Aldehydes and Ketones: Organic Chemistry Lecture Slides
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Aldehydes and Ketones Properties Aldehydes (RCHO) and ketones (R₂CO) are structurally similar because both contain a carbon–oxygen double bond called a carbonyl group (C=O). In an aldehyde, the carbonyl carbon is bonded to at least one hydrogen (R–CHO). In a ketone, the carbonyl carbon is bonded to two carbon-containing groups (R–CO– R′). Properties Simple aldehydes and ketones are industrially important. Acetone is widely used as a solvent and is a common ingredient in nail polish remover, while formaldehyde is used as a preservative (and inactivation/stabilization agent) in the production of some vaccine formulations. Formaldehyde Acetone Properties Aldehydes and ketones are also used as building blocks in the syntheses of commercially important compounds, including pharmaceuticals and polymers. Compounds containing a carbonyl group react with a large variety of nucleophiles, affording a wide range of possible products. Due to the versatile reactivity of the carbonyl group, aldehydes and ketones occupy a central role in organic chemistry. Properties In general, aldehydes are more reactive than ketones toward nucleophilic attack, due to both steric and electronic effects. Properties A ketone has two alkyl groups, one on either side of the carbonyl, which increases steric interactions in the transition state for nucleophilic attack. An aldehyde has only one alkyl group, so there is less steric hindrance to nucleophilic attack. Properties A ketone has two electron donating alkyl groups that help stabilize the partial positive charge on the carbonyl carbon, making it less electrophilic. An aldehyde has only one electron donating group, so the carbonyl carbon is more electrophilic and more reactive toward nucleophilic attack. Preparation of Aldehydes and Ketones (Review) Ozonolysis (reductive workup) of alkenes Preparation of Aldehydes and Ketones (Review) Mercury catalyzed hydration and hydroboration-oxidation of alkynes Preparation of Aldehydes and Ketones (Review) Oxidation of a secondary alcohol with chromic acid or PCC Preparation of Aldehydes and Ketones (Review) Oxidation of a primary alcohol with PCC Preparation of Aldehydes and Ketones (Review) Friedel-Crafts acylation of benzene Reactions of Aldehydes and Ketones Reaction under basic conditions Reactions of Aldehydes and Ketones Reactions under acidic conditions o Protonation of the carbonyl group generates a very powerful electrophile o This is especially important when weak nucleophiles, such as H 2O or ROH react. Reactions of Aldehydes and Ketones When a nucleophile attacks a carbonyl group under either acidic or basic conditions, the position of equilibrium depends strongly on how well that nucleophile can function as a leaving group. Reactions of Aldehydes and Ketones A Grignard reagent is a very strong nucleophile, but it does not function as a leaving group because the corresponding carbanion is far too unstable to depart. Reactions of Aldehydes and Ketones As a result, the equilibrium strongly favors product formation, so the reaction effectively proceeds in only one direction. With sufficient Grignard reagent present, the ketone is completely consumed and is not observed in the product mixture. Reactions of Aldehydes and Ketones In contrast, halides are good nucleophiles, but they are also good leaving groups. Therefore, when a halide acts as the nucleophile, an equilibrium is established, and the starting ketone is generally favored. Reactions of Aldehydes and Ketones Once equilibrium is reached, the mixture consists primarily of the ketone, with only small amounts of the addition product present. Reactions of Aldehydes and Ketones Common nucleophiles Reactions of Aldehydes and Ketones (Hydrate Formation) When an aldehyde or ketone is treated with water, the carbonyl group can be converted into a hydrate, also called a geminal diol. Reactions of Aldehydes and Ketones (Hydrate Formation) The position of equilibrium generally favors the carbonyl form rather than the hydrate, except for very simple aldehydes such as formaldehyde. Under neutral conditions, hydration is relatively slow, but the rate is readily increased in the presence of either acid or base. Reactions of Aldehydes and Ketones (Hydrate Formation) Reactions of