Experiment 20
CHEMOSELECTIVE REDUCTION
WITH NaBH4
O
O
H
H
HO
C
C
O
CH 2
O
NaBH
+
H 3C
OCH
3
OH
4 -h yd ro xy-3 -m e th o xyb e n za ld e h yd e
(p -v a n illin )
O
CH 3
4
EtOH
NaOH
OCH
a c e tic a n h yd rid e
O
OCH
3
O
CH 3
4 -a c e to xy-3 -m e th o xyb e n za ld e h yd e
(v a n illin a c e ta te )
O
3
O
CH 3
4 -a c e to xy-3 -m e th o xyb e n zyl a lc o h o l
(v a n illin a lc o h o l)
Objectives:




To synthesize vanillin acetate by
acetylation of p-vanillin, then to perform a
chemoselective reduction using NaBH4.
To use TLC to follow the course of the
reaction.
To analyze the purity of products using
TLC, HPLC and melting point analysis.
To characterize the reactants and
products using 1H-NMR and IR
spectroscopy.
Before coming to lab…

Review these techniques:

Vacuum filtration

TLC Analysis

HPLC analysis

Melting point analysis

Extraction
CHEMICAL EQUATION
(Acetylation)
O
O
H
H
C
C
O
O
+
H 3C
OCH
3
OH
4 -h yd ro xy-3 -m e th o xyb e n za ld e h yd e
(p -v a n illin )
O
CH 3
NaOH
OCH
a c e tic a n h yd rid e
O
3
O
CH 3
4 -a c e to xy-3 -m e th o xyb e n za ld e h yd e
(v a n illin a c e ta te )
MECHANISM
(Acetylation)
O
O
H
O
H
C
C
C
O
OCH
O
H
O
C
+
+
OH
OCH
3
H
H 3C
C
O
CH 3
OCH
3
3
O
O
H 3C
C
O
O
C
O
CH 3
O
H
C
O
C
+
OCH
O
H 3C
OH
+
3
O
CH 3
4 -a c e to xy-3 -m e th o xyb e n za ld e h yd e
(v a n illin a c e ta te )
H 2O
OVERVIEW
(Part 1)





Synthesize vanillin acetate.
Isolate solid product using vacuum
filtration, or oily product by extraction.
Prepare HPLC sample of pure product and
submit for analysis.
Perform TLC experiment on pure product.
Secure product and allow to dry until next
lab period.
SYNTHESIS
(Preparation of Vanillin Acetate)



Mix p-vanillin and aqueous
NaOH in flask with stir bar.
Add ice, then acetic anhydride
drop wise.
Cover loosely with cork, then
stir 15 minutes.
125 mL
PURIFICATION
(Preparation of Vanillin Acetate)

If a white solid forms…
 Suction filter
 Recrystallize with ethanol
 Cool to room temp, then in
ice bath
 Suction filter again
 Prepare HPLC and TLC
samples (LABEL CLEARLY!)
 Submit solid product to
instructor to dry until next
lab period.
PURIFICATION
(Preparation of Vanillin Acetate)

If an oil forms…
 Transfer to separatory funnel and
extract 2X with ethyl acetate.
 Wash organic layer with aqueous
NaOH and check pH.
 Dry over MgSO4.
 Evaporate solvent.
 Prepare HPLC and TLC samples
(LABEL CLEARLY!)
 Submit solid product to
instructor to dry until next lab
period.
Tables 20.1 and 20.3
Theoretical yield (g)
Calculated DAY 1 based on limiting reagent
Actual yield (g)
Obtained DAY 2 after product has dried
Percent yield
Calculated DAY 2
Product Appearance
Recorded DAY 1
Experimental Melting Point (oC)
Performed DAY 2…must record Ti-Tf range!
Atom Economy (%)
Calculated DAY 1
Experimental Atom Economy (%)
Calculated DAY 1
“Eproduct”
Calculated DAY 2
Cost per synthesis ($)
Calculated DAY 1
Cost per gram ($/g)
Calculated DAY 2
SAFETY
 Acetic
anhydride and NaOH
are both corrosive!
 Ethanol
is highly flammable!
WASTE

LIQUID WASTE: Place liquid filtrate
from vacuum filtration in this container.
CHEMICAL EQUATION
(Reduction)
O
H
NaBH
4 m o le s
EtOH
OCH
4
CH 2
CH 2
1 m o le
O
HO
HO
C
3
O
?
+
4 m o le s
OCH
O
OCH
3
O
3
OH
4 -h yd ro xy-3 -m e th o xyb e n zyl a lc o h o l
(v a n illyl a lc o h o l)
CH 3
4 -a c e to xy-3 -m e th o xyb e n za ld e h yd e
(v a n illin a c e ta te )
CH 3
4 -a c e to xy-3 -m e th o xyb e n zyl a lc o h o l
(v a n illin a lc o h o l)
*NOTE* Stoichiometry for this reaction is
4:1. This means that 1 mole of NaBH4 can
reduce 4 moles of carbonyl compound, to
produce 4 moles of the product.
REDUCING AGENTS



