Handout Esterification and Acetalization

1) Fischer Esterification:

O O

OH conc. H2SO4 OMe + xs MeOH + H2O

benzoic acid methyl benzoate Example: esterification of benzoic acid to methyl benzoate.

MECHANISM (Fischer esterification)

H O O H H H O O

R OH R OH H H R O R O Carboxylic Acid R'OH

H H O O H OH R R OH R OH OR' O O R' R' H

O Equilibrium displaced by either 1) water removal + H 2) ester distillation R OR' 3) excess alcohol Ester

The overall process of esterification is one involving an equilibrium among a variety of compounds, and for the reaction to give a high yield; the equilibrium must be shifted toward the products: the desired ester, and water. This can be accomplished either by removing one or more of the products from the reaction mixture as they are formed or by using a large excess of one of the starting reagents. The effect of the latter approach is obvious from consideration of the mass law relating starting materials and products (equation). Increasing the amount of either the alcohol or the carboxylic acid will result in an increase in the amount of products formed since the equilibrium constant. K, for the reaction-must remain constant at a given temperature, no matter what quantity of either reagent is used. Removing water is also a strategy and drying agents can be used, or azeotropic distillation. However, azeotropic distillation is not possible for all alcohols.

O K O + R'OH + H2O R OH R OR'

[RCOOR'] [H2O] K = [RCOOH] [R'OH]

Problem Assignment

THIS PROBLEM MUST BE ANSWERED IN YOUR NOTEBOOK AND WILL BE PART OF YOUR GRADE Assuming the equilibrium constant for the esterification of benzoic with methanol is K = 3, calculate the theoretical yield of methyl benzoate expected using the following conditions: 6.1 g of benzoic acid and 20 mL of methanol, and 2 mL of concentrated sulfuric acid. Concentrated sulfuric acid is added as a catalyst in the esterification procedure, even though another acid (benzoic acid) is one of the organic reagents used. Why is the sulfuric acid necessary?

Azeotropes can be distilled using a Dean-Stark trap. If the azeotrope separates into two phases upon cooling, then water can be removed. This is the case with water/toluene and water/benzene (among other).

For example benzoic acid + n-BuOH can be esterified (with H2SO4) as a catalyst, without using a large excess of alcohol. Think about how the Dean-Stark trap (glassware below) might work.

Distillation of azeotropes To remove water as it is forming, a drying agent can be used, or a Dean-Stark apparatus if the solvent forms an azeotrope

Distilling receiver - Dean-Stark apparatus

EQUILIBRIA, RATES, ENERGY DIAGRAMS, MECHANISMS JLM/05 EQUILIBRIA, RATES, ENERGY DIAGRAMS, MECHANISMS

o TABLE: Relationship between Keq and !G Note: at 25oC, the value of 2.3RT is about o More stable 1.4 kcal/mol !G K (kcal/mol) eq state (%) 0 1 50

0.1 1.2 54.5 Relationship Between Energy Difference and Distribution 0.24 1.5 60 100 0.5 2.4 69.7

0.82 4.0 80 90 1 5.4 84.4 1.30 9 90 2 29.3 96.7 state 80

2.72 99 99 stable

70

5 4631 99.98 more 7 10 2.1 x 10 99.999996 of % o o !G = -RT lnK !G = -2.3RT logK 60

-!Go/RT -!Go/2.3RT K = e 50 K = 10 0 1 2 3 4 5 6 Free energy difference (kcal/mol)

Le Chatelier’s Principle: a system at equilibrium responds to a disturbance/stress so as to mi nimize the disturbance/stress.Le Chatelier’s Principle: a system at equilibrium responds to a disturbance/stress so as to minimize the disturbance/stress. 2) Acetalization (acetal formation) TABLE: Approximate A Values (Free Energy Difference between Equatorial & Axial Substituents on a Cyclohexane Ring O 2 ROH RO OR ACETAL FORMATION + R1 R2 cat. H R1 R2

