Chemotherapeutics Laboratory Experiments Report Biology Essay

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In order to perform Parallel synthesis and Biginelli reaction, firstly, 0.70gms 3-Chlorobenzyldehyde, 1.08gms alkyl acetoacetate, 0.37gms methyl urea and 2ml ethanol were added to a 7ml reaction tube containing a magnetic stirrer. Afterwards, 2-3 drops of conc. HCl were added (Use in Hood) into the mixture and the slurry refluxed in the Greenhouse Parallel reactor for 2 h. The reaction was cooled to 0oC and the resultant precipitate collected. For better precipitates, product may be further purified by recrystallization from ethanol.

Balanced reaction Scheme

Alkyl acetoacetate

3-Chlorobenzyldehyde

1-(Aminocarbonyl)-6-(3-chlorophenyl)-1,2,3,6-tetrahydro-4-methyl-2-oxo-5-pyrimidinecarboxylic acid 1-methylethyl ester/ SQ 32926

Methyl urea

Melting point: 94oC

Yield: 0.30gm

NMR Data (Parallel Synthesis)

H NMR Data

2.468 (1, 3H), 1.433 (2, 3H, J=6.904), 1.433 (3, 3H, d, J=6.904), 7.345 (9, 1H, J=8.085, J=8.057, J=4.353), 7.251 (10, 1H, J=8.057, J=1.671, J=1.561), 7.427 (11, 1H, J=8.085, J=1.671, J=1.501), 7.521 (12, 1H, J=4.353, J=1.561, J=1.501), 4.771 (22, 1H, J=6.904), 5.885 (23, 1H)

Biginelli Reaction

For Biginelli reaction, 532mg benzaldehyde, 968µl ethyl acetoacetate, 370mg N-methyl urea and 5ml ethanol were added to a 50ml round bottom flask containing a magnetic stirrer. Further, 2-3 drops of conc. HCl were added and the mixture refluxed for 2 h. The reaction was cooled to 0oC and the resultant precipitate collected. For better precipitates, product may be further purified by recrystallization from ethanol.

O

H

C

O

2

E

t

M

e

O

N

H

2

O

N

H

2

N

H

N

H

O

C

O

2

E

t

M

e

Balanced reaction Scheme

N-methyl urea

Ethyl acetoacetate

Benzaldehyde

HCl, EtOH

Dihydropyrimidinone

Melting point: 176oC

Yield: 0.60gm

NMR Data (Biginelli reaction)

H NMR tabulate

0.826 (1, 3H, J=6.614), 1.133 (2, 3H, J=6.651), 7.222 (4, 1H, J=7.722, J=1.262, J=1.261), 7.198 (5, 1H, J=7.911, J=7.722, J=5.336, J=0.000), 7.198 (6, 1H, J=7.910, J=7.722, J=5.338, J=0.000), 7.252 (7, 1H, J=7.911, J=5.338, J=1.262, J=0.000), 7.252 (8, 1H, J=7.910, J=5.336, J=1.261, J=0.000), 1.275 (9, 2H, J=6.614, J=2.589), 3.633 (14, 1H, J=6.651, J=3.270), 1.990 (15, 1H, J=3.280, J=3.270, J=2.589), 5.434 (16, 1H, d, J=3.280)

C NMR tabulate

14.5631, 16.5469, 30.2236, 39.8088, 40.0187, 40.2285, 52.9610, 60.0474

Experiment 2

Suzuki Cross Coupling Reactions: Synthesis of Unsymmetrical Biaryls

Date of experiment:

Table of reagents:

Name/chemical formula and/or structure

4-Bromoacetophenone/ C6H4BrCOCH3

4′-Bromoacetophenone 98%

Phenyl Boronic acid/C6H7BO2

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Triphenylphosphine/PPh3

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N-propanol and Palladium acetate 1-Propanol anhydrous, 99.7%

Palladium(II) acetate reagent grade, 98%

Amounts (mmol, mg

and ml)

1gm 4-bromoacetophenone

0.69 phenyl boronic acid

26mg triphenylphosphine

10ml n-propanol and 7mg palladium acetate

Molecular weight, number of moles of the reactants

4-bromoacetophenone

Mw=199.04, 5.02mmol

Phenyl boronic acid

Mw=121.93, 5.68mmol

Triphenylphosphine

Mw=262.29, 97.6µmol

Warning about solvents

Irritant, Avoid skin, eye contact, harmful if inhaled etc.

