San Diego State University Caffeine Chlorination Lab Report

This is submitted with a fully analyzed NMR spectrum. Please also put the following information:

Your name, Compound name, Weight of product in grams, Theoretical and percent yield calculations, Lab section number, Observations (conclusions).

1. Please show your calculations for obtaining your percent yield. Include
the calculations for the theoretical yield as well. Also, if something went wrong during the course of your experiment (i.e you spilled your product, did the work-up wrong, etc.) you can explain it here. Includeany modifications made in pro
cedures, changes in colors during reaction or isolation, temperature increases, and report observed melting or boiling points.

2. Analyze your NMR spectra and upload a picture of it on this assignment. In your spectra, you should have the approximate chemical shifts of each peak. You also have to include an explanation matching up the peaks in your NMR spectra to that of the product, methyl benzoate. Explain why you think you got your product and not just starting material. If you have extra peaks in your NMR that do not match up to any proton peaks in your product, explain where they could have come from. Every peak must be accounted for!

3. Include a picture of your TLC plate (a picture of your traced TLC plate from your notebook is fine) and calculate Rf values for all spots.

THE CHLORINATION OF CAFFEINE:
An example of Electrophilic Aromatic Substitution (EAS)
Introduction:
S
P
Ph
Ph
Ph
Triphenylphosphine Sulfide
(TPPS)
Catalytic
O
6
O
5
1N
N
7
H +
N Cl
O
O
N
N
+
Cl
N H
N
N
O
Chloroform (CHCl 3)
O
O
N-Chlorosuccinimide
Caffeine
Chlorinated Caffeine
Succinimide
(NCS)
electrons on N-7 are part of aromatic system (overlap with aromatic π-orbitals)
electrons on N-9 are in plane of molecule (orthogonal to aromatic π-orbitals)
O 2 N
3
4
N
8
9
Electrophilic aromatic substitution (EAS, see Chapter 15 in Solomons Text Book) involves the
replacement of a hydrogen attached to an aromatic system with an electrophile. EAS is commonly used in the
synthesis of pharmaceuticals and other fine chemicals. In this lab experiment we will replace a hydrogen on
the electron rich imidazole of caffeine with a chlorine. As discussed in 15.3 the electrophile often needs to be
activated with a catalyst, with strong Lewis acids such as FeCl3. We will be using a new approach
(developed at SDSU) exploiting a Lewis basic catalyst, Triphenylphosphine Sulfide (TPPS) to activate NChlorosuccinimide.
O
N Cl
O
N
O
O
S
P
Ph
Ph
Ph
N
O
N
H
Cl
S
P
Ph
Ph
Ph
N
N
O
H N
O
N
N
N
+
O
O
Resonance Stabilized
Cation (see below)
Possible Catalytic
Intermediate
N-7 e- overlap with π−system and can participate in resonance
N-9 e- do not overlap with π−system and can’t participate in resonance
O
O
O
N
N
N
Cl
Cl
Cl
N
Cl
N
N
N
H N
H N
H N
H N
N
N
N
O
O
O
O
O
N
Cl
O
O
N
O
Resonance
Hybrid
N
N
N
N
O
Cl
N
N
O
In this experiment TPPS attacks NCS, likely breaking the N-Cl bond (similar to a SN2 type
mechanism) to give a cationic adduct and succinimide anion. The chlorine in the adduct is activated
(compared to NCS) as it has more partial positive charged character than in unactivated NCS,
rendering it more electrophilic. The nucleophilic C-8 position of caffeine then attacks the adduct at
chlorine (in the rate determining step) to give a resonance stabilized ‘arenium’ cation as the key
intermediate (where aromaticity has been broken), while also regenerating the catalyst (TPPS). The

