Reaction Mechanisms and Multi-Step Synthesis:
Addition of Bromine to trans-Cinnamic Acid & Elimination reactions with its product

This experiment is designed to achieve the following major objectives: 1) to use melting points and 1H NMR spectroscopy to determine the mechanisms involved in the chemical reactions you will perform and to use 1H NMR spectroscopy to identify and quantify the relative amounts of products in a product mixture; 2) to perform a multi-step synthesis and determine the overall yield for the process; 3) to practice scientific writing in the form of a formal report resembling a research publication.

Using 1H NMR spectroscopy to determine identities and relative amounts of cis/trans-isomers.

NMR spectroscopy is a powerful tool used for the identification of production.The integration and spin-spin splitting together gives information on the connectivity within a molecule.Used less often, but also useful in product identification is the coupling constant (J, the energy in Hz between adjacent peaks in a grouping).The Karplus equation (eq 1) relates the dihedral angle () with coupling constant.

(eq 1)

One of the simplest examples of this relationship is examining the difference between cis- and trans-double bonds. Protons with a cis-orientation ( = 0) typically have coupling constants between 6 - 12 Hz, while thoseon atrans-double bond ( = 180) have coupling constants ranging from 12 - 18 Hz.Your instructor will provide you with a 1H NMR spectrum for the starting material in week 1 as well as the products for weeks 1- 3. The spectra for weeks 2 and 3 will contain a mixture of both possible stereoisomeric products. The coupling constant for the protons,found between 6.4 - 7.0 ppm, can be used to determine the identities of the two sterisomers. The integration the peaks will be used to determine the relative amount of each isomer.Since the integration of a peak in a 1H NMR spectrum is proportional to the number of hydrogens in resonance, if one knows the number of protons represented by a particular integral value for more than one compound, one can use those values to determine the relative amounts of those compounds in the sample.For example, a 1H NMR spectrum is run on a sample containing two different methyl ester compounds.Ester A gives a peak for the methyl group at 3.9 ppm with an integration of 30, while ester B gives a peak for the methyl group at 3.8 ppm whose integral value is 10.Therefore, the ratio of A:B must be 30:10 (3:1) or 75%A and 25% B.

Multi-step synthesis:

The simplest example of a multi-step synthesis is to examine virtually any commercial medicine.Almost without exception that medicine was prepared by a series of reactions rather than in a single step.A multi-step synthesis generally requires a chemist to perform a chemical reaction, isolate, purify and characterize the product, then use some (or all) of the product as the starting material for the next reaction. What reasons can you think of for why someone would not want to use all of one’s product in the next reaction?In this experiment, you will be using the product of week 1 as your starting material for week 2 and week 3.It will be important for you to have the product from week 1 properly identified so you can correctly predict the product of the following weeks’ reaction.So how does one calculate the overall % yield for the two reactions when one does not use all of the product from the previous reaction?Actually, it is simple; one multiplies the % yields for the two reactions together.You will be asked to prove this in a postlab question.

Formal Report

Guidelines for formal lab report:

Scientific writing is used to provide your peers with your experimental findings. It should be written in third person, passive voice.Individuals should write in complete sentences, not phrases.Short, concise and informative sentencesare preferred. Reports must be typed on 8.5 x 11 inch paper, using chemical drawing software for all structures, and include the following sections:

1. Title Page

The title page should include the following information: title of the experiment, name(s) of the person who performed the experiment, and date(s) on which the experiment was conducted

2. Abstract

The abstract is a short summary of the report. It should be no more than one paragraph (50 – 100 words) and include the following main points: purpose of the experiment, key results and main conclusions.

3. Introduction

A 2-3 paragraph introduction to describe the experiment that you did in broad, general terms. A good introduction should have objectives of the experiment with a brief description of the theory and the experimental methods necessary to solve the problem.

