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18th January 2017 @ 21:35

synthesis of NA-04-01.png


Reagents

Equivalents

Quantity
 (mg / mL)

mmol

Molecular Weight g/mol

(E)-2-chloro-6-(2-(2-(pyrrolidin-1-yl)benzylidene)hydrazineyl)pyrazine

1

424.8 mg
 

1.41 mmol

301.7780

PIDA

1

454.2 mg

1.41 mmol

322.10

DCM
(density 1.325 g/mL)

-

(26.5 g)
20 mL

312
mmol

84.93


Procedure:

Part 1: crude product

To the RBF containing NA-03-01 (424.8 mg, 1.41 mmol, 1 eqv) 20 mL of DCM was added while stirring the mixture. PIDA (454.2 mg, 1.41 mmol, 1 eqv.) was added and the solution was left to stir over night at room temperature.

A miniwork up was done first for TLC analysis (50% EtOAc/pet. Ether). A full work-up was done by washing the reaction mixture with NaHCO3 (15 mL) and then extracting it with DCM (3x 10mL). The combined organic phases were collected in a conical flask and dried (MgSO4). The dried solution was filtered and the solvent removed in vacuo to give an oil. The crude product [NA-04-01] was weighed (491.2 mg, 1.64 mmol, 116.2% yield) and a sample was analysed by 1H NMR.

 

Rf value= 0.6

 

Part 2: pure product fractions

To remove the solvent ethyl acetate and silica were added to the crude product [NA-04-01] and rotary evaporated. The product was then purified in column chromatography using varying EtOAc-Pet. Ether eluents of increasing polarity. 

The first eluent concentration was at 5% of EtOAc-Pet.Ether and was used up to fraction 42. The polarity was then increased to 15% EtOAc-Pet.Ether from fractions 43 till 50 and then again to 20% EtOAc-Pet.Ether after fraction 51.

All the fractions were analysed by TLC (50% EtOAc/pet. Ether) and then viewed under short (254nm) and long (366nm) UV waves.  Each collection of fractions that were thought to be similar was collected and placed in vacuo to remove the solvents and produce oily products. The 5 RBF containing the pure reaction mixtures were analysed by TLC (50% EtOAc/pet. Ether) and samples of these fractions were analysed for 1H NMR using a CDCl3 solvent.

Notes:

 

Notes and observations:

RBF fraction collection
NA-04-01-(#)

Short wave
 (254nm)

Long wave
 (366nm)

Observations under long wave (numbers refer to the fraction number)

6-11

Very faintly

-

Considered to not contain any product

12-15

Showed

-

Saved as a collection and checked for product

16-24

Showed

Showed

Only16 showed two different colors under long wave (blue and green) and
20 showed (only green). The fluorescence decreased from 16 until 21 were it was very strong to a faint 24 (only blue on top).

25-43

Showed

Showed

25 to 43 showed as green but changed position to green on the lower side with the exception of 43 which showed it on top.

 

(Quick UV look without tlc showed yellow Fluorescence until 38 then and increasing blue fluorescence from 38 till 48)

44-54

Showed
(faintly
after 49)                 

Showed
(rainbow)

44 till 51 showed three fluorescent colors combined as a spherical shape (orange on top, yellow in the middle, and blue at the bottom).
52 till 54 showed the separation and spacing out of these three colors.

 

(Quick UV look without tlc showed 47 & 48 as strong blue and a combination of blue and green specs from 49 till 54)

55- (unknown)

Showed
(faintly)

Showed
(rainbow-partly)

55 showed both the separation of three colors as well as a very strong blue spot very low on the plate in comparison.

56 showed a longer blue spot (strong)

 

NA-04-01-RBF collection #

Weight, Yield

12-15

21.9 mg,  5.18%

16-24

64.4 mg,  15.24%

25-43

218.9 mg,  51.79%

44-54

87.6 mg,  20.72%

55-(unknown)

63.8 mg,  15.09%


Pictures of RM:


RM.JPG
     
RM after drying.JPG

 

TLC PLATES

TLC of RM.JPG

Rf value = 0.6 


TLC comparisons.jpg

comparisons between this TLC and former TLC plates from NA-03-01 experiment. 


