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Relative Reactivity of Aldehydes and Ketones: Generally speaking, aldehydes and ketones have a similar level of reactivity although aldehydes are slightly more reactive. Why? a. Sterics: O R O H aldehyde R R ketone Two alkyl groups versus only one alkyl group: Less sterics = less crowded transition state = lower activation barrier for aldehydes = FASTER reaction! b. Electronics: O R O H aldehyde R R ketone Aldehydes are stronger electrophiles. They have a larger partial positive charge. Why? Alkyl groups are electron-donating (see Ch. 7 in 8th edition about electron-donating effects of alkyl groups with alkenes). Ketones will be inductively stabilized by the presence of two electron-donating alkyl groups, resulting in a smaller δ+ charge on the carbonyl carbon. Aldehydes, with only one alkyl group, will be less stabilized and therefore have a larger δ+ charge. The larger the partial charge = the more reactive Electrophile. Preparation reactions for Aldehydes: • Oxidation of 1º alcohols using PCC or Dess-Martin periodinane • Ozonolysis of an alkene with hydrogen atoms on the double bond Preparation reactions for Ketones: • Oxidation of 2º alcohols using any of the five oxidizing agents we reviewed earlier. • Ozonolysis of an alkene with carbon groups attached. Reactions of Aldehydes and Ketones: 1. Reductions of aldehydes and ketones- OLD • Reagents: NaBH4 or LiAlH4 The hydride, H-, is a strong nucleophile and this reaction process is “irreversible”. Strong nucleophiles are typically poor leaving groups (cannot stabilize an anion), thus once the nucleophile has completed its bond formation, it cannot REVERSE and break that bond to come back off of the molecule. “Reversible “would mean that the following could occur: O O H + H:- And the products of this reverse reaction are much less stable (due to the high energy of the hydride) so this won’t happen! Ex: O NaBH4 H 2. Addition of Carbon Nucleophiles – • Reagent: Grignard Reagents – RMgX The Grignard is another strong nucleophile that is also not a good leaving group. Once it attaches to the carbonyl carbon, it cannot reverse and dissociate form the molecule (another “irreversible reaction” due to instability of Grignard reagent). Ex: O MgBr 3. Formation of Cyanohydrins – Addition of “HCN” HO CN Hydrogen cyanide, HCN, is a toxic gas… Would YOU want to use it? No… So – instead use: O 1. NaCN HO CN 2. H2SO4, H2O The cyanide anion, -CN, is another strong nucleophile that cannot easily stabilize an anion and is another relatively bad leaving group (a third “irreversible” reaction). Ex. O 1. NaCN H 2. H2SO4, H2O In Chapters 20/21, we will see how nitriles can be hydrolyzed to carboxylic acids or reduced to form amines (amino acid predecessor) as well as converted into aldehydes and ketones. 4. Hydration: Addition of H, OH • • Formations of hydrates can occur under either acidic or basic conditions This reaction is a reversible reaction due to the nucleophile (either H2O or –OH) having an electronegative oxygen atom that can act as a “Leaving Group”. The equilibrium reaction favors the starting material, with the carbonyl form. Based on this knowledge, which is more stable – the carbonyl or hydrate? The starting material (carbonyl form) must be more stable than the product. Why is that? O HO OH hydrate Simple sterics: Consider the hybridization of the carbon atoms involved. Sp2 versus sp3 – less steric interactions result in equilibrium moving backwards to carbonyl form AND with no driving force to make this reaction go forward, the reaction reverses 99.9% of the time. There are a couple of exceptions though. Consider formaldehyde, for instance: O H H2O, H+ H HO OH H H Formaldehyde has a carbonyl carbon that is so electron-poor that it is “starving” for electron density and forms a hydrate easily, welcoming in a second oxygen atom with electron density. But this is an exception, as is the hydration of trichloroacetaldehyde: O Cl3C H H3O+ HO Cl3C OH H Again, this particular aldehyde has an extremely large partial positive charge and the addition of the electron density from another oxygen atom stabilizes the molecule. Hydrates form in both acidic and basic aqueous solutions but they won’t be isolated in either situation since the carbonyl forms are more stable (reaction always reverses). • Basic conditions use hydroxide, -OH, as a strong nucleophile, similar to how a Grignard reagent attacks. O NaOH, H2O HO OH Mechanism: Base-catalyzed hydration Forwards: Simple Nucleophilic attack… O O OH H OH O H HO OH Reverse: HO • O H HO OH O O Acidic conditions use neutral water, H2O, as the nucleophile… Neutral carbonyl and neutral water aren’t so very attracted to each other… The oxygen atom in water is electronegative and less willing to share its electron density to form a bond to the carbonyl. We must tweak the system to make them more appealing to each other… add an acid catalyst to make the carbonyl a stronger electrophile (more electron poor, therefore more attractive to the neutral water molecule). O H+, H2O HO OH While this reaction does not typically form an actual hydrate product that is isolated, it doesn’t mean that the hydrate doesn’t form (see next reaction). It's also a good reaction to use to demonstrate the mechanistic process of acid-catalyzed nucleophilic additions. Acid-catalyzed hydration - Forward Direction: O H2O H HO OH O H O H O H H O H H O H O H O H HO H OH The purpose of the acid catalyst is to create a stronger electrophile – a full positive charge instead of a partial positive charge. Why is it necessary? The nucleophile is a weak nucleophile and unreactive with a ketone or aldehyde on its own. Acid-catalyzed hydration - Reverse Direction: HO OH O H2O H HO OH H H H O O O H H O H H O H O Mechanism? (Problem 19.8 in 8th Edition) O* = 18O isotope O H+, H2O* HO O*H H+, H2O O* 5. Oxidations of Aldehydes to Carboxylic Acids O O H OH Recall: Primary alcohols oxidize via aldehydes to carboxylic acids when using KMnO4 or Na2Cr2O7 or CrO3. All of these reactions occur under aqueous acid conditions. OH R H H O R O H R OH Under these aqueous conditions, aldehydes and ketones form hydrates. If an aldehyde converts to a hydrate while the appropriate oxidizing agent is also present, the hydrate of the aldehyde can then be further oxidized to the carboxylic acid. O HO OH H H O OH Old Reagents: • KMnO4, H2O or H3O+ • Na2Cr2O7, H3O+ • CrO3, H2SO4, H2O New Reagent: • Tollen’s Reagent: Ag2O or AgNO3, NH4OH, H2O o Mild oxidant o Selective for aldehydes ONLY Tollen’s Reaction is a Qualitative test for aldehyde Positive for aldehyde – formation of silver metal