Aldehydes and Ketones Nucleophilic Addition

 Chapter -19

Aldehydes and Ketones Nucleophilic Addition

 Structure

• Aldehydes are compounds of the general formula HCHO; ketones are compounds of the general formula RR'CO. The groups R and R' may be aliphatic or aromatic.

• Both aldehydes and ketones contain the carbonyl group, C O, and are often referred to collectively as carbonyl compounds. It is the carbonyl group that largely determines the chemistry of aldehydes and ketones.

• It is not surprising to find that aldehydes and ketones resemble each other closely in most of their properties. However, there is a hydrogen atom attached to the carbonyl group of aldehydes, and there are two organic groups attached to the carbonyl group of ketones. This difference in structure affects their properties in two ways: (a) aldehydes are quite easily oxidized, whereas ketones are oxidized only with difficulty; (b|) aldehydes are usually more reactive than ketones toward nucleophilic addition, the characteristic reaction ot carbonyl compounds.   

• The facts are consistent with the orbital picture of the carbonyl group. Electron diffraction and spectroscopic studies of aldehydes and ketones show that carbon, oxygen, and the two other atoms attached to carbonyl carbon lie in a plane; the three bond angles of carbon are very close to 120.\The large diploic moments (2.3-2.8 D) of aldehydes and ketones indicate that the electrons or the carbonyl group arc quite unequally snared. We shall see how the physical and chimerical properties of aldehydes and ketones are determined by the structure)f the carbonyl group.

Nomenclature

• The common names of aldehydes are derived from the names of the corresponding carboxylic acids by replacing -is add by -Aldah

• The IUPAC names of aldehydes follows the usual pattern. The longest chain carrying the CHO group is considered the parent structure and is named by replacing the -e of the corresponding alkane by -al. The position of a substituent is indicated by a number, the carbonyl carbon always being considered as C-l. Here, as with the carboxylic acids, we notice that C-2 of the IUPAC name corresponds to alpha of the common name.

• The simplest aliphatic ketone has the common name of acetone. For most other aliphatic ketones, we name the two groups that are attached to carbonyl carbon and follow these names by the word ketone. A ketone in which the carbonyl group is attached to a benzene ring is named as a -phenome, as illustrated below.

• According to the IUPAC system, the longest chain carrying the carbonyl group is considered the parent structure and is named by replacing the -e of the corresponding alkane with -one. The positions of various groups are indicated by numbers, the carbonyl carbon being given the lowest possible number.

Physical properties

• The polar carbonyl group makes aldehydes and ketones polar compounds, and hence they have higher Boiling polio Llia Aon Pulai compounds or comparable molecular weight. By themselves, they are not dupable of intermolecular hydrogen CTldlug since they mum hydrogen bonded brainy to carbon; as a result, they have lower boiling points than comparable alcohols or carboxylic acids. hrs.' example, compare -butyraldehyde (B.Pd., 76) and methyl ethyl ketone (bop 80 6) with w-pentane (bop 36) and ethyl ether (bop 35) on the one hand, and with w-butyl alcohol (bop 118) and propionic acid (bop 141) on the other.

 Preparation

• A few of the many laboratory methods of preparing aldehydes and ketones are outlined below; most of these are already familiar to us. Some of the methods involve oxidation or reduction in which an alcohol, hydrocarbon, or acid chloride is converted into an aldehyde or ketone of the same carbon number. Other methods involve the formation of new carbon-carbon bonds, and yield aldehydes or ketones of higher carbon number than the starting materials.

• Industrial preparation is generally patterned after these laboratory methods, but with use of cheaper reagents: alcohols are oxidized catalytically with air, or by dehydrogenation over hot copper.

Preparation of aldehydes by oxidation methods

• Aldehydes are easily oxidized to carboxylic acids bevy the same reagent, acidic chromate, that is used in their synthesis. How, is & possible, then, to stop the oxidation of a primary alcohol or a methylbenzoyl 16 (Sec- 19- 4) at the aldehyde stage? The answer is to remove the aldehyde as fast? s ** * s f armed before it can undergo further oxidation. This "removal" can be Acca? phished either physically or chemically.

