from "Master Organic Chemistry" masterorganicchemistry.wordpress.com Nine Key Mechanisms In Carbonyl Chemistry Version 1.1 Sept 2012 copyright 2012 James A. Ashenhurst [email protected] Mechanism Description Promoted by Hindered by Examples

Addition Anything that makes the carbonyl carbon a better electrophile 1) Anything that makes the carbonyl carbon Grignard reaction Attack of a nucleophile at the (more electron-poor) a poorer electrophile (more electron-rich) [sometimes "[1,2] addition"] Imine formation carbonyl carbon, breaking the 2) Sterically bulky substituents next to the carbonyl Fischer esterification Electron withdrawing groups on carbon C–O π bond. α X-groups that are strong -donors (e.g. amino, hydroxy, Aldol reaction O Electron-withdrawing X groups that are poor -donors (e.g. Cl, Br, π O Nu π alkoxy) Acetal formation I, etc.) Claisen condensation Cα X Cα X Addition of acid (protonates carbonyl oxygen, making carbonyl Sterics: X=H (fastest) > 1° alkyl > 2° alkyl > 3° alkyl (most hindered, slowest) Nu carbon more electrophilic. Note: acid must be compatible with nucleophile;alcohols are OK, X=Cl (poorest π-donor, fastest addition) > OAc > OR > NH2/NHR/NR2 strongly basic nucleophiles (e.g. Grignards) are not. (best π donor, slowest rate)

Elimination The better the leaving group X, the faster the reaction will be. The [sometimes "[1,2] elimination"] Lone pair on carbonyl oxygen comes down to carbonyl carbon, rate follows pKa very well. Acid can turn poor leaving groups Fischer esterification X groups that are strong bases are poor leaving groups. forming new π-bond and displacing (NR2, OH) into good leaving groups (HNR2, H2O) Formation of amides by Alkyl groups and hydrogens never leave. O Nu O leaving group X. treatment of acid halides Amines and hydroxy are poor leaving groups under basic with amines. conditions, but are much better leaving groups under acidic Cα X C Nu 2– H Claisen condensation α I > Br > Cl > H2O > OAc > SR > OR >> NR2, O alkyl conditions. –9 –8 –7 –2 4 12 17 35 >40

So-called "soft" nucleophiles such as Gilman reagents [1,4] addition Nucleophile attacks alkene polarized MIchael reaction (organocuprates) will add [1,4], as will amines, enolates etc. [1,2]-addition can compete in the example of Grignard reagents. by electron withdrawing group, Addition of Gilman The more stable the conjugate base (enolate) of the carbonyl, the The more electron rich the carbonyl, the slower will be the rate O O leading to formation of enolate. reagents (organocuprates) Nu faster the reaction. Extra electron withdrawing groups on the α-carbon of reaction (less able to stabilize negative charge). So addition R R will promote the reaction. to α,β-ketones > α,β−esters > α,β-amides.

Nu Nu

[1,4] elimination Lone pair on oxygen comes down Facilitated if X is a good leaving group (just like [1,2]-elimination) to form carbonyl, enol double bond Aldol condensation H In the aldol condensation, addition of acid helps OH group OH displaces leaving group on the As with [1,2]elimination, X groups that are strong bases are poor Knovenagel condensation O leave as H2O. β-carbon leaving groups. Addition of acid will promote elimination of groups Note that in the Aldol reaction run under basic conditions, the enolate R R such as NR2 and OH/OR. is a stronger base than OH(–), so in the base-promoted Aldol X β reaction, the [1,4]-elimination is favorable.

SN2 Backside attack of nucleophile Facilitated by good leaving group on electrophile (alkyl halide Enolate alkylation onto electrophile (alkyl halide Rate of reaction will go primary alkyl halide > secondary alkyl halide O or tosylate). Tertiary alkyl halides unreactive in S 2. Carboxylate alkylation O or equivalent) Polar aprotic solvent is ideal. N H R R R Enolate α-carbon is excellent nucleophile for SN2 R The higher the pKa of the carbonyl compound, the more reactive X H the conjugate base will be in the SN2.

Keto-Enol Tautomerization Internal oxygen ↔ proton transfer Facilitated by acid Tautomerism under acidic conditions only significant for ketones, with change in hybridization of The enol form is stabilized by internal hydrogen bonding if there aldehydes, and acid halides (the latter under the conditions of the Acid-catalyzed aldol O OH oxygen and carbon. is a carbonyl present at the β position. Hell-Vollhard-Zolinski reaction). Acid-catalyzed bromination H of ketones H3C R R H

The conjugate base is always a better nucleophile than the conjugate acid. H Deprotonation increases nucleophilicity. E.g. enolate > enol, alkoxide > alcohol, NH (–) > NH Base deprotonation at end of acid- Deprotonation 2 3 OH O RO OR –[H] RO OR Conjugate base can perform reactions the conjugate acid cannot. R R catalyzed acetal formation Deprotonation is also the last step in acid-catalyzed reactions, in order to generate the final forms alkoxide (more nucleophilic) R R R R provides neutral product (neutral) product

H OH HO X O H 1) catalyzes [1,2] addition to carbonyls O H O H OH Acid Base Reactions Protonation 2) promotes [1,2] elimination R R OH2 CH 3) to promote tautomerization. R H 3 H R R R R 4) quench (e.g. enolate from 1,4. faster [1,2] addition faster [1,2] elimination faster enolization reaction quench

An internal acid-base reaction. Not mechanistically H distinct from the above, but often drawn as one step. Can proceed H O O Proton Transfer either intramolecularly or intermolecularly (both pathways operate) HO OR H2O OR hence distinct arrow pushing steps often not drawn, and we just say R OH R OH R R R R "proton transfer" 2