Download Lecture 7a

Esterification
 Many esters have pleasant odors and some of them can 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.
 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
esterand 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
O
well because of non-acidic
conditions 
 Accessibility of SOCl2
 Anhydride
 Accessibility of anhydrides
 Often also requires an acidic
catalyst i.e., aspirin synthesis
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 +
OR
OH
-H2O
OR
O
 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
O
O
OH
O
O
OH
O
+
OH
[H ]
Aspirin
O
O
Serin group in cyclooxygenase
is blocked and therefore the
prostagladin synthesis suppressed
CH2OH
O
O
CH2O
+
HO
HO
 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
 Intramolecular esterification afford lactones
 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.
 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 % of the US)
 If the gasoline is also included (135 billion gallons) about 85 % of the area is needed!
 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
 Mechanism of Fischer esterification
••
••
O
R C OH
OH
R C OH
+
+H
O–
R C OH
+
(charge separation)
••
R'–OH
••
OH
R C OH
H O R'
OH
R C OH
– H+
OH
R C OH
O R'
activated carbonyl
(no charge separation)
better electrophile
+ H+
–H
+
+
OH
R C OR'
••
••
O
R C OR'
–H2O
OH
H
H2 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
 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 
 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)
 A very strong mineral acid is 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
E
doubles (Arrhenius equation)
a
rate  A * e RT
 Which compounds are present in the reaction mixture after the reaction
Water Extraction:
is completed?
 Ester (hopefully), alcohol (used in excess), carboxylic acid (should
be a small amount), sulfuric acid (used as the catalyst)
organic phase
RCO2H
R'OH
RCO2R'
H2SO4
RCO2R'
RCO2H
H2SO4
1. mix
RCO2H
ROH
H2SO4
aqueous phase
 All of the alcohols (log Kow= -0.77 (MeOH), -0.24 (EtOH), 0.05 (iso-PrOH),
t=0
t >> 0
(water just added)
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
3
organic phase
R'OH
RCO2R'
RCO2H
R'OH
RCO2R'
H2SO4
1. mix
aqueous phase
(5% NaHCO 3)
R'OH
Na+RCO2–
Na+HSO4-
t=0
(5% NaHCO3 just added)
t >> 0
O
O
+ OH-
R
OR'
R
base-catalyzed ester hydrolysis
e.g. conversion of f ats to soap
+ R'OH
O-
 Dissolve the carboxylic acid
in the alcohol in a 10 mL
round-bottomed flask (both
assigned by your TA)
 How much of the acid is used
for the reaction? 1.0 g
 How much alcohol should be
used here? 5 mol equivalents
 Why is a 10 mL round-
 Add a few drops of
concentrated sulfuric acid
 Reflux the mixture for at
least 60 minutes (the longer
the better)
bottomed flask used here?
 How much is appropriate
here? 3-4 drops
 What does this imply in terms
of equipment and setup?
1. Air condenser with wet paper towel
2. Stir bar
3. Drying tube with CaCl2
 Cool the 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?
 How much water should be
added?
Until a phase separation
is observed usually 4-8 mL
 What should the student
observe/not observe here?
The formation of a solid is bad
 Remove the organic layer
 Which one is the organic layer
here?
Usually the bottom layer=ester
 Extract the aqueous layer with
 Why is the aqueous layer
diethyl ether
extracted with ether?
To collect the suspended and
dissolved ester
 How much ether should be used
 Combine all organic layers

 Extract the combined organic

layers with sodium bicarbonate
solution


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
How many extractions should
be performed?
Until the CO2 formation ceases
Dry the organic layer over anhydrous sodium
sulfate


Remove the ether and remaining alcohol
using the rotary evaporator


Perform vacuum distillation
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)

200, 760
175, 400
151, 200
131, 100
117, 60
108, 40
100
92, 20
77, 10
10
64, 5
1
39, 1
20
70
120
Boiling Point
170
(oC)
Note that the drying tube
does not contain cotton or CaCl2!

What is the setup for the 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 semisolid) for NMR analysis (label vial and sign
in the sample as well)
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
 Infrared spectrum
n(OH)
 Benzoic acid
 n(C=O)=1689 cm-1
 n(OH)=2300-3300 cm-1
 Methanol
 n(OH)=3347 cm-1
 n(C-OH)=1030 cm-1
n(C=O)
n(OH)
n(C-OH)
 Methyl benzoate
 n(C=O)=1724 cm-1
 n(COC)=1112, 1279 cm-1
(absence of OH peak!)
n(C=O)
n(COC)
 Refractometry
light
 The refractive index is a physical property

angle
theta
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
con den sed medium
surface

angle
phi
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
 1H-NMR spectrum for methyl benzoate
9.5
O
d, 2H
ortho
9.0
8.5
O
8.0
5.5
CH3
5.0
s, 3H
OCH3
7.5
7.0
6.5
4.5
t, 2H
t, 1H 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
13C-NMR

spectrum for methyl benzoate
120
120
O
115
110
6
128.40(5;3)
129.70(2;6)
105
5
100
CH3
9
O
1
4
5
100
OH
1
8
95
2
4
90
3
2
3
85
80
80
75
75
70
70
65
65
60
60
55
132.80(4)
55
51.00(9)
133.76(4)
50
50
45
45
40
40
35
35
30
30
25
25
20
20
170.39(7)
166.80(7)
15
130.02(1)
15
76.28(Sol.)
77.08(Sol.)
77.88(Sol.)
10
76.28(Sol.)
77.08(Sol.)
77.88(Sol.)
10
5
5
0
6
128.45(5;3)
130.19(2;6)
105
8
85
9
7
110
95
90
O
115
10
7
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
 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
 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