Aldehydes and Ketones (Hydrate Formation) Reactions of Aldehydes and Ketones (Acetal Formation) Under acidic conditions, an aldehyde or ketone reacts with two molecules of alcohol to form an acetal. Reactions of Aldehydes and Ketones (Acetal Formation) Common non nucleophilic acids used for this purpose include para toluenesulfonic acid (TsOH) and sulfuric acid (H₂SO₄). Reactions of Aldehydes and Ketones (Acetal Formation) The acid catalyst plays an important role in this reaction. In the presence of acid, the carbonyl oxygen is protonated, which makes the carbonyl carbon even more electrophilic. Reactions of Aldehydes and Ketones (Acetal Formation) This activation is necessary because alcohols are weak nucleophiles. An alcohol reacts with a carbonyl group much more rapidly when the carbonyl oxygen is first protonated. Reactions of Aldehydes and Ketones (Acetal Formation) For many simple aldehydes, the equilibrium favors acetal formation. Accordingly, aldehydes are readily converted into acetals by treatment with two equivalents of an alcohol under acidic conditions. Reactions of Aldehydes and Ketones (Acetal Formation) For most ketones, the equilibrium favors reactants rather than products. In these cases, acetal formation can be driven by removing water (H₂O) as it forms using a specialized distillation technique. Reactions of Aldehydes and Ketones (Acetal Formation) By continuously removing water, the equilibrium is shifted toward acetal formation, and the reaction can be forced to completion. Reactions of Aldehydes and Ketones (Acetal Formation) Acetal formation requires two equivalents of an alcohol. That is, two molecules of ROH are needed for every molecule of ketone. Reactions of Aldehydes and Ketones (Acetal Formation) Alternatively, a diol can be used, in which case a cyclic acetal is formed. Reactions of Aldehydes and Ketones (Protecting Groups) Acetal formation is reversible, and the position of equilibrium can be controlled by carefully choosing the reagents and reaction conditions. Reactions of Aldehydes and Ketones (Protecting Groups) Acetal formation is favored by removal of water. To convert an acetal back into the corresponding aldehyde or ketone, it is treated with water in the presence of an acid catalyst. Reactions of Aldehydes and Ketones (Protecting Groups) In this way, acetals can be used to protect aldehydes and ketones. Reactions of Aldehydes and Ketones (Protecting Groups) Cyclic acetals are generally more favored at equilibrium than acyclic acetals. This is because the entropy decrease is smaller when two molecules combine to form one molecule than when three molecules combine to form one molecule. Reactions of Aldehydes and Ketones (Protecting Groups) Consider how the following transformation might be accomplished. Reactions of Aldehydes and Ketones (Protecting Groups) First, the ketone is converted into a cyclic acetal. Notice that the ester is unaffected. Reactions of Aldehydes and Ketones (Protecting Groups) Next, LAH is introduced, so only the ester is reduced to an alcohol. Finally, aqueous acid (H₃O⁺) hydrolyzes the cyclic acetal, regenerating the ketone. Reactions of Aldehydes and Ketones (Imine Formation) Under mildly acidic conditions, an aldehyde or ketone reacts with a primary amine to form an imine, also called a Schiff base. Reactions of Aldehydes and Ketones (Imine Formation) Imines are compounds that contain a carbon–nitrogen double bond (C=N) and are common in biological pathways. The pH of the solution is an important consideration during imine formation, and the reaction rate is greatest at about pH 4.5. Reactions of Aldehydes and Ketones (Imine Formation) If the pH is too high, meaning there is not enough acid present, the carbinolamine is not protonated in the dehydration step, so the reaction proceeds more slowly. Reactions of Aldehydes and Ketones (Imine Formation) If the pH is too low, meaning there is too much acid present, most of the amine is protonated to form ammonium ions, which are not nucleophilic. Preparation of Amines Ketones or aldehydes can be converted into imines when treated with ammonia in acidic conditions If the reaction is carried out in the presence of a reducing agent, such as H 2, then the imine is reduced as soon as it is formed, giving an amine. Preparation of Amines This process, called reductive amination, can be accomplished in