Understanding Ketones and Aldehydes: Nomenclature, Synthesis, and Reactions, Schemes and Mind Maps of Organic Chemistry

Download Understanding Ketones and Aldehydes: Nomenclature, Synthesis, and Reactions and more Schemes and Mind Maps Organic Chemistry in PDF only on Docsity! Ch18 Ketones and Aldehydes (landscape) Page 1 Ketones and Aldehydes The carbonyl group is of central importance in organic chemistry because of its ubiquity. Without studying the carbonyl group in depth we have already encountered numerous examples of this functional group (ketones, aldehydes, carboxylic acids, acid chlorides, etc). The simplest carbonyl compounds are aldehydes and ketones. A ketone has two alkyl (or aryl) groups bonded to the carbonyl carbon. An aldehyde has one alkyl (or aryl) group and one hydrogen bonded to the carbonyl carbon. Structure of the carbonyl group The carbonyl carbon is sp2 hybridized, and has a partially filled unhybridized p orbital perpendicular to the  framework. R C H O R C R O aldehyde ketone Ch18 Ketones and Aldehydes (landscape) Page 2 The oxygen is also sp2 hybridized, with the 2 lone pairs occupying sp2 orbitals. This leaves one electron in a p orbital. These p orbitals form the carbon oxygen  bond. The C=O double bond is like a C=C double bond except the carbonyl double bond is shorter and stronger. The carbonyl group has a large dipole moment due to the polarity of the double bond. Oxygen is more electronegative than carbon, and so the bond is polarized toward the oxygen. The attraction of the weakly held  electrons toward oxygen can be represented by the two following resonance structures. The first resonance structure is the major contributor, but the other contributes in a small amount, which helps explain the dipole moment. It is this polarization that creates the reactivity of the carbonyl groups (carbon is electrophilic/LA, and the oxygen is nucleophilic/LB). Ch18 Ketones and Aldehydes (landscape) Page 5 A ketone or aldehyde group can also be named as a substituent on a molecule with another functional group as its root. The ketone carbonyl is given the prefix oxo-, and the aldehyde group is named as a formyl- group. (This is especially common for carboxylic acids). Common Names The wide spread use of carbonyl compounds means many common names are entrenched in their everyday use. E.g. H3C C CH3 O acetone C O CH3 acetophenone C O benzophenone Ch18 Ketones and Aldehydes (landscape) Page 6 Syntheses of the Aldehydes and Ketones (Recap?) From Alcohols (Ch 11) Secondary alcohols are readily oxidized to ketones by Chromic acid (or KMnO4). Complicated ketones can be made by the oxidation of alcohols, which in turn can be made from reaction of a Grignard and an aldehyde. Aldehydes are made from the oxidation of primary alcohols. This oxidation needs to be done carefully to avoid over-oxidation to carboxylic acids. This is achieved by the use of PCC. Ch18 Ketones and Aldehydes (landscape) Page 7 Ozonolysis (Ch 8) Alkenes can be cleaved by ozone (followed by a mild reduction) to generate aldehydes and/or ketones. Phenyl Ketones and Aldehydes (Ch 17) Friedel-Crafts acylation is an excellent method for the preparation of aryl ketones. The Gattermann-Koch reaction produces benzaldehyde systems. Ch18 Ketones and Aldehydes (landscape) Page 10 This is a good route for the construction of unsymmetrical ketones. E.g. The dithiane can be thought of as a "masked" carbonyl group. Ketones from Carboxylic Acids Organolithium reagents are very reactive towards carbonyl compounds. So much so, that they even attack the lithium salts of carboxylate anions. These dianions can then be protonated, which generates hydrates, which then lose water and produce ketones. E.g. Ch18 Ketones and Aldehydes (landscape) Page 11 If the organolithium reagent is not expensive, then the carboxylic acid can be simply treated with two equivalents of the organolithium. The first equivalent just deprotonates the carboxylic acid (expensive base). Ketones from Nitriles Nitrile compounds contain the cyano group (carbon nitrogen triple bond). Since N is more electronegative than C, the triple bond is polarized toward the nitrogen, (similar to the C=O bond). Therefore nucleophiles can attack the electrophilic carbon of the nitrile group. Grignard (or organolithium) reagents attack the nitrile to generate the magnesium (or lithium) salt of an imine. Acid hydrolysis generates the imine, and under these acidic conditions, the imine is hydrolyzed to a ketone. Ch18 Ketones and Aldehydes (landscape) Page 12 The mechanism of this hydrolysis is discussed in depth (for the reverse