Chapter 14 Aldehydes and Ketones: Addition Reactions at Electrophilic Carbons Overview of Chapter Structures of aldehydes and ketones

Transcription

1 hem 215 F12 otes Dr. Masato Koreeda - Page 1 of 11. Date: September 19, 2012 hapter 14 Aldehydes and Ketones: Addition eactions at Electrophilic arbons verview of hapter Structures of aldehydes and ketones electrophilic ', ' = alkyl, aryl: ketones = alkyl, aryl; ' = : aldehydes lone pair: more basic than = π Aldehyde = carbons are less sterically hindered and more electrophilic compared with the corresponding ketone carbons (i.e., with the same ) 2. eactions of aldehydes and ketones with an electrophile and a nucleophile σ framework all of these sigma-bonds and lone pairs on the same plane ' π-bonding lone pairs with this trajectory El Two lone pairs: ighest occupied molecular orbitals (Ms) of the = group u: trajectory of a nucleophile approach ' trajectory angle of 107 Lowest unoccupied molecular orbital (LUM) empty anti-bonding orbitals ' El all atoms including El on the same plane ' u ' u sp 3 between sp 2 and sp 3 ; on its way to sp 3 3. Activation of =Z (Z = and ) with -A or a Lewis acid activates = toward a nucleophilic addition A A A Lewis acid (L.A.) becomes even more ; i.e., more electrophilic L.A. L.A. M (if M is used) or

2 hem 215 F12 otes Dr. Masato Koreeda - Page 2 of 11. Date: September 19, 2012 hapter 14: verview (continued) 4. Four categories of nucleophilic addition reactions Two classes of nucleophiles: reversible and irreversible eversible u: Irreversible u: E1 S 1 Type 3 divalent u: e.g.,, S Type 4 Trivalent u: e.g., - 2 Type 1 M Type 2 M 3 or 2 e.g., M 3 Li, or MgX 2 (Grignard reagent) ============================================================== I. ucleophilic Addition eactions of =Z (Z: electronegative atom)

3 hem 215 F12 otes Dr. Masato Koreeda - Page 3 of 11. Date: September 19, 2012 I-1 (1) ydride reducing agents (cont d) eduction with LiAl 4 : LiAl 4 anhyd. aprotic solvent (e.g., TF) Li Al 4 Al Li Al Li Al Li 3 Li Al() 3 All of these three s could be used in the reduction of a ketone. hydrolysis* note: -Al bond stronger than -Li *This acid-hydrolysis step may be quite complex, depending upon the stoichiometry between a ketone and LiAl 4. owever, all of those hydrolysis step should involve eduction with a 4 : a 4 usually in a protic solvent (e.g., ethanol) a a 4 X Al X X X: or a not very favorable; a not much Lewis acidic a 3 reacts with the solvent 3 x - to form () 3 and 3 x 2 eduction with DIAL (Al in DIAL quite Lewis acidic): DIAL anhyd. aprotic solvent (e.g., TF) Al 3 Al() 3 2 ( 3 ) 3 hydrolysis Al Al 2 Al Al

4 hem 215 F12 otes Dr. Masato Koreeda - Page 4 of 11. Date: September 19, 2012 I-1. Irreversible nucleophiles (cont d) (b) nucleophiles: Type 2 M anhydrous aprotic solvent ould be sp 3, sp 2, sp carbanions Grignard reagents (-MgX) alkyllithium (-Li) or sodium (-a) alkenyl lithium (=Li) alkynyl lithium/sodium or lithium/sodium acetylide ( -Li; -a) Grignard reagents: -MgX (X is usually r or I, sometimes X=l) Prepration of Grignard reagents: (i) Alkyl Grignard reagents from -X 3 r Mg* anhydrous TF or ether 3 Mg r polarization reversal M Formally equivalent to: 2 3 Mg r 3 hydrolysis electronegativity values: (2.5); (2.1); Li (1.0); a (0.9); Mg (1.2); Al (1.5); r (2.8) M() * X Mg Mg-X -Mg-X oxidation #: 0 oxiudation #: 2 (ii) Alkynyl Grignard reagents: 3 pka ~ Mgr 3 Mgr 3 pka ~50 note: 3 a, liq 3 or a 2, liq 3 3 Mgr 3 a (iii) Alkenyl and aryl grignard reagents from their halide precursors note: r Mg usually in anhydrous TF 2 Li Mgr r Mg anhydrous TF or ether Mgr Li Li-r alkenyllithium yanide carbanion - often reversible nucleophile a 2 a 3

5 hem 215 F12 otes Dr. Masato Koreeda - Page 5 of 11. Date: September 19, 2012 hapter 14 I-1. Irreversible nucleophiles (b) M (Type 2; organometallic reagents) (cont'd) ote: eactions with epoxides PhMgr Mgr work-up with aq 4 l* S 2! Ph Ph Ph * 4 l: weakly acdic; pka ~9.7; commonly used for the work-up of organometallic reactions; the only exception is the work-up of a carboxylate product (you need to acdity the solution to p~1-2). I-2. eversible nucleophiles Ph Mgr Ph ot with aq 4 l! Mgr 3 Ph p 1-2 pka 4.2 Mg() 2 r Type 3: Divalent nucleophiles ( & S); requires an acid catalyst Type 4: Trivalent nucleophiles (- 2 & '); w/o activation by an acid (a) (alcohols) oxygen atom ketone, hemiketal, ketal 2 oxygen atom aldehyde, meaning "mercury capturers" (b) S (thiols or mercaptans) hemiacetal, Tend to be unsatble intermediates! acetal 2 oxygen atom ketone S, S hemithioketal S, S S thioketal 2 oxygen atom aldehyde S, S hemithioacetal S, S S thioacetal 2

