EXP045.JPG



























Objective

To study the formation of an imine from 3,4-dimethoxybenzaldehyde and 5-methylfurfurylamine and to perform a 4-component Ugi reaction with 2-morpholine ethyl isocyanide and Boc-Gly-OH in deuterated chloroform as solvent.

Procedure

One Molar CDCl3 solutions of 3,4-dimethoxybenzaldehyde and 5-methylfurfurylamine are prepared in separate 1 dram vials. 800uL of the solutions are used to obtain initial H and C NMR spectra respectively.Then 400uL of each solution is transfered to a clean nmr tube and shaken vigorously for a few seconds, the reaction is monitored by H and C NMR. After a 24h monitoring of the imine formation, a 4 component ugi reaction is performed using 2-morpholine ethyl isocyanide and Boc-Gly-OH. The whole process is carried out in CDCl3, in an NMR tube with NMR monitoring.

Results

(*All Spectra have been obtained on a Varian Inova 300MHz instrument, unless specified otherwise)

5-methyl furfuryl amine solution-(MFA)

HMR
CMR

3,4-dimethoxybenzaldehyde solution-(Veratraldehyde)

HMR [1]
CMR [2]

Boc-Gly-OH

HMR [3]
CMR [3]


2-morpholine ethyl isocyanide

HMR
CMR [4]

45A - (MFA+Veratraldehyde)


HMR(t = 1min) Imine peak starting to form at 8.24, its concentration seems negligible in the given solution..

CMR(t = 11min)

HMR(t = 15min) 10.2% based on 9.84 to 8.24 ppm conversion and 10.4% based on 3.74 to 4.68 ppm.

CMR(t = 27min)

HMR(t = 29min) 18.7% based on 9.84 to 8.24 ppm

CMR(t = 40min)

HMR(t = 45min) 26.9% based on 9.84 to 8.24 ppm

CMR(t = 57min)

HMR(t = 62min) 33.5% based on 9.84 to 8.24 ppm

CMR(t = 74min)

HMR(t = 88min) 40.9% based on 9.84 to 8.24 ppm

CMR(t = 99min)

HMR(t = 102min) 44.6% based on 9.84 to 8.24 ppm

CMR(t = 122min)

HMR(t = 140min) 50.9% based on 9.84 to 8.24 ppm

CMR(t = 177min)

HMR(t = 185min) 56.1% based on 9.84 to 8.24 ppm

CMR(t = 202min)

HMR(t = 233min) 61.2% based on 9.84 to 8.24 ppm

CMR(t = 270min)

HMR(t = 273min) 65.0% based on 9.84 to 8.24 ppm

CMR(t = 287min)

HMR(t = 295min) 66.2% based on 9.84 to 8.24 ppm

CMR(t = 305min)

HMR(t = 307min) 67.4% based on 9.84 to 8.24 ppm

CMR(t = 318min)

HMR(t = 17h 24min) 85.3% based on 9.84 to 8.24 ppm

CMR(t = 17h 35min)

HMR(t = 18h 42min) 86.1% based on 9.84 to 8.24 ppm

CMR(t = 19h 53min)

HMR(t = 20h 15min) 86.2% based on 9.84 to 8.24 ppm

CMR (t = 20h 58min)

HMR(t = 23h 19min) 87.6% based on 9.84 to 8.24 ppm

HMR(t = 24h 5min) 87.6% based on 9.84 to 8.24 ppm

Figure 1.Second Order Kinetics plot of imine formation.

Based on 9.84 to 8.24 ppm shift


kinetics1.JPG
K = 1.00 x 10-2 /M*min
Excel Data Sheet

45B - [45A+ Boc-Gly-OH + 2-morpholine ethyl isocyanide]


HMR (t = 004min)

HMR (t = 008min)

HMR (t = 014min)

HMR (t = 017min)

CMR (t = 029min)

HMR (t = 032min)

HMR (t = 084min)

CMR (t = 099min)

HMR (t = 121min)

CMR (t = 159min)

HMR (t = 165min)

CMR (t = 203min)

HMR (t = 214min)

CMR (t = 252min)

HMR (t = 259min)

CMR (t = 283min)

HMR ( t = 285min)

HMR (t = 17h 46min)

CMR (t = 18h 23min)

HMR (t = 18h 36min)

CMR (t = 19h 48min)

HMR (t = 20h 00min)

CMR (t = 21h 10min)

HMR (t = 21h 49min)

CMR (t = 23h 00min)

HMR (t = 23h 03min)

CMR (t = 24h 14min)

HMR (t = 24h 29min)

CMR (t = 25h 32min)