Procedure

For Suzuki cross coupling reactions, 1gm of the aryl halide, 0.692gm of the arylboronic acid and 10ml of n-propanol were added to a 100ml round bottomed flask equipped with a magnetic stir bar and condenser. The condenser has been set up on the flask with attached balloon. Then, 7.2mg palladium acetate, 25.6mg triphenylphosphine as solid and 3.25ml 2M aqueous sodium carbonate were added along with 2ml deionised water. Allow the system to purge with nitrogen by slightly opening the flask/condenser joint for a few minutes. Heated the reaction to reflux under a nitrogen environment until approx. 3 hours.

At room temperature, 30ml water was added and mixture has stir for 5min. in the air. Then, reaction was diluted with 50ml ethyl acetate and transferred it to a separating funnel. Two layers were separated and aqueous layer has re-extracted with 50ml ethyl acetate. Afterwards, combine the organic extracts and wash them with a 5% sodium carbonate solution (2 - 20ml) and 10ml brine sequentially. Organic phase was then transferred to a conical flask equipped with a magnetic stir bar and 0.50gm activated charcoal and 1g sodium sulphate has been added. Slurry has stirred for 10min. then solution was filtered. Concentrate the resulting pale yellow filtrate under reduced pressure to yield the biaryl product as a solid. For crystals, slurry was washed with ~2ml methanol.

Melting point, IR spectra has been recorded and NMR data was collected.

Balanced reaction Scheme

aq. Na2CO3, n-propanol

Pd(OAc)2, PPh3

Phenyl boronic acid

4-Bromoacetophenone

Biaryl ketone

Melting point: 120oC

Yield: 0.1gm

NMR Data

H NMR Tabulate:

2.380 (1, 3H), 7.522 (3, 1H, J=7.171, J=7.156, J=1.317, J=1.246), 7.415 (4, 1H,J=7.938, J=7.156, J=1.502, J=1.430), 7.450 (5, 1H, J=8.083, J=7.171, J=1.502, J=1.499), 7.700 (6, 1H,J=7.938, J=1.499, J=1.471, J=1.317), 7.799 (7, 1H, J=8.083, J=1.471, J=1.430, J=1.246), 7.688 (8, 1H, J=8.649, J=1.647, J=1.065), 7.682 (9, 1H, J=8.643, J=1.647, J=0.995), 7.724 (10, 1H, J=8.649, J=1.716, J=0.995), 7.769 (11, 1H, J=8.643, J=1.716, J=1.065)

C NMR Tabulate:

26.7820, 76.8178, 77.1420, 77.4567, 127.3209, 127.3685, 128.3412, 129.0564, 135.9224, 139.9562, 145.8685, 197.8878

Experiment 3

Resolution of a -Methylbenzyl Amine

Date of experiment:

Table of reagents:

Name/chemical formula and/or structure

(2R, 3R)-Tartaric acid/HO2CCH(OH)CH(OH)CO2H

L-(+)-Tartaric acid ACS reagent, ≥99.5%

-Methylbenzyl Amine/C6H5CH(CH3)NH2

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Methanol/CH3OH

Amounts (mmol, mg

and ml)

1.60gm (2R, 3R)-Tartaric acid

1.40ml-Methylbenzyl Amine

50ml Methanol

Molecular weight, number of moles of the reactants

(2R, 3R)-Tartaric acid Mw=150.0

-Methylbenzyl Amine Mw=121.18

Warning about solvents

Irritant, Avoid skin, eye contact, harmful if inhaled, use in fume hood etc.

Procedure

Part 1: (2R, 3R)-tartaric acid and methanol were added to a 100ml round bottom flask. Solution was heated with condenser for few minutes. Measured 1.40ml of racemic -Methylbenzyl Amine in to a small vial using a disposable syringe. Flask was removed from heating and then -Methylbenzyl Amine was slowly added with a Pasteur pipette. Slurry was again heated with condenser and was refluxed gently for ~15 minutes. Solution then has positioned under room temperature and placed into the cupboard for 24 hours.

Part 2: less soluble diastereoisomer, (S)--methylbenzylammonium hydrogen (2R,3R)-tartrate was collected, via vacuum filtration and the crystals were rinsed with about 5 mL of ice-cold methanol. Then crystals were transferred to a conical flask and water was added to dissolve the solid. Then dropwise 6M NaOH solution was added to dissolve the crystals. Organic layer has separated from separating funnel with diethyl ether. Combined organic layer then dried over magnesium sulphate and solution was filtered in pre-tared flask. Solvent was removed on the rotary evaporator and mass was recorded of the isolated amine.

