Exp233

Researcher
David Bulger

media type="custom" key="4933655" Since Google Wave is "Sunsetting" in 2012, here's a zip file with all the files and discussion from the wave: [|Ugi Characterization Wave.zip]

Objective
To synthesize a Ugi product from different combinations of 3,5-Dimethoxybenzaldehyde, 1-Amino-1-Cyclohexanecarboxylic acid, Phenylpropionic acid, Boc-L-Proline, Benzylamine, t-butylisocyanide, and cyclohexyl isocyanide in methanol as a U4CR.
 * [Your selection of Ugi reactants should not have competing groups in general - for example an amine on the carboxylic acid component JCB]**
 * [The selection was based on the top 20 results from the Hex docking software results. Would this affect the reaction rate and/or the actual product of the reaction? ** DB]
 * [It would lead to multiple products with 2 reagents competing as amine groups - it should not have been added to the virtual library in the first place. But you were not able to make a solution in methanol anyway. JCB]**

Previous Experiment
Experiment can be found at [|Ugi Reaction Blog#001].

NMR Spectra: [|Sample 4], [|Sample 10]. Note: Samples analyzed in deuterated chloroform and original solvent was methanol.
 * [You will have to thoroughly dry this sample under a vacuum to get rid of methanol and get a yield and get spectra to properly characterize. Ugi products with propynoic acid are tricky because they show up as rotamers: see the** **isolated compounds list** **to compare NMRs JCB]****[A large residual CHCl3 peak just means that you have very little compound JCB]**
 * [Also your spectra are badly shifted (looks like more than 1 ppm) - you will need to resolve this to properly characterize JCB]** I am redoing the NMR spectra for this Ugi Product characterization similar to that found in Exp234. This should give a higher concentration, purity, and detail than before. Also, many more types of NMR will be run, such as NOESY, which might be able to show which rotamers are present. **[It will be interesting to see if NOESY can identify the rotamers - but it might not be easy JCB]**

Characterization by NMR
A concentrated sample of Ugi Product labeled "Ugi1.4" was prepared in CDCl** 3 **. Various ** 1 **H and ** 13 **C NMR runs will be performed on this sample, including some two-dimensional analyses. These will be used with NMR prediction software (HyperChem release 7.5 and HyperNMR) to confirm the identity. Comparing with [|173G19-4] in Exp193 should especially aid the characterization of the groups from the phenylpropionic acid, benzylamine, and dimethoxybenzaldehyde as well as the rotamers. Infrared Spectroscopy will also be used to identify key functional groups and to compare with [|173G19-4] in Exp193.

Results
[|Ugi 233 Spreadsheet] [|BenzoicAcid_CDCl3.jdx] [|Raw JCAMP-DX for BenzoicAcid_CDCl3]

__ACD/NMR Processor 12.1 Corrected Spectra with XY conversion via JSpecView__ [|Ugi233H1.jdx] [|Ugi233C13.jdx] [|Raw JCAMP-DX for Ugi233H1] [|Raw JCAMP-DX for Ugi233C13] [|Ugi233NOESY.pdf] [|Ugi233COSY.pdf] [|Ugi233CHSHF.pdf] Note: Peaks will be added to 2D .pdf spectra at a later date.

FT-IR Pressed Disk Method: [|FTIRUgi1.10close], [|FTIRUgi1.10cor]

IR (KBr, thin film) (cm-1): 3300 (s, NH), 3150-3000 (m, aromatic), 3000-2850 (s, aliphatic), 2222 (s, C≡C), 1950 (w), 1680 (s, 1,3,5-trisubstituted benzene ring aromatic), 1640 (s, C=O, amide II), 1600 (s, //m//-trisubstituted symmetric aromatic ring stretch), 1540 (s, Amide II NH bend), 1490 (s, //m//-trisubstituted symmetric aromatic ring stretch), 1150 and 1050 (s, //m//-trisubstituted symmetric aromatic in-plane CH bend), 800-666 (br, m, out-of-plane NH wagging), 680 and 775 and 820 (s, //m//-trisubstituted symmetric aromatic out-of-plane CH bend). References: (Brain C. Smith “Infrared spectral Interpretation: a systematic approach” (GoogleBooks), 78)(Silverstein 82,86,87,101)(Shriner 200,202).

