mgr Elżbieta Gońka, mgr Damian Myśliwiec 1) Nitrowanie 4,4

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Metody Laboratoryjne – Laboratorium ChOrg2
Prowadzący: mgr Elżbieta Gońka, mgr Damian Myśliwiec
1) Nitrowanie
4,4'-Dibromo-2-nitrobifenyl. Do trójszyjnej kolby o pojemności 750 mL, zaopatrzonej w rdzeń
magnetyczny, chłodnicę zwrotną z odprowadzeniem gazów, termometr i wkraplacz wprowadza się
4,4'-dibromobifenyl (0.064 mol, 20 g) oraz 300 mL lodowatego kwasu octowego. Zawartość kolby
ogrzewa się na łaźni olejowej do 100 °C. W osobnym naczyniu o poj 250 mL sporządza się roztwór
92.5 mL dymiącego kwasu azotowego, oraz 7.5 mL wody. Zawartość naczynia przenosi się do
wkraplacza i powoli wkrapla do gorącego roztworu w kolbie, tak aby wydzielające się w reakcji tlenki
azotu, nie opuszczały chłodnicy zwrotnej. Po dodaniu całej ilości kwasu, roztwór miesza się przez 1 h.
Po tym czasie roztwór przelewa się do dużej zlewki i chłodzi w łaźni z lodem w celu wytrącenia
produktu. Wytrącony osad oddziela się na lejku Schotta, przesącz należy zachować w celu
wydzielenia kolejnej porcji produktu. Osady przemywa się na lejku kilkoma porcjami wody a
następnie mrożonym etanolem. Produkt suszy się pod próżnią do następnego dnia.
2) Reakcja Cadogana (synteza 2,7-dibromokarbazolu)
A solution of 4,4'-dibromo-2-nitrobiphenyl (1.19 g, 5.98 mmol) and PPh3
Br
Br
(3.92 g, 14.85 mmol) in o-DCB (12 mL) was heated to reflux with vigorous
N
NH
stirring for 21 h, during which time the color changed from yellow to
brown. At that time, reaction was cooled to room temperature and concentrated under high
vacuum. The crude product was purified by column chromatography (silica gel, 30 % dichlorometane
in hexanes) or flash chromatography (silica gel, 5% DCM in hexanes).
3) Zautomatyzowana chromatografia flash z użyciem prekolumny
Podział surowej mieszaniny po syntezie 2,7-dibromokarbazolu.
4) Formylowanie
9-Butyl-9H-carbazole-2,7-dicarbaldehyde (S3). In a round‐bottomed flask
equipped with a stirring bar, compound 2,7-dibromo-9-butyl-9H-carbazole OHC
CHO
N
(15.03 g, 39.45 mmol) was dissolved in dry tetrahydrofuran (400 ml) under
Bu
a nitrogen atmosphere. After cooling to –78 °C with an acetone–liquid
nitrogen bath, n-butyllithium (2.5 M solution in tetrahydrofuran, 157 mmol, 63 mL) was added to the
solution, resulting in the formation of a white slurry. The mixture was stirred under nitrogen for 30
min. and N,N-dimethylformamide (30.5 mL, 394 mmol) was added. The reaction mixture was allowed
to warm to room temperature and was stirred for additional 2 h. The mixture was diluted with water
and extracted with dichloromethane. Organic extracts were dried over anhydrous magnesium sulfate
and filtered, and the solvent was removed on a rotary evaporator. The crude product was purified by
column chromatography (silicagel, 50% dichloromethane in hexanes). The second fraction was
collected and concentrated on a rotary evaporator to yield yellow crystals (11.02 g, 91%). 1H
NMR(500 MHz, chloroform‐d, 300 K): δ 10.18 (s, 2H), 8.27 (d, 2H 4J = 8.01 Hz), 7.99 (s, 2H), 7.78 dd,
1
2H, 3J = 8.0 Hz, 4J = 1.2 Hz), 4.43 (t, 2H, 3J = 7.2 Hz) 1.90 (m, 2H), 1.42 (m, 2H), 0.96 (t, 3H, 3J = 7.12
Hz). 13C NMR (125 MHz, chloroform-d, 300K): δ 192.38, 141.81, 135.21, 126.91, 121.82, 121.47,
110.24, 43.47, 31.25, 20.57, 13.82.