To measure the Optical Rotation: -Methylbenzyl Amine and ethanol were weighted into a flask. Then sample placed into the polarimeter and rotation -- the sign (+ or -) and temperature were recorded. The specific rotation, []D Temp was calculated.

Specific rotation of the product: Optical rotation is measured with an instrument called a polarimeter. There is a linear relationship between the observed rotation and the concentration of optically active compound in the sample. There is a non-linear relationship between the observed rotation and the wavelength of light used. Specific rotation is calculated using either of two equations, depending on the sample you are measuring:

For pure liquids:

[\alpha]_\lambda^T = \frac{\alpha}{l \times \rho}

In this equation, l is the path length in decimeters, and ρ is the density of the liquid in g/mL, for a sample at a temperature T (given in degrees Celsius) and wavelength λ (in nanometers). The sign of the rotation (+ or -) is always given.

=-140 optical rotation, cell length 0.02 dm, sample 10 mg, in 10 ml solution. Optical rotation=-7000o cm3dm-1g-1[α]

Yield: 0.02ml

Boiling point: 275oC

Balanced reaction Scheme

H2O, NaOH

-Methylbenzyl Amine

S-methyl benzyl amine

Methanol

(2R, 3R)-Tartaric acid

NMR Data

H NMR tabulate

1.244 (1, 3H, J=6.470), 7.316 (3, 1H, J=7.706, J=1.168), 7.331 (4, 1H, J=7.712, J=7.706, J=4.830, J=0.000), 7.331 (5, 1H, J=7.712, J=7.706, J=4.829, J=0.000), 7.289 (6, 1H, J=7.712, J=4.829, J=1.168, J=0.000), 7.289 (7, 1H, J=7.712, J=4.830, J=1.168, J=0.000), 4.253 (9, 1H, J=6.470)

Experiment 4

The synthesis of Alkenes: The Wittig and related Reactions

Date of experiment:

Table of reagents:

Name/chemical formula and/or structure

Triethylphosphono-acetate/ (C2H5O)2P(O)CH2CO2C2H5

Triethyl phosphonoacetate 98%

Benzyldehyde/C6H5CHO

Benzaldehyde purified by redistillation, ≥99.5%

Amounts (mmol, mg

and ml)

1gm Triethylphosphono-acetate

0.47gm Benzaldehyde

Molecular weight, number of moles of the reactants

Triethylphosphono-acetate Mw=224.19, 4.46mmol

Benzaldehyde Mw=106.12, 4.46mmol

Warning about solvents

Irritant, Avoid skin, eye contact, harmful if inhaled, use in fume hood etc.

Procedure

Preparation of (E)-Ethyl cinnamate

To a mixture of triethylphosphono-acetate in dry THF was added n-butyl lithium at 0oC. the mixture was stirred for 30 minutes then benzaldehyde was added and the mixture stirred for a further 2 h then allowed to warm to room temperature. After diluting with ethyl acetate, combined organic layer were dried and the solvent was evaporated in vacuo to yield a yellow oil. Purification by column chromatography gave (E)-Ethyl cinnamate a colourless oil.

Balanced reaction Scheme

n-BuLi, THF

(E)-Ethyl cinnamate

Benzyldehyde

Triethylphosphono-acetate

Melting point: 8oC

Yield: 0.2gm

NMR data

H NMR tabulate

1.217 (1, 3H, J=7.115), 6.647 (3, 1H, J=16.268), 7.726 (4, 1H, J=16.268), 7.455 (5, 1H, J=7.243, J=1.494), 7.433 (6, 1H, J=7.952, J=7.243, J=0.840, J=0.000), 7.433 (7, 1H, J=7.951, J=7.243, J=0.805, J=0.000), 7.538 (8, 1H, J=7.952, J=1.494, J=0.805, J=0.000), 7.538 (9, 1H, J=7.951, J=1.494, J=0.840, J=0.000), 4.117 (10, 2H, q, J=7.115)

C NMR tabulate

166.5914, 144.2484, 134.1211, 129.061, 128.5520, 127.7319, 117.9288, 77.3242, 77, 76.6853, 60.1307, 14.0047

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