Lab SYN1:

Two-Step Synthesis Part 1

Purpose

The goal of this experiment is to complete a two-step synthesis involving a haloform reaction and a subsequent

Fischer esterification. In the first week, m-nitroacetophenone will be converted to m-nitrobenzoic acid. The

product will then be analyzed using melting point, IR, 13C NMR, and 1H NMR spectroscopy.

Learning Objectives

Complete a two-step synthesis including a haloform reaction and a Fischer esterification.

Run a haloform reaction and purify if necessary.

Draw a mechanism for the haloform reaction.

Calculate a percent yield for the reaction.

Analyze the reaction product using melting point, IR, and 13C NMR, and 1H NMR spectroscopy.

Laboratory Skills

Set-up a reaction.

Purify a reaction using recrystallization.

Analyze the results of a reaction usingmelting point determination and a variety of spectral techniques.

Calculate percent yield.

Equipment

Stirring hot plate

800-mL beaker

Stir bar

IR spectroscopy

instrument

Vacuum filtration

set-up

Chemicals

m-

Nitroacetophenone

5% NaOCl (bleach)

10% NaOH

Acetone

Concentrated HCl

Recrystallization

solvents

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SYN1.1

Two-Step Synthesis Part 1

Introduction

Organic Synthesis

Most real-world organic synthesis involve a chain (often a long chain) of reactions where one product of a re-

action becomes the starting material of another reaction. Although organic synthesis can trace its roots back to

FriederichWohler’s synthesis of urea from ammonium cyanate in 1828, followed by Hermann Kolbe’s synthesis

of acetic acid in 1845, modern organic synthesis can be traced to the great natural product chemists (Woodward,

Robinson, Willstatter, Fischer, Eschenmoser, Corey, Nicolaou, Schreiber, Sharpless and many more) of the mid-

to late-20𝑡ℎ century. Woodward’s total synthesis of the natural product strychnine took 21 steps in 1955 (Overman

cut this down to 18 in 1993 and Bradley accomplished it in 6 steps in 2011).

Every reaction in Woodward’s initial total synthesis of strychnine used chemistry is taught in the sophomore

organic chemistry course. The elegance and complexity of this synthesis using the simplest organic reactions

earned this synthesis the place of honor as the first synthesis written about in KC Nicolaou’s ground-breaking

book, Classics in Total Synthesis.

The total synthesis of any molecule, even a simple two-step synthesis like your experiment, involves the use of

many techniques beyond the steps in the reaction, such as the isolation of the product from the solvent and

inorganic materials, the purification of the product and the characterization of the product.

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SYN1.2

Two-Step Synthesis Part 1

Overview of Reactions of Two-Step Synthesis Experiment

For this next lab, you will be performing a two-step synthesis that takes two weeks to complete. During the

first week, you will convert a methyl ketone to a carboxylic acid using a variation of the haloform reaction (Fig-

ure SYN1.1). In the second week, you will convert the carboxylic acid to an ester using Fischer esterification

(Figure SYN1.2).

Figure SYN1.1: Step 1: Modified haloform reaction to convert a methyl ke-

tone to a carboxylic acid

Figure SYN1.2: Step 2: Converting a carboxylic acid to an ester

with a Fischer esterification

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SYN1.3

Two-Step Synthesis Part 1

Week 1 Haloform Reaction

The first week of lab focuses on the use of the haloform reaction to convert a methyl ketone to a carboxylic acid.

The haloform reaction is a chemical reaction where the methyl group alpha to a ketone is exhaustively halo-

genated to –CX3 in the presence of a base as shown in Figure SYN1.3.

Figure SYN1.3: Standard haloform reaction

This reaction can be used to transform acetyl groups into carboxyl groups or to produce chloroform (CHCl3), bro-

moform (CHBr3), or iodoform (CHI3). When the alpha-carbon has been exhaustively halogenated, the molecule

undergoes a nucleophilic acyl substitution by hydroxide, with −C𝑋3 being the leaving group stabilized by three

electron-withdrawing groups. The mechanism for this reaction is shown in Figure SYN1.4.

Figure SYN1.4: Mechanism for the standard haloform reaction

Alternatively, the haloform reaction can be completed using bleach (sodium hypochlorite) as shown in Fig-

ure SYN1.5. This eliminates the need to use the toxic Cl2 or Br2 gas in this case. For this week’s experiment,

you will perform a modified haloform reaction to convert m-nitroacetophenone to a m-nitrobenzoic acid via a

modified haloform reaction as shown in Figure SYN1.1.

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SYN1.4

Two-Step Synthesis Part 1

Figure SYN1.5: Mechanism for the modified haloform reaction using bleach

This haloform reaction is done on a fairly large scale, using 8 grams of m-nitroacetophenone, 320 mL of bleach

and 20 mL of 10% NaOH. The reagents are mixed for 30-40 minutes and then acetone is added to neutralize any

remaining bleach; HCl is added to protonate the carboxylate salt to a carboxylic acid, which is isolated using fil-

tration and then purified (if necessary) using recrystallization. The product will then be analyzed (characterized)

using IR, 13C NMR, and 1H NMR spectroscopy.

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SYN1.5

Two-Step Synthesis Part 1

Procedure

Safety Precautions

Always wear safety glasses.

m-Nitroacetophenone and m-nitrobenzoic acid are both skin and eye irritants.

