Experiment 20NaBH4

Reduction of p-VanillinC

O H

OCH3

OH

+ 1. NaBH4

2. H3O+ workup

CH2

HO

OCH3

OH4-hydroxy-3-methoxybenzaldehyde

(p-vanillin)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 ccharacterize 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

CO H

OCH3

OH

+ 1. NaBH4

2. H3O+ workup

CH2

HO

OCH3

OH4-hydroxy-3-methoxybenzaldehyde

(p-vanillin)4-hydroxy-3-methoxybenzyl alcohol

(vanillyl alcohol)

This is provided as a solution. Be sure you understand how to calculate theoretical yield!

MECHANISM

CO H

OCH3

OH4-hydroxy-3-methoxybenzaldehyde

(p-vanillin)

B

H

H H

H

C

O

H

OCH3

OH

H CH2

HO

OCH3

OH4-hydroxy-3-methoxybenzyl alcohol

(vanillyl alcohol)

H

OH H(from 6M HCl)

+ H2O + B(OH)3

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 and amides.B H

H

H

H

Na+

Al H

H

H

H

Li+

H

Sodiumborohydride

Lithiumaluminumhydride

Hydrideion

TLC STAIN—2,4-DNP

HN

NO2

NH2

NO2

H R

O HNN

CR H

NO2

NO2

+

2,4-DNP(red-orange)

aldehyde or ketone

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.

123

4567

89

110

23

4567

89 11

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 ice-cold 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. Develop plate and visualize under

UV. Stain plate with 2,4-DNP TLC stain.

A B

filter paper

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.

Compound Standard

Rf

Sample Rf

TLC Diagra

m

p-vanillin

Vanillyl Alcohol

Table 20.1 TLC ResultsRf values

should always be recorded to 2 decimal places! Never more, never less!

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.

Functional Group

Base Values p-vanillin Vanillyl

alcoholFrequenc

y (cm-1)

Frequency

(cm-1)

Frequency (cm-1)

OH stretch 3200-3600C-O stretch 1000-1300C=O stretch 1680-1740

Table 20.2 IR Analysis

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.

CO H

OCH3

OH

1

2

4

3

5

6

CH2

HO

OCH3

OH

2

3

5

6

1

4

7This is where the major change is!

Tables 20.4 and 20.5

Atom Economy (%)Experimental Atom

Economy (%)“Eproduct”

Cost per synthesis ($)Cost per gram ($/g)

Theoretical yield (g)Actual yield (g)Percent yield

Product AppearanceExperimental Melting

Point (oC)

Table 20.4: Experimental Results

Table 20.5: Green Chemistry Results

C

OCH3

OH

O HCH2OH

OCH3

OH

NaBH4

CH3CH2OH

4-hydroxy-3-methoxybenzaldehyde

(p-vanillin)$13.10/100g

sodium borohydride$112.20/100g

ethanol$23.66/500mL

4-hydroxy-3-methoxybenzylalcohol

(vanillyl alcohol)$22.90/50g

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.

CompoundHPLC Retention Times

(min)Standard Sample

p-vanillinVanillyl alcohol

Table 20.6: HPLC Analysis

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.

CompoundHPLC Retention Times

(min)Standard Sample

p-vanillinVanillyl alcohol

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.

O1. NaBH4

2. H3O+ workup ?