reaction) later. E.g. Aldehydes and Ketones from Acid Chlorides Aldehydes It is very difficult to reduce a carboxylic acid back to an aldehyde and to get the reduction to stop there. Aldehydes themselves are very easily reduced (more reactive than acids), and so almost always, over-reduction occurs. Ch18 Ketones and Aldehydes (landscape) Page 15 Reactions of Aldehydes and Ketones The most common reaction of aldehydes and ketones is nucleophilic addition. This is usually the addition of a nucleophile and a proton across the C=O double bond. As the nucleophile attacks the carbonyl group, the carbon atom changes from sp2 to sp3. The electrons of the  bond are pushed out onto the oxygen, generating an alkoxide anion. Protonation of this anion gives the final product. Ch18 Ketones and Aldehydes (landscape) Page 16 We have already encountered (at least) two examples of this: Grignards and ketones  tertiary alcohols Hydride sources and ketones  secondary alcohols These reactions are both with strong nucleophiles. Under acidic conditions, weaker nucleophiles such as water and alcohols can add. Ch18 Ketones and Aldehydes (landscape) Page 17 The carbonyl group is a weak base, and in acidic solution it can become protonated. This makes the carbon very electrophilic (see resonance structures), and so it will react with poor nucleophiles. E.g. the acid catalyzed nucleophilic addition of water to acetone to produce the acetone hydrate. Ch18 Ketones and Aldehydes (landscape) Page 20 Other Reactions of Carbonyl Compounds Addition of Phosphorus Ylides (Wittig Reaction) In 1954 Wittig discovered that the addition of a phosphorus stabilized anion to a carbonyl compound did not generate an alcohol, but an alkene! (= Nobel Prize in 1979). The phosphorus stabilized anion is called an YLIDE, which is a molecule that is overall neutral, but exists as a carbanion bound to a positively charged heteroatom. Ch18 Ketones and Aldehydes (landscape) Page 21 Phosphorus ylides are produced from the reaction of triphenylphosphine and alkyl halides. This two step reaction starts with the nucleophilic attack of the Phosphorus on the (usually primary) alkyl halide. This generates an alkyl triphenylphosphonium salt. Treatment of this salt with a strong base removes a proton from the carbon bound to the phosphorus, and generates the ylide. The ylide is a resonance form of a C=P double bond. The double bond resonance form requires 10 electrons around the P atom. This is achievable through use of its d electrons (3rd row element), but the  bond to carbon is weak, and this is only a minor contributor. Ch18 Ketones and Aldehydes (landscape) Page 22 The carbanionic character of the ylide makes it a very powerful nucleophile, and so it reacts rapidly with a carbonyl group. This produces an intermediate which has charge separation - a betaine. Betaines are unusual since they have a negatively charged oxygen and a positively charged phosphorus. Phosphorus and oxygen always form strong bonds, and these groups therefore combine to generate a four membered ring - an oxaphosphetane ring. This 4 membered ring quickly collapses to generate an alkene and (very stable) triphenyl phosphine oxide. The elimination of Ph3P=O is the driving force of this reaction. This is a good general route to make new C=C double bonds starting from carbonyl compounds. Ch18 Ketones and Aldehydes (landscape) Page 25 (Acidic Conditions – Protonation followed by nuc attack) (Basic Conditions – Nuc attack followed by protonation) Ch18 Ketones and Aldehydes (landscape) Page 26 Aldehydes are more likely to form hydrates since they have the larger partial positive charge on the carbonyl carbon (larger charge = less stable = more reactive). This is borne out by the following equilibrium constants. Ch18 Ketones and Aldehydes (landscape) Page 27 Nucleophilic Addition of Hydrogen Cyanide (Cyanohydrins) Hydrogen cyanide is a toxic volatile liquid (b.p.26°C). H-CN + H2O  H3O + + ¯CN pKa = 9.2 Cyanide is a strong base (HCN weak acid) and a good nucleophile. Cyanide reacts rapidly with carbonyl compounds producing cyanohydrins, via the base catalyzed nucleophilic addition mechanism. Like hydrate formation, cyanohydrin formation is an equilibrium governed reaction (i.e. reversible reaction), and accordingly aldehydes are more reactive than ketones. Ch18 Ketones and Aldehydes (landscape) Page 30 The pH of the reaction mixture is crucial to successful formation of imines. The pH must be acidic to promote the dehydration step, yet if the mixture is too acidic, then the reacting amine will be protonated, and therefore un-nucleophilic, and this would