• An aldehyde always has a lower boiling point than tph* alcono1 from when il is formed. (Why?) Acetaldehyde, for example, has a boi4 Ing Point of 20 ' ***1 alcohol has a boiling point of 78. When a solution of Bichromate and sulfuric acid is dripped into boiling ethyl alcohol, acetaldehyde is formed in a medium whose temperature is some 60 degrees above its boiling point; before it can undergo appreciable oxidation, it escapes from the reaction medium. Reaction is carried out under a fractionating column that allows aldehyde to pass but returns alcohol to the reaction

• Optically active alcohols in which the chiral center carries the OH undergo racemization in acidic solutions. Give a detailed experimental procedure (including apparatus) for studying the stereochemistry of acidic hydrolysis of sec-butyl benzoate that would prevent racemization of the alcohol subsequent to hydrolysis. sec-Butyl benzoate has a boiling point of 234; an azeotrope of 68% sec-butyl alcohol and 32% water has a boiling point of 88.5

Preparation of ketones by Friedel-Crafts acylation

• One of the most important modifications of the Friedel-Crafts reaction involves the use of acid chlorides rather than alkyl halides. An acyl group, RCO, becomes attached to the aromatic ring, thus forming a ketone; the process is called acylation. As usual for the Friedel-Crafts reaction (Sec. 12.8), the aromatic ring undergoing substitution must be at least as reactive as that of a halobenzene; catalysis by aluminum chloride or another Lewis acid is required.

• One of the most important modifications of the Friedel-Crafts reaction involves the use of acid chlorides rather than alkyl halides. An acyl group, RCO, becomes attached to the aromatic ring, thus forming a ketone; the process is called acylation. As usual for the Friedel-Crafts reaction (Sec. 12.8), the aromatic ring undergoing substitution must be at least as reactive as that of a halobenzene; catalysis by aluminum chloride or another Lewis acid is required.

• A straight-chain alkyl group longer than ethyl generally cannot be attached in good yield to an aromatic ring by Friedel-Crafts alkylation because of rearrangement (Sec. 12.7). Such a group is readily introduced, however, in two steps: (1) formation of a ketone by Friedel-Crafts acylation (or by the reaction of an organocadmium compound with an acyl chloride, described in the following section); (2) Clemmensen or Wolff -Kashner reduction of the ketone

Preparation of ketones by use of organocadmium compounds

Grignard reagents react with dry cadmium chloride to yield the corresponding organocadmium compounds, which react with acid chlorides to yield ketones:

• Here, as in its other reactions (Sec. 20.7), the acid chloride is undergoing nucleophilic substitution, the nucleophile being the basic alkyl or aryl group of the organometallic compound.

• Only organocadmium compounds containing aryl or primary alkyl groups are stable enough for use. In spite of this limitation, the method is one of the most valuable for the synthesis of ketones.

• Grignard reagents themselves react readily with acid chlorides, but the products are usually tertiary alcohols; these presumably result from reaction of initially formed ketones with more Grignard reagent. (If tertiary alcohols are desired, they are better prepared from esters than from acid chlorides, Sec. 20.21.) Organocadmium compounds, being less reactive, do not react with ketones.

• The comparatively low reactivity of organocadmium compounds not only makes the synthesis of ketones possible, but in addition widens the applicability of the method. Organocadmium compounds do not react with many of the functional groups with which the Grignard reagent does react: NO2 , CN, CO, COOR, for example. Consequently, the presence of one of these groups in the acid chloride molecule does not interfere with the synthesis of a ketone (compare with Sec. 15.15). For example:

Reactions. Nucleophilic addition

• The carbonyl group, C O, governs the chemistry of aldehydes and ketones. It does this in two ways: (a) by providing a site for nucleophilic addition, and (b) by increasing the acidity of the hydrogen atoms attached to the alpha carbon. Both these effects are quite consistent with the structure of the carbonyl group and, in fact, are due to the same thing: the ability of oxygen to accommodate negative charge 

• In this section, we shall examine the carbonyl group as a site for nucleophilic addition; in Sec. 21.1, we shall see how the acid-strengthening effect arises.

