Lecture Outline Interconversions of Acid Derivatives

Lecture outline Interconversions of acid derivatives Again, the overarching theme here is that it's easy to convert a less stable derivative to a more stable one ("downhill") least stable O R C Cl O R C O O C R O R C O R' O most stable R C N 1. Acid chlorides —> anhydrides, esters, amides O O R C Cl R C O O O R' R C N R'' R C O R' O C R mechanisms are the usual, e.g., O R C HN R'' Cl Cl O R' R C R' – Cl– – H+ prod NH R'' 2. Anhydrides —> esters, amides ... just like rxns with RCOCl 3. Esters —> amides HN O R C O O R'' R''' mech: R' R C R' N R'' R' HN – H+ R'' OR''' O R C R' O – R'''O NH R'' R C R' NH R'' Q: Zzzzzzz z.. Snrzzzzk… A: I know — but at least try to stay awake — and stop that snoring. Can amides be converted to esters like this (i.e. amide + ROH)? How about amides to acyl chlorides? Esters to acyl chlorides? Important: Suppose we need to convert an amide to an ester. How can we accomplish this? Reductions of acids and acid derivatives 1. acids — recall that these can be reduced with LiAlH4 (not NaBH4) R LiAlH4 CO2H H+ R CH2–OH R CH2–OH 2. acyl chlorides — a. with LiAlH4 (or NaBH4) O R C H+ LiAlH4 Cl H+ H3Al—H LiAlH4 Cl O R C H O – Cl R C H Can this reaction be "stopped" half-way, i.e. at the aldehyde? The aldehyde is less reactive than the acyl chloride, so in principle, yes, if we use a hydride source that is sufficiently picky… LiAlH4 and NaBH4 are too reactive and not selective enough, even if we're careful to use just one hydride equivalent. b. lithium tri-tert-butoxyaluminum hydride, (tBuO)3AlH– Li+ is selective enough to do this. Why? 3. esters — with LiAlH4 (not NaBH4) O LiAlH4 R C OR' H+ R + CH2–OH HO–R' H+ H3Al—H LiAlH4 O OR' O – R'O R C H R C H Can this reaction be "stopped" half-way, i.e. at the aldehyde? The aldehyde is more reactive than the ester, so "tuning" the reactivity of the hydride source won't solve the problem this time. (A reagent that does convert esters to aldehydes — by a completely different mechanism — is DIBALH, iBu2AlH, at low temp. This coordinates with the carbonyl O and then delivers a hydride, but no leaving group departs. Instead, the resulting compound gets hydrolyzed to a hemiacetal upon work-up, and this spontaneously produces aldehyde. We'll skip this reaction. Q: Then why did you make me read that blow-by-blow description of the mechanism?! A: Because we're skipping it. There was also some space on this page that needed to be filled. I didn't want to waste paper.) 4. amides — with LiAlH4 (not NaBH4) — this is an anomalous reduction. O R C N R'' LiAlH4 H+ R'' CH2 N R R' R' 5. nitriles — with LiAlH4 (not NaBH4) R C N LiAlH4 H+ R CH2–NH2 Additions of carbanionic nucleophiles 1. acyl chlorides a. with Grignards (or organolithium reagents) O R C R'—MgBr H OH + R Cl C R' R' H+ R'—MgBr Cl O R C O – Cl R' R C R'—MgBr R' The ketone intermediate is less reactive than the acyl chloride, so we would expect that this rxn could be stopped at the ketone if we used 1 equivalent of nucleophile. But alas, these organometallic reagents are just not selective enough. Alas…. But all hope is not lost… cuprates to the rescue… yea, cuprates! b. lithium diorganocuprates, R'2CuLi are just reactive enough to go after the acyl chloride, but they don't bother the ketone. 2. esters — also add two equivalents of Grignard (or organolithium) reagents O R C R''—MgBr OH H+ OR' R C R'' R'' Q: Hey, this looks familiar. A: Hmmm… why is that? This one can't be stopped part way. Why? Q: That's it? No #3? But there's space left. A: No, there's no #3. I'm tired of this chemistry and I want to move on to something more interesting. Q: Are you sure there's not a page missing? What a rip off. A: wait… maybe I did forget a few rxns… I'll find them in time for class…