Items to address in your Introduction

Week 1

a.The mechanistic possibilities for this type of reaction and the resulting stereochemical outcomes.

b.An explanation of how the mode of addition can be determined experimentally

Weeks 2 & 3

a.The mechanistic possibilities for this type of reaction (including factors which favor each of mechanism) and the resulting regio and stereochemical outcomes of each.

b.An explanation of how the reaction mechanism can be determined experimentally

4. Results and Discussion

Your raw data, calculations and results have already been summarized on your data sheets. In this section, use full sentences to state your key results, backed up with the appropriate data.You will analyze and interpret the experimental results (data, observations and calculations). It is the most important part of the lab report. All the questions in the purpose of this experiment should be answered here and backed up with the relevant data. In addition, this section may include new questions that come up during the experiment and any possible changes to improve the experiment.

Items to address in your results and discussion

Week 1

a.Use the NMR and mp data to support that a chemical reaction took place and explain which isomer was the product.

b.Show a scheme (with perspective drawings) of chemical reaction you performed showing both possible products and their yields.

c.Discuss the stereochemical relationship between Isomer I and Isomer II.

d.Discuss whether the addition occurred by a syn or anti mode.Explain your reasoning. You do not need to include a scheme of the entire mechanism here, only key intermediate(s) that support your conclusion.

Weeks 2 & 3

e.Summarize the important results from weeks 2 and 3 with a table including solvents, yields (both isomers together), the cis:trans ratio, and the overall yield (two steps).

f.Providing specific data, explain how you were able to determine how much of each compound was present from each reaction (show appropriate calculations on the NMR spectra).

g.Provide a mechanistic explanation for major product in each reaction.Again, you do not have to show the entire reaction mechanism, but key intermediates that lead to the formation of one isomer or another.

h.Discuss the results of your TLC for weeks 2 and 3.

i.Discuss your reaction yields for each reaction and the overall yield (two steps)

5. Experimental Procedure

The procedure section summarizes what you did during the experiment and it must be detailed enough for someone else to successfully reproduce your experiment. You should explain in clear and concise language how you carried out the experiment. This is written in the format found in organic chemistry journal articles.

6. Conclusion

The conclusion section compares the actual results with the expected results and summarizes definitive points from the results. Normally one or two sentences will do.

7. Supplemental Information (Data Sheets, spectra, lab notebook pages and protocol)

WEEK 1: ADDITION OF BROMINE TO trans-CINNAMIC ACID

Required Prelab Readings:McMurry Chapter 5, Sections 8.2 & 21.2

Previous techniques that you must know and be able to perform: Suction Filtration, Melting Point, NMR spectroscopy

You will be performing the following reaction:

Brominetrans-Cinnamic Acid2,3-Dibromo-3-phenylpropanoic acid

MW 160 g/molMW 148 g/molMW 308 g/mol

bp 60°Cmp 133-134°Cmp 93-95 °Cmp 202-204 °C

When an electrophile, such as bromine, adds to an alkene, the addition can take place in a syn fashion, in which the two groups add to the same side of the molecule, or in an anti fashion, where the groups add to opposite sides of the molecule, or completely at random, where half the time the groups add the same side and half the time they add to opposite sides. Depending on the mode of addition, syn,antior random and the stereochemistry of the starting alkene, various stereoisomers will result. In some cases a racemic mixture of products is formed, other times a meso compound is produced. A third possibility is a mixture containing two racematesor a racemateand a meso compound.

The Fischer projections shown above are two possible stereoisomers that could form in the bromination reaction that you will perform.One is the result of a syn addition, the other is the result of an anti addition mode. Note that each would form as a racemic mixture, (+).You are to determine, based on the melting point of your product, which pair of enantiomers is produced. By knowing which enantiomeric pair is formed one can predict a plausible mechanism.Hint: you can predict the stereochemical outcome of a syn vs. anti addition of bromine to alkenes before you step foot into the laboratory.

The most time-consuming part of this experiment is setting up the glassware.Be sure all fittings are tight, well-greased, and clamped so as to prevent any escape of bromine vapors into the laboratory environment. An actual set-up is provided for you in the lab for you to look at.

