Intramolecular and Intermolecular Cyclopropanation Studies using Ethyl 2diazo3oxonon8enoate and Cyc

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   Intramolecular and Intermolecular        
Cyclopropanation Studies using       Ethyl
2-diazo-3-oxonon-8-enoate       and Cyclohexene

• Presented by Matthew Shelnutt

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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.

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Uses of Cyclopropanation

• 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.

Permethrin Structure
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Intended Products
We hoped to end up with these products according
to the following mechanisms, including the
synthesis of all of the starting materials
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Overall Chemical Equation to form the Dienolate
Reaction Mechanism
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Overall Chemical Equation to form the Keto Ester
Reaction Mechanism
ethyl 3-oxonon-8-enoate
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Overall Chemical Equation to form
para-Toluenesulfonyl azide
Reaction Mechanism
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Overall Chemical Equation to form Ethyl
2-diazo-3-oxonon-8-enoate
Reaction Mechanism
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Cyclopropanation using Ethyl 2-diazo-3-oxonon-8-en
oate, Cyclohexene, and a Rhodium (II) Catalyst
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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
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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
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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
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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
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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
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GC/MS Analysis of Products

• Product retention time is 6.310.
• Extremely small peak cant 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 wasnt there in enough quantity to be
  used, and so the procedure was deemed
  unsuccessful.

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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

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Grignard Mechanism
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Grignard Mechanism CONT.
Ethyl 3-oxooct-7-enoate
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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
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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.

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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