Thursday, June 22, 2006

Exp 015

Objective:To convert adrenaline to a catechol aldehyde using acid catalysis. How this fits into the synthesis of anti-malarials is described here.

Procedure:Taken from Preparation and Properties of p-Hydroxyphenylacetaldehyde and 3-Methoxy-4-Hydroxyphenylacetaldehyde by Jay H. Robbins Archives of Biochemistry and Biophysics.A solution of adrenaline (217 mg, 1.18 mmol) in 85% phosphoric acid (6 mL) was heated in a 12mL vial to 120C in a glycerol bath then removed from heat and allowed to cool for 30 secondsthen added to water (36 mL) and then saturated with NaCl, followed by extraction with ether (17mL, 10mL, 10mL).

Video of set upTwo stains were done without a TLC run Ninhydrin stain Ansaldehyde stainRun in pure methanol visible with iodine.HNMR was obtained of the product after it was re-dissolved with ether, dried with MgSO4, and vacuumed again to have a net weight of 15mg. There is no carbonyl peak that I can see and the NMR seems scewed. There is an expanded version as well.

Based on the published H-NMR of DOPAL alone there does not seem to be any aldehyde formed. However HMR spectra of 4-alkylcatechols, such as 4-methylcatechol, with the three aromatic hydrogens genrally appearing in the 6.5-6.9 ppm range gives reason to believe that the published spectra is incorrect.

The aldehyde was not produced however the reaction will be attempted once more.


16:55] turn on hot plate to heat glycerol
17:10] put phosphoric solution in 10mL vial and then in heated glycerol bath
17:23] solution heated to 120C, taken off of heat and cooled for 30seconds. added to 36mL distilled water.
19:00] Saturated with NaCl(didn't filter)
19:13] Poured solution without excess NaCl into a separatory funnel. Extracted with 17mL anhydrous ether
19:20] Extracted with 10mL anhydrous ether
19:24] Extracted with 10mL ether
19:30] Performed TLC 1:1 methylene chloride hexanes (no movement), pure methylenechloride (no movement), pure methanol (some movement)**Ninhydrin and Ansaldehyde stains give little information.
rotovaped ether extracts
vacuumed off remains from rotovap. wt=15mg dry product
would not disolve in methylene chloride but did disolve in methanol
TLC of 1:1 methylene chloride in hexanes showed nothing. Methanol had same movement

Thursday, June 01, 2006

Exp 014

The Ugi Rerun of experiment 006
Objective : To accomplish the Ugi Synthesis and cyclization to a diketopiperazine using phenylacetaldehyde, 5-methylfurfurylamine, N-(tert) butoxycarbonyl)L-methionine, and benzylisocyanide using the protocol described here. The target diketopiperazine is not predicted to be active but is a close analog of the product that we wish to make once the catechol aldehyde is obtained.
To a 50 ml Erlenmeyer flask added methanol (20 ml), phenyl acetaldehyde, 623µl , 5-methylfurfurylamine 555µl, benzylisocyanide 608µl, and N-(tert) butoxycarbonyl) L-methionine 1.24604 gms. The mixture was stirred for 15 h, evaporated, refluxed for 45min in 1,2-dichloroethane (27 ml) and trifluoroacetic acid (3 ml) then evaporated again to a dark oil. The crude product was taken up in dichloromethane (30 ml), washed with water, dried over anhydrous MgSO4 and evaporated again. A dark, reddish oil was obtained.

1. 9:00pm (05/30/2006) In a 50ml Erlenmeyer flask, 20ml of methanol placed. To it 623µl of phenyl acetaldehyde, 555µl of 5-methylfurfurylamine, 608µl of benzylisocyanide and
1.24604 gms of N-(tert) butoxycarbonyl) L-methionine was added.
2.The reaction was stirred at room temperature with a teflon coated stir bar on a stir plate for 15 hours (stopped stirring at 12:00 noon (05/31/2006). (Videos of the reaction being stirred)
3.Methanol was evaporated on a rotovap set at 100C, Obtained 3.239gms the crude product.
4. Added 27ml of 1,2-dichloroethane and 3ml of trifluoro acetic acid to the methanol void sample in a pre weighed round bottom flask. Refluxed the contents of the flask for 45 mins (the rheostat settings had to be adjusted because the reaction mixture has stopped refluxing during the process),the boiling points of the solvents are, TFA= 72.4 ° C and 1,2-Dichloroethane = 83 °C
5.The reaction mixture was rotovaped (set at 100C) again after 45mins on reflux.
6.The resultant compound was washed with water (twice, 70mls and 30 mls) and partitioned in methylene chloride (60mls)
7.After separation; the organic layer was dried over anhydrous Magnesium Sulfate, filtered.
8. The obtained crude product was subjected to an NMR analysis.
9.2:30pm (06/01/2006) The crude product was further dried under vacuum until it foamed and settled. The process was continued for a period of one and half hours.(4:00pm)
9. After evaporation under vacuum 3.5174gms of product was obtained.
10. 1.3051 gms of the product was weighed and intorduced on a chromtotron. Intially a 2:1 mix of hexanes and methylene chloride was used (about 400ml), 19 of 20mls portions were acuumulated.
11. Most of the compund stillremained on the rotor disc. The compound was let dry
overnight on the rotor.
Upon Dr. Bradley's suggestion the remaining compound was removed from the rotor using methanol.
12. The compound in methanol was rotovaped and evaporated under low pressure, and introduced back on the chromatotron, however the the eluent used this time was 1:1 hexanes
and methylene chloride (100mls mix) The eluent composition was changed gradually from 1:1 hexanes, methylene chloride to just methylene chloride (100mls), then it was further changed to 0.5% methanol in methylene chloride.
Polarity of the solvent was changed regularly. 0.5% methanol, 1% methanol, 2% methanol, 3% methanol,
4% methanol, 6% methanol, and 8% methanol in methylene chloride.
16 fractions were accumulated.