You will need to set up the apparatus as shown in figure 7.4 a on page 63 of Mohrig.

NOTE:You are responsible for calculating the amount of trans-cinnamic acid (in grams) equivalent to 4mmol.You must have this done before you enter the lab.

Hazards

Molecular bromine is extremely toxic and corrosive; its vapors are damaging to the skin eye and respiratory tract.Wear gloves and UNDER NO CIRCUMSTANCES ARE YOU TO REMOVE THE BROMINE STOCK SOLUTION FROM THE HOOD. Only remove your bromine solution in the stoppered funnel.Sodium thiosulfate reduces Br2 to Br-1.When working with Br2, always keep a bottle of 5% sodium thiosulfate handy for rinsing the skin in case of contact.

Experimental

Assemble a 50 mL round-bottom flask with a Claisen head, reflux condenser, and addition funnel.Into the round-bottom flask, add trans-cinnamic acid (4 mmol) and 10 mL of methylene chloride.Add a stir bar.

Obtain 4.0 mL of a 1.0 M solution of bromine in methylene chloride in the addition funnel.Attach a heating mantle and variac and heat the mixture to a gentle reflux. The variac setting should initially be 25-30.Adjust this setting as necessary until the solution is refluxing .

While it is refluxing, add the bromine solution at a rate of two drops per second.You need not loosen the stopper on the funnel for the bromine addition due to the high density of methylene chloride.The red-orange color of the bromine should dissipate as it reacts with the mixture.Continue to reflux for an additional 10 minutes after the last of the bromine has been added.

The color of your final solution should be a very pale yellow.If the red-orange color persists after the 10 min, add cyclohexene dropwise (1-2 mL) until the red color disappears.

Remove the reaction flask and cool it in an ice bath for 10 minutes with a greased stopper on top.Allow the product, 2,3-dibromo-3-phenylpropanoic acid, to crystallize.

Meanwhile, disassemble the rest of the reflux apparatus and sit it in the back of your hood to allow the fumes to dissipate.Rinse the glassware with a small amount of sodium thiosulfate to destroy any remaining bromine.

Collect the crystalline product by suction-filtration, and rinse with aminimal amount of ice-cold methylene chloride.Allow it to air-dry and record the mass and melting range of the product.Have your instructor check the weight of your product and initial this value in your lab notebook.Save all of your product as it is the starting material for next week.

WEEK 2: AN ELIMINATION REACTION WITH 2,3-DIBROMO-3-PHENYLPROPANOIC ACID TO
-BROMOSTYRENE IN ACETONE

Required prelab readings: McMurry Sections 11.7 – 11.12

Previous techniques you must understand and be able to perform:Reflux; TLC; rotary evaporation

Introduction:

In the reaction above, there is no stereochemistry implied for either the reactant or the product.You will need to re-write the equation showing the absolute configuration of both the starting material and product based on your results from last week and this week. Carbonate is a base and the first step in the reaction is formation of the conjugate base of the starting material. This intermediate can proceed through either an E1- or E2-type mechanism where CO2 is lost in place of a proton.By identifying the major product and comparing it with the two mechanistic possibilities you will be able to determine the dominant mechanism involved in the elimination. Predict which mechanism results in which -bromostyrene stereoisomer before you come to lab.

Experimental Procedure:

