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5th October 2012 @ 12:39
Sc: 1-10
Synthesis of SC3-3 and SC3-4 from SC2-1.

HIRAC

Refer to risk/hazard assessment prepared for SC3-1 and SC3-2.

3rd October 2012

Aim: to repeat SC3-1 and SC3-2.

This experiment is a repeat of SC3-1 and SC3-2. These original products were obtained on 3/9/12 as crude yellow oils. Chromatographic separation yielded the cyclised products expected, plus additional products, as was evident in significant co-spotting observed on TLCs of the fractions. Suspected contamination of the laboratory hexane supply used for the column purification warrants repetition of the reactions. The procedure is described below.

SC2-1 (0.0996 g, 0.34 mmol) was reacted with acetyl chloride (0.05 mL, 0.61 mmol) in the presence of 2,6-lutidine (0.05 mL, 0.48 mmol) in acetonitrile (0.03 M, 13 mL), under argon gas and with stirring for 25 hr, to give SC3-3.
SC2-1 (0.0975 g, 0.33 mmol) was again reacted under the same conditions, with the addition of freshly prepared Yb(OTf)3 (0.0115 g/mL, 1.0 mL, 0.018 mmol) to give SC3-4.

Both reactions changed in hue from colourless to a transparent yellow over the first two hours. Unlike the previous experiment, there were small particles visible in the SC3-4 reaction mixture after 25 hr. This is thought to be Yb(OTf)3. Since the same concentration of Yb(OTf)3 was used in SC3-2 and SC3-4, it is possible that the freshness of the Yb(OTf)3 had an effect on how readily it dissolved in the reaction mixture.

TLC analysis confirmed that both reactions had gone to completion, however, residual lutidine was present, as was the case for SC3-1 and SC3-2.

4th October 2012

Products were extracted in ethyl acetate (10mL) and sodium hydrogen carbonate (10mL). The aqueous layer was twice more extracted in ethyl acetate (i.e. 2 x 10mL). Organic fractions were combined and the solvent was removed using rotary evaporation. Crude products were dark yellow/orange oils.
20th September 2012 @ 03:14
Sc: 1-10
Synthesis of SC4-1 and SC4-2 from SC2-1.

HIRAC


SC4 HIRAC.jpeg


Procedure followed:

The procedure was identical to that used for SC3-1 and SC3-1. Reactions were also performed on a 0.1 g scale.

SC1-1 (0.1023 g, 0.41 mmol) was reacted with acetyl chloride (0.05 mL, 0.61 mmol) in the presence of 2,6-lutidine (0.05 mL, 0.48 mmol) in acetonitrile (0.03 M, 13 mL), under argon gas and with stirring, to give SC4-1.
SC1-1 (0.0997 g, 0.40 mmol) was again reacted under the same conditions, with the addition of Yb(OTf)3 (0.0085 g/mL, 1.3 mL, 0.017 mmol) to give SC4-2.

SC4%20reaction%20image.png

reaction%20values.PNG

SC4 reaction.JPG


13th September 2012

TLC analysis showed that SC4-1 and SC4-2 reactions had progressed considerably after 40 minutes of reaction time. (See TLC below.)

14th September 2012

Stirring was ceased after 21 hr.
SC4 reaction progress.JPG


SC4-2 had partially crystallised overnight as there were visible particulates in the reaction mixture. SC4-1 remained in solution. Samples refrigerated over the weekend.

18th September 2012

Products were extracted in ethyl acetate (3 x 10mL) using sodium hydrogen carbonate, as done for SC3-1 and SC3-2. The products were obtained as white/light-brown solids. Crude yields are listed below. Residual lutidine is suspected; both solids exuded an aroma characteristic of lutidine.

Crude yield for SC4-1: 0.1199 g, 0.41 mmol, 100.2%
Crude yield for SC4-2: 0.1393 g, 0.48 mmol, 119.5%

19th September 2012

SC4-1 was purified using silica column chromatography using ethyl acetate/hexane eluent. TLC analysis showed a clean reaction mixture. No co-spotting was observed, unlike during the purification of both SC3-1 and SC3-2 reaction mixtures. Fractions 15-33 were collected.

TLC analysis of SC4-1 crude sample:
column purification fractions 1-20.JPG
column purification fractions 21-40.JPG


20th September 2012

SC4-2 was column purified. A single spot was observed, indicative of one product. Fractions 15-40 were collected.

TLC analysis of SC4-2 crude sample:
SC4-2 fractions 1-20.JPG
SC4-2 fractions 21-40.JPG


21st September 2012

Final yields for purified products were obtained.
SC4-1: 0.0581g, 0.20 mmol, 48.6%, m.p.
SC4-2: 0.0539g, 0.19 mmol, 46.2%, m.p.

