Chem 215 F11 Notes – Dr. Masato Koreeda - Page 1 of 6. Date: October 14, 2011

Chapter 16-1, 3-5: Acidity and Basicity; Enolization/Enolate Formation I. Solvation, Inductive, and Resonance Effects in Acidity and Basicity

(1) Solvation effect: More effective solvation on the conjugate base increases the acidity of the original acid.

Alcohols: R OH R O + H

H3C OH CH3CH2 OH (CH3)2CH OH (CH3)3C OH pKa 15.5 15.9 17.0 19.2

Carboxylic acids: O O + H R OH R O

O O O O O

H OH H3C OH CH3CH2 OH (CH3)2CH OH (CH3)3C OH

pKa 3.75 4.76 4.88 4.85 5.05

(2) Hybridization effect on R-C(=O)OH - Inductive effect by the α-carbon

electronegativity electronegativity electronegativity electronegativity 2.48 2.78 2.71 3.07 O O O O

CH3CH2 OH CH =CH OH C OH C OH 2 C H pKa 4.88 4.20 ~4.2 1.84

3 2 2 α-C: sp C sp C sp C sp C

(3) Halogenated Carboxylic Acids pKa Examples of pKa O the Inductive Effect H C H C O 4.8 H H O H 4.52 Cl C C H H C C O O H H H H Cl C H C O 2.8 more Cl closer H Cl H O H Cl atoms to the C(=O)OH 4.05 H C C H O C C O H H H H Cl C H C O 1.3 Cl H H H O O 2.86 H C C H Cl C C O C H 0.64 C O stronger stronger H H Cl H Cl Cl acid acid

O O O F C H C O C H C F 0.23 R O R O + H F electrons are withdrawn more charge more stabilized to the O atom of the O-H by the presence of the bond by the halogen atom(s) halogen atom(s)

Chem 215 F11 Notes – Dr. Masato Koreeda - Page 2 of 6. Date: October 14, 2011

(4) Aromatic Carboxylic Acids • Inductive effect in aromatic carboxylic acids

O O O O C H C H C H C H O O O O

F F pKa 4.2 4.1 F 3.9 3.3 stronger acid; F closer to the C(=O)OH note: Inductive effect through the σ-bond framework • Combination of inductive and resonance effects O O O C H C H C H O pKa 3.4 O pKa 3.5 O pKa 2.2 O O N N O N O O O weak inductive effect mostly inductive effect strong inductive effect & & strong resonance effect extremely strong resonance effect

Resonance structures of the conjugate base of 4-nitrobenzoic acid:

O O O O C C C C O O O O O O O O N N N N O O O attractive charge- O charge interaction

(5) Aromatic amines (or anilines) Instead of using the basicity scale (pKb), the dissociation acidity (pKa) of the conjugate acids is typically used. So, a stronger base has a higher pKa of its conjugate acid.

pKa BH B + H

H H H H N H H C N H N N 3 H H H H pKa 10.6 pKa 4.6

Because of the delocalizable N lone pair in aniline (as a result of resonance with the benzene π-system), the aniline N atom is considerably less basic compared with that of R-NH2. Substituted anilines H H H H H H N N N H H H O H C N 3 pKa 5.31 pKa 4.60 pKa 1.00 O O

Chem 215 F11 Notes – Dr. Masato Koreeda - Page 3 of 6. Date: October 14, 2011

Explanation based upon resonance structures of the conjugate acids: H H H H H H H H N N N N H H H H O O H C H C N N 3 O 3 O O O charge-charge charge-charge repulsion stabilizing interaction The BH+ form is destabilized by the presence of The BH+ form is stabilized by the presence of + + the 4-nitro group. more acidic than PhNH3 the 4-OCH3 group. less acidic than PhNH3

Alternatively, these pKa values can be explained by using the resonance structures of substituted anilines (i.e., B instead of BH+).