NaOCl, NaOH, and HCl are all corrosive.

Acetone is flammable.

1. Place 8.0 g of m-nitroacetophenone in an 800-mL beaker.

2. Add 320 mL of 5% NaOCl and 20 mL of 10% NaOH to the m-nitroacetophenone in the beaker.

3. Add a stir bar to the mixture.

4. Warm this mixture to 60-70 °C with stirring for 30-45 minutes until all of the reactant has dissolved (the

starting material will appear to go into solution).

5. Remove the beaker from the heat after everything dissolves.

6. Slowly add 4 mL acetone to destroy the excess NaOCl.

Acetone is amethyl ketone so it will be converted to acetic acid as it reacts/destroys excess

NaOCl.

7. Cool the mixture in an ice bath.

8. Add concentrated HCl slowly while continuously stirring until the pH is 2-3. Use pH paper to determine

test the pH. It may take a total of 20-30 mL of HCl to neutralize excess base.

9. After neutralization, thoroughly cool the beaker in an ice bath until the entire crystalline product has pre-

cipitated out of solution.

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SYN1.6

Two-Step Synthesis Part 1

10. Filter the product using vacuum filtration.

11. Purify via recrystallization if needed. Remember, the five steps for recrystallization are:

a Choose solvent. An ideal solvent will NOT dissolve the crystalline product at room temperature but

will dissolve the product as heated.

b Dissolve in minimum amount of hot solvent.

c Cool to room temperature slowly and then cool on ice.

d Isolate with vacuum filtration.

e Dry the crystals. This could be done by using the rotary evaporator to remove excess solvent.

12. Allow the material to dry uncovered in your drawer, if needed.

13. Obtain a mass for your product.

14. Obtain a melting point for your product.

15. Obtain an IR spectrum of your product.

Laboratory Manual Prepared by Catalyst Education, LLC for Wayne State UniversityDepartment of Chemistry.

SYN1.7

Two-Step Synthesis Part 1

Laboratory Manual Prepared by Catalyst Education, LLC for Wayne State UniversityDepartment of Chemistry.

SYN1.8

Report Sheet:

Two-Step Synthesis Part 1

Name:

Section: Date:

Reaction Overview

The purpose of this experiment is to:

Balanced equations for the haloform reaction:

Mechanism for the haloform conversion of m-nitroacetophenone tom-nitrobenzoic acid (use either the standardhaloform mechanism or the modified haloform mechanism):

Laboratory Manual Prepared by Catalyst Education, LLC for Wayne State UniversityDepartment of Chemistry.

SYN1.1

Two-Step Synthesis Part 1 Report Sheet

Reagent Data For Week 1

List of all reagents, catalysts, and solvents. Include all data in Report Table SYN1.1.

Report Table SYN1.1: Reagent Table

Reagent/Catalyst Molar Mass(g/mol)

Quantity Used (gor mL

Density Moles

m-nitroacetophenone

N/A

5% NaOCl

10% NaOH

Show Calculations for Reagent Table:

Yields

Complete Report Table SYN1.2 with data for the calculation of yields.

Report Table SYN1.2: Product Table

Product Molar Mass(g/mol)

QuantityObtained (g)

Theoretical Yield(g)

% Yield

m-nitrobenzoicacid

Theoretical yield calculation for m-nitrobenzoic acid (Week 1):

Percent yield calculation for m-nitrobenzoic acid (Week 1):

Show your calculation for percent yield:

Laboratory Manual Prepared by Catalyst Education, LLC for Wayne State UniversityDepartment of Chemistry.

SYN1.2

Two-Step Synthesis Part 1 Report Sheet

Melting Point Determination

The literature value of the melting point of m-nitrobenzoic acid:

The experimental value of the melting point of m-nitrobenzoic acid:

Comment on the purity of the product based on the melting point determination.

IR Analysis

Analyze and upload an original IR spectrum of m-nitrobenzoic acid.

Laboratory Manual Prepared by Catalyst Education, LLC for Wayne State UniversityDepartment of Chemistry.

SYN1.3

Two-Step Synthesis Part 1 Report Sheet

13C NMR Analysis

Interpret the 13CNMRspectrum for them-nitrobenzoic acid product provided below. Draw the indicated producton the spectra and then draw arrows from each carbon atom on the structure to their corresponding peak in theNMR spectrum.

The NMR solvent used was deuterated chloroform (CDCl3). You will see a three-linepeak in the 13C NMR at 77 ppm. Ignore this peak.

Upload the analyzed 13C NMR spectrum.

Laboratory Manual Prepared by Catalyst Education, LLC for Wayne State UniversityDepartment of Chemistry.

SYN1.4

Two-Step Synthesis Part 1 Report Sheet

1H NMR Analysis

Interpret the 1HNMR spectrum for them-nitrobenzoic acid product provided below. Draw the indicated producton the spectra and then draw arrows from each carbon atom on the structure to their corresponding peak in theNMR spectrum.

The NMR solvent used was deuterated chloroform (CDCl3). Due to contamination withprotonated chloroform (CHCl3), you will see a singlet peak in the 1H NMR at 7.26 ppmwith NO INTEGRATION. Ignore this peak.

Upload the analyzed 1H NMR spectrum.

Laboratory Manual Prepared by Catalyst Education, LLC for Wayne State UniversityDepartment of Chemistry.

SYN1.5