27th September 2012
NMR analyses of SC4-1 and SC4-2 show that cyclisation has occurred.
Starting material (SC1-1):
SC1-1 1H-NMR.pdf.pdf

SC4-1:
SC4-1 column frac 15-33 1H-NMR.pdf.pdf

SC4-2:
SC4-2 column frac 15-40 1H-NMR.pdf.pdf


Attached Files
24th August 2012 @ 06:26
Sc: 1-10
Synthesis of SC3-1 and SC3-2 from SC2-1.

HIRAC


SC3-1 and SC3-2 synthesis.pdf


Procedure followed:

The procedure was identical to that used for MNR41-9, with the following temperature and starting material modifications: The reaction was performed at ambient temperature (not -5 degrees Celsius) without the addition of PZQ, and the amount of starting material was downscaled to 100 mg.

SC2-1 (0.1010 g, 0.34 mmol) was reacted with acetyl chloride (0.05 mL, 0.61 mmol) in the presence of 2,6-lutidine (0.05 mL, 0.48 mmol) in acetonitrile (0.03 M, 13 mL), under argon gas and with stirring, to give SC3-1.
SC2-1 (0.1008 g, 0.34 mmol) was again reacted under the same conditions, with the addition of Yb(OTf)3 (0.0085 g/mL, 1.3 mL, 0.017 mmol) to give SC3-2.

SC3%20revised.png

SC3-1%20and%20SC3-2.png

24th August 2012

It was noticed that both solutions decolourised from a dark orange to light yellow upon addition of acetyl chloride. There was no visible difference between the two reactions due to the presence of Yb(OTf)3.

TLC analysis confirmed that both reactions had gone to completion after 6 hours.

Products were extracted in ethyl acetate (3 x 10mL) using sodium hydrogen carbonate. During the extraction of SC3-1 minor bubbling was observed, which was attributed to residual acid in the glassware. The products were obtained as oils in yields of greater than 100%, possibly indicative of residual reactants.

29th August 2012

SC3-1 was purified using silica column chromatography using ethyl acetate/hexane eluent. TLC analysis showed that fractions 40-48 contained a single product, but co-spotting was observed for fractions 14-23. Samples within these ranges were combined and solvent was removed. 1H NMR analysis of fractions 40-48 indicated a single product with clear signals in the aromatic region. A noticeable shift in the triplet signals previously observed at 3.2 and 4.0 ppm was also observed (indicative of cyclisation). Fractions 14-23 did not contain product, which was deduced from a lack of 1H NMR signals in the aromatic region. However, these fractions were retained in the interests of identifying this compound, as hydrolysis product(s) have been generated in similar experiments.

TLC analysis of SC3-1 crude sample:
SC3-1 fractions 1-20.JPG
SC3-1 fractions 21-40.JPG
SC3-1 fractions 41-60.JPG


NMR analyses:
11.09.12_SC3-1_column frac 14-23_1H.pdf
30.08.12_SC3-1_column frac 40-48_1H.pdf


3rd September 2012

SC3-2 was purified in the same way as SC3-1. Fractions 9-20, 21-26 and 27-42 were pooled, respectively. It was found that the latter two combined samples contained an aromatic species. Based on TLC analysis, fractions 21-26 appeared to contain an additional compound (similar co-spotting was observed during SC3-1 column separation). 1H NMR analysis elucidated the presence of a contaminant in fractions 27-42, whereas fractions 21-26 were cleaner. Fractions 9-20 did not contain an aromatic species. The contaminant was suspected to be residual 2,6-lutidine. TLC analysis supported this possibility. 2,6-lutadine is a clear, oily liquid with a boiling point of 144 degrees Celcius, which might explain the oily nature of the substance that was obtained post solvent evaporation. We intend to repeat these reactions due to a contamination of the laboratory hexane supply, which was used for the column purification described above. Contaminant is thought to have been octane (or some other high-boiling point hydrocarbon).

TLC analysis of SC3-2 crude sample:
SC3-2 fractions 1-20.JPG
SC3-2 fractions 21-40.JPG
SC3-2 fractions 41-57.JPG


NMR analyses:
06.09.12_SC3-2_column frac 21-26_1H.pdf
06.09.12_SC3-2_column frac 27-42_1H.pdf


Mass accounting...
Total yield for SC3-1: 0.1234 g, 0.368 mmol, 108% (N.B. lutidine contamination is thought to have caused this).

  • 24-39: 0.105g
    40-48: 0.0184g

Total yield for SC3-2: 0.0882 g, 0.263 mmol, 77%.

  • 9-20: 0.0101g
    21-26: 0.0431g
    27-42: 0.0350g

11th September 2012
TLC of SC3-2 with lutidine and SC2-1 indicates lutidine contamination:
lutidine contamination of SC3-2.JPG


Attached Files
16th August 2012 @ 03:38
Sc: 1-10
Synthesis of SC2-1 from tryptamine and 4-nitrobenzaldehyde.

