Reactions of aldehydes and ketones with nucleophiles or bases all fall into one of two fundamental types of reactions. In the first class of reactions, a nucleophile is added to the carbonyl carbon (Equation 1). In the second class of reactions, the first step in the reaction is removal of the proton from the carbon adjacent to the carbonyl group to form an enolate anion (Equation 2). Both classes of transformations depend on the already discussed electron deficient nature of the carbonyl carbon.
More info: nucleophiles
Let's turn our attention first to nucleophilic additions to the carbonyl carbon. An electon pair from the nucleophile forms a new bond to the carbonyl carbon, and this forces two electrons from the carbon-oxygen double bond to move onto oxygen. The carbonyl carbon rehybridizes from sp2 to sp3, and the intermediate that is formed has a tetrahedral geometry. Once this tetrahedral intermediate has been generated, protonation by water or acid can occur to form an alcohol product. This is the most common way of completing the reaction. With nucleophiles such as amines, though, the oxygen component can be completely expelled via loss of an equivalent of water to form a double bond between carbon and the nucleophile (an imine if the nucleophile was an amine).
One specific example of nucleophilic addition to a ketone is shown in the formation of cyanohydrin. HCN can be added to aldehydes and ketones as shown in eq ?. When pure HCN is added, the reaction is slow. Adding a trace amount of base speeds up the reaction since cyanide ion is formed by the base. The rate increase comes about because HCN is a weak acid (pKa=9.3) which is not nucleophilic, but the cyanide anion is strongly nucleophilic. The cyanide ion reacts as a typical nucleophile with the electrophilic carbonyl carbon to form a tetrahedral intermediate. Protonation of the tetrahedral intermediate leads to formation of the cyanohydrin. HCN is usually generated during the reaction by adding acid to sodium or potassium cyanide, as this reduces the risks involved in using a toxic gas.
More Info: Cyanohydrins are important because they can easily be converted to other important compounds. Nitriles (RCN) can be reduced using LiAlH4 to form primary amines (RCH2NH2), or they can be hydrolyzed with aqueous acids to form carboxylic acids. How to make amino acids
Imine formation also in the strecker synthsis.
More info oxidation states
Perhaps the most common example of nucleophilic addition to carbonyl compounds is hydration. When aldehydes and ketones react with water, 1,1-diols or geminal (gem) diols are formed. Since this reaction is reversible, gem diols can eliminate water to regenerate ketones or aldehydes. The position of the equilibrium between the carbonyl compound and the gem diol depends on the type of carbonyl compound that is reacting. For a few simple aldehydes, the gem diol is favored. Usually, however, the carbonyl form is favored.
Both acid and base catalysis increase the rate of the hydration reaction. In the base-catalyzed reaction shown in Figure ?, the hydroxide ion rather than water itself serves as the nucleophile. The alkoxide ion tetrahedral intermediate abstracts a proton from water to generate the neutral gem diol product and to regenerate the hydroxide ion catalyst. In the acid-catalyzed reaction shown in Figure ?, protonation of the carbonyl oxygen increases the reactivity of the carbonyl starting material. Under acidic conditions where the carbonyl carbon is a strong electrophile, neutral water is a fine nucleophile. The final step in this reaction involves loss of a proton to give the neutral gem diol product and to regenerate the acid catalyst. (Note that in the base-catalyzed reaction, the nucleophilicity of the adding group is increased while in the acid-catalyzed reaction, the electrophilicity of the acceptor is increased.
In acid and base-catalyzed hydrations (indeed in all catalyzed reactions), the catalyst does not change the position of the equilibrium. Rather, the catalyst changes the rate at which the reaction reaches equilibrium. It was noted earlier that the hydrated form is favored mainly for simple aldehydes. Table 1 (p73 SHG) shows equilibrium constants for the hydration of some aldehydes and ketones. Noteworthy observations include stabilization of the carbonyl compound by -electron donation (entry 3) and promotion of hydrate formation by electron-withdrawing substituents adjacent to the carbonyl. Essentially, anything that stabilizes the partial cationic character of the carbonyl carbon (such as an aromatic group that can pump electron density toward the carbonyl carbon) will favor the carbonyl compound. Anything that destabilizes the partial cationic charge of the carbonyl carbon (such as a group that pulls electrons away from the carbonyl carbon) will favor the hydrated form. When running a reaction, adding aqueous acid or a large excess of water will shift the equilibrium toward the diol; eliminating all water will shift the equilibrium toward the carbonyl compound.