Reducing agents cause a reaction resulting in a product
containing more bonds from carbon to hydrogen (or
fewer bonds to oxygen).
NaBH4 (sodium borohydride) is a versatile and useful
reducing agent in organic chemistry, however will only
reduce carbonyl groups of aldehydes and ketones.
LAH (lithium aluminum hydride) is another common
reducing agent, however use of this reducing agent will
result in the reduction of many other carbonyl
containing compounds, including esters, carboxylic acids
+
+
H
H
Li
Na
and amides.
H
B
H
H
S o d iu m
b o ro h yd rid e
H
Al
H
L ith iu m
a lu m in u m
h yd rid e
H
H
H yd rid e
io n
MECHANISM
(Reduction)
O
H
C
O
H
H
HO
HO
B
H
H
C
H
H
OCH 2 CH 3
CH 2
CH 2
H
?
+
OCH
O
OCH
3
O
O
O
OCH
3
O
OCH
3
O
3
OH
4 -h yd ro xy-3 -m e th o xyb e n zyl a lc o h o l
(v a n illyl a lc o h o l)
CH 3
4 -a c e to xy-3 -m e th o xyb e n za ld e h yd e
(v a n illin a c e ta te )
CH 3
CH 3
4 -a c e to xy-3 -m e th o xyb e n zyl a lc o h o l
(v a n illin a lc o h o l)
OVERVIEW
(Part 2)



Reweigh ACYLATION PRODUCT, perform
melting point analysis.
Cool, then react with NaBH4 in ethanol.
TLC @ 30min to determine reaction
progress.

If complete, transfer to sep funnel.

Perform extraction, dry organic layer.

Evaporate solvent, obtain product mass.

Submit HPLC samples for analysis.

Perform final TLC analysis and stain in 2,4DNP.
SYNTHESIS
(Reduction)






Reweigh solid product from previous
lab, calculate % yield, and obtain mp.
Transfer solid to flask w/stir bar and
dissolve in ethanol.
Cool in ice bath, then slowly add
NaBH4 while stirring.
Stir at 0oC for 15 min, then 15 min
more at RT.
Perform TLC experiment to determine
reaction progress.
If complete, add 10 mL water and stir
5 minutes.
50
mL
filte r p a p e r
A
B
C
PURIFICATION
(Reduction)







Transfer reaction solution to
separatory funnel.
Extract 2X with diethyl ether.
Wash with water and brine.
Dry organic layer over MgSO4.
Decant liquid ONLY into tared
flask and evaporate solvent.
Obtain product mass & calculate
% yield.
Prepare HPLC and TLC samples.
Tables 20.2 and 20.4
Theoretical yield (g)
Actual yield (g)
Calculated based on DAY 1
product
Obtained NEXT LAB
Percent yield
Calculated NEXT LAB
Product Appearance
Recorded on DAY 2
Atom Economy (%)
Experimental Atom Economy (%)
Calculated DAY 2
Calculated DAY 2
“Eproduct”
Cost per synthesis ($)
Cost per gram ($/g)
Calculated NEXT LAB
Calculated DAY 2
Calculated NEXT LAB
PRODUCT ANALYSIS—HPLC

HPLC Analysis
 Used at the end of the experiment to
identify and quantify compounds present
during the synthesis, as well as the purity
of the final products from each step.
 Table 20.5:
Compound
p-vanillin
Vanillin acetate
Vanillin alcohol
Vanillyl alcohol
Standard
Retention
Times
(min)
Sample
ACYLATION
PURE REDUCTION
PRODUCT
PRODUCT
Retention
Area
Retention
Area
Times
Percent
Times
Percent
(min)
(min)
PRODUCT ANALYSIS—TLC

TLC Analysis
 Used to determine reaction progress during the
course of the experiment, as well as to identify
and determine purity of products at the end of
the experiment.
 2,4-DNP will be used as a stain to detect the
presence/absence of the aldehyde functional
group.
TLC R values
TLC Diagram
 Table 20.6:
Compound
f
p-vanillin
Vanillin acetate
Vanillin alcohol
Vanillyl alcohol
Standard
Sample
PRODUCT ANALYSIS—IR

