Experiment 20

CHEMOSELECTIVE REDUCTION WITH NaBH4

CO H

OCH3

OH

H3C O CH3

O O

+

CO H

OCH3

O

CH3

O

NaBH4EtOHNaOH

CH2

HO

OCH3

O

CH3

O

4-hydroxy-3-methoxybenzaldehyde(p-vanillin)

acetic anhydride

4-acetoxy-3-methoxybenzaldehyde(vanillin acetate)

4-acetoxy-3-methoxybenzyl alcohol(vanillin alcohol)

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 c 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)

CO H

OCH3

OH

H3C O CH3

O O

+

CO H

OCH3

O

CH3

O

NaOH

4-hydroxy-3-methoxybenzaldehyde(p-vanillin)

acetic anhydride

4-acetoxy-3-methoxybenzaldehyde(vanillin acetate)

MECHANISM(Acetylation)

CO H

OCH3

O

H3CC

OC

CH3

O O

+

CO H

OCH3

O

CH3

O

OH

4-acetoxy-3-methoxybenzaldehyde(vanillin acetate)

H

CO H

OCH3

O

+

CO H

OCH3

O

C OH3C

O

C O

CH3

H3CC

OH

O

H2O

+

+

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)

CO H

OCH3

O

CH3

O

NaBH4EtOH

CH2

HO

OCH3

O

CH3

O

4-acetoxy-3-methoxybenzaldehyde(vanillin acetate) 4-acetoxy-3-methoxybenzyl alcohol

(vanillin alcohol)

CH2

HO

OCH3

OH

4-hydroxy-3-methoxybenzyl alcohol(vanillyl alcohol)

+ ?4 moles 4 moles

1 mole

*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 and amides.B H

H

H

H

Na+

Al H

H

H

H

Li+

H

Sodiumborohydride

Lithiumaluminumhydride

Hydrideion

MECHANISM(Reduction)

CO H

OCH3

O

CH3

O

CH2

HO

OCH3

O

CH3

O

4-acetoxy-3-methoxybenzaldehyde(vanillin acetate)

4-acetoxy-3-methoxybenzyl alcohol(vanillin alcohol)

B

H

H H

H

C

O

H

OCH3

O

CH3

O

H H OCH2CH3CH2

HO

OCH3

OH

+ ?

4-hydroxy-3-methoxybenzyl alcohol(vanillyl alcohol)

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 2,4-DNP.

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

A B

filter paper

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 20.4Theoretical yield (g) Calculated based on DAY

1 productActual yield (g) Obtained NEXT LAB

Percent yield Calculated NEXT LAB

Product Appearance Recorded on DAY 2

Atom Economy (%) Calculated DAY 2Experimental Atom Economy

(%)Calculated DAY 2

“Eproduct” Calculated NEXT LABCost per synthesis ($) Calculated DAY 2Cost per gram ($/g) 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 Standard

SampleACYLATION PRODUCT

PURE REDUCTION PRODUCT

Retention Times (min)

Retention Times (min)

Area Percent

Retention Times

(min)

Area Percen

tp-vanillin

Vanillin acetateVanillin alcoholVanillyl alcohol

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.

Table 20.6: CompoundTLC Rf values TLC

Diagram

Standard Samplep-vanillinVanillin acetateVanillin alcoholVanillyl alcohol

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 p-vanillin Vanillin

acetateVanillin alcohol

Frequency

(cm-1)

Frequency (cm-1)

Frequency (cm-1)

Frequency (cm-1)

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

Aldehyde C-H stretch

2700-2800

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 Vanillin acetate Vanillin alcohol

CO H

OCH3

OH

1

2

4

3

5

6

CO H

OCH3

OC

CH3

O

1

2

3

4

5

6

CH2

OCH3

OC

CH3

O

OH1

2

3

4

5

6

7

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!)

• REFERENCE TO PROCEDURE (Must include…)• full title including edition and author names• numbers where actual procedure can be found

Compound MW (g/mol)

mp(oC) bp(oC) d (g/mL) HAZARDS

p-vanillin X XVanillin acetate X XVanillin alcohol 196.20 X X X irritant

Acetic anhydride XEthanol X

Ethyl acetate XAcetone XHexane X

Diethyl ether XSodium borohydride X X

2,4-dintrophenylhydrazine X X

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 1)

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)

LABORATORY NOTEBOOK(In-lab—Part 2)

• 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.