one reaction flask by hydrogenating a solution containing the ketone, ammonia, and a proton source. Preparation of Amines With this approach, the imine is reduced under the conditions of its formation. Many other reducing agents are also frequently employed instead of hydrogenation. Preparation of Amines The most common reducing agent for this purpose is sodium cyanoborohydride (NaBH3CN). It similar in structure to sodium borohydride (NaBH4), but a cyano group has replaced one of the hydrogen atoms. Preparation of Amines Recall that a cyano group is electron withdrawing, and its presence stabilizes the negative charge on the boron atom. NaBH3CN is a more selective hydride-reducing agent than NaBH4. Preparation of Amines This selectivity can be exploited to achieve the reductive amination of a ketone or aldehyde. Preparation of Amines This process cannot be achieved with NaBH4, which would simply reduce the ketone before it is converted into an imine. NaBH3CN does not react with ketones but will reduce an iminium ion (a protonated imine). This process enables the conversion of a ketone or aldehyde into an amine in one reaction flask. Preparation of Amines The identity of the nucleophile (NH 3) can be changed, enabling the preparation of primary, secondary, or tertiary amines: Preparation of Amines Direct alkylation of a primary amine is not efficient because polyalkylation is generally unavoidable Therefore, it is more efficient to use reductive amination as an indirect method for alkylating the nitrogen atom of an amine. Preparation of Amines This method involves treating an alkyl halide with sodium azide followed by reduction. Reactions of Aldehydes and Ketones (Other Carbonyl Derivatives) Many compounds of the form RNH₂ react with aldehydes and ketones. In these reactions, R does not have to be an alkyl group, so a variety of amine containing nucleophiles can be used to form different nitrogen containing carbonyl derivatives. The mechanism for each of these reactions is directly analogous to the mechanism of imine formation. Reactions of Aldehydes and Ketones (Oxime Formation) When hydroxylamine (NH₂OH) is used as the nucleophile, an oxime is formed. Reactions of Aldehydes and Ketones (Hydrazone Formation) When hydrazine (NH₂NH₂) is used as the nucleophile, a hydrazone is formed. Reactions of Aldehydes and Ketones (Enamine Formation) Under acidic conditions, an aldehyde or ketone reacts with a secondary amine to form an enamine. Reactions of Aldehydes and Ketones (Wolff-Kishner Reduction) Ketones can be converted into hydrazones, which is useful because hydrazones can be readily reduced under strongly basic conditions. Reactions of Aldehydes and Ketones (Wolff-Kishner Reduction) Forming a carbanion in aqueous hydroxide is thermodynamically unfavorable, meaning it is significantly uphill in energy. As a result, only a very small fraction of molecules will initially lose N₂ to generate the carbanion. Reactions of Aldehydes and Ketones (Wolff-Kishner Reduction) However, the N₂ that is produced escapes from the reaction mixture as a gas, shifting the equilibrium to generate more N₂ and ultimately driving the reaction to completion. Reactions of Aldehydes and Ketones (Wolff-Kishner Reduction) This process is called the Wolff-Kishner reduction. Reactions of Aldehydes and Ketones (Hydrolysis of Carbonyl Derivatives) In acidic solution, acetals, imines, enamines, hydrazones, and oximes are hydrolyzed to regenerate the carbonyl compound, whereas this hydrolysis generally does not occur under basic conditions. Reactions of Aldehydes and Ketones (Hydrolysis of Carbonyl Derivatives) Reactions of Aldehydes and Ketones (Thioacetal Formation) Under acidic conditions, an aldehyde or ketone reacts with two equivalents of a thiol to form a thioacetal. Reactions of Aldehydes and Ketones (Thioacetal Formation) The mechanism of thioacetal formation is directly analogous to acetal formation, except sulfur atoms take the place of oxygen atoms. If a dithiol is used, a cyclic thioacetal is formed. Reactions of Aldehydes and Ketones (Reduction Via Desulfurization) When treated with Raney nickel, thioacetals undergo desulfurization to yield an alkane. Reactions of Aldehydes and Ketones (Reduction Via Desulfurization) Raney nickel is a porous nickel aluminum alloy whose surface bears adsorbed hydrogen atoms. These surface