Lecture 8a
Esterification
Introduction
•
Many esters have pleasant odors and some of them can even be found in nature.
Compound
Isoamyl acetate
Ethyl butyrate
Octyl acetate
Methyl anthranilate
Methyl butyrate
Benzyl acetate
Methyl salicylate
Menthyl acetate
•
•
•
Flavor/Fragrance
Banana Oil
Pineapple
Orange
Grape
Apple
Peach
Oil of Wintergreen
Peppermint
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.).
Theory I
• Esters can be obtained by a broad variety of reactions
• Fischer Esterification (used in Chem 30BL)
RCO2H + R'OH
H+
O
R C OR' + H2O
acid works
alcohol
• This approach
well for primary
ester and most secondary alcohols,
but not for tertiary alcohols because of their high tendency to
eliminate water instead of forming an ester.
• Acyl chloride
• Works for tertiary alcohols as
well because of non-acidic
conditions.
• Accessibility of SOCl2
• Anhydride
• Accessibility of anhydrides
• Often also requires an acidic
catalyst i.e., aspirin synthesis.
O
O
OH
SOCl2
O
Cl ROH/Pyridine
OR
-PyH +Cl-
-HCl, SO2
Schotten-Baumann Esterification
O
O
O
O
ROH/H
+
O
O
OR
ROH/H
OH
-H2O
+
OR
OR
O
Theory II
•
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.
Methyl salicylate
Topical analgesic
The serin group the cyclooxygenase is
blocked , which causes a suppression
of the prostaglandin synthesis
• 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.
• The reaction of salicylic acid with methanol in the presence of a mineral
leads to the formation of methyl salicylate (Oil of wintergreen), which is
used as topical analgesic.
Theory III
•
•
Intramolecular esterification afford lactones (i.e., coumarins).
These reactions can usually be carried out under mild
conditions.
Example 2: GHB (g-hydroxybutyric acid)
•
O
HO
COOH
H+
O
mild conditions
GHB
•
•
•
•
Lacton
GBL
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 greatly.
More 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 IV
•
•
•
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.
O
O
O
R1
R2
R1
O
O
OH
O
NaOH
O
+ 3 CH 3OH
+
R2
O
O
O
R3
OH
OH
O
R3
Triglyceride
•
•
•
Methanol
O
Methyl esters of f atty acids
Glycerin
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 (21.6 % of the US).
If the gasoline is also included (135 billion gallons) about 70 % of the area is needed.
In 2013, industry produced 1.8 billion gallons of biodiesel.
Theory V
• In the lab, an unknown carboxylic acid is reacted with an
unknown alcohol (both assigned by the TA).
RCO2H + R'OH
acid
alcohol
H
+
O
R C OR' + H2O
ester
• Problems:
• The reaction is an equilibrium reaction with poor yields
if a 1:1-ratio of the reactants is used.
• The carboxylic acid is a poor electrophile (neutral).
• The alcohol is a poor nucleophile (neutral).
• The reaction is very slow at room temperature.
• Any water in the reaction mixture lowers the yield significantly.
Theory VI
• Mechanism of Fischer Esterification
••
••
O
R C OH
OH
R C OH
+
+H
–
O
R C OH
H O R'
OH
R C OH
+
(charge separation)
OH
••
R'–OH
••
– H+
R C OH
OH
activated carbonyl
(no charge separation)
better electrophile
R C OH
O R'
+ H+
•
•
–H
+
OH
R C OR'
••
••
O
R C OR'
+
–H 2O
OH
H
H 2 O is a
good leaving
group
R C O
OR'
H
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 VII
• 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).
Keq =
O
R C OR'
RCO2H
H2O
­ 1–10
R'OH
• One or all products have to be removed from equilibrium, which will not
work here because water and the esters have higher boiling points than the
alcohols.
• Thus, 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 VIII
• A strong mineral acid is usually used as catalyst:
• The carboxylic acid is neutral and a weak electrophile.
• The 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).
 Ea
rate  A * e RT
Theory IX
• Which compounds are present in the reaction mixture after the reaction
Water Extraction:
is completed?
• Ester, 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.
NaHCO Extraction:
• The carboxylic acid and the sulfuric acid can be
extracted with a weak base i.e., NaHCO3 while
the ester and traces of the alcohol remain in the
organic layer. They are separated by a fractionated
vacuum distillation later.
• Sodium hydroxide cannot be used for the
extraction step because it would destroy the ester
(saponification) due to its higher nucleophilicity.
organic phase
RCO2H
R'OH
RCO2R'
H2SO4
RCO2R'
RCO2H
H2SO4
1. mix
RCO2H
ROH
H2SO4
aqueous phase
t=0
t >> 0
(water just added)
3
organic phase
R'OH
RCO2R'
RCO2H
R'OH
RCO2R'
H2SO4
1. mix
R'OH
Na+RCO2–
Na+HSO4-
aqueous phase
(5% NaHCO 3)
t=0
t >> 0
(5% NaHCO3 just added)
O
O
+ OH-
R
OR'
+ R'OH
R
base-catalyzed ester hydrolysis
e.g. conversion of f ats to soap
O-
Experiment I
• Dissolve the unknown
• How much of the acid is used
carboxylic acid in the alcohol
for the reaction? 1.0 g
in a 10 mL round-bottomed
• How much alcohol should be
flask (both assigned by your
used here? 5 mol equivalents
TA)
• Why is a 10 mL roundbottomed flask used here?