5) Reakcja McMurry’ego
Br
Br
In a 250 mL three-necked round-bottomed flask with a reflux condenser
and a septum were placed zinc powder (748 mg, 11.44 mmol) and
copper(I) chloride (69 mg, 0.36 mmol). The apparatus was filled with
N
N
BuBu
argon and oxygen-free tetrahydrofuran (10 mL) was introduced through a Br
Br
Bu
syringe. Titanium tetrachloride (0.6 mL, 5.72 mmol) was added dropwise
N
over 2 minutes using a syringe. The mixture was then heated under reflux
for 3 h. Subsequently, a solution of 3,6-dibromo-9-butyl-9H-carbazoleBr
Br
2,7-dicarbaldehyde (100 mg, 0.22 mmol) in oxygen-free tetrahydrofuran
(20 ml) was slowly added to the boiling mixture using a syringe. After
completion of the addition (2 h), the septum was replaced with a glass stopper and the reaction
mixture was kept under reflux for 12 h. After that time, the mixture was cooled down to room
temperature. Aqueuous ammonia (6%, 100 mL) was added. The mixture was extracted with
dichloromethane. The organic layer was washed with brine, dried over Na2SO4, and evaporated to
give an yellow-orange oil. The crude product was purified by column chromatography (silica gel,
dichloromethane–hexanes = 1:1). and then by preparative TLC. After filtration, solvents were
removed under reduced pressure to give the product as a yellow solid (7.1 mg, 7.6%). 1H NMR (600
MHz, chloroform‐d, 300 K): δ 8.05 (s, 6H), 7.00 (s, 6H), 6.88 (s, 6H), 3.43 (t, 6H, 3J = 7.3 Hz), 0.87 (m,
6H), 0.57 (m, 6H), 0.17 (t, 9H, 3J = 7.3 Hz). 13C NMR (151 MHz, chloroform-d, 300K): δ 139.40, 134.60,
132.44, 123.84, 122.18, 113.88, 111.11, 42.49, 30.22, 19.84, 12.95. HR-MS (MALDI+): m/z 1215.8734
[M+H+, major peak], calcd. for C54H46Br6N3: 1215.8725.
6) Reakcja Williamsona
OC4H9
O
H
4-Butoxybenzaldehyde. In a 1 L round bottomed flask equipped with a reflux condenser and a
magnetic stirring bar were dissolved 4-hydroxybenzaldehyde (35 g, 287 mmol) and 1-bromobutane
(30.92 ml, 287 mmol) in N,N-dimethylformamide (750 mL). The mixture then was stirred under
nitrogen for 20 minutes. Anhydrous potassium carbonate (118.83 g, 860 mmol) was then added and
the mixture was stirred and heated at 60 °C under nitrogen. After 20 h, the reaction was allowed to
cool to room temperature, treated with excess water, and extracted with dichloromethane. The
combined organic extracts were dried over anhydrous sodium sulfate, filtered, and evaporated to
dryness under reduced pressure yielding a brown oil (49.8 g, 97%).
2
1
H NMR (600 MHz, chloroform-d, 300 K): δ 9.85 (s, 1H), 7.80 (d, 2H, 3J = 8.8 Hz), 6.96 (d, 2H, 3J = 8.8
Hz), 4.02 (t, 2H, 3J = 6.5 Hz), 1.78 (m, 2H), 1.48 (m, 2H), 0.96 (t, 3H, 3J = 7.4 Hz).
7) Reakcja Knoevenagela
General procedure for the synthesis of diarylacrylonitriles (cyanostilbenes).
Aldehyde (1 equiv.) and the corresponding acetonitrile (1 equiv.) were placed in a round‐bottomed
flask equipped with a magnetic stirring bar. Absolute ethyl alcohol (5 mL/mmol of aldehyde) was
added followed by an ethanolic solution of sodium ethoxide (1 M, ca. 1 mL/mmol of aldehyde). The
mixture was refluxed for 2 h, changing color to yellow. Towards the end of the reaction a yellow
precipitate was usually formed. After cooling the reaction mixture to room temperature, the
precipitate was filtered, washed with ethanol and dried. The product usually contained the pure Z
isomer.
OC4H9
C4H9O
CN
2,3-Bis-(4-butoxyphenyl)acrylonitrile. The mixture of 4-hydroxybenzaldehyde and 2-(4butoxyphenyl)aceonitryle was refluxed for 3 h and cooled to room temperature. The resulting
precipitate was filtered, washed with ethanol and dried, yielding yellow crystals (42.1 g, 94%).
1
H NMR (500 MHz, chloroform-d, 300 K): δ 7.81 (d, 2H, 3J = 8.5 Hz), 7.54 (d, 2H, 3J = 9.0 Hz), 7.32 (s,
1H), 6.92 (m, 4H), 3.99 (m, 4H), 1.77 (m, 4H), 1.49 (m, 4H), 0.97 (m, 6H).