When alcohol rather than water is added to an aldehyde or ketone, an acetal is formed (eq). Like hydration, acetal formation is acid-catalyzed. Addition of one equivalent of alcohol generates a hydroxy ether called a hemiacetal that resembles the gem diol discussed above. Then protonation of the hydroxyl group in the hemiacetal followed by loss of water generates a cation (R3O+). A second equivalent of alcohol can add to this cation to form the acetal. As for hydration, the additon of alcohol to a carbonyl compound is reversible, and the conditions under which the reaction is run will determine whether the carbonyl compound or the acetal compound is favored.
When a chemist does transformations on complicated molecules, care must be taken to keep one functional group from interfering with the reaction at another functional group. One common strategy for doing reactions selectively on large molecules is to temporarily hide or protect other reactive parts of the molecule. Acetals are often used to protect aldehydes and ketones. Acetals are converted to carbonyl compounds in acid but do not react with base or with reducing agents. One of the most common alcohols used to make acetals for protection of ketones is ethylene glycol. With ethylene glycol, a cyclic acetal is formed since both alcohols are on the same molecule. (eq)
Hemiacetals are rarely isolable. They are such reactive compounds that if only one equivalent of alcohol is present, then the reaction will make half as much acetal and half the starting material will be recovered unreacted. Stable hemiacetals are formed, however, when the reaction is intramolecular. Intramolecular reactions such as the one in figure ? are important because of their role in carbohydrate chemistry which is beyond the scope of this unit.
Problems other nucleophiles/practice adding to carbonyl carbons
All the reactions discussed up to this point have dealt with reversible addition of nucleophiles. A nucleophilic addition to a carbonyl compound is reversible when the nucleophile is also a good leaving group. Water and alcohol can serve as leaving groups (although hydroxide ion is not a good leaving group). If the nucleophile is also a leaving group, then the reaction is reversible and the conditions under which the reaction is run will determine which product is favored.
Sometimes a nucleophile cannot be removed after it has been added. This happens with nucleophiles that cannot serve as leaving groups. Examples of these nucleophiles include hydrides ("H-), and carbanions ("R-"). Although the overall effect in these reactions is additon of hydride or carbanion, the material actually added to the reaction is a reducing reagent such as sodium borohydrate (NaBH4) or an organometallic reagent such as a grignard reagent (RMgBr). In these compounds, the negative charge is stabilized. Since "H-" or "R-" cannot stabilize the negative charge without help, they cannot serve as leaving groups. Once they have added to the carbonyl carbon, they cannot be expelled. The addition is irreversible.
More info What's a good leaving group.
More info. Transesterifications
Nucleophilic addition of hydride reduces aldehydes and ketones to alcohols. The hydride donor is usually sodium borohydrate (NaBH4) or lithium aluminum hydride (LAlH4). NaBH4 is a milder, more selective reagent than LiAlH4 which will also reduce esters. The two reagents sometimes give different products (p76 SHG). Also, different solvents are used; alcoholic solvents such as methanol and ethanol are used with NaBH4 but ethers are used with LiAlH4 (LiAlH4 reacts violently with alcohols--fire!). The mechanism for hydride addition is shown in Figure X.
The second example of irreversible addition to a carbonyl carbon is the grignard reaction. This is a very important reaction because it results in formation of a carbon-carbon bond. Carbon-carbon bond formation is necessary for buildup of molecules, but it is much more challenging than other transformations. Addition of magnesium to an organic halide causes formation of the grignard reagent (eq). The halide can be chlorine, bromine, or iodine, although chlorides react more sluggishly than iodides or bromides. The carbon-magnesium bond is highly polarized, and this makes the carbon atom nucleophilic. Other carbanion sources such as organolithium reagents react similarly.
More info Wittig, thiols, thioacetals, wolf-kishner, organocopper, organolithium, etc.
