C

Duke University - Organic Chemistry Laboratory

Lab

ELECTROPHILIC AROMATIC SUBSTITUTION - !

IODINATION OF VANILLIN AND NITRATION OF METHYL BENZOATE1 !

Background!
Introduction! Aromatic molecules can be characterized by considerable chemical stability, especially when compared to known alkenes and cycloalkenes. More specically, they are typically inert to common addition reactions that simple alkenes readily undergo when both are exposed to similar reaction conditions (Figure 1).
D No Reaction DCl DCl Cl Cl Cl !

Reading Assignments Techniques:!

Recrystallization/Filtration: Fessenden2, p. 23-32! Controlling Exothermic Reactions: Fessenden, p. 156-157!

Chemistry:!
EAS: Loudon3, p. 750-776

No Reaction

Cl2

Cl2

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Figure 1. Contrast between reactions of normal alkenes and aromatic compounds with similar reagents.

Given these observations, how does one functionalize these highly stable molecules? In the presence of a catalyst, aromatic compounds can undergo substitution reactions whereby a hydrogen of the aromatic ring is substituted by an electrophile (Figure 2). In the reaction below one of the aromatic hydrogens is substituted with a chlorine atom. !
Cl2, FeCl3 Cl + HCl

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heat

! !

Figure 2. Substitution of a hydrogen for chlorine in benzene in the presence of a catalyst.

Other common and useful substitution reactions observed with benzene (among other aromatic compounds) include bromination, sulfonation, nitration, alkylation, and acylation. Installation of a number of these functional groups can result in compounds that often serve as precursors to more complex molecules. The reagents required for each of these substitution reactions of aromatic rings are highly electrophilic and hence the name Electrophilic Aromatic Substitution (EAS). ! Electrophilic aromatic substitution occurs in three mechanistic steps (Figure 3):! 1. 2. Generation of a highly reactive electrophile often a Lewis acid like FeBr3 is employed. ! The # electrons of the aromatic ring attack the electrophile to form a sigma bond and a resonance stabilized carbocation. Since this step requires disrupting the aromaticity of the ring, the activation energy is large and this step is rate determining.! 3. Abstraction or loss of a proton from the only sp3 hybridized carbon in the ring to reform the aromatic compound. !

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A m a n d a K a s p e r, P h . D . O r g a n i c L a b o r a t o r y M a n a g e r 1 2 2 5 F r e n c h F a m i l y S c i e n c e C e n t e r

Br
Br Fe Br Br !+

Br Br

H H

!" Br Br FeBr3

Br

Fe

Br Br
H Br

Br + HBr + FeBr3

"

"

!!

Figure 3. Mechanism and energy diagram of the electrophilic aromatic bromination of benzene.

If the aromatic ring is substituted by one or more non-hydrogen groups (for example toluene (methylbenzene) or aniline (aminobenzene)), these substituents can activate or deactivate the ring towards electrophilic aromatic substitution. Electron withdrawing groups such as nitro groups, aldehydes, ketones, and carboxylic acids are deactivating. Electron donating substituents such as amines, ethers, and alcohols are activating (see sections in Loudon, referenced above, for details). ! Along with the ability to activate or deactivate the ring, substituents have directing effects. In other words, they can inuence where the ring is substituted. These groups fall into two categories: ortho/para directors or meta directors. !
ortho meta para Directing Group ortho meta

Most activating groups are ortho/para directors and most deactivating groups are meta directors. The exceptions are the halogens, which are weakly deactivating, but ortho/para directors. The directing effect of a particular substituent can be explained by a careful examination of all the resonance structures of the carbocationic intermediate that is formed. ! In this laboratory, the iodination of vanillin and the nitration of methyl benzoate will be examined (Figure 4). Do you expect the substituent groups on vanillin and methyl benzoate to activate or deactivate the aromatic rings towards substitution? Do you expect these groups to be ortho/para or meta directing? !