• The carbonyl group contains a carbon-oxygen double bond; since the mobile TT electrons are pulled strongly toward oxygen, carbonyl carbon is electron-deficient and carbonyl oxygen is electron-rich. Because it is flat, this part of the molecule is open to relatively unhindered attack from above or below, in a direction perpendicular to the plane of the group. It is not surprising that this accessible, polarized* group is highly reactive

• What kind of reagents will attack such a group? Since the important step in these reactions is the formation of a bond to the electron-deficient (acidic) carbonyl carbon, the carbonyl group is most susceptible to attack by electron-rich, nucleophilic reagents, that is, by bases! The typical reaction of aldehydes and ketones is nucleophilic addition

• As might be expected, we can get a much truer picture of the reactivity of the carbonyl group by looking at the transition state for attack by a nucleophile. In the reactant, carbon is trigonal. In the transition state, carbon has begun to acquire the tetrahedral configuration it will have in the product; the attached groups are thus being brought closer together. We might expect moderate steric hindrance in this reaction; that is, larger groups (R and R') will tend to resist crowding more than smaller groups. But the transition state is a relatively roomy one compared, say, with the transition state for an SN2 reaction, with its pentavalent carbon; it is this comparative uncrowdedness that we are really referring to when we say that the carbonyl group is "accessible" to attack.

 Oxidation

• Aldehydes are easily oxidized to carboxylic acids; ketones are not. Oxidation is the reaction in which aldehydes differ most from ketones, and this difference stems directly from their difference in structure: by definition, an aldehyde has a hydrogen atom attached to the carbonyl carbon, and a ketone has not. Regardless of exact mechanism, this hydrogen is abstracted in oxidation, either as a proton or an atom, and the analogous reaction for a ketone abstraction of an alkyl or aryl group does not take place.

• Oxidation by chromic acid, for example, seems to involve a rate-determining step analogous to that for oxidation of secondary alcohols (Sec. 16.8): elimination (again possibly by a cyclic mechanism) from an intermediate chromate

• .The intermediate is the chromate ester of the aldehyde hydrate, RCH(OH)2 ; it seems likely |hat the ester is formed from the hydrate, which exists in equilibrium with the aldehyde I that case, what we are dealing with is essentially oxidation of a special kind of alcohol a gem-diol

• Aldehydes are oxidized not only by the same reagents that oxidize primary and secondary alcohols permanganate and dichromate but also by the very mild oxidizing agent silver ion. Oxidation by silver ion requires an alkaline medium; to prevent precipitation of the insoluble silver oxide, a complexing agent is added: ammonia

Reduction 

• Aldehydes can be reduced tertiary alcohols, and ketones to secondary alcohols, either by catalytic hydrogenation or by use of chemical reducing agents 'Ike lithium aluminum hydride, LiAlH4 . Such reduction is useful for the preparation of certain alcohols that are less available than the corresponding carbonyl compounds, in particular carbonyl compounds that can be obtained by the aldol condensation. For example:

• Sodium borohydride, NaBH4 , does not reduce carbon -carbon double bonds, not even those conjugated with carbonyl groups, and is thus useful for the reduction of such unsaturated carbonyl compounds to unsaturated alcohols.

• Aldehydes and ketones can be reduced to hydrocarbons by the action (a) of amalgamated zinc and concentrated hydrochloric acid, the Clemmensen reduction; or (b) of hydrazine, NH2 NH2 , and a strong base like Koll or potassium iertbutoxide, the Wolff-Kashner reduction. These are particularly important when applied to the Alf Taryl ketones boarded from Friedel-Crafts acylation, since this reaction sequence permits, Indi

• Let us look a little more closely at reduction by metal hydrides. Alcohols are formed from carbonyl compounds, smoothly and in high yield, by the action of such compounds as lithium aluminum hydride, LiAlH4 . Here again, we see

Addition of Grignard reagents

• The addition of Grignard reagents to aldehydes and ketones has already been discussed as one of the most important methods of preparing complicated alcohols (Sees. 15.12-15.15)

• The organic group, transferred with a pair of electrons from magnesium to carbonyl carbon, is a powerful nucleophile.