H H H H O R O Approx.O O Approx. HO O R HApprox.O Functional o Functional o Functional o + H !G !G R !GR GroupR R R R Group R1 RGroup2 1 2 1 2 kcal/mol1 2 R1 R2 kcal/mol kcal/mol hemiacetal HgClpKa - 5 to -10 - 0.25 OMe 0.6 CH=CH2 1.7 HgBr 0.0 R OHOH (protic sol) 0.9-1.0 CH3 1.8H CN 0.15-0.25 OH (aprotic sol) 0.5-0.6 C2H5 1.8 R R H H F H 0.25 NOO2 1.1 i-Pr 2.1O R R O O R O + O I 0.46 SPh 1.1-1.2 C6HO 11 H 2.2 R R R R H R R Br 1 0.52 -0.6 COOEt1 2 1.1R-1.21 R2 Me3Si 12.5 2 OTs 0.51 COOMe 1.3 Ph 2.8 Cl - H0.52 COOH R OH1.4 t-Bu 4.9 OAc 0.71 NH2 1.4 RO OR This reaction is reversible, so acetal hydrolysis has the same mechanism R1 R2 going in the backward direction. acetal The equilibria are controlled by either removal of water or by using an excess of reagents (water or alcohol)

RO OR H2O O ACETAL HYDROLYSIS R R + 1 2 cat. H R1 R2

Related reaction: alcohol protection to ROTHP (THP = tetrahydropyranyl)

H H H because of this resonance O O O stabilization the isomer does not form O H DHP less stable (dihydropyran) R OH

+ H H O O O O R R ROTHP

Related reaction: enol ether hydrolysis R H RO H RO O H2O O R O H O H H H H same intermediates as above

Hemiacetal:

HEMIACETALS ACETALS

OH OH H H H OH H H O O H O HO HO HO H H H OH H H H OR OH OH H OH OH OH OH H OH

(disaccharide, polysaccharide) !-pyranose -pyranose " R = sugar carbohydrates: [C(H2O)]n JLM/05 EQUILIBRIA, RATES, ENERGY DIAGRAMS, MECHANISMS

o TABLE: Relationship between Keq and !G Note: at 25oC, the value of 2.3RT is about !Go More stable 1.4 kcal/mol K (kcal/mol) eq state (%) 0 1 50 0.1 1.2 54.5 Relationship Between Energy Difference and Distribution 0.24 1.5 60 100 0.5 2.4 69.7 0.82 4.0 80 90 1 5.4 84.4 1.30 9 90 state 80

2 29.3 96.7 stable 70 2.72 99 99 more of

5 4631 99.98 % 7 10 2.1 x 10 99.999996 60 !Go = -RT lnK !Go = -2.3RT logK

50 o o 0 1 2 3 4 5 6 -!G /RT -!G /2.3RT Free energy difference (kcal/mol) K = e K = 10 The Anomeric Effect Le Chatelier’s Principle: a system at equilibrium responds to a disturbance/stress so as to Conformational analysis of cyclohexanesminimize the disturbance/stress.

TABLE: Approximate A Values (Free Energy Difference between Equatorial & Axial Substituents on a Cyclohexane Ring

FG equatorial axial FG FG = functional group Approx. Approx. Approx. Functional Functional Functional !Go !Go !Go Group Group Group kcal/mol kcal/mol kcal/mol

HgCl - 0.25 OMe 0.6 CH=CH2 1.7

HgBr 0.0 OH (protic sol) 0.9-1.0 CH3 1.8

CN 0.15-0.25 OH (aprotic sol) 0.5-0.6 C2H5 1.8

F 0.25 NO2 1.1 i-Pr 2.1

I 0.46 SPh 1.1-1.2 C6H11 2.2

Br 0.5-0.6 COOEt 1.1-1.2 Me3Si 2.5 OTs 0.51 COOMe 1.3 Ph 2.8 Cl 0.52 COOH 1.4 t-Bu 4.9

OAc 0.71 NH2 1.4

ANOMERIC EFFECT

O O when X is electronegative X (OH, OR, Cl, etc.) then the axial conformation is more stable X equatorial axial

Origin of the anomeric effect: the lone pair on the ring oxygen (HOMO) interacts with the C-X antibonding orbital (σ*), thus stabilizing the axial conformer.

explanation O lone pair to C-X !* orbital

X