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The Tandem Grignard Addition-Oppenauer

Oxidation

A Greener Synthesis of α-Trimethylsilyl Phenyl Vinyl Ketone

Jeanie Prosser and Maggie Hoyt

What is Green Chemistry?Applying Green Chemistry to Undergraduate ResearchBaylis-Hillman ReactionSynthesis of TMS-PVK.TMS-PVK by Tandem Grignard- Oppenauer OxidationGoal of researchPotential Oxidizing agentsTandem Grignard- Oppenauer Oxidation with acetaldehyde.Tandem Grignard- Oppenauer Oxidation with

Paraformaldehyde.Continuing Research AcknowledgementsQuestions

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What is Green Chemistry?“The utilization of a set of principles that reduces or

eliminates the use or generation of hazardous substance inthe design, manufacture and application of chemicalproducts.”

Doxsee, K.M. and Hutchison, J.E. Green Chemistry: Strategies, Tools, and Laboratory Experiments. Thomson, Brookes, and Cole. 2003.

Green Chemistry is:An emerging field within organic chemistryPollution prevention at the most fundamental level, atoms and moleculesFocuses on reducing intrinsic hazards of reactions and making them more efficient

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Applying Green Chemistry to Undergraduate Research

Assess reactions for the “greenness” of the reactionPropose safer methods or chemicals that could be usedImplement proposed changes in lab to determine effectiveness

“Greeness” of Baylis-Hillman Reaction

Mild reaction conditionsVery little waste formedAtom efficientNo need for solvent No aqueous quenchEasily recovered catalystsReagents and products low in toxicity

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Baylis-Hillman Reaction

OR

O R3NR OR

O-

H

+NR3

O

R OR

OOH

OR+NR3

O-

RCHO - R3N

Limitations of the Baylis-Hillman Reaction

Limited number of activated olefins suitable for the reaction due to competitive dimerization.Phenyl vinyl ketone (PVK), which dimerizesrapidly under Baylis-Hillman conditions, is essentially unsuitable as a substrate.

PVK Dimer FormationO

R3N2O O

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Silicon-Mediated Baylis-Hillman Reaction

Ph

OSi R Ph

O-

Si

+NR3

O

R Ph

O OSi

Ph+NR3

O-

SiR3N RCHO - R3N

Essentially eliminates head-to-tail dimerizationof PVK under reaction conditions

This methodology is allowing new applications of the Baylis-Hillman reaction to be developed

Original Synthetic Route for Preparation of TMS-PVK

Substrate preparation assessed

TMS Br Mg0 TMS MgBr PhCHO TMSOH

TMSO

PCC / SiO2

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Problems with Synthesis ofTMS-PVK

Pyridinium chlorochromate (PCC) is used to make Trimethylsilyl Phenyl Vinyl Ketone

PCC is a known carcinogenChromium waste products are formed

Oxidation reactions are generally non-green due to their use of heavy metals and toxic reagents.

TMS-PVK by the Tandem Grignard-Oppenauer Oxidation

3 equivalents of benzaldehyde were added to the Grignard reaction

1st equivalent was electrophile for Grignard2nd equivalent was oxidizing agent for the Oppenauer OxidationExcess used to ensure that the reaction went to completion

BrSi 1. Mg

2. PhCHO

3. PhCHO

4. H+, H2OSi

OMg Br

SiO

OH+

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Results

80% yield of TMS-PVK100% yield of benzyl alcoholResults demonstrate successful Grignard addition and complete oxidationBenefits

Reduced synthesis by one step and utilizes oxidizing potential of the magnesium alkoxide salt.Eliminated the use of PCC.

BrSi 1. Mg2. PhCHO3. H+, H2O

SiO

OH+

Greenest Route?Replacement of 2nd equivalent ofbenzaldehyde with smaller ketones or aldehydes will improve atom economy.Additionally, use of small ketones or aldehydes would eliminate the need for column chromatography to separate the TMS-PVK from excess benzaldehyde.

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Goal of ResearchTo find a “greener” oxidizing agent than the benzaldehyde.Find a reaction that is more atom economic.

Potential Oxidizing Agents

H

O

HH

O

O

H

O

OH

OH

OH

CH

HOHH

benzaldehyde benzyl alcohol

formaldehyde methanol

acetaldehydeethanol

acetone isopropanol

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Tandem Grignard-Oppenauer Oxidation with Acetaldehyde

Si Br 1.Mg

2.Acetaldehyde 3.H+ H2O

Si

CH3

CH3CH3

CH2

O

+ OH

H

O

acetaldehyde

Oxidation with AcetaldehydeGrignard-Oppenauer protocol repeated using acetaldehyde as oxidizing agentAcetaldehyde proved too volatile to useEvaporated immediately when added to the reaction mixture

Boiling point = 21°C

H

O

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Proposed Tandem Grignard-Oppenauer Oxidation

BrSi 1. Mg2. Paraformaldehyde3. H+, H2O

SiO

+HC OHHH

OO

Paraformaldehyde

Testing Paraformaldehyde the Tandem Grignard- Oppenauer Oxidation

1 equivalent of benzaldehyde was used as the electrophile in the Grignard reaction.1 equivalent of paraformaldehyde was used as the oxidizing agent for the Oppenauer Oxidation.Aqueous workup removes methanol.

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ResultsPreliminary results indicate that TMS-PVK was synthesized, but some alcohol precursor still remained (~2:1 ratio)Excess paraformaldehyde may be needed.

Continuing ResearchTrimer of acetaldehyde

Boiling point = 124°C

Allows for the oxidation with greater atom efficiency and a smaller waste product.Less volatile than the acetaldehyde.Preliminary results indicate formation of TMS-PVK.

O

O

O

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AcknowledgementsThanks to:

Dr. Carl LecherMarian College Department of Natural and Behavioral Sciences

Questions?