8) Reakcja Zarda-Bartona
General procedure for the synthesis of ethyl 4‐diarylpyrrole‐2‐carboxylates.
In a dry flask equipped with magnetic stirring, an appropriate cyanostilbene was dissolved in dry
tetrahydrofuran and purged with argon for 1h . Next, ethyl isocyanoacetate (1 equiv.) was added.
The mixture was cooled to 0 °C and a solution of potassium tert‐butoxide (1 M in tetrahydrofuran)
was added. The mixture was stirred under argon until thin‐layer chromatography showed complete
consumption of the starting material. The mixture was diluted with water and extracted with
dichloromethane. Combined organic extracts were dried over anhydrous sodium sulfate, filtered, and
the solvents were removed on a rotary evaporator. The product was purified by column
chromatography (silica gel, dichloromethane). The second fraction was collected, characterized by
blue fluorescence under UV light. The solvent was removed on a rotary evaporator, to yield the
product as a yellow‐orange solid.
H3CO
OCH3
N
H
COOEt
Ethyl 3,4-bis(4-methoxyphenyl)-1H-pyrrole-2-carboxylate) was obtained in 88% yield (3.93 g) on a
11.2 mmol scale.
3
1
H NMR (500 MHz, chloroform-d, 300 K): δ 9.19 (s, 1H), 7.16 (d, 2H, 3J = 8.3 Hz), 7.00 (m, 3H), 6.80 (d,
2H, 3J = 9.2 Hz), 6.72 (d, 2H, 3J = 9.2 Hz), 4.17 (q, 2H, 3J = 7.0 Hz), 3.78 (s, 3H), 3.73 (s, 2H), 1.16 (m, 3H,
3
J = 7.1 Hz).
OC4H9
C4H9O
COOEt
N
H
Ethyl 3,4-bis(4-butoxyphenyl)-1H-pyrrole-2-carboxylate) was obtained in 98% yield (6.3 g) on a 14.7
mmol scale.
1
H NMR (500 MHz, chloroform-d, 300 K): δ 9.08 (b, 1H), 7.15 (d, 2H, 3J = 8.9 Hz), 7.00 (m, 3H), 6.80 (d,
2H, 3J = 8.9 Hz), 6.72 (d, 2H, 3J = 8.9 Hz), 4.18 (q, 2H, 3J = 7.1 Hz), 3.95 (t, 2H, 3J = 6.6 Hz), 3.89 (t, 2H, 3J
= 6.5 Hz), 1.73 (m, 4H), 1.47 (m, 4H),1.17 (t, 3H, 3J = 7.1 Hz), 0.96 (m, 3H, 3J = 7.3 Hz), 0.94 (t, 3H, 3J =
7.3 Hz).
OC12H25
C12H25O
N
H
COOEt
Ethyl 3,4-bis(4-dodecyloxyphenyl)-1H-pyrrole-2-carboxylate) was obtained in 35% yield (1.28 g) on a
5.23 mmol scale.
1
H NMR (500 MHz, chloroform-d, 300 K): δ 9.19 (s, 1H), 7.13 (d, 2H, 3J = 8.80 Hz), 6.98 (m, 3H), 6.78
(d, 2H, 3J = 8.7 Hz), 6.70 (d, 2H, 3J = 8.9 Hz), 4.16 (q, 2H, 3J = 7.1 Hz), 3.92 (t, 2H, 3J = 6.6 Hz), 3.86 (t,
2H, 3J = 6.5 Hz), 1.73 (m, 4H), 1.40 (m, 4H),1.25 (m, 16H), 1.15 (m, 3H, 3J = 7.1 Hz), 0.85 (m, 6H).
9) Dekarboksylacja
General procedure for the synthesis 4-aryl-1H-pyrrole
Ethyl 4‐diarylpyrrole‐2‐carboxylates (1 equiv), potassium hydroxide (2 equiv) and ethylene glycol
(2.50 mL/mmol) were placed in a 50 mL round bottomed flask equipped with a magnetic stirring bar.
The mixture was purged with nitrogen for 1 h. The mixture was heated to 190 °C and stirred under
nitrogen for 3 h. Subsequently, the mixture was allowed to cool to room temperature, treated with
excess water and brine, and extracted with dichloromethane. The combined organic extracts were
dried over sodium sulfate, filtered and evaporated under reduced pressure, yielding yellow crystals.
H3CO
OCH3
N
H
3,4-Bis(4-methoxyphenyl)-1H-pyrrole was obtained in 91% yield (2.644 g) on a 9.6 mmol scale.