inhibit the first step. The rate of reaction varies with the pH as follows: The best pH for imine formation is around 4.5. Ch18 Ketones and Aldehydes (landscape) Page 31 Condensations with Hydroxylamines and Hydrazines Aldehydes and ketones also condense with other ammonia derivatives, such as hydroxylamine and hydrazines. Generally these reactions are better than the analogous amine reactions (i.e. give superior yields). Oximes are produced when hydroxylamines are reacted with aldehydes and ketones. Hydrazones are produced through reaction of hydrazines with aldehydes and ketones. Semicarbazones are formed from reaction with semicarbazides. These derivatives are often used in practical organic chemistry for characterization and identification of the original carbonyl compounds (by melting point comparison, etc.). Ch18 Ketones and Aldehydes (landscape) Page 32 Formation of Acetals (Addition of Alcohols) In a similar fashion to the formation of hydrates with water, aldehydes and ketones form acetals through reaction with alcohols. In the formation of an acetal, two molecules of alcohol add to the carbonyl group, and one mole of water is eliminated. Acetal formation only occurs with acid catalysis. Ch18 Ketones and Aldehydes (landscape) Page 35 Acetals as Protecting Groups Acetals will hydrolyze under acidic conditions, but are stable to strong bases and nucleophiles. They are also easily formed from aldehydes and ketones, and also easily converted back to the parent carbonyl compounds. These characteristics make acetals ideal protecting groups for aldehydes and ketones. They can be used to 'protect' aldehydes and ketones from reacting with strong bases and nucleophiles. Ch18 Ketones and Aldehydes (landscape) Page 36 Consider the strategy to prepare the following compound: We might decide to use the Grignard reaction as shown above. However, having a Grignard functionality and an aldehyde in the same molecule is bad news since they will react with one another. The strategy is still okay, we just need to 'protect' the aldehyde as some unreactive group - an acetal. The acetal group is unreactive towards Grignard reagents (strong nucleophiles), and therefore this would be a viable reagent. The "masked" aldehyde can be safely converted to the Grignard reagent, and then this can react with cyclohexanone. The acetal is easily removed with acidic hydrolysis (which is also required to remove the MgBr+ from the oxyanion), giving the final product. Ch18 Ketones and Aldehydes (landscape) Page 37 Selective Acetal Formation We have previously seen that aldehydes are more reactive than ketones (two reasons), and therefore aldehydes will react to form acetals preferentially over ketones. This means we can selectively protect aldehydes in the presence of ketones. (Remember to use only 1 equivalent!) E.g. This is a useful way to perform reactions on ketone functionalities in molecules that contain both aldehyde and ketone groups. (To selectively do reactions on the aldehyde, just do them!) Ch18 Ketones and Aldehydes (landscape) Page 40 Reduction of Ketone and Aldehydes Aldehydes and ketones are most commonly reduced by sodium borohydride (Ch12, and earlier this chapter). NaBH4 reduces ketones to secondary alcohols, and aldehydes to primary alcohols. Other Reductions Catalytic Hydrogenation Just as C=C double bonds can be reduced by the addition of hydrogen across the double bond, so can C=O double bonds. Carbonyl double bonds are reduced much more slowly than alkene double bonds. Therefore, you cannot reduce a C=O in the presence of a C=C without reducing both (by this method). E.g. The most common catalyst for these hydrogenations is Raney nickel, although Pt and Rh can also be used. Ch18 Ketones and Aldehydes (landscape) Page 41 Deoxygenation of Ketones and Aldehydes Deoxygenation involves the removal of oxygen, and its replacement with two hydrogen atoms. This reduction takes the carbonyl (past the alcohol) to a methylene group. Compare the following reduction processes: Clemmensen Reduction (recap?) This was used in the reduction of acyl benzenes into alkyl benzenes, but it also works for other aldehydes and ketones. E.g. Ch18 Ketones and Aldehydes (landscape) Page 42 Wolff-Kishner Sometimes the acidic conditions used in the Clemmensen reduction are unsuitable for a given molecule. In these cases, Wolff-Kishner reduction is employed. The ketone or aldehyde is converted to its hydrazone (by reaction with hydrazine) and is then treated with a strong base, which generates the reduced product. E.g. The mechanism of hydrazone formation is analogous to imine formation.