SC2-1 was successfully synthesised (1.4782 g, 5.040 mmol, 80.4%, m.p. 161-2 degrees).

HIRAC


SC1-1 and SC2-1 HIRAC.pdf


Procedure followed:

The basic procedure was identical to that used for SC1-1.

SC2-1%20reaction%20scheme.png

16th August 2012
Tryptamine (1.0039 g, 6.27 mmol) and 4-nitrobenzaldehyde (0.9905 g, 6.55mmol) were combined in dichloromethane (0.2 M, 33 mL). The reaction was stirred at room temperature (23 degrees) for 21 hours.

17th August 2012
Fine yellow crystals were visible in the reaction mixture. Crude product was obtained using vacuum filtration (wet yield of 1.5481 g). Further moisture was removed by drying under vacuum over the weekend. In addition, solvent was evaporated from the yellow filtrate to improve yield.

Recrystallisation experiments were performed on SC2-1 obtained from the filtrate fraction. SC2-1 (~50 mg) was heated in the presence of various solvents (~2 mL). Samples were left to recrystallise over the weekend. Solubility and crystal formation data were recorded:

Dichloromethane: compound dissolved, no immediate crystal formation. Gel-like recrystallisation observed within 3 hours.
Ethanol: compound dissolved, small crystals immediately formed.
Methanol: incomplete dissolution but immediate crystal growth was observed.
Toluene: compound dissolved, no immediate crystal formation. Small orange crystals formed over the weekend - different to the yellow coloured compounds seen in all other solvent recrystallisations. The identity of this product will be investigated using NMR.
1-propanol: compound dissolved, small crystals immediately formed.
Ethyl acetate: compound dissolved, no immediate crystal formation.
Ether: no dissolution observed.

Recrystallisation experiments for SC2-1.JPG
Recrystallisation experiments_1.JPG
Recrystallisation experiments_2.JPG


Photographs of crystals formed with chosen solvents.

20th August 2012
Dry yields of each recrystallisation were determined, as follows:

DCM: 41.6%
Ethanol: 83.4%
Methanol: 78.0%
Toluene: 68.2%
1-propanol: 78.0%
Ethyl acetate: 66.5%
Ether: not crystals.

Based on crystal appearance and yield, EtOH was found to be the optimal solvent.

Total yield for SC2-1: 1.4782 g, 5.040 mmol, 80.4%, m.p. 161-2 degrees.

22nd August 2012
As with SC1-1, NMR analysis was performed on SC2-1 to infer the formation of imine. Four independent NMR analyses were done on various samples of SC2-1. We did this to check for any chemical differences between the crude solid, solid obtained from the filtrate portion (see procedural information), and solids recrystallised from ethanol (fine yellow needles) and toluene (small orange crystals, unlike those formed using any other solvent, which was unexpected). There were no noticeable differences in the NMR spectra, indicating that despite slight differences in physical appearance, the compound present was the same in each case.
22.08.12_SC2-1_EtOH_1H.pdf


Attached Files
16th August 2012 @ 03:24
Sc: 1-10
Synthesis of SC1-1 from tryptamine and benzaldehyde.

SC1-1 was successfully synthesised (1.389 g, 5.594 mmol, 90.0%, m.p. 119 degrees).

HIRAC


SC1-1 and SC2-1 HIRAC.pdf


Procedure followed:

The synthetic strategy outlined in 'Development of the Pictet-Spengler Reaction Catalyzed by AuCl3/AgOTf' (see reference below) was used in this experiment. Molecular sieves were not used.

SC1-1%20reaction%20scheme.png

16th August 2012
Tryptamine (0.9955 g, 6.213 mmol) and benzaldehyde (9.78 M, 0.67 mL, 6.553 mmol) were combined in dichloromethane (0.2 M, 32 mL). The reaction was stirred at room temperature (23 degrees) for 21 hours.

17th August 2012
Fine light-brown crystals were visible. Solvent was removed on the rotorvap.

20th August 2012
Solid product was harvested as follows: addition and subsequent overnight evaporation of dichloromethane (0.2 M, ~1 mL) was needed to isolate the light brown solid (1.389 g, 5.594 mmol, 90.0%, m.p. 119 degrees). A recrystallisation of crude product in absolute ethanol was prepared (solvent chosen because this gave the best recrystallisation of SC2-1). SC1-1 did not crystalise.

22nd August 2012
NMR analysis was done to confirm the formation of the imine.

Tryptamine starting material:
23.08.12_Tryptamine_1H.pdf

SC1-1 product:
22.08.12_SC1-1_crude_1H.pdf


References:
Youn, S. W. (2006). Development of the Pictet-Spengler Reaction Catalyzed by AuCl3/AgOTf. J. Org. Chem. 71: 2521-2523.

Attached Files