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Lab 5: Electrophilic Aromatic Substitution!

Part One:!
O H + NaI OCH3 OH vanillin
Figure 4. Reactions carried out in todays lab.

Part Two:
O OCH3 HNO3 H2SO4 methyl benzoate nitro-substituted methy benzoate

NaOCl

iodovanillin

Safety Issues! Sodium hypochlorite (present in todays bleach solution) is a very strong oxidizer and can cause serious burns and eye damage. Inhalation should be avoided. Wear gloves and goggles at all times and handle the solution IN THE HOOD ONLY. Take care to avoid mixing it with solutions of concentrated acid. Long sleeves are recommended. Wash any exposed skin immediately and contact your TA. Neutralize spills with sodium thiosulfate. ! USE EXTREME CARE when handling the acids. Wear gloves, a long sleeved shirt and long pants when handling concentrated acids. Glacial acetic acid, conc. nitric acid, conc. sulfuric acid, and hydrobromic acid are all very corrosive. The acids can burn your skin and put holes in your clothing. Do your best not to spill the acids. If even one drop spills wipe it up immediately with a wet paper cloth. Remember that water and concentrated acid look identical. If you do get any on your skin, run the area under water IMMEDIATELY and keep it under water for 15 minutes. ! Use glass pipettes exclusively in this lab. Plastic pipettes have resulted in student injury in past semesters.! Standard uses of gloves, safety glasses, and pipettes are to be observed. See Lab 1 or consult your TA for details.!

Procedure!
PART ONE. Iodination of Vanillin.! 1. 2. Charge a 100 mL round bottom ask with a magnetic stir bar, 1.0 g of vanillin, and 20 mL of ethanol. ! While the vanillin solution is stirring, add 1.17 g of sodium iodide (NaI) and attach a Claisen adaptor to the top of the round bottom ask. Continue to stir and cool the solution to 0 C using an ice/water bath.! 3. Obtain a separatory funnel and with the stopcock closed, add 11 mL of bleach (0.77 M NaOCl). Place the separatory funnel in the neck of the Claisen adaptor directly above the round bottom ask. ! 4. While stirring, slowly open the stopcock and add the bleach dropwise over a period of 10 minutes (about 1 drop every 1-2 seconds). The solution should change color from pale yellow to dark, red-brown. Do not add the bleach too quickly! 5. !

After all of the bleach has been added, remove the ice/water bath and allow the reaction mixture to stir for an additional 20 minutes.!

6.

Add 10 mL of 1 M sodium thiosulfate solution and stir vigorously until the color dissipates. Next, acidify the solution by slowly adding 3 M HCl (approximately 5-6 mL) until a precipitate forms and remains even with vigorous stirring.!

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Lab 5: Electrophilic Aromatic Substitution!