1
H NMR (600 MHz, chloroform-d, 300 K): δ 8.19 (b, 1H), 7.17 (d, 4H, 3J = 8.8 Hz), 6.83 (d, 2H, 4J = 3.0
Hz), 6.79 (d, 4H, 3J = 8.7 Hz), 3.78 (s, 6H).
4
OC4H9
C4H9O
N
H
3,4-Bis(4-butoxyphenyl)-1H-pyrrole was obtained in 90% yield (3.1 g) on a 15.6 mmol scale.
H NMR (600 MHz, chloroform-d, 300 K): δ 8.18 (b, 1H), 7.16 (d, 4H, 3J = 8.8 Hz), 6.83 (d, 2H, 4J = 2.6
Hz), 6.78 (d, 4H, 3J = 8.8 Hz), 3.92 (t, 4H, 3J = 6.4 Hz), 1.74 (m, 4H), 1.47 (m, 4H), 0.95 (t, 6H, 3J = 7.4
Hz).
1
OC12H25
C12H25O
N
H
3,4-Bis(4-butoxyphenyl)-1H-pyrrole was obtained in 95% yield (1.43 g) on a 2.69 mmol scale.
1
Hz), 6.77 (d, 4H, 3J = 8.7 Hz), 3.90 (m, 4H, 3J = 6.5 Hz), 1.74 (m, 4H), 1.42 (m, 4H), 1.27 (m, 16H), 0.95
(t, 6H, 3J = 7.4 Hz).
Cl
Cl
N
H
3,4-bis(4-chlorophenyl)-1H-pyrrole was obtained in 95% yield (1.43 g) on a 2.69 mmol scale.
Hz), 6.88 (s, 1H), 6.87 (s, 1H).
1
10) Fotoutlenianie
Br
Br
3,6-Dibromophenanthrene. A solution of 4,4’-dibromostilbene (0.250 g, 1.11 mmol), iodine (0.309 g,
1.22 mmol, 1.1 eq.), THF (1.6 g, 1.8 mL, 22.2 mmol) and toluene (1.2 L) was irradiated using a 125W
HMPV lamp for 36 h/monitored by tlc. After the reaction was over, the excess of iodine was removed
by washing the solution with aqueous Na2S2O3, followed by distilled water. The organic layer was
concentrated under the reduced pressure. The pure product was obtained in 97% yield (0.241 g) on a
0.81 mmol scale. It was purified by column chromatography on silica gel using petroleum ether as
eluent to afford colorless solid.
1
H NMR (400 MHz, CDCl3): δ 8.75-8.76 (d, J = 1.56 Hz, 2H), 7.80-7.83 (d, J = 8.48 Hz, 2H), 7.71-7.75
(m, with overlapping d, J = 8.48 Hz, 4 H).
5
11) N-alklilowanie
Br
N
Br
In a round‐bottomed flask equipped with a stirring bar, compound 2,7-dibromo-NH-carbazole (3.0 g,
9.23 mmol), tetraethylammonium perchlorate (157.30 mg, 0.4 mmol) was dissolved in 2-butanone
(20 ml). The mixture was stirred under nitrogen for 2 min. and NaOH (740 mg, 185 mmol) was added.
The mixture was heated under a protective atmosphere and left to reflux overnight. Subsequently
the reaction mixture was cooled down to room temperature and poured into 100 mL water. The
precipitate white solid was filtered off and washed with cold methanol.
6
Metody Laboratoryjne – Laboratorium ChOrg2
Prowadzący: mgr Elżbieta Gońka, mgr Damian Myśliwiec
Poniedziałek (12 – 15:45)
6 spotkań po 5 h
Wtorek (10 – 11:30)
ok. 6 spotkań 2 h
23-24.04
30-31.04
13-14.04.
20-21.04.
27-28.04.
4-5.05
Osoba A
Osoba B
1) Nitrowanie
2) Reakcja Cadogana
(synteza 2,7dibromokarbazolu)
+
10) Fotoutlenianie
3) Zautomatyzowana
chromatografia flash z
użyciem prekolumny
+
Kończenie ćw. nr 8)
4) Formylowanie
+
10) Fotoutlenianie
9) Dekarboksylacja
+
3) Zautomatyzowana
użyciem prekolumny
7
Osoba C
Osoba D
+
10) Fotoutlenianie
9) Dekarboksylacja
+
3) Zautomatyzowana
użyciem prekolumny
11) N-alklilowanie
1) Nitrowanie
+
10) Fotoutlenianie
9) Dekarboksylacja
+
3) Zautomatyzowana
użyciem prekolumny

mgr Elżbieta Gońka, mgr Damian Myśliwiec 1) Nitrowanie 4,4

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