 Addition of cyanide

• The elements of HCN add to the carbonyl group of aldehydes and ketones to yield compounds known as cyanohydrins:

• The reaction is often carried out by adding mineral acid to a mixture of the carbonyl compound and aqueous sodium cyanide. In a useful modification, cyanide is added to the bisulfite addition product (Sec. 19.13) of the carbonyl compound, the bisulfite ion serving as the necessary acid :

• Addition appears to involve nucleophilic attack on carbonyl carbon by the strongly basic cyanide ion; subsequently (or possibly simultaneously) oxygen accepts a hydrogen ion to form the cyanohydrin product :

• Although it is the elements of HCN that become attached to the carbonyl group, a highly acidic medium in which the concentration of un-ionized HCN is highest actually retards reaction. This is to be expected, since the very weak acid HCN is a poor source of cyanide ion.

• Cyanohydrins are nitriles, and their principal use is based on the fact that, like other nitriles, they undergo hydrolysis; in this case the products are a-hydroxy acids or unsaturated acids. For example:

• Each of the following is converted into the cyanohydrin, and the products are separated by careful fractional distillation or crystallization. For each reaction tell how many fractions will be collected, and whether each fraction, as collected, will be optically active or inactive, resolvable or non-resolvable.

Addition of bisulfite

• Sodium bisulfite adds to most aldehydes and to many ketones (especially methyl ketones) to form bisulfite addition products: bisulfate

•  The reaction is carried out by mixing the aldehyde or ketone with a concentrated aqueous solution of sodium bisulfite; the product separates as a crystalline solid. Ketones containing bulky groups usually fail to react with bisulfite, presumably for steric reasons.

• Suggest a practical situation that might arise in the laboratory in which you would need to (a) separate an aldehyde from undesired non-carbonyl materials; (b) remove an aldehyde that is contaminating a non-carbonyl compound. Describe how you could carry out the separations, telling exactly what you would do and see

Addition of derivatives of ammonia 

• Certain compounds related to ammonia add to the carbonyl group to form derivatives that are important chiefly for the characterization and identification of aldehydes and ketones (Sec. 19.17). The products contain a carbon-nitrogen double bond resulting from elimination of a molecule of water from the initial addition products. Some of these reagents and their products are: 

• Like ammonia, these derivatives of ammonia are basic, and therefore react with acids to form salts: hydroxylamine hydrochloride, HONH3 + C1~; phenylhydrazone hydrochloride, C6 H 5 NHNH3 + C1~ ; and semi carbazide hydrochloride, NH2 CONHNH 1 + C1. The salts are less easily oxidized by air than the free bases, and it is in this form that the reagents are best preserved and handled. When needed, the basic reagents are liberated from their salts in the presence of the carbonyl compound by addition of a base, usually sodium acetate. 

• It is often necessary to adjust the reaction medium to just the right acidity. Addition involves nucleophilic attack by the basic nitrogen compound on carbonyl carbon. Protonation of carbonyl oxygen makes carbonyl carbon more susceptible to nucleophilic attack; in so far as the carbonyl compound is concerned, then, addition will be favored by high acidity. But the ammonia derivative, H2 N G, can also undergo protonation to form the ion, + H3 N G, which lacks unshared electrons and is no longer nucleophilic; in so far -as the nitrogen compound is concerned, then, addition is favored by low acidity. The conditions under which

• Semi carbazide (1 mole) is added to a mixture of cyclohexanone (1 mole) and benzaldehyde (1 mole). If the product is isolated immediately, it consists almost entirely of the scmicarbazone of cyclohexanone; if the product is isolated after several hours, it consists almost entirely of the semi carbazone of benzaldehyde. How do you account for these observations? (Hint: See Sec. 

