Aldo Reactions in Metabolism

Alpha-carbon Chemistry Aldo Reactions in Metabolism: Aldol and retro-aldol reaction mechanisms are common throughout different biochemical processes (such as in krebs cycle, gluconeogenesis, and even in glycolysis Aldols refer to the fact that there is an aldehyde and alcohol group Typically, aldehydes and ketones undergo this process in 3 basic steps: 1. Electrophilic attack of a base at the alpha-carbon of ald/ketone to generate the enolate carbanion 2. Nucleophilic attack of the enolate at the electrophilic carbonyl carbon of a second molecule (ald/ketone) 3. Protonation of the product formed 4. If heat is applied then a dehydration step will yield an alpha,beta-unsaturated aldehyde/ketone (irreversible) If the 4th step occurs, this is known as a condensation reaction while if only 1-3 occurs it is known as an aldol addition reaction Aldolases are enzymes used for this particular reaction Aldol reactions are very reversible since the energy levels of the products and reactants are very different and can therefore go in both directions Keto-Enol Tautomerization: Enols are alcohols formed from an aldehyde/ketone If it is acid catalyzed then the acid gives a proton to the oxygen atom If it is base catalyzed then the base takes a proton from the carbon atom Since the enol is planar, you could add in another R group, which leads to racemization Enolate Formation from Aldehydes: For an equilibrium, the keto form is strongly favored, however for certain reactions, the enol form is extra stabilized, such as with the formation of an aromatic ring pKeq = pKa acid on left - pKa acid on right Keq = 10-pKeq (therefore if the Keq > 1 than the products are favored, and if Keq < 1 than the reactants are favored Also, remember that the higher the pKa the weaker the acid (therefore the lower pKa will be favored) Enolate Formation from Ketones: LDA is a strong base that is very bulky and therefore sterically hindered Therefore, the LDA will typically have a very high pKa since it is such as weak acid Ketones are typically less acidic than an aldehyde because of the extra electron donating group Remember, the more you spread out an anion, the more stable it is (increasing its pKa value) NaOEt is not enough to get a regular ketone, but for especially acidic ketones with resonance stabilized structures, it is more than enough Kinetic & Thermodynamic Enolates: For unsymmetrical ketones, it can depend on what base you use in order to form the enolate anion LDA (at a low temperature like -78°C) will typically want to approach from the least sterically hindered side (likely the one without an R group) and forms what is known as the kinetic enolate (the option that would form the fastest) For another base, such as Na+H-, it would attack the other side forming the thermodynamic enolate (which is the one that is more substituted) Aldol Condensation: Aldol addition is when there is the conversion of an aldehyde to an aldol Enals refer to beta-unsaturated form of an enol (forms the same way as before but now you need heat) and are formed through Aldol Condensation reactions and will form the trans because this is more stable Conjugated double bonds are favored Mixed (crossed) Aldol Reaction: Using different aldehydes, first look for the alpha carbons (if the other alpha carbon is a part of a double bond it won’t work such as with the benzaldehyde molecule in the example to the right) and under heat forms an enal The alpha carbon in between two carbonyls will be the most acid proton (easiest to deprotonate) Mixed (crossed) Aldol Condensation Using a Lithium Enolate: Lithium can come in and stabilize the negative charge on the oxygens throughout the mechanism in a cyclic process Acid can come in and protonate the OH group, forming OH2 which is an amazing leaving group forming a carbocation (base such as water comes in and deprotonates the alpha carbon forming a double bond and therefor an enal) Retro-aldol & Retrosynthesis: Can reverse the aldol reaction by using a base such as Na2CO3 Basically in order to do this, you need to hydrate the double bond (Add H2O) Always just add an oxygen atom to the beta carbon Three membered rings are not really ever major products since there is so much strain