Experiment 20
NaBH4
Reduction of p-Vanillin
O
HO
H
CH2
C
+
1. NaBH4
2. H3O+ workup
OCH3
OCH3
OH
4-hydroxy-3-methoxybenzaldehyde
(p-vanillin)
OH
4-hydroxy-3-methoxybenzyl alcohol
(vanillyl alcohol)
Objectives:




To synthesize vanillyl alcohol by reduction
of p-vanillin using NaBH4.
To purify the product by recrystallization.
To identify product and analyze the purity
using TLC, HPLC and melting point analysis.
To characterize the reactants and
product using 1H-NMR and IR
spectroscopy.
Before coming to lab…

Review these techniques:

Vacuum filtration

Recrystallization

TLC Analysis

HPLC analysis

Melting point analysis
CHEMICAL EQUATION
This is provided as a
solution. Be sure you
understand how to
calculate theoretical yield!
O
HO
H
CH2
C
+
1. NaBH4
2. H3O+ workup
OCH3
OCH3
OH
4-hydroxy-3-methoxybenzaldehyde
(p-vanillin)
OH
4-hydroxy-3-methoxybenzyl alcohol
(vanillyl alcohol)
MECHANISM
O
H
C
O
H
H
B
H
H
C
HO
H
CH2
H
O
H
H
H
+ H2O + B(OH)3
(from 6M HCl)
OH
4-hydroxy-3-methoxybenzaldehyde
(p-vanillin)
OCH3
OCH3
OCH3
OH
OH
4-hydroxy-3-methoxybenzyl alcohol
(vanillyl alcohol)
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
Sodium
borohydride
H
Al
H
H
Lithium
aluminum
hydride
H
Hydride
ion
TLC STAIN—2,4-DNP
R
H
C
HN
NH 2
HN
O
NO2
N
NO2
+
H
R
aldehyde or ketone
NO2
2,4-DNP
(red-orange)
NO2
product hydrazone
(yellow-orange)
2,4-DNP is a TLC stain used to detect
aldehydes and ketones
OVERVIEW

Dissolve p-vanillin in ethanol.

Add NaBH4 solution drop-wise via addition funnel while stirring.

Add 6M HCl to hydrolyze intermediate, forming alcohol product.

Isolate crude product by vacuum filtration.

Recrystallize the product from ethanol.

Prepare TLC and HPLC samples—submit HPLC sample for analysis.

Perform TLC experiment on product, staining with 2,4-DNP stain.

Obtain final mass of product and calculate % yield.

Perform melting point analysis.

Identify IR absorptions and 1H-NMR signals using provided spectra.

Analyze HPLC results.
SYNTHESIS




Mix p-vanillin and ethanol in a
water cooled 25 mL flask with
stir bar until dissolved.
Set up apparatus shown. Add
NaBH4/NaOH solution to
separatory funnel.
Add a few ice cubes to the
water bath.
Begin adding NaBH4/NaOH
solution SLOWLY.
7
8
6 5
4
3
2
9
1
0
1
7
8
9
6 5
11
4
3
2
1
SYNTHESIS



Remove water bath. Stir 5
min.
Return ice water bath. Add
6M HCl until pH = 6.
Stir for 10 min. in ice bath.
CRUDE PRODUCT ISOLATION



Suction filter to isolate crude
solid.
Rinse solid in funnel with icecold water.
Dry solid under vacuum for a
few minutes.
PURIFICATION—
Recrystallization

Transfer crude solid to a 50 mL
Erlenmeyer flask using a powder funnel.

Rinse funnel with ethanol.

Heat to dissolve product.

Remove and filter to remove boric acid.

Transfer filtrate to preweighed 150 mL
beaker and evaporate solvent.

Reweigh to obtain final product mass.

Proceed to PRODUCT ANALYSIS.
PRODUCT ANALYSIS




Prepare TLC and HPLC sample of solid
product.
Submit HPLC sample for analysis.
Prepare TLC plate using sample and
provided standards.
filter paper
Develop plate and visualize under UV.
A

Stain plate with 2,4-DNP TLC stain.
B
C
PRODUCT ANALYSIS—TLC

TLC Analysis
 Used 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.
Table 20.1 TLC Results
Rf values
should always
be recorded to
2 decimal
places! Never
more, never
less!
Compound
p-vanillin
Vanillyl Alcohol
Standard
Rf
Sample
Rf
TLC
Diagram
Sketch the plate
as much to scale
as possible!
Include cm
measurements
for all spots and
solvent front!
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 20.2 IR Analysis
Functional Group
OH stretch
C-O stretch
C=O stretch
Base
Values
p-vanillin
Vanillyl alcohol
Frequency
(cm-1)
Frequency
(cm-1)
Frequency
(cm-1)
3200-3600
1000-1300
1680-1740
Notice that
the product
should have
2 entries for
O-H and C-O!
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.
O
This is
where the
major
change is!
H1
C
6
2
HO
7
CH2
1
6
2
5
5
OCH3
OCH3
3
3
OH
4
OH
4
Tables 20.4 and 20.5
O
H
C
Table 20.4: Experimental Results
CH2OH
Theoretical yield (g)
Actual yield (g)
Percent yield
Product Appearance
Experimental Melting Point (oC)
NaBH4
sodium borohydride
$112.20/100g
CH3CH2OH
OCH3
OH
4-hydroxy-3-methoxy
benzaldehyde
(p-vanillin)
$13.10/100g
ethanol
$23.66/500mL
OCH3
OH
4-hydroxy-3-methoxy
benzylalcohol
(vanillyl alcohol)
$22.90/50g
Table 20.5: Green Chemistry Results
Atom Economy (%)
Experimental Atom Economy (%)
“Eproduct”
Cost per synthesis ($)
Cost per gram ($/g)
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 20.6: HPLC Analysis
Compound
p-vanillin
Vanillyl alcohol
HPLC Retention Times
(min)
Standard
Sample
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.
Compound
p-vanillin
Vanillyl alcohol
HPLC Retention Times
(min)
Standard
Sample
SAFETY CONCERNS



Ethanol, ethyl acetate, hexane, 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 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.
IN LAB QUESTION
(The following question should be answered in laboratory notebook.)

Draw the product, and a complete mechanism
for its formation, for the following reaction.
In your mechanism, use only the hydride ion
as your nucleophile.
O
1. NaBH4
2. H3O+ workup
?