Review: Recrystallization 7. Cool the mixture with an ice/water bath for 10 minutes and collect the precipitate by vacuum ltration using a Buchner funnel (dont forget the clamp). Wash the precipitate with a small amount of ice-cold water and ice-cold ethanol and allow the product to dry by leaving it under vacuum for approximately 5 minutes. ! 8. 9. Weigh the dried precipitate. This is your crude mass. ! Recrystallize (see sidebar for a review) the product from a minimum amount of HOT ethyl acetate or hot isopropanol/water. What might happen if you add too much solvent? Collect the pure product by vacuum ltration. DO NOT THROW AWAY THE FILTRATE YET. Allow air to pass through the crystals for approximately 5 minutes to promote drying. Weigh the crystals again. ! Note: While there were some impurities in the crude solid, the bulk of the material was your product (~80%) and should have been recovered if the recrystallization was performed correctly. If you isolated fewer than 50% of the original crude mass, concentrate the ltrate by heating on the hot plate, crystallize, lter, etc. ! 10. Calculate a percent yield, measure the melting point, and analyze the NMR spectra available on Sapling. You may choose to obtain the IR spectrum if you wish. ! PART TWO. Nitration of Methyl Benzoate.! USE EXTREME CARE WHEN HANDLING CONCENTRATED ACIDS!! 1. Chill approximately 0.5 mL of concentrated sulfuric acid and add it dropwise to 0.25 mL of methyl benzoate in a clean test tube immersed in an ice/water bath. ! 2. In a second test tube combine 0.3 mL of concentrated sulfuric acid and 0.3 mL of nitric acid, mix well to ensure complete mixing and cool the acidic solution in an ice bath (what is happening in this step?).! 3. Add the acid mixture dropwise to the methyl benzoate solution. Mix well by swirling or using a pipette after each addition of acid. Remove the reaction mixture from the ice bath and allow it to warm to room temperature. Let the mixture sit at room temperature for at least 10 minutes mixing thoroughly. Do not rush this step!! 4. Pour the reaction mixture over approximately 5 mL of crushed ice-cold water in a small beaker. Chill the mixture completely on an ice bath until crystallization of product is complete. It may take some time for crystallization to occur. If you do not see crystals after 10 minutes please consult your TA.! 5. Vacuum lter the product and wash the crystals with three 2 mL portions of ice cold water then allow the product to dry under vacuum for approximately 5 minutes. Dry the solid further by pressing between pieces of dry lter paper. The ltrate should be neutralized using base and then discarded in the liquid waste container. ! 6. Weigh the product, calculate a percent yield, measure the melting point range, obtain an IR spectrum and analyze the NMR available on Sapling. !
You should recall the technique of recrystallization from previous laboratory experiments. The technique requires care to carry out successfully. ! Your desired compound should be more soluble in the hot recrystallization solution, but less soluble once its cooled (hopefully, impurities are soluble in hot or cold solution). However, if too much solvent is added, the desired compound will stay in solution, even after the solution is cooled. Thus, we must be careful to only add enough hot solution so that the compound just dissolves, and no more (this is what is meant when a minimum of recrystallization solvent is needed).! To carry out a successful recrystallization, the compound to be puried should be placed in a small Erlenmeyer ask. In a separate container, the recrystallization solution should be heated. Once hot, it should be added in small portions to the compound, and then swirled to dissolve. If it has not dissolved, add more solvent, with swirling in between. You may need to add heat to the ask containing your partially dissolved compound to keep the solvent hot. Do this with care, as you do not want to boil off all of the solvent that you added and subject your naked product to intense heat.! Once the compound has just fully dissolved, allow the solution to cool to room temperature. If no crystals form after a short while, place the ask on ice. You can also try using a glass rod to scratch the inside surface of the ask, or add a seed crystal. Be patient while waiting for crystals. If none of the above work, you may have added too much solvent. Carefully heat the solution back up to boiling to remove some of the solvent. Do NOT leave it unattended to avoid boiling off all of the solvent. Once a portion has evaporated, let the solution cool and attempt to recrystallize again.

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Lab 5: Electrophilic Aromatic Substitution!

Prelab Assignment!
Prereading - Be sure to read the sections pertaining to new techniques and chemistry in this lab (see the rst page).! Prelab quiz - Log on to saplinglearning.com to complete Prelab Quiz 5 prior to your lab meeting.! Prelab Notebook:! !Objective: ! Include both reactions (using structures) and predict the major product(s) of each of the reactions you will perform today. For each of the reactions predict whether the ortho, meta, or para product will predominate or if mixtures are expected. Predict the directing and activating or deactivating abilities of both the hydroxy and methoxy groups of vanillin, and the ester of methyl benzoate.! Draw out the mechanism for each of the reactions based on formation of the major product you have predicted and be sure to show all important resonance structures of the carbocation intermediate.! !Table of reagents and products: Include the reagents/products from the table below and include columns for actual amounts used (g or mL) and mol.!

