Stereo Chemistry

Friedel Crafts Alkylation 13
Friedel-Crafts Alkylation of 1,4-Dimethoxybenzene

OCH3 OCH3 CH3
CH3
CH3 H2SO4
1 CH3
+ 2 H3C OH 1
H 3C
CH3 CH3CO2H
(acetic acid, H 3C
OCH3 CH3 OCH3
solvent)
1,4-Dimethoxybenzene t-Butyl Alcohl 1,4-Di-t-butyl-2,5-dimethoxybenzene
(Hydroquinone dimethyl ether) (t-butanol, 2-methyl-2-propanol) MW = 250.37
MW = 138.16 MW = 74.1, density = 0.79g/mL mp = 80-140ºC range
mp = 57ºC mp = 26ºC
limiting reagent
General Issues with Electrophilic Aromatic Substitution Reactions

1. Polysubstitution
Aromatic substitutions always involve the issue of how many substitutions will occur.
Will reaction stop after one substitution? Will it proceed to give a second substitution? Will it
proceed further to give a third substitution? In today’s experiment the reaction does not stop
after a single substitution, but proceeds on to a second. However, it does basically stop after the
second substitution and does not proceed appreciably to a third or fourth substitution. Influential
factors are electronic and steric:
• Electronics: are new substituents electron donating or electron withdrawing? Will they stabilize
or destabilize the cation involved in subsequent substitutions? As a result will they activate or
deactivate toward subsequent substitution?
• Steric: are new substituents large enough to obstruct further substitution?
2. Position of Substitution: Ortho, Meta, or Para To a Pre-existing Substituent?

Relative to a pre-existing substituent (or several of them…), will a new substitution occur
ortho, meta, or para? Electronic and steric factors are again influential. In today’s experiment,
for example, after the first t-butyl group is attached, why does the second t-butyl group go where
it does?
3. Generation of the Electrophile

All electrophilic aromatic substitution reaction mechanisms require a strong electrophile, usually
cationic. In today’s experiment, the active electrophile is the t-butyl cation. For a general
alkylation, in which an alkyl cation is required, there are several alternate precursors:
a. Alkenes: Alkene + H →R
b. Alcohols: ROH + H → ROH2+ → R++ H2O
c. Alkyl Halides: R-X + AlX3 → R + AlX4

Reaction Procedure:
1. Weigh out 1.50 g of 1,4-dimethoxybenzene and place in a 125-mL Erlenmeyer flask
containing a stir bar.
2. Measure out 3.10 mL of warm t-butyl alcohol into a syringe, and inject into the Erlenmeyer
flask. (Note: t-butanol freezes at 26ºC, so it’s best to handle it somewhat warm so it stays
liquid. If it has much chance to cool off, it may solidify and complicate delivery.)
3. Measure out 5 mL of acetic acid from a buret. You can deliver this directly into your
Erlenmeyer, or else drain it into a small flask/beaker and pour it in. Acetic acid is smelly, so
delivering it directly in the hood is a good way to reduce smells in the lab. If you do transfer
via a small flask/beaker, rinse that out pretty quickly in the hood so that the lab doesn’t smell
too much like vinegar.
4. Cool the Erlenmeyer flask in an ice-water bath on a stir plate, and adjust to get steady
stirring.
5. Drain 10 mL of concentrated sulfuric acid from a buret into your separatory funnel. Note 1:
Make sure the stopcock on your separatory funnel is not open! Note 2: Sulfuric acid is a
very strong acid; you do not want any to touch your skin or clothes.
6. Position your separatory funnel above your Erlenmeyer flask, and then drop in the sulfuric
acid very slowly, drop by drop, over a period of 5-7 minutes into the continuously stirred
solution. Keep the Erlenmeyer flask in an ice-water bath throughout.
7. After addition of the sulfuric acid is complete, remove the cold bath and continue stirring at
room temperature for 20 minutes to allow completion of the reaction.
8. During this 20-minute wait, rinse the separatory funnel with the residual sulfuric acid with
tap-water. You can drain into the sink. This is also a good time to write up your lab report,
including stoichiometry calculations, procedure and observations, and post-lab questions.
Isolation of the Crude Product:

9. Add some ice to the Erlenmeyer flask to dilute the sulfuric acid, swirling the flask as you do
so. (One of the functions of the ice is to absorb some of the heat that is produced when
sulfuric acid and water mix.) Then add ice-cold water to a total volume of 75 mL or more,
swirling vigorously as you add.
10. Use a scoopula or micro-spatula to swirl and stir the mixture for at least two minutes.
11. At this point, you should have a lot of crystal that formed. Because the desired product has
so many carbons, it has very low solubility in water, so adding all the water basically crashes
most of the the product from solution.
12. Filter the solution using a Buchner funnel.
13. Rinse thoroughly with another 70 mL of ice-cold water. (The function of the water is to
make sure all the sulfuric acid, acetic acid, and t-butanol is washed away from the product.)
14. Take the Buchner funnel off of the filter flask, and pour the water down the drain. Then
reattach the Buchner funnel.
15. Rinse with a 5-mL portion of ice-cold methanol
16. Rinse again with a second 5-mL portion of ice-cold methanol. (The methanol washes away
some organic impurity and also functions to remove much of the water.)
17. Measure your crude mass
18. Save a small portion of the crystals for a crude melting point.
Recrystallization of the Crude Product:

19. The main batch of crystals should be purified by recrystallization. Use methanol as your
main solvent. Use your experience in recrystallization in order to figure out how to do this.
Remember, you want to dissolve the solid in a minimum of hot solvent. So if your solvent is
boiling hot and your crystals still won’t dissolve, what should you do? Add more solvent!
Conversely if you think you have too much/too good solvent, what should you do? Either
boil some off, or add some water (one drop at a time) to reduce the solubility and approach
saturation. (Mixed solvent technique).
20. Use your experience to guide your filtration and washing of the crystals.
21. Pour the methanol from the filter flask into the alcohol waste container in the hood.
22. Let the crystals vacuum dry for at least 8-10 minutes before getting mass yield and taking
melting point. When you take your melting point of the recrystallized material, also take a
melting point of the crude material in order to compare so you can see whether
recrystallizing actually helped.
23. Take a H-NMR of the product. To run an NMR on a solid, stab the tube into the crystal, like
you do to get some solid into a melting point tube. Remember that for an H-NMR of a liquid
you put in one or two drops; so try to put in enough solid that would be comparable to a drop
of liquid. Note: Students routinely put in too little solid! Remember that most of the space
in a solid crystal is just air. So compared to a drop of liquid you’d like to have 5 times as
much volume of a solid. If your tube is maybe 1/10th full, that will be good for this week.
Dilute to about 1/3 depth with D-chloroform. Note: The NMR is for instructor’s grading
purposes, just to see how clean your material is. You don’t need to explain it in your lab
report.
• Run ah1-tune
• Signup for NMR
Caution: Safety Note: Concentrated sulfuric acid is very potent and will dissolve you, your
clothes, your papers, or anything else it touches! Avoid pouring; try to use burets/pipets
exclusively, or as much as possible. Rinse your glassware thoroughly with water after usage.
Acetic acid is smelly, so avoid exposing this outside of the hood.
Cleanup: If an aqueous acid waste bottle is out, put your original solution (following filtration)
into that. If not, dilute the original solution with water, neutralize with sodium carbonate (expect
it to fizz!), and pour down the drain.
Pour the methanol from the recrystallization into the organic waste container.
Lab Report:
Standard synthesis lab report format. Data must include the crude and recrystallized
melting points; the crude and purified mass yield and percent yield; and the H-NMR.
Questions:
1. Draw a detailed mechanism for the formation of t-butyl-2,5-dimethoxybenzene. (In other words,
for the first alkylation, but not the second…).
OCH3 CH3 OCH3 CH3 CH3OCH3 CH3

CH3 CH3 H 3C CH 3
CH3 CH3 CH 3
H 3C
H 3C CH3
H 3C CH3
CH3 OCH3 OCH3 CH3 OCH3
1,4-Di-t-butyl- 1,2-Di-t-butyl- 1,3-Di-t-butyl-
2,5-dimethoxybenzene 3,6-dimethoxybenzene 2,5-dimethoxybenzene
2. The actual dialkylation product is 1,4-di-t-butyl-2,5-dimethoxybenzene. Why is this isomer
preferred rather than the alternative isomer 1,2-di-t-butyl-3,6-dimethoxybenzene (see above)?
3. The actual dialkylation product is 1,4-di-t-butyl-2,5-dimethoxybenzene. Why is this isomer

preferred rather than the alternative isomer 1,3-di-t-butyl-2,5-dimethoxybenzene (see above)?
4. From your actual calculations, how many moles of t-butyl alcohol did you use, and how many
moles of 1,4-dimethoxybenzene did you use? The major product involves only two moles of t-
butyl alcohol adding per mole of 1,4-dimethoxybenzene. The following questions relate to why
you added more than one, but not more than two…
5. Why do you think you did not stop after just a single alkylation? In other words, why were you
able to add two t-butyls, not just one?
6. Why do you think you did stop after two alkylations? In other words, why were you able to add
two t-butyls, but did not continue on to add a third t-butyl group at least to some of your
molecules, even though there was still a lot of t-butyl alcohol left at the end?
7. You used t-butanol and acid to generate the t-butyl cation used to form 1,4-di-t-butyl-2,5-
dimethoxybenzene. Suggest two organic precursors other than t-butanol that could be used as
precursors for t-butyl cation?

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Friedel Crafts Alkylation 13

Friedel-Crafts Alkylation of 1,4-Dimethoxybenzene

General Issues with Electrophilic Aromatic Substitution Reactions

2. Position of Substitution: Ortho, Meta, or Para To a Pre-existing Substituent?

3. Generation of the Electrophile

b. Alcohols: ROH + H → ROH2+ → R++ H2O

c. Alkyl Halides: R-X + AlX3 → R + AlX4

Isolation of the Crude Product:

Recrystallization of the Crude Product:

OCH3 CH3 OCH3 CH3 CH3OCH3 CH3

3. The actual dialkylation product is 1,4-di-t-butyl-2,5-dimethoxybenzene. Why is this isomer

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