presented by matthew shelnutt
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Intramolecular and Intermolecular Cyclopropanation Studies using Ethyl 2-diazo-3-oxonon-8-enoate
and Cyclohexene
Presented by Matthew Shelnutt
Research Objectives
• Nature of the competition occurring inter- and intra-molecularly during a cyclopropanation.
• Reaction utilizing rhodium (II) acetate as a catalyst and cyclohexene as an intermolecular competitor.
• The length of the carbon chain varied per research student.
Uses of Cyclopropanation
Permethrin Structure
• Cyclopropanation reactions are used in a variety of fields:– They provide “key”
intermediates in the synthesis of pyrethroid insecticides such as permethrin. Permethrin is commercially available for use in pet sprays and crop dusting.
– Pharmaceutically, they provide the cyclopropanes found in antifungal drugs such as ambruticin.
Intended Products
Intermolecular
CH2
O O
CH3O
O O
CH3O
Intramolecular
N-
N+
OO
CH3 O CH2
(AcO)4Rh2
OO
CH3 O CH2
R h 2 (O A c ) 4
C yc lo h e x e n e
We hoped to end up with these products according to the following mechanisms, including the synthesis of all of the starting materials:
Overall Chemical Equation to form the Dienolate
Reaction Mechanism
CH3
CH3
CH3
CH3
N-
+O O
CH3 O C
H
HH
Li+
O-
O-
CH3 O CH2
Li+
Li+
CH3
CH3
CH3
CH3
N-
+O O
CH3 O CH3
H
H
Li+
CH3
CH3
CH3
CH3
N-
+O O
CH3 O CH3
H
H O-
O-
CH3 O CH2
Li+
Li+
Li+
2
Overall Chemical Equation to form the Keto Ester
O-
O-
CH3 O CH2
Li+
Li+
+CH2
Br
OO
CH3 O CH2
D ilu te H 2 S O 4
O-
O-
CH3 O CH2
Li+
Li+
+CH2
Br
Reaction Mechanism
OO
CH3 O CH2
OO-
CH3 O CH2
Li+
+O
O
O OS
H
H
ethyl 3-oxonon-8-enoate
Overall Chemical Equation to form para-Toluenesulfonyl azide
Reaction Mechanism
Cl
O
O
SCH3 + N-
N+
N-
Na+
N-
N+
N
O
O
SCH3
-
Cl
O
O
SCH3 + N-
N+
N-
Na+
-
N-
N+
N
O
O
SCH3
Overall Chemical Equation to form Ethyl 2-diazo-3-oxonon-8-enoate
N-
N+
N
O
O
SCH3 +OO
CH3 O CH2
H
H
E t 2 N H
E t 2 O
N
N+
OO
CH3 O C-
CH2
..
N-
N+
OO
CH3 O CH2
OO
CH3 O CH2
H
H
CH3 CH2
CH3
CH2
NH
OO-
CH3 O CH2
NN+
N-
O
O
SCH3
OO
CH3 O CH2
H
N-
NN
O
SCH3
Reaction Mechanism
N+
OO
CH3 O C-
CH2
N
:
Cyclopropanation using Ethyl 2-diazo-3-oxonon-8-enoate, Cyclohexene, and a Rhodium (II) Catalyst
N-
N+
OO
CH3 O CH2
R h 2 (O A c ) 4(AcO)4Rh2
OO
CH3 O CH2
(AcO)4Rh2
OO
CH3 O CH2 +
Intermolecular
CH2
O O
CH3O
(AcO)4Rh2
OO
CH3 O CH2O O
CH3O
Intramolecular
Laboratory Synthesis• Initial synthesis
proceeded as follows:– LDA in a 200 mL
round bottom flask– 0 C, Nitrogenous
atmosphere – Ethyl Acetoacetate
added dropwise with stirring
– 5-bromopent-1-ene added dropwise to the resulting solution to form dienolate
Synthesis Apparatus
Laboratory Synthesis
• Wash with 10% sulfuric acid
• Solution extracted 3 times with ether
• Ether collected and dried over BaSO4
• Now anhydrous solution placed on rotary evaporator to remove solvent.