Place 300 mg of 2,3-dibromo-3-phenylpropanoic acid (save a few mg for a later TLC analysis) and 300mg of potassium carbonate in a 50 mL round bottom flask with a magnetic stir bar.Add 710 mL acetone (pre-dried over sodium sulfate) to the flask. Attach a reflux condenser and assemble the apparatus on a heating mantle with a stirrer motor. Reflux the mixture with stirring for one hour. After reflux, cool the solution to room temperature and then remove the acetone using the rotary evaporator. Add RO water (5 mL) to dissolve any remaining solids.Using a Pasteur pipet, transfer the solution to a 12 mL centrifuge tube.Rinse the round bottom flask with 2 mL methylene chloride (why?) and add the solution to the centrifuge tube. In the centrifuge tube, you should see two layers-an aqueous layer on top and an organic layer on the bottom.The organic layer contains your product and may be pale yellow. Using a clean pastuer pipet transfer the organic layer to a 50 mL Erlenmeyer flask.You will have to insert the pipet through the aqueous layer to get to the bottom of the tube to collect the organic layer.Extract the aqueous layer twice more with 2 mL portions of methylene chloride (i.e. add 2 mL of methylene chloride to the aqueous layer in the centrifuge tube, mix well and remove the organic layer with a Pasteur pipet.Repeat.)Combine all the organic extracts and dry them with anhydrous sodium sulfate for at least 10 minutes. Run a TLC plate of both your product and starting material side-by-side using 1:1 hexane/methylene chloride as the eluant.Transfer the dried solution to a tared (analytical balances) 50mL round bottom.Rinse the sodium sulfate with an approximately 1 mL of methylene chloride and add this to the flask.Concentrate the solution on the rotary evaporator being careful not to overheat (overheating or leaving the solution on a rotary evaporator for too long a period can greatly reduce your yield).You should isolate -bromostyrene as a colorless to yellow oil.Weigh to constant weight and record the final weight of your product.Save your product for TLC in week 3.

WEEK 3: AN ELIMINATION REACTION WITH 2,3-DIBROMO-3-PHENYLPROPANOIC ACID TO
-BROMOSTYRENE IN WATER

Experimental Procedure:

Place 300 mg of 2,3-dibromo-3-phenylpropanoic acid (save a few mg for a later TLC analysis) in a 50 mL round bottom flask with a magnetic stir bar.Add 5 mL 1 M aqueous sodium carbonate to the flask. Attach a reflux condenser and assemble the apparatus on a heating mantle with a stirrer motor. Reflux the mixture with stirring for 20 minutes. After reflux, cool the solution to room temperature.Using a Pasteur pipet, transfer the solution to a 12 mL centrifuge tube.Rinse the round bottom flask with 2 mL methylene chloride and add the solution to the centrifuge tube. In the centrifuge tube, you should see two layers-an aqueous layer on the top and an organic layer on bottom.The organic layer contains your product and may be pale yellow. Using a clean pastuer pipet transfer the organic layer to a 50 mL Erlenmeyer flask.Extract the aqueous layer twice more with 2 mL portions of methylene chloride (i.e. add 2 mL of methylene chloride to the aqueous layer in the centrifuge tube, mix well and remove the organic layer with a Pasteur pipet.Repeat.)Combine all the organic extracts and dry them with anhydrous sodium sulfate for at least 10 minutes. Run a single TLC plate of the starting material as well as your products from week 2 and week 3 using 3:1 hexane/methylene chloride as the eluant. Transfer the dried solution to a tared (analytical balances) 50mL round bottom.Rinse the sodium sulfate with an approximately 1mL of methylene chloride and add this to the flask. Concentrate the solution on the rotary evaporator being careful not to overheat (overheating or leaving the solution on a rotary evaporator for too long a period can greatly reduce your yield). You should isolate -bromostyrene as a yellowish oil. Weigh to constant weight and record the final weight of your product.

WEEK 1 DATA SHEET

Mechanism of Bromination of trans-Cinnamic Acid.

Name: / Section:

Overall Reaction (including stereochemistry, in perspective [not Fischer]; use chemical drawing software):

Mass of acid: / Theo mmol product:
mmol of acid: / Theo mass product:
Volume of Br2sol’n: / Mass recovered product:
mmol of Br2: / mmol recovered product:
% yield of product:
Melting point of recovered product:
Literature melting point:

Calculations (notebook):

Draw the structure of the product directly on its 1H NMR spectrum with all non-equivalent H’s labeled (a,b,c…) for NMR identification. Match each label with the corresponding peak(s) in the spectrum by writing the appropriate letter above the associated peak(s).Label any NMR solvent peaks in the spectrum by writing the solvent above them.