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6th February 2012 @ 05:15
*PS = Pictet-Spengler

Experiment Concluded.

Parallel PS reaction of KAB5-2 to give PZQ catalysed by 60, 30, 15, 10 and 5 mol% TfOH.

KEYWORDS (for search): KAB3-12, KAB3-13, KAB3-14, KAB3-15, KAB3-16.




Hazard and Risk Assessment
As for KAB3-11 (here)

Previous Related Experiments
TfOH catalysed PS* reaction to give PZQ (KAB3-11)

Following Experiments
Isolation of the TfOH catalysed PS to PZQ reaction intermediates (KAB14-1)
The TfOH catalysed PS* reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-11)
TfOH catalysed PS* reaction to give the dimethoxy PZQ analogue (KAB1-4)
TfOH catalysed PS* reaction to give the N-benzoyl PZQ analogue (KAB7-3)
TfOH catalysed PS* reaction to give PZQ (KAB3-17)
TfOH catalysed partial PS* reactions to give the enediamide intermediates of PZQ and the N-benzoyl analogue (KAB13-2 & KAB17-1)

Procedure

Stock Starting Material Solution. KAB5-2 (403.5 mg, 0.9974 mmol) was added to a 5 mL volumetric flask. The solution was made up to 5 mL with toluene to give the stock KAB5-2 solution (0.20 M).

Stock Acid Material Solution. TfOH (91.0 mg) was added to a 5 mL volumetric flask and made up to volume with toluene to give a 121.3 mM TfOH in toluene solution.

Left: KAB5-2 solution; Right: TfOH/toluene solution


07/02/12. Toluene (30 mL) was added to 5 × 50 mL conical flasks before 1 mL of the stock KAB5-2 solution was added (80.7 mg, 199 μmol). At 10:10 the stock acid was added in the following volumes:

The reaction mixtures were left to stir at rt.
Setting up the reaction
Immediately following the addition of acid
Reaction mixtures at 22 hr


Monitoring the Reaction Progress by TLC. TLCs 1 to 5 were eluted with EtOAc/hexane, 3:1, v/v, visualised under UV light and stained with KMnO4. TLCs from 6 onwards were eluted with EtOAc/hexane, 1:1, v/v. (SM = KAB5-2)

07/02/12
TLC 1 at 10 min
TLC 2 at 30 min
TLC 3 at 1 hr
TLC 4 at 2 hr
TLC 5 at ~3 hr

TLC 6 at 3 hr
TLC 7 at ~4 hr
TLC 8 at 4.5 hr
TLC 9 at ~6 hr
TLC 10 at ~6.5 hr

Annotated TLC 10


After 3 hours (TLC 5), the KAB3-14 (15 mol%), KAB3-15 (10 mol%) and KAB3-16 (5 mol%) reaction mixtures still contained the KAB5-2 starting material. Solvent system may need to be adjusted, see notes below.

Co-spot at 6.5 hr (1)

Co-spot 1 from left to right:
- KAB3-12 reaction mixture at 6.5 hours.
- Co-spot of KAB3-12 reaction mixture, PZQ and the KAB5-2 starting material.
- KAB5-2.
- PZQ.
- Co-spot of KAB3-13 reaction mixture at 6.5 hours, PZQ and KAB5-2.
- KAB3-13 reaction mixture at 6.5 hours.
- KAB3-14 reaction mixture at 6.5 hours.
- Co-spot of KAB3-14 reaction mixture at 6.5 hours, PZQ and KAB5-2.
- PZQ.
- KAB5-2.

Co-spot at 6.5 hr (2)

Co-spot 2 from left to right:
- KAB3-15 reaction mixture at 6.5 hours.
- Co-spot of KAB3-15 reaction mixture at 6.5 hours, PZQ and KAB5-2.
- KAB5-2.
- PZQ.
- Co-spot of KAB3-16 reaction mixture at 6.5 hours, PZQ and KAB5-2.
- KAB3-16 at 6.5 hours.


08/02/12
TLC 11 at 22 hr
TLC 12 at 26 hr
TLC of KAB3-12 at 26.5 hr
TLC 13 at 32 hr


Co-spot at 28 hr

Co-spot at 28 hours from left to right:

Rf Values (EtOAc/hexane, 3:1, v/v):
PZQ expected product = 0.56
KAB5-2 starting material = ~0.6
Enediamide intermediate = >>0.6

Rf Values (EtOAc/hexane, 1:1, v/v):
PZQ expected product =
KAB5-2 starting material =
Enediamide intermediate =

Summary and Conclusion
Results of the experiment, and previously performed TfOH catalysed experiments, suggest that the Pictet-Spengler cyclisation to give praziquantel will not proceed catalytically no matter how strong the Bronsted acid employed. The reaction appears to develop at a faster rate with greater loading of TfOH. Various transient intermediates are formed as indicated by TLC. The formation of the enamide intermediate was the final stage of the TfOH catalysed PS reaction in toluene before decomposition of the reaction components occurred.

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NOTES 07/02/12
- All five solutions immediately turned yellow after the addition of the TfOH/toluene solution.
- At about 1 hour, starting to see formation of a low lying spot, Rf ~0.4 in EtOAc/hexane, 3:1, v/v. More intense in higher [TfOH].
- Acid strength is too much?
- The solvent ran off the plate for TLC 1.
- Currently 11:00. PZQ may form if the solutions are gently heated.
- TLC 4 --> Just made up new batch of KMnO4 stain and hadn't let it settle before dipping the plate.
- TLC 5. PZQ and KAB5-2 were diluted for future TLCs. Still unclear whether PZQ is being formed. May require solvent system change.
- TLC 6. New solvent system. Should have STARTED with this. Starting material also co-spotted an unknown with high Rf. Contamination or enediamide?
- Circled spot in TLC 7 in KAB3-12 is most likely the enediamide intermediate, based on how it resolved after staining and heating.
- e.g. TLC 9. The spot around the KAB5-2 starting material and PZQ that appears to be sloping upwards as you look from KAB3-12 to KAB3-16 appears to do so because there is a spot in between the SM and product and some SM remaining in the KAB3-13 to KAB3-16 reaction mixtures. The decreased intensity as the SM is consumed along with the appearance of the "in-between" spot gives the effect of a migrating spot.
- The high Rf spots in the Co-spot 2 TLC plate are NOT the enediamide intermediate, which has a slightly lower Rf.
- The spot between the SM and PZQ may possibly be the aminal intermediate.

NOTES 08/02/12
- The 60 mol% reaction (KAB3-12) appears to be decomposing --> TLC 13 @ 32 hours.

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Linked Posts
Attached Files
Scheme KAB3-12 to KAB3-16
Table KAB3-12 to KAB3-16
Acid Table
Left: KAB5-2 solution; Right: TfOH/toluene solution
Setting up the reaction
Immediately following the addition of acid
TLC 1 at 10 min
TLC 2 at 30 min
TLC 3 at 1 hr
TLC 4 at 2 hr
TLC 5 at ~3 hr
TLC 6 at 3 hr
TLC 7 at ~4 hr
TLC 8 at 4.5 hr
TLC 9 at ~6 hr
TLC 10 at ~6.5 hr
Co-spot at 6.5 hr (1)
Co-spot at 6.5 hr (2)
Annotated TLC 10
TLC 11 at 22 hr
Reaction mixtures at 22 hr
TLC 12 at 26 hr
TLC of KAB3-12 at 26.5 hr
Co-spot at 28 hr
TLC 13 at 32 hr