succinimide anion then deprotonates the hydrogen at C-8 to give chlorinate caffeine. The
rearomatization that occurs at this step drives the reaction to completion.
Experimental Procedure:
Set-up:
1. Set-up stir plate in your hood
2. Obtain a 25 mL round bottom flask (labeled with name and section), add stir bar inside
3. Add 0.515 mmol of caffeine, a spatula tip’s worth mmol of TPPS (your TA will show you how much),
and 3 mL of chloroform into the flask
4. Let flask stir for about 30 seconds
5. Add 0.772 mmol of NCS to flask, let stir at room temperature for 30 minutes
Analysis:
1. After 10 minutes of stirring, obtain a TLC (thin layer chromatography) plate.
2. Lightly (with pencil) draw a starting line (not dotted) a centimeter up from the bottom (as seen in
figure3.)
*Thin layer chromatography is a way of analyzing the progress
of a reaction.
Figure 3: TLC plate example
3. With a pencil, mark 3 lines on which you will spot your starting material, reaction, and co-spot (starting

material and reaction.)
Figure 4: Spotting example
4. With a TLC spotter, take up some solution from your starting material standard and lightly (and quickly)
spot the mark you made for starting material on your TLC plate. Do not allow the spot to become too
large. A ‘quick tap’ where a small area (2-5 mm in diameter) becomes wet should be enough. Figure 4 is
an example of a spot that is too large. Also spot some starting material on the lane marked “co-spot”. *A
co-spot will help confirm the identity of starting material in the reaction mixture*
5.
(Make sure to wash your spotter in between with acetone to ensure no mixing of reaction
material with starting material. To wash: take spotter, dip into vial with a small amount of
acetone, then dry by tapping spotter onto paper towel.) Repeat the step above for the reaction
solution (on the appropriate marks). You will need to open the flask that has your reaction inside
and carefully dip your TLC spotter in the reaction solution. Lightly spot some solution on the
reaction and co-spot lane.
6. Make a 6mL solution of 1:1 hexanes: ethyl acetate (3 mL hexanes, 3 mL ethyl acetate) and pour
into a small beaker.

Figure 5: Pouring solution into TLC chamber
7. Allow thirty second for your TLC place to dry from spotting and with tweezers, place the TLC
vertically into the beaker. The 3 dots should be near the bottom but above the solvent level. The
TLC plate will lean against one of the walls of the receptacle. *Be very careful as to not let the
plate fall over AND make sure the solvent is below the line drawn.
Figure 6: Placing TLC into TLC chamber
8. Monitor the TLC by watching the solvent travel up the plate.
Figure 7: Monitoring solvent travel up TLC plate
9. When the solvent reaches a few millimeters from the top, remove the TLC plate and mark the

top of the solvent. Place the TLC plate (plastic-side) down on a paper towel.
10. Visualize the spots by a UV light (DO NOT stare directly into the UV light or shine it toward
your face or skin, this could cause irritation or sunburn to your eyes.)
This spot is the product
This spot is starting material
Figure 8: Spots on TLC visualized by UV
11. Lightly circle the spots visualized by TLC and identify the starting material and product spots.
There will be another spot for the catalyst (TPPS) which you may see at the top (with the solvent
front). You will need to keep this in mind when running your column during the next step.
(There should be no product spot in the “starting material” only lane.) Note: The starting material
may not be completely gone.
12. Approximate and write down the respective Rfs.
*(Rf= distance traveled of UV spot/distance solvent traveled)
Work-up:
1. Using a magnet, remove the stir bar from the round-bottom flask.
2. Add 10mL 1M NaOH to the flask, then transfer it to a separatory funnel.
3. Add 15mL of chloroform to the flask, then transfer it to a separatory funnel (or straight to separatory
funnel if you are repeating)
4. Place a glass stopper on the separatory funnel, shake contents inside to mix (the water layer from the
NaOH is less dense than chloroform, so the water will be the top layer. Your products will be in the
chloroform (bottom) layer).
5. Empty chloroform (bottom) layer into a 100 mL, labeled, round bottom flask (it is better to leave some
of the chloroform in with the aqueous layer than to let some of water out with the chloroform layer).
6. “Wash” aqueous layer 1 more time by repeating steps 3-6 (each chloroform layer will be added to the 100