Several reactions have been discussed, but they all fall under the overall strategy of nucleophilic addition to a carbonyl carbon. The nature of the nucleophile determines whether the addition is reversible or irreversible. The reversible reactions are usually acid or base catalyzed, and control of the conditions under which the reactions are run determines whether starting material or product predominates. Now, let's turn our attention to the second main type of reaction; the reaction whose first step involves loss of a proton from the carbon adjacent to (alpha to) the carbonyl to form an enolate anion.
Recall that the alpha-hydrogens of carbonyl compounds are quite acidic (pKa=20). This is because the adjacent carbonyl polarizes the electron pair of the C-H bond so that the proton can be removed by base and also because, once the proton has been removed, the resulting enolate anion is stabilized by resonance (eq).
After the enolate ion has been formed, it is a reactive, negatively charged compound and, thus, can behave as a nucleophile or a base. If it behaves as a base, it can pick up a proton either at carbon or at oxygen. Protonation at carbon would regenerate the starting carbonyl compound, but protonation at oxygen would generate a product called an enol. Interconversion between the keto or carbonyl form and the enol or hydroxyalkene form is called tautomerism. Because the carbon-oxygen double bond is stronger than the carbon-carbon double bond, the keto form is usually the predominate form (by more than 99%) at equilibrium. In a few special cases, however, then enol form is stabilized and the equilibrium shifts to favor the enol. (eq phenols)
Look again at the enol form. Notice that, although a carbon adjacent to a ketone can be chiral, the asymmetric center is lost in the enol form when the carbon-carbon double bond is formed. Because the enol form has sp2 hybridized carbons, reprotonation is equally likely to occur from either the top or bottom face of the enol. This means that chirality will be lost--racemization will occur--if the alpha-hydrogen is removed. (Note that racemization can only occur for an asymmetric carbon with at least one hydrogen.)
If the enolate anion behaves as a nucleophile instead of behaving as a base and being protonated, then the enolate anion can add to the carbonyl carbon of another molecule. This joins the two carbonyl compounds together into one large molecule called an aldol (part aldehyde and part alcohol). The aldol reaction is a very powerful tool in organic synthesis, and products containing a hydroxyl group two carbons away from (beta to) the carbonyl are usually formed using the aldol reaction.
Let's look at this reaction more carefully. The reaction can be either acid or base-catalyzed, although basic catalysis is more common. In a base-catalyzed reaction, the first step is generation of an enolate anion. Once this enolate anion has been formed, it has a negative charge and is nucleophilic. Just as other nucleophiles were shown to attack the carbonyl carbon of a ketone or aldehyde, the enolate anion can attack a carbonyl carbon. Then one pair of electrons from the carbon-oxygen double bond is pushed onto oxygen. Protonation of this oxygen forms the aldol product.
If only one type of carbonyl compound is present, then half of the material will be used to generate the enolate anion and the other half will be used as the carbonyl carbon that is attacked by the nucleophile (the enolate anion). Mixed aldol reactions are also possible, but they are more complicated. Mixed aldols work best when only one carbonyl compound can be enolized. If more than one carbonyl compound has alpha hydrogens, then several enolates can be formed and converted to several aldol products. (Figure )
Compounds containing a beta-hydroxy carbonyl functionality are easily dehydrated. Loss of water forms a carbon-carbon double bond that is conjugated with (adjacent to) the carbonyl group. Alternating double bonds (conjugated systems) are very stable, and for this reason the product that is isolated from an aldol reaction is often the alpha-beta unsaturated carbonyl compound (called the enone) rather than the beta-hydroxy carbonyl compound. If the beta-hydroxy carbonyl (aldol) product is isolated, it can be dehydrated simply by warming it gently in dilute mineral acid.
More info selenoxide chemistry
More info Claisen condensations and active methylene compounds
More info michael additions
More info kinetic vs thermodynamic control in enolate generation
Although other reactions on carbonyl compounds such as oxidations can also be done, the key reactions have been discussed above. The structure of the carbonyl unit lends itself readily to nucleophilic attack on the carbonyl carbon and also to deprotonation alpha to the carbonyl. These reaction behaviors are important because they allow for formation of carbon-carbon bonds. When building up large molecules, knowledge of carbon-carbon bond formation is critical.
TODO
Inhibitors stuff
Do also the more infos and the figures and equations.
Ask Clark about copywrite stuff.
Link to problems/exercizes in mcmurry and brown.