HMR (t = 25h 42min)

CMR (t = 26h 54min)

HMR (t = 27h 12min)

CMR (t = 28h 23min)

HMR (t = 29h 04min)

HMR (t = 42h 11min)

CMR (t = 43h 31min)

HMR (t = 45h 11min)

CMR (t = 45h 35min)

HMR (t = 46h 24min)

HMR (t = 47h 48min)

HMR (t = 48h 00min) [500MHz Varian Inova]

HMR (t = 64h 08min) [500MHz Varian Inova]

HMR (t = 68h 07min) [500MHz Varian Inova]

HMR (t = 69h 29min) [500MHz Varian Inova]

HMR (t = 71h 05min) [500MHz Varian Inova]

HMR (t = 72h 02min) [500MHz Varian Inova]

HMR (t = 74h 01min) [500MHz Varian Inova]

HMR (t = 88h 16min) [500MHz Varian Inova]

HMR (t = 90h 41min) [500MHz Varian Inova]

HMR (t = 95h 25min) [500MHz Varian Inova]

Spectral Overlays

Overlay1: veratraldehyde, 5-methylfurfurylamine, 45A-24h05min (88% conversion to imine)
Overlay2: veratraldehyde, 5-methylfurfurylamine, 45A-15min(10%), 45A-62min(34%),45A-24h05min(88% conversion to imine)
Overlay3: Ugi (95h 5min) Versus Imine (24h 5min), morpholino ethyl isocyanide, Boc-Glycine and veratraldehyde..

Discussion

  1. After mixing the aldehyde and amine in CDCl3, the changes in the H NMR are consistent with the clean formation of an imine. The conversion can be tracked by conversion of the singlet at 9.84 ppm to the singlet at 8.24 ppm, corresponding to the aldehyde to imine H. From Figure 1, it appears that the conversion is half done after about 2 h and 88% complete after 24 h, with no indication of having reached equilibrium. From the slope in Figure 1, using all the available data, a rate constant of 1.00 x 10-2 /M*min is calculated. Using only the data points up to 50% conversion, as suggested by Keusch, gives a rate of 1.52 x 10-2/M*min. This is within a factor of 2-6 compared with the rate reported for the reaction of benzaldehyde with aniline[6 ] and very close to the value of 1.1 x 10-2 /M*min reported for the reaction of acetophenone with aniline[7].This is considerably slower than for the reaction of phenylacetaldehyde with t-butylamine (EXP044), where equilibrium is reached within a few minutes, but also where side reactions take place. This is presumably is due to the slower reaction of aromatic aldehydes in imine formation.
  2. From Overlay3 and integration of 45B-95h25min it appears clear that the three aromatic protons of the dimethoxyphenyl ring are fully accounted for by leftover imine and reversion to the aldehyde, thus indicating that the Ugi product did not form after 94h. Other peaks match up with this mixture of imine and aldehyde. After addition of the isonitrile and acid, the 3.89 and 3.91 ppm methoxy peaks overlap at 3.90 ppm. In a few spectra on the 500 MHz instrument, such as 45B-79h05min, the presence of two close peaks can be discerned.
  3. How long does it take for the amine and isonitrile to disappear? Create an overlay of a few samples of 45B to get an idea.
  4. Most of the H NMRs taken with the 300 MHz instrument have broad peaks with side peaks, hindering some more detailed analysis, this may be overcome by better shimming.

Conclusion

In CDCl3, imine formation was confirmed but did not go on to generate the Ugi product, which is generally not performed in this solvent. This reaction should be redone in methanol-d4.

Log

2006-12-18

01. 17:20] Obtained HMR and CMR of Veratraldehyde (3,4-dimethoxybenzaldehyde) using 800uL of the 1M Solution prepared by adding CDCl3 to 332mg; 2mmol of the aldehyde and making it up to the 2ml mark in a volumetric flask.
Also HMR and CMR of 5-methyl furfuryl amine is obtained using 800uL of the 1M Solution prepared by adding 1778uL of CDCl3 to 222uL; 1mmol of the amine.
02. 18:23] Added 400uL of veratraldehyde and 400uL of 5-methyl furfurylamine to a clean NMR tube shaken it vigorously for about 30 sec to obtain 45A.
03. 18:24] HMR obtained (t = 001min)
04. 18:50] CMR obtained (t = 027min)
05. 18:52] HMR obtained (t = 029min)
06. 19:03] CMR obtained (t = 040min)
07. 19:08] HMR obtained (t = 045min)
08. 19:20] CMR obtained (t = 057min)
09. 19:25] HMR obtained (t = 062min)
10. 19:37] CMR obtained (t = 074min)
11. 19:51] HMR obtained (t = 088min)
12. 20:02] CMR obtained (t = 099min)
13. 20:05] HMR obtained (t = 102min)
14. 20:25] CMR obtained (t = 122min)
15. 20:43] HMR obtained (t = 140min)
16. 21:20] CMR obtained (t = 177min)
17. 21:28] HMR obtained (t = 185min)
18. 21:45] CMR obtained (t = 202min)
19. 22:16] HMR obtained (t = 233min)
20. 22:53] CMR obtained (t = 270min)
21. 22:56] HMR obtained (t = 273min)
22. 23:10] CMR obtained (t = 287min)
23. 23:18] HMR obtained (t = 295min)
24. 23:28] CMR obtained (t = 305min)
25. 23:30] HMR obtained (t = 307min)
26. 23:41] CMR obtained (t = 318min)