Addition of alcohols. Acetal formation      

• Alcohols add to the carbonyl group of aldehydes in the presence of anhydrous acids to yield acetals

   

•  The reaction is carried out by allowing the aldehyde to stand with an excess of the anhydrous alcohol and a little anhydrous acid, usually hydrogen chloride. In the preparation of ethyl acetals, the water is often removed as it is formed by means of the azeotrope of water, benzene, and ethyl alcohol (B.Pd. 64.9, Sec. 15.6). (Simple ketols are usually difficult to prepare by reaction of ketones with alcohols, and are made in other

Cannizzaro reaction

• In the presence of concentrated alkali, aldehydes containing no a-hydro geris undergo self-oxidation-and-reduction to yield a mixture of an alcohol and a salt of a carboxylic acid. This reaction, known as the Cannizzaro reaction, is generally brought about by allowing the aldehyde to stand at room temperature with concentrated aqueous or alcoholic hydroxide. (Under these conditions an aldehyde containing a-hydrogens would undergo aldol condensation faster, Sec.  

Analysis of aldehydes and ketones

• Aldehydes and ketones are characterized through the addition tcrt'hVcafbonyl group of nucleophilic reagents, especially derivatives of ammonia (Sec. 19.14). An aldehyde or ketonic will, for example, react with 2,4-dinitrophenylhydrazine to form an insoluble yellow or red solid.

• Aldehydes are characterized, and in particular are differentiated from ketones, through their ease of oxidation: aldehydes give a positive test with Tollens' reagent (Sec. 19.Q); ketones do not. A positive Tollens' test is also given by a few other kinds of easily oxidized compounds, e.g., certain phenols and amines; these compounds do not, however, give positive tests with 2,4-dinitrophenylhydrazine.

• Aldehydes are also, of course, oxidized by many other oxidizing agents: by cold, dilute, neutral KMnO4 and by CrO3 in H2SO4 (Sec. 6.30),

• A highly sensitive test for aldehydes is the Schiff test. An aldehyde reads with the fuchsin-aldehyde reagent to form a characteristic magenta color.

• A highly sensitive test for aldehydes is the Schiff test. An aldehyde reads with the fuchsin-aldehyde reagent to form a characteristic magenta color.

Spectroscopic analysis of aldehydes and ketones

• Infrared. Infrared spectroscopy is by far the best way to detect the presence of a carbonyl group in a molecule. The strong band due to C O stretching appears at about 1700 cm" 1 , where it is seldom obscured by other strong absorptions; it is one of the most useful bands in the infrared spectrum and is often the first one looked for. 

• The carbonyl band is given not only by aldehydes and ketones, but also by carboxylic acids and their derivatives. Once identified as arising from an aldehyde or ketone (see below), its exact frequency can give a great deal of information about the structure of the molecule.

• The CHO group of an aldehyde has a characteristic C--H stretching band near 2720 cm" 1 ; this, in conjunction with the carbonyl band, is fairly certain evidence for an aldehyde 

• Carboxylic acids and esters also show carbonyl absorption, and in the same general region as aldehydes and ketones. Acids, however, also show the broad O -H band. Esters usually show the carbonyl band at somewhat higher frequencies than ketones of the same general structure; furthermore, esters show characteristic C O stretching bands. (For a comparison of certain oxygen compounds.

• Namr. The proton of an aldehyde group, CHO, absorbs far downfield, at 8 9-10. Coupling of this proton with adjacent protons has a small constant (J 1-3 Hz), and the fine splitting is often seen superimposed on other splitting's.

• Ultraviolet. The ultraviolet spectrum can tell a good deal about the structure of carbonyl compounds: particularly, as we might expect from our earlier discussion about conjugation of the carbonyl group with a carbon -carbon double bond.

• Saturated aldehydes and ketones absorb weakly in the near ultraviolet. Conjugation moves this weak band (the R band) to longer wavelengths (why?) and, more important, moves a very intense band (the K band) from the far ultraviolet to the near ultraviolet. I