Esterification

Lecture 7a

Many esters have pleasant odors and some of them can be found in nature

Esters are often used in fragrances or flavoring agents due to their organoleptics properties

Some esters are used as sex pheromones i.e., isopropyl dodecenoates (attracts female beetles, used in alternative pest control) or alarm pheromones i.e., isoamyl acetate (honey bee))

Ester of p-aminobenzoic acid are used as local anesthetics with a short to moderate half-life (benzocaine (ethyl), procaine (2-(diethylamino)ethyl)), propoxycaine, etc.

Introduction

Compound Flavor/FragranceIsoamyl acetate Banana Oil Ethyl butyrate PineappleOctyl acetate Orange Methyl anthranilate Grape Methyl butyrate AppleBenzyl acetate PeachMethyl salicylate Oil of WintergreenMenthyl acetate Peppermint

Esters can be obtained by a broad variety of reactions Fischer esterification (used in Chem 30BL)

This approach works well for primary and most secondary alcohols, but not for tertiary alcohols because of their high tendency to eliminate water instead of forming an ester

Acyl chlorideWorks for tertiary alcohols as

well because of non-acidic conditions

Accessibility of SOCl2

AnhydrideAccessibility of anhydridesOften also requires an acidic

catalyst i.e., aspirin synthesis

Theory I

Cl

O

OH

O

SOCl2

-HCl, SO2

ROH/Pyridine

-PyH+Cl-OR

O

Schotten-Baumann Esteri fication

O

O

O

ROH/H+

O

O

OR

OH

ROH/H+

O

O

OR

OR-H2O

O

CR OR'RCO2H + R'OH + H2OH+

acid alcohol ester

Example 1: Aspirin (Bayer AG,1899) It uses salicylic acid, acetic acid anhydride and a

mineral acid as catalyst (usually conc. phosphoric acid)The phenol group acts as the alcohol in the reaction

Aspirin is considered a pro-drug for salicylic acid, which was long known (Hippocrates, bitter willow bark extract, 5th century BC) to work against inflammations and fever but it caused vomiting and nausea

Theory II

OH

OH

O

O

O O

[H+] O

OH

O

O

Aspirin

CH2OH

CH2OHO

HO

OO

+

Serin group in cyclooxygenase is blocked and therefore the prostagladin synthesis suppressed

Intramolecular esterification afford lactonesThese reactions can usually be carried out under mild conditionsExample 2: GHB (g-hydroxybutyric acid)

It is used as date rape drug: Liquid Ecstasy It is colorless, odorless and has a slightly salty taste It is very dangerous because the effect of the drug differs greatlyMore than 200 deaths and more than 5700 overdoses have been

attributed to this drug since 1990. The major problem is that humans can have very different reactions to this drug particular in connection with the consumption of alcohol.

Theory III

HO COOHH+

O

O

mild conditionsLacton

GHB GBL

Example 3: Biodiesel It has gained a lot of interest lately due to the ever increasing cost of gasoline over

the past decades It uses renewable resources i.e., plant oils, algae, grease, etc.

Trans-esterification: It converts oils into methyl esters that are much more volatile than oils due to their lower molecular weight

It is important that water is absent during the reaction to avoid the formation of soap (Na+

RCOO-, where R= C17H35, etc.)

Food vs. Fuel debate (i.e., 80 gal/acre for soy and sunflower) 42 billion gallons of diesel in 2008 in the US: 525,000,000 acre (21 % of the US) If the gasoline is also included (135 billion gallons) about 85 % of the area is needed!

Theory IV

O

O

O

O

R1

O

R2

R3

O

+ 3 CH3OHNaOH

R1 O

O

R2 O

O

R3 O

O

+

OH

OH OH

Triglyceride Methanol Methyl esters of fatty acids Glycerin

In the lab, an unknown carboxylic acid is reacted with an unknown alcohol (both assigned by the TA)

Problems:The reaction is an equilibrium reaction with poor yields

if a 1:1-ratio of the reactants is usedThe carboxylic acid is a poor electrophile (neutral)The alcohol is a poor nucleophile (neutral)The reaction is very slow at room temperatureAny water in the reaction mixture lowers the yield significantly