2006-12-19

27. 11:47] HMR obtained (t = 17hr 24min)
28. 11:58] CMR obtained (t = 17hr 35min)
29. 13:05] HMR obtained (t = 18hr 42min)
30. 14:16] CMR obtained (t = 19hr 53min)
31. 14:38] HMR obtained (t = 20hr 15min)
32. 15:21] CMR obtained (t = 20hr 58min)
35. 16:40] 1M stock solutions of the reagents are prepared; 2-morpholine ethyl isocyanide (by adding 1790uL of CDCl3 to 210uL of the isonitrile) and Boc-Gly-OH (by making-up a 2ml solution with 350mg; 2mmol of the aminoacid).
33.17:42] HMR obtained (t = 23hr 19min)
34. 17:53] Obtained HMR and CMR of 2-morpholine ethyl isocyanide solution (800uL; IM)
35. 18:10] Obtained HMR and CMR of Boc-Gly-OH (800uL; 1M)
34. 18:28] HMR obtained (t = 24hr 5min)
35] .18:35] Poured the imine solution from the nmr tube into a 1dram vial and to it, added 400uL each of Boc-Gly-OH and 2-morpholine ethyl isocyanide. The reaction mixture was shaken vigourously for about 30s, the imine nmr tube was rinsed with this mixture; 45B.
36. 18:36] Poured 800uL of 45B.
37. 18:39] HMR of 45B obtained (t = 004min)
38. 18:42] HMR of 45B obtained (t = 007min)
39. 18:48] HMR of 45B obtained (t = 013min)
40. 18:51] HMR of 45B obtained (t = 016min)
41. 19:03] CMR of 45B obtained (t = 028min)
42. 19:06] HMR of 45B obtained (t = 031min)
43. 19:54] HMR of 45B obtained (t = 083min)
44. 20:14] CMR of 45B obtained (t = 099min)
45. 20:36] HMR of 45B obtained (t = 121min)
46. 21:14] CMR of 45B obtained (t = 159min)
47. 21:20] HMR of 45B obtained (t = 165min)
48. 21:58] CMR of 45B obtained (t = 203min)
49. 22:09] HMR of 45B obtained (t = 214min)
50. 22:47] CMR of 45B obtained (t = 252min)
51. 22:54] HMR of 45B obtained (t = 259min)
52. 23:20] CMR of 45B obtained (t = 285min)
53. 23:23] HMR of 45B obtained (t = 287min)

2006-12-20

54. 12:21] HMR of 45B obtained (t = 17h 46min)
55. 12:58] CMR of 45B obtained (t = 18h 23min)
56. 13:11] HMR of 45B obtained (t = 18h 36min)
57. 14:23] CMR of 45B obtained (t = 19h 48min)
58. 14:35] HMR of 45B obtained (t = 20h 00min)
59. 15:45] CMR of 45B obtained (t = 21h 10min)
60: 16:24] HMR of 45B obtained (t = 21h 49min)
61. 17:35] CMR of 45B obtained (t = 23h 00min)
62. 17:38] HMR of 45B obtained (t = 23h 03min)
63. 18:49] CMR of 45B obtained (t = 24h 14min)
65. 19:04] HMR of 45B obtained (t = 24h 29min)
66. 20:07] CMR of 45B obtained (t = 25h 32min)
66. 20:17] HMR of 45B obtained (t = 25h 42min)
67. 21:29] CMR of 45B obtained (t = 26h 54min)
68. 21:47] HMR of 45B obtained (t = 27h 12min)
69. 22:58] CMR of 45B obtained (t = 28h 23min)
70. 23:39] HMR of 45B obtained (t = 29h 04min)

