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Summary Sheet 2: and Enolates

Name Structure Example pKA* of H Structural Features of the : Effects on acidity of alkyl groups Effect on reactivity of : 2 O O •Carbon, oxygen: sp hybridized Likewise, the presence of a carbonyl group activates alkenes toward The carbonyl is an withdrawing system with 17 •O–C–C bond angle ~120 ° π nucleophilic attack: low-lying π* orbitals. It stabilizes adjacent negative charge. R H H3C H •C=O bond strongly polarized O – δ toward oxygen. M H3C CH3 M H H H O O •Carbonyl carbon is partially positive H2C CH3 LiNEt2 CH X CH3 δ+ 2 does not form 20 therefore electrophilic! Ethane R R' H C Me Conjugate base NEt2 3 •Lone pairs render oxygen weakly pKa = ~50 H H NEt2 nucleophilic (will react with strong acid) highly unstable O O OMe OMe 25 O O O Li O O R OR H C OMe Key Concept: Tautomerism CH3 CH3 3 H t-Bu H t-Bu t-Bu M O LiNEt2 O H X O O O O OH Methyl propionate Conjugate base (enolate) lactone pKa = ~25 ~1025 more acidic just by H H Et2N Et2N O H C O H H (cyclic 2 C R R replacing H with a carbonyl! ( ) H enolate: stabilized! forms readily! ester) n 2 H Why the huge difference in acidity? The lone pair is keto form form stabilized by donation into the carbonyl π system. The reactivity of the toward nucleophilic attack is directly related O to the stability of the enolate that forms - O Tautomerism: a form of isomerism where OMe OMe amide 30 a keto converts to an enol through the movement of O O R NR CH3 CH3 O O 2 H2C NMe2 a and shifting of bonding O O O O M M NH2 = 1° amide For (R=CH ) the keto:enol ratio is ~6600:1 at 23 > > > > 3 NR2 OR Me CF RO OR NHR = 2 ° amide °C. Main reason is the difference in bond strengths between Enolate Enolate 3 ( form) (oxy-anion resonance form) NR1R2 = 3 ° amide the two species. O O The enol is most significant for and Question: How do you explain the relative acidity of the increasing reactivity toward nucleophilic attack following series? lactam NH(R) Me . (You may also encounter it with acid chlorides in increasing stability of enolate H2C N O (cyclic O O O ( )n the mechanism of the Hell-Vollhard-Zolinsky reaction). Can predict the course of the reaction by pKa! amide) and amides are less acidic and exist almost exclusively as the > > > H3C CF3 H3C CH3 H3C OR H3C NR2 O O keto form (e.g. >106 : 1 keto: enol for ethyl acetate) carboxylic Note 1 Acetone in D O will slowly incorporate deuterium at the acid R OH H C OH 2 α− most acidic least acidic Key Reaction: Enolate Formation 3 carbon. The enol form is responsible for this behavior. Enolate = deprotonated enol The rate of keto/enol tautomerism is greatly increased by Answer: The more electron-poor the carbonyl, the greater will O O acid (see below right) be its ability to stabilize negative charge. Conversely, the greater the donating ability of a substitutent on the carbonyl, i-Pr i-Pr O Li Li O acid O N * Note 2 the less it will be able to stabilize negative charge. chloride R Cl H3C Cl Five factors that influence the relative Li (LDA) H H H C OEt OEt OEt proportion of keto/enol: The aromatic electrophilic substitution chart is a good proxy 3 (or other O O O O Note 2 1. Aromaticity for the ability of a functional group to donate to a carbonyl: H H strong base) ester enolate anhydride O OH C-bound form * NR , O > OH > OR, NHAc > CH , R > Cl, Br, F, I > C(O)OR Carbonyl compound O-bound form R O R H3C O Me 2 3 CF3, etc. Substitution of the α-carbon by a second carbonyl 25 Important: the Enolate is a derivative makes the α-proton even more acidic: nitrile R–CN Me-CN Amphiphilic =nucleophilic at both O and C; note: though an ester enolate Not observed Exclusive O O O O O O here we focus on the reactions at C. is shown here, the reaction of Note 1: The is deprotonated any enolate with an aldehyde 2. Hydrogen bonding stabilizes the enol form. first. Subsequent deprotonation of the α-carbon Two key examples: is generally called an "Aldol". Me Me Me OMe MeO OMe would form a dianion, which has a high H-bond O activation barrier due to charge repulsion. It O M OH O H pKa = 9 pKa = 11 pKa = 13 can be done, but it requires a very strong base. O O O O R H OEt R OEt Note 2: It is difficult to measure the pKa of these species due to their reactivity. Me Me Me Me O 24 : 76 (at 23 °C) The rate of keto/enol interconversion isgreatly enhanced by acid: O M OH O 3. Strongly hydrogen bonding solvents can disrupt Acid makes carbonyl more electrophilic, increasing acidity of α- R OR *source: P. Y. Bruice, "Organic Chemistry" this, however. The above equilibrium is 81:19 , facilitating formation of enol: this increases K1 OEt R OEt using water as solvent. Note that some of of these values differ slightly from H 4. . Conjugation is stabilizing. O O H O textbook to textbook and instructor to instructor. H X K1 H X However, there is universal agreement that for R R R The goal here is clarity and consistency. I O OH R R R a given structure, pKas increase in the order K would greatly appreciate feedback on any aldehyde < ketone < ester < amide H H H H 2 H errors, omissions, or suggestions for Me Me Keto Enol improvements. Thanks! If you have a vastlyl different set of values I Preferred enol form X: Enol is nucleophilic at α-carbon, acid is would appreciate it if you brought it to my attention. 5. As with alkenes, increasing substitution increases version 1.0, 4/13/10 thermodynamic stability (assuming equal steric factors) excellent : this increases K2 copyright James Ashenhurst, 2010. For a comprehensive list of pKa values see: suggestions/questions/comments? 1)evans.harvard.edu/pdf/evans_pKa_table.pdf Net result: Addition of acid speeds proton [email protected] 2) www.chem.wisc.edu/areas/reich/pkatable/ exchange between the keto and enol forms. masterorganicchemistry.wordpress.com