Skript zum Praktikum Organische Chemie - uni- .Skript zum Praktikum Organische Chemie Institut für

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Skript zum Praktikum Organische Chemie

Institut fr Pharmazie und Molekulare Biotechnologie Abteilung Chemie

Ruprecht-Karls-Universitt Heidelberg

Wintersemester 2008/09

3. Semester Studiengang Molekulare Biotechnologie

Praktikumsleiter: Valeska Dernedde valeskader@yahoo.de Salifu Seidu-Larry sslarrys@hotmail.com

Begleitende Literatur zum Praktikum

1. http://www.ioc-praktikum.de/methoden/skript/Arbeitsmethoden.pdf Folgendes Kapitel ist obligatorisch durchzuarbeiten bis Beginn des Praktikums: Kapitel 2 Einleitung sowie 2.1 2.3 Folgende Kapitel werden als Grundlagenwissen zum prparativen Arbeiten sehr empfohlen und behandeln die im Laufe des Praktikums bentigten Arbeitstechniken: Kapitel 3 Einleitung sowie 3.1 und 3.4 Kapitel 5 Einleitung sowie 5.1 5.2 Kapitel 6 Einleitung sowie 6.1 6.2 Kapitel 8 Einleitung sowie 8.1 8.2 Kapitel 9 Einleitung sowie 9.1 9.3 ODER:

2. Organikum Folgendes Kapitel ist obligatorisch durchzuarbeiten bis Beginn des Praktikums: Kapitel 1: Hilfsmittel und Methoden zur Durchfhrung organisch-chemischer Reaktionen Folgende Kapitel werden als Grundlagenwissen zum prparativen Arbeiten sehr empfohlen und behandeln die im Laufe des Praktikums bentigten Arbeitstechniken: In Kapitel 2 und 3: Filtrieren, Kristallisieren, Extraktion von Flssigkeiten, Adsorptionschromatographie, Dnnschichtchromatographie, Schmelzpunktbestimmung, Polarimetrie. Bentigtes Material (mitzubringen von den Praktikumsteilnehmern)

Laborkittel Schutzbrille

Timetable

Mo, 15.12.08 Di, 16.12. Mi, 17.12. Do, 18.12. Fr, 19.12.

General organization

Safety instructions

Explanation 1st and 2nd

experiment Place assignment SR 25, INF 328

13:30-15-30

Synthesis

Free

Mo, 12.01. Di, 13.01. Mi, 14.01. Do, 15.01. Fr, 16.01.

1st protocol due

Explanation 3rd

experiment

Synthesis

Free

Synthesis

Mo, 19.01. Di, 20.01 Mi, 21.01 Do, 22.01 Fr, 23.01

2nd protocol due

Synthesis

Lab cleaning

Place return

Mo, 26.01.08 Di, 27.01. Mi, 28.01. Do, 29.02. Fr, 30.01.

3rd protocol due

Free

Mo, 02.02. Di, 03.02. Mi, 04.02. Do, 05.02. Fr, 06.02.

Test SR 20, INF 327

13:00-15:00

Introductory seminar: Monday, December 15th SR25 (INF 328) 13:30-15:30 Second seminar: Thursday, January 08th 2009, SR25 (INF 328) 13:30-15:30 Written test: Thursday, February 5th SR 20 (INF 327) 13:00-15:00 Second trial (Nachklausur): to be announced!

Experimental part

Experiment 1: Friedel-Crafts acylation of ferrocene.

Reaction: In a 100 mL, three-neck round-bottom flask equipped with a thermometer, a reflux

condenser and a drying tube are placed 2.0 g of ferrocene and 20 mL of acetic anhydride. The

mixture is stirred gently with a magnetic stirrer. 1 mL of phosphoric acid is added, and the

mixture is warmed up to 50 C until the solid dissolves completely (t=0). A small amount of

the mixture is then taken out and set aside. The temperature is increased to 100 C and the

reaction is left to react for 10 minutes at 100 C (analytical samples are taken at t=5 min, 10

min, then every 10 minutes), after which heating is interrupted. The advancement of the

reaction is checked by TLC (Silica gel F254, eluent: hexane/ethyl acetate, ratio to be

determined.

Work-up: The reaction mixture is then poured onto 50 g of crushed ice, the reaction flask

rinsed with a small amount of ice-cold water. The mixture is stirred for a few minutes with a

glass rod, and neutralized with a 3 N sodium hydroxide solution. The dark solid is collected

by vacuum filtration on a Bchner funnel (Bchnernutsche), washed several times with water

and allowed to dry on filter paper. The yield of crude product can then be determined.

Purification: Column chromatography

125 mg of crude reaction product are dissolved in 1 mL of dichloromethane and loaded on a

silica gel column (l=12 cm) conditioned with 9:1 hexane/diethylacetat. Elution is then

performed with hexane/ethyl acetate. The eluate is collected in fractions (~10 mL). The

fractions are controlled by TLC and those containing the clean product are pooled and the

solvent is removed under vacuum. The successful purification by column chromatography is

demonstrated by comparison with the crude product (before column) by means of TLC

analysis.

