from "Master Organic Chemistry"

Summary Sheet #5 - Nine Key Mechanisms In Carbonyl Chemistry masterorganicchemistry.wordpress.com

Version 1.0 July 2010, copyright 2010 James A. Ashenhurst
comments/corrections/suggestions? james@writechem.com
Mechanism Description Promoted by Hindered by Examples
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) Imine formation
[1,2] addition carbonyl carbon, breaking the 2) Sterically bulky substituents next to the carbonyl Fischer esterification
C–O π bond. Electron withdrawing groups on α carbon Aldol reaction
O X-groups that are strong π-donors (e.g. amino, hydroxy,
O Nu Electron-withdrawing X groups that are poor π-donors (e.g. Cl, Br, Acetal formation
alkoxy)
I, etc.) Claisen condensation
X R X Addition of acid (protonates carbonyl oxygen, making carbonyl
Cα 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)

Lone pair on carbonyl oxygen The better the leaving group X, the faster the reaction will be. The
[1,2] elimination
comes down to carbonyl carbon, rate follows pKa very well. Acid can turn poor leaving groups Fischer esterification
forming new π-bond and displacing (NR2, OH) into good leaving groups (HNR2, H2O) X groups that are strong bases are poor leaving groups. Formation of amides by
O leaving group X. Alkyl groups and hydrogens never leave. treatment of acid halides
O Nu Amines and hydroxy are poor leaving groups under basic with amines.
R X R Nu conditions, but are much better leaving groups under acidic Claisen condensation
I > Br > Cl > H2O > OAc > SR > OR >> NR2, O2– H alkyl conditions.
–9 –8 –7 –2 4 12 17 35 >40

[1,4] addition
O O
Nu
R R
Nucleophile attacks alkene polarized
by electron withdrawing group,
leading to formation of enolate.
So-called "soft" nucleophiles such as Gilman reagents
(organocuprates) will add [1,4], as will amines, enolates etc. MIchael reaction
[1,2]-addition can compete in the example of Grignard reagents.
The more stable the conjugate base (enolate) of the carbonyl, the Addition of Gilman
The more electron rich the carbonyl, the slower will be the rate
faster the reaction. Extra electron withdrawing groups on the α-carbon reagents (organocuprates)
of reaction (less able to stabilize negative charge). So addition
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 In the aldol condensation, addition of acid helps OH group Aldol condensation
OH H displaces leaving group on the As with [1,2]elimination, X groups that are strong bases are poor
O leave as H2O. Knovenagel condensation
β-carbon leaving groups. Addition of acid will promote elimination of groups
R Note that in the Aldol reaction run under basic conditions, the enolate such as NR2 and OH/OR.
R
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 Rate of reaction will go primary alkyl halide > secondary alkyl halide Enolate alkylation
onto electrophile (alkyl halide or tosylate).
O Tertiary alkyl halides unreactive in SN2. Carboxylate alkylation
O or equivalent) Polar aprotic solvent is ideal.
R
R H 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, NH2(–) > NH3 Base deprotonation at end of acid-
Deprotonation 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 H OH
O HO X O O H OH
1) catalyzes [1,2] addition to carbonyls H
Acid Base Reactions Protonation 2) promotes [1,2] elimination R OH2
R
R H CH3 R R R R
3) to promote tautomerization. H
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
Proton Transfer O O HO OR H2O OR
either intramolecularly or intermolecularly (both pathways operate)
hence distinct arrow pushing steps often not drawn, and we just say
R OH R OH2 R R R R
"proton transfer"