Based on a proposed Ugi mechanism, this experiment will consist of three parts all monitored by NMR. The first part will be to monitor the formation of the imine formed with piperonal and tert-butylamine. The next will be to add Boc-Gly-OH and monitor any changes by NMR. The last part will be to add 2-morpholinoethyl isocyanide and see if the Ugi product forms.


Made 2M solutions of piperonal (240mg, 1.6mmol), and Boc-Gly-OH (280mg, 1.6mmol), while 2-morpholinoethyl isocyanide (220uL, 1.6mmol) was made at a 1.56M concentration and tert-butylamine (168uL, 1.6mmol), was made at a 1.65M concentration. All solutions were made with 800uL of MeOH-d4. A volume of 400uL of each starting material was taken and diluted with another 400uL of MeOH-d4 making each 1M. HMRs were taken of each starting material. The remaining 400uL 2M of piperonal and tert-butylamine were added together giving each a concentration of 1M. HMRs were taken over a period 94mins. The remaining 400uL 2M of Boc-Gly-OH was added to the solution of aldehyde and amine giving a concentration of 0.75M for each component. HMRs were taken over the next 20mins. Because the volume of solution was becoming too much for the NMR tube, the solution in the NMR tube was transfered to a 5 dram vial and the remaining 400uL of isocyanide was added to the solution and 800uL was pipetted into the same NMR tube. HMRs were taken over 77 mins. All HMRs were done on a Varian 300MHz NMR.


Characterization of Starting Materials

2-morpholinoethyl isocyanide

Characterization of PartI - Monitoring of Imine Formation

48PtI_A t=04mins
48PtI_B t=12mins
48PtI_C t=19mins
48PtI_D t=25mins
48PtI_E t=50mins
48PtI_F t=56mins
48PtI_G t=94mins

Characterization of PartII - Addition of Boc-Gly-OH

48PtII_A t=04mins
48PtII_B t=14mins
48PtII_C t=20mins

Characterization of PartIII - Addition of Isocyanide

48PtIII_A t=07mins
48PtIII_B t=13mins
48PtIII_C t=20mins
48PtIII_D t=34mins
48PtIII_E t=77mins

Overlay1 consists of HMRs piperonal, tertbutylamine, 12min,25min,50min,94mins from Part-I
Overlay2 consists of HMRs piperonal, tertbutylamine, Boc-Gly-OH, A-C from Part-II and G from Part-I
Overlay3 consists of HMRs A-E from Part-III and all starting materials
Excel Exp048_Kinetics


  1. The rate constant of the first part of this reaction where the imine forms from piperonal and t-butylamine in methanol-d4 is 8.0*10^-3 [1/M*min]. In the same solvent, veratraldehyde and 5-methylfurfurylamine react about 14 times faster at a rate of 1.1*10^-1 [1/M*min].(EXP046) Since veratraldehyde and piperonal are closely related aromatic aldehydes, this difference suggests that t-butylamine's greater steric hindrance may be the cause. Do any refs back this up?
  2. Using the peak at 9.75 for the aldehyde and the peak at 8.22 for the imine, there is a 42% conversion of the aldehyde after 94mins. Using the peak at 1.12 for the amine and the peak at 1.29 for the imine, there is a 64% conversion of the amine to imine after the same time. This means that there was an excess of 20 % of aldehyde. If we consider that the amine will go to completion first, the imine is only 15% converted compared to the amine. The side bands were used in the calculation of the integrations of the aldehyde, amine and imine but using the central peaks alone give the same result.
  3. The imine formation was not monitored as long as it was in Exp045 or Exp046 and therefore only about 42% conversion was seen and thus the equilibrium composition was not determined. From previous experiments such as Exp046 the imine reaction of an aromatic aldehyde is faster in MeOH so if this reaction were done in CDCl3 it is expected to be even slower.
  4. The addition of the carboxylic acid reverses the imine to 0.72% after 20 minutes compared to the amine. This is surprising since in the typical Ugi reaction the four components are simply mixed together without prior isolation of the imine. The amine increases to 99% relative to the imine. Steps to remove the water should be taken to see if the addition of the acid still has an effect on the imine.
  5. Relative concentrations can not be determined accurately because there appears to be an overwhelming amount of acid compared to the imine. This can be due to a couple factors: 1) the MeOH-d4 slightly evaporated from the acid solution before it was added, 2) the imine decomposes in acid and without anything to react with reverts back to the aldehyde (and there is a slight increase in the aldehyde integration to support this), or 3) the amount of solid acid was weighed incorrectly with an un-calibrated balance.
  6. The addition of the isonitrile did not react as thought with the imine and acid. According to Overlay3, the 2-morpholinoethyl isocyanide is destroyed as the triplet of triplets around 3.6 is no longer present.


Boc-Gly-OH alone is sufficient to reverse partial imine formation between piperonal and t-butyl amine in methanol. Experiments to remove the water from the imine reaction and then add the acid should be preformed to see if the imine reversal by Boc-Gly-OH can be blocked.



Made up 2M solutions of Boc-Gly-OH and piperonal were made with a 1.65M solution of tert-butylamine and 1.56M solution of 2-morpholinoethyl isocyanide in MeOH-d4. Solutions were prepared as 800uL using 1.6mmol of each component. An amount of 168uL of tert-butylamine, 240mg of piperonal, 220uL of 2-morpholinoethyl isocyanide, and 280mg of Boc-Gly-OH was used. Liquids were measured with a micro pipette.


11:20] Took piperonal HMR
11:38] Took tert-butylamine HMR
12:00] Took 2-morphiline isocyanide HMR
12:10] Took Boc-Gly-OH HMR
12:21-12:25] Took 48PtI_A t=04mins
12:29-12:33] Took 48PtI_B t=12mins
12:35-12:39] Took 48PtI_C t=19mins
12:41-12:45] Took 48PtI_D t=25mins
13:05-13:09] Took 48PtI_E t=50mins
13:11-13:15] Took 48PtI_F t=56mins
13:49-13:53] Took 48PtI_G t=94mins
14:02-14:06] Took 48PtII_A t=04mins
14:12-14:16] Took 48PtII_B t=14mins
14:18-14:22] Took 48PtII_C t=20mins
14:39-14:43] After a 3 minute delay, took 48PtIII_A t=07mins
14:45-14:49] Took 48PtIII_B t=13mins
14:52-14:56] Took 48PtIII_C t=20mins
15:06-15:10] Took 48PtIII_D t=34mins
15:49-15:53] Took 48PtIII_E t=77mins


tert-butylamine InChI=1/C4H11N/c1-4(2,3)5/h5H2,1-3H3
2-morpholin ethyl isocyanideInChI=1/C7H12N2O/c1-8-2-3-9-4-6-10-7-5-9/h2-7H2
imine: Dead link InChI=1/C12H15NO2/c1-12(2,3)13-7-9-4-5-10-11(6-9)15-8-14-10/h4-7H,8H2,1-3H3/b13-7
ugi048: Dead link InChI=1/C26H40N4O7/c1-25(2,3)30(21(31)16-28-24(33)37-26(4,5)6)22(18-7-8-19-20(15-18)36-17-35-19)23(32)27-9-10-29-11-13-34-14-12-29/h7-8,15,22H,9-14,16-17H2,1-6H3,(H,27,32)(H,28,33)