Chapter+4+-+Imine+Synthesis

The formation of the imine is the initial step in the Ugi reaction (Ugi 2000). The imine is formed when a ketone or aldehyde (24) reacts with an amine (25) to form a dipolar intermediate (26). Intramolecular proton transfer from the nitrogen to the oxygen yields the aminoalcohol (27), which is then protonated (28). The water group leaves to form the iminium ion (29), which then transfers the proton to water to produce the imine (30) (Lee 2003).
 * 4.1 Introduction**


 * Scheme 4.1** Mechanism of Imine Formation

Synthesis of the imine in the Ugi reaction is described in this chapter.


 * 4.2 Experimental**

Piperonal and 5-methylfurfurylamine (5-MFA) were purchased from Sigma-Aldrich Chemical Company (Milwaukee, WI). Deuterated chloroform with 0.03% v/v TMS was purchased from Cambridge Isotope Laboratories, Inc. (Andover, MA). Deuterated methanol was purchased from Cambridge Isotope Laboratories, Inc. Twenty microliters (20uL) of tetramethylsilane (TMS) was added to the deuterated methanol to serve as reference peak in the NMR spectra. No modifications were made to any other materials.
 * 4.2.1 Materials and Reagents**


 * 4.2.2 Imine Synthesis (Holsey 2006A, Holsey 2006B)**


 * Scheme 4.2** Formation of the imine (31) using piperonal(16) and 5-MFA (18).

To separate 1 dram vials were added 5-methylfurfurylamine (18) (5-MFA, 111uL, 1mmol) and piperonal (16) (0.150g, 1mmol) and then diluted to 1mL with CDCl3. A NMR spectrum was taken for each 1mL solution to ensure the purity of the starting materials. To a separate 5 dram vial each 1mL solution was added and shaken vigorously. A NMR spectrum of the reaction was taken at different time intervals to monitor the progression of the reaction. The reaction was then repeated using deuterated methanol to compare the kinetics of the reaction in both solvents. Analysis and characterization for imine formation in deuterated methanol was conducted using JSpecView software.


 * 4.2.3 Instrumentation**

All NMR spectra were taken on a 300 MHz Varian Inova at room temperature to see whether the imine was formed. Proton NMR spectra were taken using 16 scans and a 3.74 second acquisition time for both experiments in CDCl3 and CD3OD. Carbon-13 (13C) NMR spectra (CNMR) were taken using 50 scans and a delay of 5 seconds.
 * 4.2.3.1 Nuclear Magnetic Resonance Spectroscopy**

JSpecView (Lancashire 2007) is a Java based internet tool used to view spectra in an online format. This program was developed by Robert Lancashire at the University of the West Indies in Jamaica. This program allows us to infinitely expand the peaks in the spectra. With this tool we are able to measure the integration of the peaks more accurately. Imine formation in deuterated methanol was analyzed with this tool using the data from this and subsequent experiments.
 * 4.2.4 JSpecView Software**


 * 4.3 Results and Discussion**

We were able to attribute the imine proton to the singlet peak at 8.2 ppm, consistent with other aromatic imines (Habibbi 2006, Knight 2003). This peak gradually increases in area as the aldehyde singlet peak at 9.8 ppm gradually disappears ([|Figures 4.1], 4[|.2]).
 * 4.3.1 Kinetics in Deuterated Chloroform**


 * Figure 4.1** HNMR spectra of after five minutes in deuterated chloroform.


 * Figure 4.2** HNMR spectra of after twenty two hours in deuterated chloroform.

Figure 4.1 shows the first spectrum taken, with the aldehyde as the main component. Figure 4.2 shows the last spectrum taken after 22 hours with mostly imine present. The area of these two peaks were used to monitor the formation of the imine in this reaction based on the assumption that one mole of aldehyde disappearing is equivalent to one mole imine appearing. The concentrations of the components can then be calculated using the areas of the peaks assuming that when they are added together, it is equivalent to 100% (Chemical Kinetics 2007). The data show that the reaction goes to 50% completion after about thirty minutes and 90% completion after twenty two hours ([|Figure 4.3], [|Table 4.1]). This is likely at equilibrium since the conversion no longer follows second order kinetics after about three hours with a rate constant of 0.07/M*min (Figure 4.3).


 * Figure 4.3** Imine Conversion Kinetics for 5-MFA and piperonal in deuterated chloroform up to 40 minutes.


 * Table 4.1** Percent conversion of imine in deuterated chloroform over time

Based on NMR integration, it is evident that there is an excess of amine by a factor of 2. Because of this we will not be able to obtain kinetics data for imine formation in methanol. However, we are still able to see the near complete disappearance of the aldehyde peak in the HNMR in three hours (Figure 4.4).
 * 4.3.2 Kinetics in Deuterated Methanol**




 * Figure 4.4** HNMR of Imine Synthesis after three hours in methanol.

From this we can gather that the formation of the imine is faster in methanol than in chloroform. The disappearance of the aldehyde peak at 190 ppm is also seen in the CNMR spectra of the imine (Figure 4.5).


 * Figure 4.5** Missing aldehyde peak in CNMR spectra of imine in deuterated methanol after 3 hours.

The formation of the imine is an important step in the Ugi Reaction. The imine formation proceeds much faster in a polar solvent. This is believed to occur because of a higher cohesive energy density (Pirrung 2003) associated with polar solvents. The imine formation seems fairly clean between piperonal and 5-methylfurfurylamine in CDCl3. At 0.50M, equilibrium is achieved after 22 hours favoring the imine to an extent of about 90% in deuterated chloroform. The conversion was 50% complete after about 30 minutes. When the reaction is performed in deuterated methanol, the reaction proceeds to completion in approximately three hours. Further investigation of imine synthesis using molecular sieves was performed by my colleague James Giammarco (Giammarco 2007). Future Ugi experiments will be performed in methanol while allowing three hours for the imine to form.
 * 4.4 Conclusion**


 * 4.5 Reference List**

Chemical Kinetics http://www-teach.ch.cam.ac.uk/teach/IA/KCR_full.pdf 2007

Giammarco, J. http://usefulchem.wikispaces.com/Exp085 2007 [|Habbibi, M., Montazerozohori, M., et al "Synthesis, Structural and Spectroscopic Properties a New Schiff Base Ligand N, N' Bis (Trifluoromethylbenzylidene) ethylenediamine" J. Fluorine Chem.127 (6), 769, 2006]

Holsey, A. http://usefulchem.wikispaces.com/exp040 2006A

Holsey, A. http://usefulchem.wikispaces.com/exp043 2006B

[|Knight, P., O'Shaughnessy, P., et al "Biaryl-bridges Schiff Base Complexes of Zirconium Alkyls: Synthesis, Structure and Stability"J. of Organometallic Chemistry 683(1), 103, 2003] Lancashire, Robert http://wwwchem.uwimona.edu.jm:1104/software/jcampdx.html 2007 [|Lee, M., et al. Reaction monitoring of imine synthesis using raman spectroscopy. Bull. Korean Chem. Soc. 24(2), 205, 2003]

[|Pirrung, M., Sarma, K. “Multicomponent Reactions are Accelerated in Water” J. American Chemical Society 126(2), 444, 2003] DOI: 10.1021/ja038583a S0002-7863(03)08583-4

[|Ugi, I. and Domling, A. Multicomponent Reactions with Isocyanides. Angew. Chem. Int. Ed. 39, 3168, 2000]

Wikipedia http://en.wikipedia.org/wiki/Ugi_reaction 2007A

Wikipedia http://en.wikipedia.org/wiki/Imine 2007B

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