2006-12-21

71. 12:46] HMR of 45B obtained (t = 42h 11min)
72. 14:06] CMR of 45B obtained (t = 43h 31min)
73. 15:46] HMR of 45B obtained (t = 45h 11min) [Sample stopped spinning; He-Cryogen was refilled earlier]
74. 16:10] CMR of 45B obtained (t = 45h 35min)
75. 16:59] HMR of 45B obtained (t = 46h 24min)
76. 18:23] HMR of 45B obtained (t = 47h 48min)
77. 18:35] HMR of 45B obtained (t = 48h 00min) [Spectrum obtained on a 500MHz Varian Inova]

2006-12-22

[500MHz Varian Inova Spectra]
78. 10:43] HMR of 45B obtained (t = 64h 08min)
79. 14:42] HMR of 45B obtained (t = 68h 07min)
81. 15:04] HMR of 45B obtained (t = 69h 29min)
82. 17:40] HMR of 45B obtained (t = 71h 05min)
82. 18:37] HMR of 45B obtained (t = 72h 02min)
83. 20:36] HMR of 45B obtained (t = 74h 01min)

2006-12-23

83. 10:51] HMR of 45B obtained (t = 88h 16min)
84. 13:16] HMR of 45B obtained (t = 90h 41min)
85. 18:00] HMR of 45B obtained (t = 95h 25min)

References


1. Claudia Crestini, Maria Chiara Caponi, Dimitris S. Argyropoulosc and Raffaele Saladinob, Bioorganic & Medicinal Chemistry 14 (2006) 5292–5302
2.Morgan, K. R.; Newman, Roger H; Journal of the American Chemical Society (1990), 112(1), 4-7
3.Houen, Gunnar; Struve, Casper; Sondergaard, Roar; Friis, Tina; Anthoni, Uffe; Nielsen, Per H.; Christophersen, Carsten; Petersen, Bent O.; Duus, Jens O. Bioorganic & Medicinal Chemistry (2005), 13(11), 3783-3796
4. Minelli, Martin; Maley, Walter J.Inorganic Chemistry (1989), 28(15), 2954-8.
5.Chai-Lin Kao and Ji-Wang Chern; J. Org. Chem.; 2002; 67(19) pp 6772 - 6787
6. Henk Wensink, Fernando Benito-Lopez, Dorothee C. Hermes, Willem Verboom, Han J. G. E. Gardeniers, David N. Reinhoudt and Albert van den Berg, Measuring reaction kinetics in a lab-on-a-chip by microcoil NMR Lab Chip, 2005, 5, 280 - 284
7.2003 Moonkwon Lee; Jaebum Choo Gives a rate of a similar imine monitored by Raman spectroscopy which is very close to the rates we have been getting - about 0.01 /M*min in CDCl3 for acetophenone and aniline derivatives
8. Synthesis and characterization of benzylideneamines from aromatic aldehydes. Proton and carbon-13 NMR; Catusse, C.; Catusse, R.; Gaset, A.; Gorrichon, J. P; Journal de la Societe Chimique de Tunisie (1985), 2(2), 11-14 (Article in French) (Private Access)

Tags

2-morpholin ethyl isocyanideInChI=1/C7H12N2O/c1-8-2-3-9-4-6-10-7-5-9/h2-7H2
VeratradehydeInChI=1/C9H10O3/c1-11-8-4-3-7(6-10)5-9(8)12-2/h3-6H,1-2H3
Boc-Gly-OH InChI=1/C7H13NO4/c1-7(2,3)12-6(11)8-4-5(9)10/h4H2,1-3H3,(H,8,11)(H,9,10)
5-methylfurfurylamineInChI=1/C6H9NO/c1-5-2-3-6(4-7)8-5/h2-3H,4,7H2,1H3
imine:[[http://www.google.com/search?hl=en&q=InChI%3D1%2FC15H17NO3%2Fc1-11-4-6-13%2819-11%2910-16-9-12-5-7-14%2817-2%2915%288-12%2918-3%2Fh4-9H%2C10H2%2C1-3H3%2Fb16-9-|InChI=1/C15H17NO3/c1-11-4-6-13(19-11)10-16-9-12-5-7-14(17-2)15(8-12)18-3/h4-9H,10H2,1-3H3/b16-9-]]
ugi045:InChI=1/C28H40N4O8/c1-19-7-9-21(39-19)18-32(26(34)30-27(35)40-28(2,3)4)24(20-8-10-22(36-5)23(17-20)37-6)25(33)29-11-12-31-13-15-38-16-14-31/h7-10,17,24H,11-16,18H2,1-6H3,(H,29,33)(H,30,34,35)