• Add a few drops of
• How much is appropriate
concentrated sulfuric acid
here? 3-4 drops
• Reflux the mixture for at least • What does this imply in terms
60 minutes (the longer the
of equipment and setup?
1. Air condenser with wet paper towel
better)
2. Stir bar
3. Drying tube with CaCl2
Experiment II
• Cool the reaction mixture down
• Add ice-cold water to the reaction
mixture
• How can this be accomplished
quickly? Ice-bath
• Which container should be
used here? Centrifuge tube
• Why is the water added?
To cause a phase separation
• How much water should be added?
Usually 4-8 mL
• What should the student observe/not
observe here?
The formation of a solid indicates
a poor conversion of the acid
• Remove the organic layer
• Which one is the organic layer here?
Usually the bottom layer=ester
Experiment III
• Extract the aqueous layer with
diethyl ether
• Why is the aqueous layer
extracted with ether?
To collect the suspended and
dissolved ester
• Combine all organic layers
• Extract the combined organic
layers with sodium bicarbonate
solution
• How much ether should be
used here? 2 x 3 mL
• Which layers does this referred
to? Ester + two ether layers
• Why is this step performed?
• How much solution is used
here? 1-2 mL portions
• How many extractions should
be performed?
Until the CO2 formation ceases
Experiment IV
•
•
•
How much drying should be used?
A small amount to start with!
•
Why is a vacuum distillation performed
here?
Vapor Pressure of Methyl Benzoate
Vapor Pressure (in mmHg)
•
Dry the organic layer over anhydrous
sodium sulfate
Remove the ether and remaining alcohol
using the rotary evaporator
Perform vacuum distillation
Note that the drying tube
does not contain cotton or CaCl2!
•
•
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)
200, 760
175, 400
151, 200
131, 100
117, 60
108, 40
92, 20
77, 10
64, 5
100
10
1
39, 1
20
70
120
170
Boiling Point (oC)
•
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 for
both liquids and only submit the
“ester” for NMR analysis
Characterization I
• Infrared Spectrum
n(OH)
• Benzoic acid
• n(C=O)=1689 cm-1
• n(OH)=2300-3300 cm-1
• n(C-OH)=1030 cm-1
n(C=O)
n(C-OH)
• Methanol
• n(OH)=3347 cm-1
• n(C-OH)=1030 cm-1
n(OH)
n(C-OH)
• Methyl benzoate
• n(C=O)=1724 cm-1
• n(COC)=1112, 1279 cm-1
• No OH peaks in the ester
n(C=O)
n(COC)
Characterization II
• Refractometry
light

• The refractive index is a physical property
specific to a compound
• Light 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
Adjust the height of the
dark field so that the edge
intersects with the crosshair
before adding sample after adding sample
to refractometer
to refractometer (ideal)
after adding sample to
refractometer (non ideal)
• The refractive index is wavelength and temperature
dependent (l=589 nm, T=recording temperature)
n DX = n TD + (T-X)*0.00045
angle
theta
con den sed medium
surface

angle
phi
Characterization III
• 1H-NMR Spectrum for Methyl benzoate
9.5
O
d, 2 H
ortho
9.0
8.5
O
8.0
5.5
CH3
5.0
s, 3 H
OCH3
7.5
7.0
6.5
4.5
t, 2 H
t, 1 H meta
para
4.0
6.0
3.5
5.5
5.0
3.0
4.5
4.0
2.5
3.5
2.0
3.0
2.5
1.5
2.0
1.0
1.5
1.0
0.5
0.5
0.0
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
0.0
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
7.00
Characterization IV
•
13C{1H}-NMR
Spectrum for Methyl benzoate
120
120
O
115
10
7
110
128.40(5;3)
129.70(2;6)
105
6
100
5
95
9
75
70
65
65
60
60
133.76(4)
50
45
45
40
40
35
35
30
30
25
25
CDCl3
170.39(7)
130.02(1)
15
76.28(Sol.)
77.08(Sol.)
77.88(Sol.)
10
5
5
0
CDCl3
20
76.28(Sol.)
77.08(Sol.)
77.88(Sol.)
10
3
55
51.00(9)
50
166.80(7)
2
80
70
15
4
85
75
20
8
90
2
132.80(4)
OH
1
95
3
55
5
100
8
80
6
128.45(5;3)
130.19(2;6)
105
CH3
O
1
4
9
7
110
90
85
O
115
170
160
150
140
130
120
110
100
90
80
70
60
50
40
0
180
170
160
150
140
130
120
110
100
90
80
70
Characterization V
• What is that?
120
115
17
110
16
128.00
128.45
129.50
130.19
105
15
65.90
15.20
100
95
14
90
13
85
12
80
75
11
70
10
65
9
60
132.40
133.76
55
8
60.80
14.40
18.14
50
7
76.28
77.08
77.88
45
6
40
35
5
30
4
25
3
20
15
170.39
166.30
2
10
1
5
0
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
0.0
0
150
100
50
0
General Hints
• The reaction should be started as soon as possible in order to have
a long enough reaction time.
• Dry glassware is very important here.
• The reaction mixture has to be properly refluxed.
• The 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 alcohol.
• Do not obtain the melting point for the carboxylic acid.