hydrogen atoms ultimately replace the sulfur atoms during desulfurization. Reactions of Aldehydes and Ketones (Reduction Via Desulfurization) The reactions below provide another two-step method for reducing a ketone. Reactions of Aldehydes and Ketones (Reduction) When treated with a hydride reducing agent such as lithium aluminum hydride (LAH) or sodium borohydride (NaBH₄), aldehydes and ketones are reduced to alcohols. Reactions of Aldehydes and Ketones (Grignard Reaction) When treated with a Grignard reagent, aldehydes and ketones are converted into alcohols with formation of a new carbon-carbon bond. Reactions of Aldehydes and Ketones (Cyanohydrin Formation) When treated with hydrogen cyanide (HCN), aldehydes and ketones are converted into cyanohydrins. Cyanohydrins are characterized by a cyano group and a hydroxyl group attached to the same carbon atom. Reactions of Aldehydes and Ketones (Cyanohydrin Formation) This reaction proceeds more rapidly under mildly basic conditions. In the presence of a catalytic amount of base, a small portion of hydrogen cyanide is deprotonated to form cyanide ions, which catalyze the reaction. Reactions of Aldehydes and Ketones (Cyanohydrin Formation) Instead of using a catalytic amount of base to generate cyanide ions, the reaction can be carried out directly in a mixture of HCN and cyanide ions supplied by KCN. Reactions of Aldehydes and Ketones (Cyanohydrin Formation) This process is reversible, so the product yield is governed by the equilibrium composition. For most aldehydes and unhindered ketones, the equilibrium favors formation of the cyanohydrin. Reactions of Aldehydes and Ketones (Cyanohydrin Formation) Hydrogen cyanide (HCN) is a liquid at room temperature and is extremely hazardous to handle because it is highly toxic and volatile, with a boiling point of about 26 °C. Reactions of Aldehydes and Ketones (Cyanohydrin Formation) To avoid handling HCN directly, cyanohydrins can also be prepared by treating an aldehyde or ketone with potassium cyanide and an alternative proton source such as HCl. Reactions of Aldehydes and Ketones (Cyanohydrin Formation) Cyanohydrins are useful synthetic intermediates because the cyano group can be transformed into a variety of functional groups, including amines and carboxylic acids. Reactions of Aldehydes and Ketones (Wittig Reaction) Georg Wittig (pronounced “Vittig”) was awarded the 1979 Nobel Prize in Chemistry for his work on phosphorus compounds and for developing a reaction of tremendous synthetic utility. Reactions of Aldehydes and Ketones (Wittig Reaction) An example of this transformation is shown below. It is called the Wittig reaction. Reactions of Aldehydes and Ketones (Wittig Reaction) This reaction converts a ketone into an alkene by forming a new carbon-carbon bond at the carbonyl carbon. The phosphorus containing reagent used for this transformation is called a phosphorus ylide, pronounced “ill lide.” Reactions of Aldehydes and Ketones (Wittig Reaction) An ylide is a neutral molecule that contains a negatively charged atom, in this case C⁻, directly attached to a positively charged heteroatom, in this case P⁺. Reactions of Aldehydes and Ketones (Wittig Reaction) A phosphorus ylide can be represented by a resonance structure that contains no formal charges. Reactions of Aldehydes and Ketones (Wittig Reaction) However, this resonance form contributes only a small amount to the overall resonance hybrid because the p orbitals on carbon and phosphorus differ greatly in size and do not overlap effectively. Reactions of Aldehydes and Ketones (Wittig Reaction) Despite this, a phosphorus ylide, also called a Wittig reagent, is commonly drawn using either resonance structure. Reactions of Aldehydes and Ketones (Wittig Reaction) Wittig reagents are readily prepared by reacting triphenylphosphine with an alkyl halide to form a phosphonium salt, followed by treatment with a strong base to generate the ylide. Reactions of Aldehydes and Ketones (Wittig Reaction) Wittig reagents are formed by an S N2 reaction to generate a phosphonium salt, followed by deprotonation with a very strong base such as butyl lithium to produce the ylide. Reactions of Aldehydes and Ketones (Wittig Reaction) The Wittig reaction is useful for preparing mono, di, and trisubstituted alkenes. Tetrasubstituted alkenes are more difficult to form because