SO+Research+Report

Introduction
My name is Shannon Oseback and I am a junior Chemistry major at Drexel University. I have been working with the Bradley research group since September 2007. My first co-op was with a process chemistry group with Johnson & Johnson, where I did process development, optimization troubleshooting, and some analytical chemistry. Although I learned a great deal from this co-op experience, upon its completion I felt that I needed to head into a more research-oriented field. I read about Dr. Bradley's CombiUgi project, aimed at finding novel anti-malarial compounds, and thought it was a great opportunity to develop skills in a research and development setting, while still satisfying my interest in pharmaceutical drug discovery. I feel that in my six months of experience in Dr. Bradley's group, I have learned a lot about the processes and coordination required to run a lab with several people, as well as being able to apply my knowledge of organic chemistry to experimental results, in order to better understand what is going on at a molecular level. My UsefulChem experience can be divided into two parts: my attempts to streamline and increase the efficiency of the wiki and communication between lab collaborators, and studying the solubility of phenanthrene-9-carboxaldehyde in the Ugi product solution.

Streamlining
One of my major contributions to the UsefulChem project has been my attempt to streamline the planning processes for the Ugi reactions. Originally, it took several hours to look at the target Ugi compound, determine which chemicals it required, calculate the amount of each other the chemicals are required, to set up the experiment on the Wiki, and ensure that the experiment has not yet been completed or prepared by another lab collaborator. I saw that a lot of the work seemed to be repeated causing a waste of time spent in the lab. I decided to try to use Google Documents to share work, in order to increase communication on what needs to be done.

Ugi Chemicals Table
My first attempt at streamlining lab prep was to create the [|Ugi Chemicals List], using an [|existing table] Khalid had made previously on the showme.physics.drexel.edu server. The problem with the existing table was there was no way to update it on the Wiki as different chemicals were used. I took the information that existed, and used that as a template to create a new version of the table on [|Google Documents]. In this table, I grouped the chemicals by their type (amine, aldehyde, carboxylic acid, and isocyanide). Physical properties such as molecular weight, density, melting point and boiling point were included in the table. The molecular weight and density were used to determine the mass (mg) or volume (ul) of the compound required to have the desired concentration in the Ugi reaction, typically 0.5mmol or 1.0mmol. The melting and boiling points are not necessary for these calculations, but they help determine if the compound is a liquid or a solid, if you are not familiar with the compound. All properties included in this table were obtained from Sigma-Aldrich’s [|website]. This table greatly decreased lab preparation time because a lot of the chemicals used are repeated in the ranking. For example, the majority of the ranked compounds in the range of 1-50 in the [|V1] docking scores included phenathrene-9-carboxaldehyde and conjugated phenyl acetic acids. Since the different ranked compounds were often different combinations of a few different reagents. With the Ugi Chemical Table a lot of times all the calculations are already completed, which saves wasted time by not having to look up all the information and then perform the calculations.

Required Reagents
Another slow step for lab preparation was determining the required reagents that each ranked compound is made out of. Originally, we only had the output SMILES for the Ugi product, and had to back-calculate to figure out what it was made out of. This did not make sense, because the docking algorithm that Rajarshi created requires the input SMILES for the available reagents. It did not make sense that the program was given the input SMILES, but then we had to manually figure them out again, when obviously the program has that information. I posed this question to Rajarshi on the UsefulChem Mailing List on this [|thread]. Rajarshi quickly came up with a fix for the dilemma. His fix uses the serial number for each ranked compound (available in original [|DEXP014-V1A] and [|DEXP014-V2A] files). These serial numbers are matched up in the following [|file]. The file gives the SMILES with a % and a number representing the functional groups. The key for the functional groups is %91 = N, %92 = C=O, %93 = [N+]#[C-] and %90 = C(=O)O. This solution from Rajarshi also saves a lot of time in lab prep, and more importantly eliminates mistakes from incorrect naming of the reagents. One thing that should be done in the future to make it easier is to include the serial numbers of the compounds in the Ugi To Do List, discussed next.

Ugi To Do List
Next, I created the [|Ugi To Do List], which compiles the information to show which experiments are ready to be performed. This enables people to work in parallel, because one person can complete all the calculations and lab prep, and someone else can go in and perform the experiment. The table shows the SMILES of the target Ugi compound, and the names of the reagents required to produce it. It is currently grouped by rank, although a column with the original serial number from the output [|DEXP014-V1A] and [|DEXP014-V2A] files should eventually be added. There are also columns for calculations and experiment, which when they are completed are filled in with the word ‘Done.’ This saves times because it shows the collaborators which experiments are ready to go, and also helps to eliminate unnecessary repetition because it is recorded when the experiments are completed. Also, to aid current and future collaborators, I created a document called [|Instructions for Bradley Research Group]. This document gives step-by-step instructions on how to use the files to speed up the lab preparation time, and provides links to the published versions.

Solubility of Phenanthrene-9-carboxaldehyde
As I was performing experiments, I noticed that there was great variability in the solubility of phenanthrene-9-carboxaldehyde. Since this compound was used in the majority of the V1 list of ranks ~1-50, I thought that predicting the solubility of phenathrene-9-carboxaldehyde would be very helpful to know which experiments are most likely to be completed successfully. The solubility of phenanthrene-9-carboxaldehyde seems to be dependent on the amine in the solution. Below is a table of the experiments, the aldehydes and the amines used, and whether or not the sample went into solution.