TLCs of the fractions 

22-11-IMG_0690.JPG
 
22-11-IMG_0688.JPG


22-11-IMG_0692.JPG
 
22-11-IMG_0691.JPG


21-11-IMG_0665.JPG
 
TLC of fractions.jpeg

 


It can be seen that there are multiple colours of fluorescences that appear in the TLC plates of the fractions

 

all fractions TLC notes.jpg


all TLCs.jpg

 

NA-04-01.JPG


NMR COLLECTION DATA


CRUDE sample NA-04-01

NA-04-01-CRUDE.jpeg

 

 

PURE FRACTIONS OF SAMPLE NA-04-01

 

NA-04-01-1215.jpeg

 FRACTIONS 12-15

 

NA-04-01-1624.jpeg

 FRACTIONS 16-24

 

NA-04-01-2543.jpeg

FRACTIONS 25-43 

 

NA-04-01-4454.jpeg

FRACTIONS 44-54 

 

NA-04-01-55XX.jpeg

 FRACTIONS 55-unknown

 

NMR proved to be inconclusive as to the formation of the desired product. 

Attached Files
18th January 2017 @ 21:32

Synthesis of NA-03-01.png


Reagents

Equivalents

Quantity
 (mg / mL)

mmol

Molecular Weight g/mol

2-chloro-6-hydrazineylpyrazine

1

200 mg

1.38 mmol

144.56

2-(pyrrolidin-1-yl)benzaldehyde

[NA-02-02-PURE]

1

240 mg

1.38 mmol

175.23

EtOH (proof.)

-

9.6 mL

2.20 mmol

 











Procedure

To a stirred solution of 200 proof EtOH (9.6 mL) 2-(pyrrolidin-1-yl)benzaldehyde (240 mg, 1.38 mmol, 1 eqv.) was diluted in a 50 mL RBF. This was followed by the addition of 2-chloro-6-hydrazineylpyrazine (200 mg, 1.38 mmol, 1 eqv.). The mixture was left to react for approx. three hours at room temperature while stirring. The reaction was monitored with the use of TLC analysis to check for completion-two plates. The reaction mixture [NA-03-01] (E)-2-chloro-6-(2-(2-(pyrrolidin-1-yl)benzylidene)hydrazineyl)pyrazine was later rotary evaporated and weighed (424.8 mg, 1.41 mmol, 102% yield). A sample of [NA-03-01] was obtained for 1H NMR analysis with the use of CDCl3 solvent and for TLC analysis (50% EtOAc/pet. Ether).

 

Notes:

The mixture looked yellow orange at the beginning and gradually got darker till it became a maroon red at the end of experiment.

At the start:

solution-10:33am.JPG
   
solution-10:40am.JPG
   
solution-11:52am.JPG

 

Rotary evaporation of RM:

 

14-11-IMG_0550.JPG
 
14-11-IMG_0552.JPG
   
14-11-IMG_0553.JPG
   
14-11-IMG_0555.JPG

 


TLC PLATES

(1)

TLC NA-03-01 (1).JPG
       
TLC NA-03-01 (11).JPG


(2)

TLC NA-03-01 (2).JPG
       
TLC NA-03-01 (22).JPG


Rf values of solution mixture:

At 12:30 PM 

Rf(1)= 0.63  -but too concentrated so done again

Rf(2)= 0.61 – might have gone to completion 

Rf value of product [NA-03-01] NMR sample:  Rf= 0.59

 


NMR

NA-03-01.jpeg
Attached Files
18th January 2017 @ 21:25

SNAr NA-02-02.png

 

Reagents

Equivalents

Quantity
 (mg / mL)

mmol

Molecular Weight g/mol

2-Fluorobenzaldehyde

1

2.5 g
2.1 mL

20.0 mmol

124.114

Pyrrolidine

1.5

(later became 2)

2.1 g (later 2.8g)
2.5 mL (+0.83mL= 3.33 mL total)

30.0 mmol
(became 40.0 mmol) 

71.123

K2CO3

1.5

4.1 g

30.0 mmol

138.205

DMF

-

20 mL

 

 

 

Procedure

Part 1: crude product

2-fluorobenzaldehyde (2.5 g, 20.0 mmol) and Pyrrolidine (2.8 g, 40.0 mmol) were added to a stirred solution of K2CO3 (4.1 g, 30.0 mmol) in 20 mL of DMF in a RBF and left to react overnight. After this time a miniwork up and TLC analysis were done (50% EtOAc/pet. Ether) and upon examination the plates showed the starting material was still present so the amine was added in excess (1 to 2 eqv of SM/amine) -amine (0.83mL) was added to the mixture in the RBF and left react futher for three hours. During that time two TLC analyses were done and showed that the reaction had still not gone to completion so it was decided that the mixture be left to react over the weekend.