steric hindrance increases in the relevant transition states. Synthesis Propose an efficient synthesis for each of the following transformations: Synthesis Synthesis Synthesis Synthesis Synthesis Baeyer-Villiger Rearrangement When treated with a peroxy acid, ketones can be converted into esters by insertion of an oxygen atom in the Baeyer Villiger reaction. Baeyer-Villiger Rearrangement Similarly, treating a cyclic ketone with a peroxy acid produces a cyclic ester called a lactone. Baeyer-Villiger Rearrangement When an unsymmetrical ketone is treated with a peroxy acid, ester formation is regioselective because one substituent migrates preferentially during the Baeyer Villiger rearrangement. Baeyer-Villiger Rearrangement In general, migratory aptitude follows this trend: hydrogen migrates fastest, followed by tertiary alkyl groups, then secondary alkyl and phenyl groups, then primary alkyl groups, with methyl migrating slowest (H > 3° > 2°, Ph > 1° > methyl). Baeyer-Villiger Rearrangement Baeyer-Villiger Rearrangement In 1,2-migrations, the migrating group retains its stereochemistry. Peracids may epoxidize alkenes faster than ketones, so unsaturated ketones are not often good substrates for Baeyer-Villiger reactions. Pinacol Rearrangement When the 1,2-diol pinacol is treated with acid, it undergoes a rearrangement. Pinacol Rearrangement Pinacol Rearrangement If there is a hydride that can shift, that will occur in preference of an alkyl group. H > aryl > 3° alkyl > 2° alkyl > 1° alkyl > methyl Pinacol Rearrangement A particularly valuable type of pinacol rearrangement produces spirocyclic ring systems. Pinacol Rearrangement Treating epoxides with acid, including Lewis acids such as MgBr₂, promotes the same type of reaction. Pinacol Rearrangement Rearrangement of epoxides in the presence of magnesium salts means that opening epoxides with Grignard reagents can give surprising results. In contrast, the alkyllithium reaction is usually straightforward if the alkyllithium is free of lithium salts. Pinacol Rearrangement With a Grignard reagent, rearrangement occurs faster than addition to the epoxide, and then the Grignard reagent adds to the aldehyde. Semi-pinacol Rearrangement When an unsymmetrical diol or epoxide rearranges, it is important which pathway the reaction follows. Most unsymmetrical diols or epoxides give mixtures of products upon rearrangement. Semi-pinacol Rearrangement There is an issue if we want the pinacol rearrangement to occur as shown below. Semi-pinacol Rearrangement The tertiary hydroxyl group is much more likely to leave because it leaves behind a more stable carbocation. The primary hydroxyl group needs to be persuaded to leave as the ring expands. Semi-pinacol Rearrangement The solution to this problem is to force the primary hydroxyl group to be the leaving group by converting it into a tosylate. The primary hydroxyl group reacts more rapidly with TsCl than the tertiary hydroxyl group because it is less hindered. This is called a semi-pinacol rearrangement. Semi-pinacol Rearrangement Semi-pinacol Rearrangement Any good leaving group can promote a semi-pinacol rearrangement, including halides. Beckmann Rearrangement The Beckmann rearrangement inserts a nitrogen atom adjacent to the carbonyl group. Beckmann Rearrangement This rearrangement is not confined to cyclic oximes. Other methods of converting OH into a leaving group also work, such as PCl₅, SOCl₂, and other acyl or sulfonyl chlorides. Beckmann Rearrangement C=N double bonds can exhibit cis/trans isomerism just as C=C double bonds can. Beckmann Rearrangement When mixtures of oxime geometrical isomers are rearranged, mixtures of products result, and the product ratio exactly mirrors the isomer ratio in the starting material. Beckmann Rearrangement The group that migrates is the group trans to the OH in the starting material. Beckmann Rearrangement The tosylated oxime rearranges on Al₂O₃ (a Lewis acid) with complete stereospecificity, and the anti methyl group migrates. Beckmann Rearrangement With protic acids (such as TsOH), the oxime geometrical isomers equilibrate, so either group can migrate. Migration rates follow the same order as in the Baeyer-Villiger rearrangement. The propyl group, which better stabilizes positive charge than a methyl group, migrates faster.
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