IR Analysis
 IR spectra of reactants and products can be
used to determine the presence and absence
of certain types of functional groups which
indicate the conversion of one compound to
another during the course of the synthesis.
 Table 20.7:
Functional Group
Base
Values
OH stretch
C-O stretch
C=O stretch
Aldehyde C-H stretch
Frequency
(cm-1)
3200-3600
1000-1300
1680-1740
2700-2800
p-vanillin
Frequency
(cm-1)
Vanillin
acetate
Frequency
(cm-1)
Vanillin
alcohol
Frequency
(cm-1)
PRODUCT ANALYSIS—NMR

NMR Analysis
 1H-NMR spectra of reactants and products can
be used to determine the presence and
absence of certain types of signals which
indicate the conversion of one compound to
another during the course of the synthesis.
 Table 20.8:
p-vanillin
O
Vanillin acetate
O
H1
C
C
Vanillin alcohol
H1
CH 2 OH
7
1
2
6
6
6
2
2
5
5
OCH
5
OCH
3
OH
3
3
O
CH 3
C
4
OCH
3
3
O
CH 3
C
4
O
O
4
3
SAFETY CONCERNS



Ethanol, ethyl acetate, hexane, diethyl
ether, and acetone are all FLAMMABLE
materials.
Sodium borohydride and 2,4-DNP are
TOXIC in large concentrations.
Sulfuric acid, used to prepare 2,4-DNP
stain, is CORROSIVE.
WASTE MANAGEMENT
o
SOLID WASTE: Place all solid waste in this
container including magnesium sulfate or any solid
product.
o LIQUID WASTE : Place all liquid waste into this
container including filtrates and aqueous washes
from extraction.
o GLASS WASTE: Place used TLC and melting point
capillary tubes in this container.
o PAPER WASTE: Place any gloves, TLC plates,
filter papers, paper towels, etc. in the yellow
trashcan.
CLEANING


Any glassware used to contain only volatile
organic solvents can simply be rinsed with
wash acetone.
All other glassware should be cleaned with
soap, water and brush, then rinsed with
wash acetone or hand dried.
LABORATORY NOTEBOOK
(Pre-lab)
• OBJECTIVE
(Must clearly state…)
• What compounds will be made and how
• What will be investigated with the compounds
• CHEMICAL EQUATION
• Include the general chemical equation from the top of page 169 from handout.
• TABLE OF PHYSICAL DATA
(Complete the following table using a site
listed on WWW Links ONLY. Wikipedia is unacceptable!)
Compound
p-vanillin
Vanillin acetate
Vanillin alcohol
Acetic anhydride
Ethanol
Ethyl acetate
Acetone
Hexane
Diethyl ether
Sodium borohydride
2,4-dintrophenylhydrazine
MW (g/mol)
mp(oC)
196.20
X
X
X
X
X
X
X
• REFERENCE TO PROCEDURE
(Must include…)
• full title including edition and author names
• numbers where actual procedure can be found
bp(oC)
X
X
X
d (g/mL)
X
X
X
X
X
X
X
HAZARDS
irritant
LABORATORY NOTEBOOK
(In-lab—Part 1)


Synthesis: Preparation of Vanillin Acetate

Weight of p-vanillin used

Weight of ice used

Volume of 10% NaOH used

Volume of acetic anhydride used

Theoretical yield calculation
Purification of Vanillin Acetate

Volume ethanol used

Weight of small filter

Weight of watch glass

HPLC vial slot # of ACYLATION PRODUCT

Weight of filter + watch glass + dry product

Final product mass

% yield calculation

Experimental melting point

Atom economy calculation

Experimental atom economy calculation

“Eproduct” calculation

Cost per synthesis calculation

Cost per gram calculation
LABORATORY NOTEBOOK
(In-lab—Part 2)

Synthesis: Reduction of Vanillin Acetate





Volume of ethanol used
Weight of sodium borohydride used
Sketch of TLC diagram (taken during experiment)
Theoretical yield calculation (based on product mass from part 1!)
Purification of Product Alcohol







Volume of diethyl ether, deionized water, and NaCl used
HPLC vial slot # of PURE REDUCTION PRODUCT
Weight of 50 mL flask
Weight of flask + product
Final product mass
% yield, Atom economy, Experimental atom economy, “Eproduct”, Cost per synthesis,
and Cost per gram calculations
Sketch of TLC diagram (taken at end of experiment)
• EXPERIMENTAL PROCEDURE
•
•
•
•
In paragraph form, BRIEFLY describe the procedure that you actually followed
during the lab.
Paragraph must be written in PAST TENSE, PASSIVE VOICE.
Include any volumes or weights of chemicals used during the experiment.
Include any mistakes, accidents or observations if applicable.