 

1/ After this time the reaction mixture was diluted in diethyl ether (30 mL) and extracted with the use of 1:1 brine to De-ionised water (10mL) to dissolve build up in the RBF. De-ionised water (5mL) was used to show the separation of phases in the funnel. Some of the mixture was lost during the shaking of the separation funnel. More Diethyl Ether (40mL), deionized water (0.5mL) and 1:1 brine to De-ionised water (30mL) were added to the reaction mixture.

 

2/ After filtering the aqueous layer out the organic layer was washed with Diethyl ether (10mL) and 1:1 brine to De-ionised water (10mL) and filtered again. 

 

3/ The organic layer was collected and the aqueous layer was washed with Diethyl ether (20mL).

 

4/ After separation the organic layer was collected and was washed with 1:1 brine to De-ionised water (10mL) to separate again.

 

5/ The Combined organic phases were washed with brine (20mL) only and placed in a pre-weighed 250mL RBF. and product must be dried.
- forgot to dry the product with MgSO4 *

 

TLC analysis (50% EtOAc/pet. Ether) was undertaken and the mixture was evaporated in vacuo to give an oily crude product (4.4024 g, 125.58% yield). 

 

Part 2: pure product

To the crude product ethyl acetate and silica were added then rotary evaporated. - Some of the product was lost *

The product was then purified by column chromatography using (5% EtOAc/Petrol) eluent system. This resulted in 111 fractions. Fractions (18-36) contained SM, fractions (37-53) were rotary evaporated in a RBF then a TLC analysis showed that it contained traces of the product under short wave 254nm. TLC analysis showed fraction from 37 to 78 showed traces of product with faint fluorescence.  Fractions 79-80 showed faintly under 366nm but nothing was seen in fractions 81-87. Fractions (54-69) were added in the RBF and rotary evaporated and in another RBF fractions (70-81) were collected and rotary evaporated. They were then combined and the RBF containing the fractions (37-81) was left over the weekend was for the solvent to evaporate. The pure product (502 mg, 14.32% yield) was then sampled for IR with DCM using (ID7-ATR DIAMOND) and 1H NMR using a CDCl3 solvent [NA-02-02 PURE].  

 

 

 

pictures :

PART 1 - first steps after mixture was left to react overnight:

solution in RBF.JPG

 

after reflux.JPG

Solution left to stir and react 

 

left to reflux again for a week.JPG

leaving the mixture to react over the weekend

 

seperation.JPG

Seperation of reaction mixture -organic phases

 

 

TLC

 

(1)

TLC(1).JPG
       
TLC(1)longwave.JPG

 

(2)

TLC(2).JPG
       
TLC(2)longwave.JPG

 

 

 

DATA COLLECTION

 

NA-02-02-PURE.jpeg

NA-02-02- PURE

 

IMG_0904.jpg

IR analysis of pure sample

 

NA-02-02-PURE-PBC.jpeg

mass spec data of pure sample

 

Reference 

X. Xia, X. Shu, K. Ji, Y. Yang, A. Shaukat, X. Liu and Y. Liang, J. Org. Chem., 2010, 75 (9), 2893–2902

Attached Files
18th January 2017 @ 19:31

SNAr mechanism for [NA-02-01].png

 

Reagents

Equivalents

Quantity
 (mg / mL)

mmol

Molecular Weight g/mol

2-Fluorobenzaldehyde

1

250 mg
0.21 mL

2.00 mmol

124.114

Pyrrolidine

1.1

156 mg
0.18 mL

2.20 mmol

71.123

K2CO3

1.1

300 mg

2.20 mmol

138.205

DMF

-

2 mL

 

 

Procedure


Part 1: crude product

2-fluorobenzaldehyde (250 mg, 2.00 mmol) and Pyrrolidine (156 mg, 2.20 mmol) were added to a stirred solution of K2CO3 (300 mg, 2.20 mmol) in 2 mL of DMF and left in a RBF for a week.

After this time a miniwork up and TLC analysis were done (50% EtOAc/pet. Ether) the plate was coated with KMnO4. The solution was diluted in diethyl ether (10 mL) and extracted with the use of De-ionised water. It was then washed with diethyl ether (2x 5mL) and water. The combined organic phases were washed with brine (7 mL) then dried with MgSO4. After filtering the solution it was rotary evaporated and the product was weighed (499 mg,  2.85 mmol, 142% yield) and sampled for 1H NMR using a CDCl3[NA-02-01 CRUDE]


IMG_0026.JPG

IMG_0027.JPG

After 7 days – change in solution colour noticed as it turned brown.