 * Experiment/Rank || Researcher || Aldehyde || Amine || Soluble (Yes/No) ||
 * 162/11 || Shannon || Phenanthrene-9-carboxaldehyde || Cyclohexylamine || No ||
 * 164/20 || Emily/Shannon || Phenanthrene-9-carboxaldehyde || Aniline || No ||
 * 177/38 || Shannon || Phenanthrene-9-carboxaldehyde || Propylamine || No ||
 * 178/29 || Shannon || Phenanthrene-9-carboxaldehyde || Furfurylamine || Yes ||
 * 179/44 || Shannon || Phenanthrene-9-carboxaldehyde || Aniline || No ||
 * 180/40 || Shannon || Phenanthrene-9-carboxaldehyde || Heptylamine || Yes ||
 * 156/155 || Emily || Phenanthrene-9-carboxaldehyde || Benzylamine || Yes ||
 * 175/18 || Emily || Phenanthrene-9-carboxaldehyde || Benzylamine || Yes ||
 * 169/23 || Tim || Phenanthrene-9-carboxaldehyde || Cyclohexylamine || No ||
 * 167/12 || Tim || Phenanthrene-9-carboxaldehyde || Propylamine || No ||

This table shows that the only samples with phenanthrene-9-carboxaldehyde that were successfully dissolved occurred with furfurylamine, heptylamine, and benzylamine. All the solutions that contained cyclohexylamine, aniline, and propylamine failed to dissolve. One possible reason that phenanthrene-9-carboxaldehyde dissolves in benzylamine and furfurylamine, but not aniline, lies in an examination of their aromaticity. For furfurylamine and benzylamine, their nitrogen groups are not directly part of the aromatic ring, like in aniline. This means that as the nitrogen donates its lone pair in the Ugi mechanism, the aromaticity and therefore stability of the ring is not compromised. In aniline, however, the nitrogen is part of the ring, and therefore the donation of a lone pair will result in the decrease of the stability of the compound because electron density is being pulled away from the ring. This leads one to hypothesize that phenanthrene-9-carboxaldehyde will dissolve in aromatic compounds in which the amine group is not part of the aromatic ring. Another comparison one can make it that the samples with propylamine did not dissolve, while the experiment with heptylamine did. This may be due to the relative polarity of the compounds in solution. Since propylamine has a short 3-membered chain, it is much more polar than heptylamine which has a 7-membered chain. It is logical that phenanthrene-9-carboxaldehyde is less polar than propylamine because it has a large phenanthrene molecule which is nonpolar, and only one carbonyl group which contributes to the dipole moment. This limited polarity inhibits it from dissolving in a strongly-polar short chain amine such as propylamine. It is likely that phenanthrene-9-carboxaldehyde is soluble in long-chain amines and insoluble in short-chain amines. Cyclohexylamine is more difficult to understand its insolubility in phenanthrene-9-carboxaldehyde. One theory is that although the nitrogen is removed from the ring which is favorable with the aromatic compounds as discussed above, perhaps the compounds lack of aromaticity inhibits its solubility. Because the six-membered ring is not aromatic, each carbon is saturated with two hydrogen atoms. This makes the molecule more sterically hindered, so perhaps it is more difficult for the molecule to have as many successful interactions with the other reagents as in the less saturated aromatic rings. More experiments must be performed to validate these theories. It would be useful to even perform strictly solubility studies, without the addition of the rest of the Ugi components, to test theories such as these that explain the seemingly-amine dependent solubility of the phenanthrene-9-carboxaldehyde in solution. Since there are a lot of compounds with this aldehyde in the top scores for the docking predictions, it would be useful to know more about how to design effective experiments involving it. Eventually, these theories could be incorporated into the solubity prediction that Rajarshi has been working on.

Conclusion
Overall, my UsefulChem experience has enriched my knowledge of organic chemistry because it has taught me to question and try to justify my results. It is easy to read that one compound is soluble in another, but knowing why is a much more valuable tool. I have learned that good research requires an inquisitive mind, and I hope to be able to take what I have learned further to learn more. The experiments I have studied and performed have given me ideas for much more work that can be done, and have taught me a lot about the academic research experience.

=Tags= [|phenanthrene-9-carboxaldehyde] [|InChI=1/C15H10O/c16-10-12-9-11-5-1-2-6-13(11)15-8-4-3-7-14(12)15/h1-10H] InChIKey: [|QECIGCMPORCORE]-[|UHFFFAOYAE] [|n-Heptylamine] : [|InChI=1/C7H17N/c1-2-3-4-5-6-7-8/h2-8H2,1H3] InChIKey: [|WJYIASZWHGOTOU]-[|UHFFFAOYAD] [|Aniline] [|InChI=1/C6H7N/c7-6-4-2-1-3-5-6/h1-5H,7H2] InChIKey: [|PAYRUJLWNCNPSJ]-[|UHFFFAOYAP] [|furfurylamine] [|InChI=1/C5H7NO/c6-4-5-2-1-3-7-5/h1-3H,4,6H2] InChIKey: [|DDRPCXLAQZKBJP]-[|UHFFFAOYAX] [|propylamine] [|InChI=1/C3H9N/c1-2-3-4/h2-4H2,1H3] InChIKey [|WGYKZJWCGVVSQN]-[|UHFFFAOYAG] [|benzylamine] [|InChI=1/C7H9N/c8-6-7-4-2-1-3-5-7/h1-5H,6,8H2] InChIKey: [|WGQKYBSKWIADBV]-[|UHFFFAOYAL] [|cyclohexylamine][|InChI=1/C6H13N/c7-6-4-2-1-3-5-6/h6H,1-5,7H2] [|PAFZNILMFXTMIY]-[|UHFFFAOYAP]