MJMResearchReportFall2013

=Research Report= Matthew McBride CHEM 496 - Senior Research Project Fall 2013 =Introduction= During this quarter, I worked as part of the Bradley Research Group on the Chemical Rediscovery Survey (CRS). CRS is a novel initiative to remove assumptions from the process of examining and studying organic chemistry and synthesis. The goal of CRS is to uncover new reactions and mechanisms as well as revisit previously documented reactions to investigate whether certain commonly held beliefs regarding the need for a particular solvent or catalyst is scientifically valid. Reactions are examined in either a hypothesis based manner or a random based manner. In the hypothesis based manner, a particular reaction of interest or one believed to be occurring will be systematically examined by mixing the reactants and analyzing for the presence of any product (or additional components that form only after mixing the reactants). Using the hypothesis based method, reactions predicted to occur by traditional organic chemistry (such as aldol condensations) can be documented. The premise behind the random based manner of documenting reactions is to remove any blinders potentially placed by a traditional organic chemistry education to discover reactions that typically would not be attempted. Using this method, two components are randomly mixed and examined for the formation of any additional components. Through this process, novel reactions and mechanisms will be discovered.

As has already been mentioned, the premise of CRS is to document the mixing of two components to analyze for the formation of any additional components. This is referred to as searching the chemical space of these simple compounds. The idea is to monitor the chemical space of these compounds by measuring the mole fraction of each component over time. When two pure components are first mixed, there are only two components that make up the mole fraction hyperspace. After that moment, the mole fraction hyperspace could remain the same (no chemical interaction between the components), the mole fraction of the two initial compounds could decrease resulting in the formation of an additional component, or a precipitate could form. At this time, we are attempting to only investigate compounds that are liquids and primarily safe. If a precipitate forms, the chemical space is marked has having an "insolubility event." By measuring the chemical space at two separate time points, it can be determined whether the reaction has reached an equilibrium (no variation in the mole fractions of the components) and provide information regarding the kinetics of the reaction. Using this method, array transformations can be generated for a chemical space as was done in CRSEXP001. Array Transformation from CRSEXP001 This array transformation shows that there was no hemiacetal present as one of the original components, but that within 30 minutes a 10:1 ratio of aldehyde to hemiacetal formed. =NMR Tube Co-Axial Inserts= One of the major components of this project is using NMR co-axial inserts for examining the chemical space by proton NMR spectroscopy. This system prevents the deuterated solvent from mixing with the components of the mixture. The co-axial insert is a narrower tube that is placed inside a thin-walled NMR tube. The diagram shown below was obtained from [|Wilmad-Labglass]. NMR co-axial insert The deuterated solvent is placed in the outer tube to allow the NMR machine to properly lock on the sample and the liquid sample is placed in the inner co-axial insert. This method allows the NMR spectrum to be obtained from the sample without causing the sample to mix with the CDCl3 or D2O. If the sample was mixed with the solvent, that would introduce an additional component to the chemical space.

The use of the co-axial insert system has been found to change the absolute peak locations in the proton NMR spectrum for a compound. In CRSEXP032, I measured the peak location of acetone, ethanol, and methanol using the co-axial insert system with both D2O and CDCl3 as the solvent. Using the traditional NMR tube and mixing with the solvent, acetone has a [|chemical shift of 2.05 ppm]. When I used the traditional NMR tube system and mixed the acetone with the CDCl3 solvent, the shift was near this expected value of 2.1 ppm and was measured to be 2.17 ppm. However, when the acetone was placed in the co-axial insert and the solvent was in the outer tube, the chemical shift of the acetone peak was 3.1 ppm. This shift of 3.1 ppm was the same when both CDCl3 and D2O was used as the solvent. Similarly, the expected shifts of the peaks for methanol are [|3.3 and 4.8 ppm]. When measured with the co-axial insert, the methanol peak shifts were 4.1 and 5.6 ppm. The expected chemical shifts for ethanol peaks using a traditional NMR tube are 1.1, 3.6 and 5.2 ppm. When measured with the co-axial insert, the chemical shifts of the ethanol peaks were shifted to 1.7, 4.1, and 5.9 ppm. The solvent used (CDCl3 or D2O) had no influence on the chemical shifts, so it can be concluded that the use of the co-axial insert shifts the proton NMR peaks downfield. =Acetone and Piperidine= In CRSEXP027, the chemical space of acetone and piperidine was examined. Each of the pure compounds was analyzed by proton NMR and three mixtures with varying amounts of each component were examined. One mixture was approximately 50/50 by volume of each component, one mixture was acetone with a single drop of piperidine, and the other mixture was piperidine with a single drop of acetone. This provides insight into the effect on the chemical space when one of the components in in excess. Acetone is known to [|undergo a self-condensation] to form [|diacetone alcohol] in the presence of a base. This experiment found that diacetone alcohol was formed in the 50/50 by volume mixture, but not in either of the other two mixtures. The mole fraction ratio of acetone to diacetone alcohol was measured to be 119:1 after 24 hours at room temperature and pressure. This showed that the self-condensation can occur using the organic base piperidine.

The mole fraction of each component is calculated using the [|Mole Fraction Template Sheet]. This template sheet automatically integrates the NMR spectrum and by assigning the correct number of hydrogens to a peak for each component, the mole fraction is calculated. =Salicylaldehyde with Ethanol, Benzene, Methanol, and Propylamine= In CRSEXP035, the the chemical space of salicylaldehyde with ethanol, benzene, methanol or propylamine was examined. The mixture of salicylaldehyde and ethanol formed both the acetal in a ratio of 19:1 and the hemiacetal in a ratio of 110:1 after 24 hours. The mixture of salicylaldehyde and methanol formed both the acetal in a ratio of 5:1 and the hemiacetal in a ratio of 90:1 after 24 hours. The mixture of salicylaldehyde and propylamine caused an insolubility event to immediately occur upon the addition of one drop of propylamine. The mixture of salicylaldehyde and benzene did not result in the formation of any additional compounds, such as 6H,12H-Dibenzo[b,f][1,5]dioxocin resulting from the joining of two salicylaldehyde molecules.

The results with salicylaldehyde showed that the smaller alcohol (methanol) produced a greater amount of the acetal and hemiacetal compared to the larger alcohol (ethanol). No catalyst was required to cause this formation. =Conclusion= In conclusion, the CRS allows for the chemical space of simple compounds to be examined and systematically analyzed for new reactions. The co-axial NMR tube system prevents the mixtures from mixing with the solvent, but has been shown to shift the absolute chemical shifts of the proton NMR peaks. Acetone underwent a self-condensation with piperidine as the base to form diacetone alcohol. Salicylaldehyde reacted with ethanol and methanol to form the acetal and hemiacetal without requiring an acid catalyst.

Through participating in CRS, I have learned how to systematically analyze the chemical space of two compounds to identify the formation of an additional compound using proton NMR spectroscopy. I have learned how design a template for calculating the mole fraction of the different components of a mixture from the proton NMR spectrum. I am excited for the potential of CRS to remove any bias that may be present from traditional organic synthesis methods and for CRS's ability to discover novel reactions using safer chemicals.