Esterification Lecture 7a
Dec 31, 2015
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