Theory V

O

CR OR'RCO2H + R'OH + H2OH+

acid alcohol ester

Mechanism of Fischer esterification

In the neutral state, the resonance structure with the charge separation is a very minor contributor making the carbonyl function of the carboxylic acid a poor electrophile

The situation changes in the protonated form of the carboxylic acid in which the carbonyl carbon bears a larger positive charge (~0.2 units in the case of acetic acid), which makes it a better electrophile

Theory VI

O

C OHR

O–

C OHR+

+ H+

OH

C OHR

OH

C OHR

activated carbonyl(no charge separation)

better electrophile(charge separation)

R'–OH••

••

OH

C OHR

O

– H+

H R'

OH

C OHR

O R'

OH

C OR

OR'

••

••

–H2OOH

C OR'R

+

+ H+

O

C OR'R

– H+

H2O is agood leaving

groupH

H

Le Châtelier Principle If equimolar amounts of the carboxylic acid and the alcohol were used, the

theoretical yield would be low i.e., 67 % (Keq=4)

One or all products have to be removed from equilibrium An excess of one the reactants has to be used

The carboxylic acids cannot be used in excess because all of them are solids

The reaction in the lab uses an excess of the alcohol The alcohol doubles up as the solvent and as a reactant in the reaction Usually about 4-10 fold molar excess in the literature (a five-fold

molar excess is used in the Chem 30BL lab i.e., 10 mmol of the carboxylic acid are reacted with 50 mmol of the alcohol)

Theory VII

Keq =

O

CR OR' H2O

RCO2H R'OH

1–10

A very strong mineral acid is used as catalyst The carboxylic acid is neutral and a weak electrophileThe mineral acid protonates the carbonyl carbon atom

and increases its electrophilic character

It is very important to reflux the mixture properly to increase the rate of the reaction i.e., for every 10 oC temperature increase, the rate of the reaction about doubles (Arrhenius equation)

Theory VIII

RT

Ea

eArate

*

Which compounds are present in the reaction mixture after the reaction is completed? Ester (hopefully), alcohol (used in excess), carboxylic acid (should

be a small amount), sulfuric acid (used as the catalyst) All of the alcohols (log Kow= -0.77 (MeOH), -0.24 (EtOH), 0.05 (iso-PrOH),

0.25 (PrOH)) and the sulfuric acid (log Kow= -2.20) are soluble in water

The carboxylic acid and the sulfuric acid can beextracted with a weak base i.e., NaHCO3 while the ester and traces of the alcohol remain in theorganic layer. They are separated by a fractionatedvacuum distillation later.

Sodium hydroxide cannot be used for theextraction step because it would destroy the ester(saponification) due to its higher nucleophilicity

Theory IX

H2SO4

H2SO4

Na+HSO4-

RCO2H

R'OH

RCO2R'organic phase

aqueous phase

t = 0(water just added)

RCO2R'

1. mix

t >> 0

RCO2H

ROH

RCO2H

Water Extraction:

RCO2H

R'OH

RCO2R'organic phase

aqueous phase(5% NaHCO3)

t = 0(5% NaHCO3 just added)

RCO2R'

1. mix

t >> 0

Na+RCO2–

R'OH

NaHCO3 Extraction:

R'OH

H2SO4

H2SO4

R OR'

O

+ OH-

R O-

O

+ R'OH

base-catalyzed ester hydrolysise.g. conversion of f ats to soap

Experiment IDissolve the carboxylic acid

in the alcohol in a 10 mL round-bottomed flask (both assigned by your TA)

Add a few drops of concentrated sulfuric acid

Reflux the mixture for at least 60 minutes (the longer the better)

How much of the acid is used for the reaction?

How much alcohol should be used here?

Why is a 10 mL round-bottomed flask used here?

How much is appropriate here?

What does this imply in terms of equipment and setup?

5 mol equivalents

3-4 drops

1. Air condenser with wet paper towel2. Stir bar3. Drying tube with CaCl2

1.0 g

Experiment IICool the mixture down

Add ice-cold water to the reaction mixture

Remove the organic layer

How can this be accomplished quickly?

Which container should be used here?

Why is the water added?How much water should be added?

What should the student observe/not observe here?

Which one is the organic layer here?Usually the bottom layer=ester

Ice-bath

Centrifuge tube

Until a phase separation is observed usually 4-8 mL

The formation of a solid is bad

Experiment IIIExtract the aqueous layer

with diethyl ether

Combine all organic layers

Extract the combined organic layers with sodium bicarbonate solution

Why is the aqueous layer extracted with ether?