6 hem 215 F12 otes Dr. Masato Koreeda - Page 6 of 11. Date: September 19, 2012 hapter 14: I-2. eversible nucleophiles (cont d) (c) Mechanism (similar for both and S nucleophile additions) 3 3 3, p-ts * 2 F 3 ( 2 3 ) 2 ** S S S S 2 3 Ts ot a base! S *p-ts (or Ts) para-toluenesufonic acid; strong, organic solvent-soluble acid. **boron trifluoride diethey etherate; gives better yields of thioketals & F thioacetals than p-ts F F pka ~ Since and S are not nucleophilic enough to add to a =, the = has to be activated by the use of or a Lewis acid. Incidentally, their conjugate bases, - /S - can add (quite easily as being highly nucleophilic) to the =, but the adducts are less stable than the original =, thus reverse back to the = and - /S -. Mechanism using - for the acid catalyst, p-ts: S 1! resonancestabilized oxoniom ion lone pair-assisted ionization!! dimethyl ketal

7 hem 215 F12 otes Dr. Masato Koreeda - Page 7 of 11. Date: September 19, 2012 hapter 14: I-2. eversible nucleophiles: Mechanism (cont d) omments: 1. The ketalization and acetalization reactions from ketone and aldehyde, respectively, under acidcatalyzed conditions are reversible. igh yields of ketals and acetals can be achieved by the use of excess alcohols and/or continuous removal of the resulting water (using, e.g., a Dean-Stark apparatus). 2. onversely, if a ketone or aldehyde is desired from its corresponding ketal or acetal, a large excess of water needs to be added to the solution of ketal of acetal in the presence of an acid catalyst. 3. Throughout the mechanism for the acid-catalized ketalization and acetalization, D T involve negatively-charged intermediates. The only negatively charged species allowed is the conjugate base (:-) of a strong acid catalyst. Lastly, Does not involve an S 2 step! x 3 3 epresentative reactions: (1) cyclic acetal formation (2) cyclic thioacetal formation (excess) p-ts Δ S S (excess) F 3 ( 2 3 ) 2 Δ 2 S S 2 (3) cyclic ketal formation from diols: acetonide formation milder reaction conditions Mechanism? acetone (excess) p-ts Δ p-ts 3 2 p-ts called (5-membered) acetonide (i.e., acetone adduct) 3 3 (excess) (excess) 3 3 3

8 hem 215 F12 otes Dr. Masato Koreeda - Page 8 of 11. Date: September 19, 2012 hapter 14: I-2 reversible nucleophiles-/s epresentative reactions (cont d) (4) Transketalization reaction: Spiroketal formation 3 3 DIAL ( 2 mol equiv) mild workup with aq 4 l 3 3 p-ts Δ spiro system 2 3 y boiling off methanol, this spiroketal can be obtained in high yield. Mechanism for the spiroketalization step: (5) ydrolysis of ketals and acetals - Acid-catalyzed ketal-acetal formation reactions from, respectively, ketones and aldehydes are reversible. Therefore, treatment of ketals or acetals with an acid and excess water should produce their corresponding carbonyl compounds. This process is called hydrolysis. Mechanism of the reaction is exactly the same as the formation of ketals and acetals except going to the opposite direction. p-ts 2 (excess) extremely acid unstable This reaction does not need to be heated! Mechanism for the hydrolysis shown on the next page.

9 hem 215 F12 otes Dr. Masato Koreeda - Page 9 of 11. Date: September 19, 2012 hapter 14: I-2 reversible nucleophiles-/s epresentative reactions (cont d) (5) ydrolysis of ketals and acetals: Mechanism: lone pair-assisted ionization! lone pair-assisted ionization! ============================================ The take-home message: Lone pair-assisted ionization! ' ' S 1! " ' ot an S 2!! ''

10 hem 215 F12 otes Dr. Masato Koreeda - Page 10 of 11. Date: September 19, 2012 hapter 14 I-2. eversible nucleophiles (cont d) Type 4 nucleophiles: Trivalent nucleophiles Amines are sufficiently nucleophilic enough to add to ketone and aldehyde = carbons without activation of the = oxygen atom by an acid. owever, the last dehydration step from the aminol intermediates requires an activation of the hydroxyl oxygen atom (by ). (1) Imine formation [from a ketone/aldehyde and a 1 -amine] 2 3 Δ or 3 2 aldehyde 1 -amine imine Mechanism: These two steps may be reversed in order. 3 aminol imine Those =-Z formation reactions from =s have the optimum rate at around p = 4.7. If the conditions are too acidic, the formation of such derivatives becomes slow, presumably due to the exclusive protonation of an amine, thus depriving the nucleophilicity of an amine. Although the protonation is required for the dehydration from the aminol intermediate, the formation of these =-Z compounds can be achieved even without adding an acid catalyst, especially when the reaction involves an aldehyde (often heating is required to complete the reaction, though). Amazingly, the formation of hydrazones ( = 2 ) can be achieved under basic conditions with strong heating.

11 hem 215 F12 otes Dr. Masato Koreeda - Page 11 of 11. Date: September 19, 2012 hapter 14 I-2. eversible nucleophiles: Type 4 nucleophiles (trivalent nucleophiles) (cont d) (2) xime formation 2 hydroxylamine or Δ, (3) ydrazone formation Δ oxime 2 Δ 2 2 hydrazine or Δ, 2 hydrazone 2 Application: Wolff-Kishner reduction eduction of = to 2 ketone 2 2 K, Δ methylene 2 (gas) hydrazone An alternative method for the formation of a methylene group from a =: eduction of thioacetal/thioketal derivatives with aney i. Type 3 reversible nucleophile! S S F 3 ( 2 3 ) 2 S S aney i ethanol, Δ thioketal