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!Separation scheme: Not required this week.! !Procedure: Reference this lab handout. !

In-Lab Notebook!
Procedure and Observations record EXACT amounts of reagents used (use table similar to one shown above), observations, and any changes you have made to the written procedure. This should be written directly in your notebook while you are in the lab. ! All information above should be written directly into your lab notebook. The duplicate pages will be turned in to your TA at the end of the lab. !

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Lab 5: Electrophilic Aromatic Substitution!

All information below will be included on the Post-Lab Report and does NOT have to be written separately in the notebook. You may choose to work through your calculations or organize your ideas for the discussion, etc. in the notebook, but this information is not required in the notebook. !

Post-Laboratory Report!
Complete the report as directed below. !

References!
Parts of this procedure have been adapted from: DSilva, Sebahar, H.L. Organic Chemistry Laboratory Handout, Duke University, 2000, 2008; !
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Fessenden, Fessenden, Feist. Organic Laboratory Techniques, 3rd Edition. Brooks/Cole, Pacic Grove, CA, 2001.! Loudon, GM. Organic Chemistry. 5th ed. Roberts & Company Publishers; 2008!

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Lab 5: Electrophilic Aromatic Substitution!

Chemistry 202L - Post Lab Report for Electrophilic Aromatic Substitution (Lab 5)!

Name:__________________________________! Iodination of Vanillin!

TA name/Section number:______________________________!

Balance the equation used in the reaction and draw the major product: !

H
+

NaI

OCH3 OH
"
vanillin sodium iodide product

Calculate amount of vanillin (in moles) actually used (based on the amount you measured):!

" Calculate amount of sodium iodide (in moles) actually used (based on the amount you measured):!

" The limiting reagent is: ______________________________________! Calculate theoretical yield for the iodination product:!

" Calculate the percent yield for the iodination product:!

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Lab 5: Electrophilic Aromatic Substitution!

Calculate the percent recovery for the iodination product:!

" In the space below, draw a curved-arrow mechanism for the iodination reaction. Show all important resonance structures for any carbocation intermediates.!

" Appearance of isolated iodination product:_________________________! Literature appearance:__________________________ ! Observed mp range:___________! Literature mp range:___________ !

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Lab 5: Electrophilic Aromatic Substitution!

Nitration of Methyl Benzoate:! Balance the equation used in the reaction: !

O O

HNO3

H 2SO4

methyl benzoate

nitric acid

sulfuric acid

product

" Calculate amount of methyl benzoate (in moles) actually used (based on the amount you measured):!

" Calculate amount of nitronium ion (NO+) (in moles) actually used (based on the amount you measured):!

" The limiting reagent is: ______________________________________! Calculate theoretical yield for the nitration product:!

" Calculate the percent yield for nitration product:!

" Appearance of isolated nitration product:_________________________! Literature appearance:__________________________ ! Observed mp range:___________! Literature mp range:___________!

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Lab 5: Electrophilic Aromatic Substitution!

In the space below, draw a curved-arrow mechanism for the nitration reaction. Show all important resonance structures for any carbocation intermediates.!

" Additionally:!

Attach a copy of the 1H NMR for each product. Draw the structure of the molecule directly on the spectrum and identify each unique proton. Clearly indicate which proton is responsible for each peak. ! Attach an IR spectrum of your nitration product. Indicate the functional group responsible for each important peak. Attempt to identify at least ve important peaks. In your discussion indicate which peak(s) were key in determining whether or not you converted the starting material to the product. ! Write a discussion of what was observed and learned from this experiment integrating answers to the following questions. What product(s) did you isolate and what evidence to you have to support this claim? Include melting point data, appearance and percent yield. In your analysis of the NMR and IR data, please be sure to address the specic pieces of information available from each spectrum that allow you to identify the product molecule as 1) a specific isomer and/or 2) different than the starting material. Include a brief error analysis.

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Lab 5: Electrophilic Aromatic Substitution!