Open Notebook Science talk at the 2012 ACS

Leveraging Open Notebook Science for solubility and melting point predictions for

optimizing reactions and recrystallizations

CINFACS Symposia #244

Philadelphia, PA

Matthew McBrideUndergraduate Chemistry Major

Drexel UniversityBradley Research Group

August 20, 2012

Advantages of ONS for Undergraduate Research

Gain organization skills and learn how to properly present experiments

Receive timely feedback and corrective input

Documentation of a student’s contribution to a project

Organization and PresentationUpdating the log the day the experiment is performed requires a student to keep an organized record of the lab work

Eliminates long term reliance on handwritten notes and allows the log to be recorded when the experiment is still fresh in the student’s memory

(http://onschallenge.wikispaces.com/EXP324)

Organization and Presentation

Teaches a student how to identify the critical elements of an experiment


Correction and InputUsing ONS allows the student to receive needed advice and guidance from the mentor directly on the experiment’s page

Allows the student to understand where an error was made and how to avoid repeating the mistake



DocumentationAllows a student’s work and contribution to a project to be documented

Provides graduate schools with the ability to view exactly what research an applicant has conducted

(http://onschallenge.wikispaces.com/list+of+experiments)

Solubility

Important when choosing a recrystallization solvent

Accurate solubility predictions for a compound allows the optimal solvent to be used

Preferred Solvent Characteristics

Does not react with the compound being recrystallized

High solubility at boiling point, but low solubility at room temperature

A boiling point that allows for easy drying of the product

Miscibility with water

Predicting Solubility with Abraham Descriptors

Five descriptors for each solute and each solvent

The descriptors for over 80 solvents, including some ethanol/water mixtures, are known

Descriptors for a solute can be experimentally determined by measuring the solubility in 5 solvents

Descriptors for a solute can be predicted using AD Model003

Using the solute descriptors, the solubility in any of the solvents with known descriptors can be predicted

[William Acree](http://onschallenge.wikispaces.com/Benzoic+acid+-+Abraham)

Solubility PredictionsUsing ONS Webservices, can list the predicted solubility for a compound

Trans-dibenzalacetone

(http://showme.physics.drexel.edu/onsc/models/solventselector.php?csids=555548)

Solvent Model003 (M)

AD Measured (M)

Experimental (M)

BP (°C)

(www.chemspider.com/555548)

[Andrew Lang]

Solubility CurvesUsing a melting point, temperature dependent solubility curves are generated

Assumes that at the melting point the compound is miscible with the solvent

Solubility in Ethanol (Concentration M vs. Temperature °C)

(http://showme.physics.drexel.edu/onsc/models/solventselector.php?csids=555548)[Andrew Lang]

Measuring Solubility Surprisingly difficult. Must be sure the solution is at saturation, while avoiding supersaturated solutions

(http://usefulchem.blogspot.com/2010/07/general-transparent-solubility.html)

Temperature Controlled Shake Flask Method

Add solute to the vials with the solvent and allow to shake in the 25°C water bath

(http://onschallenge.wikispaces.com/exp324)

Temperature Controlled Shake Flask Method

Measure the solubility using HNMR

Need to take two consecutive measurements without the solubility changing to confirm the solution is saturated


Measuring Solubility with NMRCompare integration of solute and solvent peaks in saturated solutions using google app scripts1.5M Saturated solution of dibenzalacetone in THF

Dibenzalacetone

THF

(http://onschallenge.wikispaces.com/EXP308)[Andrew Lang]

Benefits of Solubility Curves

These temperature dependent solubility curves allow a solvent with the greatest difference between solubility at room temperature and at the boiling point to be used

Reduces reliance on only recrystallizing in solvents listed in literature

Optimizes the process of choosing a recrystallization solvent

[Andrew Lang]

ExampleThe solvents used to recrystallize compounds in organic teaching labs can be improved

Trans-dibenzalacetone

Aldol condensation between two molecules of benzaldehyde and one molecule of acetone

(http://showme.physics.drexel.edu/onsc/reactionattempts/advancedsearch.php?compound=&solvent=&reactiontype=&researcher=Matthew+McBride)

[Andrew Lang]

DibenzalacetoneFirst recrystallized in ethyl acetate in 1906

Recrystallized in ethyl acetate in Organic Syntheses

(Straus and Ecker, Ber. 39, 2988 (1906))

Organic Teaching LabsMany recrystallize in ethyl acetate

Is there a different solvent that could be used?

