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22nd January 2017 @ 20:18

The aim of this experiment is to produce (E)-2-chloro-6-(2-(2-(piperidin-1-yl)benzylidene)hydrazineyl)pyrazine via condensation1 of 2-chloro-6-hydrazinylpyrazine and 2-Piperidinylbenzaldehyde.

 

Figure 1: Reaction to produce (E)-2-chloro-6-(2-(2-(piperidin-1-yl)benzylidene)hydrazineyl)pyrazine

This reaction was carried out as a trial on a small scale, to reduce wastage of the aldehyde synthesised in the previous step.

Table 1: Table of Reagents used in experiment.

Reagent


Equivalents

Moles (mmol)

Quantities

2-chloro-6-hydrazinylpyrazine

 

1

0.264

381 mg

2-Piperidinylbenzaldehyde

 

1

0.264

500 mg

Ethanol

 

-

-

~2.5 mL


Procedure
 

To a stirred solution of Ethanol (2.5 mL), 2-chloro-6-hydrazinylpyrazine (381 mg, 0.264 mmol) was added in a flask. 2-Piperidinylbenzaldehyde (500 mg, 0.264 mmol) was then added. The solution was left to stir for 5 hours.

The resulting mixture was burnt orange in colour.

TLC analysis was undertaken (EtOAc/Pet. Ether 1:1) which showed that a new product had formed.

1H NMR of the product was taken, which showed inconclusive results

 

Figure 2: NMR of product obtained.

References

  1. Synthesis of (E)-2-chloro-6-(2-(naphthalen-2-ylmethylene)hydrazinyl)pyrazine (TY 2-1), http://malaria.ourexperiment.org, (accessed November 2016)
19th January 2017 @ 13:09

 The aim of this experiment is to produce 2-piperidinylbenzaldehyde using a SNAr mechanism1.  This reaction was previously trialled on a smaller scale (AB-02-01). The previous experiment yielded the desired product but only a 28% yield. Therefore, the molar equivalents of the starting material have been altered to try to obtain a higher percentage yield. The same starting materials are being used; 2-fluorobenzaldehyde and Piperidine:

Figure 1: Preparation of 2-piperidinylbenzaldehyde via SNAr.

Table 1: Table of Reagents used in experiment.

Reagent

Equivalents

Molecular Weight (g/mol)

Density (g/mL)

Moles (mmol)

Quantities

2-fluorobenzaldehyde

1

124.11

 

1.178

8.8

1.10 g

(0.933 mL)

Potassium carbonate

1

138.205

-

8.8

1.20 g

 

Dimethylforamide (DMF)

-

-

-

-

~8 mL

 

Piperidine

 

1.5

85.15

0.862

13.2

1.14 g

(1.322 mL)

 Procedure

To a stirred solution of DMF (8 mL), Potassium carbonate (1.20 g, 8.8 mmol) was added in a flask. 2-fluorobenzaldehyde (0.933 mL, 8.8 mmol) and Piperidine (1.322 mL, 13.2 mmol) were then added. The solution was heated and left under an air condenser for 12 hours.

The resulting mixture changed from being pale yellow to dark  orange in colour.

The mixture was then extracted into Diethyl ether (3 x 20 mL). the organic phases were combined and washed with Brine (10 mL).

 

Figure 2: Separating funnel showing the two layers present after washing.

The organic phase was then dried (MgSO4), filtered and the solvent removed in vacuo to give the crude material as a yellow-orange solution

The product was purified via silica column chromatography. The eluting mixture used was EtOAc/Pet. Ether 1:9.

TLC analysis was undertaken (EtOAc/Pet. Ether 1:1) for each of the 20 fractions obtained. These were compared to the TLC taken to test whether the reaction had occurred. Spots 4, 5.2, 6.2 and 7.2 had Rf values of 0.66-0.68 which compared to the 0.64 obtained for the product initially, which suggested fractions 4-7 contained the product. Therefore, these were combined and dried under vacuo.

 Figure 3: TLC taken for the 20 fractions; showing all spots seen.

The resulting product was a yellow oily solution and a 35% yield was obtained.

1H NMR of the product was taken, which showed the presence of the desired product.

 

Figure 4: NMR spectra of fractions 4-7 combined.

 

 Further data-

AB-02-02 COSY.jpg
AB-02-02 carbon NMR.jpg
AB-02-02 DEPT.jpg
AB-02-02 IR.jpg

AB-02-02 HMBC.jpg
AB-02-02 HSQC.jpg
AB-02-02 pure proton.jpg
ab-02-02 mass spec.png


References

  1. X. XiaX. Shu, K. JiY. YangA. ShaukatX. Liu and Y. Liang, J. Org. Chem., 2010, 75 (9), 2893–2902



2nd January 2017 @ 11:31

The aim of this experiment is to produce 2-piperidinylbenzaldehyde using a SNAr mechanism1. The starting materials being used are 2-fluorobenzaldehyde and Piperidine:

Figure 1: Preparation of 2-piperidinylbenzaldehyde via SNAr.

