162_Rxn_Scheme.JPG
Reaction Scheme


Objective

To synthesize a Ugi Product following the EXPLAN005 . The compound will contribute towards a library for Falcipain2 inhibitors.
This compounds was ranked 11 in the DEXP014-V1B file from D-EXP014 .

Procedure

As described in Explan005
This reaction used Phenanthrene-9-carboxaldehyde, tert-butylisocyanide, cyclohexylamine, and phenylacetic acid.
Phenanthrene-9-Carboxaldehyde (solid from Sigma-Aldrich)
HNMR
tert-Butyl isocyanide
HNMR
ID/ Lib Rank
Solvent
Aldehyde
Amine
Carboxylic Acid
Isocyanide
Ppt Yes/No
157/11
Methanol
Phenanthrene-9-
carboxaldehyde
cyclohexylamine
Phenylacetic acid
tert-butylisocyanide
N/A
Quantity
2000uL
0.5mmol, 103.1mg
0.5mmol, 57.2uL
(density=0.867g/ml)
0.5mmol, 68.1mg
0.5mmol, 56.5uL
(density=0.735g/ml)


Density information found on the Ugi Chemicals Page in Left Navigation Bar.

Results

Photos taken directly after all the components were charged and vortexed.
162A.jpg
162A


No dissolution could be achieved during the additions even with 30 minutes of vortexing as well as further dilution.

Discussion

The experiment was repeated from Exp157 because incomplete dissolution was observed. This result was confirmed with another positive result for insolubility existing between the cyclohexylamine and phenanthrene-9-carboxaldehyde, that could not be resolved upon the addition of the carboxylic acid and isocyanide, nor the addition of extra methanol solvent.
Also, another observation to note was that upon the addition of the cyclohexylamine to the methanol, slight turbidity was noted in the solution, though it was resolved upon vortexing. This may indicate that the cyclohexylamine reagent is not pure, which was also eveident from the residue on the threads of the bottle which made it exceedingly difficult to open. It is suggested that perhaps this experiment be repeated with fresh cyclohexylamine.
Other experiments have been performed with phenanthrene-9-carboxaldehyde with a mixture of results, seen below

Experiments with phenanthrene-9-carboxaldehyde which successfully dissolved:
Exp159 - Ugi synthesis from benzylamine, phenanthrene-9-carboxaldehyde, 4-chlorophenyl acetic acid and n-butyl isocyanide in methanol which resulted in complete dissolution and the formation of a precipitate the following day.
Exp160 - Ugi synthesis using phenanthrene-9-carboxaldehyde, furfurylamine, 3,4-dihydroxyphenyl acetic acid and n-butyl isocyanide which resulted in complete dissolution but no final precipitate.
Exp156 - Ugi synthesis using phenanthrene-9-carboxaldehyde, crotonic acid, benzylamine and t-butyl isocyanide which resulted in complete dissolution and a precipitate.
Exp163 - Ugi synthesis using furfurylamine, phenanthrene-9-carboxaldehyde, mandelic acid, and tert-butyl isocyanide which resulted in full dissolution but no precipitate.

Other experiments with phenanthrene-9-carboxaldehyde which failed to dissolve:
Exp164 Ugi synthesis using aniline, phenanthrene-9-carboxaldehyde, phenyl acetic acid and n-butyl isocyanide which resulted in a failure to dissolve.

The other experiments with phenanthrene-9-carboxaldehyde are with either benzylamine or furfurylamine, while the failed dissolution occurred with cyclohexylamine and aniline. An observation is the benzylamine and furfurlamine are both smaller molecules than cyclohexylamine and aniline. Furfurylamine is a five-membered ring and aniline and cyclohexylamine are six-membered rings, so it maybe be less sterically hindered than cyclohexylamine and aniline. Also, aniline is aromatic and is very stable, thus it is less reactive. And although benzylamine is a six-membered aromatic ring, it's nitrogen is separated from its ring which means that the aromaticity is not effected when it reacts to form the Ugi product.
For future experiments with phenanthrene-9-carboxaldehyde, it would be interesting to compare the solubility to the size and properties of the amine.

All results are recorded Master Table and Workflow Tables .

Conclusion

Experiment aborted because a clear solution was never obtained immediately after mixing all reagents or the addition of extra solvent. This experiment inspired the further discussion of the apparent amine selective solubility of phenanthrene-9-carboxaldehyde is presented here.

Log

2008-01-22

15:23- Weighed out the Phenanthrene-9-carboxaldehyde.
15:26- Weighed out the phenylacetic acid.
15:29- Charged a vial with 500 ul of methanol.
15:31- Added the cyclohexylamine to the vial.
15:32 Vortexed vial 1 min
15:33- Added the phenanthrene-9-carboxaldehyde.
15:34-Vortexed vial 10 min, did not dissolve, moved on to next addition
15:45- Added the phenylacetic acid.
15:46-Vortexed vial 5 min, did not dissolve, moved on to next addition
15:51- Added the tert-butyl isocyanide.
15:52-Vortexed 5 min, still no dissolution, made decision to add methanol to dilute it.
15:57-Added extra 500ul of methanol
15:58-Vortexed 5 min, still no dissolution
16:03-Added another 500ul of methanol
16:04-Vortexed 5 min, no change in solubility
16:10-Concluded that no further dissolution possible.
16:12- A photo was taken (162A) to demonstrate insolubility.

Tags

Phenanthrene-9-carboxaldehydeInChI=1/C15H10O/c16-10-12-9-11-5-1-2-6-13(11)15-8-4-3-7-14(12)15/h1-10H QECIGCMPORCORE-UHFFFAOYAE
tert-butylisocyanideInChI=1/C5H9N/c1-5(2,3)6-4/h1-3H3 FAGLEPBREOXSAC-UHFFFAOYAL
cyclohexylamineInChI=1/C6H13N/c7-6-4-2-1-3-5-6/h6H,1-5,7H2 PAFZNILMFXTMIY-UHFFFAOYAP
phenylacetic acid InChI=1/C8H8O2/c1-7(9)10-8-5-3-2-4-6-8/h2-6H,1H3 WLJVXDMOQOGPHL-UHFFFAOYAR
Product InChI=1/C3 ​4H38N2O2/c​1-34(2,3)3​5-33(38)32​(30-23-25-​16-10-11-1​9-27(25)28​ -20-12-13-​21-29(28)3​0)36(26-17​-8-5-9-18-​26)31(37)2​2-24-14-6-​ 4-7-15-24/​h4,6-7,10-​16,19-21,2​3,26,32H,5​,8-9,17-18​,22H2,1-3H​ 3,(H,35,38​) NYDTYYMZLJAMKH-UHFFFAOYAI