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The Tandem Grignard- Oppenauer Oxidation

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The Tandem Grignard- Grignard

Oppenauer Oxidation

A Greener Synthesis of

α-Trimethylsilyl Trimethylsilyl Phenyl Vinyl Ketone

Maggie Hoyt

Marian College

Indianapolis


Outline

�� Introduction to green chemistry

�� Baylis-Hillman Baylis Hillman reaction

�� My research

�� Continuing research


What is Green Chemistry?

The The utilization of a set of principles that reduces or

eliminates the use or generation of hazardous

substance in the design, manufacture and

application of chemical products.” products.

– 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

chemistry

�� Pollution prevention at the most

fundamental level, atoms and molecules

�� Focuses on reducing intrinsic hazards of

reactions and making them more efficient


Applying Green Chemistry to

Undergraduate Research

�� Assess reactions for the “greenness greenness” of

the reaction

�� Propose safer methods or chemicals that

could be used

�� Implement proposed changes in lab to

determine effectiveness

�� Development of new methodology


O

OR

Baylis-Hillman

Baylis Hillman Reaction

R 3 N

O -

RCHO

O

H - R3N OR R OR

+ NR3

O -

+ NR3

OH

O

R OR

Utility of Baylis-Hillman Adduct

• Densely functionalized

• Broad use as substrate in other reactions


How “Green Green” is the Baylis- Baylis

Hillman Reaction?

�� Mild reaction conditions

�� Very little waste formed

�� Atom efficient

�� No need for solvent

�� No aqueous quench

�� Easily recovered catalysts

�� Reagents and products low in toxicity


Limitations of the Baylis- Baylis

Hillman Reaction

�� Limited number of activated olefins suitable for the

reaction due to competitive dimerization.

�� Phenyl vinyl ketone (PVK), which dimerizes rapidly

under Baylis-Hillman Baylis Hillman conditions, is essentially

unsuitable as a substrate.

PVK Dimer Formation

2

O

R 3 N

O O


Silicon-Mediated Silicon Mediated Baylis-Hillman

Baylis Hillman

Si

O

Ph

Reaction

O

R3N Si

Ph

RCHO

R

Si

Ph

- R3N O -

+ NR3

O -

+ NR3

Si

O O

R Ph

The addition of a silicon group prevents

the PVK from forming a dimer.

dimer


How Can the Silicon-Mediated

Silicon Mediated

Reaction be Improved?

•Assessing Assessing substrate preparation

TMS Br Mg o TMS MgBr PhCHO TMS

•I I will refer to this as TMS-PVK TMS PVK for short

OH

PCC / SiO TMS

2

Synthesis of Trimethylsilyl Phenyl Vinyl Ketone

O


Synthesis of TMS-PVK TMS PVK

�� Pyridinium chlorochromate (PCC) is used

to make Trimethylsilyl Phenyl Vinyl

Ketone

– PCC is a known carcinogen

– Chromium waste products are formed


Goal of Research

�� To find a “greener greener” route for the synthesis

of TMS-PVK TMS PVK


Getting Started

�� Our original plan was to create the

alcohol precursor and attempt greener

oxidation conditions

TMS Br Mg o TMS MgBr PhCHO TMS

Synthesis of Alcohol Precursor

OH


Surprising Result

TMS Br Mg o TMS MgBr PhCHO TMS

OH

TMS

�� Grignard addition followed by workup and

isolation afforded the alcohol precursor

�� 1H H NMR indicated that a small amount of

TMS-PVK TMS PVK was also present in the crude

reaction mixture

+

O


How Did This Happen?

�� A search on the oxidation of magnesium

alkoxide salts indicated the possible

occurrence of a Magnesium-Oppenauer

Magnesium Oppenauer

Oxidation

�� We proposed that the oxidation was working in

tandem with the Grignard Addition reaction

Byrne, B.; Karras, M. Tetrahedron 1987, 28, 769-772. 769 772.


Si

Proposed Tandem Grignard- Grignard

Br

1. Mg

2. PhCHO

Oppenauer Oxidation

Si

O

3. PhCHO

Mg Br

4. H + , H 2 O

The 1st equivalent of benzaldhyde is for the

Grignard Addition

The 2nd equivalent of benzaldehyde is for the

Oppenauer Oxidation

Si

O

+

OH


Si

Br

1. Mg

2. PhCHO

3. H+, H 2 O

Results

�� 80% yield of TMS-PVK TMS PVK

�� 100% yield of benzyl alcohol

�� No alcohol precursor observed in 1H H NMR

spectra

�� Results demonstrate successful Grignard

addition and complete oxidation

Si

O

+

OH


Success

�� Magnesium-Oppenauer Magnesium Oppenauer oxidation is greener

than previous synthetic route of TMS-PVK TMS PVK

– Reduces synthesis by one step and utilizes

oxidizing potential of the magnesium alkoxide salt

– Eliminates the use of PCC

�� Can more improvements can be made?


Improvements on the Reaction

�� Replacement of oxidizing equivalent of

benzaldehyde with smaller ketones or

aldehydes would improve atom economy.

�� Additionally, use of small ketones or aldehydes

would eliminate the need for column

chromatography to separate the TMS-PVK TMS PVK

from excess benzaldehyde and benzyl alcohol.


Oxidizing Agents and Their Waste

O

O

O

H

H

benzaldehyde

Products

O

H

H C OH

H H

H

formaldehyde methanol

acetaldehyde

OH

OH

OH

benzyl alcohol

ethanol

acetone isopropanol


Reagents Utilized

�� Grignard-Oppenauer Grignard Oppenauer protocol repeated using

acetaldehyde as oxidizing agent

�� Acetaldehyde proved too volatile to use

�� Evaporated immediately when added to the

refluxing reaction mixture

�� Boiling point = 21°C 21

O

H


Reagents Utilized

�� Grignard-Oppenauer

Grignard Oppenauer protocol repeated using

paraldehyde as oxidizing agent

�� Trimer of acetaldehyde

�� Boiling point = 124°C 124

�� No TMS-PVK TMS PVK observed in 1H H NMR spectrum of

crude product

O

O

O


Reagents Utilized

�� Also tried using trimer as the both the

solvent and oxidizing agent

– eliminated use of THF as solvent

�� No TMS-PVK TMS PVK observed in 1H H NMR

spectrum of crude product


Continuing Research

�� Paraformaldehyde (polymer of formaldehyde)

is being explored as the oxidizing agent in the

Grignard-Oppenauer Grignard Oppenauer protocol

O O

– Formaldehdye is a gas at room temperature

– Also comes in aqueous solution, but reaction

conditions must be dry


Paraformaldehyde

�� Preliminary results indicate that TMS-PVK TMS PVK was

synthesized, but some alcohol precursor still

remained (~2:1 ratio)

�� Needs to be explored further


�� Thanks to:

Acknowledgements

– Marian College Department of Natural and

Behavioral Sciences

– Jeanie Prosser

– Dr. Carl Lecher


Questions?

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