Photos of ** 1 **H NMR with TMS print-out: [|Ugi1.4tms.pdf], [|Ugi1.4tmsdoublet.pdf], [|Ugi1.4tmsclose.pdf], [|Ugi1.4jspectmsclose.pdf] Note: These two close-ups seem to show the compression distorting the resolution. The peaks look the same, except they are closer together and the bottoms are distorted in the JspecViewer. And if one looks close enough, one can even see where the spectrum was shifted together causing the compression and distortion. FT-IR Pressed Disk Method: [|FTIRUgi1.10close], [|FTIRUgi1.10cor] IR (KBr, thin film) (cm-1): 3300 (s, NH), 3150-3000 (m, aromatic), 3000-2850 (s, aliphatic), 2222 (s, C≡C), 1950 (w), 1680 (s, 1,3,5-trisubstituted benzene ring aromatic), 1640 (s, C=O, amide II), 1600 (s, //m//-trisubstituted symmetric aromatic ring stretch), 1540 (s, Amide II NH bend), 1490 (s, //m//-trisubstituted symmetric aromatic ring stretch), 1150 and 1050 (s, //m//-trisubstituted symmetric aromatic in-plane CH bend), 800-666 (br, m, out-of-plane NH wagging), 680 and 775 and 820 (s, //m//-trisubstituted symmetric aromatic out-of-plane CH bend). (Brain C. Smith “Infrared spectral Interpretation: a systematic approach” (GoogleBooks), 78)(Silverstein 82,86,87,101)(Shriner 200,202) Distortionless Enhancement by Polarization Transfer (DEPT) (135 deg) decoupled:[|ugi1.4dept135], [|ugi1.4dept135close1], [|ugi1.4dept135close2] DEPT (90 deg) decoupled:[|ugi1.4dept90] Double Quantum Filtered Correlation Spectroscopy (DFQ COSY):[|ugi1.4cosy], [|ugi1.4cosyclose1], [|ugi1.4cosyclose2] Heteronuclear shift correlation (chshf):[|ugi1.4chshf], [|ugi1.4chshfclose1], [|ugi1.4chshfclose2] Nuclear Overhauser Effect Spectroscopy (NOESY):[|ugi1.4noesy], [|ugi1.4noesyclose1], [|ugi1.4noesyclose1], [|ugi1.4noesyclose3] HyperChem screen capture of Ugi 233 Closed: [|233closed1], [|233closed2] HyperNMR Computed Coupling and Shielding Constants for all atoms with the propionic keto group in the closed position relative to the rest of the molecule: (C) HyperNMR Computed Coupling and Shielding Constants for all atoms with the propionic keto group in the closed position after molecular dynamics (300K for 1ps in vacuum): (CMD) HyperChem screen capture of Ugi 233 Open: [|233open1], [|233open2] HyperNMR Computed Coupling and Shielding Constants for all atoms with the propionic keto group in the open position: (O) HyperNMR Computed Coupling and Shielding Constants for all atoms with the propionic keto group in the open position after molecular dynamics (300K for 0.1-0.2 ps in vacuum): (OMD)
 * H NMR with TMS converted by Dr. Antony Williams: [|233hnmrtmsjdx] **
 * 1 **H NMR: [|uc233final]
 * 1 **H NMR with TMS: [|233hnmrtms]**[This is really strange - with the TMS at zero, the high field section seems reasonable but your methoxys and phenyl are definitely higher field than they should be - I can't even find the residual CHCl3 at 7.27 - it seems like the spectrum is compressed JCB]** I am almost certain that the issue resides in the exporting of the NMR spectrum. On the spectra I printed out, TMS is at zero and chloroform is at about 7.26 with the aromatic groups downfield past 7.0 ppm. Furthermore, a close-up of the peaks on the print-out shows much better resolution than on the exported spectra. For now, I will continue to upload both the interactive and paper copies of the NMR spectra.
 * 13 **C NMR: [|ugi1.4c13], [|ugi1.4c13close1], [|ugi1.4c13close2]
 * Index (C) || Shift (C) || Index (CMD) 0.1 ps || Shift (CMD) 0.1 ps || Index (O) || Shift (O) || Index (OMD) 0.2 ps || Shift (OMD) 0.2 ps ||
 * 19H || 0.693 || 15H || 0.693 || 19H || 0.896 || 14H || -0.606 ||
 * 20H || 1.044 || 20H || 0.85 || 20H || 0.904 || 13H || 0.22 ||
 * 16H || 1.188 || 18H || 0.983 || 11H || 1.051 || 11H || 1.06 ||
 * 18H || 1.244 || 19H || 1.027 || 16H || 1.107 || 16H || 1.256 ||
 * 17H || 1.339 || 16H || 1.119 || 18H || 1.286 || 19H || 1.259 ||
 * 15H || 1.373 || 17H || 1.511 || 15H || 1.338 || 20H || 1.329 ||
 * 12H || 1.531 || 10H || 1.52 || 12H || 1.347 || 15H || 1.472 ||
 * 14H || 1.617 || 11H || 1.53 || 14H || 1.352 || 18H || 1.579 ||
 * 11H || 1.65 || 14H || 1.64 || 10H || 1.379 || 17H || 1.61 ||
 * 10H || 1.69 || 12H || 1.719 || 17H || 1.452 || 10H || 1.687 ||
 * 13H || 2 || 13H || 2.635 || 13H || 1.637 || 12H || 1.854 ||
 * 46H || 3.21 || 46H || 3.196 || 38H || 3.404 || 31H || 2.804 ||
 * 52H || 3.449 || 45H || 3.545 || 32H || 3.43 || 32H || 3.973 ||
 * 45H || 4.308 || 52H || 3.571 || 31H || 3.986 || 38H || 4.606 ||
 * 61H || 5.46 || 59H || 5.359 || 45H || 6.192 || 65H || 6.559 ||
 * 59H || 6.121 || 59H || 5.982 || 47H || 6.469 || 47H || 6.656 ||
 * 34H || 6.558 || 37H || 6.33 || 66H || 6.74 || 45H || 6.661 ||
 * 37H || 6.753 || 9H || 6.675 || 64H || 6.787 || 36H || 6.664 ||
 * 49H || 6.763 || 34H || 6.769 || 65H || 6.844 || 63H || 6.671 ||
 * 33H || 6.851 || 51H || 6.852 || 35H || 6.801 || 50H || 6.695 ||
 * 51H || 6.86 || 47H || 6.894 || 63H || 6.928 || 64H || 6.791 ||
 * 36H || 6.9 || 65H || 6.945 || 36H || 6.97 || 35H || 6.812 ||
 * 50H || 6.944 || 36H || 6.968 || 37H || 6.999 || 66H || 6.983 ||
 * 35H || 6.956 || 35H || 7.002 || 62H || 7.052 || 37H || 7.004 ||
 * 47H || 6.994 || 48H || 7.037 || 34H || 7.079 || 62H || 7.141 ||
 * 48H || 7.006 || 49H || 7.076 || 33H || 7.116 || 33H || 7.158 ||
 * 9H || 7.285 || 33H || 7.089 || 50H || 7.435 || 34H || 7.612 ||
 * 65H || 7.568 || 50H || 7.113 || 51H || 7.906 || 9H || 7.839 ||
 * 66H || 7.687 || 66H || 7.578 || 46H || 7.945 || 46H || 8.142 ||
 * 60H || 7.972 || 60H || 8.155 || 9H || 8.087 || 51H || 8.186 ||