(http://classes.kvcc.edu/chm230/MIXED%20ALDOL%20CONDENSATION.pdf)

(http://www.xula.edu/chemistry/documents/orgleclab/Aldol_notes.pdf)

SmartPhone AppThis app predicts the recrystallization yields of any compound in different solvents using the solubility curves:

Provides experimental and predicted values for melting point and LogP

[Andrew Lang]

(http://onschallenge.wikispaces.com/recrystallization)

SmartPhone AppEnter compound identification (SMILES, CSID, name…etc), and desired parameters


[Andrew Lang]

SmartPhone AppLists solvents and their predicted recrystallization yield

Prediction is generated by the temperature dependent solubility curves


[Andrew Lang]

Comparison Ethyl acetate (predicted yield of 69%) vs ethanol (predicted yield of 91%)

Ethyl acetate

Ethanol

0.09M

1.1M

0.62M

2.06M


[Andrew Lang]

Solubility at BoilingCannot be too low or an impractical recrystallization solvent

Example: Dibenzalacetone in hexane (predicted yield of 90%)

Hexane

Too insoluble at the boiling point

To recrystallize 1 gram of product (4 mmol), would need approximately 13 mL of hexane


0.3M

[Andrew Lang]

Designing reactions using solubility

These solubility tools can be used to choose a solvent for a reaction

Finding a solvent in which the reactants are soluble, but the product is insoluble. This allows the product to be recovered by a simple filtration

ExampleDerivatives of dibenzalacetone may be synthesized by altering the aldehyde used

From a library of derivatives, the following compound was the top hit for the docking site of Taxol

Uses phenanthrene-9-carboxaldehyde

(http://usefulchem.wikispaces.com/D-EXP022)

(http://www.chemspider.com/28190813)

[Andrew Lang]

Synthesis PlanningDesire a solvent that the aldehyde is soluble in, but the product is not

The product was predicted as having very low solubility (<0.000M) in all solvents

NaOH used as the catalyst, so needs to be soluble in the solvent

(http://showme.physics.drexel.edu/onsc/models/solventselector.php?csids=28190813) [Andrew Lang]

Synthesis PlanningNaOH is soluble in methanol, so check aldehyde solubility

Phenanthrene-9-carboxaldehyde

SolventModel003 (M)

AD Measured (M)

Experimental (M)

BP (°C)



[Andrew Lang]

Synthesis Planning

Conclusion: Using methanol as the reaction solvent should allow the aldehyde be dissolved into solution, but will cause the product to precipitate

Synthesis

Created an approximately 0.016M solution of phenanthrene-9-carboxaldehyde in methanol

Added acetone and then a large excess of NaOH (catalyst) to the reaction mixture

Stirred mixture without heat over two days

(http://usefulchem.wikispaces.com/EXP286)

ProductReaction mixture:


Crude Product Following suction filtration: 0.0834 g of yellow crystals


Recrystallization Used benzene

Melting Point: 264-265°


HNMRSpectrum of product


16Hz Trans Coupling

Benzene peak in CDCl3


[Andrew Lang]

SummaryOpen Notebook Science provides advantages to an undergraduate researcher

Measured and predicted solubilities can be used to optimize recrystallizations

Predicted solubilities can be used to plan the synthesis and optimize the recovery of the product

Further Information

http://onschallenge.wikispaces.com/

http://usefulchem.wikispaces.com/

http://onswebservices.wikispaces.com/

Open Notebook Science talk at the 2012 ACS

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