Liquid-Liquid Extraction
The Product
Purification• To isolate our
compound from impurities, we implemented the technique of gravity column chromatography.
• The solvent used was a mixture of 2 Ligroine : 1 Petroleum Ether : 1 Ethyl Acetate
Column Chromatography Purification Apparatus
Further Purification• The initial column showed little
separation. A new column was set up, but this time with a new solvent. Possible choices were:– 3 MTBE : 1 Isopropyl
alcohol– 3 Methylene Chloride : 1
Methanol– 3 Hexanes : 1 Ethanol– Toluene, with a methanol
flush• Toluene with methanol flush
chosen to run the column.
Running TLC Plate
Vacuum Distillation
• Solution added to round bottom flask, and fitted with condenser tube.
• Hot oil bath made with electrical current.
• Heated so that impurities with lower boiling points will evaporate and condense out.
Distillation Apparatus
, 8-FEB-2008 + 18:43:47dienolate product mixture
4.00 9.00 14.00 19.00 24.00 29.00 34.00Time0
100
%
MBS83mix Scan EI+ TIC
1.98e9
2.75
18.69
GC/MS Analysis of Products • Product retention time is 6.310. • Extremely small peak – can’t be
seen
• Mass Spec. data shows molecular weights of all ions detected.
• Includes 198, the peak for the product.
• Larger ions peaks appear to be rearrangements of the product.
• The product wasn’t there in enough quantity to be used, and so the procedure was deemed unsuccessful.
Laboratory Synthesis II
• Creating our own starting products might have been a little too ambitious.
• Using the standard Grignard reaction procedure, we decided to create an enoate compound using bromobutane and Magnesium to create Grignard reagent, and then reacting that with diethyl amine and 4-bromo-pent-1-ene to produce the desired dienoate as shown:
Grignard MechanismBrCH32 + Mg2
E t 2 OMg
+CH3 Br
-2 + 2 CH3CH2NCH2CH3
H
CH3CH2N-
CH2CH3
OO
CH3 O CH3
H
H
+
CH3CH2N-
CH2CH3 +OO
O CH3
HH
H Mg2+
O-
O-
CH2 O CH3
+BrCH2
Grignard Mechanism CONT.
O O-
CH2 O CH3 + HOS
O
O
OH
O O
CH2 O CH3
Ethyl 3-oxooct-7-enoate
Grignard Procedure• Typical Grignard – Magnesium
chips, ether, and bromobutane are added to 500 mL round bottom flask.
• Reflux started by mild heating.• Diethyl amine added in dropwise to
a the resulting Grignard reagent at 0 C.
• Ethyl acetoacetate added dropwise at 0 C, and stirred for 30 minutes.
• Allyl bromide is added at 0 C and allowed to stir overnight to ensure reaction completion.
• Rinsed with acid to dissolve remaining solid, extracted using ether, and run through the GC. Synthesis Apparatus
, 22-APR-2008 + 15:59:31
3.00 5.00 7.00 9.00 11.00 13.00 15.00 17.00 19.00Time0
100
%
JPH 77 Final Final Final HM Scan EI+ TIC
5.31e62.57
18.4617.213.80
3.42
16.74
15.8515.1314.01
19.20 19.70
In the future..
• In the process of attempting to synthesize a suitable dienoate for our competition reactions, we discovered how difficult it was to use chemicals such as LDA to get a meaningful yield.
• To correct for this, and one of the last syntheses done, we utilized a Grignard mechanism to produce the dienoate.
• We are going to continue research on the production of enoates using Grignard-like reactions to make a more “undergraduate friendly” way to produce them.
• 4 or 5 other alkyl halides will be used in a similar process to ensure the same great yield and to ensure reproducibility.
Recognitions
• Dr. Hornbuckle, my wonderful advisor• Clayton State University• The Natural Sciences Faculty and Staff• The Department of Natural Sciences for funding our
research• Dr. Furlong, Department Head• Joe Holak, partner• Hieu Dinh, partner
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