mL round bottom flask of step 6). (By “washing” the aqueous layer with chloroform, you are retrieving
any product that may be “trapped” water layer.
7.
With tube connected to “air” in your fume hood, blow air into the round bottom until the solvent has
evaporated
STOP: END OF DAY 1
Purification:
1. Set-up column in fume hood so that column is running vertically.
2. Place small amount of glass wool at bottom of column.
3. Fill column 2/3 full with silica gel (make sure fume hood glass is lowered to a safe distance to prevent
silica gel from being inhaled).
4. Run 10 mL of 1:1 hexanes: ethyl acetate solution through column. (Run solution through column until
solution is right above silica gel layer.) Allow solution to run through column into a 125 mL erlenmeyer
flask.
5. Completely dissolve your product (if possible) in round-bottom flask (from step 8 above) with 5 mL of
ethyl acetate (swirl until dissolved), then add 5 mL hexanes.
6. With a pasteur pipette, mix the solution (from step 4) and transfer to the column. (Slowly add your
material to the column by pipetting the solution in the middle of gel). *Leave room at top of column for
adaptor to fit.
7. Run the solution through the gel (with air) until solution just about reaches the silica gel. Collect the
solution in a beaker.
8. Run another 10 mL 1:1 hexanes:ethyl acetate solution through the column and collect in a tared 100 mL
round bottom flask.
9. Spot a TLC plate (label the lanes) with what was collected in the round bottom flask and the beaker
(when spotting from the beaker, spot multiple times because beaker contents are dilute). Use same
conditions for the solvent as before (1:1 hexanes:ethyl acetate). Place your TLC plate in the TLC
receptacle and visualize the spots by UV. Identify the spot or spots you see. (Refer to figure 8 for help).
10. Continue column with 30 mL 1:1 hexanes:ethyl acetate solution in same 100mL round-bottom flask as
step 8.
11. Collect solutions from step 8 and 10 in a labeled and tared (weighed, weight written down) 100 mL round
bottom flask.
12. Place round-bottom flask on rotary-vap to dry contents. Allow contents to dry in locker over the week.
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Alternative work-up and
W ork-up 1:purification
1.
Using a magnet, remove the stir bar from the 25 mL round
bottom flask. !
2.
Add 10 mL of 1M NaOH to the 25 mL round bottom flask, and
then transfer it to a separatory funnel. !
3.
Add 15 mL of chloroform to the 25 mL round bottom flask, then
transfer it to a separatory funnel (or straight to separatory funnel
if you are repeating).!
4.
Place a glass stopper on the separatory funnel; shake contents
inside to mix (the water layer from the NaOH is less dense than
chloroform, the water will be the top layer). The product will be
in the chloroform (bottom layer). !
5.
Empty chloroform (bottom) layer into a 100 mL, labeled and
TARED, round bottom flask (it is better to leave some of the
chloroform in with the aqueous layer than to let some of the
water out with the chloroform layer). !
6.
“Wash” aqueous layer 1 more time by repeating steps 3-6 (each
chloroform layer will be added to the 100 mL round bottom (By
“washing” the aqueous layer with chloroform, you are retrieving
any product that may be “trapped” in the water layer.
7.
With a tube connected to “air” in your fume hood, blow air into
the 100 mL round bottom until the solvent has evaporated (about
15 minutes).
STOP: END OF DAY 1
Work-up 2:
1.
Add 10 mL of ethanol to the 100 mL round bottom flask
containing the dried product and mix thoroughly by swirling.
2. !
Scrape the dried product with a spatula to allow the product to be
free flowing in the 10 mL of ethanol (make sure product stays in
round bottom flask).
3.
Place the 100 mL round bottom flask in an ice bath (10 min) to
allow any dissolved product to precipitate while TPPS stays
dissolved in ethanol.
4.
Filter ethanol with a Buchner funnel and filter paper; when
filtering be careful to keep most of the precipitate (product) in the
100 mL round bottom flask.
5.
Add any precipitate back to the 100 mL round bottom flask by
carefully scraping the filter paper with spatula.
6.
Place the 100 mL round bottom flask on rotary evaporator
(rotovap) to dry residual ethanol.
7.
Make sure the100 mL round bottom flask is dry (wipe with a
paper towel to avoid any water on the outside of the 100 mL
round bottom flask).
8.
Weigh the 100 mL round bottom flask and determine the mass of
product.
!
!