Lecture 3: Aldehydes and ketones I want to start by talking about the mechanism of hydroboration/ oxidation, which is a way to get alcohols from alkenes. This gives the anti-markovnikov product, primarily as a result of sterics. The BH2 group goes to the less hindered side. The reaction proceeds by a concerted mechanism, which means that all the electrons move at the same time. The intermediate product is the borane that is then replaced with an OH group in the second step. Stereochemical consequence: Because the reaction is concerted, all stereochemical information is retained BH2 and H add to the same side of the double bond. Next topic: Carbonyl chemistry, in particular aldehydes and ketones. We are going to talk first about how to make these molecules. Aldehydes these are very sensitive and reactive. We are going to talk about three ways to make them: Oxidation, reduction, and ozonolysis. With oxidation and reduction, you need to carefully control the conditions so that it does not over-react. 1. Oxidation example: Swern oxidation 2. Reduction example: Diisobutyl aluminum hydride (DIBAL) DIBAL structure:
3. Or from alkenes via ozonolysis: Ketones are much less sensitive. Sample preparation methods: 1. Ozonolysis 2. Friedel Crafts acylation 3. Oxidation of secondary alcohols using Jones reagent (chromic acid) Reactivity of these compounds is based on the polarity of the C=O double bond because carbon is electrophilic, it is susceptible to attack by nucleophiles. Sample nucleophiles: OH -, which would give a carboxylic acid, amines such as primary amines (RNH 2 ) and secondary amines (R 2 NH) which gives amide products. More interesting for us is carbon nucleophiles because they can form new carbon-carbon bonds. Examples of carbon nucleophiles: Organometallics CH 3 Li (methyl lithium), CH 3 MgX (methyl Grignard), CH 3 CuLi (methyl cuprate), etc.
We can also generate nucleophiles from carbonyl compounds themselves the alpha carbon (carbon next to the carbonyl) is susceptible to deprotonation because of the electrophilic nature of the carbonyl itself when we deprotonate we generate enolates or enols Mechanism for deprotonation: Resonance form of the anion: It is most stable to put the negative charge on the oxygen, but since the enolate is always going to react from the alpha carbon (as if that has a negative charge), then you can just draw the anion there. Another interesting carbonyl-related nucleophile is called malonic acid (or malonate ester). This compound is even more susceptible to deprotonation at the alpha carbon because it has two adjacent carbonyl groups. Deprotonated malonate: Any of these carbonyl-related nucleophiles can react with another carbonyl group that is electrophilic. One example: Aldol reaction between the enolate of one carbonyl and the electrophilic carbon of the second carbonyl.
The aldol reaction can be catalyzed either by acid or base. Your initial product is an alcohol, but under the reaction conditions it will almost always dehydrate to give you the alkene. In the particular example shown below, there are three possible alkene products that can be formed: Compounds B and C are identical chemically. Product A is highly favored. Why? 1. Loss of a second alpha hydrogen is more favorable than loss of the hydrogen from either of the terminal methyl groups. 2. The resulting double bond is more highly substituted and therefore more stable. 3. The resulting double bond is also in conjugation with the carbonyl and therefore gets stability that way. Carbon nucleophiles can also react in a Michael reaction involving carbonyl compounds. Background for the Michael reaction: Let s say I have a generic nucleophile that wants to react with this alpha, beta unsaturated carbonyl compound. It has two possibilities. It can either react directly with the carbon of the carbonyl, which is called 1,2-addition (path a), or since the double bond is also in conjugation with the carbonyl, it can react here as well, which is termed 1,4-addition (path b), or conjugate addition.
We are going to talk next time about which sorts of nucleophiles favor 1,2 vs. 1,4 addition. A Michael reaction is really just a specific type of conjugate addition that involves a carbonyl enolate adding to an alpha-beta unsaturated carbonyl: But any electron withdrawing group in conjugation with a double bond can behave similarly. We are going to continue the discussion of Michael reactions next time as well. No class on Thursday because of the Jewish holiday.