Required characterizations: melting points of crude material and purified product.

Experiment 2: Synthesis of Bromocarvone (mixture of diastereoisomers)

O O

Br OMe

O

BrOMe

N

O

O

BrO

Br OMeMe

MeOH

r.t.

5.0 g of R (-)-carvone are dissolved in 50 mL of methanol in a 100 ml round-bottomed flask

with a magnetic stirring bar. The solution is cooled to 0 C and 1.2 equivalents of

N-bromosuccinimide are added. The mixture is stirred for 20 min at 0 C and then allowed to

reach room temperature. The progress of the reaction is followed by TLC (1st sample after 30

min and then every 30 min, hexane: ethylacetate 80:20). After disappearance of carvone (~ 2

h) the solution is concentrated with a rotary evaporator (100 80 mbar) and the oily residue is

dissolved in 50 mL diethylether and 50 mL of 0.5 M NaOH. The mixture is transferred into a

separatory funnel with additional 30 mL of diethylether, and the two phases are separated.

The organic phase is then washed with 0.5 M NaOH (240 mL) and brine (220 mL) and

finally dried over Na2SO4 . The drying agent is filtered away and the solvent is removed under

vacuum (rotary evaporator).

Required characterizations: purity is controlled by TLC (hexane: ethyl acetate 80:20).

Experiment 3: Synthesis of benzyloxycarbonyl-L-leucyl-glycine ethyl ester

1st step:

O Cl

O H3N COO-

H

HN COO-

HO

ONaOH

HCl

HN COOH

HO

O

Na+

In a three-neck 100 ml round-bottom flask with a magnetic stirring bar and a thermometer is

placed L-leucine (4.0 g, 0.03 mol) and 9.0 mL of water. The suspension is cooled in an ice-

water bath and 5 M NaOH (6.0 mL) is added, giving a clear solution. The temperature of the

solution is allowed to equilibrate (10 min) before benzylchloroformate (5.92 g 5.0 mL,

0.033 mol) and 2 M NaOH (16.5 mL, 0.033 mol) are added in ten portions, alternatingly,

while the mixture is vigorously stirred and its temperature maintained at about 10 C. The

additions are completed in about 1.5 h. After continued stirring at room temperature for 30

min the pH of the mixture is adjusted to 10 with 2 M NaOH and the solution is extracted with

ether (415 ml). The aqueous layer is then acidified to pH 1-2 with 5 M HCl (about 6-7 ml)

and the oil which separates is extracted into diethyl ether (320 ml). The combined organic

layers are dried over Na2SO4, filtered and the solvent is removed under vacuum. The residual

syrup is used as such for the subsequent step.

Required characterizations: purity is controlled by TLC (CHCl3: EtOH 95:5 stain the plate

with blue-shift1).

1 Blue-shift is a general purpose visualization reagent for TLC. It is prepared from 1 g Ce(SO4)2, 21 g molybdatophosphoric acid, 500 mL water, 31 mL conc. H2SO4. The obtained yellow solution is stored protected from light at 4C.

2nd step:

HN COOH

HO

OCl

O HN

HO

OO

O

OEt3N

-Cl+H3NO

OEt3N

HN

HO

OO

NH

O

O

In a three-necked 100 mL flask equipped with thermometer, a rather big magnetic stirring bar,

and a CaCl2 drying tube a solution of Cbz-Leu-OH (from step 1) (2.65 g, 10 mmol) and

triethylamine in a 1:1 mixture of toluene and chloroform (25 mL) is cooled to -5 Cl.

Isovaleryl chloride (1.27 mL, 10 mmol) is added and the mixture is maintained at -5 C for

1.5 h for the formation of the mixed anhydride. In a separate flask a solution of glycine ethyl

ester hydrochloride (1.47 g, 10.5 mmol) and triethylamine (10.5 mmol) in 25 ml of

chloroform is prepared. This solution is cooled to -5 C just before addition to the mixed

anhydride reaction mixture and the reaction is continued allowing the temperature to rise to 0

C. The progress of the reaction is followed by TLC (1st sample after 30 min and then every

hour,2 CHCl3 : EtOH 9:1, stain the plate with blue-shift). After disappearance of the starting

Cbz-Leu-OH, the solution is washed with 50 mL portions of 10% KHSO4 (twice), water, 0.5

M NaHCO3 (twice) and water again and finally dried over Na2SO4. The drying agent is

filtered away and the solution is concentrated under vacuum to approximately one fourth. On

dilution with hexane (75 mL) the product separates in crystalline form. It is collected by

filtration, washed with hexane and shortly dried in air. The crude dipeptide is dissolved in

boiling ethanol and diluted with warm water until turbid. On cooling, crystals separate.

After several hours at room temperature the product is collected by filtration, washed with a

small amount of 1:1 ethanol/water mixtu