II. Carbon Acids (1) Carbanions

pKa >50 pKa 26 C H C C H C sp3 = 25% s character sp = 50% s character extremely strong nucleophiles and bases H pKa ~40 C C sp2 = 33% s character

Inductive effect:

Cl Cl Cl C H + OH Cl C + H OH Cl Cl pKa ~25 pKa 15.7 Cl Cl C much weaker base than C Cl

But, note: H3CO H3CO C H not acidic at all! H3CO

(2) Electron-withdrawing groups (in terms of resonance) & pKa

O H H O O O H H C C H H C N H N N C C O C O C H O C H H H H H H H H H H H pKa >50 pKa 19 pKa 10.2 both inductive effect & resonance stabilization of the carbanion Chem 215 F11 Notes – Dr. Masato Koreeda - Page 4 of 6. Date: October 14, 2011

III. Enols and Enolates (16-4, 5)

(1) Deprotonation of an α-Hydrogen by a Base α−carbons (i.e., alpha or the first C's from C=O) resonance-stabilized carbanion and enolate

O O O H C H H C H C C C C C C C H H H O OH H H H H H H H H H C H H C C pKa 19 carbanion enolate α−hydrogens H H H H + H OH note: OH is also a nucleophile. pKa 15.7 So, O O OH OH takes place as well.

Ambident Nucleophilic Nature of Enolates: can react at either anionic center (i.e., C- and O-). C-: more nucleophilic site C: less electronegative and will oxygen nucleophile O share electrons with electrophiles O H C more easily H C C C C C H H H H H H H carbanion enolate H

======pKa’s of carbonyl compounds:

ketone

O O O H α C H C H C C CH3 C CH3 C CH3 H H H H pKa 19 ester

O a O b O H α C H C a C The presence of unshared pairs of C OCH3 C OCH3 H C OCH3 H H electrons on the O of the alkoxy group H a b H pKa 24 b diminishes the effectiveness of the O carbonyl group of the ester in delocalizing the charge. H C C OCH3 H

Chem 215 F11 Notes – Dr. Masato Koreeda - Page 5 of 6. Date: October 14, 2011 amide

O a O b H α C C N(CH3)2 H C H C N(CH3)2 b H pKa 27 H a Explanation for the lower acidity of the amide α-H a b is the same as the one used for an ester α-H and even more so here. O O H C H C N(CH ) C 3 2 C N(CH3)2 H H

(2) Protonation of an enolate anion H OH H pKa 10.9 O O H C H C C C H C C H H H enolate anion H enol form H H H

(3) Keto-Enol Tautomerization

stabler form of the two by ~5 Kacal/mol O OH H C H H C H C C C C H H H H H H2O H 25 °C H >99.999% (extremely slow) at equilibrium

Constitutional isomers (called tautomers or proton tautomers): different connectivity, but interconvertible constitutional isomers

(4) Acid catalyzed-Enol Formation (Enolization)

O OH + H3O H C H H C H C C C C H H H H H H enol ketone H Mechanism for the acid catalyzed-enol formation: H O H O H H O OH H C H H C H H C H C C C C C C H H H H H H H H H H H OH2

Chem 215 F11 Notes – Dr. Masato Koreeda - Page 6 of 6. Date: October 14, 2011

(5) Active methylene compounds O O O O These Hs are highly acidic as H3C CH3 OCH3 the corresponding carbanions H H active methylene group H H are doubly stabilized by resonance or active methylene Hs pKa 11 with the two C=O groups. pKa 9

(6) Racemization/epimerization of Stereocenters at the α-C Atoms

(a) Racemization α-Hydrogen atoms can be deprotonated by a base or ketones can form enols under acidic conditions, thus losing the original stereochemistry. In the example shown below, treatment of the R-enantiomer with

NaOCH3/HOCH3 results in the formation of a racemic mixture.

H CH3 H CH CH3 NaOCH 3 CH 3 CH CH 3 HOCH 3 3 R 3 S O O O via this achiral enolate anion

(b) Epimerization H H

CH3ONa/CH3OH O O H H 1,3-diaxial interactions CH3 CH H 3 H H H CH3 H O CH3 O H H H O more stable less stable H CH3 enolate intermediate Epimers: Diastereomers differing in configuration at only one of two or more chiral centers. Epimerize: To interconvert diastereomers by change of configuration at only one of two or more chiral centers.