. A C H bond on the α carbon to a carbonyl group is more acidic than many other C H bonds, because reaction with base forms a resonance-stabilized enolate anion. 1

2 1- Nucleophilic addition reaction. Two general mechanisms are usually drawn for nucleophilic addition, depending on the nucleophile (negatively charged versus neutral) and the presence or absence of an acid catalyst. With negatively charged nucleophiles, nucleophilic addition follows the two-step process first (nucleophilic attack) followed by protonation. Absence of an acid catalyzed nucleophilic addition Step [1]: The nucleophile attacks the carbonyl group, cleaving the π bond and moving an electron pair onto oxygen. This forms a sp 3 hybridized intermediate with a new C Nu bond. Step [2]: protonation of the negatively charged O atom by H 2 O forms the addition product. Acid-catalyzed nucleophilic addition The general mechanism for this reaction consists of three steps (not two), but the same product results because H and Nu - add across the carbonyl π bond. In this mechanism protonation precedes nucleophilic attack. Step [1] Protonation of the carbonyl group In Step [2], the nucleophile attacks, and then deprotonation forms the neutral addition product in Step [3]. 2

3 Steps [2] [3] Nucleophilic attack and deprotonation a) Addition of Alcohols (Acetal Formation): Aldehydes and ketones react with two equivalents of alcohol to form acetals. In an acetal, the carbonyl carbon from the aldehyde or ketone is now singly bonded to two OR" (alkoxy) groups. b) Nucleophilic Addition of H - (Reduction reaction) Treatment of an aldehyde or ketone with either Sodium borohydride (NaBH 4 ) or Lithium hydride (LiAlH 4 ) followed by protonation forms a 1 or 2 alcohol. 3

4 c) Reduction of Ketones and Aldehydes Clemmensen reduction: The Clemmensen reduction is most commonly used to convert acylbenzenes (from Friedel-Crafts acylation) to alkylbenzenes, but it also works with other ketones or aldehydes that are not sensitive to acid. The carbonyl compound is heated with an excess of amalgamated zinc (zinc treated with mercury; Zn (Hg), and concentrated hydrochloric acid (HCl). The actual reduction occurs by a complex mechanism on the surface of the zinc. 4

5 The Clemmensen reduction uses zinc and mercury in the presence of strong acid. Wolff Kishner reduction: Compounds that cannot survive treatment with hot acid can be deoxygenated using the Wolff Kishner reduction. The ketone or aldehyde is converted to its hydrazone, which is heated with Hydrazine (NH 2 NH 2 ), and strong base such as KOH. Ethylene glycol, diethylene glycol, or another high-boiling solvent is used to facilitate the high temperature ( C) needed in the second step. 5

6 O H H i) NH 2 NH 2 ii) base Cyclopentanone Cyclopentane d) Nucleophilic Addition of CN Treatment of an aldehyde or ketone with NaCN and a strong acid such as HCl adds the elements of HCN across the carbon oxygen π bond, forming a cyanohydrin. H C O Benzaldehyde NaCN NaHSO 3 H C CN OH Mandelonitrile 6

7 e) Addition of Bisulfate. Sodium bisulfate adds to most aldehydes and to many ketones (especially methyl ketones and cycloketones) to form bisulfate addition products: 7

8 f) Addition of Organo Metallic reagents The addition of Grignard reagents to aldehydes and ketones yields alcohols. The organic group, transferred with a pair of electrons from magnesium to carbonyl carbon, is a powerful nucleophile. O C + R: MgX C R OMgX H 2 O C R OH + Mg(OH)X H + Prepration of Grignard reagents Mg ++ + X - + H 2 O 8

9 g) Addition of derivatives of Ammonia:- Treatment of an aldehyde or ketone with a 1 amine affords an imine (Schiff base). Nucleophilic attack of the 1 amine on the carbonyl group forms an unstable carbinolamine, which loses water to form an imine. The overall reaction results in replacement of C=O by C=NR. 9

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11 Oxidation reaction Aldehydes are readily oxidized to yield carboxylic acids; but ketones are generally inert toward oxidation. The difference is a consequence of structure: aldehydes have a CHO proton that can be abstracted during oxidation, but ketones do not. O Hydrogen here [O] O O No hydrogen here R C H An aldehyde R C OH Carboxylic acid R C R A ketone 11

12 Many oxidizing agents, including KMnO 4 and hot HNO 3, convert aldehydes into carboxylic acid. hot HNO 3 RCHO or ArCHO KMnO 4 RCOOH or ArCOOH K 2 Cr 2 O 7 Tollen's reagent In the laboratory, oxidation of an aldehyde can be carried out using a solution of silver oxide (Ag 2 O) in aqueous ammonia, the so-called Tollen's reagent. Oxidation of aldehyde is accompanied by reduction of silver ion to free silver (in the form of a mirror under the proper conditions). 12

13 Methyl ketones: Oxidation of ketones required breaking of C C bond next to the carbonyl group and takes place only under vigorous conditions, except for methyl ketones which oxidized smoothly by mean of hypohalite (NaOX) to form Haloform (Haloform reaction). 13