 Table 1: Table of Reagents used in experiment.

Reagent

Equivalents

Molecular Weight (g/mol)

Density (g/mL)

Moles (mmol)

Quantities

2-fluorobenzaldehyde

1

124.11

 

1.178

2

0.212 mL

Potassium carbonate

 

1

138.205

-

2

0.3014 g

Dimethylforamide (DMF)

-

-

-

-

2 mL

Piperidine

 

1

85.15

0.862

2

0.220 mL

Procedure 

To a stirred solution of DMF (2 mL), Potassium carbonate (0.3014 g, 2 mmol) was added in a flask. 2-fluorobenzaldehyde (0.212 mL, 2 mmol) and Piperidine (0.220 mL, 2 mmol) were added. The solution was heated and left under an air condenser for 12 hours.

 

Figure 2: Reaction mixture before it was left under air condenser to react.

The resulting mixture was burnt orange in colour.

A mini work up was carried out and TLC analysis was undertaken (EtOAc/Pet. Ether 1:1). It showed clear presence of a new product when the resulting mixture was compared to the starting material. Rf values of 0.64 and 0.58 respectively.

The TLC plate was then stained with potassium permanganate which showed a spot present for the resulting product but not the starting material, which also indicated the reaction had taken place.

 

 Figure 3: TLC plate stained with potassium permanganate showing no spot present for A (starting material). The only spots present are for A+B (mixture of starting material and product) and B (product)

The mixture was then extracted into Diethyl ether (3 x 20 mL), the organic phases were combined and washed with Brine (10 mL). The organic phase was then dried (MgSO4), filtered and the solvent removed in vacuo to give the crude material as a yellow-orange solution (0.1074 g)

The crude NMR showed promising results, therefore the product was purified via silica column chromatography. The eluting mixture used was EtOAc/Pet. Ether 1:9.

TLC analysis was undertaken (EtOAc/Pet. Ether 1:1) for each of the 10 fractions obtained, which suggested fractions 3 and 4 contained the product. Therefore, these were combined and dried under vacuo.  The product obtained was a yellow-oily solution.

1H NMR of the product was taken, which showed the presence of the desired product.

 Figure 4: NMR spectra of fractions 3 and 4 combined.

As the yield obtained was low (28%) but it the desired product was successfully synthesised, it was decided that the experiment would be repeated on a larger scale but the equivalents of the reactants would be altered slightly.

References

  1. X. Xia, X. Shu, K. Ji, Y. Yang, A. Shaukat, X. Liu and Y. Liang, J. Org. Chem., 2010, 75 (9), 2893–2902
5th November 2016 @ 23:25

The aim of this experiment is to produce 2-piperidinylbenzaldehyde using Buchwald-Hartwig Pd (II) catalysed cross coupling1. The starting materials being used are 2-bromobenzaldehyde and Piperidine:

 

Figure 1: Preparation of 2-piperidinylbenzaldehyde via Buchwald-Hartwig amination.

Table 1: Table of Reagents used in experiment.

Reagent

Molecular Weight (g/mol)

Density

(g/mL)

Moles

(mmol)

Quantities

2-bromobenzaldehyde

 

185.02

1.585

1.08

0.130 mL

Palladium (II) acetate

 

224.50

-

0.008

0.002 g

Rac-BINAP

 

622.67

-

0.009

0.0061 g

Piperidine

 

85.15

0.862

3.28

0.324 mL

Caesium carbonate

 

325.82

-

0.859

0.2864 g

Toluene

 

92.14

-

-

5 mL

Procedure

2-bromobenzaldehyde (0.13 mL, 1.08 mmol) was taken into toluene (5 mL) and the flask placed under a nitrogen atmosphere. Piperidine (0.32 mL, 3.28 mmol), rac-BINAP (0.006 g, 0.009 mmol), Caesium carbonate (0.29 g, 0.86 mmol) and Palladium (II) acetate (0.002 g, 0.008 mmol) were added sequentially whilst maintaining the nitrogen atmosphere. The solution was then degassed for 10 minutes, after which time the reaction was heated at reflux for 12 hours.

The resulting mixture was an opaque yellow solution.

Figure 2: Apparatus showing reflux under nitrogen atmosphere.

TLC analysis was undertaken (EtOAc/Pet. Ether 1:1) but no new product was observed. The mixture was poured into half-saturated K2CO3 solution and extracted into Dichloromethane (3 x 20 mL). the organic phases were combined and washed with Brine (10 mL). The organic phase was then dried (MgSO4), filtered and the solvent removed in vacuo to give the crude material as a yellow, oily solution (0.2866 g).

1H NMR of the crude product was taken, which showed inconclusive results, therefore the reaction was terminated.

 Figure 3: NMR of crude product.

A nucleophilic aromatic substitution (SNAr mechanism) was suggested as an alternative route that may lead to a purer sample.

References

C. Rabong, C. Hametner and K. Mereiter, et al., Heterocycles, 2008, 75, 813.