How much ether should be used here?

Which layers does this referred to?

Why is this step performed?How much solution is used here?How many extractions should be

performed?

2 x 3 mL

1-2 mL

Until the CO2 formation ceases

To collect the suspended and dissolved ester

Ester + two ether layers

Experiment IV Dry the organic layer over anhydrous sodium

sulfate Remove the ether and remaining alcohol

using the rotary evaporator Perform vacuum distillation

Collect product from Hickman head Acquire an infrared spectrum and the

refractive index of the ester. Submit the rest of the sample, even if it is solid or semi-solid) for NMR analysis (label vial and sign in the sample as well)

How much drying should be used?

Why is a vacuum distillation performed here?

What is the setup for the vacuum distillation?

What should the student do if he had a liquid in the Hickman head and also in the flask/vial?Acquire an infrared spectrum forboth liquids and only submit the “ester” for NMR analysis

A small amount to start with!

Note that the drying tubedoes not contain cotton or CaCl2!

20 40 60 80 100 120 140 160 180 200

0.76

7.6

76

760

Series1; 1

510

2040

60100

200400

760Vapor Pressure of Methyl benzoate

Boiling Point (oC)

Va

po

r P

ress

ure

(in

mm

Hg

)

Infrared spectrumBenzoic acid

n(C=O)=1689 cm-1

n(OH)=2300-3300 cm-1

Methanoln(OH)=3347 cm-1

n(C-OH)=1030 cm-1

Methyl benzoaten(C=O)=1724 cm-1

n(COC)=1112, 1279 cm-1

(absence of OH peak!)

Characterization In (OH)

n (C=O)

n (C=O) n (COC)

n (OH)

n (C-OH)

RefractometryThe refractive index is a physical property

specific to a compoundLight is refracted when passing through

any medium (Snell’s Law)In the lab, it is used to determine identity and purity

of a sample using an Abbé refractometer

The refractive index is wavelength and temperature dependent (l=589 nm, T=recording temperature)

Characterization II

aa

light

angletheta

anglephi

condensed mediumsurface

before adding sample to refractometer

after adding sample to refractometer (ideal)

Adjust the height of the dark field so that the edgeintersects with the crosshair

after adding sample to refractometer (non ideal)

n XD = n T

D + (T-X)*0.00045

1H-NMR spectrum for methyl benzoate

Characterization III

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.50.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

8.0

8.5

9.0

9.5

8.40 8.30 8.20 8.10 8.00 7.90 7.80 7.70 7.60 7.50 7.40 7.30 7.20 7.10 7.000.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

O

O

CH3

s, 3HOCH3

d, 2Hortho

t, 1Hpara

t, 2Hmeta

13C-NMR spectrum for methyl benzoate

Characterization IV

170 160 150 140 130 120 110 100 90 80 70 60 50 400

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100

105

110

115

120

51.00(9)

76.28(Sol.)77.08(Sol.)

77.88(Sol.)

128.40(5;3)129.70(2;6)

132.80(4)

166.80(7)

5

43

2

16 7

O8

O10

CH39

180 170 160 150 140 130 120 110 100 90 80 700

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100

105

110

115

120

76.28(Sol.)77.08(Sol.)

77.88(Sol.)

128.45(5;3)

130.02(1)

130.19(2;6)

133.76(4)

170.39(7)

5

43

2

16 7

OH8

O9

What is that?

Characterization V

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.00

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

150 100 50 00

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100

105

110

115

120

14.40

15.20

18.1460.80

65.90

76.2877.08

77.88

128.00128.45

129.50130.19

132.40133.76

166.30170.39

The reaction should be started as soon as possible in order to have a long enough reaction time

Dry glassware is very important hereThe reaction mixture has to be properly refluxedThe air condenser has to be properly cooled with a wet paper towel,

which has to have an intimate contact with the air condenser (no Hickman head here!!)

The purer the final product is, the easier the analysis of the NMR spectra will be

The student should submit something even if it is a “solid” that just had a pleasant odor to it

It is advisable to acquire a refractive index of the alcoholDo not obtain the melting point for the carboxylic acid

General Hints