Discussion
The DEPT90 has been having problems and will not be used in the interpretation.

Conclusion
Ugi 233 was successfully synthesized.

Log
18.40 - Added Ugi 1.4 to clean NMR tube 18.42 - Auto-gradient shim and lock (Z1:-1214;Z2:-1009;Z3:-108;Z4:594) 18.45 - Setup NMR to run overnight as follows: ** 1 **H NMR (64 scans), ** 13 **C NMR, DEPT130, DEPT90, DQF (Double Quantum Filter) COSY, Heteronuclear Shift Correlation (chshf), NOESY
 * 11.16.09**

15.35 - Vaccum-desiccated with heat the equipment following washing with Methylene Chloride 15.45 - Weighed out 0.114 2 g KBr 15.55 - Lightly pressed large chunks of KBr into sand-size particles in a mortar using a pestle 15.56 - Vaccum-desiccated with heat the KBr in the mortar 16.08 - Removed KBr from dessicator (National Appliance Company Model 5831) and added ~1 mL of Methylene Chloride to Ugi 1.10 solid (dissolved readily) 16.10 - Poured solution on KBr and let evaporate 16.10 - Vaccum-desiccated with heat the Ugi 1.10/KBr sample in mortar 16.22 - Removed from dessicator 16.24 - Transferred sample from the mortar to barrel with one bolt 16.26 - Vaccum-desiccated with heat the barrel with sample 16.30 - Removed from dessicator 16.34 - Pressed other bolt into barrel using bench-press 16.35 - Vaccum-desiccated with heat the barrel 16.38 - Removed from dessicator 16.40 - Removed bolts revealing opaque disk 16.42 - Collected background and spectrum of Ugi 1.10 16.47 - Removed disk, saving in original glass vial
 * 11.23.09**

18.00 - Weighed NMR Tube (2.6846 g) 18.03 - Added Benzoic Acid and weighed NMR Tube (2.7163 g) 18.05 - Added Chloroform-d (99.8%) and weighed NMR Tube (3.7952 g) 18.20 - ** 1 **H NMR Spectrum (Gain value: 16) ([|BenzoicAcid_CDCl3.jdx]) 18.30 - Reweighed NMR tube (3.7953 g)
 * 12.06.10**

Acknowledgements
The author thanks Dr. William Collier (Instructor for CI) for his help with the characterization of these Ugi Products, and the Chemical Instrumentation (CI) Lab partners Chelsea Kimbrough, Jessica Jowers, Dustin Sprouse, and Gloria Jordan for helping with the project (use of camera) as part of the CI Lab Group Project for a few weeks during the Fall 2009 semester.