IMG_0030.JPG

Crude product oil

 

 

Part 2: pure product

TLC analysis was performed (10% EtOAc/pet. Ether). The solution was washed with ethyl acetate (x3) and mixed with silica then rotary evaporated until a solid mixture was formed. Column chromatography was done using a 5% eluent system (5% EtOAc/Petrol). 20 fraction samples were sampled for TLC  analysis (50% EtOAc/pet. Ether) but Only 7 fractions showed traces of the product (samples 11-18). These were collected in a pre-weighed RBF and rotary evaporated. The pure product was weighed (308 mg, 1.76 mmol) and sampled for 1H NMR with CDCl3 solvent along with a full analysis.  [NA-02-01-PURE]

crude oil to solid pure product.png

The process of rotary evaporating the crude solution after adding silica gel to produce a solid crude product to be purified through column chromatography

 

Column Chromatography set up.png

Column chromatography set up

 

TLC.png

  TLC of the 20 fractions from the HPLC purification. Samples 11 to 18 were collected to be rotary evaporated and analysed.

 

 NMR


CRUDE SAMPLE NA-02-01 

Scan FLUORO PROTON-17 OCT .jpeg

 

new mixture formed via polyconjugation but sample showed traces of DMF so TLC test was done under different conditions followed by coloumn chromatography purification.

 

PURE SAMPLE NA-02-01 

Scan FLUORO PURE-18 OCT.jpeg


 


FULL ANALYSIS OF PURE SAMPLE NA-02-01

NA WEEK 3 PURE PROTON-19 OCT.jpeg

NA WEEK 3 PURE CARBON-19 OCT.jpeg

NA WEEK 3 PURE DEPT-19 OCT.jpeg

NA WEEK 3 PURE COSY-19 OCT.jpeg

NA WEEK 3 PURE HSQC-19 OCT.jpeg

NA WEEK 3 PURE HMBC-19 OCT.jpeg


Reference 

X. Xia, X. Shu, K. Ji, Y. Yang, A. Shaukat, X. Liu and Y. Liang, J. Org. Chem., 2010, 75 (9), 2893–2902

Attached Files
18th November 2016 @ 19:12

Reaction Scheme

scheme1.jpg

 

Reagents used

Reagents

Equivalence
corrections

Quantity
(mg / mL)

mmol

Molecular Weight

2-Bromobenzaldehyde

1

200 mg
0.13 mL

1.08

185.02

Toluene

-

5 mL

47.21

92.14

Pyrrolidine

 

2.6

200 mg
0.24 mL

2.81

71.12

Rac-BINAP

 

0.009

6.20 mg

9.96x10-3

622.67

CsCO3

 

0.8

282.00 mg

0.86

325.82

Pd(OAc)2

 

0.008

2.00 mg

8.91x10-3

224.51

DCM

-

70 mL

 

 

 

Procedure

To 2-bromobenzaldehyde (200 mg, 1.08 mmol) in toluene (5 mL) was added pyrrolidine (0.24 mL, 2.81 mmol), rac-BINAP (6.20 mg, 9.96x10-3 mmol), CsCO3 (282.00 mg, 0.86 mmol) and Pd(OAc)2 (2.00 mg, 8.91x10-3 mmol) sequentially. The reaction was purged with N2for 15 minutes, then heated for 21 hours at reflux. 

After this time, TLC analysis (50% EtOAc/pet. Ether) was undertaken. It could be seen that starting material was still present, but the reaction was quenched anyway. The reaction was poured onto half-saturated K2CO3 solution, and extracted into CH2Cl2. The combined organic phases were washed with brine, dried (MgSO4), filtered and the solvent removed in vacuo to give an orange oil (343 mg). 1H NMR showed that the reaction was a complex mixture, still containing starting material therefore an alternative route was sought. 

 

BH-nitro-reflux.jpg

Leaving the reaction mixture to reflux under inert nitrogen atmosphere. 

 

BH-reflux.jpg

Mixture left to stir and reflux for 21 hours.

 

BH-reflux-end.jpg

After refluxing for 21 hours, 35 minutes. A change in colour was noticed as it turned to dark brown with residue. 

 

BH-TLC.jpg

Third TLC plate under 50-50% mobile phase: after the use of more dilute 2-bromobenzaldehyde a better separation was seen under UV (254nm)

 

BH-organic phases.jpg

Extracted combined organic phases that was rotary evaporated

 

Analysis: 

1H NMR data of end product 

NA-01-001.jpg

 

References


Constantin Rabong, Christian Hametner and Kurt Mereiter, et al., Heterocycles, 2008, 75, 813.

 

Attached Files